Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-20
2003-09-09
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06617461
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing optically active N-substituted azetidine-2-carboxylic acids of value as pharmaceutical intermediates, intermediate compounds of use in the above production, and a process for producing them.
BACKGROUND ART
The following processes are known for the production of optically active N-substituted azetidine-2-carboxylic acids.
(1) A process which comprises reacting a racemic di-substituted butyric acid ester with an optically active alkylbenzylamine to give a diastereomer pair of optically active N-(alkylbenzyl)azetidine-2-carboxylic acid esters and hydrolyzing the ester bond to give a diastereomer pair of optically active N-(alkylbenzyl)azetidine-2-carboxylic acids (JP 10-130231A).
(2) A process which comprises permitting an enzyme having asymmetrically hydrolyzing activity to act on an N-substituted azetidine-2-carboxylic acid ester to give a mixture of optically active N-substituted azetidine-2-carboxylic acid and optically active N-substituted azetidine-2-carboxylic acid ester and fractionating it into the respective compounds (JP 11-46784A)
(3) A process which comprises subjecting a racemic N-acylazetidine-2-carboxylic acid ester to enzymatic asymmetric hydrolysis to give a mixture of optically active N-acylazetidine-2-carboxylic acid and optically active N-acylazetidine-2-carboxylic acid ester and fractionating it into the respective compounds (WO 9802568).
(4) A process which comprises cyclizing an optically active N-substituted &agr;-amino-&ggr;-halobutyric acid ester derived from optically active methionine to give an optically active N-substituted azetidine-2-carboxylic acid ester and hydrolyzing the ester bond to give an optically active N-substituted azetidine-2-carboxylic acid (JP10-120648A).
However, the above processes have the following problems.
In the process (1), the stereoselectivity of the reaction is generally poor so that the diastereomer pair of optically active N-(alkylbenzyl)azetidine-2-carboxylic acid esters is heavily contaminated with unwanted stereoisomer. Therefore, in order to obtain the desired stereoisomer, it is necessary to separate a large amount of such unwanted isomer so that the process is not satisfactory enough in terms of efficiency and economics and can hardly be exploited for commercial production.
In the processes (2) and (3), both of which are optical resolution techniques utilizing an enzyme, the theoretical yield of the desired stereoisomer does not exceed 50% and, moreover, the remaining large amount of unwanted isomer must be separated, with the result that neither of these processes is satisfactory enough in efficiency and economics and that these processes have problems to be exploited for the commercial production.
In the process (4) wherein the starting compound having an ester group is cyclized for synthesizing an optically active N-substituted azetidine-2-carboxylic acid, a hydrolysis step is inevitably required for cleaving off the ester group from the optically active N-substituted azetidine-2-carboxylic acid ester obtained.
Thus, all of the conventional processes have inherent drawbacks in terms of efficiency and have problems to be solved as for the commercial production processes.
SUMMARY OF THE INVENTION
In the light of the above-mentioned circumstance, the inventor conducted an intensive research to provide an efficient, economical and commercially useful process for producing an optically active N-substituted azetidine-2-carboxylic acid, found that such an optically active N-substituted azetidine-2-carboxylic acid can be provided, expediently and easily, by cyclizing an optically active starting compound having a carboxy group and reached to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention, therefore, provides a production method of an optically active N-substituted azetidine-2-carboxylic acid represented by the general formula (2):
in the formula, R represents a substituted oxycarbonyl type protective group or a substituted sulfonyl type protective group and * represents an asymmetric carbon atom,
which comprises cyclizing an optically active 4-substituted amino-2-halobutyric acid represented by the general formula (1):
in the formula, R represents a substituted oxycarbonyl type protective group or a substituted sulfonyl type protective group, X represents a halogen atom and * represents an asymmetric carbon atom, in the presence of a base.
The present invention further provides a production method of an optically active 4-substituted amino-2-chlorobutyric acid represented by the general formula (3):
in the formula, R represents a substituted oxycarbonyl type protective group or a substituted sulfonyl type protective group and * represents an asymmetric carbon atom,
which comprises subjecting an optically active 4-amino-2-chlorobutyric acid represented by the general formula (4):
in the formula, * represents an asymmetric carbon atom, to amino group protection in the presence of a base.
The present invention further provides a novel compound, namely, an optically active 4-substituted amino-2-chlorobutyric acid represented by the general formula (3):
in the formula, R represents a substituted oxycarbonyl type protective group or a substituted sulfonyl type protective group and * represents an asymmetric carbon atom.
The present invention is now described in detail.
First, the optically active 4-substituted amino-2-halobutyric acid represented by the following general formula (1):
in the formula, R represents a substituted oxycarbonyl type protective group or a substituted sulfonyl type protective group, X represents a halogen atom and * represents an asymmetric carbon atom, for use in the present invention is described.
In this compound, the substituent R represents a substituted oxycarbonyl type protective group or a substituted sulfonyl type protective group. The substituted oxycarbonyl type protective group includes, for example, alkyloxycarbonyl groups which may be substituted, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-phenylethoxycarbonyl, 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, tert-butoxycarbonyl, 1-adamantyloxycarbonyl, allyloxycarbonyl, cinnamyloxycarbonyl, 4-nitrocinnamyloxycarbonyl, 2-methylthioethoxycarbonyl, isobutyloxycarbonyl, tert-amyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and 1-methylcyclohexyloxycarbonyl; and aralkyloxycarbonyl groups which may be substituted, such as 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-methylsulfinylbenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 4-decyloxybenzyloxycarbonyl, 2,4,6-trimethylbenzyloxycarbonyl, diphenylmethyloxycarbonyl and 9-anthrylmethyloxycarbonyl. In consideration of commercial availability of the protective group-providing reagent and the ease of deprotection, benzyloxycarbonyl or tert-butoxycarbonyl is preferably used.
The substituted sulfonyl type protective group includes, for example, methanesulfonyl, 2-trimethylsilylethanesulfonyl, phenylmethanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-methoxybenzenesulfonyl, 2,4,6-trimethoxybenzenesulfonyl, 2,6-dimethyl-4-methoxybenzenesulfonyl, 2,4,6-trimethylbenzenesulfonyl, pentamethylbenzenesulfonyl and 9-anthracenesulfonyl. Among these, p-toluenesulfonyl, 2-nitrobenzenesulfonyl or 4-nitrobenzenesulfonyl can be used preferably.
Referring, further, to the compound represented by the general formula (1), X represents a halogen atom which may for example be a chlorine, a bromine, an iodine or a fluorine. However, in view of the reactivity in the subsequent stage of the production and of the racemization suppression, a chlorine or a bromine is preferred and a chlorine is most preferred. When X in the general formula (1) represents a chlorine, the optically active 4-subst
Armstrong Westerman & Hattori, LLP
Kaneka Corporation
McKenzie Thomas
LandOfFree
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