WO2003014057A1 - Procedes de production d'acide halogenophenylpyruvique et d'halogenophenylalanine optiquement active - Google Patents

Procedes de production d'acide halogenophenylpyruvique et d'halogenophenylalanine optiquement active Download PDF

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Publication number
WO2003014057A1
WO2003014057A1 PCT/JP2002/007992 JP0207992W WO03014057A1 WO 2003014057 A1 WO2003014057 A1 WO 2003014057A1 JP 0207992 W JP0207992 W JP 0207992W WO 03014057 A1 WO03014057 A1 WO 03014057A1
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Prior art keywords
acid
salt
plasmid
transaminase
microorganism
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PCT/JP2002/007992
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English (en)
Japanese (ja)
Inventor
Ryuzo Yoshioka
Hiroaki Matsumae
Toshiyuki Furutani
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Tanabe Seiyaku Co., Ltd.
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Publication of WO2003014057A1 publication Critical patent/WO2003014057A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
    • C12P13/22—Tryptophan; Tyrosine; Phenylalanine; 3,4-Dihydroxyphenylalanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/373—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in doubly bound form

Definitions

  • the present invention relates to an industrially advantageous and improved process for producing halognophenylpyruvic acid.
  • the present invention also relates to an improved method for producing optically active halogenophenylalanine.
  • ⁇ -Keto acids such as phenylvirbic acid
  • phenylvirbic acid are extremely important compounds not only in organic synthetic chemistry but also in biochemistry, and are used in food additives and agrochemicals with the advancement of biotechnology in recent years.
  • halognophenylpyruvic acid has become increasingly important in recent years as a raw material for halogenogenphenylalanine used in the synthesis of agrochemicals.
  • Methods for producing halognophenylpyruvic acid include a method of hydrolyzing 5- (substituted arylidene) hydantoin (Japanese Patent Application Laid-Open No. Sho 61-22042), and a method of producing 4- (substituted benzylidene). It is known to hydrolyze a 15-oxazolone compound with acetone-water and then hydrolyze the resulting 2- (acetylamino) 13- (halogenophenyl) propenoic acid in hydrochloric acid (Matsumura et al.
  • An object of the present invention is to provide an improved method for synthesizing halogenophenyl rubic acid. Another object of the present invention is to provide a method for efficiently obtaining optically active halognoferalene from the halogen-substituted phenylpyruvic acid thus obtained. '
  • the present inventors have sought to correct the drawbacks of the prior art and to develop a method for producing halogonoful pyruvic acid in a high yield economically and industrially advantageously.
  • 1- (Halogenobenzylidene) 1-5-year-old xazolone compound is hydrolyzed with metal hydroxide hydroxide, and the obtained 2- (lower alcoholylylamino) 1-3-1 (halognophenyl) propenoic acid is soluble in water. It has been found that the above object can be achieved by hydrolysis in a mixed solvent of a suitable ether solvent and water.
  • the inventors of the present invention have prepared a halognophenylpyruvic acid obtained by adding a recombinant plasmid containing a DNA encoding a transaminase derived from a microorganism of another genus to a host microorganism.
  • the present inventors have found that an optically active halogenophenylalanine can be obtained in high yield by treating with a transaminase produced by a living organism, thereby completing the present invention.
  • the salt thereof represented by the formula: can be produced.
  • a DNA encoding a transaminase derived from a microorganism belonging to another genus is incorporated in the host microorganism into the halognophenylpyruvic acid (I) or a salt thereof obtained as described above.
  • optically active halogenophenylalanine represented by or a salt thereof can be produced.
  • the compounds used in the reaction are inorganic salts such as hydrochloride, hydrobromide, sulfate, and nitrate, for example, acetate, tartrate, quencher, and the like, as long as the reaction is not hindered.
  • Organic salts such as acid, fumarate and maleate salts; metal salts such as sodium, potassium, calcium and aluminum salts; salts with bases such as ethylamine, guanidine and ammonium salts May be used in the form of a salt.
  • the compound to be used in the reaction is obtained in a free form, it can be converted to a salt thereof by a conventional method.
  • the salt can be converted to a free form by a conventional method.
  • any of these atoms such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom can be suitably used, but a bromine atom and an iodine atom are more preferable, and a bromine atom is more preferable. Is most preferred.
  • lower alkyl group means a linear or branched anoalkyl group having 1 to 6 carbon atoms, and specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group.
  • it refers to an alkyl group having 1 to 4 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a propynole group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. More preferably, it is an alkyl group having 1 or 2 carbon atoms (that is, a methyl group or an ethyl group), and particularly preferably a methyl group.
  • lower alkanoyl means a straight-chain or branched-chain alkanoyl group having 2 to 7 carbon atoms, specifically, an acetyl group, a propioyl group, a ptyryl group, an isoptyryl group, a valeryl group. And an isovaleryl group. It is preferably an alkanoyl group having 2 to 5 carbon atoms, and more preferably an alkanoyl group. It is a tinole group or a propionyl group, particularly preferably an acetyl group.
  • Alkali metals such as sodium hydroxide, hydroxide hydroxide and lithium hydroxide have no difference in their effects, but sodium heptaoxide is inexpensive and industrially preferable.
  • the amount of the alkali metal hydroxide used is in the range of 1 molar equivalent to 3 molar equivalents to compound (III), preferably in the range of 1.1 molar equivalents to 2 molar equivalents. It is better to use 1.5 molar equivalents.
  • the reaction is usually performed at room temperature. For this reason, the reaction proceeds under milder conditions as compared with the conventional method requiring heating, which is industrially preferable. If necessary, the reaction can be carried out under cooling or heating.
  • Water is usually used as the solvent, but other organic solvents that do not affect the reaction, for example, ethers such as tetrahydrofuran and dioxane, and alcohols such as methanolic ethanol and ethanol can also be used. It is. It is also possible to use a mixed solvent of these organic solvents and water.
  • the alkali metal salt of compound (II) can be isolated and purified by a conventional method. Further, an alkali metal salt can be used in the next step.
  • the 2- (lower alkanoylamino) -13- (halogenophenyl) probenic acid compound (11) or a salt thereof is hydrolyzed with an acid and, if desired, converted to a salt to give halogenophenol-rubic acid ( I) or a salt thereof
  • an acid a mineral acid other than hydrogen halide, such as nitric acid or sulfuric acid, which usually uses hydrogen halide such as hydrogen chloride or hydrogen bromide, can also be used.
  • a mixed solvent with water-soluble ether solvent and water is used.
  • water As the soluble ether solvent, tetrahydrofuran, dioxane and the like are preferable.
  • the ether-based solvent is involved in promoting the reaction and improving the yield. If the amount of the ether-based solvent is small, the progress of the reaction is slow, and a long-time reaction is inevitably required. If the reaction time is prolonged, the produced halognophenylpyruvic acid is decomposed, and the yield decreases, which is not preferable.
  • the reaction can be carried out from room temperature to under heating, but is preferably carried out at a temperature in the range of 50 to 150 ° C, particularly preferably at around 100 ° C. Further, this reaction can be carried out under normal pressure or under calo pressure.
  • Examples of the salt of halognophenylpyruvic acid include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and amine salts such as ammonium salt and methylamine salt. Conversion to these salts and isolation / purification can be carried out by a conventional method.
  • a recombinant plasmid comprising a DNA encoding a transaminase derived from a microorganism belonging to another genus in a host microorganism, to the halogonofelpyruvate or a salt thereof obtained as described above. Is treated with an amino donor to form a treated product thereof, and further converted to a salt thereof, if desired, to obtain a compound represented by the general formula (V):
  • optically active halogenophenylalanine represented by or a salt thereof can be produced.
  • the transaminase may be any as long as it can produce halognophenylalanine (V) from halogenophenylenolepinolevic acid (I) in the presence of an amino donor, and aromatic amino acid 'transaminase (that is, Aromatic-araino ⁇ acid
  • the microorganism serving as a source of DNA encoding transaminase is not particularly limited as long as it is a microorganism capable of producing transaminase, and examples thereof include microorganisms belonging to the genus Paracoccus.
  • Paracoccus denitrificans IF012442 (Paracoccus denitrificans
  • IF012442 can be suitably used.
  • a DNA encoding a transaminase for example, a translation region encoding a phenylalanine transaminase in a phenylalanine transaminase gene derived from a microorganism of the genus Paracoccus can be used.
  • Hue from Paracoccus microorganisms - Ruaranin 'transaminase gene for example, the literature (Takagi et al., Biotechnology and Applied Biochemistry ⁇ 13 Certificates, a 112- page 119, 1991) in analogy to the method described by shotgun claw Jung It can be isolated from a microorganism of the genus Paracoccus as follows.
  • a chromosomal DNA is prepared from a microorganism of the genus Paracoccus. After treatment with an appropriate restriction enzyme (such as partial digestion with Sau3AI), the downstream of the appropriate vector plasmid promoter (BamHI cleavage site of pLG339, multicloning of UC18) Site). Next, host Escherichia coli is transformed using the obtained recombinant plasmid.
  • an appropriate restriction enzyme such as partial digestion with Sau3AI
  • the transaminase activity 1 is obtained by using microbial cells as an enzyme source in a reaction solution containing phenylinolepinoleic acid, 2-oxo-14-phenylbutyric acid, etc. as substrates and L-glutamic acid, L-aspartic acid, etc. as an amino donor. And can be measured by known methods.
  • Phenylalanine 'transaminase gene derived from a microorganism of the genus Paracoccus can also be obtained by using known nucleotide sequence information.
  • the DNA library can be prepared using the chromosome DNA of a microorganism belonging to the genus Paracoccus, for example, by the method described in "Molecular Cloning” (Sambrook et al., Cold Spring Harbor Laboratory Press, 1998).
  • the nucleotide sequence of the Phenylalanine 'transaminase gene derived from the microorganism of the genus Paracoccus isolated in this way can be determined, and the translation region can be identified.
  • a DNA fragment containing this translation region can be cut out and used as a DNA encoding phenylalanine transaminase.
  • the DNA encoding fenylalanine transaminase can use the translation region of the fenylalanine transaminase gene that exists in nature, but it has been obtained by modifying a part of its base sequence.
  • One to six codons encoding one amino acid are known, and when modifying the nucleotide sequence, it is usually designed so that the encoded amino acid sequence does not change.
  • DN a with sequence linked chemically synthesized DN a, fragmentation and bind the DN a, part mutagenesis Iriho (site specific mutagenesis) (Proceedings of National Academy of Sciences ⁇ 8 Volume 1, Chapter 5662 ⁇ 5666 page, 1984>.
  • transaminase expression plasmid Plasmid for expressing transaminase (hereinafter referred to as transaminase expression plasmid) can be obtained by ligating the DNA encoding transaminase downstream of the motor in an appropriate vector plasmid.
  • the vector plasmid is not particularly limited as long as it is a plasmid that can be replicated in a host microorganism.
  • such vector plasmids include, for example, pBluescript SK (+) (Stratagene), LG339 (Gene, Vol. 18, pp. 335, 1). 9 1982, ATCC 37131), UC 18 (Gene, Vol. 33, p. 103, 1985, ATCC 37253) and the like. Of these, pUC18 is particularly preferred.
  • the DNA encoding the transaminase is operably linked downstream of the promoter, and the transaminase is preferably expressed under the control of the promoter.
  • the promoter may be any promoter that can function in the host microorganism, and is not particularly limited.
  • a promoter includes, for example, the 1 ac promoter (E. coli lactose operon promoter).
  • the nucleotide sequence between the promoter and the translation initiation codon of the transaminase is DNA fragmentation of the DNA encoding transaminase, such as by restriction enzyme treatment, binding of fragmented DNA, and ligation of chemically synthesized linker DNA. It can be constructed by appropriately combining site-directed mutagenesis, PCR and the like.
  • a recombinant microorganism can be obtained by introducing the transaminase expression plasmid into a host microorganism by a usual transformation method.
  • host microorganisms are not particularly limited, but Escherichia coli can be preferably used.
  • Escherichia coli DH5 strain, Escherichia coli JM109 strain, Escherichia coli HB101 strain (Journal of molecular biology, vol. 41, p. 459, 1969, ATCC 33694)
  • Escherichia coli JM105 strain protein / nucleic acid enzyme, vol. 29, p. 294, 1981
  • Escherichia coli HB101 strain is preferred.
  • the recombinant microorganism (transformant) obtained by encapsulation can be used in the present invention.
  • the recombinant plasmid into which DNA encoding a transaminase derived from a microorganism belonging to the genus Paracoccus is integrated is Escherichia coli. It is preferable to use a hybrid organism contained in a host microorganism. In particular, Escherichia coli containing a recombinant plasmid into which a DNA encoding a transaminase derived from Paracoccus' denitrififans is incorporated is more preferable.
  • a deoxyribonucleic acid carrying the genetic information of phenalanalanin transaminase obtained by digesting DNA derived from the chromosome of Paracoccus ⁇ detririfans with the restriction enzyme Sau3AI, described in JP-A-11-153084, is disclosed. plus The restriction enzyme BamHI is inserted into the restriction enzyme BamHI cleavage site of pLG339, and the resulting hybrid plasmid is digested with the restriction enzymes EcoRV and Sail. Hybrid plasmid integrated into the Smal and Sail cleavage sites
  • HB101 (pPAP243) is used.
  • Plasmid PPAP243 is constructed by transcribing the approximately 300 bp DNA fragment containing the N-terminal side of the transaminase translation region (177 bp) in pPAP142 and a part of the upstream untranslated region (95 bp) into the vector plasmid pB1uescript SK (+ ) (Manufactured by Stratagene), inserted into the Eco RV cleavage site, cut the resulting plasmid with Eco RI, and integrated the resulting DNA fragment into the Eco RI cleavage site of PPAP142.
  • a transaminase-expressing plasmid pPAP243 derived from Paracoccus ⁇ denitrificans described in JP-A-2000-270882, which is contained in Escherichia coli HB101 strain, is transformed into HB101 ( p PAP 243) is particularly preferred.
  • Microorganisms live cells, cultures, etc. used in the enzyme reaction and their processed products (washed cells, dried cells, culture supernatant, crushed cells, self-erasing germs, cell extracts) Etc.) may be any as long as it has transaminase activity, and its form is not particularly limited. Cultivation of the microorganism can be performed by a conventional method.
  • the pH of a normal nutrient medium containing a carbon source, a nitrogen source, organic nutrients, inorganic salts, etc. is adjusted to 5.0 to 9.0, and after inoculating microorganisms, the temperature is 10 to 45 ° C, preferably 28 to 37 ° C. Aerobic culture may be performed at ° C.
  • Transaminase is constructed to be expressed under the control of 1 ac promoter In this case, it is desirable to add an enzyme-inducing substance such as ratatose, isopropyl-11-thiol] 3-D-galactoside to the medium in order to enhance the expression of transaminase.
  • Viable cells can be obtained from the culture of the microorganism by centrifugation or filtration. Washed cells can be obtained by washing the viable cells with physiological saline or the like, and dried cells can be obtained by freeze-drying or acetone-drying the viable cells / washed cells. .
  • live cells, washed cells, etc. are treated by various physicochemical methods (eg, ultrasonic treatment, French press, osmotic pressure, freeze-thawing, alumina destruction, lytic enzymes, surfactants, organic solvents, etc.). By the treatment, a crushed cell can be obtained, and an extract of the cell can be obtained by removing a solid substance from the crushed cell of the cell by filtration or centrifugation. .
  • the obtained enzyme, bacterial cell extract, etc. are immobilized on a suitable solid support and prepared as a reusable immobilized enzyme for a bioreactor. Is also good. Methods for immobilizing such enzymes are known in the art.
  • the halognophenylpyruvic acid and the amino donor as substrates can be supplied to the reaction system in a free form or in a salt form.
  • amino donor examples include L-aspartic acid and L-glutamic acid, and L-aspartic acid is preferred.
  • the amino donor is usually used in an amount of usually from 1 to 3 mol, particularly preferably from 1.3 to 1.5 mol, per mol of halognophenylpyruvic acid.
  • the enzymatic reaction is preferably carried out in consideration of the stability of the transaminase in less than 4 0 ° C is carried out at a good better Iga, especially 28 to 37 ° C, also becomes the P H is 7-9 It is preferable to adjust it.
  • a surfactant such as cetyltrimethylammonium bromide or cetylpyridinium bromide is added to the reaction solution in an amount of about 0.001 to 0.1%. This can promote the enzymatic reaction.
  • the starting material, 4- (halogenobenzylidene) -15-oxazolone compound (III) has the general formula (IV)
  • the condensation reaction between the compound (IV) and the compound (VI) is carried out by a conventional method, for example, in the presence of a base and a detaurant in a suitable solvent or without a solvent.
  • a base sodium acetate can be suitably used.
  • Acetic anhydride can be suitably used as the dehydrating agent.
  • a solvent there is no particular limitation as long as the solvent does not affect the reaction. This reaction is carried out at room temperature to under heating, preferably at 100 to 150 ° C.
  • Production medium (1% lactose, 0.2% pudose, 0.5% L-sodium glutamate, 2% corn steep liquor, 2% mist N, 0.3% rhodium phosphate, 0% Medium containing 7% dibasic potassium phosphate, 0.1% ammonium sulfate, 0.025% magnesium sulfate .Hydrate, 0.03% caraline (pH 7.0) 1
  • E. coli transformed HB101 (pPAP 243) was inoculated in a loop of 0 Om1 and cultured at 37 ° C. for 24 hours. The culture was centrifuged at 8000 X g to remove the supernatant. Purified water was added to the precipitated cells so that the amount of the culture broth became the initial amount of the culture solution, and an enzyme solution was obtained. 9.64 g of (4-bromophenyl) pyruvic acid obtained in Example 1 and 9.09 g of L-aspartic acid monosodium salt monohydrate were added to 700 ml of the enzyme solution thus obtained in 2 ml of 2N aqueous solution.
  • the pH was adjusted to 8.6 with an aqueous sodium oxide solution, and the mixture was stirred at 30 ° C. to perform an enzyme reaction. Two hours after the start of the reaction, 2.89 g of (4-bromopheninole) pinolevic acid and 2.73 g of L-aspartic acid monosodium monohydrate were added at 30-minute intervals until 2 hours later. At that time, 2N sodium hydroxide The pH was adjusted to 8.6 with an aqueous solution. Then, at hourly intervals until 5 hours later, 2.89 g of (4-promophenyl) pyruvic acid and 2.73 g of L-aspartic acid monosodium salt monohydrate were added (with 2N aqueous sodium hydroxide solution).
  • PPAP142 is linked downstream of the 1 ac promoter of the vector plasmid pUC18, a force of a paracoccus' denitrifinance chromosomal DNA fragment (about 2.2 kb) containing the transaminase gene.
  • a paracoccus' denitrifinance chromosomal DNA fragment about 2.2 kb
  • a promoter region and a region encoding a rhodaace-like protein derived from Paracoccus' denitrificans exist upstream of the transaminase gene translation region.
  • Plasmid p PAP142 obtained in the above (1) which is obtained by deleting a promoter region and a region encoding a rodinase-like protein derived from Paracoccus ⁇ denitrificans, is disclosed in Japanese Patent Application Laid-Open No. 2000-270882. It was constructed according to the method described in the gazette. First, PCR (polymerase chain)
  • a fragment containing the N-terminal side of the transaminase translation region (177 bp) and part of the upstream untranslated region (95 bp) in pPAP142 was amplified by the reaction).
  • synthetic oligonucleotides were used as sense primers and antisense primers.
  • the sequence of the sense primer was designed so that the N-terminal side of the upstream untranslated region partial sequence was partially modified to generate a Kp ⁇ I recognition site.
  • the sequence of the antisense primer was designed based on the partial distribution in the transaminase translation region.
  • P CR is plasmid P PAP142 of 5 ⁇ 1 (0.09 ⁇ g), primers each 4 Micromax, 1.0 units of DNA polymerase, 10 fold buffer 5 [mu] 1, Dokishi NT P and 30.5Myu 1 of each 5 [mu] 1 (2 mM) 9 using a mixture of water
  • the process of 30 for 4 seconds, 30 seconds at 55 ° C, and 1 minute at 72 was repeated 30 times.
  • the reaction solution was subjected to agarose gel electrophoresis, and a DNA fragment (approximately 300 bp) of the target PCR product was recovered from the phenol.
  • the obtained DNA fragment was subjected to Eco-coupling of the vector plasmid pB1uescript SK (+) (Stratagene). RV was inserted into the cleavage site to obtain plasmid pBSKl.
  • the plasmid pBSKl is further digested with EcoRI, and the obtained DNA fragment of about 150 bp is digested with!
  • the recombinant expression plasmid PPAP243 was obtained by ligating with the EcoRI digested fragment of PAP142 (about 3800 bp: including the ampicillin resistance gene, the 1 ac promoter and the 3 terminal end of the transaminase gene).
  • the expression plasmid ⁇ PAP 243 obtained in the above section (2) was introduced into Escherichia coli (Escherichia coli) HB101 strain by a conventional method to obtain a transformed original HB101 (pPAP243). Industrial applicability
  • the production method of the present invention is an industrially advantageous method which eliminates the drawbacks of requiring a low yield of halognophenylpyruvic acid and a long reaction time in the conventional method. Further, by the transamination method of the present invention, optically active halogenophenylalanine can be obtained in a relatively short time and in good yield.

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Abstract

L'invention concerne un procédé de production d'un acide halogénophénylpyruvique consistant à hydrolyser un 4-(halogénobenzylidène)-2-(alkyle inférieur)-5-oxazolone avec un hydroxyde de métal alcalin, puis à hydrolyser l'acide 2-(alkanoylamino inférieur)-3-(halogénophényl) propénoïque ainsi produit avec un acide dans un solvant mixte renfermant de l'eau et un éther. Cette invention concerne également un procédé de production d'une halogénophénylalanine optiquement active consistant à traiter l'acide halogénophénylpyruvique avec de la transaminase en présence d'un donneur amino.
PCT/JP2002/007992 2001-08-08 2002-08-06 Procedes de production d'acide halogenophenylpyruvique et d'halogenophenylalanine optiquement active WO2003014057A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4518800A (en) * 1983-07-18 1985-05-21 Societe Francaise Hoechst Process for preparation of crystallized monohydrated sodium phenylpyruvate
JPS6122042A (ja) * 1984-07-10 1986-01-30 Mitsui Toatsu Chem Inc α−ケト酸の製造方法
JPS6143136A (ja) * 1984-08-07 1986-03-01 Mitsui Toatsu Chem Inc α−ケト酸のアルカリ金属塩の製造法
JPS61167641A (ja) * 1985-01-21 1986-07-29 Showa Denko Kk フエニルピルビン酸の製造方法
JPS6348244A (ja) * 1986-08-13 1988-02-29 Nissan Chem Ind Ltd 置換フエニルピルビン酸の製造法
JP2000270882A (ja) * 1999-01-22 2000-10-03 Tanabe Seiyaku Co Ltd 新規微生物およびそれを用いるｌ−アミノ酸の製法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4518800A (en) * 1983-07-18 1985-05-21 Societe Francaise Hoechst Process for preparation of crystallized monohydrated sodium phenylpyruvate
JPS6122042A (ja) * 1984-07-10 1986-01-30 Mitsui Toatsu Chem Inc α−ケト酸の製造方法
JPS6143136A (ja) * 1984-08-07 1986-03-01 Mitsui Toatsu Chem Inc α−ケト酸のアルカリ金属塩の製造法
JPS61167641A (ja) * 1985-01-21 1986-07-29 Showa Denko Kk フエニルピルビン酸の製造方法
JPS6348244A (ja) * 1986-08-13 1988-02-29 Nissan Chem Ind Ltd 置換フエニルピルビン酸の製造法
JP2000270882A (ja) * 1999-01-22 2000-10-03 Tanabe Seiyaku Co Ltd 新規微生物およびそれを用いるｌ−アミノ酸の製法

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