Process for preparing esters of n-acylated amino acids with acid-labile keto protective group functions

Abstract

The present invention relates to a novel process for the esterification of N-acylated amino acids which contain an acid-labile keto protective group under alkaline conditions without using a polar aprotic solvent, in which the N-acylated amino acid with acid-labile keto protective group prepared in situ is esterified using an alkyl halide or a mono- or dialkyl ester of sulfuric acid.

1 . A compound of formula (I-a) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is methyl, ethyl, n-propyl, n-butyl or benzyl, 
 
       and
 R 3  and R 4  are an OR 5  radical or together are an —O(CH 2 ) 2 O— radical, 
 
       wherein
 R 5  is methyl, ethyl, n-propyl or n-butyl, 
 
       wherein, if R 1  is methyl, then R 5  is not methyl, 
       wherein, if R 1  is methyl, then R 3  and R 4  are not together a radical —O(CH 2 ) 2 O—. 
     
     
         2 . The compound of formula (I-a) according to  claim 1 , wherein
 R 1  is ethyl, n-propyl or n-butyl,   
       and
 R 3  and R 4  are together an —O(CH 2 ) 2 O— radical. 
 
     
     
         3 . The compound of formula (I-a) according to  claim 1 , wherein 
       wherein, if R 1  is methyl, then R 5  is not methyl, and 
       wherein, if R 1  is methyl or ethyl, then R 3  and R 4  are not together a radical —O(CH 2 ) 2 O—. 
     
     
         4 . The compound of formula (I-a) according to  claim 1 , wherein
 R 1  is n-propyl, n-butyl or benzyl.   
     
     
         5 . The compound of formula (I-a) according to  claim 2 , wherein
 R 1  is n-propyl or n-butyl.   
     
     
         6 . A compound of formula (IV-1) 
       
         
           
           
               
               
           
         
       
       wherein
 M is sodium or potassium. 
 
     
     
         7 . A process for isolating a compound of formula (IV), 
       
         
           
           
               
               
           
         
       
       wherein
 M is sodium, potassium or an NR 8   4  group, 
 R 1  is straight-chain or branched C 1 -C 6  alkyl or benzyl, 
 R 2  is straight-chain or branched C 1 -C 6  alkyl or phenyl optionally substituted by methyl, ethyl, fluorine, chlorine, methoxy or ethoxy, 
 R 3  and R 4  independently of one another are an OR 5  or SR 5  radical or together are an —O(CH 2 ) 2 O— radical or together are an ═NR 7  radical, 
 
       wherein
 R 5  is straight-chain or branched C 1 -C 6  alkyl, 
 R 6  is hydrogen, methyl, ethyl or phenyl, 
 n is 2 or 3, 
 R 7  is straight-chain or branched C 1 -C 6  alkyl, phenyl, benzyl or 4-methoxybenzyl, 
 R 8  is hydrogen or straight-chain or branched C 1 -C 6  alkyl, 
 
       wherein the cation concentration (sodium or potassium) in a solution is increased by addition of sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, sodium chloride, sodium sulfate, potassium hydroxide, potassium carbonate, potassium hydrogencarbonate, potassium chloride or potassium sulfate and as a result either forming a second aqueous phase which contains the compound of formula (IV), or the compound of formula (IV) precipitates out and is filtered off.