Process for the preparation of heterocyclic ester derivatives

Abstract

The present invention is directed to a process for the preparation of heterocyclic ester derivatives of formula I wherein A 1 , SEM, and W 1 are as defined herein. Such compounds are useful as intermediates in the synthesis of derivatives useful as protein tyrosine kinase inhibitors, more particularly inhibitors of c-fms kinase.

1 . A process for the preparation of a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         A 1  is selected from the group consisting of C 1-3 alkyl; 
         wherein 
       
       
         
           
           
               
               
           
         
          is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         wherein each R 4  is independently selected from the group consisting of H, F, Cl, Br, I, —OH, —OCH 3 , —OCH 2 CH 3 , —SC (1-4) alkyl, —SOC (1-4) alkyl, —SO 2 C (1-4) alkyl, —C (1-3) alkyl, —CO 2 R d , —CONR e R f , —CCR g , and —CN; 
         and wherein R d  is selected from the group consisting of hydrogen and —C (1-3) alkyl; R e  is selected from the group consisting of H and —C (1-3) alkyl; R f  is selected from the group consisting of H and —C (1-3) alkyl; and R g  is selected from the group consisting of H, —CH 2 OH and —CH 2 CH 2 OH; 
         or a pharmaceutically acceptable salt thereof; comprising 
       
       
         
           
           
               
               
           
         
         reacting a compound of formula (VIII) with carbon monoxide gas or a source of carbon monoxide which is a metal carbonyl selected from the group consisting of tungsten hexacarbonyl and mollibdinum hexacarbonyl; in the presence of a tertiary organic base; in the presence of coupling system wherein the coupling system is a 1:1 mixture of Pd(OAc) 2  and XantPhos; wherein the Pd(OAc) 2  is present in an amount of about 2.5 mol %; wherein the XantPhos is present in an amount of about 2.5 mol %; in an alcohol of the formula A 1 OH; at a temperature in the range of from about 60° C. to about 120° C.; to yield the corresponding compound of formula (I) 
       
     
     
         2 . A process according to  claim 1 , wherein A 1  is selected from the group consisting of methyl and ethyl; and wherein 
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
       
     
     
         3 . (canceled) 
     
     
         4 . A process according to  claim 1 , wherein the carbon monoxide or source of carbon monoxide is carbon monoxide gas. 
     
     
         5 . (canceled) 
     
     
         6 . A process according to  claim 4 , wherein the carbon monoxide gas is present at a pressure in the range of from about 40 psi to about 60 psi. 
     
     
         7 . A process according to  claim 6 , wherein the carbon monoxide gas is reacted at a pressure of about 60 psi. 
     
     
         8 . A process according to  claim 1 , wherein tertiary organic base is selected from the group consisting of TEA and DIPEA. 
     
     
         9 . A process according to  claim 8 , wherein the tertiary organic base is TEA. 
     
     
         10 . A process according to  claim 9 , wherein the TEA is present in an amount in the range of from about 1.05 to about 5.0 molar equivalents. 
     
     
         11 . A process according to  claim 10 , wherein the TEA is present in an amount in the range of from about 2.0 to about 4.0 molar equivalents. 
     
     
         12 . A process according to  claim 11 , wherein the TEA is present in an amount of about 3.0 molar equivalents. 
     
     
         13 - 30 . (canceled) 
     
     
         31 . A process according to  claim 1 , wherein the alcohol of formula A 1 OH is selected from the group consisting of methanol and ethanol. 
     
     
         32 . A process according to  claim 31 , wherein the alcohol of formula A 1 OH is ethanol. 
     
     
         33 . A process according to  claim 32 , wherein the alcohol of formula A 1 OH is present in an amount in the range of from about 1.5 molar to about 5.0 molar. 
     
     
         34 . A process according to  claim 33 , wherein the alcohol of formula A 1 OH is present in an amount in the range of from about 2.0 molar to about 4.0 molar. 
     
     
         35 . A process according to  claim 1 , wherein the compound of formula (VIII) is reacted with the carbon monoxide or source of carbon monoxide at a temperature in the range of from about 70° C. to about 90° C. 
     
     
         36 . A process according to  claim 35 , wherein the compound of formula (VIII) is reacted with the carbon monoxide or source of carbon monoxide at a temperature of about 80° C. 
     
     
         37 . A process according to  claim 1 , further comprising 
       
         
           
           
               
               
           
         
         reacting a compound of formula (VI) or mixture of corresponding SEM-protected regioisomers thereof with a source of bromine; in an organic solvent; to yield the corresponding compound of formula (VIII). 
       
     
     
         38 . A process according to  claim 37 , further comprising 
       
         
           
           
               
               
           
         
         reacting a compound of formula (V) with SEMCl; in the presence of an organic or inorganic base; in an organic solvent; to yield the corresponding compound of formula (VI) or mixture of corresponding SEM-protected regioisomers thereof. 
       
     
     
         39 - 79 . (canceled)