Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
1999-08-06
2001-04-17
O'Sullivan, Peter (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S715000, C568S810000, C568S812000, C568S814000, C568S815000
Reexamination Certificate
active
06218581
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process of producing optically active alcohol from a substrate using an immobilized water-soluble protein component, extracted from grains, beans and other plant resources, as a catalyst.
BACKGROUND ART
Optically active alcohols are extremely important substances as raw materials or intermediate raw materials for pharmaceuticals and agricultural chemicals as well as intermediates, in the field of fine chemicals, for products such as ferroelectric liquid crystals.
Known processes for producing optically active alcohols of the prior art are reacting a substrate with 1) microorganisms, 2) enzymes derived from microorganisms, 3) enzymes derived from animal tissue, and 4) cultured plant cells for biosynthesis of an optically active substance such as optically active alcohol.
The process using microorganisms of 1) above is a technique for obtaining optically active alcohol by reacting a substrate with cultured microorganisms, a known example of which is disclosed in Japanese Patent No. 2784578 (a process of producing optically active 1,2-diols).
In addition, the process using an enzyme derived from microorganisms of 2) above is a technique for obtaining optically active alcohol by reacting a substrate with a homogenized liquid of microorganisms cultured by introducing a gene, a known example of which is disclosed in Japanese Unexamined Patent Publication No. 10-210981 (novel protein that catalyzes conversion from halohydrin to optically active diol).
In addition, the process using an enzyme derived from animal tissue of 3) above is a technique for obtaining optically active alcohol by reacting a substrate with a protein isolated from animal tissue, a known example of which is disclosed in Japanese Patent No. 2756790.
In addition, the reaction using cultured plant cells of 4) above is a technique for obtaining optically active alcohol by reacting a substrate with plant cells, an example of which is reported in the literature (Chem. Pharm. Bull., 43, pp. 1458-1461).
As is known in Japanese Patent No. 2784578 (a process of producing optically active 1,2-diols) and Japanese Patent No. 2774341 (a process of producing an optically active 2-hydroxy acid derivative), processes using the “microorganisms” of 1) above synthesize optically active alcohol by growing microorganisms in a culture solution by appropriately setting culture conditions, treating this culture liquid by centrifugal separation or filtration to collect the microorganisms, and asymmetrically reducing a ketone body, which is used as a substrate, in a liquid in which the microorganisms have been suspended in 0.1 M phosphate buffer (pH 6.5) or distilled water and so forth. Since side reactions other than the substrate conversion reaction occur simultaneously caused by the diverse types of enzymes contained in the microorganisms, the yield of the target optically active alcohol is low. In addition, even if isolation and purification work to remove the target optically active alcohol from a solution containing the reaction product, due to the low purity of the resulting optically active alcohol, it is difficult to use as a synthesis intermediate in the field of fine chemicals. As disclosed in Japanese Unexamined Patent Publication No. 10-210981 (novel protein for catalyzing conversion from halohydrin to optically active diol), processes using “enzymes derived from microorganisms” of 2) above are processes for producing optically active epihalohydrins and optically active diols by using a transformed microorganism in which genes cloned by gene recombination techniques are present in large numbers in the microorganisms. Since there are no large differences in the reaction process itself from processes using microorganisms, side reactions that take place during substrate reaction cannot be controlled, thereby causing this process to have the same problems as processes using “microorganisms”. Moreover, since gene-introduced microbial strains are heterogenous varieties in the natural world, there is the risk of having detrimental effects on humans and other members of the ecosystem. Consequently, a cost burden is required for equipment for isolating from the external environment as well as incineration treatment of reaction residue and so forth. In addition, as is known in Japanese Patent No. 2756790 (a process of producing optically active cyclopentenol derivative), processes using “enzymes derived from animal tissue” of 3) above are processes for producing optically active cyclopentenol derivative using an asymmetrical hydrolysis reaction of porcine pancreatic lipase. As is described in “Organic Chemistry for Biology 3—Proteins” edited by Kazuo Satake, pages 114-172 (Asakura Shoten Publishing), since enzymes derived from animal tissue are crude enzymes, side reactions occur in the same manner as 1) and 2) above, resulting in an unavoidable decrease in yield. In addition, processes using “cultured plant cells” of 4) above have the problem of low yield of optically active alcohol due to side reactions other than the substrate conversion reaction that occur caused by the diverse types of enzymes contained in plants. In addition, raising of cultured plant cells is difficult as is indicated by the need for sterile procedures throughout the entire process. Moreover, an amount of time for repeating subculturing of 1 to 2 years along with preparation of reaction nutrient culture liquid (such as MS medium) for reacting with substrate are required, thereby creating the shortcoming of a complex reaction procedure.
DISCLOSURE OF THE INVENTION
In order to solve the above-mentioned problems, the object of the present invention is to provide a production process for obtaining optically active alcohol of high optical purity that is applied to organic synthesis chemistry by using, as an optical separation catalyst, a water-soluble protein extracted from inexpensive grains and beans that are produced worldwide, is friendly to the ecosystem, and allows a considerable reduction in reaction costs.
The production process for obtaining optically active alcohol of high optical purity by using the above-mentioned optical separation catalyst in the present invention generally includes the processes indicated below.
(1) A process for producing optically active alcohol comprising selectively oxidizing a substrate in the form of one enantiomer of a racemic alcohol to obtain ketone, allowing the other enantiomer to remain unreacted, and separating the optically active alcohol.
(2) A process for producing optically active alcohol comprising asymmetric reduction of a substrate in the form of a ketone molecule.
(3) A process for producing optically active alcohol comprising asymmetric hydrolysis of a substrate in the acylated form of a racemic alcohol.
(4) A process for producing optically active alcohol comprising selectively acylating one enantiomer of a racemic alcohol in an organic solvent, hydrolyzing the resulting acylated enantiomer, and separating the optically active alcohol.
As a result of conducting earnest research on a process for obtaining optically active alcohol of high optical purity that solves the above-mentioned problems and is safe and is easy, the inventors of the present invention found that the R or S form of optically active alcohol of high purity that can be sufficiently used as a raw material for the synthesis of synthesis intermediates in the field of fine chemicals can be obtained both safely and easily by combining a first step comprising extracting water-soluble protein from grains or beans, a second step comprising immobilization of the above-mentioned protein, a third step comprising performing an enzyme conversion reaction on a substrate using the above-mentioned immobilized protein as catalyst, a fourth step comprising extracting a mixture of the above-mentioned reaction substrate converted by said third step and the reaction product with organic solvent, and a fifth step comprising isolating and purifying optically active alcohol or the acylated form of optically active alcohol
Merchant & Gould P.C.
O'Sullivan Peter
Sanyo Shokuhin Co., Ltd.
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