Process for the racemization of chiral quinazolinones

Abstract

Racemates are obtained from one of the enantiomers, or an enantiomerically enriched mixture, of an optically active quinazolinone derivative by reaction of the compound with an alkali alkoxide of a primary alcohol and isolation of the racemate.

1 - 13 . (canceled)  
     
     
         14 . A method for making an enantiomer, or an enantiomerically enriched mixture of a compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein said method comprises the steps of: 
 contacting an enantiomer, or an enantiomerically enriched mixture of a starting compound of formula  
                     
  with an alkali alkoxide in a C 1 -C 6  primary alcohol at a selected racemization reaction temperature whereby said enantiomer or enantiomerically enriched mixture is racemized to yield a racemic mixture;  
 isolating the racemic mixture;  
 subjecting said racemic mixture to an optical resolution process whereby the racemic mixture is separated into its corresponding stereoisomers; and  
 converting desired stereoisomer to said compound using an acid chloride of the formula R 3 —C(O)—Cl  
 wherein  
 R 1  is selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;  
 R 2  and R 2′  are independently selected from the group consisting of alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;  
 R 3  is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, substituted alkyl, substituted aryl, substituted aralkyl, substituted heteroaryl, substituted heteroaralkyl, oxaalkyl, oxaaralkyl, substituted oxaaralkyl, R 15 O— and R 15 —NH—;  
 R 4  is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, substituted alkyl, substituted aryl, substituted aralkyl, substituted heteroaryl, substituted heteroaralkyl, and R 16 -alkylene-;  
 R 5 , R 6 , R 7 , R 8  are independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, fluoralkyl, nitro, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;  
 R 15  is selected from the group consisting of alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, substituted alkyl, substituted aryl, substituted aralkyl, substituted heteroaryl, and substituted heteroaralkyl; and  
 R 16  is selected from the group consisting of alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted heterocyclyl.  
 
     
     
         15 . The method of  claim 14 , wherein the C 1 -C 6  primary alcohol is ethanol.  
     
     
         16 . The method of  claim 14 , wherein the alkali alkoxide is a sodium or potassium alkoxide.  
     
     
         17 . The method of  claim 14 , wherein the alkali alkoxide is sodium ethoxide.  
     
     
         18 . The method of  claim 14 , wherein the racemization reaction temperature is less than 200° C.  
     
     
         19 . The method of  claim 14 , wherein the racemization reaction temperature is less than 100° C.  
     
     
         20 . The method of  claim 14 , wherein the racemization reaction temperature is at the boiling point of the reaction mixture.  
     
     
         21 . The method of  claim 14 , wherein the enantiomer has an R-configuration.  
     
     
         22 . The method of  claim 14 , wherein the enantiomer has an S-configuration.  
     
     
         23 . The method of  claim 14 , wherein the alkali alkoxide is derived from an alkali metal and a C 1 -C 6  primary alcohol.  
     
     
         24 . The method of  claim 23 , wherein the C 1 -C 6  primary alcohol is methanol or ethanol.