TOLVAPTAN, 的合成

TOLVAPTAN

的合成

N-(4-{[(5R)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl}-3-methylphenyl)-2-methylbenzamide

Formula	C26H25ClN2O3
Mol. mass	448.941 g/mol

150683-30-0 CAS NO
OPC-41061
Otsuka.....innovator
European Medicines Agency (EMA) Accepts Otsuka's Marketing Authorisation Application (MAA) for Tolvaptan, an Investigational Compound for Autosomal Dominant Polycystic Kidney Disease (ADPKD)
•Tolvaptan was discovered by Otsuka in Japan and, if approved by the EMA, would become the first pharmaceutical therapy in Europe for patients with ADPKD
•ADPKD is an inherited genetic disease that causes cyst growth in the kidneys, which gradually impairs their functioning. There is no current pharmaceutical treatment option
•Otsuka’s development of tolvaptan as a treatment for ADPKD illustrates the company’s commitment to address significant patient needs for diseases that traditionally have not been a priority for the pharmaceutical industry
TOKYO--(BUSINESS WIRE)--Otsuka Pharmaceutical Co., Ltd. announced today that the European Medicines Agency (EMA) has accepted the submission of a marketing authorisation application (MAA) for the potential approval of tolvaptan for the treatment of autosomal dominant polycystic kidney disease (ADPKD). Phase III clinical trial results that form the basis of the regulatory filing were published in the New England Journal of Medicine.
http://www.pharmalive.com/ema-accepts-otsukas-maa-for-tolvaptan
Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP).
Tolvaptan is (±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]-otolu-m-toluidide. The empirical formula is C₂₆H₂₅ClN₂O₃. Molecular weight is 448.94. The chemical structure is:
SAMSCA tablets for oral use contain 15 mg or 30 mg of tolvaptan. Inactive ingredients include corn starch, hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate and microcrystalline cellulose and FD&C Blue No. 2 Aluminum Lake as colorant.
Tolvaptan (INN), also known as OPC-41061, is a selective, competitive vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated withcongestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone(SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca and in India is manufactured & sold by MSN laboratories Ltd. under the trade name Tolvat & Tolsama.

Tolvaptan is also in fast-track clinical trials[2] for polycystic kidney disease. In a 2004 trial, tolvaptan, when administered with traditional diuretics, was noted to increase excretion of excess fluids and improve blood sodium levels in patients with heart failure without producing side effects such as hypotension (low blood pressure) or hypokalemia(decreased blood levels of potassium) and without having an adverse effect on kidney function.[3] In a recently published trial (TEMPO 3:4 ClinicalTrials.gov number, NCT00428948) the study met its primary and secondary end points. Tolvaptan, when given at an average dose of 95 mg per day over a 3-year period, slowed the usual increase in kidney volume by 50% compared to placebo (2.80% per year versus 5.51% per year, respectively, p<0.001) and reduced the decline in kidney function when compared with that of placebo-treated patients by approximately 30% (reciprocal serum creatinine, -2.61 versus -3.81 (mg/mL)-1 per year, p <0.001)[4]

 

Chemical synthesis:[5] 

 

Tolvaptan is chemically, N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide. Tolvaptan is represented by the following structure:

Tolvaptan, also known as OPC-41061, is a selective, competitive arginine vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan is sold by Otsuka Pharmaceutical Co. under the trade name Samsca.
Tolvaptan and its process for preparation were disclosed in U.S. Pat. No. 5,258,510.
Processes for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one, 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine and 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine were reported in Bioorganic & medicinal chemistry 7 (1999), 1743-1754. According to the journal, 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one can be prepared by reacting 7-chloro-4-ethoxycarbonyl-5-oxo-N-p-toluenesufonyl-2,3,4,5-tetrahydro-1H-1-benzazepine with acetic acid in the presence of hydrochloric acid and water to obtain 7-chloro-5-oxo-2,3,4,5-tetrahydro-1-p-toluenesulfonyl-1H-1-benzazepine, and then reacted with polyphospholic acid. According to the journal, 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine can be prepared by reacting 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-methyl-4-nitobenzoyl chloride in the presence of triethylamine.
According to the journal, 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine can be prepared by reacting 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-methylbenzoylchloride in the presence of triethylamine.
PCT publication no. WO 2007/026971 disclosed a process for the preparation oftolvaptan can be prepared by the reduction of 7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one with sodium borohydride.
7-Chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one is a key intermediate for the preparation of tolvaptan.
Biooganic and Medicinal Chemistry I (2007) 6455-6458, Biooganic andMedicinal Chemistry 14 (2000) 2493-2495 reported in the literature of the intermediate 2 - carboxylic acid -5 - (2 - methyl-benzoylamino) toluene synthesis method,

5-Chloro-2-nitrobenzoic acid (I) was converted into methyl ester (II) using dimethyl sulfate and K2CO3 in acetone. The nitro group of (II) was then reduced with SnCl2 to afford aniline (III), which was protected as the p-toluenesulfonamide (IV) with tosyl chloride in pyridine. Alkylation of (IV) with ethyl 4-bromobutyrate (V) yielded diester (VI). Subsequent Dieckmann cyclization of (VI) in the presence of potassium tert-butoxide provided benzazepinone (VIIa-b) as a mixture of ethyl and methyl esters, which was decarboxylated to (VIII) by heating with HCl in AcOH. Deprotection of the tosyl group of (VIII) was carried out in hot polyphosphoric acid. The resulting benzazepinone (IX) was condensed with 2-methyl-4-nitrobenzoyl chloride (X) to give amide (XI). After reduction of the nitro group of (XI) to the corresponding aniline (XII), condensation with 2-methylbenzoyl chloride (XIII) provided diamide (XIV). Finally, ketone reduction in (XIV) by means of NaBH4 led to the target compound.

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PATENT

CN102382053A
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PATENT
CN102060769

Synthesis of Intermediate III: 1.
Example
  2-methyl-4-nitrobenzoic acid (available from Alfa Aesar Tianjin Chemical Co., purity> 99%, 25g,
0.14mol) was added to a 250ml reaction flask, is reacted with thionyl chloride under reflux conditions for 3h, thionyl chloride was distilled off under reduced pressure to give 2-methyl-4-nitrobenzoyl chloride (26.Sg, light yellow oily liquid), without purification, was used directly in the next step.
  Intermediate II (20g, 0.1moI) and 2_ methyl _4_ nitrobenzoylchloride (22.4g, 0.llmol) was added to a 250ml reaction flask. Dichloromethane (50ml), cooled to ice bath with stirring to dissolve O~5 ° C, was slowly added dropwise N- methylmorpholine (11.2g, 0.llmol), Bi dropwise with stirring while, at room temperature the reaction 4h. TLC [developing solvent: ethyl acetate - petroleum ether (I: I), hereinafter] is displayed after completion of the reaction, saturated aqueous sodium bicarbonate (20ml), stirred for lOmin, filtered, the filter cake with dichloromethane (15ml X 2 ) washing. The filtrate and washings were combined, washed with saturated sodium chloride solution (30ml X 3), dried over anhydrous sodium sulfate and filtered. The filtrate under reduced pressure to recover the solvent, the residue was recrystallized from anhydrous methanol to give a white powder 111 (27.5g, 75.2%), mp 154.8 ~155.6 ° C. Purity 97.9% (HPLC normalization method).
Synthesis of Intermediate IV:

Intermediate III (10g, 28mmol) was added to a 250ml reaction flask, concentrated hydrochloric acid (40ml) and ethanol (50ml), with stirring, was slowly added dropwise stannous chloride (20g, 88mmol) in ethanol (40ml) . Bi room temperature drops 5h. After TLC showed completion of the reaction, ethanol was distilled off under reduced pressure to about 70ml, the residue was -10 ° C -0 ° C allowed to stand overnight to cool. Filtered, and the filter cake was washed with water poured into water (40ml) in. Plus 20% sodium hydroxide solution (approximately 60ml) was adjusted to pH 9. Filtered, washed with ethanol and recrystallized to give a pale yellow powdered solid IV (6.3g, 68.7%), mp 190.4~191.1 ° C. Purity 97.2% (HPLC normalization method).
Synthesis of intermediate V:

  Intermediate IV (5g, 15mmol) and triethylamine (2.3g, 23mmol) was added followed by IOOml reaction flask was added dichloromethane (30ml), stir until dissolved. Solution of o-methylbenzoyl chloride (2.8g, 18mmol), dropwise at room temperature completion of the reaction Ih0 TLC showed the reaction was complete was poured into ice-water (about 40ml) in, (20ml X 3) and extracted with dichloromethane, the combined organic phases, and saturated sodium chloride solution successively (25ml X 3), dried over anhydrous sodium sulfate and filtered with 5% hydrochloric acid (25ml X 3). The filtrate under reduced pressure to recover the solvent (about 50ml), dried over anhydrous methanol residue - petroleum ether (2: 1) and recrystallized to give white crystals of Intermediate V (6.2g, 90.9%), mp 121.1 ~123.6 ° C. Purity 98.6% (HPLC normalization method).
Synthesis of tolvaptan: Example 4
Intermediate V (5g, Ilmmol) IOOml added to the reaction flask, was added anhydrous methanol (25ml), stirred and then added portionwise sodium borohydride (0.65g, 17mmol) to the reaction mixture, addition was complete the reaction at room temperature lh. After TLC showed the reaction was complete, the methanol recovered under reduced pressure (approximately 20ml), the residue was added methylene chloride (25ml), (25mlX3) and washed with saturated sodium chloride solution. Anhydrous sodium sulfate and filtered, and the filtrate under reduced pressure to recover the solvent, the residue with absolute methanol - petroleum ether (2: 1) and recrystallized tolvaptan white crystals (4.85g, 96.6%), mp 220.1~221.5 ° C. Purity 99.2% (HPLC normalization method). ES1-HRMS (C26H25C1N203, m / z) found (calc): 447.1476 (447.1481) [MH] - "
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PATENT

http://www.google.com/patents/WO2012046244A1?cl=en
Tolvaptan is chemically, N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxylH-l- benzazepin- 1 -yl)carbonyl]-3-methylphenyl]-2-methylbenzamide. Tolvaptan is represented by the following structure:

Tolvaptan, also known as OPC-41061, is a selective, competitive arginine vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan is sold by Otsuka Pharmaceutical Co. under the trade name Samsca.
Tolvaptan and its process for preparation were disclosed in U.S. patent no. 5,258,510. Processes for the preparation of 7-chloro-2,3,4,5-tetrahydro-lH-l-benzazepin-5- one, 7-chloro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine and 7-chloro- 1 -[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5- tetrahydro-lH-l-benzazepine were reported in Bioorganic & medicinal chemistry 7 (1999), 1743-1754. According to the journal, 7-chloro-2,3,4,5-tetrahydro-lH-l- benzazepin-5-one can be prepared by reacting 7-chloro-4-ethoxycarbonyl-5-oxo-N-p- toluenesufonyl-2,3,4,5-tetrahydro-lH-l-benzazepine with acetic acid in the presence of hydrochloric acid and water to obtain 7-chloro-5-oxo-2,3,4,5-tetrahydro-l-p- toluenesulfonyl-lH-l-benzazepine, and then reacted with polyphospholic acid.
According to the journal, 7-chloro- 1 -(2 -methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5- tetrahydro-lH-l-benzazepine can be prepared by reacting 7-chloro-5-oxo-2,3,4,5- tetrahydro-lH-l-benzazepine with 2-methyl-4-nitobenzoyl chloride in the presence of triethylamine.
According to the journal, 7-chloro- l-[2-methyl-4-[(2- methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine can be prepared by reacting l-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro- lH-l-benzazepine with 2-methylbenzoylchloride in the presence of triethylamine.
PCT publication no. WO 2007/026971 disclosed a process for the preparation of tolvaptan can be prepared by the reduction of 7-chloro- l-[2-methyl-4-(2- methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-l-benzazepin-5-one with sodium borohydride.
7-Chloro-2,3,4,5-tetrahydro-lH-l-benzazepin-5-one is a key intermediate for the preparation of tolvaptan.



 SYNTHESIS CONSTRUCTION

Reference example 1 :
Preparation of methyl 5-chloro-2-nitrobenzoate
Potassium carbonate (515 gm) was added to a solution of 5-chloro-2-nitro benzoic acid (500 gm) in acetone (2750 ml) at room temperature. Dimethyl sulphate (306.5 gm) was added to the reaction mixture slowly and heated to reflux for 30 minutes. The reaction mass was filtered and then concentrated to obtain a residual mass. The residual mass was poured to the ice water and extracted with methylene chloride. The solvent was distilled off under reduced pressure to obtain a residual solid of methyl 5- chloro-2-nitrobenzoate (534 gm).


Reference example 2:
Preparation of methyl 2-amino-5-chlorobenzoate
A mixture of methyl 5-chloro-2-nitrobenzoate (534 gm) as obtained in reference example 1 and concentrated hydrochloric acid (2250 ml) was added to ethyl acetate (1120 ml). To the reaction mixture was added a solution of tin chloride (1680 gm) in ethyl acetate (2250 ml). The reaction mass was stirred for 16 hours at room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 8.0 to 9.0 with aqueous sodium hydroxide solution (2650 ml). The separated aqueous layer was extracted with ethyl acetate and then concentrated to obtain a residual solid of methyl 2- amino-5-chlorobenzoate (345 gm).


Reference example 3:
Preparation of methyl 5-chIoro-2-(N-p-toluenesulfonyl)aminobenzoate
To a solution of methyl-2-amino-5-chloro benzoate (345 gm) as obtained in reference example 2 in pyridine (1725 ml) was added p-toluenesulfonyl chloride (425 gm). The reaction mixture was stirred for 2 hours at room temperature and poured to the ice water. The separated solid was filtered and dried to obtain 585 gm of methyl 5- chloro-2-(N-p-toluenesulfonyl)aminobenzoate.



Reference example 4:
Preparation of methyl 5-chloro-2-[N-(3-ethoxycarbonyI)propyI-N-p- toluenesulfonyl] aminobenzoate
Methyl 5-chloro-2-(N-p-toluenesulfonyl)aminobenzoate (585 gm) as obtained in reference example 3, ethyl-4-bromo butyrate (369.6 gm) and potassium carbonate (664 gm) in dimethylformamide (4400 ml) were added at room temperature. The contents were heated to 120°C and maintained for 2 hours. The reaction mass was poured into water and filtered. The solid obtained was dried to give 726 gm of methyl 5-chloro-2-[N- (3 -ethoxycarbonyl)propyl-N-p-toluenesulfonyl] aminobenzoate.



Reference example 5:
Preparation of 7-chloro-4-ethoxycarbonyI-5-oxo-N-p-toluenesufonyl-2,3,4,5- tetrahydro-lH-l-benzazepine
To a heated mixture of potassium tetrabutoxide (363 gm) in toluene (1000 ml) at 70°C was added portion wise methyl 5-chloro-2-[N-(3-ethoxycarbonyl)propyl-N-p- toluenesulfonyl]aminobenzoate (726 gm) as obtained in reference example 4. The contents were heated to reflux and maintained for 30 minutes. The reaction mass was then cooled to room temperature and then poured to the ice water. The layers were separated and the aqueous layer was extracted with toluene. The solvent was distilled off under reduced pressure to obtain a residual solid of 7-chloro-4-ethoxycarbonyl-5-oxo-N- p-toluenesufonyl-2,3,4,5-tetrahydro-lH-l-benzazepine (455 gm).


Example 1:
Preparation of 7-chIoro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine

7-Chloro-4-ethoxycarbonyl-5-oxo-N-p-toluenesufonyl-2,3,4,5-tetrahydro- 1 H- 1 - benzazepine (455 gm) as obtained in reference example 5 was added to aqueous sulfuric acid (80%, 2275 ml). The contents heated to 75°C and maintained for 2 hours. The reaction mass was then cooled to room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 7.5 to 8.0 with sodium hydroxide solution (2575 ml). The solid obtained was collected by filtration and dried to give 160 gm of 7- chloro-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 -benzazepine.


Example 2:
Preparation of 7-chIoro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l- benzazepine
 7-Chloro-5-oxo-2,3,4,5-tetrahydro-lH-l -benzazepine
 


7-Chloro-5-oxo-2,3,4,5-tetrahydro-lH-l -benzazepine (160 gm) as obtained in example 1 was dissolved in methylene dichloride (480 ml) and then added aqueous sodium bicarbonate solution (20%, 68.75 gm). The reaction mixture was then cooled to 0 to 5°C and then added 2-methyl-4-nitrobenzoylchloride (180 gm) slowly. The pH of the reaction mass was adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate solution (170 ml). The layers were separated and the aqueous layer was extracted with methylene chloride. The solvent was distilled off under reduced pressure to obtain a residual mass. To the residual mass was dissolved in isopropyl alcohol (7300 ml) and maintained for 2 hours at reflux temperature. The separated solid was filtered and dried to obtain 250 gm of 7-chloro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine.




Example 3:
Preparation of l-(4-amino-2-methylbenzoyl)-7-chIoro-5-oxo-2,3,4,5-tetrahydro-lH- 1-benzazepine
7-Chloro- 1 -(2-methyl-4-nitrobenzoyl)-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 - benzazepine (250 gm) as obtained in example 2 was dissolved in methanol (575 ml) and then added a solution of tin chloride (630 gm) in methanol (1130 ml). The reaction mixture was stirred for 16 hours at room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 8.0 to 9.0 with sodium hydroxide solution (1250 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate. The solvent was distilled off under vacuum to obtain a residual solid of l-(4- amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine (185 gm).

 

Example 4:
Preparation of 7-chloro-l-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-dxo- 2,3,4,5-tetrahydro-lH-l-benzazepine
 2-methyl benzoyl chloride

1 -(4-Amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 - benzazepine (185 gm) as obtained in example 3 was dissolved in methylene chloride (4000 ml) and then added sodium bicarbonate solution (10%, 47.3 gm). The reaction mass was cooled to 0 to 5°C and then added 2-methyl benzoyl chloride (95.7 gm) slowly. -The pH of the reaction mass was adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate solution (120 ml). The separated aqueous layer was extracted with methylene chloride and then concentrated to obtain a residual solid of 7-chloro-l-[2- methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 - benzazepine (185 gm).
 


Example 5:
Preparation of tolvaptan
7-Chloro- 1 -[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5- tetrahydro-lH-1 -benzazepine (63 gm) as obtained in example 4 was dissolved in methanol (570 ml) and then added sodium borohydride (2.07 gm) at room temperature. The reaction mass was stirred for 1 hour and pH of the reaction mass was adjusted to 6.0 to 7.0 with hydrochloric acid solution (1%, 630 ml). The separated solid was filtered and dried to obtain 57 gm of tolvaptan.
 TOLVAPTAN




...................

.

Process used to prepare Tolvaptan involves condensing 7-chloro-1, 2, 3, 4-tetrahydro-benzo[b]azepin-5-one with 2-methyl, 4-nitro benzoyl chloride, followed by reduction using SnCl2/HCl catalyst resulting in amine which is then condensed with o-toluoyl chloride followed by reduction with sodium borohydride to give Tolvaptan
 

Title: Tolvaptan

CAS Registry Number: 150683-30-0

CAS Name: N-[4-[(7-Chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide

Additional Names: 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine

Manufacturers' Codes: OPC-41061

Molecular Formula: C26H25ClN2O3

Molecular Weight: 448.94

Percent Composition: C 69.56%, H 5.61%, Cl 7.90%, N 6.24%, O 10.69%

Literature References: Nonpeptide arginine vasopressin V2 receptor antagonist. Prepn: H. Ogawa et al., WO 9105549; eidem, US5258510 (1991, 1993 both to Otsuka); K. Kondo et al., Bioorg. Med. Chem. 7, 1743 (1999). Pharmacology: Y. Yamamura et al., J. Pharmacol. Exp. Ther. 287, 860 (1998). Clinical trial in heart failure: M. Gheorghiade et al., J. Am. Med. Assoc. 291, 1963 (2004).

Properties: Colorless prisms, mp 225.9°.

Melting point: mp 225.9°

Therap-Cat: In treatment of congestive heart failure.

Keywords: Vasopressin Receptor Antagonist.

1. Shoaf S, Elizari M, Wang Z, et al. (2005). “Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias”. J Cardiovasc Pharmacol Ther 10 (3): 165–71. doi:10.1177/107424840501000304. PMID 16211205.
2.  Otsuka Maryland Research Institute, Inc.
3. Gheorghiade M, Gattis W, O’Connor C, et al. (2004). “Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial”. JAMA 291 (16): 1963–71. doi:10.1001/jama.291.16.1963. PMID 15113814.
4. (2012) Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease
5. Kondo, K.; Ogawa, H.; Yamashita, H.; Miyamoto, H.; Tanaka, M.; Nakaya, K.; Kitano, K.; Yamamura, Y.; Nakamura, S.; Onogawa, T.; et al.; Bioor. Med. Chem. 1999, 7, 1743.
6. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm?source=govdelivery

• Gheorghiade M, Niazi I, Ouyang J et al. (2003). “Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial”. Circulation 107 (21): 2690–6. doi:10.1161/01.CIR.0000070422.41439.04.PMID 12742979.

G. R. Belum, V. R. Belum, S. K. Chaitanya Arudra, and B. S. N. Reddy, “The Jarisch-Herxheimer reaction: revisited,” Travel Medicine and Infectious Disease, vol. 11, no. 4, pp. 231–237, 2013.
H. D. Zmily, S. Daifallah, and J. K. Ghali, “Tolvaptan, hyponatremia, and heart failure,” International Journal of Nephrology and Renovascular Disease, vol. 4, pp. 57–71, 2011.
M. N. Ferguson, “Novel agents for the treatment of hyponatremia: a review of conivaptan and tolvaptan,” Cardiology in Review, vol. 18, no. 6, pp. 313–321, 2010.
H. Ogawa, H. Miyamoto, K. Kondo, et al., US5258510, 1993.
K. Kondo, H. Ogawa, H. Yamashita et al., “7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5- tetrahydro-1H-1-benzazepine (OPC-41061): a potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist,” Bioorganic and Medicinal Chemistry, vol. 7, no. 8, pp. 1743–1754, 1999.

WO2012046244A1 *	Aug 23, 2011	Apr 12, 2012	Hetero Research Foundation	Process for preparing tolvaptan intermediates
CN102060769A *	Dec 20, 2010	May 18, 2011	天津药物研究院	Preparation method of tolvaptan
CN102060769B	Dec 20, 2010	Sep 18, 2013	天津药物研究院	Preparation method of tolvaptan
US9024015	Aug 23, 2011	May 5, 2015	Hetero Research Foundation	Process for preparing tolvaptan intermediates

Cited Patent	Filing date	Publication date	Applicant	Title
CN101817783A	May 12, 2010	Sep 1, 2010	天津泰普药品科技发展有限公司	Method for preparing tolvaptan intermediate
WO2007026971A2	Sep 1, 2006	Mar 8, 2007	Otsuka Pharma Co Ltd	Process for preparing benzazepine compounds or salts thereof

Reference
1		Cordero-Vargas, Alejandro
2		Kondo, Kazumi et al.7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061): A potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist.《Bioorganic & Medicinal Chemistry》.1999,1743-1757.
3		Quiclet-Sire, Beatrice
4		Torisawa, Yasuhiro et al.Aminocarbonylation route to tolvaptan.《Bioorganic & Medicinal Chemistry Letters》.2007,6455-6458.
5		Zard, Samir Z.A flexible approach for the preparation of substituted benzazepines: Application to the synthesis of tolvaptan.《Bioorganic & Medicinal Chemistry》.2006,6165-6173.  सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये। DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE Join me on Linkedin Join me on Facebook FACEBOOK Join me on twitter Join me on google plus Googleplus Join me on Researchgate   amcrasto@gmail.com LIONEL MY SON 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 सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये। Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL

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

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

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

Yogesh S. Patil, Nilesh L. Bonde, Ankush S. Kekan, Dhananjay G. Sathe*1, and Arijit Das

Publication Date (Web): November 17, 2014 (Article)

DOI: 10.1021/op500274j

 http://pubs.acs.org/doi/full/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).

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.

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

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.

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

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PAPER

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

http://pubs.acs.org/doi/full/10.1021/jm1004286

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.

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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-methylpiperidines; Organic 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

 

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

Tetrahedron Letters

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

Asymmetric total synthesis of Tofacitinib

• Adolfo Maricán^a,
• Mario J. Simirgiotis^b,
• Leonardo S. Santos^{a, ,}

• ^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.

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Graphical abstract

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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.

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Synthesis of Tofacitinib Citrate

Author(s): ZHAO Fanglu, ,CHEN Guohua, ,YAO Shilun, ,ZHANG Zhenxia Journal: Chinese Journal of Pharmaceuticals, Year 2014 , Issue 3 , Page 201-204,253 Keyword:  tofacitinib citrate%; anti-rheumatoid arthritis drug%; synthesis%;

http://caod.oriprobe.com/articles/41372497/Synthesis_of_Tofacitinib_Citrate.htm

…………………. 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

Scheme 2

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).

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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 40-50^DC 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 (Ab_q, J=15.6 Hz, 2H), 2.71 (Ab_q, 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

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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]

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

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	US: ℞-only
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
ChEMBL	CHEMBL221959
Synonyms	CP-690550
Chemical data
Formula	C16H20N6O
Molecular mass	312.369 g/mol

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