Processes for the preparation of aminoethoxybenzyl alcohols

Abstract

The present invention provides processes and intermediates for the preparation of aminoethoxybenzyl alcohols of Formula I useful in the production of pharmaceutically useful compounds.

1 . A compound of Formula VI: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are each independently selected from the group consisting of C 1 -C 12  alkyl, heteroaryl and aryl; or 
 R 1  and R 2  together form a group of formula —(CH 2 ) n — that is optionally substituted with from 1-3 substituents selected from the group consisting of CN, NO 2 , C 1-6  alkyl, C 3-7  cycloalkyl, aryl, heteroaryl, halogen, OH, NR 5 R 5′ , CHO, COOR 5 , CONR 5 R 5′ , SR 5 , —O-aryl and —O-heteroaryl; 
 R 3  is selected from the group consisting of H, C 1-6  alkyl, C 3-7  cycloalkyl, aryl, heteroaryl, CN, NO 2  and halogen; 
 R 4  is H or C 1-6  alkoxy; 
 R 5  and R 5′  are each, independently, H or C 1-6  alkyl; and 
 n is 2, 3, 4, 5, 6 or 7. 
 
     
     
         2 . The compound of  claim 1  wherein:
 R 1  and R 2  together form a group of formula —(CH 2 ) n — that is optionally substituted with from 1-3 substituents selected from the group consisting of CN, NO 2 , C 1-6  alkyl, C 3-7  cycloalkyl, aryl, heteroaryl, halogen, OH, NR 5 R 5′ , CHO, COOR 5 , CONR 5 R 5′ , SR 5 , —O-aryl and —O-heteroaryl; and   R 4  is H.   
     
     
         3 . The compound of  claim 1  wherein:
 R 1  and R 2  together form —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 6 —; and   R 3  is H, C 1-6  alkyl or halogen.   
     
     
         4 . The compound of  claim 3  wherein R 3  is H. 
     
     
         5 . The compound of  claim 4  wherein R 4  is H. 
     
     
         6 . The compound of  claim 1  wherein:
 R 1  and R 2  together form —(CH 2 ) 6 —; and
 R 3  is H, C 1-6  alkyl or halogen. 
   
     
     
         7 . The compound of  claim 6  wherein R 3  is H. 
     
     
         8 . The compound of  claim 7  wherein R 4  is H. 
     
     
         9 . The compound of  claim 1  wherein the group represented by COR 4  is in the para position relative to OCH 2 CONR 1 R 2 . 
     
     
         10 . The compound of  claim 9  wherein:
 R 1  and R 2  together form —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 6 —; and   R 3  is H, C 1-6  alkyl or halogen.   
     
     
         11 . The compound of  claim 10  wherein R 3  is H. 
     
     
         12 . The compound of  claim 11  wherein R 4  is H. 
     
     
         13 . The compound of  claim 9  wherein:
 R 1  and R 2  together form —(CH 2 ) 6 —; and
 R 3  is H, C 1-6  alkyl or halogen. 
   
     
     
         14 . The compound of  claim 13  wherein R 3  is H. 
     
     
         15 . The compound of  claim 14  wherein R 4  is H. 
     
     
         16 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are each, independently, selected from the group consisting of C 1 -C 12  alkyl, heteroaryl and aryl; or 
 R 1  and R 2  together form a group of formula —(CH 2 ) n — that is optionally substituted with from 1-3 substituents selected from the group consisting of CN, NO 2 , C 1-6  alkyl, C 3-7  cycloalkyl, aryl, heteroaryl, halogen, OH, NR 5 R 5′ , CHO, COOR 5 , CONR 5 R 5′ , SR 5 —O-aryl and —O-heteroaryl; 
 R 3  is selected from the group consisting of H, C 1-6  alkyl, C 3-7  cycloalkyl, aryl, heteroaryl, CN, NO 2  and halogen; 
 R 5  and R 5′  are each, independently, H or C 1-6  alkyl; and 
 n is 2, 3, 4, 5, 6 or 7; 
 prepared by the process comprising: 
 a) reacting an α-haloacetamide of Formula IV: 
 
       
         
           
           
               
               
           
         
         wherein X 1  is Cl or Br, and R 1  and R 2  are defined as hereinabove; 
         with a compound of Formula V: 
       
       
         
           
           
               
               
           
         
         wherein R 4  is H or C 1-6  alkoxy, and R 3  is defined as hereinabove; 
         in the presence of base and optionally in the presence of a phase transfer catalyst for a time and under conditions effective to form a phenoxyacetamide of Formula VI: 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3  and R 4  are defined as hereinabove; and 
         b) reacting the phenoxyacetamide of Formula VI with a reducing agent for a time and under conditions effective to form said compound of Formula I. 
       
     
     
         17 . The compound of  claim 16 , wherein the reducing agent comprises lithium aluminum hydride or sodium bis(2-methoxyethoxy)-aluminum hydride. 
     
     
         18 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 2  are each, independently, selected from the group consisting of C 1 -C 12  alkyl, heteroaryl and aryl; or 
         R 1  and R 2  together form a group of formula —(CH 2 ) n — that is optionally substituted with from 1-3 substituents selected from the group consisting of CN, NO 2 , C 1-6  alkyl, C 3-7  cycloalkyl, aryl, heteroaryl, halogen, OH, NR 5 R 5′ , CHO, COOR 5 , CONR 5 R 5′ , SR 5 —O-aryl and —O-heteroaryl; 
         R 3  is selected from the group consisting of H, C 1-6  alkyl, C 3-7  cycloalkyl, aryl, heteroaryl, CN, NO 2  and halogen; 
         R 5  and R 5′  are each, independently, H or C 1-6  alkyl; and 
         n is 2, 3, 4, 5, 6 or 7; 
         prepared by the process comprising: 
         a) reacting an acid halide of Formula II: 
       
       
         
           
           
               
               
           
         
         wherein X 1  and X 2  are each, independently, Cl or Br; 
         with an amine of Formula III: 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are defined as hereinabove; 
         for a time and under conditions effective to form an α-haloacetamide of Formula IV: 
       
       
         
           
           
               
               
           
         
         wherein X 1 , R 1  and R 2  are defined as hereinabove; 
         b) reacting the α-haloacetamide of Formula IV with a compound of Formula V: 
       
       
         
           
           
               
               
           
         
         wherein R 4  is H or C 1-6  alkoxy; 
         in the presence of base and optionally in the presence of a phase transfer catalyst for a time and under conditions effective to form a phenoxyacetamide of Formula VI 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3  and R 4  are defined as hereinabove; and 
         c) reacting the phenoxyacetamide of Formula VI with a reducing agent for a time and under conditions effective to form said compound of Formula I. 
       
     
     
         19 . The compound of  claim 18 , wherein the reducing agent comprises lithium aluminum hydride or sodium bis(2-methoxyethoxy)-aluminum hydride.