Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-10-20
2000-08-15
Lambkin, Deborah C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D30792
Patent
active
061039144
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a method of producing optically active materials of cyclopenta [b] benzofuran derivatives, e.g., 3a,8b-cis-dihydro-3H-cyclopenta [b] benzofuran used as a raw material for producing 5,6,7-trinor-4,8-inter-m-phenylene PGI.sub.2 derivatives useful as medicines, particularly, an anti-thrombogenic agent.
BACKGROUND ART
Optically active materials of derivatives of 3a,8b-cis-dihydro-3H-cyclopenta [b] benzofuran, which is a tricyclic compound, are conventionally synthesized by optical resolution of [7-bromo-3a,8b-cis-dihydro-3H-cyclopenta [b] benzofuran-5-yl] formic acid with an optically active amine, as disclosed in Japanese Unexamined Patent Publication No. 59-161371, or by enzyme reaction thereof, as disclosed in J. Chem. Soc., Chem. Commun., 811, 1995. However, there has been not known yet a simplest direct method of obtaining optically active materials by asymmetric synthesis.
DISCLOSURE OF INVENTION
The optical resolution method using an optically active amine requires a complicated operation comprising forming a complex, and repeatedly carrying out recrystallization, and the enzyme reaction method requires a long reaction time because of a low substrate concentration, and frequently produces results with low reproducibility according to enzyme lots.
In consideration of the above drawbacks of conventional techniques, an object of the present invention is to provide a useful method capable of directly obtaining compounds represented by the following formula (II) using an optically active alcohol or amine: ##STR2## [wherein R.sub.1, R.sub.2, Y and Z independently represent hydrogen, halogen, an alkyl group, or an aryl group; and n represents 0 to 4].
In order to achieve the object of the invention, the inventors studied asymmetric induction by cyclization reaction for directly synthesizing 3a,8b-cis-dihyro-3H-cyclopenta [b] benzofuran derivatives as tricyclic compounds. As a result, the intended compounds having high optical purity were found to be obtained, leading to the achievement of the present invention.
The present invention provides a method of producing optically active materials of tricyclic compounds represented by the above formula (II), the method comprising cyclization reaction using an organometallic reagent and compounds represented by the following formula (I): ##STR3## [wherein X represents halogen; R.sub.1, R.sub.2, Y and Z independently represent hydrogen, halogen, an alkyl group, or an aryl group; and n represents 0 to 4], wherein in cyclization reaction, an optically active alcohol, amine, or metal salt thereof is added as an additive.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention has the construction below.
Preferable compounds as the compounds used in the present invention and represented by the above formula (I) are compounds in which X represents chlorine, bromine or iodine; R.sub.1, R.sub.2, Y and Z independently represent hydrogen, fluorine, chlorine, bromine, iodine, alkyl having 1 to 5 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, cycloalkylalkyl having 4 to 9 carbon atoms, cycloalkenylalkyl having 5 to 10 carbon atoms, aralkyl having 7 to 12 carbon atoms, alkenyl having 2 to 7 carbon atoms, or aryl having 6 to 11 carbon atoms; and n represents 0 to 4. Particularly, 3,5-bis(aryloxy)cyclopentene is preferred, in which X represents chlorine, bromine, or iodine; R.sub.1, R.sub.2, Y and Z independently represents hydrogen or alkyl having 1 to 5 carbon atoms; and n represents 1. This compound can be produced by condensation reaction of 3,5-dibromo-cyclopentene and a metal salt of a phenol derivative, as disclosed in Japanese Examined Patent Publication No. 1-31494. However, in the present invention, the method of producing 3,5-bis(aryloxy)cyclopentene is not limited to this method.
In the present invention, the thus-obtained compound represented by the formula (I) is dissolved in an organic solvent, and subjected to cyclization reaction with an organometallic reagent. At this time, an alcohol, an amine
REFERENCES:
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Morrison and Boyd, pp. 156-158, 1987.
Nagase Hiroshi
Nishiyama Hisao
Wakita Hisanori
Lambkin Deborah C.
Miller Austin R.
Toray Industries Inc.
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