Process for producing malonic acid derivatives

Details Process for producing malonic acid derivatives Process for producing malonic acid derivatives

1999-08-20

2001-05-29

Lilling, Herbert J. (Department: 1651)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing oxygen-containing organic compound

C435S170000, C435S822000, C435S843000

Reexamination Certificate

active

06238896

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a method for preparing malonic acid monoesters which are useful as intermediates in the synthesis of various chemical products, medicines, agricultural chemicals and so on.
BACKGROUND ART
As a method for preparing malonic acid monoesters, chemical hydrolysis of malonic acid diesters is commonly used. According to this method, however, it is difficult to separate the generated malonic acid monoester from the unreacted malonic acid diester and the malonic acid which is a by-product. Thus, it is impossible to obtain highly pure malonic acid monoesters.
As a method for obtaining highly pure malonic acid monoesters, a method using Meldrum's acid as a raw material is known [see, for example, Matoba Katsuhide et al., Chem. Pharm. Bull., 31 (8), 2955 (1983); or Rigo B. et al., Tetrahedron Lett., 30(23), 3073 (1989)]. However, since this method uses expensive Meldrum's acid, it cannot be said a practical method and is not suitable for industrial production.
As another method for obtaining highly pure malonic acid monoesters, a method is known in which malonic acid diesters are treated with an enzyme or microorganism having an ability to hydrolyze ester bonds (Japanese Unexamined Patent Publication No. 8-173174). However, the use of malonic acid diesters as a raw material is disadvantageous in terms of cost.
Therefore, development of a highly productive method for preparing highly pure malonic acid monoesters has been desired.
DISCLOSURE OF THE INVENTION
It is the object of the present invention to provide a highly productive method for preparing malonic acid monoesters which are useful as intermediates in the synthesis of various chemical products, medicines, agricultural chemicals, etc.
The present inventors have found that a malonic acid monoester is produced selectively when a cyanoacetic acid ester is treated with a culture, cells or a product from treated cells of a microorganism having nitrilase activity; according to that method, a highly pure malonic acid monoester can be prepared without side reactions such as hydrolysis of ester bonds. Thus, the present invention has been achieved.
The present invention includes the following inventions.
(1) A method for preparing a malonic acid monoester represented by Formula (II):
HOOCCH
2
COOR  (II)
wherein R is alkenyl, aryl, aralkyl or C
1-20
alkyl, comprising treating a cyanoacetic acid ester represented by Formula (I):
NCCH
2
COOR  (I)
wherein R is as defined in Formula (II), with a culture, cells or a product from treated cells of a microorganism belonging to the genus Corynebacterium, Gordona or Rhodococcus and having nitrilase activity to thereby hydrolyze the cyanoacetic acid ester.
(2) The method of (1) above, wherein the cyanoacetic acid ester is continuously added to the reaction solution while maintaining the concentration of the cyanoacetic acid ester in the solution in the range from 0.01 to 10% by weight during the hydrolysis.
(3) The method of (1) above, wherein the C
1-20
alkyl represented by R is C
3-20
alkyl and the microorganism having nitrilase activity is a microorganism belonging to the genus Rhodococcus.
(4) The method of (3) above, wherein the cyanoacetic acid ester is continuously added to the reaction solution while maintaining the concentration of the cyanoacetic acid ester in the solution in the range from 0.01 to 10% by weight during the hydrolysis.
(5) The method of (1) above, wherein the microorganism having nitrilase activity is
Corynebacterium nitrilophilus
ATCC 21419.
(6) The method of (1) above, wherein the microorganism having nitrilase activity is
Gordona terrae
MA-1 (FERM BP-4535).
(7) The method of (1) above, wherein the microorganism having nitrilase activity is
Rhodococcus rhodochrous
ATCC 33025.
(8) A method for preparing a malonic acid monoester represented by Formula (II′):
HOOCCH
2
COOR′  (II)
wherein R′ is alkenyl, aryl, aralkyl or C
3-20
alkyl, comprising treating a cyanoacetic acid ester represented by Formula (I′):
NCCH
2
COOR′  (I′)
wherein R′ is as defined in Formula (II′), with a culture, cells or a product from treated cells of a microorganism having nitrilase activity to thereby hydrolyze the cyanoacetic acid ester.
(9) The method of (8) above, wherein the cyanoacetic acid ester is continuously added to the reaction solution while maintaining the concentration of the cyanoacetic acid ester in the solution in the range from 0.01 to 10% by weight during the hydrolysis.
Hereinbelow, the present invention will be described in detail.
The alkyl represented by R in Formula (I) or (II) may be of either a straight-chain or branched-chain structure. The number of carbon atoms in this alkyl is 1-20, preferably 1-10 and more preferably 2-6. Specific examples of this alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, 2-ethylhexyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl and eicosyl.
The alkyl represented by R′ in Formula (I′) or (II′) may be of either a straight-chain or branched-chain structure. The number of carbon atoms in this alkyl is 3-20, preferably 3-10 and more preferably 3-6. Specific examples of this alkyl include n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, 2-ethylhexyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl and eicosyl.
The alkenyl represented by R may be of either a straight-chain or branched-chain structure. The number of carbon atoms in this alkenyl is 2-20, preferably 2-6. Specific examples of this alkenyl include vinyl, allyl, crotyl (2-butenyl) and isopropenyl (1-methylvinyl).
The alkenyl represented by R′ may be of either a straight-chain or branched-chain structure. The number of carbon atoms in this alkenyl is 3-20, preferably 3-6. Specific examples of this alkenyl include allyl, crotyl (2-butenyl) and isopropenyl (1-methylvinyl).
As the aryl represented by R or R′, an aromatic hydrocarbon group such as phenyl, 1-naphthyl, 2-naphthyl; an aromatic hetrocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl; or the like may be enumerated.
As the aralkyl represented by R or R′, benzyl, 1-naphthylmethyl, 2-naphthylmethyl, phenethyl (2-phenylethyl), 1-phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, methylbenzyl, methylphenethyl, dimethylbenzyl, dimethylphenethyl, trimethylbenzyl, ethylbenzyl, diethylbenzyl or the like may be enumerated.
Among the cyanoacetic acid esters represented by Formula (I), representative compounds are, for example, methyl cyanoacetate, ethyl cyanoacetate, n-propyl cyanoacetate, isopropyl cyanoacetate, n-butyl cyanoacetate, tert-butyl cyanoacetate, 2-ethylhexyl cyanoacetate, allyl cyanoacetate and benzyl cyanoacetate.
Among the cyanoacetic acid esters represented by Formula (I′), representative compounds are, for example, n-propyl cyanoacetate, isopropyl cyanoacetate, n-butyl cyanoacetate, tert-butyl cyanoacetate, 2-ethylhexyl cyanoacetate, allyl cyanoacetate and benzyl cyanoacetate.
The microorganism to be used in the invention is not particularly limited as long as it belongs to the genus Corynebacterium, Gordona or Rhodococcus and has nitrilase activity. Specific examples of the microorganism include
Corynebacterium nitrilophilus
ATCC 21419,
Gordona terrae
MA-1 (FERM BP-4535) and
Rhodococcus rhodochrous
ATCC 33025.
Among these microorganisms,
Gordona terrae
MA-1 has been deposited at the National Institute of Bioscience and Human-Technology, Agency of Industrial Science and Technology, 1-3, Higashi 1-chome, Tsukuba-shi, Ibaraki-ken, Japan, under the above-indicated accession number.
Corynebacterium nitrilophilus
and
Rhodococcus rhodochrous
are available from depositories such as American Type Culture Collection (ATCC), 1230

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