Enantioselective addition reaction using an organozinc reagent to produce (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

摘要

A process for the preparation of a compound of formula (I) wherein: M is Li, Na, K, Zn, MgX1, CuX1, or B(X1)2; X1 is Cl, Br, I, F or CF3SO2; A is optionally substituted alkyl, alkenyl, alkynyl, phenyl, biphenyl, or naphthyl, R5 is H, optionally substituted alkyl, alkenyl, alkynyl or perfluoroalkyl, R6 is optionally substituted alkyl, alkenyl, or alkynyl comprises: a) adding slowly a dialkylzinc either neat or in a solvent 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 exchangeable proton and a second additive in a solvent under an inert atmosphere at a temperature of -78 OC to 50 OC 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 10 OC to 70 OC to form a second additive containing chiral zinc complex, where the first chiral additive bears one and only one exchangeable proton, or alternatively, where the first chiral additive bears more than one exchangeable proton, or the second additive was added in step a), then this addition step is skipped; c) mixing the chiral zinc complex or the second additive containing chiral zinc complex with an organometallic reagent of formula R6M in a solvent at a temperature range of -20 OC to 60 OC to form a chiral organozinc complex and d) mixing a carbonyl containing compound of formula A-C(O)-R5 optionally dissolved in a solvent with the solution of the chiral organozinc complex under an inert atmosphere at a temperature of -20 oC to 60 oC for 1 to 72 hours.