Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2002-02-05
2004-04-13
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C548S954000
Reexamination Certificate
active
06720449
ABSTRACT:
TECHNICAL FIELD
This invention relates to processes for producing optically active amino acid derivatives, optically active N-protected-aziridine-2-carboxylic acid and optically active aziridine-2-carboxylic acid derivatives, which are useful as intermediates of drugs and pesticides, physiologically active substances, etc., and salts thereof.
BACKGROUND ART
There have been known a great number of optically active natural or unnatural amino acid derivatives which are useful as intermediates of drugs and pesticides, physiologically active substances, etc. It is still an important problem to develop an efficient process for producing these derivatives. As noteworthy processes, there have been reported several processes of activating the OH-group at the &bgr;-position of optically active serine and then reacting with a nucleophile or an electrophile.
Examples of these processes are as follows:
(1) a process wherein an optically active N-tosyl-aziridine-2-carboxylic acid derivative is reacted with lithium acetylide of trimethylsilyl acetylene (Tetrahedron Lett. vol. 36, 151 (1995));
(2) a process wherein an optically active N-protected-3-iodo-alanyl ester is substituted at the 3-position by reacting with a nucleophile (Tetrahedron, vol. 41, 1833 (1985));
(3) a process wherein an optically active N-protected-3-iodo-alanyl ester is converted into an organic zinc compound and then reacted with an electrophile (J.O.C., vol. 57, 3397 (1992));
(4) a process wherein a &bgr;-lactam derivative or a sulfamidate derivative is produced from a serine derivative and then reacted with a nucleophile (J. Am. Chem. Soc., vol. 107, 7105 (1985)); and
(5) a process wherein an optically active N-protected-aziridine-2-carboxylic acid ester is synthesized from a serine derivative and then reacted with an organic copper reagent (JP-A-7-252202; the term “JP-A” as used herein means an “unexamined published Japanese patent application”), etc.
In addition, there has been known a process for producing aziridine-2-carboxylic acid by treating a 3-haloalanine or its ester or a mineral acid salt thereof with an alkali metal or alkaline earth metal hydroxide or aqueous ammonia in water or an aqueous organic solvent (JP-B-60-39357; the term “JP-B” as used herein means an “examined Japanese patent publication”).
Among the processes of activating the OH-group at the &bgr;-position of optically active serine and then reacting with a nucleophile or an electrophile, the above-described process (1) is not industrially advantageous. This is because the metal acetylide reagent should be used in large excess and only a poor yield can be achieved thereby. Moreover, it is needed in this process to synthesize the substrate in plural steps, which makes the performance troublesome.
Similarly, it is also needed to synthesize the substrate in plural steps in the processes (2) to (5), which makes the performance troublesome. To maintain the optical purity of a product at a high level, it is further needed to carry out the reaction at a low temperature with the use of a less basic organic copper reagent as the nucleophile and the occurrence of partial racemization is yet unavoidable. In these processes, furthermore, only an insufficient selectivity of functional groups is achieved and thus by-products having reacted with ester group are also formed.
As discussed above, these known processes each suffers from problems to be solved as an industrial process for producing optically active natural or unnatural amino acid derivatives. Therefore, it has been required to develop an industrially applicable process for producing optically active natural or unnatural amino acid derivatives without resort to any expensive reagents or troublesome procedures.
Concerning the process for producing aziridine-2-carboxylic acid as described above, the procedures and analytical methods are described in the document as cited above. When the inventors carried out a detailed follow-up experiment after establishing an appropriate analytical method, the yield reported in the document could be hardly achieved. It has been thus revealed that there is a serious problem in efficiently producing aziridine-2-carboxylic acid by this process on an industrial scale.
DISCLOSURE OF THE INVENTION
Under these circumstances, the inventors have conducted intensive studies on a process for efficiently producing optically active natural or unnatural amino acid derivatives starting with highly available optically active 3-haloalanine derivatives, in particular, optically active 3-chloroalanine derivatives. As a result, they have successfully found out that a natural or unnatural amino acid derivative can be very efficiently produced at a high optical purity by using an optically active 3-haloalanine derivative, in particular, an optically active 3-chloroalanine derivative via an optically active aziridine-2-carboxlic acid derivative protected at the amino group by a benzenesulfonyl group substituted by nitro at the 2- and/or 4-positions, or an optically active 3-haloalanine derivative protected at the amino group by a benzenesulfonyl group substituted by nitro at the 2- and/or 4-positions.
As the results of intensive studies on a process for efficiently producing optically active aziridine-2-carboxylic acid derivatives starting with optically active 3-haloalanine derivatives, in particular optically active 3-chloroalanine derivatives, they have further found out that an optically active aziridine-2-carboxylic acid derivative can be very efficiently produced by carrying out a reaction with the use of an optically active 3-haloalanine derivative, in particular an optically active chloroalanine derivative, under definite basic conditions.
Accordingly, the invention provides a process which comprises subjecting an optically active 3-haloalanine derivative represented by the following formula (1):
wherein X represents a halogen atom; R
1
represents a hydrogen atom or a monovalent organic group which is involved in a structure represented by —CO
2
R
1
and thus is capable of serving as an ester type protective group of a carboxyl group; and * represents the position of an asymmetric carbon atom;
or its salt to an intramolecular cyclization reaction in the presence of a base followed by, if needed, ester hydrolysis to give an optically active aziridine-2-carboxylic acid derivative represented by the following formula (2):
wherein * is as defined above; and R
2
has the same meaning as R
1
as defined above;
or its salt while maintaining the configuration at the 2-position, and then protecting the amino group followed by, if needed, ester hydrolysis to thereby give an optically active N-protected-aziridine-2-carboxylic acid represented by the following formula (3):
wherein * is as defined above; and P
1
represents a benzenesulfonyl group substituted by nitro at the 2- and/or 4-positions;
further treating it with an organic metal reagent represented by the following formula (5):
R
3
M (5)
wherein R
3
represents an optionally substituted cyclic or noncyclic alkyl group having 1 to 30 carbon atoms, an optionally substituted aralkyl group having 7 to 30 carbon atoms, an optionally substituted aryl group having 6 to 30 carbon atoms, an optionally substituted alkenyl group having 2 to 30 carbon atoms, or an optionally substituted alkynyl group having 2 to 30 carbon atoms; and M represents an atomic group containing an alkali metal atom or an alkaline earth metal atom or an atomic group containing a zinc ion;
followed by, if needed, deblocking to thereby give an optically active amino acid derivative represented by the following formula (6):
wherein R
3
and * are each as defined above; and P
2
has the same meaning as P
1
as described above or represents a hydrogen atom;
or its salt.
The invention further provides a process which comprises protecting the amino group of an optically active 3-haloalanine derivative represented by the above formula (1) or its salt followed by, if needed, ester hydrolysis to thereby give an optically active N-protected-3-haloalanine derivati
Fujii Akio
Fuse Yoshihide
Inoue Kenji
Kinoshita Koichi
Moroshima Tadashi
Kaneka Corporation
Small Andrea D.
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