Cilastatin

シラスタチン

UNII141A6AMN38

CAS number 82009-34-5

WeightAverage: 358.453
Monoisotopic: 358.156242642

Chemical FormulaC₁₆H₂₆N₂O₅S

• (L)-7-(2-Amino-2-carboxy-ethylsulfanyl)-2-[(2,2-dimethyl-cyclopropanecarbonyl)-amino]-hept-2-enoic acid
• (Z)-(S)-6-carboxy-6-[(S)-2,2-dimethylcyclopropanecarboxamido]hex-5-enyl-L-cysteine
• (Z)-7-((R)-2-Amino-2-carboxy-ethylsulfanyl)-2-[((S)-2,2-dimethyl-cyclopropanecarbonyl)-amino]-hept-2-enoic acid
• (2Z)-7-{[(2R)-2-amino-2-carboxyethyl]sulfanyl}-2-{[(1S)-2,2-dimethylcyclopropyl]formamido}hept-2-enoic acid

Cilastatin inhibits the human enzyme dehydropeptidase.^[1]

Yatendra Kumar, “Process for the preparation of amorphous cilastatin sodium.” U.S. Patent US20040152780, issued August 05, 2004.US20040152780

Cilastatin is an inhibitor of renal dehydropeptidase, an enzyme responsible for both the metabolism of thienamycin beta-lactam antibiotics as well as conversion of leukotriene D4 to leukotriene E4. Since the antibiotic, imipenem, is one such antibiotic that is hydrolyzed by dehydropeptidase, cilastatin is used in combination with imipenem to prevent its metabolism. The first combination product containing both drugs was approved by the FDA in November of 1985 under the trade name Primaxin, marketed by Merck & Co.⁹ A newer triple-drug product was approved in July 2019 under the trade name Recarbrio which also contains relebactam.⁸

Cilastatin is indicated, in combination with imipenem with or without relebactam, for the treatment of bacterial infections including respiratory, skin, bone, gynecologic, urinary tract, and intra-abdominal as well as septicemia and endocarditis.^6,5

Uses

Dehydropeptidase is an enzyme found in the kidney and is responsible for degrading the antibiotic imipenem. Cilastatin can therefore be combined intravenously with imipenem in order to protect it from degradation, prolonging its antibacterial effect.

Imipenem alone is an effective antibiotic and can be given without cilastatin. Cilastatin itself does not have antibiotic activity, although it has been proved to be active against a zinc-dependent beta-lactamase that usually confers antibiotic resistance to certain bacteria, more precisely, the carbapenem family of antibiotics. This property is due to the physicochemical similarities between membrane dipeptidase (MDP), the compound it is usually set to target, and the bacterial metallo-beta-lactamase carried by the CphA gene.^[1] The combination allows the antibiotic to be more effective by changing the pharmacokinetics involved. Thus imipenem/cilastatin, like amoxicillin/clavulanic acid, is a commonly used combination product.

PATENT

https://patents.google.com/patent/EP2402312A1

Cilastatin sodium is the sodium salt of a derivatized heptenoic acid. Its chemical name is [R-[R*,S*-(Z)]]-7-[(2-amino-2-carboxyethyl)thio]-2-[[(2,2-dimethylcyclopropyl)carbonyl]amino]-2-heptenoic acid, monosodium salt. It is an off-white to yellowish-white, hygroscopic, amorphous compound. PRIMAXIN (Imipenem and Cilastatin) is a formulation of Imipenem (a thienamycin antibiotic) and Cilastatin sodium.

Imipenem with Cilastatin acts as an effective antibiotic for the treatment of infections of various body systems. PRIMAXIN is a potent broad-spectrum antibacterial agent for intramuscular administration. Imipenem can be further described as a semi-synthetic thienamycin that is administered intravenously or intramuscularly in combination with Cilastatin to reduce toxicity. Cilastatin, a renal dipeptidase inhibitor, inhibits the enzymatic breakdown of Imipenem and increases urinary excretion of the active drug.

Originally Cilastatin was disclosed in US patent number 5,147,868 . This patent also discloses various processes for the preparation of Cilastatin, particularly example 19 A of this patent disclose a process for the preparation of Cilastatin. According to this example the condensation of 7-chloro-2-oxoheptanoic acid ethyl ester (I) with (S)-2,2-dimethylcyclopropanecarboxamide (II) by means of p-toluene sulphonic acid in refluxing toluene gives (S)-7-chloro-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester (III), which is hydrolyzed in aq. NaOH to yield the corresponding carboxylic acid (IV). Finally, this compound is condensed with (R)-cysteine (V) by means of NaOH in water to afford the target Cilastatin, followed by isomerisation to at 3.0 pH. The process followed in this example is depicted as below:

WO 03/018544 claims a process for the purification of Cilastatin, which comprises contacting a solution of crude Cilastatin with a non-ionic adsorbent resin and recovering pure Cilastatin from a solution thereof. This publication also claims a process for the isomerisation of Cilastatin by heating a solution of Cilastatin containing the corresponding E isomer at a pH of about 0.5 to 1.5. This invention not suitable for plant point of view as it involves column chromatography.

US 2004/0152780 claims a process for the preparation of pure Cilastatin sodium in an amorphous form which comprises recovering Cilastatin sodium from a solution thereof which contains an organic solvent, homogeneous mixture of organic solvents, or homogeneous mixture of organic solvents and water, by solvent precipitation. According to this patent the pure Cilastatin sodium in amorphous form was recovered from the solution of Cilastatin sodium in a solvent (where Cilastatin sodium was soluble) by adding an anti-solvent (where Cilastatin sodium was insoluble).

WO 2006/022511 claims a process for preparing Cilastatin sodium via Cilastatin amine salt, also the said patent claims Cilastatin ammonium salt. However EP 0 048 301 page 2; line 33-37 & US 4,616,038 col 36; 40-44 anticipates the claim of the said publication. Also this patent utilizes the column chromatography for removing sodium chloride.

However taking the consideration the commercial importance of Cilastatin sodium and Imipenem, there remains a need of convenient process. Hence, we focused our research to find an alternative processes and succeeded with a process that eliminates the foregoing problems associated with earlier processes.

PATENT

https://patents.google.com/patent/WO2006022511A1/en

Cilasatin sodium salt i.e., [R-[R*, S*-(Z)]] –

7-[(2-amino-2-carboxyethylthio)-2-[[(2,2-dimethylcyclopropyl)carbonyl]amino-2-hepa tenoic acid monosodium salt represented by following chemical formulae (1)1 has been used with imipenem in order to prevent its renal metabolism. Imipenem/cilastatin sodium is used as a potent broad spectrum antibacterial agent. [3] There have been several reports on the method for preparing a cilastatin sodium until now: for example, EP 48301 Bl discloses a method for the preparation of a cilastatin sodium salt using by Grignard reaction started from l-bromo-5-chloropentane (2′) explained by following Reaction Scheme 1; Donald W.

Graham et al discloses a preparation method using ethyl- 1, 3-dithian-2-carboxylate as a starting material (Donald W. Graham et al, J. Med. Chem., 30, pplO74, 1987) etc. [4] [Reaction Scheme 1]

[5]

[6]

[7] [8] As shown in the above Reaction Scheme 1, l-bromo-5-chloropentane (2′) is reacted with diethyl oxalate through Grignard reaction to afford ethyl 7-chloro-2-oxo-hepanoate (3′)at the 1^st step; ethyl 7-chloro-2-oxo-heptanoate (3′) is reacted with (S)-2, 2-dimethylcyclopropanecarboxamide to obtain ethyl (Z )-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoate (4′) at the 2ⁿ step.

[9] However, present inventors has confirmed that considerable amount (about 10 to 13%) of (E)-form isomer thereof (7′)was produced during the 2^nd step as a reaction impurity by gas chromatography. The (E)-form isomer is further subjected to hydrolysis resulting in (E)-7-chloro-2-((S)-2,

2-dimethylcyclopropanecarboxamido)-2-heptenoic acid (8′)as shown in following Reaction Scheme 2.

[10] [H] However, present inventors has confirmed that considerable amount (about 10 to 13%) of (E)-form isomer thereof (7′) was produced during the 2^nd step as an reaction impurities by gas chromatography as shown in following Reaction Scheme 2. The (E )-form isomer is further subjected to hydrolysis resulting in (E)-7-chloro-2-((S)-2, 2-dimethylcyclopropylcarboxamide)-2-heptanoic acid (8′).

[12] [Reaction Scheme 2] [13]

[14] [15] There have been tried to solve the problems for example, the isomer impurity was removed by the acidification followed by recrystallization step or by adding cysteine to the reaction solution obtained in the 3^r step at the above described 4 step, reacting with together to form (E)-7-(L-amino-2-carboxyethylthio)-2-((S )-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid and finally removing the reacted impurity by acidifying and heating step in the known preparation till now. However, the present inventors found that there remained unsolved problem such that the recrystallization yield of the product, i.e., (Z)-7-chloro-2-((S )-2,2-dimethylcyclopropylcarboxamide)-2-heptanoic acid was very poor because of the formed byproduct, i.e., (E

)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid in 3^rdstep and further the unknown impurity (10′) and (S)-2,2-dimethylcyclopropanecarboxamide (H’) were produced by acidifying and heating reaction solution at the above described the 4 step as shown in following Reaction Scheme 3 confirmed by HPLC analysis, which give rise to another difficulty in the purification of final products. [16] [17] [Reaction Scheme 3] [18]

NH

(Z) and (E) m ix ture (9¹)

C ondition

(105 0 15

[19] In addition to above described problems, present inventors have found that the cilastatin isolated through the above described 4^th step consisting of eluting the cation exchange resin with ammonia solution, concentrating the eluate and solidifying with ethanol and diethyl ether exists in the form of its ammonium salt not free acid form as disclosed in the patent. Using an acid such as hydrochloric acid in order to obtain free acid accompany with unwanted formation of inorganic ammonium salt such as ammonium chloride, which could not afford high purity of cilastatin sodium salt in the end.

[20] [21] Therefore, there have been tried to solve the above-described problems: for example, PCTAVO 0318544 (Al) discloses the isolation method using by neutral HP 20 resin column instead of cationic resin disclosed in EP 48301 Bl; PCTAVO 02094742 (Al) discloses the method for preparing cilastatin sodium salt (Ia) from cilastatin (6′), the disclosure of which cited documents are incorporated herein by reference.

[22]

[23] However, the above-described methods for preparing cilastatin using column chro¬ matographic process are not suitable for commercial mass production.

[24]

[25] The present inventors have made extensive researches to discover novel method for preparing cilastatin sodium salt with high yield and mass production and finally completed the invention by founding novel preparation for obtaining purposed cilastatin sodium salt; i.e., selectively hydrolyzing (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoate, isolating (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid metal salt from the reaction mixture, adopting the cilastatin amine salt instead of free acid form disclosed in cited references and the use of sodium hydroxide and cationic exchange resin with pH control in order to obtain cilastatin sodium salt with high purity and high yield.

Example 1: Preparation of ethyl (Z)-7-chloro-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoate (4)

[67]

[68] l-bromo-5-chloropentane (29 Ig, 1.57 mol) was reacted with diethyl oxalate

(206.5g) through Grignard reaction to obtain ethyl 7-chloro-2-oxo-heptanoate (3) and the compound (3) was reacted with (S)-2,2-dimethylcyclopropanecarboxamide to obtain ethyl (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptanoate (237g, 0.79 mol). The above-described step was performed by the procedure according to the procedure disclosed in EP 48301 (Bl).

[69]

[70] Example 1: Preparation of ethyl (Z)-7-chloro-((S)-2,

2-dimethylcyclopropanecarboxamido)-2-heptenoic acid sodium salt (12)

[71]

[72] 1-1. ( Z V7-chloro-(YSV2. 2-dimethylcyclopropanecarboxamidoV2-heptanoic acid sodium salt

[73] The ethyl (Z)-7-chloro-2-((S

)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate (237g, 0.79 mol) obtained in Comparative Example 1 was dissolved in 877ml of methanol and 1.8 L of sodium hydroxide solution (0.48 M) was added with stirring at room temperature. The reaction was finished when the area ratio of (Z) isomer and (E) isomer becomes 20: 1 by HPLC analysis and the un-reacted organic reagent was extracted with 490 ml of dichloromethane. The pH of the solution was adjusted to 7-8 with 3N HCl and the un- reacted organic reagent was extracted with 490 ml of dichloromethane again. The water layer was concentrated under reduced pressure and 650ml of ethanol was added and stirred until the solid had been dissolved at 50°C, for 30 minute to 1 hour. The un- dissolved solid was removed with filtration and the filtrate was concentrated under reduced pressure. 2.4 L of acetonitrile is added thereto and stirred to obtain 140.8g of ( Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid sodium salt (12 ; 55% yield).

[74]

[75]

[76] m.p.: 219°C;

[77] ¹H-NMR (D₂O, 300MHz) δppm: 0.87 (dd, IH), 1.00 (dd, IH), 1.14 (s, 3H), 1.19 (s,

3H), 1.61 (m, 2H), 1.68 (dd, IH), 1.78 (m, 2H), 2.12 (m, 2H), 3.62 (t, 2H), 6.47 (t, IH);

[78]

13

[79] ¹³C ( -NMR (D₂O, 300MHz) δppm: 19.47, 19.99, 22.55, 25.74, 26.75, 27.53, 29.44,

32.27, 46.11, 131.41, 136.52, 172.74, 174.62.

[80] [81] [82]

[83] 1-2. ( Z V7-chloro-(YSV2. 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid

(12-D

[84] 140.8g of (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid sodium salt (12) obtained from Example 1-1 was dissolved in 422 ml of distilled water. The pH of the solution was adjusted to 2.0-3.0 with 3N HCl, extracted with 592 ml of isopropylether two times and 59.2g of anhydrous magnesium sulfate was added to isopropylether layer, stirred and subjected to filtration. The filtrate was concentrated to afford 127.7g of (Z)-7-chloro-2-((S )-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid (12-1, 98% yield).

[85]

[86] ¹H-NMR (CDCl₃, 300MHz) δppm: 0.83 (dd, IH), 1.19 (s, 7H), 1.44 (dd, IH), 1.19

(s, 3H), 1.64 (m, 2H), 1.81 (m, 2H), 2.21 (m, 2H), 3.54 (t, 2H), 6.78 (t, IH), 7.04 (br, IH);

[87]

13

[88] ¹³C ( -NMR (CDCl₃, 300MHz) δppm: 18.69, 20.82, 22.86, 25.36, 27.03, 28.53,

29.27, 32.17, 44.60, 124.88, 139.49, 168.96, 170.15.

[89]

[90]

[91] 1-3. ( Z V7-chloro-((SV2. 2-dimethylcyclopropanecarboxamidoV2-heptenoic acid ammonium salt (12-2)

[92] 127.7g of (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid (12-1) obtained from Example 1-2 was dissolved in 422 ml of EtOH. 100 ml of 25% ammonia water solution was added thereto, stirred and concentrated to obtain 135.6g of (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ammonium salt (12-2, 100% yield).

[93]

[94] Example 2: Preparation of cilastatin ammonium salt (13-1)

[95] 4Og of (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid sodium salt (12, 0.14 mol) obtained in Example 1-1 was dissolved in 120 ml of 0.48 M sodium hydroxide solution and 240 ml of ethanol and the mixture of 1.4g of NaBr (0.013 mol) and 25.3g of L-cysteineDHClDH) was added thereto, stirred at 55°C, for 8 hours.

[96] The pH of the reaction solution was adjusted to 5.5-5.0 with 3N HCl, concentrated and 800ml of methanol was added, stirred at 55°C for 1 hour and un-dissolved salt was filtered out. The filtrate was concentrated to the extent that the volume of total solution was reduced to about 1/2. The concentrate was adsorbed with cationic exchange resin (PK208 model, Samyang Co.), washed with distilled water to the extent that the con¬ ductivity of the solution became less than lθμs(microsiemens), eluted with 2N ammonia water and the eluate was concentrated under the reduced pressure to give brown solid compound. The compound was dissolved in 40 ml of distilled water. 0.8 L of 2-propanol was added thereto and the solution was subjected to salting out method with reflux for 2 hours. The resulting solid was cooled and filtered to obtain 45.66g of cilastatin ammonium salt (13-1. 90% yield).

[97]

[98] m. p.: 161°C;

[99] Element Analysis: C₁₆H₂₉N₃O₅S (MW: 375.183): CaI. Q51.18; 7.78; N:11.19; Est.

C:51.01; H: 7.97; N: 11.04;

[100] MS m/z : 375 (M+, 49), 312(36), 97 (84.2), 69 (100);

[101] ¹H-NMR (D₂O, 300MHz) δppm: 0.87 (dd, IH), 1.00 (dd, IH), 1.14 (s, 3H), 1.19 (s,

3H), 1.62 (m, 5H), 2.1 l(q, 2H), 2.62 (t, 2H), 3.06 (m, 4H), 3.91 (dd, IH), 6.47 (t, IH);

13

[102] ” (C-NMR (D₂O, 300MHz) δppm: 19.49, 19.97, 22.53, 26.74, 27.44, 27.86, 29.09,

29.43, 31.94, 32.85, 54.44, 131.23, 136.83, 172.70, 173.71, 174.64.

[103]

[104] Example 3: Preparation of cilastatin ethylamine salt (13-2)

[105] 4Og of (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid sodium salt (12-1, 0.15 mol) obtained in Example 1-2 was dissolved in 165 ml of 0.66 M sodium hydroxide solution and 330 ml of ethanol and the mixture of 1.5g of NaBr (0.015 mol) and 27.6g of L-cysteineDHClDH) was added thereto, stirred at 55°C, for 8 hours.

[106] The pH of the reaction solution was adjusted to 5.5-5.0 with 3N HCl, concentrated and 800ml of methanol was added, stirred at 55°C for 1 hour and un-dissolved salt was filtered out.. The filtrate was concentrated to the extent that the volume of total solution was reduced to about 1/2. The concentrate was adsorbed with cationic exchange resin (PK208 model, Samyang Co.), washed with distilled water to the extent that the conductivity of the solution became less than 10μs(microsiemens), eluted with 2N ethylamine water and the eluate was concentrated under the reduced pressure to give brown solid compound. The compound was dissolved in 40 ml of distilled water. 0.8 L of 2-propanol was added thereto and the solution was subjected to salting out method with reflux for 2 hours. The resulting solid was cooled and purified with filtration to obtain 49.38g of cilastatin ethylamine salt (13-2. 90% yield).

[107]

[108] ¹H-NMR (D₂O, 300MHz) δppm: 0.86 (dd, IH), 1.00 (dd, IH), 1.14 (s, 3H), 1.19 (s,

3H), 1.27 (t, 3H), 1.60 (m, 5H), 2.1 l(q, 2H), 2.62 (t, 2H), 3.06 (m, 4H), 3.91 (dd, IH), 6.47 (t, IH); [109] ¹³C-NMR (D₂O, 300MHz) δppm: 14.7, 21.57, 22.04, 24.63. 28.82, 29.52, 29.94,

31.16, 31.49, 34.00, 34.91, 37.78, 56.50, 133.27, 138.96, 174.75, 175.81, 176.74.

[HO]

[111] Example 4 : Purification of cilastatin ammonium salt

[112] 4-1. Purification using by water and ethanol

[113] 45.66g of cilastatin ammonium salt (13-1,0.12 mol) obtained in Example 2 was dissolved in 45.66 ml of distilled water and 1.3L of anhydrous ethanol was added thereto in a dropwise manner. The resulting salted out solid was filtered to obtain 38.81g of cilastatin ammonium salt (Yield: 85%, Purity: 99.8%).

[114]

[115] 4-2. Purification using by ammonia water and propanol Q)

[116] 50g of cilastatin ammonium salt (13-1) obtained in Example 2 was dissolved in 50 ml of 25% ammonia water and 1.5L of 2-propanol was added thereto in a dropwise manner. The resulting salted out solid was filtered to obtain 41.2g of cilastatin ammonium salt (Yield: 82.4%, Purity: 99.3%).

[117]

[118] 4-3. Purification using by ammonia water and propanol (1)

[119] 50g of cilastatin ammonium salt (13-1) obtained in Example 2 was dissolved in

100 ml of 25% ammonia water and 2.0L of 2-propanol was added thereto in a dropwise manner. The resulting salted out solid was purified with filtration to obtain 35.4g of cilastatin ammonium salt (Yield: 70.8%, Purity: 99.3%)

[120]

[121] 4-4. Purification using by ammonia water and ethanol

[122] 50g of cilastatin ammonium salt (13-1) obtained in Example 2 was dissolved in 50 ml of 25% ammonia water and 1.5 L of anhydrous ethanol was added thereto in a dropwise manner. The resulting salted out solid was filtered to obtain 35.6g of cilastatin ammonium salt (Yield: 71.2%, Purity: 99.8%).

[123]

[124] 4-5. Purification using by the mixture solvent mixed with water and ammonia water, and propanol (1)

[125] lOOg of cilastatin ammonium salt (13-1) obtained in Example 2 was dissolved in the mixture solvent mixed with 50 ml of distilled water and 50ml of 4N ammonia water, and 2.0 L of 1 -propanol was added thereto in a dropwise manner. The resulting salted out solid was filtered to obtain 89.3g of cilastatin ammonium salt (Yield: 89.3%, Purity: 99.6%).

[126]

[127] 4-6. Purification using by the mixture solvent mixed with water and ammonia water, and propanol (1) [128] lOOg of cilastatin ammonium salt (13-1) obtained in Example 2 was dissolved in the mixture solvent mixed with 50 ml of distilled water and 50ml of 2N ammonia water, and 2.0 L of 1-propanol was added thereto in a dropwise manner. The resulting salted out solid was filtered to obtain 95.0g of cilastatin ammonium salt (Yield: 95.0%, Purity: 99.5%).

[129]

[130] 4-7. Purification using by the mixture solvent mixed with water and ammonia water, and propanol (3)

[131] lOOg of cilastatin ammonium salt (13-1) obtained in Example 2 was dissolved in the mixture solvent mixed with 100 ml of distilled water and 50ml of 25% ammonia water, and 2.0 L of 2-propanol was added thereto in a dropwise manner. The resulting salted out solid was filtered to obtain 89.7g of cilastatin ammonium salt (Yield: 89.7%, Purity: 99.8%).

[132]

[133] 4-8. Purification using by the mixture solvent mixed with water and ammonia water, and propanol (4)

[134] lOOg of cilastatin ammonium salt (13-1) obtained in Example 2 was dissolved in the mixture solvent mixed with 50 ml of distilled water and 100ml of 25% ammonia water, and 3.0 L of 2-propanol was added thereto in a dropwise manner. The resulting salted out solid was filtered to obtain 80.Og of cilastatin ammonium salt (Yield: 80.0%, Purity: 99.7%).

[135]

[136] 4-9. Purification using by water and propanol

[137] 50g of cilastatin ammonium salt (13-1) obtained in Example 2 was dissolved in 100 ml of distilled water and 1.5 L of 2-propanol was added thereto in a dropwise manner. The resulting salted out solid was filtered to obtain 87.2g of cilastatin ammonium salt (Yield: 87.2%, Purity: 99.6%).

[138]

[139] Example 5: Preparation of cilastatin sodium salt

[140] 4.28g of sodium hydroxide (0.107 mol) was dissolved in 38.3 ml of distilled water and 191.5 ml of ethanol. 38.81g of cilastatin ammonium salt (0.1 mol) obtained in Example 4-1 was added thereto and stirred for 30 minutes. The solution was con¬ centrated under reduced pressure at 60°C and 153 ml of distilled water was added to the concentrate. The solution was stirred to dissolve the concentrate and the pH of the solution was adjusted to 7.0 using by cationic exchange resin and filtered. The filtrate was lyophilized to obtain high purity (99.4%) of cilastatin sodium salt.

[141]

[142] Experimental Example 1: Purity Determination [143] The purity of cilastatin ammonium salt obtained in Example 4 was determined by

HPLC on condition as shown in Table 1 and the determined result was shown in Table 2.

[144] Table 1

[145] Table 2

[146]

Industrial Applicability

[147] The novel method of the present invention could prevent the formation of (E )-isomer from the preparation of novel intermediate for preparing cilastatin sodium, i.e., (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid metal salt and isolate the intermediate in situ providing simpler process with high yield and purity. Furthermore, it can provide with highly purified cilastatin sodium salt by isolating novel cilastatin amine salt and using sodium hydroxide and cationic exchange resin. Accordingly, the method can be very useful in preparing cilastatin sodium salt with high yield and high purity.

Claims

Hide Dependent

Claims

[1] A method for preparing (Z)-7-chloro-2-((S)-2,

2-dimethylcyclopropanecarboxamido)-2-heptenoic acid metal salt represented by general chemical formula (12) comprising the steps consisting of: selectively hy- drolyzing (Z)-7-chloro-2-((S

)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate represented by chemical formula (4) in reaction solvent under basic condition and removing un-reacted reactant remained in reaction solvent layer with washing organic solvent with controlling the pH of reaction solution with acid at the 1^st step; concentrating remaining water layer, adding alcohol thereto with heating, stirring to the extent to dissolve the solid, filtering out un-dissolved salt, and concentrating the filtrate under reduced pressure at the 2ⁿ step; adding organic solvent thereto to solidify the concentrate, filtering the solution to isolate (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid metal salt represented by chemical formula (12) at the final step:

Wherein M⁺ is alkali metal salt.

[2] The method according to claim 1, said R group of general formula (12) is selected from lithium salt, sodium salt and potassium salt. [3] The method according to claim 1, said reaction solvent at the 1^st step is selected from the mixture of water and methanol, water and ethanol or water and propanol.

[4] The method according to claim 1, said pH of the reaction solution at the 1^ststep ranges from 6 to 8. [5] The method according to claim 1, said organic solvent for isolating final product from the salt thereof is acetonitrile, acetone or the mixture solvent mixed with water and alcohol.

[6] A method for preparing cilastatin sodium salt represented by chemical formula (1) comprising the steps consisting of: reacting (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid or the salt thereof represented by chemical formula (12) with cysteine in basic solution at the 1^ststep; controlling the pH of the reaction solution obtained in step 1, concentrating, adsorbing the concentrate with cationic exchange resin, washing with water, eluting with amine solution to concentrate the eluant at the 2^nd step; dissolving the concentrate in recrystallization solvent and subjecting to recrystallization process by adding alcohol in a dropwise manner to afford pure cilastatin amine salt (13) at the 3^r step; reacting cilastatin amine salt (13) with sodium hydroxide and controlling the pH with cationic exchange resin at the 4^thstep.

Wherein M⁺ is alkali metal salt.

Wherein R is a hydrogen atom or lower alkyl group.

[7] The method according to claim 6, said R group of general chemical formula (13) is a hydrogen atom or C1-C4 alkyl group. [8] The method according to claim 6, said recrystallization solvent at the 3 step is water, ammonia water, or the mixture thereof in the amount ranging from 1 :3 to

2:1 (w/v) of the weight of cilastatin amine salt.

[9] The method according to claim 6, said alcohol added for recrystallization at the 3 step is ethanol, 1-propanol, 2-propanol, n-butanol, or the mixture thereof. [10] The method according to claim 6, said recrystallization process at the 3^rdstep is performed at the temperature ranging from 5 to 97°C.

[H] The method according to claim 6, said cationic exchange resin at the 4^thstep is styrene strong acidic resin. [12] An intermediate represented by chemical formula (13)

Wherein R is a hydrogen atom or lower alkyl group.

References

• Keynan S, Hooper NM, Felici A, Amicosante G, Turner AJ: The renal membrane dipeptidase (dehydropeptidase I) inhibitor, cilastatin, inhibits the bacterial metallo-beta-lactamase enzyme CphA. Antimicrob Agents Chemother. 1995 Jul;39(7):1629-31. [PubMed:7492120]
• Buckley MM, Brogden RN, Barradell LB, Goa KL: Imipenem/cilastatin. A reappraisal of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1992 Sep;44(3):408-44. [PubMed:1382937]
• Balfour JA, Bryson HM, Brogden RN: Imipenem/cilastatin: an update of its antibacterial activity, pharmacokinetics and therapeutic efficacy in the treatment of serious infections. Drugs. 1996 Jan;51(1):99-136. doi: 10.2165/00003495-199651010-00008. [PubMed:8741235]
• Koller M, Brom J, Raulf M, Konig W: Cilastatin (MK 0791) is a potent and specific inhibitor of the renal leukotriene D4-dipeptidase. Biochem Biophys Res Commun. 1985 Sep 16;131(2):974-9. doi: 10.1016/0006-291x(85)91335-x. [PubMed:3863619]
• FDA: Recarbrio Label [Link]
• FDA: Primaxin Label [Link]
• ChemSpider: Cilastatin [Link]
• FDA Label: Apadaz [Link]
• Drugs@FDA: Primaxin [Link]

Synthesis

By Panchapakesan, Ganapathy et alFrom Indian, 269299, 16 Oct 2015

IN 269299

SYN

Patent

Cilastatin

Cilastatin

Clinical data
AHFS/Drugs.com	International Drug Names
MedlinePlus	a686013
Routes of administration	IV
ATC code	J01DH51 (WHO) (combination with imipenem)
Identifiers
IUPAC name[show]
CAS Number	82009-34-5
PubChem CID	5280454
IUPHAR/BPS	5166
DrugBank	DB01597
ChemSpider	4940183
UNII	141A6AMN38
KEGG	D07698
ChEBI	CHEBI:3697
ChEMBL	ChEMBL766
CompTox Dashboard (EPA)	DTXSID8048238
ECHA InfoCard	100.072.592
Chemical and physical data
Formula	C16H26N2O5S
Molar mass	358.454 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] O=C(N\C(=C/CCCCSC[C@@H](C(=O)O)N)C(=O)O)[C@H]1CC1(C)C
InChI[hide] InChI=1S/C16H26N2O5S/c1-16(2)8-10(16)13(19)18-12(15(22)23)6-4-3-5-7-24-9-11(17)14(20)21/h6,10-11H,3-5,7-9,17H2,1-2H3,(H,18,19)(H,20,21)(H,22,23)/b12-6-/t10-,11+/m1/s1  Key:DHSUYTOATWAVLW-WFVMDLQDSA-N

/////////////cilastatin, シラスタチン  , FDA 2019, циластатин , سيلاستاتين , 西司他丁 , MK-791, Recarbrio

CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O

CANERTINIB

Canertinib (CI-1033) is an experimental drug candidate for the treatment of cancer. It is an irreversible tyrosine-kinase inhibitor with activity against EGFR (IC₅₀ 0.8 nM), HER-2 (IC₅₀ 19 nM) and ErbB-4 (IC₅₀ 7 nM).^[1][2] By 2015, Pfizer had discontinued development of the drug.^[3]

Canertinib has been reported as a substrate for OATP1B3. Interaction of canertinib with OATP1B3 may alter its hepatic disposition and can lead to transporter mediated drug-drug interactions.^[4] Also, canertinib is not an inhibitor of OATP-1B1 or OATP-1B3 transporter.^[5]

SYN

J Med Chem 2000,43(7),1380

4-Chloro-7-fluoro-6-nitroquinazoline (I) was condensed with 3-chloro-4-fluoroaniline (II) to afford the 4-anilino quinazoline (III). Displacement of the activated fluorine of (III) with the potassium alkoxide of morpholinopropanol (IV) gave the morpholinopropyl ether (V). Subsequent reduction of the nitro group of (V), either using iron dust and acetic acid or catalytic hydrogenation over Raney-Ni, furnished aminoquinazoline (VI). This was finally condensed with acrylic acid (VII), via activation as the mixed anhydride with isobutyl chloroformate or using EDC as the coupling reagent, to provide the title acrylamide.

PATENT

https://patents.google.com/patent/CN103242244A/en

canertinib (Canertinib, I), chemical name 4- (3-chloro-4-fluoroanilino) -7- [3- (4_-morpholinyl) propoxy] -6-propylene quinazoline amide group, and by the US Pfizer Warner Lambert developed jointly an irreversible epidermal growth factor receptor (pan-ErbB) selective inhibitor, which is capable of binding to the cell surface of all members of the ErbB family adenosine triphosphate binding site, thereby inhibiting the activation of these receptors and their downstream mitogenic signal transduction pathways. Clinical studies show that the product has good resistance, can be effective in treating metastatic breast cancer, ovarian cancer, cervical cancer and other tumors, and can be combined with a variety of antineoplastic agents exhibit a synergistic effect.

[0004]

[0005] China Patent No. CN1160338C, CN1438994A and No. No. CN1745073A reported the preparation of canertinib: A nucleus 4- [(3-chloro-4-fluorophenyl) amino] -6-nitro 7-fluoro-quinazoline (VIII) as a starting material, under basic conditions with 3- (4-morpholinyl) -1-propanol 7-position substitution reaction occurs to give 4- [(3-chloro – 4-fluorophenyl) amino] -6-nitro-7- [3- (4-morpholinyl) -1-propoxy] quinazoline (IX); intermediate (IX) through the 6-position nitro reduction, to give the corresponding amino compound (X); amino compound (X) to give canertinib acylation reaction (I) with acrylic acid or acryloyl chloride occurs.

[0006] In addition, “Qilu Pharmaceutical Affairs” 30, 2011, Vol. 10, page 559, and “China Industrial Medicine” 2010 Volume 41, No. 6, pp. 404 also reported an improved method of the above-prepared and studied method from 7-fluoro-quinazolin-3-one (V) via nitration, chloro and condensation reaction of the preparation of intermediate (VIII) is.

[0007]

[0008] This shows that the current Kanai prepared for Nepal is mainly the 4-position through an intermediate (VII), respectively, a functional transformation of the 6-position and 7-position achieved. Since the intermediate (VII) a fluorine-containing compounds, materials are not readily available, many steps, and many steps are required to be isolated and purified by column chromatography, which is not required for industrialization.

Example a:

[0023] at room temperature, to a three-necked flask was added diisopropyl azodicarboxylate (3mL, 15mmol) and tetrahydrofuran 5mL, dropwise addition of triphenylphosphine (4.0g, 15mmol) in tetrahydrofuran 25mL solution at room temperature, kept at room temperature for 2 hours. Under nitrogen, 3- (4-morpholinyl) -1_-propanol (0.49g, 3.4mmol) in 5mL of tetrahydrofuran was added dropwise to the reaction system after the dropwise addition is complete, 6-amino – 7-hydroxy-3,4-dihydro-quinazolin-4-one (II) (0.53g,

3.0mmol), stirred at room temperature for 4 hours. Solution of 3- (4-morpholinyl) -1-propanol (0.38g, 2.6mmol) in 5mL of tetrahydrofuran was continued at room temperature for 2 hours, the end of the reaction was monitored TLC. Recovery of the solvent by distillation under reduced pressure, the residue was treated with dilute hydrochloric acid, pH = 5-6, extracted with ethyl acetate, the organic phase was washed with saturated sodium carbonate adjusted pH = 10-11. The aqueous phase was freeze-dried in vacuo to give an off-white solid 6-amino-7- [3- (4-morpholinyl) propoxy] _3,4- dihydroquinazolin-4-one (111) 0.80g yield 87.7%.

[0024] Example II:

[0025] to a three-neck flask was added 6-amino-7- [3- (4_ morpholino) propoxy] quinazolin-dihydro _3,4_ one _4_

(III) (0.76g, 2.5mmol), triethylamine (0.25g, 2.5mmol) and dichloromethane 20mL, warmed to 40-45 ° C, stirred until homogeneous dissolution system. Dropped below 10 ° C, was slowly added dropwise acryloyl chloride (0.25g, 2.8mmol) in dichloromethane IOmL solution dropwise at room temperature after continued for 6 h, TLC detection reaction was completed. The reaction solution was respectively 10% sodium bicarbonate solution and water, dried over anhydrous sodium sulfate. Recovery of the solvent under reduced pressure, the residue was recrystallized from ethyl acetate to give a white solid 7- [3- (4-morpholinyl) propoxy] -6-acrylamido-3,4-dihydro-quinazoline – 4-one (IV) 0.81g, 90.5% yield.

[0026] Example III:

Under [0027] nitrogen, to a three-necked flask was added 7- [3- (4_-morpholinyl) propoxy] -6-acrylamido-_3,4- dihydroquinazolin-4-one (IV ) (3.58g, IOmmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium iron hexafluorophosphate (BOP) (6.63g, 15mmol) and acetonitrile 100mL. Under stirring, a solution of 1,8-diazabicyclo [5.4.0] ^ a-7-ene (DBU) (2.28g, 15mmol), dropwise, at room temperature for 12 hours. Warmed to 60 ° C, the reaction was continued for 12 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added to dissolve IOOmL, washed with 2M sodium hydroxide and 20mL. The organic phase was separated, dried and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran IOOmL, 4-chloro-3-fluoroaniline (1.89g, 13mmol) and sodium hydride (0.32g, 13mmol), was heated to 50 ° C, reaction was stirred for 5 hours, the end of the reaction was monitored TLC. Quenched with saturated brine the reaction, the organic phase was separated, dried, evaporated under reduced pressure to recover the solvent to give an off-white solid. Recrystallized from ethanol to give an off-white solid canertinib (I) 4.05g, yield 83.5%.

[0028] Example IV:

Under [0029] nitrogen, to a three-necked flask was added 7- [3- (4_-morpholinyl) propoxy] -6-acrylamido-3,4-dihydro-quinazolin-4-one (IV ) (3.58g, IOmmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium iron hexafluorophosphate (BOP) (6.63g, 15mmol) and acetonitrile lOOmL. Under stirring, dropwise power port I, 5- diazabicyclo [4.3.0] – non-5-ene (DBN) (1.86g, 15mmol), dropwise, at room temperature for 12 hours. Warmed to 60 ° C, the reaction was continued for 12 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added to dissolve IOOmL, washed with 2M sodium hydroxide and 20mL. The organic phase was separated, dried and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran IOOmL, 4-chloro-3-fluoroaniline (1.89g, 13mmol) and sodium hydride (0.32g, 13mmol), was heated to 50 ° C, reaction was stirred for 5 hours, the end of the reaction was monitored TLC. Quenched with saturated brine the reaction, the organic phase was separated, dried, evaporated under reduced pressure to recover the solvent to give an off-white solid. Recrystallized from ethanol to give an off-white solid canertinib (I) 3.85g, yield 79.4%. ·

[0030] Example Five:

Under [0031] nitrogen, to a three-necked flask was added 7- [3- (4_-morpholinyl) propoxy] -6-acrylamido-3,4-dihydro-quinazolin-4-one (IV ) (3.58g, IOmmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate gun (BOP) (6.63g, 15mmol), 4_-chloro-3-fluoroaniline ( 1.89g, 13mmol) and N, N- dimethylformamide lOOmL. Under stirring, a solution of I, 8- diazabicyclo [5.4.0] – ^ a _7_ ene (DBU) (2.28g, 15mmol), dropwise, at room temperature for 12 hours. Warmed to 60 ° C, the reaction was continued for 12 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added to dissolve IOOmL, washed with 2M sodium hydroxide and 20mL. The organic phase was separated, dried and concentrated under reduced pressure. The residue was recrystallized from ethanol to give an off-white solid canertinib (1) 2.32g, yield 47.8%.

References

GW; Loo, JA; Greis, KD; Chan, OH; Reyner, EL; Lipka, E; Showalter, HD; et al. (2000). “Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4-(phenylamino)pyrido3,2-dpyrimidine-6-acrylamides bearing additional solubilizing functions”. Journal of Medicinal Chemistry. 43 (7): 1380–97. doi:10.1021/jm990482t. PMID 10753475.

Canertinib

Names
IUPAC name N-{4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)propoxy]quinazolin-6-yl}prop-2-enamide
Other names CI-1033; PD-183805
Identifiers
CAS Number	267243-28-7
3D model (JSmol)	Interactive image
ChEBI	CHEBI:61399
ChEMBL	ChEMBL31965  ChEMBL545315
ChemSpider	137741
IUPHAR/BPS	5675
PubChem CID	156414
UNII	C78W1K5ASF
CompTox Dashboard (EPA)	DTXSID8048943
InChI[show]
SMILES[show]
Properties
Chemical formula	C24H25ClFN5O3
Molar mass	485.94 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

/////////////CANERTINIB

Benvitimod, Tapinarof

3,5-dihydroxy-4-isopropyl-trans-stilbene

Launched – 2019 CHINA, Psoriasis, Tianji Pharma
тапинароф [Russian] [INN]WBI-1001

Benvitimod (also known as Tapinarof or 3,5-dihydroxy-4-isopropyl-trans-stilbene) is a bacterial stilbenoid produced in Photorhabdus bacterial symbionts of Heterorhabditis nematodes.It is a product of an alternative ketosynthase-directed stilbenoids biosynthesis pathway. It is derived from the condensation of two β-ketoacyl thioesters. It is produced by the Photorhabdus luminescens bacterial symbiont species of the entomopathogenic nematode, Heterorhabditis megidis.

Benvitimod (also known as tapinarof or 3,5-dihydroxy-4-isopropyl-trans-stilbene) is a bacterial stilbenoid produced in Photorhabdus bacterial symbionts of Heterorhabditis nematodes. It is a product of an alternative ketosynthase-directed stilbenoids biosynthesis pathway. It is derived from the condensation of two β-ketoacyl thioesters .^[1] It is produced by the Photorhabdus luminescens bacterial symbiont species of the entomopathogenic nematode, Heterorhabditis megidis. Experiments with infected larvae of Galleria mellonella, the wax moth, support the hypothesis that the compound has antibiotic properties that help minimize competition from other microorganisms and prevents the putrefaction of the nematode-infected insect cadaver.^[2]

Tapinarof is a non-steroidal anti-inflammatory drug originated by Welichem Biotech. Dermavant Sciences is developing the product outside China in phase III clinical trials for the treatment of plaque psoriasis. The company is also conducting phase II clinical trials for the treatment of atopic dermatitis. Phase II studies had also been conducted by Welichem Biotech and Stiefel (subsidiary of GlaxoSmithKline) for these indications.

Tapinarof was originated at Welichem Biotech, from which Tianji Pharma and Shenzen Celestial Pharmaceuticals obtained rights to the product in the Greater China region in 2005. In 2012, Welichem licensed development and commercialization rights in all other regions to Stiefel. In 2013, Welichem entered into an asset purchase agreement to regain Greater China rights to the product from Tianji Pharma and Celestial; however, this agreement was terminated in 2014. In 2018, Stiefel transferred its product license to Dermavant Sciences.

Medical research

Benvitimod is being studied in clinical trials for the treatment of plaque psoriasis.^[3]

PATENTS

Route 1

1. US2003171429A1.

2. US2005059733A1.

Route 2

Reference：1. CN103265412A.

Patent

https://patents.google.com/patent/CN103992212A/en

phenalkenyl Maude (Benvitimod) is a new generation of anti-inflammatory drugs, are useful for treating a variety of major autoimmune diseases, such as psoriasis, eczema, hair and more concentrated colitis allergic diseases.Phenalkenyl Maud stilbene compound, comprising cis and trans isomers, the trans alkenyl benzene Maude has a strong physiological activity, stability and physical and chemical properties, and cis alkenyl benzene Modesto predominantly trans phenalkenyl Maud byproducts during synthesis, conventional methods such as benzene alkenyl Maude Wittig reaction of cis-isomer impurity is inevitable.

[0004] benzyl trans-alkenyl Maude as main impurities in the synthesis, whether a drug is detected, or monitored during the reaction, the synthesis and analysis methods established cis alkenyl benzene Maude has very important significance.Phenalkenyl Maud conventional synthetic methods the impurity content is very low, and the properties of the cis compound is extremely unstable, easily converted to trans-structure, the synthetic method according to the preceding, the cis compound difficult to separate. The synthesis method has not been reported before in the literature. Thus, to find a synthesis route of cis-alkenyl benzene Maude critical.

[0005] The synthesis of compounds of cis-stilbene, in the prior art, there have been many reports, however, the prior art method of synthesizing a reaction product of the cis starting materials and reagents difficult source, the catalyst used is expensive higher costs, operational difficulties, is not conducive to large-scale production, such as:

① Gaukroger K, John A.Hadfield.Novel syntheses of cis and trans isomers ofcombretastatin A-4 [J] .J.0rg.Chemj 2001, (66): 8135-8138, instead of styrene and substituted phenyl bromide boric acid as the raw material, the Suzuki coupling reaction is a palladium catalyst, to give the cis compound, the reaction follows the formula:

Yield and selectivity of the process the structure is good, but the reaction is difficult source of raw materials, catalyst more expensive, limiting the use of this method.

[0006] ② Felix N, Ngassaj Erick A, Lindsey, Brandon Ej Haines.The first Cu- and

amine-free Sonogashira-type cross-coupling in the C_6 -alkynylation of protected

2, -deoxyadenosine [J] .Tetrahedron Letters, 2009, (65): 4085-4091, with a substituted phenethyl m

Alkynyl easily catalyst Pd / CaC03, Fe2 (CO) 9, Pd (OAc) 2 and the like produce cis compound to catalytic reduction. The reaction follows the formula:

Advantage of this method is stereospecific reduction of alkynes in the catalyst, to overcome the phenomenon of cis-trans isomerization of the Wittig reaction, but the reaction requires at _78 ° C, is not conducive to the operation, and the reagent sources difficult, expensive than high cost increase is not conducive to mass production.

[0007] ③ Belluci G, Chiappe C, Moro G L0.Crown ether catalyzed stereospecificsynthesis of Z_and E-stilbenes by Wittig reaction in a solid-liquid two-phasessystem [J] .Tetrahedron Letters, 1996, (37): 4225-4228 using Pd (PPh3) 4 as catalyst, an organic zinc reagent with a halide compound of cis-coupling reaction formula as follows:

The advantage of this method is that selective, high yield to give cis; deficiency is difficult to handle, the catalyst is expensive.

[0008] ④ new Wang, Zhangxue Jing, Zhou Yue, Zouyong Shun, trans-3,4 ‘, 5-trihydroxy-stilbene China Pharmaceutical Synthesis, 2005, 14 (4);. 204-208, reported that the trans compound of formula was dissolved in DMSO solution at a concentration dubbed, ultraviolet irradiation was reacted at 365nm, converted into cis compounds, see the following reaction formula:

However, the concentration of the solution preparation method, the reaction time is more stringent requirements.

The synthesis of cis-alkenyl benzene Maude application embodiments Example 1 A synthesis of cis-alkenyl Maude benzene and benzene-cis-ene prepared Maude, the reaction was carried out according to the following scheme:

Specific preparation process steps performed in the following order:

(O methylation reaction

The 195.12g (Imol) of 3, 5-hydroxy-4-isopropyl benzoic acid, 414.57g (3mol) in DMF was added 5000ml anhydrous potassium carbonate, mixing, stirred at room temperature, then cooled in an ice-salt bath next, slowly added dropwise 425.85g (3mol) of iodomethane, warmed to room temperature after the addition was complete, the reaction 2h, after completion of the reaction was stirred with water, extracted with ethyl acetate, and concentrated to give 3,5-dimethoxy-4- isopropyl benzoate; yield 93%, purity of 99%.

[0033] (2) a reduction reaction

3000ml tetrahydrofuran and 240g (Imol) 3,5-dimethoxy-4-isopropyl benzoate, 151.40g (4mol) mixing at room temperature sodium borohydride was stirred and heated to reflux was slowly added dropwise 400ml methanol, reaction 4h, was added 3L of water was stirred, extracted with ethyl acetate, washed with water, the solvent was removed by rotary evaporation to give a white solid, to give 3,5-dimethoxy-4-isopropylbenzene methanol; 96% yield purity was 99%.

[0034] (3) the oxidation reaction

The 212g (ImoI) of 3,5-dimethoxy-4-isopropylbenzene methanol, DMSO 800ml and 500ml of acetic anhydride were mixed and stirred at rt After 2h, stirred with water, extracted with ethyl acetate, washed with water, dried , and concentrated to give 3,5-dimethoxy-4-isopropyl-benzaldehyde; 94% yield, 99% purity.

[0035] (4) a condensation reaction

The mixture was 209.18g (lmol) of 3,5-dimethoxy-4-isopropyl-benzoic awake and 136.15g (Imol) phenylacetic acid was added 5000ml of acetic anhydride, stirred to dissolve, sodium acetate was added 246.09g , heating to 135 ° C, the reaction after 6h, cooled to room temperature after adjusting the dilute acid 2 was added, extracted with ethyl acetate, the pH was concentrated, added saturated sodium bicarbonate solution adjusted to pH 7, stirred 2h, and extracted with dichloromethane , adding dilute aqueous hydrochloric acid pH 2, the yellow solid was filtered, to obtain 3,5-dimethoxy-4-isopropyl-stilbene acid; 96% yield, 80% purity.

[0036] (5) decarboxylation reaction

The 327g (Imol) of 3,5-dimethoxy-4-isopropyl-stilbene acid and 384g (6mol) of copper powder were added to 5000ml of quinoline, 180 ° C reaction 3h, cooled to room temperature ethyl acetate was added with stirring, filtered, and the filtrate was washed with dilute hydrochloric acid to the aqueous layer was colorless and the aqueous phase was extracted with ethyl acetate inverted, the organic layers were combined, washed with water and saturated brine until neutral, i.e., spin-dried to give 3,5 – dimethoxy-4-isopropyl-stilbene; 92% yield, 77% purity.

[0037] (6) Demethylation

The 282.32g (Imol) of 3,5-dimethoxy-4-isopropyl-stilbene 4000ml toluene was placed in an ice bath and stirring, was cooled to 0 ° C, and dissolved slowly added 605.9g (5mol after) in N, N- dimethylaniline, was added 666.7g (5mol) of anhydrous aluminum chloride. after stirring for 0.5h, warmed to room temperature, the reaction was heated to 100 ° C 2h, cooled to 60 ° C , hot toluene layer was separated, diluted hydrochloric acid was added to the aqueous phase with stirring to adjust the PH value of 2, extracted with ethyl acetate, washed with water, and concentrated to give the cis-alkenyl benzene Modesto; crude yield 95%, purity 74 %.After separation by column chromatography using 300-400 mesh silica gel, benzene-cis-ene was isolated Maude pure, 68% yield, 98.5% purity. The resulting cis-alkenyl benzene Maud NMR shown in Figure 1, NMR data are as follows:

1HNMR (CDCl3, 500 Hz, δ: ppm), 7.255 (m, 5H), 6.558 (d, 1H), 6.402 (d, 1H), 6.218 (s, 2H), 4.872 (s, 2H), 3.423 (m , 1H), 1.359 (q, 6H). Coupling constants / = 12.

[0038] trans-alkenyl benzene Maud NMR shown in Figure 2, the following NMR data:

1HNMR (CDCl3, 500 Hz, δ: ppm), 7.477 (d, 2H), 7.360 (t, 2H), 6.969 (q, 2H), 6.501 (s, 1H), 4.722 (s, 2H), 3.486 (m , 1H), 1.380 (t, 6H). Coupling constants / = 16.

[0039] HPLC conditions a cis alkenyl benzene Maude pure product: column was Nucleosil 5 C18; column temperature was 20 ° C; detection wavelength 318nm; mobile phase consisting of 50:50 by volume of acetonitrile and water; flow rate It was 0.6mL / min, injection volume of 5 μ L; cis phenalkenyl Maude 18.423min retention time of a peak in an amount of 96.39%, see Figure 3. Trans phenalkenyl Maude 17.630min retention time of a peak, the content was 99.8%, see Figure 4.After mixing the two, trans-alkenyl benzene Maude 17.664min retention time of the peak, cis-alkenyl benzene Maude 18.458min retention time of the peak, see Figure 5.

PATENT

https://patents.google.com/patent/CN103172497A/en

phenalkenyl Maude is a natural product, a metabolite as to be symbionts.Phenalkenyl Maud Escherichia coli, Staphylococcus aureus has a very significant inhibitory effect, in addition, there is a styrenic Maude suppression of inflammation and its reactive derivative with immunomodulating activity. Alkenyl benzene Modesto topical ointment as an active ingredient, as a class of drugs has been completed two clinical treatment of psoriasis and eczema, the results of ongoing clinical phase III clinical studies, it has been shown to be completed in both psoriasis and eczema clearly effect, together with a styrenic Maude is a non-hormonal natural small molecule compounds, can be prepared synthetically prepared, therefore, it exhibits good market prospect.

[0004] a styrenic Maude initial synthesis route is as follows:

[0005]

[0006] The reaction conditions for each step: 1) isopropanol, 80% sulfuric acid, 60 ° C, 65% .2) sodium borohydride, boron trifluoride, tetrahydrofuran, 0 ° C, 90% .3). of thionyl chloride, heated under reflux, 85% .4). triethyl phosphate, 120 ° C, 80% .5). benzaldehyde, sodium hydride, 85% .6) pyridine hydrochloride, 190 ° C, 60 %.

[0007] The chemical synthesis route, although ultimately obtained a styrenic Maude, but the overall yield is low, part of the reaction step is not suitable for industrial production, due to process conditions result in the synthesis of certain byproducts produced is difficult to remove impurities, difficult to achieve the quality standard APIs.

Preparation of 4-isopropyl-dimethoxy-benzoic acid [0011] 1,3,5_

[0012] 1000 l reactor 200 liters of 80% sulfuric acid formulation (V / V), the temperature was lowered to room temperature, put 80 kg 3,5_-dimethoxybenzoate ,, stirring gradually warmed to 60 ° C, in was added dropwise within 25 kg of isopropanol I hour, the reaction was complete after 5 hours, 500 liters of hot water, filtered, the filter cake was washed with a small amount of hot water I th, crushed cake was removed and dried. The dried powder was recrystallized from toluene, the product was filtered to give 78 kg `, yield 86%. Preparation 2,3,5_ dimethoxy-4-isopropylbenzene methanol

[0013] 1000 l reactor was added 50 kg 3,5_ _4_ isopropyl dimethoxy benzoic acid, 24 kg of potassium borohydride, 400 l of THF, at room temperature was slowly added dropwise 65 kg BF3.Et2O was stirred 12 hours, the reaction was complete, pure water was added dropwise to destroy excess BF3, filtered, concentrated to dryness, methanol – water to give an off-white recrystallized 40.3 kg, yield 90.1%.

[0014] Preparation of 3,3,5-_ ■ methoxy _4- isopropyl group gas section

[0015] 1000 l autoclave, 100 kg of 3,5-dimethoxy-4-isopropylbenzene methanol, 220 l of DMF, 0 ° C and added dropwise with stirring and 50 l of thionyl chloride, 24 hours after the reaction was complete, 300 liters of water and 300 liters of ethyl acetate, the aqueous phase was stirred layered discharged, and then washed with 200 liters of water was added 3 times, until complete removal of DMF, was added concentrated crystallized from petroleum ether to give 98 kg of white solid was filtered and dried a yield of 91%.

Preparation of methyl-dimethoxy-4-isopropylbenzene of diethyl [0016] 4,3,5_

[0017] 500 l autoclave, 98 kg 3,5_ _4_ isopropyl dimethoxy benzyl chloride and 120 l of triethyl phosphite, the reaction at 120 ° C 5h, fear distilled off under reduced pressure, the collection 145-155 ° C / 4mmHg fear minutes, cured at room temperature to give a colorless light solid was 118 kg, yield 81.6%.

, 3- [0018] 5, E-1 _ ■ methoxy-2-isopropyl-5- (2-phenylethyl lean-yl) – benzene

[0019] 500 l autoclave, 33 kg 3,5_-dimethoxy-4-isopropylbenzene acid diethyl ester, 10.8 kg of benzaldehyde, and 120 l of tetrahydrofuran, at 40 ° C, and nitrogen with stirring, was added dropwise a solution of 11.8 kg potassium tert-butoxide in 50 liters of tetrahydrofuran, the temperature dropping control not to exceed 50 ° C. after the dropwise addition stirring was continued for I h, the reaction was complete, 150 liters of ethyl acetate and extracted , washed twice with 150 liters of water, 100 l I washed with brine, and the organic phase was dried and concentrated, methanol – water (I: D as a white crystalline solid 25.3 kg, yield 91%.

[0020] 6> 1, 3 ~ _ ■ Light-2-isopropyl-5- (2-phenylethyl lean-yl) – benzene (I), (De Dae dilute benzene)

[0021] 100 l autoclave, 10 kg 1,3_-dimethoxy-2-isopropyl-5- (2-styryl) benzene _ pyridine hydrochloride and 25 kg nitrogen atmosphere was heated to 180 -190 ° C, stirred for 3 hours after the reaction was completed, 20 l HCl (2N) cooling to 100 ° C, and 20 liters of ethyl acetate the product was extracted, dried and concentrated to give the product 7.3 kg, 83% yield.

[0022] The method for purifying:

[0023] 100 l added to the reaction vessel 15.5 kg of crude product and 39 liters of toluene, heated to the solid all dissolved completely, filtered hot and left to crystallize, after crystallization, filtration, the crystals with cold toluene 10 washed liter at 60 ° C, protected from light vacuo dried for 24 hours, to obtain 14 kg of white needle crystals, yield 90%.

CLIP

https://www.eosmedchem.com/article/237.html

Design new synthesis of Route of Benvitimod

Nov 26, 2018

1.Benvitimod and intermediates
Benvitimod 79338-84-4  intermediate： 1999-10-5
Benvitimod 79338-84-4  intermediate： 2150-37-0
Benvitimod 79338-84-4  intermediate： 344396-17-4
Benvitimod 79338-84-4  intermediate： 344396-18-5
Benvitimod 79338-84-4  intermediate： 344396-19-6
Benvitimod 79338-84-4  intermediate： 1080-32-6
Benvitimod 79338-84-4  intermediate： 678986-73-7
Benvitimod 79338-84-4  intermediate： 55703-81-6
Benvitimod 79338-84-4  intermediate： 1190122-19-0
Benvitimod 79338-84-4  intermediate： 443982-76-1
Benvitimod 79338-84-4  intermediate： 100-52-72.ROS-Benvitimod
(1)

(2)
3.
Name: Benvitimod
CAS#: 79338-84-4
Chemical Formula: C17H18O2
Exact Mass: 254.1307
Molecular Weight: 254.329
Elemental Analysis: C, 80.28; H, 7.13; O, 12.58

References

///Benvitimod, Tapinarof, WBI-1001, тапинароф , تابيناروف , 他匹那罗 , Welichem Biotech, Stiefel Laboratories, Shenzhen Celestial Pharmaceuticals,CHINA 2019 , Psoriasis, Tianji Pharma, Dermavant Sciences, PHASE 3

LENALIDOMIDE

• Molecular FormulaC₁₃H₁₃N₃O₃
• Average mass259.261 Da

SYN

https://link.springer.com/article/10.1007/s10593-015-1670-0

A new process for the synthesis of anticancer drug lenalidomide was developed, using platinum group metal-free and efficient reduction of nitro group with the iron powder and ammonium chloride. It was found that the bromination of the key raw material, methyl 2-methyl-3-nitrobenzoate, could be carried out in chlorine-free solvent methyl acetate without forming significant amounts of hazardous by-products. We also have compared the known synthetic methods for cyclization of methyl 2-(bromomethyl)-3-nitrobenzoate and 3-aminopiperidinedione to form lenalidomide nitro precursor.

SYN

Lenalidomide

Trade Names

Country	Trade Name	Vendor	Annotation
D	Revlimid	Celgene
GB	Revlimid	Celgene
USA	Revlimid	Celgene ,2005

Formulations

• cps. 5 mg, 10 mg

References

• • WO 9 803 502 (Celgene; 29.1.1998; USA-prior. 24.7.1996).
  • WO 2 006 028 964 (Celgene; 16.3.2006; USA-prior. 3.9.2004).
  • US 5 635 517 (Celgene; 3.6.1997; USA-prior. 24.7.1996).

• medical use for treatment of certain leukemias:

  • US 2 006 030 594 (Celgene; 9.2.2006; USA-prior. 4.10.2005).

• alternative preparation of III:

  • WO 2 005 005 409 (Siegfried Ltd.; 20.1.2005; CH-prior. 9.7.2003).

References

1. ^ Jump up to:^{a b c d e} REVLIMID [package insert]. Summit, NJ: Celgene Corporation; 2017. Accessed at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021880s055lbl.pdf on 14 September 2018.
2. ^ McCarthy PL, Owzar K, Hofmeister CC, et al. (2012). “Lenalidomide after stem-cell transplantation for multiple myeloma”. N. Engl. J. Med. 366 (19): 1770–81. doi:10.1056/NEJMoa1114083. PMC 3744390. PMID 22571201.
3. ^ Jump up to:^a b c Badros AZ (10 May 2012). “Lenalidomide in Myeloma — A High-Maintenance Friend”. N Engl J Med. 366 (19): 1836–1838. doi:10.1056/NEJMe1202819. PMID 22571206.
4. ^ “World Health Organization model list of essential medicines: 21st list 2019”. 2019. hdl:10665/325771.
5. ^ Armoiry X, Aulagner G, Facon T (June 2008). “Lenalidomide in the treatment of multiple myeloma: a review”. Journal of Clinical Pharmacy and Therapeutics. 33 (3): 219–26. doi:10.1111/j.1365-2710.2008.00920.x. PMID 18452408.
6. ^ Jump up to:^a b Li S, Gill N, Lentzsch S (November 2010). “Recent advances of IMiDs in cancer therapy”. Curr Opin Oncol. 22 (6): 579–85. doi:10.1097/CCO.0b013e32833d752c. PMID 20689431.
7. ^ Tageja N (March 2011). “Lenalidomide – current understanding of mechanistic properties”. Anti-Cancer Agents Med. Chem. 11 (3): 315–26. doi:10.2174/187152011795347487. PMID 21426296.
8. ^ Kotla V, Goel S, Nischal S, et al. (August 2009). “Mechanism of action of lenalidomide in hematological malignancies”. J Hematol Oncol. 2: 36. doi:10.1186/1756-8722-2-36. PMC 2736171. PMID 19674465.
9. ^ Yang B, Yu RL, Chi XH, et al. (2013). “Lenalidomide treatment for multiple myeloma: systematic review and meta-analysis of randomized controlled trials”. PLoS ONE. 8 (5): e64354. doi:10.1371/journal.pone.0064354. PMC 3653900. PMID 23691202.
10. ^ Dimopoulos MA, Richardson PG, Brandenburg N, et al. (22 March 2012). “A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide”. Blood. 119 (12): 2764–7. doi:10.1182/blood-2011-08-373514. PMID 22323483.
11. ^ “FDA approves lenalidomide oral capsules (Revlimid) for use in combination with dexamethasone in patients with multiple myeloma”. Food and Drug Administration (FDA). 29 June 2006. Retrieved 15 October 2015.
12. ^ “Approved Drugs – Lenalidomide (Revlimid)”. Food and Drug Administration (FDA).
13. ^ “REVLIMID Receives Positive Final Appraisal Determination from National Institute for Health and Clinical Excellence (NICE) for Use in the National Health Service (NHS) in England and Wales”. Reuters. 23 April 2009.
14. ^ Ness, Stacey (13 March 2014). “New Specialty Drugs”. Pharmacy Times. Retrieved 5 November 2015.
15. ^ Jump up to:^a b List A, Kurtin S, Roe DJ, et al. (February 2005). “Efficacy of lenalidomide in myelodysplastic syndromes”. The New England Journal of Medicine. 352 (6): 549–57. doi:10.1056/NEJMoa041668. PMID 15703420.
16. ^ “PDGFRB platelet derived growth factor receptor beta [Homo sapiens (human)] – Gene – NCBI”.
17. ^ Nimer SD (2006). “Clinical management of myelodysplastic syndromes with interstitial deletion of chromosome 5q”. Journal of Clinical Oncology. 24 (16): 2576–82. doi:10.1200/JCO.2005.03.6715. PMID 16735711.
18. ^ List AF (August 2005). “Emerging data on IMiDs in the treatment of myelodysplastic syndromes (MDS)”. Seminars in Oncology. 32 (4 Suppl 5): S31–5. doi:10.1053/j.seminoncol.2005.06.020. PMID 16085015.
19. ^ List A, Dewald G, Bennett J, et al. (October 2006). “Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion”. The New England Journal of Medicine. 355 (14): 1456–65. doi:10.1056/NEJMoa061292. PMID 17021321.
20. ^ “Revlimid Approved In Europe For Use In Myelodysplastic Syndromes”. The MDS Beacon. Retrieved 17 June 2013.
21. ^ “Phase II Study of Lenalidomide for the Treatment of Relapsed or Refractory Hodgkin’s Lymphoma”. ClinicalTrials.gov. US National Institutes of Health. February 2009.
22. ^ “276 current clinical trials world-wide, both recruiting and fully enrolled, as of 27 February 2009”. ClinicalTrials.gov. US National Institutes of Health. February 2009.
23. ^ “Celgene Discontinues Phase 3 Revlimid Study after ‘Imbalance’ of Deaths”. Nasdaq. 18 July 2013.
24. ^ Rao KV (September 2007). “Lenalidomide in the treatment of multiple myeloma”. American Journal of Health-System Pharmacy. 64 (17): 1799–807. doi:10.2146/ajhp070029. PMID 17724360.
25. ^ “Revlimid Summary of Product Characteristics. Annex I” (PDF). European Medicines Agency. 2012. p. 6.
26. ^ Bennett CL, Angelotta C, Yarnold PR, et al. (December 2006). “Thalidomide- and lenalidomide-associated thromboembolism among patients with cancer”. JAMA: The Journal of the American Medical Association. 296 (21): 2558–60. doi:10.1001/jama.296.21.2558-c. PMID 17148721.
27. ^ “Potential Signals of Serious Risks/New Safety Information Identified from the Adverse Event Reporting System (AERS) between January – March 2008”. Food and Drug Administration (FDA). March 2008.
28. ^ “FDA Drug Safety Communication: Ongoing safety review of Revlimid (lenalidomide) and possible increased risk of developing new malignancies”. Food and Drug Administration(FDA). April 2011.
29. ^ Vallet S, Palumbo A, Raje N, et al. (July 2008). “Thalidomide and lenalidomide: Mechanism-based potential drug combinations”. Leukemia & Lymphoma. 49 (7): 1238–45. doi:10.1080/10428190802005191. PMID 18452080.
30. ^ Zhu YX, Braggio E, Shi CX, et al. (2011). “Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide”. Blood. 118 (18): 4771–9. doi:10.1182/blood-2011-05-356063. PMC 3208291. PMID 21860026.
31. ^ Stewart AK (2014). “Medicine. How thalidomide works against cancer”. Science. 343(6168): 256–7. doi:10.1126/science.1249543. PMC 4084783. PMID 24436409.
32. ^ “Top 10 Best-Selling Cancer Drugs of 2018”. Genetic Engineering and Biotechnology News. 22 April 2019. Retrieved 25 April 2019.
33. ^ “Revlimid faces NICE rejection for use in rare blood cancer Watchdog’s draft guidance does not recommend Celgene’s drug for NHS use in England and Wales”. Pharma News. 11 July 2013. Retrieved 5 November 2015.

Further reading

• Chang DH, Liu N, Klimek V, et al. (July 2006). “Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications”. Blood. 108 (2): 618–21. doi:10.1182/blood-2005-10-4184. PMC 1895497. PMID 16569772.
• Anderson KC (October 2005). “Lenalidomide and thalidomide: mechanisms of action–similarities and differences”. Seminars in Hematology. 42 (4 Suppl 4): S3–8. doi:10.1053/j.seminhematol.2005.10.001. PMID 16344099.

External links

• Official website Includes list of adverse reactions
• Prescribing Information
• International Myeloma Foundation article on Revlimid
• multiplemyeloma.org Revlimid April 2007 Summary

Lenalidomide

Clinical data
Pronunciation	/ˌlɛnəˈlɪdoʊmaɪd/
Trade names	Revlimid
AHFS/Drugs.com	Monograph
MedlinePlus	a608001
License data	EU EMA: by INN
Pregnancy category	AU: X (High risk) US: X(Contraindicated)
Routes of administration	Oral (capsules)
ATC code	L04AX04 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	Undetermined
Protein binding	30%
Metabolism	Undetermined
Elimination half-life	3 hours
Excretion	Renal (67% unchanged)
Identifiers
IUPAC name[show]
CAS Number	191732-72-6
PubChem CID	216326
IUPHAR/BPS	7331
DrugBank	DB00480
ChemSpider	187515
UNII	F0P408N6V4
KEGG	D04687
ChEMBL	ChEMBL848
CompTox Dashboard(EPA)	DTXSID8046664
ECHA InfoCard	100.218.924
Chemical and physical data
Formula	C13H13N3O3
Molar mass	259.261 g/mol g·mol−1
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES[hide] O=C1NC(=O)CCC1N3C(=O)c2cccc(c2C3)N
InChI[hide] InChI=1S/C13H13N3O3/c14-9-3-1-2-7-8(9)6-16(13(7)19)10-4-5-11(17)15-12(10)18/h1-3,10H,4-6,14H2,(H,15,17,18)  Key:GOTYRUGSSMKFNF-UHFFFAOYSA-N

//////////LENALIDOMIDE, レナリドミド ,REVLIMID, Celgene Corporation, леналидомид , ليناليدوميد , 来那度胺 , 

NILOTINIB

• Molecular FormulaC₂₈H₂₂F₃N₇O
• Average mass529.516 Da

Nilotinib (AMN107, trade name Tasigna^[2]), in the form of the hydrochloride monohydrate salt, is a small-molecule tyrosine kinase inhibitor approved for the treatment of imatinib-resistant chronic myelogenous leukemia.^[3] Structurally related to imatinib,^[4] it was developed based on the structure of the Abl-imatinib complex to address imatinib intolerance and resistance.^[5][6][7] Nilotinib is a selective Bcr-Abl tyrosine kinase inhibitor^[5][6] that is 10–30 fold more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl expressing cells.^[4][6][7][8] Nilotinib was developed by Novartis and is sold under the trade name Tasigna.^[9]

Medical uses

It is FDA– (29 October 2007),^[10] EMA– (29 September 2009),^[11] MHRA– (19 November 2007)^[12] and TGA– (17 January 2008)^[13] approved for use as a treatment for Philadelphia chromosome (Ph+)-positive chronic myelogenous leukaemia.^[1]

The drug carries a black box warning for possible heart complications.^[14][15]

Clinical trials

CML

In June 2006, a phase I clinical trial found nilotinib has a relatively favorable safety profile and shows activity in cases of CML resistant to treatment with imatinib, another tyrosine kinase inhibitor currently used as a first-line treatment.^[16] In that study 92% of patients (already resistant or unresponsive to imatinib) achieved normal white blood cell counts after five months of treatment.^[17]

Contraindications

Contraindications include long QT syndrome, hypokalaemia, hypomagnesaemia, pregnancy, planned pregnancy, lactation and galactose/lactose intolerance.^[1][13]

Cautions include:^[1]

Dose reduction of nilotinib has been recommended in hepatically impaired population which involves recommendation of lower starting dose and monitoring of any hepatic function abnormalities.^[18]

Adverse effects

Nilotinib has a number of adverse effects typical of anti-cancer drugs. These include headache, fatigue, gastrointestinal problems such as nausea, vomiting, diarrhea and constipation, muscle and joint pain, rash and other skin conditions, flu-like symptoms, and reduced blood cell count. Less typical side effects are those of the cardiovascular system, such as hypertension (high blood pressure), various types of arrhythmia, and prolonged QT interval. Nilotinib can also affect the body’s electrolyte and glucosebalance.^[10] Though pulmonary-related adverse effects are rare when compared with imatinib and dasatinib, there is a case report of acute respiratory failure from diffuse alveolar hemorrhage in a patient taking nilotinib.^[19]

Interactions

Nilotinib has been reported as a substrate for OATP1B1 and OATP1B3. Interaction of nilotinib with OATP1B1 and OATP1B3 may alter its hepatic disposition and can lead to transporter mediated drug-drug interactions.^[18] Nilotinib is an inhibitor of OATP-1B1 transporter but not for OATP-1B3.^[20]

It is a substrate for CYP3A4 and hence grapefruit juice and other CYP3A4 inhibitors^[21] will increase its action and inducers like St. John’s wort^[22] will decrease it. Patients report that pomegranates and starfruit may also interfere.

Food should not be eaten two hours before or one hour afterwards because it unpredictably increases its bioavailability, approximately doubling it.

Pharmacology

Nilotinib inhibits the kinases BCR-ABL,^[23] KIT, LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11 and ZAK.^[24]

Research

Parkinson’s disease

There is weak evidence that nilotinib may be beneficial with Parkinson’s Disease (PD), with a small clinical trial suggesting it might halt progression and improve symptoms.^[25]However, there were significant side effects including infection, liver function tests abnormalities, hallucinations and heart attack, and the benefit in PD disappeared at follow up after drug discontinuation, raising question as to whether it was truly a disease modifying therapy. Nilotinib is currently undergoing phase II studies for treatment of Parkinson’s.^[26]Scientists and medical professionals have advised caution with over-optimistic interpretation of its effects in Parkinson’s due to the significant media hype surrounding the small and early clinical trial.^[27][28]

Other

Novartis announced on April 11, 2011 that it was discontinuing a phase III trial of Tasigna (nilotinib) for investigational use in the first-line treatment of gastrointestinal stromal tumor(GIST) based on the recommendation of an independent data monitoring committee. Interim results showed Tasigna is unlikely to demonstrate superiority compared to Novartis’s Gleevec (imatinib)*, the current standard of care in this setting.^[29]

Low dose nilotinib is also being investigated for use for and Alzheimer’s disease, as well as for ALS, dementia and Huntington’s disease.^[30]

Patent

WO 2016024289, NILOTINIB, New Patent by SUN

SUN PHARMACEUTICAL INDUSTRIES LTD [IN/IN]; 17/B, Mahal Industrial Estate, Off Mahakali Caves Road, Andheri (east), Mumbai 400093 (IN)

THENNATI, Rajamannar; (IN).
KILARU, Srinivasu; (IN).
VALANCE SURENDRAKUMAR, Macwan; (IN).
SHRIPRAKASH DHAR, Dwivedi; (IN)

The present invention provides novel salts of nilotinib and polymorphs thereof. The acid addition salts of nilotinib with benzenesulfonic acid, butanedisulfonic acid, 1-5- naphthalenedisulfonic acid, naphthalene-1-sulfonic acid and 1-hydroxynaphthoic acid; hydrates and anhydrates thereof.

Nilotinib, 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino] -benzamide, having the following formula

is marketed under the name Tasigna® in US and Europe. Tasigna contains nilotinib monohydrate monohydrochloride salt and is available as capsules for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. Tasigna is also indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib.

Nilotinib is considered a low solubility/low permeability (class IV) compound in the Biopharmaceutics Classification System (BCS). Therefore, dissolution of nilotinib can potentially be rate limiting step for in-vivo absorption. It is soluble in acidic media; being practically insoluble in buffer solutions of pH 4.5 and higher.

WIPO publication 2014059518A1 discloses crystalline forms of nilotinib hydrochloride and methods of the preparation of various crystalline solvates of nilotinib hydrochloride including benzyl alcohol, acetic acid and propylene glycol.

WIPO publication 2011033307A1 discloses nilotinib dihydrochloride and its hydrates and method for their preparation.

WIPO publication 2011163222A1 discloses the preparation of nilotinib salts and crystalline forms thereof. The salts of nilotinib disclosed are hydrochloride, fumarate, 2-chloromandelate, succinate, adipate, L-tartrate, glutarate, p-toluenesulfonate, camphorsulfonate, glutamate, palmitate, quinate, citrate, maleate, acetate, L-malate, L-aspartate, formate, hydrobromide, oxalate and malonate.

WIPO publication number 2011086541A1 discloses a nilotinib monohydrochloride monohydrate salt and methods for preparing.

WIPO publication number 2010054056A2 describes several crystalline forms of nilotinib hydrochloride.

WIPO publication number 2007/015871A1 discloses the preparation of nilotinib salts and crystalline forms thereof. The salts are mixtures of nilotinib and one acid wherein the acids are selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, sulfonic acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, p-toluene sul- fonic acid, citric acid, fumaric acid, gentisic acid, malonic acid, maleic acid, and tartaric acid.

WIPO publication number 2007015870A2 discloses several nilotinib salts including amorphous and crystalline forms of nilotinib free base, nilotinib HC1 and nilotinib sulfate along with their hydrate and solvates.

EXAMPLES:

Example 1: Preparation of nilotinib benzenesulfonate crystalline Form I

Nilotinib base (1 g) was suspended in water (20 ml). A solution of benzenesulfonic acid (0.4 g) in water (3ml) was added and the content was heated at 60 °C for 2-3 h. The mixture was cooled to 25-30 °C, filtered, washed with water (3 x 5 ml) and dried under vacuum for 2 h at 50-55 °C.

1H NMR (500 MHz, DMSO-d6) δ 2.40 (s,3H), 2.42 (s,3H), 7.35-7.37 (m,3H), 7.51-7.66 (m,5H),7.83 (d,lH), 7.96 (s,lH),8.08 (s,lH),8.30 (s,lH) 8.39 (s,lH),8.54 (d,lH), 8.61 (d,lH), 8.64 (s,lH), 8.75 (d,lH), 9.25 (s,lH), 9.34 (d,lH), 9.61 (s,lH), 10.84 (s,lH).

The salt provides an XRPD pattern substantially same as set forth in FIG. 1.

Example 2: Preparation of nilotinib butanedisulfonate (2: 1) crystalline Form II

Nilotinib base (100 g) was dissolved in 20 % water in THF solution (2000 ml) at 60-65 °C and insoluble matter was filtered. The filtrate was concentrated under vacuum below 60 °C. Filtered water (1000 ml) was added to the reaction mixture and it was heated at 50-55 °C, followed by addition of 1,4-butanedisulfonic acid -60% aqueous solution (28.6 ml) at same temperature. The content was stirred at 50-55 °C for 2-3h. Reaction mixture as cooled to 25-30 °C and product was filtered, washed with water (200 ml x 2) and dried in air oven at 50-55 °C (yield: 115 g).

Purity (by HPLC):99.76%

1H NMR (400 MHz,DMSO-d6) δ 1.63-1.66(m,2H), 2.40(d,3H),2.42(s,3H),2.43-2.47(m,2H), 7.51-7.62(m,3H),7.85(dd,lH),7.96(s,lH),8.08(s,lH),8.34(s,lH),8.38(d,lH),8.52-8.55(m,lH), 8.60-8.62 (m,2H), 8.75(d,lH), 9.25(S,1H),9.34(S,1H),9.59(S,1H),10.86(S,1H)

Water content: 7.95 %.

The salt has a XRPD pattern substantially same as set forth in FIG. 2.

Example 3: Preparation of nilotinib butanedisulfonate (2: 1) crystalline Form II

Nilotinib base (300 g) was suspended in methanol (3000 ml) and aqueous hydrochloric acid was added to get pH less than 2. Reaction contents were heated at reflux and was filtered and washed with methanol (100 ml). 5% (w/w) NaOH (1200 ml) solution was added at 40-45 °C within 15 min, reaction mixture was stirred for 2h. Product was filtered, washed with water

(300 ml x 3) and dried for lh. Wet material was suspended in water (3000 ml), heated at 50- 55 °C followed by addition of 1,4-butanedisulfonic acid -60% aqueous solution. The reaction mixture was stirred at 50-55°C for 2hrs. Product was filtered at room temperature, washed with water (500 ml x 2) and dried in air oven at 50-55 °C (yield: 293 g).

Purity (by HPLC): 99.88 %

¹H NMR (400 MHz,DMSO-d6+TFA-dl) δ 1.75-1.78(m,2H), 2.36(d,3H),2.38(s,3H),2.69- 2.72(m,2H),7.45(d,lH),7.68(d,lH),7.83(s,lH),7.88(dd,lH),7.97(s,lH),8.16-8.19(m,lH), 8.35

(s,2H), 8.63(d,lH),8.68(d,lH),9.04(d,lH),9.21(d,lH),9.53(br s,lH),9.69(d,lH)10.80 (s,lH)

Water content: 6.44 %

Example 4: Preparation of nilotinib butanedisulfonate (2: 1) crystalline Form III

Nilotinib butanedisulfonate (210g) was dissolved in acetic acid water mixture (50:50) (2520 ml) at 75-80 °C and was filtered to remove insoluble matter and washed with acetic acid water mixture (50:50) (210 ml). Water (3150ml) was added to the filtrate and stirred first at room temperature and then at 0-5 °C. Product was filtered and washed with water. Material was dried in air oven at 70-75 °C. Dried material was leached with methanol (3438 ml) at reflux temperature, filtered and dried in air oven 70-75°C (yield: 152.6 g)

Purity (by HPLC): 99.89 %

1H NMR (400 MHz,DMSO-d6+TFA-dl) δ 1.73-1.77(m,2H), 2.40(s,6H),2.67-2.70(m,2H), 7.50 (d,lH), 7.70(d,lH), 7.88-7.92(m,2H), 8.07(s,lH),8.23 (dd,lH), 8.34(s,2H), 8.67 (d,lH), 8.72 (d,lH), 9.09(d,lH), 9.23 (s,lH), 9.54(d,lH), 9.74(d,lH), 10.86(s,lH).

Water content: 0.61 %

The salt provides an XRPD pattern substantially same as set forth in FIG. 3.

Example 5: Preparation of crystalline form of nilotinib butanedisulfonate (2: 1)

Crystalline Nilotinib butanedisulfonate (1 g) of Example 2 was suspended in methanol (20 ml) and was stirred at reflux for 60 min. The mixture was cooled to room temperature. Solid was filtered, washed with methanol (2 ml x 3) and dried in air oven at 70-75°C (yield: 0.8 g)

Example 6: Preparation of nilotinib butanedisulfonate (1: 1) crystalline Form IV

Nilotinib base (20 g) was suspended in methanol (800 ml) and 1,4-butanedisulfonic acid -60

% aqueous solution (6 ml) was added at 50-55 °C, and was filtered to remove insoluble matter. Filtrate was stirred at room temperature for 2-3 h. Product formed was filtered, washed with methanol (20 ml x 2) and dried the product in air oven at 70-75 °C (yield: 18.4 g).

Purity (by HPLC):99.86 %

1H NMR (400 MHz,DMSO-d6) δ 1.64-1.68(m,4H), 2.47-2.5 l(m,4H), 2.41(s,3H), 2.42(d,3H), 7.52(d,lH), 7.83-7.89(m,2H), 7.99(s,lH), 8.15(s,lH), 8.36 (d,lH), 8.39(s,lH), 8.65-8.66(m,2H), 8.79(d,lH), 8.89(br s,lH), 9.36(s,lH), 9.41(br s,lH), 9.74(d,lH), 10.91(s,lH).

The salt has XRPD pattern substantially same as set forth in FIG. 4.

Example 7: Preparation of nilotinib 1,5-napthalenedisulfonic acid salt (2: 1) crystalline Form V

Nilotinib base (1 g) was suspended in water (20 ml). A solution of 1,5-napthalenedisulfonic acid (0.4 g; 0.6 eq.) in water (5ml) was added and the content was heated at 50-55 °C for lh. The mixture was cooled to 25-30 °C, filtered and washed with water (10 ml). The product was dried in air oven at 50-55°C (yield: 1.2 g).

1H NMR (400 MHz,DMSO-d6) δ 2.39 (s,3H), 2.42 (s,3H), 7.45-7.61 (m,4H),7.84 (d,lH), 7.97(s,2H),8.08 (m,lH),8.31 (s,lH) 8.38 (s,lH),8.55 (d,lH), 8.63 (s,2H), 8.75 (s,lH), 8.92 (d,lH), 9.26 (s, 1H), 9.34 (s,lH),9.62 (s,lH), 10.85 (s,lH).

The salt has a XRPD pattern substantially same as set forth in FIG. 5.

Example 8: Preparation of nilotinib 1,5-napthalenedisulfonic acid salt (1: 1) crystalline Form VI

Nilotinib base (1 g) was suspended in water (20 ml). A solution of 1,5-napthalenedisulfonic acid (0.8 g; 1.2eq) in water (5 ml) was added and the content was heated at 50-55 °C for 1 h. The mixture was cooled to 25-30 °C, filtered, washed with water (10 ml) and dried in air oven at 50-55 °C (yield: 1.4g).

1H NMR(400 MHz,DMSO-d6) δ 2.40 (s,3H),2.41 (s,3H), 7.43-7.52 (m,3H),7.61 (d,lH), 7.85-7.99(m,5H),8.11 (s,lH),8.34 (s,2H), 8.64-8.67 (m,2H), 8.89-8.92 (m,4H),9.40(d,2H), 9.72 (s,lH), 10.87 (s,lH).

The salt has a XRPD pattern substantially same as set forth in FIG. 6.

Example 9: Preparation of nilotinib napthalene-1- sulfonic acid salt crystalline Form VII Nilotinib base (1 g) was suspended in water (10 ml) and heated to 50-55 °C. A solution of napthelene-1 -sulfonic acid and methanol (10 ml) was added to it and heated at 70-75 °C for 30 min. The mixture was cooled to 25-30 °C and stirred for 10 min. The product was filtered, washed with water (2 x 2 ml) and dried under vacuum for 1-2 h at 50-55 °C.

1H NMR (400 MHz,DMSO-d6) δ 2.41 (s,3H),2.42 (s,3H), 7.46-7.58 (m,5H), 7.70-8.00 (m,7H)8.11(s,lH)8.31(s,lH),8.37(s,lH),8.63-8.66 (m,3H), 8.81-8.89 (m,2H), 9.31 (s,lH), 9.37 (d,lH), 9.71 (d,lH), 10.86 (s,lH)

The salt has a XRPD pattern substantially same as set forth in FIG. 7.

Example 10: Preparation of nilotinib l-hydroxy-2-napthoic acid salt crystalline Form VIII Nilotinib base (1 g) was suspended in water (20 ml) and heated to 50-55 °C. l-Hydroxy-2-napthoic acid was added to it and the content was heated at 50-55 °C for 1 h. Methanol (5 ml) was added to the mixture and stirred for 30 min. The content was filtered, washed with water (2 x 2 ml) and dried under vacuum for 1 h at 50-55 °C.

1H NMR (400 MHz, DMSO-d6) δ 2.25 (s,3H), 2.41 (s,3H), 7.40-7.92 (m,l lH), 8.23-8.73 (m,8H), 9.24 (s,lH), 9.34(s,lH), 10.70 (s,lH).

The salt has a XRPD pattern substantially same as set forth in FIG. 8.

PATENT

https://patents.google.com/patent/WO2010009402A2/en

Nilotinib, 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-

(trifluoromethyl)phenyl] -3 – [ [4-(3 -pyridinyl)-2-pyrimidinyl] amino] -benzamide, having the following formula

is a tyrosine kinase inhibitor used for the treatment of drug-resistant chronic myelogenous leukemia (CML), and in particular, for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukemia (CML) in adult patients whose disease has progressed on or who cannot tolerate other therapies that included imatinib. Nilotinib is administered as a hydrochloride salt in forms of capsules that are marketed in the USA and the EU under the name Tasigna®.

[0004] US patent no. 7,169,791 (“US 791”) and its parallel PCT publication WO

2004/005281, the journal article in Synthesis, 2007, vol 14, pp 2121-2124, as well as PCT publication nos.: WO 2006/135640, WO 2006/135641 (“WO “641”), WO 2007/018325 and WO 2007/017734, report processes for preparing Nilotinib intermediate, 3-(trifluoromethyl)- 5-(4-methyl-lH-imidazole-l-yl)-benzeneamine of formula I

I by reacting 3-bromo-5-trifluoromethylaniline of formula II and 4-methylimidazole of formula III in the presence of a non-alkaline hydroxide inorganic base, such as potassium carbonate, cesium carbonate and sodium hydride, a copper (I) salt, such as copper iodide and a complexing amine ligand, such as ethylene diamine. The process can be illustrated by the following scheme:

Il ‘

Scheme 1

[0005] The journal article in Synthesis, 2007, VoI 14, pp 2121-2124, describes a purification process of 3-(trifluoromethyl-5-(4-methyl-lH-imidazole-l-yl)-benzeneamine of formula I.

[0006] US 791 describes processes for preparing Nilotinib and its different intermediates, using di-ethyl cyano phosphate, as described in the following scheme:

[0007] WO ‘641 further describes a process for preparing Nilotinib according to the following scheme:

Scheme 3

[0008] The present invention provides improved processes to prepare and/or purify 3-

(trifluoromethyl)-5-(4-methyl-lH-imidazole-l-yl)-benzeneamine of formula I without requiring the use of column chromatography, and thus can be easily applied to large scale manufacture, as well as new intermediates of Nilotinib, which result in higher yields in the preparation of Nilotinib.

[0009] PCT publications WO 2007/015870 (“WO ‘870”) and WO 2007/015871

(“WO ‘871”) describe several Nilotinib salts including crystalline forms of nilotinib free base, Nilotinib hydrochloride and Nilotinib Sulfate.

[0010] The present invention also relates to the solid state physical properties of

Nilotinib^»3HCl, 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3- [[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide trihydrochloride. These properties can be influenced by controlling the conditions under which Nilotinib-3HC1 is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must necessitate the use of glidants such as colloidal silicon dioxide, talc, starch, or tribasic calcium phosphate.

[0011 ] Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient’s stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally administered active ingredient can reach the patient’s bloodstream. The rate of dissolution is also a consideration in formulation syrups, elixirs, and other liquid medicaments. The solid state form of a compound can also affect its behavior on compaction and its storage stability. [0012] These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which define a particular polymorphic form of a substance. The polymorphic form can give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form can also give rise to distinct spectroscopic properties that can be detectable by powder x-ray crystallography, solid state ¹³C NMR spectroscopy, and infrared spectrometry.

[0013] Generally, a crystalline solid has improved chemical and physical stability over the amorphous form, and forms with low crystallinity. Crystalline forms may also exhibit improved solubility, hygroscopicity, bulk properties, and/or flowability.

[0014] The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

[0015] There is a need in the art for new intermediates of Nilotinib and processes for their preparation, new processes for preparing Nilotinib and new crystalline forms of Nilotinib^»3HCl salt and processes for the preparation thereof.

xample 1: Preparation of 3-(ϊrifluoromethyl)-5-(4-methyl-lH-imidazole-l-yl)- benzeneamine of formula I

[00245] 200Og of 3-bromo-5- trifluoromethylaniline of formula II, 1368g of 4- methylimidazole of formula III , 181g of 8-hydroxyquinoline, 238g of CuI, 666.6g of NaOH, 933g of CaO and 7000ml of DMSO were loaded into a 1OL of 3-neck flask. The reaction mixture was protected with nitrogen and was then stirred at 12O⁰C for 69 hours while monitoring for the consumption of 3-bromo-5- trifluoromethy aniline by HPLC. Heating was stopped when 3-bromo-5- trifluoromethyaniline / 4-methylimidazole is not more than 5%. The reaction mixture was cooled down to 45-5O⁰C and poured into a 5OL reactor. 8.4L of 14% ammonia was added dropwise and then stirred for lhour at 45-5O⁰C. The mixture was cooled down to room temperature.16.8L of water and 1OL of ethyl acetate were added to the extract. The upper organic layer was separated and filtered through the filter aid. The lower aqueous layer was washed with 7.5L of ethyl acetate and combined with the above filtrate.

The combined organic layer was washed with 5L*3 of 5% of brine for three times. The upper organic layer was separated and dried over lkg of anhydrous Na₂SO₄overnight. The mixture was filtered and concentrated to obtain 2.3kg of solid. The residue was dissolved in 2L of ethyl acetate at 45⁰C. To the solution was then added 8L of petroleum ether dropwise at 45⁰C. The mixture was cooled down slowly to 0-15⁰C and stirred for lhour. A large amount of precipitate was formed and filtered. The filtered cake was dissolved in 2L of ethyl acetate at 45⁰C. The solution was then added 8L of petroleum ether dropwise at 45⁰C. The mixture was cooled down slowly to 15-O⁰C and stirred for lhour. A large precipitate was formed and filtered. The filter cake was dried at 45⁰C and 954g of 3-(trifluoromethyl)-5-(4-methyl-lH- imidazole-l-yl)-benzeneamine of formula I were obtained. (Yield: 47.5%). The obtained compound of formula I had purity of 99.7% on area by HPLC and contained 0.13% on area by HPLC, of the 5 methyl isomer impurity.

Example 2: Recrystallization of 3-ftrifluoromethyl)-5-f4-methyl-lH-imidazole-l-yl)- benzeneamine of formula I from IPA/water

[00246] A 5OmL flask was charged with Ig of the compound of Formula I crude

(purity of 82.5%) and 3.5mL of IPA. The mixture was heated to 45°C under stirring until the entire solid dissolved. At 45°C, 6mL of water was added drop-wise. The mixture was stirred for lOmin and cooled slowly to 0~10°C. The mixture was stirred at 0~10°C for 10 min and filtered to obtain the recrystallized compound of Formula I having a purity of 98%.

Example 3: Recrystallization of 3-ftrifluoromethyl)-5-f4-methyl-lH-imidazole-l-yl)- benzeneamine of formula I from Ethanol/water

[00247] A 5OmL flask was charged with 2g of the compound of Formula I crude

(purity of 83.1%) and 4mL of Ethanol. The mixture was heated to reflux under stirring until the entire solid dissolved. While refluxing, 1OmL of water was added drop-wise. The mixture was cooled slowly to 25±5°C. The mixture was filtered and washed with a mixture of ethanol/water to obtain the recrystallized compound of Formula I having a purity of 86.5%.

[00248] The purification factor can be seen in the following table:

Example 4: Preparation of compound of formula IV

[00249] The compound of formula X (31.Og, 0.1 Omol) was suspended in 310ml toluene, and SOCl₂ (47.6g, 0.40mol) was added to the mixture under the protection of N₂. The formed mixture was reacted at 5O⁰C for 2 h. The solvent was evaporated completely, and a compound of formula (X-Cl) was obtained as yellow solid. The compound of formula (X- Cl) was then added to a THF solution of the compound of formula II (27.Og, 0.1 lmol), DIPEA (15.Og, 0.12mol) and DMAP (0.5g, 4.0mmol). The reaction mixture was reacted at 3O⁰C for 12 h, and then quenched with 8% solution of sodium bicarbonate (620ml). The mixture was filtered, and washed with H₂O, then dried in vacuum. The solid was re-slurried with MTBE, and dried in vacuum again. 49.5g of the compound of formula IV were obtained as light yellow powder. The yield is about 93.7% by weight. The purity of the isolated product is 98% (% on area by HPLC).

Example 5: Preparation of compound of formula IV

[00250] To a 50ml 3-neck flask was charged compound of formula X 3. Ig and 21ml of toluene. The suspension was charged 5.1g dichlorosulfoxide (SOCl₂) under nitrogen protection. The reaction mixture was heated to 5O⁰C and reacted for 2hrs. The reaction was then concentrated to dry. To another 100ml 3-neck flask was charged 2.7g of compound of formula II, 1.5g of DIPEA, O.lg of DMAP and 30ml of THF. To the mixture was charged the above concentrated residue. The reaction mixture was stirred at 25±5°C overnight. The mixture was charged 45ml of ethyl acetate and 20ml of water. The mixture was then stirred at 25±5°C for lOmin, filtered and the filtrate was phase separated. The organic layer was washed by water 10ml twice. Then the organic layer was concentrated to dry. The residue was combined with the filter cake and slurried in MTBE. The mixture was filtered and dried under vacuum at 5O⁰C. The water layer was adjusted pH to 8 with NaHCO₃solution. The second crop 0.5g was thus precipitated out. Total yield was 94%.

Example 6: Preparation of compound of formula IV

[00251] To a 50ml 3-neck flask was charged compound of formula X 3. Ig, 20 mL of toluene and 18ml of dichlorosulfoxide (SOCl₂) under nitrogen protection. The reaction mixture was heated to 5O⁰C and reacted overnight. The reaction was then concentrated to dry and co-evaporated with 20ml of toluene of once. To another 100ml 3-neck flask was charged 2.7g of compound of formula II, 1.5g OfK₂CO₃, O.lg of DMAP and toluene. To the mixture was charged the above concentrated residue. The reaction mixture was stirred at 5O⁰C overnight. The mixture was charged 30ml of half saturated NaHCO₃ solution, 15ml of MTBE and stirred for lOmin. Large amount of solid was precipitated out and filtered. The filter cake was washed with MTBE and fired under vacuum at 55 ⁰C. The resulted product was of 81% of purity. There were about 9% of the compound of formula X.

Example 7: Preparation of compound of formula IV [00252] The compound of formula X (50 g), HOBt (26.5 g)/ EDCI (37.5 g) and DMF

(500 mL) were loaded into a reactor at 25±5°C. After being reacted for 3h, the compound of formula II (39 g) was added to the reactor. The reaction mixture was stirred at 80⁰C for about 18 hours while monitoring for the consumption of active ester by HPLC. After being cooled to 25±5°C, the mixture was dropped to a solution of half-saturated aqueous solution of sodium hydrogen carbonate, and the product was precipitated as canary yellow solid. [00253] The yield of this step was about 29.0% by weight. The purity of the isolated product was 95% (% on area by HPLC method described in Appendix 1).

Example 8: Preparation of Nilotinib

[00254] The compound of formula IV (21.Og, 39.7mmol), NaI (12.Og, 79.8mmol), CuI

(1.3g, β.Ommol) and N,N-Dimethylethylenediamine (1.Ig, 12.0mmol) were dissolved in DMF (105ml) under the protection of N₂. The formed solution was reacted at 12O⁰C for 24h. The temperature of the above solution was decreased to 6O⁰C.

[00255] 8-Hydroxyquinoline (1.8g, 1 l.βmmol), CuI (1.3g, β.Ommol), the compound of formula III (4.6g, 56.3mmol) and DBU (9.Og, 59.3mmol) were added to the above solution under the protection of N₂. The formed solution was reacted at 12O⁰C for 48h. After the reaction was competed (detected by the consumption of the compound of formula IV, HPLC), the reaction solution was dropped to a mixture of saturated solution of NaHCO₃ (15ml) and water (300ml) at 25±5°C. The mixture was then filtered, and the filter cake was washed with water. 26.9g crude product was obtained as pale brown powder with 69% purity after drying in vacuum.

[00256] The crude product was added to 3.8 vol. DMF, and heated to dissolution. The solution was filtered through Celite, and the filter cake was washed with 0.5 vol. DMF. 3.5 vol. of methanol/H₂O (3:1) was added to the above solution at 6O⁰C. The formed solution was stirred at 25±5°C overnight and at ice bath for 2h. The mixture was filtered, and the filter cake was washed with methanol (0.05 vol^χ3). The first round re-crystallization solid was obtained after drying in vacuum. The above solid was added to 2.9 vol DMF, and heated to dissolution. Then filtered, and the filter cake was washed with 0.1vol. DMF. The resulting solution was stirred at 25±5°C for 0.5 h, and at ice bath for 2 h. The mixture was filtered, and the cake was washed with methanol (0.05vol^χ3). 9.1g solid was obtained with 99.1% purity after drying in vacuum. The total yield was about 43.5% by weight. The purity of the isolated product is 99.1% (% on area by HPLC). Example 9: Preparation of Nilotinib

[00257] The compound of formula IV, the compound of formula III, CS2CO3, CuI , 8- hydroxyquinoline and CaO were loaded into a reactor at 25±5°C under the protection of N₂. The reaction mixture was then stirred at 120⁰C for about 24 hours while monitoring for the consumption of the compound of formula IV by HPLC. After cooled to 25±5°C, the mixture was treated with a half-saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate, then dried by Na₂SO₄. After concentration, the crude product was obtained as yellow solid. Then the solid was dissolved by CH₂CVMeOH (10 equ., 3:2), and the mixture was washed three times with water. After a period of time, the product would be crystallized from the organic solvent (purity: 95%, detected by HPLC). Few minutes later, the product would precipitate as yellow solid. Then the product was stirred in the solvent of CH₂Cl₂/Me0H (5 equ., 5:1) at 40⁰C for 1 hour. After that, the mixture would be filtered. The solid we got was dried in vacuum, and the product with 98% purity was obtained by this means.

[00258] The yield of this step was about 31.1% by weight. The purity of the isolated product was 98% (% on area by HPLC method described in Appendix 1).

Example 10: Preparation of Nilotinib:

[00259] To 250 mL glass reactor was added the compound 4-methyl-3-{[4-(pyridin-3- yl)pyrimidin-2-yl] amino} benzoic acid of formula X (10.0 g, 0.032 mol), a compound of formula I (8.7 g, 0.036 mol), SOCl₂ (7.5 mL, 0.103 mol) and N-Methyl-pyrrolidone (100 mL). The reaction mixture was stirred and heated to 90⁰C for 5 h. The reaction was then cooled to 50⁰C and an aqueous NaOH solution was added (12 g in 72 mL H₂O) until pH 10- 11. Then, the suspension was cooled to room-temperature, stirred for 30 minutes at this temperature, filtered under reduced pressure and washed with 30 mL H₂O to yield a beige solid. This material was dried under vacuum at 50⁰C and 8.2 g of Nilotinib base was obtained. To the mother-liquor was added H₂O (300 mL), and the mixture was stirred for 15 hours at room-temperature. A precipitate was formed and filtered under vacuum. The solid so-obtained was washed with H₂O (20 mL), and dried in vacuum oven at 50⁰C to yield additional 5.9 g of Nilotinib base. The total amount of Nilotinib base was 14.1 g in 81% yield. Example 11: Preparation of Nilotinib:

[00260] To 250 mL glass reactor was added the compound of formula 4-methyl-3- {[4-

(pyridin-3-yl)pyrimidin-2-yl]amino}benzoic acid of formula X (20.0 g, 0.065 mol), a compound of formula I (17.3 g, 0.072 mol), SOCl₂ (15 mL, 0.206 mol) and N-Methyl- pyrrolidone (100 mL). The reaction mixture was stirred and heated to 90⁰C for 3 h. The reaction was filtered under reduced pressure and washed with NMP (10 mL) and H₂O (10 mL). The filtrate was then cooled to 70⁰C and a 47% NaOH solution (30 mL) was added and stirred for 30 minutes until pH 11-12. Then, the suspension was cooled to 5°C during 3 hours, stirred at this temperature for 10 hours room-temperature, filtered under reduced pressure and washed with 100 mL H₂O to yield a beige solid. This material was dried under vacuum at 50⁰C and 27.1 g of Nilotinib base was obtained with 76% yield. (97.2% assay, 99.17% purity).

Example 12: Preparation of Nilotinib:

[00261] To IL glass reactor was added the compound of formula 4-methyl-3-{[4-

(pyridin-3-yl)pyrimidin-2-yl]amino}benzoic acid of formula X (80.0 g, 0.26 mol), and N- Methyl-pyrrolidone (400 mL). The mixture was heated to 60⁰C, then SOCl₂ (24 mL, 0.33 mol) was added during 15 minutes. The resulted mixture was stirred at 60⁰C for 1 h. A compound of formula I (69.2 g, 0.29 mol) was added and the reaction mixture was stirred and heated to 90⁰C for 3 h. Water (500 mL) was added and the solution was heated to 80⁰C. NaOH 47% solution (65 mL) was added until pH 11-12. Then, the suspension was cooled to 40⁰C and stirred at this temperature for 2 hours, filtered under reduced pressure at 40⁰C, and washed with 500 mL H₂O to yield a beige solid. This material was slurried in water (1 L) at 40⁰C for 1 h, filtered, washed with water (500 mL), and dried under vacuum at 50⁰C to obtain 135.25 g of Nilotinib base with 94% yield. (95.8% assay, 99.46% purity).

Example 13: Preparation of 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylbenzoyl chloride, dihydrochloride of the formula (X-C1)*2HC1:

[00262] Thionyl chloride (1400ML) was added to 3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methylbenzoic acid of formula X (39 gms). This mixture was heated to 60-70⁰C and stirred for 10-12 hours. The reaction mixture was then cooled to 30-27⁰C. The obtained slurry was filtered and the solid was washed with dichloromethane. The wet product was dried at 55-60⁰C under reduced pressure.

Dry wt: 140gm

Yield: 95.4

Purity: above 98% by HPLC

Hydrochloride content (by Argentometry titration): 27.48%

Example 14: Preparation of 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylbenzoyl chloride, dihydrochloride of the formula (X-ClWHCl:

[00263] Thionyl chloride (1000ML) was added to 3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methylbenzoic acid of formula X (100 gms). This mixture was heated to 60-70⁰C and stirred for 5-6 hours. The reaction mixture was then cooled to 30-35⁰C. Dichloromethane

(1000ML) was then added to the recation mixture and stirred for 10-15 minutes. The obtained slurry was filtered and the solid was washed with dichloromethane. The wet product was dried at 55-60⁰C under reduced pressure.

Dry wt: 100-106gm

Purity: above 98% by HPLC

Example 15: Preparation of Nilotinib*3HCl (crude):

[00264] 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylbenzoyl chloride dihydrochloride of formula (X-C1)-2HC1 (105 gms) was added to dichloromethane (1000ml) and 3-(trifluoromethyl)-5-(4-methyl-lH-imidazol-l-yl)benzenamine of formula I (71 gms) at

25-40⁰C. The temperature was raised to reflux point and was stirred at this temperature for

10-12 Hours. The reaction mixture was then cooled to 30-20⁰C. The obtained slurry was filtered and the solid was washed with dichloromethane (200ml). The wet product was dried at 40-60 ⁰C under reduced pressure.

[00265] The X-ray powder diffraction of the obtained product is shown in Figure 3.

The X-ray powder diffraction of the obtained product after exposure to 100% humidity for

96% is shown in Figure 4.

Yield: 90-92%

Purity: 85-90%

Hydrochloride content (by Argentometry titration): 16.8%.

Example 16: Preparation of Nilotinib^«3HCl: [00266] Methanol (50ml) was cooled to 0-5⁰C and acetyl chloride (2.29gm) was slowly added to it. To this mixture, 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-N-(3- (trifluoromethyl)-5-(4-methyl-lH-imidazol-l-yl)phenyl)-4-methyl benzamide (Nilotinib free base) (5.00 gms) was added slowly and mixture was stirred for 2 hours. Acetone (50ml) was then added and mixture was stirred for 60 minutes. Reaction mass was filtered and washed with acetone (10ml). The obtained product was dried at 55-60⁰C. Dry wt: 4.5gm Yield: 75% Purity: 95-98%

Example 17: Purification of Nilotinib^«3HCl (Pure):

[00267] 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-N-(3-(trifluoromethyl)-5-(4-methyl- lH-imidazol-l-yl)phenyl)-4-methylbenzamide tri hydrochloride (5gm) and water (25ml) were added and the mass was heated to 60-70⁰C. The mass was charcoalized (0.5gm carbon) and filtered through celite bed. Methanol (50ml) was added to the filtrate. The mixture was heated to 50-60⁰C and acetone (100ml) was added. It was then cooled to 30-27⁰C and stirred for 2hours. The obtained product was filtered and dried at 50-55⁰C for 12 hours under vacuum. The X-ray powder diffraction of the obtained product is shown in Figure 5. Dry wt 3.5gm Yield 0.7w/w Purity: 95-98%

Example 18: Preparation of Nilotinib:

[00268] 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-N-(3-(trifluoromethyl)-5-(4-methyl- lH-imidazol-l-yl)phenyl)-4-methylbenzamide tri hydrochloride (185gms) was dissolved in 825ml water and heated to 45-55°C. A methanolic solution of sodium hydroxide (35.9gm Sodium hydroxide dissolve in 1800 ml methanol) was added to the reaction mixture over a period of 1-2 hours. The suspension was heated to 65-70⁰C for 5-6 hours and the slurry was cooled to 35-30⁰C. The solid was filtered and washed with equal amount of water: methanol mixture 200ml. The wet product was dried at 45-55°C under reduced pressure. Yield: 90% Purity: 99.5% Example 19: Purification of Nilotinib:

[00269] 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-N-(3-(trifluoromethyl)-5-(4-methyl- lH-imidazol-l-yl)phenyl)-4-methylbenzamide (140gm) was taken into methanol (1.41it) and sodium hydroxide (14gm). The mixture was heated to reflux and stirred for 3-4 hours. The mixture was the cooled to 40-35⁰C and filtered. The product was washed with methanol (2X50ml) and dried at 50-60⁰C for 12 hours under vacuum. Dry wt. 120gm Yield: 0.85w/w

PAPER

https://pubs.rsc.org/en/content/articlelanding/2013/ob/c2ob27003j/unauth#!divAbstract

References

External links

• Discovery and development of Bcr-Abl tyrosine kinase inhibitors
• New drug information/Abbreviated Scientific Narrative
• Highlights of Prescription information Nilotinib (August 2007) Novartis Pharmaceuticals Corporation (USA)
• Summary of Product Characteristics Nilotinib (November 2007) Novartis AG (Europe)

Nilotinib

Clinical data
Trade names	Tasigna
AHFS/Drugs.com	Monograph
MedlinePlus	a608002
License data	EU EMA: by INN US FDA: Nilotinib
Pregnancy category	AU: D US: D (Evidence of risk)
Routes of administration	Oral
ATC code	L01XE08 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	30%[1]
Protein binding	98%[1]
Metabolism	Hepatic (mostly CYP3A4-mediated)[1]
Elimination half-life	15-17 hours[1]
Excretion	Faeces (93%)[1]
Identifiers
IUPAC name[show]
CAS Number	641571-10-0  (base)
PubChem CID	644241
IUPHAR/BPS	5697
DrugBank	DB04868
ChemSpider	559260
UNII	F41401512X
KEGG	D08953
ChEBI	CHEBI:52172
ChEMBL	ChEMBL255863
PDB ligand	NIL (PDBe, RCSB PDB)
CompTox Dashboard(EPA)	DTXSID5042663
ECHA InfoCard	100.166.395
Chemical and physical data
Formula	C28H22F3N7O
Molar mass	529.5245 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] Cc1ccc(cc1Nc2nccc(n2)c3cccnc3)C(=O)Nc4cc(cc(c4)n5cc(nc5)C)C(F)(F)F
InChI[hide] InChI=1S/C28H22F3N7O/c1-17-5-6-19(10-25(17)37-27-33-9-7-24(36-27)20-4-3-8-32-14-20)26(39)35-22-11-21(28(29,30)31)12-23(13-22)38-15-18(2)34-16-38/h3-16H,1-2H3,(H,35,39)(H,33,36,37)  Key:HHZIURLSWUIHRB-UHFFFAOYSA-N

Nilotinib

//////////Nilotinib, AMN107, Tasigna, ニロチニブ, 

Edotreotide gallium Ga-68

エドトレオチドガリウム (68Ga);

• Edotreotide Gallium Ga-68
• Gallium (68Ga) edotreotide
• Gallium edotreotide Ga-68
• Gallium Ga 68-dotatoc
• Gallium Ga 68-edotreotide
• Gallium Ga-68 edotreotide

gallium;2-[4-[2-[[(2R)-1-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-[[(1S,2R)-1-carboxy-2-hydroxypropyl]carbamoyl]-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]-7,10-bis(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate

L-threonine, N-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-19-[[(2R)-1-oxo-3-phenyl-2-[[2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]acetyl]amino]propyl]amino]-1,2-dithia-5,8,11,14,17-pentaazacycloeicos-4-yl]carbonyl]-, gallium salt (1:1)

FDA, 2019/8/21 APPROVED Ga-68-dotatoc

UNII Y68179SY2L

Indicated for use with positron emission tomography (PET) for the localization of somatostatin receptor positive neuroendocrine tumors (NETs)

Edotreotide gallium Ga-68 is an 8 amino acid peptide bound to the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA).⁸ Edotreotide gallium Ga-68 is indicated for localizing somatostatin receptor positive neuroendocrine tumors by positron emission tomography.⁷ Dotatate gallium Ga-68 is used for a similar indication.² Dotatate gallium Ga-68 has lower tumor uptake but this data is highly variable between patients.²

Edotreotide gallium Ga-68 was granted FDA approval on 21 August 2019.⁷

Indication

Edotreotide gallium Ga-68 is a radioactive diagnostic compound used in positron emission tomography (PET) for diagnose somatostatin receptor positive neuroendocrine tumors in pediatrics and adults.⁷

Associated Conditions

• Neuroendocrine Tumors

Pharmacodynamics

Edotreotide gallium Ga-68 binds to somatostatin receptors where it emits beta particle radiation for detection by positron emission tomography.⁷ The duration of action is short as it has short radioactive and biological half lives.^4,8 Patients should hydrate before and after the administration of this medication to encourage frequent urination and rapid clearance.⁷

Mechanism of action

Edotreotide gallium Ga-68 binds to somatostatin receptors, with higher affinity for somatostatin receptor type 2, where it emits beta particle radiation for detection by positron emission tomography (PET).⁷

Absorption

Edotreotide gallium Ga-68 reaches 80% activity in tumors within 30 minutes,⁴ and reaches its highest activity in tumors 70±20min post injection.⁸ Edotreotide is mostly taken up into the spleen, followed by kidneys, liver, pituitary, thyroid, and adrenal gland.^3,4,8 Accumulation in non-tumor tissue reaches a maximum within 40 minutes.⁴

Volume of distribution

Data regarding the volume of distribution of this medication is not readily available.⁷

Protein binding

Data suggests edotreotide gallium-Ga 68 may bind to proteins in serum.⁶ The extent of serum protein binding and which proteins it binds to are not described in the literature.

Metabolism

Edotreotide gallium Ga-68 is largely unmetabolized.⁸ 4 hours post injection there are no metabolites or degradation products detectable in serum.⁴

Route of elimination

16% of a Edotreotide gallium Ga-68 dose is eliminated in the urine within 2h.^1,7 It is expected that Edotreotide gallium Ga-68 is exclusively eliminated in the urine.^1,7 In animal studies, edotreotide Y-90 was >80% eliminated in the urine within 24h, with 95.6±3.4% being unmetabolized.^3,8 <1% of a dose is detected in the feces.⁵

Half life

Edotreotide gallium Ga-68 has a radioactive half life of 68 minutes.^4,8 Edotreotide gallium Ga-68 has two half lives, 2.0±0.3min and 48±7min for its removal from blood.^4,8

Clearance

Data regarding the clearance of this medication is not readily available.⁷

Toxicity

The LD₅₀ of this medication is not readily available.⁷

In the event of an overdose, give patients plenty of fluids and diuretics if necessary to encourage frequent urination.⁷ If possible, an estimation of radioactive dose should be performed.⁷

General References

1. Hartmann H, Zophel K, Freudenberg R, Oehme L, Andreeff M, Wunderlich G, Eisenhofer G, Kotzerke J: [Radiation exposure of patients during 68Ga-DOTATOC PET/CT examinations]. Nuklearmedizin. 2009;48(5):201-7. doi: 10.3413/nukmed-0214. Epub 2009 Jul 28. [PubMed:19639164]
2. Poeppel TD, Binse I, Petersenn S, Lahner H, Schott M, Antoch G, Brandau W, Bockisch A, Boy C: 68Ga-DOTATOC versus 68Ga-DOTATATE PET/CT in functional imaging of neuroendocrine tumors. J Nucl Med. 2011 Dec;52(12):1864-70. doi: 10.2967/jnumed.111.091165. Epub 2011 Nov 9. [PubMed:22072704]
3. de Jong M, Bakker WH, Krenning EP, Breeman WA, van der Pluijm ME, Bernard BF, Visser TJ, Jermann E, Behe M, Powell P, Macke HR: Yttrium-90 and indium-111 labelling, receptor binding and biodistribution of [DOTA0,d-Phe1,Tyr3]octreotide, a promising somatostatin analogue for radionuclide therapy. Eur J Nucl Med. 1997 Apr;24(4):368-71. doi: 10.1007/bf00881807. [PubMed:9096086]
4. Hofmann M, Maecke H, Borner R, Weckesser E, Schoffski P, Oei L, Schumacher J, Henze M, Heppeler A, Meyer J, Knapp H: Biokinetics and imaging with the somatostatin receptor PET radioligand (68)Ga-DOTATOC: preliminary data. Eur J Nucl Med. 2001 Dec;28(12):1751-7. doi: 10.1007/s002590100639. Epub 2001 Oct 31. [PubMed:11734911]
5. Kwekkeboom DJ, Kooij PP, Bakker WH, Macke HR, Krenning EP: Comparison of 111In-DOTA-Tyr3-octreotide and 111In-DTPA-octreotide in the same patients: biodistribution, kinetics, organ and tumor uptake. J Nucl Med. 1999 May;40(5):762-7. [PubMed:10319747]
6. Bangard M, Behe M, Guhlke S, Otte R, Bender H, Maecke HR, Biersack HJ: Detection of somatostatin receptor-positive tumours using the new 99mTc-tricine-HYNIC-D-Phe1-Tyr3-octreotide: first results in patients and comparison with 111In-DTPA-D-Phe1-octreotide. Eur J Nucl Med. 2000 Jun;27(6):628-37. doi: 10.1007/s002590050556. [PubMed:10901448]
7. FDA Approved Drug Products: Gallium Dotatoc GA 68 [Link]
8. EMA Assessment Report: SomaKit TOC [Link]

///////////Edotreotide gallium Ga-68, FDA 2019, エドトレオチドガリウム (68Ga),

Edotreotide

Names
IUPAC name 2-[4-[2-[[(2R)-1-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-[[(2R,3R)-1,3-dihydroxybutan-2-yl]carbamoyl]-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]-7,10-bis(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid
Identifiers
CAS Number	204318-14-9
3D model (JSmol)	Interactive image
ChemSpider	139675
PubChem CID	158782
UNII	U194AS08HZ
InChI[show]
SMILES[show]
Properties
Chemical formula	C65H92N14O18S2
Molar mass	1421.65 g·mol−1
Pharmacology
License data	EU EMA: by INN
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Edotreotide (USAN, codenamed SMT487, also known as (DOTA⁰–Phe¹–Tyr³)octreotide, or DOTATOC) is a substance which, when bound to various radionuclides, is used in the treatment and diagnosis of certain types of cancer.^[1]

Yttrium-90 labeled edoteotide has been the subject of a trial by the National Cancer Institute to determine its effects in young cancer patients (up to 25 years of age) for its ability to locate malignant cancer cells without harming normal cells. Specific cancers being included in the trial include neuroblastoma, childhood brain tumours and gastrointestinal cancer.^[2][3]

Yttrium-90 labeled edotreotide

 References

Vidofludimus

2-[[2-fluoro-4-(3-methoxyphenyl)phenyl]carbamoyl]cyclopentene-1-carboxylic acid

355.4 g/mol, C₂₀H₁₈FNO₄

CAS 717824-30-1

4SC-101

UNII-8Y1PJ3VG81

SC12267

Vidofludimus calcium anhydrous
RN: 1354012-90-0
UNII: FW5VY7926X

IM-90838
IMU-838

Molecular Formula, 2C20-H17-F-N-O4.Ca, Molecular Weight, 748.7886

1-Cyclopentene-1-carboxylic acid, 2-(((3-fluoro-3′-methoxy(1,1′-biphenyl)-4-yl)amino)carbonyl)-, calcium salt (2:1)

Inflammatory Bowel Disease,
Immunosuppressants
Multiple Sclerosis,
Rheumatoid Arthritis,
Liver and Biliary Tract Disorders,
Antipsoriatics
Systemic Lupus Erythematosus,

Dihydroorotate Dehydrogenase (DHODH) Inhibitors

phase II clinical development at Immunic (previously Immunic AG) as an induction and maintenance therapy for patients with moderate to severe ulcerative colitis, as well as for the treatment of patients with relapsed-remitting multiple sclerosis (RRMS). Immunic is also conducting early clinical evaluation of the drug as a potential treatment for Crohn’s disease, whereas a phase II clinical trial is ongoing at the Mayo Clinic in patients suffering from primary sclerosing cholangitis.

In 2016, Immunic acquired the product from 4SC.

Vidofludimus is under investigation in clinical trial NCT03722576 (Vidofludimus Calcium for Primary Sclerosing Cholangitis).

Ca salt of vidofludimus (designated as form A) as dihydroorotate dehydrogenase (DHODH) inhibitor eg graft versus host disease, rheumatoid arthritis and multiple sclerosis

Immunic AG  (a subsidiary of  Immunic Inc ), following an asset acquisition from 4SC, is developing vidofludimus an orally available, small molecule DHODH inhibitor and IL-17 blocker which inhibits pyrimidine biosynthesis, for the treatment of autoimmune and inflammatory disorders including ulcerative colitis, Crohn’s disease and multiple sclerosis

PAPER

Bioorganic & Medicinal Chemistry Letters (2005), 15(21), 4854-4857

https://www.sciencedirect.com/science/article/pii/S0960894X05010127

PRODUCT PATENT

WO 03006424

SPC protection in most of the EU states until 2021 and expire in the US in January 2022 with US154 extension

PATENT

WO2019101888 claiming composition comprising vidofludimus

PATENT

WO 2012001151

WO 2016200778

WO 2018177151

PATENT

WO2012001148 claiming similar compound (assigned to 4SC Ag ) naming the inventor Daniel Vitt. Immunic AG  (a subsidiary of  Immunic Inc ),

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=2957C3C97CE4063A06C879928DCA435C.wapp2nA?docId=WO2012001148&tab=PCTDESCRIPTION

Example 4: Preparation of the calcium salts

300.4 mg of Vidofludimus free acid was dissolved in 18 mL of DCM/MeOH (3:1) and sonicated for 8 minutes. 31.5 mg of calcium hydroxide was suspended in 3 mL of DCM/MeOH (3:1); this was slowly added to the Vidofludimus free acid solution. The slight suspension was stirred overnight at 25°C. The solvent was partially evaporated under nitrogen flow at 25°C. A thick light yellow suspension was observed. The solid was recovered by filtration and washed with DCM/MeOH (3:1). The material was dried for 15 min under vacuum at 25°C. The material was shown to be crystalline using the methods described in the following.

From elemental analysis, the ratio of fluorine to calcium was calculated. The elemental composition is essentially consistent with a hemi-calcium-salt.

The Raman spectrum of the newly formed compound demonstrated differences to that of the free acid (see Figure 3 for both spectra.). Note that a Raman spectrum that is not simply the superposition of the free acid, the salt former and the solvent spectra, e.g., a Raman spectrum where new peaks or shifted peaks are observed, may correspond to a salt.

However, from the Raman spectrum alone, it cannot be determined whether crystalline salt formation has occurred. Peak shifts could also be due, in principle, to complexation of the free acid and salt former as an amorphous product, to polymorphs of either the free acid or salt former, to impurities, or to degradation products. Therefore, the integrity of the molecular structure was confirmed by ¹H-NMR.

In addition, the powder X-ray diffraction shown in Figure 5 show that crystalline material was obtained, however with a pattern different from that of the free acid (see Figure 6). With light microscopy the crystals were visualized (Figure 4), DSC (differential scanning calorimetry) demonstrated a melting point of about 155°C (indicating a melting of a solvate and of a non-solvated form), TG-FTIR (thermogravimetric analyzer-coupled Fourier-Transform Infrared) indicates that probably a methanol solvate and a hydrate were formed and dynamic vapor sorption revealed desolvation followed by 0.3% water uptake at about 85% r.h. and 0.4% water uptake at 95% r.h. (not reversible).

PATENT

WO-2019175396

Novel white crystalline calcium salt of vidofludimus and its solvates and hydrates (designated as polymorph A), process for its preparation, composition comprising it and its use for the treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis, amyotrophic lateral sclerosis, lupus erythematosus, fibrosis, uveitis, rhinitis and Pneumocystis carinii are claimed. Vidofludimus is known to be an IL-17 antagonist, immunosuppressant and dihydroorotate dehydrogenase inhibitor.

Novel calcium salt polymorphs as Anti-Inflammatory, Immunomodulatory and Anti- Proliferatory Agents

Subject matter of the present invention is a white crystalline polymorph A of the Ca salt of a compound according to formula I or a solvate and/or a hydrate thereof with a molar ratio of a compound according to formula 1 or a solvate and/or a hydrate thereof to calcium which is 2±0.3. Subject matter of the present invention is in particular a compound according to formula I or a solvate and/or a hydrate thereof which is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2theta at ±0.2 of the values shown below: 2 theta = 5.91°, 9.64°, 16.78°, 17.81°, 19.81°, 25.41° In particular the invention refers to new polymorphs of calcium salts of the Ca salt of a compound according to formula I or a solvate and/or a hydrate thereof which inhibits dihydroorotate dehydrogenase (DHODH), a process for their manufacture, pharmaceutical compositions containing them and to their use for the treatment and prevention of diseases, in particular their use in diseases where there is an advantage in inhibiting dihydroorotate dehydrogenase (DHODH). Examples of relevant diseases are given below.

Inflammatory Bowel Disease (IBD) is a group of inflammatory conditions of the colon and small intestine. With Crohn’s Disease and Ulcerative Colitis as principal types thereof. Crohn’s disease can affect the small intestine and large intestine, as well as the mouth, esophagus, stomach and the anus. Ulcerative colitis primarily affects the colon and the rectum.

Rheumatoid arthritis (RA) is a disease that is quite common especially among elder people. Its treatment with usual medications as for example non-steroid anti-inflammatory agents is not satisfactory. In view of the increasing ageing of the population, especially in the developed Western countries or in Japan the development of new medications for the treatment of RA is urgently required.

WO 2003/006425 describes certain specific compounds, which are reported to be useful for treatment and prevention of diseases where there is an advantage in inhibiting dihydroorotate dehydrogenase (DHODH). However, the specific salts according to the present invention are not disclosed. WO 2012/001148 describes the calcium salts of said compounds. However, the specific polymorphs according to the present invention are not disclosed.

WO 99/38846 and EP 0 646 578 disclose compounds which are reported to be useful for treatment of RA.

A medicament against rheumatoid arthritis with a new mechanism of action, leflunomide, was put on the market by the company Aventis under the tradename ARAVA [EP 780128, WO 97/34600]. Leflunomide has immunomodulatory as well as anti-inflammatory properties [EP 217206, DE 2524929]. The mechanism of action is based upon the inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme of the pyrimidine biosynthesis.

De Julian-Ortiz (J. Med. Chem. 1999, 42, 3308-3314) describes certain potential Anti-Herpes compounds with cyclopentenoic acid moieties.

DE 33 46 814 A1 describes certain carbonic acid amide derivatives for the treatment, prevention and amelioration of diseases connected to cerebral dysfunction and symptoms caused thereby.

In the human body, DHODH catalyzes the synthesis of pyrimidines, which are in particular necessary for cellular metabolism. An inhibition of DHODH leads to block of transcription of sensitive genes in metabolically activated cells, whereas cells with normal metabolic activity obtain their required pyrimidine building blocks from the pyrimidine salvage pathway and show normal transcriptional activity. Disease relevant activated lymphocytes rely on de novo pyrimidine syntheses and react particularly sensitively to DHODH inhibition. Some substances that inhibit DHODH are important medicaments for the treatment of chronic inflammatory and auto-immune diseases.

A compound named leflunomide (ARAVA) has been the first approved inhibitor of DHODH and is used for the treatment of human diseases, in particular rheumatoid arthritis. WO 99/45926 is a further reference that discloses compounds which act as inhibitors of DHODH. Another drug which is targeting DHODH is teriflunomide (AUBAGIO®) is the metabolite of leflunomide. Teriflunomide is approved for the treatment of multiple sclerosis in some countries.

JP-A-50-121428 discloses N-substituted cyclopentene-l,2-dicarboxylic acid monoamides as herbicides and their syntheses. For example, N-(4-chlorophenyl)-l-cyclopentene-l,2-dicarboxylic acid monoamide is produced by reacting l-cyclopentene-l,2-dicarboxylic anhydride with 4- chloroaniline.

In the Journal of Med. Chemistry, 1999, Vol. 42, pages 3308-3314, virtual combinatorial syntheses and computational screening of new potential Anti-Herpes compounds are described. In Table 3 on page 3313 experimental results regarding IC50 and cytotoxicity are presented for 2-(2,3-difluorophenylcarbamoyl)-l -cyclopentene- 1 -carboxylic acid, 2-(2,6-difluorophenylcarbamoyl)-l -cyclopentene-l -carboxylic acid and 2-(2,3,4-trifluorophenyl-carbamoyl)- 1 -cyclopentene- 1 -carboxylic acid.

DE 3346814 and US 4661630 disclose carboxylic acid amides. These compounds are useful for diseases attended with cerebral dysfunction and also have anti-ulcer, anti-asthma, anti-inflammatory and hypo-cholesterol activities.

In EP 0097056, JP 55157547, DE 2851379 and DE 2921002 tetrahydrophthalamic acid derivatives are described.

It is an object of the present invention to provide effective agents, specifically in the form of certain polymorphs of their calcium salts, which can be used for the treatment of diseases which require the inhibition of DHODH.

It was also an object of the present invention to provide compounds that inhibit DHODH in a range similar to the compounds disclosed in W02003/006425 and WO 2012/001148 and at the same time show a white colour in order to facilitate double blind placebo controlled clinical studies.

It was also an object of the present invention to provide compounds and composition comprising that compounds that inhibit DHODH in a range similar to the compounds disclosed in

W02003/006425 and WO 2012/001148 and are characterized by having a THF content below

720 ppm in order to be in compliance with guidelines of the European Medicines Agency (e.g. with the version 6 December 2016 ; EMA/CHMP/ICH/82260/2006)

Particularly, it has previously been found that certain compounds of the general formula (I) shown herein below, such as 2-(3-Fluoro-3′-methoxy-biphenyl-4-ylcarbamoyl)-cyclopent-l-enecarboxylic acid (INN Vidofludimus), exhibit good anti-inflammatory activity and their usability in the oral therapy for the treatment of autoimmune diseases such as for example rheumatoid arthritis or inflammatory bowel diseases had been addressed.

Accordingly, a novel white polymorph of Calcium- vidofludimus named polymorph A with an inhibitory effect on DHODH, in particular human DHODH, was provided. Furthermore, a composition was provided comprising said white polymorph of Calcium-vidofludimus named polymorph A characterized by having a Tetrahydroduran (THF) content below 720 ppm.
[I,I ‘ – biphenyl] – 4 – yl}carbamoyl)cyclopent – 1 – ene – 1 – carboxylic acid) according to formula (I) or a solvate and/or a hydrate thereof, CAS-No 717824-30-1white crystalline calcium salt of 2 – ({3 – fluoro – 3’ – methoxy –

Thus, subject matter of the present invention is a white crystalline calcium salt of vidofludimus with a molar ratio of vidofludimus to calcium is 2±0.3 or a solvate and/or a hydrate thereof. In contrast to the pale yellow polymorph as described in EP 2588446B1, e.g. example 4, subject matter of the present invention is of white color.

White crystal can be defined as crystals with pure white color similar to the RAL color code RAL9010 that is equal or similar to the US Federal Standard 595 color code“White 506”, #27885.

A solvate for all embodiments of the invention maybe selected from the group comprising ethanol, propanol, isopropanol, butanol, ΊΊ IF, water. In a preferred embodiment for all embodiments of the invention the solvate is a hydrate. In one preferred embodiment the solvate is a calcium dihydrate for all embodiments of the invention.

In particular, subject matter of the present invention is a white crystalline polymorph A of the Ca salt of a compound according to formula I (vidofludimus) or a solvate and/or a hydrate thereof thereof which is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2theta at ±0.2 of the values shown below:

2 theta = 5.91°, 9.64°, 16.78°, 17.81°, 19.81°, 25.41 °

PATENT

https://patents.google.com/patent/WO2012001151A1/en

/////////vidofludimus, PHASE 2, Inflammatory Bowel Disease,  (IBD),  Crohn’s Disease, Ulcerative Colitis, 4SC-101, UNII-8Y1PJ3VG81, SC12267, IM-90838, IMU-838, Immunic, 4SC,

COC1=CC=CC(=C1)C2=CC(=C(C=C2)NC(=O)C3=C(CCC3)C(=O)O)F

[Ca+2].COc1cccc(c1)c2ccc(NC(=O)C3=C(CCC3)C(=O)[O-])c(F)c2.COc4cccc(c4)c5ccc(NC(=O)C6=C(CCC6)C(=O)[O-])c(F)c5

L-Methyldopa

• Molecular FormulaC₁₀H₁₃NO₄
• Average mass211.214 Da

3-Hydroxy-α-methyl-L-tyrosine

555-30-6 [RN],

Alanine, 3- (3,4-dihydroxyphenyl)-2-methyl-, L-

Synthesis ReferenceVincenzo Cannata, Giancarlo Tamerlani, Mauro Morotti, “Process for the synthesis of the levodopa.” U.S. Patent US4962223, issued December, 1986.

US4962223

Methyldopa USP is the L-isomer of alpha-methyldopa. Its chemical name is levo-3-(3,4-dihydroxyphenyl)- 2-methylalanine sesquihydrate. Its structural formula is:

C 10H13NO4 • 1 1/2 H2O M.W. 238.24

Levodopa is a prodrug of dopamine that is administered to patients with Parkinson’s due to its ability to cross the blood-brain barrier^Label. Levodopa can be metabolised to dopamine on either side of the blood-brain barrier and so it is generally administered with a dopa decarboxylase inhibitor like carbidopa to prevent metabolism until after it has crossed the blood-brain barrier^Label,1. Once past the blood-brain barrier, levodopa is metabolized to dopamine and supplements the low endogenous levels of dopamine to treat symptoms of Parkinson’s^Label. The first developed drug product that was approved by the FDA was a levodopa and carbidopa combined product called Sinemet that was approved on May 2, 1975^1,7.

Methyldopa, sold under the brand name Aldomet among others, is a medication used for high blood pressure.^[1] It is one of the preferred treatments for high blood pressure in pregnancy.^[1] For other types of high blood pressure including very high blood pressure resulting in symptoms other medications are typically preferred.^[1] It can be given by mouth or injection into a vein.^[1] Onset of effects is around 5 hours and they last about a day.^[1]

Common side effects include sleepiness.^[1] More severe side effects include red blood cell breakdown, liver problems, and allergic reactions.^[1] Methyldopa is in the alpha-2 adrenergic receptor agonist family of medication.^[1] It works by stimulating the brain to decrease the activity of the sympathetic nervous system.^[1]

Methyldopa was discovered in 1960.^[2] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.^[3] The wholesale cost in the developing world is about US$4.31–9.48 per month.^[4] In the United States it costs less than $25 per month.^[5]

Medical uses

Methyldopa is used in the clinical treatment of the following disorders:

• Hypertension (or high blood pressure)
• Gestational hypertension (or pregnancy-induced hypertension) and pre-eclampsia

Side effects

Methyldopa is capable of inducing a number of adverse side effects, which range from mild to severe. Nevertheless, they are generally mild when the dose is less than 1 gram per day.^[6] Side effects may include:

• Psychological
  • Depression or even suicidal ideation, as well as nightmares
  • Apathy or anhedonia, as well as dysphoria
  • Anxiety, especially of the social anxiety variant
  • Decreased alertness, awareness, and wakefulness
  • Impaired attention, focus, and concentration
  • Decreased desire, drive, and motivation
  • Fatigue or lethargy or malaise or lassitude
  • Sedation or drowsiness or somnolence or sleepiness
  • Agitation or restlessness
  • Cognitive and memory impairment
  • Derealization or depersonalization, as well as mild psychosis
  • Sexual dysfunction including impaired libido, desire, and drive
• Physiological
  • Dizziness, lightheadedness, or vertigo
  • Miosis or pupil constriction
  • Xerostomia or dry mouth
  • Gastrointestinal disturbances such as diarrhea or constipation
  • Headache or migraine
  • Myalgia or muscle aches, arthralgia or joint pain, or paresthesia (“pins and needles”)
  • Restless legs syndrome (RLS)
  • Parkinsonian symptoms such as muscle tremors, rigidity, hypokinesia, or balance or postural instability
  • Akathisia, ataxia, dyskinesia as well as even tardive dyskinesia, or dystonia
  • Bell’s palsy or facial paralysis
  • Sexual dysfunction consisting of impaired erectile dysfunction or anorgasmia
  • Hyperprolactinemia or excess prolactin, gynecomastia/breast enlargement in males, or amenorrhoea or absence of menstrual cycles in females
  • Bradycardia or decreased heart rate
  • Hypotension or decreased blood pressure (though this may also be considered a therapeutic benefit)
  • Orthostatic hypotension (also known as postural hypotension)
  • Hepatitis, hepatotoxicity, or liver dysfunction or damage
  • Pancreatitis or inflammation of the pancreas
  • Warm autoimmune hemolytic anemia or deficiency in red blood cells (RBCs)
  • Myelotoxicity or bone marrow suppression, potentially leading to thrombocytopenia or blood platelet deficiency or leukopenia or white blood cell (WBC) deficiency
  • Hypersensitivity such as lupus erythematosus, myocarditis, or pericarditis
  • Lichenoid reactions such as skin lesions or rashes
  • Pallor

Rebound/withdrawal

Rebound hypertension via withdrawal on account of tolerance upon the abrupt discontinuation of methyldopa has been reported.^[7]

Mechanism of action

Methyldopa has a dual mechanism of action:

• It is a competitive inhibitor of the enzyme DOPA decarboxylase, also known as aromatic L-amino acid decarboxylase, which converts L-DOPA into dopamine. Dopamine is a precursor for norepinephrine (noradrenaline) and subsequently epinephrine (adrenaline). This inhibition results in reduced dopaminergic and adrenergic neurotransmission in the peripheral nervous system. This effect may lower blood pressure and cause central nervous system effects such as depression, anxiety, apathy, anhedonia, and parkinsonism. In addition, decreased dopamine may reduce its inhibitory effect on prolactin leading to signs and symptoms of hyperprolactinemia.
• It is converted to α-methylnorepinephrine by dopamine beta-hydroxylase (DBH). α-Methylnorepinephrine is an agonist of presynaptic central nervous system α₂ adrenergic receptors. Activation of these receptors in the brainstem appears to inhibit sympathetic nervous system output and lower blood pressure. This is also the mechanism of action of clonidine.

Pharmacokinetics

Methyldopa exhibits variable absorption from the gastrointestinal tract. It is metabolized in the liver and intestines and is excreted in urine.

History

When methyldopa was first introduced, it was the mainstay of antihypertensive treatment, but its use has declined on account of relatively severe adverse side effects, with increased use of other safer and more tolerable agents such as alpha blockers, beta blockers, and calcium channel blockers. Additionally, it has yet to be associated with reducing adverse cardiovascular events including myocardial infarction and stroke, or overall all-cause mortality reduction in clinical trials.^[8] Nonetheless, one of methyldopa’s still current indications is in the management of pregnancy-induced hypertension (PIH), as it is relatively safe in pregnancy compared to many other antihypertensives which may affect the fetus.

PATENT

https://patents.google.com/patent/CN105693541B/en

 L-methyldopa an α2 receptor agonistic cardiovascular drugs. The structural formula is as follows:

[0003]

[0004] The product produced methyl α- demethylated metabolite of norepinephrine, blockade of central α receptor, thereby inhibiting the heart, kidney and peripheral vascular sympathetic drive output at the same time, peripheral vascular resistance in vivo and plasma renin activity is reduced, and thus decrease blood pressure. It can be used for treating hypertension, nephropathy, including hypertension time.This product is safe, is the preferred treatment during pregnancy with hypertension drugs.

[0005] In the prior art, methyldopa synthesis are the following:

[0006] 1 to veratridine-one was synthesized by the synthesis of L-hydantoin intermediate methyldopa:

[0007]

[0008] 2 to veratridine-one was synthesized by the synthesis of L-amino nitrile intermediate methyldopa:

[0009]

[0010] 3, eugenol synthesized from L-methyldopa

[0011]

[0012] The plurality of reaction have their own advantages, but in general, the reaction need to use highly toxic cyanide, have a certain impact on the environment and operating conditions.

SUMMARY

[0013] The present invention discloses a method for synthesizing methyldopa, the synthetic route without using highly toxic substances, the advantage of having a clean environment and efficient.

[00 M] methyldopa synthesis method disclosed in the present invention, is 3,4-dimethoxybenzaldehyde with 2-acetylamino-propionic acid methyl ester as a starting material synthesized by condensation, reduction, deprotection to give the crude product methyldopa, methyldopa and then purified to give pure product.Scheme with easy operation, high yield, etc. cleaning process.

[0015] The scheme is as follows:

[0016]

Example 1

[0034] (A) Weigh 3,4_-dimethoxybenzaldehyde 16.6g (0. Imol), sodium methoxide 5.4g (0. Imol), into dried dimethylformamide (150ml), stirring dissolution was complete, the reactor was placed in a cold water bath controlled at a temperature of about 20 ° C, weighed 2-acetamido-methyl 14.5g (0. Imol), successively portionwise added to the reactor, the reaction was stirred for at least 5 minutes plus complete. After all was added, maintaining the reaction temperature for 1.5h.After completion of the reaction, cold water was added Intermediate precipitated solid was filtered and washed several times with cold water.

[0035] (B) Intermediate (A) obtained was transferred to the reactor, 150ml of dichloromethane was added to dissolve, was added p-toluenesulfonyl chloride 19. Ig (0. Imol), triethylamine reactor after 10. Ig (0. Imol), the reaction was stirred for 2h, sodium boron hydride was added 4g, reaction was continued for lh. After completion of the reaction, cold water was added and sufficiently stirred, the aqueous layer was discarded liquid separation, the organic layer, the solvent was evaporated under reduced pressure to obtain an intermediate;

[0036] (C) Intermediate (B) obtained was transferred to the reactor was added 150ml 47% aqueous hydrobromic acid to the reactor, warmed to about 60 ° C, the reaction was stirred at reflux for 4h. Hydrobromic acid was distilled off under reduced pressure to about IlOml, filtered, the mother liquor was concentrated to dryness under reduced pressure, dissolve the solid with cold water, and ammonia to adjust the pH to 4.5 with a cold water bath, the precipitated white solid was large. Filtered and the solid washed with a little cold methylene chloride to give 20.8 g of crude product methyldopa, yield 98.5%.

[0037] (D) The crude product take methyldopa, add 30ml 0. Imo 1 / L dilute hydrochloric acid, an Ig activated carbon, heated, stirred until dissolution methyldopa, maintaining the temperature 〇.5h, filtered hot and allowed to cool to ammonia to adjust the pH to 4.5 to precipitate large amount of white solid was filtered, rinsed with a small amount of cold water, and dried to give 17.7 g methyldopa pure, a yield of 85.0%. Content was determined according to the “Chinese Pharmacopoeia” method and its content was 99.6%.

[0038] Example 2

[0039] (A) Weigh 166kg of 3,4-dimethoxybenzaldehyde, 54kg sodium methoxide, into dried dimethylformamide 500L stirred to dissolve completely, the reactor was placed in a cold water bath controlled temperature of about 20 ° C, 2-acetamido-Weigh 145kg methyl, successively portionwise added to the reactor, the reaction was stirred for at least 5 minutes the addition was completed. After all was added, maintaining the reaction temperature for 2 h. After completion of the reaction, cold water was added Intermediate precipitated solid was filtered and washed several times with cold water.

[0040] (B) Intermediate (A) obtained was transferred to the reactor, 500L of methylene chloride was added to dissolve, was added p-toluenesulfonyl chloride 19Ikg, triethylamine 10Ikg into the reactor, the reaction was stirred for 2.5h , sodium borohydride was added 4kg, reaction was continued for 1.3h. After completion of the reaction, cold water was added and sufficiently stirred, the aqueous layer was discarded liquid separation, the organic layer, the solvent was evaporated under reduced pressure to obtain an intermediate;

[0041] (C) Intermediate (B) obtained was transferred to the reactor, was added 500L 47% aqueous hydrobromic acid to the reactor, warmed to about 60 ° C, the reaction was stirred at reflux for 4h. Hydrobromic acid was distilled off under reduced pressure to about 375L, filtered, and the mother liquor was concentrated to dryness under reduced pressure, dissolve the solid with cold water, and ammonia to adjust the pH to 4.5 with a cold water bath, the precipitated white solid was large. Centrifuged, and the solid washed with a little cold water to give the crude product methyldopa 200kg, 94.7% yield.

[0042] (D) The crude product take methyldopa, add 300L O.lmol / L dilute hydrochloric acid, 10 kg activated carbon, heating and stirring until dissolved methyldopa, maintaining the temperature 〇.5h, filtered hot and allowed to cool to ammonia to adjust the pH to 4.5 to precipitate large amount of white solid was filtered, rinsed with a small amount of cold water, and dried to give pure methyldopa 177kg, 88.5% yield. Content was determined according to the “Chinese Pharmacopoeia” method and its content was 99.7%.

CLIP

Exists as the sesquihydrate.

Prepn: Pfister, Stein, US 2868818 (1959 to Merck & Co.). D. F. Reinhold and M. Sletzinger, GB 936074 eidem U.S. Patent 3,344,023 (1963 to Merck and Co.)

Resolution: Jones et al., US 3158648 (1964 to Merck & Co.); cf. Slates et al., J. Org. Chem. 29, 1424 (1964). Resolution and configuration: Tristram, ibid. 2053.

Synthesis from asymmetric intermediates: Reinhold et al., J. Org. Chem. 33, 1209 (1968).

Prepn of the ethyl ester hydrochloride: FR M2153 (1963 to Merck & Co.);

of pharmaceutical dosage forms: Marcus, US 3230143 (1966 to Merck & Co.).

CLIP

Reactions of D-glucose with phenolic amino acids: further insights into the competition between Maillard and Pictet-Spengler condensation pathways
Carbohydrate Research (2005), 340, (18), 2719-2727

Methyldopa

References

• •  Tristram, E.W. et al.: J. Org. Chem. (JOCEAH) 29, 2053 (1964).
  • B Stein, G.A. et al.: J. Am. Chem. Soc. (JACSAT) 77, 700 (1955).
  •  Chem. Eng. from 8.11.1965; p. 247.
  • C Reinhold, D.F. et al.: J. Org. Chem. (JOCEAH) 33, 1209 (1968).
  • A US 2 868 818 (Merck & Co.; 13.1.1959; prior. 15.12.1953).
  •  GB 936 074 (Merck & Co.; appl. 18.10.1960; USA-prior. 8.4.1960, 24.8.1960).
  •  DE 1 171 931 (Merck & Co.; prior. 6.10.1960).
  •  US 3 158 648 (Merck & Co.; 24.11.1964; prior. 11.7.1961, 9.4.1962).
  •  FR 1 492 765 (Merck & Co.; appl. 10.10.1963; USA-prior. 11.10.1962, 19.9.1963).

• similar method via l-α-acetylamino-α-vanillylpropionitrile:

  • GB 1 142 595 (Merck & Co.; appl. 23.5.1967, 12.2.1969).

• alternative syntheses:

  • D a Steinetal, G.A.: J. Am. Chem. Soc. (JACSAT) 77, 700 (1955).
  • US 3 366 679 (Merck & Co.; 30.1.1968; prior. 11.10.1962, 19.9.1963).
  • DOS 2 302 937 (Tanabe; appl. 22.1.1973; J-prior. 22.1.1972).
  • US 3 517 057 (Merck & Co.; 23.6.1970; appl. 21.9.1967).
  • DE 1 235 946 (Boehringer Mannh.; appl. 8.8.1964).
  • DE 1 235 947 (Bayer; appl. 16.1.1963).
  • DE 1 258 416 (Knoll; appl. 9.10.1964).
  • DE 1 269 622 (Knoll; appl. 22.12.1966).
  • DOS 2 406 898 (BASF; appl. 14.2.1974).
  • AT 250 936 (Egyesült; appl. 3.11.1964; HU-prior. 18.11.1963).
  • FR 1 502 972 (Merck & Co.; appl. 21.10.1966; USA-prior. 22.10.1965).
  • FR 1 531 877 (Sankyo; appl. 18.7.1967; J-prior. 11.8.1966, 21.2.1967).
  • GB 1 321 802 (D.D.S.A.; appl. 5.2.1971).
  • b GB 2 059 955 (Merck & Co.; appl. 9.9.1980; USA-prior. 13.9.1979, 28.9.1979).

• medical use:

  • US 3 344 023 (Merck & Co.; 12.4.1983; prior. 8.4.1960, 24.8.1960, 1.2.1963; reexamination request 21.12.1981).

• References

  1. ^ Jump up to:^{a b c d e f g h i j k} “Methyldopa”. The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  2. ^ Walker, S. R. (2012). Trends and Changes in Drug Research and Development. Springer Science & Business Media. p. 109. ISBN 9789400926592. Archived from the original on 2016-09-14.
  3. ^ “WHO Model List of Essential Medicines (19th List)” (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
  4. ^ “Methyldopa”. International Drug Price Indicator Guide. Retrieved 8 December 2016.
  5. ^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 140. ISBN 9781284057560.
  6. ^ British National Formulary 56. September 2008. pp. 95–96. ISBN 978-0-85369-778-7.
  7. ^ Methyldopa (PIM 342) Archived 2008-03-13 at the Wayback Machine
  8. ^ Mah GT, Tejani AM, Musini VM. Methyldopa for primary hypertension. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD003893. DOI: 10.1002/14651858.CD003893.pub3.

  External links

Methyldopa

Clinical data
Trade names	Aldomet, Aldoril, Dopamet, others
Synonyms	L-α-Methyl-3,4-dihydroxyphenylalanine
AHFS/Drugs.com	Monograph
MedlinePlus	a682242
Pregnancy category	AU: A US: B (No risk in non-human studies)
Routes of administration	by mouth, IV
ATC code	C02AB01 (WHO) C02AB02 (WHO) (racemic)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	approximately 50%
Metabolism	Liver
Onset of action	4 to 6 hrs[1]
Elimination half-life	105 minutes
Duration of action	10 to 48 hrs[1]
Excretion	Kidney for metabolites
Identifiers
IUPAC name[show]
CAS Number	555-30-6
PubChem CID	38853 40175
IUPHAR/BPS	5217
DrugBank	DB00968
ChemSpider	35562
UNII	56LH93261Y
ChEMBL	ChEMBL459
CompTox Dashboard (EPA)	DTXSID5023295
ECHA InfoCard	100.008.264
Chemical and physical data
Formula	C10H13NO4
Molar mass	211.215 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] C[C@](CC1=CC(=C(C=C1)O)O)(C(=O)O)N
InChI[hide] InChI=1S/C10H13NO4/c1-10(11,9(14)15)5-6-2-3-7(12)8(13)4-6/h2-4,12-13H,5,11H2,1H3,(H,14,15)/t10-/m0/s1  Key:CJCSPKMFHVPWAR-JTQLQIEISA-N

Other Names

• Alanine, 3-(3,4-dihydroxyphenyl)-2-methyl-, L- (8CI)
• 3-Hydroxy-α-methyl-L-tyrosine
• (-)-Methyldopa
• (-)-α-Methyl-3,4-dihydroxyphenylalanine
• (-)-α-Methyldopa

• (2S)-2-Amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid
• (S)-(-)-α-Methyldopa
• (S)-α-Methyldopa
• 2-Methyl-3-(3,4-dihydroxyphenyl)alanine
• AMD
• Aldochlor
• Aldomet
• Aldometil
• Aldomin
• Aldomine
• Alpha medopa
• Alphamethyldopa
• Bayer 1440L
• Baypresol
• Dopamet
• Dopatec
• Dopegyt
• Elanpres
• Equibar
• L-(-)-α-Methyl-β-(3,4-dihydroxyphenyl)alanine
• L-(-)-β-(3,4-Dihydroxyphenyl)-α-methylalanine
• L-2-Amino-2-methyl-3-(3,4-dihydroxyphenyl)propionic acid
• L-3,4-Dihydroxy-α-methylphenylalanine
• L-3,4-Dihydroxyphenyl-2-methylalanine
• L-Methyldopa
• L-α-Methyl-3,4-dihydroxyphenylalanine
• L-α-Methyl-3-(3,4)-dihydroxyphenylalanine
• L-α-Methyldopa
• Lederdopa
• Levo-3-(3,4-Dihydroxyphenyl)-2-methylalanine
• MK 351
• Medomet
• Medopa
• Medopren
• Methoplain
• Methyl-L-dopa
• Methyldopa
• NSC 169916
• Nr.C 2294
• Presinol
• Presolisin
• Sembrina
• l-3-(3,4-Dihydroxyphenyl)-2-methylalanine
• l-α-Methyldopa
• α-Methyl-L-3,4-dihydroxyphenylalanine
• α-Methyl-L-dopa
• α-Methyldopa

General References

1. Djamshidian A, Poewe W: Apomorphine and levodopa in Parkinson’s disease: Two revolutionary drugs from the 1950’s. Parkinsonism Relat Disord. 2016 Dec;33 Suppl 1:S9-S12. doi: 10.1016/j.parkreldis.2016.12.004. Epub 2016 Dec 22. [PubMed:28012951]
2. Meiser J, Weindl D, Hiller K: Complexity of dopamine metabolism. Cell Commun Signal. 2013 May 17;11(1):34. doi: 10.1186/1478-811X-11-34. [PubMed:23683503]
3. Elroby SA, Makki MS, Sobahi TR, Hilal RH: Toward the understanding of the metabolism of levodopa I. DFT investigation of the equilibrium geometries, acid-base properties and levodopa-water complexes. Int J Mol Sci. 2012;13(4):4321-39. doi: 10.3390/ijms13044321. Epub 2012 Apr 2. [PubMed:22605980]
4. Robertson DR, Wood ND, Everest H, Monks K, Waller DG, Renwick AG, George CF: The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa. Br J Clin Pharmacol. 1989 Jul;28(1):61-9. [PubMed:2775615]
5. Abrams WB, Coutinho CB, Leon AS, Spiegel HE: Absorption and metabolism of levodopa. JAMA. 1971 Dec 27;218(13):1912-4. [PubMed:5171067]
6. Fanali G, Rampoldi V, di Masi A, Bolli A, Lopiano L, Ascenzi P, Fasano M: Binding of anti-Parkinson’s disease drugs to human serum albumin is allosterically modulated. IUBMB Life. 2010 May;62(5):371-6. doi: 10.1002/iub.317. [PubMed:20225277]
7. FDA Approved Drug Products: Sinemet [Link]
8. Sinemet FDA Label [File]

/////////Methyl-L-dopa, Methyldopa, NSC 169916

N[C@@H](CC1=CC(O)=C(O)C=C1)C(O)=O

Desvenlafaxine

Desvenlafaxine Succinate Monohydrate

386750-22-7
93413-62-8 (free base, anhydrous)
448904-47-0 (anhydrous)
448904-48-1 (hemisuccinate)

DVS-233
PF-05212375
WY-45233 (free base)

Inventor/Developer – Wyeth Pharma Inc. 
Status/Comment – FDA approved

Desvenlafaxine Succinate Hydrate

Research Code：DVS-233

Trade Name：Pristiq^®

MOA：Serotonin and norepinephrine reuptake inhibitor (SNRI)

Indication：Major depressive disorder (MDD)

Status：Approved

Company：Pfizer (Originator)

Sales：$715 Million (Y2015); 
$737 Million (Y2014);;
$698 Million (Y2013);;
$630 Million (Y2012);;
$577 Million (Y2011);ATC Code：N06AX23

Desvenlafaxine succinate hydrate was approved by the U.S. Food and Drug Administration (FDA) on February 29, 2008.It was developed by Pfizer, then marketed as Pristiq^® by Pfizer in the US.

The exact mechanism of the antidepressant action of Desvenlafaxine is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Non-clinical studies have shown that Desvenlafaxine is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI). It is indicated for the treatment of major depressive disorder (MDD).

Pristiq^® is available as extended release tablet for oral use, containing 50 mg or 100 mg of free Desvenlafaxine. The recommended dose is 50 mg once daily with or without food.

PRISTIQ®
(desvenlafaxine) Extended-release Tablets

WARNING

SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see WARNINGS AND PRECAUTIONS].

In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see WARNINGS AND PRECAUTIONS].

PRISTIQ is not approved for use in pediatric patients [ see Use in Specific Populations].

DESCRIPTION

PRISTIQ is an extended-release tablet for oral administration that contains desvenlafaxine succinate, a structurally novel SNRI for the treatment of MDD. Desvenlafaxine (O-desmethylvenlafaxine) is the major active metabolite of the antidepressant venlafaxine, a medication used to treat major depressive disorder.

Desvenlafaxine is designated RS-4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol and has the empirical formula of C₁₆H₂₅NO₂ (free base) and C₁₆H₂₅NO₂ •C₄H₆O₄•H₂O (succinate monohydrate). Desvenlafaxine succinate monohydrate has a molecular weight of 399.48. The structural formula is shown below.

Desvenlafaxine succinate is a white to off-white powder that is soluble in water. The solubility of desvenlafaxine succinate is pH dependent. Its octanol:aqueous system (at pH 7.0) partition coefficient is 0.21.

PRISTIQ is formulated as an extended-release tablet for once-a-day oral administration.

Each tablet contains 38 mg, 76 mg or 152 mg of desvenlafaxine succinate equivalent to 25 mg, 50 mg or 100 mg of desvenlafaxine, respectively.

Osmotica Pharmaceutical, Par Pharmaceutical and Pernix Therapeutics are marketing the product in the U.S. under the brand name Khedezla (TM) for the treatment of major depressive disorder.

In 2019, Pfizer and Mochida signed an agreement for joint development and commercialization of the product in Japan.

Desvenlafaxine, sold under the brand name Pristiq among others, is a medication used to treat major depressive disorder.^[1] It is recommended that the need for further treatment be occasionally reassessed.^[1] It appears less effective than its parent compound venlafaxine.^[2] It is taken by mouth.^[1]

Common side effects include dizziness, trouble sleeping, increased sweating, constipation, sleepiness, anxiety, and sexual problems.^[1]Serious side effects may include suicide in those under the age of 25, serotonin syndrome, bleeding, mania, and high blood pressure.^[1]A withdrawal syndrome may occur if the dose is rapidly decreased.^[1] It is unclear if use during pregnancy or breastfeeding is safe.^[3] It is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class.^[1]

Desvenlafaxine was approved for medical use in the United States in 2008.^[1] Use in Europe was declined in 2009.^[2] In the United States the wholesale cost is about 25.20 USD per month.^[4] In 2016, it was the 272nd most prescribed medication in the United States, with more than a million prescriptions.^[5]

Medical uses

Desvenlafaxine is primarily used as a treatment for major depressive disorder.^[6] Use has only been studied up to 8 weeks.^[1] It, however, appears less effective than venlafaxine.^[2]

Doses of 50-400 mg/day appear effective for major depressive disorder, although no additional benefit was demonstrated at doses greater than 50 mg/day, and adverse events and discontinuations were more frequent at higher doses.^[7]

Desvenlafaxine improves the HAM-D17 score^[8] and measures of well being such as the Sheehan Disability Scale (SDS) and 5-item World Health Organization Well-Being Index (WHO-5).^[9]

Adverse effects[edit]

Frequency of adverse effects:^[6][10][11]

Very common adverse effects include:

Common adverse effects include:

Uncommon adverse effects include:

Rare adverse effects include:

Common however unknown intensity of adverse effects include:

Pharmacology

Desvenlafaxine is a synthetic form of the isolated major active metabolite of venlafaxine, and is categorized as a serotonin-norepinephrine reuptake inhibitor (SNRI). When most normal metabolizers take venlafaxine, approximately 70% of the dose is metabolized into desvenlafaxine, so the effects of the two drugs are expected to be very similar.^[12] It works by blocking the “reuptake” transporters for key neurotransmitters affecting mood, thereby leaving more active neurotransmitters in the synapse. The neurotransmitters affected are serotonin (5-hydroxytryptamine) and norepinephrine (noradrenaline). It is approximately 10 times more potent at inhibiting serotonin uptake than norepinephrine uptake.^[13]

Approval status

United States

Wyeth announced on 23 January 2007 that it received an approvable letter from the Food and Drug Administration for desvenlafaxine. Final approval to sell the drug was contingent on a number of things, including:

• A satisfactory FDA inspection of Wyeth’s Guayama, Puerto Rico facility, where the drug is to be manufactured;
• Several postmarketing surveillance commitments, and follow-up studies on low-dose use, relapse, and use in children;
• Clarity by Wyeth around the company’s product education plan for physicians and patients;
• Approval of desvenlafaxine’s proprietary name, Pristiq.^[15]

The FDA approved the drug for antidepressant use in February 2008, and was to be available in US pharmacies in May 2008.^[16]

In March 2017, the generic form of the drug was made available in the US.

Canada

On February 4, 2009, Health Canada approved use of desvenlafaxine for treatment of depression.^[17][18]

European Union

In 2009, an application to market desvenlafaxine for major depressive disorder in the European Union was declined.^[2] In 2012, Pfizer received authorization in Spain to market desvenlafaxine for the disorder but it is not being sold.^[19][20]

Australia

Desvenlafaxine is classified as a schedule 4 (prescription only) drug in Australia. It was listed on the PBS (Pharmaceutical Benefits Scheme) in 2008 for the treatment of major depressive disorders.

PATENT

https://patents.google.com/patent/CN104326923A/en

Sign succinic acid desvenlafaxine (Desvenlafaxinesuccinate, tradename Pristiq), chemical name RS-4- [2- dimethylamino-1- (1-hydroxycyclohexyl) ethyl] phenol succinic acid salt monohydrate; English name RS-4- (2 – (dimethylamino) -I- (1-hydroxycyclohexyl) ethyl) phenolsuccinatehydrate; formula C16H25NO2 · C4H6O · 4H20; relative molecular mass:. 399 48; CAS Registry number: 386750-22-7; of formula of formula I:

[0003]

[0004] The drug is produced by the US company Wyethphainsinc, February 29, 2008 listed by the US FDA approved, a serotonin – norepinephrine reuptake inhibitor is venlafaxine main active metabolite primarily for the treatment of major depressive disorder (MDD).

[0005] desvenlafaxine succinate is generally made with 0- desvenlafaxine succinate, aqueous salt synthesized, synthesized 0- desvenlafaxine earlier reports found in US Patent US4535186 discloses a method to 4-oxo-acetonitrile was synthesized from benzyl phenyl 0- desvenlafaxine, wherein the methylation step due to the use of formaldehyde as a methylating agent such that the reaction yield is very low, only 39 %, thereby affecting the overall yield of the overall reaction.

[0006] Currently many reported synthesis method of desvenlafaxine succinate is mostly based on the prior art (US4535186) Synthesis of venlafaxine, venlafaxine as a raw material to another, for which demethylation step reaction process improvement to synthesize 0- desmethylvenlafaxine, succinic acid and finally with water to a salt of desvenlafaxine succinate synthesis. The patent CN 1319934C, W0 0059851, CN101823969A venlafaxine are disclosed in as raw materials, the thiolate anion, lithium diphenylphosphide, HBr / HOAc as demethylating agent norepinephrine synthesis 0- venlafaxine oct, yields were> 73%. The reaction equation is as follows:

[0007]

[0008] In this class synthesis process, the raw material venlafaxine is synthesized by known techniques, the thiol compound used in the step of methylation away easily air pollution toxic, flammable irritant diphenyl compound and using a phosphine compound for corrosive HBr, increasing the difficulty of the operation and the post-treatment process such that the reaction unsuitable for industrial production.

[0009] Patent US7026508, US6689912 and US2005 / 0197392 each discloses a hydroxyphenyl acetonitrile as raw material, hydroxymethylated, α- ketone containing active hydrogen compound condensation, reducing the cyano group, an amino group and removal of methyl synthesis of methyl 〇- reaction desvenlafaxine, which synthetic route is shown below:

[0011] In such processes, the raw materials used are expensive cyano reagent, wherein the reagent lithium tri-secondary butyl borohydride risk patents US7026508 and method disclosed in patent US 6689912 to use, the patent US2005 / 0197392 use flammable irritating to diphenylphosphine compound, in addition, such methods involve harsh reaction conditions the reduction step cyano.Therefore, this method does not meet the economy, and is not suitable for industrial production.

[0012] Chinese Patent CN101781221Α discloses a synthetic method for the synthesis of 0- hydroxyphenylacetic acid desvenlafaxine, the acid-halo – aminolysis cyclohexanone condensation, amide reduction Synthesis 〇- desvenlafaxine, which scheme is as follows:

[0014] World Patent WO2008 / 093142 discloses a method similar to the above kind of oxygen acid as a raw material by benzyl, and finally debenzylation by synthesis 0- desvenlafaxine.

[0015] In such methods, the former are in a condensation reaction step with reduction of the amide using an unstable compound n-butyllithium, lithium tetrahydroaluminate; then using a compound unstable to hexamethyldisilazide amide, borane, this two-step reaction be carried out under an inert gas, dangerous reagents used twice, is not suitable for industrial operation.

Example 1

Synthesis [0041] The compound of formula III

The [0042] room temperature, was added the compound of formula II (81.69g, 0. 60mol), 1200mL acetone 3L reaction flask, stirred and dissolved. To this was added 1〇) 3 (265.368,1.92111〇1) was slowly added dropwise (112.888,0.65111〇1) of benzyl bromide was heated at reflux for LH, starting material after the reaction was cooled to room temperature, filtered off with suction, the filter cake was washed with a suitable amount of acetone , the filtrate by rotary evaporation, 50 ° C to give a compound of formula blast drying ΠI134 7g, yield 99% ZHNMR (300MHz, DMS0):… δ7 50-7 22 (m, 7H), δ6.93 (d, 2H) , S5.03 (s, 2H), S2.53 (s, 3H); 13C-NMR:… S197.02, δ163 · 42, δ136 · 51, δ129 · 83, δ129 02, δ128 91, δ127 64 , δ127. 10, δ114. 29, δ70. 13, δ26. 6.

[0043] Example 2

[0044] following the experimental procedure of Example 1, benzyl bromide (112. 88g, 0. 65mol) is replaced with benzyl chloride (82. 28g, 0. 65mol), heated at reflux overnight, cooled to room temperature after completion of the reaction evacuated filter cake washed with a suitable amount of acetone, the filtrate by rotary evaporation, 50 ° C to give a compound of formula blast drying III103. 17g, yield 76%.

[0045] Example 3

Synthesis [0046] The compound of Formula IV

[0047] The compound of formula III is added to the 3L reaction flask (67. 9g, 0 · 30mol), Cufc2 (147. 4g, 0 · 65mol), 0 · 9L methylene chloride, I. 35LEA, heated to reflux, after completion of the reaction cooling suction filtered, the filter cake was washed with 200mL dichloromethane. The filtrates were combined, and the filtrate was washed with hydrochloric acid and then washed twice with water, dried, rotary evaporation, 50 ° C overnight blast drying. A compound of formula IV to give the crude 89.438, yield 98%.

[0048] 89. 43g was added the compound of formula IV (crude) was added to IL-neck round bottom flask, recrystallized from isopropanol, filtered off with suction, the filter cake was dried by blowing 45 ° C. Refined products 84. 9g, 95% yield. .. 1Hnmr (SoomhzJMSO-CI6): δ7 53-7 20 (m, 7H), 5 6. 95 (d, 2H), δ5 09 (s, 2H), δ4 69 (s, 2H); 13C-.. NMR:. δ190 83, 5 164.12, 5 136.71, δ129 96, δ128 91, δ128 31, δ127 00, δ126 73, δ114 37, δ70 82, δ32 45………

[0049] Example 4

Synthesis [0050] The compound of formula V

[0051] Add the compound of formula IV (36. 6g, 0. 12mol) A 250mL round bottom flask, 120mL of ethanol was stirred. Aqueous solution was slowly added dropwise thereto 39mL of dimethylamine (33%), dropwise, with stirring until completion of the reaction starting material. Rotary evaporation and water, to which ethanol was added, under ice-water bath, thereto was slowly added dropwise 12mL hydrobromic acid. After stirring 30min 25 ° C incubation rotary evaporation and water was added thereto and dissolved with 70mL of methylene chloride over anhydrous sodium sulfate, after rotary evaporation, and thereto was added 60mLEA refluxed 30min, 30min stirring ice-water bath. Filtered off with suction, 45 ° C blast drying to give the purified product compound of formula V41.lg, yield 98%.1H NMR (300MHz, DMS0-d6): δ7 · 55-7 · 24 (πι, 7Η), S6.97 (d, 2H), S5.13 (s, 2H), S3.79 (s, 2H), 5 2. 23 (s, 6H); 13C-NMR:….. δ195 45, 5 163.12, 5 136.53, 5 129.85, 5 128.96, 5 127.61, δ127 27, δ127 06, δ114 65, δ75 31, δ70 . 72, δ46. 55.

[0052] Example 5

Synthesis [0053] The compound of formula VI

[0054] Compound of formula V was added to 500mL round bottom flask (41g, 0. 12mol), 205mL of ethanol under ice-water bath, to which was added a likelihood of 0! 1 (9.368,0.23111〇1), after stirring for 11 ^ 301, to which was added portionwise like 8! 14 (8.888,0.23111〇1). The reaction was stirred for 4h at End material to room temperature. Rotary evaporation, and thereto was added 60mL of water, 120mL of methylene chloride, stirred, separated, the aqueous phase was extracted twice with 120mL dichloromethane. The organic phases were combined, spin dry.The crude 31. 0g, 98% yield.

[0055] The crude product 31g was dissolved in 180mL of ethanol, under ice-water bath, was slowly added dropwise thereto 16mL of concentrated hydrochloric acid to pH = 1-2, stirred at room temperature for 30 min. Rotary evaporation, 45 ° C blast drying. A compound of formula VI to give crude product 31. 2g, 89% yield.

[0056] To a 250mL round-bottom flask was added 31. 2g crude compound of formula VI, 78 mL ethyl acetate, heated to reflux to dissolve, cooled to room temperature naturally, filtered off with suction, the filter cake was washed with the amount of EA. Refined products 29. 3g, 94% yield. 1HNMR (300MHz, DMS0-d6):….. Δ7 45-7 24 (m, 7H), δ6 95 (d, 2H), δ5 07 (s, 2H), δ4 88 (br, 1H), δ4 . 60 (m, 1Η), δ2 48-2 27 (m, 2H), 52.19 (s, 6H); 13C-NMR:…. δ157 26, 5 137.21, 5 136.83, δ128 · 35, δ127 68, δ127. 52, δ127. 17, δ114. 19, δ69. 62, δ69. 13, δ67. 57,45.56.

[0057] Example 6

[0058] Following the procedure of Example 5 experiments embodiment, the shame 0! 1 (9.368,0.23111〇1) shame Alternatively 0! 1 (14.048,0.72111〇1), and NaBH4 (8. 88g, 0. 23mol) is replaced with NaBH4 (13. 32g, 0. 72mol), stirred Ih at room temperature the reaction was complete feed. Rotary evaporation, and thereto was added 60mL of water, burning 120mL dichloromethane, stirred, separated, the aqueous phase was extracted twice with 120mL dichloromethane. The organic phases were combined, spin dry. The crude 31. 33g, yield 99%.

[0059] Example 7

Synthesis [0060] The compound of formula VII

[0061] was added (24g, 0.078 mol) compound of formula VI to a 500mL round bottom flask, 240 mL of toluene, under ice-water bath, and thereto is added thionyl chloride (10. 2g, 0. 086mol), the reaction was heated to 60 ° C 4h, cooled, stirred for about 25 ° C 2h, filtered off with suction, the filter cake washed with 30mL toluene, and drying, the product compound of formula to give an off-white VII22. 4g, 88% yield. 1H NMR (300MHz, DMS〇-d6):… Δ7 44-7 29 (m, 7H), δ7 07 (d, 2Η), δ5 12 (s, 2Η), δ4 69 (m, 1Η).. , δ3 37-3 15 (m, 2H), δ2 80 (s, 6H); 13C-NMR:…. δ158 26, 5 137.33, 5 136.71, 5 128.31, δ127 72, δ127 47, δ127… 13, δ114. 21, δ69. 62, δ67. 57, δ59. 39, δ46. 74.

[0062] Example 8

Synthesis [0063] The compound of formula VIII

[0064] Add the compound of formula ¥ 11 (218,0.064 11〇1!) Was added to a round bottom flask, 2001 ^ toluene, triethylamine (7.21 8, 0.071mol), stirred for 3h, filtered off with suction, washed with a little toluene; the 500mL three-neck flask was added to the toluene solution, cooled to -80 ° C, n-butyllithium was slowly added dropwise 35mL (2. 5mol / L), dropwise with stirring incubated 0. 5h, 9. 48g was slowly added dropwise cyclohexanone, After dropping the reaction 4h, slowly warmed to room temperature, the reaction was quenched with saturated ammonium chloride, using lmol / L sodium hydroxide to adjust pH = about 9, EA extraction, rotary evaporation, the crude product was slurried with diethyl ether, dried to obtain a compound of formula VIII19. 56g, yield 86%. 1H bandit R (300MHz, DMS0-d6): δ7 · 45-7 · 23 (πι, 7Η), S6.87 (d, 2H), S5.09 (s, 2H), S3.05 (t, 1H) , S2.75 (t, lH), δ2 · 41-2 · 34 (πι, 1Η), S2.18 (s, 6H), Sl.58-0.92 (m, 10H); 13C-Mffi:. δ157 32 , δ136. 73, δ134. 73, δ129. 11, δ128. 90, δ127. 65, δ127. 16, δ114. 23, δ73. 42, δ70. 87, δ59. 85, δ48. 52, δ47. 35, δ38 . 95, δ26. 33, δ22. 30.

[0065] Example 9

After the [0066] following the experimental procedure of Example 8, the reaction temperature is added dropwise n-butyllithium was replaced _65 ° C, to give compound VIII crude, beaten with ether and drying to give pure 15. 33g, yield 67 %.

[0067] Example 10

Synthesis [0068] The compound of formula IX

[0069] The compound of formula ¥ 111 (1 (^, 0.028111〇1) was dissolved in ^ booklet 1,501,111, was added 18 10% wet palladium on carbon, into hydrogen, I.SMPa at room temperature for 5h, filtration, rotary evaporation as a white solid compound of formula 1X6 83g, yield 92% 1HNMR (300MHz, DMSO- (I6):… δ9 13 (br, 1H), 5 6.96 (d, 2H), 5 6.64 (d, 2H), 53.01 (t, 1H), S2.72 (t, lH), δ2 · 39-2 · 35 (πι, 1Η), S2.15 (s, 6H), Sl.57-0.90 (m, 10H); 13C, MR:. δ155 56, δ131 56, δ130 04, δ114 23, δ72 52, δ60 36, δ51 57, δ45 21, δ37 11, δ32 38, δ25 67, δ21 23〇………..

[0070] Example 11

Synthesis [0071] The compounds of formula I

Under [0072] nitrogen, the compound of formula IX is added to the three-necked flask (4g, 0. 015mol), succinic acid (1.85g, 0. 015mol), IOOmL acetone / water mixed solvent = 71/19 was heated at reflux for 3h proceeds down to room temperature to crystallization under ice-cooling, filtered off with suction, 40 ° C dried to give 5. 13g as a white solid compound of formula I, yield 85%.

PATENT

https://patents.google.com/patent/WO2008090465A2/en

Desvenlafaxine (Formula I, below) is an active pharmaceutical substance with an empirical formula of C16H₂5NO₂ and a molecular weight of 263.38. Desvenlafaxine, which can also be referred to as desmethylvenlafaxine and/or O-desmethylvenlafaxine, is the major active metabolite of venlafaxine, an active pharmaceutical ingredient indicated for the treatment of major depressive disorder.

U.S. Patent No. 4,535, 186 discloses the first process for preparing desvenlafaxine. In U.S. Patent No.4,535,186, desvenlafaxine is synthesized by the process illustrated in Scheme 1:

Scheme 1 Additional alternative processes for preparing desvenlafaxine are described in the literature. These alternative processes generally proceed via the demethylation of venlafaxine, see, for example, U.S. Patent Application Publication No. 2005/197392, U.S. Patent Nos. 7,026,508, and 6,689,912, and International Patent Publication No. WO07/071404. These processes make use of different demethylating agents, such as lithium diphenylphosphide, alkali metal salts of trialkylborohydrides, high molecular weight thiolate anions, and metal sulfides. However, the use of the aforementioned demethylating agents presents several drawbacks, i.e., requires extensive purification procedures aimed to isolate desvenlafaxine from said demethylating agents and/or corresponding by-products, and involve odor workups, which make these processes unsuitable for industrial implementation.

In view of the foregoing, there is a need for an alternative process for preparing desvenlafaxine from venlafaxine including, for instance, an alternative process which avoids the drawbacks of current state of the art processes (e.g., makes use of simpler and shorter purification procedures, allows an essentially odorless workup, and which is well suited for industrial implementation).

Salts of O-desmethylvenlafaxine, including the fumarate, succinate and formate salts, have been described in the literature. For example, U.S. Patent No. 4,535,186 reports the preparation of O-desmethylvenlafaxine fumarate salt. More recently, the preparation of several polymorphic forms of the succinate salt have been reported in U.S. Patent No. 6,673,838 B2. Additionally, U.S. Patent Application Publication No. 2006/0058552 discloses the preparation of the formate salt.

HPLC Method

In the examples described below, the following analytical chromatographic HPLC method was used:

The chromatographic separation was carried out in a Kromasil C8, 5 μm, 25 cm x 4.6 mm. I. D column at room temperature.

The mobile phase was prepared by mixing 1,600 g of (NH₄)H₂P(I_t buffer solution pH = 4.4 and 313.2 g of acetonitrile HPLC grade. The pH of the mixture should be 4.9, adjust if necessary.

A (NH₄)H₂PO₄ buffer solution (pH = 4.4) was prepared by dissolving 17 g of (NH₄)H₂PO₄ in 1600 mL of water and adjusting the pH = 4.4 with HaPO₄ or ammonium hydroxide.

The chromatograph was equipped with a 225 nm detector, and the flow rate was 1.2 mL per minute at room temperature. Test samples (20 μl) were prepared by dissolving the appropriate amount of sample to obtain 1 mg per mL concentration in the mobile phase.

In those conditions the retention time of desvanlafaxine, compound (I), is about 7 minutes, and the retention time of venlafaxine, compound (IV), is about 22 minutes.

EXAMPLE 1: Preparation of Desvenlafaxine (Le., Compound I).

This example illustrates a process for converting Compound IV into desvenlafaxine {i.e., Compound I) according to one aspect of the invention.

In a 100 mL flask 8 g (0.027 mol) of Venlafaxine free base, 13 mL of polyethylene glycol 400 (PEG400) and 6.9 g (0.041 mol) of 2-(diethylamino)ethanothiol were charged. 13.2 g (13.6 mL, 0.073 mol) of 30 % w/w solution of sodium methanolate in methanol were slowly added. The resulting suspension was heated to about 195° C and methanol was distilled off in the meantime. The stirring was continued for four hours at that temperature and then was cooled down to 20-25° C. 30 mL of 1 M hydrochloric acid were added to adjust pH to approx. 9.5. The resulting suspension was filtered at 20-25° C and the solid was dried at 50° C. The solid corresponded to desvenlafaxine (3.4 g; yield: 45 %; purity HPLC: 96.8 %).

EXAMPLE 2: Preparation of Desvenlafaxine Succinate Monohydrate.

This example illustrates a process for converting desvenlafaxine (i.e., Compound I) into desvenlafaxine succinate monohydrate according to one aspect of the invention.

Desvenlafaxine base (18.1 g, 0.069 mol) was charged into a 500 mL round bottomed flask under nitrogen atmosphere with 9.75 g (0.083 mol) of succinic acid, 135 g (170 mL) of acetone and 54 g of deionized water. The suspension was heated to reflux temperature and maintained at this temperature 30 minutes. The resulting solution was cooled to 50-55° C and filtered.

The filtered solution was cooled to 30-35° C in approximately 1 hour. In the interim, seeding was performed at approximately 40-45° C. The suspension was maintained for 3 hours at 30-35° C. Thereafter, the suspension was cooled to 20-25° C in approximately 1 hour, and maintained at this temperature for 2 hours. Then, the suspension was cooled to 10 ± 3° C in approximately 30 minutes and maintained at this temperature for 1 hour. Finally, the suspension was filtered and washed twice with 2 x 7.5 g (2 x 9.4 mL) of acetone. The wet solid was dried under vacuum at 60 ± 5° C to yield 22.96 g of desvenlafaxine succinate (yield: 83.6 %). Analytical data: HPLC Purity: 99.9 %; assay: 99.6 %.

Desvenlafaxine

Trade Names

Country	Trade Name	Vendor	Annotation
USA	Pristiq	Wyeth ,2008

Formulations

• tabl. 50 mg, 100 mg (as succinate)

References

• • a EP 1 973 866 (Synthon; 1.10.2008; appl. 19.12.2006; USA-prior. 20.12.2005).
  • b WO 2 008 090 465 (Medichem SA; 31.7.2008; appl. 22.1.2008; USA-prior. 22.1.2007).
  • c US 7 026 508 (Wyeth; 5.5.2005; appl. 10.11.2004; USA-prior. 12.2.2001).
  • d US 4 535 186 (American Home Products; 13.8.1985; appl. 26.10.1983; USA-prior. 19.4.1983).

• new polymorph:

  • WO 2 008 110 338 (Synthon; 18.9.2008; appl. 6.3.2008; USA-prior. 9.3.2007).

• crystalline polymorphs of Desvenlafaxine succinate:

  • CN 101 274 897 (Mai DE Ltd.; 1.10.2008; appl. 4.1.2008; USA-prior. 8.1.2007).
  • US 20 080 188 567 (Mai DE Ltd.; 8.7.2008; USA-prior. 8.1.2006).

• enantiomers of Desvenlafaxine:

  • US 2 002 022 662 (American Home Products; 21.2.2002; appl. 21.9.2001; USA-prior. 15.6.1999).

References

1. ^ Jump up to:^{a b c d e f g h i} “Desvenlafaxine Succinate Monograph for Professionals”. Drugs.com. American Society of Health-System Pharmacists. Retrieved 18 March 2019.
2. ^ Jump up to:^a b c d “Withdrawal Assessment Report for Dessvenlafaxime” (PDF). EMA. p. 3. Retrieved 22 March 2019.
3. ^ “Desvenlafaxine Pregnancy and Breastfeeding Warnings”. Drugs.com. Retrieved 19 March 2019.
4. ^ “NADAC as of 2019-02-27”. Centers for Medicare and Medicaid Services. Retrieved 3 March 2019.
5. ^ “The Top 300 of 2019”. clincalc.com. Retrieved 22 December 2018.
6. ^ Jump up to:^a b “PRODUCT INFORMATION PRISTIQ® desvenlafaxine (as succinate)” (PDF). TGA eBusiness Services. Pfizer Australia Pty Ltd. 10 December 2012. Retrieved 8 November2013.
7. ^ Perry, Richard; Cassagnol, Manouchkathe (2009). “Desvenlafaxine: a new serotonin-norepinephrine reuptake inhibitor for the treatment of adults with major depressive disorder”. Clinical Therapeutics. 31 Pt 1: 1374–1404. doi:10.1016/j.clinthera.2009.07.012. ISSN 1879-114X. PMID 19698900.
8. ^ Thase ME, Kornstein SG, Germain JM, Jiang Q, Guico-Pabia C, Ninan PT (March 2009). “An integrated analysis of the efficacy of desvenlafaxine compared with placebo in patients with major depressive disorder”. CNS Spectr. 14 (3): 144–54. PMID 19407711.
9. ^ Soares CN, Kornstein SG, Thase ME, Jiang Q, Guico-Pabia CJ (October 2009). “Assessing the efficacy of desvenlafaxine for improving functioning and well-being outcome measures in patients with major depressive disorder: a pooled analysis of 9 double-blind, placebo-controlled, 8-week clinical trials”. J Clin Psychiatry. 70 (10): 1365–71. doi:10.4088/JCP.09m05133blu. PMID 19906341.
10. ^ “DESVENLAFAXINE tablet, extended release [Ranbaxy Pharmaceuticals Inc.]”. DailyMed. Ranbaxy Pharmaceuticals Inc. March 2013. Retrieved 9 November 2013.
11. ^ “desvenlafaxine (Rx) – Pristiq, Khedezla”. Medscape Reference. WebMD. Retrieved 9 November 2013.
12. ^ Lemke, Thomas L.; Williams, David A. (2012). Foye’s Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. p. 609. ISBN 978-1-60913-345-0.
13. ^ Jump up to:^a b Deecher, DC; Beyer, CE; Johnston, G; Bray, J; Shah, S; Abou-Gharbia, M; Andree, TH (August 2006). “Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor” (PDF). The Journal of Pharmacology and Experimental Therapeutics. 318 (2): 657–665. doi:10.1124/jpet.106.103382. PMID 16675639.
14. ^ Roth, BL; Driscol, J (Dec 2012). “PDSP K_i Database”. Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 7 July 2018.
15. ^ “Wyeth Receives Approvable Letter From FDA For Pristiq (Desvenlafaxine Succinate) For The Treatment Of Major Depressive Disorder” (Press release). 2007-01-23. Retrieved 2007-04-04.
16. ^ “FDA Approves Pristiq” (Press release). Wyeth. 2008-02-29. Archived from the original on 2008-03-05. Retrieved 2008-02-29.
17. ^ Health Canada Notice of Compliance – Pristiq^{[permanent dead link]}. February 4, 2009, retrieved on March 9, 2009.
18. ^ “Summary Basis of Decision (SBD) ^PrPristiq”. Health Canada. 2009-05-29. Retrieved 2016-12-30.
19. ^ “Pristiq 100 mg Comprimidos de Liberacion Prolongada”. AEMPS Medicines Online Information Center – CIMA. Retrieved 2016-12-30.
20. ^ “Pristiq 50 mg Comprimidos de Liberacion Prolongada”. AEMPS Medicines Online Information Center – CIMA. Retrieved 2016-12-30.

External links

• Drug information from the NIH

Route 1

Reference：1. US4535186.

2. WO2008093142 / US2010076086.

3. WO2002064543 / US20030045583.

4. WO2003048104 / US20030105358.

5. WO2003103603 / US20030236309.

6. J. Med. Chem. 1990, 33, 2899-2905.

Route 2

Reference：1. WO2008013990 / US20080183016.

Route 3

Reference：1. WO2008015584 / US20100121108.

2. WO2009034434.

3. WO2009053731 / US20110118357.

4. US20110098506.

5. WO2009009665A2 / US20100210719.

Route 4

Reference：1. WO2008013993.

Route 5

Reference：1. WO2009084037.

Route 6

Reference：1. WO2008013994 / US20080177110.

Update Date：2015-08-31

• China

No.	Major Technical Classification	Publication No.	Patent No.	Legal Status	Filling Date	Estimated Expiry Date
1	Salt	CN1501909A	CN100567253C	Granted	2002/2/11	2022/2/11
2	Preparation	CN101671260A		Withdrawn	2002/2/11
3	Combination	CN1705474A		Withdrawn	2003/10/15
4	Combination	CN1705484A		Withdrawn	2003/10/15
5	Combination	CN101146539A		Withdrawn	2006/2/16
6	Formulation	CN101304734A		Withdrawn	2006/9/6
7	Combination	CN101410112A		Withdrawn	2007/3/23
8	Others	CN101528667A		Withdrawn	2007/10/24

Patent

Publication numberPriority datePublication dateAssigneeTitle

WO2008093142A1 *2007-01-312008-08-07Generics [Uk] LimitedProcess for the preparation of o-desmethyl venlafaxine

WO2010028130A2 *2008-09-032010-03-11Concert Pharmaceuticals, Inc.Antidepressant compounds

CN101781221A *2010-02-112010-07-21上海凯米侬医药科技有限公司Preparation method of O-desmethylvenlafaxine

CN102249936A *2010-05-192011-11-23江苏豪森医药研究院有限公司Hydrate of O-desmethylvenlafaxine hydrochloride and preparation method thereof

Title

FUJII, TOZO等: “Quinolizidines. XXII. An extension of the “3-acetylpyridine route” to the syntheses of 9-hydroxy-10-methoxy- and 10-hydroxy-9-methoxybenzo[a]quinolizidine-type Alangium alkaloids”, 《CHEMICAL & PHARMACEUTICAL BULLETIN》, vol. 35, no. 9, 31 December 1987 (1987-12-31), XP002311646 *

周金培等: “抗抑郁药文拉法辛的合成研究”, 《中国药科大学学报》, vol. 30, no. 4, 31 December 1999 (1999-12-31) *

///////DVS-233 , PF-05212375  , WY-45233,    DESVENLAFAXINE SUCCINATE, WYETH

54143-56-5
54143-55-4 (free base)

Flecainide is a medication used to prevent and treat abnormally fast heart rates.^[1] This includes ventricular and supraventricular tachycardias.^[1] Its use is only recommended in those with dangerous arrhythmias or when significant symptoms cannot be managed with other treatments.^[1] Its use does not decrease a person’s risk of death.^[1] It is taken by mouth or injection into a vein.^[1][2]

Common side effects include dizziness, problems seeing, shortness of breath, chest pain, and tiredness.^[1] Serious side effects may include cardiac arrest, arrhythmias, and heart failure.^[1] It may be used in pregnancy, but has not been well studied in this population.^[2][3] Use is not recommended in those with structural heart disease or ischemic heart disease.^[1] Flecainide is a class Ic antiarrhythmic agent.^[1] It works by decreasing the entry of sodium in heart cells, causing prolongation of the cardiac action potential.^[1]

Flecainide was approved for medical use in the United States in 1985.^[1] It is available as a generic medication.^[2] A month supply in the United Kingdom costs the NHS about £7.68 as of 2019.^[2] In the United States the wholesale cost of this amount is about 18.60 USD.^[4]In 2016 it was the 273rd most prescribed medication in the United States with more than a million prescriptions.^[5]

Medical uses

Flecainide is used in the treatment of many types of supraventricular tachycardias, including AV nodal re-entrant tachycardia (AVNRT) and Wolff-Parkinson-White syndrome (WPW).

It also has limited use in the treatment of certain forms of ventricular tachycardia (VT). In particular, flecainide has been useful in the treatment of ventricular tachycardias that are not in the setting of an acute ischemic event. It has use in the treatment of right ventricular outflow tract (RVOT) tachycardia^[6] and in the suppression of arrhythmias in arrhythmogenic right ventricular dysplasia (ARVD).^[7]Studies (notably the Cardiac Arrhythmia Suppression Trial) have shown an increased mortality when flecainide is used to suppress ventricular extrasystoles in the setting of acute myocardial infarction.^[8][9]

In individuals suspected of having the Brugada syndrome, the administration of flecainide may help reveal the ECG findings that are characteristic of the disease process. This may help make the diagnosis of the disease in equivocal cases.^[10]

Flecainide has been introduced into the treatment of arrhythmias in children.

In the long-term, flecainide seems to be safe in people with a healthy heart with no signs of left ventricular hypertrophy, ischemic heart disease, or heart failure.^[11]

Side effects

Results of a medical study known as the Cardiac Arrhythmia Suppression Trial (CAST) demonstrated that patients with structural heart disease (such as a history of MI (heart attack), or left ventricular dysfunction) and also patients with ventricular arrhythmias, should not take this drug. The results were so significant that the trial was stopped early and preliminary results were published.^[12]

The dose may need to be adjusted in certain clinical scenarios. As with all other antiarrhythmic agents, there is a risk of proarrhythmiaassociated with the use of flecainide. This risk is probably increased when flecainide is co-administered with other class Ic antiarrhythmics, such as encainide. The risk of proarrhythmia may also be increased by hypokalemia.^[13] The risk of proarrhythmia is not necessarily associated with the length of time an individual is taking flecainide, and cases of late proarrhythmia have been reported.^[14] Because of the role of both the liver and the kidneys in the elimination of flecainide, the dosing of flecainide may need to be adjusted in individuals who develop either liver failure or renal failure.

Because of the negative inotropic effects of flecainide, it should be used with caution in individuals with depressed ejection fraction, and may worsen congestive heart failure in these individuals. It should be avoided in people with ischaemic heart disease and the elderly.^[15]

As with all class I antiarrhythmic agents, Flecainide increases the capture thresholds of pacemakers.^[16]

Heart

Due to the narrow therapeutic index of flecainide, physicians should be alert for signs of toxicity before life-threatening arrhythmias occur like torsades de pointes. While the toxic effects of flecainide are closely related to the plasma levels of the drug,^[17] it is unfeasible to check the plasma concentration in an individual on a regular basis.

Signs of flecainide toxicity include marked prolongation of the PR interval and widening of the QRS duration on the surface ECG. There may be signs and symptoms attributable to overt heart failure secondary to sudden decreased myocardial contractility.

Treatment

Treatment of flecainide cardiac toxicity involves increasing the excretion of flecainide, blocking its effects in the heart, and (rarely) institution of cardiovascular support to avoid impending lethal arrhythmias. Modalities that have had success include administration of a beta-sympathomimetic agent,^[17] and administration of a sodium load^[17](often in the form of hypertonic sodium bicarbonate). Placing the individual on cardiopulmonary bypass support may be necessary in order to temporarily remove the need for a beating heart and to increase blood flow to the liver.^[18][19]

Lungs

Flecainide has a very high affinity for lung tissue ^[20] and is associated with drug-induced interstitial lung disease.^{[21][22][23][24][25]}