Asymmetric synthesis of (S)-(-)-6-chloro-4- cyclopropyl-3,4-dihydro-4-[(2-pyridyl)ethynyl]-2(1H)-quinazolinone

Claim 1

A process for the preparation of a compound of structural formula: ##STR15## wherein R is --CH 2 --A, and A is i) phenyl unsubstituted or substituted one or more times with B, wherein B is C 1-4 alkyl, C 1-4 alkoxy, or halo; ii) naphthyl unsubstituted or substituted one or more times with B; or iii) anthryl unsubstituted or substituted one or more times with B; said process comprising the steps of: (a) mixing one equivalent of 2-ethynylpyridine with about one equivalent of a chiral modifier selected from quinine or dihydroquinine, in a solvent comprising an ethereal solvent selected from THF, diethyl ether, 1,2-dimethoxyethane or dioxane, said ethereal solvent optionally combined with toluene, hexanes, or other less polar solvents; (b) mixing thereto, at between about -70° to about -20° C., two or more equivalents of either n-butyl lithium or lithium hexamethyldisilazane; (c) mixing thereto, between about 0.5 and 1.0 equivalents of a compound of structural formula ##STR16## at about -50° to 0° C.; (c) maintaining the resulting mixture at about -40° C. to about 0° C. for 2-24 hours; (d) to give a compound of Formula I.