Stereoselective Alkylation of Chiral 2-Methly-4 Protected Piperazines

Abstract

In an illustrative embodiment, the present invention describes the synthesis of the following compound and similar compounds, in high stereochemical purity by a novel stereoselective alkylation process:

1 . A process to selectively prepare a mono-4-protected 2-methylpiperazine from its corresponding 2-methylpiperazine, said process comprising reacting said 2-methylpiperazine with about one mole of a protecting reagent in a solvent in the presence of an acid catalyst or a base catalyst. 
   
   
       2 . The process of  claim 1 , wherein said mono-4-protected 2-methylpiperazine forms in at least about 80 molar percent. 
   
   
       3 . The process of  claim 2 , wherein said catalyst is a base, said solvent is an organic solvent, and said protecting agent is an ester. 
   
   
       4 . The process of  claim 3 , wherein said base catalyst is selected from the group consisting of potassium carbonate, sodium bicarbonate, pyridine, triethylamine, diisopropylethylamine and DABCO. 
   
   
       5 . The process of  claim 3 , wherein said catalyst is an acid catalyst, said solvent is selected from the group consisting of water, alcohol, ether and mixtures thereof, and said protecting agent is an acid halide, a halocarbonyloxyalkyl or an acid anhydride. 
   
   
       6 . The process of  claim 5 , wherein said acid catalyst is selected from the group consisting of acetic acid, propionic acid, benzoic acid, oxalic acid and citric acid. 
   
   
       7 . The process of  claim 6 , wherein said solvent is selected from the group consisting of water, alcohol, ether and mixtures thereof. 
   
   
       8 . The process of  claim 5 , wherein said protecting agent is selected from the group consisting of acetic anhydride, benzoyl chloride, benzyl chloroformate, di-t-butyl dicarbonate, benzoic anhydride, and ethyl chloroformate. 
   
   
       9 . A compound of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       10 . A compound of Formula A: 
     
       
         
         
             
             
         
       
     
     prepared by a process comprising:
 (a) reacting a compound of Formula XI, 
 
     
       
         
         
             
             
         
       
       
         where Y is selected from the group consisting of alkyl, halogenated alkyl, or aryl with said aryl being optionally substituted with alkyl, nitro or halogen, with a compound of Formula X: 
       
     
     
       
         
         
             
             
         
       
       
         where G is selected from the group consisting of alkyl, halogenated alkyl, alkoxy, aryl aryloxy and arylalkoxy, in the presence of an inorganic catalyst in a solvent, wherein said compound of Formula XIV forms in at least 50% yields with at least about a 2:1 ratio of R,S stereochemistry to S,S stereochemistry respectively; and 
       
       (b) further reacting said compound of formula XIV with an acid to form the compound of the Formula A. 
     
   
   
       11 . A tartrate salt of the compound of  claim 10 . 
   
   
       12 . A compound of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       13 . A process to prepare 4-trifluoromethyl methoxyacetophenone comprising:
 (a) reacting the compound of Formula XIII with the compound of formula XIX to form the product of formula XX:   
     
       
         
         
             
             
         
       
     
     and
 (b) hydrolyzing the compound of formula XX to 4-trifluoromethyl methoxyacetophenone: