Asymmetric synthesis of (-)-6-chloro-4-cyclopropyl-ethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1- benzoxanzin-2-one
AssigneeMerck & Co., Inc.
InventorsAndrew S. Thompson, Edward G. Corley, Edward J.J. Grabowski, Nobuyoshi Yasuda
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Abstract
An improved synthesis of a highly potent HIV reverse transcription inhibitor is disclosed, involving an acetylide and a trifluoromethyl ketone which produces a chiral product in the presence of a chiral amino alcohol.
Claims6
A process for the asymmetric synthesis of the chiral compound of the structure ##STR36## wherein P is an amino protecting group;
- comprising the steps of:
- (a) providing a mixture of excess (1R,2S)-N-substituted norephedrine, of the structure ##STR37## wherein R is C.sub.1-4 alkyl, or --NR.sub.2 forms pyrrolidinyl or piperidinyl;
- with an excess of cyclopropylacetylene and an excess of a lithiating agent selected from n-butyllithium or sec-butyllithium or tert-butyllithium, at a temperature of between about -78.degree. C. and about 10.degree. C., in aprotic solvent;
- (b) mixing with the mixture of Step (a) about one equivalent of reactant of the structure ##STR38## wherein P is an amino protecting group;
- and maintaining the resulting reaction mixture at a temperature between about -78.degree. C. and about -20.degree. C.;
- (c) quenching by adding a proton source;
- (d) to give the desired compound.
A process for the asymmetric synthesis of the chiral compound N-(4-methoxybenzyl)-6-chloro-2-[(R)-cyclopropylethynyl-hydroxy-trifluorome thyl]-methyl-aniline, of the structure ##STR39## comprising the steps of:
- (a) providing a mixture of excess (1R,2S)-N-substituted norephedrine, of the structure ##STR40## wherein R is C.sub.1-4 alkyl, or --NR.sub.2 forms pyrrolidinyl or piperidinyl;
- with an excess of cyclopropylacetylene and an excess of a lithiating agent selected from n-butyllithium, sec-butyllithium or tert-butyllithium, at a temperature of between about -78.degree. C. and about 10.degree. C., in aprotic solvent;
- (b) mixing with the mixture of Step (a) about one equivalent of reactant N-(4-methoxybenzyl)-6-chloro-2-(2-trifluoro-1-oxo-ethyl)-aniline, of the structure ##STR41## and maintaining the resulting reaction mixture at a temperature between about -78.degree. C. and about -20.degree. C.;
- (c) quenching by adding a proton source;
- (d) to give the desired compound.
A process for the asymmetric synthesis of the chiral compound of the structure ##STR42## wherein P is an amino protecting group;
- comprising the steps of:
- (a) providing a mixture of excess (1R,2S)-N-pyrrolidinyl norephedrine, of the structure ##STR43## with an excess of cyclopropylacetylene and an excess of a lithiating agent selected from n-butyllithium or sec-butyllithium or tert-butyllithium, at a temperature of about -15.degree. C., in aprotic solvent;
- (b) mixing with the mixture of Step (a) about one equivalent of reactant of the structure ##STR44## wherein P is an amino protecting group;
- and maintaining the resulting reaction mixture at about -40.degree. C.;
- (c) quenching by adding a proton source;
- (d) to give the desired compound.
A process for the asymmetric synthesis of the chiral compound N-(4-methoxybenzyl)-6-chloro-2-[(R)-cyclopropylethynyl-hydroxy-trifluorome thyl]-methyl-aniline, of the structure ##STR45## comprising the steps of:
- (a) providing a mixture of excess (1R,2S)-N-pyrrolidinyl norephedrine, of the structure ##STR46## with an excess of cyclopropylacetylene and an excess of n-butyllithium, at a temperature of about -15.degree. C., in aprotic solvent;
- (b) mixing with the mixture of Step (a) about one equivalent of reactant N-(4-methoxybenzyl)-6-chloro-2-(2-trifluoro-1-oxo-ethyl)-aniline, of the structure ##STR47## and maintaining the resulting reaction mixture at about -40.degree. C.;
- (c) quenching by adding a proton source;
- (d) to give the desired compound, in .gtoreq.85% yield, .gtoreq.95% ee.
Dependencies are inferred from the claim text.