Process for the preparation of C-FMS kinase inhibitors

摘要

The present invention is directed to a process for the preparation of heterocyclic derivatives of formula I;
wherein J, X, Z, and R2 are as defined herein. Such compounds are 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 W is selected from the group consisting of each R4 is independently selected from the group consisting of hydrogen, 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; wherein Rd is selected from the group consisting of H 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 hydrogen, —CH2OH and —CH2CH2OH; J is selected from the group consisting of CH and N; R2 is selected from the group consisting of cycloalkyl, spiro-substituted cycloalkenyl, thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl and dihydropyranyl; any of which may be independently substituted with one or two of each of the following: chloro, fluoro, hydroxy, and C(1-4)alkyl; Z is selected from the group consisting of hydrogen, F, Cl and CH3; X is selected from the group consisting of wherein Rw is selected from the group consisting of hydrogen, —C(1-4)alkyl, —CO2C(1-4)alkyl, —CONH2, —CONHC(1-4)alkyl, —CON(C(1-4)alkyl)2 and —COC(1-4)alkyl;
or a tautomer or pharmaceutically acceptable salt thereof; comprising reacting a compound of formula (X) with a compound of formula (XI) or a mixture of SEM protected region-isomers thereof, whereinis selected from the group consisting of in the presence of carbon monoxide gas or a source of carbon monoxide; in the presence of an organic or inorganic base; in the presence of a suitably selected coupling system comprising a palladium compound selected from the group consisting of Pd(OAc)2 and Pd2(dba)3 and a ligand selected from the group consisting of XantPhos and BINAP; in an organic solvent; at a temperature in the range of from about 60° C. to about 120° C. to yield the corresponding compound of formula (XII); de-protecting the compound of formula (XII), to yield the corresponding compound of formula (I).