Processes of making and crystalline forms of a mdm2 inhibitor

Abstract

The present invention provides processes for making 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid as well as intermediates and processes for making the intermediates. Also provided are crystalline forms of the compound and the intermediates.

1 - 5 . (canceled) 
     
     
         6 . A method of treating bladder cancer, breast cancer, colon cancer, rectal cancer, kidney cancer, liver cancer, small cell lung cancer, non-small-cell lung cancer, esophagus cancer, gall-bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervix cancer, thyroid cancer, prostate cancer, squamous cell carcinoma, melanoma, acute lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burkett's lymphoma, acute myelogenous leukemia, chronic myelogenous leukemia, endometrial cancer, head and neck cancer, glioblastoma, osteosarcoma, or rhabdomyosarcoma, the method comprising administering to a patient in need thereof, a therapeutically acceptable amount of a pharmaceutical composition comprising crystalline anhydride 
       
         
           
           
               
               
           
         
       
     
     
         7 - 12 . (canceled) 
     
     
         13 . A process for making 
       
         
           
           
               
               
           
         
       
       the process comprising: reacting 
       
         
           
           
               
               
           
         
       
       under dehydrating conditions with 
       
         
           
           
               
               
           
         
       
       to form 
       
         
           
           
               
               
           
         
       
     
     
         14 . The process of  claim 14 , wherein the dehydrating conditions are azeotropic distillation with toluene. 
     
     
         15 . A process of making 
       
         
           
           
               
               
           
         
       
       the process comprising: reacting 
       
         
           
           
               
               
           
         
       
       with 
       
         
           
           
               
               
           
         
       
       to form 
       
         
           
           
               
               
           
         
       
       wherein X is CF 3 SO 3   −  or 
       
         
           
           
               
               
           
         
       
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . A process of making 
       
         
           
           
               
               
           
         
       
       the process comprising reacting 
       
         
           
           
               
               
           
         
       
       in presence of a base, to form 
       
         
           
           
               
               
           
         
       
       oxidising 
       
         
           
           
               
               
           
         
       
       to form 
       
         
           
           
               
               
           
         
       
       which is further converted to 
       
         
           
           
               
               
           
         
       
     
     
         19 - 38 . (canceled) 
     
     
         39 . The process of  claim 18 , wherein the base is sodium tert-butoxide.