Process for preparing chiral tetralone

Details Process for preparing chiral tetralone Process for preparing chiral tetralone

1996-05-29

1998-05-12

Reamer, James H.

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

Organic compounds

Oxygen containing

568808, 568814, C07C 4539

Patent

active

057507945

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The present invention relates to a novel process for asymmetrically reducing racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone (hereinafter also referred to as "the tetralone" or "the racemic tetralone") and for preparing chiral (4S)-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone (hereinafter also referred to as "the chiral tetralone"), which has utility as an intermediate in the production of pure cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthal eneamine (sertraline). Sertraline is a known antidepressant agent. This invention also relates to novel intermediates in the synthesis of chiral tetralone.
Several documents relate to the synthesis of pure racemic N-methyl4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine starting with 3,4-dichlorobenzophenone and proceeding via racemic (.+-.)-4-(3,4-dichlorophenyl)-4-butanoic acid and then to (.+-.)-4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone. See, e.g., U.S. Pat. No. 4,536,518 (Aug. 20, 1985); U.S. Pat. No. 4,556,676 (Dec. 3, 1985); U.S. Pat. No. 4,777,288 (Oct. 11, 1988); and U.S. Pat. No. 4,839,104 (Jun. 13, 1989); and Journal of Medicinal Chemistry, Vol. 27, No. 11, p. 1508 (1984).
Tetrahedron, Vol. 48, No. 47, pp. 10239-10248 (1992) relates to a process for preparing the (4S)-enantiomer of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone comprising reducing the 4-ketobutanoic acid ester with a carbonyl reducing agent, as outlined in E. J. Corey et al., Journal of Organic Chemistry, Vol. 53, p. 2861 (1988), to ultimately afford chiral tetralone.
Other asymmetric methods of synthesis have been employed in the art, such as those described by W. M. Whitesides et al., Journal of the American Chemical Society, Vol. 91, No. 17, p. 4871 (1969); K. Mori et al., Synthesis, p. 752 (1982); B. H. Lipshutz et al., Journal of Organic Chemistry, Vol. 49, p. 3928 (1984); B. H. Lipshutz et al., Journal of the American Chemical Society, Vol. 104, p. 4696 (1982); G. M. Whitesides et al., Journal of the American Chemical Society, Vol. 91, No. 17 (1969); C. R. Johnson et al., Journal of the American Chemical Society, Vol. 95, No. 23, p. 7783 (1973); B. H. Lipshutz et al., Tetrahedron, Vol. 40, No. 24, p. 5005 (1984); and C. R. Johnson et al., Journal of the American Chemical Society, Vol. 95, No. 23, p. 7777 (1973).
All of the documents cited herein, including the foregoing, are incorporated herein in their entireties.


SUMMARY OF THE INVENTION

Broadly, the present invention relates to a process for asymmetrically reducing racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone comprising reacting the racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone with an asymmetric ketone reducing agent. The asymmetric ketone reducing agent is preferably a catalytic chiral oxazaborolidine compound.
Preferred chiral oxazaborolidine compounds have the formula: ##STR1## wherein: R.sup.1 is hydrogen, (C.sub.1 -C.sub.8)alkyl, benzyl, phenyl or phenyl substituted with up to three substituents independently selected from (C.sub.1 -C.sub.8)alkyl, (C.sub.1 -C.sub.8)alkoxy and halo; and substituted with up to three substituents independently selected from (C.sub.1 -C.sub.8)alkyl, (C,-C.sub.8)alkoxy and halo.
Other preferred chiral oxazaborolidine compounds have the formula: ##STR2## wherein: R.sup.4 is hydrogen, lower alkyl or aralkyl; the oxazaborolidine nitrogen and adjacent carbon, a 4-, 5- or 6-membered ring; and
Another preferred asymmetric ketone reducing agent comprises either enantiomer of the compound having the formula:
The reduction of the racemic tetralone, depending on the asymmetric ketone reducing agent chosen, will yield either cis and trans alcohols having the following formulae: ##STR3## or cis and trans alcohols having the following formulae: ##STR4##
The enantiomer of the asymmetric reducing agent determines whether (I) and (III) or (II) and (IV) is produced.
The present invention also relates to each of the two reduction processes described above (i.e., that wh

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