Process for the preparation of acid halides

Abstract

A process for the preparation of acid halides of formula I which are useful as intermediates in the preparation of i.a. pharmaceutically active compounds.

1 . A process for the preparation of a compound of formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from the group consisting of:
 (1) hydrogen, 
 (2) C 1 -C 8 alkyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of C 1 -C 8 alkoxy and C 3 -C 8 cycloalkyl, and 
 (3) C 2 -C 8 alkenyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of C 1 -C 8 alkoxy and C 3 -C 8 cycloalkyl; and 
 
         R 2  and R 3  are combined with the carbon atom to which they are attached to form C 3 -C 7 cycloalkyl or C 5 -C 8 cycloalkenyl; 
       
       comprising reacting a compound of formula II: 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  have the above meanings; 
       with thionylchloride in the presence of a tri-C 1 -C 5 alkylamine and an aliphatic hydrocarbon solvent. 
     
     
         2 . The process according to  claim 1  additionally comprising the step of acylating a compound of the formula III: 
       
         
           
           
               
               
           
         
       
       with a compound of formula I to yield a compound of formula IV: 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are as defined in  claim 1 . 
     
     
         3 . The process according to  claim 2  additionally comprising the step of reducing the compound of formula IV with a reducing agent to yield a compound of formula V: 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are as defined in  claim 1 . 
     
     
         4 . The process according to  claim 3  additionally comprising the step of acylating the compound of formula V with R 4 C(O)Cl to yield a compound of formula VI: 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are as defined in  claim 1  and R 4  is C 1 -C 8 alkyl. 
     
     
         5 . The process according to  claim 4  wherein R 4  is isopropyl. 
     
     
         6 . The process according to  claim 1  wherein the thionyl chloride is present in the range from 1.0 to 2.0 equivalents of thionylchloride in relation to the compound of formula II. 
     
     
         7 . The process according to  claim 1  wherein the amount of the tri-C 1 -C 5 alkylamine in relation to the amount of the compound of formula II is at a ratio of from 5 mol % to 0.1 mol %. 
     
     
         8 . The process according to  claim 1  wherein thionylchloride is continuously added. 
     
     
         9 . The process according to  claim 1  wherein in formula I R 2  and R 3  are combined with the carbon atom to which they are attached to form C 3 -C 7 cycloalkyl. 
     
     
         10 . The process according to  claim 1  wherein in formula I, R 1  is CH 2 CH(CH 2 CH 3 ) 2  and R 2  and R 3  are combined with the carbon atom to which they are attached to form cyclohexyl. 
     
     
         11 . The process according to  claim 1  wherein the tri-C 1 -C 5 alkylamine is triethylamine or tributylamine. 
     
     
         12 . The process according to  claim 1  wherein the tri-C 1 -C 5 alkylamine is tributylamine. 
     
     
         13 . The process according to  claim 2  wherein the acylating steps are performed in the presence of a base. 
     
     
         14 . The process according to  claim 13  wherein the base is an organic base. 
     
     
         15 . The process according to  claim 14  wherein the organic base is N-methylmorpholine.