Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-05-26
2001-08-28
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S170000, C562S444000, C562S567000, C564S340000
Reexamination Certificate
active
06281379
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for producing a &bgr;-amino-&agr;-hydroxy acid derivative of use as an intermediate in the production of pharmaceuticals and agrochemicals, particularly an optically active threo-phenylnorstatin derivative, and to a process for producing a &bgr;-amino-&agr;-keto ester derivative or a &ggr;-amino-&agr;-halo-&bgr;-keto sulfoxide derivative of use as an intermediate thereof.
PRIOR ART
The hitherto-known technology for producing an optically active threo-phenylnorstatin derivative includes:
(1) the process in which an N-protected aldehyde derivative of phenylalanine is treated with a silyl cyanide and the resulting cyanohydrin compound is hydrolyzed (Japanese Kokai Publication Hei-2-28144);
(2) the process in which an N-protected aldehyde derivative of phenylalanine is cyanated in the presence of a phase transfer catalyst and acetic anhydride (Japanese Kokai Publication Hei-2-56547);
(3) the process in which an N-protected aldehyde derivative of phenylalanine is cyanated to a cyanohydrin derivative, followed by being subjected to isomerization-crystallization in the presence of an amine (Japanese Kokai Publication Hei-9-27834);
(4) the process which comprises converting N-phthaloyl-protected phenylalanine to an acid chloride, reacting it with a silyl cyanide to give a cyanoketone, converting it to a keto ester, and reducing the same with zinc borohydride or the like (EP-553343);
(5) the multi-step process utilizing an optically active 3,4-butenediol wherein a phenylnorstatin derivative is synthesized through an aziridine derivative and an oxazolidone derivative [Bioorg. Med. Chem. Lett. (1995), 5 (24), 2959]; and
(6) the process in which an N-protected &agr;-aminoacetophenone derivative is reacted with glyoxylic acid and the reaction product is subjected to optical resolution, crystallization and catalytic reduction (Japanese Kokai Publication Sho-55-79353).
However, the processes (1) through (4) invariably require the use of a cyanating agent which is highly toxic and calls for meticulous care in handling, while the process (5) involves many steps and requires costly reagents. The process (6) requires a complicated procedure for isolating the desired optically active threo-compound from a mixture of 4 different isomers. Thus, any of the known processes has some disadvantages or others to be overcome for exploitation as an industrially profitable method for production of optically active threo-norstatin derivatives.
SUMMARY OF THE INVENTION
In view of the above state of the art, the present invention has for its object to provide a process for producing an optically active threo-phenylnorstatin derivative which does not require a toxic cyanating agent or a costly reagent, or a complicated procedure, and can be practiced on a commercial scale.
Under the circumstances the inventors of the present invention explored enthusiastically for a production technology by which an optically active threo-norstatin derivative, particularly an optically active threo-phenylnorstatin derivative, may be produced efficiently from an optically active amino acid ester derivative which is readily available, particularly an optically active phenylalanine derivative, as an starting material. As a result, they discovered a process by which a &bgr;-amino-&agr;-hydroxy acid derivative, particularly an optically active threo-phenylnorstatin derivative and an intermediate thereof, can be produced with good efficiency from an amino acid ester derivative, particularly an optically active phenylalanine ester.
The present invention, therefore, is directed to a process for producing a &bgr;-amino-&agr;-hydroxy acid derivative
which comprises treating either a &ggr;-amino-&bgr;-keto sulfoxide derivative of the formula (1);
wherein R
1
represents a substituted or unsubstituted alkyl group of 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group of 7 to 30 carbon atoms or a substituted or unsubstituted aryl group of 6 to 30 carbon atoms; R
2
represents a substituted or unsubstituted alkyl group of 1 to 10 carbon atoms, a substituted or unsubstituted aralkyl group of 7 to 20 carbon atoms or a substituted or unsubstituted aryl group of 6 to 20 carbon atoms; P
1
and P
2
may be the same or different and each represents a substituted or unsubstituted benzyl group, or a &ggr;-amino-&bgr;-keto sulfoxide derivative metal salt of the formula (6);
wherein R
1
, R
2
, P
1
and P
2
are as defined above; M represents an alkali metal or an alkaline earth metal halide,
with a halogenating agent to produce a &ggr;-amino-&agr;-halo-&bgr;-keto sulfoxide derivative of the formula (2);
wherein R
1
, R
2
, P
1
and P
2
are as defined above; X represents a halogen atom,
treating the derivative (2) with an acid and an alcohol of the formula (3);
R
3
OH (3)
wherein R
3
represents a substituted or unsubstituted alkyl group of 1 to 10 carbon atoms or a substituted or unsubstituted aralkyl group of 7 to 20 carbon atoms,
to produce a &bgr;-amino-&agr;-keto ester derivative or &bgr;-amino-&agr;-keto acid derivative of the formula (4);
wherein R
1
, P
1
and P
2
are respectively as defined above; R
4
represents a hydrogen atom, or a substituted or unsubstituted alkyl group of 1 to 10 carbon atoms or substituted or unsubstituted aralkyl group of 7 to 20 carbon atoms which corresponds to R
3
in the above formula (3),
and reducing the same derivative (4), optionally followed by cleaving the ester and/or deprotecting the amino group to give a &bgr;-amino-&agr;-hydroxy acid derivative of the formula (5);
wherein R
1
and R
4
are respectively as defined above; Q
1
represents a hydrogen atom, or a substituted or unsubstituted benzyl group corresponding to P
1
in the above formula (1); Q
2
represents a hydrogen atom, or a substituted or unsubstituted benzyl group corresponding to P
2
in the above formula (1).
The present invention is further directed to a process for producing a &bgr;-amino-&agr;-keto ester derivative or &bgr;-amino-&agr;-keto acid derivative of the above formula (4)
which comprises treating a &ggr;-amino-&bgr;-keto sulfoxide derivative of the above formula (1) or &ggr;-amino-&bgr;-keto sulfoxide derivative of the above formula (6) with a halogenating agent to produce a &ggr;-amino-&agr;-halo-&bgr;-keto sulfoxide derivative of the above formula (2) and treating the derivative (2) with an acid and an alcohol of the above formula (3).
The present invention is further directed to a process for producing a &ggr;-amino-&agr;-halo-&bgr;-keto sulfoxide derivative of the above formula (2)
which comprises treating a &ggr;-amino-&bgr;-keto sulfoxide derivative of the above formula (1) or a &ggr;-amino-&bgr;-keto sulfoxide derivative metal salt of the above formula (6) with a halogenating agent.
The present invention is further directed to a compound of the above formula (2).
The present invention is now described in detail.
DETAILED DESCRIPTION OF THE INVENTION
Referring to the &ggr;-amino-&bgr;-keto sulfoxide derivative of the formula (1), R
1
represents a substituted or unsubstituted alkyl group of 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group of 7 to 30 carbon atoms or a substituted or unsubstituted aryl group of 6 to 30 carbon atoms.
The substituted or unsubstituted alkyl group of 1 to 20 carbon atoms is not particularly restricted but includes methyl, ethyl, isopropyl, isobutyl, t-butyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl and methylthiomethyl, among others.
The substituted or unsubstituted aralkyl group of 7 to 30 carbon atoms is not particularly restricted, either, but includes benzyl, p-hydroxybenzyl, p-methoxybenzyl, p-chlorobenzyl, phenylthiomethyl and &agr;-phenethyl, among others.
The substituted or unsubstituted aryl group of 6 to 30 carbon atoms is not particularly restricted but includes phenyl, p-hydroxyphenyl and p-methoxyphenyl, among others.
R
1
above represents the side chain of an ordinary &agr;-amino acid or the side chain of an &agr;-amino acid
Fujii Akio
Inoue Kenji
Sugawara Masanobu
Chaudhry Mahreen
Kaneka Corporation
Killos Paul J.
Sughrue Mion Zinn Macpeak & Seas, PLLC
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