Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-07
2002-05-07
Badio, Barbara P. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S333000, C548S452000, C560S204000
Reexamination Certificate
active
06384228
ABSTRACT:
TECHNICAL FIELD PERTINENT TO THE INVENTION
The present invention relates to a method for synthesis of halopyridyl-azacyclopentane derivative such as epibatidine, which is an alkaloid having a strong analgesic activity as its pharmacological effect, and the intermediate thereof. In more particular, the present invention relates to a novel method for synthesis of halopyridyl-azacyclopentane derivative and the intermediate thereof, which comprises preparing an optically active allene compound from an acetonedicarboxylic acid as a starting material, then preparing 7-azabicyclo[2.2.1]heptane derivative as an intermediate through Diels-Alder reaction of the optically active allene compound obtained above with pyrrole, so as to prepare halopyridyl-azacyclopentane derivative.
BACKGROUND ART
(−)-Epibatidine, which is an alkaloid isolated from the skin of the Ecuadorian poison frog, is attracting attention as an analgesic agent of utterly new type because it has as its pharmacological effect a strong analgesic activity of about 200 times more potent than that of morphine and moreover it has been suggested that its analgesic action is exhibited without the intermediation of opioid receptor. On the other hand, though it has a strong toxicity, it possesses a very interesting physiological activity; for example, it has recently been revealed that it acts as an agonist for nicotinic acetylcholine receptors of the central nerve (Daly, J. W., et at., Mol. Pharm., 1994, 45, 563) and it has been disclosed that its radiolabelled form is useful as an imaging agent for nicotinic acetylcholine receptors (U.S. Pat. No. 5,726,189). In addition to the interesting physiological activities described above, (−)-epibatidine has a unique mother skeleton, 7-azabicyclo[2.2.1]heptane, so that a variety of methods for synthesizing the compound have been studied.
For example, attempts have been made to synthesize an intermediate having the 7-azabicyclo-[2.2.1]heptane core and obtain (+) and (−)-epibatidine therefrom through the alkylation of N-[(trifluoroacetyl)amino]cyclohex-3-ene (Fletcher, S. R. et al., J. Org. Chem., 1994, 59, 1771-1778), the Diels-Alder reaction of p-toluylsulfonyl-acetylene with N-(t-butoxycarbonyl)pyrrole (Carrol, F. I. et al., J. Med. Chem., 1997, 40, 2293-2295), the Diels-Alder reaction of methyl 3-bromopropiolate with N-(t-butoxycarbonyl)pyrrole (Zhang, C. et al., J. Org. Chem., 1996, 61, 7189-7179) and method of synthesis which uses levulinic acid as the starting material (Rapoport, H. et al., J. Org. Chem., 1995, 60, 2683-2691). These methods, however, have the disadvantage of very low yield because the racemate obtained must be subjected to optical resolution to obtain the intended optically active epibatidine. On the other hand, with regards to the asymmetric synthesis of epibatidine, there have been reported, for example, an asymmetric azidation which uses an asymmetric ligand and Pd (Trost, B. M. et al., Tetrahedron Lett., 1996, 37, 7485-7488), an asymmetric protonation which uses an asymmetric alcohol (Kosugi, H. F. et al., Chem. Commun., 1997, 1857-1858), an asymmetric desulfonation which uses an asymmetric amine (Simpkins, N. S. et al., Tetrahedron Lett., 1998, 39, 1023-1024) and an asymmetric oxidation which uses microbial oxidation (Olivo, H. F. et al., Tetrahedron Lett., 1998, 39, 1309-1312). However, these methods have disadvantages of requiring lengthy process steps or of a low optical purity of the product.
An allene compound is a useful substance which has the 1,2-diene structure and, by virtue of its unique reactivity, can be used for synthesis of various compounds in organic synthesis. A generally used method for synthesizing an allene compound is the substitution reaction starting from a propargyl compound which accompanies isomerization to an allene compound (Alexakis, A. et al., J. Am. Chem. Soc., 1990, 112, 8042-8047). Other known methods include a substitution reaction using a Grignard's reagent which starts from a dithioacetal derivative (Luh, T. Y. et al., J. Org. Chem., 1996, 61, 8685) and synthesis of an allene compound by Wittig reaction in which attention is directed to the species of ketene (Fuji, K. et al., Synlett, 1995,933), but these methods cannot be applied to the synthesis of allene-1,3-dicarboxylic acid derivatives. Further, a method has been reported (Bryson, T. A. et al., Org. Synth., 1988, coll. VI, 505) which comprises chlorinating diethyl 1,3-acetone dicarboxylate with phosphorus pentachloride and then treating the resulting product with triethylamine to obtain ethyl allene-1,3-dicarboxylate. This method, however, has the disadvantage of requiring lengthy process steps and of a low yield of the product.
With regard to the example of using an allene compound for synthesizing the bicyclo[2.2.1]heptane core, the synthesis of the bicyclo[2.2.1]heptane core through the Diels-Alder reaction of menthyl allenecarboxylate with cyclopentadiene has been reported (Kanematsu, K. et al., J. Org. Chem., 1996, 61, 2031). A method of synthesis has been recently reported that the 7-azabicyclo[2.2.1]heptane core is synthesized through the Diels-Alder reaction of methyl allenecarboxylate with a pyrrole derivative and the racemate of epibatidine is obtained therefrom (Trudell, M. L. et al., Tetrahedron Lett., 1997, 38, 7993-7996). This method also has the disadvantage of requiring an optical resolution step.
In view of the situations, the object of the present invention is to provide a method for synthesis of an optically active halopyridyl-azacyclopentane derivative wherein an optically active allene-1,3-dicarboxylic acid derivative and a 7-azabicyclo[2.2.1]-heptane core derivative are employed as the intermediates and wherein the synthesis routes are shortened, the operations are simple and a high optical yield can be obtained, and also a method for synthesis of the intermediates.
DISCLOSURE OF THE INVENTION
According to the present invention, there is provided a method for synthesis of a an optically active halopyridyl-azacyclopentane derivative which comprises the first step of allowing an optically active acetonedicarboxylic acid ester derivative to react in the presence of a basic substance and a dehydrating agent to obtain a diastereomer mixture of an allene-1,3-dicarboxylic acid ester derivative and then subjecting the diastereomer mixture to asymmetric transformation to obtain an optically active (R)- or (S)-allene-1,3-dicarboxylic acid ester derivative, the second step of subjecting the optically active allene-1,3-dicarboxylic acid ester derivative to an optically active Diels-Alder reaction with a dienophile to obtain a 7-azabicyclo[2.2.1]heptene derivative and then reducing the optically active 7-azabicyclo[2.2.1]heptene derivative to obtained an optically active 7-azabicyclo[2.2.1]heptane derivative, and the third step of preparing an optically active halopyridyl-azacyclopentane derivative from the optically active 7-azabicyclo[2.2.1]-heptane derivative.
More specifically, there is provided a method for synthesis of an optically active halopyridyl-azacyclopentane derivative, wherein the optically active acetone-dicarboxylic acid ester derivative is represented by the formula (1)
(wherein R
1
and R
2
are each a group derived from an optically active alcohol and R
3
and R
4
are each a member selected from the group consisting of a hydrogen atom, alkyl group and aryl group, which may be the same or different from each other),
the optically active allene-1,3-dicarboxylic acid ester derivative is R- or S-enantiomer represented by the formula (2)
(wherein R
1
and R
2
are each a group derived from an optically active alcohol and R
3
and R
4
are each a member selected from the group consisting of a hydrogen atom, alkyl group and aryl group, which may be the same or different from each other),
the optically active 7-azabicyclo[2.2.1]heptene derivative is represented by the formula (3), or its e
Fujiwara Toshio
Ichihashi Shogo
Nakamura Daisaku
Node Manabu
Badio Barbara P.
Nihon Medi+Physics Co., Ltd.
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