PROCESS FOR MAKING (R)-3-(2,3-DIHYDROXYPROPYL)-6-FLUORO-5-(2-FLOURO-4-IODOPHENYLAMINO)-8-METHYLPYRIDO[2,3-d]PYRIMIDINE-4,7(3H,8H)-DIONE AND INTERMEDIATES THEREOF

Abstract

The present invention relates generally to processes of making (R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione, intermediates thereof, and a process for making a particular polymorph of (R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione.

1 . A process for making (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H, 8H)-dione, comprising the step of reacting a compound of the formula 
     
       
         
         
             
             
         
       
       wherein G 1  is halogen and R 3  and R 4  are independently selected from the group consisting of hydrogen and suitable hydroxyl protecting groups with 2-fluoro-4-iodoaniline to give a compound of the formula 
     
     
       
         
         
             
             
         
       
       wherein R 3  and R 4  are as defined above and optional deprotection and optional resolution. 
     
   
   
       2 . A process for making (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione, comprising the step of reacting a compound of the formula 
     
       
         
         
             
             
         
       
       wherein G 1  is halogen and R 3  and R 4  are independently selected from the group consisting of suitable hydroxyl protecting groups with 2-fluoro-4-iodoaniline to give a compound of the formula 
     
     
       
         
         
             
             
         
       
       wherein R 3  and R 4  are the selected hydroxyl protecting groups and deprotection and optional resolution. 
     
   
   
       3 . A process according to  claim 1  wherein G 1  is chloro, R 3  and R 4  taken together are acetonide, and the stereochemistry of the starting material and product is the (R)-configuration. 
   
   
       4 . A compound of the formula 
     
       
         
         
             
             
         
       
       wherein R 1  is a suitable carboxy protecting group. 
     
   
   
       5 . The compound of  claim 3  wherein R 1  is methyl. 
   
   
       6 . The compound 4,4-dicyano-1-fluoro-3-hydroxy-N-methylbut-3-enamide. 
   
   
       7 . A compound of the formula 
     
       
         
         
             
             
         
       
       wherein Q 1  is selected from the group consisting of amino, hydroxyl, and halogen. 
     
   
   
       8 . The compound of  claim 6  wherein Q 1  is hydroxyl. 
   
   
       9 . The compound of  claim 6  wherein Q 1  is chloro. 
   
   
       10 . A compound the of formula 
     
       
         
         
             
             
         
       
       wherein G 1  is halogen. 
     
   
   
       11 . A compound of the formula 
     
       
         
         
             
             
         
       
       wherein G 1  is halogen. 
     
   
   
       12 . A compound of formula 
     
       
         
         
             
             
         
       
       wherein G 1  is halogen. 
     
   
   
       13 . The compound of  claim 11  wherein G 1  is chloro. 
   
   
       14 . A compound of the formula 
     
       
         
         
             
             
         
       
       wherein G 1  is halogen and R 3  and R 4  are independently selected from the group consisting of hydrogen and suitable hydroxy protecting groups. 
     
   
   
       15 . A compound of the formula 
     
       
         
         
             
             
         
       
       wherein G 1  is halogen and R 3  and R 4  are independently selected from the group consisting of suitable hydroxy protecting groups. 
     
   
   
       16 . The compound of  claim 14  wherein the stereochemistry is the (R)-configuration. 
   
   
       17 . The compound of any one of  claims 13 ,  14 , and  15  wherein G 1  is chloro. 
   
   
       18 . The compound of  claim 15  wherein G 1  is chloro and R 3  and R 4  taken together are acetonide. 
   
   
       19 . A process for making Form A polymorph of (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione, comprising: crystallizing (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione in a solvent at a temperature of about greater than or equal to 40° C.