Method for isolation of n-protected s-phenylcysteine

Details Method for isolation of n-protected s-phenylcysteine Method for isolation of n-protected s-phenylcysteine

2000-12-14

2001-11-20

Geist, Gary (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C562S426000

Reexamination Certificate

active

06320072

ABSTRACT:

CONTINUING DATA
This application is the national phase of PCT international application number PCT/JP00?00274, filed on Jan. 21, 2000.
TECHNICAL FIELD
The present invention relates to a method of isolating an N-protected-S-phenylcysteine of the following formula (1) [hereinafter referred to sometimes as N-protected-S-phenylcysteine (1)]. N-protected-S-phenylcysteines, such as N-benzyloxycarbonyl-S-phenyl-L-cysteine, are compounds of importance as synthetic intermediates of HIV-protease inhibitors as described in WO 96/23756 and EP 604185A1.
wherein R
1
represents an amino-protecting group; R
2
represents hydrogen or, either independently of R
1
or taken together with R
1
, represents an amino-protecting group.
BACKGROUND ART
N-protected-S-phenylcysteine (1) can be synthesized by, for example, treating a compound of the formula (2):
(wherein R
1
and R
2
are as defined above; X represents a leaving group) with thiophenol under basic conditions as described in Japanese Application Hei-10-264397. By way of illustration, N-benzyloxycarbonyl-S-phenylcysteine can be synthesized by treating N-benzyloxycarbonyl-&bgr;-chloroalanine with thiophenol in an aqueous alkaline solution.
The N-protected-S-phenylcysteine (1) thus synthesized can be recovered typically by adding an acid to the basic aqueous solution thereof to precipitate the N-protected-S-phenylcysteine as a free acid. As a version of this technology, Japanese Kokai Publication Hei-10-29973 describes a process in which hydrochloric acid is added to an aqueous sodium hydroxide solution containing an N-benzyloxycarbonyl-S-phenylcysteine to cause the N-benzyloxycarbonyl-S-phenylcysteine to crystallize out as a free acid. In this process, the base salt of N-benzyloxycarbonyl-S-phenylcysteine (in this case, N-benzyloxycarbonyl-S-phenylcysteine sodium salt), which is readily soluble in water, is converted to the hardly-soluble free N-benzyloxycarbonyl-S-phenylcysteine by acidification. However, the process is not free from the disadvantage that, as pointed out in the same literature cited above, the free N-benzyloxycarbonyl-S-phenylcysteine tends to undergo gelation in the course of crystallization, and to fail in being crystallized in a good manner, in addition to the above problems, the process has also the problem that structurally related contaminant compounds cannot be easily removed. Thus, the methods heretofore known for crystallizing N-protected-S-phenylcysteine (1) as a free acid is not necessarily an effective isolation procedure.
SUMMARY OF THE INVENTION
Under the circumstances, the present invention has for its object to provide a method of isolating N-protected-S-phenylcysteine (1) of high purity, expediently, efficiently and in good yield.
The present invention, therefore, is directed to a method of isolating N-protected-S-phenylcysteine (1) which comprises causing said N-protected-S-phenylcysteine to be salted out in the form of a base salt in the presence of water.
The present inventors have discovered for the first time that a water-soluble base salt of N-protected-S-phenylcysteine (1) can be easily salted out in the presence of water with efficiency and in good yield and high purity.
The present invention is now described in detail.
DETAILED DESCRIPTION OF THE INVENTION
In the present specification, the term “base salt” as used with reference to N-protected-S-phenylcysteine means a compound such that a cation such as a metal ion and an ammonium ion has been substituted for the hydrogen ion of the carboxyl group of an N-protected-S-phenylcysteine. Moreover, the term “free” or “free acid” as used with reference to N-protected-S-phenylcysteine in this specification means that the N-protected-S-phenylcysteine has not formed a salt with any basic substance; stated differently that a hydrogen ion has been substituted for the cation, e.g. the metal ion or ammonium ion, of a base salt of N-protected-S-phenylcysteine or the compound in such condition.
The term “salting out” (and “salt out”) as used with reference to a base salt of N-protected-S-phenylcysteine in this specification means that the base salt of N-protected-S-phenylcysteine is caused to separate out from an aqueous solution containing the salt by causing another substance (chiefly an inorganic salt) to be present in said aqueous solution.
In the above formula (1), R
1
represents an amino-protecting group. R
2
represents a hydrogen atom or, either independently of R
1
or taken together with R
1
, an amino-protecting group.
In the method of the present invention, it is essential that an amino-protecting group be present on S-phenylcysteine.
The above-mentioned amino-protecting group is not particularly restricted but may, for instance, be a group selected from among the protective groups mentioned in Protective Groups in Organic Synthesis, 2nd Ed., John Wiley & Sons (1991) as well as an alkyl, aralkyl or aryl group.
When a further derivatization of N-protected-S-phenylcysteine (1) is contemplated, an urethane-type or acyl-type protective group capable of masking the basicity of the amino group is preferably used. Among specific examples of such protective groups, there can be mentioned benzyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, acetyl, tosyl, benzoyl and phthaloyl, among others. Moreover, (3S)-tetrahydrofuranyloxycarbonyl and 3-hydroxy-2-methylbenzoyl whose hydroxyl group may optionally be protected can also be selectively employed. Particularly, urethane-type protective groups are preferred and aralkyloxycarbonyl and lower alkoxycarbonyl groups are still more preferred. More particularly, benzyloxycarbonyl, tert-butoxycarbonyl, methoxycarbonyl and ethoxycarbonyl are preferred and, among them, benzyloxycarbonyl is still more preferred. When the amino-protecting group is a benzyloxycarbonyl group, N-protected-S-phenylcysteine (1) is a compound of great importance as a synthetic intermediate of HIV-protease inhibitors as described in WO 96/23756 and EP 604185A1, for instance.
N-protected-S-phenylcysteine (1) may be an optically active compound. Even when such an optically active compound is used in the present invention, the salting out can be achieved without detracting from optical purity.
The base salt of N-protected-S-phenylcysteine (1) is not particularly restricted but includes, among others, the metal salts, such as alkali metal salts, e.g. lithium salt, sodium salt, potassium salt, etc., alkaline earth metal salts, and ammonium salts of N-protected-S-phenylcysteine (1). Among them, the metal salts are preferred, the alkali metal salts are particularly preferred, and the sodium salt is most preferred.
The base for use in converting N-protected-S-phenylcysteine (1) to its base salt is not particularly restricted but includes alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogencarbonates, alkaline earth metal hydroxides, alkaline earth metal carbonates, and ammonia, among others. Preferred are alkali metal hydroxides, alkali metal carbonates and alkali metal hydrogencarbonates. More particularly, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate can be mentioned. The most preferred is sodium hydroxide.
The preferred method for converting N-protected-S-phenylcysteine (1) to a base salt comprises reacting the N-protected-S-phenylcysteine (1) with said base under neutral to basic conditions. In terms of pH, the system should be maintained at not less than pH 7, preferably not less than pH 8, more preferably not less than pH 9, in order to retain the stability of the amino-protecting group. Generally speaking, the reaction can be conducted with advantage in the neighborhood of pH 9 to 11. The use of a pH less than 7 is objectionable because such a pH level induces conversion of the base salt of N-protected-S-phenylcysteine to free N-protected-S-phenylcysteine. Moreover, when the amino-protecting group is a protective group which is not so stable under basic conditions, s

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