Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-11-18
2004-03-30
Rotman, Alan L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S322500, C548S533000, C546S134000
Reexamination Certificate
active
06713628
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for economically preparing N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-amino acid represented by a formula (2):
wherein a group:
is, for example, a group represented by a formula:
or a pharmacologically acceptable salt thereof having high quality, in high yield advantageously in a commercial scale. The N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-amino acid (2) and the pharmacologically acceptable salt thereof are very useful compounds as various antihypertensive agents, such as N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (enalapril) and its maleate (enalapril maleate).
BACKGROUND ART
As a method for obtaining the N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-amino acid (2) or the pharmacologically acceptable salt thereof, there has been known a method wherein an N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-amino acid (2) is produced starting from an amino acid represented by a formula (1):
wherein a group:
is the same as defined above, and N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine.N-carboxyanhydride represented by a formula (8):
and then a pharmacologically acceptable salt thereof is formed therefrom. For example, there has been known a method for preparing N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline or its maleate as described in Japanese Unexamined Patent Publication No. 48696/1987.
The above-mentioned Japanese Unexamined Patent Publication No. 48696/1987 describes a method shown below.
1. N-(1(S)-Ethoxycarbonyl-3-phenylpropyl)-L-alanine.N-carboxyanhydride and 1 to 1.5 time molar amount of L-proline are condensed in a mixed solvent system of water and an organic solvent having high or low miscibility with water under basic condition (preferably pH 9 to 10) and, then, the condensation product is decarboxylated to obtain a reaction mixture containing N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline. The above-mentioned patent publication describes that high reaction yield is obtained in a mixed solvent system of water and an organic solvent having a high miscibility with water such as acetone.
2. The organic solvent having a high miscibility with water such as acetone is distilled away from the above-mentioned reaction mixture, and replaced with ethyl acetate which is an organic solvent having a low miscibility with water, and N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline is extracted therewith. In this procedure, the aqueous layer is saturated with sodium chloride to enhance the extraction efficiency of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline having high water-solubility.
3. The extraction solution is dehydrated using anhydrous sodium sulfate and, then, the solvent is removed by concentration to obtain N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline.
4. N-(1(S)-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline and acetonitrile are mixed and to this mixture is added maleic acid with heating at 70° C. and the mixture is gradually cooled to obtain N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate.
5. N-(1(S)-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate is purified by recrystallization from acetonitrile.
However, it was found that methods in which N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-amino acid (2) is produced from an amino acid (1) and N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine.N-carboxyanhydride, and then converted to a pharmacologically acceptable salt thereof, including the method described in the above-mentioned publication, potentially include problems of production of by-products, which causes disadvantages in yield and quality, a diketopiperazine derivative represented by a formula (3):
wherein a group:
is the same as defined above, an N-(1(S)-carboxy-3-phenylpropyl)-L-alanyl-amino acid (hereinafter, also referred to as “carboxy derivative (4)”) represented by a formula (4):
wherein a group:
is the same as defined above, and N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine represented by a formula (5):
In particular, in the production in a commercial scale requiring longer operation time, production of a by-product diketopiperazine derivative (3) becomes remarkable, leading to unexpected reduction in the yield of a desired compound. Furthermore, when by-products, a carboxy derivative (4) and N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine (5), are produced, the removal of these compounds is extremely difficult and causes load in purification.
Moreover, the method described in Japanese Unexamined Patent Publication No. 48696/1987 has problems of complicated processes such as use of a large amount of an extraction solvent, use of various kinds of solvents, replacement of a reaction solvent with an extraction solvent and saturation of an aqueous layer with an inorganic salt, and problems of consumption of longer time, enlargement of the apparatus, increase in cost, and the like, due to such complicated processes.
As described above, it is very important to develop a simple method for economically preparing N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-amino acid (2) or a pharmacologically acceptable salt thereof having high quality with high yield in a commercial scale.
An object of the present invention is to provide an extremely simple method for economically preparing an N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-amino acid (2) and a pharmacologically acceptable salt thereof having high quality with high yield in a commercial scale whereby the production of the by-products, diketopiperazine derivative (3), carboxy derivative (4) and N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine (5), is suppressed.
An object of the present invention is, in particular, to provide an extremely simple method for economically preparing N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline and its maleate having high quality with high yield in a commercial scale, which method solves the above-mentioned problems.
First, it has been found that the production of the by-product diketopiperazine derivative (3) can be suppressed by carrying out, in the presence of water, a series of operations for producing an N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-amino acid (2) from an amino acid (1) and N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine.N-carboxyanhydride and forming a pharmacologically acceptable salt thereof and by reason of the protection effect from cyclization reaction by solvation as a protic solvent in addition to the dehydration suppressing effect which water essentially possesses, and also by selecting the condition that the N-carbamic acid produced in the reaction system is maintained as a basic salt.
Further it has been found that an N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-amino acid (2) having a low content of a diketopiperazine derivative (3), a carboxy derivative (4) and N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine (5) can be obtained by carrying out, in the presence of water under specific reaction conditions, the production of the N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-amino acid (2) from an amino acid (1) and N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine.N-carboxyanhydride.
Further it has been found that an N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-amino acid (2) and a pharmacologically acceptable salt thereof having high quality can be prepared with high yield according to an extremely simple process by combining the above-mentioned two methods.
Furthermore, it has been found that N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline can be separated extremely simply and efficiently, without saturation of an aqueous phase with an inorganic salt and without use of a large amount of extraction solvent, by carrying out extraction, and separation operations under specific temperature condition, especially for the N-(1(S)-ethoxycarbonyl-3-phenylpropyl )-L-alanyl-L-proline having high water-solubility which requires complicated extraction and separation operations.
DISCLOSURE OF THE INVENTION
The present invention relate
Fuse Yoshihide
Kinoshita Koichi
Moroshima Tadashi
Ueda Yasuyoshi
Yanagida Yoshifumi
Armstrong, Kratz, Qunitos, Hanson & Brooks, LLP
Kaneka Corporation
Rotman Alan L.
Shameem Golam M M
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