Patent ID: 6015926
Filing Date: 2000-01-18
Classification: A61P,C07B,C07C,C07D

Abstract:
A process for the preparation of a compound of formula I: ##STR59## or its enantiomer, wherein A is:(a) C.sub.1 -C.sub.6 -alkyl, C.sub.2 -C.sub.6 -alkenyl, or C.sub.2 -C.sub.6 -alkynyl, unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of: halo, CF.sub.3, CN, NO.sub.2, NH.sub.2, NH(C.sub.1 -C.sub.6 -alkyl), N(C.sub.1 -C.sub.6 -alkyl).sub.2, CONH.sub.2, CONH(C.sub.1 -C.sub.6 -alkyl), CON(C.sub.1 -C.sub.6 -alkyl).sub.2, NHCONH.sub.2, NHCONH(C.sub.1 -C.sub.6 -alkyl), NHCON(C.sub.1 -C.sub.6 -alkyl).sub.2, CO.sub.2 --C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, or C.sub.1 -C.sub.6 -alkoxy;(b) phenyl, biphenyl, or naphthyl, unsubstituted or substituted with one to four substituents selected from R.sup.1, R.sup.2, R.sup.3, and R.sup.4 ;R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently:halo, CF.sub.3, CN, NO.sub.2, NH.sub.2, NH(C.sub.1 -C.sub.6 -alkyl), N(C.sub.1 -C.sub.6 -alkyl).sub.2, CONH.sub.2, CONH(C.sub.1 -C.sub.6 -alkyl), CON(C.sub.1 -C.sub.6 -alkyl).sub.2, NHCONH.sub.2, NHCONH(C.sub.1 -C.sub.6 -alkyl), NHCON(C.sub.1 -C.sub.6 -alkyl).sub.2, aryl, CO.sub.2 --C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkyl, C.sub.2 -C.sub.6 -alkenyl, C.sub.2 -C.sub.6 -alkynyl, C.sub.3 -C.sub.7 -cycloalkyl, or C.sub.1 -C.sub.6 -alkoxy, such that C.sub.1 -C.sub.6 -alkyl is unsubstituted or substituted with aryl, aryl is defined as phenyl, biphenyl, or naphthyl, unsubstituted or substituted with C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkoxy, NO.sub.2, or halo;R.sup.5 is:(a) H,(b) C.sub.1 -C.sub.6 -alkyl, C.sub.2 -C.sub.6 -alkenyl, or C.sub.2 -C.sub.6 -alkynyl, unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of: halo, CF.sub.3, CN, NO.sub.2, NH.sub.2, NH(C.sub.1 -C.sub.6 -alkyl), N(C.sub.1 -C.sub.6 -alkyl).sub.2, CONH.sub.2, CONH(C.sub.1 -C.sub.6 -alkyl), CON(C.sub.1 -C.sub.6 -alkyl).sub.2, NHCONH.sub.2, NHCONH(C.sub.1 -C.sub.6 -alkyl), NHCON(C.sub.1 -C.sub.6 -alkyl).sub.2, CO.sub.2 --C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, or C.sub.1 -C.sub.6 -alkoxy;(c) C.sub.1 -C.sub.4 -perfluoroalkyl,R.sup.6 is:C.sub.1 -C.sub.6 -alkyl, C.sub.2 -C.sub.6 -alkenyl, or C.sub.2 -C.sub.6 -alkynyl, unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of: halo, CF.sub.3, CN, NO.sub.2, NH.sub.2, NH(C.sub.1 -C.sub.6 -alkyl), N(C.sub.1 -C.sub.6 -alkyl).sub.2, CONH.sub.2, CONH(C.sub.1 -C.sub.6 -alkyl), CON(C.sub.1 -C.sub.6 -alkyl).sub.2, NHCONH.sub.2, NHCONH(C.sub.1 -C.sub.6 -alkyl), NHCON(C.sub.1 -C.sub.6 -alkyl).sub.2, CO.sub.2 --C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl or C.sub.1 -C.sub.6 -alkoxy;comprising the steps of:a) adding slowly a dialkylzinc in a solvent or neat, to a first chiral additive bearing one or more exchangeable protons, or alternatively, to a mixture of a first chiral additive bearing one and only one exchangeable proton and a second additive, in a solvent under an inert atmosphere at a temperature of about -78.degree. C. to about 50.degree. C. to form a chiral zinc complex or a second additive containing chiral zinc complex;b) adding a second additive to a chiral zinc complex, and heating the reaction to about 10.degree. C. to about 70.degree. C. to form a second additive containing chiral zinc complex, where the first chiral additive bears one and only one exchangeable proton, or alternatively, skipping this addition step where the first chiral additive bears more than one exchangeable proton, or the second additive was added in step a);c) mixing the chiral zinc complex or the second additive containing chiral zinc complex with an organometallic reagent of formula, R.sup.6 M, where M is: Li, Na, K, Zn, MgX.sub.1, CuX.sub.1, or B(X.sub.1).sub.2 ; and X.sub.1 is Cl, Br, I, F, or CF.sub.3 SO.sub.2 ; in a solvent at a temperature range of -20.degree. C. to about 60.degree. C. to form a chiral organozinc complex; andd) mixing a carbonyl-containing compound of formula: ##STR60## optionally dissolved in a solvent with the solution of the chiral organozinc complex under an inert atmosphere at a temperature of about -20.degree. C. to about 60.degree. C. for about 1 hour to about 72 hours.