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||||||||||||III USOO5296373A United States Patent (19) 11 Patent Number: 5,296,373 Endo Et Al ||||||||||||III USOO5296373A United States Patent (19) 11 Patent Number: 5,296,373 Endo et al. (45) Date of Patent: Mar. 22, 1994 54 PROCESS FOR PRODUCING R(-)-MANDELIC ACID OR A DERVATIVE OTHER PUBLICATIONS THEREOF FROMA MANOELONTRLE Kakeya Het al., Agric Biol. Chem. 55:1877-81 (1991). USING RHODOCOCCUS ATCC Catalog of Bacteria & Bacteriophages pp. 184-188 (1989). 75) Inventors: Takakazu Endo; Koji Tamura, both of Mori et al., "Synthesis of Optically Active Alkynyl . Kanagawa, Japan Acetates', Tetrahedron, vol. 36, pp. 91-96 (1980). Evans et al., “Asymmetric Oxygenation of Chiral . 73) Assignee: Nitto Chemical Industry Co., Ltd., Acid Synthons', J. An. Chen. Soc, vol. 107, pp. Tokyo, Japan 4346-4348 (1985). Yamazaki et al., "Enzymatic Synthesis of Optically . (21) Appl. No.: 904,335 and Use", Agric. Biol. Chem, vol. 50, pp. 2621-2631 (1986). 22 Filed: Jun. 25, 1992 Primary Examiner-Douglas W. Robinson Assistant Examiner-S. Saucier (30) Foreign Application Priority Data Attorney, Agent, or Firm-Sughrue, Mion, Zinn, Jun. 26, 1991 JP Japan .................................. 3-180475 Macpeak & Seas 51) Int, Cl........................... C12P 41/00; C12P 7/42 57 ABSTRACT 52 U.S.C. .................................... 435/280; 435/146; A process for treating R,S-mandelonitrile or a deriva 435/822 tive thereof or a mixture of benzaldehyde or a deriva 58) Field of Search ........................ 435/280, 146,822 tive thereof, and; hydrogen cyanide, with a microor ganism belonging to the genus Rhodococcus sp. HT29 (56) References Cited 7 (FERM BP-3857) in an almost neutral or basic aque U.S. PATENT DOCUMENTS ous medium to thereby directly produce a predominant amount of R(-)-mandelic acid or a derivative thereof, 4,859,784 8/1989 Effenberger et al................ 549/491 whereby the racemic R,S-mandelonitrile or a derivative 5,008,192 4/1991 Neidermeyer et al.............. 435/128 thereof or benzaldehyde or a derivative thereof and FOREIGN PATENT DOCUMENTS hydrogen cyanide can be directly converted into R(-)- mandelic acid or a derivative thereof at a ratio of about 0098.707 1/1984 European Pat. Off. 0348901 1/1990 European Pat. Off. 80 to 100% and at an optical purity of almost 100%ee 0449648 10/1991 European Pat. Off. without performing any optical resolution. 57-198096 12/1982 Japan. 58-177933 10/1983 Japan. 5 Claims, No Drawings 5,296,373 1. 2 delic acid derivative from a substituted derivative of PROCESS FOR PRODUCING RO-)-MANDELEC mandelonitrile. Therefore, it is unknown whether an ACID OR A DERVATIVE THEREOF FROM A R(-)-mandelic acid derivative of a high optical purity MANDELONTRILE USING RHODOCOCCUS can be efficiently obtained or not. As described above, these known methods suffer FIELD OF THE INVENTION from various problems. Thus, none of these known This invention relates to R(-)-mandelic acid or a methods is an industrially advantageous method for derivative thereof. More particularly, it relates to a producing R(-)-mandelic acid or derivatives thereof. process for producing R(-)-mandelic acid represented The present inventors conducted extensive investiga by the following general formula (III) or a derivative O tions to establish a method for advantageously produc thereof. The process is carried out by using a microor ing RC-)-mandelic acid on an industrial scale. As a ganism belonging to the genus Rhodococcus which is result, the present inventors discovered that R,S,-man capable of effecting nitrile asymmetric hydrolysis of delonitrile could be easily racemized through dissocia R,S-mandelonitrile represented by the following gen tion equilibrium into benzaldehyde and hydrogen cya eral formula () or a derivative thereof. Compounds 5 nide in an almost neutral or basic aqueous medium, and having a mandelic acid skeleton are highly valuable that R,S-mandelonitrile or benzaldehyde and hydrogen from an industrial viewpoint as starting materials for producing cephen-series antibiotics and a number of cyanide could be directly converted into R(-)-man medicines and agricultural chemicals. delic acid in conjunction with this racemization system 20 together with a microorganism capable of asymmetric BACKGROUND OF THE INVENTION hydrolysis of mandelonitrile. Based on these findings, Known methods for producing R(-)-mandelic acid they disclosed a process for producing R(-)-mandelic or derivatives thereof include: racemic resolution of acid by using a microorganism belonging to the genus chemically synthesized RS-mandelic acid (racemic Pseudomonas, Alcaligenes, Acinetobacter or Caseobac modification) by (1) fractional crystallization as de 25 ter as described in European Patent Publication No. 0 scribed in JP-A-58-177933 (the term "JP-A' as used 449 648A and another process for producing R(-)- herein means an "unexamined published Japanese pa mandelic acid with the use of a microorganism belong tent application); (2) chromatography as described in ing to the genus Nocardia, Bacillus, Brevibacterium or European Patent Publication No. 0 098 707A; and (3) Aureobacterium as described in European Patent Publi conversion of the racemic modification into racemic 30 cation No. 0449 648A. Subsequently, they further ap esters followed by racemic resolution thereof by enzy plied the above-mentioned findings to substituted man matic asymmetric hydrolysis as described in K. Mori et delonitrile derivatives and, as a result, proposed a pro al., Tetrahedron, 36, 91-96 (1980); and (4) chemical cess for producing R(-)-mandelic acid derivatives asymmetric synthesis with the use of a chiral reagent as with the use of a microorganism belonging to the genus described in D. A. Evans et al., J. Am. Chen. Soc., 107, 35 Aureobacterium, Pseudomonas, Caseobacter, Alcalige 4346-4348 (1985). Biological methods therefor include nes, Acinetobacter, Brevibacteriumn or Nocardia as the asymmetric hydrolysis of the abovementioned es described in European Patent Publication No. 0 449 ters formed by process (3) above and (5) microbiologi 648A. cal asymmetric reduction of benzoylformic acid as de However, the R-stereoselectivities of the hydroge scribed in JP-A-57-198096; (6) hydrolysis of R(-)-man nases produced by these bacteria are not always satis delonitrile or substituted derivatives thereof which are factory and thus further evaluation has been required asymmetrically synthesized with the use of D-oxynitri for the steroeselectivities. lase as described in U.S. Pat. Nos. 4,859,784 and 5,008, 192; and (7) asymmetric hydrolysis of mandeloni SUMMARY OF THE INVENTION trile, mandelamide or substituted derivatives thereof 45 with the use of microorganisms belonging to the genus The present inventors have further attempted to find Alcaligenes, Pseudomonas, Rhodopseudomonas, Cory a microorganism possessing an excellent capability of nebacterium, Acinetobacter, Bacilius, Mycobacterium, asymmetrically hydrolyzing mandelonitrile or deriva Rhodococcus or Candida as described in European tives thereof. As a result, they have successfully discov Patent Publication No. 0 348 901A. ered that an extremely high R-stereoselectivity can be However, each of the racemic resolution methods (1) achieved by using a microorganism belonging to the to (3) requires a complicated process and a decrease in genus Rhodococcus, thus completing the present inven the yield occurs in each step. In method (4), using a tion. chiral reagent as a catalyst, an expensive chiral reagent Accordingly, the present invention provides a pro is required and a product of high optical purity is almost 55 cess for producing a predominant amount of R(-)- impossible to obtain. mandelic acid represented by the following general The above-mentioned biological methods also have formula (III) or a derivative thereof from RS-man some disadvantages. Namely, in method (5) it is difficult delonitrile represented by the following general for to synthesize the substrate for the asymmetric reduction mula (I) or a derivative thereof or from benzaldehyde of benzoylformic acid. It is further difficult to maintain represented by the following general formula (II) or a the NADH-regeneration system. The D-oxynitrilase derivative thereof and hydrogen cyanide, by treating a method (6) is merely a basic finding that an optically R.S.-mandelonitrile of general formula (I) or a deriva active substance is obtained. The asymmetric hydrolysis tive thereof or a mixture of benzaldehyde of general method (7) requires a post treatment of another opti formula (II) or a derivative thereof and hydrogen cya cally active substance remaining after the completion of 65 nide, using a microorganism, which may be treated, the hydrolysis. In addition, the above-mentioned Euro belonging to the genus Rhodococcus and capable of pean Patent Publication No. 0 348 901A contains no stereoselectively hydrolyzing the nitrile group in a RS particular example of the production of a R(-)-man mandelonitrile represented by the general formula (I) or 5,296,373 3 4. a derivative thereof in a substantially neutral or basic -continued aqueous medium: Strain HT29-7: Colony color: pink to orange H (I) Rod-coccus cycle: -- Elongation of cell around colonies: yes Formation of mycelia: O -CN Oxidase: - X OH Catalase: -H Oxygen requirement: aerobic (II) Diamino acid in cell wall: meso-diaminopimelic acid 10 Glycolyl test: + (glycolyl type) CHO Sugar composition of cell wall: arabinose: -H X galactose: -- Quinone system: MK-90H2) H (III) 15 Based on these bacteriological properties, this strain -cooh HT29-7 was identified as a bacterium belonging to the X OH genus Rhodococcus
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