Process for producing optically active cysteine derivatives

Details Process for producing optically active cysteine derivatives Process for producing optically active cysteine derivatives

2000-08-25

2002-06-18

Killos, Paul J. (Department: 1623)

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

Organic compounds

Carboxylic acid esters

C560S152000, C560S153000, C560S147000, C560S009000

Reexamination Certificate

active

06407281

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a process for producing a D-form or L-form optically active cysteine derivative represented by the general formula (2) (hereinafter, such derivatives are also referred to as “cysteine derivatives (2)”):
wherein R
1
represents an amino-protecting group of the urethane or acyl type, R
0
represents a hydrogen atom or, taken together with the above R
1
, an amino-protecting group, R
2
represents a univalent organic group selected from the group consisting of a substituted or unsubstituted alkyl group containing 1 to 7 carbon atoms, a substituted or unsubstituted aryl group containing 6 to 10 carbon atoms and a substituted or unsubstituted aralkyl group containing 7 to 10 carbon atoms, R
3
represents a univalent organic group capable of functioning as an ester-type carboxyl-protecting group by its being included in the structure represented by —COOR
3
and * represents the position of an asymmetric carbon atom.
BACKGROUND ART
The cysteine derivatives (2), particularly in L form, which are obtainable by the present invention are compounds of importance as starting materials for the production of intermediates of HIV protease inhibitors. For example, said derivatives are useful as starting materials in the reaction scheme shown below, as described in WO 96/23756 and EP 604185 A1, for instance.
A production technology for the above cysteine derivatives (2) which is so far known in the art comprises introducing an R
2
S group (R
2
being as defined above) into a corresponding compound whose amino and carboxyl groups are protected.
Referring to this technology, a method is known which comprises converting the hydroxyl group of a serine derivative to a leaving group and then carrying out the substitution reaction [Tetrahedron Lett., vol. 28, p. 6069 (1987); ibid., vol. 34, p. 6607 (1993); EP 604185 A1].
In this way, the hydroxyl group of a serine derivative is converted to a sulfonyloxy group, followed by substitution reaction with a thiol derivative in an aprotic solvent. However, as a result of investigations made by the present inventors, it was revealed that the yield of the desired cysteine derivative (2) is not always high and that there are other problems; the quality is poor and, in particular, the optical purity decreases.
Further, there is no detailed description of the method of isolation of the desired cysteine derivative (2), and the above method cannot be said to be a production technology leading to good yields.
Thus, any method of producing those cysteine derivatives (2), which are important as raw materials for the production of intermediates of HIV protease inhibitors, has not been established as yet.
In view of the current state of the art as mentioned above, the primary object of the present invention is to provide a process for producing cysteine derivatives (2) which is economically advantageous and insures high productivity even on a commercial scale, together with high optical purity and good quality.
DISCLOSURE OF INVENTION
Investigations made by the present inventors revealed that the above cysteine derivatives (2) are unexpectedly unstable and, in particular, highly basic conditions bring about such undesirable events as racemization and decreases in yield. This is presumably because abstraction of the hydrogen atom at position a to the carbonyl group or E2 elimination is caused by high basicity, leading to formation of a dehydroalanine derivative as a byproduct, and, on the other hand, the elimination product thiol derivative reacts with the byproduct dehydroalanine derivative in the manner of Michael addition, as shown by the following reaction formula:
It is therefore believed that it is not easy to suppress decomposition or racemization of the above cysteine derivatives (2) when such a prior art technology as the one mentioned above, that generally requires highly basic reaction conditions, is used.
Based on the above finding, the present inventors made intensive investigations in search of a process for allowing the reaction to proceed smoothly and recovering the above cysteine derivatives (2) while suppressing the decomposition and racemization of the cysteine derivatives (2) and, as a result, found out a process favorable for carrying out the procedural series from reaction to recovery under acidic to weakly basic conditions while avoiding highly basic conditions.
Thus, the present invention is related to a process for producing the above optically active cysteine derivative (2) which comprises reacting a D-form or L-form optically active amino acid derivative represented by the general formula (1) (hereinafter also referred to as “amino acid derivative (1)”):
wherein R
0
, R
1
, R
2
and * are as defined above, with an alcohol represented by the general formula (3) (hereinafter also referred to as “alcohol (3)”):
R
3
OH  (3)
wherein R
3
is as defined above, and a strong acid and/or a thionyl halide to synthesize a D-form or L-form optically active cysteine derivative represented by the above general formula (2)
and recovering the above optically active cysteine derivative (2) from the reaction mixture,
the procedural series from reaction to recovery being carried out under a condition such that the medium contacting the above optically active cysteine derivative (2) is within the range from acidic to weakly basic to thereby recover the above optically active cysteine derivative (2) from the reaction mixture while suppressing the decomposition and racemization thereof.
In the following, the present invention is described in detail.
In the production process of the present invention, by carrying out the reaction using a strong acid and/or a thionyl halide, the reaction system can be maintained under acidic conditions under which the decomposition and racemization of the above cysteine derivative (2) can be completely inhibited. Thus, the reaction system is maintained under acidic conditions throughout the process, or the conditions therein favorably shift to acidic conditions as the reaction proceeds, namely with the formation of the cysteine derivative (2).
Referring to the above general formula (1) or (2), R
1
represents a urethane-type or acyl-type amino-protecting group. The urethane-type or acyl-type protective group is not particularly restricted but may be any one having an amino-protecting effect. For example, it can be selected from among those protective groups described in Protective Groups in Organic Synthesis, 2nd edition, published by John Wiley & Sons (1991).
Under such reaction conditions as mentioned above, urethane-type and acyl-type protective groups are judiciously used for masking the basicity of the amino group. Among them, urethane-type protective groups such as aralkyloxycarbonyl groups and lower alkyloxycarbonyl groups are preferred from the viewpoint of ease of handling, inexpensiveness and convenience in substrate compound synthesis, among others. In particular, benzyloxycarbonyl, tert-butoxycarbonyl, methoxycarbonyl and ethoxycarbonyl are preferred, and benzyloxycarbonyl is more preferred.
The above symbol R
0
usually represents a hydrogen atom. When the above amino-protecting group is a phthaloyl group or the like, however, it, together with the above R
1
, represents an amino-protecting group.
The above R
2
represents an alkyl group containing 1 to 7 carbon atoms, an aryl group containing 6 to 10 carbon atoms or an aralkyl group containing 7 to 10 carbon atoms. These groups may optionally be substituted according to need. Preferred as R
2
is phenyl, however.
The amino acid derivatives (1) to which the process of the present invention is favorably applicable are those S-phenylcysteines (R
2
=phenyl) whose amino group is protected by a urethane-type or acyl-type protective group. Among them, those S-phenylcysteines (R
2
=phenyl) whose amino group is protected by a urethane-type protective group are more preferred, and that S-phenylcysteines (R
2
=phenyl) whose amino group is protected by benzyloxycarbonyl, namely D-form or L-f

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