Process for Producing Malonic Acid Derivatives
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Europäisches Patentamt (19) European Patent Office Office européen des brevets (11) EP 1 008 655 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 158(3) EPC (43) Date of publication: (51) Int. Cl.7: C12P 7/62 14.06.2000 Bulletin 2000/24 (86) International application number: (21) Application number: 98904405.2 PCT/JP98/00711 (22) Date of filing: 20.02.1998 (87) International publication number: WO 98/37219 (27.08.1998 Gazette 1998/34) (84) Designated Contracting States: • ENOMOTO, Kanehiko CH DE ES FR GB IT LI Otake-shi, Hiroshima 739-060606 (JP) • ENDO, Takakazu, (30) Priority: 20.02.1997 JP 3650897 Mitsubishi Rayon Co Ltd 20.02.1997 JP 3651097 Yokohama-shi, Kanagawa 230-0053 (JP) (71) Applicant: (74) Representative: HOFFMANN - EITLE Mitsubishi Rayon Co., Ltd. Patent- und Rechtsanwälte Tokyo 108-8506 (JP) Arabellastrasse 4 81925 München (DE) (72) Inventors: • OZAKI, Eiji , Otake-shi, Hiroshima 739-0606 (JP) (54) PROCESS FOR PRODUCING MALONIC ACID DERIVATIVES (57) A process for producing malonic monoesters represented by the following general formula (II): HOOCCH2COOR, wherein R represents alkenyl, aryl, aralkyl or C1-20 alkyl, characterized by hydrolyzing a cyanoacetate represented by the following general for- mula (I): NCCH2COOR, wherein R is as defined above, by treating with a culture of a microorganism belonging to the genus Corynebacterium, Gordona or Rhodococcus and having a nitrilase activity or option- ally treated cells of the same. EP 1 008 655 A1 Printed by Xerox (UK) Business Services 2.16.7 (HRS)/3.6 12EP 1 008 655 A1 Description HOOCCH2COOR (II) TECHNICAL FIELD wherein R is alkenyl, aryl, aralkyl or C1-20 alkyl, comprising treating a cyanoacetic acid ester [0001] The present invention relates to a method for 5represented by Formula (I): preparing malonic acid monoesters which are useful as intermediates in the synthesis of various chemical prod- NCCH2COOR (I) ucts, medicines, agricultural chemicals and so on. wherein R is as defined in Formula (II), with BACKGROUND ART 10 a culture, cells or a product from treated cells of a microorganism belonging to the genus [0002] As a method for preparing malonic acid Corynebacterium, Gordona or Rhodococcus and monoesters, chemical hydrolysis of malonic acid having nitrilase activity to thereby hydrolyze the diesters is commonly used. According to this method, cyanoacetic acid ester. however, it is difficult to separate the generated malonic 15 (2) The method of (1) above, wherein the acid monoester from the unreacted malonic acid diester cyanoacetic acid ester is continuously added to the and the malonic acid which is a by-product. Thus, it is reaction solution while maintaining the concentra- impossible to obtain highly pure malonic acid tion of the cyanoacetic acid ester in the solution in monoesters. the range from 0.01 to 10% by weight during the [0003] As a method for obtaining highly pure 20 hydrolysis. malonic acid monoesters, a method using Meldrum's (3) The method of (1) above, wherein the C1-20 alkyl acid as a raw material is known [see, for example, represented by R is C3-20 alkyl and the microorgan- Matoba Katsuhide et al., Chem. Pharm. Bull., 31 (8), ism having nitrilase activity is a microorganism 2955 (1983); or Rigo B. et al., Tetrahedron Lett., 30(23), belonging to the genus Rhodococcus. 3073 (1989)]. However, since this method uses expen- 25 (4) The method of (3) above, wherein the sive Meldrum' s acid, it cannot be said a practical cyanoacetic acid ester is continuously added to the method and is not suitable for industrial production. reaction solution while maintaining the concentra- [0004] As another method for obtaining highly pure tion of the cyanoacetic acid ester in the solution in malonic acid monoesters, a method is known in which the range from 0.01 to 10% by weight during the malonic acid diesters are treated with an enzyme or 30 hydrolysis. microorganism having an ability to hydrolyze ester (5) The method of (1) above, wherein the microor- bonds (Japanese Unexamined Patent Publication No. ganism having nitrilase activity is Corynebacterium 8-173174). However, the use of malonic acid diesters as nitrilophilus ATCC 21419. a raw material is disadvantageous in terms of cost. (6) The method of (1) above, wherein the microor- [0005] Therefore, development of a highly produc- 35 ganism having nitrilase activity is Gordona terrae tive method for preparing highly pure malonic acid MA-1 (FERM BP-4535). monoesters has been desired. (7) The method of (1) above, wherein the microor- ganism having nitrilase activity is Rhodococcus DISCLOSURE OF THE INVENTION rhodochrous ATCC 33025. 40 (8) A method for preparing a malonic acid [0006] It is the object of the present invention to pro- monoester represented by Formula (II'): vide a highly productive method for preparing malonic acid monoesters which are useful as intermediates in HOOCCH2COOR' (II') the synthesis of various chemical products, medicines, agricultural chemicals, etc. 45 wherein R' is alkenyl, aryl, aralkyl or C3-20 [0007] The present inventors have found that a alkyl, comprising treating a cyanoacetic acid ester malonic acid monoester is produced selectively when a represented by Formula (I'): cyanoacetic acid ester is treated with a culture, cells or a product from treated cells of a microorganism having NCCH2COOR' (I') nitrilase activity; according to that method, a highly pure 50 malonic acid monoester can be prepared without side wherein R' is as defined in Formula (II'), with reactions such as hydrolysis of ester bonds. Thus, the a culture, cells or a product from treated cells of a present invention has been achieved. microorganism having nitrilase activity to thereby [0008] The present invention includes the following hydrolyze the cyanoacetic acid ester. inventions. 55 (9) The method of (8) above, wherein the cyanoacetic acid ester is continuously added to the (1) A method for preparing a malonic acid reaction solution while maintaining the concentra- monoester represented by Formula (II): tion of the cyanoacetic acid ester in the solution in 2 34EP 1 008 655 A1 the range from 0.01 to 10% by weight during the cyanoacetate. hydrolysis. [0018] The microorganism to be used in the inven- tion is not particularly limited as long as it belongs to the [0009] Hereinbelow, the present invention will be genus Corynebacterium, Gordona or Rhodococcus described in detail. 5and has nitrilase activity. Specific examples of the [0010] The alkyl represented by R in Formula (I) or microorganism include Corynebacterium nitrilophilus (II) may be of either a straight-chain or branched-chain ATCC 21419, Gordona terrae MA-1 (FERM BP-4535) structure. The number of carbon atoms in this alkyl is 1- and Rhodococcus rhodochrous ATCC 33025. 20, preferably 1-10 and more preferably 2-6. Specific [0019] Among these microorganisms, Gordona examples of this alkyl include methyl, ethyl, n-propyl, 10 terrae MA-1 has been deposited at the National Insti- isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n- tute of Bioscience and Human-Technology, Agency of pentyl, isopentyl, hexyl, heptyl, octyl, 2-ethylhexyl, Industrial Science and Technology, 1-3, Higashi 1- decyl, dodecyl, tetradecyl, hexadecyl, octadecyl and chome, Tsukuba-shi, Ibaraki-ken, Japan, under the eicosyl. above-indicated accession number. Corynebacterium [0011] The alkyl represented by R' in Formula (I') or 15 nitrilophilus and Rhodococcus rhodochrous are availa- (II') may be of either a straight-chain or branched-chain ble from depositories such as American Type Culture structure. The number of carbon atoms in this alkyl is 3- Collection (ATCC), 12301 Parklawn Drive, Rockville, 20, preferably 3-10 and more preferably 3-6. Specific Maryland 20852, U.S.A. examples of this alkyl include n-propyl, isopropyl, n- [0020] When a cyanoacetic acid ester represented butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, isopentyl, 20 by Formula (I) wherein R is alkenyl, aryl, aralkyl or C3-20 hexyl, heptyl, octyl, 2-ethylhexyl, decyl, dodecyl, tetra- alkyl [i.e. a cyanoacetic acid ester represented by For- decyl, hexadecyl, octadecyl and eicosyl. mula (I')] is used as the substrate, the microorganism to [0012] The alkenyl represented by R may be of be used is not particularly limited as long as it has nitri- either a straight-chain or branched-chain structure. The lase activity. In addition to the above-described microor- number of carbon atoms in this alkenyl is 2-20, prefera- 25 ganisms, a microorganism belonging to the genus bly 2-6. Specific examples of this alkenyl include vinyl, Pseudomonas, Brevibacterium, Nocardia, allyl, crotyl (2-butenyl) and isopropenyl (1-methylvinyl). Arthrobacter, Bacillus, Escherichia, Micrococcus, [0013] The alkenyl represented by R' may be of Streptomyces, Aeromonas, Mycoplana, Cellulomonas, either a straight-chain or branched-chain structure. The Erwinia or Candida , for example, and having nitrilase number of carbon atoms in this alkenyl is 3-20, prefera- 30 activity may be used in the invention. bly 3-6. Specific examples of this alkenyl include allyl, [0021] More specifically, Pseudomonas synxanta crotyl (2-butenyl) and isopropenyl (1-methylvinyl). IAM 12356, Brevibacterium acetylicum IAM 1790, [0014] As the aryl represented by R or R', an aro- Nocardia asteroides IFO 3384, Arthrobacter oxydans matic hydrocarbon group such as phenyl, 1-naphthyl, 2- IFO 12138, Bacillus subtills ATCC 21697, Escherichia naphthyl; an aromatic hetrocyclic group such as furyl, 35 coli IFO 3301, Micrococcus luteus ATCC 383, Strepto- thienyl,