Novel processes for the production of useful intermediates

Abstract

The present application relates to a new process for the asymmetric production of 3-(pyridin-4-yl)-3-hydroxy-pentanoic acid derivatives, which are useful intermediates in the manufacture of compounds that are known to show antiproliferative activity.

1 - 17 . (canceled) 
   
   
       18 . A process for the production of a compound of formula (I), wherein said compound of formula (I) 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt or ester thereof, wherein
 R and R 1  are independently, alkyl or benzyl, which benzyl is optionally substituted by one, two or three substituents including —O-alkyl; alkyl or halogen; with the proviso that: 
 if R is alkyl, R 1  in formula (I) may also be hydrogen or silyl, and R 1  in formula (II) may also be silyl; 
 R 2  is hydrogen or halogen; 
 
       is converted into a compound of formula (D) 
     
     
       
         
         
             
             
         
       
       by: 
       a) converting said compound of formula (I) into a compound formula (A) 
     
     
       
         
         
             
             
         
       
       in the presence of a mineral acid and an ethereal solvent at temperatures between room temperature (RT) and 60° C.; and 
       b) further reacting said compound of formula (A) with a compound of formula (B) 
     
     
       
         
         
             
             
         
       
       in the presence of diisopropyl azodicarboxylate (DIAD), ethyldiphenylphosphine (EtPPh 2 ) and dimethylacetamide (DMA), to give a compound of formula (C) 
     
     
       
         
         
             
             
         
       
       and 
       c) said compound of formula (C) is further reacted in the presence of palladium (II) acetate (Pd(OAc) 2 ), potassium acetate (KOAc), triphenylphosphine (Ph 3 P), tetrabutyl ammonium bromide (Bu 4 NBr) and acetonitrile (MeCN) to give the corresponding compound of formula (D) 
     
     
       
         
         
             
             
         
       
       wherein 
       R 2  is defined in claim  1 ; 
       R 8  and R 9  are independently alkyl or halogen; and 
       R 10  is 4-methyl-piperidin-1-ylmethyl or hydrogen. 
     
   
   
       19 . The process according to  claim 18 , wherein R 2  and R 10  are both hydrogen, and R 8  and R 9  are both fluorine. 
   
   
       20 . The process according to  claim 18 , wherein R 2  is hydrogen, R 10  is 4-methyl-piperidin-1-ylmethyl, R 8  is chlorine and R 9  is methyl. 
   
   
       21 . The process according to  claim 18 , wherein the process step a) is carried out in the presence of hydrobromic acid (HBr) and dimethoxyethane (DME) at temperatures between 45 and 55° C. 
   
   
       22 . A compound of general formula (I) 
     
       
         
         
             
             
         
       
       wherein 
       R and R 1  are independently alkyl or benzyl, which benzyl is optionally substituted by —O-alkyl; alkyl or halogen; and 
       R 2  is hydrogen or halogen. 
     
   
   
       23 . The compound of formula (I) according to  claim 22 , which is (R)-3-(3-benzyloxymethyl-2-methoxy-pyridin-4-yl)-3-hydroxy-pentanoic acid. 
   
   
       24 . A process for converting a compound of formula (I) as claimed in  claim 22  into a compound of formula (D) 
     
       
         
         
             
             
         
       
       said process comprising the steps of: 
       a) converting said compound of formula (I) into a compound formula (A) 
     
     
       
         
         
             
             
         
       
       in the presence of a mineral acid and an ethereal solvent at temperatures between room temperature (RT) and 60° C.; and 
       b) further reacting said compound of formula (A) with a compound of formula (B) 
     
     
       
         
         
             
             
         
       
       in the presence of diisopropyl azodicarboxylate (DIAD), ethyldiphenylphosphine (EtPPh 2 ) and dimethylacetamide (DMA), to give a compound of formula (C) 
     
     
       
         
         
             
             
         
       
       and 
       c) further reacting said compound of formula (C) in the presence of palladium (II) acetate (Pd(OAc) 2 ), potassium acetate (KOAc), triphenylphosphine (Ph 3 P), tetrabutyl ammonium bromide (Bu 4 NBr) and acetonitrile (MeCN) to give the corresponding compound of formula (D) 
     
     
       
         
         
             
             
         
       
       wherein; 
       R 8  and R 9  are independently alkyl or halogen; and 
       R 10  is 4-methyl-piperidin-1-ylmethyl or hydrogen. 
     
   
   
       25 . The process of  claim 24 , wherein the compound of formula (I) is 
     
       
         
         
             
             
         
       
       and the compound produced is: 
     
     
       
         
         
             
             
         
       
     
   
   
       26 . A process for the preparation of the compounds of formula (I) according to  claim 22  comprising:
 a) reacting a compound of formula (II),   
     
       
         
         
             
             
         
       
       with a compound of formula (III), 
     
     
       
         
         
             
             
         
       
       and 
       b) further reacting in the presence of alkali- or earth alkali metal hydroxides to give the compounds of formula (I), 
       wherein
 R and R 1  are independently, alkyl or benzyl, which benzyl is optionally substituted by —O-alkyl; alkyl or halogen; 
 R 2  is hydrogen or halogen; 
 X is 
 
     
     
       
         
         
             
             
         
       
       
         R 3  and R 4  are hydrogen, phenyl, alkyl or —C(CH 3 ) 2 -phenyl; 
         R 5  is phenyl, benzyl or alkyl; 
         R 6  is hydrogen, alkyl or phenyl; and 
         R 7  is hydrogen, methyl or phenyl; or alternatively 
         R 5  and R 6 , together with the carbon atoms to which they are attached form an indan moiety and R 7  is hydrogen; 
         R 11  and R 12  are independently alkyl, cycloalkyl, benzyl or phenyl; and 
         R 13  is phenyl or alkyl. 
       
     
   
   
       27 . The process of  claim 18 , wherein the compound of formula (D) is: 
     
       
         
         
             
             
         
       
     
   
   
       28 . A compound prepared by a process according to  claim 18 . 
   
   
       29 . (canceled)