WO2002079485A1 - Procede de production de derive de (r)-2-hydroxy-1-phenoxypropane avec prevention de la formation de produits secondaires de transfert - Google Patents

Procede de production de derive de (r)-2-hydroxy-1-phenoxypropane avec prevention de la formation de produits secondaires de transfert Download PDF

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Publication number
WO2002079485A1
WO2002079485A1 PCT/JP2002/003138 JP0203138W WO02079485A1 WO 2002079485 A1 WO2002079485 A1 WO 2002079485A1 JP 0203138 W JP0203138 W JP 0203138W WO 02079485 A1 WO02079485 A1 WO 02079485A1
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product
hydroxy
group
derivative
enzyme
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PCT/JP2002/003138
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English (en)
Japanese (ja)
Inventor
Shigeru Kawano
Miho Horikawa
Naoaki Taoka
Yoshihiko Yasohara
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Kaneka Corporation
Ueda, Makoto
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Publication of WO2002079485A1 publication Critical patent/WO2002079485A1/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
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
    • C12P7/22—Preparation of oxygen-containing organic compounds containing a hydroxy group aromatic

Definitions

  • An object of the present invention is to provide a (R) -2-hydroxy-1-phenoxypropane derivative useful as an intermediate of a drug, and in particular, a 2,3-difluoro-6-nitro-1-nitro [useful as an intermediate of a synthetic antibacterial agent.
  • (R)-(2-Hydroxypropyl)] oxy] Benzene can be obtained by using an enzyme derived from a microorganism, a culture of a microorganism capable of producing the enzyme, or a processed product thereof, and using the resulting phenoxyacetone as an inexpensive raw material.
  • An object of the present invention is to provide a method for efficiently producing a hydroxy-11-hydroxypropane derivative.
  • the present inventors have conducted intensive studies and, as a result, have found that the transfer reaction can be suppressed by controlling the pH, temperature conditions, and the like during the reduction reaction, and have completed the present invention.
  • R represents a phenyl group which may have a substituent
  • the R-selective reduction of the phenoxyacetone derivative represented by the above formula (1) using a culture of a microorganism capable of producing an enzyme or a treated product thereof yields the general formula (2);
  • R represents the same group as described above
  • R represents the same group as described above
  • the by-product amount of the ⁇ -1-hydroxy-12-phenoxypropane derivative is 2% or less as a ratio in the product.
  • R 2-Hydroxy-1-phenyl; related to the production of nonoxypropane derivatives.
  • the present invention provides the above-mentioned production method, wherein the by-product amount of the (R) -1-hydroxy-2-phenoxypropane derivative is 1% or less in the product; (R) -1-hydroxy-2- The above-mentioned production method, wherein the by-produced amount of the phenoxypropane derivative is 0.5% or less in the product; the above-mentioned production method, wherein R is a 2,3-difluoro-6-nitrophenyl group.
  • the present invention provides the above-mentioned production method wherein the reduction is carried out under the condition of ⁇ 2 to 7; the production method wherein the reduction is carried out under the condition of ⁇ 2 to 6.5; and adjusting the ⁇ by using a weak base.
  • the above method wherein the weak base is ammonia, carbonate or phosphate;
  • the above-mentioned production method which is ammonium carbonate, sodium carbonate, calcium carbonate, disodium hydrogen phosphate or dihydrogen hydrogen phosphate; the above-mentioned production method in which the reduction is carried out at 10 to 36 ° C; the substrate concentration is 5% ( w / v) The above-mentioned production method.
  • the present invention provides the above-mentioned production method, wherein the enzyme is derived from Candida maris (C andida maris); the above-mentioned production method, wherein the enzyme is derived from Candida maris (C andida maris I FO 10003);
  • the present invention relates to the above-mentioned production method, wherein the microorganism capable of producing the enzyme is Escherichiacoli HB101 (NT FPG) accession number FERM BP-71117.
  • R represents a phenyl group which may have a substituent.
  • substituents include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a nitro group, a nitroso group, a cyano group, an amino group, a hydroxyamino group, an alkylamino group having 1 to 10 carbon atoms, and a carbon number of 2 ⁇ 10 dialkylamino groups, N-protected amino groups, azide groups, trifluoromethyl groups, carboxynore groups, honoleminolele groups, acetinole groups, benzoyl groups, hydroxynole groups, carbon number :! An alkyloxy group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, an alkylthio group having 1 to 10 carbon atoms, and the like.
  • alkylamino group having 1 to 10 carbon atoms as the substituent examples include, for example, methyl and ethyl. , N-propyl, isopropyl, n-butyl, isobutynole, sec-butyl, tert-butylinole, pentyl, n-hexyl, heptyl, octyl, noel, decyl and the like.
  • the alkyl group may be selected so that the total carbon number of the two alkyl groups is 2 to 10.
  • examples of the C 1-10 acryloxy group include a formyloxy group, an acetyloxy group, a propionyloxy group, a ptyryloxy group, a valeryloxy group, a bivaloyloxy group and a hexanoloxy group.
  • protecting groups for N-protected amino groups include, for example, Protective 'Groups'in' Organic Synthesis, 2nd edition (Protective Group Organic Synthesis, 2nd Ed.) And Ao dora double. Protective groups described in Theodora W.
  • aralkyl-type protecting groups such as a benzyl group, a phenethyl group, and a triphenylmethyl group; a methanol phenol group, a trifluoromethyl phenol group, a benzene phenol group, a benzene phenol group, and a phenol group.
  • o-Nitrobenzenesnolephoninole group m-2-nitrobenzens / lefonyl group, s-lefonyl-type protecting group such as benzenesulfo- / le-group; methoxycarbonyl group, ethoxycarbol Protective groups such as phthaloyl, acetyl, chloroacetyl, trifluoroacetyl, bivaloyl, benzoyl and the like; and the like.
  • a protecting group such as a methoxycaponyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, or a benzyloxycarbonyl group, and more preferably a benzyloxycarbonyl group.
  • the substituent is preferably a halogen such as a fluorine atom, a nitro group, a cyano group, or the like, and more preferably a fluorine atom, a nitro group, or the like.
  • the number of the substituents is 0 to 3, preferably 3.
  • the phenoxyacetone derivative represented by the general formula (1) which is a raw material of the present invention, is, for example, 2-acetoeroxy-1,3,4-difluorobenzene, and 2,3-difluoro-6-nitro. It is known that phenol can be easily synthesized by reacting with chloroacetone in the presence of a strong base (JP-A-61-246151).
  • the (R) -1-hydroxy-2-phenoxypropane derivative represented by the general formula (3) by-produced by the rearrangement reaction is, for example, 2,3-difluoro-6-nitro [[(R ) — (1—Hydroxyisopropyl)] benzene]
  • 2,3,4-trifluoroetrobenzene is reacted under basic conditions with (R) — 1,2 monopropanediol It is known that synthesis is possible by such a method (Japanese Patent Application Laid-Open No. 2-178287).
  • Examples of the enzyme derived from a microorganism having the ability to R-selectively reduce the hepatic group used in the present invention include an enzyme derived from a microorganism belonging to the genus Candida, preferably Candida maris. (C andida maris), and more preferably an enzyme derived from Candida's Maris (C andida maris I FO 1 0003), in view of the strength of its reducing ability to the phenoxyacetone derivative (1). It is.
  • the microorganism capable of producing the enzyme may be any of a wild strain or a mutant strain.
  • a microorganism induced by a genetic technique such as cell fusion or genetic manipulation can also be used.
  • a microorganism capable of producing the above-mentioned enzyme, which has been genetically engineered, may be, for example, a step of isolating and / or purifying the enzyme and determining a part or all of the amino acid sequence of the enzyme, based on the amino acid sequence.
  • the above-mentioned transformed cells the above-mentioned transformed cells wherein the plasmid is pNTFPG, the above-mentioned transformed cells wherein the transformed cells are Escherichia coli, and the like. More preferably, Escherichiaco 1 i HB101 (pNTFPG) accession number FERM BP-71 17 is mentioned. This is located at the National Institute of Advanced Industrial Science and Technology, Patent Organism Depositary at the National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1, Tsukuba-Higashi, Ibaraki, Japan, on April 11, 2012. Deposited internationally under a treaty.
  • AIST National Institute of Advanced Industrial Science and Technology
  • the culture medium for the microorganism capable of producing the enzyme is not particularly limited as long as the microorganism can grow.
  • carbon sources include sugars such as glucose and sucrose, alcohols such as ethanol and glycerol, fatty acids and esters thereof such as oleic acid and stearic acid, and oils such as rapeseed oil and soybean oil.
  • the cultivation is performed aerobically, and can usually be performed at a culturing time of about 5 to 120 hours, a pH of the medium of 3 to 9, and a culturing temperature of 10 to 50 ° C.
  • the immobilization can be performed by a method well known to those skilled in the art (for example, a crosslinking method, a physical adsorption method, an entrapment method, etc.).
  • suitable solvent include water or a mixed solvent of water and an organic solvent such as toluene, ethyl acetate, and hexane, and preferably water.
  • the acceptable amount of (R) -1-hydroxy-2-phenoxypropane derivative as a by-product is the ratio in the product, that is, the amount of transfer product Z (the amount of target product + the amount of transfer product) (Amount) X 100% is 2% or less, preferably 1% or less, more preferably 0.5% or less (wherein, the transition form is (R) -1-hydroxy-2-phenoxypropane). Represents a derivative, and the intended substance is (R) -2-hydroxy-11-phenoxypropane derivative).
  • the reaction conditions for suppressing the above by-products are as follows: to avoid contact with the base as much as possible, adjust the pH from acidic to near neutral using a weak base, and react at a relatively low temperature. Is desirable. In addition, it is desirable to shorten the reaction time as much as possible, for example, by using a substrate concentration as high as possible or using an enzyme having a strong reducing ability. Further, it is desirable to gradually add a base (to avoid local strong alkaline conditions). These reaction conditions may be used alone as long as the by-product amount of the (R) -1-hydroxy-2-phenoxypropane derivative is 2% or less in the product. , Or two or more of them may be used in combination.
  • the pH in the above reduction reaction is usually 2 to 8, preferably 2 to 7, more preferably 2 to 6.5, and still more preferably 5.0 to 6.5.
  • a strong base such as sodium hydroxide can be used if other conditions (temperature, substrate concentration, enzyme used, etc.) are sufficiently appropriate.
  • ammonia carbonic acid
  • a weak base such as a carbonate such as ammonium, sodium carbonate and calcium carbonate
  • a weak base such as a phosphate such as dihydrogen phosphate and sodium phosphate sodium is preferably used, and more preferably ammonium carbonate and the like are used.
  • the reaction temperature in the above reduction reaction is usually 10 to 36 ° C, preferably 15 to 30 ° C, more preferably 15 to 27 ° C.
  • the substrate concentration in the above reduction reaction is usually 1% (w / v) as a percentage of the weight (g) of the phenoxyacetone derivative (1) as the substrate with respect to the solvent volume (ml) used at the start of the reaction. ), Preferably at least 5% (w / v), more preferably at least 10% (w / v). Also, the base is adjusted to satisfy the substrate concentration. The quality can be added together or continuously. Examples of the solvent used at the start of the reaction include water, a mixed solvent of water and an organic solvent, and the like. The volume of the culture solution, buffer, etc. shall be included in the solvent volume.
  • the reaction time in the above-mentioned reduction reaction varies depending on the type and concentration of the enzyme, microorganism or its processed substance, and the substrate used, but it is usually 1 to 96 hours, preferably 1 to 96 hours.
  • the above-described reduction reaction can greatly reduce the amount of expensive coenzyme used by using a commonly used NADH regeneration system in combination.
  • a typical NADH regeneration system for example, a method using gnorecose dehydrogenase and glucose can be mentioned.
  • a culture of a transformed microorganism into which a gene for a carbohydrate reductase gene and a gene for an enzyme (eg, glucose dehydrogenase) having the ability to regenerate a coenzyme dependent on the enzyme are introduced into the same host microorganism; If the same reaction as above is carried out using a product or the like, it is not necessary to separately prepare an enzyme source required for coenzyme regeneration, so that (R) — 2-hydroxyl-one-fuoxy Propane derivatives can be produced.
  • an enzyme eg, glucose dehydrogenase
  • the (R) -2-hydroxy-11-phenoxypropane derivative generated by the above reduction reaction can be purified by a conventional method.
  • the (R) -2-hydroxy-1-phenoxypropane derivative may be subjected to treatment such as centrifugation or filtration to remove suspended cells such as bacterial cells, if necessary. Then, after extraction with an organic solvent such as ethyl acetate or toluene, the organic solvent is removed under reduced pressure, and further purified by distillation under reduced pressure or a process such as mouth chromatography.
  • ERM BP—7117 was sterilized in a 500 ml volume flask with 100 ml medium (tryptone 16 g, yeast extract 10 g, sodium chloride 5 g, water 1 Littoner was inoculated at pH 7.0 before sterilization, and cultured with shaking at 37 ° C for 13 hours. After centrifuging 100 ml of the obtained culture solution, the cells without the supernatant were suspended in 5 ml of 50 mM phosphate buffer (pH 6.5), and then disrupted by sonication. Thus, a cell-free extract was prepared.
  • 100 ml medium tryptone 16 g, yeast extract 10 g, sodium chloride 5 g, water 1 Littoner was inoculated at pH 7.0 before sterilization, and cultured with shaking at 37 ° C for 13 hours. After centrifuging 100 ml of the obtained culture solution, the cells without the supernatant were suspended in 5 ml of 50 mM phosphate buffer (pH 6.5), and then
  • Metabolite by-product (%) Ab p / (Ap + Ab p) X I 00
  • Peak area of 2-acetonyloxy 3,4 difluoro mouth-trobenzene Peak area of 2,3-difluoro-6-tro [[(R)-(2-hydroxypropynole)] oxy] benzene
  • Example 1 0.1 ml of the cell-free extract used in Example 1 was added to 1.9 ml of 0.5 M phosphate buffer (pH 6.5), 23 mg of gnorecose, 0.1 mg of NAD and 0.1 mg of NAD. Ninoreokishi 3, was added 4-difluoromethyl O b nitrobenzene 2 Omg (substrate concentration 1% (w / v)) , 1M 1 ⁇ 2 ⁇ 1 0 4 1 with water) ⁇ : 6. adjusted to 5 Meanwhile, the reaction was carried out at 27, 30, 33, 36 or 40 ° C. with stirring for 67 hours.
  • Example 2 0.5 ml of the cell-free extract used in Example 1, 49.5 ml of deionized water, 5.9 g of dalcose, 5.6 mg of NAD, 2-acetonyloxy 3,4-difluoro Add 5 g of nitrobenzene (substrate concentration 10% (w / v)) and 20% (w / v) in aqueous ammonium carbonate solution; adjust the H to 6.5, and react for 32 hours with stirring at 30 ° C Went. At 6 hours and 20 hours after the start of the reaction, 5.6 mg of NAD was added, respectively.
  • Escherichiacoli HB101 accession number F ERM BP—5835 (producing reductase from Candida magnoliae) was sterilized in a 500-ml flask with a 100-ml medium (tryptone 16). g, 10 g of yeast extract, 5 g of Shiridani sodium, 1 liter of water, pH 7.0 before sterilization), and cultured with shaking at 37 ° C for 20 hours.

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Abstract

L'invention concerne un procédé de production efficace d'un dérivé de (R)-2-hydroxy-phénoxypropane de qualité supérieure à partir d'une substance bon marché, celui-ci étant utilisé comme intermédiaire médicamenteux. On obtient le dérivé de (R)-2-hydroxy-1-phénoxypropane de qualité supérieure par réaction d'un phenoxyacétone à réduction sélective de R bon marché, et en utilisant une enzyme de micro-organisme ou une culture éventuellement traitée d'un micro-organisme pouvant produire cette enzyme, tout en régulant le pH de réaction, les conditions thermiques, etc., de manière à empêcher la formation d'un dérivé de (R)-1-hydroxy-2-phénoxypropane comme produit secondaire.
PCT/JP2002/003138 2001-03-29 2002-03-29 Procede de production de derive de (r)-2-hydroxy-1-phenoxypropane avec prevention de la formation de produits secondaires de transfert WO2002079485A1 (fr)

Applications Claiming Priority (2)

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JP2001095938A JP2002281991A (ja) 2001-03-29 2001-03-29 転移体の副生を抑制した（ｒ）−２−ヒドロキシ−１−フェノキシプロパン誘導体の製造法
JP2001-095938 2001-03-29

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03183489A (ja) * 1989-12-13 1991-08-09 Dai Ichi Seiyaku Co Ltd 光学活性プロポキシベンゼン誘導体の製法
JPH04267890A (ja) * 1991-02-20 1992-09-24 Dai Ichi Seiyaku Co Ltd （ｒ）−２−プロポキシベンゼン誘導体の製造法
JPH0568577A (ja) * 1990-12-11 1993-03-23 Mercian Corp プロポキシベンゼン誘導体の製造方法
WO2000037666A1 (fr) * 1998-12-18 2000-06-29 Kaneka Corporation Procede de production de derive (r)-2-hydroxy-1-phenoxypropane
JP2002085085A (ja) * 2000-09-11 2002-03-26 Daicel Chem Ind Ltd （ｒ）−プロポキシベンゼン誘導体の製造方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03183489A (ja) * 1989-12-13 1991-08-09 Dai Ichi Seiyaku Co Ltd 光学活性プロポキシベンゼン誘導体の製法
JPH0568577A (ja) * 1990-12-11 1993-03-23 Mercian Corp プロポキシベンゼン誘導体の製造方法
JPH04267890A (ja) * 1991-02-20 1992-09-24 Dai Ichi Seiyaku Co Ltd （ｒ）−２−プロポキシベンゼン誘導体の製造法
WO2000037666A1 (fr) * 1998-12-18 2000-06-29 Kaneka Corporation Procede de production de derive (r)-2-hydroxy-1-phenoxypropane
JP2002085085A (ja) * 2000-09-11 2002-03-26 Daicel Chem Ind Ltd （ｒ）−プロポキシベンゼン誘導体の製造方法

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