WO2007097336A1 - Procede de production de derives de la (2r,3r)- et (2s,3s)-3-phenylisoserine - Google Patents

Procede de production de derives de la (2r,3r)- et (2s,3s)-3-phenylisoserine Download PDF

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WO2007097336A1
WO2007097336A1 PCT/JP2007/053097 JP2007053097W WO2007097336A1 WO 2007097336 A1 WO2007097336 A1 WO 2007097336A1 JP 2007053097 W JP2007053097 W JP 2007053097W WO 2007097336 A1 WO2007097336 A1 WO 2007097336A1
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formula
genus
compound represented
candida
compound
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Takahiro Ohishi
Naoaki Taoka
Akira Nishiyama
Tozo Nishiyama
Daisuke Moriyama
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Kaneka Corporation
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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
    • C12P13/06—Alanine; Leucine; Isoleucine; Serine; Homoserine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation
    • 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 (2R, 3R) and (2S, 3S) -3-phenylisoserine derivatives useful as pharmaceutical intermediates.
  • Phenyl isoserine derivatives are produced by, for example, 3-phenol glycidate having a phenyl group and a carboxyl group in the trans position.
  • Patent Document 1 a method in which the obtained erythro 3-phenylisoserine salt is esterified and then separated using optically active tartaric acid.
  • Non-Patent Documents 1 to 3 many examples of methods for obtaining an optically active 3-phenyl darisidate by asymmetric epoxies of cinnamic acid derivatives have been reported (for example, Non-Patent Documents 1 to 3), but all of them are expensive. It is necessary to use reagents and catalysts for which toxicity is a concern, and there are many points that need to be improved in order to obtain an industrially advantageous production method.
  • the optically active 3-phenylglycidate is an optically active 2-chloro-3hydroxy-3-phenol--obtained by asymmetric reduction of 2-chloro-3-oxo-3phenol-propionic acid ester.
  • Lupropionic acid ester is mixed with a suitable solvent (eg, lower alkyl alcohol) )
  • a suitable solvent eg, lower alkyl alcohol
  • a base for example, alkali metal alkoxide
  • Patent document 1 WO2003Z003804
  • Patent Document 2 WO2005Z058893
  • Patent Document 3 Japanese Patent Publication No. 7-79706
  • Patent Document 4 Japanese Patent Publication No. 6-504549
  • Non-Patent Document 1 Tetrahedron 1994, 50, 4323
  • Non-Patent Document 2 Am. Chem. Soc. 2002, 124, 14544
  • Non-Patent Document 3 Org. Chem. 2004, 69, 4217
  • Non-Patent Document 4 Tetrahedron: Asymmetry 1995, 6, 2199
  • Non-Patent Document 5 Org. Chem. 2005, 70, 342
  • an object of the present invention is to provide a practical method by which (2R, 3R) and (2S, 3S) -3 phenol isoserine derivatives can be produced conveniently and industrially advantageously. is there. Means for solving the problem
  • R 1 represents a phenyl group which may have a substituent
  • R 2 represents a hydrogen atom, an alkali metal, an alkaline earth metal or a nitrogenous base
  • * represents an asymmetric group.
  • a general formula (2) obtained by reaction of a compound having a carbon atom and a configuration of (representing 2R, 3S) or (2S, 3R) with ammonia.
  • R 1 and R 2 represent the same meaning as described above, and * represents an asymmetric carbon atom, and its configuration Relates to a method for producing a compound represented by the above formula (2), wherein the compound represented by (2R, 3R) or (2S, 3S) is further subjected to a crystallization step .
  • the present invention provides a compound represented by the above formula (2) by reaction of the compound represented by the above formula (1) with ammonia, followed by esterification of the compound represented by the general formula obtained. (3);
  • R 1 and * represent the same meaning as described above, and R 3 represents a C to C alkyl group
  • the present invention relates to a method for producing a compound represented by the formula (3), which is further subjected to a crystallization step.
  • the present invention relates to a general formula (5);
  • the present invention relates to a method for producing the compound.
  • “may have a substituent” means that it may be substituted by another atom or substituent.
  • the “substituent” is not particularly limited as long as it does not adversely influence the reaction. Specifically, a hydroxyl group, an alkyl group, an alkoxy group, Examples thereof include an alkylthio group, a nitro group, an amino group, a cyan group, a carboxyl group, and a halogen atom. Further, the number of carbon atoms in the alkyl group, alkoxy group, and alkylthio group is not particularly limited, but it is preferably 1 to 20 respectively. Examples of the halogen atom include fluorine, bromine, chlorine, and iodine.
  • R 1 represents a phenyl group which may have a substituent.
  • the phenyl group which may have a substituent include a 4-hydroxyphenol group, a 4-methoxyphenyl group, a 4-chlorophenol group, and a phenol group.
  • it is a phenyl group.
  • R 2 represents a hydrogen atom, an alkali metal, an alkaline earth metal, or a nitrogenous base.
  • compound (1) is in the form of a carboxylate salt with R 2 when it is an alkali metal, alkaline earth metal, or nitrogenous base.
  • the alkali metal include lithium, sodium, and potassium.
  • the alkaline earth metal include magnesium, strength russium, and sodium.
  • nitrogenous bases include primary amines such as ammonia, methylamine, benzylamine and cyclohexylamine; secondary amines such as dimethylamine, dibenzilamine and dicyclohexylamine; tertiary amines such as triethylamine and tributylamine.
  • R 2 is preferably a hydrogen atom or an alkali metal such as lithium, sodium or potassium, more preferably a hydrogen atom or sodium, and particularly preferably sodium.
  • the method for obtaining the compound (1) is not particularly limited, a method for obtaining (2R, 3S) -3-phenol glycidate that can be carried out on an industrial scale will be described below.
  • a method obtained by hydrolyzing the ester group after treatment with a base and cyclizing the compound represented by [0034] is preferred.
  • R 1 is as described above.
  • R 3 represents a C to C alkyl group.
  • Examples of the C to C alkyl group include a methyl group and an ethyl group.
  • n-propyl group isopropyl group
  • n-butyl group isobutyl group
  • sec-butyl group isobutyl group
  • t-butyl group preferably ethyl group.
  • X represents a halogen atom, and examples thereof include a fluorine atom, a bromine atom, a chlorine atom, and an iodine atom.
  • a chlorine atom and a bromine atom are preferable, and a chlorine atom is particularly preferable.
  • Compound (5) can be produced by treating the corresponding benzoyl acetate derivative with a chlorinating agent such as sulfuryl chloride and chlorinating.
  • a chlorinating agent such as sulfuryl chloride and chlorinating.
  • the method for obtaining compound (6) or (7) by asymmetric reduction of compound (5) is not particularly limited as long as it provides compound (6) or compound (7) with high selectivity.
  • Reduction using a hydride reducing agent modified with an optically active compound Method of hydrogenation in the presence of an asymmetric transition metal catalyst; Method of reduction in a hydrogen transfer type in the presence of an asymmetric transition metal catalyst;
  • a reduction method using an enzyme derived from a microorganism can be used.
  • a reduction method using an enzyme derived from a microorganism is preferred.
  • a compound (7) is obtained by stereoselectively reducing the compound (5) in the presence of an enzyme source having the ability to stereoselectively reduce the carbonyl group of the compound (5). Will be described.
  • the "enzyme source” includes not only the enzyme having the reducing activity itself, but also a culture of microorganisms having the reducing activity and processed products thereof.
  • the “microorganism culture” means a culture solution or culture containing cells, or a processed product thereof.
  • the “processed product” means, for example, a crude extract, freeze-dried cells, acetone-dried cells, or a crushed product of these cells.
  • the above enzyme source can be immobilized by known means and used as a fixed enzyme or a fixed bacterial cell. The fixation can be performed by a method well known to those skilled in the art (for example, a crosslinking method, a physical adsorption method, a comprehensive method, etc.).
  • the enzyme source having the ability to selectively reduce the carbonyl group of compound (5) by 3S includes the genus Debarvomvces, the genus Pichia, the genus Acidiphilium, Devosia genus, Microba cterium fe, Micrococcus, Ochrobactrum genus, Qerskovia genus, Paenibacillus genus, Pseudomonas. And enzyme sources derived from microorganisms belonging to the genus.
  • the enzyme sources having the ability to selectively reduce (2S, 3S) the carbonyl group of compound (5) include the genus Debarvomvces, the genus Pichia, the assidy filyum ( Acidinhilium), Devosia ⁇ , Microbac terium genus, Micrococcus genus, Ochrobactrum ⁇ , Qerskovia genus, Paenibacillus genus, Enzyme source derived from microorganism belonging to the genus Pseudomonas is bald
  • Preferable enzyme sources are, specifically, Candida tenuis, Candida tenuis, Candida utilis, Anrio Riomyces polymonore. Fas (Debarvomvces polvmorphus), Tenorio Myces. Orbenoretoshae (Debarvomvces robertsiae), Pichia bovis, Acidinhilium crvptum, Arsrobacta ⁇ Cris Talopoi tes Arthrobacter nicotianae), Ahona Lihonovhi, Na (Devosia ribofiavma, Microno arborescens, Micrococcus luteus, Micrococcus luteus Oerskovia 'Oerskovia Bae-Bacillus' Paenibacillus alvei, Nyu , ⁇ Tomonas Puita (Pseudomonas putitda, Pseudomonas stutzeri), Streptomyces' Kakaoi Safs
  • the enzyme source capable of 3R-selectively reducing the carbonyl group of compound (5) includes the genus Brettanomvces, the genus Debarvomvces, and the genus Hanseniaspora. , Issatchenkia genus, Tanorebero genus Kluweromvces genus, Metschnikowia genus, Ogataa gataea genus, Pachvsolen genus, Pichia genus, Saccharomycocium osaccharses Therefore, Toru Genus TorulasOora, genus Williamopsis, genus Cornepacteria, genus Devosia, genus Streptomvces, genus Auxarthron, genus Coriolus, The genus Crinipel, the genus Mvrothecium, the genus Panus, the genus Phane rochaete, the genus Plectosphaerella
  • the microorganism from which the reductase is derived may be either a wild strain or a mutant strain.
  • microorganisms induced by genetic techniques such as cell fusion or gene manipulation can also be used.
  • a recombinant microorganism having the ability to produce a reductase derived from these microorganisms may be used.
  • the recombinant microorganism producing the enzyme encodes the enzyme based on, for example, a step of isolating and Z or purifying the enzyme to determine part or all of the amino acid sequence of the enzyme.
  • WO98Z35025 comprising a step of obtaining a DNA sequence to be obtained, a step of introducing the DNA into another microorganism to obtain a recombinant microorganism, and a step of culturing the recombinant microorganism to obtain the enzyme (WO98Z35025). No. gazette).
  • Examples of the recombinant microorganism as described above include a transformed microorganism transformed with a vector having a DNA encoding the reductase.
  • Escherichia coli is preferred! / !.
  • the carbocyclic reductase gene derived from the above-mentioned ⁇ evosia riboflavina NBRC 13584 strain Escherichia coli HB101 (pNTDR), accession number FERM BP— 08457 (May 29, 2002 (original deposit day), 1-chome Tsukuba, Ibaraki, Japan) No. 1 1 Central 6th National Institute of Advanced Industrial Science and Technology (AIST), which is internationally deposited at the Patent Biological Deposit Center).
  • (2S, 3S) as a selective enzyme source Devosia 'riboflaviner
  • 2S, 3S as a selective enzyme source, Devosia 'riboflaviner
  • a recombinant Escherichia coli culture transformed with a carbonyl reductase derived from riboflavina or a treated product thereof is more preferred.
  • the culture medium for the microorganism used as the enzyme source is not particularly limited as long as the microorganism can grow.
  • a carbon source carbohydrates such as glucose and sucrose, alcohols such as ethanol and glycerol, fatty acids such as oleic acid and stearic acid and esters thereof, oils such as rapeseed oil and soybean oil; sulfuric acid as a nitrogen source Ammonium, sodium nitrate, peptone, casamino acid, corn steep liquor, bran, yeast extract, etc .; inorganic salts such as magnesium sulfate, sodium chloride sodium, calcium carbonate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, etc .;
  • a normal liquid medium containing a malt extract, meat extract or the like can be used. Cultivation is carried out aerobically. Usually, the cultivation time is about 1 to 5 days, the pH of the medium is 3 to 9, and the cultivation temperature is 10 to 50 ° C.
  • the reduction reaction of the carbonyl group of compound (5) is carried out by using, as a suitable solvent, compound (5) serving as a substrate, coenzyme NAD (P) H, a culture of the microorganism or a treated product thereof, etc. was added, under P H adjustment can be performed ⁇ Koyori stirring.
  • the reaction conditions vary depending on the enzyme, microorganism or treated product thereof, substrate concentration, etc., but the substrate concentration is usually about 0.1 to: L00% by weight, preferably 1 to 60% by weight; coenzyme NAD (P) H is 0.1 relative to the substrate 0001 to 100 mole 0/0, preferably from 0.001 to 0 1 mole 0/0;.
  • the reaction temperature is 10 to 60 ° C, preferably 20 to 50 ° C
  • the pH of the reaction is 4 to 9, preferably 5 to 8; the reaction time is 1 to 120 hours, preferably 1 to 72 hours.
  • an organic solvent may be mixed and used.
  • organic solvent examples include toluene, ethyl acetate, n -butyl acetate, hexane, isopropanol, methanol, diisopropyl ether, acetone, dimethyl sulfoxide and the like.
  • the substrate can be added by batch or continuous addition.
  • the reaction can be performed in a notched manner or a continuous manner. it can.
  • a typical NAD (P) H regeneration system includes, for example, a method using glucose dehydrogenase and glucose.
  • a transformed microorganism in which a gene of a reductase gene and an enzyme (for example, glucose dehydrogenase) capable of regenerating a coenzyme on which the enzyme depends is introduced into the same host microorganism, that is, encodes the reductase of the present invention.
  • a transformant microorganism culture in which a gene of an enzyme having an ability to regenerate a DNA and a coenzyme on which the enzyme depends (for example, glucose dehydrogenase) is introduced into the same host microorganism or a processed product thereof, etc. If the reaction similar to the above is performed, it is necessary to separately adjust the enzyme source necessary for the regeneration of the coenzyme V, and therefore the compound (7) can be produced at a lower cost.
  • the transformed microorganism as described above includes a trait transformed with a plasmid having both the DNA encoding the reductase and the DNA encoding the enzyme having the ability to regenerate the coenzyme on which the enzyme depends.
  • Examples include converted microorganisms.
  • the enzyme having the ability to regenerate the coenzyme glucose dehydrogenase derived from Bacillus megaterium, which is preferable to glucose dehydrogenase, is preferable.
  • the host microorganism is preferably Escherichia i.
  • Such preferred transforming microorganisms include both DNA encoding a carboxyreductase derived from Devosia riboflavina and DNA encoding a glucose dehydrogenase derived from Bacillus megaterium.
  • Escherichia coli HB101 pNTDRGl
  • accession number F ERM BP—08458 May 29, 2002 (original deposit date)
  • 1-chome Tsukuba, Ibaraki, Japan No. 1 1 Central 6th National Institute of Advanced Industrial Science and Technology, Patent Biological Deposit Center, which is internationally deposited).
  • Culture of transformed microorganisms can be performed using a normal liquid nutrient medium containing a carbon source, a nitrogen source, inorganic salts, organic nutrients and the like as long as they grow.
  • activity of an enzyme having a coenzyme regeneration ability in a transformed microorganism can be measured by a conventional method.
  • the activity of glucose dehydrogenase is determined by adding 100 mM glucose, 2 mM coenzyme NADP or NAD +, and enzyme to 1 M Tris-HCl buffer (pH 8.0) at 25 ° C. It is also possible to calculate the rate of increase in absorbance at a wavelength of 340 nm when the reaction is performed for a minute.
  • the compound (7) produced by the reduction reaction can be purified by a conventional method.
  • the reaction solution is subjected to treatment such as centrifugation and filtration to remove suspensions such as bacterial cells, followed by extraction with an organic solvent such as ethyl acetate and toluene, and the organic solvent is removed under reduced pressure.
  • treatment such as centrifugation and filtration to remove suspensions such as bacterial cells
  • organic solvent such as ethyl acetate and toluene
  • It can be purified by a treatment such as distillation or chromatography.
  • the cyclization reaction of compound (7) can be carried out by treating with a base in an appropriate solvent.
  • a base examples include sodium methoxide, sodium ethoxide, sodium t-butoxide, lithium methoxide.
  • Alkali metal alkoxides such as lithium ethoxide, lithium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide; alkali hydrides such as lithium hydride, sodium hydride, potassium hydride; calcium hydride, etc.
  • Alkali earth metal hydrides alkali metal hydroxides such as sodium hydroxide, potassium potassium and hydroxide cesium; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide Porcelain; alkaline metal charcoal such as lithium carbonate, potassium carbonate, sodium carbonate Salts; lithium hydrogen carbonate, potassium hydrogen carbonate, alkali metals bicarbonates sodium hydrogen carbonate and the like.
  • alkali metal alkoxide is preferable, and sodium ethoxide is particularly preferable.
  • the amount of the base used is not particularly limited as long as the reaction proceeds smoothly, but 1 to 2 mol times is preferred from the economical viewpoint that 1 to 5 mol times the amount of compound (7) is preferred. The amount is particularly preferred.
  • the solvent to be used is not particularly limited.
  • alcohols such as methanol and ethanol
  • aprotic polar solvents such as dimethyl sulfoxide and dimethylformamide
  • ethers such as tetrahydrofuran and 1,4 dioxane And the like Alcohols are preferred, especially ethanol! /.
  • the reaction temperature for cyclization is not particularly limited, but is preferably ⁇ 20 to 50 ° C., more preferably 0 to 30 ° C.
  • the reaction time is not particularly limited, but is generally 5 to 60 minutes.
  • Subsequent ester hydrolysis is not particularly limited as long as it is carried out in a usual manner (see, for example, Experimental Science Course 22, The Chemical Society of Japan, Maruzen Co., Ltd.).
  • an acid method or an alkali method is possible, but when excess sodium ethoxide is used for the cyclization reaction of compound (7), water can be added to the system. The remaining sodium ethoxide becomes sodium hydroxide and can be hydrolyzed as it is. Further, when the amount of remaining sodium ethoxide is small, a necessary alkali may be added and added.
  • the alkali to be used include the bases mentioned in the cyclization reaction of the compound (7), preferably sodium hydroxide.
  • examples of the acid include acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, p-toluenesulfonic acid, and the like.
  • the reaction temperature for ester hydrolysis is not particularly limited, but is preferably 20 to 50 ° C, more preferably 0 to 30 ° C.
  • the reaction time is not particularly limited, but is generally 5 to 60 minutes.
  • R 1 and R 2 are as described above.
  • the amino group in formula (2) may form a salt with an appropriate acid.
  • the acid that forms the salt is not particularly limited.
  • formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfone Examples include acid, p-toluenesulfonic acid, and the like, preferably hydrochloric acid, sulfuric acid, and methanesulfonic acid.
  • the (2R, 3R) compound (2) is used.
  • the (2S, 3S) compound (2) is used. can get.
  • the step of converting the compound (1) into the compound (2) by amination reaction with ammonia will be described.
  • the compound (1) used here may be obtained by the method described above or may be obtained separately.
  • R 1 and R 2 are as described above.
  • the amino group may form a salt with an appropriate acid.
  • the acid that forms the salt is not particularly limited, and examples include formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid. Preferred are hydrochloric acid, sulfuric acid, and methanesulfonic acid. * Is the same as above. The configuration of compound (8) is superior to that of the produced compound (2).
  • the one opposite to the previous configuration is preferentially generated.
  • the amination reaction is carried out in an organic solvent and in Z or water.
  • organic solvents include chloroalkanes such as dichloromethane, chloroform and dichloroethane; substituted benzenes such as benzene and toluene; ethers such as jetyl ether, tetrahydrofuran and 1,4 dioxane; methanol, ethanol, isopropanol, Alcohols such as t-butanol Power
  • One or more selected solvents can be used.
  • the mixing ratio is not particularly limited.
  • water or a mixed solvent of water and an organic solvent is preferable as the solvent, and water is more preferable.
  • the amount of ammonia used is not particularly limited as long as the reaction proceeds smoothly and the compound (2) is obtained in good yield, but is preferably 1 to LOO with respect to the compound (1). In order to suppress the by-product of the compound (8), which is a positional isomer, and to obtain the compound (2) with good yield, it is particularly preferably 5 to 50 mole times. .
  • Ammonia may be used as a gas, or as an aqueous solution or a solution of an appropriate organic solvent.
  • reaction temperature is too low, it may take a long time to decrease the reaction yield or complete the reaction. Conversely, if the reaction temperature is too high, only the by-product of the compound (8) will increase. Due to the high pressure inside the reactor, it is not practical for industrial scale production.
  • the reaction time is generally about 1 to 36 hours as long as the disappearance of the compound (1) is confirmed.
  • R 2 is an alkali metal, alkaline earth metal or nitrogenous base and is in the form of a carboxylate (2); a compound (2) in which R 2 is a hydrogen atom; Even when the compound (2) is a hydrogen atom and the amino group forms a salt with an acid, the compound (2) can be carried out. Considering production on an industrial scale, the number of processes can be shortened, and there are few complicated operations. Therefore, R 2 is an alkali metal, alkaline earth metal, or nitrogenous base and is in the form of a carboxylate. Crystallization is preferably performed as a certain compound (2) or as a compound (2) in which R 2 is a hydrogen atom. More preferably, R 2 is an alkali metal, alkaline earth metal, or nitrogenous base, and crystallization is performed as the compound (2) in the form of a carboxylate.
  • the compound represented by the compound (8) can be efficiently removed.
  • Crystallization solvents include chloroalkanes such as dichloromethane, chloroform, and dichloroethane; substituted benzenes such as benzene and toluene; ethers such as jetyl ether, methyl tert-butyl ether, tetrahydrofuran, and 1,4 dioxane; methanol , Ethanol, isopropanol, n-butanol, sec butanol, t-butanol and other alcohols; hexane, pentane and other alkanes; ethyl acetate, isopropyl acetate and other esters; acetone, methyl ethyl ketone, etc. Ketones; and water.
  • the crystallization can be performed with one or more solvents selected from these, and an optimal solvent should be selected according to the form of the compound (2) to be crystallized.
  • R 3 is the same as described above
  • R 2 is an alkali metal, alkaline earth metal, or nitrogenous base, and an example of a method for crystallization as a compound (2) in the form of a strong rubonic acid salt is R 2 This is explained in the case where is sodium.
  • the crystallization solvent in this case, it is preferable to use two or more selected from the group of solvents described above such as water and alcohols.
  • the alcohol include alcohols represented by the above formula (4), and more specifically, methanol, ethanol, isopropanol, n-butanol, sec butanol, and t-butanol. Crystallization may be performed with two or more alcohols selected from these groups, or may be performed with one or more alcohols selected from these groups and water. A combination of water and alcohol is preferable, and water and ethanol are particularly preferable.
  • Crystallization can be performed by adding ethanol to an aqueous solution of the compound (2) in which R 2 is sodium, but when the amination reaction solvent in the previous step is water, ammonia is removed. Then, the reaction solution can be concentrated to a predetermined amount and ethanol can be added. The method will be described below. [0072] As the concentration when removing ammonia after the amination reaction and concentrating with water, the concentration of the compound (2) in which R 2 is sodium is preferably in the range of 5 to 50 wt%. In order to obtain the compound (2) in which R 2 is sodium in the analysis yield, 10 to 40 wt% is particularly preferable.
  • the amount of ethanol is preferably 1 to 20 times the weight of water, particularly preferably 5 to 15 times the weight. Crystallization is performed by heating to a predetermined temperature after adding ethanol, and then cooling to a predetermined temperature.
  • the temperature range is -20 to 80 ° C. More preferably, it is in the range of 5 to 60 ° C from the viewpoint of the deposition yield.
  • the crystallization solvent it is preferable to use at least one selected from the group of solvents described above, such as water and alcohols.
  • the alcohol include alcohols represented by the formula (4). Crystallization can also be carried out with one or more alcohols selected from these groups and water, or water, preferably water and ethanol, or water alone.
  • the concentration when removing ammonia after the amination reaction and concentrating with water is preferably such that the concentration of the compound (2) in which R 2 is a hydrogen atom is in the range of 5 to 50 wt%. In order to obtain the compound (2) in which R 2 is a hydrogen atom in the crystallization yield, 10 to 40 wt% is particularly preferable. After the concentration is completed, crystallization is performed by adding an appropriate acid and adjusting to a predetermined pH.
  • the acid to be added is not particularly limited, but examples include formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid, trifluoromethanesulfonic acid, ⁇ -toluenesulfonic acid, and the like, preferably hydrochloric acid, sulfuric acid It is.
  • the pH is not particularly limited as long as the crystals can be obtained in good yield, but is preferably in the range of 4 to 9, particularly preferably in the range of 5 to 8.
  • the crystallization yield can be improved by adding an alcohol such as ethanol.
  • Ethanol to be added The amount of potassium is not particularly limited, and may be added until sufficient crystal precipitation is observed.
  • the temperature range for crystallization is preferably in the range of 20 to 80 ° C., more preferably in the range of ⁇ 5 to 60 ° C. from the viewpoint of impurity removal rate and crystallization yield.
  • R 2 is a hydrogen atom and the amino group forms a salt with an acid to obtain a compound.
  • the above method is used.
  • the obtained compound (2) in which R 2 is a hydrogen atom is dissolved in an appropriate solvent, and an acid is added to form a salt.
  • Solvents include chloroalkanes such as dichloromethane, chloroform, and dichloroethane; substituted benzenes such as benzene and toluene; ethers such as jetyl ether, methyl-butyl ether, tetrahydrofuran, and 1,4 dioxane; From the group consisting of alcohols such as methanol, ethanol, isopropanol, t-butanol; alkanes such as hexane and pentane; esters such as ethyl acetate and isopropyl acetate; ketones such as methyl ethyl ketone; One or more selected solvents are used.
  • the solvent can be used for both salt formation and crystallization. A solvent in which the generated salt precipitates as crystals with high yield and an improvement in quality is recognized may be selected.
  • Examples of the acid used for salt formation include formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and the like, preferably hydrochloric acid, Sulfuric acid and methanesulfonic acid.
  • the concentration of the compound (2) is in the range of 5 to 50 wt%. preferable. Further, the temperature range for crystallization is preferably in the range of ⁇ 20 to 80 ° C.
  • R 1 and R 3 are the same as described above.
  • the amino group may form a salt with an appropriate acid.
  • the acid that forms the salt of compound (3) is not particularly limited, but for example, formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p toluenesulfone Examples thereof include hydrochloric acid, sulfuric acid, and methanesulfonic acid, and hydrochloric acid is particularly preferable.
  • the compound (2) obtained by the reaction of the compound (1) and ammonia by the above-mentioned method may be used as it is and subjected to the crystallization step. Can be used.
  • the esterification is not particularly limited as long as it is carried out in a usual manner (for example, see Experimental Science Course 22, edited by The Chemical Society of Japan, Maruzen Co., Ltd.).
  • the method carried out by the reaction with the alcohol represented by the formula (4) will be described.
  • the alcohol to be used an alcohol corresponding to the desired ester may be selected.
  • the amount to be used is preferably 5 to 200 mol times the compound (2), more preferably 10 to 100 mol times.
  • the acid to be used is not particularly limited as long as the reaction proceeds in good yield.
  • the amount of the acid used is 2 to 20 mole times, preferably 2 to 10 mole times the compound (2).
  • the reaction temperature is not particularly limited, but is preferably in the range from 25 ° C to the boiling point of the alcohol used, and particularly preferably in the range of the boiling point of the alcohol used at 40 ° C force. .
  • the reaction time is not particularly limited as long as the disappearance of the compound (2) is confirmed, but is generally about 1 to 24 hours.
  • the post-treatment after the reaction is not particularly limited as long as it is carried out by a usual method.
  • water is added and the alcohol is removed after neutralization with a suitable base.
  • the compound (3) can be efficiently separated from the inorganic salts in the system by performing extraction with an appropriate organic solvent.
  • the base for making the aqueous layer alkaline after neutralization and alcohol removal is not particularly limited, and examples thereof include alkali metals such as sodium hydroxide, potassium hydroxide, potassium hydroxide and cesium hydroxide.
  • alkali metals such as sodium hydroxide, potassium hydroxide, potassium hydroxide and cesium hydroxide.
  • Hydroxides; alkaline earth metals such as magnesium hydroxide and calcium hydroxide; alkali metal carbonates such as lithium carbonate, potassium carbonate and sodium carbonate; lithium hydrogen carbonate, hydrogen carbonate Mention may be made of alkali metal hydrogen carbonates such as potassium and sodium hydrogen carbonate.
  • alkali metal hydroxides or alkaline earth metal hydroxides is preferred from the economical viewpoint and because no gas is generated by reaction with acids, and sodium hydroxide is particularly preferred.
  • the extraction solvent is not particularly limited as long as it is a solvent that can efficiently extract compound (3) from the aqueous layer.
  • black alkanes such as dichloromethane, black mouth form, and dichloroethane
  • Substituted benzenes such as toluene
  • ethers such as jetyl ether and methyl-butyl ether
  • alkanes such as hexane and pentane
  • esters such as ethyl acetate and isopropyl acetate; preferably dichloromethane, toluene, methyl- t Butyl ether, ethyl acetate, particularly preferably ethyl acetate
  • the obtained extract can be subjected to a crystallization step as necessary after concentration to obtain a highly pure compound (3).
  • R 1 and R 3 are as described above.
  • the amino group may form a salt with an appropriate acid.
  • Forming salt The acid to be used is not particularly limited, but examples include formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and the like. Are hydrochloric acid, sulfuric acid and methanesulfonic acid, with hydrochloric acid being particularly preferred.
  • the one opposite to the previous configuration is preferentially generated.
  • the compound (9) contained as an impurity in the compound (3) can be removed by crystallization. Therefore, when obtaining the compound (3) or a salt thereof, the compound (1) is reacted with the ammonia, and then the obtained compound (2) is subjected to a crystallization step to obtain the compound (8 ) And other impurities; a method of removing compound (9) and other impurities in the crystallization step after performing esterification without crystallization of compound (2); There is a method of performing a crystallization process both after the reaction of (1) with ammonia and after the esterification reaction. Which method should be selected should also determine the required quality. In order to obtain a compound (3) with higher purity, it is preferable to perform crystallization after both the amination reaction and the esterification reaction. Needless to say, crystallization should not be performed according to the required quality of the compound (3).
  • Solvents used for crystallization of compound (3) are, for example, chloroalkanes such as dichloromethane, chloroform, dichloroethane, and the like; substituted benzenes such as benzene and toluene; jetyl ether, methyl-butyl ether, tetrahydrofuran, 1 , 4 Ethers such as dioxane; Alcohols such as methanol, ethanol, isopropanol, n-butanol, sec butanol and t-butanol; Alkanes such as hexane and pentane; Esters such as ethyl acetate and isopropyl acetate; Acetone And ketones such as methyl ethyl ketone; and water.
  • chloroalkanes such as dichloromethane, chloroform, dichloroethane, and the like
  • substituted benzenes such as benzene and toluen
  • the crystallization can be performed by selecting one or more solvents from these.
  • ethyl acetate is used as the extraction solvent, it is possible to concentrate the extract to a predetermined amount and perform crystallization from the ethyl acetate solution as it is, or an appropriate one selected from the above group. It is also possible to use a solvent as a poor solvent.
  • the crystallization method using ethyl acetate as the extraction solvent and hexane as the poor solvent after concentrating the extract is described below.
  • the concentration of the extract is particularly preferably from 10 to 30 wt% in order to obtain the compound (3) with a good crystallization yield in which the concentration of the compound (3) is preferably in the range of 5 to 50 wt%.
  • the amount of hexane is preferably 30 to 200 vZv%, particularly preferably 30 to 150 vZv% with respect to ethyl acetate.
  • Crystallization is performed by concentrating the extract and heating to a specified temperature, dissolving the precipitated solids, adding force hexane, and cooling to the specified temperature.
  • the temperature range is 20 to 80 ° C.
  • the range is preferably 5 to 60 ° C, more preferably from the viewpoint of the removal rate of impurities and the crystallization yield.
  • the compound (3) when it is desired to obtain the compound (3) as a salt with an acid, it can be obtained by adding an appropriate acid to the compound (3) obtained above, and the extract or the extract can be obtained. It is also possible to obtain the salt of compound (3) directly as crystals by adding an acid after concentration and substitution with an appropriate solvent.
  • Examples of the solvent to be used include black alkanes such as dichloromethane, chloroform, and dichloroethane; substituted benzenes such as benzene and toluene; ethers such as jetyl ether, methyl-butyl ether, tetrahydrofuran, and 1,4 dioxane.
  • Alcohols such as methanol, ethanol, isopropanol, and t-butanol
  • alkanes such as hexane and pentane
  • esters such as ethyl acetate and isopropyl acetate
  • ketones such as acetone and methyl ethyl ketone
  • the mixing ratio is not particularly limited.
  • the acid to be used is not particularly limited, and examples thereof include formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and the like. Hydrochloric acid and sulfuric acid are preferred, and hydrochloric acid is particularly preferred.
  • the crystallization temperature is more preferably in the range of ⁇ 5 to 60 ° C. from the viewpoint of the impurity removal rate and the crystallization yield that are preferably performed in the range of 20 to 80 ° C.
  • the crystallization is performed twice or more. be able to. When crystallization is performed twice or more, it may be repeated with the same solvent or with different solvents.
  • (2R, 3R) and (2S, 3S) -3-phenol-lysoserine derivatives useful as pharmaceutical intermediates can be conveniently and industrially advantageously produced.
  • reaction solution was concentrated to about 30 wt% before concentration, and 28 wt% aqueous ammonia solution (124.9 mL, 1.85 mol) was added to the resulting orange slurry.
  • the reaction solution was transferred to a pressure resistant reactor, heated to 50 ° C. and stirred for 19 hours, then cooled to room temperature, and ammonia was removed under reduced pressure.
  • the amount of (2R, 3R) -3 phenol isoserine sodium salt in the obtained reaction solution was quantified by HPLC analysis using a sample, and the yield was 68.8%. Further, the yield of the regioisomer (2S, 3S) -3 phenolserine sodium salt was similarly determined by quantitative analysis by HPLC, and the yield was 18.4%.
  • a liquid medium (rho 7.0) was prepared, and 5 ml was dispensed into a large test tube and steam sterilized at 120 ° C for 20 minutes.
  • 1 yeast each of the yeasts shown in Tables 1 to 2 was inoculated and cultured at 30 ° C for 2 to 3 days with shaking. Bacteria were collected from this culture by centrifugation, suspended in 1 ml of 0.1 M phosphate buffer (pH 5.5) containing 2-% benzoyl acetate ethyl ester and 0.2% glucose, and a stoppered test. Shake for 20 hours at 30 ° C.
  • liquid medium consisting of 1% meat extract, 1% polypeptone, 0.5% yeast extract, 0.3% NaCl, and dispense 5 ml into a large test tube at 120 ° C. Steam sterilized for 20 minutes. Each of these liquid media was inoculated with 1 platinum ear of each of the bacteria shown in Table 3, and cultured at 30 ° C for 2 to 3 days with shaking. Bacteria were collected from this culture by centrifugation, and reacted and analyzed under the same conditions as in Example 4. Yield (%), isomer ratio at 3rd position (%), antiZsyn, and optical purity (% ee). The results are shown in Table 3.
  • a liquid medium (pH 7.2) consisting of 3% tributotic soy broth and 1% soluble starch was prepared, dispensed in 5 ml portions into a large test tube, and steam sterilized at 120 ° C for 20 minutes.
  • One platinum ear of each of the actinomycetes shown in Table 4 was inoculated into these liquid media, and cultured at 30 ° C for 2 to 3 days with shaking. Bacteria were collected from this culture by centrifugation, and reacted and analyzed under the same conditions as in Example 4. Yield (%), 3-position isomer ratio (%), antiZsyn, and optical purity (% ee). The results are shown in Table 4.
  • Example 7 Dispersion of 2-black-mouthed benzoyl acetate ethyl ester by mold Prepare a liquid medium ( ⁇ 7.0) consisting of 1% meat extract, 1% polypeptone, 1% glucose, 0.5% yeast extract, 0.1% NaCl, and MgSO ⁇ 7 ⁇ ⁇ 0.05%.
  • (2R, 3R) and (2S, 3S) -3-phenol-leucinerine derivatives useful as pharmaceutical intermediates can be conveniently and industrially advantageously produced.

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Abstract

La présente invention concerne un procédé selon lequel les dérivés de la (2R,3R)- et (2S,3S)-3-phénylisosérine, utiles en tant qu'intermédiaires pour des médicaments, peuvent être produits avantageusement, de manière facile et à l'échelon industriel. Dans la présente invention, un sel de l'acide (2R,3S)- ou (2S,3R)-3-phénylglycidique est mis à réagir avec de l'ammoniac pour former un sel de (2R,3R)- ou (2S,3S)-3-phénylisoserine. Le sel est facultativement neutralisé pour former de la (2R,3R)- ou (2S,3S)-3-phénylisosérine. Ensuite, le composé isosérine est purifié par cristallisation. Dès lors, les isomères de position générés comme sous-produits peuvent être efficacement éliminés. Le composé qui a été soumis ou non à la cristallisation est estérifié selon un procédé ordinaire et l'ester (2R,3R)- ou (2S,3S)-3-phénylisosérine résultant est purifié par cristallisation. Dès lors, les isomères de position et autres impuretés peuvent être efficacement éliminés.
PCT/JP2007/053097 2006-02-21 2007-02-20 Procede de production de derives de la (2r,3r)- et (2s,3s)-3-phenylisoserine WO2007097336A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106811432A (zh) * 2016-12-31 2017-06-09 浙江医药高等专科学校 一种骚动厄斯考维菌及在制备(r)‑3‑氯苯乙醇中的应用

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Publication number Priority date Publication date Assignee Title
ATE449062T1 (de) * 2007-02-22 2009-12-15 Indena Spa Verfahren zur herstellung von (2r,3s)-3- phenylisoserin-methylester-acetatsalz
CN101907263B (zh) 2009-05-09 2013-08-28 西铁城电子股份有限公司 透镜部件和使用该透镜部件的光学单元

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998035025A1 (fr) * 1997-02-07 1998-08-13 Kaneka Corporation Nouvelle carbonyle reductase, gene codant celle-ci et procede d'utilisation
JP2003340287A (ja) * 1991-08-26 2003-12-02 Research Corp Technologies Inc キラル触媒、接触酸化及び不均化反応並びにエポキシクロマン及びタキソルの製造方法
WO2004027055A1 (fr) * 2002-09-19 2004-04-01 Kaneka Corporation Nouvelle carbonyle reductase, son gene et sa methode d'utilisation
JP2005500322A (ja) * 2001-07-03 2005-01-06 アルタナ　ファルマ　アクチエンゲゼルシャフト ３−フェニルイソセリンの製法
JP2005507859A (ja) * 2001-06-27 2005-03-24 ナプロ バイオセラピューティクス，インコーポレイテッド タキサンの合成に有用な化合物を製造するためのキラル分割法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003340287A (ja) * 1991-08-26 2003-12-02 Research Corp Technologies Inc キラル触媒、接触酸化及び不均化反応並びにエポキシクロマン及びタキソルの製造方法
WO1998035025A1 (fr) * 1997-02-07 1998-08-13 Kaneka Corporation Nouvelle carbonyle reductase, gene codant celle-ci et procede d'utilisation
JP2005507859A (ja) * 2001-06-27 2005-03-24 ナプロ バイオセラピューティクス，インコーポレイテッド タキサンの合成に有用な化合物を製造するためのキラル分割法
JP2005500322A (ja) * 2001-07-03 2005-01-06 アルタナ　ファルマ　アクチエンゲゼルシャフト ３−フェニルイソセリンの製法
WO2004027055A1 (fr) * 2002-09-19 2004-04-01 Kaneka Corporation Nouvelle carbonyle reductase, son gene et sa methode d'utilisation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SCOLASTICO C. ET AL.: "Diastereo- and Enantioselective Synthesis of Fluorinated Threonines", SYNTHESIS, no. 9, 1985, pages 850 - 855, XP001183196 *
WUTS P.G.M. ET AL.: "Synthesis of (2R,3S)-isobutyl phenylisoserinate, the Taxol side chain, from ethyl benzoylacetate", TETRAHEDRON: ASYMMETRY, vol. 11, no. 10, 2000, pages 2117 - 2123, XP004205768 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106811432A (zh) * 2016-12-31 2017-06-09 浙江医药高等专科学校 一种骚动厄斯考维菌及在制备(r)‑3‑氯苯乙醇中的应用
CN106811432B (zh) * 2016-12-31 2020-04-28 浙江医药高等专科学校 一种骚动厄斯考维菌及在制备(r)-3-氯苯乙醇中的应用

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