PROCESS FOR THE PREPARATION OF HETEROCYCLIC ESTER DERIVATIVES

摘要

The present invention is directed to a process for the preparation of heterocyclic ester derivatives of formula I;wherein A1, SEM, and W1 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.

主权项

1. A process for the preparation of a compound of formula (I) wherein A1 is selected from the group consisting of C1-3alkyl; wherein  is selected from the group consisting of wherein each R4 is independently selected from the group consisting of H, F, Cl, Br, I, —OH, —OCH3, —OCH2CH3, —SC(1-4)alkyl, —SOC(1-4)alkyl, —SO2C(1-4)alkyl, —C(1-3)alkyl, —CO2Rd, —CONReRf, —CCRg, and —CN; and wherein Rd is selected from the group consisting of hydrogen and —C(1-3)alkyl; Re is selected from the group consisting of H and —C(1-3)alkyl; Rf is selected from the group consisting of H and —C(1-3)alkyl; and Rg is selected from the group consisting of H, —CH2OH and —CH2CH2OH; 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 A1OH; at a temperature in the range of from about 60° C. to about 120° C.; to yield the corresponding compound of formula (I)