Processes and intermediates for preparing steric compounds

Abstract

This invention relates to processes and intermediates for the preparation of an alpha-amino beta-hydroxy acid of Formula 1 wherein the variables R 1 , R′ 1 and R 2 are defined herein and the compound of Formula 1 has an enantiomeric excess (ee) of 55% or greater.

1 . A process for preparing an optically enriched compound of Formula 1 
     
       
         
         
             
             
         
       
     
     wherein: 
 the carbon atoms alpha and beta to the carboxy group are stereocenters;  
 R 1  and R′ 1  are each independently H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic;  
 R′ 2  is —NHR 2  or —OE;  
 R 2  is H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic; and  
 E is C 1 -C 6  alkyl or benzyl;  
 comprising the steps of:  
 a) forming a salt of a compound of Formula 1  
 b) crystallizing said salt to give a compound of greater than 55% enantiomeric excess.  
 
   
   
       2 . The process of  claim 1 , wherein R 1  is C 1 -C 6  alkyl, R′ 1  is H and R′ 2  is —NHR 2  wherein R 2  is C 1 -C 6  alkyl or C 1 -C 6  cycloalkyl.  
   
   
       3 . The process of  claim 2 , wherein R 1  is propyl and R 2  is cyclopropyl.  
   
   
       4 . The process of  claim 1 , further comprising aminating a compound of Formula ii  
     
       
         
         
             
             
         
       
     
     with an aminating reagent to provide a compound of Formula iii  
     
       
         
         
             
             
         
       
     
   
   
       5 . The process of  claim 4 , wherein the aminating reagent is an azide salt and the intermediate azido compound is reduced by hydrogenation.  
   
   
       6 . The process of  claim 4 , further comprising oxidizing an unsaturated compound of Formula i  
     
       
         
         
             
             
         
       
     
     wherein R 12  is —NHR 2  or —OE, wherein E is C 1 -C 5  alkyl or optionally substituted benzyl, with an oxidizing reagent to provide a compound of Formula ii.  
     
       
         
         
             
             
         
       
     
   
   
       7 . The process of  claim 6 , wherein the oxidizing reagent is t-butyl hydroperoxide.  
   
   
       8 . The process of  claim 6 , wherein the oxidizing reagent includes a chiral reagent.  
   
   
       9 . The process of  claim 8 , wherein the oxidizing reagent is a mixture of samarium (III) isopropoxide, triphenyl arsine oxide, S-(−)1,1′-bi-2-naphthol and 4 Å molecular sieves.  
   
   
       10 . The process of  claim 6 , wherein the oxidizing reagent is urea-hydrogen peroxide in the presence of trifluoroacetic anhydride.  
   
   
       11 . The process of  claim 6 , wherein R′ 2  is —OE.  
   
   
       12 . The process of  claim 6 , wherein R′ 2  is —NHR 2 .  
   
   
       13 . The process of  claim 11 , further comprising hydrolyzing the compound of Formula ii to give an acid and then converting the acid to an amide compound of Formula ii wherein R′ 2  is —NHR 2 .  
   
   
       14 . A process for preparing a compound of Formula 1 
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  and R′ 1  are each independently H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic;  
 R 2  is H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic; and  
 the compound of Formula 1 has an enantiomeric excess of greater than 55%, comprising the steps of:  
 a) oxidation of an unsaturated compound of Formula i  
                     
 to provide a compound of formula ii  
                     
 b) reacting a compound of Formula ii with an aminating reagent to provide a compound of Formula iii  
                     
 c) forming a salt of a compound of Formula iii with an optically active organic acid;  
 d) crystallizing said salt to give a compound of greater than 55% enantiomeric excess.  
 
   
   
       15 . The process of  claim 14 , wherein the compound of Formula 1 is (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide.  
   
   
       16 . The process of  claim 14 , wherein the organic acid is L-tartaric acid.  
   
   
       17 . The process of  claim 14 , wherein the organic acid is deoxycholic acid.  
   
   
       18 . A compound which is N-cyclopropyl-3-propyloxirane-2-carboxamide.  
   
   
       19 . A compound which is N-cyclopropyl-3-propyloxirane-2-carboxamide.  
   
   
       20 . A compound which is 3-azido-N-cyclopropyl-2-hydroxyhexanamide.  
   
   
       21 . A compound which is 3-amino-N-cyclopropyl-2-hydroxyhexanamide, L-tartaric acid salt.  
   
   
       22 . A compound which is 3-amino-N-cyclopropyl-2-hydroxyhexanamide, deoxycholic acid salt.