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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Vismodegib


Vismodegib3Dan.gif

Vismodegib2DACS.svg

 

 

Vismodegib

2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide

Vismodegib; 879085-55-9; GDC-0449; 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide; Erivedge; HhAntag691; CUR-691
GDC-449
Hh-Antag691
HhAntag
R-3616
RG-3616

421.29706 g/mol

C19H14Cl2N2O3S

LAUNCHED 2012

Vismodegib is a Hedgehog Pathway Inhibitor. The mechanism of action of vismodegib is as a Smoothened Receptor Antagonist.

Hedgehog Antagonist GDC-0449 is an orally bioavailable small molecule with potential antineoplastic activity. Hedgehog antagonist GDC-0449 targets the Hedgehog signaling pathway, blocking the activities of the Hedgehog-ligand cell surface receptors PTCH and/or SMO and suppressing Hedgehog signaling. The Hedgehog signaling pathway plays an important role in tissue growth and repair; aberrant constitutive activation of Hedgehog pathway signaling and uncontrolled cellular proliferation may be associated with mutations in the Hedgehog-ligand cell surface receptors PTCH and SMO.

NMR from net

 

 

Vismodegib.png

Vismodegib is an active pharmaceutical ingredient produced by Genentech (Roche) and sold under the trade name Erivedge® (which contains crystalline Vismodegib as the active ingre-dient). Erivedge® is an oral Hedgehog signaling pathway inhibitor approved for the treatment of basal-cell carcinoma (BCC).

Developed and launched by Roche and its subsidiary Genentech, under license from Curis. Family members of the product Patent of vismodegib (WO2006028958),

Vismodegib was first disclosed in WO Patent Publication No. 06/028959. Vismodegib, chem-ically 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide, is represented by the following structure:

Vismodegib (trade name Erivedge) is a drug for the treatment of basal-cell carcinoma (BCC). The approval of vismodegib on January 30, 2012, represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administration (FDA) approval.[1] The drug is also undergoing clinical trials for metastatic colorectal cancer, small-cell lung cancer, advanced stomach cancer, pancreatic cancer, medulloblastoma and chondrosarcoma as of June 2011.[2] The drug was developed by thebiotechnology/pharmaceutical company Genentech, which is headquartered at South San Francisco, California, USA.

Indication

Vismodegib is indicated for patients with basal cell carcinoma (BCC) which has metastasized to other parts of the body, relapsed after surgery, or cannot be treated with surgery or radiation.[3] [4]

Mechanism of action

The substance acts as a cyclopamine-competitive antagonist of the smoothened receptor (SMO) which is part of the hedgehog signaling pathway.[2] SMO inhibition causes the transcription factors GLI1 and GLI2 to remain inactive, which prevents the expression of tumor mediating genes within the hedgehog pathway.[5] This pathway is pathogenetically relevant in more than 90% of basal-cell carcinomas.[6]

 

PAPER

Bioorg Med Chem Lett 2009, 19(19): 5576

http://www.sciencedirect.com/science/article/pii/S0960894X10012709

Schematic for the discovery of 2 (GDC-0449) from 1, and the inspiration for ...

Figure 1.

Schematic for the discovery of 2 (GDC-0449) from 1, and the inspiration for further analogs 3 and 4

 

CN 103910671

http://www.google.com/patents/CN103910671A?cl=en

In embryonic development, Hedgehog signaling in cell differentiation, tissue development and organogenesis play an important role. In the adult body, Hedgehog signaling pathway is mainly in slumber, but when abnormal tissue growth and self-healing, Hedgehog pathway may be activated. With the in-depth study of the tumor, the presence of numerous evidence of abnormal tumor occurrence and the close relationship between Hedgehog signaling pathway, such as sporadic basal cell carcinoma, medulloblastoma, small cell lung cancer and gastrointestinal cancer and other diseases, therefore Hedgehog signaling pathway targeted anti-cancer therapy inhibitors become hot.

 Vismodegib chemical name 2_ chlorine -N_ (4_ chlorine _3_ (_2_ pyridyl) phenyl) _4_ (methylsulfonyl) benzamide, is by Roche’s Genentech (Genentech) Hedgehog pathway inhibitors developed, and can be inhibited by binding seven transmembrane protein Smoothened (Smo), thereby preventing signal transduction. Vismodegib capsule in January 2012 I was approved and listed by the US Food and Drug Administration, under the trade name Erivedge, for the treatment of adults with the most common type of skin cancer – basal cell carcinoma. This medicine is not intended for surgery or radiotherapy of cancer and basal cell skin cancer locally advanced patients have been transferred. This was the first drug approved for the treatment of basal cell carcinoma.

 

Figure CN103910671AD00051

W02006028958 Vismodegib disclose the following synthesis route:

 Route One Negishi coupling reactions

 

Figure CN103910671AD00052

wherein, X1 is chloro, bromo or iodo; X2 is bromo, iodo or tosylate. The route to the 2-halo-pyridine as starting material an organic zinc compound, and then prepared by Negishi coupling reaction to give 2- (2-chloro-5-nitrophenyl) pyridine. 2- (2-chloro-5-nitrophenyl) pyridine in turn through a reduction reaction with acylation reaction, to give the final product Vismodegib. The key coupling step of the route using an organic zinc reagent required to react under strict anhydrous, anaerobic conditions.

 The second route Suzuki coupling reaction [0010]

Figure CN103910671AD00061

 wherein, X2 is bromo, iodo or tosylate. The route from 3-halo-4-chloro-nitrobenzene as raw material, and 2-chloro-5-nitrophenyl boronic acid pinacol ester, and then reacted with a 2-halo-pyridine was prepared to give 2- (2-chloro 5-nitrophenyl) pyridine. 2- (2-chloro-5-nitrophenyl) pyridine then after reduction and acylation reaction, to give the final product Vismodegib. The key coupling step of the route using the Suzuki coupling reaction, organic boron reagent price to use expensive, high production costs.

 The route three Suzuki coupling reaction

 

Figure CN103910671AD00062

wherein, X2 is bromo, iodo or tosylate. Similar to the second route, the route is still critical coupling step using a Suzuki coupling reaction, the same need to use expensive organic boron reagents, higher production costs.

 route four Stille coupling reaction

 

Figure CN103910671AD00063

 The route to 2-p-toluenesulfonyl pyridine as starting material, is reacted with an organotin reagent, prepared to give pyridin-2-yl trimethyltin, then by Stille coupling reaction, was prepared to give 2- (2-chloro – 5- nitrophenyl) pyridine, followed by reduction reaction, acylation prepared to give Vismodegib. The key step of the route using the Stille coupling reaction, this step need to use expensive and toxic organotin reagents, and the need to carry out the reaction under strict anhydrous, anaerobic conditions.

A process for preparing 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide, comprising: a compound of formula III was prepared as a compound of Formula II;

Figure CN103910671AC00021

Then, the compound of formula II with a compound of formula I, to give 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide;

Figure CN103910671AC00022

Wherein, R1 is halogen or hydroxy, preferably chlorine, or a hydroxyl group.

2. A process for preparing 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide, comprising:

Figure CN103910671AC00023

Wherein, X is halogen, preferably bromo or iodo condition is halo or hydroxy, preferably chlorine, or a hydroxyl group.

3. A process for preparing 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide, comprising:

Figure CN103910671AC00031

Wherein, X is halogen, preferably bromo or iodo condition is halo or hydroxy, preferably chlorine, or a hydroxyl group.

Method 2 or claim 3,

Example 1: N–oxo-2- (2-chloro-5-nitrophenyl) pyridine

 

Figure CN103910671AD00121

[0108] To a 100mL three-necked flask were added 30mmoll- oxopyrido, 10mmol2- bromo-1-chloro-4-nitrobenzene, 12mmol potassium carbonate, 0.05mmol tri-butyl acetate button and 0.15mmol phosphorus tetrafluoroborate salt, 40ml of toluene, IS gas exchange three times, under argon at reflux for 2 days, then the reaction mixture was poured into 100mL of ethyl acetate, filtered, and the filtrate was washed with saturated brine, dried and the solvent was distilled off under reduced pressure, column chromatography (mobile phase V / V: methanol / dichloromethane = 1/50), fractions were collected and the solvent was distilled off under reduced pressure to give a pale yellow solid, yield 60%.

 1HMffi (500Hz, DMS0_d6): 8.35 (m, 3H), 7.90 (d, 1Η), 7.62 (q, 1Η), 7.55 (m, 1Η), 7.48 (m, 1Η);

 MS: 251.1,253.1 ([Μ + Η] +).

2  Example: Ν–oxo-2- (2-chloro-5-nitrophenyl) pyridine

 

Figure CN103910671AD00131

 To a 100mL three-necked flask 30mmoll- oxopyrido, 10mmol2- bromo-1-chloro-4-nitrobenzene, 12mmol of potassium carbonate, 0.05mmol iodide and 0.1Ommoll, 10- Fei Luo Jie morpholine, 40ml of xylene, an argon gas exchange three times, under argon at reflux for 2 days, cooled to room temperature and then the reaction system was poured into 100mL methylene chloride, filtered and the filtrate washed with saturated brine, dried, filtered, The filtrate solvent was distilled off under reduced pressure, column chromatography (mobile phase V / V: methanol / dichloromethane = 1/50) to give a pale yellow solid, yield 42%. .

3  Example: 2- (2-chloro-5-nitrophenyl) pyridine

 

Figure CN103910671AD00132

After 3.0mmol N- oxo added to 100mL of Lord vial _2_ (2_ chloro _5_ nitrophenyl) pyrazole 唳, 15mmol phosphorus trichloride and 30ml of chloroform was heated at reflux for 12h, the reaction It was poured into 100mL of water and extracted with ethyl acetate (50ml X 2), and the combined organic phase was dried and the solvent was distilled off under reduced pressure, column chromatography (mobile phase V / V: petroleum ether / ethyl acetate = 20/1) , fractions were collected, the solvent was distilled off under reduced pressure to give a white solid, yield 95%.

 1Hnmr (SooHzJDCI3): 8.78 (d, 1H), 8.51 (d, 1H), 8.20 (m, 1H), 7.85 (m, 1H), 7.72 (d, 1H), 7.65 (d, 1H), 7.40 (m, 1H);

MS: 235.1,237.1 ([M + H] +).

4 Example 2: Preparation 4_ chlorine _3_ (topiramate 唳 _2_ yl) aniline

 

Figure CN103910671AD00133

 To a vial was added 100mL of Lord 20mmol2- (2- chloro-5-nitrophenyl) pyridine 唳, 50ml of acetic acid, heated to 80 ° C and stirred, and then slowly added IOOmmol iron, reaction 0.5h The reaction solution was poured into 200ml water and extracted with dichloromethane (150ml X 3), the combined organic phases, the organic phase was washed with saturated sodium carbonate solution (50ml X 3), the organic phase was dried, evaporated under reduced pressure to give the crude product, n-propyl alcohol weight crystallized to give a pale yellow solid, yield 75%.

1HMflUSOOHz, DMS0_d6): 8.63 (m, 1H), 7.84 (m, 1H), 7.56 (d, 1H), 7.37 (m, 1H),

7.13 (d, 1H), 6.76 (d, 1H), 6.61 (q, 1H), 5.32 (s, 2H);

 MS: 205.1,207.1 ([M + H] +).

5 Example: 4-chloro-3- (pyridin 唳-2-yl) aniline

 

Figure CN103910671AD00141

to 100mL of God-shaped flask 20mmol2_ (2_ chlorine _5_ nitrophenyl) pyridine Jie set, 50ml of methanol, Ig activated carbon, 2mmol FeOOH and 60mmol85% of hydrazine hydrate, heated to reflux and stirred for 6 ~ 8h, after the completion of the reaction, was filtered, spin-dry the solvent, dissolved in 150ml of dichloromethane, the organic phase was washed with saturated sodium bicarbonate solution (20ml X3), the organic phase was dried, evaporated under reduced pressure to give the crude product was recrystallized from n-propanol to give a pale yellow solid, yield 96%.

6 Example 2: Preparation 4_-chloro-3- (2-yl) aniline

 

Figure CN103910671AD00142

 20mmol N- oxo added to 100mL eggplant-shaped flask _2_ (2_ chloro _5_ nitrophenyl) pyridine, 50ml of acetic acid, heated to 80 ° C and stirred, and then iron powder was slowly added IOOmmol After 0.5h the reaction the reaction solution was poured into 200ml water and extracted with dichloromethane (150ml X3), the combined organic phases were washed with saturated sodium carbonate solution (50ml X3), the organic phase was dried, evaporated under reduced pressure to give the crude product, n-propanol recrystallized to give a white solid, yield 70%.

Preparation 7.Α ~ chlorine -3_ (topiramate 唳 2-yl) aniline [0130] Example

 

Figure CN103910671AD00143

 20mmol N- oxo added to 100mL eggplant type flask _2_ (2_ chloro _5_ nitrophenyl) pyridine, 50ml of methanol, Ig active carbon, 2mmol FeOOH 60mmol85% hydrazine hydrate and heated to reflux and stirred for 6 ~ 8h, after the completion of the reaction, was filtered, spin-dry the solvent, dissolved in 150ml of dichloromethane, washed with saturated aqueous sodium bicarbonate solution, the organic phase (20mlX3), the organic phase was dried, evaporated under reduced pressure to give the crude product, n-propyl alcohol weight crystallized to give a white solid, yield 82%.

Vismodegib Preparation: 8 Example

 

Figure CN103910671AD00144

In the Lord 50ml vial, the 1.50mmol2- chloro-4-methanesulfonyl-chloride in 15ml of dry tetrahydrofuran, cooled to ice bath O ~ 10 ° C, a solution of 4-chloro-3 – (pyridin-2-yl) aniline in anhydrous tetrahydrofuran (1.47mmol / 10ml), triethylamine was added dropwise and then finished 2.5mmol of dropwise addition, the reaction at room temperature 4h, the reaction was completed, the reaction system was poured into 50ml water and stirred, precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 88%.

1HNMR (500Hz, DMS0_d6): 10.90 (s, 1H), 8.70 (d, 1H), 8.12 (d, 1H), 8.01 (t, 2H), 7.92 (m, 2H), 7.74 (q, 1H ), 7.69 (d, 1H), 7.58 (d, 1H), 7.44 (m, 1H), 3.34 (s, 3H).

 MS: 421.1,423.1 ([M + H] +).

Vismodegib Preparation: 9  Example

 

Figure CN103910671AD00151

 In 50ml vial of God, will 1.50mmol2_ chlorine _4_ methylsulfonyl benzoic acid, 1.47mmol4_ chlorine _3_ (batch 唳 2-yl) aniline and triethylamine were dissolved in 25ml 2.5mmol anhydrous tetrahydrofuran in an ice bath to cool to O ~ 10 ° C, was added in portions N, N ‘- dicyclohexyl carbodiimide (DCC) 1.50mmol, After the addition, the reaction at room temperature 6h, after the reaction, white solid was removed by filtration, the filtrate was poured into 50ml water and stirred, precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 84%.

Vismodegib Preparation: 10 [0141] Example

 

Figure CN103910671AD00152

 In 50ml eggplant-shaped flask, 1.50mmol2- chloro-4-methanesulfonyl-benzoic acid was dissolved in 15ml of dichloromethane, cooled to ice bath O ~ 5 ° C, thionyl chloride was added dropwise 3.0mmol After stirring at room temperature 30min, removed by rotary evaporation dichloromethane and excess thionyl chloride, 15ml of anhydrous tetrahydrofuran was added, the ice bath was cooled to O ~ 10 ° C, solution of 4-chloro-3- (pyridin-2- yl) aniline in anhydrous THF (1.47mmol / 10ml), triethylamine was added dropwise and then finished 2.5mmol of dropwise addition, the reaction at room temperature 4h, the reaction was completed, the reaction was poured into 50ml water system and stirring, the precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 88%.

 

PATENT

CN 103910672

http://www.google.com/patents/CN103910672A?cl=en

Vismodegib PreparatioN

Figure CN103910672AD00192

 In 50ml eggplant-shaped flask, 1.50mmol2- chloro-4-methanesulfonyl-benzoic acid was dissolved in 15ml of dichloromethane, cooled to ice bath O ~ 5 ° C, thionyl chloride was added dropwise 3.0mmol After stirring at room temperature 30min, removed by rotary evaporation dichloromethane and excess thionyl chloride, 15ml of anhydrous tetrahydrofuran was added, the ice bath was cooled to O ~ 10 ° C, solution of 4-chloro-3- (pyridin-2- yl) aniline in anhydrous THF (1.47mmol / 10ml), triethylamine was added dropwise and then finished 2.5mmol of dropwise addition, the reaction at room temperature 4h, the reaction was completed, the reaction was poured into 50ml water system and stirring, the precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 88%.

PATENT

WO2006028958

https://www.google.co.in/patents/WO2006028958A2?cl=en

Example 1 General Procedure

Compounds of examples 2-51 were prepared according to the following general procedures.

A: Suzuki Coupling Procedure

Figure imgf000069_0001

2 M aq. Potassium carbonate (5.0 eq) and 4:1 toluene :ethanol mixture (2.5 mL) were added to a microwave vial charged with the appropriate boronate ester (2.6 eq), aryl halide (0.35 mmol, 1.0 eq), and Pd(PPh3)4 (0.04 eq). The vial was sealed and heated with stirring in the microwave to 160 0C for ten minutes. The solution was poured onto 2 M aq. Sodium hydroxide (20 mL), extracted with ethyl acetate (2 x 20 mL), dried (MgSO4), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product.

B: Negishi Coupling Procedure

Figure imgf000070_0001

X = I or Br R = H, 3-Me, 4-Me5 5-Me, 6-Me

Aryl zinc bromide (0.5 M in THF, 2.5 eq) was added to an oven-dried microwave vial charged with the appropriate aryl halide (1.0 eq) and Pd(PPh3)4 (0.04 eq). The vial was sealed and heated with stirring in the microwave to 140 0C for 10 minutes. The crude reaction mixture was concentrated and purified by chromatography on silica gel (conditions given below) to afford the desired product.

C: Iron Reduction of Aryl Nitro Group

Figure imgf000070_0002

R = I or pyridin-2-yl

The appropriate nitro aryl (1 mmol, 1 eq) in AcOH/EtOH (1:1, 0.42 M) was added slowly to a solution of Iron powder (6.0 eq) in AcOH/EtOH (1:2, 2 M) at 60 °C. The solution was stirred at 70 0C for 30-60 minutes. The reaction mixture was cooled to 23 0C, filtered through celite, washed with ethyl acetate, and concentrated. The oily residue was dissolved in ethyl acetate (30 mL), washed with saturated aq. NaHCO3 (2 x 15 rnL) and water (2 x 10 niL), dried (MgSO4), and concentrated. The oily residue was used with out further purification.

D: Amide Bond Formation

Figure imgf000071_0001

R = I or pyridin-2-yI

Acid chloride (1.05-1.1 eq) was added to a solution of aniline (1.0 eq) and TEA (1.1-1.5 eq) in methylene chloride at the indicated temperature. The solution was stirred for 0.5-3 hours, poured onto saturated aq. NaHCO3, extracted twice with methylene chloride, dried (MgSO4), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product.

E: EDC Amide Bond Formation

Figure imgf000071_0002

R = I or pyridin-2-yl

Carboxylic acid (1.1 eq) was added to a solution of aniline (1.0 eq) and EDC (1.4 eq) in methylene chloride (0.7 M in aniline). The solution was stirred at 23 0C for 2 hours, poured onto a 1 :1 mixture of saturated aq. NH4Cl and water, extracted twice with methylene chloride, dried (MgSO4), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product. F: addition of amines to 2-chloropyridine

Figure imgf000072_0001

NHRR’ = ethanolamine, analine, benzylamine, 2-methylpropylamine, N-methylpiperazine, morpholine, 2-morpholinoethylamine

Primary or secondary amine (5 eq) in either BuOH or a mixture of BuOH/ethylene gylcol was heated to 170 to 220 0C for 20 min in a sealed tube. The BuOH was removed under reduced pressure. In cases where ethylene glycol was used, the reaction was diluted with water, and the product was extracted into ethyl acetate, dried (MgSO^, and concentrated. The crude residue was purified by reverse phase HPLC to afford the desired product.

G: Amide bond coupling with HATU

HATU, DIPEA, DMF NaOH or NaHCO3

Figure imgf000072_0002

ethyl acetate extraction

Figure imgf000072_0003

Aniline (1.0 eq) was added to a mixture of carboxylic acid (1.1 eq), HATU (1.1 eq) and DIPEA (2 eq) in DMF (0.1 – 0.2 M). After stirring overnight, the reaction mixture was diluted with 0.1 N sodium hydroxide or saturated NaHCθ3, extracted into ethyl acetate and the combined organic layers were washed with brine. The organic layer was dried (MgSO4), concentrated and the crude mixture was purified by reverse phase HPLC. H: Preparation of sulfonamide benzoic acids

Figure imgf000073_0001

Chlororsulfonylbenzoic acid (1.0 eq) was added to a solution of amine (1.1 eq) in 10-20% DEPEA/methanol (1 M) at 4 0C. After 1 h, the reaction mixture was concentrated, and the crude residue was purified by reverse phase HPLC.

I : Stannylation of 2-pyridyl triflates

Figure imgf000073_0002

A solution of tetrakis-triphenylphosphinepalladium (0.04 eq.) in toluene (1 mL) was added to degassed solution of aryltriflate (1 eq), bis-trialkyltin (1.05 eq), and lithium chloride (3 eq) in dioxane. Heated to reflux for 2 hours, cooled to 23 0C, diluted with ethyl acetate, washed with 10% NH4θH(aq) and brine, dried (MgSO4) and concentrated. The crude material was used without further purification.

J: Stannylation of substituted pyridines

Figure imgf000073_0003

ιMmβco3 n-Butyl lithium (6 eq, 2.5 M in hexanes) was added dropwise to a solution of dimethylaminoethanol (3 eq) in hexane at 0 0C. The solution was stirred at 0 0C for thirty minutes before dropwise addition of the substituted pyridine (1 eq). The solution was stirred at 0 0C for an additional hour, then cooled to -78 0C. A solution of trialkyltin in hexane was added dropwise. The solution was stirred at -78 0C for thirty minutes, warmed to 0 0C, quenched with water, extracted twice with ether, dried (MgSO4), and concentrated. K: Stille Coupling

Figure imgf000074_0001

Palladium catalyst (0.02 eq) was added to a degassed solution of aryliodide (1 eq), arylstannane (2 eq), and triphenylphosphine (0.16 eq) in NMP. Heated in the microwave to 130 0C for 15 minutes. The reaction mixture was diluted with ethylacetate, washed with 10% NH4θH(aq) and brine, dried (MgSC>4), concentrated and purified by silica gel chromatography.

L: Synthesis of alky lethers

Figure imgf000074_0002

A solution of hydroxypyridine (1 eq), alkyliodide (excess), and cesium carbonate in NMP was heated in the microwave to 1000C for ten minutes. The reaction mixture was diluted with ethylacetate, washed with 10% NH4θH(aq) and brine, dried (MgSC^), concentrated and purified by silica gel chromatography.

M: Methyl Ester Saponification

Figure imgf000074_0003

The methyl ester (leq) was hydrolyzed with LiOH (2eq) in 50/50 THF/water mix. Upon completion of the reaction the THF was evaporated under reduced pressure and the solution is acidified with HCl to pH 2. The resultant solid was filtered and dried to give the pure acid.

N: Bromination in the presence of a free acid functionality

Figure imgf000075_0001

The paramethylbenzoic acid (leq) was combined with Benzoyl Peroxide (O.leq) and N- Bromosuccinimde (0.9eq) in a solution of 5%AcOH in Benzene and heated in the microwave at 120°C for 5-15minutes. The product was separated from the starting material and di-bromo product via ISCO flash chromatography with an ethyl acetate (with 1% AcOH) and hexanes solvent system.

O: Sodium Methanesulfinate displacement of Bromine

Figure imgf000075_0002

To the bromine starting material (leq) was added sodium methanesulfinate (2eq) in DMF and heated to 120°C in the microwave for 5 minutes. Alternatively, the reaction was heated to 60°C in an oil bath for several hours until completed. Reaction mixture was concentrated under reduced pressure and extracted in ethyl acetate and water. The organic layer was dried over Magnesium Sulfate, filtered and concentrated in vacuo to yield generic methylsulfone.

P: Amine displacement of Bromine

Figure imgf000076_0001

To the bromo starting material (leq) was added appropriate amine (3eq) in either DMSO or BuOH and stirred at room temperature until complete. For less nucleophilic amines or anilines, the reactions were forced to completion using microwave conditions ranging from 150°-170°C for 15 minutes. Crude reactions were concentrated to dryness and either extracted with ethyl acetate and saturated bicarbonate if the reaction resulted in an intermediate or purified via HPLC if the reaction resulted in a final product.

Q: Thiol displacement of halogen

Figure imgf000076_0002

The paramethylbromo benzoate (leq) was treated with Potassium (or Cesium) Carbonate (1.5eq) and appropriate thiol derivative (l,leq) in DMF (or CH3CN) and stirred overnight at room temperature. The DMF was evaporated in vacuo and the reaction was extracted with ethyl acetate and water. The organic layer was dried over Magnesium Sulfate , filtered and concentrated to yield the thiol or derivatized thiol compound.

R: Oxone Oxidation

oxone 2:1 MeOHTH2O

Figure imgf000076_0004
Figure imgf000076_0003

Derivatized thiol (leq) was dissolved in MeOH while Oxone (2eq) was seperately dissolved in half the amount of water. Once all the oxone was dissolved, the solution was added to the thiol in MeOH solution at once and stirred until complete. The MeOH was evaporated in vacuo and the remaining water was extracted twice with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate and concentrated to yield the sulfone.

S: Thio lysis of epoxides at alumina surfaces

Figure imgf000077_0001

A mixture of epoxides (1.0 eq), thiophenol (1.5 eq) and neutral aluminum oxide (~70 eq) in diethyl ether was stirred for 3 h at room temperature while being monitored by TLC. The reaction mixture was filtered through Celite, washed with ethyl acetate and concentrated. Purified by silica gel chromatography (0-40% ethyl acetate/hexane) to yield β -hydroxysulfide product.

T: Conversion of nitrile group to carboxylic acid

Figure imgf000077_0002

R

A solution of benzonitrile (1.0 eq) and sodium hydroxide (2.0 eq) in H2O was heated to 120 ° C for 2h. The reaction mixture was cooled to room temperature and acidified with HCl to pH 2. The resulting solid was filtered to afford the pure acid product.

U. Alkylation of phenols

Figure imgf000078_0001

The phenol was dissolved in DMF (1.0 ml). Cesium carbonate (1.0 eq.) and an alkyl bromide or alkyl iodide (1.0 to 2.0 eq.) were added, and the reaction was stirred at room temperature for 18 hrs or 5O0C for 1 to 24 hours. The reaction was quenched in water, and extracted with ethyl acetate twice. The organic extracts were washed with water once, brine once, dried with MgSC>4, and evaporated to a crude oil which was purified on reverse phase HPLC.

V. Amide bond formation with an acid chloride and an aniline

Figure imgf000078_0002

The aniline was dissolved in THF (1.5 ml) and dichloromethane (1.5 ml). MP-Carbonate (1.5 eq.) and an acid chloride (1.1 eq.) were added, and the solution was stirred at room temperature for 18 hours. The reaction was diluted with methanol and dichloromethane, and filtered to remove the MP-Carbonate. The mother liquors were evaporated to a solid and purified by reverse phase HPLC.

W. Amidine formation from an imidate

Figure imgf000078_0003

A solution of freshly formed imidate in methanol was treated with a primary or secondary amine (1.5 eq.) at room temperature for 18 hours. The methanol was removed on a rotary evaporator and the residue purified by reverse phase HPLC.

 

Example 37 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide

Figure imgf000097_0002

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 2-chloro-4- methylsulfonylbenzoic acid to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide. MS (Ql) 421.0 (M)+. The product was then dissolved in 1 Ν HCI solution followed by freebasing with 0.5 Ν NaOH solution (pH to 11). The resulting precipitate was filtered and vacuum-dry.

Procedure D may also be used to couple 4-chloro-3-(pyridin-2-yl)aniline and 2-chloro-4- (methylsulfonyl)benzoyl chloride to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-

(methylsulfonyl)benzamide which is collected by suction filtration and the HCl salt is washed with

Et2O (or alternatively with MTBE). This material is freebased using EtOAc/aq NaHCO3 and the organics are dried and concentrated to the solid freebase. This material is then crystallized from acetone :EtOAc (80:20, approx lOmL/g) which is then finally recrystallized from hot slurry of iPrOAc. 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide HCl salt may also be dissolved in distilled water followed by freebasing with 0.5 N NaOH solution (pH to 11) and filtering and vacuum drying the precipitate.

Patent

 

 

 

WO 2016020324, BASF AG, vismodegib , new patent

WO2016020324,  MULTI-COMPONENT CRYSTALS OF VISMODEGIB AND SELECTED CO-CRYSTAL FORMERS OR SOLVENTS

BASF SE [DE/DE]; 67056 Ludwigshafen (DE)

VIERTELHAUS, Martin; (DE).
CHIODO, Tiziana; (DE).
SALVADOR, Beate; (DE).
VOSSEN, Marcus; (DE).
HAFNER, Andreas; (CH).
HINTERMANN, Tobias; (CH).
WEISHAAR, Walter; (DE).
HELLMANN, Rolf; (DE)

The present invention primarily relates to multi-component crystals comprising a compound of formula 1 and a second compound selected from the group consisting of co-crystal formers and sol-vents. The invention is further related to pharmaceutical compositions comprising such multi-component crystals. Furthermore, the invention relates to processes for preparing said multi-component crystals. The invention also relates to several aspects of using said multi-component crystals or pharmaceutical compositions to treat a disease.front page image

Developed and launched by Roche and its subsidiary Genentech, under license from Curis. Family members of the product Patent of vismodegib (WO2006028958),

Vismodegib was first disclosed in WO Patent Publication No. 06/028959. Vismodegib, chem-ically 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide, is represented by the following structure:

formula 1

Vismodegib is an active pharmaceutical ingredient produced by Genentech (Roche) and sold under the trade name Erivedge® (which contains crystalline Vismodegib as the active ingre-dient). Erivedge® is an oral Hedgehog signaling pathway inhibitor approved for the treatment of basal-cell carcinoma (BCC).

The present invention primarily relates to multi-component crystals comprising a compound of formula 1 (cf. above) and a second compound selected from the group consisting of co-crystal formers and solvents.

The invention is further related to pharmaceutical compositions comprising said multi-component crystals. Furthermore, the invention also relates to processes for preparing said multi-component crystals. The invention also relates to several aspects of using said multi-component crystals or pharmaceutical compositions to treat a disease. Further details as well as further aspects of the present invention will be described herein below.

Vismodegib is a BCS class II compound with a high permeability but a low solubility where enhanced solubility or dissolution rates can lead to a significant advantage in respect to bio-availability.

Vismodegib is known to exist as crystalline free base. Salts of Vismodegib are men-tioned in US 7,888,364 B2 but not specified. In particular, the HCI salt is mentioned as intermediate but not characterized. Co-crystals or solvates are not reported at all.

The solubility of Vismodegib is reported to be 0.1 μg/mL at pH 7 and 0.99 mg/mL at pH 1 for Erivedge®. The absolute bio-availability after single dose is reported to be 31.8 % and the ex-posure is not linear at single doses higher than 270 mg. Erivedge® capsules do not have a food label. The estimated elimination half-life (t1/2) after continuous once-daily dosing is 4 days and 12 days after a single dose treatment (Highlights of Prescribing Information: ERIVEDGE® (vismodegib) capsule for oral use; Revised: 01/2012).

The discovery and preparation of new co-crystals or solvates offer an opportunity to improve the performance profile of a pharmaceutical product. It widens the reservoir of techniques/materials that a formulation scientist can use for designing a new dosage form of an active pharmaceutical ingredient (API) with improved characteristics. One of the most important characteristics of an API such as Vismodegib is the bio-availability which is often determined by the aqueous solubility.

A compound like Vismodegib may give rise to a variety of crystalline forms having dis-tinct crystal structures and physical characteristics like melting point, X-ray diffraction pattern, infrared spectrum, Raman spectrum and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetry (TG), and differential scanning calorimetry (DSC) as well as content of sol-vent in the crystalline form, which have been used to distinguish polymorphic forms.

Multi-component crystals comprising Vismodegib and selected co-crystal formers or solvents may improve the dissolution kinetic profile and allow to control the hygrosco-picity of Vismodegib.

Therefore, there is a need for multi-component crystals comprising Vismodegib that avoid the above disadvantages. In particular, it is an object of the present invention to provide multi-component crystals of Vismodegib with optimized manufacture, formula-tion, stability and/or biological efficacy

.

Example 1 :

314 mg Vismodegib and 86 mg maleic acid are suspended in toluene saturated with maleic acid for 2 d, filtered and dried.

TG data shows a mass loss of about 2.3 wt % between 100 and 1 18 °C which is attributed to rest solvent. DSC data shows a single endothermal peak with an onset of about 1 15 °C (99 J/g).

H-NMR spectroscopy indicates a molar ratio of Vismodegib to maleic acid of about 1 :1 .3. However single crystal X-ray data confirms a ratio of 1 :2 (Table 1 ).

 

update……………

Vismodegib Synthesis

WO2009126863A2: also see Ref. 1. It all started from here.


Identification:

1H NMR (Estimated) for Vismodegib

Experimental: 1H NMR (400MHz, CDCl3) δ (ppm): 9.58 (bs, 1H), 8.43 (d, J = 4.7Hz, 1H), 8.03 (dd, J = 2.6, 8.7Hz, 1H), 7.90 (d, J = 1.6Hz, 1H), 7.67-7.78 (m, 4H), 7.60 (d, J = 8.0Hz, 1H), 7. 51 (d, J = 8.8Hz, 1H), 7.23-7.24 (m, 1H), 3.01 (s, 3H).

UPDATES…….

Manufacturing Development and Genotoxic Impurity Control Strategy of the Hedgehog Pathway Inhibitor Vismodegib

Small Molecule Process Chemistry, Small Molecule Analytical Chemistry, Genentech, A Member of the Roche Group, 1 DNA Way, South San Francisco, California 94080, United States
§ Siegfried AG, Untere Brühlstrasse 4, CH-4800 Zofingen, Switzerland
Org. Process Res. Dev., Article ASAP
Abstract Image

The development work toward the robust and efficient manufacturing process to vismodegib, the active pharmaceutical ingredient (API) in Erivedge, is described. The optimization of the four-stage manufacturing process was designed to produce the API with the required critical quality attributes: (1) the selective catalytic hydrogenation reduction of the nitro compound 3 to the corresponding aniline 4 while minimizing the formation of potential genotoxic (mutagenic) impurities; (2) the control of the polymorphic phase and multipoint specification for particle size distribution.

Vismodegib2DACS.svg

Vismodegib

 

1H

 

13C

 

 

////////////////

References

External links

PatentSubmittedGranted

Pyridyl inhibitors of hedgehog signalling [US7888364]2006-03-232011-02-15

PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING [US2009281089]2009-11-12

ANTI-HEDGEHOG ANTIBODIES [US8030454]2010-01-072011-10-04

PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING [US2011092461]2011-04-21

PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING [US2012094980]2011-10-142012-04-19

COMBINATION THERAPY WITH NANOPARTICLE COMPOSITIONS OF TAXANE AND HEDGEHOG INHIBITORS [US2013045240]2010-08-252013-02-21

COMBINATION THERAPY WITH NANOPARTICLE COMPOSITIONS OF TAXANE AND HEDGEHOG INHIBITORS [US2014072630]2013-02-282014-03-13

Acyl guanidine derivatives modulating the hedgehog protein signaling pathway [US8889678]2010-07-192014-11-18

COMBINATION THERAPY [US2012184529]2012-01-032012-07-19

METHOD OF INHIBITING DYRK1B [US2014371251]2014-06-182014-12-18

USE OF SUBSTITUTED HEXITOLS INCLUDING DIANHYDROGALACTITOL AND ANALOGS TO TREAT NEOPLASTIC DISEASE AND CANCER STEM AND CANCER STEM CELLS INCLUDING GLIOBLASTOMA MULTIFORME AND MEDULLOBLASTOMA [US2014377336]2013-01-222014-12-25

SHH Regulation and Methods Thereof [US2012082623]2011-09-302012-04-05

NOVEL 2-PIPERIDIN-1-YL-ACETAMIDE COMPOUNDS FOR USE AS TANKYRASE INHIBITORS [US2015025070]2012-07-132015-01-22

Compositions and Methods for Modulating Neuron Degeneration and Neuron Guidance [US2011065645]2010-09-102011-03-17

SMOOTHENED ANTAGONISM FOR THE TREATMENT OF HEDGEHOG PATHWAY-RELATED DISORDERS [US2014200217]2014-01-242014-07-17

 

CN101072755A * Sep 2, 2005 Nov 14, 2007 遗传技术研究公司 Pyridyl inhibitors of hedgehog signalling
CN102731373A * Jul 19, 2012 Oct 17, 2012 南京药石药物研发有限公司 Preparation method of intermediate of antitumor drug GDC-0449 (vismodegib)
US20080132698 * Nov 30, 2006 Jun 5, 2008 University Of Ottawa Use of N-oxide compounds in coupling reactions
US20090076266 * Sep 10, 2008 Mar 19, 2009 The University Of Houston System Copper-catalyzed c-h bond arylation

NON-PATENT CITATIONS

Reference
1 * GEORGETTE M. CASTANEDO,等: “Second generation 2-pyridyl biphenyl amide inhibitors of the hedgehog pathway“, 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 20, 15 September 2010 (2010-09-15), pages 6748 – 6753
2 * 曹萌,等: “Vismodegib 的合成“, 《第十一届全国青年药学工作者最新科研成果交流会论文集》, 21 June 2012 (2012-06-21)
3 * 耿一丁: “Vismodegib“, 《中国药物化学杂志》, vol. 22, no. 3, 20 June 2012 (2012-06-20)
4 * 邢其毅,等: “《基础有机化学》”, 31 December 2005, article “201310019450.0“, pages: 896-897
Vismodegib
Vismodegib2DACS.svg
Vismodegib3Dan.gif
Systematic (IUPAC) name
2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide
Clinical data
Trade names Erivedge
AHFS/Drugs.com monograph
Licence data EMA:Link, US FDA:link
Pregnancy
category
  • AU: X (High risk)
  • US: D (Evidence of risk)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 31.8%
Protein binding >99%
Metabolism <2% metabolised byCYP2C9, CYP3A4, CYP3A5
Biological half-life 4 days (continuous use),
12 days (single dose)
Excretion Faeces (82%), urine (4.4%)
Identifiers
CAS Number 879085-55-9
ATC code L01XX43
PubChem CID 24776445
IUPHAR/BPS 6975
DrugBank DB08828
ChemSpider 23337846
UNII 25X868M3DS
ChEBI CHEBI:66903 Yes
ChEMBL CHEMBL473417
Synonyms GDC-0449, RG-3616
Chemical data
Formula C19H14Cl2N2O3S
Molar mass 421.30 g/mol

SEE…http://apisynthesisint.blogspot.in/2016/02/vismodegib.html

/////

CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl

CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl

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MIRABEGRON


ChemSpider 2D Image | Mirabegron | C21H24N4O2SMIRABEGRON
  • Betanis
  • Myrbetriq
  • UNII-MVR3JL3B2V
  • YM 178
  • YM178
Мирабегрон ميرابيغرون 米拉贝隆
2-(2-Amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide
MF: C21H24N4O2S =396.5
Mirabegron (YM-178, Astellas Pharma), is an orally active, first-in-class selective β₃-adrenoceptor agonist for the symptomatic treatment of overactive bladder (OAB), and has been approved for urinary frequency and urinary incontinence associated with OAB

Mirabegron (YM-178) is the first β3-adrenoceptor agonist that is clinically effective for overactive bladder. Mirabegron (0.3 and 1 mg/kg) inhibits mechanosensitive single-unit afferent activities (SAAs) of Aδ fibers in response to bladder filling. Mirabegron activates the β3 adrenergic receptor in the detrusor muscle in the bladder, which leads to muscle relaxation and an increase in bladder capacity. Mirabegron (YM-178) acts partly as an irreversible or quasi-irreversible metabolism-dependent inhibitor of CYP2D6. Mirabegron at a dose of 3 mg/kg i.v. decreased the frequency of rhythmic bladder contraction induced by intravesical filling with saline without suppressing its amplitude in anesthetized rats. Mirabegron decreases primary bladder afferent activity and bladder microcontractions in rats. Mirabegron (YM-178) also reduced non-micturition bladder contractions in an awake rat model of bladder outlet obstruction.

Mirabegron is a white crystalline powder, not hygroscopic and freely soluble in dimethyl sulfoxide, soluble in methanol and soluble in water between neutral to acidic pH. The chemical name is 2-(2- Amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2- phenylethyl]amino}ethyl)phenyl]acetamide., Mirabegron exhibits stereoisomerism due to the presence of one chiral centre. The R enantiomer has been used in the manufacture of the finished product. The enantiomeric purity is controlled routinely by chiral HPLC-UV. Polymorphism has been observed for the active substance. The polymorphic form α is routinely and consistently produced by the synthetic process and it is used in the manufacture of the finished product…….http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002388/WC500137308.pdf

Mirabegron (formerly YM-178, trade name MyrbetriqBetmiga in Spain) is a drug for the treatment of overactive bladder.[2] It was developed by Astellas Pharma and was approved in the United States in July 2012.[3]
Mirabegron activates the β3 adrenergic receptor in the detrusor muscle in the bladder, which leads to muscle relaxation and an increase in bladder capacity.[4]\
NMR PREDICT
NMR CHEMDOODLE
PAPER
Journal of Chemical and Pharmaceutical Research, 2015, 7(4):1473-1478
In the first approach, the introduction of the chiral hydroxyl group was planned at the later stage (Scheme 1). Accordingly, 2-(4-nitrophenyl)ethyl amine 4 was protected as the Boc-derivative 5, followed by the reduction of the nitro group using stannous chloride to furnish corresponding aniline 6. Alternate reducing conditions such as hydrogenation in the presence of 10% Pd-C were also provided the desired 6 in good yield. Amide coupling of the aniline 6 with 2-(2-aminothiazol-4-yl) acetic acid 7 in the presence of EDC, HOBt/DIPEA furnished the desired amide 8. Interestingly, lower reactivity of 2-aminothiazole precluded any self-coupling of 7.
MIRA SYN 1
Removal of Boc-group in 8, set the stage for the critical step of introducing the chiral hydroxyl by means of stereocontrolled ring opening of the chiral (R)-styrene epoxide 10. Epoxide opening reaction of 10 was initially attempted with amine 9 in the presence of Et3N in MeOH as the solvent. Alternatively, epoxy opening was also performed under simple isopropanol reflux condition to get the desired 1. The desired product 1 was isolated in 27% yield after purification by column chromatography. This is due to the formation of N-alkylated derivatives of 1 by undesired reaction of 10 with amino functionalities of 1. However, the inefficiency of the epoxide opening reaction precluded a high purity of final product, Mirabegron 1. Since it is not practical to embark on repeated purifications at the last stage (which leads to poor yields), this route was not pursued for further optimization.
13C NMR PREDICT
C-NMR MOLBASE
1H NMR PREDICT
H-NMR MOLBASE
………………
1H NMR PREDICT
H EXPLODED H-NMR NMRDB GRAPHH-NMR NMRDB VAL
13C NMR PREDICT
C-NMR NMRDB GRAPH C-NMR NMRDB VAL
COSY PREDICT
COSY NMR prediction (24)CN 103896872
http://www.google.com/patents/CN103896872A?cl=en

Figure CN103896872AD00082
Figure CN103896872AD00091

Third, Mira Veron synthesis:
reaction:

Figure CN103896872AD00092

in 500mL three-necked flask, 2- (2-aminothiazol-4-yl) acetic acid 17.42g (0.086mol), N, N- dimethylformamide 180mL, then added H0BT15.12g (0.104 mol), was added (R) _2 _ ((4- aminophenyl) amino) phenyl-ethan-l-ol -1_ 20g (0.078mol), was added triethylamine 13.04g (0.13mol), was added portionwise EDCI21. 46g (0.104mol), under magnetic stirring, room temperature for 5h, TLC until the reaction was complete tracking.
After treatment: After the completion of the reaction, the reaction solution was poured into 900mL saturated saline water, and then extracted with 400mL of dichloromethane each time, and extracted three times, each time the organic phase is then washed with 200mL of saturated aqueous sodium carbonate solution, washed three times, each time with distilled water and then 200mL of water, washed three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid in methylene chloride was distilled off Mira Veron crude, the crude product was recrystallized from methanol solution, wherein the methanol solution of methanol and water, the volume ratio of 10: 4, and recrystallized to give 25.08g, yield 81.0%.
The present embodiment Mira Veron synthesized for testing and structural identification:
mp138 ~ 140 ° C (137 ~ 139 ° C)
[α] 20-18. ~ -22. (CH3OH)
chemical purity HPLC: 99.96%
Optical purity: 97.55ee%
HRMS (ES1-MS, m / z) calcd: for C21H25N4O2S [M + H] + 397.16.Found:. 397.16
1H Mffi (400MHz, DMS0) Sl0.00 (s, lH), 7.50 ( d, J = 8.5Hz, 2H), 7.30 (dd, J = 9.5,5.1Hz, 4H), 7.23 (dd, J = 6.0, 2.7Hz, 1H), 7.12 (d, J = 8.5Hz, 2H), 6.90 (s, 2H), 6.30 (s, 1H), 5.24 (s, 1H), 4.60 (s, 1H), 3.45 (s, 2H), 2.74 (dd, J = 9.8, 3.5Hz, 2H), 2.64 (m, 4H).
13C NMR (101MHz, DMSO) δ 168.69 (s), 168.26 (s), 146.35 (s), 145.03 (s), 137.66 (s), 135.51 (s), 129.24 (s ), 128.38 (s), 127.22 (s), 126.33 (s), 119.46 (s), 103.03 (s), 71.88 (s), 57.94 (s), 51.20 (s), 40.40 (s), 40.20 (s ), 39.99 (s), 39.78 (s), 39.57 (s), 35.77 (s)

1H NMR FIG2…SEE…….http://orgspectroscopyint.blogspot.in/2015/08/mirabegron.html

1H NMR

13C NMR FIG3

 13C NMR

………….

CN 103193730
http://www.google.com/patents/CN103193730A?cl=en
Figure CN103193730AD00081

By and O ° C under nitrogen protection temperature conditions, 7.3g (R) -2- amino _1_ benzeneethanol added 250mL three-necked flask, the stirring was dissolved in 50mL of dichloromethane Mira Veron Intermediate C was added dropwise to the reaction solution to form three-necked flask. Stirred for I hour under nitrogen, with stirring 4.12g of sodium borohydride was added to the reaction mixture. The reaction mixture was stirred (under TC 3 hours to TLC the reaction was complete. The reaction is complete the reaction mixture was added dropwise a saturated aqueous ammonium chloride solution IOmL quenched reaction was washed twice with 40mL of water, the organic phase was separated. The The organic phase at the conditions at 0 ° C was added concentrated sulfuric acid was stirred IOmL until TLC after 0.5 hours the reaction was complete, then was added 20mL of 20% aqueous sodium hydroxide solution to complete the reaction of the organic phase was adjusted to pH 10 and stirred for 15 minutes minutes solution. The organic phase first with 50mL saturated brine I times with IOg anhydrous sodium sulfate and concentrated to give crude product was recrystallized from methanol and water to give 18.7g of the final product Mira Veron purity of 99.33%, chiral purity of 99.01%, a yield of 88.12%.
Mira Veron use randomly selected samples prepared by the synthesis method of the present invention is detected by liquid chromatography.
Test conditions: Instrument: Agilent 1100 HPLC;
Column: Luna C18, 4.6mmX 250mm, 5 μ m;
Column temperature: 25 ° C;
flow rate: 1.0mL / min;
The detection wavelength: 2IOnm;
Injection volume: 5ul;
Mobile phase A: acetonitrile;
Mobile phase B: 0.1% phosphoric acid aqueous solution;
Running time: 40min.
FIG liquid chromatography after detection of the sample shown in Figure 1; results are shown in Table I.
Table 1: The Mira Veron chromatographic analysis sample preparation method of the present invention

Figure CN103193730AD00121

……….

http://www.google.co.in/patents/EP1440969A1?cl=en

Figure 00090001

      Example 4 (Production of the α-form crystal from wet cake of the β-form crystal) :
  • The same procedures as in Example 2 were followed to obtain 23.42 kg of a wet cake of the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide from 6.66 kg of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrochloride. This cake was added with and dissolved in 92 L of water and 76 L of ethanol by heating at about 80°C, and the solution was cooled at a rate of about 10°C per hour, to which was then added 8.4 g of the α-form crystal at 55°C. Thereafter, the mixture was cooled to 20°C. A crystal was filtered and dried to obtain 6.56 kg of the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide.
  • Powder X-ray diffraction diagram and thermal analysis diagram of the α-form crystal are shown in Fig. 4 and Fig. 5, respectively.
    1H-NMR (DMSO-d 6, 500 MHz) δ (ppm) = 1.60 (1H, s), 2.59 to 2.66 (4H, m), 2.68 to 2.80 (2H, m), 3.45 (2H, s), 4.59 (1H, br), 5.21 (1H, br), 6.30 (1H, s), 6.89 (2H, s), 7.11 (2H, d, J = 8.5 Hz), 7.19 to 7.23 (1H, m), 7.27 to 7.33 (4H, m), 7.49 (2H, d, J = 8.5 Hz), 9.99 (1H,s). FAB-MS m/z: 397 (M+H)+.

References

  1.  “mirabegron (Rx) – Myrbetriq”Medscape Reference. WebMD. Retrieved 17 November 2013.
  2.  Gras, J (2012). “Mirabegron for the treatment of overactive bladder”. Drugs of today (Barcelona, Spain : 1998) 48 (1): 25–32. doi:10.1358/dot.2012.48.1.1738056PMID 22384458.
  3.  Sacco, E; Bientinesi, R et al. (Apr 2014). “Discovery history and clinical development of mirabegron for the treatment of overactive bladder and urinary incontinence”. Expert Opin Drug Discov9 (4): 433–48. doi:10.1517/17460441.2014.892923PMID 2455903.
  4.  “New Drug Approvals 2012 – Pt. XIV – Mirabegron (MyrbetriqTM)”ChEMBL. 5 July 2012. Retrieved 28 September 2012.
  5.  “MYRBETRIQ (mirabegron) tablet, film coated, extended release [Astellas Pharma US, Inc.]“DailyMed. Astellas Pharma US, Inc. September 2012. Retrieved 17 November 2013.
  6.  “Betmiga 25mg & 50mg prolonged-release tablets”electronic Medicines Compendium. Astellas Pharma Ltd. 22 February 2013. Retrieved 17 November 2013.
  7.  Cypess, Aaron; Weiner, Lauren; Roberts-Toler, Carla; Elía, Elisa; Kessler, Skyler; Kahn, Peter; English, Jeffrey; Chatman, Kelly; Trauger, Sunia; Doria, Alessandro; Kolodny, Gerald (6 January 2015). “Activation of Human Brown Adipose Tissue by a β3-Adrenergic Receptor Agonist”Cell Metabolism 21 (1): 33–38. doi:10.1016/j.cmet.2014.12.009PMID 25565203. Retrieved 26 January 2015.

External links

Mirabegron
Mirabegron2DACS2.svg
Systematic (IUPAC) name
2-(2-Amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide
Clinical data
Trade names Myrbetriq (US), Betanis (Japan), Betmiga (EU)
Licence data EMA:LinkUS FDA:link
Pregnancy
category
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 29-35%[1]
Protein binding 71%[1]
Metabolism Hepatic via (direct) glucuronidation, amide hydrolysis, and minimal oxidative metabolism in vivo byCYP2D6 and CYP3A4. Some involvement of butylcholinesterase[1]
Biological half-life 50 hours[1]
Excretion Urine (55%), faeces (34%)[1]
Identifiers
CAS Registry Number 223673-61-8
ATC code G04BD12
PubChem CID: 9865528
ChemSpider 8041219
Synonyms YM-178
Chemical data
Formula C21H24N4O2S
Molecular mass 396.506 g/mol
Patent Submitted Granted
Alpha-form or beta-form crystal of acetanilide derivative [US7342117] 2005-01-06 2008-03-11
Pharmaceutical composition for treating stress incontinence and/or mixed incontinence [US2006004105] 2006-01-05
Pharmaceutical composition comprising a beta-3-adrenoceptor agonist and a serotonin and/or norepinephrine reuptake inhibitor Pharmaceutical composition comprising a beta-3-adrenoceptor agonist and a serotonin and/or norepinephrine reuptake inhibitor [US2009012161] 2005-11-24
Pharmaceutical composition consisting of a beta-3-adrenoceptor agonist and alpha-agonist [US2005154041] 2005-07-14
Pharmaceutical composition consisting of a beta-3-adrenoceptor agonist and an active substance which influences prostaglandin metabolism [US2005119239] 2005-06-02
Pharmaceutical Composition For Treating Stress Incontinence And/Or Mixed Incontinence [US2007129435] 2007-06-07
Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient [US7750029] 2006-06-01 2010-07-06
[alpha]-form or [beta]-form crystal of acetanilide derivative [US7982049] 2008-09-04 2011-07-19
BETA ADRENERGIC RECEPTOR AGONISTS FOR THE TREATMENT OF B-CELL PROLIFERATIVE DISORDERS [US2010009934] 2010-01-14
PHARMACEUTICAL COMPOSITION FOR IMPROVING LOWER URINARY TRACT SYMPTOMS [US2010261770] 2010-10-14
11 to 16 of 16
Patent Submitted Granted
PHARMACEUTICAL COMPOSITION FOR MODIFIED RELEASE [US2010144807] 2010-06-10
BENZYLAMINE DERIVATIVE OR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALT THEREOF, AND USE THEREOF FOR MEDICAL PURPOSES [US8148427] 2010-04-22 2012-04-03
Pharmaceutical composition containing a beta-3-adrenoceptor agonist and an alpha antagonist and/or a 5-alpha reductase inhibitor [US2005101607] 2005-05-12
REMEDY FOR OVERACTIVE BLADDER COMPRISING ACETIC ACID ANILIDE DERIVATIVE AS THE ACTIVE INGREDIENT [US2009093529] 2009-04-09
PHARMACEUTICAL COMPOSITION FOR TREATING OVERACTIVE BLADDER [US2010240697] 2010-09-23
Pharmaceutical composition comprising beta-3-adrenoceptor-agonists and antimuscarinic agents [US2005261328] 2005-11-24
US Patent No Patent Expiry patent use
6346532 Oct 15, 2018
6562375 Aug 1, 2020
6699503 Sep 10, 2013
7342117 Nov 4, 2023
7750029 Dec 18, 2023 U-913
7982049 Nov 4, 2023
Exclusivity Code Exclusivity Date
NCE Jun 28, 2017

U-913……….TREATMENT OF OVERACTIVE BLADDER WITH SYMPTOMS OF URGE URINARY INCONTINENCE, URGENCY, AND FREQUENCY

//////Mirabegron, Overactive bladder, FDA 2012, ASTELLAS PHARMA, YM-178, MyrbetriqBetmiga

Updates…….

Figure

Overactive bladder (OAB) is characterized by symptoms of urinary urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia.(1-3) Current guidelines recommend oral antimuscarinics drugs as the first-line pharmacologic therapy in the management of OAB despite the companion adverse effects.(4, 5) Mirabegron is an orally active β3 adrenoceptor agonist approved by the FDA for treatment of OAB in 2012, which is an important step toward the better treatment options for the management of OAB.(6)

(R)-Styrene oxide 1 and 4-nitrophenethylamine 2 were exploited as starting materials in the first synthesis of mirabegron (Scheme 1). Heating 1 and 2 in i-propanol afforded amino alcohol 3, and then the amino group was protected by di-tert-butyl dicarbonate (Boc2O), followed by a condensation with 2-aminothiazol-4-acetic acid. Deprotection of the condensation product 7 finally afforded mirabegron.(7-10) Although reactions in the whole process were all conventional reactions, optically pure 1 was not industrially available, which restricted its application in industry.

(R)-Mandelic 8 and 4-nitrophenethylamine hydrochloride 9 were exploited as starting materials in an alternate route (Scheme 2). Condensation of 8 and 9 in the presence of 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), and triethylamine in N,N-dimethylformamide (DMF) furnished the corresponding amide 10, which was further reduced in the presence of borane-tetrahydrofuran complex in a mixed solution of 1,3-dimethyl-2-imidazolidinone (DMI) and tetrahydrofuran (THF), affording amine 11. The nitro group of 11 was then reduced by hydrogenation affording aniline 12 which was further amidated by an aqueous EDCI coupling affording mirabegron. This route was rather concise with only four steps, in which the sole stereogenic center was introduced via a bulk starting material 8.(11-13) However, usage of the costly EDCI twice, especially in the first step, led to a high cost and more impurities.

Figure

mail: chm_zhenggx@ujn.edu.cn,  chm_zhenggx@ujn.edu.cn

  1. 1   AbramsP.CardozoL.FallM.GriffithsD.RosierP.UlmstenU.Van KerrebroeckP.VictorA.Wein,A. UROLOGY 20036137DOI: 10.1016/S0090-4295(02)02243-4

  2. 2.AbramsP.ChappleC.KhouryS.RoehrbornC.de la RosetteJ. J. Urol. 20091811779DOI: 10.1016/j.juro.2008.11.127

  3. 3.JaiprakashH.BenglorkarG. M. RJPBCS 20145 ( 3213

  4. 4.LucasM. G.RuudJ. L.BoschR. J. L.BurkhardF. C.CruzF.MaddenT. B.NambiarA. K.Neisius,A.de RidderD. J. M. K.TubaroA.TurnerW.PickardR. Eur. Urol. 2012621130DOI: 10.1016/j.eururo.2012.08.047

  5. 5.GormleyE. A.LightnerD. J.BurgioK. L.ChaiT. C.ClemensJ. Q.CulkinD. J.DasA. K.FosterH. E.ScarperoH. M.TessierC. D.VasavadaS. P. J. Urol. 20121882455DOI: 10.1016/j.juro.2012.09.079

  6. 6.SaccoE.BientinesiR. World J. Obstet Gynecol 20132 ( 465DOI: 10.5317/wjog.v2.i4.65

  7. 7.MaruyamaT.SuzukiT.OndaK.HayakawaM.MoritomoH.KimizukaT.MatsuiT. US6346532,2002.

  8. 8.KawazoeS.SakamotoK.AwamuraY.MaruyamaT.SuzukiT.OndaK.TakasuT. EP144096A1,2004.

  9. 9.TakasuT.SatoS.UkaiM.MaruyamaT. EP1559427A1, 2005.

  10. 10ZhangH.LiY.ChenS.ShenM.WangX. CN103896872A, 2014

//////////

TOFACITINIB 的合成, トファシチニブ, Тофацитиниб, توفاسيتين يب SPECTRAL VISIT


Tofacitinib Citrate, 的合成

托法替布,  トファシチニブクエン酸塩, Тофацитиниба Цитрат

 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile citrate salt

CAS : 540737-29-9

ROTATION +

Tofacitinib; Tasocitinib;

477600-75-2 base ; CP-690550;

3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile;

3-{(3R,4R)-4-methyl-3-rmethyl-(7H-pyrrolor2,3-dlpyrimidin-4-yl)-amino1- piperidin-1-yl}-3-oxo-propionitrile mono citrate salt

CP 690550 Tofacitinib; CP-690550; CP-690550-10; Xeljanz; Jakvinus; Tofacitinib citrate

Trademarks: Xeljanz; Jakvinus

MF: C16H20N6O

CAS : 477600-75-2 BASE ; 540737-29-9(citrate) 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile

Molecular Weight: 312.369

SMILES: C[C@@H]1CCN(C[C@@H]1N(C)C2=NC=NC3=C2C=CN3)C(=O)CC#N

Activity: Treatment of Rheumatoid Arthritis; RA Treatment, JAK Inhibitor; Protein Kinase Inhibitor; JAK3 Inhibitor; Janus Kinase 3 Inhibitor; JAK-STAT Signaling Pathway; JAK1 Kinase Inhibitor; Selective Immunosuppressants

Status: Launched 2012

Originator: Pfizer
Pfizer Inc’s oral JAK inhibitor tofacitinib was approved on November 6, 2012 by US FDA for the treatment of rheumatoid arthritis.
सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..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.

Tofacitinib (trade names Xeljanz and Jakvinus, formerly tasocitinib,[1] CP-690550[2]) is a drug of the janus kinase (JAK) inhibitor class, discovered and developed by Pfizer. It is currently approved for the treatment of rheumatoid arthritis (RA) in the United States,Russia, Japan and many other countries, is being studied for treatment of psoriasis, inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection.

An Improved and Efficient Process for the Preparation of Tofacitinib Citrate

Publication Date (Web): November 17, 2014 (Article)
DOI: 10.1021/op500274j
 
MS m/z 313 (M+ + 1);
mp 201–202 °C;  
1H NMR (CDCl3) δ 8.34 (s, 1H), δ 7.38 (d, 1H, J = 2.4 Hz), δ 6.93 (d, 1H, J = 2.4 Hz), δ 4.97 (m, 1H), δ 3.93–4.03 (m, 4H), δ 3.66 (m, 1H), δ 3.50 (m, 4H), δ 2.91 (d, 2H, J = 15.6 Hz), δ 2.80 (t, 2H, J = 12.8 Hz), δ 2.55 (m, 1H), δ 1.99 (m, 1H), δ 1.77 (m, 1H), δ 1.13–1.18 (m, 3H).
Print
09338-acsnews1-pfizercxd
TEAMWORK
Part of the Pfizer group responsible for Xeljanz: Front row, from left: Sally Gut Ruggeri, Chakrapani Subramanyam, Eileen Elliott Mueller, and Frank Busch. Second row, from left: Matthew Brown, Mark Flanagan, and Robert Dugger. Back row, from left: Elizabeth Kudlacz and Douglas Ball.
Credit: Pfizer
Mark Flanagan, who was on the team at Pfizer that discovered Xeljanz, (tofacitinib citrate), an oral treatment for rheumatoid arthritis, remembers testing the drug in a rat model and seeing the drug decrease the level of inflammation in the rats’ footpads. “What we look for is physical measurements of the size of the joint. In the control animals, there was quite a bit of inflammation in the joints, whereas animals treated with different doses of the drug showed a dose-dependent decrease in the size of the joint. “Tofacitinib showed robust efficacy in the first such study run. I can remember the excitement that this data generated on the team,” he says.

Tofacitinib, chemically known as (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3- d]pyrimidin-4-ylamino)-B-oxo-l -piperidinepi panenitrile, is represented Formula I. Tofacitinib citrate, a janus kinase inhibitor, is approved as XELJANZ® tablets for treatment .of rheumatoid arthritis.

Figure imgf000002_0001

Various intermediates and processes for preparation of tofacitinib are disclosed in patents like US7301 023 and US8232394.

Figure imgf000020_0001

Formula I or isomers or a mixture of isomers thereof by following any method provided in the prior art, for example, by following Example 14 of U.S. Patent No. RE41,783 or by following Example 6 of U.S. Patent No. 7,301,023. Tofacitinib of Formula I or isomers of tofacitinib or a mixture of isomers thereof may be converted into a salt by following any method provided in the prior art, for example, by following Example 1 of U.S. Patent No. 6,965,027 or by following Example 1 or Example 8 of PCT Publication No. WO 2012/135338. The potential significance of JAK3 inhibition was first discovered in the laboratory of John O’Shea, an immunologist at the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH).[5] In 1994, Pfizer was approached by the NIH to form a public-private partnership in order to evaluate and bring to market experimental compounds based on this research.[5] Pfizer initially declined the partnership but agreed in 1996, after the elimination of an NIH policy dictating that the market price of a product resulting from such a partnership would need to be commensurate with the investment of public taxpayer revenue and the “health and safety needs of the public.”[5] The drug discovery, preclinical development, and clinical development of tofacitinib took place exclusively at Pfizer.[6] In November 2012, the U.S. Food and Drug Administration (FDA) approved tofacitinib for treatment of rheumatoid arthritis. Once on the market, rheumatologists complained that the $2,055 a month wholesale price was too expensive, though the price is 7% less than related treatments.[6] A 2014 study showed that tofacitinib treatment was able to convert white fat tissues into more metabolically active brown fat, suggesting it may have potential applications in the treatment of obesity.[7] It is an inhibitor of the enzyme janus kinase 1 (JAK1) and janus kinase 3 (JAK 3) , which means that it interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription.[3] Recently it has been shown in a murine model of established arthritis that tofacitinib rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. This efficacy in this disease model correlated with the inhibition of both JAK1 and 3 signaling pathways, suggesting that tofacitinib may exert therapeutic benefit via pathways that are not exclusive to inhibition of JAK3.[4]

Preparation of 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile citrate salt (Tofacitinib citrate, Xeljanz, CP-690550-10)
To a round-bottomed flask fitted with a temperature probe, condenser, nitrogen source, and heating mantle, methyl-[(3R,4R)-4-methyl-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (5.0 g, 20.4 mmol) was added followed by 1-butanol (15 mL), ethyl cyanoacetate (4.6 g, 40.8 mmol), and DBU (1.6 g, 10.2 mmol). The resulting amber solution was stirred at 40 °C for 20 h. Upon reaction completion, citric acid monohydrate (8.57 g, 40.8 mmol) was added followed by water (7.5 mL) and 1-butanol (39.5 mL). The mixture was heated to 81 °C and held at that temperature for 30 min. The mixture was then cooled slowly to 22 ºC and stirred for 2 h. The slurry was filtered and washed with 1-butanol (20 mL). The filter cake was dried in a vacuum oven at 80 °C to afford 9.6 g (93%) of tofacitinib citrate as an off-white solid.
1H NMR (500 MHz, d6-DMSO): δ 8.14 (s, 1H), 7.11 (d, J=3.6 Hz, 1H), 6.57 (d, J=3.6 Hz, 1H), 4.96 (q, J=6.0 Hz, 1H), 4.00-3.90 (m, 2H), 3.80 (m, 2H), 3.51 (m, 1H), 3.32 (s, 3H), 2.80 (Abq, J=15.6 Hz, 2H), 2.71 (Abq, J=15.6 Hz, 2H), 2.52-2.50 (m, 1H), 2.45-2.41 (m, 1H), 1.81 (m, 1H), 1.69-1.65 (m, 1H), 1.04 (d, J=6.9 Hz, 3H).
सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..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.
PAPER
3-((3R,4R)-4-Methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (1) Monocitrate
J. Med. Chem., 2010, 53 (24), pp 8468–8484
DOI: 10.1021/jm1004286
1monocitrate as a white crystalline solid (mp = 201 dec).
LRMS: m/z 313.2 (MH+).
1H NMR (400 MHz) (D2O) δ HOD: 0.92 (2 H, d, J = 7.2 Hz), 0.96 (1 H, d, J = 7.6 Hz), 1.66 (1 H, m), 1.80 (1 H, m), 2.37 (1 H, m), 2.58 (2 H, 1/2 ABq, J = 15.4 Hz), 2.70 (2 H, 1/2 ABq, J = 15.4 Hz), 3.23 (2 H, s), 3.25 (1 H, s), 3.33 (1 H, m), 3.46 (1 H, m), 3.81 (4 H, m), 4.55 (1 H, m), 6.65 (1 H, d, J = 3.2 Hz), 7.20 (1 H, t, J = 3.2 Hz), 8.09 (1 H, m).
Anal. Calcd for C22H28N6O8: C, 52.38; H, 5.59; N, 16.66. Found: C, 52.32; H, 5.83; N, 16.30. For additional characterization of the monocitrate salt of 1 see WO 03/048162.
NMR PREDICT
References:
Weiling Cai, James L. Colony,Heather Frost, James P. Hudspeth, Peter M. Kendall, Ashwin M. Krishnan,Teresa Makowski, Duane J. Mazur, James Phillips, David H. Brown Ripin, Sally Gut Ruggeri, Jay F. Stearns, and Timothy D. White; Investigation of Practical Routes for the Kilogram-Scale Production of cis-3-Methylamino-4-methylpiperidinesOrganic Process Research & Development 2005, 9, 51−56
Ripin, D. H.B.; 3-amino-piperidine derivatives and methods of manufacture, US patent application publication, US 2004/0102627 A1
Ruggeri, Sally, Gut;Hawkins, Joel, Michael; Makowski, Teresa, Margaret; Rutherford, Jennifer, Lea; Urban,Frank,John;Pyrrolo[2,3-d]pyrimidine derivatives: their intermediates and synthesis, PCT pub. No. WO 2007/012953 A 2, US20120259115 A1, United States Patent US8232393. Patent Issue Date: July 31, 2012
Kristin E. Price, Claude Larrive´e-Aboussafy, Brett M. Lillie, Robert W. McLaughlin, Jason Mustakis, Kevin W. Hettenbach, Joel M. Hawkins, and Rajappa Vaidyanathan; Mild and Efficient DBU-Catalyzed Amidation of Cyanoacetates, Organic Letters, 2009, vol.11, No.9, 2003-2006
MORE NMR PREDICT

tofacitinib Molbase str

Tofacitinib TOFA  1H proton NMR spectra

tofacitinib 1h values

13C NMR PREDICT  TOFA  13C NMR spectra

 

 

SEE…….https://newdrugapprovals.org/2015/07/24/tofacitinib-%E7%9A%84%E5%90%88%E6%88%90-spectral-visit/

 

 

COSY PREDICT COSY NMR prediction सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..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.

SEE………http://orgspectroscopyint.blogspot.in/2014/12/tofacitinib-citrate.html

 

NMR PICTURE FROM THE NET

tofacitinib ABMOLE NMR BASE

 

PAPER

Volume 54, Issue 37, 11 September 2013, Pages 5096–5098

Asymmetric total synthesis of Tofacitinib

  • a Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, University of Talca, P.O. Box 747, Talca, Chile
  • b Laboratory of Natural Products, Department of Chemistry, University of Antofagasta, P.O. Box 170, Antofagasta, Chile

http://dx.doi.org/10.1016/j.tetlet.2013.07.042

Abstract

A novel stereoselective synthesis of Tofacitinib (CP-690,550), a Janus tyrosine kinase (JAK3) specific inhibitor, has been achieved starting from (5S)-5-hydroxypiperidin-2-one in 10 steps from 2 with a 9.5% overall yield. The potentiality of this synthetic route is the obtention of tert-butyl-(3S,4R)-3-hydroxy-4-methylpiperidine-1-carboxylate (6b) as a new chiral precursor involved in the synthesis of CP690,550, in a three-step reaction, without epimerizations, rather than the 5 or more steps used in described reactions to achieve this compound from analogues of 6b.


Graphical abstract

Image for unlabelled figure

…………………. Tofacitinib synthesis: US2001053782A1

Tofacitinib synthesis: WO2002096909A1
 
Tofacitinib synthesis: Org Process Res Dev 2014, 18(12), 1714-1720 (also from a chinese publication, same procedure just slight changes in reagents/conditions)
 
References:
1. Blumenkopf, T. A.; et. al. Pyrrolo[2,3-d]pyrimidine compounds. US2001053782A1
2. Flanagan, M. E.; et. al. Optical resolution of (1-benzyl-4-methylpiperidin-3-yl) -methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors. WO2002096909A1
3. Das, A.; et. al. An Improved and Efficient Process for the Preparation of Tofacitinib Citrate. Org Process Res Dev2014, 18(12), 1714-1720.

 

PATENT https://www.google.co.in/patents/WO2003048162A1?cl=en The crystalline form of the compound of this invention 3-{4-methyl-3-[methyl- (7H-pyrrolot2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile mono citrate salt is prepared as described below. Scheme 1

Figure imgf000005_0001
Figure imgf000005_0002

Scheme 2

Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000006_0003
Figure imgf000006_0004

Example 1 3-{(3R,4R)-4-methyl-3-rmethyl-(7H-pyrrolor2,3-dlpyrimidin-4-yl)-amino1- piperidin-1-yl}-3-oxo-propionitrile mono citrate salt Ethanol (13 liters), (3R, 4R)-methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-amine (1.3 kg), cyano-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester (1.5 kg), and triethylamine (1.5 liters) were combined and stirred at ambient temperature. Upon reaction completion (determined by High Pressure Liquid Chromotography (HPLC) analysis, approximately 30 minutes), the solution was filtered, concentrated and azeotroped with 15 liters of methylene chloride. The reaction mixture was washed sequentially with 12 liters of 0.5 N sodium hydroxide solution, 12 liters of brine and 12 liters of water. The organic layer was concentrated and azeotroped with 3 liters of acetone (final pot temperature was 42°C). The resulting solution was cooled to 20°C to 25°C followed by addition of 10 liters of acetone. This solution was filtered and then aqueous citric acid (0.8 kg in 4 liters of water) added via in-line filter. The reaction mixture was allowed to granulate. The slurry was cooled before collecting the solids by filtration. The solids were dried to yield 1.9 kg (71 %) (3R, 4R)- 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo- propionitrile mono citrate. This material was then combined with 15 liters of a 1:1 ratio of ethanol/water and the slurry was agitated overnight. The solids were filtered and dried to afford 1.7 kg (63% from (3R, 4R)-methyl-(4-methyl-piperidin-3-yl)-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-amine) of the title compound as a white crystalline solid. 1H NMR (400 MH2)(D20) δ HOD: 0.92 (2H, d, J = 7.2 Hz), 0.96 (1H, d, J = 7.6 Hz), 1.66 (1H, m), 1.80 (1H, m), 2.37 (1H, m), 2.58 (2H, 1/2 ABq, J = 15.4 Hz), 2.70 (2H, 3 ABq, J = 154 Hz), 3.23 (2H, s), 3.25 (1H, s), 3.33 (1H, m), 3.46 (1H, m), 3.81 (4H, m), 4.55 (1 H, m), 6.65 (1 H, d, J = 3.2 Hz), 7.20 (1 H, t, J = 3.2 Hz), 8.09 (1 H, m).

 

Patent

http://www.google.co.in/patents/EP1913000A2?cl=en Example 10 Preparation of methyl-[(3R, 4R)-4-methyl-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine:

KEY INTERMEDIATE

To a clean, dry, nitrogen-purged 2 L hydrogenation reactor were charged 20 wt% Pd(OH)2/C (24.0 g, 50% water wet), water (160 ml), isopropanol (640 ml), (1-benzyl-4-methyl-piperidin-3-yI)-methyi- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (160.0 g, 0.48 mol), and acetic acid (28.65 g, 0.48 mol). The reactor was purged with three times at 50 psi with nitrogen and three times at 50 psi with hydrogen. Once purging was complete, the reactor was heated to 45-55°C and pressurized to 50 psi with hydrogen through a continuous feed. The hydrogen uptake was monitored until no hydrogen was consumed for 1 hour. The reactor was cooled to 20-300C and purged three times at 50 psi with nitrogen. The reaction mixture was filtered through wet Celite and the filtrate was sent to a clean, dry, nitrogen-purged vessel. A solution of sodium hydroxide (39.33 g) in water (290 ml) was charged and the mixture was stirred for a minimum of 1 hour then heated to 75-900C. The isopropanol was removed by distillation. The reaction mixture was cooled to 20-30°C and 2-methyltetrahydrofuran (1.6 L) was added. The aqueous layer was drained off and the 2-methyltetrahydrofuran was displaced with toluene (1.6 L). The distillation was continued until the final volume was 800 ml. The slurry was cooled to 20-30°C and held for a minimum of 7 hours. The resulting solids were isolated by filtration and washed with toluene (480 ml). After drying under vacuum between 40-50DC for a minimum of 24 hours with a slight nitrogen bleed 102.3 g (87.3%) of the title compound were isolated. Mp 158.6-159.8°C. 1H NMR (400 MHz, CDCI3): δ 11.38 (bs, 1H), 8.30 (s, 1H), 7.05 (d, J=3.5 Hz, 1H), 6.54 (d, J=3.5 Hz, 1H), 4.89-4.87 (m, 1H), 3.39 (s, 3H), 3.27 (dd, J=12.0, 9.3 Hz, 1 H), 3.04 (dd, J=12.0, 3.9 Hz, 1H), 2.94 (td, J=12.6, 3.1 Hz, 1H0, 2.84 (dt, J=12.6, 4.3 Hz, 1H), 2.51-2.48 (m, 1H), 2.12 (bs, 2H), 1.89 (ddt, J=13.7, 10.6, 4 Hz, 1 H), 1.62 (dq, J=13.7, 4Hz, 1 H), 1.07 (d, J=7.3 Hz, 3H). 13C NMR (400 MHz, CDCI3): δ 157.9, 152.0, 151.0, 120.0, 103.0, 102.5, 56.3, 46.2, 42.4, 34.7, 33.4, 32.4, 14.3. KEY INT

 

Example 11 Preparation of 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3- oxo-propionitrile….TOFACITINIB BASE

 

To a clean, dry, nitrogen-purged 1.0 L reactor were charged methyl-(4-methyl-piperidin-3-yI)-(7H- pyrroIo[2,3-d]pyrimidin-4-yl)-amine (32.0 g, 0.130 mol), toluene (160 ml), ethyl cyanoacetate (88.53 g, 0.783 mol) and triethyl amine (26.4 g, 0.261 mol). The reaction was heated to 1000C and held for 24 hours. The reaction was washed with water (160 ml). The organic layer concentrated to a volume of 10 ml and water (20 ml) was added. The residual toluene was removed by distillation and the mixture was cooled to room temperature. Acetone (224 ml) was added followed by citric acid (27.57 g, 0.144 mol) in water (76 ml). The resulting slurry was stirred for 7 hours. The solids were isolate by filtration, washed with acetone (96 ml), and dried under vacuum to afford 42.85 g (65.3%) of the title compound. Example 13 Preparation of 3-{(3R, 4R)~4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo- propionitrile citrate salt:…………..TOFACITINIB CITRATE To a clean, dry, nitrogen-purged 500 ml reactor were charged methyl-(4-methyl-piperidin-3-yl)-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-amine (25.0 g, 0.102 mol) and methylene chloride (250 ml). The mixture was stirred at room temperature for a minimum of 2.5 hours. To a clean, dry, nitrogen-purged 1 L reactor were charged cyanoacetic acid (18.2 g, 0.214 mol), methylene chloride (375 ml), and triethyl amine (30.1 ml, 0.214 mol). The mixture was cooled to -15.0— 5.00C over one hour and trimethylacetyl chloride (25.6 ml, 0.204 mol) was added at a rate to maintain the temperature below O0C. The reaction was held for a minimum of 2.5 hours, then the solution of the amine was added at a rate that maintained the temperature below O0C. After stirring for 1 hour, the mixture was warmed to room temperature and 1 M sodium hydroxide (125 ml) was added. The organic layer was washed with water (125 ml) The methylene chloride solution.was displaced with acetone until a volume of 500 ml and a temperature of 55-650C had been achieved. Water (75 ml) was charged to the mixture while maintaining the temperature at 55-65°C. A solution of citric acid (20.76 g, 0.107 mol) in water (25.0) was charged and the mixture was cooled to room temperature. The reactor was stirred for a minimum of 5 hours and then the resulting solids were isolated by filtration and washed with acetone (2×75 ml), which was sent to the filter. The salt was charged into a clean, dry, nitrogen-purged 1L reactor with 2B ethanol (190 ml) and water (190 ml). The slurry was heated to 75-850C for a minimum of 4 hours. The mixture was cooled to 20-300C and stirred for an additional 4 hours. The solids were isolated by filtration and washed with 2B ethanol (190 ml). After drying in a vacuum oven at 500C with a slight nitrogen bleed, 34.6 g (67.3%) of the title compound were isolated. 1H NMR (500 MHz, CZ6-DMSO): δ 8.14 (s, 1 H), 7.11 (d, J=3.6 Hz, 1 H), 6.57 (d, J=3.6 Hz, 1 H), 4.96 (q, J=6.0 Hz, 1 H), 4.00-3.90 (m, 2H), 3.80 (m, 2H), 3.51 (m, 1 H), 3.32 (s, 3H), 2.80 (Abq, J=15.6 Hz, 2H), 2.71 (Abq, J=15.6 Hz, 2H), 2.52-2.50 (m, 1 H), 2.45-2.41 (m, 1 H), 1.81 (m, 1 H), 1.69-1.65 (m, 1 H), 1.04 (d, J=6.9 Hz, 3H)

 

 

PAPER

Org. Lett., 2009, 11 (9), pp 2003–2006
DOI: 10.1021/ol900435t

http://pubs.acs.org/doi/full/10.1021/ol900435t Figure

 

PATENT

http://www.omicsonline.org/open-access/advances-in-the-inhibitors-of-janus-kinase-2161-0444.1000540.php?aid=29799   …………….. सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..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.

Clinical trials

Rheumatoid arthritis

Phase II clinical trials tested the drug in rheumatoid arthritis patients that had not responded to DMARD therapy. In a tofacitinib monotherapy study, the ACR score improved by at least 20% (ACR-20) in 67% of patients versus 25% who received placebo; and a study that combined the drug with methotrexate achieved ACR-20 in 59% of patients versus 35% who received methotrexate alone. In a psoriasis study, the PASI score improved by at least 75% in between 25 and 67% of patients, depending on the dose, versus 2% in the placebo group.[8] The most important side effects in Phase II studies were increased blood cholesterol levels (12 to 25 mg/dl LDL and 8 to 10 mg/dl HDL at medium dosage levels) andneutropenia.[8] Phase III trials testing the drug in rheumatoid arthritis started in 2007 and are scheduled to run until January 2015.[9] In April 2011, four patients died after beginning clinical trials with tofacitinib. According to Pfizer, only one of the four deaths was related to tofacitinib.[10] By April 2011, three phase III trials for RA had reported positive results.[11] In November 2012, the U.S. FDA approved tofacitinib “to treat adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of, methotrexate.”[12]

Psoriasis

As of April 2011 a phase III trial for psoriasis is under way.[11]

Alopecia

In June 2014, scientists at Yale successfully treated a male patient afflicted with alopecia universalis. The patient was able to grow a full head of hair, eyebrows, eyelashes, facial, armpit, genitalia and other hair. No side effects were reported in the study.[13]

Ulcerative colitis

The OCTAVE study of Tofacitinib in Ulcerative Colitis started in 2012. It is currently enrolling patients, though the NIH trials page states that they expect the trial to close in June 2015.[14]

Vitiligo

In a June 2015 study, a 53-year-old woman with vitiligo showed noticeable improvement after taking tofacitinib for five months.[15]

Development of Safe, Robust, Environmentally Responsible Processes for New Chemical Entities

– Dr. V. Rajappa, Director & Head-Process R&D, Bristol-Myers Squibb, India

A PRESENTATION

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  1. Herper, Matthew (2 March 2011). “Why Pfizer’s Biggest Experimental Drug Got A Name Change”. Forbes. Retrieved 3 March 2011.
  2.  Kremer, J. M.; Bloom, B. J.; Breedveld, F. C.; Coombs, J. H.; Fletcher, M. P.; Gruben, D.; Krishnaswami, S.; Burgos-Vargas, R. N.; Wilkinson, B.; Zerbini, C. A. F.; Zwillich, S. H. (2009). “The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo”. Arthritis & Rheumatism 60 (7): 1895–1905. doi:10.1002/art.24567. PMID 19565475. edit
  3.  “Tasocitinib”. Drugs in R&D 10 (4): 271–284. 2010. doi:10.2165/11588080-000000000-00000. PMC 3585773. PMID 21171673. edit
  4.  Ghoreschi, K.; Jesson, M. I.; Li, X.; Lee, J. L.; Ghosh, S.; Alsup, J. W.; Warner, J. D.; Tanaka, M.; Steward-Tharp, S. M.; Gadina, M.; Thomas, C. J.; Minnerly, J. C.; Storer, C. E.; Labranche, T. P.; Radi, Z. A.; Dowty, M. E.; Head, R. D.; Meyer, D. M.; Kishore, N.; O’Shea, J. J. (2011). “Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550)”. J Immunol. 186 (7): 4234–4243. doi:10.4049/jimmunol.1003668. PMC 3108067. PMID 21383241. edit
  5. ^ Jump up to:a b c “Seeking Profit for Taxpayers in Potential of New Drug”, Jonathan Weisman, New York Times, March 18, 2013
  6. Ken Garber (9 January 2013). “Pfizer’s first-in-class JAK inhibitor pricey for rheumatoid arthritis market”. Nature Biotechnology 31 (1): 3–4. doi:10.1038/nbt0113-3. PMID 23302910.
  7. Jump up^ Moisan A, et al. White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nature Cell Biology, 8 December 2014. DOI 10.1038/ncb3075
  8.  “EULAR: JAK Inhibitor Effective in RA But Safety Worries Remain”. MedPage Today. June 2009. Retrieved 9 February 2011.
  9.  Clinical trial number NCT00413699 for “Long-Term Effectiveness And Safety Of CP-690,550 For The Treatment Of Rheumatoid Arthritis” at ClinicalTrials.gov
  10.  Matthew Herper. “Pfizer’s Key Drug Walks A Tightrope”. Forbes.
  11.  “Two Phase III Studies Confirm Benefits of Pfizer’s Tofacitinib Against Active RA”. 28 Apr 2011.
  12.  “FDA approves Xeljanz for rheumatoid arthritis”. 6 Nov 2012.
  13.  “Hairless man grows full head of hair in yale arthritis drug trial”. 19 Jun 2014.
  14.  https://clinicaltrials.gov/ct2/show/NCT01465763?term=A3921094&rank=1
  15. “This Drug Brought Pigment Back for Woman with Vitiligo”. TIME. June 27, 2015. Retrieved June 29, 2015.
  16. Nordqvist, Christian (27 April 2013). “Pfizer’s Arthritis Drug Xeljanz (tofacitinib) Receives A Negative Opinion In Europe”. Medical News Today. Retrieved 2 August 2013.
  17. “”XALEJANZ PRESCRIBING INFORMATION @ Labeling.Pfizer.com””.

SEE………http://orgspectroscopyint.blogspot.in/2014/12/tofacitinib-citrate.html

Tofacitinib
Tofacitinib2DACS.svg
Systematic (IUPAC) name
3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile
Clinical data
Trade names Xeljanz, Jakvinus
AHFS/Drugs.com entry
Licence data US FDA:link
Pregnancy category
  • US: C (Risk not ruled out)
Legal status
Routes of administration Oral
Pharmacokinetic data
Bioavailability 74%
Protein binding 40%
Metabolism Hepatic (via CYP3A4 andCYP2C19)
Biological half-life 3 hours
Excretion Urine
Identifiers
CAS Registry Number 477600-75-2
ATC code L04AA29
PubChem CID: 9926791
IUPHAR/BPS 5677
DrugBank DB08183
ChemSpider 8102425
UNII 87LA6FU830
ChEBI CHEBI:71200 Yes
ChEMBL CHEMBL221959
Synonyms CP-690550
Chemical data
Formula C16H20N6O
Molecular mass 312.369 g/mol

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..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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He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy
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European Commission Approves Genzyme’s Once-Daily, Oral Multiple Sclerosis Treatment Aubagio® (teriflunomide)


Teriflunomide,

Teriflunomide, HMR-1726, 1726, A-771726, RS-61980, SU-0020,
(Z)-2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide
108605-62-5, 282716-73-8 (monosodium salt)
C12-H9-F3-N2-O2
270.2091
Aventis Pharma (Originator), Sanofi-Aventis U.S. Llc
Sugen (Licensee)
Antiarthritic Drugs, Disease-Modifying Drugs, Immunologic Neuromuscular Disorders, Treatment of, IMMUNOMODULATING AGENTS, Immunosuppressants, Multiple Sclerosis, Agents for, NEUROLOGIC DRUGS, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Dihydroorotate Dehydrogenase Inhibitors

CAMBRIDGE, Mass.–Aug. 30, 2013–(BUSINESS WIRE)–Genzyme, a Sanofi company (EURONEXT: SAN and NYSE: SNY), announced today that the European Commission has granted marketing authorization for Aubagio® (teriflunomide) 14 mg, a once-daily, oral therapy indicated for the treatment of adult patients with relapsing remitting multiple sclerosis (RRMS).

read all at

http://www.pharmalive.com/ec-approves-genzyme-s-aubagio-for-ms

Teriflunomide (trade name Aubagio, marketed by Sanofi, also known as A77 1726) is the active metabolite of leflunomide.[1]Teriflunomide was investigated in the Phase III clinical trial TEMSO as a medication for multiple sclerosis (MS). The study was completed in July 2010.[2] 2-year results were positive.[3] However, the subsequent TENERE head-to-head superiority trial reported that “although permanent discontinuations [of therapy] were substantially less common among MS patients who received teriflunomide compared with interferon beta-1a, relapses were more common with teriflunomide.”[4] The drug was approved by the FDA on September 13, 2012.[5]

Mechanisms of action

Teriflunomide is an immunomodulatory drug inhibiting pyrimidine de novo synthesis by blocking the enzyme dihydroorotate dehydrogenase. It is uncertain whether this explains its effect on MS lesions.[6]

Teriflunomide inhibits rapidly dividing cells, including activated T cells, which are thought to drive the disease process in MS. Teriflunomide may decrease the risk of infections compared to chemotherapy-like drugs because of its more-limited effects on the immune system.[7]

It has been found that teriflunomide blocks the transcription factor NF-κB. It also inhibits tyrosine kinase enzymes, but only in high doses not clinically used.[8]

Activation of leflunomide to teriflunomide

Leflunomide.svgE-Teriflunomide structure.svgTeriflunomide structure.svg

The structure which results from ring opening can interconvert between the E and Z enolic forms (and the corresponding keto-amide), with the Z enol being the most stable and therefore most predominant form.

Space filling model of the E isomer of teriflunomide


  1. ^
     Magne D, Mézin F, Palmer G, Guerne PA (2006). “The active metabolite of leflunomide, A77 1726, increases proliferation of human synovial fibroblasts in presence of IL-1beta and TNF-alpha”. Inflamm. Res. 55 (11): 469–75. doi:10.1007/s00011-006-5196-xPMID 17122964.
  2. ^ ClinicalTrials.gov Phase III Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO)
  3.  “Sanofi-Aventis’ Teriflunomide Comes Up Trumps in Two-Year Phase III MS Trial”. 15 Oct 2010.
  4.  Gever, John (June 4, 2012). “Teriflunomide Modest Help but Safe for MS”medpage. Retrieved June 04, 2012. Unknown parameter |source= ignored (help)
  5. ^ “FDA approves new multiple sclerosis treatment Aubagio” (Press release). US FDA. Retrieved 2012-09-14.
  6. ^ H. Spreitzer (March 13, 2006). “Neue Wirkstoffe – Teriflunomid”. Österreichische Apothekerzeitung (in German) (6/2006).
  7.  Dr. Timothy Vollmer (May 28, 2009). “MS Therapies in the Pipeline: Teriflunomide”. EMS News (in English) (May 28, 2009).
  8. ^ Breedveld, FC; Dayer, J-M (November 2000). “Leflunomide: mode of action in the treatment of rheumatoid arthritis”Ann Rheum Dis 59 (11): 841–849. doi:10.1136/ard.59.11.841.PMC 1753034PMID 11053058.

SYNTHESIS

………………………

http://www.google.com/patents/WO2014177978A3?cl=en

Formula i

Teriflunomide is an immunosuppressant, acting as a tyrosine kinase inhibitor. It is also evaluated in the treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis. An oral film coated tablet containing teriflunomide as the active ingredient is marked in the United States by Sanofi Aventis US using brand AUBAGIO™. AUBAGIO is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

U.S. Patent No. 5,679,709 appears to claim teriflunomide and its pharmaceutically acceptable salts, the same patent also further covers pharmaceutical composition and method of administering top a patients suffering from autoimmune disease.

U.S. Patent No. 5,494,91 I disclosesthe process for the preparation of teriflunomide by reacting 5-methylisoxazole-4-carbonyl chloride with trifluoromethyl aniline in the presence of acetonitrile to yield Leflunomide with on further hydrolysis with aqueous sodium hydroxide solution in methanol gives teriflunomide of formula I.

U.S. Patent No. 5,990,141 discloses the process for the preparation of teriflunomide by reacting 4-trifluoromethyl aniline with cyano acetic acid ethyl ester to yield cyanoaceto-(4-trifluromethyl)-aniline, with on further reacted with acetyl chloride in the presence of sodium hydride base and THF and acetonitrile solvent to give teriflunomide of formula I.

U.S. patent No. 6,365,626 discloses the process for the preparation of teriflunomide by reacting 4-trifluromethylaniline with cyanoacetic acid to give cyanoacet-(4- trifluoromethyl)anilide which on further reacted with acetyl chloride in the presence of sodium hydride to give teriflunomide of formula I.

U.S. Patent No. 6,894,184 discloses the process for the preparation of teriflunomide involves reacting 4-trifluromethylaniline with cyanoacetic acid to give cyanoacet-(4- trifluoromethyl)anilide which on further reacted with acetic anhydride in the presence of base to give teriflunomide of formula I.

International PCT application No. WO 2009/147624 discloses the process for the preparation of teriflunomide involves condensation of ethyl-2-cyano-3-hydroxybut-2-enoate and 4-(trifluoromethyl) aniline in presence of xylene solvent at reflux temperatures for 16 hours to give teriflunomide of formula I.

preparation of teriflunomide (I) comprises steps of;

1 ) condensation of cyanoacetic acid of formula (II) with 4-trifluoromethyl aniline of formula (III) in the presence of chlorinating agent to give 2-cyano-N-[4-(trifluromethyl)phenyl]acetamide of formula (IV);

(II I) (IV)

2) acetylation of 2-cyano-N-[4-(trifluromethyl)phenyl] acetamide of

formula (IV) with an acetylating agent in the presence of base and suitable solvents to yield teriflunomide of formula (I).

EXAMPLE 1 : Preparation of 2-cvano-N-f4-(trifluoromethyl> phenyl! acetamide (IV)

A round bottom flask is charged with cyanoacetic acid (100 g) and phosphorous pentachloride and tetrahydrofuran (300 ml) and the reaction mixture is stirred at room temperature for 4 hours. 4-trifluoromethyl aniline (161 g) dissolved in tetrahydrofuran (100 ml) is slowly added to the reaction mixture and stirred for completion of reaction. The resultant reaction mass is cooled and separated solid is filtered and washed with slurry of Isoproapnol and cyclohexane and dried under reduced pressure to afford the title compound. Weight: 196 gm.

Purity by HPLC: 98%

EXAMPLE 2: preparation of 2-cyano-3-hvdroxy-N-f4-( trifluoromethyl) phenyl] but-2-enamide (Teriflunomide crude)

A round bottom flask is charged with 2-cyano-N-[4-{trifluromethyl} phenyl] acetamide (100g), sodium hydroxide (70 gm) and dimethyl formamide is added and the reaction mixture is stirred for 30 minutes. Isopropenyl acetate (60 ml) is added slowly and the resultant mixture is stirred for about 4-5 hours at room temperature. After completion of the reaction, the resulting reaction mixture is diluted with water and acidified with Cone. HCI solution and stirred for solid separation. The separated solid is filtered and washed with water and dried under reduced pressure to afford Teriflunomide.

The obtained teriflunomide is charged in round bottom flask and aqueous solution of sodium hydroxide solution (29.6 g in 300 ml water) is added slowly at 25-35°C and stirred for 1 to 2 hours. The mixture is brought to 5 to 10°C and dichloromethane is added, the mixture is stirred for 15 minutes. The organic and the aqueous layer are separated, and the resultant aqueous layer is acidified with aq. Hcl and stirred. The separated solid is filtered and washed with water and dried under vacuum at 65-70°C for 10-12 hours to afford teriflunomide.

Weight: 101 gm

Purity by HPLC: 95%

EXAMPLE 3; Purification of Teriflunomide:

Teriflunomide (5 g) is charged into a flask followed by addition of acetonitrile (125 ml) and heated to reflux and stirred for 2 hours. The resultant reaction solution is filtered through highflow bed to obtain a clear solution and cooled to room temperature and stirred for solid separation. The separated solid is filtered, washed with Isopropanol (50 ml) and dried under vacuum to afford pure teriflunomide.

Weight: 3.8 gm

Purity by HPLC: 99.7%

…………………………………………………………………………………………………………

EP 0527736; JP 1993506425; JP 1999322700; JP 1999343285; US 5494911; US 5532259; WO 9117748

5-Methylisoxazole-4-carboxylic acid (I) was converted to the corresponding acid chloride (II) upon refluxing with SOCl2. Coupling of acid chloride (II) with 4-(trifluoromethyl)aniline (III) produced anilide (IV). Finally, isoxazole ring opening in the presence of NaOH gave rise to the title cyano amide.

Teriflunomide, a dihydroorotate dehydrogenase (DHODH) inhibitor, is the active metabolite of leflunomide a synthetic, low-molecular-weight drug currently used in the treatment of rheumatoid arthritis. The mechanisms by which teriflunomide exerts its antiinflammatory, antiproliferative and immunosuppressive effects are not yet completely understood, although inhibition of pyrimidine biosynthesis (via suppression of DHODH) and interference with tyrosine kinase activity both appear to be involved. Based on its efficacy shown in animal models of experimental allergic encephalomyelitis, teriflunomide was tested in a phase II study in patients with multiple sclerosis with relapses. Recruitment is ongoing for a phase III study to determine the efficacy of teriflunomide in reducing the frequency of relapses and accumulation of disability in multiple sclerosis patients.

The chemical name of Teriflunomide is 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide and formula is C12H9F3N2O2 and molecular weight is 270.207.

Teriflunomide is used as Immunosupressant. It acts as tyrosine kinase inhibitor. It is used in treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis.

Teriflunomide was first disclosed and claimed in U.S. Pat. No. 5,679,709 but this patent does not mention any process of preparation for salt formation.

U.S. Pat. No. 5,494,911, U.S. Pat. No. 5,990,141 disclose various processes for preparing Teriflunomide. These patents do not disclose process for preparation Teriflunomide salts or mention any its polymorphic form.

EP 2280938 A2

HISTORY OF SYNTHESIS

The chemical name of Teriflunomide is

2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide and formula is Ci2H9 F3N2O2 and molecular weight is 270.207.

Teriflunomide is used as Immunosupressant. It acts as tyrosine kinase inhibitor. It is used in treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis.

Teriflunomide was first disclosed and claimed in US patent no. 5,679,709 but this application does not mention the process of preparation.

US patent no. 5,494,911 discloses a process for preparation of Teriflunomide as shown in given below

Figure imgf000002_0002

4-trifluoromethylaniline (IV) in acetonitrile to give leflunomide (VI). The subsequent hydrolysis with aqueous sodium hydroxide solution in methanol gives Teriflunomide (I). US patent 5,990,141 discloses a process for preparation of Teriflunomide as shown in given below

Figure imgf000003_0001

Teriflunomide (I)

The process involves reacting 4-trifluorometyl aniline (IV) with cyanoacetic acid ethyl ester (II) to give cyanoacet-(4-trifluoromethyl)-anilide (VII). This compound is further reacted first with sodium hydride in acetonitrile and then with acetylchloride in THF to give Teriflunomide (I).

US patent no. 6,365,626 discloses a process for preparation of Teriflunomide  which is as given in below

Figure imgf000003_0002

Teriflunomide

ONE MORE

Graphical abstract: Mechanosynthesis of amides in the total absence of organic solvent from reaction to product recovery

http://pubs.rsc.org/en/content/articlelanding/2012/cc/c2cc36352f GET ABOVE DETAILS HERE

Teriflunomide is used as Immunosupressant. It acts as tyrosine kinase inhibitor. It is used in treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis.

Teriflunomide was first disclosed and claimed in US patent no. 5,679,709 but this application does not mention the process of preparation.

[H] US patent no. 5,494,911 discloses a process for preparation of Teriflunomide in Example-4 as shown in given below scheme-I

(V) (IV) (VI) (D

Scheme-I

The proces; 5 involves re acting 5-metlr

4-trifluoromethylaniline (IV) in acetonitrile to give leflunomide (VI). The subsequent hydrolysis with aqueous sodium hydroxide solution in methanol gives Teriflunomide (I). US patent 5,990,141 discloses a process for preparation of Teriflunomide as shown in given below scheme-II.

Teriflunomide (I)

Scheme-II  The process involves reacting 4-trifluorometyl aniline (IV) with cyanoacetic acid ethyl ester (II) to give cyanoacet-(4-trifluoromethyl)-anilide (VII). This compound is further reacted first with sodium hydride in acetonitrile and then with acetylchloride in THF to give Teriflunomide (I).

US patent no. 6,365,626 discloses a process for preparation of Teriflunomide in Fig. 19 which is as given in below scheme-Ill.

Teriflunomide

(I)

Scheme-Ill  The process involves reacting 4-trifluoromethyl aniline (IV) with cyanoacetic acid (Ha) to give compound of formula (VII). This compound is further reacted first with sodium hydride and then with acetylchloride to give Teriflunomide (I)

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Example-1  Preparation of Ethyl-2-cyano-3-hydroxy-but-2-enoate (III) [77] Potassium carbonate (73.3 g) was added to the well stirred solution of Ethylcy- anoacetate (50 g) in Dimethylformamide (250 ml) and stirred for 15 minute at ambient temperature. Acetic anhydride (90.25 g) was added drop wise to the above well stirred solution during 2 to 3 hours at ambient temperature. Reaction mixture was stirred at ambient temperature for 15 to 20 hours. Reaction mixture was diluted with water (500 ml) and extracted with dichloromethane (3 xlOO ml). Combined organic layer was washed with saturated sodium carbonate solution (3x100ml). Aqueous carbonate layer was separated and acidified with 50% HCl solution and extracted with dichloromethane (3x100ml). Combined organic layer was washed with brine solution (100 ml), dried over sodium sulfate and evaporated to yield Ethyl 2-cyano-3-hydroxy-but-2-enoate (58 g).

Yield: 84.6%Example-2 ] Preparation of Teriflunomide (I) [82] Ethyl 2-cyano-3-hydroxybut-2-enoate (III) (50 g) and 4-(trifluoromethyl) aniline (51.9 g) in xylene (1000 ml) was refluxed for 48 hours. The reaction mixture was allowed to cool at room temperature. Separated solid was filtered and washed with xylene (2×100 ml). Solid was dried under vacuum at 700C to yield (62 g) of Teri- flunomide.

Yield: 71.0%

Purity: 99.4%

! HNMR (DMSO, 300MHz) :δ 2.24(s, 3H); 5.36(bs, IH); 7.65(d, J=8.7Hz, 2H);

7.76(d, J=8.6Hz, 2H); 10.89(s, IH) ppm.

13 CNMR (DMSO, 75MHz) :δ 23.5, 82.1, 118.3, 122.2, 126.5, 126.9, 142.1, 167.4,

187.8 ppm.

MS(FD) : m/e 269(M”, 100). [88] IR : 3305, 2220, 1633, 1596, 1554, 1418, 1405, 1325, 1247, 1114, 1157, 1073, 971,

842, 684 cm-1.

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see

http://pubs.rsc.org/en/Content/ArticleLanding/2004/OB/b312682j#!divAbstract

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http://www.google.com/patents/CN103848756A?cl=en

Currently, for the preparation of teriflunomide mainly in the following three categories:

The first synthetic methods: mainly 5-methyl-isoxazole-4-carboxylic acid starting materials or by Synthesis of 5-methyl-isoxazole-4-carboxylic acid intermediate, then reacted with 4- trifluoromethyl base – aniline was synthesized teriflunomide, specific synthetic route is as follows:

[0007]

Figure CN103848756AD00042

The general reaction step above normal class methods, not easy to intermediate purification, total yield is low, and the synthesis process using a large number of chloride corrosion of equipment can easily produce large amounts of acid mist and acidic water, thus polluting the environment .

  The second class of methods: 2-cyano-acetic acid derivatives and 4-trifluoromethyl aniline. Such methods will be first prepared as a 2-cyano acetic acid chloride, and then 4-trifluoromethyl-aniline to give the corresponding amide, and then acetyl chloride for

With, the condensation reaction between the molecules to give the desired product, the synthesis route is as follows:

Figure CN103848756AD00051

This class methods used in the reaction process large amounts of chloride reagent for large equipment and environmental damage.

The third method: This method is quite similar to the second type of method, mainly in the 2-cyano-acetic acid derivatives and 4-trifluoromethyl-aniline; The method of the second type is different, In the last step with 1-methyl-2-chloro-propylene oxide as raw materials to build α, β-unsaturated nitrile of the enol structure, i.e., to give the desired product, the synthesis route is as follows:

Figure CN103848756AD00052

Teriflunomide Preparation Example 18 [0185] Implementation

Example 17 was obtained as a pale yellow solid of 61.2g crude compound was used directly in the synthesis of teriflunomide. In a 2L round bottom flask was added compound 27.2g (0.32mol) having the structure shown in formula IV, dry dioxane (620mL), sodium hydride 4g (0.16mol, in g / mL count, mass volume ratio 60% saving in kerosene), calcium hydride

6.7g (0.16mol), 15 ° C was stirred for I h, then slowly added dropwise in Example 17 was obtained as a pale yellow solid compound 61.2g (0.32mol) embodiment of dioxane 200mL, approximately I hour addition was complete, After the addition was complete the reaction was heated to reflux, the reaction at 80 ° C for 24 hours, the reaction process using a nitrogen blanket. After completion of the reaction was added 500mL of ice water to quench the reaction, with 2mol / L of HCl (aq.) And the reaction solution was adjusted to neutral pH, and extracted with EtOAc three times each in an amount of 500mL, and the combined organic phase was washed with saturated aqueous NaCl solution 800mL, dried over anhydrous Na2SO4, concentrated under reduced pressure, the mixed solution was twice recrystallized from methanol i_PrOH, the volume ratio of 1-PrOH and methanol is 2: 1, by volume of each recrystallized with a mixed solution of methanol with i_PrOH for 600mL, the crystallization temperature of 10 ° C, to give 58.8g of white solid compound in a yield of 66%, the total yield of 54% ο

Figure CN103848756AD00221

using mass spectrometry, nuclear magnetic resonance spectroscopy and NMR spectra of the resulting white solid carbon compound structures were identified. MS data [M-H +] = 269.1, H NMR data = 1H-NMR (DMSO-Cie) δ the white solid compound: 10.88 (s, 1Η), 10.07 (br, s, 1H), 7.79 ( d, 2H), 7.66 (d, 2H), 2.26 (s, 3H), carbon NMR spectral data for: 13C-NMR (DMS0-d6) δ: 23.5,80.2,119.1,119.9,120.3,122.4,122.0, 123.5,125.3,126.2,141.8,166.2,186.0. Structural analysis by a white solid compound obtained in the present embodiment example for teriflunomide. Cases detected by HPLC obtained teriflunomide the embodiment of purity, calculated based on the peak area normalization method available, the present embodiment obtained teriflunomide a purity of 99.9%.

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http://www.google.com/patents/WO2015029063A2?cl=en

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Scheme-A

Scheme-A

Pure Teriflunomide ………………………………………….Crude Teriflunomide

xamples

Example- 1: Preparation of N-(4′-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide (Formula-2)

Methylene chloride (125 ml) and dimethyl formamide (2.87 gms) were added to 5-methylisoxazole-4-carboxylic acid (25 gms) at 25-30°C. Heated the reaction mixture to 35-40°C and thionyl chloride (47.59 gms) was slowly added and stirred for 4 hours at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture. To the obtained compound, dichloromethane was added at 25-30°C. Distilled off the solvent completely from the reaction mixture. Acetonitrile (50 ml) was added to the obtained compound at 25-30°C and slowly added to a mixture of acetonitrile (300 ml) and 4-(trifluoromethyl)aniline (64.45 gms) at 25-30°C and stirred the reaction mixture for 5 hours at the same temperature. Filtered the reaction mixture and distilled off the solvent completely from the filtrate. Methanol (225 ml), followed by activated carbon (2.5 gms) were added to the obtained compound at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Water (250 ml) was slowly added to the obtained filtrate at 25-30°C and stirred the reaction mixture for 2 hours. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 39.8 gms; Melting point: 165-168°C. Purity by HPLC: 99.63%.

Example-2: Preparation of N-(4′-trifluoromethylphenyl)-5-methylisoxazoIe-4-carboxamide (FormuIa-2)

Methylene chloride (15 Its) and dimethyl formamide (40 ml) were added to 5-methylisoxazole-4-carboxylic acid (3 kgs) at 25-30°C. Thionyl chloride (5.70 kgs) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 4 hours at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture. Cooled the reaction mixture to 25-30°C and dichloromethane was added at the same temperature. Distilled off the solvent completely from the reaction mixture. Cooled the reaction mixture to 25-30°C and dissolved the obtained compound in acetonitrile (6.0 Its) at the same temperature. Slowly added to a mixture of acetonitrile (36 Its) and 4-(trifluoromethyl)aniline (7.70 kgs) at 25-30°C and stirred the reaction mixture for 5 hours at the same temperature. After completion of the reaction, filtered the reaction mixture and distilled off the solvent completely from the filtrate. Methanol (27 Its), followed by activated carbon (30 gms) was added to obtained compound at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Water (30 Its) was slowly added to the obtained filtrate at 25-30°C and stirred the reaction mixture for 2 hours. Filtered the precipitated solid, washed with water. To the obtained wet compound, toluene (9 Its) was added at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with toluene and dried to get the title compound. Yield: 4.7 kg.

Example-3: Preparation of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide (Formula-l)

Methanol (150 ml) was added to N-(4′-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide (50 gms) at 25-30°C. Cooled the reaction mixture to 0-5°C and aqueous sodium hydroxide solution was slowly added to the reaction mixture at the same temperature. Stirred the reaction mixture for 2 hours at 0-5°C. Water was added to the reaction mixture. Adjust the pH of the reaction mixture to 7.5 by using dilute hydrochloric acid at 25-30°C. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 46.0 gms;

Example-4: Preparation of crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide (Formula-1)

Dimethylformamide (300 ml) was added to (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide (50 gms) at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture and washed with dimethyl formamide. To the obtained filtrate, methanol (350 ml) was added at 25-30°C. Cooled the reaction mixture to 10-15°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with chilled methanol and dried to get the title compound. Yield: 41 gms;

Melting point: 228-231°C; Water content: 0.06% w/w; Phenyl isoxazole impurity: 0.004%; Purity by HPLC: 99.97%.

Particle size distribution before micronisation: D10: 6.71 μιτι; D50: 34.4 μπι; D90: 109.8 μηι; Particle size distribution after micronisation: DIO: 1.35 μητ, D50: 4.52 μητ, D90: 10.26 μιη.

The P-XRD of the obtained compound is shown in figure- 1.

The DSC thermogram of the obtained compound is shown in figure-2.

Reference Example- 1: Preparation of (Z)-2-cyano-3-hydroxy-but-2-enoicacid-(4-trifluoromethylphenyl)-amide according to US5494911 (Formula-1)

Methanol (74 ml) was added to N-(4′-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide (20 gms) at 25-30°C. Cooled the reaction mixture to 0-5°C and aqueous sodium hydroxide solution {prepared by dissolving sodium hydroxide (3.26 gms) in water (74 ml)} was slowly added to the reaction mixture at the same temperature. Stirred the reaction mixture for 1 hour at 0-5°C. After completion of the reaction, 20% aqueous hydrochloric acid solution was added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 8.7 gms.

The P-XRD pattern of the obtained compound is shown in figure-3.

The DSC thermogram of the obtained compound is shown in figure-4.

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TERIFLUNOMIDE SPECTRAL DATA


Teriflunomide,
HMR-1726, 1726, A-771726, RS-61980, SU-0020,
(Z)-2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide
108605-62-5, 282716-73-8 (monosodium salt)
C12-H9-F3-N2-O2 270.2091

17= US2011/0105795A1

NMR DASTA

1H NMR AND 13C NMR

1H NMR 13C NMR

above 13C NMR

! HNMR (DMSO, 300MHz) :δ 2.24(s, 3H); 5.36(bs, IH); 7.65(d, J=8.7Hz, 2H);

7.76(d, J=8.6Hz, 2H); 10.89(s, IH) ppm.
 
13 CNMR (DMSO, 75MHz) :δ 23.5, 82.1, 118.3, 122.2, 126.5, 126.9, 142.1, 167.4,
187.8 ppm.
MS(FD) : m/e 269(M”, 100).
 IR : 3305, 2220, 1633, 1596, 1554, 1418, 1405, 1325, 1247, 1114, 1157, 1073, 971,
842, 684 cm-1.

REF EP 2280938 A2

Example-1  Preparation of Ethyl-2-cyano-3-hydroxy-but-2-enoate (III) [77] Potassium carbonate (73.3 g) was added to the well stirred solution of Ethylcy- anoacetate (50 g) in Dimethylformamide (250 ml) and stirred for 15 minute at ambient temperature. Acetic anhydride (90.25 g) was added drop wise to the above well stirred solution during 2 to 3 hours at ambient temperature. Reaction mixture was stirred at ambient temperature for 15 to 20 hours. Reaction mixture was diluted with water (500 ml) and extracted with dichloromethane (3 xlOO ml). Combined organic layer was washed with saturated sodium carbonate solution (3x100ml). Aqueous carbonate layer was separated and acidified with 50% HCl solution and extracted with dichloromethane (3x100ml). Combined organic layer was washed with brine solution (100 ml), dried over sodium sulfate and evaporated to yield Ethyl 2-cyano-3-hydroxy-but-2-enoate (58 g).

Yield: 84.6% Example-2 Preparation of Teriflunomide (I) [82] Ethyl 2-cyano-3-hydroxybut-2-enoate (III) (50 g) and 4-(trifluoromethyl) aniline (51.9 g) in xylene (1000 ml) was refluxed for 48 hours. The reaction mixture was allowed to cool at room temperature. Separated solid was filtered and washed with xylene (2×100 ml). Solid was dried under vacuum at 700C to yield (62 g) of Teri- flunomide.

Yield: 71.0%

Purity: 99.4%

! HNMR (DMSO, 300MHz) :δ 2.24(s, 3H); 5.36(bs, IH); 7.65(d, J=8.7Hz, 2H);

7.76(d, J=8.6Hz, 2H); 10.89(s, IH) ppm.

13 CNMR (DMSO, 75MHz) :δ 23.5, 82.1, 118.3,

122.2, 126.5,

126.9, 142.1, 167.4,

187.8 ppm.

MS(FD) : m/e 269(M”, 100).

IR : 3305, 2220, 1633, 1596, 1554, 1418, 1405, 1325, 1247, 1114, 1157, 1073, 971,

842, 684 cm-1.

1H NMR PREDICT

2-Cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)but-2-enamide,teriflunomide NMR spectra analysis, Chemical CAS NO. 108605-62-5 NMR spectral analysis, 2-Cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)but-2-enamide,teriflunomide H-NMR spectrum

2-Cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)but-2-enamide,teriflunomide NMR spectra analysis, Chemical CAS NO. 108605-62-5 NMR spectral analysis, 2-Cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)but-2-enamide,teriflunomide C-NMR spectrum

COSY

COSY

HPLC

HPLC method of analysis:

N-(4′-trifluoromethylphenyI)-5-methylisoxazole-4-carboxamide of formula-2:

Apparatus: A liquid chromatographic system equipped with variable wavelength UV- detector; Column: Cosmicsil APT CI 8, 100 x 4.6 mm, 3 μιη (or) equivalent; Flow rate: 1.5 ml/min; Wavelength: 210 nm; Column Temperature: 25°C; Injection volume: 20 μί; Run time: 40 min; Diluent: Mobile phase; Needle wash: Tetrahydrofuran; Elution: Isocratic; Mobile phase: 5 ml of triethyl amine into a 650 ml of water. Adjusted the pH to 3.4 with dil. Orthophosphoric acid and filter this solution through 0.22 μπι nylon membrane filter paper and sonicate to degas it. (Z)-2-cyano-3-hydroxy-but-2-enoicacid-(4-trifluoromethyl phenyl)-amide compound of formula- 1:

Apparatus: A liquid chromatographic system equipped with variable wavelength UV- detector; Column: Kromasil 100 C18, 250 x 4.6 mm, 5 μηι (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 250 nm; Column Temperature: 35°C; Injection volume: 5 μί; Run time: 37 min; Diluent: 0.01 M dipotassium hydrogen orthophosphate in 1000 ml of water; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile : Buffer (70:30 v/v); Buffer: 1 ml of ortho phosphoric acid into a 1000 ml of water and 3.0 grams of 1 -octane sulfonic acid sodium salt anhydrous. Adjust pH to 6.0 with potassium hydroxide solution and filtered through 0.22μηι Nylon membrane filter paper and sonicate to degas it……..http://www.google.com/patents/WO2015029063A2?cl=en

WO2009147624A2 * 3 Jun 2009 10 Dec 2009 Alembic Limited A process for preparing teriflunomide
WO2011004282A2 * 22 Jun 2010 13 Jan 2011 Alembic Limited Novel polymorphic form of teriflunomide salts
US5494911 24 Oct 1990 27 Feb 1996 Hoechst Aktiengesellschaft Isoxazole-4-carboxamides and hydroxyalkylidenecyanoacetamides, pharmaceuticals containing these compounds and their use
US5679709 7 Jun 1995 21 Oct 1997 Hoechst Aktiengesellschaft N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide or salts, used for reduction of b-cell produced self-antibodies
US5990141 6 Jan 1995 23 Nov 1999 Sugen Inc. Administering 5-methyl-isoxazole-4-carboxylic acid-n-(4-trifluoromethyl)anilide or 2-cyano-3-hydroxy-n-(4-trifluoro-methyl)phenyl-2-butenamide; antitumor,-carcinogenic and proliferative agents; kinase inhibitors
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