J. Org. Chem., 2015, 80 (3), pp 1915–1919

DOI: 10.1021/jo5025333

http://pubs.acs.org/doi/abs/10.1021/jo5025333?source=chemport&journalCode=joceah

A direct and efficient total synthesis has been developed for telmisartan, a widely prescribed treatment for hypertension. This approach brings together two functionalized benzimidazoles using a high-yielding Suzuki reaction that can be catalyzed by either a homogeneous palladium source or graphene-supported palladium nanoparticles. The ability to perform the cross-coupling reaction was facilitated by the regio-controlled preparation of the 2-bromo-1-methylbenzimidazole precursor. This convergent approach provides telmisartan in an overall yield of 72% while circumventing many issues associated with previously reported processes.

International Journal of Research in Pharmaceutical and Biomedical Sciences (2013), 4(1), 293-295

telmisartan1. [Yield 87%, Purity 99.97% by HPLC.M.P. 260 – 262°C, Sulphated ash < 0.01%].

1H NMR (DMSO-d6): δ 0.98-1.03 (t,3H), 1.73- 1.86 (m, 2H), 2.5 – 2.63 (s, 3H), 2.90-2.95 (s, 2H),3.82 (s, 3H), 5.62 (s, 2H), 7.16-7.34 (m,7H), 7.40-7.59 (m,4H), 7.68-7.70 (m, 3H), 12.86 (s, 1H).

M/Z: 515.50 [M + H]+

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PATENT

WO 2014027280

http://www.google.com/patents/WO2014027280A1?cl=en

Scheme 1 given below:

Formula .

Example 1:

4′-[2-n^ropyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-ylmeth^

carboxylic acid

In a 2 litre reaction flask was added 400 ml methylene chloride, followed by 100 gm of 2- cyano-4′ -methyl biphenyl. The reaction mass was stirred to get a clear solution and cooled to 20 °C. Chlorine gas was sparged into the reaction mass for a period of 15 hours till completion of the reaction. The reaction was monitored by TLC using mobile phase n-hexane: ethyl acetate (8:2). The excess chlorine from the reaction mass was removed by flushing with nitrogen. The solvent was distilled out completely by distillation at atmospheric pressure and removal of the final traces under vacuum. To the residual mass, 500 ml of methyl isobutyl ketone was added. The reaction mass was stirred and washed with a solution of 300 ml of 5% sodium bicarbonate solution. The lower aqueous layer was separated and the upper organic layer was washed with 300 ml water. The lower aqueous layer was separated. To the organic layer containing 4-chloromethyl-2′-cyanobiphenyl, the compound 2-n-propyl-4-methyl-6-(l’- methylbenzimidazol-2′-yl)benzimidazole was added, followed by a solution of 40 gm sodium hydroxide in 300 ml water. The reaction mass was stirred for 10 minutes and 10 gm of tetrabutyl ammonium hydrogen sulphate was added. The reaction mass was heated to 80 ^UC and maintained at 80 to 85 °C for 4 hours.

The completion of the reaction was monitored by TLC using mobile phase chloroform: methanol (9: 1). After completion of reaction, the lower aqueous layer was separated. The solvent was distilled out till mass temperature 120 °C and final traces were removed completely under vacuum. To the residual mass, 50 ml of n-butanol was added and the solvent distilled out under vacuum below 100 °C to remove all traces of methyl isobutyl ketone. The residue was dissolved in 750 ml of n-butanol and 83 gm sodium hydroxide added. The reaction mass was heated to reflux and maintained for 24 hours at 123 to 126 °C. The completion of the reaction was monitored by TLC using mobile phase chloroform: methanol (9: 1). The solvent was distilled out at atmospheric pressure till the mass temperature reached 140 C. The residual mass was cooled to 100 °C and 300 ml water was added. The solvent was distilled out azeotropically till the mass temperature reached 120 °C. To the reaction mass 750 ml of water was added, the solution warmed to 80 °C. The pH of the reaction mass was adjusted to 8.0 with hydrochloric acid. Finally the pH was adjusted to 6.0 with acetic acid, and the reaction mass maintained at 80 to 85 °C for one hour. The product obtained was filtered, washed with water and dried to yield 120 gm of 4′-[2-n-propyl-4-methyl-6-(l- methylbenzimidazol-2-yl)benzimidazol-l-ylmethyl]biphenyl-2-carboxylic acid, which can be purified as per the procedure described mentioned in Example 5. Example 2:

4-chloromethyl-2 ‘-cyanobiphenyl

In a 1 litre reaction flask 400 ml of methylene chloride was added followed by 100 gm of 2- cyano-4′ -methyl biphenyl. The reaction mass was stirred to get a clear solution and cooled to 20 °C. Chlorine gas was sparged into the reaction mass for a period of 15 hours at 20 to 25 °C till completion of the reaction. The reaction was monitored by TLC using mobile phase n- hexane: ethyl acetate (8:2). The excess chlorine from the reaction mass was removed by flushing with nitrogen. The solvent was distilled out completely by distillation at atmospheric pressure and removal of the final traces under vacuum. To the residual mass, 400 ml of n- heptane was added. The reaction mass was stirred and warmed to 60 °C. The clear solution obtained was cooled to 10 °C and the product precipitated was filtered, washed with n-heptane and dried. Further crystallization with n-heptane yielded 80 gm of pure 4-chloromethyl-2′- cyanobiphenyl.

C 73.87%, H 4.41%, N 6.19%; m/z 192.25; 1H NMR DMSO d₆400 Mhz : 5ppm 4.84 (s, 2H) 7.32 – 7.66 (aromatic 8H). Example 3:

2-cyano-4^,-(2^,,-n-propyl-4^,,-methyl-6^,,-{V”-methylbenzim

ylmethyl) biphenyl

In a 2 litre reaction flask 500 ml of methyl isobutyl ketone was added followed by 100 gm of 2-n-propyl-4-methyl-6-( -methylbenzimidazol-2′-yl)benzimidazole. The reaction mass was stirred and a solution of 40 gm sodium hydroxide in 300 ml water was added. To this solution, 10 gm tetra butyl ammonium hydrogen sulphate and 80 gm of 4-chloromethyl-2′- cyanobiphenyl was added. The reaction mass was warmed to 80 °C and maintained for 4 hours at 80 to 85 °C.

The completion of the reaction was monitored by TLC using mobile phase chloroform : methanol (9:1). After completion of the reaction, the mass was cooled to 20 °C, maintained 3 hours at 15 to 20 °C. The product which precipitated out was filtered, washed with methyl isobutyl ketone, followed by water to yield 126 gm of 2-cyano-4′-(2″-n-propyl-4″-methyl- 6″-(r”-methylbenzimidazol-2″‘-yl)benzimidazol-l”- ylmethyl) biphenyl, melting at 196 – 198 °C. C 80.53%, H 5.70%, N 14.20%; m/z = 496.64 ^lH NMR DMSO d₆ 400 Mhz : 5ppm 0.96 – 0.99 (t, 3H) 1.75 – 1.84 (m, 2H) 2.62 (s, 3H) 2.89 – 2.93 (t, 2H) 3.80 (s, 3H) 5.67 (s, 2H) 7.18 – 7.92 (m, 14H)

Example 4:

4′-[2-n^ropyl-4-methyl-6-(l-methylbenzi idazol-2-yl)benzi idazol-ylmethyl]bipheny carboxylic acid

126 gm of 2-cyano-4′-(2″-n-propyl-4″-methyl-6″-(l “‘-methylbenzimidazol-2″‘-yl) benzimidazol-1″- ylmethyl) biphenyl was dissolved in 750 ml of n-butanol and 83 gm sodium hydroxide added. The reaction mass was heated to reflux and maintained for 15 hours at 123 to 126 °C. The completion of the reaction was monitored by TLC using mobile phase chloroform: methanol (9: 1).

The solvent was distilled out at atmospheric pressure till the mass temperature reached 140 °C. The residual mass was cooled to 100 °C and 300 ml water was added. The solvent was distilled out azeotropically till the mass temperature reached 120 °C. To the reaction mass 750 ml of water was added, the solution warmed to 80 °C. The pH of the reaction mass was adjusted to 8.0 with hydrochloric acid. Finally the pH was adjusted to 6.0 with acetic acid, and the reaction mass maintained at 80 to 85 °C for one hour. The product obtained was filtered, washed with water and dried to yield 120 gm of 4′-[2-n-propyl-4-methyl-6-(l- methylbenzimidazol-2-yl)benzimidazol-l-ylmethyl]biphenyl-2-carboxylic acid. Example 5:

Purification of 4′-[2-n^ropyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l- ylmethyl]biphenyl-2-carboxytic acid

In a 3 litre reaction flask, 1000 ml of methanol was added followed by the addition of 120 gm of 4′-[2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-ylmethyl]biphenyl- 2-carboxylic acid obtained by procedure described in Example 4. The solution was warmed to 50 °C and pH adjusted to 10.0 to 10.5 with 100 ml of a 10% methanolic potassium hydroxide solution. The reaction mass became a clear solution, and 6 gm activated carbon was added. The mass was maintained at 50 to 55 °C for one hour and filtered through hyflo supercel to remove the activated carbon. The clear filtrate obtained was collected and its pH adjusted to 6.0 to 6.5 with 130 ml of acetic acid, maintaining the temperature between 50 to 55 °C. The mass was cooled to 15 °C and maintained one hour at 10 to 15 °C. The product which precipitated out was filtered, washed with 50 ml of methanol followed by 500 ml of water. The wet product was dried to yield 107 gm of 4′-[2-n-propyl-4-methyl-6-(l- methylbenzimidazol-2-yl)benzimidazol-l-ylmethyl]biphenyl-2-carboxylic acid.

C 76.49%; H 5.74%, N 11.02%; m/z 515.45.; 1H NMR DMSO d₆ 400 Mhz : 5ppm 0.97 – 1.01 (t, 3H) 1.76 – 1.85 (m, 2H) 2.62 (s, 3H) 2.90 – 2.94 (t, 3H) 3.81 (s, 3H) 5.61 (s, 2H) 7.15 – 7.71 (14H aromatic);

Melting point of purified telmisartan: 269 °C.

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PAPER

Journal of Organic Chemistry (2014), 79(21), 10568-10580

http://pubs.acs.org/doi/abs/10.1021/jo501665e

On the basis of our recently reported aniline aqueous borylation, molecular diversity was achieved in a one-pot process by combining other reactions such as esterification, Suzuki–Miyaura coupling, hydrogenolysis, or Petasis borono-Mannich.

TELMISARTAN IS COMPD 9

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US 20150031768

(EN)

Methods of halogenating a carbon containing compound having an sp3 C—H bond are provided. Methods of fluorinating a carbon containing compound comprising halogenation with Cl or Br followed by nucleophilic substitution with F are provided. Methods of direct oxidative C—H fluorination of a carbon containing compound having an sp3 C—H bond are provided. The halogenated products of the methods are provided.

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PATENT

WO 2014067237

http://www.google.com/patents/WO2014067237A1?cl=en

Telmisartan Preparation: 12 Examples

The title compound (III, R = COOCH ₃₎ (52.8g, O. lmol) of Example 11 with glacial acetic acid

(200ml) and concentrated hydrochloric acid (250ml) mixing, 100 ° C to react for 5 to 6 hours. Evaporated to most mixed acid, residue slowly poured into crushed ice, under ice cooling with saturated K ₂ CO ^ solution to adjust the pH to neutral, solid precipitation, filtration, filtrate was washed with water, was for Mischa Tan crude, recrystallization telmisartan (40.1g), liquid purity greater than 99%.

Example 13: Preparation of telmisartan of formula I compound (0.62g, leq) was added to acetonitrile (10ml). After stirring evenly, the KOH (0.14g, 1. leq) was slowly added, after stirring for 10 plus minutes, the title compound of Example 10 of the embodiment (11, R = COOCH ₃₎ (0.5g, leq) was slowly added, stirred for 3-4 hours, TLC the reaction was complete, the direct addition of 50% ethanol (30mL), reflux The reaction for 6 hours. After completion of the reaction by TLC, recovering the organic solvent under reduced pressure, the remaining solution was added dropwise hydrochloric acid (1: 1) to neutral pH. The precipitated solid was filtered, washed with water to give crude telmisartan, telmisartan recrystallized (yield 75.1%), the liquid phase is greater than 98% purity.

Chloromethyl biphenyl -2- (II, R = CN) Preparation of 4′-nitrile:

…………………

Journal of Pharmaceutical and Biomedical Analysis (2015), 108, 86-96.

………………..

IN 262831/EP 1912975

……………………….

JP 2014201585

……………………..

 IN 2013KO00463/WO 2014174397

…………………………….

PATENT

http://www.google.com/patents/CN1768044A?cl=en

Example 7: Telmisartan make 5.51 g telmisartan × HCl was dissolved in 50 ml of 40% acetic acid while refluxing. The brown solution was then filtered hot through 1.1 g of carbon, 2.5 ml of 40% acetic acid and washed, and at 80-90 ℃ 2.5 ml of 4N NaOH was added dropwise with stirring to light brown filtrate. Telmisartan crystallization, the suspension was diluted with 30 ml of water, and slowly cooled to ambient temperature. Telmisartan suction filtration, and washed with 50 ml of water. And dried in vacuo at 80 ℃ drying cabinet telmisartan.

Yield: 4.80 g (93.3% of the theoretical yield).

……………………………….

PATENT

http://www.google.com/patents/CN102731407A?cl=en

Example 4 Preparation of telmisartan

[0031] 2-n-propyl group as shown in Formula I-4-methyl-6- (benzimidazol-2-yl-methyl 1’_) benzimidazole (30. 4g, O. 10mol), 4_ bromomethyl-biphenyl-2-carboxylic acid (43. 6g, O. 15mol), three ko amine (12. Ig, O. 15mol) and ko ni ni ether 500ml alcohol were mixed and reacted at 100 ° C for 6 inches The reaction solution was poured into ice water, acidified with dilute hydrochloric acid and slowly adjusted PH2-3, to precipitate a solid. Filtration, 70 ° C drying crude, the resulting crude product ko ko acid ester 300ml heating beating again. Filtered, 70 ° C dry. Recrystallization from DMF telmisartan of formula III as shown in 25. Ig, yield: 50%.

…………………….

PATENT

http://www.google.com/patents/WO2010146187A2?cl=en

For example, WO 2004/087676 describes the hydrolysis of a compound with the chemical name 4 ‘-((1,7′- dimethyl-2 ‘ -propyl-lH, 3 ‘H-2, 5 ‘ -bibenzo [d] imidazol-3 ‘ -yl) – methyl) biphenyl-2-carbonitrile and having formula 2

which is hereinafter referred to as cyanotelmisartan . In par- ticular, the hydrolysis of cyanotelmisartan is carried out at elevated temperatures using strong alkaline conditions. Also, CN 1412183 discloses the hydrolysis of cyanotelmisartan.

US 2006/0264491 Al discloses the hydrolysis of 4′-((l,7′- dimethyl-2 ‘ -propyl-lH, 3 ‘H-2, 5 ‘ -bibenzo [d] imidazol-3 ‘ – yl) methyl) biphenyl-2-carboxamide having formula 3

Example 2: Preparation and isolation of telmisartan

Into a reaction vessel 20.5g (40 mmol) 4 ‘ – ( (1, 7 ‘ -dimethyl-2 ‘ – propyl-IH, 3 ‘ H-2 , 5 ‘ -bibenzo [d] imidazol-3 ‘ -yl) methyl) biphenyl-2- carboxamide and 20 ml (lδOmmol) H₂SO₄ (1:1) were added. The re- action mixture was heated to about 125°C and stirred at this temperature for 28 h. A sample of the reaction mixture was analyzed by Area% HPLC (starting compound below 0.1%, telmis- artan over 97%) . The reaction mixture was cooled below 80⁰C and 250 ml of water were added. Then, 200 ml of dichloro- methane were added and pH value of mixture was adjusted to 5.4 by addition of 6M NaOH. The mixture was stirred for approximately 5 min and then the phases were separated. The water phase was reextracted by 136 ml of dichloromethane . Collected organic phases were washed with water (2^χl36ml) and then treated with activated charcoal (5.3 g) . Subsequently, the organic phase was evaporated an oily residue (26g) . 264 ml of acetone were added. The mixture was stirred at room temperature for at least 6 hours. The precipitated product was sepa- rated and washed with fresh acetone and dried at 65°C under reduced pressure for 3 hours. Yield: 18.3g (89%) Area % HPLC: Telmisartan 99.80%

Example 3: Isolation of telmisartan

Into a reaction vessel 7.5g (15 mmol) of cyanotelmisartan, 30 ml of propylene glycol, 0.8 ml of water and 3g (45 mmol) of 85% KOH were added. The reaction mixture was heated to around 160⁰C to 170 ⁰C and stirred at this temperature for 24 h. The reaction mixture was cooled below 80⁰C and 75 ml of water were added. Then, pH value of the mixture was adjusted to 4.8 (by addition of 6M HCl) and then 150 ml of dichloromethane were added. The mixture was stirred for approximately 5 min and then the phases were separated. The water phase is reextracted by 50 ml of dichloromethane. Collected organic phases were washed with water (2^χ50ml) and then treated with activated charcoal (2 g) . After that the organic phase was evaporated to an oily residue (9.8g) . 100 ml of acetone were added. The mix- ture was stirred at room temperature for at least 6 hours. The precipitated product was separated and washed with fresh acetone and dried at 65°C under reduced pressure for 3 hours. Yield: 6.8g (88%) Area % HPLC: Telmisartan 99.60%

…………………….

PATENT

http://www.google.com/patents/CN1548421A?cl=en

Specific embodiments

14 ‘Example – [(1,4′-dimethyl-2′-propyl [2,6′- two-1H – benzoimidazol] 1′-yl) methyl] – [1, 1′-biphenyl] -2-carboxylic acid sodium salt in 250ml reaction flask, telmisartan 10g (0.0195mol), NaOH0.75g (0.0189mol) and water 100ml, stirred for 1 hour (30 ℃), filtered insoluble materials are removed and concentrated to a small volume, plus ethanol 30ml, concentrated, washed with 30ml of n-hexane, decanted, plus ethanol 30ml, concentrated, and then repeat again, and concentrated to dryness to obtain telmisartan sodium salt 9.9g yield 95.2%. Melting point: 223-225 ℃.

Elemental analysis: C33H29N4O2Na · H2O Calcd: C71.48 H5.10 N10.11 Found: C71.42 H5.08 N10.22 Example 24 ‘- [(1,4′-dimethyl-2′-n propyl [2,6′- two-1H – benzoimidazol] 1′-yl) methyl] – [1,1′-biphenyl] -2-carboxylic acid potassium salt in 250ml reaction flask, Telmisartan 10g (0.0195mol), KOH1.06g (0.0188mol) and water 100ml, stirred for 1 hour (30 ℃), filtered to remove insolubles, and concentrated to a small volume, ethanol 30ml, concentrated, hexane 30ml washed, decanted, plus ethanol 30ml, concentrated, and then repeat again, and concentrated to dryness to obtain telmisartan potassium 10.6g, yield 95.6%. Melting point: 203-205 ℃.

Elemental analysis: C33H29N4O2K · H2O Calcd: C69.04 H5.40 N9.76 Found: C69.01 H5.28 N9.88 Example 3 starting material and the mixed powder was sieved excipients, 5% polyethylene pyrrolidone was granulated and dried. After dried particles were sieved magnesium stearate was added mixed tabletted.

mg / tablet of telmisartan sodium salt 20 Lactose 170 Sodium carboxymethyl starch 10 mg Magnesium stearate 8 meglumine 25% polyvinyl pyrrolidone solution q.s. Example 4 A mixed powder of raw materials and auxiliary materials sieved, added 5 % solution of polyvinylpyrrolidone is granulated and dried. After dried particles were sieved magnesium stearate was added mixed tabletted.

mg / tablet telmisartan sodium Lactose 200 40 140 DCP sodium carboxymethyl starch 16 mg Magnesium stearate 45% povidone solution appropriate amount of Example 5 of this product, according to the dissolution assay (Chinese Pharmacopoeia 2000 edition Appendix II XC second method), phosphate buffer 900ml solvent, the speed of 75 revolutions per minute, operate according to the law, after 30 minutes, take the solution as spectrophotometry (Chinese Pharmacopoeia 2000 edition of the test solution, according to the spectrophotometric two Appendix IVA), absorbance was measured at 295nm wavelength. Another reference standard stock solution 10ml precise amount of determination under set 100ml flask, diluted with phosphate buffer to the mark, then the precise amount of 5ml, set 10ml volumetric flask, dilute to the mark with phosphate buffer , shake, the same method absorption, calculated for each piece of the dissolution of the limits of 80% scalar, should be specified. Dissolution test results in Table.

Table dissolution test results Dissolution (%) telmisartan sodium 97.29 99.65 102.55 95.83 101.10 98.92 99.20 ± 2.45

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PATENT

http://www.google.com/patents/CN1412183A?cl=en

Example 5 4 ‘- [(1,4′-dimethyl-2′-propyl [2,6′- two -1H- benzimidazol] -1′-yl) methyl] – [1,1′ – biphenyl] -2-carboxylic acid (III) IV (24.8g, 0.05mol) was added ethylene glycol (100ml) and water (150ml) (or other previously described a mixed solvent), sodium ethoxide (or as previously said other alcohols sodium) (13.6g, 0.2mol), was refluxed for 10 hours. After no starting material by TLC was cooled to room temperature, hydrochloric acid was added dropwise (1/1) to pH 5-6, the precipitated solid was filtered, washed with water to give III.

……………………

PATENT

http://www.google.com/patents/CN101550107B?cl=en

Example 3

[0047] 1) Preparation of telmisartan crude methyl ester

Compound II into 50g in 500mL reaction flask, 200mL of methyl isobutyl ketone (MIBK), 25 ° C _30 ° C with stirring until dissolved, was added dropwise 35mL of triethylamine was added 55. Og After the completion of the compound III, 5 (T60 ° C or so for about 4_5 hours, TLC monitoring completion of the reaction, filtered and the filter cake washed with a small amount of MIBK, and then washed with water, dried to give 70. 3g of crude product. 81% yield, purity of about 98%.

(TLC test conditions: ethyl acetate: methanol = 8: 1)

 2) preparation of high purity methyl telmisartan

 IOOOmL reaction flask, the input step to give the crude methyl ester telmisartan, add 500mL of isopropanol was heated to dissolve, 2gX 2 activated bleaching filtrate was heated to about 90 ° C, added dropwise with stirring 150mL 7jC insulation 0. 5~Ih, cooled slowly to room temperature with stirring. Filtered, and the filter cake washed sequentially with MIBK and water washing, and drying, the yield of about 82%, HPLC purity 99.5%, the single impurities less than 0.1%.

3) Preparation of telmisartan with high purity

[0053] A reaction flask was put in a 500mL high purity 15g telmisartan ester, 3. Og sodium, 200mL of isopropanol, water, 80ml, was heated to reflux for 5 ~ 7 h, TLC monitoring of the reaction was complete, the distillation Isopropanol was removed, and water was added to completely dissolve the solid 40ml, 0. 5g of activated carbon bleaching, the filtrate was added 50ml of water, heated to 80 ° C, lmol / L of acetic acid to adjust the pH to 5. (Γ5. 5, filtered, and the filter cake dried to give 13. 14g of solid, yield 90%, HPLC purity 99.7%, the single impurities less than 0.1%.

(TLC test conditions: ethyl acetate: methanol = 8: 1)

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http://www.google.com/patents/CN101172968B?cl=en

Example 1

[0023] 1, 100gPPA, 21. 8g (0. Lmol) 2_ n-propyl _4_ _6_ carboxyl methyl benzimidazole and 21. 5gN- methyl-o-phenylenediamine added to the reaction flask in under N2 protection feeding, heated to IO (TC _1601 :, reaction 8-20 hours, down 70-80.C 200ml water was added and the reaction with hydrochloric acid to adjust ffl = 1~2, put charcoal 5_8%,, 8 (TC about 5 to 10 minutes, filtered, and the reaction repeated, the adjustment ra 12-14 with NaOH, for several hours, and filtered to give the crude intermediate 2-n-propyl -4-methyl-6- (benzimidazol-2-yl-methyl ) benzimidazole sodium salt. [0024] 2, the product of the previous step, 2-n-propyl -4-methyl–6_ (methyl benzimidazol-_2_ yl) benzimidazole sodium salt crude product was dissolved into 200 ml of ethanol , and dissolved by heating, cooling to room temperature, 400 ml 1N NaOH, to precipitate the compound 2-n-propyl -4-methyl-6- (methyl benzimidazol-2-yl) benzimidazole .50-8 ( TC dried in vacuo. [0025] 3, product of the previous step -4-methyl-2-n-propyl -6_ (methyl benzimidazol-_2_ yl) benzimidazole into 200 ml of dimethyl sulfoxide was stirred was added at room temperature and 4-bromomethyl – biphenyl-2-carboxylic acid methyl ester 33.55 g, was stirred for 14 hours, extracted with dichloromethane (200, 100, 100), and evaporated to dryness under reduced pressure, 300 ml of methanol and 10% potassium hydroxide (240 ml, 0. 6mo1) mixture was refluxed for 6 hours, cooled, washed with 80 ml of methylene chloride, adjusted with glacial acetic acid ffl = 6, a lot of white floc precipitated precipitate was filtered and dried to give a white Tilmicosin 49.6 g of crude product, the crude product was added 100 ml of chloroform was heated to reflux, activated carbon decolorization, crystallization, filtration, 8 (TC dried in vacuo to give a white pure telmisartan (HLPC> 99. 0%) 41 克, purification yield 82%. mp 261~263.C, H-NMR (d6-DMS0) S 1. 05t, 3H), 1. 83 (m, 2H), 2. 71 (s, 3H), 2. 94 (t, 2H), 3. 81 (s, 3H), 5. 57 (s, 2H), 7. 16-7. 83 (m, 14H) • C33H33N402 [0026] Example 2 Preparation of telmisartan

 1, 100gPPA, 21. 8g (0. 1) 2_ [4-methyl-n-propyl-benzimidazole and _6_ 21. 5gN- carboxy-o-phenylenediamine added to the reaction flask in N2 Under the protection of feeding, heated to 100 ° C _160 ° C, the reaction for 8-20 hours, down 70-80. C, the reaction was added 200ml of water, adjusted with hydrochloric acid ffl = 1~2, into charcoal 5_8%, about 8 (TC 5_10 minutes filtered again reacted with K0H ra adjusted to 12-14 for several hours and filtered to give Intermediate crude 2-n-propyl -4-methyl-6- (benzimidazol-2-yl-methyl) benzimidazole potassium salt.

 2, the product of the previous step, 2-n-propyl -4-methyl–6_ (methyl benzimidazol-_2_ yl) benzimidazole potassium salt of the crude product into 200 ml of ethanol, and dissolved by heating, cooling to room temperature was added 400 ml 1N K0H, a precipitated compound is 2-n-propyl -4-methyl-6- (benzimidazol-2-yl-methyl) benzimidazole potassium salt. 50-8 (TC dried in vacuo. [0029] 3, 2-n-propyl prepared in the previous step -4-methyl-6- (benzimidazol-2-yl-methyl) benzimidazole potassium salt and 27.2 g of 4-bromomethyl-2-cyanobiphenyl, 10.4 g of triethylamine and DMF (DMA, dichloromethane, dichloroethane) were mixed and reacted for 5-10 hours at 35-40 °, TLC detection After no starting material the reaction mixture was poured into 600 g of ice water, extracted with ethyl acetate (300ml * 3), the combined organic phases were washed with water (300ml * 2), dried and desolvation, and then petroleum ether was added and stirred until a solid precipitated was The crude product was 45.6 g.

4, the upper step of the solid 45.6 grams, was added 200ml of ethylene glycol, 150ml water, 12 g of sodium hydroxide, the reaction was refluxed for 10 hours, TLC detected no starting material and then cooled to room temperature, acidified with hydrochloric ra is 5 to 6, there is solid precipitation, filtration, washing, telmisartan was crude, DMF and recrystallized to give 44.5 g of telmisartan pure product (HLPC> 99. 0%) mp261~263 ° C. Force -NMR (de-DMS0) S 1. 05t, 3H), 1. 83 (m, 2H), 2. 71 (s, 3H), 2. 94 (t, 2H), 3. 81 (s, 3H ), 5. 57 (s, 2H), 7. 16-7. 83 (m, 14H) • C33H33N402 [0031]

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Olanzapine (sold under the brand names Zyprexa, Zypadhera and Lanzek or in combination with fluoxetine, Symbyax) is anatypical antipsychotic. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia and bipolar disorder.^[4]

Olanzapine is structurally similar to clozapine and quetiapine, but is classified as a thienobenzodiazepine. The olanzapine formulations are manufactured and marketed by the pharmaceutical company Eli Lilly and Company; the drug went generic in 2011. Sales of Zyprexa in 2008 were $2.2B in the US, and $4.7B worldwide.^[5]

Medical uses

Schizophrenia

The first-line psychiatric treatment for schizophrenia is antipsychotic medication which includes olanzapine.^[6] A Cochrane reviewfound that the usefulness for maintenance therapy; however, is difficult to determine as more than half of people in trials quit before the six week completion date.^[7]

Zyprexa (olanzapine) 10 mg tablets (AU)

Olanzapine has a higher affinity for 5-HT_2A serotonin receptors than D₂ dopamine receptors, which is a common property of all atypical antipsychotics, aside from the benzamide antipsychotics such as amisulpride. Olanzapine also had the highest affinity of any second-generation antipsychotic towards the P-glycoprotein in one in vitro study.^[60] P-glycoprotein transports a number of drugs across a number of different biological membranes including the blood-brain barrier, which could mean that less brain exposure to olanzapine results from this interaction with the P-glycoprotein.^[61]

Olanzapine is a potent antagonist of the muscarinic M₃ receptor,^[65] which may underlie its diabetogenic side effects.^[64][66] Additionally, olanzapine also exhibits a relatively low affinity for serotonin 5-HT₁, GABA_A, beta-adrenergic receptors, and benzodiazepine binding sites.^{[67] [27]}

The mode of action of olanzapine’s antipsychotic activity is unknown. It may involve antagonism of dopamine and serotonin receptors. Antagonism of dopamine receptors is associated with extrapyramidal effects such as tardive dyskinesia(TD), and with therapeutic effects. Antagonism of muscarinic acetylcholine receptors is associated withanticholinergic side effects such as dry mouth and constipation, in addition it may suppress or reduce the emergence of extrapyramidal effects for the duration of treatment, however it offers no protection against the development of tardive dyskinesia. In common with other second generation (atypical) antipsychotics, olanzapine poses a relatively low risk of extrapyramidal side effects including TD, due to its high affinity for the D₁ receptor over the D₂ receptor.^[68]

Antagonizing H₁ histamine receptors causes sedation and may cause weight gain, although antagonistic actions at serotonin 5-HT_2C and dopamine D₂ receptors have also been associated with weight gain and appetite stimulation.^[69]

Dosage forms[edit]

Olanzapine is marketed in a number of countries, with tablets ranging from 2.5 to 20 milligrams. Zyprexa (and generic olanzapine) is available as an orally-disintegrating “wafer” which rapidly dissolves in saliva. It is also available in 10 milligram vials for intramuscular injection.^[4]

Metabolism[edit]

Olanzapine is metabolized by the cytochrome P450 system; principally by isozyme 1A2 and to a lesser extent by 2D6. By these mechanisms more than 40% of the oral dose, on average, is removed by the hepatic first-pass effect.^[27] Drugs or agents that increase the activity of CYP1A2, notably tobacco smoke, may significantly increase hepatic first-pass clearance of Olanzapine; conversely, drugs which inhibit 1A2 activity (examples: Ciprofloxacin, Fluvoxamine) may reduce Olanzapine clearance.^[4]

Society and culture[edit]

Regulatory status[edit]

Olanzapine is approved by the Food and Drug Administration (FDA) for:

• Treatment — in combination with fluoxetine — of depressive episodes associated with bipolar disorder (December 2003).^[70]

• Long-term treatment of bipolar I disorder (January 2004).^[71][72]

• Treatment — in combination with fluoxetine — of resistant depression (March 2009).^[73]

• Oral formulation: acute and maintenance treatment of schizophrenia in adults, acute treatment of manic or mixed episodes associated with bipolar I disorder (monotherapy and in combination with lithium or sodium valproate)
• Intramuscular formulation: acute agitation associated with schizophrenia and bipolar I mania in adults
• Oral formulation combined with fluoxetine: treatment of acute depressive episodes associated with bipolar I disorder in adults, or treatment of acute, resistant depression in adults ^[74]

• Treatment of the manifestations of psychotic disorders (September 1996^[75]—March 2000).^[76]

• Short-term treatment of acute manic episodes associated with bipolar I disorder (March 2000).^[76]

• Short-term treatment of schizophrenia instead of the management of the manifestations of psychotic disorders (March 2000).^[76]

• Maintaining treatment response in schizophrenic patients who had been stable for approximately eight weeks and were then followed for a period of up to eight months (November 2000).^[76]

Controversy, prosecution, lawsuits and settlements[edit]

Eli Lilly has faced many lawsuits by from people who claimed they developed diabetes or other diseases after taking Zyprexa. In 2006, Lilly paid $700 million to settle 8,000 of these lawsuits.^[77] In 2007, Eli Lilly agreed to pay up to $500 million to settle 18,000 more lawsuits.^{[citation needed]}

In 2009 Eli Lilly pled guilty to a criminal misdemeanor charge of illegally marketing Zyprexa for off-label use and agreed to pay $1.4 billion.^[78][79]

A New York Times article based on leaked company documents concluded that the company had engaged in a deliberate effort to downplay olanzpine’s side effects.^[80] The company denied these allegations and stated that the article had been based on cherry picked documents. Most of the documents were disclosed as the result of lawsuits by individuals who had taken the drug, though other documents had been stolen.^[81] Eli Lilly filed a protection order to stop the dissemination of some of the documents which the judge believed to be confidential and “not generally appropriate for public consumption”.^[81] Temporary injunctions required those who had received the documents to return them and to remove them from websites.^[82] Judge Jack B. Weinstein issued a permanent judgement against further dissemination of the documents and requiring their return by a number of parties named by Lilly.^[81] On January 8, 2007, Judge Jack B. Weinstein refused the Electronic Frontier Foundation‘s motion to stay his order.^[83] The documents given to The New York Times by Jim Gottstein show that senior Lilly executives may have kept important information from doctors about Zyprexa’s links to obesity and its tendency to raise blood sugar — both known risk factors for diabetes.^{[citation needed]} The Times of London also reported that as early as 1998, Lilly considered the risk of drug-induced obesity to be a “top threat” to Zyprexa sales.^[84] On October 9, 2000, senior Lilly research physician Robert Baker noted that an academic advisory board he belonged to was “quite impressed by the magnitude of weight gain on olanzapine and implications for glucose.”^[84]

Research[

Olanzapine has been investigated for use as an antiemetic, particularly for the control of chemotherapy-induced nausea and vomiting (CINV). A 2007 study demonstrated its successful potential for this use, achieving a complete response in the acute prevention of nausea and vomiting in 100% of patients treated with moderately and highly-emetogenic chemotherapy, when used in combination with palonosetron and dexamethasone.^[85]

Olanzapine has been considered as part of an early psychosis approach for schizophrenia. The Prevention through Risk Identification, Management, and Education (PRIME) study, funded by the National Institute of Mental Health and Eli Lilly, tested the hypothesis that olanzapine might prevent the onset of psychosis in people at very high risk forschizophrenia. The study examined 60 patients with prodromalschizophrenia, who were at an estimated risk of 36–54% of developing schizophrenia within a year, and treated half with olanzapine and half with placebo.^[86] In this study, patients receiving olanzapine did not have a significantly lower risk of progressing to psychosis. Olanzapine was effective for treating the prodromal symptoms, but was associated with significant weight gain.^[87]

References

External links

• Zyprexa.com – official Zyprexa brand website from Eli Lilly and Company
• Zyprexa package insert
• Berenson, Alex (December 17, 2006). “Lilly Settles With 18,000 Over Zyprexa”. New York Times.

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Vortioxetine

O N Sept. 30, 2013 — The U.S. Food and Drug Administration today approved Brintellix (vortioxetine) to treat adults with major depressive disorder.

Major depressive disorder (MDD),

Commonly referred to as depression, is a mental disorder characterized by mood changes and other symptoms that interfere with a person’s ability to work, sleep, study, eat and enjoy once-pleasurable activities. Episodes of depression often recur throughout a person’s lifetime, although some may experience a single occurrence.

READ ALL AT

http://www.drugs.com/newdrugs/fda-approves-brintellix-major-depressive-disorder-3918.html

SYNTHESIS……..http://newdrugapprovals.org/2013/10/01/vortioxetine-fda-approves-brintellix-to-treat-major-depressive-disorder/

NEW PATENT

WO 2015044963

An amorphous vortioxetine and salts thereof

Cadila Healthcare Ltd

Singh, Kumar Kamlesh; Gajera, Jitendra Maganbhai; Raikwar, Dinesh Kumar; Khera, Brij; Dwivedi, Shri Prakash Dhar

Stable amorphous form of vortioxetine hydrobromide, useful for treating depression, major depressive disorder (MDD) and generalized anxiety disorder. Also claims a process for preparing the amorphous form and solid dispersions comprising the same.

This API, which was originally developed and launched by Lundbeck and Takeda for treating MDD.

A phase IV trial (NCT02357797) for schizophrenia was scheduled to begin in March 2015. Family members of the product case, WO03029232, hold SPC protection in the EP until 2027 and one of its Orange Book listed filings, US7144884, expire in the US in 2023 with US154 extension.

The US FDA Orange Book also lists patents describing crystalline forms of vortioxetine/Brintellix, US8722684 and US8969355, that are due to expire in 2030 and 2027 respectively. The drug also has NCE exclusivity expiring in September 2018.

Cadila is potentially interested in vortioxetine hydrobromide.

PART 1…..http://newdrugapprovals.org/2015/04/08/olanzepine/

PART 2….http://newdrugapprovals.org/2015/04/09/olanzepine-visited-part-22/

WATCHOUT………..

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PART 1…..http://newdrugapprovals.org/2015/04/08/olanzepine/

PART 2….http://newdrugapprovals.org/2015/04/09/olanzepine-visited-part-22/

PART 3…….http://newdrugapprovals.org/2015/04/09/olanzepine-visited-part-33/

review……http://cosmos.ucdavis.edu/archives/2011/cluster8/JAIN_VINEET.pdf

WATCHOUT………..

…………….

DOI: 10.1039/C3OB27424A

http://pubs.rsc.org/en/Content/ArticleLanding/2013/OB/c3ob27424a#!divAbstract

A new strategy for converting antipsychotic drug olanzapine into PDE4 inhibitors is describedvia the design and Pd/C mediated synthesis of novel N-indolylmethyl olanzapine derivatives. One compound showed good inhibition (IC₅₀ 1.1 μM) and >10 fold selectivity towards PDE4B over D that was supported by docking studies. This compound also showed significant inhibition of TNF-α and no major toxicities in cell lines and a zebrafish embryo model except the teratogenic effects to be re-assessed in rodents.

…………..

http://www.google.com/patents/US7329747

Olanzapine or 2-methyl-4-[4-methyl-1-piperazinyl]-10H-thieno[2,3b][1,5]-benzodiazepine is a pharmaceutically active compound that can be represented by the formula (1).

It was disclosed in EP 454436 and corresponding U.S. Pat. No. 5,229,382 as a useful antipsychotic agent. Olanzapine acts as a serotonin (5-HT2) and dopamine (D1/D2) receptor antagonist with anticholinergic activity. In commercially available final forms, the active substance is marketed as a free base, which is a white to yellow crystalline solid that is insoluble in water.

One synthetic route for making olanzapine starts from “des-methylpiperazine olanzapine precursor” of formula (3), which reacts with piperazine to form a “des-methyl olanzapine precursor” of formula (2) (see Jun-Da Cen, Chinese Journal of Pharmaceuticals 2001, 32(9),391-393). The compound (2) can be methylated to form olanzapine (see U.S. Pat. No. 4,115,568 for such suggestion). The methylation reaction can be carried out using formaldehyde under conditions of Eschweiler-Clarke reaction (see Jun-Da Cen) or by classical methylation agents such as methyl iodide (see WO 04-000847).

This synthetic pathway has the disadvantage that the reaction with piperazine may lead to formation of dimeric impurities and that the methylation with formaldehyde or other methylation agent may lead to side products, e.g. products of multiple methylation. All these contaminants are difficult to remove from the product. Also, methylation agents are, in general, toxic and mutagenic compounds.

An alternative of the above process was suggested in WO 04/000847 and comprises converting the compound (2) into a “formyl-olanzapine precursor” of formula (4) by a reaction with a methyl formate, and converting the compound (4) into olanzapine by a reduction with a metal borohydride.

In comparison with the preceding procedure, the alternate procedure is one step longer and suffers from the same problems in the step of making compound (2). Furthermore, the reported purity of the actually obtained olanzapine product is only 88%, which is not sufficient for pharmaceutical applications.

The present invention relates to the formation, purification and/or use of an N-formyl olanzapine. Accordingly, a first aspect of the present invention relates to a process, which comprises reacting a des-piperazine olanzapine of formula (3) or a salt thereof

with an N-formyl piperazine of formula (5)

to form an N-formyl olanzapine of formula (4) or a salt thereof

The reaction can be carried out in an inert solvent, generally a dipolar aprotic solvent, and is typically accomplished by heating. The N-formyl olanzapine can be converted to olanzapine.

Another aspect of the invention relates to a process for making an olanzapine salt, which comprises: reducing an N-formyl olanzapine of formula (4) or a salt thereof

with a reducing agent in a solvent to form olanzapine or a salt thereof dissolved in said solvent; reacting said dissolved olanzapine or a salt thereof with an acid to form an acid addition salt of olanzapine; and precipitating said olanzapine acid addition salt from said solution. Precipitating the salt of olanzapine can avoid the formation of technical grade olanzapine. That is, the olanzapine salt can be obtained in a purified state and then converted to olanzapine base, if desired, in high purity.

A further aspect of the present invention relates to purifying the N-formyl olanzapine, which process which comprises:

(1) dissolving and/or slurrying an N-formyl olanzapine of formula (4)

or a salt thereof in a solvent selected from the group consisting of an aliphatic alcohol, an aromatic hydrocarbon, and mixtures thereof, at a temperature of at least 35° C. to form a crystallization treatment medium;

(2) cooling said crystallization treatment medium; and

(3) isolating solid N-formyl olanzapine of formula (4) having improved purity. The steps (1)-(3) can be repeated if necessary until the desired purity is reached. Generally, such a process can achieve purity of greater than 95% and preferably greater than 98%.

An overall synthetic scheme for making olanzapine, which combines various aspects of the present invention, is set forth below:

Example 1

N-Formyl Olanzapine (4)

In a 1000 ml flask, a mixture of 12.0 g of “des-methylpiperazine olanzapine precursor” (compound of formula (2)) hydrochloride and 40 ml of N-formyl piperazine in a mixture of 60 ml of dimethylsulfoxide and 60 ml of toluene was heated at reflux under a nitrogen atmosphere overnight. Progress was monitored by HPLC. After cooling to 40° C., 160 ml of water was added. The resulting mixture was cooled and stirred at 0° C. The solid material was isolated by filtration and washed with 2×40 ml of water. Wet solid was dried overnight at ambient conditions and subsequently at 40° C. under vacuum.

Isolated yield: 12.19 gram, Purity (HPLC): 91.6%

Example 2

Crystallization of the Compound (4)

8.0 g of crude N-formyl olanzapine precursor (compound (4)) of a purity of about 89% (HPLC) was suspended in 50 ml of methanol and heated at 60° C. for 3 hours. The hot suspension was allowed to cool to room temperature and was subsequently cooled to 5° C. under stirring. The solid material was isolated by filtration, washed with 5 ml of cold methanol and 10 ml of cold diethyl ether and dried overnight at 40° C. under vacuum.

Yield: 3.97 g, purity 96.7% (HPLC)

……………….

PATENT

http://www.google.com/patents/WO2004056833A1?cl=en

…………………………….

http://www.google.com/patents/WO2002018390A1?cl=en

Olanzapine is represented by the following structure.

Olanzapine

Olanzapine is useful for treating psychotic patients and mild anxiety states. Preparation of Olanzapine and its acid salts, having pharmaceutical properties particularly in the treatment of disorders ofthe central nervous system has been discussed in U.S. Patent No. 5,229,382.

U.S. Patent No. 5,229,382 does not refer to any specific polymorphic crystalline form of Olanzapine. European patent specification No. 733635A1 claims Form-2 of Olanzapine. The process under this patent describes preparation of Form-2 from ethyl acetate. This patent also designated the product obtained according to the process described in U.S. Patent No. 5,229,382 as Form-1. Furthermore, EP 733635 Al discloses the d values for Form-1 and Form-2 from their X-ray Diffractograms. The values are: d value d value

Form-1 Form-2 9.94 10.26

8.55 8.57 8.24 7.47 6.88 7.12 6.37 6.14 6.24 6.07 5.58 5.48 5.30 5.21 4.98 5.12 4.83 4.98 4.72 4.76 4.62 4.71 4.53 4.47 4.46 4.33 4.29 4.22 4.23 4.14 4.08 3.98 3.82 3.72 3.74 3.56 3.69 3.53 3.58 3.38 3.50 3.25 3.33 3.12 3.28 3.08

3.21 3.06

3.11 3.01

3.05 2.87 2.94 2.81

2.81 ^‘ 2.72

2.75 2.64

2.65 2.60

2.63 2.59

It is noteworthy to mention that EP 0 831 098 A2 discloses the preparation of a series of dihydrates of olanzapine namely Dihydrate B, Dihydrate D and Dihydrate E.

The d values from the X-ray Diffractograms for these forms are listed in EP 0 831

098 A2. We conducted experiments to obtain Olanzapine Form I by recrystallization of olanzapine from acetonitrile using the process described in Example 1, sub example 4 of U.S. Patent No. 5,229,382. The process is described herein for reference: A mixture of 4-amino-2-methyl-10H-thieno-[ 2,3-b] [l,5]benzodiazepine HCl (100 g),

N-methyl piperizine (350ml), DMSO (465 ml) and toluene (465 ml) was heated to reflux. The reaction mass was maintained at reflux for 19 hours and then cooled to

50°C and water was added. The reaction mass was cooled to 0-10°C and stirred at the same temperature for 6 hours. The crude Olanzapine separated was filtered and dried in oven to a constant weight (76.5 g). The crude compound was added to acetonitrile (750 ml) at boiling temperature. The mixture was boiled for further 5 minutes. The mixture was filtered to remove the undissolved solid. The filtrate was treated with carbon and filtered. The filtrate was distilled to a minimum volume, cooled to 0-5 °C and maintained at the same temperature for 1.0 hour and filtered.

The compound was dried to a constant weight in an oven (51.6g).

The polymorphic form obtained from these experiments was characterized for its X-ray Powder Diffraction on Rigaku D / Max 2200. As clearly observed, the d values for this product (Fig. 1) matched with those of Olanzapine Form-2 claimed in EP 733635A1. It is therefore inferred that the recrystallization of Olanzapine in acetonitrile produces Form-2 and not Form-1.

Accordingly, the present invention provides a novel method for preparation of hydrates of olanzapine, which are different from those reported in the literature. These hydrates are named Olanzapine monohydrate-I and Olanzapine dihydrate-I for convenience.

Accordingly, the present invention also provides a novel method for preparation of Olanzapine Form-1 by recrystallization of olanzapine or its hydrates in dichloromethane . The present invention also provides a novel method for converting Olanzapine

Form-2 to Olanzapine Form-1

PREPARATION OF OLANZAPINE MONOHYDRATE-1

EXAMPLE 1 A mixture of 4-amino-2-methyl-10H-thieno-[2,3-b][l,5]benzodiazepine hydrochloride (20 Kg), N-methyl piperazine (42 lit), dimethyl sulfoxide (40 lit) and toluene (95 lit) was heated to reflux. The reaction mass was maintained at reflux for

17 hours and 15 minutes and then cooled to 40-50°C. Water (95 lit) was added slowly at40-50°C. The reaction mass was cooled to -0.6 to 1.2°C and stirred at the same temperature for six hours. The Olanzapine crude that separated was filtered and washed with water (10 lit). The product was dried at 30.5 to 31.8°C for 10 hrs and 50 minutes. Yield: 20 Kg. A 20 gm sample from the above material after prolonged heating for an additional 72 hours gave the product with a moisture content of 5.22%.

PREPARATION OF OLANZAPINE DIHYDRATE-I EXAMPLE 2

A mixture of 4-amino-2-methyl-l OH-thieno- [2,3-b] [ 1 ,5]benzodiazepine hydrochloride (200 g), N-methyl piperazine (420 ml), dimethyl sulfoxide (200 ml) and toluene (940 ml) was heated to reflux. The reaction mass was maintained at reflux for 12 hours and then cooled to 40°C. Water (940 ml) was added slowly at 40-44°C. The reaction mass was cooled to 0-5°C and stirred at the same temperature for five hours. The Olanzapine crude that separated was filtered and washed with water (100 ml). The solid obtained was dried atmospherically (25-35°C) for 24 hours (Yield :

241 g).

PREPARATION OF FORM-1

EXAMPLE 3 Crude 2-methyl-4-(4-methyl- 1 -piperazinyl)- 1 OH-thieno- [2,3 -b] [ 1 ,5] benzodiazepine (35.0 g) was suspended in dichloromethane (160.0 ml). The suspension was heated to reflux to obtain a clear solution. The resultant solution was then treated with carbon (3.5 g) followed by filtration. Upon completion of this step the filtrate was cooled to 0 to 5°C and stirred at the same temperature for one hour. The separated solid was filtered and washed with chilled dichloromethane (10.0ml). The product obtained on drying in oven at 65 to 70°C to a constant weight gave Form-1 of Olanzapine (Yield 22.0 g).

CONVERSION OF FORM-2 TO FORM-1 EXAMPLE 4 The stirred suspension of pure form-2 of 2-methyl-4-(4-methyl-l-piperazinyl)-

10H-thieno-[2,3-b][l,5]benzodiazepine (20.0 g) in dichloromethane (90.0 ml) was heated to reflux to obtain a clear solution. The clear solution was filtered and the filtrate was then cooled to 3 to 5°C and stirred at same temperature for one hour. The crystalline solid separated was filtered and washed with dichloromethane (4.0 ml). Subsequent drying at 60 to 70°C to a constant weight yielded Olanzapine Form-1. (Yield: 12.7 g).

PREPARATION OF FORM-1 FROM MONOHYDRATE-I OF OLANZAPINE

EXAMPLE 5 Monohydrate-I of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno-[2,3- b][l,5] benzo- diazepine (25.0 g) prepared as per Example- 1 was suspended in dichloromethane (325.0 ml). The suspension was heated to reflux to obtain a clear solution. The resultant solution was then treated with carbon (2.5 g) followed by filtration. Upon completion of this step the filtrate was distilled to a minimum volume and then cooled to 2 to 4°C and stirred at the same temperature for 90 minutes. The product separated was filtered arid washed with chilled dichloromethane (10 ml). The product obtained on drying in oven at 60 to 70°C to a constant weight gave Form-1 of Olanzapine (Yield 16.5 g)

PREPARATION OF FORM-1 FROM DIHYDRATE-I OF OLANZAPINE

EXAMPLE 6 Dihydrate-I of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno-[2,3-b][l,5] benzodiazepine (40.0 g) prepared as per Example-2 was suspended in dichloromethane (520.0 ml). The suspension was heated to reflux to obtain a clear solution. The resultant solution was then treated with carbon (4.0 g) followed by filtration. Upon completion of this step the filtrate was distilled to a minimum volume and the left over reaction mass was cooled to 0 to 2°C and stirred at the same temperature for one hour. The separated solid was filtered and washed with dichloromethane (10.0ml). The product obtained on drying in oven at 65 to 70°C to a constant weight renders Form-1 of Olanzapine (Yield 26.0 g).

The aforementioned crystalline forms in examples 1 to 6 have been examined for their structural and analytical data viz., Powder X-Ray Diffraction, Differential Scanning Calorimetry, and Infrared Absorption Spectroscopy. The results obtained are discussed and the respective drawings attached (Fig. 2 -19).

………………………………..

 http://www.google.com/patents/EP2292624A1?cl=en

• Olanzapine is a pharmaceutical active substance from the group of antipsychotics, applicable for the treatment of different mental diseases and conditions, such as, for example, disorders of the central nervous system, schizophrenia, hallucination, acute mania, depression, and the like.
• Chemically, it belongs to the group of the benzodiazepines and is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (formula 1).
• Olanzapine and analogues thereof are encompassed for the first time within a general formula in the patent GB 1,533,235 and specifically described in EP 454 436 B1 . The patents disclose two different one-step processes for olanzapine preparation. The first described process is a reaction of 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride with N-methylpiperazine in an organic solvent, such as anisole, toluene, dimethyl formamide or dimethyl sulfoxide, preferably at a temperature from 100 to 150°C to yield olanzapine (Scheme 1).
• The second process disclosed in EP 454 436 B1 is the reaction of N-methylpiperazine with methyl-2-(2-aminoanilino)-5-methylthiophene-3-carboxylate in the presence of titanium tetrachloride (Scheme 2).
• The same patent also mentions the formation of acid addition salts of olanzapine and their potential use as intermediates in olanzapine purification process and for a pharmaceutical use.
• As disclosed in EP 454 436 B1 and US equivalent US 5,229,382 , olanzapine obtained according to the first synthesis (Scheme 1) is purified by recrystallization from acetonitrile, whereas olanzapine prepared according to the second route (Scheme 2) is further purified by column chromatography on Florisil^® and recrystallization from acetonitrile. This purification procedure lacks on industrial applicability.
• Some other synthetic approaches for the preparation of olanzapine describe two steps for creating 4-methylpiperazinyl side chain (Scheme 3). Firstly, 4-amino-2-methyl-10H-thieno [2,3-b][1,5] benzodiazepine hydrochloride reacts with piperazine to yield 2-methyl-4-(1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (i.e. N-desmethylolanzapine; Bioorganic & Medicinal Che-mistry Letters, Vol. 7, No. 1, pp. 25-30, 1997), then the methyl group is introduced either by reductive N-methylation (using formaldehyde and metal boron hydride -WO 04/000847) or by nucleophylic substitution reaction with methyl iodide (WO 05/090359). The two-step approach reduces the dark colour appearance but it does not solve the problem of purification from similar by-products.
• It is well known to a skilled person that most chemical reactions are not completely finished, may be reversible or are driven simultaneously with some other parallel reactions. Starting materials or side reaction products are usually found as impurities in the isolated main product which should therefore be further purified. The simplest way of purification includes various recrystallization and precipitation procedures which are usually less effective if the impurities have physico-chemical properties very similar to the main product.
• In the case where olanzapine is prepared according to the one step processes disclosed in EP 454 436 B1 , the starting material, 4-amino-2-methyl-10H-thieno[2,3-b][1,5]-benzodiazepine, is found as an impurity in the final product olanzapine.
• In the case of preparation of olanzapine via the two-step process, as disclosed also in the patent application WO 04/000847 , the presence of 4-amino-2-methyl-10H-thieno[2,3-b][1,5]-benzodiazepine hydrochloride is not critical but various other similar compounds could be found as impurities, such as 4-(4-formylpiperazinyl)-2-methyl-10H-thieno[2,3-b][1,5]-benzo diazepine and N-desmethylolanzapine. In the case of preparation of olanzapine by a two-step process with methyl iodide, an overmethylated N,N-dimethylpiperazinium analogue can be formed.
• A further undesired impurity which accompanies olanzapine is obtained when olanzapine compound is dissolved in methylene chloride. It is so called olanzapine-CM, being (E)-1-(chloromethyl)-1-methyl-4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)piperazin-1-ium chloride). Olanzapine-CM is formed by alkylation of olanzapine with methylene chloride in methylene chloride solution, for example during evaporation of methylene chloride before the crystallization (Scheme 4).
• According to the Regulatory Toxicology and Pharmacology 44, pp. 198-211, 2006, classification of potential genotoxic impurities, olanzapine-CM is a potential genotoxic substance due to its R-CH₂-Cl structural element, which is known to be involved in reactions with DNA.
• For all impurities that have a thienobenzodiazepine ring system as a part of the molecule skeleton and because it represents a great part of the molecule, said ring system is crucial for the similarity of physico-chemical properties of said impurities compared to olanzapine.
• Different salts and crystal forms of an active pharmaceutical ingredient are an important tool for modulating pharmacokinetic properties but can be also a tool for purification.
• WO 04/089313 discloses olanzapine acid salts, solvates and co-crystals and their use as active pharmaceutical ingredients in formulations. The preparation of fumaric, maleic and malonic acid addition salts of olanzapine is disclosed in WO 04/089313 . Olanzapine acid addition salts disclosed in this application exhibit specific aqueous solubility from 50 µg/ml to 100 mg/ml.
• WO 05/090359 discloses a method for the purification of olanzapine which has on one hand been prepared by the one-step-process according to Scheme 1, and on the other hand by the process according to Scheme 3, by preparing an addition salt of at least one carboxylic salt, purification of said salt and transfer into purified olanzapine.
• Neutral olanzapine can be isolated in various crystal forms, hydrates and other solvates. However crystal forms I and II are the most often mentioned as an active pharmaceutical ingredient. Both forms were first disclosed in EP 733 635 alleging that form II is thermodynamically more stable than form I which had been prepared already by the basic patent procedures ( EP 454 436 B1 ).
• Crystal Growth & Design, Vol. 3, No. 6, pp. 897-907, 2003 discloses anhydrates and hydrates of olanzapine.
• Olanzapine form I is thermodynamically less stable but it can possess specific kinetic properties which can be applied in designing a final dosage form. Many procedures are known how to prepare it but a person skilled in the art can soon find that the use of methylene chloride is unavoidable to develop a repeatable process. Because this solvent is used in the final step of preparation of olanzapine form I, previous purification methods cannot prevent the presence of the impurity olanzapine-CM in the final product.
• WO 03/101997 A1 discloses a process for the preparation of a pure olanzapine form I by an addition of methyl-piperazine to the hydrochloride salt of the corresponding benzodiazepine derivative. The purification of olanzapine is conducted by recrystallization. Olanzapine-CM is not disclosed as a disturbing side product which can be removed by recrystallization.
• WO 02/18390 discloses a process for the preparation of hydrates of olanzapine and the conversion thereof into crystalline forms of olanzapine by recrystallization from methylene dichloride. It is not disclosed that essentially pure olanzapine can be obtained by the removal of olanzapine-CM.
• WO 04/056833 A1 discloses a process for the preparation of essentially pure olanzapine by removing olanzapine-CM, which is obtained from a solution of olanzapine in methylene chloride, by treating this solution with SiO₂, followed by the removal of SiO₂. According to the examples, olanzapine is obtained having a purity of 99.92 %, whereas olanzapine-CM is present in an amount of 0.05 %, corresponding to 500 ppm. But SiO₂ is acidic, so it adsorbs well also the basic olanzapine what leads to considerable losses of the mother compound.
• Olanzapin-CM has to be removed in order to obtain essentially pure olanzapine with a high purity which can be further used in pharmaceutical applications. It has been found that olanzapine cannot be efficiently separated from its highly related impurities, in particular from olanzapine-CM, using repeated crystallizations of crude olanzapine. It would therefore be desirable to develop a purification process, in order to provide pharmaceutically acceptable pure and discoloured olanzapine, in particular to provide pharmaceutically acceptable pure olanzapine, being essentially free of the olanzapine-CM impurity. A further object of the present invention is to provide a process for the purification of olanzapine which can also and preferably be conducted in a large scale synthesis.

Example 1 – Synthesis of olanzapine oxalic salt

• [0093]
  A solution of 12.0 g of N-desmethylolanzapine in 90 mL of THF and 36 mL of dimethylacetamide (DMAc) is cooled to approx. -20 °C. At -20 °C, 8.19 g of diisopropylamine is added to the solution and afterwards, 8.14 g of methyl iodide is added over 30 min. After stirring the reaction mixture for 65 minutes at -20 °C, 6.4 mL of concentrated hydrochloric acid in 50 mL of water and a solution of 6.36 g of thiourea in 50 mL of water is added and the reaction mixture is stirred for 15 minutes at 20 °C. Then THF is evaporated off and 120 mL of methylene chloride is added and the pH is adjusted to 8.6 with a 40 % water solution of NaOH. After the separation of the phases, the water phase is washed twice with 60 and 30 mL of methylene chloride. The organic phases are combined and 380 mg of acetic anhydride is added and the mixture is stirred for 5 minutes. Then 6.20 g of oxalic acid in 24 mL of methanol is added within 15 minutes. The resulting suspension is stirred for about 1 hour at approx. 20 °C and afterwards 1 hour at approx. 0 °C. The product is isolated by filtration, washed with 100 mL of methylene chloride and dried for 15 hours at 25 °C in vacuo. Yield: 15 g (93 %).

Example 2 – Formation of olanzapine form I

• [0094]
  5 g of olanzapine oxalate is dissolved in 50 mL of water and the pH of the solution is adjusted to 2.0 by the addition of 6 N HCl. To the resulting clear solution of olanzapine oxalate, 0.5 g of charcoal is added. After stirring for 5 minutes, the charcoal is filtered off and the cake is washed with 10 mL of water. The filtrate and wash water are combined and after the addition of 60 mL of methylene chloride, the pH of the combined mixture is adjusted to 9.0 by the addition of a 40 % water solution of NaOH. After stirring for 5 minutes, the layers are separated and the water phase is extracted twice with 10 mL of methylene chloride. The organic layers are combined and washed twice with 20 mL of water. After the solution is concentrated in vacuo to the volume of 15 mL, the solution is immediately cooled on an ice/salt bath. The resulting suspension is stirred for 15 minutes, and then olanzapine is isolated by filtration. The wet cake is washed with 3 mL of methylene chloride of the temperature of -20 °C. The product is dried for four hours at 100 °C in vacuo.

  HPLC-Purity:	99.9 %
  olanzapine-CM	380 ppm
  IR	Form I
  XRD	Form I

Example 3 – Formation of olanzapine form I (scale up)

• [0095]
  24 kg of olanzapine oxalate is dissolved in 240 L of water and the pH of the solution is adjusted to 2.0 by the addition of 6 N HCl. To the resulting clear solution of olanzapine oxalate, 2.4 kg of charcoal is added. After stirring for 5 minutes, the charcoal is filtered off and the cake is washed with 10 L of water. The filtrate and wash water are combined and after the addition of 300 L of methylene chloride, the pH of the combined mixture is adjusted to 9.0 by the addition of a 40 % water solution of NaOH. After stirring for 15 minutes, the layers are separated and the water phase is extracted twice with 50 L of methylene chloride. The organic layers are combined and washed twice with 100 L of water. After the solution is concentrated in vacuo to the volume of 50 L, the solution is immediately cooled to -15 °C. The resulting suspension is stirred for 30 minutes, then olanzapine is isolated by filtration. The wet cake is washed with 10 L of methylene chloride of the temperature of -20 °C. The product is dried for 10 hours at 100 °C in vacuo.

  HPLC-Purity:	99.7 %
  olanzapine-CM	1000 ppm
  IR	Form I
  XRD	Form I

Example 4 – Formation of olanzapine form I

(

Al₂O₃ fluidized bed adsorption

)
• [0096]
  5 g of olanzapine oxalate is dissolved in 50 mL of water and the pH of the solution is adjusted to 2.0 by the addition of 6 N HCl. To the resulting clear solution of olanzapine oxalate, 0.5 g of charcoal is added. After stirring for 5 minutes, the charcoal is filtered off and the cake is washed with 10 mL of water. The filtrate and wash water are combined and after the addition of 60 mL of methylene chloride, the pH of the combined mixture is adjusted to 9.0 by the addition of a 40 % water solution of NaOH. After stirring for 5 minutes, the layers are separated and the water phase is extracted twice with 10 mL of methylene chloride. The organic layers are combined and washed twice with 20 mL of water. After 0.2 g of Al₂O₃ is added and the methylene chloride suspension is stirred for 5 minutes, Al₂O₃ is filtered off and the methylene chloride solution is concentrated to the volume of 15 mL. The solution is immediately cooled on an ice/salt bath. The resulting suspension is stirred for 15 minutes, and then olanzapine is isolated by filtration. The wet cake is washed with 3 mL of methylene chloride of the temperature of -20 °C. The product is dried for four hours at 100 °C in vacuo.

  HPLC-Purity:	99.9 %
  olanzapine-CM	214 ppm
  IR	Form I
  XRD	Form I

Example 5 – Formation of olanzapine form I (Al₂O₃ fluidized bed adsorption

)
• [0097]
  5 g of olanzapine oxalate is dissolved in 50 mL of water and the pH of the solution is adjusted to 2.0 by the addition of 6 N HCl. To the resulting clear solution of olanzapine oxalate, 0.5 g of charcoal is added. After stirring for 5 minutes, the charcoal is filtered off and the cake is washed with 10 mL of water. The filtrate and wash water are combined and after the addition of 60 mL of methylene chloride, the pH of the combined mixture is adjusted to 9.0 by the addition of a 40 % water solution of NaOH. After stirring for 5 minutes, the layers are separated and the water phase is extracted twice with 10 mL of methylene chloride. The organic layers are combined and washed twice with 20 mL of water. Afterwards, the methylene chloride solution is concentrated to 30 mL and 0.2 g of Al₂O₃is added. After stirring for 5 minutes, Al₂O₃ is filtered off and the methylene chloride solution is concentrated to the volume of 15 mL. The solution is immediately cooled on an ice/salt bath. The resulting suspension is stirred for 15 minutes, and then olanzapine is isolated by filtration. The wet cake is washed with 3 mL of methylene chloride of the temperature of -20 °C. The product is dried for four hours at 100 °C in vacuo.

  HPLC-Purity:	99.9 %
  Olanzapine-CM	321 ppm
  IR	Form I
  XRD	Form I

Example 6 – Formation of olanzapine form I (Al₂O₃ fluidized bed adsorption

)
• [0098]
  5 g of olanzapine oxalate is dissolved in 50 mL of water and the pH of the solution is adjusted to 2.0 by the addition of 6 N HCl. To the resulting clear solution of olanzapine oxalate, 0.5 g of charcoal is added. After stirring for 5 minutes, the charcoal is filtered off and the cake is washed with 10 mL of water. The filtrate and wash water are combined and after the addition of 60 mL of methylene chloride, the pH of the combined mixture is adjusted to 9.0 by the addition of a 40 % water solution of NaOH. After stirring for 5 minutes, the layers are separated and the water phase is extracted twice with 10 mL of methylene chloride. The organic layers are combined and washed twice with 20 mL of water. Then the methylene chloride solution is concentrated to 30 mL and 1 g of Al₂O₃ is added. After stirring for 5 minutes, Al₂O₃ is filtered off and the methylene chloride solution is concentrated to the volume of 15 mL. The solution is immediately cooled on an ice/salt bath. The resulting suspension is stirred for 15 minutes, and then olanzapine is isolated by filtration. The wet cake is washed with 3 mL of methylene chloride of a temperature of -20 °C. The product is dried for four hours at 100 °C in vacuo.

  HPLC-Purity:	99.9 %
  olanzapine-CM	138 ppm
  IR	Form I
  XRD	Form I

Example 7 – Formation of olanzapine form I (Al₂O₃ short column adsorption)

• [0099]
  5 g of olanzapine oxalate is dissolved in 50 mL of water and the pH of the solution is adjusted to 2.0 by the addition of 6 N HCl. To the resulting clear solution of olanzapine oxalate, 0.5 g of charcoal is added. After stirring for 5 minutes, the charcoal is filtered off and the cake is washed with 10 mL of water. The filtrate and wash water are combined and after the addition of 60 mL of methylene chloride, the pH of the combined mixture is adjusted to 9.0 by the addition of a 40 % water solution of NaOH. After stirring for 5 minutes, the layers are separated and the water phase is extracted twice with 10 mL of methylene chloride. The organic layers are combined and washed twice with 20 mL of water. Then the methylene chloride solution is concentrated to 30 mL and filtered through 20 g of Al₂O₃ (h = 2 cm). After the methylene chloride solution is concentrated to the volume of 15 mL, the solution is immediately cooled on an ice/salt bath. The resulting suspension is stirred for 15 minutes, and then olanzapine is isolated by filtration. The wet cake is washed with 3 mL of methylene chloride of the temperature of-20 °C. The product is dried for four hours at 100 °C in vacuo.

  HPLC-Purity:	99.9 %
  olanzapine-CM	162 ppm
  IR	Form I
  XRD	Form I

Example 8 – Formation of olanzapine form I (Al₂O₃ short column adsorption)

• [0100]
  5 g of olanzapine oxalate is dissolved in 50 mL of water and the pH of the solution is adjusted to 2.0 by the addition of 6 N HCl. To the resulting clear solution of olanzapine oxalate, 0.5 g of charcoal is added. After stirring for 5 minutes, the charcoal is filtered off and the cake is washed with 10 mL of water. The filtrate and wash water are combined and after the addition of 60 mL of methylene chloride, the pH of the combined mixture is adjusted to 9.0 by the addition of a 40 % water solution of NaOH. After stirring for 5 minutes, the layers are separated and the water phase is extracted twice with 10 mL of methylene chloride. The organic layers are combined and washed twice with 20 mL of water. Afterwards, the methylene chloride solution is concentrated to 30 mL and filtered through 20 g of Al₂O₃ (h = 5 cm). After the methylene chloride solution is concentrated to the volume of 15 mL, the solution is immediately cooled on an ice/salt bath. The resulting suspension is stirred for 15 minutes, and then olanzapine is isolated by filtration. The wet cake is washed with 3 mL of methylene chloride of the temperature of-20 °C. The product is dried for four hours at 100 °C in vacuo.

  HPLC-Purity:	99.9 %
  olanzapine-CM	73 ppm
  IR	Form I
  XRD	Form I

  Table 1. Comparison and overview of beneficial effect of Al₂O₃ treatment

  Ex.	Scale	Treatment	Mass (Al2O3) [g]	Al2O3 pad height [cm]	CM assay [ppm]
  2	5 g	none	/	/	380
  3	24 kg	none	/	/	1000
  4	5 g	fluidized bed adsorption	0.2	/	214
  5	5 g	fluidized bed adsorption (concentrated to 30 mL)	0.2	/	321
  6	5 g	fluidized bed adsorption (concentrated to 30 mL)	1.0	/	138
  7	5 g	short column adsorption (concentrated to 30 mL)	20	2	162
  8	5 g	short column adsorption (concentrated to 30 mL)	20	5	73

  Table 2. As comparative data, olanzapine obtained by processes according to the prior art comprises the following amounts of olanzapine-CM:

  No.	prior art	amount of olanzapine-CM
  1	WO 2005/090359 , lab. scale	300 – 400 ppm
  2	WO 2005/090359 , industrial scale	800 – 2000 ppm
  3	WO 2004/056833	<0.15%

………………………………

 

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part 1………http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine.html  /  http://newdrugapprovals.org/2015/04/09/venlafaxine-part-12/

part 2……..http://newdrugapprovals.org/2015/04/09/venlafaxine-22/

PART 3…..http://orgspectroscopyint.blogspot.in/2015/04/venlafaxine-part-33.html

http://www.google.com/patents/WO2008059525A2?cl=en

WILL BE UPDATED………..

………………….

……………………….

PAPER

DOI: 10.1039/C4RA00840E

http://pubs.rsc.org/en/content/articlelanding/2014/ra/c4ra00840e#!divAbstract

A protecting group free asymmetric total synthesis of (−)-venlafaxine is reported. The strategy employs Sharpless epoxidation and regio-selective epoxide ring opening by an in situgenerated Gilman reagent as key steps. This paper reports a 53% overall yield in 6 steps for total synthesis of (−)-venlafaxine.

…………………

http://www.google.com/patents/EP2181982B1?cl=en

Examples:Example 1 – Preparation of venlafaxine from N,N-didesmethyl venlafaxine hydrochloride

• A 50 % aqueous NaOH solution (4 ml, 74 mmol) was added to a stirred solution of N,N-didesmethyl venlafaxine hydrochloride (5.72 g, 20 mmol) in water (16 ml) at room temperature. Formic acid (98 %, 11.5 ml, 305 mmol) and 37 % aqueous solution of formaldehyde (8.4 ml, 113 mmol) were added to this mixture. The mixture was stirred under reflux temperature and the conversion was completed in 5 h (HPLC: 98.67 area %). Then the solution was cooled to room temperature and adjusted with 50 % aequous NaOH to pH 12. The mixture was extracted twice with 66 ml of isopropyl acetate. The collected organic phases were washed three times with water (66 ml). The isolated solution of venlafaxine base was very pure (HPLC: 98.9 area%).

Example 2 – Preparation of venlafaxine hydrochloride form I from the solution of venlafaxine base in isopropyl acetate

• To the solution of venlafaxine base in isopropyl acetate from example 1 (66 ml, 10 mmol) 5 ml of 2 M aqueous HCl were added. The mixture was heated and water was removed by azeotropic distillation using a Dean-Starck trap. When all water was removed from the mixture, the product began slowly to crystallize. The obtained suspension was heated under reflux temperature for 1.5 h, then cooled and filtered. 2.75 g (88 % from N,N-didesmethyl venlafaxine hydrochloride) of pure venlafaxine hydrochloride form I (HPLC: 99.65 area %) were obtained.

Example 3 (exemplary) – Preparation of venlafaxine hydrochloride form I from the solution of venlafaxine base in isopropyl acetate

• The solution of venlafaxine in isopropyl acetate from example 1 (66 ml, 10 mmol) was concentrated to ½ of the volume. Then 10 to 50 mg of venlafaxine hydrochloride form I was added to the solution. Subsequently, a 2.5 M solution of HCl in ethanol (4.0 ml) was slowly added within 30 min. After the whole amount of acid was added, the obtained suspension was stirred for another 2 h. Then the mixture was filtered and the product was washed with isopropyl acetate and dried. We obtained 2.69 g (86 % from N,N-didesmethyl venlafaxine hydrochloride) of pure venlafaxine hydrochloride form I (HPLC: 99.65 area %).

…………………..

PATENT

http://www.google.com/patents/WO2006035457A1?cl=en

Venlafaxine is known by the chemical name 1-[2-dimethylamino-1-(4 methoxyphenyl ethyl Cyclohexanol hydrochloride and structure of formula (V).

(V)

Venlafaxine is a useful pharmaceutical agent as an antidepressant. Venlafaxine, the intermediates in the manufacture of Venlafaxine, the process of preparing said Venlafaxine and their intermediates are well known from US Patents 4,535,186, US Patent No. 6,350,912, and CN 1225356.

Further International Publication No. WO03/050074 discloses the manufacture of Venlafaxine Hydrochloride and crystalline polymorphs Form I, Form II, Form III and optically pure (R) and (S) enantiomers exhibiting different crystalline structures of Venlafaxine hydrochloride. The preparation of all the forms of Venlafaxine and their inter-conversion are also described in said WO03/0500074 publication. U.S. Patents 4535186, 4761501 disclose a process for manufacture of 1-[2- amino-i-(p-methoxyphenyl) ethyljcyclohexanol (free base of formula IV), an intermediate produced during the preparation of Venlafaxine in two stages by reacting p-methoxyphenyl acetonitrile with cyclohexanone in the presence of n- butyl lithium (Stage 1) to form 1-[cyano(p-methoxyphenyl) methyl] Cyclohexanol of formula III

(111)

This process is commonly used for the preparation of formula III. The US Patent 4,535,186 produces a yield of about 30% based on p-methoxyphenyl acetonitrile.

WO/03/050074 suggests an alternate way of preparing compound of formula III without using butyl lithium i.e. by reacting p-methoxyphenyl acetonitrile with cyclohexanone in the presence of alkali metal hydroxide in a mixture of toluene and hexane. The publication WO/03/050074 also suggests a material yield of 74% based upon p-methoxyphenyl acetonitrile and purity.

The drop wise addition of butyl lithium to p-methoxyphenyl acetonitrile is hazardous and hence it requires skill and safety measures to be taken by the person skilled in the art for handling butyl lithium over the addition period to avoid any accidents during the preparation process.

The second stage i.e. conversion of compound of formula III to formula IV described in US patent US 4,535,186 is by hydrogenating compound of formula III using Rhodium on alumina. The catalyst Rhodium is recycled by filtering and washing the catalyst with ethanol and the combined filtrate evaporated and dried under vacuum yielding free base as an oil. However, the cost of Rhodium catalyst is very high and hence the catalyst has to be recovered.

WO/02/500017 suggests the use of a Nickel or cobalt catalyst for the hydrogenation, which is highly economical when compared with the Rhodium catalyst as suggested by US Patent No. 4,535,186. The International Publication WO/02/500017 teaches that the hydrogenation reaction of Stage Il may be carried out in the presence of an organic solvent preferably an alcohol. The international publication also suggests the pretreatment of the catalyst with ethanol.

The US Patent 4,535,186 describes the third stage in the process of preparing Venlafaxine i.e. conversion of compound of formula IV (free base) to compound V i.e. Venlafaxine by methylating the compound of formula IV (free base) with a mixture of formaldehyde and formic acid in water.

(IV)

US Patent Publication No. 2005/0033088 describes a process for preparing phenylethylamine derivative, an intermediate of Venlafaxine hydrochloride; said process comprising steps of reduction of compound of formula III with palladium on charcoal in an organic acid selected from formic acid, acetic acid or propionic acid, preferably acetic acid in an autoclave at a pressure of 5 to 25 kg/cm2 preferably 10 to 15 kg/cm2 at a temperature in the range of 30 to 75°C, preferably at 50 to 55°C till the hydrogenation substantially complete, filtering the palladium catalyst and evaporating the filtrate. Extracting the filtrate with halogenated hydrocarbon solvent and purifying the same. The process also describes the preparation of Venlafaxine hydrochloride without isolation of freebase.

The route of synthesis for Venlafaxine (formula V) and intermediate of Venlafaxine (formula IV) is depicted in the following scheme:

Step -I

(I) (II) (III) Step-ll

…………..(III) ……………………(IV)

Step-ll I

(IV) (V)

Accordingly, the present invention relates to an improved process for the preparation of compound of formula IV

(IV)

comprising the step of hydrogenating a compound of formula

(Hi)

in the presence of toluene, water, and a catalyst wherein the said process yields 66% formula (IV) with 99% HPLC purity.

The compound of formula IV is further methylated using formaldehyde and formic acid mixture to form Venlafaxine (formula V) followed by the treatment with HCL gas dissolved in Isopropanol.

(IV) (V)

According to the preferred embodiment of the present invention, nickel catalyst, preferably Raney nickel catalyst is used. The catalyst is washed in water to remove the alkali. No pretreatment of the nickel catalyst is required.

(HI) (IV)

According to another embodiment of the present invention, compound of formula IV is prepared by hydrogenating compound of formula III in the presence of Raney Nickel and water. According to another embodiment of the present invention, compound of formula III is prepared by charging p-methoxyphenyl acetonitrile into butyl lithium at -70 to -75°C and tetrahydrofuran; cooling the reaction mixture to about -50°C to -75⁰C; adding cyclohexanone at a temperature below -50⁰C quenching with ice and saturated ammonium chloride solution below 0^°C; and stirring and filtering the product of formula (III) wherein the said process yields 89% of compound of formula III with 99.8% purity. The reaction scheme is depicted as follows:

…………(I) …………(H)………………………………. (III)

Example 1 :

Preparation of 1-[cyano-(4-methoxyphenyl) methyl Icvclohexanol.

In a 2 ltr 4 necked round bottom flask equipped with a overhead stirrer, thermometer and dropping funnel, 100 ml dry THF followed by 210 ml Butylithium (1.6 M solution in Hexane) was charged. The reaction mixture was cooled to – 70⁰C. Added gradually a solution of 50 gm p-methoxyphenyl acetonitrile dissolved in 50 ml dry THF at -70 to -75°C. After 30 min, added solution of 33.1 gm Cyclohexanone in 50 ml THF. After the addition, maintained at -65 to -70⁰C and monitored by TLC. After 4 hrs, reaction mixture was gradually added over mixture of ice and 150 ml saturated ammonium chloride solution below 0°C and adjusted pH to 7 with dilute Hydrochloric acid. Stirred for 1 hr and filtered the product. Washed the product with 200 ml hexane and dried to obtain 74.3 gm. (The yield based on p-methoxyphenyl acetonitrile 89%, Melting range 123- 125°C, HPLC purity of 99.8%).

Example 2:

Preparation of 1-[2-amino-(4-methoxyphenyl) ethyl] Cyclohexanol acetate

In an autoclave are charged 100 gm 1-[cyano(4- methoxyphenyl)ethyl]cyclohexanol, 100 ml toluene and 400 ml water at RT. Stirred and cooled to 10°C. Charged 20 gm Raney Nickel (which was prewashed with water to make it free of Alkali) and 100 ml liquor ammonia (20%). Then pressurized the autoclave with hydrogen to 4 – 5 kg pressure and maintained for 120 minutes below 12⁰C. Then the reaction temperature slowly raised to bout 50⁰C along with the increase in the hydrogen pressure to 7 to 8 kg. Maintained between 45 – 50°C for 8 hr. After the completion of the reaction, cooled the reaction to RT, released the hydrogen pressure and charged 400 ml toluene. Filtered the catalyst and washed bed with 100 ml toluene. Separated the organic layer from the filtrate. The organic layer was washed with 10% Sodium chloride solution. To the organic layer was added 40 ml methanol followed by 10 ml acetic acid. Stirred for 15 minutes and then again charged 10 ml acetic acid. Then heated to 75-8O⁰C and maintained for 15 minutes. Cooled to 0 – 5⁰C. Filtered the product. Washed the product with 100 ml ethyl acetate and dried: 83.5 gm (Yield 66%, Melting range 164-166°C, HPLC purity 99%).

Example 3:

Preparation of H2-dimethylamino-1-(4-methoxyphenyl) ethvH Cyclohexanol Hydrochloride

To a stirred solution of 100 gm of 1-[2-amino-(4-methoxyphenyl) ethyl] Cyclohexanol acetate in 300 ml water was added 117 gm of formic acid (88%) and 91 gm of formaldehyde (40% solution). The solution was heated to 98°C and maintained for 20 hrs. Reaction mixture was cooled to about 10⁰C and added 500 ml ethyl acetate. The pH was adjusted to about 7 with sodium hydroxide solution and further to 10 – 10.5 with ammonium hydroxide solution. Layers were separated. Aqueous layer was extracted with ethyl acetate. Combined organic layers were washed with water. Combined organic extract was stirred with activated carbon (5 gm) and filtered. Filtrate was concentrated in vacuum to completely remove ethyl acetate. Residue was dissolved in isopropanol (300 ml) and acidified at 30⁰C (pH 1-1.5) with the solution of HCI in isopropanol. Temperature was then raised to 60⁰C and maintained for 60 to 90 min. The reaction mass was cooled under agitation to 10°C and maintained under agitation at 10°C for 60 min. Product was isolated by filtration. Finally it was washed with isopropanol and dried at 60°C.

Dry wt. : 85 gm (84% yield, HPLC 99.9% purity with all individual impurities below 0.1% concentration). This material exhibited following characteristic x-ray powder diffraction pattern with characteristic peaks expressed in d-values (A) at.

(The abbreviations in brackets mean : (vs) = Relative intensity above 80%; (s) = 30% – 80%; (m) = 15% – 30%; (w) = 8% to 15% and (vw) = below 8%.) 2.23 (VW), 2.29(VW), 2.32 (VW)₁ 2.35(VW), 2.38(VW), 2.43(VW), 2.46(VW), -2.48(VW)₁2.55(M), 2.64(W), 2.69(W), 2.73(VW), 2.8(W), 2.83(W), 2.88(W), 2.93(VW), 3.09(VW), 3.12(M), 3.26(VM), 3.31(VM), 3.38(W), 3.45(VW), 3.5(VW), 3.55(M), 3.69(VW), 3.87(VW), 3.99(VW), 4.07(M), 4.18(S), 4.35(VS), 4.48(VW), 4.68(M), 5.1 (VW), 5.27(W), 5.42(VW), 5.55(VW), 5.63(M), 5.68(M), 5.76(VW), 6.5(S), 6.95(VS), 8.65(VW), 10.56(M), 13.06(M).

Example 4 :

Preparation of 1-f2-amino-(4-methoxyphenyl) ethyl] Cyclohexanol acetate (IV)

In an autoclave charged 150 gm 1-[cyano(4-methoxyphenyl)ethyl]cyclohexanol, and 675 ml water at RT. Stirred and cooled to 1O⁰C. Charged 30 gm Raney Nickel (prewashed with water to make it free of Alkali) and 150 ml liquor Ammonia (20%). Then pressurized the autoclave with hydrogen to 4 – 5 kg pressure and maintaind for 120 minutes below 12°C. After completion of 120 minutes slowly raised the temperature to about 50⁰C along with the increase in the hydrogen pressure to 7 to 8 kg. Maintained between 45 – 5O⁰C for about 20 hrs. Monitored reaction by TLC to ensure disappearance of starting material. After the completion of the reaction cooled the reaction to RT, released the hydrogen pressure and filtered through celite bed. Washed bed with 300 ml toluene. To the filtrate added 300 ml toluene. Shaken well and separated the organic layer. The organic layer was washed with 5% Sodium chloride solution. To the organic layer was added 45 ml methanol and 15 ml acetic acid. Stirred for 15 minutes and then again charged 15 ml acetic acid. Then heated to 75-8O⁰C and maintained for 15 mins. Cooled to 0 – 5°C. Filtered the product. Washed the product with 100 ml ethyl acetate and dried: 104 gm (Yield 53%, Melting range 152-153°C, HPLC purity 90%).

……………….

PATENT

http://www.google.com/patents/WO2008059525A2?cl=en

Venlafaxine acts by inhibiting re-uptake of norepinephrine and serotonin. It has been reported that its (-) enantiomer is a more potent inhibitor of norepinephrine synaptosomal uptake while its (+) enantiomer is more selective in inhibiting serotonin uptake (J. Med. Chem. 1990, 33(10), 2899-2905) In humans, venlafaxine is transformed by a metabolic pathway into two minor metabolites, N-desmethylvenlafaxine of formula II, N,O-di- desmethylvenlafaxine of formula IV and one major metabolite, O-desmethylvenlafaxine of formula III.

formula I formula II

formula III formula IV

In the literature there are several processes reported for the synthesis of venlafaxine of formula I and venlafaxine hydrochloride of formula Ia.

formula Ia

The synthesis of venlafaxine from 2-(l-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile (hereinafter called as cyano-intermediate and represented by formula V) involving two step synthesis is known in the prior art.

formula V

US 4,535,186 discloses the preparation of venlafaxine of formula I by the reaction of p- methoxyphenylacetonitrile with cyclohexanone at -78 ⁰C in the presence of n-butyllithium as a base which yields 2-(l -hydroxy cyclohexyl)-2-(4-methoxyphenyl)acetonitrile of formula V. Reduction of the cyano-intermediate under hydrogen pressure with rhodium on alumina catalyst gives l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol. N-Methylation of the amino compound is accomplished employing formaldehyde and formic acid (Eschweiler- Clarke reaction) to give venlafaxine of formula I.

The reaction is as shown in the Scheme- 1.

Reduction

Scheme-1

Another prior art reference, Zhou Jinpei et.al, J. China Pharm. University, 1999, 30(4), 249- 50) discloses the preparation of venlafaxine starting from anisole. Anisole is acylated to the chloroacetyl derivative, which is then animated using N,N-dirnethylamine. The carbonyl group of this compound is reduced to the alcohol using KBH₄ and is converted to the bromo- derivative using PBr₃ which in turn when reacted with Mg and cyclohexanone undergoes a Grignard reaction to provide venlafaxine of formula I.

The reaction is as shown in the Scheme-2.

Scheme-2

US 2005033088 discloses a two step process for venlafaxine starting from the cyano- intermediate. The cyano-intermediate is reduced in the presence of palladium on charcoal in acetic acid at a hydrogen pressure of 5-25 kg/cm² at a temperature in the range of 30-75 ⁰C. The product of step 1 is N-methylated using formic acid, formaldehyde solution at a temperature of 90-98 ⁰C for 19 hrs to yield venlafaxine, which is then converted to its hydrochloride salt.

WO2006035457 also discloses a process of making venlafaxine and its intermediates. The process comprises the step of hydrogenating the cyano-intermediate in the presence of toluene, water, and Raney nickel where in the said process yields 66% of an intermediate with 99% HPLC purity. This reaction is carried out at 10-12 ⁰C and at 4-5 kg/cm² of hydrogen pressure for 2 hrs and further at 50 ⁰C at 7-8 kg/cm² for 7-8 hrs. This intermediate is N-methylated using formaldehyde and formic acid mixture to form venlafaxine, which is treated with IPA/HC1 to get venlafaxine hydrochloride.

US 6,350,912 discloses a one pot process for the preparation of venlafaxine in 15-28 % yield from the cyano-intermediate. In the said patent venlafaxine has been prepared by the reduction of cyano-intermediate in the presence of Raney nickel and without isolation of intermediate l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol

CN 1850781 discloses a process for the preparation of venlafaxine by following steps: (1) carrying out condensation of 4-methoxyphenylacetonitrile and cyclohexanone in presence of base to obtain 2-(l-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile, (2) reacting 2-(l- hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile with cuprous chloride and dimethylamine to obtain 2-(l -hydroxy cyclohexyl)-2-(4-methoxyphenyl)-N,N- dimethylacetimidamide, and (3) reacting 2-(l-hydroxycyclohexyl)-2-(4-methoxyphenyl)- N,N-dimethylacetimidamide with KBH₄ to obtain 1 – [2-dimethylamino)- 1 -(4-methoxyphenyl) ethyl)cyclohexanol (venlafaxine).

The reaction is as shown in the Scheme-3.

Scheme-3

The processes disclosed in the prior art have many disadvantages. Most of the prior art processes employ formaldehyde as a reactant for N-methylation step which is known to be a carcinogen. Acute exposure of the same is highly irritating to the eyes, nose and throat. Ingestion of formaldehyde is fatal and long term exposure causes respiratory problems and skin irritation.

Another disadvantage is the formation of an impurity (represented by formula VI), which is formed during N-methylation step using formaldehyde as a reagent.

formula VI

As may be appreciated, all the above well-known processes share the same strategy of synthesis, consisting of two steps for the synthesis of venlafaxine from cyano-intermediate or are prepared in one pot with poor yield.

Yet another drawback of the processes disclosed in the prior art is the use of expensive catalysts like rhodium on alumina and use OfBF₃ etherate which is highly corrosive.

The prior art references disclose the synthesis of alkoxyphenylethyldimethylamine from alkoxyphenylacetonitrile using excess dimethylamine and palladium catalyst in methanol solution which is firstly reported by Kindler and Hensse. (1. Kindler and Hesse; Arch. Pharm., 1933, 271, 439. 2. Johannes S. Buck, Richard Baltzly and Walter S. Ide; J. Am. Chem. Soc. 1938, 60(8), 1789-1792; 3. Albert J. Schuster and Eugene R. Wagner; J. Labelled Compounds and Radiopharmaceuticals 1992, XXXIII(3), 213-217).

The reaction is as shown in the Scheme-5.

Scheme-5

According to an aspect of the invention there is provided a novel single step process for the synthesis of venlafaxine of formula I and N-desmethylvenlafaxine of formula II from 2-(l- hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile of formula V comprising reaction of 2- (l-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile with an alkylamine and/or its salt in a solvent in the presence of a transition metal catalyst, under hydrogen atmosphere.

formula I formula II formula V DETAILED DESCRIPTION OF THE INVENTION

The present invention describes a single step process for venlafaxine and its analog starting from the cyano-intermediate. The present invention circumvents the difficulties encountered in the prior art and is an economically viable process.

The present invention particularly relates to a single step synthesis of venlafaxine of formula I, and N-desmethylvenlafaxine of formula II from the cyano-intermediate of formula V.

The reaction of the present invention is as shown in Scheme-4:

formula V formula L R = CH₃ (Venlafaxine) formula II. R = H (N-desmethylvenlafaxine)

formula Ia. R = CH₃, X = Cl formula Ha. R = H, X = Cl

Example-1:

General procedure for synthesis of venlafaxine and N-desmethylvenlafaxine To the, stirred solution of 2-(l -hydroxy cyclohexyl)-2-(4-methoxyphenyl)acetonitrile (1.0 equiv.) in methanol (10-20 volumes), alkylamine (3-5 equiv.) was added and the mixture was stirred for 5-10 minutes to get a clear solution. Palladium catalyst (10-50 wt %) was added under nitrogen atmosphere to the above reaction mixture. The reaction mixture was purged with hydrogen gas (three times) and allowed to stir under hydrogen (1-2 atmospheric pressure.) at room temperature for 5 to 40 hrs. The progress of the reaction was monitored by TLC and HPLC. After completion of the reaction, the catalyst was filtered through celite and washed with methanol. The combined filtrate was concentrated to dryness under reduced pressure and the residue was poured in water. The aqueous layer was basifϊed with 10% aq. NaOH to pH 8-10 and extracted with ethyl acetate (3 times). The combined ethyl acetate layers were washed with brine and dried over sodium sulphate. Ethyl acetate was evaporated under vacuum to obtain the title compound.

Example-2: Venlafaxine

To the stirred solution of 2-(l-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile (20.0 g, 1 equiv.) in methanol (460.0 ml), dimethylamine hydrochloride (26.6 g, 4 equiv.) was added and the mixture was stirred for 5-10 minutes at room temperature to obtain a clear solution. 5% Palladium on alumina (4.0 g, 20 wt %) was added under nitrogen to the above clear solution. The reaction mixture was purged with hydrogen gas (three times) and allowed to stir under hydrogen (1-2 atmospheric pressure.) at room temperature for 20 hrs. After completion of the reaction product was isolated by the procedure as described in Example- 1 above to obtain light yellow viscous liquid (18.Og) which was directly converted to its hydrochloride salt using IPA/HC1. HPLC purity of the crude reaction mixture (18.Og) = 81.64%.

Venlafaxine-free base:

¹H NMR in CDCl₃ (300 MHz): δ 7.05 (d, 2H), 6.81 (d, 2H), 3.79 (s, 3H), 3.27 (t, IH), 2.94 , (dd, IH), 2.31 (s, 6H), 2.28 (dd, IH), 1.71-0.94 (m, 10H). 1³C NMR in CDCl₃: δ 158.16,’ 132.65, 130.01, 113.20, 74.14, 61.14, 55.05, 51.52, 45.37, 37.99, 31.07, 25.91, 21.52, 21.23.

IR (KBr): 3152, 2980, 2941, 2895, 1728, 1607, 1512, 1462, 1439, 1358, 1279, 1204, 1186, 1177, 1146, 1103, 1040, 1011, 968, 851 cm^“1. HPLC Purity: 99.37 % (area %). GC-MS: 178 (M+H⁺).

Venlafaxine hydrochloride salt:

¹H NMR in D₂O (300 MHz): δ 7.23 (d, 2H), 6.91 (d, 2H), 3.71 (s, 3H), 3.54 (t, IH), 3.48 (dd, IH), 2.97 (dd, IH), 2.69 (s, 6H), 1.41-1.0 (m, 10H).

¹³C NMR in D₂O: δ 158.52, 130.86, 128.16, 114.25, 73.23, 58.26, 55.25, 50.38, 44.87, 41.41, 35.07, 33.34, 24.76, 21.08, 20.86.

IR (KBr): 3321, 2941, 2928, 2675, 2644, 2623, 2611, 2587, 2521, 2482, 2359, 2330, 1512, 1441, 1242, 1179, 1038, 829 cm^“1. HPLC Purity: 99.64 % (area %). GC-MS: 178 (M+H⁺).

Example-3: N-Desmethyl venlafaxine To the stirred solution of 2-(l -hydroxy cyclohexyl)-2-(4-methoxyphenyl)acetonitrile (20.0 g, 1 equiv.) in methanol (350.0 ml), monomethylamine hydrochloride (27.7 g, 4 equiv.) was added and the mixture was stirred for 5-10 minutes at room temperature to obtain a clear solution. 5% Palladium on alumina (4.0 g, 20 wt %) was added under nitrogen to the above clear solution. The reaction mixture was purged with hydrogen gas (three times) and allowed to stir under hydrogen (1-2 atmospheric pressure.) at room temperature for 24 hrs. After completion of the reaction product was isolated by the procedure as described in Example- 1 above to obtain light yellow viscous liquid (18.5g) which was directly converted to its hydrochloride salt using IPA/HCl.

HPLC conversion to N-desmethylvenlafaxine (in the crude reaction mixture = 18.5g): 35.46%. N-Desmethyl venlafaxine-free base:

¹H NMR in CDCl₃ (300 MHz): δ 7.23 (d, 2H), £91 (d, 2H), 3.71 (s, 3H), 3.54 (t, IH), 3.48 (dd, IH), 2.97 (dd, IH), 2.69 (s, 3H), 1.41-1.0 (m, 10H)

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ZYH-7

By January 2012 phase II trials had begun for Diabetes type 2 Lipoprotein disorders
Obesity

In August 2007, an IND was filed , and by March 2008, a phase I trial was underway ; by April 2011, the trial had been completed

Zydus Cadila has filed an Investigational New Drug (NID) application for seeking DCGI’s permission for conducting clinical trials for its New Molecular Entity (NME) ZYH7.

According to a company release, it claims that ZYH7 is a novel drug candidate for treating dyslipidemia and metabolic disorders. The company inform that ZYH7 had been conceptualised and developed by its scientists from Zydus Research Centre.

The company has its in-house research centre and it had recently concluded pre-clinical studies on ZYH7, which have reported interesting and encouraging finding which indicate a novel molecule to treat dyslipidemia and associated metabolic disorders.

Commenting on the new development, Pankaj Patel, chairman and managing director, Zydus Cadila said, “We have been building a promising pipeline of new molecular entities at the Zydus Research Centre and ZYH7 is an important step in this direction”.

Starting with its first IND filing in 2005, Zydus today has four INDs in various stages of clinical trials. NME – ZYH1 for treating dyslipidemia and ZYI1 for treating pain and inflammation are undergoing Phase II trials. ZYH2 for treating diabetes and the novel CB-1 antagonist, ZYO1 for treating obesity, are undergoing Phase I trials.

Diabetes, a worldwide health problem, affects more than 150 million people, a number expected to double to 300 million by 2025. People with diabetes are at especially high risk for dyslipidemia, particularly high triglyceride levels and low HDL levels.

Dyslipidemia is also a key independent risk factor for cardiovascular disease (CVD), which is the largest therapeutic segment in the world pharmaceutical market.

With an increasing correlation between several endocrine and metabolic disorders, there has been considerable emphasis in recent times on metabolic syndrome. The metabolic components of cardiovascular disease, diabetes and obesity, are linked in numerous ways with each having an impact on the other.

For instance, it is also well known that patients with Type 2 diabetes have a two to four-fold excess risk of coronary heart disease and that these patients very often have increased cardiovascular risk factors even before the onset of their diabetes.

Dyslipidemia is an abnormal amount of lipids (e.g. cholesterol and/or fat) in the blood. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin levels can also lead to dyslipidemia. Likewise, increased levels of O-GlcNAc transferase (OGT) may cause dyslipidemia.

Dyslipidemia
Classification and external resources
ICD–10	E78
ICD–9	272
DiseasesDB	33452
MeSH	D050171

Classification

Physicians and basic researchers classify dyslipidemias in two distinct ways:

• Phenotype, or the presentation in the body (including the specific type of lipid that is increased)
• Etiology, or the reason for the condition (genetic, or secondary to another condition). This classification can be problematic, because most conditions involve the intersection of genetics and lifestyle issues. However, there are a few well-defined genetic conditions that are usually easy to identify.

Fredrickson Classification:^[1]

WO 2008035359

https://www.google.com/patents/WO2008035359A2?cl=en

Scheme 1 below which comprises:

Scheme 2 below which comprises

ORGANIC SPECTROSCOPY INTERNATIONAL

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Organic Chemists from Industry and academics to Interact on Spectroscopy
Techniques for Organic Compounds ie NMR, MASS, IR, UV Etc. Starters,
Learners, advanced, all alike, contains content which is basic or advanced,
by Dr Anthony Melvin Crasto, Worlddrugtracker,
email me ……….. amcrasto@gmail.com, call +91 9323115463

 

DR ANTHONY MELVIN CRASTO,WorldDrugTracker, helping millions, A 90 % paralysed man in action for you, I am suffering from transverse mylitis and bound to a wheel chair, This will not stop me
DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai), INDIA, worlddrugtracker, 25Yrs Exp.
in the feld of Organic Chemistry,Working for GLENMARK GENERICS at Navi Mumbai, INDIA.
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contribution, सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।

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FRANCE

Republican march, Place de la République, Paris.

The St. Bartholomew’s Day massacre (1572) was the climax of theFrench Wars of Religion, which were brought to an end by the Edict of Nantes (1598).

One of the Lascaux paintings: a horse – Dordogne, approximately 18,000 BC

With Clovis‘ conversion to Catholicism in 498, theFrankish monarchy, electiveand secular until then, became hereditary and ofdivine right.

Frankish expansion from 481 to 843/870.

The Storming of the Bastille on 14 July 1789 was the starting event of theFrench Revolution.

Louis XIV, the “sun king” was the absolute monarch of France and made France the leading European power.

Napoleon, Emperor of the French, and his Grande Armée built a vast Empire across Europe. He helped spread the French revolutionary ideals and his legal reforms had a major influence worldwide.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

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Amgen receives FDA approval for chronic heart failure medicine Corlanor
Amgen has received approval from the US Food and Drug Administration (FDA) for its Corlanor (ivabradine) to treat patients with chronic heart failure.

read at http://www.pharmaceutical-technology.com/news/newsamgen-receives-fda-approval-chronic-heart-failure-medicine-corlanor-4555383?WT.mc_id=DN_News

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will be updated………………..

SMU-B

A series of novel aminopyridyl/pyrazinyl-substituted spiro[indoline-3,4′-piperidine]-2-ones were designed, synthesized, and tested in various in vitro/in vivo pharmacological and antitumor assays. 6-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridyl]-1′-methylspiro[indoline-3,4′-piperidine]-2-one (compound 5b or SMU-B) was identified as a potent, highly selective, well-tolerated, and orally efficacious c-Met/ALK dual inhibitor, which showed pharmacodynamics effect by inhibiting c-Met phosphorylation in vivo and significant tumor growth inhibitions (>50%) in GTL-16 human gastric carcinoma xenograft models.

see..http://pubs.acs.org/doi/abs/10.1021/ml400203d

cas 1253286-90-6

Spiro[3H-​indole-​3,​4′-​piperidin]​-​2(1H)​-​one, 6-​[6-​amino-​5-​[(1R)​-​1-​(2,​6-​dichloro-​3-​fluorophenyl)​ethoxy]​-​3-​pyridinyl]​-​1′-​methyl-

6-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridyl]-1′-methylspiro[indoline-3,4′-piperidine]-2-one (compound 5b or SMU-B)

SEE

CN 101851237

南方医科大学

1_4,3_ [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] -2-nitro-approved P set

  obtained in Step 1-3 (IS) -I- (2,6- dichloro-3-fluorophenyl) ethanol (2. 09g, IOmmol) was dissolved in dry THF (80 ml). Then, at room temperature under a nitrogen atmosphere, a solution of 3-hydroxy-2-nitro-pyridine (1.54g, llmmol) and triphenylphosphine (3. 409g, 13mmol), and so is completely dissolved, cooled to 0 ° C, was added Diisopropyl azodicarboxylate (DIAD, 2.63g, 13mmol), After the addition, the mixture was stirred at 0 ° C for 16 hours, the solvent was removed by rotary evaporation and the oily residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate : 4/1) to give the desired product as a white solid (3. 046g, yield: 92%) o 1H-NMR (CDClySOOMHz): 8 (ppm) I. 86 (d, J = 6. 4Hz, 3H), 6 . 10 (q, J = 6. 4Hz, 1H), 7. 09 (dd, J = 7. 6,8. 8Hz, 1H), 7. 21 (dd, J = 8. 4, I. 2Hz, 1H ), 7. 31 (dd, J = 4. 8,8. 8Hz, 1H),

7. 37 (dd, J = 4. 8,8. OHz, 1H), 8. 04 (dd, J = L 6,4. 4Hz, 1H). Mass spectrum m / z:. 330 94 [M + H, 35C1,35Cl], 332. 92 [M + H, 35Cl, 37Cl].

  1_5,3_ [(IR) -I- (2,6_ two gas -3- gas phenyl) ethoxy] -2_ atmosphere based grant given P

to take steps 1-4 to get the 3 – [(lR) _l- (2,6_ dichloro-3-fluorophenyl) ethoxy] -2_ nitro than Li Jie (2. 649g, 8mmol) was dissolved in ethanol (15mL) was added iron powder (3. 575g, 64mmol) were mixed under nitrogen with vigorous stirring at 90 ° C oil bath, was added via syringe 0.8mL IM HCl (aq), after 10 minutes, was added 0. 8mL IMHCl (aq). Stirring was continued for 30 minutes, TLC showed the reaction. Cooled to room temperature, filtered through Celite, the filter residue washed with ethanol (3X IOmL). The combined organic phase was removed by rotary evaporation of the solvent gave the desired product as a light brown solid (2. 41g, yield: 100%) o 1H-Nmr (Cdci3JOOmHz): 8 (ppm) I. 81 (d, J = 6. 8Hz, 3H ), 5. 03 (s, br, 2H), 6. 01 (q, J = 6. 8Hz, 1H), 6. 47 (dd, J = 4. 8,7. 6Hz, 1H), 6. 70 (d, J = 8. OHz, 1H), 7. 05 (t, J = 8. 8Hz, 1H), 7. 28 (dd, J = 4. 0,8. 0Hz, 1H), 7. 57 ( d, J = 5.2Hz, lH). Mass spectrum m / z:. 301 00 [M + H, 35Cl, 35Cl], 302. 77 [M + H, 35Cl, 37Cl].

  l-6,5_ desert _3_ [(IR) -I- (2,6_ two gas -3- gas phenyl) ethoxy] -2_ atmosphere base than Li Jie

The steps 1-5 obtained 3_ [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] -2-yl atmosphere than Li Jie (1.506g, 5mmol) dissolved in acetonitrile (20mL) in. Then, at 0 ° C and the degree of stirring in added portionwise N- bromosuccinimide (0.908g, 5. Lmmol), After the addition, stirring was continued for 30 minutes. The solvent was removed by rotary evaporation, the crude product was obtained as a white solid was the desired product (1.045g, yield: 55%) was purified by column chromatography on silica gel. 1H-NMR (⑶Cl3,500MHz): 8 (ppm) I. 81 (d, J = 6. 8Hz, 3H), 4 85 (s, br, 2H), 6 98 (q, J = 6. 8Hz.. , 1H), 6. 82 (d, J =

2. 0Hz, 1H), 7. 08 (t, J = 8. 4Hz, 1H), 7. 31 (dd, J = 4. 8,8. 8Hz, 1H), 7. 65 (d, J = 2 . OHz, 1H). Mass spectrum m / z:… 378 84 [M + H, 35Cl, 35Cl, 79Br], 380 82 [M + H, 35Cl, 35Cl, 81Br or 35Cl, 37Cl, 79Br], 382 80 [M + H, 35Cl , 37Cl, 81Bror 37Cl, 37Cl, 79Br].

Step 2, I ‘- methyl-5- (4,4,5,5-tetramethyl -I, 3,2- dioxolane boron-2-yl) spiro [indoline Spray – 3,4 ‘- piperidin] -2_ one

  2-1,5- bromo -I ‘- methyl-spiro [indoline-3,4′ – piperidin] _2_ one

[0300] 5-bromo – indol-2-one (I. 272g, 6mmol) was suspended THF (15mL) at, and cooled to -78 ° C, added dropwise with stirring IM NaN (SiMe3) THF solution of 2 (30mL, 30mmol). After the addition was stirred at _78 ° C 30 min, then 2-chloro -N- (2- chloro-ethyl) -N- methyl-ethylamine hydrochloride solid (I. 155g, 6mmol). After the addition stirring was continued for 30 minutes, then warmed to room temperature and stirred for two days. TLC showed the reaction was completed, to the pink suspension was carefully added aqueous 4M hydrochloric acid (IOmL), and then adjusted with concentrated aqueous ammonia to pH ^ 9, and extracted with DCM (3 X 80mL). The organic phases were combined, dried (Na2SO4), and concentrated to give the crude product was purified by silica gel column chromatography (7M NH3 in methanol solution / DCM: 5/95) to give the desired product (I. 38g, yield: 78%) was purified. 1H-NMR (CD3ODjOOMHz):. 8 (ppm) I. 86-1 92 (m, 2H), I 94-1 98 (m, 2H), 2 44 (s, 3H), 2 62-…. 2. 68 (m, 2H), 2. 86-2. 91 (m, 2H), 6. 76 (d, J = 7. 6Hz, 1H), 7. 33 (dd, J = I. 2,7 . 6Hz, 1H), 7. 44 (d, J = I. 6Hz, 1H), 7. 81 (s, br, 1H). Mass spectrum m / z:. 294 99 [M + H, 79Br], 296 82 [M + H, 81Br]..

2-2, V – methyl-5- (4,4,5,5-tetramethyl–1,3,2_ dioxolane Borane _2_ yl) spiro [indoline – 3,4 ‘- piperidin] -2_ one

Under nitrogen, obtained in Step 2-1 to 5-bromo -I ‘- methyl-spiro [indoline-_3,4′ – piperidin] _2_ one (147. 6mg, 0. 5mmol) , the United pinacols drop acid unitary purpose (140mg, 0. 55mmol) and acetic acid Bell (147mg, I. 5mmol) in DMSO (0. 2ml) was added in PdCl2 (dppf) • CH2Cl2 (20. 4mg, 0. 025mmol ), to the resulting solution was bubbled with nitrogen for 2 minutes, and then stirred at 80 ° C of 16 hours. LC-MS showed completion of the reaction, after cooling to room temperature, water (2mL), extracted with DCM (3X5mL). The organic phases were combined, dried (Na2SO4), and concentrated to give the desired product (170mg, yield: 100%) o MS m / z:. 342 07 [M + H], 343. 08 [M + H, 100%], 344. 11 [M + H].

  Step 3,5_ [6_ atmosphere base _5_ [(IR) -I- (2,6_ two gas -3- gas phenyl) ethoxy] -3_ batch P fixed base] -I ‘- A group spiro [indoline-3,4 ‘- piperidin] -2_ one

The steps 1-6 5_ desert obtained _3_ [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] -2-yl batch atmosphere pyridine (75. 8mg , 0. 2mmol), I’- step 2_2 obtained methyl 5- (4,4,5,5-tetramethyl-l, 3,2-dioxolane Borane 2-yl) spiro [ indoline-3,4′-piperidin] -2-one (82mg, 0. 24mmol) and potassium carbonate (82. 9mg, 0. 6mmol) was dissolved in DME / water mixture solution (4 / 1,2. Oml ). Then, under nitrogen, was added Pd (PPh3) 4 (II. 6mg, 0. Olmmol), to the resulting mixture was bubbled with nitrogen for 2 minutes, and then stirred at 80 ° C of 18 hours. LC-MS showed completion of the reaction, after cooling to room temperature, water (5mL), extracted (3 X IOmL) with DCM. The organic phases were combined, dried (Na2SO4), and concentrated to give the crude product was purified by silica gel column chromatography (7M NH3 in methanol solution / DCM: 5/95) to give the desired product (88. 6mg, yield: 86%) was purified. 1H-Nmr (Cdci3JOOmHz): 8 (ppm) I. 86 (d, J = 6. 4Hz, 3H), I 93-2 02 (m, 4H), 2 44 (s, 3H),…

2. 66-2. 72 (m, 2H), 2. 89-2. 93 (m, 2H), 4. 87 (s, br, 2H), 6. ll (q, J = 6. 4Hz, 1H ), 6. 88 (d, J =

8. OHz, 1H), 6. 94 (d, J = I. 2Hz, 1H), 7. 06 (t, J = 8. 4Hz, 1H), 7. 19 (dd, J = I. 2,8 . OHz, 1H),

7. 31 (m, 1H), 7. 36 (s, 1H), 7. 66 (s, br, 1H), 7. 80 (d, J = 2. OHz, 1H). Mass spectrum m / z:.. 515 05 [M + H, 35Cl, 35Cl], 517 03 [M + H, 35Cl, 37Cl].

  Example 2: 6_ [6_ atmosphere base _5_ [(IR) -I- (2,6_ two gas -3- gas phenyl) ethoxy] -3_ than Li Jie base] -I ‘ – methyl-spiro [indoline-3,4 ‘- piperidin] -2_ one

Step I, I ‘- methyl-6- (4,4,5,5-tetramethyl–I, 3,2- dioxolane boron-2-yl) spiro [indoline Spray – 3,4 ‘- piperidin] -2_ one

  1-1,6- bromo -I ‘- methyl-spiro [indoline-3,4′ – piperidin] -2_ one

  As described in Example I steps 2-1 of the method from the commercially available 6-bromo – indol-2-one was prepared, Yield: 82%. Analysis of the data obtained the desired product are = 1H-Nmr (Cd3OdJOOmHz): 8 (ppm) 1.90-1.98 (m, 4H),

2. 44 (s, 3H), 2. 64-2. 68 (m, 2H), 2. 86-2. 92 (m, 2H), 7. 05 (d, J = 2. 0Hz, 1H), 7. 16-7. 21 (m, 2H), 7. 91 (s, br, 1H). Mass spectrum m / z: 295 00 [M + H, 79Br], 296 78 [M + H, 81Br]… [0312] 1-2, 1 ‘- methyl-6- (4,4,5,5-tetramethyl-_1,3,2_ dioxolane Borane _2_ yl) spiro [indoline – 3,4 ‘- piperidin] -2_ one

In the step 1-1 of the obtained 6-bromo -I ‘- methyl-spiro [indoline-_3,4′ – piperidin] -2_ ketone and commercially available linking pinacol boronic ester material, the method of Example I was prepared in accordance with steps 2-2, Yield: 95%. Analysis of the data obtained of the target product are as follows: Mass spectrum m / z:. 342 06 [M + H], 343 04 [M + H, 100%], 344. 12 [M + H]..

  Step 2,6_ [6_ atmosphere base _5_ [(IR) -I- (2,6_ two gas -3- gas phenyl) ethoxy] -3 ratio Li Jie base] -I ‘- methyl-spiro [indoline-3,4 ‘- piperidin] -2_ one

  Example I steps 1-6 to obtain 5-bromo -3 – [(IR) -I- (2,6- dichloro-3-fluorophenyl) ethoxy] -2-amino- pyridine, I obtained in Example 1-2 of the present embodiment in step ‘- methyl-6- (4,4,5,5-tetramethyl-l, 3,2-dioxolane-2-yl borane) spiro [indoline-_3,4 ‘- piperidin] -2-one, prepared as in Example I Step 3. Yield: 82%. 1H-Nmr (Cdci3JOOmHz): 8 (ppm) I. 86 (d, J = 6. 4Hz, 3H), I. 91-1 95 (m, 2H), I 97-2 03 (m, 2H… ), 2. 45 (s, 3H), 2. 65-2. 72 (m, 2H), 2. 89-2. 95 (m, 2H), 5. 12 (s, hr, 2H),

6. 12 (q, J = 6. 4Hz, 1H), 6. 94-7. 00 (m, 3H), 7. 06 (t, J = 8. 4Hz, 1H), 7. 31 (m, 1H ), 7. 35 (d, J = 7. 2Hz, 1H), 7. 90 (d, J = 2. 0Hz, 1H), 9. 28 (s, br, 1H). Mass spectrum m / z:.. 515 05 [M + H, 35Cl, 35Cl], 517 03 [M + H, 35Cl, 37Cl].

5- [6-amino-5 – [(2,6-dichloro-3-fluorophenyl) methoxy] _3_ pyridinyl] -I’–methyl-spiro [indole: 3 [0317] Example morpholine-3,4 ‘- piperidin] -2-one

H2N N

Step I, 5_ desert _3_ (2,6_ two gas -3- integrity oxy) _2_ atmosphere based grant given P

  1-1,2,6_ two gas acid gas _3_

Cl OF

Sodium hydroxide (13g, 325mmol) in water (IlOmL) was cooled to _5 ° C was added dropwise under vigorous stirring of liquid bromine (12. 5g, 78. 2mmol), added after the addition of pre-cooled to 10 ° C dioxane (75mL). The above mixture under vigorous stirring was added dropwise a pre-cooled to 5 ° C of I- (2,6- dichloro-3-fluorophenyl) ethanone (5g, 21. 2mmol) in dioxane (330mL) and water (90mL) was added. After the addition, at room temperature for 2 hours Lan Xiang, Xiang Lan then 90 C for 30 minutes. TLC was not shown with the S starting material disappeared, and was acidified with concentrated hydrochloric acid to PH~9. The resulting mixture was rotary evaporated to dryness, added water (20mL), and extracted with diethyl ether (2X80mL), the organic phases were combined, dried (Na2SO4), and concentrated to give an oily product solidified after cooling to a transparent, slightly yellow solid (3. 4g, Yield: 67%). 1H-Nmr (Cdci3AOOmHz):. 8 (ppm) 7. 21 (. Dd, J = 8. 0,8 8Hz, 1H), 7 35 (. Dd, J = 4. 4,9 2Hz, 1H), 9 . 79 (s, br, 1H). Mass spectrum m / z (ES “:. 207 11 [M_H, 35Clj35Cl], 209 10 [MH, 35Cl, 37Cl]..

  1-2,2,6–dichloro-3-fluoro-benzyl alcohol

^ Coh

F

[0325] To be filled with 2,6-dichloro-3-fluoro benzoic acid (3g, 14. 35mmol) added dropwise to the flask IM BH3. THF (43mL, 43mmol), added after the mixture was stirred under reflux for 24 hours. TLC showed the reaction was complete, methanol (50mL) to destroy excess borane, and the solvent was distilled off under reduced pressure and the resulting trimethyl borate, the process is repeated twice more to give a viscous product 2. I g, yield: 75% . 1H-Nmr (Cdci3JOOmHz): 8 (ppm) 2. 09 (t, J = 6. 4Hz, 1H), 4. 97 (d, J = 6. 4Hz, 2H), 7 09 (t, J = 8. . 8Hz, 1H), 7. 32 (dd, J = 4. 8,9. 1Hz, 1H). Mass spectrum m / z (ES-):.. 193 08 [M_H, 35Cl, 35Cl], 195 12 [MH, 35Cl, 37Cl].

  1-3,3_ (2,6-gas _3_ integrity oxy) _2_ nitro grant given P

Following the procedure of steps 1-4 of Example I, was prepared from 2,6-dichloro-3-fluoro-benzyl alcohol and 3-hydroxy-2-nitropyridine prepared in yield (in this example embodiment steps 1_2) : 90%. 1H-Nmr (Cdci3AOOmHz): 8 (ppm) 5. 45 (s, 2H), 7 20, 7 37 (dd, J = 4. 8. (Dd, J = 8. 0,9 2Hz, 1H.). , 9. 2Hz, 1H), 7. 59 (dd, J = 4. 4,8. 4Hz, 1H),

7. 74 (dd, J = L 2,8. 4Hz, 1H), 8. 17 (dd, J = L 6,4. 4Hz, 1H). Mass spectrum m / z:. 316 89 [M + H, 35Cl, 35Cl], 318. 89 [M + H, 35Cl, 37Cl].

  1_4,3_ (2,6-gas _3_ integrity oxy) _2_ atmosphere based grant given P

The method according to Example I step 1_5 from 3- (2,6-gas -3- integrity oxy) _2_ nitro Jie ratio 唳 preparation (in this case, steps 1-3), that Yield: 95% o 1H-Nmr (Cdci3JOOmHz):. 8 (ppm) 4 65 (s, br, 2H), 5 31 (s, 2H), 6 66 (dd, J = 5. 2,8.. . 0Hz, 1H), 7. 14 (dd, J = I. 2,8. 0Hz, 1H), 7. 18 (dd, J =

8. 4,9. 2Hz, 1H), 7. 37 (dd, J = 4. 8,8. 8Hz, 1H), 7. 73 (dd, J = I. 6,5. 6Hz, 1H). Mass spectrum m / z:. 286 95 [M + H, 35Cl, 35Cl], 288 85 [M + H, 35Cl, 37Cl]..

  1-5,5_ desert -3- (2,6-gas -3_ integrity oxy) ~ 2 ~ atmosphere based grant given P

Following the procedure of Example I step 1_6 embodiment, starting from 3- (2,6-gas _3_ integrity yloxy) _2_ atmosphere group given the preparation of the batch P (in the example of the present embodiment in step 1-4), Yield: 60% o 1H-Nmr (Cdci3JOOmHz):. 8 (ppm) 4 68 (s, br, 2H), 5 28 (s, 2H), 7 21 (dd, J = 8. 0,8.. . 8Hz, lH), 7. 24 (dd, J = 2. OHz, 1H), 7. 39 (dd, J = 4. 8,

9. 2Hz, 1H), 7. 78 (d, J = 2. OHz, 1H). Mass spectrum m / z:. 364 83 [M + H, 35Cl, 36Cl, 79Br], 366 77 [M + H], 368 69 [M + H]…

  Step 2,5_ [6_ atmosphere base _5_ [(2,6_ two gas -3- gas) methoxy] -3_ than Li Jie base] -I-methyl-spiro [indoline _ 3,4 ‘- piperidin] -2-one

The present embodiment 5_ desert steps 1_5 obtained _3_ (2,6_ two gas _3_ integrity yloxy) pyridine ~ 2 ~ atmosphere, Examples 2-2 obtained in step I I ‘- methyl-5- (4,4,5,5-tetramethyl-borane _1,3,2- dioxolane-2-yl) spiro [indoline-_3,4′ – piperidine ] -2-one, prepared as in Example I Step 3. Yield: 85 V0o 1H-Nmr (Cdci3JOOmHz):.. 8 (ppm) I. 92-2 02 (m, 4H), 2. 43 (s, 3H), 2. 65-2 71 (m, 2H) , 2. 90-2. 91 (m, 2H), 4. 92 (s, br, 2H), 5. 52 (s, 2H), 6. 89 (d, J = 8. 4Hz, 1H), 6 . 90 (d, J = L 2Hz, 1H), 7. 06 (t, J = 8. OHz, 1H), 7. 21 (dd, J = L 2,8. OHz, 1H), 7. 31 ( m, 1H),

7. 37 (s, 1H), 7. 79 (s, br, 1H), 7. 80 (d, J = 2.0Hz, lH). MS m / z:. 501 06 [M + H, 35Cl, 35Cl], 503 04 [M + H, 35Cl, 37Cl]..

6- [6-amino-5 – [(2,6-dichloro-3-fluorophenyl) methoxy] _3_ pyridinyl] -I’- methyl-spiro [indole: 4 [0337] Example morpholine _3,4 ‘- piperidin] -2-one

H2N N

  Following the procedure in Example I step of Example 3, the procedure of Example 3 to give 5-bromo-1-5 _3_ (2,6-dichloro-3-fluoro-benzyloxy) -2-amino-pyridine and Step 2 in Example I to give the embodiment 1-2 ‘- methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxolane Borane 2-yl) spiro [ indoline-3,4 ‘- piperidine] _2_ ester -one, yield:. 78 V0o 1H-Nmr (Cdci3JOOmHz): 8 (ppm) I. 96-2 00 (m, 2H), 2. 01 -2. 12 (m, 2H), 2. 46 (s, 3H), 2. 66-2. 73 (m, 2H), 2. 90-2. 96 (m, 2H), 5. 30 (s , hr, 2H), 6. 94-7. 01 (m, 3H), 7. 07 (t, J =

8. 4Hz, 1H), 7. 30 (m, 1H), 7. 34 (d, J = 7. 2Hz, 1H), 7. 89 (d, J = 2. OHz, 1H), 8. 56 ( s, br, 1H). MS m / z:. 501 06 [M + H, 35Cl, 35Cl], 503 04 [M + H, 35Cl, 37Cl]..

  Example 5: 5_ [5_ atmosphere base -6- [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] Batch-2-yl] -I ‘ – methyl-spiro [indoline-3,4 ‘- piperidin] -2-one

J0A = o

. | J: too

[0342] Step 1,5_ desert _2_ atmosphere base _3_ [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] Jie than exposure

Cl 6, / ISL / Br

xy

H2N N

  In at 0 ° C, NaH (80mg of NaH in mineral oil, 2mmol) force the mouth (1R) -1_ (2,6- dichloro-3-fluorophenyl) ethanol (418mg, 2mmol. See example Example I Step 1_3) in anhydrous THF (6mL) and stirred for half an hour, a solution of 2-amino-3,5-dibromo-pyrazine (506mg, 2mmol) in THF (6mL) was added. The resulting mixture was warmed to room temperature, heated under reflux for 20 hours. TLC showed the reaction was substantially complete. After cooling to room temperature, water was added (IOmL), the mixture was extracted three times with ethyl acetate (3x20mL), the organic phases were combined, dried, concentrated, and the residue to give 594mg product was purified by column chromatography (l-3Me0H inhexanes), yield: 78%. 1H-NMR (O) Cl3, 500MHz):. 8 (ppm) I. 83 (d, J = 7. 2Hz, 3H), 5. 12 (s, br, 2H), 6 73 (q, J = 6 . 8Hz, 1H), 7. 05 (t, J = 8. OHz, 1H), 7. 28 (dd, J = 4. 8,

8. 8Hz, 1H), 7. 58 (s, 1H). Mass spectrum m / z:. 379 83 [M + H, 35Cl, 35Cl, 79Br], 381. 81 [M + H, 35Cl, 35Cl, 81Br], 383 79 [M + H, 35Cl, 37Cl, 81Br]..

Step 2,5_ [5_ atmosphere base _6_ [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] Batch-2-yl] -I ‘- A group spiro [indoline-3,4 ‘- piperidin] -2-one

  5_ bromide present embodiment obtained in step I _2_ amino _3_ [(IR) -I- (2,6_ dichloro _3_ fluorophenyl) ethoxy] pyrazine, implemented I’- methyl step 2-2 obtained in Example I-5 (4,4,5,5-tetramethyl -I, 3,2- dioxolane boron

2-yl) spiro [indoline-3,4 ‘- piperidin] -2-one, prepared as in Example I Step 3. Yield: 54%. 1H-NMR (CD3ODjOOMHz): 8 (ppm) I. 85 (d, J = 6. 8Hz, 3H), I 85-1 88 (m, 2H), I 97-2 04 (m, 2H…. ), 2. 46 (s, 3H), 2. 76-2. 82 (m, 2H), 2. 97-3. 02 (m, 2H), 6. 74 (q, J = 6. 4Hz, 1H ), 6. 85 (d, J = 8. OHz, 1H), 7. 15 (t, J = 8. 4Hz, 1H), 7. 41 (dd, J = 4. 8,9. 2Hz, lH) , 7. 54 (dd, J = I. 6,

8. OHz, 1H), 7. 69 (d, J = I. 8Hz, 1H), 7. 81 (dt, J = 2. 0,8. 0Hz, 1H), 7. 87 (s, 1H). Mass spectrum m / z:. 515 92 [M + H, 35Cl, 35Cl], 517. 90 [M + H, 35Cl, 37Cl].

Example 6: 6- [5-amino -6 – [(lR) -l_ (2,6- dichloro _3_ fluorophenyl) ethoxy] pyrazin-2-yl] -I ‘ – methyl-spiro [indoline-3,4 ‘- piperidin] -2-one

The embodiment of Example 5, 5_ bromo obtained in step I _2_ amino _3_ [(IR) -I- (2,6_ dichloro _3_ fluorophenyl) ethoxy] pyrazine, Example I’- methyl-2 obtained in steps 1-2 6- (4,4,5,5-tetramethyl–I, 3,2- dioxolane boron-2-yl) spiro [indole morpholine -3,4’_ piperidin] -2-one, prepared as in Example I Step 3. Yield: 67% 0

1H-NMR (CD3ODjOOMHz): 8 (ppm) I. 85 (d, J = 6. 8Hz, 3H), I 88-1 96 (m, 4H), 2 48 (s… , 3H), 2. 76-2. 82 (m, 2H), 2. 98-3. 05 (m, 2H), 6. 75 (q, J = 6. 4Hz, 1H), 7. 16 (t , J = 8. 8Hz, 1H), 7. 31 (d, J = 2. OHz, 1H), 7. 36-7. 43 (m, 3H), 7. 88 (s, 1H).

Mass spectrum m / z:. 515 99 [M + H, 35Clj35Cl], 517 90 [M + H, 35Cl, 37Cl]..

SEE

Bioorganic & Medicinal Chemistry Letters (2014), 24(16), 3673-3682.

School of Pharmaceutical Sciences, Southern Medical University,

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO

FLAGS AND HITS

DR ANTHONY MELVIN CRASTO

MY BLOGS……… ALL ABOUT DRUGS,WORLD DRUG TRACKER,MEDICINAL CHEM INTERNATIONAL,DRUG SYN INTERNATIONALSCALEUP OF DRUGS,MEDICINAL CHEM INTERNATIONAL,DRUG SYN INTERNATIONAL,SCALEUP OF DRUGS, EUREKAMOMENTS

Tazemetostat

Current developer:  Epizyme, Inc., Cambridge, MA 02139.

EPZ-6438 (Tazemetostat)
CAS: 1403254-99-8

Chemical Formula: C34H44N4O4
Exact Mass: 572.33626

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide
SIMLES: O=C(C1=CC(C2=CC=C(CN3CCOCC3)C=C2)=CC(N(CC)C4CCOCC4)=C1C)NCC5=C(C)C=C(C)NC5=O

(1,1′-Biphenyl)-3-carboxamide, N-((1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(4-morpholinylmethyl)-

N-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(oxan-4-yl)amino)-4-methyl-4′-((morpholin-4-yl)methyl)(1,1′-biphenyl)-3-carboxamide

UNII-Q40W93WPE1

WO 2012142504 PRODUCT PAT

SEE  Proceedings of the National Academy of Sciences of the United States of America (2013), 110(19), 7922-7927, S7922/1-S7922/5….http://www.pnas.org/content/110/19/7922.abstract

http://www.epizyme.com/wp-content/uploads/2014/11/Ribrag-ENA-FINAL.pdf

Tazemetostat, also known as EPZ-6438,  is a potent, selective, and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity. EPZ-6438 induces apoptosis and differentiation specifically in SMARCB1-deleted MRT cells.

Treatment of xenograft-bearing mice with EPZ-6438 leads to dose-dependent regression of MRTs with correlative diminution of intratumoral trimethylation levels of lysine 27 on histone H3, and prevention of tumor regrowth after dosing cessation.

These data demonstrate the dependency of SMARCB1 mutant MRTs on EZH2 enzymatic activity and portend the utility of EZH2-targeted drugs for the treatment of these genetically defined cancers. EPZ-6438 is currently in clinical trials.

Epizyme, Inc., Eisai R&D Management Co.Ltd.

Epizyme is developing tazemetostat, a lead from several small molecule EZH2 inhibitors, for treating cancer (phase 1 clinical, as of April 2015). Japanese licensee Eisai was developing the program for the potential oral treatment of cancers, including non-Hodgkin’s lymphoma; however, in March 2015, Epizyme regained worldwide, ex-Japan, rights to the program.

It appeared that Eisai was planning to investigate the program in Japan .

WO-2015057859 From, Eisai Research Institute; Epizyme Inc, indicates Novel crystalline polymorphic form C of tazemetostat, useful for treating an EZH2-mediated cancer, including non-Hodgkin’s lymphoma and breast cancer.

see WO2013155317, claiming novel hydrobromide salt of tazemetostat.

PREDICT

………………………………….

PATENT

WO 2012142504

http://www.google.com/patents/WO2012142504A1?cl=en

Example 44: Synthesis of N-((4,6-dimethyl-2-oxo-l ,2-dihydropyridin-3- yl)methyl)-5-(ethyl (tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(moφholinomethyl)-[l , – biphenyl]-3-carboxamide

Compound 44

[Step 1 : Synthesis of 5-brom -2-methyl-3-nitrobenzoic acid

To stirred solution of 2-methyl-3-nitrobenzoic acid ( 100 g, 552 mmol) in cone. H₂S0₄ (400 mL), 1 ,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (88 g, 308 mmol) was added in a portion wise manner at room temperature and the reaction mixture was then stirred at room temperature for 5 h. The reaction mixture was poured onto ice cold water, the precipitated solid was filtered off, washed with water and dried under vacuum to afford the desired compound as a solid ( 140 g, 98%). The isolated compound was taken directly into the next step. Ή NMR (DMSO-4$, 400 MHz) δ 8.31 (s, 1 H), 8.17 (s, 1 H), 2.43 (s, 3H).

Step 2: Synthesis of methyl -bromo-2-methyl-3-nitrobenzoate

To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (285 g, 1 105 mmol) in DMF (2.8L) at room temperature was added sodium carbonate (468 g, 4415 mmol) followed by addition of methyl iodide (626.6 g, 4415 mmol). The resulting reaction mixture was heated at 60 °C for 8 h. After completion (monitored by TLC), the reaction mixture was filtered (to remove sodium carbonate) and washed with ethyl acetate ( 1 L X 3). The combined filtrate was washed with water (3L X 5) and the aqueous phase was back extracted with ethyl acetate (1L X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a solid (290g, 97% yield). The isolated compound was taken directly into the next step. Ή NMR (CDC1₃, 400 MHz) δ 8.17 (s, 1H), 7.91 (s, 1H), 3.96 (s, 3H), 2.59 (s, 3H).

Step 3: Synthesis of methyl 3-amino-5-bromo-2-methylbenzoate

To a stirred solution of methyl 5-bromo-2-methyl-3-nitrobenzoate (290 g,

1058 mmol) in ethanol (1 .5L) was added aqueous ammonium chloride (283 g, 5290 mmol dissolved in 1.5L water). The resulting mixture was stirred at 80°C to which iron powder (472 g, 8451 mmol) was added in a portion wise manner. The resulting reaction mixture was heated at 80 °C for 12 h. Upon completion as determined by TLC, the reaction mixture was hot filtered over celite® and the celite bed was washed with methanol (5L) followed by washing with 30% MeOH in DCM (5L). The combined filtrate was concentrated in-vacuo, the residue obtained was diluted with aqueous sodium bicarbonate solution (2L) and extracted with ethyl acetate (5L X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a solid (220 g, 85%). The compound was taken directly into the next step. Ή NMR (CDC1₃, 400 MHz) δ 7.37 (s, 1 H), 6.92 (s, 1 H), 3.94 (s, 3H), 3.80 (bs, 2H), 2.31 (s, 3H).

Step 4: Synthesis of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl) amino) benzoate

To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (15 g, 61 .5 mmol) and dihydro-2H-pyran-4(3)-one (9.2 g, 92 mmol) in dichloroethane (300 mL) was added acetic acid (22 g, 369 mmol) and the reaction mixture stirred at room temperature for 15 minutes, then the reaction mixture was cooled to 0°C and sodium triacetoxyborohydnde (39 g, 184 mmol) was added. The reaction mixture was stirred overnight at room temperature. Upon completion of the reaction as determined by TLC, aqueous sodium bicarbonate solution was added to the reaction mixture until a pH of 7-8 was obtained. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel) eluting with ethyl acetate: hexane to afford the desired compound as a solid ( 14 g, 69%). ‘H NMR (DMSO-<fc, 400 MHz) δ 7.01 (s, 1 H), 6.98 (s, 1 H), 5.00 (d, 1 H, J=7.6 Hz), 3.84-3.87 (m, 2H), 3.79 (s, 31 1), 3.54-3.56 (m_f 1 H), 3.43 (L 21 1, J 12 Hz), 2.14 (s. 31 1). 1 . 1 – 1 .84 (m_: 211). 1 .47- 1 .55 (m, 2H).

Step 5: Synthesis of methyl 5-bromo-3-(ethyl (tetrahydro-2H-pyran-4-yl) amino)-2- methylbenzoate

To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl) amino) benzoate (14 g, 42.7 mmol) in dichloroethane (150 mL) was added acetaldehyde (3.75 g, 85.2 mmol) and acetic acid ( 15.3 g, 256 mmol). The resulting reaction mixture was stirred at room temperature for 15 minutes. The mixture was cooled to 0 °C and sodium

triacetoxyborohydnde (27 g, 128 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Upon completion of the reaction as determined by TLC, aqueous sodium bicarbonate solution was added to the reaction mixture until a pH 7-8 was obtained, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100- 200 mesh silica gel) eluting with ethyl acetate: hexane to afford the desired compound as a viscous liquid (14 g, 93%). Ή NMR (DMSO-cfo 400 MHz) δ 7.62 (s, 1 H), 7.52 (s, 1 H), 3.80 (bs, 5H), 3.31 (t, 2H), 2.97-3.05 (m, 2H), 2.87-2.96 (m, 1 H), 2.38 (s, 3H), 1.52-1.61 (m, 2H), 1 .37-1.50 (m, 2H), 0.87 (t, 3H, J=6.8 Hz).

Step 6: Synthesis of 5-bromo-N-((4, 6-dimethyl-2-oxo-l , 2-dihydropyridin-3-yl) methyl)-3 -(ethyl (tetrahydro-2H-pyra -4-yl) amino)-2-methylbenzamide

To a stirred solution of 5-bromo-3-(ethyl (tetrahydro-2H-pyran-4-yl) amino)-2- methylbenzoate (14 g, 39.4 mmol) in ethanol ( 100 mL) was added aqueous NaOH (2.36 g, 59.2 mmol in 25mL water) and the resulting mixture was stirred at 60 °C for 1 h. Upon completion of the reaction as determined by TLC, the solvent was removed under reduced pressure and the residue obtained was acidified with IN HC1 until a pH 7 was obtained and then aqueous citric acid solution was added until a pH 5-6 was obtained. The aqueous layer was extracted with 10% MeOH in DCM (200mL X 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the respective acid (14 g, 100%).

The above acid (14 g, 40.9 mmol) was then dissolved in DMSO (70 mL) and 3- (amino methyl)-4, 6-dimethylpyridin-2( l H)-one ( 12.4 g, 81 .9 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 minutes, then PYBOP (31.9 g, 61.4 mmol) was added and stirring was continued for overnight at room temperature. Upon completion of the reaction as determined by TLC, the reaction mixture was poured onto ice- cold water (700 mL), stirred for 30 minutes and the precipitated solid was collected by filtration, washed with water (500 mL) and air dried. The solid obtained was stirred with acetonitrile (75mL X 2), filtered and air dried. The solid obtained was again stirred with 5% MeOH in DCM ( l OOmL), filtered and dried completely under vacuum to afford the title compound as a solid ( 14 g, 74 %). Ή NMR (DMSO- ₆, 400 MHz) δ 1 1.47 (s, 1 H), 8.23 (t, 1 H), 7.30 (s, 1 H), 7.08 (s, 1 H), 5.85 (s, 1 H), 4.23 (d, 2H, J=4.4 Hz), 3.81 (d, 2H, J=l 0.4 Hz), 3.20-3.26 (m, 2H), 3.00-3.07 (m, I H), 2.91 -2.96 (m, 2H), 2.18 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.58-1.60 (m, 2H), 1.45-1.50 (m, 2H), 0.78 (t, 3H, J=6.8 Hz).

Step 7: Synthesis of N-((4, 6-dimethyl-2-oxo-l , 2-dihydropyridin-3-yl) methyl)-5- (ethyl (tetrahydro-2H-pyran-4-yl) amino)-4-methyl-4′-(morpholinomethyl)-[l , l ‘-biphenyl]-3- carboxamide

TITLE COMPD

To a stirred solution of 5-bromo-N-((4, 6-dimethyl-2-oxo-l , 2-dihydropyridin-3-yl) methyl)-3-(ethyl (tetrahydro-2H-pyran-4-yl) amino)-2-methylbenzamide (14 g, 29.5 mmol) in dioxane/ water mixture (70 mL/ 14 mL) was added 4-(4-(4, 4, 5, 5-tetramethyl- l , 3, 2- dioxaborolan-2-yl) benzyl) morpholine (13.4 g, 44.2 mmol) followed by addition of Na₂C0₃ (1 1 .2 g, 106.1 mmol). The solution was purged with argon for 15 minutes and then Pd (PPh₃)₄ (3.40 g, 2.94 mmol) was added and the solution was again purged with argon for a further 10 min. The reaction mixture was heated at 100°C for 4 h. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with 10% MeOH/DCM.

The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100- 200 mesh silica gel) eluting with methanol: DCM to the title compound as a solid (12 g, 71 %).

Analytical Data: LCMS: 573.35 (M + 1 )⁺; HPLC: 99.5% (@ 254 nm) (R,;3.999; Method: Column: YMC ODS-A 1 50 mm x 4.6 mm x 5 μ; Mobile Phase: A; 0.05% TFA in water/ B; 0.05% TFA in acetonitrile; Inj. Vol : 10 μΐ, Col. Temp.: 30 °C; Flow rate: 1 .4 mL/min.;

Gradient: 5% B to 95% B in 8 min, Hold for 1 .5 min, 9.51 -12 min 5% B);

Ή NMR (DMSO-i ₆, 400 MHz) 5 1 1 .46 (s, I H), 8. 19 (t, 1 H), 7.57 (d, 2H, J=7.2 Hz), 7.36-7.39 (m, 3H), 7.21 (s, I H), 5.85 (s, I H), 4.28 (d, 2H, J=2.8 Hz), 3.82 (d, 2H, J=9.6 Hz), 3.57 (bs, 4H), 3.48 (s, 2H), 3.24 (t, 2H, J=10.8Hz), 3.07-3.09 (m, 2H), 3.01 (m, I H), 2.36 (m, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1 .64-1 .67 (m, 2H), 1 .51 – 1 .53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).

TRIHYDROCHLORIDE

Step 8: Synthesis of N-((4,6-dimethyl-2-oxo-l ,2-dihydropyridin-3-yl)methyl)-5- (ethyl (tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[ 1 , 1 ‘-biphenyl]-3- carboxamide trihydrochloride

N-((4, 6-dimethyl-2-oxo-l , 2-dihydropyridin-3-yl) methyl)-5-(ethyl (tetrahydro- 21 l-pyran-4-yl) amino)-4-methyI-4′-(niorpholinornethyl)-[ 1 , 1 ‘-biphenyl]-3-carboxamide ( 12 g, 21.0 mmol) was dissolved in methanolic HC1 (200 mL) and stirred at room temperature for 3 h. After three hours of stirring, the reaction mixture was concentrated under reduced pressure. The solid obtained was stirred with ether ( l OOmL X 2) to afford the desired salt as a solid ( 1 1 g, 77 %).

Analytical Data of the tri-HCl salt: LCMS: 573.40 (M + 1 )⁺; HPLC: 99.1 % (@ 254 nm) (R,;3.961 ; Method: Column: YMC ODS-A 150 mm x 4.6 mm x 5 μ; Mobile Phase: A; 0.05% TFA in water/ B; 0.05% TFA in acetonitrile; Inj. Vol: 10 pL, Col. Temp.: 30 °C; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51 -12 min 5% B);

Ή NMR (D₂0 400 MHz) δ 7.92 (bs, I H,) 7.80 (s, I H), 7.77 (d, 2H, J=8 Hz), 7.63 (s, I H), 7.61 (s, I H), 6.30 (s, I H), 4.48 (s, 2H), 4.42 (s, 2H), 4.09-4.1 1 (m, 4H), 3.95-3.97 (m, 2H), 3.77 (t, 3H, J=10.4 Hz), 3.44-3.47 (m, 3H), 3.24-3.32 (m, 3H), 2.42 (s, 3H), 2.35 (s, 3H), 2.26 (s, 3H), 2.01 (m, 2H), 1 .76 (m, 2H), 1 .04 (t, 3H, J=6.8 Hz).

…………………………………………

PATENT

WO2013155317

 http://www.google.com/patents/WO2013155317A1?cl=en

N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)-5-(ethyl (tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[l,l’- biphenyl] -3-carboxamide hydrobromide:

N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-5-(ethyl

(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[l,l’-biphenyl]-3- carboxamide hydrobromide:

As used herein, “Compound I” refers to N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)-5-(ethyl (tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[l,l’- biphenyl]-3-carboxamide. The hydrobromide of Compound I can be used to inhibit the histone methyltransferase activity of EZH2, either in a subject or in vitro. The hydrobromide of Compound I can also be used to treat cancer in a subject in need thereof.

Scheme 1

……………………………………..Compound I                                       Compound I – HBr

HPLC

HPLC was conducted on an Agilent 1200 HPLC quaternary pump, low pressure mixing, with an in-line degasser. Analytical method conditions: 8 μΐ_^ sample (20 mg of ER-581982-06 diluted with 50 mL of a methanol to provide approximately 0.4 mg/mL solution) was injected onto a Agilent Zorbax Eclipse XDB-C18 (4.6 x 150 mm, 3.5 um), Chromatography conditions: mobile phase A, water with 5mM ammonium formate; mobile phase B, 5 mM ammonium formate in 50/45/5 acetonitrile/methanol/water; flow rate, 1.5 ml/min.; gradient: isocratic at 10% B from 0 to 3 min; linear increase to 70% B from 3 to 7 min; isocratic at 70% B from 7 to 12 min; linear increase to 100% B from 12 to 15 min isocratic at 100% B from 15 to 20 min;

column temperature, 35 °C; detection, UV 230 nm. Approximate retention time of Compound I = 10.7 min.

Synthesis of Polymorph A

5-bromo-2-methyl-3-nitrobenzoic acid stirred solution of 2-methyl-3-nitrobenzoic acid (100 g, 552 mmol) in cone. H₂S0₄ (400 mL), l,3-dibromo-5,5-dimethyl-2,4- imidazolidinedione (88 g, 308 mmol) was added in a portion wise manner at room temperature and the reaction mixture was then stirred at room temperature for 5 h. The reaction mixture was poured onto ice cold water, the precipitated solid was filtered off, washed with water and dried under vacuum to afford the desired compound as a solid (140 g, 98%). The isolated compound was taken directly into the next step. 1H NMR (DMSO-J₆, 400 MHz) δ 8.31 (s, 1H), 8.17 (s, 1H), 2.43 (s, 3H).

Methyl 5-bromo-2-methyl-3-nitrobenzoate To a stirred solution of 5-bromo-2- methyl-3-nitrobenzoic acid (285 g, 1105 mmol) in DMF (2.8L) at room temperature was added sodium carbonate (468 g, 4415 mmol) followed by addition of methyl iodide (626.6 g, 4415 mmol). The resulting reaction mixture was heated at 60 °C for 8 h. After completion (monitored by TLC), the reaction mixture was filtered (to remove sodium carbonate) and washed with ethyl acetate (1L X 3). The combined filtrate was washed with water (3L X 5) and the aqueous phase was back extracted with ethyl acetate (1L X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a solid (290g, 97% yield). The isolated compound was taken directly into the next step. 1H NMR (CDC1₃, 400 MHz) δ 8.17 (s, 1H), 7.91 (s, 1H), 3.96 (s, 3H), 2.59 (s, 3H).

Methyl 3-amino-5-bromo-2-methylbenzoate (1) To a stirred solution of methyl 5- bromo-2-methyl-3-nitrobenzoate (290 g, 1058 mmol) in ethanol (1.5L) was added aqueous ammonium chloride (283 g, 5290 mmol dissolved in 1.5L water). The resulting mixture was stirred at 80°C to which iron powder (472 g, 8451 mmol) was added in a portion wise manner. The resulting reaction mixture was heated at 80 °C for 12 h. Upon completion as determined by TLC, the reaction mixture was hot filtered over celite® and the celite bed was washed with methanol (5L) followed by washing with 30% MeOH in DCM (5L). The combined filtrate was concentrated in- vacuo, the residue obtained was diluted with aqueous sodium bicarbonate solution (2L) and extracted with ethyl acetate (5L X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a solid (220 g, 85%). The compound was taken directly into the next step. 1H

NMR (CDCI₃, 400 MHz) δ 7.37 (s, 1H), 6.92 (s, 1H), 3.94 (s, 3H), 3.80 (bs, 2H), 2.31 (s, 3H).

Methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl) amino) benzoate (2) A reactor was charged with methyl 3-amino-5-bromo-2-methylbenzoate (455.8 g, 1.87 mol), 1,2- Dichloroethane (4.56 L), and acetic acid (535 ml, 9.34 mol). To the mixture were added dihydro-2H-pyran-4(3H)-one (280 g, 2.80 mol) and sodium triacetoxyborohydride (594 g, 2.80 mol) maintaining the internal temperature below 40 °C. The mixture was stirred at 25 °C for 2.5 h and then the reaction was quenched with a solution of sodium hydroxide (448 g, 11.20 mol) in water (5.61 L). After stirring for 20 minutes at ambient temperature, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (3.65 L). The organic layers were combined, washed with brine (1.5 L), and concentrated under vacuum.

The residue was treated with ethyl acetate (1.8 L) and heated to 65-70 °C. The mixture was stirred at 65-70 °C for 15 minutes to give a clear solution and then treated with n-heptane (7.3 L) maintaining the temperature between 60-70 °C. Once the heptane was completely added to the solution, the mixture was held at 65-70 °C for 15 minutes and then allowed to cool to 18- 22 °C over 3 h. The resulting suspension was stirred at 18-22 °C for 4 h, cooled to 0-5 °C over 1 h, and held at 0-5 °C for 2 h. The precipitate was filtered, washed twice with n-heptane (1.4 L), and dried under vacuum to give the title compound (540 g, 88%). The XRPD pattern of this compound is shown in Figure 17.

Methyl 5-bromo-3-(ethyl (tetrahydro-2H-pyran-4-yl) amino)-2-methylbenzoate (3)

To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl) amino) benzoate (14 g, 42.7 mmol) in dichloroethane (150 mL) was added acetaldehyde (3.75 g, 85.2 mmol) and acetic acid (15.3 g, 256 mmol). The resulting reaction mixture was stirred at room temperature for 15 minutes. The mixture was cooled to 0 °C and sodium triacetoxyborohydride (27 g, 128 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Upon completion of the reaction as determined by TLC, aqueous sodium bicarbonate solution was added to the reaction mixture until a pH 7-8 was obtained, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel) eluting with ethyl acetate: hexane to afford the desired compound as a viscous liquid (14 g, 93%). 1H NMR DMSO-d₆, 400 MHz) δ 7.62 (s, 1H), 7.52 (s, 1H), 3.80 (bs, 5H), 3.31 (t, 2H), 2.97-3.05 (m, 2H), 2.87-2.96 (m, 1H), 2.38 (s, 3H), 1.52-1.61 (m, 2H), 1.37-1.50 (m, 2H), 0.87 (t, 3H, J=6.8 Hz).

Methyl 5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-

[l,l’-biphenyl]-3-carboxylate (4): A mixture of methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-2-methylbenzoate (580 g, 1.63 mol), 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)benzyl)morpholine (592 g, 1.95 mol), 1,4-dioxane (3.86 L), sodium carbonate (618 g, 5.83 mol), and water (771 ml) was degassed by bubbling nitrogen through the mixture at 20 °C for 20 minutes and treated with tetrakis(triphenylphosphine)palladium(0) (14.11 g, 12.21 mmol). The resulting mixture was degassed for an additional 20 minutes and then heated to 87-89 °C for 17 h. After cooling to 20 °C, the mixture was diluted with ethyl acetate (5.80 L) and a solution of (R)-2-Amino-3-mercaptopropionic acid (232 g) in water (2.320 L). After stirring for 1 h at 20 °C, the organic layer was separated and washed again with a solution of (R)-2-Amino-3- mercaptopropionic acid (232 g) in water (2.320 L). The aqueous layers were combined and extracted with ethyl acetate (5.80 L). The organic layers were combined, washed with a solution of sodium hydroxide (93 g) in water (2.32 L), and concentrated under vacuum at 35 °C to give the title compound as an orange oil (1.21 kg, 164% yield).

5-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[l,l’- biphenyl]-3-carboxylic acid (5): Methyl 5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′- (morpholinomethyl)-[l,l’-biphenyl]-3-carboxylate (69.0 g, 152.5 mmol) (based on the theoretical yield from the previous step) was suspended in ethanol (380 mL) and treated with a solution of sodium hydroxide (24.84 g, 621.0 mmol) in water (207 mL). The mixture was stirred at 40°C for 18 h. After cooling to 0-5 °C, the mixture was neutralized to pH 6.5 with 1 N hydrochloric acid (580 mL) maintaining the temperature below 25 °C. Then, the mixture was extracted twice with a mixture of dichloromethane (690 mL) and methanol (69.0 mL). The organic layers were combined and concentrated under vacuum to give a crude product as a yellow solid (127g).

The crude product was dissolved in 2-methyltetrahydrofuran (656 mL) at 70 °C and then treated with IPA (828 mL). The mixture was allowed to cool to rt over 3-4 h and then stirred overnight at rt. The precipitate was filtered, washed twice with IPA (207 mL), and dried under vacuum to give the title compound as an off white solid (53.54 g, 80%). The XRPD pattern of this compound is shown in Figure 9.

N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[l,l’-biphenyl]-3-carboxamide

(Compound I): A mixture of 5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′- (morpholinomethyl)-[l,l’-biphenyl]-3-carboxylic acid (540 g, 1.23 mol) and 3-(aminomethyl)- 4,6-dimethyl-dihydro-pyridin-2(lH)-one hydrochloride (279 g, 1.48 mol) was suspended in DMSO (2.70 L) and treated with triethylamine (223 ml, 1.60 mol). The mixture was stirred at 25 °C for 30 min and treated with EDC-HC1 (354 g, 1.85 mol) and HOBT hydrate (283 g, 1.85 mol). The reaction mixture was stirred at rt for 16 h. After addition of triethylamine (292 ml, 2.09 mol), the mixture was cooled to 15 °C, diluted with water (10.1 L) maintaining the temperature below 30 °C, and stirred at 19-25 °C for 4 h. The resulting precipitate was filtered, washed twice with water (2.70 L), and dried under vacuum to give a crude product (695 g, wt-wt analysis = 78%).

For the further purification of the product, recrystallization was conducted. A crude product (20.00 g, 34.92 mmol) was suspended in a mixture of ethanol (190 ml) and water (10.00 ml) and heated to 75°C until a clear solution was obtained. The solution was allowed to cool to rt overnight. The precipitate was filtered, washed twice with a mixture of ethanol (30.0 ml) and water (30.0 ml), and dried under vacuum at 35 °C to give the title compound as an off white solid (14.0 g, 70% recovery from the crude and 90% yield based on wt-wt assay).

4-((3′-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[l,l’-biphenyl]-4-yl)methyl)morpholin- 4-ium bromide (Polymorph A): A crude N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)am

biphenyl]-3-carboxamide (595 g, 464 g based on wt-wt assay, 810.3 mmol) was suspended in ethanol (3.33 L). After heating to 70 °C, the mixture was treated with 48% aqueous HBr (97 ml, 850.8 mmol) and stirred at 70 °C for 30 min. The resulting orange-red solution was treated with ethyl acetate (3.33 L) maintaining the temperature above 60 °C. The mixture was slowly cooled to rt over 18 h. The mixture was cooled to 0 °C over 1 h and stirred at that temperature for 5.5 h. The resulting precipitate was filtered, washed twice with ethyl acetate (1.39 L), and dried under vacuum to give the title compound as an off white solid (515 g, 97% yield).

Recrystallization of Polymorph A: 4-((3′-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[l,l’-biphenyl]-4- yl)methyl)morpholin-4-ium bromide (0.50 g, 0.77 mmol; 95.6% pure by HPLC) was suspended in ethanol (3.0 mL) and heated to 80 °C until a clear solution was obtained. To the solution was added MTBE (5.0 mL) slowly. The resulting solution was allowed to cool to 18-22 °C over 3 h and stirred at 18-22 °C for 15 h. The precipitate was filtered, washed twice with MTBE (2 mL) and dried under vacuum to give 0.45 g of the title compound (89% recovery, 96.6% pure by HPLC).

Compound I is protonated at the nitrogen of the morpholino substituent, providing a monohydrobromide of Compound I having the following structure:

This particular monohydrobromide can be referred to as “4-((3′-(((4,6-dimethyl-2-oxo- l,2-dihydropyridin-3-yl)methyl)carbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′- methyl-[l, -biphenyl]-4-yl)methyl)morpholin-4-ium bromide.” Figure 11 depicts the X-ray crystal structure of this particular salt form.

…………………………………………………………..

see

WO-2015057859

Eisai Research Institute; Epizyme Inc

Novel crystalline polymorphic form C of tazemetostat, useful for treating an EZH2-mediated cancer, including non-Hodgkin’s lymphoma and breast cancer.

…………………

PAPER

RSC Advances (2015), 5(33), 25967-25978

http://pubs.rsc.org/en/content/articlelanding/2015/ra/c5ra02365c#!divAbstract

DOI: 10.1039/C5RA02365C

The histone lysine methyltransferase EZH2 has been implicated as a key component in cancer aggressiveness, metastasis and poor prognosis. This study discovered a new class of hexahydroisoquinolin derivatives as EZH2 inhibitors. A structure–activity relationship study showed that the steric hindrance was important to the activity for EZH2. A preliminary optimization study led to the discovery of several potent compounds with low nanomolar to sub-nanomolar potency for EZH2. Biological evaluation indicated that SKLB1049 was a highly potent with improved solubility compared to EPZ6438, SAM-competitive, and cell-active EZH2 inhibitor that decreased global H3K27me3 in SU-DHL-6 and Pfeiffer lymphoma cells in a concentration- and time-dependent manner. Further study indicated that SKLB1049 caused cell arrest in G₀/G₁ phase. These compounds would be useful as chemical tools to further explore the biology of EZH2 and provided us with a start point to develop new EZH2 inhibitors.

1: Knutson SK, Warholic NM, Johnston LD, Klaus CR, Wigle TJ, Iwanowicz D, Littlefield BA, Porter-Scott M, Smith JJ, Moyer MP, Copeland RA, Pollock RM, Kuntz KW, Raimondi A, Keilhack H. Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas. PLoS One. 2014 Dec 10;9(12):e111840. doi: 10.1371/journal.pone.0111840. eCollection 2014. PubMed PMID: 25493630; PubMed  Central PMCID: PMC4262195.

2: Knutson SK, Kawano S, Minoshima Y, Warholic NM, Huang KC, Xiao Y, Kadowaki T,  Uesugi M, Kuznetsov G, Kumar N, Wigle TJ, Klaus CR, Allain CJ, Raimondi A, Waters NJ, Smith JJ, Porter-Scott M, Chesworth R, Moyer MP, Copeland RA, Richon VM, Uenaka T, Pollock RM, Kuntz KW, Yokoi A, Keilhack H. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther. 2014 Apr;13(4):842-54. doi: 10.1158/1535-7163.MCT-13-0773. Epub 2014 Feb 21. PubMed PMID: 24563539

3. Inhibitors of human histone methyltransferase EZH2, and methods of use thereof for treating cancer. By Kuntz, Kevin W.; Knutson, Sarah K.; Wigle, Timothy James Nelson . From U.S. Pat. Appl. Publ. (2013), US 20130040906 A1 20130214.

4. Aryl-or heteroaryl-substituted benzamide compounds as anticancer agents and their preparation By Kuntz, Kevin Wayne; Chesworth, Richard; Duncan, Kenneth William; Keilhack, Heike; Warholic, Natalie; Klaus, Christine; Zheng, Wanjun; Seki, Masashi; Shirotori, Syuji; Kawano, Satoshi From PCT Int. Appl. (2012), WO 2012142504 A1 20121018.

5: Knutson SK, Warholic NM, Wigle TJ, Klaus CR, Allain CJ, Raimondi A, Porter Scott M, Chesworth R, Moyer MP, Copeland RA, Richon VM, Pollock RM, Kuntz KW, Keilhack H. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7922-7. doi: 10.1073/pnas.1303800110. Epub 2013 Apr 25. PubMed PMID: 23620515; PubMed Central PMCID: PMC3651445.

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Jason Rhodes (left) has been appointed to president of Epizyme Inc.,

100 Technology Square

AzilsartanMedoxomil Potassium

(5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2- ethoxy- 1 – { [2′-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4yl]methyl} – 1 H- benzimidazole-7-carboxylate monopotassium salt

NMR  http://file.selleckchem.com/downloads/nmr/S305702-Azilsartan-Medoxomil-NMR-Selleck.pdf

AzilsartanMedoxomil Potassium is chemically named as (5-Methyl-2-oxo-1, 3-dioxol-4yl) methyl 2-ethoxy-1-{[2- (5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) biphenyl-4-yl]methyl}- 1H-benzimidazole-7-carboxylatemonopotassium salt. Azilsartanmedoxomil is the prodrug of 2-ethoxy-1-([2′-(5-oxo4,5 – dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4- yl]methyl) 1H-benimidazole-7-carboxylic acid.It is a white crystalline powder insoluble in water, slightly soluble in solvents such as acetone, and acetonitrile, freely soluble in methanol, dimethylsulfoxide, and dimethylformamide, soluble in solvents such as acetic acid, and very slightly soluble in solvents tetrahydrofuran and 1-octanol.

The US Food and Drug Administration (FDA) has approved Edarbi tablet (AzilsartanMedoxomil Potassium) on February 25, 2011, to treat hypertension in adults. It is available in 80mg and 40 mg dosages, with the recommended dosage set at 80mg once in a day [1].

Angiotensin II hormone plays a vital role in activation of renin-angiotensinaldosterone systems well as in regulation of blood pressure, fluid-electrolyte balance, and also in pathophysiology of hypertension. Activation of type 1 angiotensin receptor which is a member of G protein coupled receptor efficiently controls the numerous effects of AII which are vasoconstriction, secretion of aldosterone and vasopressin and cellular proliferation. So blocking of AII receptor will also block receptor-1, and it will lead to termination of the whole course of action mentioned above;

so all blocker will be helpful in the management of cardiovascular and renal diseases as therapeutic agent.The active moiety of AMP is revealed by hydrolysis of the medoxomil ester and it converts into azilsartan which is an active angiotensin II receptor blocker and more effective in lowering blood pressure within 24 hours as compared to valsartan and olmesartan[2-5].There are several methods that are reported for preparation of azilsartan [6-15].

The presence of related substances in an active pharmaceutical ingredient (API) can have a significant impact on the quality and safety of the drug products. Therefore, it is necessary to study the impurity (related substance) profile of the API to be used in the manufacturing of the drug product. International Conference on Harmonization (ICH)guidelines recommends identifying and characterizing all related substancesthat are present at level less than 0.10% [16].

AZILSARTAN

1H NMR

13 C NMR

AZILSARTAN MEDOXIMIL

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[4] D. Sica, W.B. White, M.A. Weber, G.L. Bakris, A. Perez,C. Cao,A. Handley, S. Kupfer, J. Clin. Hypertens. 2011, 13, 467.

[5] H. Rakugi, K. Enya, K. Sugiura, Y. Ikeda, Hypertens. Res.2012, 35, 552.

[6] Y. Kohara, E. Imamiya, K. Kubo, T. Wada, Y. Inada, T. Naka, Bioorg. Med. Chem. Lett.1995, 5, 1903.

[7] T. Naka,Y. Inada, U.S. Patent 5583141 (1996) [8] T. Naka, Y. Inada, Eur Pat. Appl. EP 0520423, (1992)

[9] Y. Kohara, K. Kubo,E. Imamiya, T. Wada, Y. Inada, T. Naka, J. Med. Chem.1996, 39, 5228.

[10] T. Kuroita, H. Sakamoto,M.Ojima, U.S. Pat. Appl. 0187269 (2005) [11] T. Kuroita, H. Sakamoto, M. Ojima, U.S. Pat. Appl. 7157584 (2007) [12] S. Radl, J. Cerny,J. Stach, Z. Gablíkova, Org. Process Res. Dev.2013, 17, 77

[13] A. Agarwal, D. Bansal, A.S. Choudhary, S.K. Dubey, H. Mishra, D. Vir, WO 2012107814 A8 (2012)

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