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.

What is claimed is: 
     
         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, 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′ 2  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.