JPH06237781A - Production of d-biotin intermediate - Google Patents

Abstract

PURPOSE:To obtain a method for producing an optically active intermediate for producing D-biotin useful as a medicine and an additive for animals. CONSTITUTION:An esterase, derived from a mold and having the ability to more rapidly acylate either of hydroxyl groups than the other is brought into contact with a mixture of the (+)-isomer with the (-)-isomer of (3aalpha, 6aalpha)- tetrahydro-4-hydroxy-1H-thieno[3,4-d] imidazol-2 (3H)-one in the presence of an acyl group donor to produce a (+)- or (-)-(3aalpha,6aalpha)-tetrahydro-4-acyloxy-1H- thieno[3,4-d]imidazol-2(3H)-one. Thereby, the optically active intermediate for the D-biotin is obtained in high yield and purity.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an intermediate for producing D-biotin. D-Biotin, also called Vitamin H, is a water-soluble vitamin required by higher animals and many microorganisms. D-biotin is a known compound represented by the formula below.

[0002]

[Chemical 6]

[0003]

As a method for synthesizing D-biotin, for example, a method using a sugar as a starting material [Tetrahedron Letters 2765 (1975)] or a method using L-cysteine as a starting material [Journal Of the American Chemical Society (JA
m. Chem. Soc. ) 97 , 5936 (1975)] is known. In these methods, an optically active substance is used as a starting material, and optically active D-biotin is obtained by a stereoselective reaction. In addition, as another method for producing D-biotin, for example, the reaction formula:

[0004]

[Chemical 7]

As shown in the above, a method for producing D-biotin using an optically active lactone obtained by selectively reducing only the carboxyl group of a half ester (JP-A-59-59).
No. 84888), reaction formula:

[0006]

[Chemical 8]

As shown in the above, a method for producing D-biotin using an optically active lactone obtained by esterification, reduction and hydrolysis from an optically active amide carboxylic acid.
(Japanese Patent Publication No. 60-3387). In addition, JP-A-5
Japanese Patent Publication No. 7-198098 discloses a method for producing an optically active monoester monocarboxylic acid by asymmetrically hydrolyzing a corresponding diester using an ester hydrolase. This optically active monoester monocarboxylic acid is reduced with lithium borohydride or the like and further lactonized to give cis-1,3-dibenzylhexahydro-1H- used as an intermediate for producing D-biotin. Flow
It can be converted to [3,4-d] imidazole-2,4-dione. In addition, tetrahedron (Tetrahedron),
46 , 7667 (1990), the reaction formula:

[0008]

[Chemical 9]

A method and formula for producing D-biotin by the reaction represented by:

[0010]

[Chemical 10]

The compound represented by the formula: is reduced with triethylsilane and boron trifluoride, and the formula:

[0012]

[Chemical 11]

A method for producing the above halogen compound by halogenating the compound represented by the formula is described.

[0014]

All of these methods are not suitable as an industrial production method of D-biotin because they have a large number of reaction steps, the reaction operation is complicated, and the total yield is low.

[0015]

In view of the above circumstances, the inventors of the present invention have diligently studied a method for producing D-biotin, and have conducted extensive studies on an advantageous method for producing an optically active intermediate. As a result, an enzyme is used as a catalyst. The kinetic resolution method is the D-biotin intermediate (3aα, 6aα) -tetrahydro-
1,3- (unsubstituted or substituted) dibenzyl-4-acyloxy-1H-thieno [3,4-d] imidazole-2
It has been found to be extremely effective in the production of optical isomers of (3H) -one and its 4-hydroxy derivative. That is, it was found that the esterase derived from bacteria stereospecifically acylates one of the D-biotin intermediates (racemates) in the presence of an acyl group donor to produce a D-biotin intermediate with high optical purity. . After that, based on these findings, as a result of further research, it was found that an esterase derived from filamentous fungus catalyzes the above reaction, and using these enzymes, an efficient and inexpensive optically active D-biotin intermediate The body manufacturing method was established. Generally, filamentous fungal esterase is inexpensive because it is produced in a large amount in a medium, and most of them are thermostable, which is extremely advantageous when used in an enzymatic reaction. Thus, the present invention provides an industrially advantageous method for producing an intermediate for producing D-biotin. That is, in the present invention, (1) (3aα, 6aα) -tetrahydro-4 in which two nitrogen atoms of the imidazole ring are protected by a benzyl group which may have a substituent.
-Hydroxy-1H-thieno [3,4-d] imidazol-2 (3H) -one in (+)-isomer and (-)-isomer mixture in the presence of an acyl group donor, either Is contacted with an esterase derived from a filamentous fungus having the ability to acylate more quickly than the other, and the two nitrogen atoms of the imidazole ring are protected by a benzyl group which may have a substituent ( +)-Or (-)-
(3aα, 6aα) -Tetrahydro-4-acyloxy-1H-thieno [3,4-d] imidazole-2 (3H)
-A method of manufacturing the on, in particular the general formula:

[0016]

[Chemical 12] [In the formula, X represents an alkyl group, a nitro group or an alkoxy group, and n represents an integer of 0 to 3]

Using a mixture of compounds of the general formula:

[0018]

[Chemical 13]

A method for producing a compound represented by
(2) Two nitrogen atoms of the imidazole ring are protected by a benzyl group which may have a substituent (3aα, 6a
α) -Tetrahydro-4-hydroxy-1H-thieno
(+) Of [3,4-d] imidazol-2 (3H) -one
-A mixture of isomers and (-)-isomers is contacted with an esterase derived from a filamentous fungus having the ability to acylate one of them faster than the other in the presence of an acyl group donor, and the resulting imidazole ring Two nitrogen atoms are protected with a benzyl group which may have a substituent (-)-
Or (+)-(3aα, 6aα) -tetrahydro-4
-Acyloxy-1H-thieno [3,4-d] imidazol-2 (3H) -one is removed, and two nitrogen atoms of the imidazole ring may have a benzyl group which may have a substituent. Protected by (+)-or (-)-
(3aα, 6aα) -tetrahydro-4-hydroxy-
1H-thieno [3,4-d] imidazole-2 (3H)-
A rapid acylated compound of the general formula [II '] or [II "] which is produced by using a method for producing ON, particularly a mixture of the compounds of the formulas [I'] and [I"] To provide a method for producing a compound represented by the formula [I ′] or [I ″] (3aα, 6aα).
-Tetrahydro-4-hydroxy-1H-thieno [3,4
-D] imidazol-2 (3H) -one is represented by the following structural formula.

[0020]

[Chemical 14]

In the general formulas [II '] and [II "],

[0022]

[Chemical 15]

As the acyl group represented by, an acyl group derived from an organic monocarboxylic acid, for example, a formyl group,
A lower alkylcarbonyl group (lower alkanoyl group), preferably a C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl etc.) and the like can be mentioned.

In the present invention, the nitrogen of the imidazole ring of the starting compound and the target compound is protected by a benzyl group which may have a substituent, and the substituent is not directly involved in the reaction, The present invention is not particularly limited as long as it does not interfere with the intended reaction. Examples of such substituents include compounds [I ′], [I ″], [II ′] and [I ”
As represented by X in I ″], there may be mentioned an alkyl group (preferably a lower alkyl group such as methyl group), a nitro group or an alkoxy group (preferably a lower alkoxy group such as methoxy group). These substituents may be present at any substitutable position on the benzene ring, and may be plural, for example, 2 to 3. Of course, the benzyl group may be unsubstituted. Hereinafter, two nitrogen atoms of the imidazole ring are protected by a benzyl group which may have a substituent (3aα, 6aα) -tetrahydro-4-hydroxy-
1H-thieno [3,4-d] imidazole-2 (3H)-
On and (3aα, 6aα) -tetrahydro-4-acyloxy-1H-thieno [3,4-d] imidazole-
Examples of 2 (3H) -one are compounds [I ′], [I ″],
The present invention will be specifically described using [II ′] and [II ″].

In the present invention, the compound [II '] or
[II "] is an esterase derived from a filamentous fungus capable of acylating a mixture of compounds [I '] and [I"] more quickly than the other, and is specific in the presence of an acyl group donor. It can be produced by acylation. Examples of the esterase derived from filamentous fungi include compound [I ′] and
Those having the ability to acylate one of [I ″] more rapidly than the other are used. Examples of filamentous fungi that produce esterase include genus Mucor, genus Rhizopus, genus Penicillium,
Humico (Humico), genus Aspergillus
la) and those belonging to the genus Phycomyces. Of these, Mucor strains are preferred. Specific examples include Mucor miehei (British Patent No. 1577833) and the like.

The esterase can be prepared by a usual method. To prepare an esterase from a filamentous fungus, the filamentous fungus is cultured by a usual method, and the obtained culture is centrifuged to obtain a culture supernatant and cells. A purified preparation of esterase is obtained from the above culture supernatant by organic solvent precipitation, ammonium sulfate fractionation, ion exchange chromatography, adsorption chromatography, gel filtration, affinity chromatography and the like. The esterase used in this reaction may be an unpurified preparation (for example, the above-mentioned culture supernatant), a partially purified preparation, or a single purified preparation. As the esterase, the culture solution as it is or the culture solution or the culture supernatant prepared may be used. The esterase used in the present invention may be a commercially available product, and for example, it can be purchased as an immobilized esterase derived from a bacterium belonging to the genus Mucor (Lipozyme IM60, Novo Nordisk, product list, 1992). The above esterase may be used as it is for the acylation reaction, or may be immobilized on a suitable carrier. Examples of the carrier include polysaccharide derivatives such as cellulose, amino acid copolymers, synthetic polymers such as maleic anhydride derivatives and styrene resins, activated carbon, porous glass, diatomaceous earth, alumina, silica gel, and other inorganic substances.

In the present invention, the compound [I ′] is used as it is as a raw material for synthesizing D-biotin, so that an esterase that acylates the compound [I ″] more quickly than the compound [I ′] is preferable. Even if the compound [I '] is acylated more quickly than the compound [I "], the compound [II'] obtained by the reaction is recovered and deacylated chemically or enzymatically. Can be converted to compound [I ′].

The acyl group donor in the present invention is a compound
It may be any as long as it can acylate [I ′] and [I ″]. The acyl group donor is not particularly limited as long as it can donate a corresponding acyl group, but an acid anhydride,
Acid esters and the like are advantageously used. When the acyl group is an acetyl group, the acyl group donor may be, for example, acetic anhydride,
When ethyl acetate or vinyl acetate has a propionyl group as the acyl group, propionic anhydride, ethyl propionate or the like is preferably used.

Although the acylation reaction in the present invention proceeds in water, it is preferably in an organic solvent. Any organic solvent may be used as long as it does not inhibit the acylation reaction. Examples of the organic solvent that does not inhibit the reaction include ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, tetrahydrofuran and dioxane, nitriles such as acetonitrile, hydrocarbons such as benzene, toluene and xylene, dimethylformamide and dimethyl. Examples thereof include amides such as acetamide and halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane. These may be used alone or in combination of two or more at an appropriate ratio. In this reaction, the concentration of the compounds [I '] and [I "] in the reaction solution is about 0.1-100 mg / ml, preferably about 1-10 mg / ml. The reaction temperature is about 15-80 ° C.
It is preferably about 24 to 42 ° C. The reaction time is about 10 minutes to 72 hours, preferably about 1 to 24 hours. If desired, an enzyme stabilizer, a dehydrating agent such as molecular sieves, or a water substitute such as DMSO, formamide, or ethylene glycol may be added to the reaction solution. The reaction may be any of standing, shaking, and stirring. When esterase is immobilized on a carrier, it may be reacted in a bioreactor.

The reaction product can be isolated and purified by known means, for example, solvent extraction, liquid conversion, phase transfer, salting out, crystallization, recrystallization, chromatography and the like. A method known per se or a method analogous thereto is applied to separate the desired compound [I ′] from the mixture. As such methods, for example, a fractionation method utilizing a difference in solubility or crystallinity, a separation method by chromatography, and the like are used. For example, a method for obtaining the compound [I ′] using the fractionation method will be shown below. The mixture of the above optical isomers is heated and dissolved in a specific solvent to prepare a supersaturated solution, which is cooled, concentrated, or a solvent that reduces the solubility of the compound [I ′] is added to the compound [I ′]. ] Separately crystallize.
This fractional crystallization is performed in an inert solvent, but the compound [I '] can be efficiently crystallized only when a specific solvent is used.

Suitable solvents include ketones such as acetone, alcohols such as isopropyl alcohol, and mixed solvents of esters such as ethyl acetate and hydrocarbons such as hexane. Particularly suitable solvents include ketones such as acetone. When only compound [I '] is obtained by fractional crystallization, it is desirable that the content of compound [I'] is high. When acetone is used as a solvent, the content of the compound [I '] may be about 14% by weight based on the compound [II "] in the above mixture. The boiling point of the solvent is preferable, it is advantageous that the temperature is lower than the crystallization temperature of the compound [I ′], and seed crystals of the compound [I ′] can be inoculated, but in this supersaturated solution, the compound [I ′] ] Is not always necessary because spontaneous crystallites of [] occur.However, when produced by the above reaction, the compound [II "] may be converted to the compound [IV] by a deacyloxy reaction.

The deacyloxy reaction of the present invention has the following reaction formula

[0033]

[Chemical 16]

As shown in, the compound [II "] is hydrolyzed to the compound [I"], which is then converted into a halogen compound,
This is reduced to give compound [IV]. The hydrolysis of the compound [II "] shown in the above reaction scheme to the compound [I"] can be carried out in an arbitrary organic solvent under ordinary basicity. Suitable solvents include lower alcohols such as methanol and ethanol, and ethers such as diethyl ether, tetrahydrofuran and dioxane. As the base, any ordinary base can be arbitrarily used, but suitable bases include, for example, alkali metal carbonates such as sodium carbonate, sodium hydrogen carbonate and potassium carbonate, such as sodium hydroxide, potassium hydroxide and water. Examples thereof include alkali metal hydroxides such as lithium oxide, and alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide. The amount of base used is about 1
To 10 mol, preferably about 1 to 3 mol.
In this hydrolysis, the reaction temperature is not particularly limited and is about 0.
To 100 ° C, preferably about 15 to 40 ° C. The reaction temperature is about several minutes to several tens of hours.

The compound [I "] can be halogenated with any ordinary halogenating agent. Examples of the halogenating agent include hydrogen halides such as hydrogen chloride, hydrogen bromide and hydrogen iodide, and trichloride. Phosphorus, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus triiodide and other phosphorus halides, thionyl chloride, thionyl bromide and other thionyl halides, sulfuryl chloride and other sulfuryl halides, triphenylphonsphine And carbon tetrachloride, diphenyltrihalogenophosphorane, triphenylphosphinedihalogenide, triphenyldihalogenide phosphonate, and the like active alkyl halides, etc. The amount of halogenating agent used is usually about 0. The amount is 0.3 to 10 moles, preferably about 0.3 to 3 moles. Chirueteru, ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile, benzene, hydrocarbons such as toluene, esters such as ethyl acetate, dichloromethane, chloroform,
Examples thereof include halogenated hydrocarbons such as 1,2-dichloroethane. These may be used alone or as a mixture of two or more kinds at an appropriate ratio. The reaction temperature is not particularly limited, but is usually about −30 to 100 ° C., preferably
It is about -10 to 30 ° C. The reaction time is several minutes to several tens of hours. Further, although this halogen compound can be isolated, it can be directly subjected to the next step without further purification.

The reduction of the halogen compound can be carried out by catalytic hydrogenation or a hydride reducing agent. Catalytic hydrogenation can be carried out by any ordinary method. Examples of the catalyst include palladium on charcoal, palladium on barium sulfate, platinum and Raney nickel. As the solvent used for catalytic hydrogenation, usual organic solvents, for example, lower alcohols such as methanol and ethanol, diethyl ether, tetrahydrofuran, ethers such as dioxane, nitriles such as acetonitrile,
Hydrocarbons such as benzene and toluene, esters such as ethyl acetate, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, and organic acids such as acetic acid. These solvents may be used alone or in 2
You may use it as a mixture of 2 or more types. The reaction temperature and pressure are not particularly limited, but are about 5 ° C. to 100 ° C. and atmospheric pressure to 100 atm, respectively. The reaction time is several minutes to several tens of hours.

In the reduction with a hydride reducing agent, borohydrides such as sodium borohydride, magnesium borohydride and diborane, aluminum hydrides such as aluminum lithium hydride, diisobutylaluminum hydride and diethylaluminum sodium hydride are used. It can be carried out. The solvent is preferably a solvent which is inactive to the reducing agent under the reaction conditions, and in which the reactant is at least partially soluble, and an ordinary organic solvent such as diethyl ether, tetrahydrofuran, dioxane or ether such as diethylene glycol dialkyl ether. Kind,
Hydrocarbons such as benzene and toluene, dichloromethane,
Halogenated hydrocarbons such as chloroform and 1,2-dichloroethane are used. For reducing agents usable in an aqueous solvent such as sodium borohydride, water and alcohols such as methanol, ethanol and diethylene glycol are also effective. These solvents alone,
Alternatively, it can be used as a mixture of two or more kinds. The reaction temperature is not particularly limited, but is preferably about -10 to 100 ° C. The reaction time is several minutes to several tens of hours.

The compound [IV] obtained by the above-mentioned method can be prepared by a known method, for example, tetrahedron (Tetrahedron) 46 ,
The method by chlorination and hydrolysis described in 7667 (1990) gives compound [I ′], which can be converted to compound [III] in the following scheme by Swann oxidation or the like.

Compound [III] is disclosed in JP-B-53-27279.
According to the method disclosed in Japanese Patent Publication No.
-Can be induced to biotin.

[0040]

[Chemical 17]

[In the formula, Bz represents a benzyl group which may have a substituent] D-biotin is also called vitamin H and is widely used for addition of pharmaceuticals and feed.

[0042]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto. The NMR spectrum uses tetramethylsilane as an internal standard, and JASCO JNM-GSX270 (270
MHz) type spectrometer, and all δ values are shown in ppm. In the mixed solvent, the value shown in parentheses is the volume mixing ratio of each solvent. % Means percent by weight unless otherwise stated. The symbols in the examples have the following meanings. s: singlet, d: doublet, t: triplet,
q: quartet, dd: double doublet, m: multiplet, br: wide range, J: coupling constant, ph: phenyl group, Ac: acetyl group from compound [I '] + compound [I "] to compound [II'] ＋ [II "]
The conversion rate to the above is determined by measuring the content of each component in the reaction solution by high performance liquid chromatography and using the measured value by the following formula.

[0043]

[Equation 1]

Specifically, the reaction solution is a suitable organic solvent.
(E.g., ethyl acetate) and extract this extract with a chiral column.
(Eg, Chiralcel OD, manufactured by Daicel Industries, Ltd.) and subjected to high performance liquid chromatography.

Example 1 (±)-(3aα, 4α, 6aα) -Tetrahydro-1,3-dibenzyl-4-hydroxy-1H-thieno [3,4-d] imidazol-2 (3H) -one (1 Toluene (50 g)
0 ml) and dissolve in Mucor miehei
Immobilized esterase (lipozyme IM60, Novo N
ordisk) (10 g), vinyl acetate (1.0 ml), and molecular sieves 4A 1/16 (5.0 g) were added to a 1-liter Erlenmeyer flask, and the mixture was stirred at 37 ° C. for 20 hours. The reaction solution obtained was passed through a membrane filter (pore size 0.45).
μm, manufactured by Advantech) to remove the immobilized esterase and molecular sieves. When the filtrate was analyzed by high performance liquid chromatography, the conversion rate was 61%, and (-)-(3aα, 4α, 6aα) -tetrahydro-1,3-dibenzyl-4-hydroxy-1H-thieno was obtained.
No peak of [3,4-d] imidazol-2 (3H) -one [I "] was observed.The pattern of high performance liquid chromatography is shown in Fig. 1. Then, the reaction solution was concentrated under reduced pressure to give crystals. The crystals taken out were filtered and found to be (+)-(3aα, 4
α, 6aα) -Tetrahydro-1,3-dibenzyl-4-hydroxy-1H-thieno- [3,4-d] imidazole-2
(3H) -one [I '] (285 mg, yield: 28.5%) was obtained. The structure was confirmed by melting point, IR, NMR and specific rotation.

Melting point: 166-168 ° C. IR (KBr) cm ^-1 : 3300, 1680. NMR (CDCl ₃ ): 1.7 (1H, br.s, OH), 2.86
(1H, d, J = 12.7, C (6) -H), 3.01 (1H, dd,
J = 12.7, 4.7, C (6) -H), 4.02 (1H, d, J =
7.9, C (3a) -H), 4.21 (1H, dd, J = 7.9, 4.
6, C (6a) -H), 4.21, 4.32, 4.66, 4.7
4 (1H, d, J = 15.5, NCH _{2 respectively} ), 5.18 (1
H, s, C (4) -H), 7.2-7.4 (10H, m, Ph). Specific rotation: [α] _D ²⁷ = + 71.7 (C = 0.87, chloroform) Further, the mother liquor was concentrated under reduced pressure to obtain an oily substance, which was subjected to silica gel chromatography (hexane / ethyl acetate = 2).
Purified by (/ 1), (+)-(3aα, 4α, 6a
α) -Tetrahydro-1,3-dibenzyl-4-hydroxy-1H-thieno [3,4-d] imidazole-2 (3H)-
On (87 mg, 8.7%) and (-)-(3aα, 4α, 6a
α) -Tetrahydro-1,3-dibenzyl-4-acetoxy-1H-thieno [3,4-d] imidazole-2 (3H)-
On (600 mg, yield: 53.4%) was obtained.

[0047]

Industrial Applicability The mixture of the compounds [I '] and [I "] of the present invention is contacted with an esterase derived from a filamentous fungus in the presence of an acyl donor to give an optically active D-biotin intermediate [I']. The compound [I ′] is used as a starting material to produce optically active D-biotin in high yield, high purity and at low cost.

[Brief description of drawings]

FIG. 1 shows a chromatogram obtained by high performance liquid chromatography of the reaction solution obtained in Example 1. The horizontal axis of the figure shows the retention time (unit: minutes), and on the peak,
The corresponding compounds are shown.

Claims (13)

[Claims] 1. The two nitrogen atoms of the imidazole ring are protected by a benzyl group which may have a substituent (3a
α, 6aα) -Tetrahydro-4-hydroxy-1H-
A thieno [3,4-d] imidazol-2 (3H) -one (+)-isomer and a mixture of (-)-isomers were mixed with each other in the presence of an acyl group donor more quickly than the other. The two nitrogen atoms of the imidazole ring are protected by a benzyl group which may have a substituent (+)-or (, characterized by contacting an esterase derived from a filamentous fungus having the ability to acylate. −) − (3aα, 6aα) −
Tetrahydro-4-acyloxy-1H-thieno [3,4
-D] Method for producing imidazol-2 (3H) -one. 2. A general formula: [Wherein X represents an alkyl group, a nitro group or an alkoxy group, and n represents an integer of 0 to 3], and a mixture of compounds represented by the general formula: The method according to claim 1, wherein the compound represented by 3. The two nitrogen atoms of the imidazole ring are protected with a benzyl group which may have a substituent (3a
α, 6aα) -Tetrahydro-4-hydroxy-1H-
A thieno [3,4-d] imidazol-2 (3H) -one (+)-isomer and a mixture of (-)-isomers were mixed with each other in the presence of an acyl group donor more quickly than the other. An esterase derived from a filamentous fungus having an ability to acylate is contacted, and two nitrogen atoms of the resulting imidazole ring are protected with a benzyl group which may have a substituent (-)-or (+)- (3aα, 6aα) -tetrahydro-4-acyloxy-1H-thieno [3,4-d] imidazol-2 (3H) -one is removed, and the two nitrogen atoms of the imidazole ring are substituted by a substituent. (+)-Or (-)-(3aα, 6aα) -tetrahydro-4-hydroxy-1H-thieno [3,4-d] imidazole-2 protected with a benzyl group optionally having
(3H) -On manufacturing method. 4. A general formula: [Wherein each symbol has the same meaning as in claim 2] using a mixture of compounds represented by the general formula: By removing the compound represented by the general formula: The process according to claim 3, wherein a compound represented by the formula: wherein each symbol has the same meaning as in claim 2 is obtained. 5. The method according to claim 1 or 3, wherein the filamentous fungus is a Mucor bacterium. 6. An esterase is a compound [I ″]
3. A compound that acylates more rapidly than [I '].
Or the manufacturing method according to 4. 7. The method according to claim 1, wherein the acyl group is a C _1-6 alkyl-carbonyl group. 8. The method according to claim 7, wherein the acyl group is an acetyl group. 9. The method according to claim 1, wherein the acyl group donor is an acetyl group donor. 10. The method according to claim 9, wherein the acyl group donor is acetic anhydride, ethyl acetate or vinyl acetate. 11. The manufacturing method according to claim 2, wherein n is 0. 12. The production method according to claim 2, wherein X is a methyl group, a nitro group or a methoxy group. 13. (+)-(3aα, 6aα) -tetrahydro-1,3-dibenzyl-4-hydroxy-1H-
The production method according to claim 3, wherein thieno [3,4-d] imidazol-2 (3H) -one is obtained.