Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-06-22
2000-09-12
Seaman, D. Margaret
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D21172, C07D21184
Patent
active
061180068
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a method for the preparation of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyri dine and its pharmaceutically acceptable salts.
1-[2-(2-Naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid ine, hereafter designated by its code number SR 57746, and its pharmaceutically acceptable salts were first described in EP 0 101 381 as anorexigenic agents and subsequently as antianxiodepressants (U.S. Pat. No. 5,026,716), anticonstipation agents (U.S. Pat. No. 5,109,005), neurotrophic agents (U.S. Pat. No. 5,270,320), free radical scavengers (U.S. Pat. No. 5,292,745) and cardioprotective agents (U.S. Pat. No. 5,378,709).
The document EP 0 101 381 describes a series of 1-(hetero)aralkyl-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridines prepared by condensing 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine: iodide, or an analogous derivative containing an electrophilic leaving group such as the methanesulfonyloxy or p-toluenesulfonyloxy group; halide, said condensation reaction being followed by reduction of the resulting amide.
According to the document cited above, 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyri dine is prepared in the form of the hydrochloride by reacting 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine with 2-naphthylacetyl chloride and reducing the resulting product with lithium aluminum hydride. This method proceeds satisfactorily in the first step, but the subsequent reduction causes a loss of yield due to attack of the trifluoromethyl group by the reducing agent, as demonstrated by the yield of 42.73% of theory obtained in the preparation described.
The same document describes the preparation of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyri dine hydrochloride by condensing 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine with 2-(2-chloroethyl)naphthalene in the presence of triethylamine, but gives no indication of the yields obtained. Independently of the yields which can be obtained by this alkylation, however, the use of 2-(2-chloroethyl)naphthalene gives rise to problems associated with the manufacture of this intermediate, which involves heating 2-(2-naphthyl)ethanol in thionyl chloride. This reaction gives very low yields of chlorinated derivative, on the one hand because the naphthylethanol does not react completely and on the other hand because the reaction gives variable amounts--according to the operating conditions--of 2-vinylnaphthalene.
Better yields (83.9%) are obtained by reacting 2-naphthalenethanol with thionyl chloride in ether in the presence of pyridine (J. Am. Chem. Soc., 1982, 104 (19): 5171), but this type of reaction has to be followed with very great care and, in particular, is difficult to exploit on the industrial scale.
It has also been found that the reaction of 2-(2-chloroethyl)naphthalene with 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine under the conditions described in EP 0 101 381, i.e. in ethanol under reflux for 20-24 hours, gives 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyri dine hydrochloride with very low yields.
It has now been found that by reacting 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine or one of its salts with 2-(2-bromoethyl)naphthalene, 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyri dine and its salts can be obtained with yields well above those obtained according to EP 0 101 381.
It has also been found that the products obtained in this way are purer than the 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyri dine hydrochloride prepared using 2-(2-chloroethyl)naphthalene according to EP 0 101 381, because they are practically devoid of vinyl derivatives. Furthermore, the 2-(2-bromoethyl)naphthalene used as reactant can be prepared very easily, with yields in excess of 90%, from 2-naphthylethanol and hydrobromic acid, and the product obtained contains 2-vinylnaphthalene in amounts of not more t
REFERENCES:
patent: 3910931 (1975-10-01), Cavalla et al.
patent: 4521428 (1985-06-01), Nisato et al.
Verlag, Georg Thieme, "Method der Organischen Chemie", Band V/4, Stuttgart, pp. 679-685 (1960).
Novak, Lajos et al., "Synthesis of Novel HMG-CoA Reductase Inhibitors. I. Naphthalene anaglos of mevinolin", Liebigs Ann. Chem. (1992), (2), pp. 145-157.
Lawesson, "Anomalous reactions of 2-naphthylmethylmagnesium bromide", Acta Chemical Scandinavica, No. 12, 1958, pp. 1-7.
Buj Michel
Filhol Robert
Alexander Michael D.
Sanofi-Synthelabo
Seaman D. Margaret
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