Methods for the Preparation of HCV Polymerase Inhibitors

Abstract

The present invention relates to methods and compounds useful in the preparation of compounds of the formula (I).

1 . A crystalline form of ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one exhibiting at least one characteristic peak in the powder x-ray diffraction pattern, expressed in degrees two-theta, selected from the group consisting of 7.1±0.1, 12.1±0.1, 16.1±0.1, 17.5±0.1, and 23.5±0.1. 
     
     
         2 . The crystalline form of  claim 1 , exhibiting at least two characteristic peaks in the powder x-ray diffraction pattern, expressed in degrees two-theta, selected from the group consisting of 7.1±0.1, 12.1±0.1, 16.1±0.1, 17.5±0.1, and 23.5±0.1. 
     
     
         3 . A crystalline form of ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one, exhibiting at least one characteristic peak in the solid state  13 CNMR spectrum, expressed in ppm, selected from the group consisting of 154.6±0.2, 153.0±0.2, 151.2±0.2, 146.4±0.2, 146.0±0.2, 121.6±0.2, 120.4±0.2, 119.7±0.2, 118.8±0.2, 110.2±0.2, 100.7±0.2, and 100.3±0.2. 
     
     
         4 . The crystalline form of  claim 3  exhibiting at least one characteristic peak in the powder x-ray diffraction pattern, expressed in degrees two-theta, selected from the group consisting of 7.1±0.1, 12.1±0.1, 16.1±0.1, 17.5±0.1, and 23.5±0.1. 
     
     
         5 . A crystalline form of ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one, exhibiting a characteristic peak in the powder x-ray diffraction pattern, expressed in degrees two-theta, at 7.1±0.1, a peak in the solid state NMR spectrum, expressed in ppm, at 154.6±0.2, and a melting temperature in the range of between about 162° C. and about 165° C. 
     
     
         6 . A pharmaceutical composition comprising the crystalline form of  claim 1 , in admixture with a pharmaceutically acceptable carrier. 
     
     
         7 . A pharmaceutical composition comprising the crystalline form of  claim 3  in admixture with a pharmaceutically acceptable carrier. 
     
     
         8 . The pharmaceutical composition of  claim 6  in combination with one or more other antiviral substances. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the one or more other antiviral substances are HCV inhibitors. 
     
     
         10 . The pharmaceutical composition of  claim 8 , wherein said HCV inhibitors are selected from the group consisting of interferon alphacon-1, natural interferon, interferon beta-1a, interferon omega, interferon gamma-1b, Pegylated forms of IFN-α, interleukin-10, BILN 2061, amantadine, thymozine alpha-1, ribavirin and viramidine. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein said HCV inhibitors are Pegylated forms of IFN-α and ribavirin. 
     
     
         12 . The pharmaceutical composition of  claim 8 , wherein the one or more other antiviral substances are HIV inhibitors. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein said HIV inhibitors are selected from the group consisting of such as nelfinavir, delavirdine, indinavir, nevirapine, saquinavir, and tenofovir. 
     
     
         14 . A method for treating Hepatitis C virus (HCV) in an HCV-infected mammal comprising administering an effective amount of the crystalline form of  claim 1  to a mammal in need thereof. 
     
     
         15 . A method for treating Hepatitis C virus (HCV) in an HCV-infected mammal comprising administering an effective amount of the crystalline form of  claim 3  to a mammal in need thereof.