Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1994-01-10
1995-10-31
Kumar, Shailendra
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
564217, 564218, 564221, C07C23303, C07C23304, C07C23118
Patent
active
054631262
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US 92/01497 filed Jul. 3, 1992.
BACKGROUND OF THE INVENTION
This invention relates to novel cis-N-alkanoyl-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphth ylamine analogues, which are key intermediates in a new process for preparing sertraline, together with intermediates thereto and processes for the preparation thereof.
A specific embodiment of the invention relates to the (1S,4S)-stereoisomeric form of such cis-N-alkanoyl-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphth ylamines, intermediates thereto and processes for the preparation thereof. These novel cis-1,4-disubstituted tetrahydronaphthylamines and processes thereto are particularly advantageous in the synthesis of the antidepressant agent known as sertraline, or cis-(1S,4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthyla mine, which is disclosed in U.S. Pat. No. 4,536,518 and in the Journal of Medicinal Chemistry, 1984, 27, 1508.
SUMMARY OF THE INVENTION
The novel compounds of the present invention have been made available by the unexpected discovery that the required cis-isomer may be generated stereoselectively, in high yield, by catalytic hydrogenation of the appropriate N-alkanoyl-N-methyl-4-(3,4-dichlorophenyl)-1,2-dihydro-1-naphthylamine precursor, allowing ready removal of the unwanted trans-ismore. More importantly, when the precursor itself is optically pure and the 1-(N-alkanoyl)methylamino substituent possesses the S-configuration, catalytic hydrogenation thereof affords the cis- (1S,4S)-enantiomer in high yield and with high stereoselectivity, thus obviating the need for a final stage optical resolution to separate sertraline from the unwanted cis-(1R,4R)-enantiomer.
Thus the present invention provides: of a racemic mixture of the cis-(1S,4S) and the cis-(1R,4R) enantiomers, of a compound of formula: ##STR2## wherein R.sup.1 is H or C.sub.1 -C.sub.4 alkyl and * denotes an unresolved asymmetric centre; form, consisting of the cis-(1S,4S) enantiomer, of a compound of formula: ##STR3## wherein R.sup.1 is H or C.sub.1 -C.sub.4 alkyl and S represents the absolute configuration of a resolved asymmetric centre; cis-stereisomeric form of a compound of formula (I) or the substantially geometrically and optically pure cis-stereoisomeric form of a compound of formula (II) by subjecting, respectively, a compound of formula: ##STR4## wherein R.sup.1 and S are as previously defined for formulae (I) and (II), in a suitable solvent, to hydrogenation in the presence of platinum or palladium as catalyst;
Alkyl groups containing three or four carbon atoms may be straight or branched chain.
The term "substantially geometrically pure" means that the compounds of the formula (I) contain less than 4%, and preferably less than 2%, of the undesired diastereoisomeric pair of trans-(1S,4R) and (1R,4S)-enantiomers. The term "substantially geometrically and optically pure" means that the compound of formula (II) contains less than 4%, and preferably less than 2%, of the undesired trans-(1S,4R)-enantiomer.
In the above definitions of the compounds of formulae (I), (II), (III) and (IV), preferably R.sup.1 is H or methyl.
The compounds provided by the present invention may be prepared as follows:
DETAILED DESCRIPTION OF THE INVENTION
1. A compound of formula (I) is prepared by hydrogenation of a compound of formula (III), in the presence of platinum oxide, in a suitable solvent, e.g. tetrahydrofuran, ethyl acetate or ethanol. Typically, the reaction is conducted under pressure at about 50 p.s.i. (3.45 bar) of hydrogen and at a temperature of from 20.degree. to 25.degree. C. for 1 to 2 hours. The product of formula (I) may then be isolated and purified by conventional techniques, e.g. by removal of the catalyst by filtration, evaporation under vacuum of the filtrate, and then crystallisation of the crude residue to remove minor amounts of the unwanted trans- isomer. Alternatively, the separation of cis- and trans-isomers can be effected after removal of the N-alkanoyl group to furnish a
REFERENCES:
patent: 4536518 (1985-08-01), Welch et al.
patent: 4882339 (1989-11-01), Wasley
patent: 5071875 (1991-12-01), Horn et al.
Ginsburg Paul H.
Kumar Shailendra
Pfizer Inc.
Richardson Peter C.
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