Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-02-22
2001-12-25
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S040000
Reexamination Certificate
active
06333427
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for purifying an optically active N-t-butoxycarbonylphenylalanine ester used widely as a pharmaceutical intermediate, and a process for preparing an optically active N-t-butoxycarbonylphenylalanine ester, including said purification process.
DESCRIPTION OF THE RELATED ART
As a process for preparing an N-t-butoxycarbonylphenylalanine ester, a process including reaction of an amino group of an optically active phenylalanine ester with a t-butoxycarbonylating agent (BOC agent) such as di-t-butyl dicarbonate hitherto is known. For example, a process using reaction of a phenylalalanine ester hydrochloride with di-t-butyl dicarbonate in an organic solvent in the presence of an inorganic base such as potassium carbonate is known (Japanese Patent Laid-Open (Kokai) No. 233138/95). According to this process, an N-t-butoxycarbonylphenylalanine ester preparation retaining a high optical purity can be prepared.
However, when the BOC agent is industrially prepared, since this process causes problems on the reaction and operation, the BOC agent can not be prepared at a low cost. Therefore, this process using the BOC agent is considered to be not economical. In addition, when the optical purity of the optically active phenylalanine ester preparation as a starting material is low, the optical purity of the desired final product is also low.
On the other hand, a process for preparing an N-t-butoxycarbonylphenylalanine ester at a low cost is known (Japanese Patent Laid-Open (Kokai) No. 133301/74), in which an N-carbonylphenylalanine ester is obtained from a phenylalanine ester hydrochloride and phosgene, and, then, reacted with t-butanol in the presence of a tin compound such as dibutyltin dichloride to obtain the N-t-butoxycarbonylphenylalanine ester.
However, since the reaction between an amino acid ester and phosgene is generally effected at high temperature of 100° C. or higher, the optical purity of the reaction product is often lowered. As a result, the N-t-butoxycarbonylamino acid ester obtained by reacting the N-carbonylphenylalanine ester with t-butanol can not always have a high optical purity. According to the present inventors' knowledge, the N-carbonyl-L-phenylalanine methyl ester obtained by the above technique through the reaction using the phenylalanine ester hydrochloride and phosgene has no satisfactory optical purity because of racemization during the reaction.
As a general process for purifying an N-t-butoxycarbonylphenylalanine ester, there is a process for extracting an N-t-butoxycarbonylphenylalanine ester with an organic solvent such as dichloromethane. However, any knowledge with respect to an optical purity of an N-t-butoxycarbonylphenylalanine ester in these purification processes has never been obtained.
The N-t-butoxycarbonylphenylalanine ester, in particular the N-t-butoxycarbonylphenylalanine ester, wherein phenylalanine is L-phenylalanine and an ester is a methyl ester is expected to be used as an intermediate of a drug for treatment of HIV. Thus, it has been required to develop a product having a high optical purity and an industrially low production cost.
SUMMARY OF THE INVENTION
An object of the present invention is to provide an industrially advantageous process for purifying an N-t-butoxycarbonylphenylalanine ester preparation to improve its optical purity. Another object of the present invention is to provide an industrially advantageous process for producing an N-t-butoxycarbonylphenylalanine ester preparation with a high optical purity using the above purification process. Another object of the present invention is to provide a process for producing a N-t-butoxycarbonylphenylalanine ester preparation with a low production cost.
To achieve the above objects, the present inventors have studied intensively so as to obtain an N-t-butoxycarbonylphenylalanine ester preparation having a high optical purity. As a result, they have found that the racemic compound of the N-t-butoxycarbonylphenylalanine ester hardly dissolves in an aliphatic hydrocarbon, however, the optically active form thereof sufficiently dissolves in the aliphatic hydrocarbon and, therefore, only the optically active form of the N-t-butoxycarbonylphenylalanine ester can be efficiently extracted with the aliphatic hydrocarbon. Thus, the present invention has been completed.
The process for purifying an N-t-butoxycarbonylphenylalanine ester according to the present invention is a purification process for improving an optical purity of an N-t-butoxycarbonylphenylalanine ester preparation, which comprises the steps of:
bringing a crude preparation containing an optically active form of an N-t-butoxycarbonylphenylalanine ester into contact with an aliphatic hydrocarbon, and extracting the optically active form in the crude preparation into the aliphatic hydrocarbon to prepare an extract; and
recovering the optically active form from the extract to obtain a purified N-t-butoxycarbonylphenylalanine ester preparation having an improved optical activity.
The process for preparing an N-t-butoxycarbonylphenylalanine ester according to the present invention is a process for preparing an optically pure N-t-butoxycarbonylphenylalanine ester preparation, which comprises the following steps (1) to (3) of:
(1) reacting a phenylalanine ester salt with phosgene in an organic solvent, thereby to introduce a carbonyl group into an amino group of the phenylalanine ester to prepare an N-carbonylphenylalanine ester;
(2) reacting the N-carbonylphenylalanine ester obtained in the step (1) with t-butanol to prepare a crude N-t-butoxycarbonylphenylalanine ester preparation; and
(3) bringing the crude N-t-butoxycarbonylphenylalanine ester preparation obtained in the step (2) into contact with an aliphatic hydrocarbon, extracting an optically active form of the N-t-butoxycarbonylphenylalanine ester into the aliphatic hydrocarbon, and recovering the optically active form from the resulting extract to obtain a purified N-t-butoxycarbonylphenylalanine ester preparation containing the optical active form with an improved optical purity.
According to the present invention, an N-t-butoxycarbonylphenylalanine ester preparation can be purified by a simple purification process comprising the step of extracting the optically active form of an N-t-butoxycarbonylphenylalanine ester into an aliphatic hydrocarbon. Furthermore, the N-t-butoxycarbonylphenylalanine ester preparation having a high optical purity can be efficiently prepared by the above simple purification process. When the ester to be purified is obtained from a phenylalanine ester salt via phosgenation and butoxycarbonylation, an N-t-butoxycarbonylphenylalanine ester preparation with a high optical purity can be efficiently produced with a low production cost.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
A crude preparation of an N-t-butoxycarbonylphenylalanine ester used in the purification process according the present invention contains an optically active form of the N-t-butoxycarbonylphenylalanine ester, and examples thereof include a preparation comprising a mixture of the optically active form and the racemic form of the N-t-butoxycarbonylphenylalanine ester. The N-t-butoxycarbonylphenylalanine ester preparation, to which the purification process of the present invention can be applied, may be those prepared by any known preparation process. As the preparation process, for example, a process for preparing an N-t-butoxycarbonylphenylalanine ester via an N-carbonylphenylalanine ester is industrially advantageous because of its low production cost.
When the N-t-butoxycarbonylphenylalanine ester is produced by a process using reaction by BOC agent and its optical purity is low, the optical purity can be also increased by the purification process according to the present invention.
As described hereinafter, the N-carbonylphenylalanine ester can be easily synthesized from a phenylalanine ester hydrochloride and phosgene by a conventional procedure, and the resulting N-carbonylphenylal
Fukuhara Nobuhiro
Koito Mitsuo
Miyake Hitoki
Osabe Masami
Yoshino Setsuo
Burns Doane Swecker & Mathis L.L.P.
Chaudhry Mahreen
Killos Paul J.
Mitsui Chemicals Inc.
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