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WO2001057229A1 - Procede de production d'esters optiquement actifs de l'acide 4-benzyloxy-3-hydroxybutirique - Google Patents

Procede de production d'esters optiquement actifs de l'acide 4-benzyloxy-3-hydroxybutirique Download PDF

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Publication number
WO2001057229A1
WO2001057229A1 PCT/JP2001/000735 JP0100735W WO0157229A1 WO 2001057229 A1 WO2001057229 A1 WO 2001057229A1 JP 0100735 W JP0100735 W JP 0100735W WO 0157229 A1 WO0157229 A1 WO 0157229A1
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WO
WIPO (PCT)
Prior art keywords
genus
benzyloxy
ifo
hydroxybutyrate
optically active
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2001/000735
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English (en)
Japanese (ja)
Inventor
Yoshihiko Yasohara
Junzo Hasegawa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kaneka Corp
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Kaneka Corp
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Publication date
Application filed by Kaneka Corp filed Critical Kaneka Corp
Priority to AU2001230568A priority Critical patent/AU2001230568A1/en
Publication of WO2001057229A1 publication Critical patent/WO2001057229A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters

Definitions

  • the present invention relates to a method for producing optically active 4-benzyloxy-3-hydroxybutyrate.
  • Optically active 4-benzyloxy-3-hydroxybutyrate is used as a raw material for the synthesis of various pharmaceuticals.
  • An object of the present invention is to provide an efficient method for producing optically active 4- ⁇ -hydroxyl-3-hydroxybutyrate, which is a useful synthetic intermediate for various pharmaceuticals.
  • the present inventors have developed a simple and efficient optically active 4- (1-benzyloxy) -3-hydroxy compound.
  • a microorganism having the ability to asymmetrically reduce the 3-position propyl group of the 4-benzyloxyacetoacetate ester to a hydroxyl group was found and completed the present invention. Reached.
  • the present invention relates to the genera Arturoascus, Brettanomyces, Candida, Taliptococcus, Cisteromyces, Debaryomyces, Dipodascus, Genus Geotricum, Hormoascus, Isakenkia, Kluyveromyces, Komagataera , Rhodamyces, Mesienicobia, Ogataea, Pazosolen, Pichia, Rhodosporidium, Rhodotorula, Saccharomyces, Saccharomycopsis, Schizosaccharomyces, Sporoboromyces, Sizoblastosporion , Stefanoascus, Pseudomyces, Torulaspora, Trichosporon, Willioptis, Yamadaji genus, Chigosaccharomyces, Alcaligenes, Arthrobacter Genus, Genus Cyrus, Genus Brevibacterium, Genus Butyiaxella, Genus Sercoum, Genus
  • the 4-benzyloxyacetoacetate ester used as a substrate in the present invention can be synthesized by a known method (see JP-A-6-87851 or Synthesis, page 104, 1995). .
  • the ester chain of 4-benzyloxyacetate used in the present invention includes, for example, a saturated or unsaturated alkyl group such as a methyl group, an ethyl group, an isopropyl group, an n-butyl group, an isobutyl group and a tert-butyl group;
  • An aryl group such as a phenyl group and a naphthyl group, and an aralkyl group such as a benzyl group can be used.
  • microorganism used in the present invention for reducing 4-benzyloxyacetoacetate to 4-benzyloxy-3-hydroxybutyrate can be found, for example, by the method described below.
  • yeast for example, Darcos 3%, Peptone 0.5%, Potassium dihydrogen phosphate 0.2%, Nyanmonium phosphate 0.65%, Dipotassium hydrogen phosphate 0 1%, magnesium sulfate heptahydrate 0.006%, iron sulfate dehydrate 0.009%, copper sulfate pentahydrate 0.0005 ° /.
  • the objective reduction ability was determined by adding 2.5 ml of methanol to the reaction solution after shaking culture, mixing well, and then forming 4-ethylbenzyl-3-hydroxybutyrate ethyl by high performance liquid chromatography.
  • Column: YMC I-Pack ODS-A (4.6 mm x 250 mm), eluent: water Zacetonitrile 55/45, flow rate: 0.8 ml / in, detection: 225 nm, column temperature : 30.
  • C elution time: 4-benzyloxy-3-ethylbutyrate; 8.4 minutes, 4-benzyloxyacetoacetate; 12.8 minutes. Note that this condition is merely an example].
  • the optical purity of the produced 4-benzyloxy-3-ethylbutyrate was determined by high performance liquid chromatography [column: Chira 1 ce 1 ⁇ OD (4.6 mm x 250 mm), eluent: hexane Z ethanol: 95 Z5, flow rate: 0.8 ml Zmin, detection: 225 nm, column temperature: room temperature, elution time: (S) 1-4 1-benzyloxyethyl 3-ethylbutyrate; 12 min, (R) -4 ethylbenzyloxyacetoacetate; 13.5 min. This condition is merely an example].
  • a B medium having a composition of 1% peptone, 1% meat extract, and 0.5% yeast extract is used.
  • a C medium (pH 6.0) consisting of 5% and 5% corn steep liquor, for example, a composition of 3% tryptic soybean soup made by Dico and 1% soluble starch
  • Microorganisms are cultured using each of the D media ( ⁇ 7.2) consisting of the following, and microorganisms having the intended ability can be found by the same operation as described above.
  • Microorganisms that can be used in the present invention include those that give the (S) form of 4-benzyloxy-3-hydroxybutyrate, including those belonging to the genera Arthroascus, Brettanomyces, Candida, Cryptococcus, Devaliomyces, and Dipodascus.
  • saccharomyces Alcaligenes, Arthrobacter, Brevipacterium, Butyiaxella, Serum monas, Corynebacterium, Comamonas, Enterobacter, Ervinia, Escherichia, Micrococcas, Providencia Genus Proteus, Serratia, Staphylococcus, Abscissia, Acremonium, Afanoascus, Vasoclimis, Chiyaetmidium, Coprinas, Corinascus, Cubularia, Dendrifiera, Jemelera, Giberella , Macroforma, Melanospora, Morterella, Mucor, Proutus, Pycnopora, Microorganisms belonging to a genus selected from the group consisting of the genus Rhizopus, Sporotrichum and Streptomyces, and the like. More specifically, for example, microorganisms shown in Tables 1, 2, and 3 can be used.
  • Rhodotorula IFO 0415 dairenensis
  • Wili opsis is IFO 0992 Saturnas saturnus
  • Microorganisms that give (R) -form 4-benzyloxy-13-hydroxybutyrate esters include Candida spp., Cisteromyces spp., Kluyveromyces spp. Genus Magataera, Genus Pichia, Genus Yamada, Genus Arthrobacter, Genus Bacillus, Genus Sermouth, Genus Enterobacter, Klebsiella, Nocardia, Proteus, Pseudomonas, Rhodococcus, Abscissia, Acremonium , Aspergillus, Emelysacea, Eudisinium, Monascus, Moretera, Neocosmosbora, Penicillium, Rhizopus, Shreoch-na, Schizophyllam, Sporomyela or Streptomyces Microorganisms to which they belong. More specifically, for example, microorganisms shown in Table 4 can be used.
  • microorganisms can generally be obtained from stocks that are easily available or purchased. It can also be separated from nature. In addition, by mutating these microorganisms, strains having more advantageous properties for this reaction can be obtained.
  • any nutrient sources that these microorganisms can usually utilize Anything can be used.
  • sugars such as glucose, sucrose and maltose
  • organic acids such as lactic acid, acetic acid, cunic acid, and propionic acid
  • alcohols such as ethanol and glycerin
  • hydrocarbons such as paraffin, soybean oil, rapeseed oil, etc.
  • Carbon sources such as oils and fats or a mixture thereof
  • nitrogen sources such as ammonium sulfate, ammonium phosphate, urea, yeast extract, meat extract, peptone, corn steep liquor and the like can also be mixed.
  • other nutrients such as inorganic salts and vitamins may be appropriately mixed.
  • the cultivation of microorganisms can be carried out under general conditions, for example, pH 4.0 to 9.5, temperature range 20 to 45 ° C, aerobically 10 to 96. Incubate for hours. 4
  • a culture solution of the microorganism can usually be used for the reaction as it is, but a concentrate of the culture solution can also be used.
  • components in the culture solution adversely affect the reaction, it is preferable to use cells obtained by treating the culture solution by centrifugation or the like, or processed cells.
  • the treated cells of the microorganisms are not particularly limited, and include, for example, dried cells obtained by dehydration with acetone or diphosphorus pentoxide or drying using a desiccator or a fan, treated with surfactants, Examples thereof include a lysate-treated product, immobilized cells or a cell-free extract prepared by crushing cells. Furthermore, an enzyme that catalyzes an asymmetric reduction reaction may be purified from a culture, and may be used without immobilization or immobilization.
  • the substrate 4 ⁇ -dioxy xyacetoacetate may be added all at once at the beginning of the reaction, or may be added in portions as the reaction progresses.
  • the temperature during the reaction is usually from 10 to 60 ° C, preferably from 20 to 40 ° C.
  • the pH at the time of the reaction is 2.5-9, preferably 5-9.
  • the concentration of the microorganism in the reaction solution may be appropriately determined according to the ability to reduce these substrates.
  • the substrate concentration in the reaction solution is preferably from 0.01 to 50% (W / V), and more preferably from 0.1 to 30%.
  • reaction time depends on substrate concentration, fine It is appropriately determined depending on the concentration of the organism and other reaction conditions. Usually, it is preferable to set each condition so that the reaction is completed in 2 to 168 hours.
  • an energy source such as dalcos or ethanol at a ratio of 1 to 30% to the reaction solution, since excellent results can be obtained.
  • coenzymes such as reduced nicotine amide 'adenine dinucleotide (NADH) and reduced nicotinamide-adenedin dinucleotide phosphate (NADPH), which are generally required for reduction by biological methods, are added.
  • NADH nicotine amide 'adenine dinucleotide
  • NADPH reduced nicotinamide-adenedin dinucleotide phosphate
  • these may be added directly to the reaction solution, or the reaction system for producing NADH and NADPH may be added to the reaction solution together with the oxidized coenzyme.
  • a reaction system in which formate dehydrogenase reduces NAD to NADH when producing carbon dioxide and water from formic acid or a reaction system in which glucose dehydrogenase produces dalconolactone from dalcose converts NAD or NADP to NADH.
  • a reaction system in which formate dehydrogenase reduces NAD to NADH when producing carbon dioxide and water from formic acid or a reaction system in which glucose dehydrogenase produces dalconolactone from dalcose converts NAD or NADP to NADH.
  • a reaction system for reducing each to DPH can be used.
  • a surfactant such as Triton (trade name, manufactured by Nakarai Tesque), Span (trade name, manufactured by Kanto Kagaku), Tween (trade name, manufactured by Nakarai Testa) to the reaction solution.
  • a surfactant such as Triton (trade name, manufactured by Nakarai Tesque), Span (trade name, manufactured by Kanto Kagaku), Tween (trade name, manufactured by Nakarai Testa)
  • water-insoluble organic solvents such as ethyl acetate, butyl acetate, isopropyl ether, and toluene are added to the reaction solution to avoid inhibition of the reaction by the substrate and Z or the alcohol product that is the product of the reduction reaction. You may do it.
  • a water-soluble organic solvent such as methanol, ethanol, acetone, tetrahydrofuran or dimethyl sulfoxide can be added.
  • optically active 4- benzyloxy-3-hydroxybutyrate produced by the reduction reaction can be collected directly from the reaction solution, or after separating cells by centrifugation, etc., extracting with a solvent such as ethyl acetate, toluene, etc. This is performed by dissolving the solvent. Furthermore, high-purity optically active 4-benzyloxy-3-hydroxybutyrate can be obtained by purification by distillation, silica gel column chromatography, or the like.
  • Orientalis 1 ssatchenkta or ientaf is IFO ⁇ 279 90.8 86.6 s Isagenkia terricola 1 ssatchenkia terricola IFO 0933 98.2 87.0 s Kluyveromyces marcianus Kluyveronyces narxianus IFO 0277 98.1 40.0 s sloga 10 s sloga 10 s sloga o porus IFO 1676 94.4 ⁇ 2 s
  • Pichia binundal is IFO 1366 84.4 53.0 s Pichia trehalo phi la IFO 1282 89.0 83.1 s Vi
  • the microorganisms shown in Table 8 were cultured in the same manner as in Example 1 using 5 ml of the B medium. Thereafter, the same reaction was performed, and the results are shown in Table 8.
  • microorganisms shown in Tables 9 and 10 were used as in Example 1 using 5 ml of the C medium described above.
  • a 50 Om 1 Sakaguchi flask containing 5 Om 1 of the B medium was inoculated with Brevibateterium 'Stationis (FOV 1244), and cultured with shaking at 30 ° C for 24 hours. After completion of the culture, the cells were collected by centrifugation and suspended in 25 ml of lOOmM phosphate buffer (pH 6.5). This The mixture was transferred to a Mitsuro flask, to which 0.5 g of glucose and ethyl 4-pentinoleoxyacetate were added, and reacted at 30 ° C. for 24 hours with stirring. During this time, the pH of the reaction solution was maintained at 6.5 with a 5N aqueous sodium hydroxide solution.
  • Penicillium etaspansum (Penilicliumumexpansum) IFO 5854 was cultured in the same manner as in Example 6.
  • ethyl 4-benzyloxyacetoacetate was reduced in the same manner as in Example 6 to obtain 230 mg of ethyl (R) -4-benzyloxy-3-hydroxybutyrate (23% yield).

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Abstract

L'invention porte sur un procédé pratique et efficace de production industrielle d'esters optiquement actifs de l'acide 4-benzyloxy-3-hydroxybutirique, utilisables comme intermédiaires de médicaments, etc. A cet effet, on traite un ester dudit acide par une culture de micro-organismes capable de réduire asymétriquement les dits esters dudit acide, ou par des cellules microbiennes séparées de la culture et ayant reçues un traitement facultatif, puis on recueille l'ester optiquement actif de l'acide 4-benzyloxy-3-hydroxybutirique ainsi formé.
PCT/JP2001/000735 2000-02-02 2001-02-02 Procede de production d'esters optiquement actifs de l'acide 4-benzyloxy-3-hydroxybutirique Ceased WO2001057229A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001230568A AU2001230568A1 (en) 2000-02-02 2001-02-02 Process for producing optically active 4-benzyloxy-3-hydroxybutyric acid esters

Applications Claiming Priority (2)

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JP2000-025617 2000-02-02
JP2000025617 2000-02-02

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WO2001057229A1 true WO2001057229A1 (fr) 2001-08-09

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0665226A (ja) * 1992-08-13 1994-03-08 Takasago Internatl Corp （３ｒ，５ｓ）−３，５，６−トリヒドロキシヘキサン酸誘導体及びその製造方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0665226A (ja) * 1992-08-13 1994-03-08 Takasago Internatl Corp （３ｒ，５ｓ）−３，５，６−トリヒドロキシヘキサン酸誘導体及びその製造方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CARBON O. ET AL.: "the microbial reduction of 2-chloro-3-oxoesters", TETRAHEDRON: ASYMMETRY, vol. 6, no. 9, 1995, pages 2199 - 2210, XP002942030 *
HAYAKAWA R. ET AL.: "The bakers' yeast reductions of .alpha.- and .beta.-keto ester derivatives in the presence of a sulfur compound", TETRAHEDRON, vol. 55, no. 24, 1999, pages 7519 - 7528, XP002942029 *

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