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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5-fluoro-2- (4,4,5,5, - tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde

 

5-fluoro-2- (4,4,5,5, - tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde

SYNTHESIS 94)

2-bromo-5-fluorobenzaldehyde 26.1g (129mmol), 4,4,4 ', 4', 5,5,5 ', 5'- octamethyl-2,2'-bi-1,3,2- dioxaborolane 39.2g (154mmol), N of potassium acetate 25.2g (257mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloro palladium (II) dichloromethane adduct 5.25g (6.43mmol), It was stirred for 16 hours at 100 ℃ the N- dimethylformamide (200mL) solution.Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the crude product obtained was concentrated and purified by silica gel chromatography (5% -25% ethyl acetate / hexanes), the title compound 16.6g of (52%) pale yellow crystals It was obtained as a. ¹ H-NMR (300MHz, CDCl₃₎ ^δ1.38 (12H, s), 7.27 (1H, td, J = 2.7,8.1Hz), 7.65 (1H, dd, J = 2. 7,9.3Hz), 7.92 (1H, dd, J = 6.3,8.1Hz), 10.62 (1H, d, J = 3.3Hz), melting point 55-58 ℃. Starting materials

2-Bromo-5-fluorobenzaldehyde

• CAS Number 94569-84-3

 

Bis(pinacolato)diboron

4,4,4',4',5,5,5',5'-octamethyl-2,2'-Bi-(1,3,2-dioxaborolane

Identifiers
CAS Registry Number	73183-34-3
Jmol-3D images	Image
PubChem	2733548
Properties
Chemical formula	C12H24B2O4
Molar mass	253.94 g·mol−1
Melting point	137 to 140 °C (279 to 284 °F; 410 to 413 K)

  Bis(pinacolato)diboron is a boron containing two pinacolato ligands. With the formula [(CH₃)₄C₂O₂B]₂, it is a colourless solid that is soluble in organic solvents. It is a commercially available reagent for making pinacol boronic esters for organic synthesis.

Preparation and structure

This compound may be prepared by reacting tetrakis(dimethylamino)diboron with pinacol in acidic conditions.^[1] The B-B bond distance is 1.711(6) Å.^[2]

References

1. Tatsuo Ishiyama, Miki Murata, Taka-aki Ahiko, and Norio Miyaura (2004). "Bis(pinacolato)diboron". Org. Synth.; Coll. Vol. 10, p. 115
2. C.Kleeberg, A.G.Crawford, A.S.Batsanov, P.Hodgkinson, D.C.Apperley, Man Sing Cheung, Zhenyang Lin, T.B.Marder "Spectroscopic and Structural Characterization of the CyNHC Adduct of B₂pin₂ in Solution and in the Solid State" J. Org. Chem 2012, vol. 77, pp. 785.doi:10.1021/jo202127c
3. Xinyu Liu "Bis(pinacolato)diboron" Synlett 2003, pp 2442–2443. doi:10.1055/s-2003-43344
4. http://www.google.fr/patents/WO2010110400A1?cl=en&hl=fr

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////////////5-fluoro-2- (4,4,5,5, - tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde