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Friday 31 July 2015

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
FormulaC26H25ClN2O3 
Mol. mass448.941 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® (tolvaptan) Structural Formula Illustration
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 failurecirrhosis, 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.
ChemSpider 2D Image | Tolvaptan | C26H25ClN2O3
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.png

 


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:
Figure US20130190490A1-20130725-C00001
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.
..............................................
PATENT
CN102382053AFigure CN102382053AD00031
.....................................................
PATENT
CN102060769
Figure CN102060769BC00021


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] - "
..............
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
to1




to2


to3
to4
to5
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




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

t1.

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
t2 t3 t4 


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:10.1177/107424840501000304PMID 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.291.16.1963PMID 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, 2011Apr 12, 2012Hetero Research FoundationProcess for preparing tolvaptan intermediates
CN102060769A *Dec 20, 2010May 18, 2011天津药物研究院Preparation method of tolvaptan
CN102060769BDec 20, 2010Sep 18, 2013天津药物研究院Preparation method of tolvaptan
US9024015Aug 23, 2011May 5, 2015Hetero Research FoundationProcess for preparing tolvaptan intermediates
Cited PatentFiling datePublication dateApplicantTitle
CN101817783AMay 12, 2010Sep 1, 2010天津泰普药品科技发展有限公司Method for preparing tolvaptan intermediate
WO2007026971A2Sep 1, 2006Mar 8, 2007Otsuka Pharma Co LtdProcess for preparing benzazepine compounds or salts thereof
Reference
1Cordero-Vargas, Alejandro
2Kondo, 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.
3Quiclet-Sire, Beatrice
4Torisawa, Yasuhiro et al.Aminocarbonylation route to tolvaptan.《Bioorganic & Medicinal Chemistry Letters》.2007,6455-6458.
5Zard, Samir Z.A flexible approach for the preparation of substituted benzazepines: Application to the synthesis of tolvaptan.《Bioorganic & Medicinal Chemistry》.2006,6165-6173.


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Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL  






Thursday 30 July 2015

DACLATASVIR, 达拉他韦 , Даклатасвир , داكلاتاسفير ,


Daclatasvir.svg

Daclatasvir

BMS-790052, 
EBP 883; BMS 790052
THERAPEUTIC CLAIM Treatment of hepatitis C
CHEMICAL NAMES
1. Carbamic acid, N,N’-[[1,1′-biphenyl]-4,4′-diylbis[1H-imidazole-5,2-diyl-(2S)-2,1-
 pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]]bis-, C,C’-dimethyl ester
2. dimethyl N,N’-(biphenyl-4,4′-diylbis{1H-imidazole-5,2-diyl-[(2S)-pyrrolidine-2,1-
 diyl][(1S)-1-(1-methylethyl)-2-oxoethane-2,1-diyl]})dicarbamate
MF C40H50N8O6
MW 738.9
SPONSOR Bristol-Myers Squibb
CODE  BMS-790052
CAS  1009119-64-5
SMILES:CC(C)C(C(=O)N1CCCC1C2=NC=C(N2)C3=CC=C(C=C3)C4=CC=C(C=C4)C5=CN=C(N5)C6CCCN6C(=O)C(C(C)C)NC(=O)OC)NC(=O)OC
 UNII-LI2427F9CI
Activity: Treatment of Hepatitis C; HCV Drug; Treatment of HCV; Inhibitor of NS5A

 


Status: Launched 2014 (EU, Japan)
Originator: Bristol-Myers Squibb

NMR
FDA APPROVAL........July 24th, 2015
Daklinza (daclatasvir) is an NS5A inhibitor indicated for use in combination with sofosbuvir for the treatment of chronic hepatitis C virus (HCV) genotype 3 infection.
 
Daclatasvir dihydrochloride
1. Carbamic acid, N,N’-[[1,1′-biphenyl]-4,4′-diylbis[1H-imidazole-5,2-diyl-(2S)-2,1-
 pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]]bis-, C,C’-dimethyl ester,
 hydrochloride (1:2)
2. dimethyl N,N’-(biphenyl-4,4′-diylbis{1H-imidazole-5,2-diyl-[(2S)-pyrrolidine-2,1-
 diyl][(1S)-1-(1-methylethyl)-2-oxoethane-2,1-diyl]})dicarbamate dihydrochloride
MF C40H50N8O6 . 2 HCl, MW 811.8
SPONSOR Bristol-Myers Squibb
CODE BMS-790052-05
CAS  1009119-65-6
 
Daclatasvir (USAN[1]) (formerly BMS-790052, trade name Daklinza) is a drug for the treatment of hepatitis C (HCV). It is was developed by Bristol-Myers Squibb and was approved in Europe on 22 August 2014.
Daclatasvir inhibits the HCV nonstructural protein NS5A.[2][3] Recent research suggests that it targets two steps of the viral replication process, enabling rapid decline of HCV RNA.[4]
Daclatasvir has been tested in combination regimens with pegylated interferon and ribavirin,[5] as well as with other direct-acting antiviral agents including asunaprevir[6][7][8][9] and sofosbuvir.[10][11]





It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.[12]
 ChemSpider 2D Image | Daclatasvir | C40H50N8O6
Hepatitis C virus (HCV) is a major global health problem, with an estimated 150-200 million people infected worldwide, including at least 5 million in Europe (Pawlotsky, Trends Microbiol, 2004, 12: 96-102). According to the World Health Organization, 3 to 4 million new infections occur each year. The infection is often asymptomatic; however, the majority of HCV-infected individuals develop chronic infection (Hoof agle, Hepatology, 2002, 36: S21-S29; Lauer et al, N. Engl. J. Med., 2001, 345: 41-52; Seeff, Semin. Gastrointest., 1995, 6: 20-27). Chronic infection frequently results in serious liver disease, including fibrosis and steatosis (Chisari, Nature, 2005, 435: 930-932).
About 20% of patients with chronic HCV infection develop liver cirrhosis, which progresses to hepatocellular carcinoma in 5% of the cases (Hoofnagle, Hepatology, 2002, 36: S21-S29; Blonski et al, Clin. Liver Dis., 2008, 12: 661-674; Jacobson et al, Clin. Gastroenterol. Hepatol, 2010, 8: 924-933; Castello et al., Clin. Immunol, 2010, 134: 237-250; McGivern et al., Oncogene, 2011, 30: 1969-1983).
Chronic HCV infection is the leading indication for liver transplantations (Seeff et al., Hepatology, 2002, 36: 1-2). Unfortunately, liver transplantation is not a cure for hepatitis C; viral recurrence being an invariable problem and the leading cause of graft loss (Brown, Nature, 2005, 436: 973-978; Watt et al, Am. J. Transplant, 2009, 9: 1707-1713). No vaccine protecting against HCV is yet available. Current therapies include administration of ribavirin and/or interferon-alpha (IFN-Cc), two non-specific anti-viral agents.
Using a combination treatment of pegylated IFN-CC and ribavirin, persistent clearance is achieved in about 50% of patients with genotype 1 chronic hepatitis C. However, a large number of patients have contraindications to one of the components of the combination; cannot tolerate the treatment; do not respond to interferon therapy at all; or experience a relapse when administration is stopped. In addition to limited efficacy and substantial side effects such as neutropenia, haemo lytic anemia and severe depression, current antiviral therapies are also characterized by high cost.
To improve efficacy of standard of care (SOC), a large number of direct acting antivirals (DAAs) targeting viral polyprotein processing and replication have been developed (Hofmann et al, Nat. Rev; Gastroenterol. Hepatol., 2011, 8: 257-264). These include small molecule compounds targeting HCV nonstructural proteins including the HCV protease, polymerase and NS5A protein.

Although a marked improvement of antiviral response was observed when protease inhibitors were combined with SOC (Hofmann et al, Nat. Rev; Gastroenterol. Hepatol, 2011, 8: 257-264; Bacon et al, New Engl. J. Med., 2011, 364: 1207-1217; McHutchison et al, New Engl. J. Med., 2010, 362: 1292-1303; Poordad et al, New Engl. J. Med., 201 1, 364: 1195-1206; Hezode et al, New Engl. J. Med., 2009, 360: 1839-1850; Kwo et al, Lancet, 2010, 376: 705-716), toxicity of the individual compounds and rapid development of viral resistance in a substantial fraction of patients remain major challenges (Pawlotsky, Hepatology, 2011, 53: 1742-1751; Pereira et al, Nat. Rev. Gastroenterol. Hepatol., 2009, 6: 403-411; Sarrazin et al, Gastroenterol., 2010, 138: 447-462).
New therapeutic approaches against HCV are therefore still needed. HCV entry into target cells is a promising target for antiviral preventive and therapeutic strategies since it is essential for initiation, spread, and maintenance of infection (Timpe et al, Gut, 2008, 57: 1728-1737; Zeisel et al, Hepatology, 2008, 48: 299-307). Indeed, HCV initiates infection by attaching to molecules or receptors on the surface of hepatocytes.
Current evidence suggests that HCV entry is a multistep process involving several host factors including heparan sulfate (Barth et al, J. Biol. Chem., 2003, 278: 41003-41012), the tetraspanin CD81 (Pileri et al, Science, 1998, 282: 938-941), the scavenger receptor class B type I (SR-BI) (Zeisel et al, Hepatology, 2007, 46: 1722-1731; Bartosch et al, J. Exp. Med., 2003, 197: 633-642; Grove et al, J. Virol, 2007, 81 : 3162-3169; Kapadia et al, J. Virol, 2007, 81 : 374- 383; Scarselli et al, EMBO J., 2002, 21 : 5017-5025), Occludin (Ploss et al, Nature, 2009, 457: 882-886) and Claudin-1 (CLDN1), an integral membrane protein and a component of tight-junction strands (Evans et al, Nature, 2007, 446: 801-805).
Furthermore, Niemann-Pick CI -like cholesterol absorption receptor has been identified as a new hepatitis C virus entry factor (Sainz et al, Nature Medicine, 2012, 18: 281-285).
Daclatasvir (BMS-790052; EBP 883) is a first-in-class, highly-selective oral HCV NS5A inhibitor. NS5A is an essential component for hepatitis C virus (HCV) replication complex.Daclatasvir (BMS-790052; EBP 883)has broad genotype coverage and exhibits picomolar in vitro potency against genotypes 1a (EC50 50pm) and 1b (EC50 9pm).Daclatasvir (BMS-790052; EBP 883) produces a robust decline in HCV RNA (-3.6 logs after 48 hours from a single 100 mg) dosefollowing a single dose in patients chronically infected with HCV genotype 1.
It may be many years before the symptoms of hepatitis C infection appear. However, once they do, the consequences are significant: patients may have developed fibrosis, cirrhosis or even liver cancer, with the end result being liver failure. Even if diagnosed early, there’s no guarantee of a cure.
Only around half of patients respond to the standard therapy of an interferon plus the antiviral drug ribavirin, and while two add-on antiviral therapies were approved in 2011, the treatment period is long with no guarantee of a cure, and for non-responders treatment options remain limited.
A new drug with a different mechanism is being developed by Bristol-Myers Squibb, in conjunction with Pharmasset. Daclatasvir targets non-structural protein 5A, which is an important component of the viral replication process, although its precise role in this remains unclear. The drug is active in single oral doses, and may have potential as part of a treatment regimen that avoids the use of interferon, and in patients who do not respond to standard therapy.
In an open label Phase IIa study, 10 patients with chronic hepatitis C genotype 1b infection who did not respond to standard therapy were given daclatasvir in once daily 60mg doses, plus another experimental drug, BMS-790052, which is an NSP 3 protease inhibitor, in initial twice-daily 600mg doses, later reduced to 200mg twice a day.2 Nine patients completed 24 weeks of treatment, with the 10th discontinuing after 10 weeks. In those who completed the course, HCV RNA was undetectable at week 8, and remained so until the end of the trial, with all achieving a sustained virologic response. It was also undetectable post-treatment in the patient who discontinued.
Daclatasvir has also been investigated as monotherapy in a double blind, placebo-controlled, sequential panel, multiple ascending dose study.3 Thirty patients with chronic geno-type 1 hepatitis C infection were randomised to receive a 14 day course of the drug, in once daily doses of 1, 10, 30, 60 or 100mg, 30mg twice a day, or placebo. There was no evidence of antiviral activity in the placebo group, but the mean maximum decline of 2.8 to 4.1 log IU/ml. Most experienced viral rebound on or before day 7 of treatment, which was associated with viral variants that had previously been implicated in resistance development. It was well tolerated in all dose groups.
 M. Gao et al. Nature 2010, 465, 96
22/11/2013

EUROPEAN MEDICINES AGENCY ADVISES ON COMPASSIONATE USE OF DACLATASVIR

Opinion concerns use in combination with sofosbuvir in patients with chronic hepatitis C in urgent need of therapy to prevent progression of liver disease
The European Medicines Agency’s Committee for Medicinal Products for Human Use(CHMP) has given an opinion on the use of daclatasvir in combination with sofosbuvir in the treatment of chronic (long-term) hepatitis C virus (HCV) infection, in a compassionate-use programme.
Compassionate-use programmes are set up at the level of individual Member States. They are intended to give patients with a life-threatening, long-lasting or seriously disabling disease with no available treatment options access to treatments that are still under development and that have not yet received amarketing authorisation. In this specific case, Sweden has requested an opinion from the CHMP on the conditions under which early access through compassionate use could be given to daclatasvir, for the use in combination with sofosbuvir, with or without ribavirin, for a specific patient population.
The recommended compassionate use is intended for adult patients at a high risk of their liver being no longer able to function normally (decompensation) or death within 12 months if left untreated, and who have a genotype 1 infection. Further, it is recognised that the potential benefit of such combination therapy may extend to patients infected with other HCV genotypes.
Daclatasvir and sofosbuvir are both first-in-class anti-viral medicines against HCV. These medicines have been studied in combination, with or without ribavirin, in aclinical trial which included treatment-naive (previously untreated) HCV genotype-1, -2 and -3 infected patients, as well as patients with genotype 1 infection who have previously failed telaprevir or boceprevir treatment. Results from the trial indicate high efficacy, also in those who have failed treatment with these protease inhibitors. Many such patients have very advanced liver disease and are in urgent need of effective therapy in order to cease the progression of liver injury.
This is the second opinion provided by the CHMP on compassionate use of medicines in development for the treatment of hepatitis C. Overall, it isthe fourth time compassionate use has been assessed by the CHMP.
The aim of the CHMP assessment and opinion on a compassionate-use programme for new medicinal products is to ensure a common approach, whenever possible, regarding the criteria and conditions of use under Member States’ legislation. The opinion provides recommendations to the EU Member States that are considering setting up such a programme, and its implementation is not mandatory. In addition to describing which patients may benefit from the medicine, it explains how to use it and gives information on safety.
The assessment report and conditions of use of daclatasvir in combination with sofosbuvir with or without ribavirin in this setting will be published shortly on the Agency’s website.
Notes
  • The first compassionate-use opinion for a hepatitis C treatment was adopted by the CHMP in October 2013.
  • Sofosbuvir, which is part of this compassionate-use opinion, received a positive opinion from the CHMP recommending granting of a marketing authorisation at its November 2013 meeting.
  • Daclatasvir is developed by Bristol-Myers Squibb and sofosbuvir is developed by Gilead.

 

1-6-2012
Anti-Viral Compounds
2-13-2009
CRYSTALLINE FORM OF METHYL ((1S)-1-(((2S)
-2-(5-(4′-(2-((2S)-1((2S)-2-((METHOXYCARBONYL)AMINO)-3-METHYLBUTANOYL)-2-PYRROLIDINYL)
-1H-IMIDAZOL-5-YL)-4-BIPHENYLYL)-1H-IMIDAZOL-2-YL)-1-PYRROLIDINYL)CARBONYL)
-2-METHYLPROPYL)CARBAMATE DIHYDROCHLORIDE SALT
Synthesis
https://www.google.co.in/patents/US20090041716?pg=PA1&dq=us+2009041716&hl=en&sa=X&ei=3ki4Uo-jEsTirAfzwoHQBQ&ved=0CD4Q6AEwAQ
EXAMPLES
Figure US20090041716A1-20090212-C00015
A 1 L, 3-neck round bottom flask, fitted with a nitrogen line, overhead stirrer and thermocouple, was charged with 20 g (83.9 mmol, 1 equiv) 1,1′-(biphenyl-4,4′-diyl)diethanone, 200 mL CH2Cl2 and 8.7 mL (27.1 g, 169.3 mmol, 2.02 quiv) bromine. The mixture was allowed to stir under nitrogen for about 20 hours under ambient conditions. The resulting slurry was charged with 200 mL CH2Cl2 and concentrated down to about 150 mL via vacuum distillation. The slurry was then solvent exchanged into THF to a target volume of 200 mL via vacuum distillation. The slurry was cooled to 20-25° C. over 1 hour and allowed to stir at 20-25° C. for an additional hour. The off-white crystalline solids were filtered and washed with 150 mL CH2Cl2. The product was dried under vacuum at 60° C. to yield 27.4 g (69.2 mmol, 82%) of the desired product  : 1H NMR (400 MHz, CDCl3) δ 7.95-7.85 (m, 4H), 7.60-7.50 (m, 4H), 4.26 (s, 4H); 13C NMR (100 MHz, CDCl3) 6 191.0, 145.1, 133.8, 129.9, 127.9, 30.8; IR (KBr, cm−1) 3007, 2950, 1691, 1599, 1199; Anal calcd for C16H12Br2O2: C, 48.52; H, 3.05; Br, 40.34. Found: C, 48.53; H, 3.03; Br, 40.53 HRMS calcd for C16H13Br2O2 (M+H; DCI+): 394.9282. Found: 394.9292. mp 224-226° C.

Figure US20090041716A1-20090212-C00016
A 500 mL jacketed flask, fitted with a nitrogen line, thermocouple and overhead stirrer, was charged with 20 g (50.5 mmol, 1 equiv) of Compound 2, 22.8 g (105.9 moles, 2.10 equiv) 1-(tert-butoxycarbonyl)-L-proline and 200 mL acetonitrile. The slurry was cooled to 20° C. followed by the addition of 18.2 mL (13.5 g, 104.4 mmol, 2.07 equiv) DIPEA. The slurry was warmed to 25° C. and allowed to stir for 3 hours. The resulting clear, organic solution was washed with 3×100 mL 13 wt % aqueous NaCl. The rich acetonitrile solution was solvent exchanged into toluene (target volume=215 mL) by vacuum distillation until there was less than 0.5 vol % acetonitrile.

Figure US20090041716A1-20090212-C00017
The toluene solution of Compound 3 was charged with 78 g (1.011 moles, 20 equiv) ammonium acetate and heated to 95-100° C. The mixture was allowed to stir at 95-100° C. for 15 hours. After reaction completion, the mixture was cooled to 70-80° C. and charged with 7 mL acetic acid, 40 mL n-butanol, and 80 mL of 5 vol % aqueous acetic acid. The resulting biphasic solution was split while maintaining a temperature >50° C. The rich organic phase was charged with 80 mL of 5 vol % aqueous acetic acid, 30 mL acetic acid and 20 mL n-butanol while maintaining a temperature >50° C. The resulting biphasic solution was split while maintaining a temperature >50° C. and the rich organic phase was washed with an additional 80 mL of 5 vol % aqueous acetic acid. The rich organic phase was then solvent exchanged into toluene to a target volume of 215 mL by vacuum distillation. While maintaining a temperature >60° C., 64 mL methanol was charged. The resulting slurry was heated to 70-75° C. and aged for 1 hour. The slurry was cooled to 20-25° C. over 1 hour and aged at that temperature for an additional hour. The slurry was filtered and the cake was washed with 200 mL 10:3 toluene:methanol. The product was dried under vacuum at 70° C., resulting in 19.8 g (31.7 mmol, 63%) of the desired product: 1H NMR (400 MHz, DMSO-d6) δ 13.00-11.00 (s, 2H), 7.90-7.75 (m, 4H), 7.75-7.60 (m, 4H), 7.60-7.30 (s, 2H), 4.92-4.72 (m, 2H), 3.65-3.49 (m, 2H), 3.49-3.28 (m, 2H), 2.39-2.1 (m, 2H), 2.10-1.87 (m, 6H), 1.60-1.33 (s, 8H), 1.33-1.07 (s, 10H); 13C NMR (100 MHz, DMSO-d6) δ 154.1, 153.8, 137.5, 126.6, 125.0, 78.9, 78.5, 55.6, 55.0, 47.0, 46.7, 33.7, 32.2, 28.5, 28.2, 24.2, 23.5; IR (KBr, cm−1) 2975, 2876, 1663, 1407, 1156, 1125; HRMS calcd for C36H45N6O4 (M+H; ESI+): 625.3502. Found: 625.3502. mp 190-195° C. (decomposed).

Figure US20090041716A1-20090212-C00018
To a 250 mL reactor equipped with a nitrogen line and overhead stirrer, 25.0 g of Compound 4 (40.01 mmol, 1 equiv) was charged followed by 250 mL methanol and 32.85 mL (400.1 mmol, 10 equiv) 6M aqueous HCl. The temperature was increased to 50° C. and agitated at 50° C. for 5 hours. The resulting slurry was cooled to 20-25° C. and held with agitation for about 18 hours. Filtration of the slurry afforded a solid which was washed successively with 100 mL 90% methanol/water (V/V) and 2×100 mL of methanol. The wet cake was dried in a vacuum oven at 50° C. overnight to give 18.12 g (31.8 mmol, 79.4%) of the desired product.
Recrystallization of Compound 5
To a 250 mL reactor equipped with a nitrogen line and an overhead stirrer, 17.8 g of Compound 5 from above was charged followed by 72 mL methanol. The resulting slurry was agitated at 50° C. for 4 hours, cooled to 20-25° C. and held with agitation at 20-25° C. for 1 hour. Filtration of the slurry afforded a crystalline solid which was washed with 60 mL methanol. The resulting wet cake was dried in a vacuum oven at 50° C. for 4 days to yield 14.7 g (25.7 mmol, 82.6%) of the purified product: 1H NMR (400 MHz, DMSO-d6) δ 10.5-10.25 (br, 2H), 10.1-9.75 (br, 2H), 8.19 (s, 2H), 7.05 (d, J=8.4, 4H), 7.92 (d, J=8.5, 4H), 5.06 (m, 2H), 3.5-3.35 (m, 4H), 2.6-2.3 (m, 4H), 2.25-2.15 (m, 2H), 2.18-1.96 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 156.6, 142.5, 139.3, 128.1, 127.5, 126.1, 116.9, 53.2, 45.8, 29.8, 24.3; IR (KBr, cm−1) 3429, 2627, 1636, 1567, 1493, 1428, 1028. Anal calcd for C26H32N6Cl4: C, 54.75; H, 5.65; Cl, 24.86; Adjusted for 1.9% water: C, 53.71; H, 5.76; N, 14.46; Cl, 24.39. Found: C, 53.74; H, 5.72; N, 14.50; Cl, 24.49; KF=1.9. mp 240° C. (decomposed).

Figure US20090041716A1-20090212-C00019
A 1 L jacketed flask equipped with a nitrogen line and an overhead stirrer was sequentially charged with 100 mL acetonitrile, 13.69 g (89.4 mmol, 2.5 equiv) hydroxybenzotriazole hydrate, 15.07 g (86 mmol, 2.4 equiv) N-(methoxycarbonyl)-L-valine, 16.46 g (85.9 mmol, 2.4 equiv) 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride and an additional 100 mL acetonitrile. The resulting solution was agitated at 20° C. for 1 hour and charged with 20.4 g (35.8 mmol, 1 equiv) of purified Compound 5. The slurry was cooled to about 0° C. and 18.47 g (142.9 mmol, 4 equiv) diisopropylethylamine was added over 30 minutes while maintaining a temperature below 10° C. The solution was slowly heated to 15° C. over 3 hours and held at 15° C. for 12 hours. The resulting solution was charged with 120 mL 13 wt % aqueous NaCl and heated to 50° C. for 1 hour. After cooling to 20° C., 100 mL of isopropyl acetate was added. The biphasic solution was filtered through a 0.45 μm filter and the mixture split. The rich organic phase was washed with 2×240 mL of a 0.5 N NaOH solution containing 13 wt % NaCl followed by 120 mL 13 wt % aqueous NaCl. The mixture was then solvent exchanged into isopropyl acetate by vacuum distillation with a target volume of 400 mL. The resulting hazy solution was cooled to 20° C. and filtered through a 0.45 μm filter. The clear solution was then solvent exchanged into ethanol by vacuum distillation with a target volume of 140 mL. While maintaining a temperature of 50° C., 66.4 mL (82.3 mmol, 2.3 equiv) of 1.24M HCl in ethanol was added. The mixture was then charged with 33 mg (0.04 mmol, 0.001 equiv) of seed crystals of Compound (I) (see preparation below) and the resulting slurry was stirred at 50° C. for 3 hours. The mixture was cooled to 20° C. over 1 hour and aged at that temperature for an additional 22 hours. The slurry was filtered and the wet cake was washed with 100 mL of 2:1 acetone:ethanol. The solids were dried in a vacuum oven at 70° C. to give 22.15 g (27.3 mmol, 76.3%) of the desired product.

Figure US20090041716A1-20090212-C00020
A solution of Compound (I) was prepared by dissolving 3.17 g of Compound (I) from above in 22 mL methanol. The solution was passed through a 47 mm Cuno Zeta Carbon® 53SP filter at ˜5 psig at a flow rate of ˜58 mL/min. The carbon filter was rinsed with 32 mL of methanol. The solution was concentrated down to 16 mL by vacuum distillation. While maintaining a temperature of 40-50° C., 15.9 mL acetone and 5 mg of seed crystals of Compound (I) (see procedure below) were added. The resulting slurry was then charged with 32 mL acetone over 30 minutes. The slurry was held at 50° C. for 2 hours, cooled to 20° C. over about 1 hour and held at 20° C. for about 20 hours. The solids were filtered, washed with 16 mL 2:1 acetone:methanol and dried in a vacuum oven at 60° C. to give 2.14 g (67.5%) of purified Compound (I):
1H NMR (400 MHz, DMSO-d6, 80° C.): 8.02 (d, J=8.34 Hz, 4 H), 7.97 (s, 2 H), 7.86 (d, J=8.34 Hz, 4 H), 6.75 (s, 2 H), 5.27 (t, J=6.44 Hz, 2 H), 4.17 (t, J=6.95 Hz, 2 H), 3.97-4.11 (m, 2 H), 3.74-3.90 (m, 2 H), 3.57 (s, 6 H), 2.32-2.46 (m, 2 H), 2.09-2.31 (m, 6 H), 1.91-2.07 (m, 2 H), 0.88 (d, J=6.57 Hz, 6 H), 0.79 (d, J=6.32 Hz, 6 H);
13C NMR (75 MHz, DMSO-d6): δ 170.9, 156.9, 149.3, 139.1, 131.7, 127.1, 126.5, 125.9, 115.0, 57.9, 52.8, 51.5, 47.2, 31.1, 28.9, 24.9, 19.6, 17.7;
IR (neat, cm−1): 3385, 2971, 2873, 2669, 1731, 1650.
Anal. Calcd for C40H52N8O6Cl2: C, 59.18; H, 6.45; N, 13.80; Cl, 8.73. Found C, 59.98; H, 6.80; N, 13.68; Cl, 8.77. mp 267° C. (decomposed).
Preparation of Seed Crystals of Compound (I)
A 250 mL round-bottom flask was charged with 6.0 g (10.5 mmol, 1 equiv) Compound 5, 3.87 g (22.1 mmol, 2.1 equiv) N-(methoxycarbonyl)-L-valine, 4.45 g (23.2 mmol, 2.2 equiv) 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.289 g (2.14 mmol, 0.2 equiv) 1-hydroxybenzotriazole, and 30 mL acetonitrile. The resulting slurry was then charged with 7.33 mL (42.03 mmol, 4 equiv) diisopropylethylamine and allowed to stir at 24-30° C. for about 18 hours. The mixture was charged with 6 mL of water and heated to 50° C. for about 5 hours. The mixture was cooled and charged with 32 mL ethyl acetate and 30 mL water. The layers were separated and the rich organic layer was washed with 30 mL of 10 wt % aqueous NaHCO3, 30 mL water, and 20 mL of 10 wt % aqueous NaCl. The rich organic layer was then dried over MgSO4, filtered, and concentrated down to a residue. The crude material was then purified via flash chromatography (silica gel, 0-10% methanol in dichloromethane) to provide the free base of Compound (I).
The free-base of Compound (I) (0.03 g) was dissolved in 1 mL isopropanol at 20° C. Anhydrous HCl (70 μL, dissolved in ethanol, approximately 1.25M concentration) was added and the reaction mixture was stirred. To the solution was added methyl tert-butyl ether (1 mL) and the resulting slurry was stirred vigorously at 40° C. to 50° C. for 12 hours. The crystal slurry was cooled to 20° C. and filtered. The wet cake was air-dried at 20° C. A white crystalline solid (Form N-2 of Compound (I)) was obtained.

.....................
Daclatasvir synthesis: WO2009020828A1
Procedure:
Step a: A 1 L, 3 -neck round bottom flask, fitted with a nitrogen line, overhead stirrer and thermocouple, was charged with 20 g (83.9 mmol, 1 equiv) 1,1'-(biphenyl-4,4'-diyl)diethanone, 200 mL Dichloromethane and 8.7 mL (27.1g, 169.3 mmol, 2.02 equiv) bromine. The mixture was allowed to stir under nitrogen for about 20 hours under ambient conditions. The resulting slurry was charged with 200 mL Dichloromethane and concentrated down to about 150 mL via vacuum distillation. The slurry was then solvent exchanged into THF to a target volume of 200 mL via vacuum distillation. The slurry was cooled to 20-25 0C over 1 hour and allowed to stir at 20-25 0C for an additional hour. The off-white crystalline solids were filtered and washed with 150 mL Dichloromethane. The product was dried under vacuum at 60 0C to yield 27.4 g (69.2 mmol, 82%) of the desired product: 1H NMR (400 MHz, CDCl3) d 7.95-7.85 (m, 4H), 7.60-7.50 (m, 4H), 4.26 (s, 4H); 13C NMR 100 MHz, CDCl3) d 191.0, 145.1, 133.8, 129.9, 127.9, 30.8; IR (KBr, cm-1) 3007, 2950, 1691, 1599, 1199; Anal calcd for C16H12Br2O2: C, 48.52; H, 3.05; Br, 40.34. Found: C, 48.53; H, 3.03; Br, 40.53. HRMS calcd for C16H12Br2O2 (M + H; DCI+): 394.9282. Found: 394.9292. mp 224-226 0C.
Step b: A 500 mL jacketed flask, fitted with a nitrogen line, thermocouple and overhead stirrer, was charged with 20 g (50.5 mmol, 1 equiv) of Compound 2, 22.8 g (105.9 moles, 2.10 equiv) 1-(tert-butoxycarbonyl)-L-proline and 200 mL acetonitrile. The slurry was cooled to 20 0C followed by the addition of 18.2 mL (13.5 g, 104.4 mmol, 2.07 equiv) DIPEA. The slurry was warmed to 25 0C and allowed to stir for 3 hours. The resulting clear, organic solution was washed with 3 x 100 mL 13 wt% aqueous NaCl. The rich acetonitrile solution was solvent exchanged into toluene (target volume = 215 mL) by vacuum distillation until there was less than 0.5 vol% acetonitrile.
Step c: The toluene solution of Compound 3 was charged with 78 g (1.011 moles, 20 equiv) ammonium acetate and heated to 95-100 0C. The mixture was allowed to stir at 95-100 0C for 15 hours. After reaction completion, the mixture was cooled to 70- 80 0C and charged with 7 mL acetic acid, 40 mL n-butanol, and 80 mL of 5 vol% aqueous acetic acid. The resulting biphasic solution was split while maintaining a temperature > 50 0C. The rich organic phase was charged with 80 mL of 5 vol% aqueous acetic acid, 30 mL acetic acid and 20 mL n-butanol while maintaining a temperature > 50 0C. The resulting biphasic solution was split while maintaining a temperature > 50 0C and the rich organic phase was washed with an additional 80 mL of 5 vol% aqueous acetic acid. The rich organic phase was then solvent exchanged into toluene to a target volume of 215 mL by vacuum distillation. While maintaining a temperature > 60 0C, 64 mL methanol was charged. The resulting slurry was heated to 70-75 0C and aged for 1 hour. The slurry was cooled to 20-25 0C over 1 hour and aged at that temperature for an additional hour. The slurry was filtered and the cake was washed with 200 mL 10:3 toluene:methanol. The product was dried under vacuum at 70 0C, resulting in 19.8 g (31.7 mmol, 63%) of the desired product: 1H NMR (400 MHz, DMSO-^) d 13.00-11.00 (s, 2H), 7.90-7.75 (m, 4H), 7.75-7.60 (m, 4H), 7.60-7.30 (s, 2H), 4.92-4.72 (m, 2H), 3.65-3.49 (m, 2H), 3.49-3.28 (m, 2H), 2.39-2.1 (m, 2H), 2.10-1.87 (m, 6H), 1.60-1.33 (s, 8H), 1.33-1.07 (s, 10H); 13C NMR (100 MHz, DMSO-?fe) d 154.1, 153.8, 137.5, 126.6, 125.0, 78.9, 78.5, 55.6, 55.0, 47.0, 46.7, 33.7, 32.2, 28.5, 28.2, 24.2, 23.5; IR (KBr, cm-1) 2975, 2876, 1663, 1407, 1156, 1125; HRMS calcd for C36H45N6O4 (M + H; ESI+): 625.3502. Found: 625.3502. mp 190-195 0C (decomposed).
Step d: To a 250 mL reactor equipped with a nitrogen line and overhead stirrer, 25.0 g of Compound 4 (40.01 mmol, 1 equiv) was charged followed by 250 mL methanol and 32.85 mL (400.1 mmol, 10 equiv) 6M aqueous HCl. The temperature was increased to 50 0C and agitated at 50 0C for 5 hours. The resulting slurry was cooled to 20-25 0C and held with agitation for about 18 hours. Filtration of the slurry afforded a solid which was washed successively with 100 mL 90% methanoI/water (WV) and 2 x 100 mL of methanol. The wet cake was dried in a vacuum oven at 50 0C overnight to give 18.12 g (31.8 mmol, 79.4%) of the desired product.
CUT PASTE.......WO2009020825
Figure imgf000022_0001
Preparation of Compound (I)
A 1 L jacketed flask equipped with a nitrogen line and an overhead stirrer was sequentially charged with 100 mL acetonitrile, 13.69 g (89.4 mmol, 2.5 equiv) hydroxybenzotriazole hydrate, 15.07 g (86 mmol, 2.4 equiv) N-(methoxycarbonyl)- L-valine, 16.46 g (85.9 mmol, 2.4 equiv) l-(3-dimethyaminopropyl)-3- ethylcarbodiimide hydrochloride and an additional 100 mL acetonitrile. The resulting solution was agitated at 20 0C for 1 hour and charged with 20.4 g (35.8 mmol, 1 equiv) of purified Compound 7. The slurry was cooled to about 0 0C and 18.47 g (142.9 mmol, 4 equiv) diisopropylethylamine was added over 30 minutes while maintaining a temperature below 10 0C. The solution was slowly heated to 15 0C over 3 hours and held at 15 0C for 12 hours. The resulting solution was charged with 120 mL 13 wt% aqueous NaCl and heated to 50 0C for 1 hour. After cooling to 20 0C, 100 mL of isopropyl acetate was added. The biphasic solution was filtered through a 0.45 μm filter and the mixture split. The rich organic phase was washed with 2 x 240 mL of a 0.5 Ν NaOH solution containing 13 wt% NaCl followed by 120 mL 13 wt% aqueous NaCl. The mixture was then solvent exchanged into isopropyl acetate by vacuum distillation with a target volume of 400 mL. The resulting hazy solution was cooled to 20 0C and filtered through a 0.45 μm filter. The clear solution was then solvent exchanged into ethanol by vacuum distillation with a target volume of 140 mL. While maintaining a temperature of 50 0C, 66.4 mL (82.3 mmol, 2.3 equiv) of 1.24M HCl in ethanol was added. The mixture was then charged with 33 mg (0.04 mmol, 0.001 equiv) of seed crystals of Compound (I) (see preparation below) and the resulting slurry was stirred at 50 0C for 3 hours. The mixture was cooled to 20 0C over 1 hour and aged at that temperature for an additional 22 hours. The slurry was filtered and the wet cake was washed with 100 mL of 2: 1 acetone:ethanol. The solids were dried in a vacuum oven at 70 0C to give 22.15 g (27.3 mmol, 76.3%) of the desired product.
Figure imgf000023_0001
Alternative Preparation of Compound (I)
A jacketed reactor equipped with a mechanical agitator, a thermocouple and a nitrogen inlet was sequentially charged with 10 L acetonitrile, 0.671 kg (4.38 moles, 2.50 equiv) 1-hydroxybenzotriazole, 0.737 kg (4.21 moles, 2.40 equiv) N- (methoxycarbonyl)-L-valine and 0.790 kg (4.12 moles, 2.35 equiv) l-(3- dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was agitated at 200C for 1 hour, cooled to 5 0C and charged with 1 kg (1.75 moles, 1.00 equiv) Compound 7. While maintaining a temperature < 10 0C, 0.906 kg (7.01 moles, 4 equiv) diisopropylethylamine was added. The mixture was heated to 15-20 0C over 2 hours and agitated for an additional 15 hours. After the reaction was complete, the mixture was washed once with 6.0 L 13 wt% aqueous NaCl, twice with 6.1 L (6.12 moles, 3.5 equiv) 1.0 M aqueous NaOH containing 13 wt% NaCl and once with 6.0 L 13 wt% aqueous NaCl. Water was then removed from the rich organic solution via azeotropic distillation. The mixture was cooled to 20 0C, agitated for 1 hour and filtered. The rich organic solution was then solvent exchanged into EtOH via vacuum distillation to a target volume of 5 L. While maintaining a temperature of 50 0C, 3.2 L (4.0 moles, 2.3 equiv) 1.25M HCl in EtOH was charged. The mixture was seeded with 1.6 g Compound (I) (see preparation below) and agitated at 50 0C for 3 hours. The resulting slurry was cooled to 20 0C and agitated for at least 3 hours. The product was collected by filtration and washed with 5 L 2: 1 acetone:
EtOH to give 1.29 kg (ca. 90 wt% product) of wet crude product. A reactor equipped with an overhead agitator, nitrogen inlet and thermocouple was charged with 1.11 kg of the above crude product and 7 L methanol. The resulting solution was treated with Cuno Zeta Carbon (TM) 55SP. The carbon was washed with 15 L MeOH and the combined filtrate and wash was concentrated down to 4 L via vacuum distillation. The concentrated solution was charged with 5 L acetone and seeded with 1.6 g Compound (I) (see preparation below) while maintaining a temperature of 50 0C. An additional 10 L acetone was charged and the resulting slurry was stirred at 50 0C for 3 hours. The slurry was cooled to 20 0C and allowed to agitate at 200C for 3 hours. The product was collected by filtration, washed with 5 L 2: 1 acetone: EtOH and dried under vacuum at 50-60 0C to give 0.900 kg (1.11 moles, 74% adjusted) of Compound (I)-
Figure imgf000025_0001
Carbon Treatment and Recrystallization of Compound (I) A solution of Compound (I) was prepared by dissolving 3.17 g of Compound (I) from above in 22 mL methanol. The solution was passed through a 47mm Cuno Zeta Carbon 53SP filter at ~5 psig at a flow rate of~58mL/min. The carbon filter was rinsed with 32 mL of methanol. The solution was concentrated down to 16 mL by vacuum distillation. While maintaining a temperature of 40-50 0C, 15.9 mL acetone and 5 mg of seed crystals of Compound (I) (see procedure below) were added. The resulting slurry was then charged with 32 mL acetone over 30 minutes. The slurry was held at 50 0C for 2 hours, cooled to 20 0C over about 1 hour and held at 20 0C for about 20 hours. The solids were filtered, washed with 16 mL 2: 1 acetone:methanol and dried in a vacuum oven at 60 0C to give 2.14 g (67.5%) of purified Compound (I):
1H NMR (400 MHz, DMSO-έfc, 80 0C): 8.02 (d, J=8.34 Hz, 4 H), 7.97 (s, 2 H), 7.86 (d, J=8.34 Hz, 4 H), 6.75 (s, 2 H), 5.27 (t, J=6.44 Hz, 2 H), 4.17 (t, J=6.95 Hz, 2 H), 3.97 - 4.11 (m, 2 H), 3.74 - 3.90 (m, 2 H), 3.57 (s, 6 H), 2.32 - 2.46 (m, 2 H), 2.09 - 2.31 (m, 6 H), 1.91 - 2.07 (m, 2 H), 0.88 (d, J=6.57 Hz, 6 H), 0.79 (d, J=6.32 Hz, 6 H);
13C NMR (75 MHz, DMSO-έfc): δ 170.9, 156.9, 149.3, 139.1, 131.7, 127.1, 126.5, 125.9, 115.0, 57.9, 52.8, 51.5, 47.2, 31.1, 28.9, 24.9, 19.6, 17.7;
IR (neat, cm"1): 3385, 2971, 2873, 2669, 1731, 1650.
Anal. Calcd for C40H52N8O6Cl2: C, 59.18; H, 6.45; N, 13.80; Cl, 8.73. Found C, 59.98; H, 6.80; N, 13.68; Cl, 8.77. mp 267 0C (decomposed).
Characteristic diffraction peak positions (degrees 2Θ + 0.1) @ RT, based on a high quality pattern collected with a diffractometer (CuKa) with a spinning capillary with 2Θ calibrated with a NIST other suitable standard are as follows: 10.3, 12.4, 12.8, 13.3, 13.6, 15.5, 20.3, 21.2, 22.4, 22.7, 23.7
Daclatasvir faces problems in USA
The US-FDA in 2014 issued a complete response letter for NS5A inhibitor daclatasvir saying it was unable to approve the drug because the marketing application was for its use in tandem with asunaprevir, an NS3/NS4A protease inhibitor discontinued in the US by BMS for commercial reasons. Daclatasvir is already on the market in Europe-where it is sold as Daklinza-and also in Japan where it was approved alongside asunaprevir in July as the country's first all-oral HCV therapy. However, a delay in the large US market is clearly a major setback for BMS' ambitions in hepatitis therapy.
To make the matter worse, US FDA has rescinded breakthrough therapy designation status from Bristol-Myers Squibb for Daclatasvir for the treatment of hepatitis C virus infection in Feb 2015.
....................
PAPER
Makonen, B.; et. al. Hepatitis C Virus NS5A Replication Complex Inhibitors: The Discovery of Daclatasvir. J Med Chem 2014, 57(5), 2013–2032.
http://pubs.acs.org/doi/abs/10.1021/jm401836p
..........................
PATENT
http://www.google.com/patents/WO2008021927A2?cl=en
Example 24-23
Figure imgf000157_0001
methyl ((lS)-l-(((2S)-2-(5-(4'-(2-((2S)-l-((2S)-2-((methoxycarbonyl)amino)-3- methylbutanoyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-
1 -pyrrolidinyl) carbonyl) -2-methylpropyl) carbamate
A 50 mL flask equipped with a stir bar was sequentially charged with 2.5 mL acetonitrile, 0.344 g (2.25 mmol, 2.5 equiv) hydroxy benzotriazole hydrate, 0.374 g (2.13 mmol, 2.4 equiv) N-(methoxycarbonyl)-L-valine, 0.400 g (2.09 mmol, 2.4 equiv) 1 -(3 -dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride and an additional 2.5 mL acetonitrile. The resulting solution was agitated at 20 0C for 1 hour and charged with 0.501 g (0.88 mmol, 1 equiv) Example A-le-4. The slurry was cooled to about 0 0C and 0.45 g (3.48 mmol, 4 equiv) diisopropylethylamine was added over 30 minutes while maintaining a temperature below 10 0C. The solution was slowly heated to 15 0C over 3 hours and held at 15 0C for 16 hours. The temperature was increased to 20 0C and stirred for 3.25 hours. The resulting solution was charged with 3.3 g of 13 wt% aqueous NaCl and heated to 50 0C for 1 hour. After cooling to 20 0C, 2.5 mL of isopropyl acetate was added. The rich organic phase was washed with 2 x 6.9 g of a 0.5 N NaOH solution containing 13 wt% NaCl followed by 3.3 g of 13 wt% aqueous NaCl. The mixture was then solvent exchanged into isopropyl acetate by vacuum distillation to a target volume of 10 mL. The resulting hazy solution was cooled to 20 0C and filtered through a 0.45 μm filter. The clear solution was then solvent exchanged into ethanol by vacuum distillation with a target volume of 3 mL. 1.67 mL (2.02 mmol, 2.3 equiv) of 1.21 M HCl in ethanol was added. The mixture was then stirred at 25 0C for 15 hours. The resulting slurry was filtered and the wet cake was washed with 2.5 mL of 2: 1 acetone:ethanol. The solids were dried in a vacuum oven at 50 0C to give 0.550 g (0.68 mmol, 77 %) of the desired product.
RecrystalHzation of Example 24-23
A solution of Example 24-23 prepared above was prepared by dissolving 0.520 g of the above product in 3.65 mL methanol. The solution was then charged with 0.078 g of type 3 Cuno Zeta loose carbon and allowed to stir for 0.25 hours. The mixture was then filtered and washed with 6 ml of methanol. The product rich solution was concentrated down to 2.6 mL by vacuum distillation. 7.8 mL acetone was added and allowed to stir at 25 0C for 15 h. The solids were filtered, washed with 2.5 mL 2: 1 acetone:ethanol and dried in a vacuum oven at 70 0C to give 0.406 g (57.0%) of the desired product as white crystals: 1H NMR (400 MHz, OMSO-d6, 80 0C): 8.02 (d, J=8.34 Hz, 4 H), 7.97 (s, 2 H), 7.86 (d, J=8.34 Hz, 4 H), 6.75 (s, 2 H), 5.27 (t, J=6.44 Hz, 2 H), 4.17 (t, J=6.95 Hz, 2 H), 3.97 - 4.11 (m, 2 H), 3.74 - 3.90 (m, 2 H), 3.57 (s, 6 H), 2.32 - 2.46 (m, 2 H), 2.09 - 2.31 (m, 6 H), 1.91 - 2.07 (m, 2 H), 0.88 (d, J=6.57 Hz, 6 H), 0.79 (d, J=6.32 Hz, 6 H); 13C NMR (75 MHz, DMSO- d6): δ 170.9, 156.9, 149.3, 139.1, 131.7, 127.1, 126.5, 125.9, 115.0, 57.9, 52.8, 51.5, 47.2, 31.1, 28.9, 24.9, 19.6, 17.7; IR (neat, cm"1): 3385, 2971, 2873, 2669, 1731, 1650. Anal. Calcd for C40H52N8O6Cl2: C, 59.18; H, 6.45; N, 13.80; Cl, 8.73. Found C, 59.98; H, 6.80; N, 13.68; Cl, 8.77. mp 267 0C (decomposed). Characteristic diffraction peak positions (degrees 2Θ ± 0.1) @ RT, based on a high quality pattern collected with a diffractometer (CuKa) with a spinning capillary with 2Θ calibrated with a NIST other suitable standard are as follows: 10.3, 12.4, 12.8, 13.3, 13.6, 15.5, 20.3, 21.2, 22.4, 22.7, 23.7
..................
Bioorganic & Medicinal Chemistry Letters (2015), 25(16), 3147-3150
http://www.sciencedirect.com/science/article/pii/S0960894X15005995
Synthetic route for the preparation of the target compounds 8a–8y. Reagents and ...
Scheme 1.
Synthetic route for the preparation of the target compounds 8a8y. Reagents and conditions: (a) Br2, CH2Cl2, rt, overnight, 86%; (b) N-Boc-l-proline, MeCN, Et3N, rt, 2 h, 98%; (c) NH4OAc, toulene, 130 °C, 15 h, 85%; (d) 6 N HCl, MeOH, 50 °C, 4 h, 87%; (e) HATU, N-(methoxycarbonyl)-l-valine, DIPEA, rt, 14 h, 83%; (f) RCOCl, TEA, CH2Cl2, rt, 3 h, 64–87%.

Dimethyl((2S,2'S)-((2S,2'S)-2,2'-(5,5'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-
5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-
diyl))dicarbamate 7...............FREE BASE
To a solution of 5 (90 mg, 0.181 mmol), N-me-thoxycarbonyl-l-valine 6 (92 mg,0.525 mmol) and DIPEA (0.18 mL, 1.03 mmol) in DMF (5 mL) was added HATU(165.5 mg, 0.434 mmol). The resulting reaction was allowed to stir at room temperature for 15 h, the reaction mixture was filtered and the residue was partitioned between EtOAc and H2O, The aqueous phase was extracted with EtOAc, and the combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel; 5% Methanol /CH2Cl2) to
afford 7 (0.11 g, 83 %)as white solid.
1H NMR (DMSO-d6, 500 MHz) δ: 11.56 (s, 2H), 7.69-7.48 (m, 8H), 7.26-7.03 (m, 4H), 5.24-5.05 (m, 2H), 4.09-4.04 (m, 2H), 3.85-3.75 (m, 4H), 3.58 (s, 6H), 2.24-1.98 (m, 10H), 0.87 (d, J = 3.6 Hz, 12H).
Anal. calcd. (%) for C40H50N8O6: C 65.02, H 6.82, N 15.17; found: C 65.20, H 6.79, N 15.31.
ESI-MS m/z: 739.5 (M+H)+.
.................

1H NMR PREDICT

dacla 1 dacla 2 dacla 3

......................
13C NMR PREDICT

dacla 4 dacla 5
DACLA 6

COSY PREDICT

DACLA 7


Patents
http://www.who.int/phi/implementation/ip_trade/daclatasvir_report_2014_09-02.pdf
d70 d71 d72 d73 d74 d75 d76 d77 d78 d79 d80 d81
Click on images to view
http://www.who.int/phi/implementation/ip_trade/daclatasvir_report_2014_09-02.pdf
d1
d2
d3
d4
d5
d6
Click on images to view
Daclatasvir






Daclatasvir
Daclatasvir.svg
Names
IUPAC name
Methyl [(2S)-1-{(2S)-2-[4-(4’-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-pyrrolidinyl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}-3-methyl-1-oxo-2-butanyl]carbamate
Other names
BMS-790052
Identifiers
1009119-64-5 Yes
ATC codeJ05AX14
ChEBICHEBI:82977 Yes
ChEMBLChEMBL2023898
ChEMBL2303621
ChemSpider24609522
Jmol-3D imagesImage
Properties
C40H50N8O6
Molar mass738.89 g·mol−1

References


WO2004005264A2 *7 Jul 200315 Jan 2004Axxima Pharmaceuticals AgImidazole compounds for the treatment of hepatitis c virus infections
WO2008021927A2 *9 Aug 200721 Feb 2008Squibb Bristol Myers CoHepatitis c virus inhibitors
WO2008021928A2 *9 Aug 200721 Feb 2008Squibb Bristol Myers CoHepatitis c virus inhibitors
WO2008021936A2 *9 Aug 200721 Feb 2008Squibb Bristol Myers CoHepatitis c virus inhibitors

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