Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Patent
1992-02-14
1993-03-23
Brust, Joseph Paul
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
570184, 558388, 568319, 568322, 568323, 568338, 568809, C07C 4541, C07C 4546
Patent
active
051966077
ABSTRACT:
A novel multi-step process for preparing the (4S)-enantiomer of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone in a highly-optically pure form is disclosed. The process involves (1) first reacting 3,4-dichlorocinnamyl chloride with L-(-)-ephedrine in a chlorinated lower hydrocarbon solvent to form the corresponding chiral N-methyl-N-(.beta.-hydroxy-.beta.-phenylisopropyl)-3-(3,4-dichlorophenyl)p ropenoamide; (2) then subjecting the chiral .alpha.,.beta.-unsaturated amide formed in the first step to a Grignard reaction with phenyl magnesium chloride or bromide, followed by hydrolysis, to effect a conjugate addition of the phenyl group and the hydrogen element to the aforesaid .alpha.,.beta.-unsaturated propenoamide and so selectively form the corresponding chiral N-methyl-N-(.beta.-hydroxy-.beta.-phenylisopropyl)-3-(3,4-dichlorophenyl)- 3-phenylpropanoamide; (3) hydrolyzing the aforesaid chiral 3-phenylated propanoamide compound to yield the corresponding 3-(3,4-dichlorophenyl)-(3R)-propanoic acid; (4) next esterifying the stereospecific (3R)-phenylated propanoic acid obtained in the third step with an appropriate lower alkanol in the presence of thionyl chloride or a lower alkanoyl chloride to form the corresponding lower alkyl 3-(3,4-dichlorophenyl)-(3R)-phenylpropanoate; (5) then reducing the stereospecific (3R)-phenylated propanoic acid ester with an appropriate carbonyl reducing agent to form the desired 3-(3,4-dichlorophenyl)-(3R)-phenylpropanol intermediate; (6) then chlorinating the stereospecific (3R)-phenylated n-propanol compound to afford the corresponding 3-(3,4-dichlorophenyl)-(3R)-phenylpropyl chloride; (7) next reacting the stereospecific (3R)-phenylated n-propyl chloride with an alkali metal cyanide to form the corresponding 4-(3,4-dichlorophenyl)-(4R)-phenylbutyronitrile; (8) and then hydrolyzing the stereospecific (4R)-phenylated butyronitrile compound to form the corresponding 4-(3,4-dichlorophenyl)-(4R)-phenylbutanoic acid; and (9) thereafter converting the stereospecific (4R)-phenylated n-butanoic acid compound to the corresponding 4-(3,4-dichlorophenyl)-(4R)-phenylbutanoyl chloride by treatment with thionyl chloride, followed cyclization of the aforesaid butanoyl chloride compound in the presence of a Friedel-Crafts type catalyst to finally yield the corresponding (4S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone enantiomer in the desired isomer weight ratio in the resultant isomeric product mixture that allows for the recovery of said individual isomer therefrom in a highly optically-pure form. The desired (4S)-enantiomer has utility as an intermediate that ultimately leads to pure cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthaleneamine (sertraline), which is a known antidepressant agent. The aforementioned 3-(3,4-dichlorophenyl)-(3R)-phenylpropyl alcohol and chloride compounds, as well as the corresponding 4-(3,4-dichlorophenyl)-(4R)-phenylbutyronitrile, are all novel products per se, which are useful as key intermediates in the overall process of the present invention.
REFERENCES:
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W. M. Welch Jr. et al., In The Journal of Medicinal Chemistry, vol. 27, No. 11, (1984); pp. 1508-1519.
T. Mukaiyama et al., in Chemistry Letters, pp. 913-916, (1981).
Brust Joseph Paul
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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