ZY 19489, MMV 253

C24 H32 FN9, 465.5

CAS 1821293-40-6

MMV253, GTPL10024, MMV674253

N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-5-((3R)-2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-3,4-dimethylpiperazin-1-yl)pyrimidin-2-amine

2-N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-5-[(3R)-3,4-dimethylpiperazin-1-yl]-4-N-(1,5-dimethylpyrazol-3-yl)pyrimidine-2,4-diamine

• N²-(4-Cyclopropyl-5-fluoro-6-methyl-2-pyridinyl)-5-[(3R)-3,4-dimethyl-1-piperazinyl]-N⁴-(1,5-dimethyl-1H-pyrazol-3-yl)-2,4-pyrimidinediamine
• (R)-N²-(4-Cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N⁴-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-1-yl)pyrimidine-2,4-diamine

SYN

IN 201721031453

The invention relates to triaminopyrimidine compd. of formula I, pharmaceutically acceptable salts thereof, hydrates, solvates, polymorphs, optically active forms thereof, in solid state forms useful for preventing or treating malaria.  The invention also relates to a process for prepn. of triaminopyrimidine compd. and intermediates thereof.  Compd. I was prepd. by condensation of 5-bromouracil with tert-Bu (R)-2-methylpiperazine-1-carboxylate to give tert-Bu (R)-4-(2,4-dichloropyrimidin-5-yl)-2-methylpiperazine-1-carboxylate, which underwent chlorination followed by condensation with 1,5-dimethyl-1H-pyrazol-3-amine followed by condensation with 4-cyclopropyl-5-fluoro-6-methylpyridin-2-amine hydrochloride to give (R)-N²-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N⁴-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diamine, which underwent Boc-deprotection followed by methylation to give I.

SYN

WO 2019049021

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019049021

Malaria is caused by protozoan parasites of the genus Plasmodium that infect and destroy red blood cells, leading to fever, severe anemia, cerebral malaria and, if untreated, death.

International (PCT) Publication No. WO 2015/165660 (the WO ‘660) discloses triaminopyrimidine compounds, intermediates, pharmaceutical compositions and methods for use for preventing or treating malaria. The WO ‘660 discloses a process for preparation of 4-cyclopropyl-5-fluoro-6-methylpyridin-2-amine (compound 5) as depicted in scheme-1.

Scheme 1

WO ‘660 discloses a process for preparation of triaminopyrimidine compounds depicted in scheme-2.

WO ‘660 discloses the preparation of compounds 8 and 4 by using microwave technique using Biotage microwave vial. WO ‘660 in example- 13, discloses the isolation of compound 1 by concentration of reaction mixture to obtain crude product, which was purified through reverse phase HPLC GILSON instrument to obtain pure solid compound 1 in 40.8% yield, without providing the purity of the solid compound 1. The process disclosed in WO ‘660 is not industrially advantageous as it requires microwave conditions as well as chromatographic purification and provides compound 1 with lower yields. The compound 1 prepared may not be suitable for pharmaceutical preparations based on various regulatory requirements.

Polymorphism, the occurrence of different crystalline forms, is a property of some molecules. A single molecule can exist in different crystalline forms having distinct physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis – TGA, or different scanning calorimetry – DSC, Powder x-ray diffraction pattern – PXRD, infrared absorption – IR). One or more these techniques may be used to distinguish different polymorphic forms of a compound.

Different salts and solid states (e.g. solvates, hydrates) of an active pharmaceutical ingredient may possess different physio-chemical properties. Such variation in the properties of different salts and solid states forms may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (both chemical and polymorph) and shelf-life. These variations in the properties of different salts and solid states forms may offer improvements to the final dosage form for example, to improve bioavailability. Different salts and solid state forms of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms or amorphous form, which may in turn provide additional opportunities to assess variations in the properties and characteristics of an active pharmaceutical ingredient.

In view of the above, the present invention provides a process for the preparation of triaminopyrimidine compound 1 or pharmaceutically acceptable salts thereof or hydrates or solvates or polymorphs or optically active forms thereof, which is industrially scalable, environment friendly and efficient so as to obtain compounds of the invention in higher yields and purity.

The process for the preparation of triaminopyrimidine compound 1 or intermediates thereof of the present invention, takes the advantage by using appropriate solvent systems and isolation techniques as well as purification techniques, thereby to overcome problems of lower yields, chromatography purifications and microwave reactions of the prior art.

SUMMARY OF THE INVENTION

The present invention provides solid state forms of triaminopyrimidine compound

1,

1

Examples: Preparation of Intermediates

Example-1: Preparation of 6-chloro-4-cyclopropyl-3-fluoro-2-methylpyridine

In a 250 mL 4N round bottom flask, process water (30 ml) and cyclopropanecarboxylic acid (14.19 g, 164.88 mmol) were added at 25 to 35°C and started stirring. Sulphuric acid (4.4 ml, 82.44 mmol) was charged to the reaction mixture. Silver nitrate (4.18 g, 24.73 mmol), 6-Chloro-3-fluoro-2-methylpyridine (6 g, 41.22 mmol) were charged to the reaction mixture. Aqueous solution of ammonium persulphate (65.85 g, 288.54 mmol in 90 mL water) was added to the reaction mixture in 30 to 60 min at temperature NMT 60 °C. After the completion of the reaction as monitored by HPLC, toluene (30 ml) was added to the reaction mixture and stirred for 15 min. The reaction mixture filtered, separated layers from filtrate and extracted aqueous layer using toluene (30 mL). The organic layer was washed with aqueous sodium carbonate solution (30 mL) and water. The organic layer was distilled completely under vacuum at 60 °C to obtain 3.37 g syrupy mass as titled compound.

Example-2: Preparation of 6-chloro-4-cyclopropyl-3-fluoro-2-methylpyridine

In a suitable glass assembly, process water (7.5 L) and cyclopropanecarboxylic acid (3.55 Kg, 41.24 mol) were added at 25 to 35 °C and stirred. Sulphuric acid (2.02 Kg, 20.59 mol), silver nitrate (1.05 Kg, 6.21 mol), 6-chloro-3-fluoro-2-methylpyridine (1.5 Kg, 10.3 mol) were added to the reaction mixture. Aqueous solution of ammonium persulphate (16.46 g, 72.13 mmol in 22.5 L water) was added to the reaction mixture at 55 to 60 °C and maintained. After the completion of the reaction as monitored by HPLC, toluene (7.5 L) was added to the reaction mixture and stirred for 15 min. The reaction mixture was filtered, organic layer was separated and aqueous layer was extracted using toluene (6 L), filtered the reaction mixture and washed the solid with toluene (1.5 L). The combined organic layer was washed with 20% sodium carbonate solution (9 L) and water. The organic layer was concentrated completely under vacuum at 60 °C to obtain 880 g (86.50%) syrupy mass of titled compound.

Example-3: Preparation of N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-l,l-diphenyl-methanimine

In a 100 mL 3N round bottom flask, 6-chloro-4-cyclopropyl-3-fluoro-2-methylpyridine (2.69 g, 14.48 mmol) and toluene (30 mL) were added at 25 to 35 °C. Diphenylmethanimine (3.15 g, 17.38 mmol) was charged to the reaction mixture and stirred for 5-10 min under nitrogen purging. Racemic BINAP (270 mg, 0.43 mmol) and palladium acetate (98 mg, 0.43 mmol) were added to the reaction mixture. Sodium-ie/ -butoxide (2.78 g, 28.96 mmol) was added to the reaction mixture and heated to 100 to 110° C under nitrogen. After the completion of the reaction as monitored by HPLC, the reaction mixture was cooled to 25 to 35 °C and filtered over hyflo bed and washed with toluene. The filtrate containing titled compound was preserved for next stage of reaction.

Example-4: Preparation of N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-l,l-diphenyl-methanimine

In a suitable assembly, 6-chloro-4-cyclopropyl-3-fluoro-2-methylpyridine (880) and toluene (7.5 L) were added at 25 to 35 °C. Diphenylmethanimine (787 g, 4.34 mmol) and BOC anhydride (237 g, 1.086 mol) was added to the reaction mixture and stirred for 5-10 min under nitrogen purging. Racemic BINAP (67.6 g, 0.108 mmol) and palladium acetate (24.4 g, 0.108 mol) were added to the reaction mixture. S odium- ieri-butoxide (870 g, 9.05 mol) was added to the reaction mixture and heated to 100 to 110 °C under nitrogen. After the completion of the reaction as monitored by HPLC, the reaction mixture was cooled to 25 to 35 °C, water (6 L) was added. The reaction mixture was filtered over hyflo bed and washed with toluene. The filtrate containing titled compound was preserved for next stage of reaction.

Example-5: Preparation of 4-cyclopropyl-5-fluoro-6-methylpyridin-2-amine hydrochloride monohydrate

In a 100 mL 3N round bottom flask, N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-l,l-diphenylmethanimine in toluene as obtained in example-3 was added water (25 mL) at 25 to 35° C. The cone. HCl (3 mL) was charged to the reaction mixture and heated to 40 to 50 °C. After the completion of the reaction as monitored by HPLC, the reaction mixture was cooled to 25 to 35 °C. Layers were separated. The aqueous layer was treated with methylene dichloride and pH was adjusted to 7.5 to 8.5 using sodium carbonate solution, stirred for 15 min and layers were separated. Aqueous layer was extracted with methylene dichloride, charcoaled and acidified to pH 3 to 4 with aqueous HCl. The solvent was distilled completely and acetonitrile (9 mL) and ethyl acetate (9 mL) was added. The reaction mixture was stirred for 1 hour at 25 to 35° C. The product was filtered and washed with ethyl acetate. The product was dried at 50° C for 4 hours under vacuum to obtain 1.62 g title compound as monohydrate yellow crystalline solid having 99.51% HPLC purity.

Example-6: Preparation of 4-cyclopropyl-5-fluoro-6-methylpyridin-2-amine hydrochloride monohydrate

In a suitable glass assembly, N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-l,l-diphenylmethanimine in toluene as obtained in example-4 was added water (6 L) at 25 to 35° C. The cone. HCl (750 mL) was charged to the reaction mixture and heated to 40 to 50 °C. After the completion of the reaction as monitored by HPLC, the reaction mixture was cooled to 25 to 35 °C. Layers were separated. The aqueous layer was treated with methylene dichloride (3 L) and pH was adjusted to 7.5 to 8.5 using sodium carbonate solution, stirred for 15 min and layers were separated. Aqueous layer was extracted with methylene dichloride (3 L), charcoaled and acidified to pH 3 to 4 with aqueous HCl. The solvent was distilled completely and acetonitrile (1.5 L) and ethyl acetate (1.5 L) were added. The reaction mixture was stirred for 1 hour at 25 to 35° C. The product was filtered and washed with ethyl acetate. The product was dried at 50° C for 4 hours under vacuum to obtain 489 g (96.80%) title compound as monohydrate yellow crystalline solid having 99.51% HPLC purity. The crystalline compound is characterized by Powder x-ray diffraction pattern (FIG.5), Differential scanning calorimetry (FIG.6) and Thermogravimetric analysis (FIG.7).

Example 7: Preparation of 2,3-dibromobutanenitrile

In a 2 L round bottom flask, dichloromethane (550 mL) and 2-butenenitrile 110 g

(1.64 mol) were cooled to 20 to 25 °C. A solution of bromine 275 g (1.72 mol) in dichloromethane (220 mL) was dropwise added at 20 to 25 °C. Hydrobromic acid 1.43 ml (0.0082 mol) in acetic acid (33%) solution was added into the reaction mixture and stirred for 4 hours. After the completion of reaction, Na₂S₂0₃ (550 mL) 4% aqueous solution was added and the reaction mixture was stirred for 15 min. The separated organic layer was distilled under vacuum completely to obtain 364.2 g (97.9%) of title compound as an oil.

Example 8: Preparation of l,5-dimethyl-lH-pyrazol-3-amine

In a 5 L round bottom flask, water (1. 36 L), sodium hydroxide 340 g (8.99 mol) were added and the reaction mixture was cooled to 0 to 5°C. A solution of methyl hydrazine sulphate 237.8 g (1.65 mol) in 680 mL water was added dropwise to the reaction mixture and stirred below 10 °C. 2,3-dibromobutanenitrile 340 g (1.5 mol) prepared in example-7 was added and the reaction mixture was stirred below 10 °C for 2 hours. After the completion of reaction, toluene (630 mL) was added and the reaction mixture was stirred for 15 min. The aqueous layer was separated and the organic layer was removed. The aqueous layer was extracted with dichloromethane (5.1 L). The combined organic layer was distilled completely under vacuum to obtain residue. Diisopropyl ether (680 mL) was added and the reaction mixture was stirred at 0 to 5 °C for 1 hour. The reaction mixture was filtered, washed with diisopropyl ether and dried to obtained 121.5 g (72.93%) of title compound having 95.63% purity.

Examples: Preparation of triaminopyrimidine compounds

Example-9: Preparation of tert-butyl (R)-4-(2,4-dioxo-l,2,3,4-tetrahydro- pyrimidin-5-yl)-2-methylpiperazine-l-carboxylate

In 2 L four neck round bottom flask, 1.25 Kg (6.545 mol) 5-bromouracil, 1.87 Kg (9.360 mol) tert-butyl (R)-2-methylpiperazine-l-carboxylate and 5L pyridine were added at 25 to 35° C. The reaction mass was stirred for 15 hours at 115 to 120°C. After completion, the reaction mass was cooled to 25 to 35°C. 12.5 L water was added and stirred for 1 hour. The reaction mass was filtered, washed with 2.5 L water and dried to obtain 1.37 Kg (67.4%) of title compound.

Example-10: Preparation of tert-butyl (R)-4-(2,4-dichloropyrimidin-5-yl)-2-methylpiperazine- 1 -carboxylate

In 20 L four neck round bottom flask, 1.36 Kg (4.382 mmol) tert-butyl (R)-4-(2,4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl)-2-methylpiperazine-l -carboxylate and 6.8 L phosphorus oxychloride were added at 25 to 35° C. 26.5 mL pyridine (0.329 mol) was added and the reaction mass was heated to 105 to 110 °C and stirred for 4 hours. After the completion of the reaction, phosphorus oxychloride was distilled completely at atmospheric pressure. 2.72 L acetone was added and the reaction mixture was quenched into 4.08 L water. Acetone was removed by distillation under vacuum. 20% sodium carbonate solution was added to adjust pH 7.5-8.5 of the reaction mixture. 1.14 Kg (5.258 mol) di-tert-butyl dicarbonate and 9.52 L ethyl acetate were added and stirred for 2 hours at 25 to 35 °C. After the completion of the reaction, the organic layer was separated and aqueous layer was extracted with 6.8 L ethyl acetate. The combined ethyl layers were distilled to remove ethyl acetate completely under vacuum to obtain residue. 1.36 L isopropyl alcohol was added to the residue and isopropyl alcohol was removed completely. 4.08 L isopropyl alcohol and 6.8 L water were added to the residue and stirred for 1 hour. The reaction mass was filtered, washed with water and dried to obtain 1.25 Kg of title compound.

Example-11: Preparation of tert-butyl (R)-4-(2-chloro-4-[(l,5-dimethyl-lH-pyrazol-3-yl)amino)pyrimidin-5-yl]-2-methylpiperazine-l-carboxylate

In 20 L round bottom flask, 640 g (1.843 mol) tert-butyl (R)-4-(2, 4-dichloropyrimidin-5-yl)-2-methylpiperazine-l -carboxylate, 225.3 g (2.027 g) 1,5-dimethyl-lH-pyrazol-3-amine and 9.6L toluene were added at 25 to 35°C. 1.2 Kg (3.686 mol) cesium carbonate was added. The reaction mixture was purged for 15 min under nitrogen. 12.41 g (0.0553 mol) palladium acetate and 34.43 g (0.0553 mol) racemic 2,2′-bis(diphenylphosphino)-l,l’-binaphthyl were added and the reaction mass was maintained for 16 hours at 110 to 115 °C under nitrogen. After the completion of the reaction, the reaction mixture was filtered through a celite bed and washed the bed with 1.28 L toluene. Toluene was distilled completely and 2.56 L dichlromethane was added. The compound was adsorbed by 1.92 Kg silica gel (60-120 mesh). The dichloromethane was distilled completely under vacuum and 12.8 L mixture of ethyl acetate and hexane was added to the residue and stirred for 2 hours. The silica gel was filtered and the filtrate was distilled completely under vacuum to obtain 595 g title compound.

Example-12: Preparation of tert-butyl (R)-4-(2-((4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)amino)-4-((l,5-dimethyl-lH-pyrazol-3-yl)amino) pyrimidin-5-yl)-2-methylpiperazine-l-carboxylate

In 20 L round bottom flask, 595 g (1.40 mol) tert-butyl (R)- 4-(2-chloro-4-[(l,5-dimethyl-lH-pyrazol-3-yl)amino)pyrimidin-5-yl]-2-methylpiperazine-l-carboxylate, 305 g (1.38 mol) 4-cyclopropyl-5-fluoro-6-methylpyridin-2-amine hydrochloride and 11.5 L toluene were added at 25 to 35°C. 1.08 Kg (3.32 mol) cesium carbonate was added. The reaction mixture was purged for 15 min under nitrogen. 17.21 g (27.6 mmol) palladium acetate and 6.21 g (27.6 mmol) racemic 2,2′-bis(diphenylphosphino)-l, -binaphthyl were added. The reaction mass was stirred for 6 hours at 110 tol l5 °C under nitrogen. After the completion of the reaction, the reaction mixture was filtered through a celite bed and washed with toluene. The filtrate was used as such in the next step without further treatment.

Example-13: Preparation of tert-butyl (R)-4-(2-((4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)amino)-4-((l,5-dimethyl-lH-pyrazol-3-yl)amino) pyrimidin-5-yl)-2-methylpiperazine-l-carboxylate

In 500 mL four neck round bottom flask, 7.5 g (17.77 mmol) (R)-tert-butyl 4-(2-chloro-4-[(l,5-dimethyl-lH-pyrazol-3-yl)amino)pyrimidin-5-yl]-2-methylpiperazine-l-carboxylate, 3.92 g (17.77 mmol) 4-cyclopropyl-5-fluoro-6-methylpyridin-2-amine hydrochloride compound and 150 mL toluene were added at 25 to 35 °C. 20 g (61.3 mmol) cesium carbonate was added. The reaction mixture was purged for 15 min under nitrogen. Then, 130 mg (0.58 mmol) palladium acetate and 360 mg (0.58 mmol) racemic 2,2′-bis(diphenylphosphino)-l,l’-binaphthyl were added. The reaction mass was stirred for 18 hours at 110 to 115° C under nitrogen. After completion, the reaction mixture was filtered through a celite bed and washed with toluene. The filtrate was used as such in the next step without further treatment.

2 4

Example-14: (R)-N -(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N -(1, 5-dimethyl-lH-pyrazol-3-yl)-5-(3-methylpiperazin-l-yl)pyrimidine-2,4-diamine

In 50 L glass assembly, the filtrate containing tert-butyl (R)-4-(2-((4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)amino)-4-((l,5-dimethyl-lH-pyrazol-3-yl)amino) pyrimidin-5-yl)-2-methylpiperazine-l-carboxylate from example 13 was taken. 11.5 L water and 1.28 L Cone. HC1 were added at 25 to 35 °C. The reaction mass was stirred for 2 hours at 50 to 55 °C. After the completion of the reaction, reaction mixture was cooled to room temperature and filtered over celite bed and washed with water. The separated the aqueous layer from filtrate was basified by using 20% sodium carbonate solution and extracted with 12.8 L methylene dichloride. The organic layer was distilled completely under vacuum to obtain residue. 9.6 L acetonitrile was added to the residue and heated to reflux for 30 min. The reaction mixture was cooled and stirred at 25 to 35 °C for 1 hour. The reaction mixture was filtered, washed with 640 mL acetonitrile and dried to obtain 360 g titled compound.

2 4

Example-15: (R)-N -(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N -(1,5-dimethyl-lH-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-l-yl)pyrimidine-2,4-diamine

In 250 mL four neck round bottom flask, 4.7 g (10.4 mmol) (R)-N -(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N⁴-(l,5-dimethyl-lH-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-l-yl)pyrimidine-2,4-diamine was dissolved in 56 mL ethanol. 1.89 g (23.32 mmol) formaldehyde and 1.44 g (22.90 mmol) sodium cyanoborohydride were added. Adjusted pH 5-6 using acetic acid and stirred the reaction mass at 25 to 35 °C for 2 hours. After completion, ethanol was distilled completely under vacuum. 47 mL water was added to the residue. The reaction mass was basified by 20% sodium carbonate solution and extracted with methylene dichloride. Both the organic layers were combined and distilled completely under vacuum. 94 mL acetonitrile was added to the residue and heated to reflux for 15 min. The reaction mass was cooled to 25 to 35° C and stirred for 1 hour. The reaction mass was filtered, washed with 5 mL acetonitrile and dried to obtain 3.7 g title compound as crystalline solid, having HPLC purity of about 99.61%.

2 4

Example-16: (R)-N -(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N -(1,5-dimethyl-lH-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-l-yl)pyrimidine-2,4-diamine

In 20 L round bottom flask, 725 g (1.60 mol) (R)-N²-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N⁴-(l,5-dimethyl-lH-pyrazol-3-yl)-5-(3,4-dimethylpiperazine-l-yl)pyrimidine-2,4-diamine was dissolved in 6.52 L dichloromethane. 261.5 g (3.2 mol) formaldehyde and 510.4 g (2.4 mol) sodium triacetoxyborohydride were added and stirred the reaction mixture at 25 to 35 °C for 2 hours. After the completion of the reaction, 3.63 L water was added into the reaction mixture. The reaction mixture was basified by 20% sodium carbonate solution and the organic layer was separated. The aqueous layer was extracted with 1.45 L methylene dichloride. The combined organic layers were distilled completely under vacuum. 14.5 L acetonitrile was added to the residue and heated to reflux for 15 min. The reaction mixture was cooled to 25 to 35° C and stirred for 1 hour. The reaction mass was filtered, washed with 1.45 L acetonitrile and dried to obtain 632 g of title compound as crystalline solid having 99.01% HPLC purity. The crystalline compound is characterized by Powder x-ray diffraction pattern (FIG.l) and Differential Scanning Calorimetry (FIG.2).

2 4

Example-17: Preparation of (R)-N -(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N -(l,5-dimethyl-lH-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-l-yl)pyrimidine-2,4-diamine In a 10 mL round bottom flask, 300 mg (0.644 mmol) (R)-N²-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N⁴-(l,5-dimethyl-lH-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-l-yl)pyrimidine-2,4-diamine, 2.7 mL acetonitrile and 0.3 mL water were added and the reaction mixture was heated to reflux for 15 min. The reaction mixture was cooled to 25 to 35 °C and stirred for 1 hour. The reaction mass was filtered, washed with acetonitrile and dried to obtain 201 mg (67%) title compound as crystalline solid. The crystalline compound is characterized by Powder x-ray diffraction pattern (FIG.3) and Differential Scanning Calorimetry (FIG.4).

SYN

WO 2015165660

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015165660

Example 13

Synthetic scheme 1

Synthetic scheme 2

(R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-1-yl)pyrimidine-2,4-diamine

In a 50 mL round-bottomed flask (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3-methylpiperazin-1-yl)pyrimidine-2,4-diamine hydrochloride (190 mg, 0.42 mmol, Example 2) was taken in DCM (2 mL) to give a yellow suspension. To this Hunig’s Base (0.184 mL, 1.05 mmol) was added and the suspension turned clear. After 10 minutes, it turned into a white suspension. After another 10 minutes, the mixture was concentrated to dryness. Resultant residue was dissolved in ethanol (absolute, 99.5%) (3 mL) and formaldehyde (0.042 mL, 0.63 mmol) was added and stirred for 10 minutes. White suspension slowly cleared to yellow solution. To this clear solution sodium cyanoborohydride (26.4 mg, 0.42 mmol) was added in one portion to get white suspension. After 30 minutes LCMS showed completion of reaction. The reaction mixture was concentrated and the crude was purified through reverse phase HPLC GILSON instrument to get the pure solid of (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-1-yl)pyrimidine-2,4-diamine (80 mg, 40.8 %).¹H NMR (300

MHz, DMSO-d₆) δ ppm 0.67 – 0.78 (m, 2 H) 1.00 (d, J=6.22 Hz, 3 H) 1.02 – 1.08 (m, 2 H) 1.96 – 2.10 (m, 1 H) 2.23 (s, 7 H) 2.30 – 2.38 (m, 4 H) 2.73 – 2.96 (m, 4 H) 3.33 (s, 3 H) 6.83 (s, 1 H) 7.67 (d, J=5.09 Hz, 1 H) 8.00 (s, 1 H) 8.03 (s, 1 H) 9.26 (s,1 H) MS (ES⁺), (M+H)⁺ = 466.45 for C₂₁H₃₂FN₉.

SYN

Nature Communications (2015), 6, 6715.

https://www.nature.com/articles/ncomms7715

Hameed P., S., Solapure, S., Patil, V. et al. Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate. Nat Commun 6, 6715 (2015). https://doi.org/10.1038/ncomms7715

The widespread emergence of Plasmodium falciparum (Pf) strains resistant to frontline agents has fuelled the search for fast-acting agents with novel mechanism of action. Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (compound 12) is efficacious in a mouse model of Pf malaria with an ED₉₉ <30 mg kg⁻¹ and displays good in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4–5 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of Pf malaria in combination with other agents in clinical development.

Zydus receives Orphan Drug Designation from USFDA for ZY-19489, a novel compound to treat malaria;

https://www.indiainfoline.com/article/news-top-story/zydus-receives-orphan-drug-designation-from-usfda-for-zy-19489-a-novel-compound-to-treat-malaria-stock-down-1-121121600282_1.html

ZY19489 is a novel antimalarial compound active against all current clinical strains of P. falciparum and P. vivax, including drug-resistant strains.

////////////ZY 19489, MMV 253, Orphan Drug Designation, PHASE 1, ZYDUS CADILA, ANTIMALARIAL

Cn1nc(Nc2nc(Nc3cc(C4CC4)c(F)c(C)n3)ncc2N2C[C@@H](C)N(C)CC2)cc1C

CC1CN(CCN1C)C2=CN=C(N=C2NC3=NN(C(=C3)C)C)NC4=NC(=C(C(=C4)C5CC5)F)C

Rabeximod, ROB 803

C22H24ClN5O,  409.92

2-(9-chloro-2,3-dimethylindolo[3,2-b]quinoxalin-6-yl)-N-[2-(dimethylamino)ethyl]acetamide

CAS 872178-65-9UNII-J4D3K58W3Z, рабексимод , رابيكسيمود 雷贝莫德 
6H-Indolo[2,3-b]quinoxaline-6-acetamide, 9-chloro-N-[2-(dimethylamino)ethyl]-2,3-dimethyl-
872178-65-9[RN]8866, J4D3K58W3Z

• OriginatorOxyPharma
• DeveloperCyxone; University of California
• ClassAcetamides; Anti-inflammatories; Disease-modifying antirheumatics; Heterocyclic compounds with 4 or more rings; Small molecules
• Mechanism of ActionCell differentiation modulators; Macrophage inhibitors
• Phase IICOVID 2019 infections; Rheumatoid arthritis

• 12 Oct 2021Cyxone terminates a phase-II trial in COVID-2019 infections in Slovakia (PO) (EudraCT2020-004571-41)
• 10 Aug 2021Cyxone completes a phase-II trial in COVID-2019 infections in Slovakia (PO) (EudraCT2020-004571-41)
• 23 Feb 2021Phase-II clinical trials in COVID-2019 infections in Slovakia (PO) (EudraCT2020-004571-41)

SYN

US 20050288296

https://patents.google.com/patent/US20050288296

SYN

 WO 2014140321 

https://patents.google.com/patent/WO2014140321A1/en Example 29-chloro-7V- [2-(dimethylamino)ethyl] -2,3-dimethyl-6H-Indolo [2,3-6] quinoxaline-6- acetamide

This compound was prepared as described in PCT/SE2005/000718 (WO 2005/123741), cf. “Compound E” at page 12 of said WO pamphlet.SYNWO 2005/123741https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2005123741

Compound E

9-Chloro-2,3-dimerthyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo- [2,3-b]quinoxaline (R¹=Cl, R²=CH₃, X=CO, Y=NH-CH₂-CH₂-R³; R³=NR⁵R⁶;

R⁵=R⁶=CH₃)

Yield: 58%; ¹H-NMR δ: 8.29 (d, 1H), 8.23 (t, 1H), 7.98 (s, 1H), 7.82 (s, 1H), 7.71

(dd, 1H), 7.61 (d, 1H), 5.09 (s, 2H), 3,16 (q, 2H), 2.47 (s, 6H), 2.28 (t, 2H), 2,12

(s, 6H);

SYN

Rabeximod is an orally administered compound for treatment of moderate or severe active rheumatoid arthritis that is currently undergoing phase II clinical testing in eight European countries.

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PATENT

The compound rabeximod has been described in European patent application publication EP1756111A1 later granted as EP1756111 B1. The preparation of rabex imod, as compound E, is specifically described in EP1756111A1 as a small-scale process without any description on how to develop a process that can be used for GMP and upscaled. Rabeximod was made in a 58% yield in a small-scale lab pro cess, but no parameters for scaling up have been disclosed.

The objective of the present invention is to provide a process that is suitable for large scale synthesis in good yield, with stable process parameters, and suitable for GMP production.

Experimental

The current process to manufacture Rabeximod involves several process steps as illustrated in below reaction scheme and as described in detail hereunder.

Manufacturing Process OXY001-01 Intermediate

Starting materials: 5-Chloroisatin (CIDO) and 4,5-Dimethyl-1 ,2-phenylenediamine (DAX)

Table 1: Overview Required Raw Materials and Quantities Step 1 

Table 2: Raw Materials Specifications Step 1

Resulting Product (Intermediate): OXY001-01

Batch size: 13.03 kg of OXY001-01

Process description: 4,5-Dimethyl-1 ,2-phenylenediamine (1.1 equivalent) was added to acetic acid (4.7 volumes) in reactor (reactor was running under nitrogen at atmospheric pressure) and stirred up to 3 hours at moderate rate at +20 to +25 °C until clear dark brown solution was formed. 4, 5-Dimethyl-1 ,2-phenylenediamine so lution in acetic acid solution was transferred to intermediate feeding vessel. 5-chloro-isatin (1 .0 equivalent) was added to acetic acid (14.3 volumes) in reactor and stirred while jacket temperature of reactor was adjusted to approximately +150 °C to achieve a reflux temperature for active reflux of solvents. When reflux temperature was reached the 4, 5-Dimethyl-1 ,2-phenylenediamine solution in acetic acid was slowly added over 2-3 hours while distilling acetic acid (4.7 volumes) from the reaction mix ture. A fresh portion of acetic acid (4.7 volumes) was added to the reactor at about the same rate as distillation (4.7 volumes) occurred. After distillation the reaction mixture was stirred at reflux temperature for at least another 2 hours. The expected appearance of content in the reactor was a dark yellow to orange slurry. The reaction mixture was cooled to +65 to +70 °C and filtered using a Nutsche filter using Polyes ter filter cloth (27 pm) or similar as filter media. The filter cake was washed 3 times with fresh ethanol (3 x 4.2 volumes) and 1 time with water (1 x 4.2 volume). After washing the filter cake was dried at +40 to +45 °C for 12 hours and additionally in a vacuum tray dryer for 12 hours at +40 °C resulting in a yellow to orange/brown solid. An in-process control sample was taken and analysed for loss on drying (LOD). LOD should be < 2% (w/w). If the LOD is > 2%, the vacuum tray dryer step was repeated.

Theoretical yield: 18.62 kg

Yield: 70±5% (13.03±0.96kg)

Maximum volume: 216 L

Manufacturing Process OXY001-03 HCI Intermediate

CAC DMEN OXY001-03 HCI

Starting materials: Chloroacetyl chloride (CAC) and N,N-Dimethylethylene diamine (DMEN)

Table 3: Overview Required Raw Materials and Quantities Step 2

a) mol//mol of DMEN; b) kg/kg of DMEN; c) L/kg of DMEN

Table 4: Raw Materials Specifications Step 2

Resulting Product (Intermediate): OXY001-03 HCI

Batch size: 22.6 kg of OXY001 -03 HCI

Process description: Chloroacetyl chloride (1.03 equivalents) was dissolved in ethyl acetate (15 volumes) in reactor (reactor was running under nitrogen at atmos pheric pressure) at +20 °C. The solution was stirred and cooled down to +10 °C.

N,N-dimethylethylene diamine (1.00 equivalent) solution in ethyl acetate (1.0 volume) was slowly charged to the reactor when the temperature reached a range from +10 to +25 °C and at such a rate over 1-2 hours that the internal temperature did not exceed +25 °C. The slurry was stirred for 5 to 30 minutes at +20 to +25 °C and filtered using a Nutch filter using Polyamide filter cloth (25 pm) or similar as filter media. The product was washed 3 times on the filter with ethyl acetate (3 x 5 volumes) and dried on the filter for at least 16 hours and additionally in a vacuum tray dryer for 12 hours at +40 °C resulting in an off-white to beige solid.

Theoretical yield: 25.09 kg

Yield: 90±5% (22.6±1 .25 kg)

Maximum volume: 202 L

Manufacturing Process OXY001 Crude

– OXY001 Crude Starting materials: OXY001-01 and OXY001-03 HCI

Table 5: Overview Required Raw Materials and Quantities Step 3

Table 6: Raw/Intermediate Materials Specifications Step 3

Resulting Product: OXY001 Crude (crude rabeximod) Batch size: 11.38 kg of OXY001 Crude

Process description: OXY001-01 (1.0 equivalent) was dissolved in tetrahydrofuran (15.4 volumes) and 50% NaOH aqueous solution (8.0 equivalents in relation to OXY001 -01 ) in reactor (reactor was running under nitrogen at atmospheric pressure) and mixed at +55 to +60 °C up to approximately 1 hour until clear dark red solution was formed. Potassium iodide (0.81 equivalents) was added under vigorous stirring and mixed for 10 to 30 minutes at +55 to +60 °C. OXY001-03 HCI (2.0 equivalents) was added to the solution and mixed for at least 2 hours at +55 to +60 °C. Following completion of the reaction, the mixture was quenched with water (15.4 volumes) and tetrahydrofuran removed (15.4 volumes) by evaporation under reduced pressure. The slurry was cooled to +20 to +25 °C and stirred for 1 hour and filtered with a Nutch filter using Polyamide filter cloth (25 pm) or similar as filter media. Resulting cake was washed 3 times with water (3 x 5 volumes) until the pH of the filtrate was between 8-7 and dried on the filter at +40 to +45 °C for at least 12 hours by air suction and additionally in a vacuum tray dryer for 12 hours at +40 °C. Afterwards resulting ma terial was suspended in in tetrahydrofuran (25 volumes) at +45 to +50 °C for at least 1 hour. OXY001 Crude was isolated by filtration with a Nutch filter using Polyamide filter cloth (25 pm) or similar as filter media and washed 2 times on the filter with tetrahydrofuran (2 x 7 volumes). Resulting cake was dried on the filter at +40 to +45 °C for at least 12 hours and additionally in a vacuum tray dryer for 12 hours at +40 °C.

Theoretical yield: 18.96 kg

Yield: 60±5% (11 38±0.95 kg)

Maximum volume: 500 L

Purification of crude Rabeximod:

OXY001 crude (1 .0 equivalent) was dissolved in tetrahydrofuran (10 volumes), water (3 volume), and 2M HCI (1.4 volumes) mixture. The solution was clear filtered and heated to +50 °C. pH of mixture was adjusted to 10-12 by addition of 2M NaOH (1.3 volume). The formed slurry was cooled to +20 to +25 °C and diluted with water (12 volumes).

After stirring for at least 12 hours the slurry was filtered at +20 to +25 °C and washed on the filter with tetrahydrofuran:water (5:2) mixture (2×3 volumes). Rabeximod has a molecular weight of 409.92 g/mol and is isolated as a crystalline free base having a melting point of 259-261 °C.

Batch release results of batches used in Phase 2 and Phase 1 clinical studies are provided in Table 7.

Purity is equal to or above 98% as measured by HPLC.

Table 7: Batch release results of Rabeximod drug substance batches used in Phase 1 and phase 2 clinical studies

/////////////////Rabeximod, ROB 803, UNII-J4D3K58W3Z, рабексимод , رابيكسيمود 雷贝莫德 ,OXYPHARMA, PHASE 2, CYXONE

CC1=CC2=C(C=C1C)N=C3C(=N2)C4=C(N3CC(=O)NCCN(C)C)C=CC(=C4)Cl

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4-Hydroxy-TEMPO, TEMPOL, MBM-02, MTS 01

• Molecular FormulaC₉H₁₈NO₂
• Average mass172.245 Da

2,2,6,6-Tetramethyl-4-hydroxypiperidinooxy
2,2,6,6-Tetramethyl-4-hydroxypiperidinooxy radical
2,2,6,6-Tetramethyl-4-piperidinol 1-oxyl
CAS 2226-96-2[RN]
4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine
4-Hydroxy-2,2,6,6-tetramethyl-1-piperidin-1-yloxy, free radical
4-Hydroxy-2,2,6,6-tetramethylpiperidine N-oxide
4-Hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl
TEMPOLCAS Registry Number: 2226-96-2 
CAS Name: 4-Hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy 
Additional Names: 4-hydroxy-TEMPO; 4-hydroxy-2,2,6,6-tetramethyl piperidine N-oxide; 4-hydroxy-2,2,6,6-tetramethylpiperidinooxy 
Molecular Formula: C9H18NO2, Molecular Weight: 172.24 
Percent Composition: C 62.76%, H 10.53%, N 8.13%, O 18.58% 
Literature References: Stable nitroxyl radical; water-soluble analogue of TEMPO, q.v. Functions as a membrane-permeable radical scavenger. Prepn: E. G. Rozantsev, Bull. Acad. Sci. USSR Div. Chem. Sci.12, 2085 (1964). Energy transfer studies: N. N. Quan, A. V. Guzzo, J. Phys. Chem.85, 140 (1981). IR conformation study: W. A. Bueno, L. Degrève, J. Mol. Struct.74, 291 (1981).Solid state NMR spectra: C. J. Groombridge, M. J. Perkins, J. Chem. Soc. Chem. Commun.1991, 1164. LC/MS/MS determn: I. D. Podmore, J. Chem. Res. Synop.2002, 574. Use as a phase transfer catalyst: X.-Y. Wang et al.,Synth. Commun.29, 157 (1999). Review of effects in animal models for shock, ischemia-reperfusion injury, and inflammation: C. Thiemermann, Crit. Care Med.31, S76-S84 (2003). 
Properties: Crystals from ether + hexane, mp 71.5°. uv max (hexane): 240, 450-500 (e ~1800, ~5). uv max (ethanol): 242, 435-455 (e ~3800, ~10). Sol in water. 
Melting point: mp 71.5° 
Absorption maximum: uv max (hexane): 240, 450-500 (e ~1800, ~5); uv max (ethanol): 242, 435-455 (e ~3800, ~10) 
Use: Spin label for EPR studies; phase transfer dehydration catalyst; antioxidant; inhibitor of olefin free radical polymerization.Topical PiperidineNitroxide MTS-01 is a topical gel containing a cell permeable hydrophilic piperidinenitroxide with potential radioprotective and antioxidant activity. As a stable, free radical compound, MTS-01 may be able to protect cells against the damaging effects of reactive oxygen species (ROS), upon exposure to ionizing radiation and oxidative stress. The topically applied MTS-01 may protect normal tissue from radiation-induced toxicity, such as radiation dermatitis, during radiation therapy. 
4-Hydroxy-TEMPO is a member of aminoxyls and a member of piperidines. It has a role as a radical scavenger and a catalyst. It derives from a TEMPO.

4-Hydroxy-TEMPO or TEMPOL, formally 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl, is a heterocyclic compound. Like the related TEMPO, it is used as a catalyst and chemical oxidant by virtue of being a stable aminoxyl radical. Its major appeal over TEMPO is that is less expensive, being produced from triacetone amine, which is itself made via the condensation of acetone and ammonia. This makes it economically viable on an industrial scale.^[3]

Example synthesis of 4-Hydroxy-TEMPO from phorone, which is itself made from acetone and ammonia

In biochemical research, 4-hydroxy-TEMPO has been investigated as an agent for limiting reactive oxygen species. It catalyzes the disproportionation of superoxide, facilitates hydrogen peroxide metabolism, and inhibits Fenton chemistry.^[4] 4-Hydroxy-TEMPO, along with related nitroxides, are being studied for their potential antioxidant properties.^[5]

On an industrial-scale 4-hydroxy-TEMPO is often present as a structural element in hindered amine light stabilizers, which are commonly used stabilizers in plastics, it is also used as a polymerisation inhibitor, particularly during the purification of styrene.

It is a promising model substance to inhibit SARS-CoV-2 RNA-dependent RNA polymerase.^[6]

SYN

SYN

Inorganica Chimica Acta, 370(1), 469-473; 2011

SYN

Bioorganic & Medicinal Chemistry Letters, 22(2), 920-923; 2012

SYN

https://pubs.acs.org/doi/10.1021/ol0712024

SYN

https://pubs.acs.org/doi/10.1021/es302157j

PAT

CN 113429392

SYN

 Journal of the American Chemical Society, 138(29), 9069-9072; 2016

https://pubs.acs.org/doi/10.1021/jacs.6b05421

file:///C:/Users/Inspiron/Downloads/ja6b05421_si_001.pdf

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Thursday, June 3, 2021

NIH researchers identify potential new antiviral drug for COVID-19

Compound targets essential viral enzyme and prevents replication in cells.https://www.nih.gov/news-events/news-releases/nih-researchers-identify-potential-new-antiviral-drug-covid-19small spherical structures in the center of the image are SARS-CoV-2 virus particles. The string-like protrusions extending from the cells are cell projections or pseudopodium. NIAID

The experimental drug TEMPOL may be a promising oral antiviral treatment for COVID-19, suggests a study of cell cultures by researchers at the National Institutes of Health. TEMPOL can limit SARS-CoV-2 infection by impairing the activity of a viral enzyme called RNA replicase. The work was led by researchers at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The study appears in Science.

“We urgently need additional effective, accessible treatments for COVID-19,” said Diana W. Bianchi, M.D., NICHD Director. “An oral drug that prevents SARS-CoV-2 from replicating would be an important tool for reducing the severity of the disease.”

The study team was led by Tracey A. Rouault, M.D., head of the NICHD Section on Human Iron Metabolism. It discovered TEMPOL’s effectiveness by evaluating a more basic question on how the virus uses its RNA replicase, an enzyme that allows SARS-CoV-2 to replicate its genome and make copies of itself once inside a cell.

Researchers tested whether the RNA replicase (specifically the enzyme’s nsp12 subunit) requires iron-sulfur clusters for structural support. Their findings indicate that the SARS-CoV-2 RNA replicase requires two iron-sulfur clusters to function optimally. Earlier studies had mistakenly identified these iron-sulfur cluster binding sites for zinc-binding sites, likely because iron-sulfur clusters degrade easily under standard experimental conditions.

Identifying this characteristic of the RNA replicase also enables researchers to exploit a weakness in the virus. TEMPOL can degrade iron-sulfur clusters, and previous research from the Rouault Lab has shown the drug may be effective in other diseases that involve iron-sulfur clusters. In cell culture experiments with live SARS-CoV-2 virus, the study team found that the drug can inhibit viral replication.

Based on previous animal studies of TEMPOL in other diseases, the study authors noted that the TEMPOL doses used in their antiviral experiments could likely be achieved in tissues that are primary targets for the virus, such as the salivary glands and the lungs.

“Given TEMPOL’s safety profile and the dosage considered therapeutic in our study, we are hopeful,” said Dr. Rouault. “However, clinical studies are needed to determine if the drug is effective in patients, particularly early in the disease course when the virus begins to replicate.”

The study team plans on conducting additional animal studies and will seek opportunities to evaluate TEMPOL in a clinical study of COVID-19.

NIH authors on the study include researchers from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Institute of Neurological Disorders and Stroke. Authors from the Pennsylvania State University are funded by NIH’s National Institute of General Medical Sciences.

About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): NICHD leads research and training to understand human development, improve reproductive health, enhance the lives of children and adolescents, and optimize abilities for all. For more information, visit https://www.nichd.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH…Turning Discovery Into Health^®

Article

Maio N, et al. Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets. Science DOI: 10.1126/science.abi5224(link is external) (2021)

References

1. ^ Zakrzewski, Jerzy; Krawczyk, Maria (1 January 2011). “Reactions of Nitroxides. Part XII [1]. – 2,2,6,6-Tetramethyl-1-oxyl- 4-piperidyl Chloroformate – A New Reactive Nitroxyl Radical. A One-pot Synthesis of 2,2,6,6-Tetramethyl-1-oxyl-4-piperidyl N,N-Dialkyl-carbamates”. Zeitschrift für Naturforschung B. 66 (5). doi:10.1515/znb-2011-0509.
2. ^ Jump up to:^a b c d Sigma-Aldrich Co., 4-Hydroxy-TEMPO. Retrieved on 2015-08-24.
3. ^ Ciriminna, Rosaria; Pagliaro, Mario (15 January 2010). “Industrial Oxidations with Organocatalyst TEMPO and Its Derivatives”. Organic Process Research & Development. 14 (1): 245–251. doi:10.1021/op900059x.
4. ^ Wilcox, C. S.; Pearlman, A. (2008). “Chemistry and Antihypertensive Effects of Tempol and Other Nitroxides”. Pharmacological Reviews. 60 (4): 418–69. doi:10.1124/pr.108.000240. PMC 2739999. PMID 19112152.
5. ^ Lewandowski, M; Gwozdzinski, K. (2017). “Nitroxides as Antioxidants and Anticancer Drugs”. International Journal of Molecular Sciences. 18 (11): 2490. doi:10.3390/ijms18112490. PMC 5713456.
6. ^ Maio, N.; Lafont, B.A.P.; Sil, D.; Li, Y.; Bollinger, M.; Krebs, C. (2021). “Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets”. Science. 373 (6551): 236–241. doi:10.1126/science.abi5224.

Names
Preferred IUPAC name(4-Hydroxy-2,2,6,6-tetramethylpiperidin-1-yl)oxyl
Other namestempol; tanol; TMPN; 4-Oxypiperidol; nitroxyl 2; HyTEMPO
Identifiers
CAS Number	2226-96-2
3D model (JSmol)	Interactive image
ChEBI	CHEBI:180664
ChEMBL	ChEMBL607023
ChemSpider	121639
ECHA InfoCard	100.017.056
PubChem CID	137994
UNII	U78ZX2F65X
CompTox Dashboard (EPA)	DTXSID4041280
showInChI
showSMILES
Properties
Chemical formula	C9H18NO2
Molar mass	172.248 g·mol−1
Appearance	Orange crystals
Melting point	71–73 °C (160–163 °F; 344–346 K)[1]
Solubility in water	629.3 g/l (20 °C)
Hazards
GHS labelling:
Pictograms	[2]
Signal word	Warning[2]
Hazard statements	H302, H315, H319, H335[2]
Precautionary statements	P261, P305+P351+P338[2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
verify (what is  ?)
Infobox references

//////////////////4-Hydroxy-TEMPO,  TEMPOL, MBM-02, MTS 01, ZJ 701, CORONA VIRUS, COVID 19

https://www.clinicaltrials.gov/ct2/show/NCT04729595

CC1(CC(CC(N1[O])(C)C)O)C

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Povidone-iodine

PVP 1

UNII85H0HZU99M, BETADINE

CAS number 25655-41-8, Molecular Formula, (C6-H9-N-O)x-.x-I2, Molecular Weight, 364.9431

1-ethenylpyrrolidin-2-one;molecular iodine Povidone-Iodine
CAS Registry Number: 25655-41-8
CAS Name: 1-Ethenyl-2-pyrrolidinone homopolymer compd with iodine
Additional Names: 1-vinyl-2-pyrrolidinone polymers, iodine complex; iodine-polyvinylpyrrolidone complex; polyvinylpyrrolidone-iodine complex; PVP-I
Trademarks: Betadine (Purdue Frederick); Betaisodona (Mundipharma); Braunol (Braun Melsungen); Braunosan H (Braun Melsungen); Disadine D.P. (Stuart); Efodine (Fougera); Inadine (J & J); Isodine (Blair); Proviodine (Rougier); Traumasept (Wolff)
Literature References: An iodophor, q.v., prepd by Beller, Hosmer, US2706701; Hosmer, US2826532; Siggia, US2900305 (1955, 1958, and 1959, all to GAF). Prepn, history and use: Shelanski, Shelanski, J. Int. Coll. Surg.25, 727 (1956).
Properties: Yellowish-brown, amorphous powder with slight characteristic odor. Aq solns have a pH near 2 and may be made more neutral (but less stable) by the addition of sodium bicarbonate. Sol in alc, water. Practically insol in chloroform, carbon tetrachloride, ether, solvent hexane, acetone. Solns do not give the familiar starch test when freshly prepared.
Therap-Cat: Anti-infective (topical).
Therap-Cat-Vet: Anti-infective (topical).
Keywords: Antiseptic/Disinfectant; Halogens/Halogen Containing Compounds.

• An iodinated polyvinyl polymer used as topical antiseptic in surgery and for skin and mucous membrane infections, also as aerosol. The iodine may be radiolabeled for research purposes.

Povidone-iodine is a stable chemical complex of polyvinylpyrrolidone (povidone, PVP) and elemental iodine. It contains from 9.0% to 12.0% available iodine, calculated on a dry basis. This unique complex was discovered in 1955 at the Industrial Toxicology Laboratories in Philadelphia by H. A. Shelanski and M. V. Shelanski. During in vitro testing to demonstrate anti-bacterial activity it was found that the complex was less toxic in mice than tincture of iodine. Human clinical trials showed the product to be superior to other iodine formulations. Povidone-iodine was immediately marketed, and has since become the universally preferred iodine antiseptic.

Povidone-iodine (PVP-I), also known as iodopovidone, is an antiseptic used for skin disinfection before and after surgery.^[1][2] It may be used both to disinfect the hands of healthcare providers and the skin of the person they are caring for.^[2] It may also be used for minor wounds.^[2] It may be applied to the skin as a liquid or a powder.^[2]

Side effects include skin irritation and sometimes swelling.^[1] If used on large wounds, kidney problems, high blood sodium, and metabolic acidosis may occur.^[1] It is not recommended in women who are less than 32 weeks pregnant or are taking lithium.^[2] Frequent use is not recommended in people with thyroid problems.^[2] Povidone-iodine is a chemical complex of povidone, hydrogen iodide, and elemental iodine.^[3] It contains 10% Povidone, with total iodine species equaling 10,000 ppm or 1% total titratable iodine.^[3] It works by releasing iodine which results in the death of a range of microorganisms.^[1]

Povidone-iodine came into commercial use in 1955.^[4] It is on the World Health Organization’s List of Essential Medicines.^[5] Povidone-iodine is available over the counter.^[6] It is sold under a number of brand names including Betadine.^[2]

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Medical uses

 Wound area covered in povidone-iodine. Gauze has also been applied.

Povidone-iodine is a broad spectrum antiseptic for topical application in the treatment and prevention of wound infection. It may be used in first aid for minor cuts, burns, abrasions and blisters. Povidone-iodine exhibits longer lasting antiseptic effects than tincture of iodine, due to its slow absorption via soft tissue, making it the choice for longer surgeries. Chlorhexidine provides superior results with equivalent adverse events.^[7]

Consequently, PVP-I has found broad application in medicine as a surgical scrub; for pre- and post-operative skin cleansing; for the treatment and prevention of infections in wounds, ulcers, cuts and burns; for the treatment of infections in decubitus ulcers and stasis ulcers; in gynecology for vaginitis associated with candidal, trichomonal or mixed infections. For these purposes PVP-I has been formulated at concentrations of 7.5–10.0% in solution, spray, surgical scrub, ointment, and swab dosage forms; however, use of 10% povidone-iodine though recommended, is infrequently used, as it is poorly accepted by health care workers and is excessively slow to dry.^[8][9]

Because of these critical indications, only sterile povidone-iodine should be used in most cases. Non-sterile product can be appropriate in limited circumstances in which people have intact, healthy skin that will not be compromised or cut. The non-sterile form of Povidone iodine has a long history of intrinsic contamination with Burkholderia cepacia (aka Pseudomonas cepacia), and other opportunistic pathogens. Its ability to harbor such microbes further underscores the importance of using sterile products in any clinical setting. Since these bacteria are resistant to povidone iodine, statements that bacteria do not develop resistance to PVP-I,^[10] should be regarded with great caution: some bacteria are intrinsically resistant to a range of biocides including povidone-iodine.^[11]

Antiseptic activity of PVP-I is because of free iodine (I2) and PVP-I only acts as carrier of I2 to the target cells. Most commonly used 10% PVP-I delivers about 1-3 ppm of I2 in a compound of more than 31,600 ppm of total iodine atoms. All the toxic and staining effects of PVP-I is due to the inactive iodine only.

Eyes

A buffered PVP-I solution of 2.5% concentration can be used for prevention of neonatal conjunctivitis, especially if it is caused by Neisseria gonorrhoeae, or Chlamydia trachomatis. It is currently unclear whether PVP-I is more effective in reducing the number of cases of conjunctivitis in neonates over other methods.^[12] PVP-I appears to be very suitable for this purpose because, unlike other substances, it is also efficient against fungi and viruses (including HIV and Herpes simplex).^[13]

Pleurodesis

It is used in pleurodesis (fusion of the pleura because of incessant pleural effusions). For this purpose, povidone-iodine is equally effective and safe as talc, and may be preferred because of easy availability and low cost.^[14]

Alternatives

There is strong evidence that chlorhexidine and denatured alcohol used to clean skin prior to surgery is better than any formulation of povidone-iodine^[7]

Contraindications

PVP-I is contraindicated in people with hyperthyroidism (overactive thyroid gland) and other diseases of the thyroid, after treatment with radioiodine, and in people with dermatitis herpetiformis^[why?] (Duhring’s disease).^[15]

Side effects

The sensitization rate to the product is 0.7%.^[16]

Interactions

The iodine in PVP-I reacts with hydrogen peroxide, silver, taurolidine and proteins such as enzymes, rendering them (and itself) ineffective. It also reacts with many mercury compounds, giving the corrosive compound mercury iodide, as well as with many metals, making it unsuitable for disinfecting metal piercings.^[15]

Iodine is absorbed into the body to various degrees, depending on application area and condition of the skin. As such, it interacts with diagnostic tests of the thyroid gland such as radioiodine diagnostics, as well as with various diagnostic agents used on the urine and stool, for example Guaiacum resin.^[15]

Structure

 Structure of povidone-iodine complex.

Povidone-iodine is a chemical complex of the polymer povidone (polyvinylpyrrolidone) and triiodide (I₃⁻).^[17]

It is soluble in cold and mild-warm water, ethyl alcohol, isopropyl alcohol, polyethylene glycol, and glycerol. Its stability in solution is much greater than that of tincture of iodine or Lugol’s solution.

Free iodine, slowly liberated from the povidone-iodine (PVP-I) complex in solution, kills cells through iodination of lipids and oxidation of cytoplasmic and membrane compounds. This agent exhibits a broad range of microbiocidal activity against bacteria, fungi, protozoa, and viruses. Slow release of iodine from the PVP-I complex in solution minimizes iodine toxicity towards mammalian cells.

PVP-I can be loaded into hydrogels, which can be based on carboxymethyl cellulose (CMC), poly(vinyl alcohol) (PVA), and gelatin, or on crosslinked polyacrylamide. These hydrogels can be used for wound dressing. The rate of release of the iodine in the PVP-I is heavily dependent on the hydrogel composition: it increases with more CMC/PVA and decreases with more gelatin.

History

PVP-I was discovered in 1955, at the Industrial Toxicology Laboratories in Philadelphia by H. A. Shelanski and M. V. Shelanski.^[18] They carried out tests in vitro to demonstrate anti-bacterial activity, and found that the complex was less toxic in mice than tincture of iodine. Human clinical trials showed the product to be superior to other iodine formulations.^[19]

Following the discovery of iodine by Bernard Courtois in 1811, it has been broadly used for the prevention and treatment of skin infections, as well as the treatment of wounds. Iodine has been recognized as an effective broad-spectrum bactericide, and is also effective against yeasts, molds, fungi, viruses, and protozoans. Drawbacks to its use in the form of aqueous solutions include irritation at the site of application, toxicity, and the staining of surrounding tissues. These deficiencies were overcome by the discovery and use of PVP-I, in which the iodine is carried in a complexed form and the concentration of free iodine is very low. The product thus serves as an iodophor.

Research

 Schematic of povidone-iodine complex wrapping a single wall carbon nanotube (black).^[20]

Povidone-iodine has found application in the field of nanomaterials. A wound-healing application has been developed which employs a mat of single wall carbon nanotubes (SWNTs) coated in a monolayer of povidone-iodine.^[20]

Research has previously found that the polymer polyvinylpyrrolidone (PVP, povidone) can coil around individual carbon nanotubes to make them water-soluble.^[21]

References

1. ^ Jump up to:^a b c d World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. pp. 321–323. hdl:10665/44053. ISBN 9789241547659.
2. ^ Jump up to:^{a b c d e f g} British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 840. ISBN 9780857111562.
3. ^ Jump up to:^a b Encyclopedia of polymer science and technology (3 ed.). John Wiley & Sons. 2013. p. 728. ISBN 9780470073698. Archived from the original on 2017-01-13.
4. ^ Sneader W (2005). Drug Discovery: A History. John Wiley & Sons. p. 68. ISBN 9780470015520. Archived from the original on 2017-01-13.
5. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06.
6. ^ “Povidone/iodine solution: Indications, Side Effects, Warnings – Drugs.com”. http://www.drugs.com. Archived from the original on 13 January 2017. Retrieved 11 January 2017.
7. ^ Jump up to:^a b Wade RG, Burr NE, McCauley G, Bourke G, Efthimiou O (September 2020). “The Comparative Efficacy of Chlorhexidine Gluconate and Povidone-iodine Antiseptics for the Prevention of Infection in Clean Surgery: A Systematic Review and Network Meta-analysis”. Annals of Surgery. Publish Ahead of Print. doi:10.1097/SLA.0000000000004076. PMID 32773627.
8. ^ Slater K, Cooke M, Fullerton F, Whitby M, Hay J, Lingard S, et al. (September 2020). “Peripheral intravenous catheter needleless connector decontamination study-Randomized controlled trial”. American Journal of Infection Control. 48 (9): 1013–1018. doi:10.1016/j.ajic.2019.11.030. PMID 31928890.
9. ^ Slater K, Fullerton F, Cooke M, Snell S, Rickard CM (September 2018). “Needleless connector drying time-how long does it take?”. American Journal of Infection Control. 46 (9): 1080–1081. doi:10.1016/j.ajic.2018.05.007. PMID 29880433. S2CID 46968733.
10. ^ Fleischer W, Reimer K (1997). “Povidone-iodine in antisepsis–state of the art”. Dermatology. 195 Suppl 2 (Suppl 2): 3–9. doi:10.1159/000246022. PMID 9403248.
11. ^ Rose H, Baldwin A, Dowson CG, Mahenthiralingam E (March 2009). “Biocide susceptibility of the Burkholderia cepacia complex”. The Journal of Antimicrobial Chemotherapy. 63 (3): 502–10. doi:10.1093/jac/dkn540. PMC 2640157. PMID 19153076.
12. ^ Martin I, Sawatzky P, Liu G, Mulvey MR (February 2015). “Neisseria gonorrhoeae in Canada: 2009-2013”. Canada Communicable Disease Report. 41 (2): 35–41. doi:10.1002/14651858.CD001862.pub3. PMC 6457593.
13. ^ Najafi Bi R, Samani SM, Pishva N, Moheimani F (2003). “Formulation and Clinical Evaluation of Povidone-Iodine Ophthalmic Drop”. Iranian Journal of Pharmaceuticical Research. 2 (3): 157–160.
14. ^ Agarwal R, Khan A, Aggarwal AN, Gupta D (March 2012). “Efficacy & safety of iodopovidone pleurodesis: a systematic review & meta-analysis”. The Indian Journal of Medical Research. 135: 297–304. PMC 3361864. PMID 22561614.
15. ^ Jump up to:^a b c Jasek W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 983–5. ISBN 978-3-85200-181-4.
16. ^ Niedner R (1997). “Cytotoxicity and sensitization of povidone-iodine and other frequently used anti-infective agents”. Dermatology. 195 Suppl 2 (Suppl 2): 89–92. doi:10.1159/000246038. PMID 9403263.
17. ^ Kutscher, Bernhard (2020). “Dermatologicals (D), 4. Antiseptics and Disinfectants (D08), Anti‐Acne Preparations (D10), and Other Dermatological Preparations (D11)”. Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. pp. 1–22. doi:10.1002/14356007.w08_w03.
18. ^ U.S. Patent 2,739,922
19. ^ Sneader W (2005). Drug Discovery: A History. New York: John Wiley & Sons. p. 68. ISBN 978-0-471-89979-2.
20. ^ Jump up to:^a b Simmons TJ, Lee SH, Park TJ, Hashim DP, Ajayan PM, Linhardt RJ (2009). “Antiseptic Single Wall Carbon Nanotube Bandages” (PDF). Carbon. 47 (6): 1561–1564. doi:10.1016/j.carbon.2009.02.005. Archived from the original (PDF) on 2010-06-21.
21. ^ Simmons TJ, Hashim D, Vajtai R, Ajayan PM (August 2007). “Large area-aligned arrays from direct deposition of single-wall carbon nanotube inks”. Journal of the American Chemical Society. 129 (33): 10088–9. doi:10.1021/ja073745e. PMID 17663555.

Further reading

• Wong RH, Hung EC, Wong VW, Wan IY, Ng CS, Wan S, Underwood MJ (2009). “Povidone-iodine wound irrigation: A word of caution”. Surgical Practice. 13 (4): 123–4. doi:10.1111/j.1744-1633.2009.00461.x. S2CID 71797553.
• Wong RH, Wong VW, Hung EC, Lee PY, Ng CS, Wan IY, Underwood MJ (2011). “Topical application of povidone-iodine before wound closure is associated with significant increase in serum iodine level”. Surgical Practice. 19 (3): 79–82. doi:10.1111/j.1744-1633.2011.00547.x. S2CID 70528331.
• Wong RH, Ng CS, Underwood MJ (May 2012). “Iodine pleurodesis–a word of caution”. European Journal of Cardio-Thoracic Surgery. 41 (5): 1209. doi:10.1093/ejcts/ezr137. PMID 22219431.

External links

“Povidone-iodine”. Drug Information Portal. U.S. National Library of Medicine.

///////////Povidone-iodine, PVP 1, BETADINE

C=CN1CCCC1=O.II

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CITICOLINE

CDP-choline

• Molecular FormulaC₁₄H₂₆N₄O₁₁P₂
• Average mass488.324 Da

5′-O-[Hydroxy({[2-(trimethylammonio)ethoxy]phosphinato}oxy)phosphoryl]cytidine
987-78-0[RN]
1-{5-O-[({Hydroxy[2-(trimethylammonio)ethoxy]phosphoryl}oxy)phosphinato]-β-D-ribofuranosyl}-4-imino-1,4-dihydro-2-pyrimidinol
213-580-7[EINECS], 2290
2-Pyrimidinol, 1,4-dihydro-1-[5-O-[hydroxy[[hydroxy[2-(trimethylammonio)ethoxy]phosphinyl]oxy]phosphinyl]-β-D-ribofuranosyl]-4-imino-, inner salt
CiticolineCAS Registry Number: 987-78-0 
CAS Name: Cytidine 5¢-(trihydrogen diphosphate) P¢-[2-(trimethylammonio)ethyl] ester inner salt 
Additional Names: choline cytidine 5¢-pyrophosphate (ester); cytidine diphosphate choline ester; CDP-choline 
Trademarks: Difosfocin (Magis); Nicholin (Wyeth); Recognan (Asahi); Rexort (Hoechst); Somazina (Ferrer) 
Molecular Formula: C14H26N4O11P2, Molecular Weight: 488.32 
Percent Composition: C 34.43%, H 5.37%, N 11.47%, O 36.04%, P 12.69% 
Literature References: Naturally occurring nucleotide; intermediate in the major pathway of lecithin biosynthesis. Identification: E. P. Kennedy, S. B. Weiss, J. Am. Chem. Soc.77, 250 (1955).Crystallization from yeast extract: I. Lieberman et al.,Science124, 81 (1956).Synthesis: E. P. Kennedy, J. Biol. Chem.222, 185 (1956); K. Kikugawa et al.,Chem. Pharm. Bull.19, 1011, 2466 (1971). Molecular structure: M. A. Viswamitra et al.,Nature258, 497 (1975). Series of articles on pharmacology and toxicology: Arzneim.-Forsch.33, 1009-1080 (1983). Acute toxicity: T. Grau et al.,ibid. 1033. Clinical trial in ischemic stroke: W. M. Clark et al.,Neurology49, 671 (1997).Review of biosynthesis, metabolism, pharmacology: G. B. Weiss, Life Sci.56, 637-660 (1995); and clinical experience: J. J. Secades, G. Frontera, Methods Find. Exp. Clin. Pharmacol.17, Suppl. B, 1-54 (1995).Properties: Amorphous, somewhat hygroscopic powder. [a]D25 +19.0° (c = 0.86 in H2O). uv max (pH 1): 280 nm (e 12800). Dissolves readily in water to form acidic soln. Practically insol in most organic solvents. pKa 4.4. LD50 in mice, rats (mg/kg): 4600 ±335, 4150 ±370 i.v.; both species 8 g/kg orally (Grau). 
pKa: pKa 4.4Optical Rotation: [a]D25 +19.0° (c = 0.86 in H2O) 
Absorption maximum: uv max (pH 1): 280 nm (e 12800) 
Toxicity data: LD50 in mice, rats (mg/kg): 4600 ±335, 4150 ±370 i.v.; both species 8 g/kg orally (Grau) 
Derivative Type: Sodium saltCAS Registry Number: 33818-15-4 
Trademarks: Acticolin (Upsamedica); Brassel (Searle); Ceraxon (Ferrer); Neuroton (Berlin-Chemie); Sintoclar (Pulitzer) 
Molecular Formula: C14H25N4NaO11P2, Molecular Weight: 510.31 
Percent Composition: C 32.95%, H 4.94%, N 10.98%, Na 4.51%, O 34.49%, P 12.14% 
Properties: White, crystalline, spongy, hygrosopic powder, dec 250°. [a]D20 +12.5° (c = 1.0 in H2O). Sol in water. Practically insol in alcohol. 
Optical Rotation: [a]D20 +12.5° (c = 1.0 in H2O) 
Therap-Cat: Neuroprotective. In treatment of ischemic stroke and head trauma. 
Keywords: Neuroprotective.

Citicoline (INN), also known as cytidine diphosphate-choline (CDP-Choline) or cytidine 5′-diphosphocholine is an intermediate in the generation of phosphatidylcholine from choline, a common biochemical process in cell membranes. Citicoline is naturally occurring in the cells of human and animal tissue, in particular the organs.

Studies suggest that CDP-choline supplements increase dopamine receptor densities.^[1] Intracerebroventricular administration of citicoline has also been shown to elevate ACTH independently from CRH levels and to amplify the release of other HPA axis hormones such as LH, FSH, GH and TSH in response to hypothalamic releasing factors.^[2] These effects on HPA hormone levels may be beneficial for some individuals but may have undesirable effects in those with medical conditions featuring ACTH or cortisol hypersecretion including PCOS, type II diabetes and major depressive disorder.^[3][4]

Citicoline was originally developed in Japan for stroke. Citicoline or its sodium salt was later introduced as a prescription drug in many European countries. In these countries it is now frequently prescribed for thinking problems related to circulation problems in the brain. In the US, citicoline is marketed as a dietary supplement. Citicoline or its sodium salt is used for Alzheimers disease and other types of dementia, head trauma, cerebrovascular disease such as stroke, age-related memory loss, Parkinsons disease, and glaucoma.

Citicoline sodium is chemically known as 5-0-[hydroxy({hydroxy[2-(trimethylammonio)ethoxy]phosphoryl}oxy)phosphoryl]cytidine sodium which is represented by formula I,

There are many process described in the art for the preparation of citicoline. Japanese patent 51028636 describes a process for the preparation of citicoline by neutralisation of Calcium salt of phosphorylcholine chloride with 98% H2SO4 to make phosphorylcholine chloride, which is further treated with cytidine-5-phosphate in presence of DCC and pyridine at 70 C to obtain citicoline hydrate. The drawback of this process is that citicoline is very unstable

in this harsh reaction condition such as formamide, 98% H2SO4 and high temperature of 70 C.

Chinese patent 1944661 describes an enzymatic process for the preparation of citicoline which involves twice pH adjustment to precipitatethe product,filtration of the solids, charcolisation, washing with pure water, eluting through chloride type ion exchange resin with water ethanol/alcohol reagents, desalting the eluate, decoloring and collecting the liquid, vacuum-concentration of the eluate by adding an alcohol solvent to get the solid to obtain the crude product and dissolving the crude product, microfiltering, ultrafiltering, adding an alcoholic solvent, to obtain the wet productand drying to obtain the final product. The primary disadvantage of this process is that the above reaction involves water and ethanol mixture for elution of ion exchange column and also vacuum concentration of water ethanol mixture which requires high energy, more time, leads to decomposition of product and also leads to the formation of more effluent hence it is not suitable for large scale production.

The primary disadvantage of this process is that the above reaction involves water and ethanol mixture for elution of ion exchange column and also vacuum concentration of water ethanol mixture which requires high energy, more time, leads to decomposition of product and also leads to the formation of more effluent hence it is not suitable for large scale production.

US20090286284 describes a microbial process for preparation of citicoline. This patent also discloses a process for purification of citicoline by passing through acidic cation exchange and anion exchange resin. The drawback of this process is that in this process citicoline is passed through cation /anion exchange resin in free form which is unstable and liable to formation of unwanted impurities. Therefore for the purification it needs very high volume of resin (200 times) and high volume (100 times) of solvent. This process further needs reconcentration of huge volume of solvents, which is time taking and energy consuming.

Chemical and Pharmaceutical Bulletin 1971, 19(5), 1011-16 describes a process for the preparation of citicoline by direct condensation of cytidine 5-

monophosphate and choline phosphate by using p-toluenesulfonyl chloride or methanesulfonyl chloride combined with DMF. After completion of reaction the mass was diluted with water, pH was adjusted with ammonia solution to 9.5 and product was purified by using Dowex-1 ion exchange resin by eluting with formic acid. Another Chemical and Pharmaceutical Bulletin 1971, 19(12), 2499-71 describes a process for the preparation of citicoline by direct condensation cytidine 5-monophosphate and choline phosphate in presence of thionyl chloride and DMF.The product obtained was further purified by using Dowex-1 ion exchange resin by eluting with formic acid.

Journal of Biological Chemistry, 1956, 185-191 describes a process for the preparation of citicoline by direct condensation5-cytidylic acid and phosphorylcholine in a mixture of water and pyridine in presence of DCC, stirred for few days by adding DCC in lots, after completion of reaction, reaction mass was diluted with water and filtered. The pH of the filtrate was adjusted 8-9 using 0.5N KOH, diluted further with water and passed through Dowex-1 formate resin by eluting with formic acid and water.

The drawbacks of these processes are that they use hazardous reagents such as p-toluenesulfonyl chloride, methanesulfonyl chloride, thionyl chloride etc. Hence they are not suitable for large scale production. Also, the prior art processes pass citicoline solution, without isolating it, to ion exchange resins for purification. During this process most of the inorganic impurities present along with citicoline or its salt pass through the column, thus making purification difficult.

SYN

Journal of Chemical Research, 40(6), 358-360; 2016

An improved, three-step synthesis of cytidine diphosphate choline (CDP-choline) from cytidine was achieved in 68% overall yield. Selective phosphorylation of cytidine was accomplished by the use of morpholinophosphodichloridate to give cytidine-5′-phosphomorpholide, which was condensed with choline phosphate chloride in the presence of a catalytic amount of H₂SO₄ to give CDP-choline. The intermediates and products could be efficiently purified by recrystallisation, thus avoiding the use of chromatography at all stages. The reaction could be scaled up to 200 g in 64% overall yield, making this route attractive for industrial application.

Cytidine diphosphate choline (CDP-choline 1) is a nucleotide coenzyme and serves as a choline donor in the biosynthesis of lipids,1 lecithins,2 and sphingomyelin.3 It is a clinical drug for the treatment of several illnesses involving disturbance of the central nervous system, in particular, for regaining a patient’s consciousness and for treatment of neuropsychic symptoms occurring during skull traumas and brain surgery.4 Among various methods for the synthesis of CDP-choline in the literature, the current preferred method is via the condensation of cytidine-5’-phosphomorpholide (2) with choline phosphate chloride (3) under mild reaction conditions.5–7 Compound 2 was synthesised from 5’-cytidine monophosphate (4) and morpholine in the presence of DCC (N,N’-dicyclohexylcarbodiimide)8 or via the controlled hydrolysis of cytidine-5’-phosphodichloride (5) followed by P–N bond formation with morpholine (Scheme 1, route a).7 However, DCC is toxic and converted into urea which is difficult to separate from the mixture, thus leading to poor purity of product. Furthermore, phosphorylation with POCl3 always meets with side reactions from the 2’ or 3’ hydroxyls and detracts from the acceptance of this method in industry.9 In the context of ongoing projects on the synthesis of nucleoside drugs,10–14 herein we report the synthesis of CDP-choline via the selective phosphorylation of 6 wiResults and discussion Central to our approach for the synthesis of CDP-choline is the selective phosphorylation of 6 using sterically-hindered 7 as phosphorylation regent. 7 was synthesised by the direct phosphorylation of morpholine with POCl3 , a compound whose utility for the conversion of alcohols and amines into various phosphorylation derivatives.15 Due to the reactivity of three chloro atoms in POCl3 , gradually adding POCl3 to excess morpholine avoids the bifunctional reaction exclusively. After reaction, 7 could be purified by fractional distillation to yield as a colourless oil (b.p. 124–126 °C at 1.33 KPa). Due to the presence of the electron-donating morpholino group, 7 displays lower reactivity than POCl3 and could tolerate moisture and air better. Usefully, 7 could be synthesised on the 200 g scale and stored at 4 °C. The major concern of utilising 7 as phosphorylation reagent is its selectivity for the 5’ hydroxyl group. We therefore assessed the selectivity for 5’ hydroxylation using 6 and 7 in the presence of various organic bases. After phosphorylation, H2 O was added to destroy the excess of 7, and 2 was obtained in a single step. The solvent, the base, temperature and the ratio of substrates were evaluated and the results are summarised in Table 1

https://journals.sagepub.com/doi/pdf/10.3184/174751916X14628025243831

Cytidine-5’-phosphomorpholide (2): Cytidine (0.243 g, 1.0 mmol) and DMAP (0.183 g, 1.5 mmol) in MeCN (10 mL) were stirred slowly and cooled to 0 °C, and 7 (2.0 mmol) was added slowly. The mixture was heated to 50 °C and kept at this temperature for 2 h. The solvent was removed in vacuo and the residue was purified by recrystallisation from EtOH to give 2 as a white semi-solid (0.318 g); yield 81%; m.p. 62–64 °C; 1 H NMR (400 MHz, DMSO-d6 ) δ 8.43 (d, J = 7.6 Hz, 1H), 7.39 (s, 2H), 7.19 (d, J = 7.6 Hz, 1H), 5.77 (d, J = 2.8 Hz, 1H), 5.51 (d, J = 4.8 Hz, 1H), 5.18 (t, J = 5.2 Hz, 1H), 5.08 (d, J = 5.6 Hz, 1H), 3.76–3.71 (m, 1H), 3.61–3.56 (m, 1H), 3.45–3.42 (m, 4H), 3.03–2.99 (m, 4H); 13C NMR (100 MHz, DMSO-d6 ) δ 166.5, 157.8, 145.9, 141.6, 88.1, 86.2, 74.3, 70.7, 65.1, 65.0, 60.3, 60.2; HRMS calcd for C13H22N4 O8 P [M + H]+ 393.1170, found: 393.1172.

CDP-choline (1): 2 (0.392 g, 1.0 mmol) was added to MeOH (10 mL) followed by the addition of 3 (0.310 g, 1.2 mmol) and was stirred at room temperature for 10 min. Then 98% H2 SO4 (0.005 mL, 10 mol%) was added. The mixture was kept at 50 °C for 3 h. The solvent was removed in vacuo and the residue was purified by recrystallisation from EtOH to give 1 as a white solid (0.410 g); yield 85%. 1 H NMR (400 MHz, D2 O) δ 7.86 (s, 2H), 6.04 (d, J = 5.2 Hz, 1H), 5.91 (d, J = 5.2 Hz, 1H), 4.32 (brs, 2H), 4.26–4.22 (m, 2H), 4.18 (brs, 2H), 4.11 (t, J = 3.2 Hz, 1H), 3.60 (t, J = 2.4 Hz, 2H), 3.14 (s, 9H); 13C NMR (100 MHz, D2 O) δ 166.1, 157.7, 141.5, 96.6, 89.3, 82.6, 74.1, 69.3, 66.0, 65.9, 64.8, 59.9, 54.0; HRMS calcd for C14H27N4 O11P2 [M + H]+ 489.1146, found: 489.1140.

SYNKikugawa, Kiyomi; Ichino, MotonobuChemical & Pharmaceutical Bulletin (1971), 19, (5), 1011-16.https://www.jstage.jst.go.jp/article/cpb1958/19/5/19_5_1011/_pdf/-char/enCytidine diphosphate choline (CDP-choline), one of the nucleotide coenzymes, is known to be a precursor of phospholipid and play an important role in the living organisms. The coenzyme was synthesized in a fairly good yield by direct condensation of cytidine-5′ monophosphate (5′-CMP) and choline phosphate (P-choline) by the use of p-toluenesulfonyl chloride or methanesulfonyl chloride combined with dimethylformamide 
Method B, with Methanesulfonyl Chloride and DMF: A mixture of 1.3g (11.5 mmole) of methanesulfonyl chloride and 3ml of DMF was added to the gummy mixture containing 10 mmole of P-choline (II). It was shaken at room temperature for 10 min, and 1.0g (3.1 mmole) of 5′-CMP (I) was added to the viscous solution. It was then stirred at room temperature for one hour. Paper chromatography and paper electrophoresis of the reaction mixture showed that CDP-choline (III) was a major reaction product. The separa tion, isolationand identification of the product (III) were same as in method A. Crystalline white powder of CDP-choline was obtained in a yield of 50.0%. Method C, with p-Toluenesulfonyl Chloride and HMPA: A mixture of 2.2g (11.5 mmole) of p-toluene sulfonyl chloride and 3ml of HMPA was added to the gummy mixture containing 10 mmole of P-choline (II). 5′-C1IP (I) (1.0g, 3.1 mmole) was reacted under the same condition as in method A, and isolation was performed similarly. Crystalline powder of CDP-choline (III) was obtained in a yield of about 10%. Method D according to the Morpholidate Method 6): 5′-CMP-Morpholidate (4-morpholine-N, N’-dicyclohexylcarboxamidinium salt) (1.28g, 2 mmole) was reacted with 8 mmole of P-choline (II) according to the method of Tanaka, et al. 6) Separation and isolation of the product were similarly performed as in method A. Crystalline powder of the authentic CDP-choline was obtained in a yield of 55%. CDP-Choline Monosodium Salt Monosodium salt of CDP-choline (III) was prepared from the product (III) obtained by method A. Thus, 200mg of CDP-choline (III) was dissolved in 1.0ml of water, and after the pH of the solution was adjusted to 6.0 with 2N NaOH, 3ml of ethanol was added. Crystallization occurred after standing at room temperature overnight to afford plates of 130 mg of CDP-choline monosodium salt. Determination of the Yield of CDP-Choline (III) in the Condensation with p-Toluenesulfonyl Chloride and DMF In the condensation reaction using p-toluenesulfonyl chloride and DMF, the effects of the amount of p-toluenesulfonyl chloride and the reaction temperature were examined. 5′-CMP (I) (1.0g, 3.1 mmole) was added to the mixture of 10 mmole of P-choline (II), 3ml of DMF and p-toluenesulfonyl chloride which were previously mixed and treated at room temperature for 10 min. The reaction mixtures were stirred at 25•‹for one hour with the varying amounts of p-toluenesulfonyl chloride of 1.5g (7.9 mmole), 1.9g (10 mmole), 2.2g (11.5 mmole), 3g (15.8 mmole), 4g (21.0 mmole) and 5g (26.3 mmole). The yields of the compound (III) estimated were 30, 50, 60, 49, 44 and 37% respectively.

SYN

 Indian Pat. Appl., 2014MU00923

SYN

CN 111647636

Syn

Biotechnology and Bioengineering, 117(5), 1426-1435; 2020

https://onlinelibrary.wiley.com/doi/10.1002/bit.27291

Cytidine-5′-diphosphocholine (CDP-choline) is a widely used neuroprotective drug for multiple indications. In industry, CDP-choline is synthesized by a two-step cell culture/permeabilized cell biotransformation method because substrates often do not enter cells in an efficient manner. This study develops a novel one-step living cell fermentation method for CDP-choline production. For this purpose, the feasibility of Pichia pastoris as a chassis was demonstrated by substrate feeding and CDP-choline production. Overexpression of choline phosphate cytidylyltransferase and choline kinase enhanced the choline transformation pathway and improved the biosynthesis of CDP-choline. Furthermore, co-overexpression of ScHnm1, which is a heterologous choline transporter, highly improved the utilization of choline substrates, despite its easy degradation in cells. This strategy increased CDP-choline titer by 55-folds comparing with the wild-type (WT). Overexpression of cytidine-5′-monophosphate (CMP) kinase and CDP kinase in the CMP transformation pathway showed no positive effects. An increase in the ATP production by citrate stimulation or metabolic pathway modification further improved CDP-choline biosynthesis by 120%. Finally, the orthogonal optimization of key substrates and pH was carried out, and the resulting CDP-choline titer (6.0 g/L) at optimum conditions increased 88 times the original titer in the WT. This study provides a new paradigm for CDP-choline bioproduction by living cells.

SYN

Citicoline sodium is a chemically designate as Cytidine 5’-(trihydrogendiphosphate) P’-[2-(trimethylammonio) ethyl] ester monosodium salt, its molecular formula is C14H25N4NaO11P2 and molecular weight is 510.31(salt) and 488.32 (base- C14H26N4O11P2). It is a white crystalline, hygroscopic powder and readily soluble in water but practically insoluble in alcohol. Its melting point was 259 – 268°C and dissociation constant (Pka) was 4.4 [1]. Biopharmaceutical classification system (BCS) for Citicoline is Class – I (High solubility and High Permeability) [3]. Citicoline has a broad spectrum of therapeutic index, as a Neuroprotectant or Cerebroprotectant, in particular citicoline is useful the victims of ischemic stroke, head trauma and neurodegenerative disease. Citicoline is also used to treat unconsciousness resulting from cerebral thrombosis, hemorrhages, demyelinating diseases, cranial trauma and cerebropathies due to atherosclerosis [2]. Citicoline was originally developed in Japan for stroke. It was later introduced as a prescription drug in many European countries. In these countries it is now frequently prescribed for thinking problems related to circulation problems in the brain. In the US, citicoline is marketed as a dietary supplement [3]. Citicoline daily dosages may range from 250 mg to about 3000 mg and more preferably from 500 mg to about 2000 mg up to four or more times daily, duration of the treatment may vary from several weeks to several years, dosages may be varied over time depending on the severity of symptoms [4].

SYN

192/MUM/2012

The present invention discloses a novel, cost-effective process for preparing psychostimulant drug cytidinediphosphate-choline (CDP-Choline) commonly known as citicoline. The process comprises reacting cytidine 5-monophosphate with morpholine in presence of a coupling reagent and an organic solvent to form morpholidate compound; condensing morpholidate compound with calcium salt of phosphorylcholinehalide in presence of an acid to form citicoline calcium chloride; and purifying the citicoline calcium chlorideby passing through cationic and anionic resinsand eluting by water to form citicoline sodium of formula I.

Example:

(a) Preparation of citicoline calcium chloride:

S-Cytidine mono phosphate (1.25 kg)and morpholine (1.12 kg) were added into methanol {6.25 L) and DCC (1.50 kg) at 25 to 35 C.The reaction mixture was heated to 50 to 55 C and stirred for 7 hours. After completion of the reaction, the reaction mass was cooled to 25 to 35 C and the obtained reaction mass was added slowly to phosphoryl choline chloride calcium salt (1.9 kg) in methanol (8.75 L) solution. The pH was maintained to 3.8 to 4.2 using HC1 gas in IPA and stirred for 6 hours at 25 to 35 . The reaction mass was further heated to 45 to 5Q C. After completion of reaction the yeactkm mass was cooled and stirced for 1 hour. The product was filtered, washed with chilled methanol at 0 to 5 Cand suck dried to obtain citicoline calcium chloride.

Yield; 3.70-4.0 kg (b) Preparation of citicoline sodium:

The above obtained crude citicolinecalcium chloride was dissolved in water (6.25 L), filtered, washed with water and suck dried. Filtrate containing the product was re-filtered through Hyflo bed. The clear filtrate was eluted through column containing acidic cation exchange resins (12.5 L). The material was washed with water. The eluent was further passed through anion exchange resin (12.5 L). column and washed with water.

Complete aqueous solution after the passing through an-ion exchange resin was collected, pH of the solution was adjusted to 6.5 to 7.0 using 30 % sodium hydroxide solution (0.3Kg in 0.45L) and solution was concentrated using reverse osmosis. The solution was cooled to 25 to 35 C and charcoalated. The solution was filtered through hyflo bed at 25 to 35 C, washed with water. The solution was further filtered through ultra-filter at 25 to 35 C.

Clear filtrate and mixture of isopropanol and Methanol (1:1) (25 L) were stirred, the reaction mass was cooled to 0 to 5 C, and stirred for 2 hours. The product was filtered under nitrogen atmosphere, solid was washed with the mixture of IPA and methanol (1:1) (1.25 L) at 0 to 5 C and dried under vacuum below 95 C until moisture/LOD is less the 2.0%.

Yield: 1 to 1.2 kg

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PATENT

https://patents.google.com/patent/CN1944661A/enEmbodiment 1:With 30 kilograms of quick-frozen yeast, 3 kilograms of phosphorylcholines, 1 kilogram 5 ‘-cytidylic acid, 10 kilograms of glucose, 2 kilograms of potassium hydroxide, 800 kg of water are mixed back temperature adjustment to 25 ℃, PH=6 carries out 65 rev/mins of stirring reactions and it was fully reacted in 6 hours; Reaction solution is warming up to 50 ℃ of deactivations, carries out liquid-solid separation; Transfer PH=8.0, part basic protein and nucleic acid precipitation are carried out liquid-solid separation, and then are transferred PH=2.5, make the acidic protein precipitation, carry out liquid-solid separation, sediment separate out; Use Activated Carbon Adsorption Separation, PH=2.5 washs with pure water; Carry out wash-out with the molten reagent of ethanol alkali, elutriant carries out desalination, decolouring is handled, and collects liquid; The elutriant vacuum concentration; Concentrated solution adds 2 times of ethanol, crystallization, liquid-solid separate crude product; Dissolving crude product, ultrafiltration behind the micro-filtration adds 2 times of ethanol, crystallization, liquid-solid separate wet product, after the drying finished product.Embodiment 2:With 80 kilograms of quick-frozen yeast, 4 kilograms of phosphorylcholines, 4 kilogram 5 ‘-cytidylic acid, 16 kilograms of glucose, 4 kilograms of potassium hydroxide, 1100 kg of water are mixed back temperature adjustment to 30 ℃, and add 0.5 kilogram of MgSO ₄Solution, PH=6 carries out 120 rev/mins of stirring reactions and it was fully reacted in 8 hours; Reaction solution is warming up to 70 ℃ of deactivations, carries out liquid-solid separation; Transfer PH=10, part basic protein and nucleic acid precipitation are carried out liquid-solid separation, and then are transferred PH=4, make the acidic protein precipitation, carry out liquid-solid separation, sediment separate out; Use Activated Carbon Adsorption Separation, PH=4 washs with pure water; Carry out wash-out with the molten reagent of ethanol alkali, elutriant carries out desalination, decolouring is handled, and collects liquid; The elutriant vacuum concentration; Concentrated solution adds 2 times of methyl alcohol, crystallization, liquid-solid separate crude product; Dissolving crude product, ultrafiltration behind the micro-filtration adds 2 times of methyl alcohol, crystallization, liquid-solid separate wet product, after the drying finished product.Embodiment 3:With 100 kilograms of quick-frozen yeast, 8 kilograms of phosphorylcholines, 5 kilogram 5 ‘-cytidylic acid, 20 kilograms of glucose, 5 kilograms of potassium hydroxide, 1500 kg of water are mixed back temperature adjustment to 40 ℃, and add 6 kilograms of MgSO ₄Solution, PH=8 carries out 150 rev/mins of stirring reactions and it was fully reacted in 10 hours; Reaction solution is warming up to 90 ℃ of deactivations, carries out liquid-solid separation; Transfer PH=12.0, part basic protein and nucleic acid precipitation are carried out liquid-solid separation, and then are transferred PH=5.5, make the acidic protein precipitation, carry out liquid-solid separation, sediment separate out; Use Activated Carbon Adsorption Separation, PH=5.5 washs with pure water; Carry out wash-out with the molten reagent of ethanol alkali, elutriant carries out desalination, decolouring is handled, and collects liquid; The elutriant vacuum concentration; Concentrated solution adds 2 times of first and second alcoholic solution, crystallization, liquid-solid separate crude product; Dissolving crude product, ultrafiltration behind the micro-filtration adds 2 times of first and second alcoholic solution, crystallization, liquid-solid separate wet product, after the drying finished product. 
PATENThttps://patents.google.com/patent/WO2013128393A1/enCiticoline (CDP-Choline), naturally occurring nucleotide, is a neuroprotective indicated for the treatment of ischemic stroke and head trauma in patients. Citicoline (CDP-Choline) is represented by formula (I).

US patent no. 3,666,748 discloses a process for preparing Citicoline sodium by reaction of 4- morpholino-N,N’-dicyclohexylcarboxamidine chloride salt of choline phosphormorpholidate (I) with cytidine-5-monophosphate in free form or its salts with base in a solvent such as o- chlorophenol, m-cresol, acetonitrile, pyridine and the like. The Citicoline thus obtained is purified through a column chromatograph packed with activated carbon followed by elution to get ammonium salt of citicoline, which is further converted to citicoline followed by citicoline sodium.US patent no. 3,787,392 discloses a process for preparing Citicoline by adding the acidic calcium phosporyl choline chloride tetra hydrate to the solution of morpholidiate cytidine 5- monophosphate and DCC in methanol followed by isolation and purification by means of chromatography column containing anion exchanger (Dowex 1×2 type formate form; 50-100 mesh) which is further converted to its sodium salt by neutralizing with sodium hydroxide. Further, US patent no. 3,803,125 discloses a process for preparing citicoline by reacting morpholidiate cytidine 5 ‘-monophosphate with calcium phosporyl choline chloride tetra hydrate in solvent system of an aliphatic alcohol or dialkyl ketone or dimethyl formamide at pH from 1 to 6.5. The product thus obtained is further isolated; purified by means of chromatography column containing anion exchanger; concentrated; and neutralized with aqueous solution of sodium hydroxide to get citicoline sodium.Example 1To a solution of calcium phosphoryl choline chloride tetra hydrate (50.0 gm) in water, a solution of oxalic acid in RO water (19.5 gm oxalic acid in 90 ml RO water) was added at 45- 50°C. The reaction mass was filtered and distilled out to get residue followed by addition of methanol. To the above solution, solution of morpholine and DCC in methanol was added. The temperature of the reaction was raised to 50-55°C and to this, solution of cytidine 5′- monophospahte in methanol (12.2 gm in 40 ml methanolic HCl and 20 ml methanol) was added and reaction was maintained. The pH 3.5 of reaction mixture was maintained by methanolic HCl. Reaction mass was cooled and IPA was added after completion of the reaction. The precipitated product, citicoline, was filtered and dried. The crude Citicoline (16.0 gm) was dissolved in water and treated with charcoal to get the purified Citicoline acid which on reaction with aqueous sodium hydroxide gave Citicoline Sodium with purity > 99%.Example 2To the solution of cytidine 5′-monophospahate (5′-CMP) (100 gm) in methanol (750 ml), solution of morpholine (75 gm) and DCC (100 gm) in methanol was added at room temperature. The temperature of the reaction was raised to 50-55°C for a time period of 3-7 hrs followed by cooling the reaction mass and filtered to get morpholidiate cytidine 5’- monophospahate in mother liquor. To this, solution of calcium phosphoryl choline chloride (200 gm) in methanol was added and the temperature of reaction mass was raised to 50-55°C and maintained at pH of 3.5 by methanolic HCl. The reaction mass was cooled and filtered to get crude Citicoline by adding IPA. Further, morpholidiate salt of oxalic acid (138.3 gm) was added to the solution of crude citicoline in methanol at 30-35°C followed by the addition of IPA to get the precipitated Citicoline, which is further treated with activated charcoal in water followed by filtration. To filtrate containing purified Citicoline, aqueous solution of sodium hydroxide was added at room temperature followed by addition of ethanol and the temperature of reaction mass was raised to 50-55°C. The precipitated product was filtered and dried where the purity of citicoline sodium is > 99% measured by HPLC. (265 gm). 
ClaimsHide Dependent 

We Claim:1. A process for preparing pure Citicoline (CDP-Choline), the process comprising:reacting a cytidine 5′-monophospahte or its amide salts with calcium phosphoryl choline chloride tetra hydrate or its amide salts in presence of dicyclohexyl carbodiimide (DCC) and a solvent,wherein a dicarboxylic acid or its salt is employed in the process to obtain citicoline with a purity of more than 99% measured by HPLC.2. The process as claimed in claim 1, further comprising preparing highly pure sodium salt of citicoline by reacting the pure citicoline with sodium hydroxide.3. The process as claimed in claim 1, wherein the dicarboxylic acid is used either in the form of free acid or its base salts.4. The process as claimed in any one of the preceding claims, wherein dicarboxylic acid is selected from the group consisting of oxalic acid, malonic acid, succininc acid and glutaric acid.5. The process as claimed in any one of the preceding claims, wherein the base of dicarboxylic acid is selected from the group consisting of organic bases such as amidates, amines or inorganic base such as alkali or alkaline earth metal.6. The process as claimed in claim 1, wherein the solvent is selected from the group consisting of aliphatic alcohols from C atoms, ketones such as acetone, methyl isobutyl ketone and the like or mixture thereof.7. The process as claimed in claim 1, wherein the solvent is methanol.8. The process as claimed in any of the preceding claims, wherein the dicarboxylic acid or its salts lessen the solubility of inorganic impurities such as calcium chloride, calcium hydroxide, unreacted choline phosphate, 5-CMP. 

Patent

US3666748A *1967-12-181972-05-30Takeda Chemical Industries LtdMethod for production of cytidine (or deoxycytidine)-5{40 -diphosphate choline and intermediates thereforUS3787392A *1970-12-021974-01-22Boehringer Mannheim GmbhProcess for the preparation of nucleoside diphosphate estersFamily To Family CitationsCN102010454B *2010-12-022012-03-07胡建荣Citicoline sodium compound and new method thereofPublication numberPriority datePublication dateAssigneeTitleCN104031105A *2014-06-062014-09-10浙江天冉药物研究有限公司Method for preparing citicoline sodiumCN105732752A *2016-03-182016-07-06新乡学院Citicoline and synthetic method thereofCN106146590A *2016-06-292016-11-23陈建峰A kind of preparation method of C14H25N4NaO11P2CN110684066A *2019-05-222020-01-14广东金城金素制药有限公司Cytophosphocholine medicinal preparation and new application thereof in cerebral infarction acute-stage disturbance of consciousness

Use as a dietary supplement

Citicoline is available as a supplement in over 70 countries under a variety of brand names: Cebroton, Ceraxon, Cidilin, Citifar, Cognizin, Difosfocin, Hipercol, NeurAxon, Nicholin, Sinkron, Somazina, Synapsine, Startonyl, Trausan, Xerenoos, etc.^[5] When taken as a supplement, citicoline is hydrolyzed into choline and cytidine in the intestine.^[6] Once these cross the blood–brain barrier it is reformed into citicoline by the rate-limiting enzyme in phosphatidylcholine synthesis, CTP-phosphocholine cytidylyltransferase.^[7][8]

Research

Memory and cognition

Studies have failed to confirm any potential benefits of citicoline for cognitive impairment.^[9]

Ischemic stroke

Some preliminary research suggested that citicoline may reduce the rates of death and disability following an ischemic stroke.^[10][11] However, the largest citicoline clinical trial to date (a randomised, placebo-controlled, sequential trial of 2298 patients with moderate-to-severe acute ischaemic stroke in Europe), found no benefit of administering citicoline on survival or recovery from stroke.^[12] A meta-analysis of seven trials reported no statistically significant benefit for long-term survival or recovery.^[13]

Vision

The effect of citicoline on visual function has been studied in patients with glaucoma, with possible positive effect for protecting vision.^[14]

Mechanism of action

Enzymes involved in reactions are identified by numbers. See file description.

Neuroprotective effects

Citicoline may have neuroprotective effects due to its preservation of cardiolipin and sphingomyelin, preservation of arachidonic acid content of phosphatidylcholine and phosphatidylethanolamine, partial restoration of phosphatidylcholine levels, and stimulation of glutathione synthesis and glutathione reductase activity. Citicoline’s effects may also be explained by the reduction of phospholipase A2 activity.^[15] Citicoline increases phosphatidylcholine synthesis.^[16][17][18] The mechanism for this may be:

• By converting 1, 2-diacylglycerol into phosphatidylcholine
• Stimulating the synthesis of SAMe, which aids in membrane stabilization and reduces levels of arachidonic acid. This is especially important after an ischemia, when arachidonic acid levels are elevated.^[19]

Neuronal membrane

The brain preferentially uses choline to synthesize acetylcholine. This limits the amount of choline available to synthesize phosphatidylcholine. When the availability of choline is low or the need for acetylcholine increases, phospholipids containing choline can be catabolized from neuronal membranes. These phospholipids include sphingomyelin and phosphatidylcholine.^[15] Supplementation with citicoline can increase the amount of choline available for acetylcholine synthesis and aid in rebuilding membrane phospholipid stores after depletion.^[20] Citicoline decreases phospholipase stimulation. This can lower levels of hydroxyl radicals produced after an ischemia and prevent cardiolipin from being catabolized by phospholipase A2.^[21][22] It can also work to restore cardiolipin levels in the inner mitochondrial membrane.^[21]

Cell signalling

Citicoline enhances cellular communication by increasing the availability of neurotransmitters, including acetylcholine, norepinephrine, and dopamine.^[23] In simple terms, the choline component of citicoline is used to create acetylcholine, which is a primary executive neurotransmitter in the human brain. Clinical trials have found that citicoline supplementation improves attention, focus and learning in large part due to the increase in acetylcholine that results.^[24]

Glutamate transport

Citicoline lowers increased glutamate concentrations and raises decreased ATP concentrations induced by ischemia. Citicoline also increases glutamate uptake by increasing expression of EAAT2, a glutamate transporter, in vitro in rat astrocytes. It is suggested that the neuroprotective effects of citicoline after a stroke are due in part to citicoline’s ability to decrease levels of glutamate in the brain.^[25]

Pharmacokinetics

Citicoline is water-soluble, with more than 90% oral bioavailability.^[20] Plasma levels peak one hour after oral ingestion, and a majority of the citicoline is excreted as CO2 in respiration, and again 24 hours after ingestion, where the remaining citicoline is excreted through urine.^[26]

Side effects

Citicoline has a very low toxicity profile in animals and humans. Clinically, doses of 2000 mg per day have been observed and approved. Minor transient adverse effects are rare and most commonly include stomach pain and diarrhea.^{[17][unreliable medical source?]} There have been suggestions that chronic citicoline use may have adverse psychiatric effects. However, a meta-analysis of the relevant literature does not support this hypothesis.^[27][28] At most, citicoline may exacerbate psychotic episodes or interact with anti-psychotic medication.

Synthesis

In vivo

Phosphatidylcholine is a major phospholipid in eukaryotic cell membranes. Close regulation of its biosynthesis, degradation, and distribution is essential to proper cell function. Phosphatidylcholine is synthesized in vivo by two pathways

• The Kennedy pathway, which includes the transformation of choline to citicoline, by way of phosphorylcholine, to produce phosphatidylcholine when condensed with diacylglycerol.
• Phosphatidylcholine can also be produced by the methylation pathway, where phosphatidylethanolamine is sequentially methylated.^[29]

References

1. ^ Giménez R, Raïch J, Aguilar J (Nov 1991). “Changes in brain striatum dopamine and acetylcholine receptors induced by chronic CDP-choline treatment of aging mice”. British Journal of Pharmacology. 104 (3): 575–8. doi:10.1111/j.1476-5381.1991.tb12471.x. PMC 1908237. PMID 1839138.
2. ^ Cavun S, Savci V (Oct 2004). “CDP-choline increases plasma ACTH and potentiates the stimulated release of GH, TSH and LH: the cholinergic involvement”. Fundamental & Clinical Pharmacology. 18 (5): 513–23. doi:10.1111/j.1472-8206.2004.00272.x. PMID 15482372. S2CID 33866107.
3. ^ Benson S, Arck PC, Tan S, Hahn S, Mann K, Rifaie N, Janssen OE, Schedlowski M, Elsenbruch S (Jun 2009). “Disturbed stress responses in women with polycystic ovary syndrome”. Psychoneuroendocrinology. 34 (5): 727–35. doi:10.1016/j.psyneuen.2008.12.001. PMID 19150179. S2CID 13202703.
4. ^ Florio P, Zatelli MC, Reis FM, degli Uberti EC, Petraglia F (2007). “Corticotropin releasing hormone: a diagnostic marker for behavioral and reproductive disorders?”. Frontiers in Bioscience. 12: 551–60. doi:10.2741/2081. PMID 17127316.
5. ^ Single-ingredient Preparations (: Citicoline). In: Martindale: The Complete Drug Reference [ed.by Sweetman S], 35th Ed. 2007, The Pharmaceutical Press: London (UK); e-version. .
6. ^ Wurtman RJ, Regan M, Ulus I, Yu L (Oct 2000). “Effect of oral CDP-choline on plasma choline and uridine levels in humans”. Biochemical Pharmacology. 60 (7): 989–92. doi:10.1016/S0006-2952(00)00436-6. PMID 10974208.
7. ^ Alvarez XA, Sampedro C, Lozano R, Cacabelos R (Oct 1999). “Citicoline protects hippocampal neurons against apoptosis induced by brain beta-amyloid deposits plus cerebral hypoperfusion in rats”. Methods and Findings in Experimental and Clinical Pharmacology. 21 (8): 535–40. doi:10.1358/mf.1999.21.8.794835. PMID 10599052.
8. ^ Carlezon WA, Pliakas AM, Parow AM, Detke MJ, Cohen BM, Renshaw PF (Jun 2002). “Antidepressant-like effects of cytidine in the forced swim test in rats”. Biological Psychiatry. 51 (11): 882–9. doi:10.1016/s0006-3223(01)01344-0. PMID 12022961. S2CID 21170398.
9. ^ Gareri P, Castagna A, Cotroneo AM, Putignano S, De Sarro G, Bruni AC (2015). “The role of citicoline in cognitive impairment: pharmacological characteristics, possible advantages, and doubts for an old drug with new perspectives”. Clin Interv Aging. 10: 1421–9. doi:10.2147/CIA.S87886. PMC 4562749. PMID 26366063.
10. ^ Warach S, Pettigrew LC, Dashe JF, Pullicino P, Lefkowitz DM, Sabounjian L, Harnett K, Schwiderski U, Gammans R (Nov 2000). “Effect of citicoline on ischemic lesions as measured by diffusion-weighted magnetic resonance imaging. Citicoline 010 Investigators”. Annals of Neurology. 48 (5): 713–22. doi:10.1002/1531-8249(200011)48:5<713::aid-ana4>3.0.co;2-#. PMID 11079534.
11. ^ Saver JL (Fall 2008). “Citicoline: update on a promising and widely available agent for neuroprotection and neurorepair”. Reviews in Neurological Diseases. 5 (4): 167–77. PMID 19122569.
12. ^ Dávalos A, Alvarez-Sabín J, Castillo J, Díez-Tejedor E, Ferro J, Martínez-Vila E, Serena J, Segura T, Cruz VT, Masjuan J, Cobo E, Secades JJ (Jul 2012). “Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial)”. Lancet. 380 (9839): 349–57. doi:10.1016/S0140-6736(12)60813-7. hdl:10400.10/663. PMID 22691567. S2CID 134947.
13. ^ Shi PY, Zhou XC, Yin XX, Xu LL, Zhang XM, Bai HY (2016). “Early application of citicoline in the treatment of acute stroke: A meta-analysis of randomized controlled trials”. J. Huazhong Univ. Sci. Technol. Med. Sci. 36 (2): 270–7. doi:10.1007/s11596-016-1579-6. PMID 27072975. S2CID 25352343.
14. ^ Roberti G, Tanga L, Michelessi M, Quaranta L, Parisi V, Manni G, Oddone F (2015). “Cytidine 5′-Diphosphocholine (Citicoline) in Glaucoma: Rationale of Its Use, Current Evidence and Future Perspectives”. Int J Mol Sci. 16 (12): 28401–17. doi:10.3390/ijms161226099. PMC 4691046. PMID 26633368.
15. ^ Jump up to:^a b Adibhatla RM, Hatcher JF, Dempsey RJ (Jan 2002). “Citicoline: neuroprotective mechanisms in cerebral ischemia”. Journal of Neurochemistry. 80 (1): 12–23. doi:10.1046/j.0022-3042.2001.00697.x. PMID 11796739.
16. ^ López-Coviella I, Agut J, Savci V, Ortiz JA, Wurtman RJ (Aug 1995). “Evidence that 5′-cytidinediphosphocholine can affect brain phospholipid composition by increasing choline and cytidine plasma levels”. Journal of Neurochemistry. 65 (2): 889–94. doi:10.1046/j.1471-4159.1995.65020889.x. PMID 7616250. S2CID 10184322.
17. ^ Jump up to:^a b Conant R, Schauss AG (Mar 2004). “Therapeutic applications of citicoline for stroke and cognitive dysfunction in the elderly: a review of the literature”. Alternative Medicine Review. 9 (1): 17–31. PMID 15005642.
18. ^ Babb SM, Wald LL, Cohen BM, Villafuerte RA, Gruber SA, Yurgelun-Todd DA, Renshaw PF (May 2002). “Chronic citicoline increases phosphodiesters in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy study”. Psychopharmacology. 161 (3): 248–54. doi:10.1007/s00213-002-1045-y. PMID 12021827. S2CID 28454793.
19. ^ Rao AM, Hatcher JF, Dempsey RJ (Dec 1999). “CDP-choline: neuroprotection in transient forebrain ischemia of gerbils”. Journal of Neuroscience Research. 58 (5): 697–705. doi:10.1002/(sici)1097-4547(19991201)58:5<697::aid-jnr11>3.0.co;2-b. PMID 10561698.
20. ^ Jump up to:^a b D’Orlando KJ, Sandage BW (Aug 1995). “Citicoline (CDP-choline): mechanisms of action and effects in ischemic brain injury”. Neurological Research. 17 (4): 281–4. doi:10.1080/01616412.1995.11740327. PMID 7477743.
21. ^ Jump up to:^a b Rao AM, Hatcher JF, Dempsey RJ (Mar 2001). “Does CDP-choline modulate phospholipase activities after transient forebrain ischemia?”. Brain Research. 893 (1–2): 268–72. doi:10.1016/S0006-8993(00)03280-7. PMID 11223016. S2CID 37271883.
22. ^ Adibhatla RM, Hatcher JF (Aug 2003). “Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia”. Journal of Neuroscience Research. 73 (3): 308–15. doi:10.1002/jnr.10672. PMID 12868064. S2CID 17806057.
23. ^ Secades JJ, Lorenzo JL (Sep 2006). “Citicoline: pharmacological and clinical review, 2006 update”. Methods and Findings in Experimental and Clinical Pharmacology. 28 Suppl B: 1–56. PMID 17171187.
24. ^ Tardner, P. (2020-08-30). “The use of citicoline for the treatment of cognitive decline and cognitive impairment: A meta-analysis of pharmacological literature • International Journal of Environmental Science & Technology”. International Journal of Environmental Science & Technology. Retrieved 2020-08-31.
25. ^ Hurtado O, Moro MA, Cárdenas A, Sánchez V, Fernández-Tomé P, Leza JC, Lorenzo P, Secades JJ, Lozano R, Dávalos A, Castillo J, Lizasoain I (Mar 2005). “Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport”. Neurobiology of Disease. 18 (2): 336–345. doi:10.1016/j.nbd.2004.10.006. PMID 15686962. S2CID 2818533.
26. ^ Dinsdale JR, Griffiths GK, Rowlands C, Castelló J, Ortiz JA, Maddock J, Aylward M (1983). “Pharmacokinetics of 14C CDP-choline”. Arzneimittel-Forschung. 33 (7A): 1066–70. PMID 6412727.
27. ^ Tardner, P. (2020-08-28). “Can Citicoline Cause Depression?: A review of the clinical literature • International Journal of Environmental Science & Technology”. International Journal of Environmental Science & Technology. Retrieved 2020-08-31.
28. ^ Talih, Farid; Ajaltouni, Jean (2015). “Probable Nootropicinduced Psychiatric Adverse Effects: A Series of Four Cases”. Innovations in Clinical Neuroscience. 12 (11–12): 21–25. ISSN 2158-8333. PMC 4756795. PMID 27222762.
29. ^ Fernández-Murray JP, McMaster CR (Nov 2005). “Glycerophosphocholine catabolism as a new route for choline formation for phosphatidylcholine synthesis by the Kennedy pathway”. The Journal of Biological Chemistry. 280 (46): 38290–6. doi:10.1074/jbc.M507700200. PMID 16172116.

//////////CITOCOLINE, CDP-choline, Neuroprotective,  ischemic stroke, head trauma,

C[N+](C)(C)CCOP(=O)(O)OP(=O)([O-])OCC1C(C(C(O1)N2C=CC(=NC2=O)N)O)O

NEW DRUG APPROVALS

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ALLUPURINOL

• Molecular FormulaC₅H₄N₄O
• Average mass136.111 Da
• аллопуринол [Russian]ألوبيرينول [Arabic]别嘌醇 [Chinese]

1H-Pyrazolo(3,4-d)pyrimidin-4-ol
2,5-Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
206-250-9[EINECS], 315-30-0[RN]
4H-Pyrazolo[3,4-d]pyrimidin-4-one, 1,5-dihydro-, radical ion(1+)
4H-Pyrazolo[3,4-d]pyrimidin-4-one, 1,7-dihydro-
691008-24-9[RN]
7H-Pyrazolo[3,4-d]pyrimidin-4-ol

Allopurinol is a medication used to decrease high blood uric acid levels.^[2] It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy.^[3][4] It is taken by mouth or injected into a vein.^[4]

Common side effects when used by mouth include itchiness and rash.^[4] Common side effects when used by injection include vomiting and kidney problems.^[4] While not recommended historically, starting allopurinol during an attack of gout appears to be safe.^[5][6] In those already on the medication, it should be continued even during an acute gout attack.^[5][3] While use during pregnancy does not appear to result in harm, this use has not been well studied.^[1] Allopurinol is in the xanthine oxidase inhibitor family of medications.^[4]

Allopurinol was approved for medical use in the United States in 1966.^[4] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.^[7] Allopurinol is available as a generic medication.^[4] In 2019, it was the 43rd most commonly prescribed medication in the United States, with more than 15 million prescriptions.^[8][9]

ALLUPRINOLCAS Registry Number: 315-30-0 
CAS Name: 1,5-Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 
Additional Names: 1H-pyrazolo[3,4-d]pyrimidin-4-ol; 4-hydroxypyrazolo[3,4-d]pyrimidine; HPP 
Manufacturers’ Codes: BW-56158 
Trademarks: Adenock (Mitsubishi); Allurit (Aventis); Aloral (Lagap); Alositol (Tanabe); Allo-Puren (Isis); Allozym (Sawai); Allural (Rovi); Anoprolin (Azwell); Anzief (Nippon Chemiphar); Apulonga (Dorsch); Apurol (Siegfried); Apurin (GEA); Bleminol (Gepepharm); Caplenal (Teva); Cellidrin (Hennig); Cosuric (DDSA); Dabroson (Hoyer); Embarin (Merckle); Epidropal (Teofarma); Foligan (DESMA); Gichtex (Gerot); Hamarin (Roche); Hexanurat (Durascan); Ketanrift (Ohta); Lopurin (Abbott); Lysuron (Roche); Miniplanor (Galen); Monarch (SS Pharm.); Remid (TAD); Riball (Schering AG); Sigapurol (Siegfried); Suspendol (Merckle); Takanarumin (Takata); Uricemil (Molteni); Uripurinol (Azupharma); Urosin (Roche); Urtias (Novartis); Zyloprim (GSK); Zyloric (GSK) 
Molecular Formula: C5H4N4O, Molecular Weight: 136.11 
Percent Composition: C 44.12%, H 2.96%, N 41.16%, O 11.75% 
Literature References: Xanthine oxidase inhibitor; decreases uric acid production. Prepn: Robins, J. Am. Chem. Soc.78, 784 (1956); Schmidt, Druey, Helv. Chim. Acta39, 986 (1956); Druey, Schmidt, US2868803 (1959 to Ciba); GB798646 (1958 to Wellcome Found.); Hitchings, Falco, US3474098 (1969 to Burroughs Wellcome). Physiological and biochemical studies: Hitchings, in Biochem. Aspects Antimetab. Drug Hydroxylation, D. Shugar, Ed. (Academic Press, London, 1969) pp 11-22, C.A.75, 3531h (1971). Clinical trial in treatment of renal calculi: M. J. V. Smith, J. Urol.117, 690 (1977); B. Ettinger et al.,N. Engl. J. Med.315, 1386 (1986). Use in hyperuricemia and gout: G. R. Boss, J. E. Seegmiller, ibid.300, 1459 (1977). Effect on renal function in treatment of gout: T. Gibson, Ann. Rheum. Dis.41, 59 (1982). Comprehensive description: S. A. Benezra, T. R. Bennett, Anal. Profiles Drug Subs.7, 1-17 (1978). 
Properties: Crystals, mp above 350°. uv max (0.1N NaOH): 257 nm (e 7200); (0.1N HCl): 250 nm (e 7600); (methanol): 252 nm (e 7600). Soly in mg/ml at 25°: water 0.48; n-octanol <0.01; chloroform 0.60; ethanol 0.30; DMSO 4.6. pKa 10.2. 
Melting point: mp above 350° 
pKa: pKa 10.2 
Absorption maximum: uv max (0.1N NaOH): 257 nm (e 7200); (0.1N HCl): 250 nm (e 7600); (methanol): 252 nm (e 7600) 
Derivative Type: Sodium salt 
CAS Registry Number: 17795-21-0 
Trademarks: Aloprim (Nabi) 
Molecular Formula: C5H3N4NaO, Molecular Weight: 158.09Percent Composition: C 37.99%, H 1.91%, N 35.44%, Na 14.54%, O 10.12% 
Properties: White amorphous mass. pKa 9.31. 
pKa: pKa 9.31 
Therap-Cat: Treatment of hyperuricemia and chronic gout. Antiurolithic. 
Keywords: Antigout; Antiurolithic; Xanthine Oxidase Inhibitor.

Synthesis ReferenceDruey, J. and Schmidt, P.; US. Patent 2868,803; January 13,1959; assigned to Ciba Pharmaceutical Products Inc. Hitchings, G.H. and Falco, EA.; U.S. Patent 3,474,098; October 21,1969; assigned to Bur- roughs Wellcome & Co. Cresswell, R.M.and Mentha, J.W.; US.Patent4,146,713; March27,1979; assigned to Bur- roughs Wellcome & Co.
SYN 

SYN

http://drugsynthesis.blogspot.co.uk/2011/11/laboratory-synthesis-of-allopurinol.html

Reference(s):

1. US 2 868 803 (Ciba; 13.1.1959; CH-prior. 10.2.1956).
2. DAS 1 720 024 (Wellcome Found; appl. 12.7.1967; GB-prior. 14.7.1966).

Similar process:

1. DAS 1 904 894 (Wellcome Found; appl. 31.1.1969; GB-prior. 2.2.1968).
2. US 4 146 713 (Burroughs Wellcome; 27.3.1979; GB-prior. 2.2.1968).

Alternative syntheses:

1. US 3 474 098 (Burroughs Wellcome; 21.10.1969; prior. 29.3.1956).
2. DAS 2 224 382 (Henning Berlin; appl. 18.5.1972).
3. DE 1 118 221 (Wellcome Found; appl. 4.8.1956; GB-prior. 10.8.1955).
4. DAS 1 814 082 (Wellcome Found; appl. 11.12.1968).
5. DAS 1 950 075 (Henning Berlin; appl. 3.10.1969).

SYNCondensation of hydrazine with ethoxymethylenemalononitrile (I) leads to 3-amino-4-cyanopyrazole (II), which, by hydrolysis with sulphuric acid, gives the corresponding amide (III); heating III with formamide in excess results in allopurinol (IV). The synthesis of allopurinol can be illustrated as below: 

SYN

Synthesis

IR

https://www.sciencedirect.com/science/article/abs/pii/S0099542808600878

Infrared Spectrum The infrared spectrum of allopurinol is shown in Figure 1 . in KBr with a Perkin Elmer model 457 infrared spectrophotometer. with the structure of allopurinol . It was taken as a 0.2% dispersion of allopurinol Table I gives the infrareg assignments consistent Table I Infrared Spectral Assignments for Allopurinol Frequency (cm-l) Assignment

3060 CH stretching vibrations of the pyrimidine ring

1700 CO stretching vibration of the keto form of the 4-hydroxy tautomer 1

590 ring vibrations

1245 CH in-plane deformation

NMR

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Medical uses

Gout

Allopurinol is used to reduce urate formation in conditions where urate deposition has already occurred or is predictable. The specific diseases and conditions where it is used include gouty arthritis, skin tophi, kidney stones, idiopathic gout; uric acid lithiasis; acute uric acid nephropathy; neoplastic disease and myeloproliferative disease with high cell turnover rates, in which high urate levels occur either spontaneously, or after cytotoxic therapy; certain enzyme disorders which lead to overproduction of urate, for example: hypoxanthine-guanine phosphoribosyltransferase, including Lesch–Nyhan syndrome; glucose 6-phosphatase including glycogen storage disease; phosphoribosyl pyrophosphate synthetase, phosphoribosyl pyrophosphate amidotransferase; adenine phosphoribosyltransferase.

It is also used to treat kidney stones caused by deficient activity of adenine phosphoribosyltransferase.

Tumor lysis syndrome

Allopurinol was also commonly used to treat tumor lysis syndrome in chemotherapeutic treatments, as these regimens can rapidly produce severe acute hyperuricemia;^[10] however, it has gradually been replaced by urate oxidase therapy.^[11] Intravenous formulations are used in this indication when people cannot take medicine by mouth.^[12]

Inflammatory bowel disease

Allopurinol cotherapy is used to improve outcomes for people with inflammatory bowel disease and Crohn’s disease who do not respond to thiopurine monotherapy.^[13][14] Cotherapy has also been shown to greatly improve hepatoxicity side effects in treatment of IBD.^[15] Cotherapy invariably requires dose reduction of the thiopurine, usually to one-third of the standard dose depending upon the patient’s genetic status for thiopurine methyltransferase.^[16]

Psychiatric disorders

Allopurinol has been tested as an augmentation strategy for the treatment of mania in bipolar disorder. Meta-analytic evidence showed that adjunctive allopurinol was superior to placebo for acute mania (both with and without mixed features).^[17] Its efficacy was not influenced by dosage, follow-up duration, or concurrent standard treatment.^[17]

Side effects

Because allopurinol is not a uricosuric, it can be used in people with poor kidney function. However, for people with impaired kidney function, allopurinol has two disadvantages. First, its dosing is complex.^[18] Second, some people are hypersensitive to the drug; therefore, its use requires careful monitoring.^[19][20]

Allopurinol has rare but potentially fatal adverse effects involving the skin. The most serious adverse effect is a hypersensitivity syndrome consisting of fever, skin rash, eosinophilia, hepatitis, and worsened renal function, collectively referred to as DRESS syndrome.^[19] Allopurinol is one of the drugs commonly known to cause Stevens–Johnson syndrome and toxic epidermal necrolysis, two life-threatening dermatological conditions.^[19] More common is a less-serious rash that leads to discontinuing this drug.^[19]

More rarely, allopurinol can also result in the depression of bone marrow elements, leading to cytopenias, as well as aplastic anemia. Moreover, allopurinol can also cause peripheral neuritis in some patients, although this is a rare side effect. Another side effect of allopurinol is interstitial nephritis.^[21]

Allopurinol should not be given to people who are allergic to it.^[10]

Drug interactions

Drug interactions are extensive, and are as follows:^[10]

• Azathioprine and 6-mercaptopurine: Azathioprine is metabolised to 6-mercaptopurine which in turn is inactivated by the action of xanthine oxidase – the target of allopurinol. Giving allopurinol with either of these drugs at their normal dose will lead to overdose of either drug; only one-quarter of the usual dose of 6-mercaptopurine or azathioprine should be given;
• Didanosine: plasma didanosine Cmax and AUC values were approximately doubled with concomitant allopurinol treatment; it should not be co-administered with allopuroinol and if it must be, the dose of should be reduced and the person should be closely monitored.

Allopurinol may also increase the activity or half-life of the following drugs, in order of seriousness and certainty of the interaction:^[10]

• Ciclosporin
• Coumarin anticoagulants, such as warfarin (reported rarely, but is serious when it occurs)
• Vidarabine
• Chlorpropamide
• Phenytoin
• Theophylline
• Cyclophosphamide, doxorubicin, bleomycin, procarbazine, mechlorethamine

Co-administration of the following drugs may make allopurinol less active or decrease its half-life:^[10]

• Salicylates and medicines that increase the secretion of uric acid
• furosemide (see more on diuretics below)

Co-administration of the following drugs may cause hypersensitivity or skin rash:^[10]

• Ampicillin and amoxicillin
• Diuretics, in particular thiazides, especially in renal impairment
• Angiotensin-converting-enzyme inhibitors (ACE inhibitors)

Pharmacology

A common misconception is that allopurinol is metabolized by its target, xanthine oxidase, but this action is principally carried out by aldehyde oxidase.^[22] The active metabolite of allopurinol is oxipurinol, which is also an inhibitor of xanthine oxidase. Allopurinol is almost completely metabolized to oxipurinol within two hours of oral administration, whereas oxipurinol is slowly excreted by the kidneys over 18–30 hours. For this reason, oxipurinol is believed responsible for the majority of allopurinol’s effect.^[23]

Mechanism of action

Allopurinol is a purine analog; it is a structural isomer of hypoxanthine (a naturally occurring purine in the body) and is an inhibitor of the enzyme xanthine oxidase.^[2] Xanthine oxidase is responsible for the successive oxidation of hypoxanthine and xanthine, resulting in the production of uric acid, the product of human purine metabolism.^[2] In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine. While xanthine cannot be converted to purine ribotides, hypoxanthine can be salvaged to the purine ribotides adenosine and guanosine monophosphates. Increased levels of these ribotides may cause feedback inhibition of amidophosphoribosyl transferase, the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases uric acid formation and may also inhibit purine synthesis.^[24]

Pharmacogenetics

The HLA-B*5801 allele is a genetic marker for allopurinol-induced severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).^[25][26] The frequency of the HLA-B*5801 allele varies between ethnicities: Han Chinese and Thai populations have HLA-B*5801 allele frequencies of around 8%, as compared to European and Japanese populations, who have allele frequencies of around 1.0% and 0.5%, respectively.^[27] The increase in risk for developing allopurinol-induced SJS or TEN in individuals with the HLA-B*5801 allele (as compared to those who do not have this allele) is very high, ranging from a 40-fold to a 580-fold increase in risk, depending on ethnicity.^[25][26] As of 2011 the FDA-approved drug label for allopurinol did not contain any information regarding the HLA-B*5801 allele, though FDA scientists did publish a study in 2011 which reported a strong, reproducible and consistent association between the allele and allopurinol-induced SJS and TEN.^[28] However, the American College of Rheumatology recommends screening for HLA-B*5801 in high-risk populations (e.g. Koreans with stage 3 or worse chronic kidney disease and those of Han Chinese and Thai descent), and prescribing patients who are positive for the allele an alternative drug.^[29] The Clinical Pharmacogenetics Implementation Consortium guidelines state that allopurinol is contraindicated in known carriers of the HLA-B*5801 allele.^[30][31]

History

Allopurinol was first synthesized and reported in 1956 by Roland K. Robins (1926-1992), in a search for antineoplastic agents.^[2][32] Because allopurinol inhibits the breakdown (catabolism) of the thiopurine drug mercaptopurine, and it was later tested by Wayne Rundles, in collaboration with Gertrude Elion‘s lab at Wellcome Research Laboratories to see if it could improve treatment of acute lymphoblastic leukemia by enhancing the action of mercaptopurine.^[2][33] However, no improvement in leukemia response was noted with mercaptopurine-allopurinol co-therapy, so that work turned to other compounds and the team then started testing allopurinol as a potential for gout.^[34] Allopurinol was first marketed as a treatment for gout in 1966.^[33]

Society and culture

Pure allopurinol is a white powder.

Formulations

Allopurinol is sold as an injection for intravenous use^[12] and as a tablet.^[10]

Brands

Allopurinol has been marketed in the United States since 19 August 1966, when it was first approved by FDA under the trade name Zyloprim.^[35] Allopurinol was marketed at the time by Burroughs-Wellcome. Allopurinol is a generic drug sold under a variety of brand names, including Allohexal, Allosig, Milurit, Alloril, Progout, Ürikoliz, Zyloprim, Zyloric, Zyrik, and Aluron.^[36]

See also

• Lesinurad/allopurinol, a fixed-dose combination drug
• Hydroxychavicol, potent xanthine oxidase inhibitor

References

1. ^ Jump up to:^a b “Allopurinol Use During Pregnancy”. Drugs.com. Archived from the original on 20 August 2016. Retrieved 20 December 2016.
2. ^ Jump up to:^{a b c d e} Pacher P, Nivorozhkin A, Szabó C (March 2006). “Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol”. Pharmacological Reviews. 58 (1): 87–114. doi:10.1124/pr.58.1.6. PMC 2233605. PMID 16507884.
3. ^ Jump up to:^a b World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 39. hdl:10665/44053. ISBN 9789241547659.
4. ^ Jump up to:^{a b c d e f g} “Allopurinol”. The American Society of Health-System Pharmacists. Archived from the original on 29 April 2016. Retrieved 8 December 2016.
5. ^ Jump up to:^a b Robinson PC, Stamp LK (May 2016). “The management of gout: Much has changed”. Australian Family Physician. 45 (5): 299–302. PMID 27166465.
6. ^ Satpanich, P; Pongsittisak, W; Manavathongchai, S (18 August 2021). “Early versus Late Allopurinol Initiation in Acute Gout Flare (ELAG): a randomized controlled trial”. Clinical Rheumatology. doi:10.1007/s10067-021-05872-8. PMID 34406530. S2CID 237156638.
7. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
8. ^ “The Top 300 of 2019”. ClinCalc. Retrieved 16 October 2021.
9. ^ “Allopurinol – Drug Usage Statistics”. ClinCalc. Retrieved 16 October 2021.
10. ^ Jump up to:^{a b c d e f g} “300 mg Allopurinol tables”. UK Electronic Medicines Compendium. 7 April 2016. Archived from the original on 11 September 2016.
11. ^ Jeha S (October 2001). “Tumor lysis syndrome”. Seminars in Hematology. 38 (4 Suppl 10): 4–8. doi:10.1016/S0037-1963(01)90037-X. PMID 11694945.
12. ^ Jump up to:^a b “Label for injectable Allopurinol”. DailyMed. June 2014. Archived from the original on 13 September 2016.
13. ^ Bradford K, Shih DQ (October 2011). “Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease”. World Journal of Gastroenterology. 17 (37): 4166–73. doi:10.3748/wjg.v17.i37.4166. PMC 3208360. PMID 22072847.
14. ^ Sparrow MP, Hande SA, Friedman S, Cao D, Hanauer SB (February 2007). “Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine”. Clinical Gastroenterology and Hepatology. 5 (2): 209–14. doi:10.1016/j.cgh.2006.11.020. PMID 17296529.
15. ^ Ansari A, Patel N, Sanderson J, O’Donohue J, Duley JA, Florin TH (March 2010). “Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease”. Alimentary Pharmacology & Therapeutics. 31 (6): 640–7. doi:10.1111/j.1365-2036.2009.04221.x. PMID 20015102. S2CID 6000856.
16. ^ Ansari AR, Duley JA (March 2012). “Azathioprine co-therapy with allopurinol for inflammatory bowel disease: trials and tribulations” (PDF). Rev Assoc Med Bras. 58 (Suppl.1): S28–33.
17. ^ Jump up to:^a b Bartoli F, Cavaleri D, Bachi B, Moretti F, Riboldi I, Crocamo C, Carrà G (September 2021). “Repurposed drugs as adjunctive treatments for mania and bipolar depression: A meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials”. Journal of Psychiatric Research. 143: 230–238. doi:10.1016/j.jpsychires.2021.09.018. PMID 34509090. S2CID 237485915.
18. ^ Dalbeth N, Stamp L (2007). “Allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and adverse events”. Seminars in Dialysis. 20 (5): 391–5. doi:10.1111/j.1525-139X.2007.00270.x. PMID 17897242. S2CID 1150852.
19. ^ Jump up to:^a b c d Chung WH, Wang CW, Dao RL (July 2016). “Severe cutaneous adverse drug reactions”. The Journal of Dermatology. 43 (7): 758–66. doi:10.1111/1346-8138.13430. PMID 27154258. S2CID 45524211.
20. ^ Tsai TF, Yeh TY (2010). “Allopurinol in dermatology”. American Journal of Clinical Dermatology. 11 (4): 225–32. doi:10.2165/11533190-000000000-00000. PMID 20509717. S2CID 36847530.
21. ^ De Broe ME, Bennett WM, Porter GA (2003). Clinical Nephrotoxins: Renal Injury from Drugs and Chemicals. Springer Science+Business Media. ISBN 9781402012778. Acute interstitial nephritis has also been reported associated with by the administration of allopurinol.
22. ^ Reiter S, Simmonds HA, Zöllner N, Braun SL, Knedel M (March 1990). “Demonstration of a combined deficiency of xanthine oxidase and aldehyde oxidase in xanthinuric patients not forming oxipurinol”. Clinica Chimica Acta; International Journal of Clinical Chemistry. 187 (3): 221–34. doi:10.1016/0009-8981(90)90107-4. PMID 2323062.
23. ^ Day RO, Graham GG, Hicks M, McLachlan AJ, Stocker SL, Williams KM (2007). “Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol”. Clinical Pharmacokinetics. 46 (8): 623–44. doi:10.2165/00003088-200746080-00001. PMID 17655371. S2CID 20369375.
24. ^ Cameron JS, Moro F, Simmonds HA (February 1993). “Gout, uric acid and purine metabolism in paediatric nephrology”. Pediatric Nephrology. 7 (1): 105–18. doi:10.1007/BF00861588. PMID 8439471. S2CID 34815040.
25. ^ Jump up to:^a b “Uric Acid-Lowering Drugs Pathway, Pharmacodynamics”. PharmGKB. Archived from the original on 8 August 2014.
26. ^ Jump up to:^a b “PharmGKB”. Archived from the original on 8 August 2014. Retrieved 1 August 2014.
27. ^ “Allele Frequency Net Database”. Archived from the original on 28 August 2009.
28. ^ Zineh I, Mummaneni P, Lyndly J, Amur S, La Grenade LA, Chang SH, et al. (December 2011). “Allopurinol pharmacogenetics: assessment of potential clinical usefulness”. Pharmacogenomics. 12 (12): 1741–9. doi:10.2217/pgs.11.131. PMID 22118056.
29. ^ Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. (October 2012). “2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia”. Arthritis Care & Research. 64 (10): 1431–46. doi:10.1002/acr.21772. PMC 3683400. PMID 23024028.
30. ^ “Annotation of CPIC Guideline for allopurinol and HLA-B”. PharmGKB. Archived from the original on 8 August 2014. Retrieved 1 August 2014.
31. ^ Hershfield MS, Callaghan JT, Tassaneeyakul W, Mushiroda T, Thorn CF, Klein TE, Lee MT (February 2013). “Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing”. Clinical Pharmacology and Therapeutics. 93 (2): 153–8. doi:10.1038/clpt.2012.209. PMC 3564416. PMID 23232549.
32. ^ Robins RK (1956). “Potential Purine Antagonists. I. Synthesis of Some 4,6-Substituted Pyrazolo \3,4-d] pyrimidines1”. J. Am. Chem. Soc. 78 (4): 784–790. doi:10.1021/ja01585a023.
33. ^ Jump up to:^a b Sneader W (2005). Drug Discovery: A History. John Wiley & Sons. p. 254. ISBN 9780471899792.
34. ^ Elion GB (April 1989). “The purine path to chemotherapy”. Science. 244 (4900): 41–7. Bibcode:1989Sci…244…41E. doi:10.1126/science.2649979. PMID 2649979.
35. ^ “FDA Approved Drug Products”. Drugs@FDA. Archived from the original on 14 August 2012. Retrieved 8 November 2013.
36. ^ “Search Results for Allopurinol”. DailyMed. Archived from the original on 25 March 2012. Retrieved 27 July 2011.

Further reading

• Dean L (March 2016). “Allopurinol Therapy and HLA-B*58:01 Genotype”. In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520356.

External links

• “Allopurinol”. Drug Information Portal. U.S. National Library of Medicine.
• “PRODUCT INFORMATION Allopurinol Tablets USP”. U.S. National Library of Medicine. Medication handout sheet (Revised: 07/2019 0603-2115)
• Allopurinol pathway on PharmGKB

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FOMEPIZOLE

• Molecular FormulaC₄H₆N₂
• Average mass82.104 Da

4-Methylpyrazole, 4-MP
7554-65-6[RN]
105204[Beilstein]
1H-Pyrazole, 4-methyl-
231-445-0[EINECS]фомепизол , فوميبيزول 
甲吡唑

Fomepizole, also known as 4-methylpyrazole, is a medication used to treat methanol and ethylene glycol poisoning.^[2] It may be used alone or together with hemodialysis.^[2] It is given by injection into a vein.^[2]

Common side effects include headache, nausea, sleepiness, and unsteadiness.^[2] It is unclear if use during pregnancy is safe for the baby.^[2] Fomepizole works by blocking the enzyme that converts methanol and ethylene glycol to their toxic breakdown products.^[2]

Fomepizole was approved for medical use in the United States in 1997.^[2] It is on the World Health Organization’s List of Essential Medicines.^[3]FomepizoleCAS Registry Number: 7554-65-6 
CAS Name: 4-Methyl-1H-pyrazole 
Additional Names: 4-MP 
Trademarks: Antizol (Orphan Med.) 
Molecular Formula: C4H6N2, Molecular Weight: 82.10 
Percent Composition: C 58.52%, H 7.37%, N 34.12% 
Literature References: Alcohol dehydrogenase inhibitor. Prepn: H. Pechmann, E. Burkard, Ber.33, 3590 (1900); D. S. Noyce et al.,J. Org. Chem.20, 1681 (1955); T. Momose et al.,Heterocycles30, 789 (1990). Inhibition of human liver alcohol dehydrogenase: T.-K. Li, H. Theorell, Acta Chem. Scand.23, 892 (1969). Toxicity study: G. Magnusson et al.,Experientia28, 1198 (1972). GC determn in plasma and urine: R. Achari, M. Mayersohn, J. Pharm. Sci.73, 690 (1984). Clinical pharmacology: D. Jacobsen et al.,Alcohol. Clin. Exp. Res.12, 516 (1988). Pharmacokinetics: eidem,Eur. J. Clin. Pharmacol.37, 599 (1989). Clinical trial in ethylene glycol poisoning: J. Brent et al.,N. Engl. J. Med.340, 832 (1999); in methanol poisoning: idem et al., ibid.344, 424 (2001). Review: J. Likforman et al.,J. Toxicol. Clin. Exp.7, 373-382 (1987). Review of use in methanol poisoning: M. B. Mycyk, J. B. Leikin, Am. J. Therapeut.10, 68-70 (2003). 
Properties: mp 15.5-18.5°. bp18mm 98.5-99.5°; bp730 204-205°. nD22 1.4913. uv max in 95% ethanol: 220 nm (log e 3.47); in 6N HCl: 226 nm (log e 3.65). Sol in water, alcohol. LD50 (7 days) in mice, rats (mmol/kg): 3.8, 3.8 i.v.; 7.8, 6.5 orally (Magnusson). 
Melting point: mp 15.5-18.5° 
Boiling point: bp18mm 98.5-99.5°; bp730 204-205° 
Index of refraction:nD22 1.4913 
Absorption maximum: uv max in 95% ethanol: 220 nm (log e 3.47); in 6N HCl: 226 nm (log e 3.65) 
Toxicity data: LD50 (7 days) in mice, rats (mmol/kg): 3.8, 3.8 i.v.; 7.8, 6.5 orally (Magnusson) 
Therap-Cat: Antidote to methanol and ethylene glycol poisoning. 
Therap-Cat-Vet: Antidote to ethylene glycol poisoning in dogs. 
Keywords: Antidote (Methanol and Ethylene Glycol Poisoning).

Fomepizole was approved by the U.S. Food and Drug Administration (FDA) on Dec 4, 1997. It was developed and marketed as Antizol^® by Paladin in the US.

Fomepizole is a competitive alcohol dehydrogenase inhibitor, Alcohol dehydrogenase catalyzes the oxidation of ethanol to acetaldehyde, and it also catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites. Antizol^® is indicated as an antidote for ethylene glycol (such as antifreeze) or methanol poisoning, or for use in suspected ethylene glycol or methanol ingestion, either alone or in combination with hemodialysis.

Antizol^® is available as injection solution for intravenous use, containing 1 g/ml of free Fomepizole. The recommended dose is 15 mg/kg should be administered, followed by doses of 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours thereafter until ethylene glycol or methanol concentrations are undetectable or have been reduced below 20 mg/dL.

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Reference：

US7553863B2.

https://patents.google.com/patent/US7553863B2/enEthylene glycol is commonly available as automobile radiator antifreeze. Because of its sweet taste, improperly stored antifreeze is a common source of ethylene glycol poisoning, particularly in children. Ethylene glycol is rapidly absorbed from the gastrointestinal tract. Toxicity can be divided into three stages:

• Stage 1—Neurological (0.5-12 hours post-ingestion)
• Stage 2—Cardiopulmonary (12-24 hours post-ingestion)
• Stage 3—Renal (24-72 hours post-ingestion)

4-Methylpyrazole, marketed as Antizol® (fomepizole) by Orphan Medical, Inc. is a specific antidote for the treatment of ethylene glycol poisoning. It works by inhibiting the enzyme alcohol dehydrogenase which is responsible for the conversion of ethylene glycol, which itself is relatively non-toxic, into its toxic metabolites that in turn cause the renal injury and metabolic acidosis. Antizol® is currently approved by the FDA as an antidote for ethylene glycol poisoning or suspected ethylene glycol poisoning and is recommended by poison control centers as first line therapy. See Antizol® (fomepizole) Injection, Product Monograph, Orphan Medical, Inc., 2001, the entire contents of which are hereby incorporated by reference.Methanol is commonly available in the home in automobile windshield washer fluid and as a gas line anti-icing additive. Methanol has a minor degree of direct toxicity. Its major toxicity follows its metabolism to formic acid. Antizol® is also a specific antidote for the treatment of methanol toxicity. It works by inhibiting the enzyme alcohol dehydrogenase which is responsible for the conversion of methanol into its toxic metabolites, formaldehyde and formic acid. Again, Antizol® is approved by the FDA for use in treating methanol poisoning or suspected methanol poisoning and is recommended by poison control centers as first line therapy.Known methods of preparing 4-methylpyrazole include the reaction of alpha, beta-unsaturated carbonyl compounds or diketones with hydrazine or hydrazine derivatives or the dehydrogenation of the corresponding 2-pyrazoline. See U.S. Pat. Nos. 3,200,128, 4,996,327, and 5,569,769. Other processes for preparing 4-methylpyrazole are disclosed in U.S. Pat. Nos. 6,229,022, 5,569,769, and 4,996,327.4-methylpyrazole prepared by synthetic routes employed heretofore may contain impurities and toxic by-products, including pyrazole, hydrazine, and nitrobenzaldehyde. Pyrazole, like 4-methylpyrazole, is also an inhibitor of alcohol dehydrogenase, but is more toxic than 4-methylpyrazole. Pyrazole is a known teratogen (Eisses, 1995) with 10 fold less potency against alcohol dehydrogenase (T. Li et al., Acta Chem. Scan. 1969, 23, 892-902). In addition, Ewen MacDonald published a paper in 1976 that showed pyrazole in contrast to 4-methylpyrazole has a detrimental effect on brain levels of noradrenaline (E. MacDonald, Acta Pharmacol. et Toxicol. 1976, 39, 513-524). Hydrazine and nitrobenzaldehyde are known mutagens and carcinogens (H. Kohno et al., Cancer Sci. 2005, 96, 69-76).These impurities and toxic by-products have been tolerated heretofore because methods of making ultrapure 4-methylpyrazole have not been available. The FDA has previously approved up to 0.5% pyrazole in Antizol®, but recently is requesting a higher level of purity of less than 0.1% pyrazole to qualify such high levels with animal and other studies. Therefore, while the purity of Antizol® is sufficiently high for its antidotal use in emergency medicine, such toxic impurities are not ideal. For example a pregnant woman who needs antidote therapy would risk exposure of a fetus to potentially toxic pyrazole of known teratogenicity and potentially high levels of known carcinogens. Therefore, a need exists for a 4-methylpyrzaole with even lower amounts of pyrazole and other impurities and for a synthesis of such an ultrapure 4-methylpyrazole.The process of the present invention is set forth in the following exemplary scheme:

EXAMPLE 1Preparation of 1,1-diethoxypropane 1Into a 2-liter flask under nitrogen were added 586 g (3.96 moles) of triethyl orthoformate, 46 g (56 ml, 1 mole) of ethanol, and 16 g of ammonium nitrate. Over the course of one hour 232 g (4 moles) of propionaldehyde were added with stirring. An ice bath was used as necessary to keep maintain the mixture at 30-36° C. The mixture turned yellow orange after one-third of the propionaldehyde had been added. The mixture was stirred overnight at room temperature and then brought to pH 7.5±0.2 with 10% aqueous sodium carbonate (about 30 ml). The aqueous layer was decanted, and the organic layer was distilled over sodium carbonate at atmospheric pressure to produce 124 g (81.6%) of 1.

EXAMPLE 2Preparation of 1-ethoxy-1-propene 2Into a 500 ml flask equipped with a 12″×¾″ packed column were added 0.25 g (0.0013 moles) of p-toluene sulfonic acid, followed by 241 g (1.82 moles) of 1. Nitrogen was bubbled into the mixture while 0.157 g (0.00065 moles) of bis(2-ethylhexyl)amine were added. The nitrogen flow was reduced, and the mixture was distilled to 160° C. to partially remove ethyl alcohol and 1-ethoxy-1-propene. The reaction mixture washed with 320 ml of water and then with 70 ml of water. The organic layer was dried over magnesium sulfate and filtered to produce 121 g (77.5%) of 2, bp 67-76° C., as a clear, colorless liquid. Gas chromatographic analysis showed less than 0.01% ethylvinyl ether.

EXAMPLE 3Preparation of 1,1,3,3-tetraethoxy-2-methylpropane 3Into a 5 liter flask equipped with a mechanical stirrer were added 790 g (5.34 moles) of triethyl orthoformate and 4.28 ml of boron trifluoride-diethyl etherate under a nitrogen atmosphere. Temperature was maintained at 25° C. with cooling as needed. To this mixture were added 230 g (2.67 moles) of 1-ethoxy-1-propene were added slowly and dropwise. The reaction mixture was exothermic; the temperature rose to about 35-38° C. The pot was cooled to 25° C. and stirring was continued for one hour. Solid anhydrous sodium carbonate (32.1 g, 0.3 moles) was added in one portion to the flask and stirring was continued for one hour. The mixture was filtered and the filtrate was fractionally distilled under reduced pressure. The light fraction was removed at a pot temperature of 55-60° C. at 10 mm pressure. The vacuum was improved to 3 mm and the pot temperature was permitted to rise to about 100-140° C. to produce 500 g (80%) of 3, bp 80-81° C. at 3 mm, as a clear, colorless to yellow-brown liquid.

EXAMPLE 4Preparation of 4-methylpyrazoleInto a 5 liter flask equipped with a mechanical stirrer were added 1750 ml of sterile USP water to which 266.7 g (2.05 moles) of hydrazine hydrosulfate were added gradually over one hour with stirring. To the above mixture was added dropwise 481 g (2.053 moles) of 3 and the reaction mixture was warmed to 80° C. Heating and stirring were maintained for 3 hours, the flask was cooled to 40° C., and the volatile components were distilled off under a reduced pressure of about 125 mm. The resulting mixture was cooled to 10° C. first with water and then with glycol; 20 ml of water were added to the flask, and cooling was continued to a temperature of 3° C. Thereafter 50% sodium hydroxide solution was added with cooling so as to maintain the temperature below 30° C. The pH of the reaction mixture should be between 4 and 6. A solution of sodium bicarbonate containing 4.9 g of sodium bicarbonate to 55 ml of water was added to the flask. Additional sodium bicarbonate solution was added until the pH reached 7.0. The flask temperature was allowed to rise to 27° C. with continued stirring. The contents of the flask were extracted with ethyl acetate and the aqueous layer was separated. The organic layer was dried over magnesium sulfate, filtered, and the extract was distilled under vacuum. The light fraction was removed at a pot temperature of 55-60° C. at 125 mm pressure. The vacuum was improved to 5 mm for the remainder of the distillation; pot temperatures were permitted to rise to 100-110° C. to produce 134.8 g (84% based on 3) of 4-methylpyrazole, bp 77-80° C. at 5 mm, as a clear, colorless to yellow liquid. Gas chromatographic analysis showed less than 0.1% pyrazole and less than 10 ppm hydrazine.

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Journal of the American Chemical Society (1949), 71, 3994-4000.

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Journal of Organic Chemistry (1962), 27, 2415-19.

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Medical use

Fomepizole is used to treat ethylene glycol and methanol poisoning. It acts to inhibit the breakdown of these toxins into their active toxic metabolites. Fomepizole is a competitive inhibitor of the enzyme alcohol dehydrogenase,^[4] found in the liver. This enzyme plays a key role in the metabolism of ethylene glycol, and of methanol.

• Ethylene glycol is first metabolized to glycolaldehyde by alcohol dehydrogenase. Glycolaldehyde then undergoes further oxidation to glycolate, glyoxylate, and oxalate. Glycolate and oxalate are the primary toxins responsible for the metabolic acidosis, and for the renal damage, seen in ethylene glycol poisoning.
• Methanol is first metabolized to formaldehyde by alcohol dehydrogenase. Formaldehyde then undergoes further oxidation, via formaldehyde dehydrogenase, to become formic acid.^[5] Formic acid is the primary toxin responsible for the metabolic acidosis, and for the visual disturbances, associated with methanol poisoning.

By competitively inhibiting the first enzyme, alcohol dehydrogenase, in the metabolism of ethylene glycol and methanol, fomepizole slows the production of the toxic metabolites. The slower rate of metabolite production allows the liver to process and excrete the metabolites as they are produced, limiting the accumulation in tissues such as the kidney and eye. As a result, much of the organ damage is avoided.^[6]

Fomepizole is most effective when given soon after ingestion of ethylene glycol or methanol. Delaying its administration allows for the generation of harmful metabolites.^[6]

Interaction with alcohol

Concurrent use with ethanol is contraindicated because fomepizole is known to prolong the half-life of ethanol via inhibiting its metabolism. Extending the half-life of ethanol may increase and extend the intoxicating effects of ethanol, allowing for greater (potentially dangerous) levels of intoxication at lower doses. Fomepizole slows the production of acetaldehyde by inhibiting alcohol dehydrogenase, which in turn allows more time to further convert acetaldehyde into acetic acid by acetaldehyde dehydrogenase. The result is a patient with a prolonged and deeper level of intoxication for any given dose of ethanol, and reduced “hangover” symptoms (since these adverse symptoms are largely mediated by acetaldehyde build up).

In a chronic alcoholic who has built up a tolerance to ethanol, this removes some of the disincentives to ethanol consumption (“negative reinforcement“) while allowing them to become intoxicated with a lower dose of ethanol. The danger is that the alcoholic will then overdose on ethanol (possibly fatally). If alcoholics instead very carefully reduce their doses to reflect the now slower metabolism, they may get the “rewarding” stimulus of intoxication at lower doses with less adverse “hangover” effects – leading potentially to increased psychological dependency. However, these lower doses may therefore produce less chronic toxicity and provide a harm minimization approach to chronic alcoholism.

It is, in essence, the antithesis of a disulfiram approach which tries to increase the buildup of acetaldehyde resulting in positive punishment for the patient. Compliance, and adherence, is a substantial problem in disulfiram-based approaches. Disulfiram also has a considerably longer half-life than that of fomepizole, requiring the person to not drink ethanol in order to avoid severe effects. If the person is not adequately managed on a benzodiazepine, barbiturate, acamprosate, or another GABA_A receptor agonist, the alcohol withdrawal syndrome, and its attendant, life-threatening risk of delirium tremens “DT”, may occur. Disulfiram treatment should never be initiated until the risk of DT has been evaluated, and mitigated appropriately. Fomepizole treatment may be initiated while the DT de-titration sequence is still being calibrated based upon the person’s withdrawal symptoms and psychological health.^{[citation needed]}

Adverse effects

Common side effects associated with fomepizole use include headache and nausea.^[7]

Kinetics

Absorption and distribution

Fomepizole distributes rapidly into total body water. The volume of distribution is between 0.6 and 1.02 L/kg. The therapeutic concentration is from 8.2 to 24.6 mg (100 to 300 micromoles) per liter. Peak concentration following single oral doses of 7 to 50 mg/kg of body weight occurred in 1 to 2 hours. The half-life varies with dose, so has not been calculated.

Metabolism and elimination

Hepatic; the primary metabolite is 4-carboxypyrazole (about 80 to 85% of an administered dose). Other metabolites include the pyrazoles 4-hydroxymethylpyrazole and the N -glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole.

Following multiple doses, fomepizole rapidly induces its own metabolism via the cytochrome P450 mixed-function oxidase system.

In healthy volunteers, 1.0 to 3.5% of an administered dose was excreted unchanged in the urine. The metabolites also are excreted unchanged in the urine.

Fomepizole is dialyzable.

Other uses

Apart from medical uses, the role of 4-methylpyrazole in coordination chemistry has been studied.^[8]

References

1. ^ “Antizol- fomepizole injection”. DailyMed. Retrieved 24 December 2020.
2. ^ Jump up to:^{a b c d e f g} “Fomepizole”. The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
3. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
4. ^ Casavant MJ (January 2001). “Fomepizole in the treatment of poisoning”. Pediatrics. 107 (1): 170–171. doi:10.1542/peds.107.1.170. PMID 11134450.
5. ^ “Forensic Pathology”. Archived from the original on 2008-09-17.
6. ^ Jump up to:^a b Brent, J (May 2009). “Fomepizole for Ethylene Glycol and Methanol Poisoning”. N. Engl. J. Med. 360 (21): 2216–23. doi:10.1056/NEJMct0806112. PMID 19458366.
7. ^ Lepik, KJ; Levy, AR; Sobolev, BG; Purssell, RA; DeWitt, CR; Erhardt, GD; Kennedy, JR; Daws, DE; Brignall, JL (April 2009). “Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole”. Annals of Emergency Medicine. 53 (4): 439–450.e10. doi:10.1016/j.annemergmed.2008.05.008. PMID 18639955.
8. ^ Vos, Johannes G.; Groeneveld, Willem L. (1979). “Pyrazolato and related anions. Part V. Transition metal salts of 4-methylpyrazole”. Transition Metal Chemistry. 4 (3): 137–141. doi:10.1007/BF00619054. S2CID 93580021.

External links

• “Fomepizole”. Drug Information Portal. U.S. National Library of Medicine.

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L-CARNOSINE

• Molecular FormulaC₉H₁₄N₄O₃
• Average mass226.232 Da

(2S)-2-(3-aminopropanamido)-3-(1H-imidazol-5-yl)propanoic acid
(E)-N-(3-Amino-1-hydroxypropylidene)-L-histidine [ACD/IUPAC Name] 
206-169-9[EINECS], 305-84-0[RN]
8HO6PVN24Wカルノシン , Dragosine, Ignotin, Ignotine, Karnozin, L-Carnosine, N-(β-Alanyl)-L-histidine, NSC 524045, Sevitin, β-Alanylhistidine 
CarnosineCAS Registry Number: 305-84-0CAS Name: b-Alanyl-L-histidine 
Additional Names: ignotine 
Molecular Formula: C9H14N4O3, Molecular Weight: 226.23 
Percent Composition: C 47.78%, H 6.24%, N 24.77%, O 21.22% 
Literature References: Naturally occurring dipeptide found in large amounts in skeletal muscle. Also present in other tissues such as brain, cardiac muscle, kidney. Water soluble antioxidant; functions as a free-radical scavenger. Isoln: Gulewitsch, Amiradzibi, Ber.33, 1902 (1900); Wolff, Wilson, J. Biol. Chem.95, 495 (1932); 109, 565 (1935). Synthesis from histidine and b-iodo- or b-nitropropionyl chloride: Baumann, Ingvaldsen, ibid.35, 271 (1918); Barger, Tutin, Biochem. J.12, 406 (1918). Later syntheses: Sifford, du Vigneaud, J. Biol. Chem.108, 753 (1935); R. A. Turner, J. Am. Chem. Soc.75, 2388 (1953); F. J. Vinick, S. Jung, J. Org. Chem.48, 392 (1983). Crystal structure: H. Itoh et al.,Acta Crystallogr.33B, 2959 (1977). Possible role in wound healing: D. E. Fischer et al.,Proc. Soc. Exp. Biol. Med.158, 402 (1978). Review of physiological properties and therapeutic potential: S. E. Gariballa, A. J. Sinclair, Age Ageing29, 207-210 (2000). 
Properties: Crystals from aqueous ethanol, mp 262° (dec) (Vinick, Jung); also reported as mp 260° (capillary tube) and as mp 308-309° (Dennis bar) (Sifford, du Vigneaud). [a]D25 +21.0° (c = 1.5 in water). pK1 2.64; pK2 6.83; pK3 9.51. Alkaline reaction. One gram dissolves in 3.1 ml water at 25°. 
Melting point: mp 262° (dec) (Vinick, Jung); mp 260° (capillary tube) and as mp 308-309° (Dennis bar) (Sifford, du Vigneaud) 
pKa: pK1 2.64; pK2 6.83; pK3 9.51 
Optical Rotation: [a]D25 +21.0° (c = 1.5 in water) 
Derivative Type: Nitrate 
CAS Registry Number: 5852-98-2 
Molecular Formula: C9H15N5O6, Molecular Weight: 289.25 
Percent Composition: C 37.37%, H 5.23%, N 24.21%, O 33.19% 
Properties: Crystals, dec 222°. [a]D20 +24.1° (c = 1.5 in water). Very sol in water. 
Optical Rotation: [a]D20 +24.1° (c = 1.5 in water) 
Derivative Type: Hydrochloride 
CAS Registry Number: 5852-99-3 
Molecular Formula: C9H15ClN4O3, Molecular Weight: 262.69 
Percent Composition: C 41.15%, H 5.76%, Cl 13.50%, N 21.33%, O 18.27% 
Properties: Crystals, dec 245°. Very sol in water. 
Derivative Type: D-Form 
CAS Registry Number: 5853-00-9 
Properties: Crystals, mp 260°. [a]D28 -20.4° (c = 1.5). 
Melting point: mp 260° 
Optical Rotation: [a]D28 -20.4° (c = 1.5)

Carnosine (beta-alanyl-L-histidine) is a dipeptide molecule, made up of the amino acids beta-alanine and histidine. It is highly concentrated in muscle and brain tissues.^{[citation needed]} Carnosine was discovered by Russian chemist Vladimir Gulevich.^[2]

Carnosine is naturally produced by the body in the liver^[3] from beta-alanine and histidine. Like carnitine, carnosine is composed of the root word carn, meaning “flesh”, alluding to its prevalence in meat.^[4] There are no plant-based sources of carnosine,^[5] however synthetic supplements do exist.

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

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WO2009033754 PAGE: 98 claimed protein

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009033754

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 US 4446149 A 1984 

 JP 02221230 A 1990

Showa Igakkai Zasshi 1974, V34(3), P271-83 

 Russian Journal of General Chemistry 2007, V77(9), P1576-1579 

 Chemische Berichte 1961, V94, P2768-78 

 Farmaco, Edizione Scientifica 1968, V23(9), P859-69

Paper

 Journal of the American Chemical Society 1953, V75, P2388-90 

Conc: 3.0 g/100mL;water ; Wavlenght: 589.3 nm; Temp: 20 °C

 Annali di Chimica (Rome, Italy) 1968, V58(11), P1431-4 

DE 3540632 A1 1986 

 Z. physiol. Chem. 1914, V87, P1-11 

PAPER

Chemistry – A European Journal (2003), 9, (8), 1714-1723.

PAPER

Journal of Magnetic Resonance (2003), 164, (2), 256-269.

SYN

WO  2001064638

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2001064638

Example 1
(S) -2- (Cyanoacetylamino) -3- (l_ * H-imidazol-4-yl) propionic acid, sodium salt

To a solution of sodium ethoxide obtained by dissolving 5.57 g (0.24 mol) of sodium in 800 ml of ethanol was added 40.0 g (0.26 mol) of L-histidine at room temperature. After 15 minutes, 44.12 g (0.39 mol) of ethyl cyanoacetate were added and the suspension was refluxed for 16 hours. After cooling to room temperature, the mixture was filtered. The yellowish filtrate was concentrated in vacuo, the residue was slurried in ethyl acetate, filtered, washed with ethyl acetate and purified by flash chromatography on silica gel (eluent: gradient ethyl acetate → methanol / ethyl acetate 3: 1).
Yield: 28.42 g (46%)
1HNMR (DMSO- ^ ₆, 00 MHz): δ = 8,28 (d, 1H); 7,45 (s, 1H); 6,7 (s, 1H); 5,5 (br. s, 1H); 4,12-4,20 (m, 1H); 3,65 (s, 2H); 2,95-3,05 (m, 1H); 2,8-2,9 (m, 1H).
¹³C NMR (DMSO- ₆, 100 MHz): δ = 174,05; 161,09; 134,25; 131,97; 119,66; 116,43; 54,83; 29,13; 25,20.

Example 2
(• S) -2- (Cyanoacetylamino) -3- (1-δ-imidazol-4-yl) propionic acid, sodium salt

9.80 g of sodium hydride (60% in mineral oil) and 50.6 g
(0.51 mol) were added at room temperature to a suspension of 40.0 g (0.26 mol) of L-histidine in 750 ml of N, N-dimethylformamide Given methyl cyanoacetate. The mixture was heated to 155 ° C. for 2 h in an open flask and the solution thus obtained was analyzed by means of HPLC.
Histidine (8 area%) and (S) -2- (cyanoacetylamino) -3- (1H-imidazol-4-yl) propionic acid sodium salt (38 area%) were identified.

Example 3
(S) -2- (Cyanoacetylamino) -3- (l-ö ^r -imidazol-4-yl) propionic acid

To a solution of sodium ethoxide obtained by dissolving 4.02 g (0.175 mol) of sodium in 280 ml of ethanol, 28.27 g (0.18 mol) of L-Ηistidine were added at room temperature. The mixture was heated slowly and 30.92 g (0.27 mol) of ethyl cyanoacetate were added dropwise at a temperature of 60.degree. The mixture was heated further and the ethanol was distilled off, the amount of ethanol distilled off being continuously replaced in portions by N, N-dimethylformamide. At the end of the reaction, the temperature of the solution was 130 ° C. The mixture was stirred at this temperature for a further 2 hours. The brown reaction mixture (200 g) was cooled to 50 ° C. and 30 g of concentrated hydrochloric acid were metered in. About 70 g of solvent (Η ₂O / N, N-dimethylformamide mixture) distilled off. The viscous suspension was mixed with 200 g of acetone, cooled to -10 ° C. and filtered. For recrystallization, the residue was dissolved in water and the pH was adjusted to 5.0. On cooling (<5 ° C.) a white solid precipitated out, which was filtered off, washed with ethanol and dried at 40 ° C./20 mbar.
Yield: 26.39 g (66%).
IR (KBr): v = 3421, 3240, 3149, 3059, 2970, 2255, 1653, 1551, 1396, 1107, 1088, 979, 965, 826, 786, 638 cm ^{is “1} .
1HΝMR (DMSO-c ₆ , 400 MHz): δ = 11.0 (br., 2H); 8.50 (d, 1H); 7.68 (s, 1H); 6.85 (s, 1H); 4.35-4.48 ( m, 1H); 3.68 (s, 2H); 2.92-3.03 (, 1H); 2.82-2.91 (m, 1H).

¹³ C NMR (DMSO- ₆ , 100 MHz): δ = 172.23; 161.92; 134.55; 132.70; 116.73; 115.87; 52.80; 28.68; 25.06.
LC-MS: mlz = 223 ([M + H]), 205, 177, 156, 110.
The optical purity was determined to be> 99.8% on a sample obtained according to the above procedure. The determination was carried out by hydrolysis of the amide bond (6 N hydrochloric acid, 110 ° C., 24 h), followed by derivatization of the released histidine with trifluoroacetic anhydride and isobutyl chloroformate. A D-histidine content of <0.1% was detected by gas chromatography on a chiral stationary phase.

Example 4
L-Carnosine

To a solution of 1.90 g (7.8 mmol) of (<S) -2- (cyanoacetylamino) -3- (1H-imidazol-4-yl) propionic acid sodium salt (prepared according to Example 1) in 50 ml of ethanol / conc.
Ammonia solution (V: V- 4: 1) were given 0.3 g of rhodium / activated charcoal (5% Rh). The

The mixture was hydrogenated at 110 ° C. and 45 bar for 1 hour. The catalyst was then filtered off and the filtrate was adjusted to pH 8.2 with formic acid. After the solution had been concentrated in vacuo, the residue was suspended in 200 ml of ethanol and heated to 60 ° C. for 30 minutes. The product was filtered off, washed successively with ethanol, ethyl acetate and diethyl ether and finally dried.
Yield: 1.33 g (76%)
1H NMR (D ₂ O, 400 MΗz): δ = 7.70 (s, 1Η); 6.93 (s, 1Η); 4.43-4.50 (m, 1Η); 3.20-3.28 (m, 2Η); 3.11-3.19 (m, 1H); 2.95-3.03 (m, 1H); 2.61-2.71 (m, 2H).
The optical purity was determined by the method described in Example 3 to be 99.5%.

Example 5
(S) -2- (Cyanoacetylamino) -3- (1-O-imidazol-4-yl) propionic acid methyl ester

To a solution of sodium methoxide obtained by dissolving 0.94 g (40.7 mmol; 1.95 equiv.) Of sodium in 100 ml of methanol, 5.0 g (20.4 mmol) were added at room temperature

L-histidine methyl ester dihydrochloride added. After 30 minutes, 3.03 g
(30.6 mmol) of methyl cyanoacetate were added and the mixture was left on for 16 hours

Boiled under reflux. After cooling to room temperature, the mixture was filtered.

The yellowish filtrate was concentrated in vacuo and the residue was purified by means of flash chromatography on silica gel (eluent: gradient ethyl acetate – »ethyl acetate / methanol 3: 1).
Yield: 1.51 g (31%)
1H MR (OMSO-de, 400 MHz): δ = 8.65 (d, 1H); 7.52 (s. 1H); 6.8 (s, 1H); 4.45 ^ 1.55 (m,

1H); 3,69 (s, 2H); 3,62 (s, 3H); 3,3 (br., 1H); 2,82-2,98 (m, 2H).

Example 6
L-Carnosine

1.76 g of Rh / C (0.4 mol% of pure Rh based on the starting material used) in a mixture of 94.2 g of ammonia solution (25% in H ₂ O) and 62.8 g of methanol were placed in a 1 liter pressure autoclave . The autoclave was closed, the contents were heated to 90 ° C. and 40 bar hydrogen was injected. A solution of 20.0 g (0.09 mol) (* S) -2- (cyanoacetylamino) -3- (1H-imidazol-4-yl) propionic acid (prepared according to Example 3) was then within one hour Mixture 94.2 g ammonia solution (25% in Η ₂O) and 62.8 g of methanol are metered in. After a one hour post-reaction at 90 ° C., the reaction mixture was cooled to room temperature. The pressure in the autoclave was released and the catalyst was filtered off over activated charcoal. An HPLC in-process analysis showed that the clear greenish reaction solution (326.2 g) contained 5.74% (m / m) carnosine, which corresponds to a selectivity of 92% with complete conversion. The reaction mixture was then concentrated to approx. 60 g on a rotary evaporator. As a result of the dropwise addition of 174 g of ethanol, a white solid precipitated out, which was filtered off and dried at 50 ° C./20 mbar.

Ausbeute: 13,0 g (64%)
1H NMR (D₂O, 400 MHz): δ = 7,70 (s, 1H); 6,93 (s, 1H); 4,43-4,50 (m, 1H); 3,20-3,28 (m, 2H); 3,11-3,19 (m, 1H); 2,95-3,03 (m, 1H); 2,61-2,71 (m, 2H).
^I3C NMR (D₂0, 100 MHz): δ = 178,58; 172,39; 136,46; 133,90; 118,37; 55,99; 36,65; 33,09; 29,74.
LC-MS: m/z = 227 ([M+H]⁺), 210, 192, 164, 146, 136, 110.

Example 7
L-Carnosine

In a 1 liter pressure autoclave, a solution of 10.00 g (45.0 mmol) (S) -2- (cyanoacetylamino) -3 was added to 0.88 g of Rh / C (0.4 mol% of pure Rh based on the starting material used) – (1H-imidazol-4-yl) propionic acid (prepared according to Example 3) in a mixture of 157 g conc. NΗ ₃/ Methanol (m / m = 3: 2) was added. The autoclave was closed and flushed twice with 40 bar nitrogen and once with hydrogen. The mixture was heated to 90 ° C. and 40 bar hydrogen was injected. After 3 h at 90 ° C., the reaction mixture was cooled to room temperature, the autoclave was depressurized and the catalyst was separated off by filtration. An in-process analysis (HPLC) showed that the reaction solution (147.2 g) contained 6.38% (m / m) carnosine, which corresponds to a selectivity of 92% when the conversion is complete. The reaction mixture was then concentrated to 41.2 g on a rotary evaporator. 124 g of ethanol were added dropwise at room temperature and the flask was placed in a refrigerator overnight. The next day the precipitate was filtered off, washed with ethanol and dried in a drying cabinet at 40 ° C./20 mbar. 7.96 g (78%) of a slightly greenish solid with a content (HPLC) of 98.0% (m / m) were obtained.

Example 8
L-Carnosine

The procedure was as described in Example 7, with the difference that 5% Rh on aluminum oxide was used as the catalyst. Under these conditions, L-carnosine was formed with 83% selectivity.

Example 9
L-Carnosine

4.5 g of Raney cobalt (doped with 0.3% iron) in 195 g of methanol were placed in a 1 liter pressure autoclave. A solution of 30.0 g (0.135 mol) (S) -2- (cyanoacetylamino) -3- (1H-imidazol-4-yl) propionic acid (prepared according to Example 3) in 375 g ammonia solution (25% in Η O) was admitted. The autoclave was closed and flushed twice with 40 bar nitrogen. Then 45 bar of hydrogen were injected and the contents were heated to 100 ° C. within half an hour. After an after-reaction of 3 hours at 100 ° C., the reaction mixture was cooled to room temperature and the pressure in the autoclave was released. An HPLC in-process analysis showed that the reaction solution (590.8 g) contained 4.68% (mim) carnosine, which corresponds to a selectivity of 91% with complete conversion.

Example 10
L-Carnosine

In a 100 ml
pressure autoclave were to a solution of 2.0 g (9.0 mmol) (ιS) -2- (cyanoacetylamino) -3- (lH-imidazol-4-yl) propionic acid (prepared according to Example 3) in a Mixture of 25 g of ammonia solution (25% in Η ₂ O) and 13 g of methanol, 1.1 g of Raney nickel (doped with 1.8% molybdenum) were added. The autoclave was closed and placed in an oil bath preheated to 100.degree. After 10 minutes, 50 bar of hydrogen were injected. After 2.5 hours at 100 ° C., the reaction mixture was
cooled to room temperature and the pressure on the autoclave was released. An HPLC in-process analysis showed that the reaction solution (39.4 g) contained 4.54% (m / m) carnosine, which, with a conversion of 99%, corresponds to a selectivity of 89%.

Example 11
L-Carnosine

In a 1 liter pressure autoclave, 4.50 g of Raney cobalt (doped with 0.3% iron) in a mixture of 285 g of conc. Ammonia / methanol (mim = 1.9: 1) submitted. The autoclave was closed and flushed twice with 40 bar nitrogen. Then 45 bar of hydrogen were injected and the mixture was heated to 100.degree. A solution of 30.0 g (0.135 mol) of (S) -2- (cyanoacetylamino) -3- (1H-imidazol-4-yl) propionic acid (prepared according to Example 3) in a mixture of 285 g was then obtained within one hour conc. Ammonia / methanol (m / m = 1.9: 1) metered in. After a one hour post-reaction at 100 ° C., the reaction mixture was cooled to room temperature. The pressure in the autoclave was released and the catalyst was filtered off. A ΗPLC in-process analysis showed that the reddish brown reaction solution (310.5 g) contained 9.57% (m / m) carnosine,

Example 12
(S) -2- (Cyanoacetylamino) -3- (3-methyl-3-ö ^r -imidazol-4-yl) propionic acid, sodium salt

0.50 g (2.95 mmol) of 3-methyl-L-histidine were added at 40 ° C. to a solution of 0.20 g (2.94 mmol) of sodium ethoxide in 5.60 g of ethanol. The clear solution was heated to 60 ° C. and 0.50 g (4.43 mmol) ethyl cyanoacetate was added dropwise. The mixture was refluxed for 1 hour. Then 10 mg (0.15 mmol) of imidazole were added. The ethanol was then slowly distilled off and the amount of ethanol distilled off was continuously replaced in portions by N, N-dimethylformamide. After a subsequent reaction time of 2 h at 125 ° C., the reaction mixture was carefully concentrated and the residue was purified by means of flash column chromatography on silica gel (eluent: gradient ethyl acetate → ethyl acetate / methanol 2: 1). 0.49 g (64%) of a slightly yellowish solid were obtained.

DC: R_f ^•= 0,46 (Ethanol/H₂O 3:7).
1H NMR (DMSO-öfe, 400 MHz): δ = 7,91 (d, 1H); 7,38 (s, 1H); 6,58 (s, 1H); 3,97 (q, 1H);

3,68 (s, 2H); 3,50 (s, 3H); 3,01 (dd, 1H); 2,85 (dd, 1H).
¹³C NMR (DMSO-^6, 100 MHz): δ = 171,54; 160,80; 136,95; 128,68; 126,91; 116,40;

54,26; 30,65; 25,97; 25,11.
LC-MS: m/z = 237 ([M+H]⁺), 219, 193, 191, 176, 166, 164, 150, 109.

Example 13
(S) -2- (3-aminopropionylamino) -3- (3-methyl-3Jϊ-imidazol-4-yl) propionic acid
(= anserine)

To a solution of 0.20 g (0.77 mmol) (5) -2- (cyanoacetylamino) -3- (3-methyl-3H-imidazol-4-yl) propionic acid sodium salt (prepared according to Example 12) in 2 , 4 g of methanol and 1.6 g of ammonia solution (25% in Η ₂ O), 16 mg of rhodium / Al ₂ O ₃ (5% Rh) were added. The mixture was hydrogenated at 85 ° C. and 50 bar for 1 hour. The catalyst was then filtered off. Anserine could be clearly detected in the filtrate by means of thin-layer chromatography, HPLC (by co-injection with a commercial reference substance) and LC-MS.
Gross yield: approx. 45%.
TLC: R _f = 0.25 (ethyl acetate / methanol / Ammom ^‘ ak H ₂ O 43: 35: 8: 10).
LC-MS: m / z = 241 ([M + H] ⁺), 224, 206, 180, 170, 126, 109.

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Synthesis of L-carnosine from two amino acids β -alanine-amide and L-histidine

SYN

https://pubs.rsc.org/en/content/articlelanding/2019/cy/c9cy01622h

L-Carnosine (L-Car, β-alanyl-L-histidine) is a bioactive dipeptide with important physiological functions. Direct coupling of unprotected β-Ala (β-alanine) with L-His (L-histidine) mediated by an enzyme is a promising method for L-Car synthesis. In this study, a new recombinant dipeptidase (SmPepD) from Serratia marcescens with a high synthetic activity toward L-Car was identified by a genome mining approach and successfully expressed in Escherichia coli. Divalent metal ions strongly promoted the synthetic activity of SmPepD, with up to 21.7-fold increase of activity in the presence of 0.1 mM MnCl₂. Higher temperature, lower pH and increasing substrate loadings facilitated the L-Car synthesis. Pilot biocatalytic syntheses of L-Car were performed comparatively in batch and continuous modes. In the continuous process, an ultra-filtration membrane reactor with a working volume of 5 L was employed for catalyst retention. The dipeptidase, SmPepD, showed excellent operational stability without a significant decrease in space–time yield after 4 days. The specific yield of L-Car achieved was 105 g_Car g_catalyst⁻¹ by the continuous process and 30.1 g_Car g_catalyst⁻¹ by the batch process. A nanofiltration membrane was used to isolate the desired product L-Car from the reaction mixture by selectively removing the excess substrates, β-Ala and L-His. As a result, the final L-Car content was effectively enriched from 2.3% to above 95%, which gave L-Car in 99% purity after ethanol precipitation with a total yield of 60.2%. The recovered substrate mixture of β-Ala and L-His can be easily reused, which will enable the economically attractive and environmentally benign production of the dipeptide L-Car.

SYNhttps://patents.google.com/patent/US20170211105A1/en

• Carnosine is a dipeptide of the amino acids beta-alanine and histidine. It is highly concentrated in muscle and brain tissues.
• [0005]
  β-Alanine (or beta-alanine) is a naturally occurring beta amino acid, which is an amino acid in which the amino group is at the β-position from the carboxylate group (i.e., two atoms away).
• [0006]
  β-Alanine is not used in the biosynthesis of any major proteins or enzymes. It is formed in vivo by the degradation of dihydrouracil and carnosine. It is a component of the naturally occurring peptides carnosine and anserine and also of pantothenic acid (vitamin B5), which itself is a component of coenzyme A. Under normal conditions, β-alanine is metabolized into acetic acid.
• [0007]
  β-Alanine is the rate-limiting precursor of carnosine, which is to say carnosine levels are limited by the amount of available β-alanine, not histidine. Supplementation with β-alanine has been shown to increase the concentration of carnosine in muscles, decrease fatigue in athletes and increase total muscular work done.
• [0008]
  Carnosine and beta-alanine are popular dietary supplements currently produced using chemical methods. Beta-alanine is also a synthetic precursor to pantothenic acid, the essential vitamin B5. Beta-alanine can also be used as a monomer for the production of a polymeric resin (U.S. Pat. No. 4,082,730).
• [0009]
  Naturally, carnosine is produced exclusively in animals from beta-alanine (via uracil) and histidine. In yeasts and animals, beta-alanine is typically produced by degradation of uracil. Chemically, carnosine can be synthesized from histidine and beta-alanine derivatives. For example, the coupling of an N-(thiocarboxy) anhydride of beta-alanine with histidine has been described (Vinick et al. A simple and efficient synthesis of L-carnosine. J. Org. Chem, 1983, 48(3), pp. 392-393).
• [0010]
  Beta-alanine can be produced synthetically by Michael addition of ammonia to ethyl- or methyl-acrylate. This requires the use of the caustic agent ammonia and high pressures. It is also natively produced in bacteria and yeasts in small quantities. In bacteria, beta-alanine is produced by decarboxylation of aspartate. Lysates of bacteria have been used in biocatalytic production from aspartate (Patent CN104531796A).
• [0011]
  There remains a need in the industry for a safer, more economical system for the production of carnosine and beta-alanine.

• [0105]
  The present disclosure provides methods for the biosynthetic production of beta-alanine and carnosine using engineered microorganisms of the present invention.
• [0106]
  In one embodiment, a method of producing beta-alanine is provided. The method comprises providing a fermentation media comprising a carbon substrate, contacting said media with a recombinant yeast microorganism expressing an engineered beta-alanine biosynthetic pathway wherein said pathway comprises an aspartate to beta-alanine conversion (pathway step a), and culturing the yeast in conditions whereby beta-alanine is produced.
• [0107]
  In another embodiment of the present invention, a method of producing carnosine is provided. The method comprises providing a fermentation media comprising a carbon substrate, contacting said media with a recombinant yeast microorganism expressing an engineered carnosine biosynthetic pathway wherein said pathway comprises (i) an aspartate to beta-alanine conversion (pathway step a) and (ii) a beta-alanine to carnosine conversion (pathway step b), and culturing the yeast in conditions whereby carnosine is produced.
• [0108]
  In another embodiment of the present invention, a method of producing carnosine via biotransformation is provided. The method comprises providing a media comprising a carbon substrate and exogenously added beta-alanine, contacting said media with a recombinant yeast microorganism expressing an engineered carnosine biosynthetic pathway wherein said pathway comprises (i) a beta-alanine to carnosine conversion (pathway step b), and culturing the yeast in conditions whereby carnosine is produced.
• [0109]
  Some embodiments of the present invention comprise yeast strains designated ca1 and ca2 and are derived from S. cerevisiae strain S288C. Each encodes at least 2 foreign genes under inducible Gal promoters. Strain ca1 also contains an additional gene, panM. The specific proteins encoded by each strain and their sequences, source, and accession numbers are provided in Table 1. The genes for these proteins are synthesized with yeast-optimized codon usage, assembled into singular genetic cassettes, and then inserted into the HO locus of S288C under URA2 selection. Strains ca1 and ca2 served as parent strains to derivatives comprising various heterologous genes. Ca2 served as a parent strain for ca7, ca8, ca9, ca10, ca11, ca12, ca14, ca15 in which the carnosine synthase is a different ortholog. Strain ca1 served as the parent strain to strains ca19, ca20, ca21, ca22, ca23, ca24, ca27, and ca28 in which the aspartate decarboxylase is a different ortholog. The specific proteins encoded by each strain and their sequences, source, and accession numbers are provided in Table 2.
• [0110]
  Aspartate, histidine, and the cofactors involved in the carnosine and beta-alanine pathway are universal to all organisms, and thus the host organism could be any genetically tractable organism (plants, animals, bacteria, or fungi). Amongst yeasts, other species such as S. pombe or P. pastoris are plausible alternatives. Within the S. cerevisiae species, other strains more amenable to large-scale productions, such as CENPalpha, may be utilized.
• [0111]
  The Gal promoter used in embodiments of the present invention could be replaced with constitutive promoters, or other chemically-inducible, growth phase-dependent, or stress-induced promoters. Heterologous genes of the present invention may be genomically encoded or alternatively encoded on plasmids or yeast artificial chromosomes (YACs). All genes introduced could be encoded with alternate codon usage without altering the biochemical composition of the system. All enzymes used in embodiments of the present invention have extensive orthologs in the biosphere that could be encoded as alternatives.
• [0112]
  Aspartate, histidine, and the cofactors involved in this pathway are universal to all organisms, and thus the host organism could be any genetically tractable organism (plants, animals, bacteria, or fungi). Among yeast, other species such as S. pombe or P. pastoris are plausible alternatives. Within the S. cerevisiae species, other strains more amenable to large scale productions, such as CENPalpha, may be preferable. The panD gene can replaced with orthologs from other bacteria. Examples include Corynebacterium glutamicum Escherichia coli, Helicobacter pylori, Tribolium castaneum, Pectobacterium carotovorum, Actinoplanes sp. SE50/110, Taoultella ornithinolytica, Methanocaldococcus jannaschii DSM 2661 and Methanocaldococcus bathoardescens. This is shown in Table 2. Carnosine synthase is natively found in mammals, birds, and reptiles. Therefore, the chicken enzyme used in ca1 and ca2 could be replaced by various orthologs. Examples include Gorilla gorilla, Falco perefrinus, Allpiucator mississsippiensis, Ailuoropoda melanoleuca, Ursus maritimus, Python bivittatus, and Orcinus orca. This is shown in Table 2.

Culture Conditions

• [0113]
  The growth medium used to test for production of carnosine by the engineered strains was Teknova SC Minimal Broth with Raffinose supplemented with 1% galactose.
• [0114]
  A variety of purification protocols including solid phase extraction and cation exchange chromatography may be employed to purify the desired products from the culture supernatant or the yeast cell pellet fraction.

SYN

https://pdfs.semanticscholar.org/4dc4/f6e93a62e630429c7830f117ab2564e124a2.pdf?_ga=2.190125161.395277661.1640054641-1458054132.1640054641

Names
Preferred IUPAC name(2S)-2-(3-Aminopropanamido)-3-(3H-imidazol-4-yl)propanoic acid
Other namesβ-Alanyl-L-histidine
Identifiers
CAS Number	305-84-0
3D model (JSmol)	Interactive imageInteractive image
ChEBI	CHEBI:15727
ChEMBL	ChEMBL242948
ChemSpider	388363
ECHA InfoCard	100.005.610
IUPHAR/BPS	4559
KEGG	C00386
PubChem CID	439224
UNII	8HO6PVN24W
CompTox Dashboard (EPA)	DTXSID80879594
showInChI
showSMILES
Properties
Chemical formula	C9H14N4O3
Molar mass	226.236 g·mol−1
Appearance	Crystalline solid
Melting point	253 °C (487 °F; 526 K) (decomposition)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

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Biosynthesis

Carnosine is synthesized within the body from beta-alanine and histidine. Beta-alanine is a product of pyrimidine catabolism^[6] and histidine is an essential amino acid. Since beta-alanine is the limiting substrate, supplementing just beta-alanine effectively increases the intramuscular concentration of carnosine.^[7][8]

Physiological effects

pH buffer

Carnosine has a pK_a value of 6.83, making it a good buffer for the pH range of animal muscles.^[9] Since beta-alanine is not incorporated into proteins, carnosine can be stored at relatively high concentrations (millimolar). Occurring at 17–25 mmol/kg (dry muscle),^[10] carnosine (β-alanyl-L-histidine) is an important intramuscular buffer, constituting 10-20% of the total buffering capacity in type I and II muscle fibres.

Anti-oxidant

Carnosine has been proven to scavenge reactive oxygen species (ROS) as well as alpha-beta unsaturated aldehydes formed from peroxidation of cell membrane fatty acids during oxidative stress. It also buffers pH in muscle cells, and acts as a neurotransmitter in the brain. It is also a zwitterion, a neutral molecule with a positive and negative end.^{[citation needed]}

Antiglycating

Carnosine acts as an antiglycating agent, reducing the rate of formation of advanced glycation end-products (substances that can be a factor in the development or worsening of many degenerative diseases, such as diabetes, atherosclerosis, chronic kidney failure, and Alzheimer’s disease^[11]), and ultimately reducing development of atherosclerotic plaque build-up.^[12][13][14]

Geroprotective

Carnosine is considered as a geroprotector.^[15] Carnosine can increase the Hayflick limit in human fibroblasts,^[16] as well as appearing to reduce the telomere shortening rate.^[17] Carnosine may also slow aging through its anti-glycating properties (chronic glycolysis is speculated to accelerate aging).^[18]

Other

Carnosine can chelate divalent metal ions.^[12]

Carnosine administration has been shown to have cardioprotective properties, protecting against ischaemia-reperfusion injury, and doxorubicin-induced cardiomyopathy.^[19]

Carnosine demonstrated neuroprotective effects in multiple animal studies.^[20][21][22]

Research has demonstrated a positive association between muscle tissue carnosine concentration and exercise performance.^[23][24][25] β-Alanine supplementation is thought to increase exercise performance by promoting carnosine production in muscle. Exercise has conversely been found to increase muscle carnosine concentrations, and muscle carnosine content is higher in athletes engaging in anaerobic exercise.^[23]

Carnosine appears to protect in experimental ischemic stroke by influencing a number of mechanisms that are activated during stroke. It is a potent pH buffer and has anti matrix metalloproteinase activity, antioxidant and antiexcitotoxic properties and protects the blood brain barrier [26], [27], [28], [29], [30], [31], [32]. [33], [34], [35].

References

1. ^ “C9625 L-Carnosine ~99%, crystalline”. Sigma-Aldrich.
2. ^ Gulewitsch, Wl.; Amiradžibi, S. (1900). “Ueber das Carnosin, eine neue organische Base des Fleischextractes”. Berichte der Deutschen Chemischen Gesellschaft. 33 (2): 1902–1903. doi:10.1002/cber.19000330275.
3. ^ Trexler, Eric T.; Smith-Ryan, Abbie E.; Stout, Jeffrey R.; Hoffman, Jay R.; Wilborn, Colin D.; Sale, Craig; Kreider, Richard B.; Jäger, Ralf; Earnest, Conrad P.; Bannock, Laurent; Campbell, Bill (2015-07-15). “International society of sports nutrition position stand: Beta-Alanine”. Journal of the International Society of Sports Nutrition. 12: 30. doi:10.1186/s12970-015-0090-y. ISSN 1550-2783. PMC 4501114. PMID 26175657.
4. ^ Hipkiss, A. R. (2006). “Does chronic glycolysis accelerate aging? Could this explain how dietary restriction works?”. Annals of the New York Academy of Sciences. 1067 (1): 361–8. Bibcode:2006NYASA1067..361H. doi:10.1196/annals.1354.051. PMID 16804012. S2CID 41175541.
5. ^ Alan R. Hipkiss (2009). “Chapter 3: Carnosine and Its Possible Roles in Nutrition and Health”. Advances in Food and Nutrition Research.
6. ^ “beta-ureidopropionate + H2O => beta-alanine + NH4+ + CO2”. reactome. Retrieved 2020-02-08. Cytosolic 3-ureidopropionase catalyzes the reaction of 3-ureidopropionate and water to form beta-alanine, CO2, and NH3 (van Kuilenberg et al. 2004).
7. ^ Derave W, Ozdemir MS, Harris R, Pottier A, Reyngoudt H, Koppo K, Wise JA, Achten E (August 9, 2007). “Beta-alanine supplementation augments muscle carnosine content and attenuates fatigue during repeated isokinetic contraction bouts in trained sprinters”. J Appl Physiol. 103 (5): 1736–43. doi:10.1152/japplphysiol.00397.2007. PMID 17690198. S2CID 6990201.
8. ^ Hill CA, Harris RC, Kim HJ, Harris BD, Sale C, Boobis LH, Kim CK, Wise JA (2007). “Influence of beta-alanine supplementation on skeletal muscle carnosine concentrations and high intensity cycling capacity”. Amino Acids. 32 (2): 225–33. doi:10.1007/s00726-006-0364-4. PMID 16868650. S2CID 23988054.
9. ^ Bate-Smith, EC (1938). “The buffering of muscle in rigor: protein, phosphate and carnosine”. Journal of Physiology. 92 (3): 336–343. doi:10.1113/jphysiol.1938.sp003605. PMC 1395289. PMID 16994977.
10. ^ Mannion, AF; Jakeman, PM; Dunnett, M; Harris, RC; Willan, PLT (1992). “Carnosine and anserine concentrations in the quadriceps femoris muscle of healthy humans”. Eur. J. Appl. Physiol. 64 (1): 47–50. doi:10.1007/BF00376439. PMID 1735411. S2CID 24590951.
11. ^ Vistoli, G; De Maddis, D; Cipak, A; Zarkovic, N; Carini, M; Aldini, G (Aug 2013). “Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation”. Free Radic. Res. 47: Suppl 1:3–27. doi:10.3109/10715762.2013.815348. PMID 23767955. S2CID 207517855.
12. ^ Jump up to:^a b Reddy, V. P.; Garrett, MR; Perry, G; Smith, MA (2005). “Carnosine: A Versatile Antioxidant and Antiglycating Agent”. Science of Aging Knowledge Environment. 2005 (18): pe12. doi:10.1126/sageke.2005.18.pe12. PMID 15872311.
13. ^ Rashid, Imran; Van Reyk, David M.; Davies, Michael J. (2007). “Carnosine and its constituents inhibit glycation of low-density lipoproteins that promotes foam cell formation in vitro”. FEBS Letters. 581 (5): 1067–70. doi:10.1016/j.febslet.2007.01.082. PMID 17316626. S2CID 46535145.
14. ^ Hipkiss, A. R. (2005). “Glycation, ageing and carnosine: Are carnivorous diets beneficial?”. Mechanisms of Ageing and Development. 126 (10): 1034–9. doi:10.1016/j.mad.2005.05.002. PMID 15955546. S2CID 19979631.
15. ^ Boldyrev, A. A.; Stvolinsky, S. L.; Fedorova, T. N.; Suslina, Z. A. (2010). “Carnosine as a natural antioxidant and geroprotector: From molecular mechanisms to clinical trials”. Rejuvenation Research. 13 (2–3): 156–8. doi:10.1089/rej.2009.0923. PMID 20017611.
16. ^ McFarland, G; Holliday, R (1994). “Retardation of the Senescence of Cultured Human Diploid Fibroblasts by Carnosine”. Experimental Cell Research. 212 (2): 167–75. doi:10.1006/excr.1994.1132. PMID 8187813.
17. ^ Shao, Lan; Li, Qing-Huan; Tan, Zheng (2004). “L-Carnosine reduces telomere damage and shortening rate in cultured normal fibroblasts”. Biochemical and Biophysical Research Communications. 324 (2): 931–6. doi:10.1016/j.bbrc.2004.09.136. PMID 15474517.
18. ^ Hipkiss, A. R. (2006). “Does Chronic Glycolysis Accelerate Aging? Could This Explain How Dietary Restriction Works?”. Annals of the New York Academy of Sciences. 1067 (1): 361–8. Bibcode:2006NYASA1067..361H. doi:10.1196/annals.1354.051. PMID 16804012. S2CID 41175541.
19. ^ McCarty, Mark F; DiNicolantonio, James J (2014-08-04). “β-Alanine and orotate as supplements for cardiac protection”. Open Heart. 1 (1): e000119. doi:10.1136/openhrt-2014-000119. ISSN 2053-3624. PMC 4189254. PMID 25332822.
20. ^ Virdi, Jasleen Kaur; Bhanot, Amritansh; Jaggi, Amteshwar Singh; Agarwal, Neha (2020-10-02). “Investigation on beneficial role of l -carnosine in neuroprotective mechanism of ischemic postconditioning in mice: possible role of histidine histamine pathway”. International Journal of Neuroscience. 130 (10): 983–998. doi:10.1080/00207454.2020.1715393. ISSN 0020-7454. PMID 31951767. S2CID 210710039.
21. ^ Rajanikant, G.K.; Zemke, Daniel; Senut, Marie-Claude; Frenkel, Mark B.; Chen, Alex F.; Gupta, Rishi; Majid, Arshad (November 2007). “Carnosine Is Neuroprotective Against Permanent Focal Cerebral Ischemia in Mice”. Stroke. 38 (11): 3023–3031. doi:10.1161/STROKEAHA.107.488502. ISSN 0039-2499. PMID 17916766.
22. ^ Min, Jiangyong; Senut, Marie-Claude; Rajanikant, Krishnamurthy; Greenberg, Eric; Bandagi, Ram; Zemke, Daniel; Mousa, Ahmad; Kassab, Mounzer; Farooq, Muhammad U.; Gupta, Rishi; Majid, Arshad (October 2008). “Differential neuroprotective effects of carnosine, anserine, and N -acetyl carnosine against permanent focal ischemia”. Journal of Neuroscience Research. 86 (13): 2984–2991. doi:10.1002/jnr.21744. PMC 2805719. PMID 18543335.
23. ^ Jump up to:^a b Culbertson, Julie Y.; Kreider, Richard B.; Greenwood, Mike; Cooke, Matthew (2010-01-25). “Effects of Beta-Alanine on Muscle Carnosine and Exercise Performance:A Review of the Current Literature”. Nutrients. 2 (1): 75–98. doi:10.3390/nu2010075. ISSN 2072-6643. PMC 3257613. PMID 22253993.
24. ^ Baguet, Audrey; Bourgois, Jan; Vanhee, Lander; Achten, Eric; Derave, Wim (2010-07-29). “Important role of muscle carnosine in rowing performance”. Journal of Applied Physiology. 109 (4): 1096–1101. doi:10.1152/japplphysiol.00141.2010. ISSN 8750-7587. PMID 20671038.
25. ^ Varanoske, Alyssa N.; Hoffman, Jay R.; Church, David D.; Wang, Ran; Baker, Kayla M.; Dodd, Sarah J.; Coker, Nicholas A.; Oliveira, Leonardo P.; Dawson, Virgil L.; Fukuda, David H.; Stout, Jeffrey R. (2017-09-07). “Influence of Skeletal Muscle Carnosine Content on Fatigue during Repeated Resistance Exercise in Recreationally Active Women”. Nutrients. 9 (9): 988. doi:10.3390/nu9090988. ISSN 2072-6643. PMC 5622748. PMID 28880219.

26. Kim EH, Kim ES, Shin D, Kim D, Choi S, Shin YJ, Kim KA, Noh D, Caglayan AB, Rajanikant GK, Majid A, Bae ON. Carnosine Protects against Cerebral Ischemic Injury by Inhibiting Matrix-Metalloproteinases. Int J Mol Sci. 2021 Jul 13;22(14):7495. doi: 10.3390/ijms22147495. PMID: 34299128; PMCID: PMC8306548.

27. Jain S, Kim ES, Kim D, Burrows D, De Felice M, Kim M, Baek SH, Ali A, Redgrave J, Doeppner TR, Gardner I, Bae ON, Majid A. Comparative Cerebroprotective Potential of d- and l-Carnosine Following Ischemic Stroke in Mice. Int J Mol Sci. 2020 Apr 26;21(9):3053. doi: 10.3390/ijms21093053. PMID: 32357505; PMCID: PMC7246848.

28. Kim ES, Kim D, Nyberg S, Poma A, Cecchin D, Jain SA, Kim KA, Shin YJ, Kim EH, Kim M, Baek SH, Kim JK, Doeppner TR, Ali A, Redgrave J, Battaglia G, Majid A, Bae ON. LRP-1 functionalized polymersomes enhance the efficacy of carnosine in experimental stroke. Sci Rep. 2020 Jan 20;10(1):699. doi: 10.1038/s41598-020-57685-5. PMID: 31959846; PMCID: PMC6971073.

29. Schön M, Mousa A, Berk M, Chia WL, Ukropec J, Majid A, Ukropcová B, de Courten B. The Potential of Carnosine in Brain-Related Disorders: A Comprehensive Review of Current Evidence. Nutrients. 2019 May 28;11(6):1196. doi: 10.3390/nu11061196. PMID: 31141890; PMCID: PMC6627134.

30. Davis CK, Laud PJ, Bahor Z, Rajanikant GK, Majid A. Systematic review and stratified meta-analysis of the efficacy of carnosine in animal models of ischemic stroke. J Cereb Blood Flow Metab. 2016 Oct;36(10):1686-1694. doi: 10.1177/0271678X16658302. Epub 2016 Jul 8. PMID: 27401803; PMCID: PMC5046161.

31. Baek SH, Noh AR, Kim KA, Akram M, Shin YJ, Kim ES, Yu SW, Majid A, Bae ON. Modulation of mitochondrial function and autophagy mediates carnosine neuroprotection against ischemic brain damage. Stroke. 2014 Aug;45(8):2438-2443. doi: 10.1161/STROKEAHA.114.005183. Epub 2014 Jun 17. PMID: 24938837; PMCID: PMC4211270.

32. Bae ON, Majid A. Role of histidine/histamine in carnosine-induced neuroprotection during ischemic brain damage. Brain Res. 2013 Aug 21;1527:246-54. doi: 10.1016/j.brainres.2013.07.004. Epub 2013 Jul 11. PMID: 23850642.

33. Bae ON, Serfozo K, Baek SH, Lee KY, Dorrance A, Rumbeiha W, Fitzgerald SD, Farooq MU, Naravelta B, Bhatt A, Majid A. Safety and efficacy evaluation of carnosine, an endogenous neuroprotective agent for ischemic stroke. Stroke. 2013 Jan;44(1):205-12. doi: 10.1161/STROKEAHA.112.673954. Epub 2012 Dec 18. PMID: 23250994; PMCID: PMC3678096.

34. Min J, Senut MC, Rajanikant K, Greenberg E, Bandagi R, Zemke D, Mousa A, Kassab M, Farooq MU, Gupta R, Majid A. Differential neuroprotective effects of carnosine, anserine, and N-acetyl carnosine against permanent focal ischemia. J Neurosci Res. 2008 Oct;86(13):2984-91. doi: 10.1002/jnr.21744. PMID: 18543335; PMCID: PMC2805719.

35. Rajanikant GK, Zemke D, Senut MC, Frenkel MB, Chen AF, Gupta R, Majid A. Carnosine is neuroprotective against permanent focal cerebral ischemia in mice. Stroke. 2007 Nov;38(11):3023-31. doi: 10.1161/STROKEAHA.107.488502. Epub 2007 Oct 4. PMID: 17916766.

////////L-CARNOSINE, カルノシン , b-Alanyl-L-histidine, ignotine, 8HO6PVN24W, カルノシン , Dragosine, Ignotin, Ignotine, Karnozin, L-Carnosine, N-(β-Alanyl)-L-histidine, NSC 524045, Sevitin, β-Alanylhistidine

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Methocarbamol

• Molecular FormulaC₁₁H₁₅NO₅
• Average mass241.240 Da
• метокарбамол , ميثوكاربامول , 美索巴莫

1,2-Propanediol, 3-(2-methoxyphenoxy)-, 1-carbamate
208-524-3[EINECS]
2-Hydroxy-3-(2-methoxyphenoxy)propyl carbamate
532-03-6[RN]
MethocarbamolCAS Registry Number: 532-03-6
CAS Name: 3-(2-Methoxyphenoxy)-1,2-propanediol 1-carbamate
Additional Names: 3-(o-methoxyphenoxy)-2-hydroxypropyl 1-carbamate; 2-hydroxy-3-(o-methoxyphenoxy)propyl 1-carbamate; guaiacol glyceryl ether carbamate
Manufacturers’ Codes: AHR-85Trademarks: Neuraxin; Miolaxene (Lepetit); Lumirelax; Etroflex; Delaxin (Ferndale); Robamol (Cenci); Traumacut (Brenner-Efeka); Tresortil; Relestrid; Robaxin (Robins)
Molecular Formula: C11H15NO5, Molecular Weight: 241.24Percent Composition: C 54.77%, H 6.27%, N 5.81%, O 33.16%
Literature References: Prepn from 3-(o-methoxyphenoxy)-2-hydroxypropyl chlorocarbonate: Murphey, US2770649 (1956 to A. H. Robins). Comprehensive description: S. Alessi-Severini et al.,Anal. Profiles Drug Subs. Excip.23, 371-399 (1994).
Properties: Crystals from benzene, mp 92-94°. uv max (water): 222, 274 nm (E1%1cm 298, 94). 1og P -0.06. Soly in water at 20°: 2.5 g/100 ml. Sol in alcohol, propylene glycol. Sparingly sol in chloroform. Practically insol in n-hexane.
Melting point: mp 92-94°
Absorption maximum: uv max (water): 222, 274 nm (E1%1cm 298, 94)
Therap-Cat: Muscle relaxant (skeletal).
Therap-Cat-Vet: Muscle relaxant (skeletal).
Keywords: Muscle Relaxant (Skeletal).

Methocarbamol, sold under the brand name Robaxin among others, is a medication used for short-term musculoskeletal pain.^[3][4] It may be used together with rest, physical therapy, and pain medication.^[3][5][6] It is less preferred in low back pain.^[3] It has limited use for rheumatoid arthritis and cerebral palsy.^[3][7] Effects generally begin within half an hour.^[3] It is taken by mouth or injection into a vein.^[3]

Methocarbamol is a CNS depressant indicated with rest, physical therapy and other treatments to control the discomfort associated with various acute musculoskeletal conditions.

Methocarbamol was developed in the early 1950s as a treatment for muscle spasticity and the associated pain.^6,7 It is a guaiacol glyceryl ether.⁷

Methocarbamol tablets and intramuscular injections are prescription medicines indicated in the United States as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions.^Label,9 In Canada, methocarbamol can be sold as an over the counter oral medicine at a lower dose that may be combined with acetaminophen or ibuprofen.¹⁰ A combination product with acetylsalicylic acid and codeine is available in Canada by prescription.¹⁰

Methocarbamol was FDA approved on 16 July 1957.⁸

Common side effect include headaches, sleepiness, and dizziness.^[3][8] Serious side effects may include anaphylaxis, liver problems, confusion, and seizures.^[4] Use is not recommended in pregnancy and breastfeeding.^[3][4] Because of risk of injury, skeletal muscle relaxants should generally be avoided in geriatric patients.^[3] Methocarbamol is a centrally acting muscle relaxant.^[3] How it works is unclear, but it does not appear to affect muscles directly.^[3]

Methocarbamol was approved for medical use in the United States in 1957.^[3] It is available as a generic medication.^[3][4] It is relatively inexpensive as of 2016.^[9] In 2019, it was the 136th most commonly prescribed medication in the United States, with more than 4 million prescriptions.^[10][11]

SYN

CN  109970606

SYN

Synthesis of methocarbamol from guaifenesin. (a) methocarbamol and (b) β-isomer of methocarbamol.

SYN

https://www.sciencedirect.com/science/article/abs/pii/S0957416607003801

The muscle relaxant methocarbamol 2 and tranquilizer mephenoxalone 3, as well as intermediate cyclic carbonate 4, have been prepared in enantiopure form by starting from enantiopure guaifenesin 1 easily available by an entrainment resolution procedure. Thermal investigations reveal that 2 is probably a conglomerate forming substance, 3 forms a stable racemic compound, and 4 occupies an intermediate position. The enantiomeric excess of a binary phase eutectic point for these substances comprises 0%, 85%, and 10%, respectively.

Graphical abstract

PATENT

 US 2770649

https://patents.google.com/patent/US2770649A/en

PAPER

Journal of pharmaceutical sciences (1970), 59(7), 1043-4

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Medical use

Methocarbamol is a muscle relaxant used to treat acute, painful musculoskeletal spasms in a variety of musculoskeletal conditions.^[12] However, there is limited and inconsistent published research on the medication’s efficacy and safety in treating musculoskeletal conditions, primarily neck and back pain.^[12]

Methocarbamol injection may have a beneficial effect in the control of the neuromuscular spasms of tetanus.^[6] It does not, however, replace the current treatment regimen.^[6]

It is not useful in chronic neurological disorders, such as cerebral palsy or other dyskinesias.^[3]

Currently, there is some suggestion that muscle relaxants may improve the symptoms of rheumatoid arthritis; however, there is insufficient data to prove its effectiveness as well as answer concerns regarding optimal dosing, choice of muscle relaxant, adverse effects, and functional status.^[7]

Comparison to similar agents

The clinical effectiveness of methocarbamol compared to other muscle relaxants is not well-known.^[12] One trial of methocarbamol versus cyclobenzaprine, a well-studied muscle relaxant, in those with localized muscle spasm found there was no significant differences in their effects on improved muscle spasm, limitation of motion, or limitation of daily activities.^[12]

Contraindications

There are few contraindications to methocarbamol. They include:

• Hypersensitivity to methocarbamol or to any of the injection components.^[6]
• For the injectable form, suspected kidney failure or renal pathology, due to large content of polyethylene glycol 300 that can increase pre-existing acidosis and urea retention.^[6]

Side effects

Methocarbamol is a centrally acting skeletal muscle relaxant that has significant adverse effects, especially on the central nervous system.^[3]

Potential side effects of methocarbamol include:

• Most commonly drowsiness, blurred vision, headache, nausea, and skin rash.^[8]
• Possible clumsiness (ataxia), upset stomach, flushing, mood changes, trouble urinating, itchiness, and fever.^[13][14]
• Both tachycardia (fast heart rate) and bradycardia (slow heart rate) have been reported.^[14]
• Hypersensitivity reactions and anaphylatic reactions are also reported.^[5][6]
• May cause respiratory depression when combined with benzodiazepines, barbiturates, codeine, or other muscle relaxants.^[15]
• May cause urine to turn black, blue or green.^[13]

While the product label states that methocarbamol can cause jaundice, there is minimal evidence to suggest that methocarbamol causes liver damage.^[8] During clinical trials of methocarbamol, there were no laboratory measurements of liver damage indicators, such as serum aminotransferase (AST/ALT) levels, to confirm hepatotoxicity.^[8] Although unlikely, it is impossible to rule out that methocarbamol may cause mild liver injury with use.^[8]

Elderly

Skeletal muscle relaxants are associated with an increased risk of injury among older adults.^[16] Methocarbamol appeared to be less sedating than other muscle relaxants, most notably cyclobenzaprine, but had similar increased risk of injury.^[15][16] Methocarbamol is cited along with “most muscle relaxants” in the 2012 Beers Criteria as being “poorly tolerated by older adults, because of anticholinergic adverse effects, sedation, increased risk of fractures,” noting that “effectiveness dosages tolerated by older adults is questionable.”^[17]

Pregnancy

Methocarbamol is labeled by the FDA as a pregnancy category C medication.^[6] The teratogenic effects of the medication are not known and should be given to pregnant women only when clearly indicated.^[6]

Overdose

There is limited information available on the acute toxicity of methocarbamol.^[5][6] Overdose is used frequently in conjunction with CNS depressants such as alcohol or benzodiazepines and will have symptoms of nausea, drowsiness, blurred vision, hypotension, seizures, and coma.^[6] There are reported deaths with an overdose of methocarbamol alone or in the presence of other CNS depressants.^[5][6]

Abuse

Unlike other carbamates such as meprobamate and its prodrug carisoprodol, methocarbamol has greatly reduced abuse potential.^[18] Studies comparing it to the benzodiazepine lorazepam and the antihistamine diphenhydramine, along with placebo, find that methocarbamol produces increased “liking” responses and some sedative-like effects; however, at higher doses dysphoria is reported.^[18] It is considered to have an abuse profile similar to, but weaker than, lorazepam.^[18]

Interactions

Methocarbamol may inhibit the effects of pyridostigmine bromide.^[5][6] Therefore, methocarbamol should be used with caution in those with myasthenia gravis taking anticholinesterase medications.^[6]

Methocarbamol may disrupt certain screening tests as it can cause color interference in laboratory tests for 5-hydroxy-indoleacetic acid (5-HIAA) and in urinary testing for vanillylmandelic acid (VMA) using the Gitlow method.^[6]

Pharmacology

Mechanism of action

The mechanism of action of methocarbamol has not currently been established.^[3] Its effect is thought to be localized to the central nervous system rather than a direct effect on skeletal muscles.^[3] It has no effect on the motor end plate or the peripheral nerve fiber.^[6] The efficacy of the medication is likely related to its sedative effect.^[3] Alternatively, methocarbamol may act via inhibition of acetylcholinesterase, similarly to carbamate.^[19]

Pharmacokinetics

In healthy individuals, the plasma clearance of methocarbamol ranges between 0.20 and 0.80 L/h/kg.^[6] The mean plasma elimination half-life ranges between 1 and 2 hours, and the plasma protein binding ranges between 46% and 50%.^[6] The elimination half-life was longer in the elderly, those with kidney problems, and those with liver problems.^[6]

Metabolism

Methocarbamol is the carbamate derivative of guaifenesin, but does not produce guaifenesin as a metabolite, because the carbamate bond is not hydrolyzed metabolically;^[8][6] its metabolism is by Phase I ring hydroxylation and O-demethylation, followed by Phase II conjugation.^[6] All the major metabolites are unhydrolyzed carbamates.^[20][21] Small amounts of unchanged methocarbamol are also excreted in the urine.^[5][6]

Society and culture

Methocarbamol was approved as a muscle relaxant for acute, painful musculoskeletal conditions in the United States in 1957.^[8] Muscle relaxants are widely used to treat low back pain, one of the most frequent health problems in industrialized countries. Currently, there are more than 3 million prescriptions filled yearly.^[8] Methocarbamol and orphenadrine are each used in more than 250,000 U.S. emergency department visits for lower back pain each year.^[22] In the United States, low back pain is the fifth most common reason for all physician visits and the second most common symptomatic reason.^[23] In 80% of primary care visits for low back pain, at least one medication was prescribed at the initial office visit and more than one third were prescribed two or more medications.^[24] The most commonly prescribed drugs for low back pain included skeletal muscle relaxants.^[25] Cyclobenzaprine and methocarbamol are on the U.S. Medicare formulary, which may account for the higher use of these products.^[16]

Economics

The generic formulation of the medication is relatively inexpensive, costing less than the alternative metaxalone in 2016.^[26][9]

Marketing

Generic methocarbamol 750mg tablet.

Methocarbamol without other ingredients is sold under the brand name Robaxin in the U.K., U.S., Canada^[27] and South Africa; it is marketed as Lumirelax in France, Ortoton in Germany and many other names worldwide.^[28] In combination with other active ingredients it is sold under other names: with acetaminophen (paracetamol), under trade names Robaxacet and Tylenol Body Pain Night; with ibuprofen as Robax Platinum; with acetylsalicylic acid as Robaxisal in the U.S. and Canada.^[29][30] However, in Spain the tradename Robaxisal is used for the paracetamol combination instead of Robaxacet.^{[citation needed]} These combinations are also available from independent manufacturers under generic names.^{[citation needed]}

Research

Although opioids are a typically first line in treatment of severe pain, several trials suggest that methocarbamol may improve recovery and decrease hospital length of stay in those with muscles spasms associated with rib fractures.^[31][32][33] However, methocarbamol was less useful in the treatment of acute traumatic pain in general.^[34]

Long-term studies evaluating the risk of development of cancer in using methocarbamol have not been performed.^[5][6] There are currently no studies evaluating the effect of methocarbamol on mutagenesis or fertility.^[5][6]

The safety and efficacy of methocarbamol has not been established in pediatric individuals below the age of 16 except in tetanus.^[5][6]

References

1. ^ “Robaxin-750 – Summary of Product Characteristics (SmPC)”. (emc). 8 August 2017. Retrieved 19 April 2020.
2. ^ Sica DA, Comstock TJ, Davis J, Manning L, Powell R, Melikian A, Wright G (1990). “Pharmacokinetics and protein binding of methocarbamol in renal insufficiency and normals”. European Journal of Clinical Pharmacology. 39 (2): 193–4. doi:10.1007/BF00280060. PMID 2253675. S2CID 626920.
3. ^ Jump up to:^{a b c d e f g h i j k l m n o p q r} “Methocarbamol Monograph for Professionals”. Drugs.com. American Society of Health-System Pharmacists.
4. ^ Jump up to:^a b c d British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 1093. ISBN 9780857113382.
5. ^ Jump up to:^{a b c d e f g h i} “Robaxin- methocarbamol tablet, film coated”. DailyMed. 18 July 2019. Retrieved 19 April 2020.
6. ^ Jump up to:^{a b c d e f g h i j k l m n o p q r s t u v w x} “Robaxin- methocarbamol injection”. DailyMed. 10 December 2018. Retrieved 19 April 2020.
7. ^ Jump up to:^a b Richards, Bethan L.; Whittle, Samuel L.; Buchbinder, Rachelle (18 January 2012). “Muscle relaxants for pain management in rheumatoid arthritis”. The Cochrane Database of Systematic Reviews. 1: CD008922. doi:10.1002/14651858.CD008922.pub2. ISSN 1469-493X. PMID 22258993.
8. ^ Jump up to:^{a b c d e f g h} “Methocarbamol”. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 30 January 2017. PMID 31643609.
9. ^ Jump up to:^a b Fine, Perry G. (2016). The Hospice Companion: Best Practices for Interdisciplinary Care of Advanced Illness. Oxford University Press. p. PT146. ISBN 978-0-19-045692-4.
10. ^ “The Top 300 of 2019”. ClinCalc. Retrieved 16 October 2021.
11. ^ “Methocarbamol – Drug Usage Statistics”. ClinCalc. Retrieved 16 October 2021.
12. ^ Jump up to:^a b c d Chou, Roger; Peterson, Kim; Helfand, Mark (August 2004). “Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review”. Journal of Pain and Symptom Management. 28 (2): 140–175. doi:10.1016/j.jpainsymman.2004.05.002. ISSN 0885-3924. PMID 15276195.
13. ^ Jump up to:^a b “Methocarbamol”. MedlinePlus. Retrieved 18 April 2020.
14. ^ Jump up to:^a b “Methocarbamol Side Effects: Common, Severe, Long Term”. Drugs.com. Retrieved 18 April 2020.
15. ^ Jump up to:^a b See, Sharon; Ginzburg, Regina (1 August 2008). “Choosing a skeletal muscle relaxant”. American Family Physician. 78 (3): 365–70. ISSN 0002-838X. PMID 18711953.
16. ^ Jump up to:^a b c Spence, Michele M.; Shin, Patrick J.; Lee, Eric A.; Gibbs, Nancy E. (July 2013). “Risk of injury associated with skeletal muscle relaxant use in older adults”. The Annals of Pharmacotherapy. 47 (7–8): 993–8. doi:10.1345/aph.1R735. ISSN 1542-6270. PMID 23821610. S2CID 9037478.
17. ^ “Beers Criteria Medication List”. DCRI. Retrieved 18 October 2020.
18. ^ Jump up to:^a b c Preston KL, Wolf B, Guarino JJ, Griffiths RR (1992). “Subjective and behavioral effects of diphenhydramine, lorazepam and methocarbamol: evaluation of abuse liability”. Journal of Pharmacology and Experimental Therapeutics. 262 (2): 707–20. PMID 1501118.
19. ^ PubChem. “Methocarbamol”. pubchem.ncbi.nlm.nih.gov. Retrieved 6 July 2020.
20. ^ Methocarbamol. In: DRUGDEX System [intranet database]. Greenwood Village, Colorado: Thomson Healthcare; c1974–2009 [cited 2009 Feb 10].
21. ^ Bruce RB, Turnbull LB, Newman JH (January 1971). “Metabolism of methocarbamol in the rat, dog, and human”. J Pharm Sci. 60 (1): 104–6. doi:10.1002/jps.2600600120. PMID 5548215.
22. ^ Friedman BW, Cisewski D, Irizarry E, Davitt M, Solorzano C, Nassery A, et al. (March 2018). “A Randomized, Double-Blind, Placebo-Controlled Trial of Naproxen With or Without Orphenadrine or Methocarbamol for Acute Low Back Pain”. Annals of Emergency Medicine. 71 (3): 348–356.e5. doi:10.1016/j.annemergmed.2017.09.031. ISSN 1097-6760. PMC 5820149. PMID 29089169.
23. ^ Chou, Roger; Huffman, Laurie Hoyt (2 October 2007). “Medications for Acute and Chronic Low Back Pain: A Review of the Evidence for an American Pain Society/American College of Physicians Clinical Practice Guideline”. Annals of Internal Medicine. 147 (7): 505–14. doi:10.7326/0003-4819-147-7-200710020-00008. ISSN 0003-4819. PMID 17909211. S2CID 32719708.
24. ^ Cherkin, D. C.; Wheeler, K. J.; Barlow, W.; Deyo, R. A. (1 March 1998). “Medication use for low back pain in primary care”. Spine. 23 (5): 607–14. doi:10.1097/00007632-199803010-00015. ISSN 0362-2436. PMID 9530793. S2CID 23664539.
25. ^ Luo, Xuemei; Pietrobon, Ricardo; Curtis, Lesley H.; Hey, Lloyd A. (1 December 2004). “Prescription of nonsteroidal anti-inflammatory drugs and muscle relaxants for back pain in the United States”. Spine. 29 (23): E531–7. doi:10.1097/01.brs.0000146453.76528.7c. ISSN 1528-1159. PMID 15564901. S2CID 72742439.
26. ^ Robbins, Lawrence D. (2013). Management of Headache and Headache Medications. Springer Science & Business Media. p. PT147. ISBN 978-1-4612-2124-1.
27. ^ “ROBAXIN product appearance in Canada”. ctchealth.ca. Retrieved 13 December 2021.
28. ^ “Methocarbamol”. Drugs.com. Retrieved 12 May 2018.
29. ^ “New Drugs and Indications Reviewed at the May 2003 DEC Meeting” (PDF). ESI Canada. Archived from the original (PDF) on 10 July 2011. Retrieved 14 November 2008.
30. ^ “Tylenol Body Pain Night Overview and Dosage”. Tylenol Canada. Archived from the original (website) on 31 March 2012. Retrieved 23 April 2012.
31. ^ Patanwala, Asad E.; Aljuhani, Ohoud; Kopp, Brian J.; Erstad, Brian L. (October 2017). “Methocarbamol use is associated with decreased hospital length of stay in trauma patients with closed rib fractures”. The American Journal of Surgery. 214 (4): 738–42. doi:10.1016/j.amjsurg.2017.01.003. ISSN 0002-9610. PMID 28088301.
32. ^ Deloney, Lindsay; Smith, Melanie; Carter, Cassandra; Privette, Alicia; Leon, Stuart; Eriksson, Evert (January 2020). “946: Methocarbamol reduces opioid use and length of stay in young adults with traumatic rib fractures”. Critical Care Medicine. 48 (1): 452. doi:10.1097/01.ccm.0000633320.62811.06. ISSN 0090-3493.
33. ^ Smith, Melanie; Deloney, Lindsay; Carter, Cassandra; Leon, Stuart; Privette, Alicia; Eriksson, Evert (January 2020). “1759: Use of methocarbamol in geriatric patients with rib fractures is associated with improved outcomes”. Critical Care Medicine. 48 (1): 854. doi:10.1097/01.ccm.0000649332.10326.98. ISSN 0090-3493.
34. ^ Aljuhani, Ohoud; Kopp, Brian J.; Patanwala, Asad E. (2017). “Effect of Methocarbamol on Acute Pain After Traumatic Injury”. American Journal of Therapeutics. 24 (2): e202–6. doi:10.1097/mjt.0000000000000364. ISSN 1075-2765. PMID 26469684. S2CID 24284482.

External links

• “Methocarbamol”. Drug Information Portal. U.S. National Library of Medicine.

1. Sica DA, Comstock TJ, Davis J, Manning L, Powell R, Melikian A, Wright G: Pharmacokinetics and protein binding of methocarbamol in renal insufficiency and normals. Eur J Clin Pharmacol. 1990;39(2):193-4. [Article]
2. Bruce RB, Turnbull LB, Newman JH: Metabolism of methocarbamol in the rat, dog, and human. J Pharm Sci. 1971 Jan;60(1):104-6. [Article]
3. Witenko C, Moorman-Li R, Motycka C, Duane K, Hincapie-Castillo J, Leonard P, Valaer C: Considerations for the appropriate use of skeletal muscle relaxants for the management of acute low back pain. P T. 2014 Jun;39(6):427-35. [Article]
4. Crankshaw DP, Raper C: Mephenesin, methocarbamol, chlordiazepoxide and diazepam: actions on spinal reflexes and ventral root potentials. Br J Pharmacol. 1970 Jan;38(1):148-56. doi: 10.1111/j.1476-5381.1970.tb10343.x. [Article]
5. Muir WW 3rd, Sams RA, Ashcraft S: The pharmacology and pharmacokinetics of high-dose methocarbamol in horses. Equine Vet J Suppl. 1992 Feb;(11):41-4. [Article]
6. Authors unspecified: Methocarbamol-A New Lissive Agent. Can Med Assoc J. 1958 Dec 15;79(12):1008-9. [Article]
7. O’DOHERTY DS, SHIELDS CD: Methocarbamol; new agent in treatment of neurological and neuromuscular diseases. J Am Med Assoc. 1958 May 10;167(2):160-3. [Article]
8. FDA Approved Drug Products: Robaxin [Link]
9. FDA Approved Drug Products: Robaxin Intramuscular Injection [Link]
10. Pfizer Canada: Robax [Link]

////////////////Methocarbamol, метокарбамол , ميثوكاربامول , 美索巴莫, AHS 85, Muscle Relaxant

COC1=C(OCC(O)COC(N)=O)C=CC=C1

NEW DRUG APPROVALS

ONE TIME

$10.00

Click here to purchase.

SEVELAMER

2-(chloromethyl)oxirane;prop-2-en-1-amine

CAS 52757-95-6, Molecular Formula, (C3-H7-N.C3-H5-Cl-O)x, Molecular Weight, 149.6198, HSDB 7608

Sevelamer hydrochloride [USAN]
152751-57-0, (C3-H7-N.C3-H5-Cl-O.Cl-H)x-, 186.0807, GT 16-026A

• A crosslinked polymeric amine that binds PHOSPHATES and BILE ACIDS; it is nonabsorbed; used for hyperphosphatemia during HEMODIALYSIS and in END-STAGE RENAL DISEASE; used like calcium acetate.

Sevelamer carbonate [USAN]
845273-93-0, (C3-H7-N.C3-H5-Cl-O)x-.x-C-H2-O3, 211.6436, GT335-012

• A polymeric amine that binds phosphate and is used to treat HYPERPHOSPHATEMIA in patients with kidney disease.

Drug Name：Sevelamer Carbonate,

Trade Name：Renvela^®

MOA：Phosphate binder

Indication：Hyperphosphatemia

Company：Genzyme (Originator)

Sales：$1,037.9 Million (Y2015); 
$902.9 Million (Y2014);
$997.5 Million (Y2013);
$842.4 Million (Y2012);
$581 Million (Y2011);ATC Code：

Sevelamer Carbonate was first approved by the U.S. Food and Drug Administration (FDA) on Jul 19, 2007, then approved by European Medicine Agency (EMA) on Jun 21, 2009. However, till 2013, China Food and Drug Administration approved this drug. It was developed by Genzyme, and the trade name is Renvela^®. On the other hand, US FDA firstly approved Sevelamer HCl (Renagel^®) on Oct 30, 1998.

Renvela^® is a non-absorbed phosphate binding crosslinked polymer, containing multiple amines separated by one carbon from the polymer backbone. These amines exist in a protonated form in the intestine and interact with phosphate molecules through ionic and hydrogen bonding. By binding phosphate in the gastrointestinal tract and decreasing absorption, sevelamer carbonate lowers the phosphate concentration in the serum (serum phosphorus).

Renvela^® is available as film-coated tablet for oral use, containing 800 mg of free sevelamer carbonate on an anhydrous basis. The initial dose is 0.8 or 1.6 grams orally three times per day with meals.SevelamerCAS Registry Number: 52757-95-6 
CAS Name: 2-Propen-1-amine polymer with (chloromethyl)oxirane 
Additional Names: allylamine polymer with 1-chloro-2,3-epoxypropane; allylamine-epichlorohydrin copolymer; poly(allylamin-co-N,N¢-diallyl-1,3-diamino-2-hydroxypropane) 
Literature References: Polymeric non-absorbed phosphate binder consisting of polyallylamine crosslinked with epichlorohydrin to form a hydrogel where 40% of the amines are protonated. Follows the general formula of (C3H7N.C3H5ClO)n. Binds dietary phosphate leading to increased fecal excretion, decreased absorption and decreased serum phosphorous levels. Prepd not claimed: S. R. Holmes-Farley et al.,WO9505184; eidem,US5496545 (1995, 1996 both to GelTex). Mechanism of action: S. R. Holmes-Farley et al.,J. Macromol. Sci. Pure Appl. Chem.A36, 1085 (1999). Determn of phosphate binding capacity: J. R. Mazzeo et al.,J. Pharm. Biomed. Anal.19, 911 (1999). Clinical studies in end stage renal disease: E. A. Slatopolsky et al.,Kidney Int.55, 299 (1999). 
Derivative Type: Hydrochloride 
CAS Registry Number: 152751-57-0 
Manufacturers’ Codes: PB-94; GT16-026A 
Trademarks: Renagel (Genzyme) 
Properties: Insol in water. Hydrophilic. 
Therap-Cat: Antihyperphosphatemic. 
Keywords: Antihyperphosphatemic.

Sevelamer (rINN) is a phosphate binding medication used to treat hyperphosphatemia in patients with chronic kidney disease. When taken with meals, it binds to dietary phosphate and prevents its absorption. Sevelamer was invented and developed by GelTex Pharmaceuticals. Sevelamer is marketed by Sanofi under the brand names Renagel (sevelamer hydrochloride) and Renvela (sevelamer carbonate).

Chemistry and pharmacology

Sevelamer consists of polyallylamine that is crosslinked with epichlorohydrin.^[1] The marketed form sevelamer hydrochloride is a partial hydrochloride salt being present as approximately 40% amine hydrochloride and 60% sevelamer base. The amine groups of sevelamer become partially protonated in the intestine and interact with phosphate ions through ionic and hydrogen bonding.

Medical uses

Sevelamer is used in the management of hyperphosphatemia in adult patients with stage 4 and 5 chronic kidney disease (CKD) on hemodialysis. Its efficacy at lowering phosphate levels is similar to that of calcium acetate, but without the accompanying risk of hypercalcemia and arterial calcification.^[2][3] In patients with CKD, it has also been shown to reduce triglycerides and LDL, and increase HDL.^[4]

This is a phosphate binder.

Contraindications

Sevelamer therapy is contraindicated in hypophosphatemia or bowel obstruction. In hypophosphatemia, sevelamer could exacerbate the condition by further lowering phosphate levels in the blood, which could be fatal.^[5]

Adverse effects

Common adverse drug reactions (ADRs) associated with the use of sevelamer include: hypotension, hypertension, nausea and vomiting, dyspepsia, diarrhea, flatulence, and/or constipation.

Other effects

Sevelamer can significantly reduce serum uric acid.^[6] This reduction has no known detrimental effect and several beneficial effects, including reducing hyperuricemia, uric acid nephrolithiasis, and gout.

Sevelamer is able to sequester advanced glycation end products (AGEs) in the gut, preventing their absorption into the blood. AGEs contribute to oxidative stress, which can damage cells (like beta cells, which produce insulin in the pancreas). As Vlassara and Uribarri explain in a 2014 review on AGEs, this may explain why sevelamer, but not calcium carbonate (a phosphate binder that does not sequester AGEs), has been shown to lower AGEs in the blood, as well as oxidative stress and inflammatory markers.^[7]

SYN

https://www.oatext.com/polymer-and-heterocyclic-compounds-their-utility-and-application-as-drug.php

Sevelamer hydrochloride (Renagel VR ) was the first polymeric phosphate control and removal of excess phosphate is of benefit to patients with chronic kidney disease CKD where dialysis is unable to maintain safe phosphorus levels. Sevelamer limits the absorption of dietary phosphorus by binding phosphate in the intestine through ionic interaction with the polyamine polymer. Sevelamer is across linked form of poly(allylamine) containing primary and secondary aliphatic amine residues and was approved for the treatment of hyperphosphatemia by the FDA in 1998.The following Scheme 5 shows the synthetic lines for Sevelamer hydrochloride.

Scheme 5. Represent the formation of poly allylamine as a residue of sevelamer structure

Synthesis of Sevelamer Hydrochloride. Approximately 40 percent of the amine moieties are in the HCl form. Crosslinking degree is 10%.

SYN

• The synthesis of Sevelamer consists of crosslinkung poly(allylamine hydrochloride) with epichlorohydrin. The product is washed, dried and ground to the desired particle size to give the active substance.

SynRoute 1

Reference：1. US2009155368A1.Route 2

Reference：1. WO2011099038A2.

2. CN103159880A.Route 3

Reference：1. WO2010146603A1.Route 4

Reference：1. CN102796262A.

SYN

https://patents.google.com/patent/US20100331516A1/en

• The present invention relates to the process for preparation of carbonate salt of amine polymers, preferably Poly(allylamine-co-N,N′-diallyl-1,3-diamino-2-hydroxypropane)carbonate Formula-I, an antihyperphosphatemic agent.
• a, b=number of primary amine groups a+b=9
  c=number of crosslinking groups c=1
  m=large number to indicate extended polymer network

• Sevelamer carbonate is non-absorbable polymer marketed as Renvela by Genzyme Corporation. It is known chemically as poly(allylamine-co-N,N′-diallyl-1,3-diamino-2-hydroxypropane) carbonate salt. It was developed as a pharmaceutical alternative to Sevelamer hydrochloride (Renagel®). Renvela contains Sevelamer carbonate, a non-absorbed phosphate binding crosslinked polymer, free of metal and calcium. It contains multiple amines separated by one carbon from the polymer backbone. These amines exist in a protonated form in the intestine and interact with phosphate molecules through ionic and hydrogen bonding. By binding phosphate in the dietary tract and decreasing absorption, Sevelamer carbonate lowers the phosphate concentration in the serum.
• [0004]
  Sevelamer carbonate is an anion exchange resin with the same polymeric structure as Sevelamer hydrochloride in which carbonate replaces chloride as the counterion. While the counterions differ for the two salts, the polymer itself, the active moiety, is the same. The protonated amines can be indirectly measured as carbonate content in meq/gm. Renvela is used in End Stage Renal Disease (ESRD) which leads to hyperphosphatemia due to retention of phosphorous. This condition can lead to ectopic calcification. Renvela binds dietary phosphate in GI tract and thus controls the serum phosphate levels. The potency of Renvela is measured in terms of its Phosphate Binding Capacity (PBC) by Phosphate Assay (PA). Treatment of hyperphosphatemia includes reduction in dietary intake of phosphate, inhibition of intestinal phosphate absorption with phosphate binders, and removal of phosphate with dialysis. Sevelamer carbonate taken with meals has been shown to control serum phosphorus concentrations in patients with CKD who are on dialysis. Currently Sevelamer hydrochloride is used to cure hyperphosphatemia. As a consequence ESRD patients still need a high dosage of Renagel® to meet clinical end-points, leading to adverse effect such as gastrointestinal discomfort and problems with patient compliance. But systemic acidosis development or worsening of pre-existing acidosis has been reported in many patients on long term dialysis who are given Sevelamer hydrochloride (Perit Dial Int. 2002, 22, 737-738, Nephron 2002, 92, 499-500, Kidney Int. 2004, 66, S39-S45, Ren. Fail 2005, 27,143-147).
• [0005]
  Administration of Sevelamer hydrochloride adds to metabolic acid load because the resin removes some bicarbonate or bicarbonate precursor (mainly short chain fatty acid anions) from the body and replaces it with chloride. Each molecule of chloride contributed to the body in exchange for carbonate or bicarbonate precussor is equivalent to a molecule of hydrochloric acid added to the body, so the tendency of patients on long term haemodialysis to acidosis is inevitably increased when they take Sevelamer hydrochloride. (Kidney Int., 2005; 67: 776-777)
• [0006]
  This problem can be countered by an increase in the dialysate concentration of bicarbonate used in each dialysis session. A more fundamental solution, suitable for both dialyzed and non-dialyzed patients, would be the administration of Sevelamer free base, or any other suitable resin, not as the chloride but as body suitable counterion such as bicarbonate. Anion exchange resins have traditionally been synthesized in the chloride form, but the chloride in the current Sevelamer preparation is of no benefit to patients with renal failure. A change in the formulation of Sevelamer from its current chloride form to Sevelamer attached to bicarbonate would convert an acid load into a mild alkali load. (Cli. Sci. 1963; 24:187-200)
• [0007]
  U.S. Pat. No. 6,858,203 relates to phosphate-binding polymers provided for removing phosphate from the gastrointestinal tract. These polymers are useful for the treatment of hyperphosphatemia.
• [0008]
  WO 2006/050315 describes pharmaceutical compositions comprising a carbonate salt of an aliphatic amine polymer wherein the monovalent anion can prevent or ameliorate acidosis, in particular acidosis in patients with renal disease.
• [0009]
  HPLC Ion Chromatography PA method is used for the determination of PBC of Sevelamer HCl which can be adopted for determining the carbonate content from Sevelamer carbonate (J R Mazzeo et al, J. Pharm. Biomed. Anal. 19 (1999) 911-915).
• [0010]
  Our co-pending application number 1402/MUM/2006 dated 1 Sep. 2006 discloses process for preparation of Sevelamer HCl having phosphate binding capacity in the range of about 5.0 meq/gm to about 6.0 meq/gm and chloride content in the range of about 3.74 to about 5.60 meq/gm.
• [0011]
  The prior art mentioned above discussed advantages of Sevelamer carbonate over Sevelamer hydrochloride thus there remains need for commercially viable and industrially useful process for the preparation of Sevelamer carbonate having consistency in phosphate binding capacity, degree of cross linking, chloride content and carbonate content.

• The reaction is represented by the following reaction scheme:
•  
• [0078]
  100 gm Sevelamer hydrochloride was dispersed in 500 ml purified water and sodium hydroxide solution [20 gm sodium hydroxide dissolved in 500 ml purified water] was added to the obtained suspension followed by stirring at 25-35° C. for 30 minutes. The obtained material was filtered and wet cake was stirred in 1.0 L purified water for an hour. The material was filtered and cake was washed twice. Wet cake was dried at 50-90° C. for 5-6 hrs to get Sevelamer base (70 gm). LOD: 0.4% Chloride content: Nil.

Example 2

• [0079]
  10 gm Sevelamer was suspended in 200 ml water and stirred. Carbon dioxide gas was purged into the obtained suspension at 25-35° C. for 8 hrs using dry ice. The obtained material was filtered and washed with 100 ml water [3×100] and the wet cake was dried on rotavapor at 90-95° C. to get Sevelamer carbonate (11.5 gm). Yield—115% w/w [Chloride content: 0.3%, Phosphate binding: 5.75 mMole/g, Carbonate content: 4.78 meq/g and Degree of crosslinking—16.4%], Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.

Example 3

• [0080]
  10 gm Sevelamer was added to 200 ml water and reacted with carbon dioxide gas under pressure at 25-35° C. for 7-8 hrs with stirring. The obtained material was filtered and washed with 100 ml water thrice [3×100]. The wet cake thus obtained was dried on rotavapor at 90-95° C. to get Sevelamer carbonate (11.3 gm). Yield—113% w/w Degree of crosslinking—16.4%, Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.

Example 4

• [0081]
  Sevelamer (7 gm) was added to 150 ml water and reacted with carbon dioxide gas under pressure at 60-65° C. for 7-8 hrs with stirring. The material obtained was filtered and washed with 100 ml purified water thrice [3×100]. The wet cake thus obtained was dried on rotavapor at 90-95° C. to get Sevelamer carbonate (9.3 gm).
• [0082]
  Yield—120% w/w Degree of crosslinking—16.4%, Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.

Example 5

• [0083]
  Sevelamer (7 gm) was added to 150 ml water and reacted with carbon dioxide gas by purging under pressure at 60-65° C. for 7-8 hrs with stirring. The material obtained was filtered and washed with 100 ml purified water thrice [3×100]. The wet cake thus obtained was dried on rotavapor at 90-95° C. to get Sevelamer carbonate (9.0 gm).
• [0084]
  [Degree of crosslinking—16.4%, Chloride content: 0.5%, Phosphate binding: 5.56 mMole/g and Carbonate content: 4.46 meq/g] Yield—110% w/w Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.

Example 6

• [0085]
  Sevelamer hydrochloride (10 gm) was treated Sodium hydroxide solution (2M) for 1 hr at temperature 25 to 35° C. to get Sevelamer base. Filter the free base and was added to 150 ml water and reacted with carbon dioxide gas by purging under pressure at 60-65° C. for 7-8 hrs with stirring. The material obtained was filtered and washed with 100 ml purified water thrice [3×100]. The wet cake thus obtained was dried on rotavapor under vacuum at 90-95° C. to get Sevelamer carbonate (9.3 gm). Yield—120% w/w.
• [0086]
  [Degree of crosslinking—16.4%, Chloride content: 0.2%, Phosphate binding: 5.45 mMole/g and Carbonate content: 4.36 meq/g].
• [0087]
  Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.

Example 7

• [0088]
  Sevelamer hydrochloride (10 gm) was treated sodium hydroxide solution (2M) for 1 hr at temperature 25 to 35° C. to get Sevelamer base. Filter the free base and was added to 100 ml water. Sodium bicarbonate (10 gm dissolved in 1000 ml purified water) solution was added at temperature 60-65° C. for 4 hrs with stirring. Sevelamer Carbonate thus obtained was filtered and again subjected to for treatment of sodium bicarbonate solution (10 gm in 1000 ml). Reaction mixture was heated for 4 hrs at 60-65° C. with stirring. The material obtained was filtered and washed with 100 ml purified water thrice [3×100]. The wet cake thus obtained was dried under vacuum tray dryer at 80-90° C. for 24 hrs and further dried in atmospheric tray dryer at 100° C. for 36 hrs to get Sevelamer carbonate (9.0 gm). The loss of drying of material was about 5-7% achieved as per requirement. Yield—120% w/w, [Degree of crosslinking—16.4%, Chloride content: 0.01%, Phosphate binding: 5.68 mMole/g and Carbonate content: 4.85 meq/g]

Example 8

• [0089]
  Sodium hydroxide pellets (41 gm) is dissolved in 600 ml methanol at 25-35° C. and polyallylamine hydrochloride (100 gm) is added to it followed by stirring for 5-6 hrs at temperature 25-35° C. The obtained reaction mass is filtered through hyflobed and filtrate is concentrated to reduce to half volume and the separated inorganic salt is filtered off over hyflobed. The obtained filtrate is concentrated completely under vacuum to get sticky mass (61 gm) of polyallylamine. Yield—61% w/w

Example 9

• [0090]
  Polyallylamine (27.5 gm) dissolved in 100 ml water is charged into 1 L SS 316 autoclave and interacted with carbon dioxide gas under pressure (5.0 Kg/cm²). Initially 2-3 Kg/cm2 gas is consumed by the reaction mass and exotherm is observed from 28 C to 35° C. Then 5 Kg/cm² pressure is maintained for 5-6 hours. After completion of the reaction the reaction mass is slowly added to 700 methanol and stirred for 3-4 hours. The separated solid (31 gm) is filtered, washed with 50 ml methanol and dried at 40-50° C. in vacuum oven. Yield—112% w/w

Example 10

• [0091]
  Polyallylamine carbonate (20 gm) is dissolved in 30 ml water and cooled at 5-15° C. under stirring. The aqueous sodium hydroxide solution [dissolving 4.23 gm sodium hydroxide pellets into 4.2 ml of water] is added to reaction mass dropwise at 10-15° C. with continued stirring for 30 minutes. 101 ml toluene and 0.6 ml SPAN-85 is added to it and heated at 55-60° C. Epichlorohydrin (1.06 gm) is added to the reaction mass followed by stirring and heating for 3 hrs. The reaction mass is cooled at 25-35° C. and filtered through Buchner funnel. The obtained wet cake is added to 1 L acetone followed by stirring for 1 hour to get solid which was filtered through Buchner funnel. The aqueous organic washings are repeated for 7-10 times till polymer is free from excess alkalinity and the obtained wet cake is dried at 40-50° C. on rotavapor and then at 90-95° C. till constant weight of polymer is obtained (9 gm). Yield—45% w/w, Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.

Example 11

• [0092]
  Polyallylamine carbonate (20 gm) is dissolved in 30 ml water and cooled at 5-15° C. under stirring. The aqueous sodium hydroxide solution [dissolving 4.23 gm sodium hydroxide pellets into 4.2 ml of purified water] is added to obtained reaction mass dropwise at 10-15° C. with continued stirring for 30 minutes. 150 ml water and 0.6 ml SPAN-85 is added to it and heated at 60-80° C. Epichlorohydrin (1.06 gm) is added followed by stirring and heating is continued for 3 hours. The reaction mass is cooled at 25-35° C. and filtered through Buchner funnel. The obtained wet cake is added to 1 L acetone followed by stirring for 1 hour to get solid which is filtered through Buchner funnel. This aqueous organic washings are repeated for 7-10 times till the polymer is free from excess alkalinity and the obtained material is dried at 40-50° C. on rotavapor and/or Fluidised bed dryer then at 90-95° C. till constant weight of polymer is obtained (9 gm).

Example 12

• [0093]
  Polyallylamine carbonate (20 gm) is dissolved in 30 ml water and cooled at 5-15° C. under stirring. The aqueous sodium hydroxide solution [dissolving 4.23 gm sodium hydroxide pellets into 4.2 ml of purified water] is added to the obtained reaction mass dropwise at 10-15° C. with continued stirring for 30 minutes. 150 ml water and 0.6 ml SPAN-85 is added to it and heated at 60-80° C. Epichlorohydrin (1.06 gm) is added followed by stirring and heating is continued for 3 hours. The reaction mass is cooled at 25-35° C. and filtered through Buchner funnel. The obtained wet cake is added to 1 L isopropyl alcohol (IPA) followed by stirring for 1 hour to get solid which is filtered through Buchner funnel. The obtained material is washed with water and organic solvents for 4-5 times till the polymer is free from excess alkalinity. The obtained wet cake is dried under vacuum tray dryer at 80-90° C. for 24 hrs and further dried in atmospheric tray dryer at 100° C. for 36 hrs till constant weight of dried polymer is obtained (15 gm). The loss on drying of material is around 6% as per requirement.

Example 13

• [0094]
  In 1 L SS 316 autoclave, 75 gm allylamine and 200 ml water is charged and carbon dioxide gas under pressure (5 Kg/cm2) is purged into autoclave for 3-4 hours followed by stirring. Nitrogen gas is purged for 15 minutes. 9.8 gm VA-086 is added to the reaction mass and stirred at 70-80° C. for 12 hours and this solution is added to 1 L methanol under stirring. The separated material is filtered and washed with 100 ml methanol, suck dried and dried in vacuum oven at 50-60° C. to get 90 gm of polyallylamine carbonate. Yield—120% w/w

Example 14

• [0095]
  Polyallylamine carbonate (20 gm) dissolved in 30 ml water is cooled at 5-15° C. under stirring and sodium hydroxide solution [dissolving 4.23 gm sodium hydroxide pellets into 4.2 ml of purified water] is added to the obtained reaction mass dropwise at 10-15° C. followed by continued stirring for 30 minutes. 101 ml toluene and 0.6 ml SPAN-85 is added to it and heated at 55-60° C. Epichlorohydrin (1.06 gm) is added and reaction mass is stirred and heated for 3 hours. Then it is cooled to 25-35° C. and filtered through Buchner funnel. The wet cake obtained is added to 1 to 1.5 L acetone followed by stirring for 1 hour to get solid which is filtered through Buchner funnel. The washings are repeated for 7-10 times till polymer is free from excess alkalinity. Wet cake (9 gm) is dried at 40-50° C. on rotavapor and then at 90-95° C. till constant weight of polymer is obtained. Yield—45% w/w

Example 15

• [0096]
  Sevelamer hydrochloride (10 gm) was added to 10% aqueous sodium bicarbonate solution at 25-35° C. and stirred for 7-8 hrs. The material obtained was filtered and washed with 100 ml purified water thrice and the wet cake was dried on rotavapor at 90-95° C. to get Sevelamer carbonate (7.5 gm). Yield—75% w/w
• [0097]
  Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.
• [0098]
  [Chloride content: 0.4%, Phosphate binding: 5.45 mMole/g and Carbonate content: 4.85 meq/g]

Example 16

• [0099]
  Sevelamer hydrochloride (10 gm) was added to 10% aqueous sodium bicarbonate solution. The mixture was stirred at 60-65° C. for 4 hrs. The material obtained was filtered and the obtained wet cake was again subjected to the treatment of 10% sodium bicarbonate solution. Reaction mixture was heated for 4 hrs at 60-65° C. with stirring. The material obtained was filtered and washed with 100 ml purified water four times and the wet cake was dried on rotavapor under vacuum at 90-95° C. to get Sevelamer carbonate (7.5 gm). Yield—75% w/w, Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate, [Chloride content: 0.03%, Phosphate binding: 5.25 mMole/g and Carbonate content: 4.65 meq/g].

Example 17

• [0100]
  Sevelamer hydrochloride (10 gm) was added into 130 ml solution of sodium bicarbonate (10 gm NaHCO3 in 130 ml water) and the mixture was stirred at 60-65° C. for 4 hrs. The material was filtered using Buckner funnel assembly. The obtained wet cake was added into 130 ml solution of sodium bicarbonate (10 gm NaHCO3 in 130 ml water) and stirred at 60-65° C. for 4 hrs. The material was filtered using Buckner funnel assembly and the wet cake was washed by stirring it in 100 ml water for 1 hr at 60-65° C. The material was filtered using Buckner funnel assembly. The wet cake was washed twice at 60-65° C. and dried on rotavapor at 90-95° C. to get Sevelamer carbonate (8.5 gm). Yield—75% w/w, Chloride content: 0.03%

Example 18

• [0101]
  Sevelamer hydrochloride (1.1 Kg) was added into 15.5 L solution of sodium bicarbonate (1.1 Kg NaHCO₃ in 14.3 L water). The obtained mixture was stirred at 60-65° C. for 4 hrs. The obtained material was filtered by centrifuge filter. The obtained wet cake was added into 15.5 L solution of sodium bicarbonate (1.1 Kg NaHCO₃ in 14.3 L water) and maintained stirring at 60-65° C. for 4 hrs. The material was filtered by centrifuge filter assembly and obtained wet cake was stirred in 11 L water for 1 hr at 60-65° C. The material was filtered by centrifuge filter and the washing of wet cake was repeated at 60-65° C. for two more times. The obtained wet cake was dried in air tray dryer (ATD) at 90-100° C. for 30-36 hrs and LOD was checked after every five hours till LOD was in the range of 5 to 10%. to get Sevelamer carbonate (0.995 Kg), [Chloride content: 0.03%, Phosphate binding capacity: 5.5 mmole/gm, Carbonate content: 5.1 meq/gm]

Example 19

• [0102]
  Sevelamer hydrochloride (10 gm) was added to sodium bicarbonate solution (10 gm in 200 ml) at 25-35° C. The reaction mixture was heated for 4 hrs at 60-65° C. with stirring. Sevelamer Carbonate thus obtained was filtered and again subjected to treatment of Sodium bicarbonate solution (10 gm in 200 ml). Reaction mixture was heated for 4 hrs at 60-65° C. with stirring. The material was filtered off and washed with 100 ml purified water four times (4×100 ml) and the wet cake was dried under vacuum tray dryer at 80-90° C. for 24 hrs and further dried in atmospheric tray dryer at 100° C. for 36 hrs till constant weight of dried polymer was obtained. The loss on drying of material was around 6% (Limit: 4-10%), achieved as per requirement. Sevelamer carbonate (7.5 gm) was obtained which can be sieved through 30 mesh for uniformity of the sample. Yield—75% w/w. Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate. [Chloride content: 0.02%, Phosphate binding: 5.56 mMole/g and Carbonate content: 4.74 meq/g].

Example 20

• [0103]
  10 g wet cake of Sevelamer carbonate was subjected to drying in air tray dryer at 80-100° C. at atmospheric pressure for 36 hours and LOD was measured after every five hours. LOD: 7.5% Yield: 3.1 gm

Example 21

• [0104]
  100 g wet cake of Sevelamer carbonate was subjected to drying in air tray dryer at 80-100° C. at atmospheric pressure for 37 hours and LOD was measured. LOD: 8.4% Yield: 30 gm

Example 22

• [0105]
  10 g wet cake of Sevelamer carbonate was subjected to drying in vacuum tray dryer at 50-100° C. at reduced pressure for 24 hours and LOD was measured. LOD: 8.5% Yield: 3.2 gm

Example 23

• [0106]
  100 g wet cake of Sevelamer carbonate was subjected to drying in vacuum tray dryer at 50-100° C. at reduced pressure for 24 hours and LOD was measured. LOD: 8.9% Yield: 31 gm

Example 24

• [0107]
  10 Kg wet cake of Sevelamer carbonate was subjected to drying in fluidized bed dryer at 80-100° C. for 16 hours and LOD was measured after every five hours. LOD: 7.9% Yield: 3.4 kg

Example 25

• [0108]
  15 Kg wet cake of Sevelamer carbonate was subjected to drying in fluidised bed dryer at 80-110° C. for 16 hours and LOD was measured. LOD: 8.8% Yield: 4.9 kg.

Example 26

• [0109]
  10 g wet cake of Sevelamer carbonate was subjected to drying in rotary evaporator at 50-100° C. at reduced pressure for 16 hours and LOD was measured after every five hours.
• [0110]
  LOD: 9.1% Yield: 3.1 gm

Example 27

• [0111]
  100 g wet cake of polyallylamine carbonate is subjected to drying in rotary evaporator at 50-100° C. at reduced pressure for 16 hours and LOD is measured. LOD: 8.9% Yield: 33 gm.

SYN

https://patents.google.com/patent/CN102675510A/enHyperphosphatemia is a kind of patient’s disease on one’s body that often appears at renal tubal dysfunction, hypothyroidism, acute acromegaly or phosphoric acid salt drug overdose; Its treatment is normal adopts the pharmacotherapy of regimen or oral phosphorus adsorbent to carry out; But it has been generally acknowledged that the regimen effect is relatively poor, the use of phosphorus adsorbent is essential.In recent years; Discover that the compound that contains the polyallylamine structure has good phosphorus adsorptive power (as: USP 5496545,20040191212, Chinese patent 95193521.6 etc.), crosslinked polyallylamine class medicine is evident in efficacy especially; Wherein, SEVELAMER (Sevelamer) is because of its good clinical manifestation, and granted listing is used to treat hyperphosphatemia.The structural formula of SEVELAMER is following: 
Synthesizing of crosslinked polyallylamine class medicine SEVELAMER (Sevelamer); Be to react by polyallylamine hydrochloride and linking agent; Different because of used linking agent, the phosphorus adsorptive power of product has than big-difference, and the most option table chloropharin of the present document of reporting is a linking agent.For example: in USP 5496545; Introduced the synthetic of a series of crosslinked allyl amine polymers oral, that the phosphorus adsorptive power is arranged, listed linking agent has: Epicholorohydrin, 1,4-butanediol diglycidyl ether, 1; 2-ethylene glycol bisthioglycolate glycidyl ether, 1; 3-propylene dichloride, 1,2-ethylene dichloride, 1,3-dibromopropane, 1; 2-ethylene dibromide, succinyl dichloride, dimethyl succinate salt, TDI, acrylate chloride and pyromellitic dianhydride, preferred cross-linking agents is an Epicholorohydrin.U.S. Pat 5496545 described SEVELAMER building-up processes are: in the alkaline aqueous solution, polyallylamine hydrochloride and Epicholorohydrin carry out crosslinking reaction under room temperature, react agglutination thing after 18 hours; Pour into and make its curing in the Virahol; Filter, repeatedly washing back redispersion is in water, after the filtration; Be scattered in a large amount of Virahols, obtain product through filtration, drying.The required reaction times of this technology is longer, and multiple times of filtration and washing in the operating process need be used a large amount of organic solvents, and in the series product, the highest phosphorus adsorptive power is 3.1mmol/g.Embodiment 1: sevelamer hydrochloride syntheticIn the 500mL flask; Add 46.2g (0.374mol) PAH hydrochloride, the 108.0mL deionized water dissolving adds sodium hydroxide and regulates pH=10-11; Drip the toluene solution of 11.0g (0.042mol) 1-chloro-3-p-toluenesulfonyl-2-propyl alcohol, heat up in 70-75 ℃ of reaction 4 hours.Reaction finishes, and adds hydrochloric acid and regulates pH=1-2, filters, and obtains the sevelamer hydrochloride bullion.The sevelamer hydrochloride bullion is scattered in the 300.0mL deionized water, and hydro-oxidation sodium is regulated pH=10.0-11.0, filters; Deionized water wash; The gained white solid through pulverizing, gets product sevelamer hydrochloride 38.8g again 70 ℃ of vacuum-dryings 8 hours; The phosphorus adsorptive value is 5.5mmol/g, and chloride ion content is 16.5%.Embodiment 2: carbonic acid SEVELAMER syntheticIn the 500mL flask; Add 150.0g (0.404mol; Weight concentration is 30%) the PAH hydrochloride aqueous solution; Add sodium hydroxide and regulate pH=10-11, drip the acetonitrile solution of 13.0g (0.042mol) 1-bromo-3-p-toluenesulfonyl-2-propyl alcohol, heat up in 70-75 ℃ of reaction 4 hours.Reaction finishes, and adds hydrochloric acid and regulates pH=1-2, filters, and obtains the sevelamer hydrochloride bullion.The sevelamer hydrochloride bullion is scattered in the 300.0mL deionized water, adds yellow soda ash and regulate pH=8.5-9.5, filter; Deionized water wash, gained white solid are 70 ℃ of vacuum-dryings 8 hours, again through pulverizing; Get product carbonic acid SEVELAMER 36.4g, the phosphorus adsorptive value is 5.4mmol/g.Embodiment 3: carbonic acid SEVELAMER syntheticIn the 500mL flask; Add 46.2g (0.374mol) PAH hydrochloride, the 108.0mL deionized water dissolving adds sodium hydroxide and regulates pH=10-11; Drip the toluene solution of 7.9g (0.042mol) 1-chloro-3-methylsulfonyl-2-propyl alcohol, heat up in 70-75 ℃ of reaction 4 hours.Reaction finishes, and adds hydrochloric acid and regulates pH=1-2, filters, and obtains the sevelamer hydrochloride bullion.The sevelamer hydrochloride bullion is scattered in the 300.0mL deionized water, and hydro-oxidation sodium is regulated pH=12.0-12.5, feeds dioxide gas to saturated; Filter; Deionized water wash, gained white solid are 70 ℃ of vacuum-dryings 8 hours, again through pulverizing; Get product carbonic acid SEVELAMER 40.5g, the phosphorus adsorptive value is 5.0mmol/g.

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References

1. ^ Ramsdell R (June 1999). “Renagel: a new and different phosphate binder”. review. ANNA Journal. 26 (3): 346–7. PMID 10633608.
2. ^ Burke SK (September 2000). “Renagel: reducing serum phosphorus in haemodialysis patients”. review. Hospital Medicine. 61 (9): 622–7. doi:10.12968/hosp.2000.61.9.1419. PMID 11048603.
3. ^ Habbous S, Przech S, Acedillo R, Sarma S, Garg AX, Martin J (January 2017). “The efficacy and safety of sevelamer and lanthanum versus calcium-containing and iron-based binders in treating hyperphosphatemia in patients with chronic kidney disease: a systematic review and meta-analysis”. review. Nephrology, Dialysis, Transplantation. 32 (1): 111–125. doi:10.1093/ndt/gfw312. PMID 27651467.
4. ^ Patel L, Bernard LM, Elder GJ (February 2016). “Sevelamer Versus Calcium-Based Binders for Treatment of Hyperphosphatemia in CKD: A Meta-Analysis of Randomized Controlled Trials”. review. Clinical Journal of the American Society of Nephrology. 11 (2): 232–44. doi:10.2215/CJN.06800615. PMC 4741042. PMID 26668024.
5. ^ Emmett M (September 2004). “A comparison of clinically useful phosphorus binders for patients with chronic kidney failure”. review. Kidney International Supplements. 66 (90): S25–32. doi:10.1111/j.1523-1755.2004.09005.x. PMID 15296504.
6. ^ Locatelli F, Del Vecchio L (May 2015). “Cardiovascular mortality in chronic kidney disease patients: potential mechanisms and possibilities of inhibition by resin-based phosphate binders”. review. Expert Review of Cardiovascular Therapy. 13 (5): 489–99. doi:10.1586/14779072.2015.1029456. PMID 25804298. S2CID 32586527.
7. ^ Vlassara H, Uribarri J (January 2014). “Advanced glycation end products (AGE) and diabetes: cause, effect, or both?”. review. Current Diabetes Reports. 14 (1): 453. doi:10.1007/s11892-013-0453-1. PMC 3903318. PMID 24292971.

External links

• “Sevelamer”. Drug Information Portal. U.S. National Library of Medicine.
• “Sevelamer hydrochloride”. Drug Information Portal. U.S. National Library of Medicine.
• “Sevelamer carbonate”. Drug Information Portal. U.S. National Library of Medicine.

//////////////////////SEVELAMER, HSDB 7608, GT335-012, GT 16-026A, PB 94, Antihyperphosphatemic

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Clobetasol propionate

• Molecular FormulaC₂₅H₃₂ClFO₅
• Average mass466.970 Da

CCI 4725, CCI-4725, GR 2/925, GR-2/925,(8S,9R,10S,11S,13S,14S,16S,17R)-17-(chloroacetyl)-9-fluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl propanoate
246-634-3[EINECS], 25122-46-7[RN]
(11β,16β)-21-chloro-9-fluoro-11-hydroxy-16-methyl-3,20-dioxopregna-1,4-dien-17-yl propanoate

Active Moieties

Clobetasol 
CAS Registry Number: 25122-41-2 
CAS Name: (11b,16b)-21-Chloro-9-fluoro-11,17-dihydroxy-16-methylpregna-1,4-diene-3,20-dione 
Molecular Formula: C22H28ClFO4, Molecular Weight: 410.91 
Percent Composition: C 64.30%, H 6.87%, Cl 8.63%, F 4.62%, O 15.57% 
Literature References: Topical corticosteroid. Prepn: Elks et al.,DE1902340; eidem,US3721687 (1969, 1973 both to Glaxo). Review of pharmacology and clinical efficacy in skin disorders: E. A. Olsen, R. C. Cornell, J. Am. Acad. Dermatol.15, 246-255 (1986). 
Derivative Type: 17-Propionate 
CAS Registry Number: 25122-46-7 
Manufacturers’ Codes: GR-2/925 
Trademarks: Clobesol (GSK); Dermovate (GSK); Olux (Connetics); Psorex (GSK); Temovate (GSK) 
Molecular Formula: C25H32ClFO5 
Molecular Weight: 466.97 
Percent Composition: C 64.30%, H 6.91%, Cl 7.59%, F 4.07%, O 17.13% 
Properties: White or almost white colorless, crystalline powder, mp 195.5-197°. [a]D +103.8° (c = 1.04 in dioxane). uv max (ethanol): 237 nm (e 15000). Insol in water. 
Melting point: mp 195.5-197° 
Optical Rotation: [a]D +103.8° (c = 1.04 in dioxane) 
Absorption maximum: uv max (ethanol): 237 nm (e 15000) 
Therap-Cat: Glucocorticoid; anti-inflammatory. 
Keywords: Glucocorticoid. 
Clobetasol propionate is a corticosteroid used to treat corticosteroid-responsive dermatoses and plaque psoriasis.

Clobetasol propionate is a corticosteroid used to treat skin conditions such as eczema, contact dermatitis, seborrheic dermatitis, and psoriasis.^[2] It is applied to the skin as a cream, ointment, or shampoo.^[2][3] Use should be short term and only if other weaker corticosteroids are not effective.^[3] Use is not recommended in rosacea or perioral dermatitis.^[2]

Common side effects include skin irritation, dry skin, redness, pimples, and telangiectasia.^[2] Serious side effects may include adrenal suppression, allergic reactions, cellulitis, and Cushing’s syndrome.^[2] Use in pregnancy and breastfeeding is of unclear safety.^[4] Clobetasol is believed to work by activating steroid receptors.^[2] It is a US Class I (Europe: class IV) corticosteroid, making it one of the strongest available.

Clobetasol propionate was patented in 1968 and came into medical use in 1978.^[5] It is available as a generic medication.^[3] In 2019, it was the 180th most commonly prescribed medication in the United States, with more than 3 million prescriptions.^[6][7]

SYNTHESIS OF KEY INTERMEDIATE

SYN

DE 1902340

US 3992422

DE 2613875

EP 72200

WO 2012122452

CN 112110972

PATENT

IN 201821008147

Clobetasol propionate (C25H32ClFO5); CAS Registry No.[25112-46-7]; IUPAC name: 17-(2′- Chloroacetyl)-9-fluoro-l l-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,l 1,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] propionate is a potent halogen adrenal corticosteroid of the gluco-corticoid class used to treat various skin disorders including eczema and psoriasis. It is also highly effective for contact dermatitis caused by exposure to poison ivy/oak.In the US 3721687Apatentshow use of methanesulfonyl chloride and Pyridine as base to protect alcohol and at the time of LiCI reaction results with 10-15%ene impurity and less yield.In the methanesulfonyl chloride step used with pyridine as base which is a hazardous.Mesyl compound converted to Clobetasol propionate by using LiCl in Dimethylformamide reaction at IOO-IlO0C forms 10-15% with ene impurity. The synthesis of Clobetasol propionate results in small quantities of the eneimpurity. Clobetasol propionate desired compound to be with impurities which must be minimized. Ene impurity can be reduced to very low levels by reaction itself. However, if used recrystallization reduce ene impurity it is time consuming and very expensive. Further, because recrystallizations have high losses, unacceptably low yields.

Example I: Betamethasone to betamethasone 17- propionate To a 100 ml 4-neck round bottom flask (RBF) equipped with halfmoon stirrer, thermowelland addition funnel, mounted in a tub bath, was charged betamethasone (5.0g, 0.0127mole), Dimethylformamide (20ml). Cooled the reaction mass to 10-15°C. Slowly added trimethyl ortho propionate (3.42g, 0.0255mole) and p-toluenesulfonic acid (PTSA)(0.30g, 0.00174 mole) to the reaction mass at 10-15°C. Stirred the contents 10-15°C for 4 hr. The reaction was monitored for completion by TLC. Further continued stirring at the same temperature for Ihr till reaction complies by TLC. After reaction completion, added H2SO4UP to pH=1.0-2.0 in to reaction mass.Reaction mass was quenched in Purified water (25ml) at 25-30°C. Cooled reaction mass temperature to 0-5°C. Stirred for I hr and filtered and washed with Purified water (10mlX2). Suck dried under vacuum completely to get cream coloured solid. Dried in tray drier at 50-55°C.Dry weight-5.40g(94.50%); HPLC: 98.5%;mp215-218°C. IR (KBr, on’):3454.90, 3370.99 (-OH); 1719.86, 1659.10 (C=O)iC25H33FO6;

MS 448.52m/z 449.2255 [M+H]; 1HNMR (300MHz, CDCl3S ppm): Spectrum is recorded on Varian, and Tetra Methyl Silane (TMS) as internal standard. 1H-NMR Spectrum shows Aromatic-HK-7.17-7.22(d,lH); Hj-6.37-6.38 (d,lH);Hr6.14 (s,lH); HF-4.04-4.06(s,2H);HE2.23-2.28 (q,2H);Hc-l.39-1.43 (d,3H); HB-1.14 (t,3H);HA-0.96-2.96 (m,20H). 13CMR (300MHz, CDCl3Sppm): 8.692 (CH2-CH3); 16.693; 19.664; 21.353; 23.042; 27.568; 30.387; 36.456; 43.400; 46.547; 47.422; 71.760; 93.547; 124.307; 125.728; 127.903; 129.222; 130.443; 132.472; 145.632; 153.044; 167.424; 175.031 (O-C=O); 185.772 (Cyclic C=O); 196.732 (CH-CO-CH2-OH).

Example 2: Betamethasone 17- propionateto betamethasone 21-tosylate 100ml 4-neck RBF equipped with halfmoon stirrer, thermowell, reflux condenser mountained in water bath, was charged Stage-1 (5.0g, O.Olllmole), Dimethylformamide (20ml). Added 4-Dimethylaminopyridine as base (4.10g, 0.0335mole) and p-toluenesulfonyl chloride (4.24.Og, 0.0222mole)slowly, Stirredfor2-3 hr at 25-30°C. Stirred reaction mass at 25-30°C till reaction complies by TLC.As such reaction mass used insitue for next step. Reaction mass aliquot taken (2ml) and quenched in DM water (20ml), precipited material fdtered and washed with DM water (20ml). Suck dried well. Dried in tray drier at 50-55°C to get dry white solid. Dry weight-0.598g, (89.0%); HPLC: 98.5%; mp-170-175°C (dec). IR (KBr,cm”1):3291.91, 2980.39 (-OH); 1739.15, 1661.99 (C=O); C32H39FO8S; MS 602.71mA 603.2317 [M+H]; 1HNMR (300MHz, CDCl3Sppm): Spectrum is recorded on Varian, and Tetra Methyl Silane (TMS) as internal standard. 1H-NMR Spectrum shows Aromatic-Ηκ7.17-7.22(d,lH); Hj-6.37-6.38 (d,lH);Hr6.14 (s,lH); HG-4.334-4.393 (m,lH);HF-3.846- 4.007(d,2H);HE-2.273-2.349 (q,2H);HD-l.671-1.688 (s,lH); Hc-I-306-1.331 (d,3H); Hb1.055-1.105 (t,3H);HA-0.941 -2.634 (m,18H).13CMR (300MHz, CDCl3Sppm): 9.055 (CH2- CH3); 17.244; 20.002; 21.353; 23.168; 27.901; 30.622; 33.508; 34.881; 36.783; 43.642; 46.637; 47.330; 48.113; 48.417; 66.613; 70.902; 93.801; 102.732; 124.415; 129.324; 130.443; 132.472; 145.632; 153.583; 168.042; 174.853 (O-C=O); 186.208 (Cyclic C=O); 205.491 (CH-CO-CH2-OAr).

Example 3:Betamethasone 21-tosylateto Clobetasol propionate As such reaction mass used insitue for next step. Added. lithium chloride (LiCl)1.04 gm (0.0245mole). Stirred the reaction mass at 60-65°C for 5-6 hr.Reaction completion checked by TLC.After reaction completion, Added DM water (200ml). Stirred the reaction mass at 10-15°C for Ihr and Filtered washed with DM water (30mlx2).Dried in oven at 50-55°C to get white crystalline powder. Dry weight-4.42gm, (85.0%); HPLC:99.70%;mp-158-161°C. IR (KBr, cm_1):3299.62, 2976.53 (-OH); 1734.32, (C=0);1662.95 (C=C);C25H32C1F05; MSΑβ6.9Ίτη/ζ 467 [M+H];’HNMR (300MHz, CDCl35ppm): Spectrum is recorded on Varian, and Tetra Methyl Silane (TMS) as internal standard. 1H-NMR Spectrum shows AromaticHk-7.094-7. 128(d,IH); Hj-6.267-6.307 (d,lH); Hr6.066-6.076 (s,IH); H0-4.334-4.393 (m,lH); Hf-3.846-4.007 (d,2H); HE-2.273-2.349 (q,2H); Hd-I .671-1.688 (s,lH); Hc-1.306- 1.331 (d,3H); Hb-I .055-1.105 (t,3H); HA-0.941-2.634 (m,17H).13CMR (300MHz, CDCl35ppm): 8.692 (CH2-CH3); 16.693; 19.664; 21.353; 23.042; 27.568; 30.387; 36.456; 41.104; 46.547; 47.422; 71.760; 93.547; 124.307; 125.728; 127.903; 129.222; 130.443; 132.472; 145.632; 153.044; 168.312; 173.101 (O-C=O); 185.802 (Cyclic C=O); 204.602(CH-CO-CH2-C1)