Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Patent
1994-06-09
1995-11-14
Reamer, James H.
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
560 51, 560 55, 560101, 562459, 558 51, C07C 4545
Patent
active
054668808
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This application is a 371 of PCT U.S. 92/07,654 filed Sep. 15, 1992.
This invention relates to a new and useful process for preparing a ketone enantiomer. More particularly, it is concerned with a novel multi-step process for preparing the (4S)-enantiomer of4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone in a highly-optically pure form. The latter compound, which is a novel (4S)-enantiomer per se, has utility as a key intermediate that ultimately leads to the production of pure cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthal eneamine (sertraline), which is a known antidepressant agent. The invention also includes within its scope certain other novel compounds which are useful as intermediates in the various stages of the overall process.
BACKGROUND ART
There is described in U.S. Pat. Nos. 4,536,518 and 4,556,676 to W. M. Welch, Jr. et al., as well as in the paper of W. M. Welch, Jr. et al., appearing in the Journal of Medicinal Chemistry, Vol. 27, No. 11, p. 1508 (1984), a multi-step method for synthesizing pure racemic cis-(1S) (4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro -1-naphthaleneamine, starting from the readily available 3,4-dichlorobenzophenone and proceeding via the known racemic or (.+-.)-4-(3,4-dichlorophenyl)-4-butanoic acid and then to (.+-.) -4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone (see also U.S. Pat. Nos. 4,777,288 and 4,839,104 to G. J. Quallich et al. for improved methods leading to these intermediates), with the latter ketone then being condensed with methylamine in the presence of titanium tetrachloride to yield N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine. In the last step of the overall synthesis, the aforementioned imine is then readily reduced by means of catalytic hydrogenation or by the use of a metal hydride complex to yield N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine, which is actually a mixture of the cis- and trans-isomers in the form of a racemate. The aforesaid isomeric mixture is then separated into its component parts by conventional means, e.g., by fractional crystallization of the hydrochloride salts or by column chromatography on silica gel of the corresponding free base. Resolution of the separated cis-racemate free base compound while in solution with an optically-active selective precipitant acid, such as D-(-)-mandelic acid, in a classical manner then ultimately affords the desired cis-(1S)(4S)-enantiomer (sertraline).
Nevertheless, the above described production of pure cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthal eneamine (sertraline) is disadvantageous in that equal amounts of the unwanted cis -(1R)(4R)-enantiomer are co-produced and must eventually be discarded, thereby lowering the overall yield of the desired cis-(1S)(4S)-enantiomer and increasing the total costs of production.
In accordance with the prior art, other asymmetric methods of induction (e.g., asymmetric syntheses) have been employed in the past with variable success in the field of organo-metallic chemistry to stereoselectively convert (and thereby resolve) other specific substrates. For instance, in a paper by W. M. Whitesides et al., appearing in the Journal of the American Chemical Society, Vol. 91, No. 17, p. 4871 (1969), as well as in an article by K. Mori et al., as reported in Synthesis, p. 752 (1982), there are described certain copper-assisted coupling reactions of various organic halides and tosylates that illustrate non-benzylic S.sub.N 2 displacement with cuprates at a secondary position in the substrate molecule. Additionally, B. H. Lipshutz et al., in the Journal of Organic Chemistry, Vol. 49, p. 3928 (1984), refer to various substitution reactions of secondary organic halides and epoxides with higher order, mixed organocuprates from both a synthetic and stereochemical point of view. They specifically report that the diphenyl(cyano)cuprate reagent of the formula (.phi.).sub.2 Cu(CN)Li.sub.2 routinely displaces secondary o
REFERENCES:
patent: 4556676 (1985-12-01), Welch et al.
patent: 4777288 (1988-10-01), Quallich et al.
patent: 4921999 (1990-05-01), O'Brien
Ginsburg Paul H.
Pfizer Inc.
Reamer James H.
Richardson Peter C.
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