Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2000-02-01
2002-01-29
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S402000, C562S445000
Reexamination Certificate
active
06342629
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel process for producing an optically active N-protected-N-methyl-phenylalanine derivative; more specifically, the invention relates to a novel process for producing an optically active N-protected-N-methyl-4-halogenophenylalanine purified chemically and optically to a high purity. The derivative is important as an intermediate for the production of pharmaceutical agents; and in accordance with the invention, the derivative at such a high purity chemically and optically that the derivative can sufficiently be used as the intermediate for the production of pharmaceutical agents can be produced very efficiently and industrially.
2. Description of the Background
Optically active N-protected-N-methyl-4-halogenophenylalanine, for example N-tert-butyloxycarbonyl-N-methyl-L-4-chlorophenylalanine, is known to be useful as an intermediate for the production of pharmaceutical agents (see PCT Japanese Patent Kohyou Publication No. JP-A-10-509151).
So as to use the phenylalanine derivative as an intermediate for the production of pharmaceutical agents, it is required to industrially produce the compound purified chemically and optically to a high purity.
SUMMARY OF THE INVENTION
According to the findings of the present inventors, optically active N-protected-N-methyl-4-halogenophenylalanine can be produced by subjecting optically active N-protected-4-halogenophenylalanine, for example N-tert-butyloxycarbonyl-L-4-chlorophenylalanine to N-methylation step but contains the optical isomer thereof as a part of impurities therein. However, it is difficult to remove the optical isomer as an impurity contained in the derivative thus prepared, even by subjecting the derivative to crystallization step, so the intended optical purity cannot readily be yielded. Thus, it is difficult to produce the derivative at a high purity chemically and optically, and at a high yield by such a method. The repetition of the crystallization step makes the production process laborious and involves the reduction of the yield, which is not preferable industrially. Therefore, it is needed to develop a process for industrially and efficiently producing an optically active N-protected-N-methyl-4-halogenophenylalanine, chemically and optically purified to a high purity.
It is a purpose of the present invention to develop a process for industrially and efficiently producing the optically active form purified to such a high purity that the optically active form can sufficiently be used as an intermediate for the production of pharmaceutical agents.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
So as to solve the problem, the present inventors have made investigations with efforts and have found that when a salt is recovered (deposited) by subjecting an optically active N-protected-N-methyl-4-halogenophenylalanine at least containing the optical isomer thereof as an impurity to a step of salt formation and is then isolated, the optical isomer and the like as impurities contained therein are nearly removed from the resulting salt and that an optically active N-protected-N-methyl-4-halogenophenylalanine purified to a high purity can be recovered at a high yield by subjecting the salt thereby recovered to desalting. Thus, the present invention has been achieved.
The isolation of the optical isomer as an impurity is not readily done by the crystallization procedure of the free form, but through the process of salt formation, the impurity can be removed very efficiently. Hence, the intended compound at a highly chemical and a highly optical purity can be recovered at a high yield, taking the subsequent crystallization procedure of the free form into consideration.
In other words, the present invention relates to a process for producing an optically active N-protected-N-methyl-4-halogenophenylalanine at a high purity (including a free form thereof and/or a salt form thereof), comprising the steps of: subjecting an optically active N-protected-N-methyl-4-halogenophenylalanine containing at least the optical isomer thereof as an impurity to a process of salt formation to deposit (precipitate) it and isolating the salt of the optically active form. The production of an optically active form, which may be in the free form or in the salt form such as dicyclohexylamine salt) of the intended compound, at least by way of the separation or isolation step in the form of salt in such manner, is encompassed with the scope of the present invention.
Additionally, the ultimate purpose in accordance with the present invention is the acquisition (recovery) of the optically active form purified to a high purity at a high yield, which is useful as an intermediate for the production of pharmaceutical agents.
Meanwhile, the DCHA salt of an optically active N-protected-N-methyl-phenylalanine with no substituent at 4-position of the phenyl group has already been known (see Memoirs of the Faculty of Science, Kyushu University Ser. C, Vol. 9, No. 1, 1974, 131-138). According to the reference, however, the free form of the N-protected-N-methyl-phenylalanine is in the form of oily matter and has therefore physical properties different from those of the subject compound of the present invention, of which the free form is recovered in a solid state. According to the reference, additionally, the compound is first prepared as DCHA salt and is then isolated in a solid state, but the reference never includes any description suggesting the purification effect as described in the present invention. Further, the problem to be solved by the present invention, namely final efficient acquisition (recovery) of the free form at a high purity, is never present in the reference.
The substance to be purified in accordance with the present invention is an optically active N-protected-N-methyl-4-halogenophenylalanine containing at least the optical isomer thereof as an impurity. A halogen atom, preferably chlorine atom or bromine atom, is present at 4-position of the phenyl group composing the phenylalanine derivative.
The purpose lies in the production of the optically active form as an intermediate for the production of pharmaceutical agents and the optically active form then may satisfactorily be any of the L and D forms. For producing the L form at a high purity as the intended compound, the optical isomer as an impurity corresponds to the D form of the intended compound; for producing the D form, the impurity corresponds to the L form.
Such impurity in the form of isomer contained in the substance to be purified in accordance with the present invention generally contaminates the substance through side reactions in the course of the production for the intended compound. From the respect of purification efficiency, the content of the isomer as an impurity is preferably about 1 to 10% by weight, more preferably about 1 to 5% by weight, and still more preferably about 1 to 3% by weight. By the process of the present invention, a purified product (in the form of salt or in the free form) can be obtained at an optical purity of 99.0% ee or more, optically preferably.
The amino group of the above-mentioned phenylalanine derivative as the intended compound in accordance with the present invention has a protective group; and as the protective group, protective groups for general use for amino group are illustrated, such as tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl group (Z), and 9-fluorenylmethyloxycarbonyl group (Fmoc).
The optically active N-protected-N-methyl-4-halogenophenylalanine of the present invention can be produced by the N-protection and N-methylation of 4-halogenophenylalanine (optically active form).
For carrying out the N-protection and N-methylation of 4-halogenophenylalanine (optically active form), the protective method for the amino group of amino acid and general methods known as N-methylation method can be adopted. For the N-methylation, a method comprising the reaction of sodium hydride with methyl iodide is general. For the production in practice, sati
Ajinomoto Co. Inc.
Chaudhry Mahreen
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