HCV NS5A Inhibitor from Theravance, Inc. to treat hepatitis C virus infection

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((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-dimethyl-4-methylcarbamoyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester
N-​[(1S)​-​1-​[[(2S)​-​2-​[5-​[4'-​[[[6-​[(2R,​5S) ​-​2,​5-​dimethyl-​4-​[(methylamino)​carbonyl]​-​1-​piperazinyl]​-​3-​ pyridinyl]​carbonyl]​amino]​-​2'-​(trifluoromethoxy)​[1,​1'-​biphenyl]​- ​4-​yl]​-​1H-​imidazol-​2-​yl]​-​1-​pyrrolidinyl]​carbonyl]​-​2-​methylpropyl]​-​, Carbamic acid, methyl ester
Carbamic acid, N-​[(1S)​-​1-​[[(2S)​-​2-​[5-​[4'-​[[[6-​[(2R,​5S) ​-​2,​5-​dimethyl-​4-​[(methylamino)​carbonyl]​-​1-​piperazinyl]​-​3-​ pyridinyl]​carbonyl]​amino]​-​2'-​(trifluoromethoxy)​[1,​1'-​biphenyl]​- ​4-​yl]​-​1H-​imidazol-​2-​yl]​-​1-​pyrrolidinyl]​carbonyl]​-​2-​methylpropyl]​-​, methyl ester
CAS 1374883-22-3, 819.87, C₄₁ H₄₈ F₃ N₉ O₆
Theravance, Inc.  INNOVATOR
To treat hepatitis C virus infection

• ((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-dimethyl-4-methylcarbamoyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (compound 1):
• 
  Recent estimates place the number of people infected with the hepatitis C virus (HCV) worldwide at more than 170 million, including 3 million people in the United States. The infection rate is thought to be roughly 4 to 5 times that of the human immunodeficiency virus (HIV). While in some individuals, the natural immune response is able to overcome the virus, in the majority of cases, a chronic infection is established, leading to increased risk of developing cirrhosis of the liver and hepatocellular carcinomas. Infection with hepatitis C, therefore, presents a serious public health problem.
  read at
   http://newdrugapprovals.org/2015/11/03/hcv-ns5a-inhibitor-from-theravance-inc-to-treat-hepatitis-c-virus-infection/
  
  
  
  
  
  

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(3Z) -1,1,1- trifluoro-4-methoxy-4- (2-methylphenyl) but-3-en-2-one

 

(3Z) -1,1,1- trifluoro-4-methoxy-4- (2-methylphenyl) but-3-en-2-one

[Step 1] 1- (1,1-dimethoxy-ethyl) -2-methyl-benzene

2 methylacetophenone 5.36g (40mmol), trimethyl orthoformate 5.0g (47mmol), methanol - Le 7.7g (240mmol), and methane sulfonic in toluene solution (100mL) containing sodium sulfate 14.2g (100mmol) and adding an acid 92mg (0.8mmol) was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, and dried over magnesium sulfate and concentrated. The crude product was basic silica gel column and purified by (0-10% ethyl acetate / hexanes) to give the title compound 5.5g (76%) I was obtained as a colorless oil. ¹ H-NMR (400MHz, CDCl ₃₎ ^δ: 1.56 (3H, s), 2.46 (3H, s), 3.19 (6H, s), 7.09-7.24 (3H, m ), 7.60-7.68 (1H, m).


 [Step 2] (3Z) -1,1,1- trifluoro-4-methoxy-4- (2-methylphenyl) but-3-en-2-one


 

Reference Examples were synthesized in Step 1 of 8 1- (1,1-dimethoxy-ethyl) -2-methylbenzene 900mg (5mmol), pyridine 790mg of (10mmol) was dissolved in THF (15mL), 0 ℃ to the cooled trifluoroacetic anhydride fluoro acetate 2.1g the (10mmol) we were slowly dropping. After stirring at room temperature for 18 hours, the reaction mixture was washed with 0.1N aqueous hydrochloric acid and diluted with ethyl acetate. The crude product and the organic layer was obtained by drying your concentrated magnesium sulfate and purified by silica gel chromatography (0-10% ethyl acetate / hexanes) to give the title compound 1.0g (82%) was obtained as a colorless oil. ¹ H-NMR (400MHz, CDCl ₃₎ ^δ: 2.22 (3H, s), 3.94 (3H, s), 5.96 (1H, s), 7.11-7.18 (1H, m ), 7.20-7.30 (2H, m), 7.33-7.40 (1H, m). LC-MS, 245 (M + 1).


References 1 http://www.google.fr/patents/WO2010110400A1?cl=en&hl=fr


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