Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-03-20
1998-03-31
Morris, Patricia L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D40104
Patent
active
057340595
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/JP95/01911 filed Sep. 21, 1995.
TECHNICAL FIELD
This invention relates to novel production intermediates to be used for the production of pyridine derivatives (e.g., anabaseine), which are useful for the treatment of central nervous system diseases such as Alzheimer's disease and Parkinson's disease, and industrial processes for producing the same.
BACKGROUND ART
A pyridine derivative represented by formula (III): ##STR2## anabaseine represented by formula (IV): ##STR3## and anabaseine derivatives obtained by using the above-mentioned compound (III) or (IV) as a synthesis intermediate are publicly known compounds described in, for example, Brit. J. Pharmacol., 18, 543 (1962), Agr. Biol. Chem, 26, 709 (1962), Toxicon, 9, 23 (1971), Amer. Zoologist, 25, 99 (1985), Drug Development Research, 31, 127 (1994) or 31, 135 (1994), International Publication Nos. WO 92/15306 and WO 94/05288. These compounds are useful as a remedy for central nervous system diseases such as Alzheimer's disease and Parkinson's disease.
As processes for producing the pyridine derivatives represented by the formula (III) and their analogous compounds, there have been publicly known some methods with the use of a sodium alkoxides as a base, for example, (1) a method for producing nicotine by reacting a nicotinate with N-methylpyrrolidone with the use of sodium ethoxide (Ber., 61., 327 (1928)); and (2) another method for producing anabaseine from N-benzoylpiperidone and ethyl nicotinate with the use of sodium ethoxide (Chem. Ber., 69, 1082-1085 (1936)). However, these methods can achieve furthermore, the reaction is accompanied by a rapid increase in temperature, which makes it difficult to control the reaction temperature. In this case, moreover, 2-phenyl-3,4,5,6-tetrahydropyridine is formed as a side-product which can be hardly eliminated on an industrial scale. Accordingly, these existing methods are not preferable form an industrial viewpoint.
Subsequently, there have been proposed some methods wherein the sodium alkoxide is replaced by sodium hydride with an elevated basicity to thereby accelerate the progress of the reaction. Examples of these methods include (3) a method for producing nicotinoyl-N-methylpyrrolidone from a nicotinate and N-methylpyrrolidone with the use of sodium hydride (JP-B-39-25048; the term "JP-B" as used herein means an "examined Japanese patent publication"); and (4) a method for producing myosmin from N-vinylpyrrolidone and a nicotinate with the use of sodium hydride (Acta Chem. Scand., 30B, 93 (1976)). Although these methods contribute to the improvement in yield, the industrial application thereof is accompanied by serious problems. That is to say, the sodium hydride employed as a reagent in these methods spontaneously ignites when it comes in contact with air. Also, it catches fire easily in the presence of water. At the reaction, it undergoes vigorous foaming and causes heat generation and evolution of hydrogen gas. Due to these characteristics, it is highly dangerous to use sodium hydride in the synthesis on a large scale. To ensure the security, therefore, specific devices and techniques are required. Moreover, sodium hydride is usually marketed in a state of being dispersed in liquid paraffin in an amount of about 60%. Accordingly, the production process should involve an additional step of completely eliminating the liquid paraffin. Thus, it is to be concluded that the above-mentioned methods with the use of sodium hydride are unsuitable for industrial purposes from an economical viewpoint too.
Examples of other production methods include (5) a method starting from N-nicotinoylpiperidone with the use of calcium oxide (Synth. Commun., 2 (4), 187-200 (1972)); (6) a method starting from bromopyridine and cyclopentanone with the use of n-butyllithium (Tetrahedron Lett., 24 (18), 1937-1940 (1983)); (7) a method wherein bromopyridine is condensed with N-tert-butyloxycarbonylpiperidone with the use of n-butyllithium (J. Org. Chem., 54 (1), 228-234 (1989)); and (8) a method wherein
REFERENCES:
Ber., 61, 327 (1928).
Chem. Ber., 69, 1082-1085 (1936).
Chemical Abstract of JP-B-39-25048 (1965).
Acta Chem. Scand., 30B, 93 (1976).
Synth. commun., 2(4), 187-200 (1972).
Tetrahedoron lett., 24, (18), 1937-1940 (1983).
J. Org. Chem., 54(1), 228-234 (1989).
Kajitani Makoto
Kem William R.
Lee Hun Ju
Maruhashi Kazuo
Watanabe Syotaro
Morris Patricia L.
Taiho Pharmaceutical Co. Ltd.
University of Florida
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