Improved process for preparing substituted crotonic acids

Abstract

A process to prepare a compound of Formula (I) wherein R 3 , R 4 and R 5 are each selected independently from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxyl, and wherein the alkyl, alkenyl, alkynyl, and alkoxyl may be optionally substituted with one or more halogen, alkyl, alkenyl, alkynyl, and alkoxyl.

1 . A process to prepare a compound of Formula (I) 
       
         
           
           
               
               
           
         
         wherein R 3 , R 4  and R 5  are each selected independently from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxyl, and wherein the alkyl, alkenyl, alkynyl, and alkoxyl may be optionally substituted with one or more halogen, alkyl, alkenyl, alkynyl, and alkoxyl; 
         comprising
 a) reacting a compound of Formula (V) 
 
       
       
         
           
           
               
               
           
         
         
           wherein R 3 , R 4  and R 5  are defined as above, and R 6  is alkyl; 
           with methane sulfonyl chloride and a base to form a compound of Formula (VI) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 3 , R 4 , R 5  and R 6  are defined as above; and 
           b) reacting a compound of Formula (VI) with a reagent to form a compound of Formula (I). 
         
       
     
     
         2 . The process of  claim 1 , wherein the base of step a) is an amine. 
     
     
         3 . The process of  claim 1 , wherein the reagent of step b) is an acid or a base. 
     
     
         4 . The process of  claim 3 , wherein the base is sodium hydroxide, lithium hydroxide or potassium hydroxide. 
     
     
         5 . The process of  claim 1 , further comprising the steps for preparing a compound of Formula (V) 
       
         
           
           
               
               
           
         
         wherein R 3 , R 4 , R 5 , and R 6  are defined as above; 
       
       comprising
 i. reacting a compound of Formula (II) 
 
       
         
           
           
               
               
           
         
         wherein R 3 , R 4  and R 5  are defined as above and R 7  is alkyl; with a compound of Formula (III) 
       
       
         
           
           
               
               
           
         
         wherein R 6  is alkyl, 
         and a base to form a compound of Formula (IV) 
       
       
         
           
           
               
               
           
         
         wherein R 3 , R 4 , R 5  and R 6  are defined as above; and 
         ii. reducing the compound of Formula (IV) with a reducing agent to form a compound of Formula (V). 
       
     
     
         6 . The process of  claim 5 , wherein the steps i), ii), a) and b) are conducted without isolation of the intermediate compounds of Formulas IV, V or VI. 
     
     
         7 . The process of  claim 5 , wherein the base of step i) is LiHMDS, sodium hydride, LDA, KOtBu or NaOEt. 
     
     
         8 . The process of  claim 5 , wherein the reducing agent of step ii) is lithium borohydride, sodium borohydride, disiamylborane, hydrogen with platinum (IV) oxide, hydrogen with palladium/carbon or zinc borohydride. 
     
     
         9 . The process of  claim 1 , wherein at least one of R 3 , R 4  and R 5  is halogen. 
     
     
         10 . The process of  claim 9 , wherein the halogen is bromine, chlorine or fluorine. 
     
     
         11 . The process of  claim 1 , wherein at least one of R 3 , R 4  and R 5  is alkyl. 
     
     
         12 . The process of  claim 1 , wherein R 3  is CH 3  and R 4  and R 5  are both fluorine. 
     
     
         13 . The process of  claim 1 , wherein R 6  is ethyl. 
     
     
         14 . The process of  claim 5 , wherein R 7  is methyl or ethyl. 
     
     
         15 . The process of  claim 1 , wherein R 3  is Cl and R 4  and R 5  are both fluorine. 
     
     
         16 . The process of  claim 1 , wherein R 3  is Br and R 4  and R 5  are both fluorine. 
     
     
         17 . The process of  claim 1 , wherein R 3  is CF 3 , R 4  is CH 3 O and R 5  is fluorine. 
     
     
         18 . The process of  claim 1 , wherein R 3  is CH 3  and R 4  and R 5  are both chlorine. 
     
     
         19 . The process of  claim 1 , wherein R 3  is CF 3 , R 4  is chlorine and R 5  is fluorine. 
     
     
         20 . The process of  claim 2 , wherein the amine is triethylamine.