Process for preparing sertraline intermediates

Details Process for preparing sertraline intermediates Process for preparing sertraline intermediates

1994-01-10

1995-08-15

Kumar, Shailendra

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

564215, 564217, 564218, 564219, C07C23303, C07C23304, C07C23118

Patent

active

054421160

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

This application is a 371 of PCT/EP92/01496 filed Jul. 3, 1992.
This invention relates to novel trans-N-alkanoyl-N-methyl-4-(3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine analogues, which are intermediates in a new process for preparing sertraline, together with intermediates thereto and processes for the preparation thereof.


SUMMARY OF THE INVENTION

More specifically, the invention relates to the (1R,4S)-stereoisomeric form of the said trans-1,4-disubstituted tetrahydronaphthylamines which, upon N-deacylation, afford trans-(1R,4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthy lamine. The latter, which is disclosed in U.S. Pat. No. 4,556,676 and in the Journal of Medicinal Chemistry, 1984, 27, 1508, is isomeric with 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, in turn, is disclosed in U.S. Pat. No. 4,536,518 and in the Journal of Medicinal Chemistry, 1984, 27, 1508. The trans-(1R,4S)-isomer may be converted to the cis-(1S,4S)-isomer (sertraline) by the conventional procedures subsequently summarised.
The novel compounds of the present invention have been made available by the unexpected discovery that the required trans-isomer may be generated stereoselectively, in high yield, by ionic hydrogenation of the appropriate (1R, 4S)-N-alkanoyl-N-methyl-4-(3,4-dichlorophenyl)-4-hydroxy-1,2,3,4-tetrahydr o-1-naphthylamine precursor, allowing ready removal of the unwanted (1R,4R)-isomer. Importantly, since the said precursor possesses the 1-(N-alkanoyl)methylamino substituent in the R-configuration, ionic hydrogenation thereof affords the trans-(1R,4S)-enantiomer in high yield and with high stereoselectivity, thus obviating the need for a subsequent optical resolution to remove the unwanted trans-(1S,4R)-enantiomer.
Thus the present invention provides: form, consisting of the trans-(1R,4S)-enantiomer, of a compound of formula: ##STR2## wherein R.sup.1 is H or C.sub.1 -C.sub.4 alkyl, and R and S represent the absolute configurations of the asymmetric centres; pure trans-stereoisomeric form of a compound of formula (I) by subjecting a compound of formula: ##STR3## wherein R.sup.1, R and S are as previously defined for formula (I), in a suitable solvent, to ionic hydrogenation conditions.
Alkyl groups containing three or four carbon atoms may be straight or branched chain.
The term "substantially geometrically and optically pure" means that the compound of the formula (I) contain less than 4%, and preferably less than 2%, of the undesired cis-(1R,4R)-enantiomer.
In the above definitions of the compounds of formulae (I) and (II), preferably R.sup.1 is H.


DETAILED DESCRIPTION OF THE INVENTION

The compounds provided by the present invention may be prepared as follows.
A compound of formula (I) is obtained by ionic hydrogenation of a compound of formula (II) in a suitable solvent, such as dichloromethane, using a combination of either a protic acid, e.g. trifluoroacetic acid, or preferably a Lewis acid, e.g. boron trifluoride, with a hydride donor, e.g. triethylsilane. Typically the reaction is conducted at from -40.degree. to +25.degree. C. for up to to 40 hours, preferably about 20 hours. The product of formula (I) may then be isolated and purified by conventional techniques, e.g. by extractive work-up, followed by chromatographic purification and/or crystallisation of the crude product, to remove any recovered starting material and minor amounts of the unwanted cis-(1R,4R)-isomer. Alternatively, the separation of trans- and cis-isomers can be effected after removal of the N-alkanoyl group, to furnish a compound of formula (VI), wherein R and S are as previously defined, in the next stage of the synthetic sequence depicted in the following Scheme. ##STR4##
The N-alkanoyl group of a compound of formula (I), the major isomer of the aforementioned crude product, is removed by hydrolysis,using an aqueous inorganic base such as an alkali metal hydroxide salt, preferably potas

REFERENCES:
patent: 4536518 (1985-08-01), Welch, Jr. et al.
Tremaine ete al., Drug Metabol. Dispos., 17(5) 1989 542-550.
Welch et al. J. Med. Chem., 1984, 27, 1508-1515.

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