Methods of preparing 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds

Abstract

Methods useful for preparing compounds of formula I: and salts thereof are disclosed. Also disclosed are intermediates useful in the preparation of such compounds.

1 . A method of preparing a compound of formula I: 
     
       
         
         
             
             
         
       
     
     or a salt thereof, which comprises contacting a compound of formula II: 
     
       
         
         
             
             
         
       
     
     with a compound of formula III: 
     
       
         
         
             
             
         
       
     
     under conditions sufficient for the formation of the compound of formula I, wherein:
 A 1  is optionally substituted heterocycle; 
 Y 1  is halogen or pseudohalogen; 
 each R 1  is independently amino, halogen, hydrogen, C(O)R A , OR A , NR B R C , S(O 2 )R A , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; 
 R 2  is independently amino, halogen, hydrogen, C(O)R A , OR A , NR B R C , S(O 2 )R A , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; 
 R 3  is hydrogen, C(O)R A , C(O)OR A , or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; 
 R 4  is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; 
 each R A  is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; 
 each R B  is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; 
 each R C  is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and 
 m is 1-4. 
 
   
   
       2 . (canceled) 
   
   
       3 . (canceled) 
   
   
       4 . (canceled) 
   
   
       5 . The method of  claim 1 , wherein the compound of formula I is of formula I(a): 
     
       
         
         
             
             
         
       
     
   
   
       6 . The method of  claim 5 , wherein the compound of formula I(a) is formula I(b): 
     
       
         
         
             
             
         
       
     
     wherein: each R 5  is independently amino, halogen, hydrogen, C(O)R A , OR A , NR B R C , S(O 2 )R A , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and n is 1-3. 
   
   
       7 . (canceled) 
   
   
       8 . (canceled) 
   
   
       9 . The method of  claim 1 , wherein R 2  is hydrogen or amino. 
   
   
       10 . The method of  claim 1 , wherein R 3  is hydrogen or lower alkyl. 
   
   
       11 . The method of  claim 1 , wherein R 3  is C(O)OR A  and R A  is alkyl. 
   
   
       12 . The method of  claim 1 , wherein R 4  is hydrogen or lower alkyl. 
   
   
       13 . The method of  claim 1 , wherein R 5  is hydrogen or lower alkyl. 
   
   
       14 . The method of  claim 1 , wherein n is 1. 
   
   
       15 . The method of  claim 6 , wherein the compound of formula I(a) is (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate. 
   
   
       16 . The method of  claim 1 , wherein the compound of formula II is of formula II(a): 
     
       
         
         
             
             
         
       
     
   
   
       17 . The method of  claim 16 , wherein R 1  is chloro. 
   
   
       18 . The method of  claim 16 , wherein m is 1. 
   
   
       19 . The method of  claim 16 , wherein the compound of formula II is (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol. 
   
   
       20 . (canceled) 
   
   
       21 . (canceled) 
   
   
       22 . (canceled) 
   
   
       23 . The method of  claim 1 , wherein the compound of formula II is prepared by reducing a compound of formula IV: 
     
       
         
         
             
             
         
       
     
   
   
       24 - 29 . (canceled) 
   
   
       30 . The method of  claim 23 , wherein the compound of formula IV is 1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanone. 
   
   
       31 . The method of  claim 23 , wherein the compound of formula IV is prepared by reacting a compound of formula V with a trifluoroacetylating agent under transmetalation conditions 
     
       
         
         
             
             
         
       
     
     wherein X is bromine or iodine. 
   
   
       32 . The method of  claim 31 , wherein the compound of formula V is 1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole. 
   
   
       33 - 36 . (canceled) 
   
   
       37 . A method of preparing a compound of formula III: 
     
       
         
         
             
             
         
       
     
     which comprises contacting a compound of formula III(a): 
     
       
         
         
             
             
         
       
     
     with 2-amino-4,6-dichloropyrimidine and a palladium catalyst under conditions sufficient to provide the compound of formula III, wherein:
 Y 1  is halogen or pseudohalogen; 
 each R′ is independently hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle, or are taken together with the oxygen atoms to which they are attached to provide a cyclic dioxaborolane; 
 R 2  is independently amino, halogen, hydrogen, C(O)R A , OR A , NR B R C , S(O 2 )R A , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; 
 R 3  is hydrogen, C(O)R A , C(O)OR A , or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; 
 R 4  is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; 
 each R A  is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and 
 the palladium catalyst is not bis(triphenylphosphine)-palladium(II) chloride. 
 
   
   
       38 . The method of  claim 37 , wherein Y 1  is chloro. 
   
   
       39 . The method of  claim 37 , wherein the compound of formula III(a) is of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       40 . (canceled) 
   
   
       41 . (canceled) 
   
   
       42 . A method of crystallizing a compound of formula I: 
     
       
         
         
             
             
         
       
     
     or a salt thereof, which comprises contacting a compound of formula I with a pharmaceutically acceptable amino acid under conditions sufficient to provide a co-crystal of the compound of formula I and the amino acid, wherein:
 A 1  is optionally substituted heterocycle; 
 each R 1  is independently amino, halogen, hydrogen, C(O)R A , OR A , NR B R C , S(O 2 )R A , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; 
 R 2  is independently amino, halogen, hydrogen, C(O)R A , OR A , NR B R C , S(O 2 )R A , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; 
 R 3  is hydrogen, C(O)R A , C(O)OR A , or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; 
 R 4  is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; 
 each R A  is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; 
 each R B  is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; 
 each R C  is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and 
 m is 1-4. 
 
   
   
       43 . A compound of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       44 . A compound of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       45 . A compound of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       46 . The compound of formula 45, which is of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       47 . (canceled) 
   
   
       48 . (canceled) 
   
   
       49 . (canceled) 
   
   
       50 . A compound of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       51 . (canceled) 
   
   
       52 . (canceled) 
   
   
       53 . (canceled) 
   
   
       54 . A compound of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       55 . (canceled) 
   
   
       56 . (canceled) 
   
   
       57 . (canceled)