Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-06-29
2000-05-23
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546245, 546236, 546220, 514317, C07D21122, C07D21160, C07D21120, C07D21140
Patent
active
060667370
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to optically-enriched N-acylpiperidines and their use.
BACKGROUND OF THE INVENTION
Certain chiral 3,4-disubstituted piperidines are pharmaceutically-active. The desired activity normally resides in only one of the single isomeric forms. In particular, the trans-(3S,4R)-isomer of such a compound, where the 3-substituent is 4-fluorophenyl and the 4-substituent is 3,4-methylenedioxyphenoxymethyl, i.e. paroxetine, is a potent anti-depressant drug that is widely prescribed for the treatment of depression.
Existing methods for the synthesis of single isomer paroxetine involve a resolution step. This means that the unwanted enantiomer, following resolution, is either wasted or must be converted to the desired enantiomer by an inversion process.
Willcocks et al, Journal of Labelled Compounds and Radiopharmaceuticals (1993) XXXIII(8):784-94, disclose the synthesis of .sup.14 C-labelled paroxetine. A key intermediate in this synthesis is 4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine, obtained by reduction of the tetrahydropyridine. This key intermediate is converted to paroxetine by reaction with benzenesulphonyl chloride, then sesamol (with inversion), and removal of the N-methyl group. The starting material for the synthesis is a neurotoxin.
Mangeney et al, J. Org. Chem. (1994) 59:1877-85, disclose an asymmetric synthesis of 3-formyl-1,4-dihydropyridines, comprising the addition of organocopper reagents to activated 3-imidazolidinylpyridine, prepared using chiral diamines. This methodology was used for the asymmetric synthesis of indoloquinolizine and benzoquinolizine alkaloid frameworks.
SUMMARY OF THE INVENTION
This invention is based in part on the realisation that aspects of known procedures can be combined, to provide an elegant, stereoselective synthesis of paroxetine and analogues thereof. The novel synthesis provides a compound of the formula ##STR2## wherein Ar is a C.sub.6-20 aryl group; and R.sup.1 and R.sup.2 are independently H, alkyl or aryl, e.g. of up to 10 or 20 C atoms.
This novel synthon can readily be reduced to a 1-alkylpiperidine of the type disclosed by Willcocks et al as a key intermediate en route to paroxetine. It may be prepared by reduction of the corresponding 1,4-dihydropyridine-3-aldehyde, e.g. using hydrogen and a catalyst. The aldehyde may be prepared by reduction of the dihydropyridine ring in an aminal obtainable by the reaction of 3-pyridinecarboxaldehyde and a chiral C-2 symmetric diamine, and then stereoselective 1,4-addition of the Ar and COOCHR.sup.1 R.sup.2 groups.
DESCRIPTION OF THE INVENTION
A total synthesis of single isomer paroxetine (when Ar is 4-fluorophenyl), by means of the present invention, is shown in Scheme 1. The reactions shown in Scheme 1 are equally applicable to the preparation of the analogues that are the subject of the claims; any modifications that may be necessary will be readily apparent to one of ordinary skill in the art.
Step (i) of Scheme 1 is generally as described by Mangeney et al, supra. The aminal that is formed may be derived from a chiral C-2 symmetric diamine such as N,N'-dimethyl-1,2-cyclohexanediamine or N,N'-dimethyl-1,2-diphenylethylenediamine.
Step (ii) is the stereoselective 1,4-addition reaction. This is achieved using an appropriate organocopper reagent, and by use of a Grignard reagent using a copper catalyst. A copper (I)-catalysed coupling reagent is preferred. For example, the reagents are ArMgBr, CuBr.MeS and XCOOCHR.sup.1 R.sup.2 where X is a reactive atom or group, e.g. a halogen atom and preferably Cl. Preferably, R.sup.2 is H. More preferably, R.sup.1 is also H.
Any aryl or alkyl group may include substituents that do not affect the reactions. Examples of suitable substituents will be readily apparent to those of ordinary skill in the art. For example, Ar may be halophenyl. For the COOCHR.sup.1 R.sup.2 group, it is necessary only to convert it to alkyl, e.g. methyl, to allow the reactions described by Willcocks et al.
Step (iii) comprises hydrolytic cleavage.
REFERENCES:
patent: 3912743 (1975-10-01), Christensen et al.
patent: 5258517 (1993-11-01), Zepp et al.
Pierre Mangeney et al XP 000645443 J. Org. Chem. Prep and Utilization of Chiral . . . pp. 1877-1888, Aug. 4, 1994.
Pierre Mangeney et al Prep. and Utilization of Chiral Dihydrpyridine . . . J.Org. Chem. 1994 vol. 59 pp. 1877-1888, Jun. 9, 1993.
Mangeney, P., et al. (1994) Preparation and Utilization of Chiral Dihydrophyridines. Synthesis of Chiral Indoloquinolizines and Benzoquinolozines. J. Org. Chem. 59: 1877-1888.
Willcocks, K., et al. (1993) The synthesis of [.sup.14 C]-3S,4R-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl) piperidine hydrochloride (BRL 29060A), and mechanistics studies using carbon-13 labelling. Journal of Labelled Compounds and Radiopharmaceuticals 33(8): 783-794.
Amat, M., Hidalgo, J., Bosch, J. (1996) Synthesis of Enantiopure 3,4-Disubstituted Piperidines. An Asymmetric Synthesis of (+)-Paroxetine. Tetrahedron: Asymmetry 7(6): 1591-1594.
Engelstoft, M., Hansen, J.B. (1996) Synthesis and 5HT Modulating Activity of Stereoisomers of 3-Phenoxymethyl-4-phenylpiperidines. Acta Chemica Scand. 50: 164-169.
Adger Brian Michael
Fox Martin Edward
Potter Gerard Andrew
Chirotech Technology, Ltd.
Desai Rita
Rotman Alan L.
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