Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-07-23
2002-12-10
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S060000, C560S126000, C560S184000, C558S252000, C564S201000
Reexamination Certificate
active
06492545
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel process for producing an optically active alcohol. More particularly, the invention relates to a novel process suitable for the practical production of an optically active &bgr;-hydroxy acid compound useful as an intermediate for medicines or as a functional material, etc.
BACKGROUND ART
Conventionally known methods for synthesizing an optically active alcohol compound include 1) a method in which an enzyme such as a baker's yeast is used and 2) a method in which a metal complex is used to asymmetrically hydrogenate a carbonyl compound. In particular, with respect to the latter method for asymmetric hydrogenation, many proposals have been made. Known examples thereof include: (1) a method in which a carbonyl compound having a functional group is asymmetrically hydrogenated in the presence of an optically active ruthenium complex catalyst (R. Noyori,
Asymmetric Catalysis in Organic Synthesis,
pp.56-82 (1994)); (2) a method in which a 1,3-dicarbonyl compound is asymmetrically hydrogenated with the aid of a ruthenium-diphosphine complex (
Tetrahedron Asymmetry,
Vol.8, pp.3327-3355 (1997)); (3) a method of asymmetric hydrogenation using a ruthenium-optically active phosphine complex (JP-B-6-99367) (the term “JP-B” as used herein means an “examined Japanese patent publication”); (4) a method in which the hydrogen transfer reduction reaction of a carbonyl compound is utilized in the presence of an asymmetric complex catalyst comprising ruthenium, rhodium, or iridium (
Chem. Rev.,
Vol.92, pp.1051-1069 (1992)); (5) a method in which a carbonyl compound is asymmetrically hydrogenated with the aid of a nickel complex modified with tartaric acid (
Yu Kagaku,
pp.828-831 (1980), and Y. Izumi,
Advances in Catalysis,
Vol.32, p.215 (1983)); (6) a method in which the asymmetric hydrosilylation reaction of a carbonyl compound is utilized (J. D. Morrison,
Asymmetric Synthesis,
Vol.5, Chap.4 (1985), and
J. Organomet. Chem.,
Vol.346, pp.413-424 (1988)); (7) a method in which a carbonyl compound is reduced with a borane in the presence of an asymmetric ligand (
J. Chem. Soc., Perkin Trans. I,
pp.2039-2044 (1985), and
J. Am. Chem. Soc.,
Vol.109, pp.5551-5553 (1987)); and (8) a method in which an acetophenone compound is asymmetrically hydrogenated in the presence of potassium hydroxide, an optically active diamine, and an asymmetric ruthenium complex catalyst (
J. Am. Chem. Soc.,
Vol.117, pp.2675-2676 (1995)).
However, the above-described conventional methods for synthesizing an optically active alcohol have the following drawbacks. The synthesis method using an enzyme requires a complicated procedure and is restricted in substrates usable in the reaction. In addition, the alcohol compounds which can be obtained by the method are limited to those having a specific absolute configuration. On the other hand, the synthesis methods using a transition metal catalyst for asymmetric hydrogenation have problems that the rate of reaction is low and the optical purity of the optically active alcohol compound obtained by the asymmetric hydrogenation of a &bgr;-keto ester compound is insufficient, although various transition metal complex catalysts have been reported.
Especially in the fields of medicines and functional materials, it is important to obtain an optically active alcohol compound having a specific absolute configuration and a high optical purity and it has hence been necessary to overcome the above-described problems of the conventional methods.
Accordingly, an object of the invention is to provide a novel process in which an optically active alcohol compound having a desired absolute configuration and a high optical purity can be obtained through the asymmetric hydrogenation of a &bgr;-keto ester compound.
SUMMARY OF THE INVENTION
Under these circumstances, the present inventors made intensive investigations. As a result, it has been found that when a &bgr;-keto ester compound is asymmetrically hydrogenated with the aid of a ruthenium metal complex having as a ligand an optically active [4,4′-bis-1,3-benzodioxol]-5,5′-diylbis(diphenylphosphine) (hereinafter also referred to as “SEGPHOS” simply), then the corresponding optically active alcohol having a high optical purity is obtained. As a result of further extensive studies by the present inventors, the invention has finally been completed.
The invention provides a process for producing an optically active alcohol represented by the following general formula (III):
(wherein R
1
represents a C
1
-C
15
alkyl group which may have one or more substituents (selected from halogen atoms, a hydroxyl group, an amino group, amino groups protected by a protective group, amino groups substituted with one or more C
1
-C
4
lower alkyl groups, amino groups protected by a mineral acid or organic acid, a benzyloxy group, C
1
-C
4
lower alkoxy groups, C
1
-C
4
lower alkoxycarbonyl groups, and aryl groups) or an aryl group; and R
2
represents a C
1
-C
8
lower alkyl group, or a benzyl group which may have one or more substituents)
which comprises asymmetrically hydrogenating a &bgr;-keto ester compound represented by the following general formula (I):
(wherein R
1
and R
2
are the same as defined above) in the presence of at least one ruthenium complex having as a ligand an optically active tertiary diphosphine compound represented by the following general formula (II):
(wherein R
3
and R
4
each independently represent a cycloalkyl group, an unsubstituted or substituted phenyl group, or a five-membered heteroaromatic ring residue).
The invention further provides a process for producing the optically active alcohol which comprises conducting the asymmetric hydrogenation reaction in the presence of a specific ruthenium complex.
The invention furthermore provides a process for producing the optically active alcohol which comprises conducting the asymmetric hydrogenation reaction in the presence of a specific acid.
DETAILED DESCRIPTION OF THE INVENTION
The invention will be explained below in detail.
Preferred examples of R
1
in the &bgr;-keto ester compound (I) for use as a starting material in producing the optically active alcohol by the process of the invention include C
1
-C
15
alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, decyl, undecyl, dodecyl, and tridecyl; C
1
-C
15
alkyl groups having one or more substituents (examples of the substituents include halogen atoms, hydroxyl, amino, amino groups protected by a protective group (e.g., acetyl, benzyloxycarbonyl, or t-butoxycarbonyl), amino groups protected by a mineral acid (e.g., hydrochloric acid, sulfuric acid, bromic acid, phosphoric acid, or hydriodic acid) or by an organic acid (e.g., p-toluenesulfonic acid, methanesulfonic acid, or acetic acid), amino groups substituted with one or more C
1
-C
4
lower alkyl groups, C
1
-C
4
lower alkoxy groups such as benzyloxy, methoxy, ethoxy, and t-butoxy, C
1
-C
4
lower alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl, and aryl groups such as phenyl, p-methoxyphenyl, p-tolyl, and 2-naphthyl), and aryl groups such as phenyl, p-methoxyphenyl, p-tolyl, and 2-naphthyl.
Preferred examples of R
2
in the &bgr;-keto ester compound (I) include alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, and octyl and a benzyl group which may have one or more substituents. Preferred examples of the substituents include methyl, ethyl, and methoxy.
Specific examples of the &bgr;-keto ester compound (I) include methyl acetoacetate, ethyl acetoacetate, n-propyl acetoacetate, isopropyl acetoacetate, n-butyl acetoacetate, t-butyl acetoacetate, n-pentyl acetoacetate, n-hexyl acetoacetate, n-octyl acetoacetate, benzyl acetoacetate, methyl 4-chloroacetoacetate, ethyl 4-chloroacetoacetate, methyl 3-oxopentanoate, methyl 3-oxohexanoate, methyl 3-oxoheptanoate, methyl 6-methyl-3-oxoheptanoate, methyl 3-oxooctanoate, methyl 3-oxononanoate, methyl 3-oxodecanoate, methyl 3-oxoundecanoate, methyl 3-oxododecanoate, methyl 3-oxo
Matsumura Kazuhiko
Saito Takao
Sayo Noboru
Yokozawa Tohru
Reyes Hector M
Rotman Alan L.
Sughrue & Mion, PLLC
Takasago International Corporation
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