Asymmetric process for making substituted 2-amino-thiazolones

Abstract

The invention provides two process for synthesizing substituted aminothiazolone compounds as inhibitors of 11-β-hydroxy steroid dehydrogenase type 1. The processes allow the stereoselective synthesis of the desired compounds without the use of stoichiometric amounts of chiral catalysts.

We claim: 
     
         1 . A process for the preparation of a compound of formula 2, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         comprising reacting a compound of formula 1: 
       
       
         
           
           
               
               
           
         
         with a compound of formula R a R b NH; wherein
 X is selected from the group consisting of S, O, and NR; 
 Y is R″C(O)NH, or SR″; 
 R is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 8 )fluoroalkyl, (C 1 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )bicycloalkyl, (C 3 -C 8 )heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl and aryl(C 1 -C 6 )alkyl; 
 R″ is selected from the group consisting of (C 1 -C 8 )alkyl, aryl, (C 3 -C 8 )cycloalkyl, and aryl(C 1 -C 6 )alkyl; 
 R 1  and R 2  are each independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 8 )fluoroalkyl, (C 1 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )aminoalkyl, (C 3 -C 8 )haloalkyl, (C 3 -C 8 )heteroalkyl, (C 3 -C 8 ) heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl and aryl(C 1 -C 6 )alkyl; wherein R 1  and R 2  are not simultaneously hydrogen; 
 R a  is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 8 )fluoroalkyl, (C 1 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )bicycloalkyl, (C 3 -C 8 )heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl and aryl(C 1 -C 6 )alkyl; and 
 R b  is selected from the group consisting of (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 8 )fluoroalkyl, (C 1 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )bicycloalkyl, (C 3 -C 8 )heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl and aryl(C 1 -C 6 )alkyl. 
 
       
     
     
         2 . The process of  claim 1 , further comprising the formation of the compound of formula 1, comprising reacting a compound of the formula 3 
       
         
           
           
               
               
           
         
         with a compound of formula Y—CN; wherein
 X and Y are as defined in  claim 1 . 
 
       
     
     
         3 . The process of  claim 2 , wherein the compound of formula 3 is (S)-2-mercapto-2,3-dimethylbutanoic acid and the compound of formula Y—CN is methylisocyanate. 
     
     
         4 . The process of  claim 1 , wherein R 1  and R 2  are independently selected from (C 1 -C 8 )alkyl. 
     
     
         5 . The process of  claim 1 , wherein the compound of formula 1 is (S)-5-isopropyl-5-methyl-2-(methylthio)thiazole-4(5H)-one. 
     
     
         6 . The process of  claim 1 , wherein R a  is H. 
     
     
         7 . The process of  claim 6 , wherein R a R b NH is (S)-exo-aminonorbornane. 
     
     
         8 . The process of  claim 1 , comprising reacting (S)-5-isopropyl-5-methyl-2-(methylthio)thiazole-4(5H)-one with (S)-exo-aminonorbornane. 
     
     
         9 . The process of  claim 1 , wherein the compound of formula 2 is