WO2007097336A1

WO2007097336A1 - Process for producing (2r,3r)- and (2s,3s)-3-phenylisoserine derivatives

Info

Publication number: WO2007097336A1
Application number: PCT/JP2007/053097
Authority: WO
Inventors: Takahiro Ohishi; Naoaki Taoka; Akira Nishiyama; Tozo Nishiyama; Daisuke Moriyama
Original assignee: Kaneka Corporation
Priority date: 2006-02-21
Filing date: 2007-02-20
Publication date: 2007-08-30
Also published as: JP2009114065A

Abstract

A process by which (2R,3R)- and (2S,3S)-3-phenylisoserine derivatives useful as an intermediate for medicines can be easily and industrially advantageously produced. A salt of (2R,3S)- or (2S,3R)-3-phenylglycidic acid is reacted with ammonia to form a (2R,3R)- or (2S,3S)-3-phenylisoserine salt. The salt is optionally neutralized to form (2R,3R)- or (2S,3S)-3-phenylisoserine. Thereafter, the isoserine compound is purified by crystallization. Thus, position isomers which have generated as by-products can be efficiently removed. The compound which has been or not been subjected to the crystallization is esterified by an ordinary method and the resultant (2R,3R)- or (2S,3S)-3-phenylisoserine ester is purified by crystallization. Thus, position isomers and other impurities can be efficiently removed.

Description

Process for producing (2R, 3R) and (2S, 3S) _ 3_phenylisoserine derivatives

The present invention relates to a method for producing (2R, 3R) and (2S, 3S) -3-phenylisoserine derivatives useful as pharmaceutical intermediates.

Background art

[0002] (2R, 3R) and (2S, 3S) -3 Phenyl isoserine derivatives are produced by, for example, 3-phenol glycidate having a phenyl group and a carboxyl group in the trans position. There is known a method (Patent Document 1) in which the obtained erythro 3-phenylisoserine salt is esterified and then separated using optically active tartaric acid.

However, since the above method is a splitting method, the maximum yield is 50%, which is difficult to say that it is a practical and economical method for industrial production.

[0003] Optically active (2R, 3R) and (2S, 3S) -3 phenol glycidate and ammonia react with (2R, 3R) and (2S, 3S) -3 Ruisoserine salt can be obtained, and by neutralizing (2R, 3R) and (2S, 3S) -3 phenol isoserine, further esterifying (2R, 3R) and (2S, 3S) — 3 Ferrous isosterin ester can be obtained. As such a method, although a method of ring-opening an optically active 3-phenyldaricidic acid derivative obtained by asymmetric epoxies of cinnamic acid derivatives is known, a specific method is not disclosed and industrially available. Whether it is feasible is unknown (Patent Document 2).

[0004] In addition, 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.

[0005] On the other hand, 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) ) In the presence of a base (for example, alkali metal alkoxide) at 10 to 50 ° C., particularly 0 ° C. to room temperature, and water is added thereto to hydrolyze the ester group. You can get it.

[0006] As a method for producing an optically active 2-chloro-3hydroxy-3phenolpropionic acid ester derivative, there is known a method of asymmetric reduction of a 2-chloro-3-oxo-3 phenylpropionic acid ester derivative using a microorganism or a reductase. (Patent Document 3, Non-Patent Documents 4 to 5). However, it is difficult to say that these are practical production methods in which the feed concentration (0.1 to 0.2%) and the yield (1 to 60%) are low. In addition, as a microorganism that highly selectively produces anti-isomers, particularly (2S, 3S) isomers, Althropacter 'protoformier and Streptomyces' olivochromogenes have been reported (Patent Document 3), and the yields of both are high. 5% or less.

[0007] Even if an optically active 3-phenylglycidate is obtained, it is difficult to avoid by-production of 3-phenylserine salt, which is a regioisomer, in the reaction with ammonia. An efficient removal method is known.

[0008] As an isolation and purification method, an isolation and purification method by crystallization of a diastereomer of the compound (2R, 3S) -3 phenol isoserine salt is known (Patent Document 4). It is unclear whether (2R, 3R) and (2S, 3S) -3 phenol isoserine salts are isolated by the law.

[0009] Therefore, development of a practical and economical production method of (2R, 3R) and (2S, 3S) -3-phenol isoserine derivatives useful as pharmaceutical intermediates is strongly desired. 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

Disclosure of the invention

Problems to be solved by the invention

[0010] In view of the above, 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

[0011] As a result of intensive studies in view of the above, the present inventors have reacted (2R, 3S) or (2S, 3R) -3 phenolglycidic acid or a salt thereof with ammonia to produce (2R, 3R) or (2S, 3S) —3 Phenol isoserine or its salt, then esterified by the usual method to give (2 R, 3R) or (2S, 3S) —3 phenol isoserine alkyl ester or its salt In the process, (2S, 3S) or (2S, 3R) -3 phleglycidic acid or its alkali salt and by-product (2S, 3S) or (2R, 3R) -3 phenserine or its It is found that (2S, 3S) or (2R, 3R) -3 phenolserine ester or its salt power crystallization can be efficiently removed by mixing with salt or subsequent esterification, and the present invention is completed. It came to.

That is, the present invention relates to general formula (1);

[0013] [Chemical 1]

[Wherein 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, and * 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.

[0015] [Chemical 2]

[Wherein 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 .

[0017] Further, 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);

[0018] [Chemical 3]

[Wherein R ¹ and * represent the same meaning as described above, and R ³ represents a C to C alkyl group]

2 1 4

Further, the present invention relates to a method for producing a compound represented by the formula (3), which is further subjected to a crystallization step.

Furthermore, the present invention relates to a general formula (5);

[0020] [Chemical 4]

[0021] (wherein R ¹ and R ³ represent the same meaning as described above, and X represents a halogen atom), the carbonyl group of the compound is stereoselectively reduced. A general formula (6) or a general formula (7) by acting an enzyme source having the ability;

[0022] [Chemical 5]

[0023] (wherein R \ R ³ , X and * represent the same meaning as above, * represents an asymmetric carbon atom)

2

The present invention relates to a method for producing the compound.

Hereinafter, the present invention will be described in detail.

In the present invention, “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.

[0025] First, the general formula (1);

[0026] [Chemical 6]

[0027] The production method of the compound represented by

In the compound represented by the formula (1) (hereinafter referred to as the compound (1)), R ¹ represents a phenyl group which may have a substituent. Examples of 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. Preferably, it is a phenyl group.

R ² represents a hydrogen atom, an alkali metal, an alkaline earth metal, or a nitrogenous base. Needless to say, 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. Examples of the alkali metal include lithium, sodium, and potassium. Examples of the alkaline earth metal include magnesium, strength russium, and sodium. Examples of 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. Kind. 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.

* Represents an asymmetric carbon atom, and the configuration is (2R, 3S) or (2S, 3R), preferably (2R, 3S).

[0028] Although 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.

Formula (5); [0029]

[0030] The carbonyl group of the compound represented by general formula (6) obtained by asymmetric reduction:

[0031] [Chemical 8]

Or a general formula (7);

[0033] [Chemical 9]

[0034] A method obtained by hydrolyzing the ester group after treatment with a base and cyclizing the compound represented by [0034] is preferred.

Here, the compound represented by the formula (5) (hereinafter referred to as the compound (5) t), the compound represented by the formula (6) (hereinafter referred to as the compound (6) t) and the above formula ( In the compound represented by 7) (hereinafter referred to as compound (7)), 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.

1 4 1 4

Group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group and 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.

* Represents an asymmetric carbon atom, and the configuration is preferably S.

* Is an asymmetric carbon atom and its configuration is (2R, 3R) or (2S, 3S)

2

And preferably (2S, 3S).

Compound (5) can be produced by treating the corresponding benzoyl acetate derivative with a chlorinating agent such as sulfuryl chloride and chlorinating. [0035] First, the selection of the compound (6) and the compound (7) will be described. It is known that when compound (6) is treated with a base and subjected to a cyclization reaction, a trans-type glycidic acid derivative is produced regardless of the configuration at the 2-position (see Tetrahedron 1995, 6, 2211). In other words, since compound (1) can be obtained regardless of the configuration at the 2-position, either compound (6) or compound (7) may be selected, but cyclization is possible with higher selectivity. In order to carry out the reaction, it is preferable to select the compound (7) in which the configuration at the 2- and 3-positions is specified.

[0036] 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; Alternatively, a reduction method using an enzyme derived from a microorganism can be used. For industrial implementation, a reduction method using an enzyme derived from a microorganism is preferred.

Hereinafter, for example, 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.

[0037] Here, 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. Furthermore, 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.).

[0038] In the present invention, 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. [0039] Among them, 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 鼠, Microbac terium genus, Micrococcus genus, Ochrobactrum 、, Qerskovia genus, Paenibacillus genus, Enzyme source derived from microorganism belonging to the genus Pseudomonas is bald

[0040] 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 Safsuhi ~~, No '~~ asreptomvces cacaoi subsp. asoensis), Streptomyces coelescens, Streptomices hydrogenase (Streptomvces hvdrogenans) and other sources of microorganisms.

[0041] 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 genus Umbel opsis, the genus Verticillium Sources of microorganism-derived enzymes can be raised.

[0042] Among these, as an enzyme source capable of (2R, 3R) selective reduction of the carbonyl group of the compound (5), the genus Brettanomvces, Denori myces ( Genus Debarvo mvces, genus Hanseniaspora, genus Issatchenkia, genus Tanoreberomyces (Kluweromvces), genus Metschnikowia, genus Pachvsolen, genus Pichiazo ), Torulasnora, Willopsis, Corvnebacterium, Devosia, Auxarthron, Coriolus, Panus, Fanerocate There are enzyme sources derived from microorganisms belonging to the genus (Phanerochaete), Plectosphaerella, and Verticillium. I can get lost.

[0043] Preferred enzyme sources include, more specifically, Brettanomyces * castelcianus (Eisli anomvces custersianus), Candida cantarellii, Candida guilliermondii, candy Candida haemulonii, = Candida pararugosa, Candida pini, Candida QU ercitrusa, Candida stellata ), Taryptococcus terreus (Cryptococcus terreus, Debarvomvces maramu s) ), Kunore Belomyces Police Hofs (K luweromvces polvsp orus), Kunore Beromaisesu Sa ¹ ~ ~ Motorefunsu (Kluyveromyces thermotolerans) , Metschnikowia gruessii, Pachivhenen (Pachvsolen tannophilus), Pichia angusta, Pichia finlandica, Pichia henricii, Pichia henricii (Pichia holstii), Saccharomyces no Janus (Saccharomvces ba vanus), Saccharomyces no Strianes (Saccharomvces pastorianus), Schizosaccharomvces pombe, Tonorevus bru sul var. saturnus), Cory nebacterium flavumens (Cory nebacterium flavescens), Coryneno qualum 'Corvnebacterium glutamicum, Devosia riboflavina, Oksanolesulon' Saxteri (Auxarthron thaxteri), Colliolus consorres (Coriolus consors), Nonus lacomtei (Phaneroch aete chrvsosporium, Plectosfarev cucuerer pi An enzyme source derived from microorganisms such as Verticillium niveostratosum can be mentioned.

[0044] The microorganism from which the reductase is derived may be either a wild strain or a mutant strain.

In addition, microorganisms induced by genetic techniques such as cell fusion or gene manipulation can also be used. Furthermore, 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).

[0045] Examples of the recombinant microorganism as described above include a transformed microorganism transformed with a vector having a DNA encoding the reductase. As the host microorganism, Escherichia coli is preferred! / !. More preferably, the carbocyclic reductase gene (WO20) derived from the above-mentioned β 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).

In addition, (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.

[0046] The culture medium for the microorganism used as the enzyme source is not particularly limited as long as the microorganism can grow. For example, as 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 .; As another nutrient source, 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.

[0047] In the present invention, 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.

[0048] 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. In the reaction, an organic solvent may be mixed and used. Examples of the organic solvent 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. In addition, the reaction can be performed in a notched manner or a continuous manner. it can.

[0049] By using a commonly used coenzyme NAD (P) H regeneration system in the reduction step of the present invention, the amount of expensive coenzyme used can be greatly reduced. 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.

[0050] 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. Here, as 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).

[0051] 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. In addition, the activity of an enzyme having a coenzyme regeneration ability in a transformed microorganism can be measured by a conventional method. example For example, 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. When the reduction process of the present invention is carried out in combination with a coenzyme regeneration system, or when a culture or treated product of the above-mentioned transformed microorganism is used as the enzyme source, a cheaper oxidation is performed as a coenzyme. It is also possible to carry out the reaction by adding a type of NAD (P).

[0052] The compound (7) produced by the reduction reaction can be purified by a conventional method. For example, 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. 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. Examples of the base used 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. Of the above-mentioned bases, 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.

[0054] The solvent to be used is not particularly limited. For example, 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.

[0055] 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.). For example, either 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. Examples of the alkali to be used include the bases mentioned in the cyclization reaction of the compound (7), preferably sodium hydroxide.

When hydrolyzing using an acid, 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.

When compound (6) is used, the cyclization reaction can be carried out in the same manner as in compound (7).

[0056] The compound (1) obtained by force is reacted with ammonia to give a general formula (2);

[0057] [Chemical 10]

[0058] (hereinafter referred to as compound (2)).

Here, R ¹ and R ² are as described above.

When R ² is a hydrogen atom, the amino group in formula (2) may form a salt with an appropriate acid. The acid that forms the salt is not particularly limited. For example, 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.

* Is the same force as described above, preferably (2R, 3R). (2R, 3S) body as raw material

2

When the compound (1) is used, the (2R, 3R) compound (2) is used. When the (2S, 3R) compound (1) is used, the (2S, 3S) compound (2) is used. can get.

[0059] 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.

In this step, the general formula (8);

[0060] [Chemical 11]

[0061] The regioisomer represented by the above is generated as a by-product.

In the compound represented by the formula (8) (hereinafter referred to as compound (8) t), R ¹ and R ² are as described above.

When R ² is a hydrogen atom, 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).

2

The one opposite to the previous configuration is preferentially generated.

[0062] The amination reaction is carried out in an organic solvent and in Z or water. Examples of 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. When two or more kinds of mixed solvents are used, the mixing ratio is not particularly limited. To obtain the compound (2) with good yield For this purpose, water or a mixed solvent of water and an organic solvent is preferable as the solvent, and water is more preferable.

[0063] 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.

[0064] If the 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. Preferably 0 to: LOO ° C, particularly preferably 20 to 80 ° C. The reaction time is generally about 1 to 36 hours as long as the disappearance of the compound (1) is confirmed.

[0065] By subjecting the compound (2) obtained in this reaction to a crystallization step, the compound (8) and other impurities can be efficiently removed. Needless to say, it is not necessary to carry out the crystallization step according to the required quality of the compound (2).

[0066] First, a method for crystallizing the compound (2) obtained after the reaction between the compound (1) and ammonia will be described.

In crystallization, 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.

Even in the case of crystallization of V and deviation, if the desired quality cannot be obtained in one crystallization, the crystallization can be performed twice or more to improve the quality. Repeat the same crystallization method You can crystallize in the form of a different compound (2)!

[0067] In the crystallization step, 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.

[0068] Preferably, the general formula (4);

R ³ OH (4)

(R ³ is the same as described above) and at least one solvent selected from the group power that is also hydropower, and more preferably water and ethanol.

[0069] After the amination reaction, 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.

[0070] As 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. Examples of 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.

[0071] 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. Ability to add a predetermined amount of ethanol after the completion of concentration 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.

[0073] A method of performing crystallization as a compound (2) in which R ² is a hydrogen atom after the amination reaction will be described.

[0074] As the crystallization solvent, it is preferable to use at least one selected from the group of solvents described above, such as water and alcohols. Examples of 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.

[0075] When the solvent of the amination reaction in the previous step is water, crystallization is performed by removing the ammonia, concentrating the reaction solution up to a predetermined amount, and adjusting to an appropriate pH by adding an acid. can do. The method will be described below.

[0076] 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, ρ-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.

[0077] If the crystal acquisition rate is low even after adjusting to a predetermined pH with water alone, 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.

In the above formula (2), R ² is a hydrogen atom and the amino group forms a salt with an acid to obtain a compound. In this case, for example, 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.

[0079] 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.

[0080] 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.

In the case of crystallization of a compound in which R ² is a hydrogen atom in the formula (2) and an amino group forms a salt with an 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.

Next, the compound (2) is converted into a general formula (3);

[0082] [Chemical 12]

The method for obtaining the compound represented by

In the compound represented by formula (3) (hereinafter referred to as compound (3) t), R ¹ and R ³ are the same as described above. In the compound (3), 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.

* Is the same as described above, and preferably (2R, 3R). (2R, 3R) form as raw material

2

When compound (2) is used, (2R, 3R) compound (3) is used. When (2S, 3S) compound (2) is used, (2S, 3S) compound (3) is used. Is obtained.

[0084] As the compound (2) used here, 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.

[0085] 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.). For example, in the presence of an appropriate acid, The method carried out by the reaction with the alcohol represented by the formula (4) will be described. As 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.

[0086] The acid to be used is not particularly limited as long as the reaction proceeds in good yield. For example, formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p Examples include toluenesulfonic acid, and hydrochloric acid, sulfuric acid, methanesulfonic acid, and p-toluenesulfonic acid are preferable, and methanesulfonic acid is particularly preferable. The amount of the acid used is 2 to 20 mole times, preferably 2 to 10 mole times the compound (2).

[0087] 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.

[0088] The post-treatment after the reaction is not particularly limited as long as it is carried out by a usual method. For example, after completion of the reaction, water is added and the alcohol is removed after neutralization with a suitable base. Then, after making the pH of the remaining aqueous layer alkaline, the compound (3) can be efficiently separated from the inorganic salts in the system by performing extraction with an appropriate organic solvent.

[0089] 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. 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. The use of 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.

[0090] The extraction solvent is not particularly limited as long as it is a solvent that can efficiently extract compound (3) from the aqueous layer. For example, 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

[0091] The obtained extract can be subjected to a crystallization step as necessary after concentration to obtain a highly pure compound (3).

When the compound (2) contains a compound (8) which is a regioisomer as an impurity! /, The compound (8) is subjected to the esterification reaction to give a general formula (9);

[0092] [Chemical 13]

(Hereinafter referred to as compound (9) ヽぅ).

In the compound (9), R ¹ and R ³ are as described above.

In compound (9), 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.

* Is the same as above. The configuration of compound (9) is superior to that of the produced compound (3).

2

The one opposite to the previous configuration is preferentially generated.

[0094] 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).

[0095] 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. The crystallization can be performed by selecting one or more solvents from these. When 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.

[0096] 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%. Ability to hold a predetermined amount of hexane after the completion of concentration 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.

[0097] 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.

[0098] 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; and water . One or more solvents can be selected from these to perform solvent substitution, and an optimal solvent may be selected according to the type of acid used. In addition, when two or more kinds of mixed solvents are used, the mixing ratio is not particularly limited.

[0099] 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.

[0100] Regardless of whether the compound (3) or the salt of the compound (3) is obtained as the final product, if the desired quality cannot be obtained by one crystallization, 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.

The invention's effect

[0101] According to the present invention, (2R, 3R) and (2S, 3S) -3-phenol-lysoserine derivatives useful as pharmaceutical intermediates can be conveniently and industrially advantageously produced.

BEST MODE FOR CARRYING OUT THE INVENTION

[0102] The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to these examples.

Example 1 (2R, 3R) -3 Phenol Isoserine Sodium Salt

(2S, 3S) -2 black port 3 hydroxy - 3 Hue - Rupuropion acid Echiruesuteru (1 4. 33g, 62. 67mmol) , in Etanonore (30 mL) Power et al made solution, 20 wt ^_0/0 sodium ethoxy at room temperature Z ethanol (23.46g, 68.94mmol) was added and stirred for 40 minutes. The precipitated inorganic salt was filtered off and washed with ethanol (30 mL), and water (30 mL) and 30 wt% aqueous sodium hydroxide solution (9.19 g, 68.94 mmol) were added to the filtrate. After stirring for 35 minutes at room temperature, the content of (2R, 3S) 3-phenyldaricidic acid sodium salt in the reaction solution was determined by HPLC analysis using separately synthesized racemic 3-phenylglycidic acid sodium salt as a standard sample. The rate was calculated to be 98.3%.

Under reduced pressure, the 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%.

Concentrate under reduced pressure until (2R, 3R) -3 phenol isoserine sodium salt content is about 30 wt%, add ethanol (255 mL) to the resulting slurry, and stir at 50 ° C for 30 minutes The mixture was allowed to cool to room temperature with stirring, further cooled to 0 to 1 ° C, and stirred at the same temperature for 30 minutes. The precipitated crystals were separated by filtration, washed with ethanol (80 mL), and then at about 50 ° C under reduced pressure. White crystals (8.21 g) were obtained by drying for 18 hours. From the content of (2R, 3R) -3 FU-iso-serine sodium salt and (2S, 3S) -3 FERSERIN sodium salt in the filtrate, (2R, 3R) -3 FE-Louis in the crystal When the soserine sodium salt content was measured, the (2R, 3R) -3 phenol isoserine sodium salt content was 90.4 wt% (crystallization yield 86.2%), and (2S, 3S) -3 The content of sodium ferrine salt was 1.4 wt% (removal rate 95.2%).

[Yield Analysis]

(2R, 3S) — 3-Ferglycidic acid sodium salt

Column: Nacalai COSMOSIL C18 AR (4.6 mm x 250 mm), eluent: acetonitrile ZO. 5 wt% KH PO aqueous solution (pH = 3.0) = 5/5, flow rate: lmlZmin, test

twenty four

Source: 210 nm, column temperature: 40 ° C, elution time: (2R, 3S) —3 sodium salt of ferric glycidate 3.4 min.

(2R, 3R) — 3 Phenol isoserine sodium salt

Column: Luna 5 C18 (2) (4.6 mm X 250 mm) manufactured by Phenomenex, Eluent: Acetonitrile ZO. 5 wt% KH PO aqueous solution (pH = 2.0) = 1/9, Flow rate: 0.5 ml / mi

twenty four

n, detection: 210 nm, column temperature: 40 ° C, elution time: (2R, 3R) -3 phenol isoserine sodium salt 5.7 min, (2S, 3S) -3 phenol-serine sodium salt 6.7 min .

¾ NMR (D 0, 400MHZ) δ 7. 27— 7. 38 (m, 5H), 4. 18 (d, 1H, J = 4.4H

2

z), 4.14 (d, 1H ゝ J = 4.2 Hz)

Example 2 (2R, 3R) -3 Phenol Isoserine Ethyl Ester

White crystals (8.21 g) obtained in Example 1 ((2R, 3R) —3 phenol isoserine sodium salt: 36. 54 mmol, (2S, 3S) —3 phenol sodium salt H, ethanolol (200 mL) and MsOH (methane sulphonic acid) (18.37 g, 191.2 mmol) were added and heated to reflux for 20 hours, and then allowed to cool to room temperature, water (200 mL) was added. In addition, the pH was adjusted to 6.67 with 30 wt% sodium hydroxide aqueous solution, ethanol was distilled off under reduced pressure, and the pH was adjusted to 11.87 with 30 wt% sodium hydroxide aqueous solution. (3 X 150 mL), and the extract was washed with saturated brine (200 mL). (2R, 3R) -3-phenylisoserine ester and (2S, 3S 3 Hue-Ruserin Ethyl Este As a result of quantitative analysis by HPLC using a standard sample, (2R, 3R) -3-phenol isoserethyl ester was 32.62 mmol (yield 89.3%), ( The amount of 2S, 3S) -3-ferrine ether ester was 0.38 mmol. The extract was concentrated until (2R, 3R) -3-phenylisoserine ethyl ester was about 17 wt%, and the resulting slurry was heated to 40 ° C. to obtain a homogeneous solution. Hexane (25 mL) was added at the same temperature, allowed to cool to room temperature with stirring, further cooled to 0 to 2.5 ° C, and stirred at the same temperature for 1 hour. The precipitated crystals were separated by filtration, washed with hexane (30 mL), and dried under reduced pressure at 50 ° C. for about 12 hours to obtain white crystals (5.82 g). The contents of (2R, 3R) -3-phenol isoserine ester and (2S, 3S) 3 -phenylserine ester were determined by HPLC analysis. -Luisoserine ethyl ester was> 99.9 wt% (crystallization yield 85.2%), and (2S, 3S) -3 phenol ester was not detected.

[Yield Analysis]

Column: Nacalai COSMOSIL C18 AR (4.6 mm x 250 mm), eluent: acetonitrile ZO. 5 wt% KH PO aqueous solution (pH = 2.0) = 2/8, flow rate:

2 4 lmlZmin, detection: 210 nm, column temperature: 40 ° C, elution time: (2R, 3R) —3 phenol isoselin ethyl ester 3.3 min, (2S, 3S) —3 phenol serine ethyl ester 3 9 minutes.

¾ NMR (CDC1, 400MHZ) δ 7. 23 7. 33 (m, 5H), 4.44 (d, 1H, J = 4.1

Three

Hz), 4.30 (d, 1H, J = 3.9Hz), 4.06—4.12 (m, 2H), 1.16 (t, 3H, J = 7.1 Hz)

Example 3 (2R, 3S) -3 Phenyldaricidic acid sodium salt

(2S, 3S) -2 Black mouth 3 Hydroxy-3 Phenylpropionic acid ethyl ester (3.72 g, 16.3 mmol) and ethanol (lOmL) at room temperature with 20 wt% sodium ethoxide Z ethanol (12. 19 g, 35. 86 mmol) was added and stirred for 1 hour. The precipitated inorganic salt was filtered off and washed with ethanol (10 mL). A solution of water (323 mg, 17.93 mmol) in ethanol (5 mL) was added to the filtrate, and the mixture was stirred at room temperature for 1 hour. Since the fluidity of the contents was low, water (10 mL) was added and the precipitated white crystals were filtered off.

The crystals are washed with ethanol (20 mL) and then vacuum-dried for about 12 hours. Crystals (1.46 g) were obtained. When this product was analyzed by HPLC, it was found that it contained 84. lwt% of (2R, 3S) -3 phenol glycidic acid sodium salt (yield 37.2%) o [0108] (Example 4) Reduction of 2-chloroethyl acetyl acetate by yeast

Glucose 4%, yeast extract 0.3%, KH PO 1.3%, (NH) HPO 0.7

2 4 4 2 4

%, NaCl 0.01%, MgSO 7% 0.08%, ZnSO 7% 0.006%, FeSO

4 2 4 2

7Η Ο 0.009%, CuSO5Η Ο 0.005%, MnSO 4-5〜〜 0.001%

4 2 4 2 4 2

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. Into these liquid media, 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. After the reaction, it was extracted with an equal volume of ethyl acetate, and the product in the extract was analyzed by HPLC, yield (%), isomer ratio at 3rd position (%), antiZsyn, and optical purity ( % E.e.) And the results are shown in Tables 1-2. Here, the isomer ratio and optical purity at the 3-position were calculated by the following formulas.

[0109] Isomeric ratio (%) = AZ (A + B) X 100 (A and B represent stereoisomers at the 3-position, and A> B)

[0110] Optical purity (% e. E.) = (C D) Z (C + D) X 100 (C and D represent the amount of the corresponding enantiomer, C> D)

[0111] [Yield Analysis]

Column: YMC YMC—Pack Pro C18 AS—303 (4.6 mm x 250 mm) ゝ Eluent: 0.1% Z-nitronitrile phosphate = 5Z5, Flow rate: lmlZmin, Detection: 220nm, Force Ram temperature: 30 ° C , Elution time: 2 Chloro-3 hydroxy 3 -phenylpropionic acid ethyl ester 8.9 min, 2-chlorobenzoic acid ethyl ester 13.8 min.

[Analysis of diastereomeric ratio and optical purity]

Column: Daicel Chemical Industries CHIRALCEL OJ—H (4.6 mm x 250 mm), eluent: hexane Z isopropyl alcohol = 9 Zl, flow rate: lmlZmin, detection: 220 nm, ram temperature: 30 ° C, elution time: (2R , 3R) —2 Black mouth 3 Hydroxy 1 3 Ferrule Lopionic acid ethyl ester 14. 4 min, (2S, 3S) — 2 Black mouth 3 Hydroxy-3-phenyl propionic acid ethyl ester 15. 1 min, (2R, 3S) — 2 Black mouth 3 Hydroxy 3 phenol Propionic acid ethyl ester 20. 5 min. (2S, 3R) — 2 Black mouth 3 Hydroxy-3 phenol propionic acid ethyl ester 24.5 min.

[table 1]

^ [] 0114

([] 0115

Prepare a liquid medium (pH 7.0) 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.

[Table 3]

([S

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.

[Table 4]

Example 7) Dispersion of 2-black-mouthed benzoyl acetate ethyl ester by mold Prepare a liquid medium (ρΗ7.0) consisting of 1% meat extract, 1% polypeptone, 1% glucose, 0.5% yeast extract, 0.1% NaCl, and MgSO · 7Η Η 0.05%.

4 2

5ml was dispensed into the test tube and steam sterilized at 120 ° C for 20 minutes. Each of these liquid media was inoculated with 1 platinum ear of each of the molds shown in Table 5, and cultured with shaking at 30 ° C for 2 to 3 days. Bacteria were collected from this culture solution by suction filtration and subjected to reaction and analysis 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 5.

[Table 5]

3rd place Anti body Syn body

Microbe Yield (%) Isomeric ratio Anti / yn Optical purity Optical purity

3D Solid 3D

_ (%) One (ee) (% ee) _

Axarthron thaxteri NBRC 8451 99 3R 99 /> 99 (2R, 3R)

Coriolus consors NBRC 9078 87 3R 74/26> 99 (2 .3R) (2S.3) CriniDellis stipitaria NBRC 30259 75 3R 40/60 35 (2R'3R) 60 (2S, 3R) Myrothecium verrucaria IAM 5063 73 3R 56/44> 99 (2R'3R) (2R3S)

'Panus lacomtei NBRC 31653 99 3R 91/9> 99 (2R, 3R) 73 (2S, 3R) Phanerochaete' Phanerochaete chrvsosporium NBRC

22 89 3R 95/5 78 (2R, 3R) 81 (2S.3R) 31249

PlectosphaereHa cucumerina) NBRC

82 3R 73/27> 99 C2R.3R) 36 (2R.3S) 30005

Umbeloqsis vinacea NBRC 6738 93 3R 15/85> 99 (2R.3R) 96 (2S.3R) Lecho Indium-Verbicillium niveostratosum

96 3R 73/27〉 99 (2R, 3R) 71 (2S, 3R) NBRC 5435

Ester

Put 50 ml of medium consisting of Bacto-tryptone 1.6%, Bacto-yeast extract 1%, sodium chloride 1% (ρΗ7.0) into a 500 ml Sakaguchi flask and sterilize it. Escherichia coli HB10 l (pNTDRGl) FERM BP — 08458 was inoculated and cultured with shaking at 37 ° C for 24 hours. After completion of the culture, add 5 g of 2-chlorobenzoyl acetate ethyl ester, 4.8 g of glucose and 15 mg of oxidized nicotinamide adenine dinucleotide (NAD +), and maintain the pH at 6.5 with 30% aqueous sodium hydroxide solution. The reaction was allowed to proceed for 44 hours. After completion of the reaction, the reaction mixture was extracted twice with 150 ml of ethyl acetate, and the resulting organic phase was concentrated under reduced pressure to obtain 4.8 g of oily 2-chloro-3-hydroxy-3-phenylpropionic acid ethyl ester. The obtained product was analyzed according to the method described in Example 4. As a result, Anti / Syn = 99.2 / 0.8, and the optical purity of the Anti form (2S, 3S) was 99.4% ee. .

Industrial applicability

According to the present invention, (2R, 3R) and (2S, 3S) -3-phenol-leucinerine derivatives useful as pharmaceutical intermediates can be conveniently and industrially advantageously produced.

Claims

The scope of the claims

[1] General formula (1);

[Chemical 1]

(In the formula, R ¹ represents an optionally substituted phenol group, R ² represents a hydrogen atom, an alkali metal, an alkaline earth metal, or a nitrogenous base, and * represents an asymmetric carbon atom. There is a general configuration (2) obtained by reacting a compound represented by (2R, 3S) or (2S, 3R) and ammonia.

[Chemical 2]

(Wherein R ¹ and R ² represent the same meaning as described above, * is an asymmetric carbon atom and its configuration

2

Wherein the compound represented by (2R, 3R) or (2S, 3S) is further subjected to a crystallization step, wherein the compound represented by the formula (2) is produced. .

[2] The compound represented by the formula (2) obtained by the method according to claim 1, is esterified, and is represented by the general formula (3);

[Chemical 3]

(Wherein R ¹ and * represent the same meaning as described above, and R ³ represents a C alkyl group).

2 1 to C

Four

A method for producing a compound represented by the formula (3), characterized in that:

[3] The process for producing a compound represented by the formula (3) according to claim 2, wherein the obtained compound represented by the formula (3) is further subjected to a crystallization step.

[4] The crystallization process of the compound represented by the formula (2) is performed by selecting a group force consisting of chloroalkanes, substituted benzenes, industrial esters, alcohols, alkanes, esters, ketones and water. The production method according to any one of claims 1 to 3, which is carried out using one or more selected solvents. [5] A crystallization step of the compound represented by the formula (2) is performed by the general formula (4);

R ³ OH (4)

(Wherein R ³ represents a C to C alkyl group)

14

The production method according to claim 4, which is carried out using one or more kinds of solvents.

6. The production method according to any one of claims 1 to 5, wherein the crystallization temperature of the compound represented by the formula (2) is -20 to 80 ° C.

[7] General formula (1);

[Chemical 4]

(In the formula, R ¹ represents an optionally substituted phenol group, R ² represents a hydrogen atom, an alkali metal, an alkaline earth metal, or a nitrogenous base, and * represents an asymmetric carbon atom. The steric configuration is represented by (2R, 3S) or (2S, 3R), and the reaction between the compound represented by general formula (2);

[Chemical 5]

2

Is a compound represented by (2R, 3R) or (2S, 3S)), which is then esterified, and the resulting general formula ( ₃ );

[Chemical 6]

(Wherein R ¹ and * represent the same meaning as described above, and R ³ represents a C to C alkyl group).

2 1 4

The method for producing a compound represented by the formula (3), wherein the compound is further subjected to a crystallization step.

The crystallization process of the compound represented by the formula (3) is carried out by chloroalkanes, substituted benzenes, 8. The production method according to claim 7, wherein the process is carried out using one or more solvents selected from the group consisting of monotels, alcohols, alkanes, esters, ketones and water.

[9] The crystallization method according to claim 7 or 8, wherein the crystallization temperature is -20 to 80 ° C.

[10] In the reaction of the compound represented by the formula (1) with ammonia, the amount of ammonia used is 1 to 100 mole times the compound represented by the formula (1). The manufacturing method in any one of.

[11] The process according to any one of [1] to [10], wherein in the reaction of the compound represented by the formula (1) and ammonia, the reaction temperature is 0 to LOO ° C.

[12] The process according to any one of claims 1 to 11, wherein the reaction between the compound represented by the formula (1) and ammonia is carried out in water or a mixed solvent of water and an organic solvent. .

[13] The compound represented by the formula (1) is represented by the general formula (5);

[Chemical 7]

(Wherein R ¹ and R ³ represent the same meaning as described above, and X represents a halogen atom), the carbonyl group of the compound represented by the following general formula (6) ;

[Chemical 8]

(Where

R ³ and X have the same meaning as described above, * represents an asymmetric carbon atom), and obtained by hydrolyzing the ester group after treatment with a base and cyclization The production method according to any one of claims 1 to 12.

[14] The compound represented by the formula (1) asymmetrically reduces the carbonyl group of the compound represented by the formula (5), and the resulting general formula (7);

[Chemical 9]

(Wherein R \ R ³ , X and * represent the same meaning as described above)

2

The production method according to any one of claims 1 to 13, which is obtained by hydrolyzing an ester group after cyclization.

[15] The asymmetric reduction of the compound represented by the formula (5) is performed by acting an enzyme source capable of 3S-selectively or 3R-selectively reducing the compound. Item 15. The method according to Item 13 or 14.

[16] 3S selective enzyme potential Debarvomvces, Pichia, Acidiohilium, Devosiahi, thigh crobacterium fe, micrococcus 16.The process according to claim 15, which is an enzyme source derived from a microorganism belonging to the genus (Micrococcus) f 禺, the genus Chrono kuttoum (Ochrobactr urn), the genus Oenoscovia (Oerskovia), the genus Paenibacillus, or the genus Pseudomonas. .

[17] (2S, 3S) Selective enzyme source Debarvomvces, Pichia

), AcidiOhilium, Devosia, Microbacterium, Micrococcus, Ochr obactrum, Oerskovia, The production method according to claim 16, which is an enzyme source derived from a fine cattle belonging to the genus Paenibacillus or the genus Pseudomonas.

[18] (2S, 3S) Selective enzyme source: Candida solani, Candida

'Candida tenuis, Candida utilis, Debario myces .Polymonorefus (Debarvomvces polvmorphus), Deno riomyces .Debarvomvces robertsiae, Pi ³ r, Bovis (Pichia bovis) ), 7 affilium cryptam (AcidiOhilium crvptum), Arthrobacter crvstallopoietes (Arthrobacter crvstallopoietes) ), Micrococcus luteus, Ochrobactrum sp., Oerskovia turbata, and Baeni-Bacillus albei (Paeni) bacillus alvei), ^Gerhard, ~ ~ Pseudomonas-Puteida (Pseudomonas putitda), ^Gerhard, ~ ~ de, mode eggplant 'Sutoutozeri (Pseudomonas stutzeri), Streptomyces Kakaoi Sabusupi ~ ~ ~ ~ Shi's 7 Noen'nsu (atreptomvces cacaoi suosp. asoensis), Sulev. 16. The production method according to claim 15, which is an enzyme source derived from a microorganism selected from the group consisting of Streptomvces coelescens and Streptomvces hvdrogenans.

[19] (2S, 3S) Selective enzyme source: The recombinant Escherichia coli culture transformed with a carbonyl reductase derived from Devosia riboflavina (too ^ k riboflavina) or a processed product thereof. Manufacturing method.

[20] 3R-selective enzyme powers Brettanomvces, Debarvomvces, Hanseniaspora, Issat chenkia, Kluweromvces , Genus Metschni kowia, genus Qgataea, genus Pachvsolen, genus Pichia, genus SaccharomvcoOsis, genus Schizos accharomvces, genus Tonorella pora Williopsis, Corvnebacterium, Devosia, Streptomvces, Auxarthron, Coriolus, CriniOellis, Myrothecium, Panus, Phanerochaete, Plectosfaerella (Plect 16. The production method according to claim 15, which is an enzyme source derived from a microorganism belonging to the genus osuhaerella, the genus Umbelopsis, or Verticillium.

[21] (2R, 3R) Selective Enzyme Power Brettanomyces (Brettanomvces), Debarvomvces, Hanseniaspora, Issatchenkia, Tanoleberomyces ( Genus Kluweromvces, Metschnikowia, Pachvsolen, Pichia, Schizosaccharomvces, Torulaspora, Williopsis, Genus, Devosia, Auxarthron, Coriolus, Panus The method according to claim 20, which is an enzyme source derived from a microorganism belonging to the genus, genus Phanerochaete, genus Plectosphaerella, or genus Verticillium.

(2R, 3R) Selective enzyme source Brettanomvces custersianus, Cantigue * Candida cantarellii, Candida guilliermondii, Candida 'Candida haemulonii', 'Candida pararugosa', 'Candida pini', 'Candida auercitr usa', 'Candida stellata' , Cryptococcus terreus, Anno riomyces' mahummus Police Hoffs (Kluweromvces polvsporus), Kleweromvces thermotolerans, Meckschnikowia gruessii, Pa chvsolen tannophilus, Pichia aneusta, Pichia finland ica, Pichia finland landica Henrici (Pichia henricii), Pichia holstii (Pichia holstii), Saccharomyces nojanus (Saccharomvces bavanus), Saccharomvces pastorianus, Schizosaccharomyces bombes (Schizosaccharom) Ryeky (Torulaspora delbrueckii), Williopsis. Saturnas bar Sanorenas (Willi opsis saturnus var. Saturnus), Corvinebact erium flavescens, Corineno quarium, Gnoretamicam (Corvnebacterium glutam icum), Devosia riboflavina, Auxarthron thaxteri, Coriolus consors, Panus lacomtei, Phanerochaete, Chrvospolet From Plectosphaerella cucumerina and Verticillium niveostratosum 16. The production method according to claim 15, which is a source of an enzyme derived from a microorganism selected from the group consisting of:

Formula (5);

[Chemical 10]

(In the formula, R ¹ represents a phenyl group which may have a substituent, and R ³ represents a C to C alkyl group.

14

And X represents a halogen atom) by reacting an enzyme source capable of stereoselectively reducing the carbonyl group of the compound with a compound represented by the general formula (7);

(Wherein RR ³ and X are as defined above, * is an asymmetric carbon atom and

2

Producing a compound represented by (2R, 3R) or (2S, 3S), and

The genus Debarvomvces, Pichia, Acid iphilium, Devosia, Microbacterium, Micrococcus, Ochrobactrum, The compounds represented by the formula (5) are selectively (2S, 3S) derived from microorganisms belonging to the genus Enerskovia, Paenibacillus, or Pseud mso ^. (2S, 3S) of the compound represented by the formula (7) is produced using an enzyme source having the ability to reduce, or

Brettanomvces, Tenbariomyces, Debarvomvces, Hanseniaspora, Issatchenkia, Tanolei, Kluweromvces, Metschnikv , Pichia, Schizosaccharomvces, Torulasnora, Willopsis, Corynebacterium, Tebosia (I) evosi¾, Oak sanorethron ) Derived from a microorganism belonging to the genus, Coriolus, Panus, Phanerochaete, Plectosnhaerella, or Verticilliu, and represented by the formula (5) (2R, 3R) of the compound represented by the formula (7) is produced using an enzyme source having the ability to selectively reduce the compound (2R, 3R) A method for producing a compound represented by formula (7):

[24] (2S, 3S) Selective enzyme source Candida 'sola- (C ^ did ^ solani), Candida

'Candida tenuis, Candida utilis, Debario myces .Polymonorefus (Debarvomvces polvmorphus), Deno riomyces .Debarvomvces robertsiae, Pi ³ r, Bovis (Pichia bovis) ), 7 affilium cryptam (AcidiOhilium crvptum), Arthrobacter crvstallopoietes (Arthrobacter crvstallopoietes), Arthr obacter nicotianae, Flavor (Microbacterium arborescens), Micrococcus luteus, Ochrobactrum sp., Qerskovia turbata, Paeni bacillus alvei, N ' Tomonas Puida (Pseudomonas putitaa), ~~ Monas, Stoutzeri (Pseudomonas stutzeri), Streptomyces cacaoi subspice ~~ Shi ~~ s 7 Noens (atreptomvces cacaoi suosp. Asoensis), Su 卜 refu. 卜 StylPtomvces coelescens, and Streptomyces 24. The production method according to claim 23, which is an enzyme source derived from a microorganism selected from the group consisting of Streptomvces hvdrogenans.

[25] (2S, 3S) Selective enzyme source 25 The production according to claim 24, which is a recombinant Escherichia coli culture transformed with a carbonyl reductase derived from Devosia riboflavina or a treated product thereof. Law.

[26] (2R, 3R) Selective Enzyme Source Brettanomvces custersianus, Candida cantarellii, and Candida guilliermondii , Candida haemulonii, Candida haemulonii, andida pararugpsa Candida pini, Candida auercitr usa, Candida stellata, Crvnt ococcus terreus, Debarvomvces maramus, Debarvomvces maramus Debarvomvces nepalensis, Hanseniaspora valbvensis, Issatchenk ia terricola, Thermos , Metschnikowia gruessii, Pachvsolen tannophilus, Pichia angusta, Pichia finlandica, Pichia henricii, Pichia henricii Pichia holstii, Saccharomvces bavanus, Saccharomyces' Storiacharus (Saccharomvces pastorianus), Schizosaccharomes pombeJ Bar sagnolenus (Willi opsis saturnus var. Saturnus), Corinebacterium flavescens, Coryneno cuterium, Gnoretamicum (Diorvnebacterium glutam icum), Devosia riboflavina (Devosia riboflavina) (Auxarthron thaxteri), Coriolus consors, Pannus lacomtei, Phanerochaete ch rvsosporium, Plectosphaerella cucumerina 24. The production method according to claim 23, which is an enzyme source derived from a microorganism selected from the group consisting of na), and Verticillium niveostratosum.

27. The production method according to claim 1, wherein R ¹ is an unsubstituted phenol group.

28. The production method according to claim 1, wherein R ² is a hydrogen atom or an alkali metal.

[29] The production method according to any one of [1] to [22], wherein the configuration of the formula (2) is a (2R, 3R) isomer.