Method of Preparing Amine Stereoisomers

Abstract

This invention provides intermediates useful in a method of preparing amine stereoisomers. It also provides a method of preparing sulfoxide and sulfinylamine stereoisomers using certain of the intermediates.

1 . A compound of formula 
       
         
           
           
               
               
           
         
       
       wherein:
 R 5  and R 6  are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or R 5  and R 6  together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl group; 
 A 1′  is (R 7 )HN or (R 7′ )R 7″ N; 
 R 7  represents hydrogen or -L-R 7a  in which -L- represents a bond, —CO—, —(CO)O—, —(CO)NR 7b —, —SO—, —SO 2 —, or —(SO 2 )O—, each of R 7a  and R 7b  independently represents substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and R 7′  and R 7″  are as defined for R 7a , or R 7′  and R 7″  together with the nitrogen atom to which they are attached and, optionally R 8 , form an unsubstituted or substituted heterocyclic group, or R 7′  together with the nitrogen atom to which it is attached and the carbon atom to which the nitrogen atom is attached forms an unsubstituted or substituted heterocyclic group; A 2  is O, S or NR 7c  in which R 7c  is substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and each of R 8 , R 9 , R 10  and R 11  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or R 8  and R 11  together form a substituted or unsubstituted alkylene or heteroalkylene chain; 
 A 2  is O, S or NR 7c  in which R 7c  is substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and 
 each of R 8 , R 9 , R 10  and R 11  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or R 8  and R 11  together form a substituted or unsubstituted alkylene or heteroalkylene chain, 
 or a salt thereof. 
 
     
     
         2 . A compound as claimed in  claim 1 , which is a stereoisomer of formula 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound as claimed in  claim 2 , wherein A 2  is O. 
     
     
         4 . A compound as claimed in  claim 1 , wherein A 1′  represents (R 7 )HN and R 7  represents R 7a SO 2  in which R 7a  represents a (1-6C)alkyl, (6-10C)aryl(1-6C)alkyl or (6-10C) aryl group, in which the aryl group is unsubstituted or substituted by one, two or three substituents selected independently from a halogen atom, a (1-4C)alkyl group and a (1-4C)alkoxy group, or A 1′  represents (R 7′ )R 7″ N in which R 7′  and R 7″  each independently represents a (1-4C)alkyl group or together with the nitrogen to which they are attached represent a pyrrolidine group that may bear one or two methyl substituents, and each of R 8 , R 9 , R 10  and R 11  is independently selected from hydrogen, (1-4C)alkyl and phenyl, or the group 
       
         
           
           
               
               
           
         
       
       is selected from a residue of (N-methylpyrrolidin-2-yl)diphenylmethanol, 1-pyrrolidin-1-ylindan-2-ol, 3-benzyloxy-2-N,N-dimethylamino-1-phenylpropan-2-ol, quinine, quinidine, hydroquinine, cinchonidine, cinchonine, hydrocinchonidine and ethyl hydrocupreine. 
     
     
         5 . A compound as claimed in  claim 1 , which is of the formula 
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound as claimed in  claim 1 , wherein A 1′  represents (R 7a )HSO 2 N in which R 7a  represents a (1-6C)alkyl, (6-10C)aryl(1-6C)alkyl or (6-10C) aryl group, in which the aryl group is unsubstituted or substituted by one, two or three substituents selected independently from a halogen atom, a (1-4C)alkyl group and a (1-4C)alkoxy group; or the group 
       
         
           
           
               
               
           
         
       
       is a residue of 2-N,N-dimethylamino-1-phenylpropanol, 2-N,N-dibutylamino-1-phenylpropanol, 2-pyrrolidin-1-yl-1-phenylpropanol, 2-(2-methylpyrrolidin-1-yl)-1-phenylpropanol, 2-(2,5-dimethylpyrrolidin-1-yl)-1-phenylpropanol, 2-N,N-dimethylamino-2-methyl-1-phenylpropanol, (N-methylpyrrolidin-2-yl)diphenylmethanol, 1-pyrrolidin-1-ylindan-2-ol, 3-benzyloxy-2-N,N-dimethylamino-1-phenylpropan-2-ol, quinine, quinidine, hydroquinine, cinchonidine, cinchonine, hydrocinchonidine or ethyl hydrocupreine. 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . A method of preparing a sulfinylamine or sulfoxide stereoisomer, which comprises reacting a compound of formula 
       
         
           
           
               
               
           
         
       
       wherein A 1  is (R 7 )R 7′ N + Q −  in which Q- is an anion and each of R 7  and R 7′  independently represents substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or two substituents R 7  together with the nitrogen atom to which they are attached and, optionally R 8 , form an unsubstituted or substituted heterocyclic group, or one R 7  substituent together with the nitrogen atom to which it is attached and the carbon atom to which the nitrogen atom is attached form an unsubstituted or substituted heterocyclic group; A 2  is O, S or NR 7c  in which R 7c  is substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and each of R 8 , R 9 , R 10  and R 11  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or R 8  and R 11  together form a substituted or unsubstituted alkylene or heteroalkylene chain with a first organometallic reagent of formula R 1 M to afford a compound of formula 
       
         
           
           
               
               
           
         
       
       is which A 1′  represents (R 7′ )R 7″ N and then either reacting this compound with a second organometallic reagent of formula R 2 M to afford a sulfoxide stereoisomer of formula
   R 1 —SO—R 2    
 
       in which R 1  and R 2  each independently represents an organic group, or with an alkali metal amide to afford a sulfinylamine stereoisomer. 
     
     
         12 . A method as claimed in  claim 11 , in which the first organometallic reagent is an organomagnesium halide. 
     
     
         13 . A method as claimed in  claim 12 , in which the first organomagnesium halide is an alkyl or arylmagnesium halide.