JP4907486B2 - Grignard reagent manufacturing method - Google Patents

Description

  The present invention relates to a Grignard reagent, in particular a biotin synthesis intermediate and a method for producing a Grignard reagent that can be advantageously used for the production of biotin.

で示されるチエノイミダゾ−ル化合物を合成中間体として用いる製法（ケミカル・レビューズ（Ｃｈｅｍｉｃａｌ Ｒｅｖｉｅｗｓ），９７巻，６号，１７５５−１７９２頁，１９９７年、特公昭４９−３２５５１号、特公昭５３−２７２７９号、特公平３−６６３１２号、特公平５−９０６４号）等が知られている。 Biotin is a vitamin useful as a feed additive, a pharmaceutical product, and the like.

(Chemical Reviews), Vol. 97, No. 6, pp. 1755-1792, 1997, Japanese Patent Publication No. 49-32551, Japanese Patent Publication No. 53-27279 No. 3, JP-B 3-66312, JP-B 5-9064) and the like are known.

  However, these known production methods have a drawback that the production process is long and complicated optical division is required in the middle of the production process.

  It is an object of the present invention to provide a method for producing a Grignard reagent that can be advantageously used for producing industrially advantageous biotin.

  In order to solve the problems, the inventors of the present invention have arrived at a novel Grignard reagent production method as a result of diligent research. This Grignard reagent can efficiently produce compound (IX), for example, biotin production. In this method, biotin can be produced at low cost by using it when producing compound (VI) from compound (III), which is an industrially excellent production method.

That is, the present invention relates to the general formula (VIII):
R-I (VIII)
In the formula, R is an alkyl group which may have a substituent, a bicyclo group which may have a substituent, an alkenyl group which may have a substituent, a nitrogen atom as a hetero atom, an oxygen atom And a heterocyclic group containing 1 to 4 atoms selected from sulfur atoms (the heterocyclic group may have a substituent) or an aryl group which may have a substituent,
The compound represented by the general formula (IX) is reacted with zinc or magnesium treated with chlorine, bromine, hydrogen chloride or hydrogen bromide:
R-X-Y (IX)
Wherein X represents zinc or magnesium, Y represents iodine, bromine or chlorine.
It relates to a process for producing a compound represented by the formula:

Furthermore, the present invention provides a compound of the general formula (VIII):
R-I (VIII)
In the formula, R represents the same meaning as described above.
A compound represented by the general formula (X):
MY (X)
In the formula, M represents a metal atom, and Y represents the same meaning as described above.
In the presence of a salt represented by the general formula (IX):
R-X-Y (IX)
In the formula, the symbols have the same meaning as described above.
It relates to a process for producing a compound represented by the formula:

  A method for producing compound (IX) is described in HANDBOOK OF GRIGNARD REAGENTS, pages 53-77, 1996, ORGANOSINC REGENENTS in ORGANIC SYNTHIS. 18-67, 1996, etc.

  In the present invention, compound (IX) can be produced more efficiently than the methods described in these documents.

  Compound (IX) can be produced by suspending zinc or magnesium in a solvent, adding chlorine, bromine, hydrogen chloride or hydrogen bromide and then reacting with compound (VIII). Any solvent may be used as long as it does not adversely affect the reaction. Examples thereof include tetrahydrofuran, toluene, diethyl ether, 1,2-dimethoxyethane, acetonitrile, 1,4-dioxane, and a mixed solvent thereof is also used. be able to. This reaction suitably proceeds at −50 ° C. to 150 ° C., particularly 5 ° C. to 80 ° C.

  Examples of the substituent for the alkyl group of R include alkoxycarbonyl group, alkoxy group, alkoxycarbonylalkenyl group, alkoxycarbonylalkynyl group, alkanoyl group, alkylaminocarbonyl group, alkynyl group, cyano group, alkoxycarbamoyl group, alkylcarbamoyl group, di (Alkanoyl) amino group, halogen atom, alkanoyloxy group, phenylthio group, phenoxythio group, phenoxyoxythio group, benzoylthio group, di (alkoxy) phosphono group, trimethylsilyl group, di (alkoxy) boryl group, cycloalkyl group, A heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom (the heterocyclic group may have a substituent) or a substituent May be aryl And the like. As the substituent of the alkyl group of R, an alkoxy carbo group, a cyano group or an alkoxyalkyl group is preferably used. Specifically, those in which R is a 4-alkoxycarbonylbutyl group, a 4-cyanobutyl group, a 4-alkoxybutyl group, or a 3-alkoxybutyl group are preferably used.

  Examples of the heterocyclic group which is a substituent of the alkyl group of R include saturated or unsaturated monocyclic or bicyclic heteroaromatic groups, such as thienyl group, furyl group, tetrahydrofuryl group, pyranyl group, pyrrolyl group. Group, imidazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, piperidyl group, piperidyl group Morpholinyl group, benzothienyl group, benzofuryl group, isobenzofuranyl group, chromenyl group, indolyl group, isoindolyl group, indazolyl group, purinyl group, quinolidinyl group, naphthyridinyl group, quinoxalinyl group, cinnolinyl group, quinolyl group, Soquinolyl, benzothiazolyl, benzisothiazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, benzimidazolyl, pteridinyl, pyridopyrimidinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl, tetrahydroquino Examples include a ryl group, a tetrahydroisoquinolyl group, a tetrahydroquinoxalinyl group, and a dihydrophthalazinyl group. Examples of the substituent of the heterocyclic group include a dialkylamino group, an alkoxycarbonyl group, an alkyl group, and a formyl group.

  Examples of the aryl group that is a substituent of the alkyl group of R include a phenyl group, a naphthyl group, an anthracenyl group, and the like, and a phenyl group is preferably used. Examples of the substituent for the aryl group include an alkoxycarbonyl group, an alkanoyl group, a cyano group, an alkanoyloxy group, an alkoxy group, and a di (trimethylsilyl) amino group.

  Examples of the bicyclo group of R include a bicyclo [2.2.1] heptan-7-yl group and a bicyclo [4.1.0] heptan-7-yl group. Examples of the substituent for the bicyclo group include an alkanoylamino group.

  As the substituent of the alkenyl group of R, a cycloalkyl group, an aryl group which may have a substituent, an alkanoyloxy group, an alkanoyl group, an alkylphenylsulfoxy group, a phenylsulfoxyamino group, a halogenoalkyl group Etc. Examples of the aryl group include a phenyl group, a naphthyl group, and an anthracenyl group, and a phenyl group is preferably used. Examples of the substituent for the aryl group include an alkoxycarbonyl group.

  Examples of the substituent for the aryl group of R include an alkyl group, a halogenoalkyl group, an alkoxycarbonyl group, an alkanoyl group, a dialkylaminocarbonyl group, a cyano group, and a halogen atom. Examples of the aryl group include a phenyl group, a naphthyl group, and an anthracenyl group, and a phenyl group is preferably used.

  Examples of the heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as the heteroatom of R include saturated or unsaturated monocyclic or bicyclic heteroaromatic groups, , Thienyl group, furyl group, tetrahydrofuryl group, pyranyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, Imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, piperidyl group, piperazinyl group, morpholinyl group, benzothienyl group, benzofuryl group, isobenzofuranyl group, chromenyl group, indolyl group, isoindolyl group, indazolyl group, purinyl group, quinolidinyl group, naphthyl Dinyl group, quinoxalinyl group, cinnolinyl group, quinolyl group, isoquinolyl group, benzothiazolyl group, benzisothiazolyl group, quinazolinyl group, phthalazinyl group, benzoxazolyl group, benzimidazolyl group, pteridinyl group, pyridopyrimidinyl group, isochromanyl group , Chromanyl group, indolinyl group, isoindolinyl group, tetrahydroquinolyl group, tetrahydroisoquinolyl group, tetrahydroquinoxalinyl group, dihydrophthalazinyl group, etc., among which pyridyl group, thienyl group, imidazolyl group A thiazole group is preferably used. Examples of the substituent of the heterocyclic group include an alkyl group, an alkoxycarbonyl group, a benzoyl group, an alkanoyl group, and a cyano group.

  Furthermore, in the method of the present invention, it is preferable that R is an alkyl group which may have a substituent, and the substituent of the alkyl group is preferably an alkoxycarbonyl group, a cyano group or an alkoxy group. Specifically, R is preferably a 4-alkoxycarbonylbutyl group, a 4-cyanobutyl group, a 4-alkoxycarbonyl group, or a 3-alkoxybutyl group. Examples of 4-alkoxycarbonylbutyl group include 4-ethoxycarbonylbutyl group.

  In particular, in the method of the present invention, R is preferably an alkoxycarboalkyl group, a cyanoalkyl group or an alkoxyalkyl group, and it is preferable to react in the presence of bromine using zinc.

  Compound (IX) can be produced by suspending zinc or magnesium in a solvent, adding salt (X), and then reacting with compound (VIII). Any solvent may be used as long as it does not adversely affect the reaction. Examples thereof include tetrahydrofuran, toluene, diethyl ether, 1,2-dimethoxyethane, acetonitrile, 1,4-dioxane, and a mixed solvent thereof is also used. be able to. This reaction suitably proceeds at −50 ° C. to 150 ° C., particularly 5 ° C. to 80 ° C. Examples of the metal atom (M) of the salt (X) include typical metals and transition metals. Typical metals include lithium, sodium, potassium, cesium, magnesium, calcium, barium, aluminum, zinc, silicon, tin, etc., and transition elements include titanium, chromium, molybdenum, tungsten, manganese, iron, ruthenium, Examples include cobalt, rhodium, nickel, palladium, platinum, copper, and the like.

  In the present specification, examples of the alkyl group or alkoxy group include linear or branched ones having 1 to 6 carbon atoms, particularly linear or branched ones having 1 to 4 carbon atoms. Examples of the alkanoyl group, alkoxycarbonyl group or alkylthiocarbonyl group include straight or branched chain groups having 2 to 7 carbon atoms, especially straight chain or branched chains having 2 to 5 carbon atoms. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the halogenoalkyl group include a trifluoromethyl group.

The Grignard reagent obtained in the present invention can be used for general reactions. For example, it can be advantageously used for the production of the biotin intermediate described below and the production of biotin using the biotin intermediate.
That is, the Grignard reagent obtained in the present invention has the following production method:
Formula (II-a):

In the formula, R ¹ and R ² may be the same or different, and each has a hydrogen atom, a benzyl group optionally having a substituent on the benzene ring, and a substituent on the benzene ring. A benzhydryl group, or a trityl group which may have a substituent on the benzene ring, R ³ is a cyano group, a carboxyl group, an alkoxycarbonyl group, an alkylthiocarbonyl group, or a carbamoyl group which may have a substituent Represents a group,
A compound represented by the formula (I):

In the formula, the symbols have the same meaning as described above.
A method for producing a compound represented by the formula:

General formula (I):

In the formula, the symbols have the same meaning as described above.
Or a salt thereof, and if necessary hydrolyzed, the compound represented by the general formula (Ia):

In the formula, the symbols have the same meaning as described above.
Or a salt thereof, and then cyclizing and epimerizing the obtained compound (Ia):

式中、記号は前記と同一意味を表す、
で示される化合物の製法；

In the formula, the symbols have the same meaning as described above.
A process for producing a compound represented by:

式中、記号は前記と同一意味を表す、
で示される化合物又はその塩を、環変換および環化させることを特徴とする一般式（ＩＶ）： Moreover, general formula (II):

In the formula, the symbols have the same meaning as described above.
A compound represented by formula (IV):

式中、記号は前記と同一意味を有する、
で示される化合物の製法；

Wherein the symbols have the same meaning as above.
A process for producing a compound represented by:

In addition, according to the above method, the general formula (IV-a):

式中、記号は前記と同一意味を有する、
で示される化合物又はその塩を製し、次いで得られた化合物（Ｉ−ａ）を環化及びエピ化することを特徴とする、一般式（ＩＩＩ）： Wherein the symbols have the same meaning as above.
Or a salt thereof is hydrolyzed as necessary to give a compound of the general formula (Ia):

Wherein the symbols have the same meaning as above.
Or a salt thereof, and then cyclizing and epimerizing the obtained compound (Ia):

Wherein the symbols have the same meaning as above.
A process for producing a compound represented by:

Moreover, general formula (II-b):

In the formula, R ³¹ represents a carboxyl group, an alkoxycarbonyl group, an alkylthiocarbonyl group, or a carbamoyl group which may have a substituent, and other symbols have the same meaning as described above.
A compound represented by formula (III) or a salt thereof: ring conversion and cyclization:

In the formula, the symbols have the same meaning as described above.
A process for producing a compound represented by:

Moreover, general formula (5-a):

In the formula, the symbols have the same meaning as described above.
A compound represented by the following formula (7):
R ² —NH ₂ (7)
In the formula, the symbols have the same meaning as described above.
A compound represented by the general formula (6-a):

式中、記号は前記と同一意味を表す、
で示される化合物又はその塩の製法；

In the formula, the symbols have the same meaning as described above.
A method for producing a compound represented by the formula:

Furthermore, general formula (4-a):

In the formula, the symbols have the same meaning as described above.
And a compound represented by the general formula (5-a):

In the formula, the symbols have the same meaning as described above.
Or a salt thereof, and then the obtained compound (5-a) is added to the general formula (7):
R ² —NH ₂ (7)
In the formula, the symbols have the same meaning as described above.
A compound represented by the general formula (6-a):

式中、記号は前記と同一意味を表す、
で示される化合物又はその塩の製法；

In the formula, the symbols have the same meaning as described above.
A method for producing a compound represented by the formula:

式中、記号は前記と同一意味を表す、
で示される化合物又はその塩を製し、得られた化合物（６−ａ）を加水分解し、一般式（ＩＩ−ｃ）： Further, according to the above method, the general formula (6-a):

In the formula, the symbols have the same meaning as described above.
Or a salt thereof, and the resulting compound (6-a) is hydrolyzed to give a general formula (II-c):

In the formula, the symbols have the same meaning as described above.
Then, the compound (II-c) obtained is subjected to ring transformation to give a compound represented by the general formula (Ib):

In the formula, the symbols have the same meaning as described above.
Or a salt thereof, and the obtained compound (Ib) is hydrolyzed to give a compound represented by the general formula (Ia):

式中、記号は前記と同一意味を表す、
で示される化合物又はその塩を製し、次いで得られた化合物（Ｉ−ａ）を環化及びエピ化することを特徴とする、一般式（ＩＩＩ）：

式中、記号は前記と同一意味を表す、
で示される化合物の製法；

In the formula, the symbols have the same meaning as described above.
Or a salt thereof, and then cyclizing and epimerizing the obtained compound (Ia):

In the formula, the symbols have the same meaning as described above.
A process for producing a compound represented by:

式中、記号は前記と同一意味を表す、
で示される化合物を製し、次いで得られた化合物（ＩＩＩ）に、一般式（Ｖ）：
Ｘ^１Ｚｎ−（ＣＨ_２）_４Ｒ^４ （Ｖ） Further, according to the above method, the general formula (III):

In the formula, the symbols have the same meaning as described above.
And then the obtained compound (III) was converted to the general formula (V):
_{^{X 1 Zn- (CH 2) 4}} R 4 (V)

In the formula, X ¹ represents a halogen atom, R ⁴ represents an esterified carboxyl group or an amidated carboxyl group,
And a compound represented by the general formula (VI):

In the formula, the symbols have the same meaning as described above.
Or a salt thereof obtained, and then reducing the obtained compound (VI), hydrolyzing if necessary, and further converting R ¹ and / or R ² to a hydrogen atom if necessary. Formula (VII):

で示される化合物の製法において、一般式（ＩＩＩ）の化合物から一般式（ＶＩ）の化合物を製造する際に使用する一般式（Ｖ）の化合物として使用できる。

Can be used as the compound of the general formula (V) used when producing the compound of the general formula (VI) from the compound of the general formula (III).

式中、記号は前記と同一意味を表す、
で示されるジ（イミダゾリジニルメチル）ジスルフィド化合物又はその塩に関する。
Furthermore, the Grignard reagent obtained in the present invention has the general formula (IV):

In the formula, the symbols have the same meaning as described above.
It relates to a di (imidazolidinylmethyl) disulfide compound represented by the formula (I) or a salt thereof.

  The compound (I) used or obtained in the present specification can be produced by subjecting compound (II-a) to ring transformation. This reaction can be carried out in the absence of oxygen, for example, under an air stream such as nitrogen or argon. This reaction can be carried out in a suitable solvent or without a solvent. The solvent may be any solvent that does not adversely affect the reaction. For example, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, or a mixed solvent thereof is appropriately used. be able to. This reaction suitably proceeds at 0 ° C to 200 ° C, particularly 80 ° C to 100 ° C.

Compound (I), Compound (Ia), Compound (Ia ′), Compound (Ib), Compound (II), Compound (II ′), Compound (I) used or obtained in the present specification II-a), compound (II-b), compound (II-c), compound (III), compound (III-a), compound (IV), compound (IV-a), compound (VI), compound ( 6) and R ¹ and R ² of compound (6-a), and compound (3), compound (4), compound (4-a), compound (5) and compound used or obtained in the present specification. In R ¹ of compound (5-a) and R ² of compound (7), examples of the substituent on the benzene ring of the benzyl group include a group selected from a halogen atom, an alkyl group, and an alkoxy group. On the benzene ring of the group Examples of the substituent include groups selected from the same or different halogen atoms, alkyl groups, and alkoxy groups. Substituents on the benzene ring of the trityl group are selected from the same or different halogen atoms, alkyl groups, and alkoxy groups. Groups.

  On each benzene ring in the benzyl group, benzhydryl group or trityl group, 1 to 3 substituents may be the same or different.

R ^{3 of} compound (II), compound (II), compound (II-a), compound (IV) and compound (IV-a) R ^{3 and} compound (II-b) used or obtained herein ^{In 31} , examples of the substituent of the carbamoyl group include the same or different alkyl groups.

Compound (I), Compound (Ia), Compound (Ia ′), Compound (Ib), Compound (II), Compound (II ′), Compound (I) used or obtained in the present specification II-a), compound (II-b), compound (II-c), compound (III), compound (III-a), compound (IV), compound (IV-a), compound (VI), compound ( As 6) and compound (6-a), a compound in which R ¹ and R ² are both a benzyl group, a benzhydryl group or a trityl group is preferable. Among these, a compound in which R ¹ and R ² are both benzyl groups is particularly preferable. Further, as the compound (I), the compound (II), the compound (II-a), the compound (IV) and the compound (IV-a), a compound in which R ³ is a carboxyl group, an alkoxycarbonyl group or a carbamoyl group is preferable. .

  The compound (IV) used or obtained in the present specification can be produced by subjecting compound (II) to ring conversion in the presence of a base.

  Bases include alkali metal carbonates (sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen carbonates (sodium bicarbonate, etc.), organic acid alkali metal salts (sodium acetate, etc.), alkali metal hydroxides (sodium hydroxide, potassium hydroxide, etc.) Etc.), alkali metal hydrides (such as sodium hydride), alkali metal amides (such as sodium amide, lithium amide), alkali metal alkoxides (such as sodium methoxide), alkali metal phosphates, alkali metals (such as sodium) or organic bases (Triethylamine, diisopropylethylamine, morpholine, N-methylmorpholine, pyridine, piperidine, dimethylaniline, dimethylaminopyridine, etc.) can be suitably used. Of these, sodium hydrogen carbonate and sodium acetate are particularly preferred.

  The amount of the base used is preferably 0.1 molar equivalent to 100 molar equivalents, more preferably 1 molar equivalent to 3 molar equivalents, relative to compound (II).

  This reaction can be carried out in a suitable solvent or without a solvent. The solvent may be any solvent that does not adversely influence the reaction. For example, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, N-methylpyrrolidine, or a mixed solvent thereof can be appropriately used. This reaction suitably proceeds at 0 to 200 ° C, particularly 80 to 100 ° C.

Compound (IV) used in the present specification has an optical isomer based on an asymmetric carbon and may be either a racemate or an optical isomer, but optically active (+)-biotin. In order to efficiently lead to (+)-biotin, only an optically active substance having an R configuration at the 5-position of the imidazolidine ring (position where —CH ₂ S— is bonded) is obtained. preferable.

As the compound (VI) used or obtained in the present specification, a compound in which R ¹ and R ² are both a benzyl group, a benzhydryl group or a trityl group, and R ⁴ is an alkoxycarbonyl group or an alkylcarbamoyl group is preferable. . Among these, a compound in which R ¹ and R ² are both a benzyl group, a benzhydryl group, or a trityl group, and R ⁴ is an alkoxycarbonyl group is particularly preferable.

  Compound (II) and Compound (II-a) were obtained from Bulletin of Chemical Society of Japan, Vol. 37, No. 2, pp. 242-244, 1964, Analytical Biochemistry. 138, 449-450, 1984, Heterocycles, Vol. 18, 259-263, 1982, etc., or the like. In this way, it can be manufactured.

In the formula, X ² represents a halogen atom, R ³² represents a carboxyl group or a carbamoyl group, and other symbols have the same meaning as described above.

  The step of producing compound (2) from compound (1) and phenyl chloroformate (or alkyl chloroformate) can be carried out in the presence of a base or in the absence of a solvent. As the base, alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal alkoxide, organic base, and the like can be preferably used. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include toluene, benzene, xylene, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, water and the like. This reaction suitably proceeds at −30 ° C. to 120 ° C., particularly 20 ° C. to 50 ° C.

In the compound (3), the compound in which R ¹ has a substituent other than a hydrogen atom is obtained by combining the compound (2) and R ¹ -X ² (such as chloride and bromide of R ¹ ) with a base and a highly polar solvent such as dimethyl sulfoxide. In the presence of the compound, it can be produced by reacting in a solvent or without a solvent. As the base, alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal alkoxide, organic base, and the like can be preferably used. The solvent may be any solvent that does not adversely affect the reaction, and examples thereof include water, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, methanol and the like. This reaction suitably proceeds at -20 ° C to 120 ° C, particularly 15 ° C to 40 ° C.

  Compound (4) can be produced by reacting compound (3) with a reducing agent in the presence of an acid or an alkylating agent in a solvent or without a solvent. As the reducing agent, sodium borohydride, lithium borohydride, lithium aluminum hydride, Red-Al (sodium bis (2-methoxyethoxy) aluminum hydride), diborane, borane methyl sulfide complex, etc. are preferably used. be able to. As the acid, sulfuric acid, hydrogen chloride, Lewis acid (trimethylsilyl chloride, iodine, chlorine, borane trifluoride ether complex, etc.) and the like can be suitably used. As the alkylating agent, dimethyl sulfate, methyl iodide, benzyl halide and the like can be suitably used. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include tetrahydrofuran and ethanol. This reaction suitably proceeds at -30 ° C to 120 ° C, particularly 0 ° C to 40 ° C.

  Compound (5) can be produced by reacting compound (4) in the presence of an oxidizing agent in a solvent or without a solvent. The oxidizing agent includes (1) dimethyl sulfoxide, sulfur trioxide pyridine complex salt and amine (diisopropylethylamine, triethylamine etc.), (2) dimethyl sulfoxide, oxalyl chloride and amine (diisopropylethylamine, triethylamine etc.), (3) Consisting of dimethyl sulfide, chlorine and amine (diisopropylethylamine, triethylamine, etc.), (4) sodium hypochlorite, sodium hydrogen carbonate, sodium bromide, and 4-hydroxytetramethylpiperidine oxide or derivatives thereof (4 -Aminotetramethylpiperidine oxide, 4-carboxytetramethylpiperidine oxide, 4-cyanotetramethylpiperidine oxide, etc.), (5) chromic acid and its salts, 6) Metal catalyst (platinum, palladium, etc.) and oxygen, (7) Peracid and peroxide, or (8) Dimethyl sulfoxide, DCC (dicyclohexylcarbodiimide), base (pyridine, etc.), acid (trifluoroacetic acid, phosphoric acid) Etc.) (Pfitzner-Moffatt oxidation) or the like can be suitably used. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include dimethyl sulfoxide, dichloromethane, water, benzene, toluene and the like. This reaction suitably proceeds at -78 ° C to 100 ° C, particularly at -78 ° C to 25 ° C.

  Further, the compound (5) is obtained by halogenating the carboxyl group of the compound (3) with thionyl chloride, oxalyl chloride, etc., and then catalytically reducing the compound (4) with a metal catalyst (platinum, palladium, etc.) and hydrogen. It can also be manufactured without going through.

Compound (6) can be produced by carrying out the step of reacting compound (5) with R ² —NH ₂ and the step of reacting with cyanide compound in a solvent or without solvent. The reaction between the compound (5) and R ² —NH ₂ can be suitably carried out by reacting with a cyanide compound in the presence of a dehydrating agent (molecular sieve 4A, magnesium sulfate, sodium sulfate, etc.). The cyanide compound is a compound usually used for cyanation, and examples thereof include hydrocyanic acid, alkali metal cyanide, organic cyanide, and the like, among which alkali metal cyanide is preferably used. Examples of the alkali metal cyanide compound include lithium cyanide, sodium cyanide, potassium cyanide and the like, and examples of the organic cyanide include trimethylsilyl cyanide, tributyltin cyanide, dimethylaluminum cyanide, tetraethylammonium cyanide and the like. Is mentioned.

The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include dichloromethane, toluene, acetonitrile, acetone, ethyl acetate, diethyl ether, tetrahydrofuran, 1,4-dioxane and the like. The reaction between the compound (5) and R ² —NH ₂ preferably proceeds at −50 ° C. to 100 ° C., particularly 0 ° C. to 20 ° C. The step of reacting with the cyanide compound preferably proceeds at −78 ° C. to 100 ° C., particularly −20 ° C. to 20 ° C.

  Compound (II ′) can be produced using compound (6) as follows.

Compound (II) in which R ³ is a carboxyl group and compound (II-a) in which R ³¹ is a carboxyl group can be produced by reacting compound (6) in the presence of an acid or base in a solvent or without a solvent. . As the acid, sulfuric acid, hydrochloric acid and the like can be preferably used. As the base, alkali metal hydroxide, alkali metal alkoxide and the like can be preferably used. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include dichloromethane, water, tetrahydrofuran, ethanol and the like. This reaction suitably proceeds at −30 ° C. to 200 ° C., particularly 0 ° C. to 100 ° C.

Compound (II) in which R ³ is a carbamoyl group and compound (II-a) in which R ³¹ is a carbamoyl group are obtained by reacting compound (6) in the presence of an acid in a solvent or in the absence of a solvent, It can manufacture by neutralizing. As the acid, hydrogen peroxide, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid and the like can be suitably used. As the base, it is preferable to use ammonia, monomethylamine, dimethylamine, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, potassium phosphate, dipotassium hydrogen phosphate and the like. it can. The solvent may be any solvent that does not adversely affect the reaction. For example, toluene, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, methyl ethyl ketone, acetone, chloroform, 1,2- Examples include dichloroethane, xylene, mesitylene, tert-butyl methyl ether, and the like. This reaction suitably proceeds at 0 ° C to 100 ° C, particularly 30 ° C to 50 ° C.

  In the above reaction, a combination of hydrogen peroxide solution as an acid, potassium carbonate as a base, and dimethyl sulfoxide as a solvent is preferable.

As for compound (1), compound (2), compound (3), compound (4), compound (5), compound (6) and compound (II ′) used in the present specification, an optical system based on asymmetric carbon There is an isomer, which may be either a racemate or an optical isomer, but since only optically active (+)-biotin is biologically active, (+)- In order to efficiently lead to biotin, the following optically active substances are preferred. Moreover, the compound whose R < ³¹ > of a compound (II'-a) is a carboxyl group is a compound (II-c).

式中、記号は前記と同一の意味を有する。

In the formula, the symbols have the same meaning as described above.

  Compound (4) can be produced by a known production method described in Heterocycles, Vol. 18, pp. 259-263, 1982 or the like, or a production method analogous thereto, for example, as follows. You can also.

式中、記号は前記と同一の意味を有する。

In the formula, the symbols have the same meaning as described above.

  Compound (11) is prepared by combining cysteine and triphosgene (or phosgene, phenyl chloroformate, alkyl chloroformate, etc.) in the presence of a base (alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, etc.) in a solvent or without solvent. In the presence of ethanol and an activator (thionyl chloride, sulfuric acid, hydrogen chloride, oxalyl chloride, etc.). As a solvent, what is necessary is just a solvent which does not exert a bad influence on reaction, For example, water, 1, 4- dioxane, tetrahydrofuran, diethyl ether etc. are mentioned. This reaction suitably proceeds at −20 ° C. to 100 ° C., particularly 0 ° C. to 40 ° C.

In the compound (12), the compound in which R ¹ has a substituent other than a hydrogen atom is obtained by combining the compound (11) and R ¹ -X ² (such as chloride or bromide of R ¹ ) in a solvent or in the presence of a base. It can be produced by reacting with a solvent. As the base, alkali metal carbonate, alkali metal hydride, alkali metal amide and the like can be preferably used. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include N, N-dimethylacetamide, acetone, acetonitrile, tetrahydrofuran and the like. This reaction suitably proceeds at −20 ° C. to 100 ° C., particularly 15 ° C. to 35 ° C.

  Compound (4) can be produced by reacting compound (12) in the presence of a reducing agent in a solvent or without a solvent. As the reducing agent, sodium borohydride, lithium borohydride, lithium aluminum hydride, Red-Al, DIBAL (diisobutylaluminum hydride), calcium borohydride, zinc borohydride, etc. are preferably used. Can do. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include ethanol, methanol, water, diethyl ether, tetrahydrofuran, 1,4-dioxane and the like. This reaction suitably proceeds at −78 ° C. to 50 ° C., particularly −20 ° C. to 20 ° C.

  In addition, compound (5) is disclosed in J. Am. Chem. Soc. 112, 7050-7051, 1990, etc., or a production method according to them, for example, it can also be produced as follows.

式中、記号は前記と同一の意味を有する。

In the formula, the symbols have the same meaning as described above.

  Compound (13) can be produced by reacting compound (3) with ethanethiol in the presence of an activator in a solvent or without solvent. Activating agents include DCC, EDC.HCl (1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride), chlorocarbonates, isocyanuric chloride, CDI (carbonyldiimidazole), etc. It can be used suitably. In this reaction, addition of DMAP (1,4-dimethylaminopyridine) is preferred because the reaction proceeds rapidly. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include acetonitrile, acetone, tetrahydrofuran, benzene, toluene and the like. This reaction suitably proceeds at −50 ° C. to 100 ° C., particularly 0 ° C. to 20 ° C.

  Compound (5) can be produced by reacting compound (13) in the presence of a reducing agent and a catalyst in a solvent or without a solvent. As the reducing agent, silanes such as triethylsilane, trichlorosilane, and triphenylsilane can be suitably used. As the catalyst, palladium catalysts such as palladium hydroxide, palladium carbon, palladium black and the like can be suitably used. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include dichloromethane, acetone, tetrahydrofuran, and the like. This reaction suitably proceeds at −20 ° C. to 100 ° C., particularly 0 ° C. to 20 ° C.

  In addition, biotin which is the final target is obtained by converting compound (I) or compound (II-a) to compound (III), followed by JP-A-8-231553, JP-A-2000-191665, Chemical Reviews (Chemical Reviews). Reviews), Vol. 97, No. 6, pp. 1755-1792, 1997, and the like, or a production method according to them, for example, can also be produced as follows.

In the formula, X ¹ represents a halogen atom, R ⁴ represents an esterified carboxyl group or an amidated carboxyl group, and other symbols have the same meaning as described above.

Furthermore, in the compound (I), when R ³ is a cyano group, an alkoxycarbonyl group, an alkylthiocarbonyl group, or a carbamoyl group which may have a substituent, the carboxyl group of R ³ (compound (Ia)) The conversion can be performed by a conventional method, for example, Nobuo Izumiya et al., “Basics and Experiments of Peptide Synthesis” (Maruzen 1985) and Green et al., “Protective Groups in Organic Synthesis”. It can be carried out by hydrolysis according to the method described in the second edition (Joan Willie & Sons 1991) or a method analogous thereto. Specifically, it can be converted into a carboxyl group by hydrolysis using a base such as an alkali metal hydroxide or alkali metal alkoxide, or an acid such as a mineral acid (hydrochloric acid, sulfuric acid or the like). The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include acetic acid, water, ethanol, tetrahydrofuran, and dichloromethane. This hydrolysis reaction suitably proceeds at 0 ° C to 200 ° C, particularly 50 ° C to 80 ° C.

  Compound (III) is obtained by subjecting compound (II-b) to ring conversion and cyclization in the absence of oxygen, for example, in a solvent or without solvent in a stream of nitrogen or argon, or compound (Ia) Alternatively, compound (IV-a) can be produced by cyclization and epimerization in a solvent or without solvent.

  The solvent used in the step of ring conversion and cyclization of compound (II-b) may be any solvent that does not adversely affect the reaction. For example, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide N-methyl-2-pyrrolidone and the like. This reaction suitably proceeds at 0 ° C to 200 ° C, particularly 80 ° C to 100 ° C.

  The cyclization and epimerization of the compound (Ia) or the compound (IV-a) in the present specification is performed after cyclization and epimerization (step via the compound (III-a)) and epimerization. Any step of cyclization (step through compound (Ia ′)) is included.

  The cyclization step of compound (Ia) or compound (IV-a) can be preferably carried out in the presence of an activating agent. As the activator, DCC, EDC · HCl, cyanuric chloride, and the like can be suitably used. Moreover, a cyclization process can be implemented in presence of the base used at the following epimerization process as needed. The epimerization step can be preferably carried out only by heating in the presence of a base or without an additive. As the base, organic bases such as pyridine, DBU (1,8-diazabicyclo [5.4.0] undec-7-ene), triethylamine and the like can be preferably used. Moreover, an epimerization process can be implemented in presence of an acid (p-toluenesulfonic acid, hydrogen chloride, etc.) as needed.

  The solvent used in the cyclization and epimerization step may be any solvent that does not adversely influence the reaction, and examples thereof include pyridine, toluene, tetrahydrofuran, acetone, acetonitrile, ethanol and the like. This reaction suitably proceeds at -20 ° C to 120 ° C, particularly 0 ° C to 70 ° C.

  Compound (VI) can be produced by reacting compound (III) and compound (V) in the presence of a catalyst in a solvent or in the absence of a solvent, followed by hydrolysis. As the catalyst, palladium hydroxide, palladium carbon, palladium oxide, palladium black, tetrakistriphenylphosphine palladium, dichlorobistriphenylphosphine palladium and the like can be suitably used. The hydrolysis reaction can be preferably carried out in the presence of water or an acid (p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, etc.). The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include tetrahydrofuran, N, N-dimethylformamide, toluene and the like. This reaction suitably proceeds at -20 ° C to 200 ° C, particularly 30 ° C to 50 ° C.

Biotin (VII) is obtained by reducing Compound (VI) in a solvent or without a solvent, followed by hydrolysis, and when R ¹ and / or R ^{2 of} Compound (VI) is a group other than a hydrogen atom, R ¹ And / or R ² can be produced by converting it into a hydrogen atom (deprotection reaction of a protecting group).

  The reduction reaction can be preferably carried out by hydrogenation in the presence of a catalyst such as palladium hydroxide, palladium carbon, palladium black, palladium chloride, palladium acetate, palladium oxide and the like. The hydrolysis reaction can be suitably carried out by using a base such as sodium hydroxide. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, water, or a mixed solvent thereof. This reaction suitably proceeds at 0 ° C to 200 ° C, particularly 50 ° C to 80 ° C.

Further, when R ¹ and / or R ^{2 of the} compound (VI) is a group other than a hydrogen atom, the step of converting R ¹ and / or R ² to a hydrogen atom (deprotection reaction of a protecting group) is usually performed. For example, the method described in Greene et al., “PROTECTIVE GROUPS IN ORGANIC SYNTHESIS” 2nd edition (Joan Willie & Sons 1991) or a method analogous thereto Can be performed. As a specific example, it can be suitably carried out by treating with hydrohalic acid such as hydrobromic acid or treating with mesitylene and an acid (methanesulfonic acid, sulfuric acid, acetic acid, etc.). The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include water, benzene, toluene, dichloromethane and the like. This reaction suitably proceeds at 0 ° C to 200 ° C, particularly 80 ° C to 100 ° C.

  Compound (I), compound (Ia), compound (Ib), compound (II), compound (II ′), compound (II-a), compound (II) used or obtained in the present specification -B), compound (II-c), compound (III), compound (III-a), compound (IV), compound (IV-a), compound (VI), compound (6) or compound (6-a) ), For example, inorganic salts (hydrochloride, phosphate, hydrobromide, sulfate, etc.) or organic acids (acetate, formate, propionate, fumarate, Maleate, succinate, tartrate, citrate, malate, succinate, benzoate, methanesulfonate, benzenesulfonate, tosylate, etc.). Further, when the compound of the present invention has an acidic group such as a carboxylic acid, the compound of the present invention may be an inorganic base (an alkali metal salt such as sodium salt or potassium salt, an alkaline earth such as calcium salt or magnesium salt). Metal salts, ammonium salts, etc.) or organic bases (amino acid salts such as triethylamine salts, lysine salts, etc.) may be formed. The educt and the salt can be converted into each other by a known method or a method analogous thereto.

  Next, the present invention will be described in more detail based on examples, but the present invention is not limited to such examples.

Example 1
(1) 92.8 g of zinc powder was suspended in a mixed solution of 180 ml of tetrahydrofuran and 120 ml of toluene, 58 g of bromine was added at 10 ° C. to 37 ° C. over 15 minutes, and the solution was heated to 50 ° C. over 15 minutes. To the solution, 186.4 g of 5-iodovaleric acid ethyl ester was added dropwise at 50 ° C. to 55 ° C. over 3.5 hours.
(2) After cooling the solution obtained in Example 1- (1) to 30 ° C., 360 ml of toluene, (3aS, 6aR) -1,3-dibenzyl-hexahydro-4H-thieno [3,4-d] imidazole 176 g of 2,4-dione and 4.8 g of N, N-dimethylformamide 44 ml suspension in the order of 176 g of palladium catalyst (Degussa; E 1002 NN / D 10% Pd) were added at 28 ° C. to 40 ° C. for 17 hours. Stir. Hydrochloric acid (concentrated hydrochloric acid 157 ml + water 184 ml) was added to the solution at 10 ° C. to 30 ° C., and the mixture was stirred at 20 ° C. for 1 hour. After filtering the solution, the filtrate was heated to 40 ° C. over 40 minutes and separated. The organic layer was washed with water, an aqueous sodium bicarbonate solution, an aqueous sodium sulfite solution, and water in this order and concentrated. Toluene was added to the residue and further concentrated. After the residue was dissolved in 67 ml of methanol, 6.7 g of activated carbon was added, stirred and filtered. The residue was washed with 67 ml of methanol, combined with the filtrate and used in the next step.
The product obtained in the above reaction was partially saponified to give (5Z) -5-[(3aS, 6aR) -1,3-dibenzyl-hexahydro-2-oxo-4H-thieno [3,4-d] imidazole- (5Z) -5-[(3aS, 6aR) -1,3-dibenzyl-hexahydro-2-oxo-4H- obtained by the above reaction by quantifying by HPLC under the following conditions as 4-ylidene] pentanoic acid It was confirmed that 220 g of thieno [3,4-d] imidazol-4-ylidene] pentanoic acid ethyl ester was obtained.

(HPLC conditions)
Column: L-column ODS (4.6 × 150 mm) (manufactured by Shimadzu Corporation), moving bed: acetonitrile / potassium hydrogen diphosphate (pH 3) = 40/60, flow rate: 1.0 ml / min, UV detection: 254 nm, Column temperature 40 ° C
(3) 88 ml of the methanol solution obtained in Example 1- (2) was added with 313 ml of methanol, 110 ml of water, and 9.06 g of palladium catalyst (Degussa; E 106 NN / W 5% Pd). The mixture was stirred at a temperature of 110 ° C. for 16 hours. After cooling the solution, the catalyst was filtered and washed with 350 ml of methanol. A sodium hydroxide aqueous solution (14.6 g of sodium hydroxide + 55 ml of water) was added to the filtrate, and the mixture was stirred at 50 ° C. for 1 hour. To the solution was added 10% hydrochloric acid at 30 ° C. or lower until pH 7, and then concentrated. Toluene was added to the residue and further concentrated. The residue was dissolved in 300 ml of toluene and then washed with 10% hydrochloric acid and water while heating at 40 ° C. (3aS, 4S, 6aR) -1,3-dibenzyl-hexahydro-2-oxo-4H-thieno [3,4-d] imidazole obtained by the above reaction by quantifying the organic layer by HPLC under the following conditions It was confirmed that 52 g of -4-pentanoic acid was obtained.

(HPLC conditions)
Column: L-column ODS (4.6 × 150 mm) (manufactured by Shimadzu Corporation), moving bed: acetonitrile / potassium hydrogen diphosphate (pH 3) = 40/60, flow rate: 1.0 ml / min, UV detection: 254 nm, Column temperature 40 ° C
(4) After concentrating the toluene solution obtained in Example 1- (3), it was substituted and concentrated with mesitylene. The residue was dissolved in 166 ml of mesitylene, 108 ml of methanesulfonic acid was added, and the mixture was stirred at 133 ° C. for 1 hour. The solution was cooled to 80 ° C., 15 ml of acetic acid was added, and the solution was added dropwise to 1040 ml of purified water at 30 ° C. or lower. The solution was cooled with ice for 1 hour, and the precipitated crystals were collected by filtration, washed with water and acetone, and dried under reduced pressure to obtain 25.7 g of crude biotin.
24.6 g of crude biotin was dissolved in an aqueous sodium hydroxide solution (4.42 g of sodium hydroxide + 330 ml of water) and adjusted to pH 8.5 with dilute hydrochloric acid at 50 ° C. to 60 ° C. The solution was added with 16 g of activated carbon at 50 ° C. to 60 ° C., stirred for 10 minutes, and then filtered. The filtrate was heated to 90 ° C. to 95 ° C., the solution was adjusted to pH 1.8-2.2 with concentrated hydrochloric acid, and neutralized crystallization was performed. Stir at the same temperature for 30 minutes to grow. The solution was slowly cooled and ice-cooled, and the precipitated crystals were filtered off. The crystals were air-dried at 50 ° C. overnight to obtain 22.4 g of (+)-biotin.

Reference example Reference example 1
(1) 20 g of (4R) -3-benzyl-4-hydroxymethylthiazolidine-2-one was dissolved in 45 ml of dimethyl sulfoxide at room temperature, and 1.45 ml of pyridine, 1.38 ml of trifluoroacetic acid, and 30 ml of ethyl acetate were sequentially added. . At 25 ° C., 22.2 g of dicyclohexylcarbodiimide and 15 ml of ethyl acetate are added, and the mixture is stirred at 50 ° C. for 3 hours. 100 ml of ethyl acetate was added to the reaction solution, stirred at 10 ° C. or lower for 30 minutes, and the precipitate was separated by filtration. The filtrate was washed with brine (saturated brine: water = 1: 1), and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with brine (saturated brine: water = 1: 1), dried and concentrated to give (4R) -2-oxo-3-benzylthiazolidine-4-carbaldehyde. .
(2) The compound obtained in Reference Example 1- (1) is dissolved in 50 ml of dichloromethane, and 5 g of magnesium sulfate is added at 20 ° C. to 25 ° C. At 5 ° C. or lower, 4.89 ml of benzylamine was added to the solution, and the mixture was stirred at 20 ° C. to 25 ° C. for 1 hour 30 minutes. After cooling the solution to −5 ° C., 4.39 g of sodium cyanide and 15 ml of an aqueous solution of 5.1 ml of acetic acid were added at −5 ° C. to 0 ° C. Next, the solution was heated to 20 ° C. to 25 ° C. over 4 hours and then stirred for 12 hours. To the solution was added 50 ml of dichloromethane, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was dried and concentrated to obtain 13.47 g of a mixture of syn and anti isomers of (4R) -4- [1- (N-benzylamino) -1-cyanomethyl] -3-benzylthiazolidin-2-one. Was obtained as pale yellow crystals. When the optical purity of the mixture was analyzed by high performance liquid chromatography (HPLC), it was a ratio of syn isomer: anti isomer = 14: 1.
(HPLC conditions)
Column: L-column ODS (4.6 × 150 mm) (manufactured by Shimadzu Corporation), moving bed: 0.01M KH ₂ PO ₄ (pH = 3) / acetonitrile = 50/50, flow rate: 0.5 ml / minl, UV detection: 225 nm, column temperature: 40 ° C.
Syn body:
Melting point: 124-125 ° C
[Α] _D ²⁵ : + 46.1 ° (C = 1.0, chloroform)
Optical purity (HPLC): 99% ee
(HPLC conditions)
Column: Chiralcel AD-H (4.6 × 250 mm) (manufactured by Daicel Chemical Industries), moving bed: ethanol / n-hexane = 10/90, flow rate: 0.8 ml / min, UV detection: 225 nm, column temperature: 40 ° C.
anti body:
MS APCI (m / z): 338 [(M + H) ^<+ >].
(3) The compound obtained in Reference Example 1- (2) was suspended in 30 ml of toluene, and 1.44 ml of water and 14.8 ml of concentrated sulfuric acid were added under ice cooling, followed by stirring at 40 ° C. for 24 hours. At 30 ° C. or lower, 7 ml of water, 39 ml of acetone, and 45 ml of water were sequentially added to the solution. Subsequently, 45 ml of concentrated aqueous ammonia was added to the solution at 40 ° C. or lower, and the mixture was stirred at 25 ° C. for 30 minutes. The precipitated crystals are collected by filtration, washed with acetone, water and acetone in this order, and dried to give (4R) -4-[(1R) -1- (N-benzylamino) -1-carbamoylmethyl] -3. -12.6 g of benzylthiazolidine-2-one was obtained as pale yellow crystals.
Melting point: 194-195 ° C
ESI · MS (m / z): 356 (M ⁺ +1)
[Α] ^{_{D 20: -38.8 ° (C =}} 0.45, N, N- dimethylformamide).

Reference example 2
100 g of (4R) -4-[(1R) -1- (N-benzylamino) -1-carbamoylmethyl] -3-benzylthiazolidine-2-one was dissolved in 200 ml of N, N-dimethylformamide, and the nitrogen stream was used. , And stirred at 85 ° C. for 5 hours. At 90 ° C. to 95 ° C., 200 ml of 35% hydrochloric acid was added dropwise to the solution and stirred for 1 hour and 15 minutes. Furthermore, 100 ml of 35% hydrochloric acid was added dropwise and stirred for 2 hours. Subsequently, 200 ml of water was added dropwise at 85 ° C. The solution is ice-cooled, and the precipitated crystals are collected by filtration, washed with water, and dried at 50 ° C. for 17 hours to give (4R, 5R) -1,3-dibenzyl-2-oxo-5- (mercaptomethyl). ) 93.1 g of imidazolidine-4-carboxylic acid was obtained as colorless crystals.
Melting point: 159-160 ° C
ESI · MS (m / z): 357 (M ⁺ +1)
[Α] ^{_{D 20: + 48.8 ° (C}} = 0.62, N, N- dimethylformamide).

Reference example 3
To a 240 ml chloroform solution of 30 g of (4R, 5R) -1,3-dibenzyl-2-oxo-5- (mercaptomethyl) imidazolidine-4-carboxylic acid, 22.7 g of pyridine, and 2.6 ml of trifluoroacetic acid, dicyclohexylcarbodiimide was added. A solution of 17.4 g of chloroform in 60 ml was added dropwise at 5 ° C. over 30 minutes. The solution was refluxed for 5 hours and then concentrated under reduced pressure. After concentration by substitution twice with ethyl acetate, 300 ml of ethyl acetate was added to the residue, and the mixture was stirred at 50 ° C. for 30 minutes. After cooling to 25 ° C., insoluble matters were filtered off. After the filtrate was concentrated, 85 ml of methanol was added and dissolved by heating. After cooling the solution, the precipitated crystals were collected by filtration and washed with cold methanol. The precipitated crystals were blown and dried at 50 ° C. to give 21.3 g of (3aS, 6aR) -1,3-dibenzyl-hexahydro-4H-thieno [3,4-d] imidazole-2,4-dione as colorless crystals. Got as.
Melting point: 122-123 ° C
[Α] _D ²⁵ : + 90.5 ° (C = 1.0, chloroform).

Reference example 4
Under a nitrogen atmosphere, 30.4 g of zinc powder was suspended in 55 ml of tetrahydrofuran, 3.5 ml of trimethylsilyl chloride was added, and the mixture was stirred for 15 minutes. After heating to 40 ° C., dropwise addition of 102.9 g of 5-iodovaleric acid ethyl ester was started. Although heat was generated simultaneously with the dropwise addition, the dropwise addition was continued so as to maintain a temperature of 60 ° C to 65 ° C. After completion of the dropwise addition, the mixture was washed with 5 ml of tetrahydrofuran, immersed in an outer bath at 55 ° C. and continuously stirred (total time for dropwise addition and stirring: 50 minutes). After confirming disappearance of 5-iodovaleric acid ethyl ester by high performance liquid chromatography, Cooled to 23 ° C. 125 ml of toluene, (3aS, 6aR) -1,3-dibenzyl-hexahydro-4H-thieno [3,4-d] imidazole-2,4-dione 52.5 g, 1.09 g of 10% palladium hydroxide carbon, Toluene 50 ml and N, N-dimethylformamide 11.5 ml were sequentially added, and the mixture was stirred at 24 ° C. to 35.5 ° C. for 50 minutes. The reaction solution was filtered using 12 g of activated carbon and 32.5 g of celite, and washed with 200 ml of tetrahydrofuran. The filtrate and washings were combined, washed with 2M hydrochloric acid, washed with water, and concentrated. The concentrated residue was dissolved in 390 ml of toluene, 2.95 g of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at 20 ° C. to 25 ° C. for 1.5 hours. About 100 ml of the solvent was distilled off at 40 ° C. to 45 ° C., and the remainder was washed with water, an aqueous solution of sodium thiosulfate and water in this order, and further concentrated to give (5Z) -5-[(3aS, 6aR) -1,3. 60.6 g of -dibenzyl-hexahydro-2-oxo-4H-thieno [3,4-d] imidazol-4-ylidene] pentanoic acid ethyl ester were obtained as an oil.

Reference Example 5
400 ml of purified water, 12.85 g of 20% palladium hydroxide on carbon (50% wet), (5Z) -5-[(3aS, 6aR) -1,3-dibenzyl-hexahydro-2-oxo-4H-thieno [3 4-d] imidazol-4-ylidene] pentanoic acid ethyl ester 249.5 g of methanol in 900 ml was added in this order, and the mixture was replaced with hydrogen at 490 kPa three times. Further, 627 kPa hydrogen pressure was applied at 6.5 ° C., and the mixture was stirred at 500 rpm. 50 minutes after the start of heating, 92.5 ° C. and 843 kPa, 4 hours later, 117 ° C. and 921 kPa, and 11 hours later, 116 ° C. and 853 kPa, so hydrogen was charged to 882 kPa. After 24 hours, the reaction solution was cooled at 115 ° C. and 892 kPa, washed with methanol, and the catalyst was filtered. The filtrate was concentrated, and 400 ml of toluene was added to the residue, followed by displacement concentration three times at 65 ° C. in the outer bath. To the above residue, 1206 ml of methanol, 402 ml of water and 53.3 g of sodium hydroxide were added and stirred at 40 ° C. for 2 hours. 300 g of 10% aqueous hydrochloric acid was added to the reaction solution to neutralize the pH to 7, 6 g of activated carbon was added, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was precoated and filtered with 6 g of activated carbon. Methanol is distilled off under reduced pressure, and 600 ml of ethyl acetate is added. 10% aqueous hydrochloric acid was added for extraction (pH of the aqueous layer was 0.7), and the organic layer was washed with 10% brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The extract was concentrated under reduced pressure, and when ethyl acetate no longer flew off, it was substituted and concentrated twice with 170 ml of mesitylene, and (3aS, 4S, 6aR) -1,3-dibenzyl-hexahydro-2-oxo-4H-thieno [3,4- d] 170.1 g of imidazole-4-pentanoic acid was obtained as a colorless oil.

Reference Example 6
A mixture of 3.0 g of (3aS, 4S, 6aR) -1,3-dibenzyl-hexahydro-2-oxo-4H-thieno [3,4-d] imidazol-4-pentanoic acid and 24 ml of 48% hydrobromic acid. , And refluxed at 110 to 120 ° C. for 48 hours. Hot extraction with 10 ml of toluene was performed 4 times to remove benzyl bromide. The aqueous layer was concentrated, and 15 ml of water and 11.5 ml of 6M aqueous sodium hydroxide solution were added to the residue. Subsequently, 3.36 g of ethoxycarbonyl chloride was added dropwise, the pH was kept at 8-10, and the reaction was performed at room temperature for 3 hours. . Thereafter, the temperature of the reaction solution was raised to 70 ° C. to 80 ° C., and the reaction was performed for 20 hours (while maintaining the pH at 12 by adding a 6M aqueous sodium hydroxide solution). The pH was adjusted to 7.4 to 7.8 with 7 ml of 16% hydrochloric acid, and filtration was performed using 1.0 g of activated carbon at 90 to 95 ° C. The filtrate was heated to 80 ° C. to 85 ° C., adjusted to pH 1.8 to 2.2 using 6 ml of 16% hydrochloric acid, and neutralized crystallization was performed. After cooling, it was collected by filtration, washed with water, and dried by blowing at 50 ° C. to obtain 1.38 g of (+)-biotin as colorless crystals.

Reference Example 7
(1) 79.3 g of (4R) -3-benzyl-4-hydroxymethylthiazolidine-2-one was treated in the same manner as in Reference Example 1- (2), and the precipitated crystals were filtered off. Concentrated. The residue was purified by silica gel chromatography (hexane: chloroform: ethyl acetate = 5: 5: 1), and (4R) -4-[(1S) -1- (N-benzylamino) -1-cyanomethyl] -3- 9.3 g of benzylthiazolidin-2-one was obtained.
Melting point: 131-132 ° C
[Α] _D ²³ : -174.7 ° (C = 1.0, chloroform)
MS APCI (m / z): 338 [(M + H) ^<+ >].
(2) 6.0 g of (4R) -4-[(1S) -1- (N-benzylamino) -1-cyanomethyl] -3-benzylthiazolidine-2-one was used in the same manner as in Reference Example 1- (3). By processing, colorless oily (4R) -4-[(1S) -1- (N-benzylamino) -1-carbamoylmethyl] -3-benzylthiazolidin-2-one was obtained. Next, the resultant was dissolved in ethyl acetate, 6 ml of 4M hydrogen chloride-ethyl acetate solution was added, and the precipitated crystals were collected by filtration to give (4R) -4-[(1S) -1- (N-benzylamino) -1-carbamoyl. 4.3 g of methyl] -3-benzylthiazolidine-2-one hydrochloride was obtained.
ESI · MS (m / z): 356 (M ⁺ +1)
[Α] _D ²³ : −32.6 ° (C = 1.0, methanol).
(3) 0.541 g of (4R) -4-[(1S) -1- (N-benzylamino) -1-carbamoylmethyl] -3-benzylthiazolidin-2-one hydrochloride was added to 10 ml of N, N-dimethylformamide. And stirred at 100 ° C. for 3 hours under a nitrogen stream. Ethyl acetate was added to the reaction mixture, washed with water and saturated brine, dried and concentrated. The residue was crystallized from hexane to obtain 342 mg of (3aS, 6aR) -1,3-dibenzyl-hexahydro-4H-thieno [3,4-d] imidazole-2,4-dione as colorless crystals.
Optical purity (HPLC):> 91% ee
(HPLC conditions)
Column: Chiralcel AD (4.6 × 250 mm) [manufactured by Daicel Chemical Industries, Ltd.], moving layer: ethanol / hexane = 15/85, flow rate: 0.8 ml / min, UV detection: 225 nm, column temperature: 40 ° C.

Reference Example 8
20 g of (4R, 5R) -1,3-dibenzyl-2-oxo-5- (mercaptomethyl) imidazolidine-4-carboxylic acid is dissolved in 160 ml of chloroform, 6.2 g of pyridine is added, and dicyclohexyl is added under ice cooling. A solution of 12.7 g of carbodiimide in 40 ml of chloroform was added at 15 ° C. or lower. The mixture was stirred at room temperature for 1 hour, and ethyl acetate was added to the reaction solution, followed by filtration. The filtrate was washed with 2M hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried and concentrated. The residue was recrystallized with ethyl acetate to obtain 8.0 g of (3aR, 6aR) -1,3-dibenzyl-hexahydro-4H-thieno [3,4-d] imidazole-2,4-dione.
Melting point: 115-116 ° C
[Α] _D ²⁶ : + 10.6 ° (C = 1.0, chloroform).

Reference Example 9
100 mg of (3aR, 6aR) -1,3-dibenzyl-hexahydro-4H-thieno [3,4-d] imidazole-2,4-dione is dissolved in 1 ml of chloroform, 0.5 ml of pyridine is added, and the mixture is stirred at room temperature for 23 hours. did. The reaction solution was washed with 2M hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried and concentrated. Isopropyl ether was added and the precipitated crystals were separated by filtration to obtain 75.1 mg of (3aS, 6aR) -1,3-dibenzyl-hexahydro-4H-thieno [3,4-d] imidazole-2,4-dione. .
Melting point: 122-123 ° C
[Α] _D ²⁵ : + 90.5 ° (C = 1.0, chloroform).

Reference Example 10
To a solution of 14 g of (4R) -4-[(1R) -1- (N-benzylamino) -1-carbamoylmethyl] -3-benzylthiazolidine-2-one in 39 ml of N, N-dimethylformamide was added 3.96 g of sodium bicarbonate. In addition, the mixture was stirred at 80 to 85 ° C. for 17 hours. The reaction solution was concentrated under reduced pressure, 40 ml of methanol and 20 ml of water were added to the concentrated residue, and the mixture was stirred at 5 ° C. or lower for 1 hour. The precipitated crystals were collected by filtration, washed with a mixed solution of 80 ml of methanol and 40 ml of water, and then blown and dried at 50 ° C. for 17 hours to obtain (4S, 4 ′S, 5R, 5′R) -5, 5 ′-[ 12.14 g of dithiobis (methylene)] bis (1,3-dibenzyl-2-oxoimidazolidine-4-carboxamide) was obtained as pale yellow crystals.
Melting point: 208-211 ° C
ESI · MS (m / z): 709 (M ⁺ +1)
[Α] _D ²⁰ : + 55.4 ° (C = 0.29, N, N-dimethylformamide).

Reference Example 11
497 mg of (4S, 4 ′S, 5R, 5′R) -5,5 ′-[dithiobis (methylene)] bis (1,3-dibenzyl-2-oxoimidazolidine-4-carboxamide) was dissolved in 5 ml of acetic acid. Then, 249 mg of zinc powder is added and stirred at 90 ° C. for 1.5 hours. Ethyl acetate was added to the reaction solution and filtered through celite. The filtrate was concentrated under reduced pressure, and ether and hexane were added to the residue. The precipitated crystals were collected by filtration, washed with water and hexane, and then dried under reduced pressure to give 482 mg of (4R, 5R) -1,3-dibenzyl-2-oxo-5- (mercaptomethyl) imidazolidine-4-carboxamide as colorless matter. Obtained as crystals.
Melting point: 119-122 ° C
ESI · MS (m / z): 356 (M ⁺ +1)
[Α] _D ²⁰ : −1.2 ° (C = 0.33, N, N-dimethylformamide).

Reference Example 12
12 g of the compound obtained in Reference Example 10 was dissolved in 24 ml of acetic acid, 7.2 g of zinc powder was added, and the mixture was stirred at 55-60 ° C. for 1 hour. After cooling the reaction solution to 20 ° C., 72 ml of concentrated hydrochloric acid was added and stirred at 80 to 90 ° C. for 2 hours. 120 ml of water was added to the reaction solution, cooled to 25 ° C. over 1 hour, and stirred at 5 ° C. or lower for 1 hour. The precipitated crystals were collected by filtration, washed with 95 ml of water and dried under reduced pressure to give 11.05 g of (4R, 5R) -1,3-dibenzyl-2-oxo-5- (mercaptomethyl) imidazolidine-4-carboxylic acid. Was obtained as colorless crystals.
The physical property values of this product coincided with those of Reference Example 2.

Reference Example 13
23.5 g of (4R) -4-[(1R) -1- (N-benzylamino) -1-cyanomethyl] -3-benzylthiazolin-2-one was dissolved in 210 ml of dimethyl sulfoxide, and potassium carbonate (fine powder) 1.35 g was added, and 12 ml of 30% hydrogen peroxide was added dropwise at 20 ° C. to 25 ° C., followed by stirring at room temperature for 1 hour. An additional 12 ml of 30% aqueous hydrogen peroxide was added to the solution and stirred at 20 ° C. for 13 hours, and then 210 ml of water was added at room temperature and stirred for 3 hours. The precipitated crystals were collected by filtration, washed with water and acetone, and then air-dried overnight at 50 ° C. to give colorless powder of (4R) -4-[(1R) -1- (N-benzylamino) -1 -Carbamoylmethyl] -3-benzylthiazolin-2-one 21.8 g was obtained. The physical property values of this product coincided with those of Reference Example 1- (3).

Reference Example 1B
(1) 175.6 g of L-cysteine monohydrochloride monohydrate was dissolved in a solution of 184.0 g of sodium hydroxide in 0.88 liters of water under ice-cooling, and phenyl chloroformate 313 was added within a range not exceeding 30 ° C. Add dropwise 2 g of 0.35 liter solution of toluene. After stirring at room temperature for 2 hours, the solution is allowed to stand and separate. The aqueous layer was washed with 0.35 liter of toluene, separated, and the aqueous layer was concentrated to obtain 139.84 g of (4R) -2-oxothiazolidine-4-carboxylic acid as colorless crystals.
Melting point: 168-170 ° C
MS / APCI (m / z): 148 [(M + H) ⁺ ]
[Α] _D ²⁵ : −62.8 ° (C = 1.0, H ₂ O).
(2) To 1.47 g of the compound obtained in Reference Example 1B- (1), a solution of 0.6 g of sodium hydroxide in 1.5 ml of water and 4.4 ml of dimethyl sulfoxide were sequentially added under ice cooling. Thereto was added 2.3 ml of benzyl chloride at room temperature, and the mixture was stirred for 15 hours. The mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the insoluble material was filtered off and concentrated to give (4R) -2-oxo-3-benzylthiazolidine-4-carboxylic acid. 24 g were obtained as colorless crystals.
Melting point: 95-97 ° C
MS · APCI (m / z): 238 [(M + H) ⁺ ]
[Α] _D ²⁵ : -102.2 ° (C = 1.0, chloroform).
(3) 1.53 g of sodium borohydride was added to 32 ml of tetrahydrofuran at room temperature and cooled to 10 ° C. Thereto was added 8.0 g of the compound obtained in Reference Example 1B- (2), and further 2 g of tetrahydrofuran in 2.0 g of sulfuric acid was added. After stirring at 40 ° C. to 50 ° C. for 3 hours, the reaction solution was ice-cooled and pH was adjusted. 2M hydrochloric acid was added until. The reaction solution was diluted with ethyl acetate and separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized with diisopropyl ether to obtain 6.82 g of (4R) -3-benzyl-4-hydroxymethylthiazolidin-2-one as colorless crystals.
Melting point: 87-90 ° C
MS · APCI (m / z): 224 [(M + H) ⁺ ]
[Α] _D ²⁵ : −26.7 ° (C = 1.0, methanol)
Optical purity (HPLC):> 99% ee

(HPLC conditions)
Column: Chiralcel AD (4.6 × 250 mm) [manufactured by Daicel Chemical Industries, Ltd.], moving layer: ethanol / hexane = 10/90, flow rate: 0.8 ml / min, UV detection: 225 nm, column temperature: 40 ° C.
(4) 1.0 g of the compound obtained in Reference Example 1B- (3) was dissolved in 5.0 ml of dimethyl sulfoxide, and 1.95 ml of diisopropylethylamine was added dropwise at room temperature. The reaction mixture was ice-cooled, 1.78 g of sulfur trioxide pyridine complex salt was added at 12 ° C. to 20 ° C., and the mixture was stirred at the same temperature for 30 min. The reaction solution was added to 30 ml of ice water and extracted with 20 ml of ethyl acetate. The aqueous layer was re-extracted with 10 ml of ethyl acetate. The ethyl acetate layers were combined and washed twice with 10 ml of 10% citric acid, and then washed with 10 ml of water and 10 ml of saturated saline. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 985.9 mg of (4R) -2-oxo-3-benzylthiazolidine-4-carbaldehyde as a colorless oil.
MS.APCI (m / z): 222 [(M + H) ^<+ >].

Reference Example 2B
2.34 g of dimethyl sulfoxide was dissolved in 22 ml of dichloromethane, and 1.31 ml of oxalyl chloride was added thereto at −78 ° C. After stirring for 10 minutes at the same temperature, a solution of 2.23 g of the compound obtained in Reference Example 1B- (3) in 11 ml of dichloromethane was added dropwise at −60 ° C. or lower. After stirring at −78 ° C. for 20 minutes, 5.58 ml of triethylamine was added dropwise at −60 ° C. or lower. After raising the reaction temperature to −20 ° C. over 1.5 hours, the reaction mixture was added to 10% citric acid water and separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2.20 g of the same target product as Reference Example 1B- (4). The physical property values of this product coincided with those of Reference Example 1B- (4).

Reference Example 3B
532 mg of chlorine was dissolved in 11 ml of dichloromethane, and 0.73 ml of dimethyl sulfide was added at −20 ° C. to −10 ° C. After stirring at the same temperature for 10 minutes, a solution of 1.12 g of the compound obtained in Reference Example 1B- (3) in 5.5 ml of dichloromethane was added dropwise at -25 ° C. After stirring at −25 ° C. for 20 minutes, 2.79 ml of triethylamine was added dropwise at −25 to −18 ° C. After stirring at −25 ° C. for 10 minutes, the reaction mixture was added to 10% citric acid water and separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.17 g of the same target product as Reference Example 1B- (4). The physical property values of this product coincided with those of Reference Example 1B- (4).

Reference Example 4B
447 mg of the compound obtained in Reference Example 1B- (3), 6.9 mg of 4-hydroxytetramethylpiperidine oxide and 206 mg of sodium bromide were dissolved in a mixed solvent of 6 ml of dichloromethane and 1 ml of water, and ice-cooling was performed while bubbling nitrogen. Below, a mixture of 1.49 g of sodium hypochlorite water, 491 mg of sodium bicarbonate and 5 ml of water was slowly added dropwise. After stirring for 1 hour, the layers were separated, and the organic layer was washed with 16 mg of potassium iodide, 10% aqueous potassium hydrogen sulfate solution and hypo water, respectively. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 147.5 mg of the same target product as Reference Example 1B- (4). The physical property values of this product coincided with those of Reference Example 1B- (4).

Reference Example 5B
(1) 175.6 g of L-cysteine monohydrochloride monohydrate was dissolved in a 2 liter solution of 180 g of sodium hydroxide in an ice-cooled nitrogen stream. In this solution, a solution of 118.7 g of triphosgene in 700 ml of 1,4-dioxane was added dropwise at 25 ° C. to 29 ° C. over 1 hour and 30 minutes, and further stirred at the same temperature for 3 hours. Concentrated hydrochloric acid was added to this reaction mixture to adjust to weak acidity, and then the solvent was distilled off under reduced pressure. 200 ml of toluene was added to the concentrated residue, and the mixture was again distilled off under reduced pressure. After adding 700 ml of ethanol to this concentrated residue, 131 g of thionyl chloride was added over 40 minutes under ice cooling, followed by stirring for 19 hours while raising the temperature to room temperature. After distilling off the solvent under reduced pressure, the concentrated residue was dissolved in 1 liter of ethyl acetate and washed with 700 ml of water, 300 ml of saturated aqueous sodium bicarbonate, and 500 ml of saturated brine in this order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 162 g of (4R) -2-oxothiazolidine-4-carboxylic acid ethyl ester as an oil.
MS / APCI (m / z): 176 [(M + H) ⁺ ]
[Α] _D ²⁵ : −52.7 ° (C = 1.0, chloroform).
(2) 1.79 g of sodium bromide, 5 ml of N, N-dimethylacetamide and 1 ml of benzyl chloride were stirred at 23 ° C. to 26 ° C. for 15 hours to obtain benzyl bromide. To this solution, 1.27 g of the compound obtained in Reference Example 5B- (1), 2 ml of N, N-dimethylacetamide and 1.1 g of potassium carbonate were added, and after reacting at 23 ° C. to 30 ° C. for 93 hours, ethyl acetate and 10% aqueous citric acid was added and the aqueous layer was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to obtain 2.29 g of a residue. The residue was purified by silica gel column chromatography (solvent: n-hexane: ethyl acetate = 5: 1) to give 1.67 g of (4R) -2-oxo-3-benzylthiazolidine-4-carboxylic acid ethyl ester as a colorless oil. Obtained as a thing.
MS · APCI (m / z): 266 [(M + H) ⁺ ]
[Α] _D ²⁴ : −96.6 ° (C = 1.0, chloroform)
Optical purity (HPLC): 98.1% ee

(HPLC conditions)
Column: Chiralcel OD (4.6 × 250 mm) [manufactured by Daicel Chemical Industries, Ltd.], moving bed: ethanol / hexane = 5/95, flow rate: 0.8 ml / min, UV detection: 225 nm, column temperature: 40 ° C.

Reference Example 6B
28.4 g of (4R) -2-oxo-3-benzylthiazolidine-4-carboxylic acid ethyl ester was dissolved in 227 ml of ethanol, 2.26 g of sodium borohydride was added, and the mixture was stirred at room temperature for 15 hours. Further, 0.76 g of sodium borohydride was added and stirred at room temperature for 2 hours. Concentrated hydrochloric acid was added thereto and neutralized so that the pH was 6-7, and then the solution was concentrated. The concentrated residue was dissolved in ethyl acetate and washed three times with water, and the aqueous layer was back extracted once with ethyl acetate. The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, and concentrated to obtain 22.6 g of an oily residue. The residue is crystallized by adding isopropyl ether, further filtered, washed with isopropyl ether, and dried under reduced pressure to give 18.4 g of (4R) -3-benzyl-4-hydroxymethylthiazolidine-2-one as colorless crystals. Got as. The physical property values of this product coincided with those of Reference Example 1B- (3).

Reference Example 7B
(1) 10 g of (4R) -2-oxo-3-benzylthiazolidine-4-carboxylic acid was dissolved in 200 ml of acetonitrile, and 9.2 g of dicyclohexylcarbodiimide was added at room temperature. Subsequently, 3.3 ml of ethanethiol and 670 mg of 4-dimethylaminopyridine were sequentially added to the solution under ice cooling, and the mixture was stirred at room temperature for 2 hours. The insoluble material was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane: ethyl acetate = 10: 1) to obtain 10.8 g of (4S) -4-ethylthiocarbonyl-3-benzylthiazolidin-2-one as an oil. It was.
MS · APCI (m / z): 282 [(M + H) ⁺ ]
[Α] _D ²⁵ : -110.8 ° (C = 1.04, chloroform).
(2) 0.5 g of the compound obtained in Reference Example 7B- (1) was dissolved in 5.0 ml of dichloromethane, and 284 mg of palladium hydroxide was added under a nitrogen stream. At room temperature, 0.85 ml of triethylsilane was added and stirred at the same temperature for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 0.5 g of (4R) -2-oxo-3-benzylthiazolidine-4-carbaldehyde as an oil. The physical property values of this product coincided with those of Reference Example 1B- (4).

Reference Example 8B
35.34 g of the compound obtained in Reference Example 5, 121 ml of mesitylene and 116.1 g of methanesulfonic acid were heated at an internal temperature of 130 ° C. The reaction starting time was reached at 125 ° C., stirred at 128 ° C. to 133 ° C. for 4 hours, and disappearance of monobenzylbiotin was confirmed by high performance liquid chromatography. The reaction solution was cooled to 80 ° C., 30 ml of acetic acid was added, and the methanesulfonic acid layer was dropped into 710 ml of purified water. The mesitylene layer was separated, and after 1 hour on ice, the crude crystals were collected by filtration, washed with 200 ml of water and then methanol until the washing liquid disappeared black. By air drying overnight at 50 ° C., 15.89 g of crude (+)-biotin was obtained.
The obtained crude (+)-biotin was dissolved in 160 ml of purified water (2.73 g) in purified water and the pH was adjusted to 7 with dilute hydrochloric acid at 90 ° C to 95 ° C. Charcoal powder 4 g was added to the system at 90 ° C. to 95 ° C., and after stirring for 10 minutes, charcoal powder precoat filtration was performed. The filtrate was reheated to 90 ° C. to 95 ° C., 4 g of charcoal powder was added to the system again, and after stirring for 10 minutes, charcoal powder precoat filtration was performed. The filtrate was reheated to 80 ° C. to 85 ° C., and the pH was adjusted to 1.8 to 2.2 with concentrated hydrochloric acid for neutralization crystallization. Stir at the same temperature for 1 hour to grow. After slow cooling and ice cooling, the crystals were filtered. The crystals were blown and dried overnight at 50 ° C. to obtain 13.86 g of (+)-biotin as colorless crystals.

  According to the present invention, the Grignard reagent represented by the general formula (IX) can be efficiently produced. The present invention relates to a method for producing biotin via compound (IV) as a synthetic intermediate or a method for producing biotin via compound (I) and compound (III) produced by the above production method as a synthetic intermediate (a method known in the literature). Since biotin can be produced at a low cost, it can be advantageously used in an industrially advantageous method for producing biotin.

Claims (4)

General formula (VIII):
R-I (VIII)
In the formula, R is an alkyl group which may have a substituent, a bicyclo group which may have a substituent, an alkenyl group which may have a substituent, a nitrogen atom as a hetero atom, oxygen Represents an aryl group which may have a heterocyclic group which may have a substituent, or an aryl group which may have a substituent, including 1 to 4 atoms selected from an atom and a sulfur atom;
A compound represented by the general formula (IX) is reacted with zinc or magnesium treated with chlorine or bromine:
R-X-Y (IX)
In the formula, X represents zinc or magnesium, Y represents iodine, bromine or chlorine.
The manufacturing method of the compound shown by these.   The process according to claim 1, which is carried out in the presence of a solvent selected from tetrahydrofuran, toluene, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, and a mixed solvent thereof. General formula (VIII):
R-I (VIII)
In the formula, R is an alkyl group which may have a substituent, a bicyclo group which may have a substituent, an alkenyl group which may have a substituent, a nitrogen atom as a hetero atom, oxygen Represents an aryl group which may have a heterocyclic group which may have a substituent, or an aryl group which may have a substituent, including 1 to 4 atoms selected from an atom and a sulfur atom;
A compound represented by the general formula (X):
MY (X)
In the formula, M represents zinc or magnesium , Y represents iodine, bromine or chlorine.
In the presence of a salt represented by the general formula (IX):
R-X-Y (IX)
In the formula, X represents zinc or magnesium, and Y represents the same meaning as described above.
The manufacturing method of the compound shown by these.   The process according to claim 3, which is carried out in the presence of a solvent selected from tetrahydrofuran, toluene, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, and a mixed solvent thereof.