Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1998-02-25
1999-07-13
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
544289, 544290, C07F 932, C07F 940, C07D23991, C07D23996
Patent
active
059228660
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel processes for preparing quinazolin-4-one derivatives, in particular quinazolin-4-one derivatives which are valuable as intermediates for synthesis of compounds for use in pharmaceuticals for diabetes, or which are useful by themselves as active ingredients of therapeutic agents for diabetes.
BACKGROUND ART
Conventionally, quinazolin-4-one derivatives are prepared, for example by the process disclosed in J. Org. Chem., 41 (10), 1763 (1976) which comprises heating a diamide derivative for cyclization. However, since the process employs a high heating temperature (250.degree. C. or above), it produces the quinazolin-4-one derivative in a very low yield and generates large amounts of byproducts.
An object of the present invention is to provide a novel process for preparing a series of quinazolin-4-one derivatives useful as pharmaceuticals or intermediates for synthesis thereof in higher yields with reduced amounts of byproducts.
The present inventors carried out extensive research and found that the following process can achieve the above object. The present invention has been accomplished based on the finding.
DISCLOSURE OF INVENTION
The present invention provides a process for preparing a quinazolin-4-one derivative, the process comprising reacting, in the presence of a base, a trialkylsilyl halide with a compound represented by the formula ##STR4## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are the same or different and each represent a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a lower alkoxy group, a cyano group, an N-lower alkylcarbamoyl group, a lower alkoxycarbonyl group or a halogen-substituted lower alkyl group, R.sup.5 is a phenyl group which may have 1 to 3 substituents each selected from a lower alkyl group, a lower alkoxy group or a halogen atom, a lower alkyl group, a phenyl-lower alkyl group which may have a halogen atom as a substituent on the phenyl ring, a lower alkenyl group, a lower alkoxy-lower alkyl group or a lower alkynyl group; R.sup.6 is a lower alkyl group, a halogen-substituted lower alkyl group, a lower alkoxycarbonyl group or a phenyl group which may have, as a substituent, a lower alkyl group or a group of the formula ##STR5## wherein A is an oxygen atom or a single bond, Z is a lower alkylene group, R.sup.7 is a lower alkyl group and R.sup.8 is a lower alkoxy group, a phenyl group or a phenyl-lower alkoxy group which may have a halogen atom on the phenyl ring;
to produce quinazolin-4-one derivative represented by the formula ##STR6## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined above.
More specifically, the present invention provides the processes as defined above wherein the base is a tertiary amine, wherein the trialkylsilyl halide is chlorotrialkylsilane, wherein the base and trialkylsilyl halide are used each in an amount of 3 to 20 equivalents, and wherein the reaction temperature is in the range of 0 to 100.degree. C.
In the above formula representing the quinazolin-4-one derivative prepared by the process of the invention, the groups represented by R.sup.1 to R.sup.6 are as follows.
The halogen atom may be a fluorine, chlorine, bromine or iodine atom.
Examples of the lower alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and like groups.
Examples of the lower alkyl group include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and like groups.
Examples of the phenyl-lower alkyl group which may have a halogen atom as a substituent on the phenyl ring include benzyl, .alpha.-phenetyl, .beta.-phenetyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-iodobenzyl, 2-bromo-4-fluorobenzyl, 2-fluoro-4-bromobenzyl, 2-chloro-4-fluorobenzyl, 2-fluoro-4-chlorobenzyl, 2-bromo-4-chlorobenzyl, 2-chloro-4-bromobenzyl, 2-iodo-4-bromobenzyl, 3-chloro-5-bromobenzyl, 3-bromo-5-fluo
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Kurogi Yasuhisa
Miyata Kazuyoshi
Sakai Yasuhiro
Tsuda Yoshihiko
Berch Mark L.
Otsuka Pharmaceutical Factory Inc.
Razgunas Ann
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