Process for the preparation of cetp(1)

Abstract

The present invention relates to a process for the preparation of 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid which is useful as an intermediate in the preparation of pharmaceutical active compounds.

1 . A process for the preparation of the 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid of formula (I): 
       
         
           
           
               
               
           
         
         which comprises reacting the cyclohexanecarboxylic acid derivative of formula (II): 
       
       
         
           
           
               
               
           
         
         wherein Y is an alkali metal, with an alkylating agent, in the presence of: (1) a secondary amine and (2) a (C 1 -C 6 )alkyllithium, a (C 3 -C 6 )cycloalkyllithium, or phenyllithium. 
       
     
     
         2 . The process according to  claim 1  for the preparation of the 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid of formula (I): 
       
         
           
           
               
               
           
         
         which comprises the following steps: 
         a) alkylating a cyclohexanecarboxylic acid derivative of formula (II): 
       
       
         
           
           
               
               
           
         
         wherein Y is an alkali metal, with an alkylating agent, in the presence of (1) a secondary amine and (2) a (C 1 -C 6 )alkyllithium, a (C 3 -C 6 )cycloalkyllithium, or phenyllithium, and 
         b) purifying of the compound of formula (I) by extraction in the presence of an aqueous solution with a pH in the range of 7.5-11. 
       
     
     
         3 . The process according  claim 1 , which further comprises the preparation of a cyclohexanecarboxylic acid sodium salt of formula (II): 
       
         
           
           
               
               
           
         
         wherein Y is an alkali metal, by reacting cyclohexanecarboxylic acid with a basic alkali metal compound. 
       
     
     
         4 . The process according to  claim 1 , wherein the (C 1 -C 6 )alkyllithium, (C 3 -C 6 )cycloalkyllithium or phenyllithium is added first to the cyclohexanecarboxylic acid alkali salt of formula (II) in the presence of a secondary amine, followed by the addition of an alkylating agent. 
     
     
         5 . The process according to  claim 1 , wherein the alkylating step is performed in the presence of an organic solvent. 
     
     
         6 . The process according to  claim 5  wherein the organic solvent is a nonprotic solvent. 
     
     
         7 . The process according to  claim 6  wherein the nonprotic solvent is tetrahydrofuran. 
     
     
         8 . The process according to  claim 1  wherein there is a catalytic amount of the secondary amine. 
     
     
         9 . The process according to  claim 1 , wherein the secondary amine is diethylamine. 
     
     
         10 . The process according to  claim 3 , wherein the basic alkali metal compound used is sodium methoxide. 
     
     
         11 . The process according to  claim 3 , wherein the basic alkali metal compound used is sodium hydride. 
     
     
         12 . The process according to  claim 1 , wherein the alkali metal is sodium. 
     
     
         13 . The process according to  claim 1 , wherein the alkylating agent is 1-bromo-2-ethylbutane. 
     
     
         14 . The process according to  claim 2 , wherein the aqueous solution has a pH of 9. 
     
     
         15 . The process according to  claim 1 , wherein the (C 1 -C 6 )alkyllithium is butyllithium. 
     
     
         16 . The process according to  claim 1  additionally comprising the step of halogenating the compound of formula (I) as defined in  claim 1 , to obtain a compound of formula (III), wherein X is I, Br, Cl or F: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The process according to  claim 16  additionally comprising the step of acylating a compound of formula IV′: 
       
         
           
           
               
               
           
         
         with the compound of formula III to obtain a compound of formula IV: 
       
       
         
           
           
               
               
           
         
       
     
     
         18 . The process according to  claim 17  additionally comprising the step of reducing the compound of formula IV to obtain a compound of formula V: 
       
         
           
           
               
               
           
         
       
     
     
         19 . The process according to  claim 18  additionally comprising the step of acylating the compound of formula V with R 4 C(O)X′, wherein X′ is I, Br, Cl or F and R 4  is C 1 -C 8 alkyl, to obtain a compound of formula VI: 
       
         
           
           
               
               
           
         
       
     
     
         20 . A process for the preparation of S-[2-([[1-(2-ethylbutyl)-cyclohexyl]-carbonyl]amino)phenyl]2-methylpropanethioate comprising the formation of a compound of formula (I): 
       
         
           
           
               
               
           
         
         by reacting a cyclohexanecarboxylic acid derivative of formula (II): 
       
       
         
           
           
               
               
           
         
         wherein Y is an alkali metal, with an alkylating agent, in the presence of: (1) a secondary amine and (2) (C 1 -C 6 )alkyllithium, (C 3 -C 6 )cycloalkyllithium, or phenyllithium.