Method for producing hydroxybiotin derivative and vinylbiotin derivative

Abstract

The purpose of the present invention is to provide a method for producing a hydroxybiotin derivative and a vinylbiotin derivative with which it is possible to carry out, in a smooth and highly efficient manner, a coupling reaction between a thiolactone derivative and a zinc reagent containing a halogen atom other than an iodine atom by using an inexpensive metal catalyst. The present invention provides a method for producing a hydroxybiotin derivative, the method including a step for bringing a thiolactone derivative represented by formula (1) into contact with a zinc reagent represented by formula (2) in the presence of a copper catalyst and an amine compound, thereby obtaining a hydroxybiotin derivative represented by formula (3).

Description

Method for producing hydroxybiotin derivatives and vinylbiotin derivatives

[0001] The present invention relates to a novel method for producing hydroxybiotin derivatives and vinylbiotin derivatives, which are useful as synthetic intermediates for biotin.

[0002] Biotin is a useful compound used in various pharmaceuticals, food additives, feed additives, etc. Biotin is synthesized using the following manufacturing method.

[0003]

[0004] That is, first, (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione represented by formula (1A) (hereinafter referred to as "thiolactone derivative (1A)") and (5-ethoxy-5-oxopentyl)zinc halide represented by formula (2A) (hereinafter referred to as "zinc reagent (2A)") are subjected to a coupling reaction to produce ethyl 5-[(3aS,6aR)-1,3-dibenzyl-4-hydroxy-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanoate represented by formula (3A) (hereinafter referred to as "hydroxybiotin derivative (3A)"). In formula (2A), X is a halogen atom. Next, the hydroxybiotin derivative (3A) is dehydrated to give ethyl 5-[(3aS,6aR)-1,3-dibenzyl-2-oxohexahydro-4H-thieno[3,4-d]imidazol-4-ylidin]pentanoate (hereinafter referred to as "vinylbiotin derivative (4A)") represented by formula (4A). After that, biotin is produced through reduction, deprotection, and hydrolysis reactions.

[0005] The hydroxybiotin derivative (3A) is an important synthetic intermediate for biotin, and its synthesis has been extensively studied.

[0006] For example, Non-Patent Document 1 describes a method for synthesizing a hydroxybiotin derivative (3A) by reacting a thiolactone derivative (1A) with a zinc reagent (2A) in which X is an iodine atom in the presence of a bis(triphenylphosphine)palladium dichloride catalyst. However, this production method requires an expensive reagent containing an iodine atom as the zinc reagent (2A) and also requires expensive palladium as the metal catalyst, leaving room for improvement in terms of cost.

[0007] Therefore, active research has been conducted on production methods that avoid the use of the expensive zinc reagent (2A) containing an iodine atom. Non-Patent Documents 2 and 3 describe a method for synthesizing a hydroxybiotin derivative (3A) by reacting a thiolactone derivative (1A) with a zinc reagent (2A) in which X is a bromine atom in the presence of a palladium catalyst.

[0008] Tetrahedron Letters 41,2000,5099-5101Advanced Synthesis and Catalysis2008,350,1635-1641Tetrahedron Asymmetry 21, 2010, 665-669

[0009] However, in the prior art disclosed in Non-Patent Documents 2 and 3, it was found that there is room for improvement in the production of the hydroxybiotin derivative (3A) using the zinc reagent (2A) in which X is bromine, in the following respects.

[0010] Non-Patent Document 3 describes a method for producing a hydroxybiotin derivative (3A) by carrying out a reaction in the presence of a palladium-carbon catalyst at 30° C. for 30 hours. However, in this production method, even though 2.8 equivalents of zinc reagent (2A) are used relative to the thiolactone derivative (1A), the yield of the hydroxybiotin derivative (3A) after the reaction was as low as 75%.

[0011] In contrast, Non-Patent Document 2 describes that a hydroxybiotin derivative (3A) can be obtained in 85% yield by reacting 2.0 equivalents of zinc reagent (2A) at 35°C for 10 hours. However, this reaction requires a special nanopalladium catalyst that was independently prepared, posing a challenge for industrial use. Furthermore, both of the methods described in Non-Patent Documents 2 and 3 require expensive palladium, and the development of a reaction using a cheaper metal catalyst has been desired.

[0012] Therefore, an object of the present invention is to smoothly carry out a coupling reaction between a thiolactone derivative and a zinc reagent containing a halogen atom other than iodine (e.g., a bromine atom or a chlorine atom) using an inexpensive metal catalyst. In addition, an object of the present invention is to provide a method for producing hydroxybiotin derivatives and vinylbiotin derivatives with high efficiency.

[0013] As a result of intensive research aimed at solving the above-mentioned problems, the present inventors have surprisingly discovered that a hydroxybiotin derivative can be synthesized with a high conversion rate by contacting a thiolactone derivative with a zinc reagent in the presence of a copper catalyst and an amine compound, thereby completing the present invention.

[0014] That is, a first aspect of the present invention provides the following method for producing a hydroxybiotin derivative: [1] reacting a compound represented by the following formula (1): in the presence of a copper catalyst and an amine compound: [In the formula, R １ and R ２ and each independently represent a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent.] and a thiolactone derivative represented by the following formula (2): [wherein X represents a bromine atom or a chlorine atom; R ３ represents a direct bond or an alkylene group having 1 to 7 carbon atoms which may have a substituent, R ４ is -C(=O)OR ５ a monovalent group represented by -OR ５ or a cyano group,５ represents a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent.] is contacted with a zinc reagent represented by formula (3): [In the formula, R １ and R ２ is the same as in formula (1), and R ３ and R ４ is defined as formula (2).] [2] A method for producing a hydroxybiotin derivative according to [1], wherein an amine compound is used in an amount of 0.1 mol to 5.0 mol per mol of copper catalyst. [3] A method for producing a hydroxybiotin derivative according to [1] or [2], wherein the amine compound is at least one selected from the group consisting of multidentate aliphatic amines and tertiary aromatic amines. [4] A method for producing a hydroxybiotin derivative according to any one of [1] to [3], comprising mixing the thiolactone derivative, the zinc reagent, and the amine compound, and then mixing the resulting mixture with the copper catalyst, thereby contacting the thiolactone derivative with the zinc reagent in the presence of the copper catalyst and the amine compound. [5] A method for producing a hydroxybiotin derivative according to any one of [1] to [4], comprising contacting the thiolactone derivative with the zinc reagent in the presence of the copper catalyst and the amine compound in a solvent containing a polar solvent having a dielectric constant of 15 or more at 25° C. [6] A method for producing a hydroxybiotin derivative according to [5], wherein the polar solvent is N,N-dimethylacetamide [7] A method for producing a hydroxybiotin derivative according to [5] or [6], comprising contacting the thiolactone derivative with the zinc reagent in the presence of the copper catalyst and the amine compound by mixing the thiolactone derivative, the amine compound, and the copper catalyst in the solvent and then mixing the resulting mixture with the zinc reagent, or by mixing the thiolactone derivative, the amine compound, and the zinc reagent in the solvent and then mixing the resulting mixture with the copper catalyst.

[0015] The second aspect of the present invention provides the following method for producing a vinylbiotin derivative: [8] After producing a hydroxybiotin derivative represented by the formula (3) by the method according to any one of [1] to [7], the obtained hydroxybiotin derivative is dehydrated to produce a vinylbiotin derivative represented by the formula (4): [In the formula, R １ and R ２ is the same as in formula (1), and R ３ and R ４ has the same meaning as the above formula (2).] (hereinafter, may be referred to as "vinylbiotin derivative (4)")

[0016] According to the method of the first aspect of the present invention, the hydroxybiotin derivative (3) can be produced with a high conversion rate using a copper catalyst, which is a cheaper metal. According to the method of the second aspect of the present invention, the hydroxybiotin derivative (3) can be produced by the method of the first aspect of the present invention, and then the vinylbiotin derivative (4) can be produced simply and efficiently by dehydrating the hydroxybiotin derivative (3) obtained.

[0017] In this specification, the expression "value A to value B" means value A or more and value B or less, unless otherwise specified.

[0018] First Aspect of the Present Invention The first aspect of the present invention relates to a method for producing a hydroxybiotin derivative, the method comprising the step of contacting a thiolactone derivative (1) with a zinc reagent (2) in the presence of a copper catalyst and an amine compound to obtain a hydroxybiotin derivative (3).

[0019] Hereinafter, an embodiment of the first aspect of the present invention (hereinafter referred to as "this embodiment") will be described.

[0020] <Thiolactone Derivative> The thiolactone derivative (1) used in this embodiment is a compound represented by formula (1).

[0021]

[0022] In formula (1), R１ and R ２ are each independently a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent. １ and R ２ may be the same functional group or different types of functional groups.

[0023] The alkyl group which may have a substituent, the aralkyl group which may have a substituent, and the aryl group which may have a substituent will be described below.

[0024] (Optionally substituted alkyl group) In one embodiment, R １ or R ２ At least one of the groups is an alkyl group which may have a substituent. The alkyl group which may have a substituent will be described below.

[0025] The alkyl group may be either linear or branched. The number of carbon atoms in the alkyl group is, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 6, even more preferably 1 to 3, and particularly preferably 1 or 2. The alkyl group may have a substituent. Examples of substituents that the alkyl group may have include an aryl group having 6 to 22 carbon atoms (preferably 6 to 14, more preferably 6 to 10), an alkoxy group having 1 to 6 carbon atoms (preferably 1 to 3, more preferably 1 or 2), a carboxyl group, a halogen group, etc. The aryl group may be monocyclic or polycyclic (e.g., bicyclic or tricyclic). The polycyclic group may be a fused ring system. The aryl group is particularly preferably a phenyl group. The alkoxy group may be either linear or branched. Examples of halogen groups include a fluoro group, a chloro group, a bromo group, and an iodo group. The substituent that the alkyl group may have is preferably an aryl group having 6 to 14 carbon atoms, more preferably an aryl group having 6 to 10 carbon atoms, and particularly preferably a phenyl group. When the alkyl group has a substituent, the number of the substituents is preferably 1 to 5, more preferably 1 to 3, and particularly preferably 1 or 2.

[0026] (Optionally substituted aralkyl group) In one embodiment, R１ or R ２ At least one of the groups is an aralkyl group which may have a substituent. The aralkyl group which may have a substituent will be described below.

[0027] An aralkyl group refers to an alkyl group containing one aryl group. That is, an aralkyl group is a group formed by substituting one hydrogen atom of an alkyl group with an aryl group. The alkyl group may be either linear or branched. The alkyl group may have, for example, 1 to 10 carbon atoms, preferably 1 to 6, more preferably 1 to 3, and even more preferably 1 or 2 carbon atoms. The aryl group may have, for example, 6 to 22 carbon atoms, preferably 6 to 14, and more preferably 6 to 10 carbon atoms. The aryl group may be monocyclic or polycyclic (e.g., bicyclic or tricyclic). The polycyclic group may be a fused ring system. The aryl group is particularly preferably a phenyl group. The aralkyl group is preferably an aralkyl group having 7 to 11 carbon atoms. Suitable aralkyl groups include, for example, benzyl, phenylethyl, phenylpropyl, phenylbutyl, and naphthylmethyl. The aralkyl group may have a substituent. Examples of substituents that the aralkyl group may have include an alkyl group having 1 to 6 carbon atoms (preferably 1 to 3, more preferably 1 or 2), an alkoxy group having 1 to 6 carbon atoms (preferably 1 to 3, more preferably 1 or 2), a carboxyl group, a halogen group, and the like. The alkyl group and the alkoxy group may each be linear or branched. Examples of halogen groups include a fluoro group, a chloro group, a bromo group, and an iodo group. When the aralkyl group has a substituent, the number of substituents is preferably 1 to 5, more preferably 1 to 3, and particularly preferably 1 or 2. When the aralkyl group has a substituent, either or both of the alkyl and aryl portions of the aralkyl group may have a substituent; however, it is preferable that at least the aryl portion has a substituent.

[0028] (Optionally substituted aryl group) In one embodiment, R １ or R ２At least one of the groups is an aryl group which may have a substituent. The aryl group which may have a substituent will be described below.

[0029] The aryl group may be monocyclic or polycyclic (e.g., bicyclic or tricyclic). The polycyclic group may be a fused ring system. The aryl group may have, for example, 6 to 22 carbon atoms, preferably 6 to 14 carbon atoms, and more preferably 6 to 10 carbon atoms. The aryl group is particularly preferably a phenyl group. The aryl group may have a substituent. Examples of the substituent that the aryl group may have include an alkyl group having 1 to 6 carbon atoms (preferably 1 to 3, more preferably 1 or 2 carbon atoms), an alkoxy group having 1 to 6 carbon atoms (preferably 1 to 3, more preferably 1 or 2 carbon atoms), a carboxyl group, a halogen group, and the like. The alkyl group and the alkoxy group may each be linear or branched. Examples of the halogen group include a fluoro group, a chloro group, a bromo group, and an iodo group. When the aryl group has a substituent, the number of the substituent is preferably 1 to 5, more preferably 1 to 3, and particularly preferably 1 or 2.

[0030] (Suitable R １ and R ２ In one embodiment, R １ and R ２ are each independently an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent. １ and R ２ In consideration of the fact that the group will be finally deprotected, it is preferably an aralkyl group which may have a substituent, and particularly preferably a benzyl group.

[0031] (Suitable Thiolactone Derivative) Considering its usefulness, the thiolactone derivative (1) is preferably a thiolactone derivative represented by formula (1A) ((3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione) (hereinafter referred to as "thiolactone derivative (1A)"). In formula (1A), "Bn" represents a benzyl group. The thiolactone derivative (1A) is preferably a thiolactone derivative represented by formula (1A) ((3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione) (hereinafter referred to as "thiolactone derivative (1A)"). In formula (1A), "Bn" represents a benzyl group. １ and R ２is a thiolactone derivative (1) in which both are benzyl groups.

[0032]

[0033] <Zinc Reagent> The zinc reagent (2) used in this embodiment is a compound represented by formula (2).

[0034]

[0035] In formula (2), X is a chlorine atom or a bromine atom, and R ３ is a direct bond or an alkylene group having 1 to 7 carbon atoms which may have a substituent, and R ４ is -C(=O)OR ５ a monovalent group represented by -OR ５ or a cyano group, ５ represents a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent.

[0036] R １ and R ２ The above explanations regarding the alkyl group which may have a substituent, the aralkyl group which may have a substituent, and the aryl group which may have a substituent in R ５ The same also applies to an alkyl group which may have a substituent, an aralkyl group which may have a substituent, and an aryl group which may have a substituent in the above formula (I).

[0037] (R ３ ) R ３ is a direct bond or an alkylene group. One end of the alkylene group is —CH ２ -, and the other end of the alkylene group is bonded to -R ４is bonded to the alkylene group. The number of carbon atoms in the alkylene group is 1 to 7, preferably 1 to 5, and more preferably 1 to 3. The alkylene group may have a substituent. Examples of the substituent that the alkylene group may have include an aryl group having 6 to 22 carbon atoms (preferably 6 to 14, more preferably 6 to 10), an alkoxy group having 1 to 6 carbon atoms (preferably 1 to 3, more preferably 1 or 2), a carboxyl group, a halogen group, and the like. The aryl group may be monocyclic or polycyclic (e.g., bicyclic or tricyclic). The polycyclic group may be a fused ring system. The aryl group is particularly preferably a phenyl group. The alkoxy group may be either linear or branched. Examples of the halogen group include a fluoro group, a chloro group, a bromo group, and an iodo group. When the alkylene group has a substituent, the number of the substituent is preferably 1 to 5, more preferably 1 to 3, and particularly preferably 1 or 2. However, in this embodiment, R ３ is most preferably an alkylene group having no substituent.

[0038] (R ４ and R ５ ) R ４ is preferably a cyano group or a carboxyl group (R ５ is a hydrogen atom, -C(=O)OR ５ a monovalent group represented by R ５ is an alkyl group which may have a substituent, ５ a monovalent group represented by R ５ is an alkyl group which may have a substituent, ５ and a carboxyl group (R ５ is a hydrogen atom, -C(=O)OR ５ a monovalent group represented by R ５ is an alkyl group which may have a substituent, ５ a monovalent group represented by R ５ is an alkyl group which may have a substituent, ５ It is particularly preferred that the aryl group is a monovalent group represented by the following formula:

[0039] (Suitable Zinc Reagent) The zinc reagent (2) is preferably selected from the zinc reagent represented by formula (2A) (5-ethoxy-5-oxopentyl)zinc halide) (hereinafter referred to as "zinc reagent (2A)") and the zinc reagent represented by formula (2B) (3-methoxypropylzinc halide) (hereinafter referred to as "zinc reagent (2B)"). "Et" in formula (2A) represents an ethyl group, and "Me" in formula (2B) represents a methyl group. Hereinafter, similar explanations may be omitted. X in formulas (2A) and (2B) has the same meaning as in formula (2). The zinc reagent (2A) is a zinc reagent represented by formula (2A) (3-methoxypropyl)zinc halide) (hereinafter referred to as "zinc reagent (2B)". ３ is an unsubstituted alkylene group having 3 carbon atoms (i.e., an n-propylene group), and R ４ is an ester group (R ５ is an ethyl group, —C(═O)OR ５ Zinc reagent (2B) is a monovalent group represented by R ３ is an unsubstituted alkylene group having 2 carbon atoms (i.e., an n-ethylene group), and R ４ is an alkoxy group (R ５ is a methyl group, -OR ５ The zinc reagent (2) is a monovalent group represented by

[0040]

[0041]

[0042] In one embodiment, X in formula (2A) is a bromine atom.

[0043] In one embodiment, X in formula (2B) is a bromine atom.

[0044] The amount of zinc reagent (2) used in this embodiment is not particularly limited, but is preferably 1.0 to 2.0 moles, and particularly preferably 1.0 to 1.5 moles, per mole of thiolactone derivative (1) in order to avoid complicated post-treatment procedures. In this embodiment, the reaction efficiency is significantly improved, and the reaction proceeds sufficiently even with an amount of zinc reagent used within the above range.

[0045] <Method for Producing Zinc Reagent> The method for producing zinc reagent (2) in this embodiment is not particularly limited, and zinc reagent (2) produced by a known method can be used. For example, zinc reagent (2) produced by the method described in Non-Patent Document 2 or 3, or a purified product thereof, can be used. Specifically, zinc reagent (2) can be produced according to the following reaction scheme.

[0046]

[0047] Specifically, the zinc reagent (2) can be easily prepared by contacting the corresponding halide (2') with zinc. ３ and R ４ are the same as those in formula (2).

[0048] (Zinc) The zinc used in the above reaction is elemental zinc. The form of zinc is not particularly limited, but examples thereof include powder, shavings, and strips. The amount of zinc used can be determined appropriately depending on the type of halide (2'), and is, for example, 1.0 to 5.0 mol, preferably 1.0 to 3.0 mol, per mol of halide (2').

[0049] (Activator) The contact of the halide (2') with zinc is preferably carried out in the presence of a zinc activator. Examples of zinc activators include bromine, iodine, 1,2-dibromoethane, trimethylsilyl chloride, tetra-n-butylammonium iodide (TBAI), tetramethylammonium iodide (TMAI), tetra-n-butylammonium bromide (TBAB), tetra-n-butylammonium chloride (TBAC), tetramethylammonium chloride (TMAC), tetra-n-butylammonium fluoride (TBAF), lithium iodide (LiI), sodium iodide (NaI), potassium iodide (KI), and cesium iodide (CsI). In consideration of reactivity, the zinc activator is preferably selected from quaternary ammonium salts such as TBAI and TMAI, and alkali metal iodide salts such as NaI and KI. Considering safety, cost, etc., it is particularly preferable that the zinc activator is selected from NaI and KI. The amount of the zinc activator used is, for example, 0.01 to 1.5 mol, preferably 0.05 to 0.8 mol, per mol of zinc.

[0050] (Reaction Solvent) The preparation of zinc reagent (2) is preferably carried out in a first reaction solvent. The first reaction solvent is preferably an organic solvent. As the first reaction solvent, one organic solvent may be used alone, or a mixture of two or more organic solvents may be used. The first reaction solvent can be selected from, for example, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), toluene, cyclopentyl methyl ether (CPME), N,N-dimethylacetamide (DMAC), N,N-dimethylformamide (DMF), N,N-dimethylimidazolidinone (DMI), tert-butyl methyl ether (TBME), diisopropyl ether (IPE), diglyme, and the like. In consideration of the progress of the reaction, the influence on the subsequent step, and the like, it is particularly preferable that the first reaction solvent is a polar solvent having a relative dielectric constant of 15 or more at 25°C. Examples of polar solvents having a dielectric constant of 15 or more at 25°C include N,N-dimethylacetamide (DMAC) (dielectric constant = 37.78), N,N-dimethylformamide (DMF) (dielectric constant = 36.71), N,N-dimethylimidazolidinone (DMI) (dielectric constant = 37.6), etc. Of the organic solvents exemplified above, one organic solvent may be used alone, or a mixture of two or more organic solvents may be used.

[0051] The amount of the first reaction solvent used is not particularly limited, but is, for example, 0.1 to 20 mL, preferably 0.5 to 10 mL, per gram of halide (2'). When a mixture of two or more organic solvents is used as the first reaction solvent, the "amount of the first reaction solvent used" refers to the amount of the mixture used.

[0052] (Method for Contacting Halide with Zinc) The temperature for contacting halide (2′) with zinc may be appropriately determined depending on the first reaction solvent used, and is, for example, 20 to 120° C., preferably 30 to 80° C. The contact time is, for example, 0.1 to 15 hours, preferably 1 to 8 hours.

[0053] The zinc reagent (2) is preferably prepared by the following method. First, the first reaction solvent and zinc are mixed, and then an activator is added to activate the zinc. Next, the halide (2') is added and mixed to prepare the zinc reagent (2). The obtained zinc reagent (2) can be used in the form of a solution in the production of a hydroxybiotin derivative without separation and purification. Of course, the zinc reagent (2) can also be used after separation and purification to increase the purity.

[0054] By reacting halide (2') with zinc under the above conditions, zinc reagent (2) can be prepared efficiently and simply. The purity of zinc reagent (2) obtained in the above reaction is not particularly limited, but it can be 80.0 to 95.0%. Furthermore, the subsequent coupling reaction can be carried out without post-treatment of the post-reaction solution containing excess zinc.

[0055] The atmosphere for the reaction is not particularly limited, and the reaction may be carried out in an atmosphere of an inert gas such as nitrogen or argon.

[0056] <Copper Catalyst> In the present invention, the thiolactone derivative (1) is contacted with the zinc reagent (2) in the presence of a copper catalyst and an amine compound, thereby smoothly promoting the coupling reaction between the thiolactone derivative (1) and the zinc reagent (2), and efficiently converting the thiolactone derivative (1) into the hydroxybiotin derivative (3).

[0057] The copper catalyst used in this embodiment is not particularly limited, and either monovalent or divalent copper compounds can be used as the copper catalyst. One type of copper catalyst may be used alone, or two or more types of copper catalysts may be used in combination. Examples of copper catalysts include copper(I) chloride, copper(II) chloride, copper(I) bromide, copper(II) bromide, copper(I) cyanide, copper(I) 3-methylsalicylate, copper(I) mesitylene, copper(I) isopropoxy, copper(I) iodide, copper(II) iodide, copper(I) acetate, copper(II) acetate, copper(II) sulfate, copper(I), copper(II) oxide, copper(II), copper(I) pivalate, and copper(II) pivalate. The copper catalyst used in this embodiment is preferably selected from monovalent copper compounds (e.g., copper chloride(I), copper bromide(I), copper cyanide(I), copper 3-methylsalicylate(I), copper mesitylene(I), copper isopropoxy(I), copper iodide(I), copper acetate(I), copper oxide(I), copper pivalate(I), etc.), and more preferably selected from monovalent copper halides containing a halogen atom (e.g., copper chloride(I), copper bromide(I), copper iodide(I), etc.).

[0058] The amount of copper catalyst used may be determined appropriately, and is preferably 0.01 to 10 mol, more preferably 0.1 to 8.0 mol, and particularly preferably 1.0 to 5.0 mol per mol of thiolactone derivative (1). When two or more copper catalysts are used, the "amount of copper catalyst used" refers to the total amount of the two or more copper catalysts used. Naturally, the copper catalyst can be added later depending on the progress of the reaction, or can be added in portions while monitoring the progress of the reaction.

[0059] <Amine Compound> The amine compound used in this embodiment is not particularly limited, and any of aliphatic amines and aromatic amines can be used. One type of amine compound may be used alone, or two or more types of amine compounds may be used in combination.

[0060] Examples of aliphatic amines include methylamine, ethylamine, n-propylamine, isopropylamine, butylamine, 2-ethylhexylamine, cyclohexylamine, allylamine, aniline, o-toluidine, p-toluidine, o-chloroaniline, 2-aminoethanol, dimethylamine, diethylamine, di-n-propylamine, dibutylamine, diisobutylamine, diallylamine, dicyclohexylamine, ethanolamine, N-methylethanolamine, diethanolamine, trimethylamine, triethylamine, tri-n-propylamine, N,N-diethylethanolamine, di-n-butylethanolamine, triethanolamine, 3-amino-1,2-propanediol, ethylenediamine, propanediamine, butanediamine, diethylenetriamine, N,N linear amines such as N,N',N'-tetramethylethylenediamine, N,N,N',N'-tetramethyl-1,3-propanediamine, N,N,N',N'-tetramethyl-1,4-butanediamine, bis(dimethylaminoethyl)ether, and N,N,N',N',N''-pentamethyldiethylenetriamine; and cyclic amines such as piperidine, 1-methylpiperidine, 4-methylpiperidine, 4-hydroxypiperidine, 4-hydroxy-1-methylpiperidine, 1-piperidineethanol, 2-piperidineethanol, 4-piperidineethanol, 1-aminopiperidine, 4-amino-2,2,6,6-tetramethylpiperidine, 4-piperidinopiperidine, 1,3-di-4-piperidylpropane, morpholine, N-methylmorpholine, pyrrolidine, piperazine, and 1,4-dimethylpiperazine. Among these, polydentate aliphatic amines are preferred, and N,N,N',N'-tetramethylethylenediamine and bis(dimethylaminoethyl)ether are more preferred.

[0061] Examples of aromatic amines include pyrrole, 2-methylpyrrole, 3-methylpyrrole, 2-cyanopyrrole, 3-cyanopyrrole, 2-aminopyrrole, 3-aminopyrrole, 2,3-dimethylpyrrole, 2,5-dimethylpyrrole, 2-ethylpyrrole, 3-ethylpyrrole, pyrazole, 3-methylpyrazole, 4-methylpyrazole, 3-cyanopyrazole, 4-cyanopyrazole, 3-aminopyrazole, 4-aminopyrazole, 3,4-dimethylpyrazole, 3,5-dimethylpyrazole, imidazole, 2-methylimidazole, 4-methylimidazole, 2-aminoimidazole, 4-aminoimidazole, 2-cyanoimidazole, 4- Examples of the aromatic amine include secondary aromatic amines such as cyanoimidazole, 2,4-dimethylimidazole, and 4,5-dimethylimidazole; and tertiary aromatic amines such as pyridine, α-picoline, β-picoline, γ-picoline, 2,6-lutidine, 4-cyanopyridine, 2-cyanopyridine, 2-hydroxypyridine, 4,4-dimethylaminopyridine, 1-methylpyrrole, 1-ethylpyrrole, 1-methylpyrazole, 1-ethylpyrazole, 1-methylimidazole, 1-ethylimidazole, 1,2-dimethylimidazole, 1,4-dimethylimidazole, pyrazine, 2-methylpyrazine, 2-aminopyrazine, 2-cyanopyrazine, and 2,3-dimethylpyrazine.

[0062] The amine compound used in this embodiment is preferably an aromatic amine, and more preferably a tertiary aromatic amine. Although the details are unclear, aromatic amines, especially tertiary aromatic amines, are known to form chelate compounds with copper catalysts and activate the reaction. Furthermore, tertiary aromatic amines are expected to dissolve the thiolactone derivative (1) and promote the reaction.

[0063] In one embodiment, the amine compound is at least one selected from the group consisting of polydentate aliphatic amines and tertiary aromatic amines.

[0064] The amount of the amine compound used may be determined appropriately, and is preferably 0.1 to 5.0 mol, more preferably 0.5 to 4.0 mol, and particularly preferably 1.0 to 3.0 mol per mol of the copper catalyst. When two or more amine compounds are used, the "amount of amine compound used" refers to the total amount of the two or more amine compounds used. Using the amine compound within the above range can increase the reaction rate. Furthermore, the purity of the resulting hydroxybiotin derivative can be increased, and as a result, the purity of the vinylbiotin derivative obtained by dehydrating the hydroxybiotin derivative can be increased. Naturally, the amine compound can be added later depending on the progress of the reaction, or it can be added in portions while monitoring the progress of the reaction.

[0065] <Reaction Solvent> The contact of the thiolactone derivative (1) with the zinc reagent (2) in the presence of a copper catalyst and an amine compound is preferably carried out in a second reaction solvent.

[0066] The second reaction solvent is preferably an organic solvent. As the second reaction solvent, one organic solvent may be used alone, or a mixture of two or more organic solvents may be used.

[0067] The second reaction solvent is not particularly limited and can be appropriately selected from solvents that do not inhibit the reaction. The second reaction solvent can be selected from, for example, nonpolar solvents such as toluene, benzene, diethyl ether, and chloroform, and aprotic polar solvents such as dichloromethane, tetrahydrofuran, acetonitrile, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylimidazolidinone, N-methylpyrrolidone, dimethyl sulfoxide, and sulfolane.

[0068] In this embodiment, it is preferable to use a solvent containing a polar solvent having a dielectric constant of 15 or more at 25°C (hereinafter referred to as the "desired polar solvent") as the second reaction solvent. In other words, it is preferable to contact the thiolactone derivative (1) with the zinc reagent (2) in the presence of the copper catalyst and the amine compound in a highly polar solvent. The dielectric constant is a parameter that indicates the approximate polarity of an organic solvent; the larger the dielectric constant, the higher the polarity. Although the reason is unclear, it is thought that using a solvent containing the desired polar solvent as the second reaction solvent improves the solubility of the zinc reagent and the copper catalyst, thereby accelerating the coupling reaction. As the desired polar solvent, one polar solvent may be used alone, or a mixture of two or more polar solvents may be used.

[0069] Examples of the desired polar solvent include N,N-dimethylacetamide (DMAC) (dielectric constant = 37.78), N,N-dimethylformamide (DMF) (dielectric constant = 36.71), N,N-dimethylimidazolidinone (DMI) (dielectric constant = 37.6), acetonitrile (dielectric constant = 37.5), N-methylpyrrolidone (NMP) (dielectric constant = 32.0), dimethyl sulfoxide (DMSO) (dielectric constant = 48.9), and sulfolane (dielectric constant = 43.3). From the standpoint of reaction rate, the desired polar solvent is preferably selected from DMAC, DMF, and DMI, and DMAC is most preferred. In other words, the desired polar solvent is preferably a polar solvent having a dielectric constant of 15 to 40, more preferably a polar solvent having a dielectric constant at 25°C of 30 to 40, and even more preferably a polar solvent having a dielectric constant at 25°C of 35 to 40. Of the desired polar solvents exemplified above, one polar solvent may be used alone, or a mixture of two or more polar solvents may be used.

[0070] By increasing the ratio of the desired polar solvent in the second reaction solvent, the reaction can proceed more efficiently and effectively, and can be completed in a short time. In consideration of the reaction rate, the ratio of the desired polar solvent in the second reaction solvent is preferably 15% by volume or more, more preferably 30% by volume or more, even more preferably 50% by volume or more, and most preferably 100% by volume. It should be noted that a ratio of the desired polar solvent in the second reaction solvent of 100% by volume does not exclude the inclusion of unavoidable impurities in the second reaction solvent.

[0071] In this embodiment, the amount of the second reaction solvent used is not particularly limited, but taking into consideration post-treatment of the reaction, it is, for example, 0.1 to 20 mL, preferably 0.5 to 10 mL, and more preferably 1 to 7 mL per gram of thiolactone derivative (1). When a mixture containing a desired polar solvent and another solvent is used as the second reaction solvent, the "amount of the second reaction solvent used" refers to the amount of the mixture used.

[0072] The second reaction solvent is preferably the same as the first reaction solvent used in the preparation of zinc reagent (2), thereby eliminating the need for an operation involving solvent switching.

[0073] <Method for Producing a Hydroxybiotin Derivative> In this embodiment, a thiolactone derivative (1) and a zinc reagent (2) are contacted and reacted in the presence of a copper catalyst and an amine compound to produce a hydroxybiotin derivative (3). All components are mixed so that they are in sufficient contact with each other. This method can be carried out under normal pressure, reduced pressure, or increased pressure. This method can be carried out not only in the presence of oxygen, such as air, but also in an inert gas atmosphere, such as nitrogen, argon, or carbon dioxide. The method for mixing the components is not particularly limited. For example, all components may be simultaneously added to a reaction vessel or reactor and mixed. Alternatively, one component may be added to a reaction vessel or reactor in advance, and the remaining components may be sequentially added to the reaction vessel or reactor and mixed. However, to maximize the effects of the present invention, it is preferable to add the copper catalyst last. That is, it is preferable to mix the thiolactone derivative (1), the zinc reagent (2), and the amine compound, and then mix the resulting mixture with the copper catalyst. Since this reaction is initiated by the addition of the copper catalyst, adding the copper catalyst last allows for efficient utilization of the amine compound's effects. Alternatively, each component can be diluted with a solvent and then supplied to the reaction vessel or reactor. To further reduce by-products and increase the purity of the hydroxybiotin derivative (3), it is preferable to contact the thiolactone derivative (1) with the zinc reagent (2) in the presence of the copper catalyst and the amine compound by mixing the thiolactone derivative (1), the amine compound, and the copper catalyst in a second reaction solvent and then mixing the resulting mixture with the zinc reagent (2). Alternatively, it is preferable to mix the thiolactone derivative (1), the amine compound, and the zinc reagent (2) in a second reaction solvent and then mixing the resulting mixture with the copper catalyst. This method can suppress rapid decomposition of the zinc reagent (2) and allow the reaction to proceed smoothly. This method can be carried out under an inert gas atmosphere.

[0074] In this embodiment, the reaction temperature (here, "reaction temperature" refers to the temperature in the reaction system after all components are mixed) is not particularly limited, but the reaction can be carried out in the range of -10 to 50°C. In particular, considering the reaction rate, the purity of the resulting hydroxybiotin derivative (3), and the like, the reaction is preferably carried out in the range of -5 to 35°C. By carrying out the reaction within this range, the thiolactone derivative (1) can be converted to the hydroxybiotin derivative (3) efficiently in a short time. The reaction time is also not particularly limited and can be appropriately determined while checking the reaction conversion rate described in the Examples below. However, under the above reaction conditions, the reaction time is preferably 1 to 30 hours, more preferably 1 to 20 hours. The reaction time refers to the time during which the thiolactone derivative (1), zinc reagent (2), copper catalyst, and amine compound are mixed in a solvent, optionally added, at the set reaction temperature.

[0075] <Hydroxybiotin Derivative> The hydroxybiotin derivative obtained in this embodiment is a compound represented by formula (3).

[0076]

[0077] In formula (3), R １ and R ２ is the same as in formula (1), and R ３ and R ４ is synonymous with formula (2).

[0078] In one embodiment, the hydroxybiotin derivative (3) is a hydroxybiotin derivative represented by formula (3A) (hereinafter referred to as "hydroxybiotin derivative (3A)"). The hydroxybiotin derivative (3A) is a hydroxybiotin derivative represented by formula (3A) (hereinafter referred to as "hydroxybiotin derivative (3A)"). １ and R ２ are both benzyl groups, and R ３ is an unsubstituted alkylene group having 3 carbon atoms (i.e., an n-propylene group), and R ４ is an ester group (R ５ is an ethyl group, —C(═O)OR ５The hydroxybiotin derivative (3A) can be produced by contacting the thiolactone derivative (1A) with the zinc reagent (2A) in the presence of a copper catalyst and an amine compound.

[0079]

[0080] In one embodiment, the hydroxybiotin derivative (3) is a hydroxybiotin derivative represented by formula (3B) (hereinafter referred to as "hydroxybiotin derivative (3B)"). The hydroxybiotin derivative (3B) is a hydroxybiotin derivative represented by formula (3B) (hereinafter referred to as "hydroxybiotin derivative (3B)"). １ and R ２ are both benzyl groups, and R ３ is an unsubstituted alkylene group having 2 carbon atoms (i.e., an n-ethylene group), and R ４ is an alkoxy group (R ５ is a methyl group, -OR ５ The hydroxybiotin derivative (3B) can be produced by contacting the thiolactone derivative (1A) with the zinc reagent (2B) in the presence of a copper catalyst and an amine compound.

[0081]

[0082] <<Second Aspect of the Present Invention>> The second aspect of the present invention relates to a method for producing a vinylbiotin derivative, comprising the steps of producing a hydroxybiotin derivative (3) by the method according to the first aspect of the present invention, and then dehydrating the resulting hydroxybiotin derivative (3) to obtain a vinylbiotin derivative (4).

[0083] Hereinafter, an embodiment of the second aspect of the present invention (hereinafter referred to as "this embodiment") will be described.

[0084] The vinylbiotin derivative (4) obtained in this embodiment is a compound represented by formula (4).

[0085]

[0086] In formula (4), R １ and R ２is the same as in formula (1), and R ３ and R ４ is synonymous with formula (2).

[0087] Examples of dehydration treatments for the hydroxybiotin derivative (3) include acid treatment and heat treatment. However, considering the purity of the product, acid treatment is preferred. The acid treatment involves contacting the hydroxybiotin derivative (3) with an acid catalyst. The reaction solution containing the hydroxybiotin derivative (3) obtained by the method according to the first aspect of the present invention can also be subjected to the acid treatment as is. The acid catalyst can be, for example, any of inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, and organic acids such as formic acid, acetic acid, methanesulfonic acid, and p-toluenesulfonic acid.

[0088] One type of acid catalyst can be used alone, or two or more types of acid catalysts can be used in combination. The amount of acid catalyst used can be determined appropriately depending on the type of acid used, but is, for example, 1 to 1,000 moles, preferably 20 to 200 moles, per mole of hydroxybiotin derivative (3). When two or more types of acids are used, the "amount of acid catalyst used" refers to the total amount of the two or more acid catalysts used. The temperature during the acid treatment is not particularly limited, but is usually 0 to 100°C, preferably 10 to 60°C. The reaction time is, for example, about 0.1 to 15 hours, preferably 1 to 10 hours.

[0089] In one embodiment, the vinylbiotin derivative (4) is a vinylbiotin derivative represented by formula (4A) (hereinafter referred to as "vinylbiotin derivative (4A)"). The vinylbiotin derivative (4A) is a vinylbiotin derivative represented by formula (4A) (hereinafter referred to as "vinylbiotin derivative (4A)"). １ and R ２ are both benzyl groups, and R ３ is an unsubstituted alkylene group having 3 carbon atoms (i.e., an n-propylene group), and R ４ is an ester group (R ５ is an ethyl group, —C(═O)OR ５ The vinylbiotin derivative (4A) can be produced by dehydrating the hydroxybiotin derivative (3A).

[0090]

[0091] In one embodiment, the vinylbiotin derivative (4) is a vinylbiotin derivative represented by formula (4B) (hereinafter referred to as "vinylbiotin derivative (4B)"). The vinylbiotin derivative (4B) is a vinylbiotin derivative represented by formula (4B) (hereinafter referred to as "vinylbiotin derivative (4B)"). １ and R ２ are both benzyl groups, and R ３ is an unsubstituted alkylene group having 2 carbon atoms (i.e., an n-ethylene group), and R ４ is an alkoxy group (R ５ is a methyl group, -OR ５ The vinylbiotin derivative (4B) can be produced by dehydrating the hydroxybiotin derivative (3B).

[0092]

[0093] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. In the production examples and examples, the purity evaluation and concentration calculation of the zinc reagent were carried out by the following method using gas chromatography (GC), and the calculation of the reaction conversion rate and purity evaluation in the examples and comparative examples were carried out by the following method using high performance liquid chromatography (HPLC).

[0094] <GC measurement conditions> Zinc reagent (BrZn-(CH ２ ) ４ -CO ２ The purity of the zinc reagent (BrZn-(CH)-Et) (2Aa) was evaluated by dissolving a portion of the reaction mixture in chloroform, adding 10% aqueous hydrochloric acid to completely convert the zinc reagent (2Aa) to ethyl valerate, separating the solution, and analyzing the purity of the ethyl valerate in the resulting organic layer by gas chromatography. ２ ) ３The same procedure was performed for the zinc reagent (2Ba), and after the zinc reagent (2Ba) was completely converted to methyl propyl ether, the purity of the methyl propyl ether was evaluated by analyzing it by gas chromatography. The conversion of the zinc reagent (2Aa) to ethyl valerate and the conversion of the zinc reagent (2Ba) to methyl propyl ether were assumed to proceed 100%. Under the GC measurement conditions below, peaks were observed for the halide (2Aa') at approximately 15.7 minutes, ethyl valerate at approximately 10.0 minutes, halide (2Ba') at approximately 6.7 minutes, and methyl propyl ether at approximately 3.6 minutes.

[0095] The GC measurement conditions were as follows: Apparatus: Gas chromatograph (GC) Model: 7820A (Agilent Technologies) Detector: Flame ionization detector (FID) Column: HP-5, inner diameter 0.32 mm, length 30 m, film thickness 0.25 μm (Agilent Technologies) Column temperature: After injection at a constant temperature of around 50°C, this was maintained for 5 minutes and then heated to 150°C at 10°C / min. The temperature was then raised to 250°C at 20°C / min and maintained at 250°C for 5 minutes. Injection port temperature: 300°C Detector temperature: 300°C Carrier gas: Helium Column pressure: 5.35 psi

[0096] <HPLC Measurement Conditions> The analytical conditions for HPLC analysis are as follows. Apparatus: High performance liquid chromatography (HPLC) Model: 2695-2489-2998 (Waters Corporation) Detector: Ultraviolet absorption photometer (measurement wavelength: 210 nm) Column: XBridge-C18, inner diameter 4.6 mm, length 15 cm (particle diameter: 5 μm) (Waters Corporation) Column temperature: Constant at 30°C Sample temperature: Constant at 25°C Mobile phase A: Acetonitrile Mobile phase B: 0.25% aqueous acetic acid Mobile phase delivery: The concentration gradient is controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 1 below. Flow rate: 0.6 mL / min Measurement time: 40 minutes

[0097]

[0098] Under the above HPLC conditions, thiolactone derivative (1A) (R １ , R ２=Bn) at approximately 20.7 minutes, and the hydroxybiotin derivative (3A) (R １ , R ２ = Bn, R ３ =CH ２ CH ２ CH ２ , R ４ =CO ２ Et) at approximately 25.5 minutes, and hydroxybiotin derivative (3B) (R １ , R ２ = Bn, R ３ =CH ２ CH ２ , R ４ = OR ５ , R ５ =Me) at approximately 20.9 minutes, and vinylbiotin derivative (4A) (R １ , R ２ = Bn, R ３ =CH ２ CH ２ CH ２ , R ４ =-CO ２ Et) at approximately 28.5 minutes, and vinylbiotin derivative (4B) (R １ , R ２ = Bn, R ３ =CH ２ CH ２ , R ４ = OR ５ , R ５ =Me) peaks are observed at approximately 24.5 minutes. In the examples, the purity of each of the hydroxybiotin derivative (3A), hydroxybiotin derivative (3B), vinylbiotin derivative (4A), and vinylbiotin derivative (4B) is the percentage of the peak area of ​​the hydroxybiotin derivative (3A), hydroxybiotin derivative (3B), vinylbiotin derivative (4A), and vinylbiotin derivative (4B) relative to the total area of ​​all peaks (excluding peaks derived from the solvent) measured under the above-mentioned HPLC measurement conditions. The reaction conversion is the percentage of the peak area of ​​the reaction product relative to the total peak area of ​​the thiolactone derivative (1A) and the peak area of ​​the reaction product. The reaction products referred to here are the hydroxybiotin derivative (3A), hydroxybiotin derivative (3B), vinylbiotin derivative (4A), and vinylbiotin derivative (4B).

[0099] <Production Example 1: Synthesis of zinc reagent 2Aa> As shown in the following reaction formula, a zinc reagent represented by formula (2Aa) was synthesized from a halide represented by formula (2Aa'). In the formula, "Et" represents an ethyl group.

[0100]

[0101] In a 100 mL three-necked flask equipped with a 2.5 cm diameter stirrer piece, 2.35 g (35.87 mmol) of zinc powder and 10 mL of N,N-dimethylacetamide were added under a nitrogen atmosphere and mixed and stirred at 25 ° C. While maintaining the temperature at 30 ° C or less, 0.54 g (3.59 mmol) of sodium iodide was added and the temperature was raised to 50 ° C. Next, 5.00 g (23.91 mmol) of ethyl 5-bromovalerate (2Aa') was added dropwise over 0.5 hours and stirred at the same temperature for 6 hours. The reaction solution was cooled to 30 ° C., and excess zinc was removed by filtration through Celite to obtain a solution of zinc reagent (2Aa). A portion of the reaction solution was analyzed by GC, and the purity was 91.3% and the concentration of the zinc reagent (2Aa) solution was confirmed to be 2.18 mol / L.

[0102] <Production Example 2: Synthesis of zinc reagent 2Ba> As shown in the following reaction formula, a zinc reagent represented by formula (2Ba) was synthesized from a halide represented by formula (2Ba'). In the formula, "Me" represents a methyl group.

[0103]

[0104] In a 100 mL three-necked flask equipped with a 2.5 cm diameter stirrer piece, 2.99 g (45.75 mmol) of zinc powder and 10 mL of N,N-dimethylacetamide were added under a nitrogen atmosphere and mixed and stirred at 25 ° C. While maintaining the temperature at 30 ° C or less, 0.73 g (4.90 mmol) of sodium iodide was added and the temperature was raised to 50 ° C. Next, 5.00 g (32.67 mmol) of 1-bromo-3-methoxypropane (2Ba') was added dropwise over 0.5 hours and stirred at the same temperature for 6 hours. The reaction solution was cooled to 30 ° C., and excess zinc was removed by filtration through Celite to obtain a solution of zinc reagent (2Ba). A portion of the reaction solution was analyzed by GC, and the purity was 94.4% and the concentration of the zinc reagent (2Ba) solution was confirmed to be 3.08 mol / L.

[0105] Example 1 Synthesis of Hydroxybiotin Derivative and Vinylbiotin Derivative As shown in the following reaction scheme, a hydroxybiotin derivative represented by formula (3A) was synthesized from a thiolactone derivative represented by formula (1A) and a zinc reagent represented by formula (2Aa). In the formula, "Bn" represents a benzyl group and "Et" represents an ethyl group.

[0106]

[0107] A 100 mL three-neck flask equipped with a 2.5 cm diameter stirrer was charged with 5.20 g (15.37 mmol) of the thiolactone derivative (1A) and 5 mL of N,N-dimethylacetamide under a nitrogen atmosphere and stirred at 25°C. Next, 9.87 mL (21.52 mmol) of the zinc reagent (2Aa) prepared in Production Example 1 (2.18 mol / L solution) was added, and the mixture was cooled to 0°C. 3.04 g (30.75 mmol) of copper(I) chloride and 2.43 mL (30.75 mmol) of pyridine were added, followed by stirring at 0°C for 10 hours. Confirmation by high-performance liquid chromatography (HPLC) revealed that the reaction conversion was 94.0%.

[0108] 20 μL of the reaction solution was mixed with 500 μL of 18% aqueous hydrochloric acid and 500 μL of ethyl acetate to convert all of the hydroxybiotin derivative (3A) to the vinylbiotin derivative (4A). The organic layer was then analyzed by high-performance liquid chromatography (HPLC), and the purity of the vinylbiotin derivative (4A) was found to be 84.6%.

[0109] Example 2 A reaction was carried out in the same manner as in Example 1, except that the equivalent of pyridine was changed to 2.0 equivalents relative to the copper catalyst. The conversion rate of the thiolactone derivative (1A) to the hydroxybiotin derivative (3A) was 99.0%, and the purity of the vinylbiotin derivative was 88.6%. The results are shown in Table 2.

[0110] Example 3 A reaction was carried out in the same manner as in Example 1, except that pyridine was added first, followed by copper(I) chloride. The conversion rate of the thiolactone derivative (1A) to the hydroxybiotin derivative (3A) was 98.0%, and the purity of the vinylbiotin derivative was 93.0%. The results are shown in Table 2.

[0111] Example 4 The reaction was carried out in the same manner as in Example 1, except that the equivalent of the zinc reagent was changed to 1.2 equivalents relative to the thiolactone derivative (1A). The conversion rate of the thiolactone derivative (1A) to the hydroxybiotin derivative (3A) was 99.0%, and the purity of the vinylbiotin derivative was 89.1%. The results are shown in Table 2.

[0112] Example 5 A reaction was carried out in the same manner as in Example 1, except that pyridine was replaced with 2,6-lutidine. The conversion rate of the thiolactone derivative (1A) to the hydroxybiotin derivative (3A) was 96.2%, and the purity of the vinylbiotin derivative was 85.2%. The results are shown in Table 2.

[0113] Example 6 A reaction was carried out in the same manner as in Example 1, except that pyridine was replaced with N,N,N',N'-tetramethylethylenediamine. The conversion rate of the thiolactone derivative (1A) to the hydroxybiotin derivative (3A) was 94.1%, and the purity of the vinylbiotin derivative was 81.4%. The results are shown in Table 2.

[0114] Example 7 A reaction was carried out in the same manner as in Example 1, except that pyridine was replaced with bis(2-dimethylaminoethyl) ether. The conversion rate of the thiolactone derivative (1A) to the hydroxybiotin derivative (3A) was 99.4%, and the purity of the vinylbiotin derivative was 89.3%. The results are shown in Table 2.

[0115] Example 8 As shown in the following reaction scheme, a hydroxybiotin derivative represented by formula (3B) was synthesized from a thiolactone derivative represented by formula (1A) and a zinc reagent represented by formula (2Ba), where "Bn" represents a benzyl group and "Me" represents a methyl group.

[0116]

[0117] A 100 mL three-neck flask equipped with a 2.5 cm diameter stirrer was charged with 5.20 g (15.37 mmol) of the thiolactone derivative (1A) and 5 mL of N,N-dimethylacetamide under a nitrogen atmosphere and stirred at 25°C. Next, 6.99 mL (21.52 mmol) of the zinc reagent (2Ba) prepared in Production Example 2 (3.08 mol / L solution) was added, and the mixture was cooled to 0°C. 3.04 g (30.75 mmol) of copper(I) chloride and 2.43 mL (30.75 mmol) of pyridine were added, and the mixture was stirred at 0°C for 10 hours. Confirmation by high-performance liquid chromatography (HPLC) revealed that the reaction conversion was 99.0%.

[0118] 20 μL of the reaction solution was mixed with 500 μL of 18% aqueous hydrochloric acid and 500 μL of ethyl acetate to convert all of the hydroxybiotin derivative (3B) to the vinylbiotin derivative (4B). The organic layer was then analyzed by high-performance liquid chromatography (HPLC), and the purity of the vinylbiotin derivative (4B) was found to be 89.1%.

[0119] Comparative Example 1 A reaction was carried out in the same manner as in Example 1, except that pyridine was not added. The results are shown in Table 2.

[0120] Example 9: Synthesis of hydroxybiotin derivative As shown in the following reaction formula, a zinc reagent (2Aa) was synthesized, and then a thiolactone derivative represented by formula (1A) was added to carry out a coupling reaction to synthesize a hydroxybiotin derivative represented by formula (3A). In the formula, "Bn" represents a benzyl group, and "Et" represents an ethyl group.

[0121]

[0122]

[0123] A 100 mL three-neck flask equipped with a 2.5 cm diameter stirrer was charged with 2.35 g (35.87 mmol) of zinc powder and 10 mL of N,N-dimethylacetamide under a nitrogen atmosphere and mixed and stirred at 25°C. While maintaining the temperature at 30°C or below, 0.54 g (3.59 mmol) of sodium iodide was added and the mixture was heated to 50°C. Next, 5.00 g (23.91 mmol) of ethyl 5-bromovalerate (2Aa') was added dropwise over 0.5 hours and stirred at the same temperature for 6 hours. The reaction solution was cooled to 30°C to obtain a solution of zinc reagent (2Aa). A portion of the reaction solution was analyzed by GC, confirming that the purity was 90.9% and the concentration of the zinc reagent (2Aa) solution was 2.17 mol / L.

[0124] To an N,N-dimethylacetamide solution (21.71 mmol; 2.17 mol / L) of the zinc reagent (2Aa), 5.20 g (15.37 mmol) of the thiolactone derivative (1A) and 2.43 mL (30.75 mmol) of pyridine were added, and the mixture was stirred at 0°C. Next, 3.04 g (30.75 mmol) of copper(I) chloride was added, and the mixture was stirred at 0°C for 10 hours. When confirmed by high performance liquid chromatography (HPLC), the reaction conversion was 99.0%.

[0125] The reaction mixture was filtered through Celite to remove excess metal, and the resulting filtrate was concentrated under reduced pressure to obtain 7.15 g of the hydroxybiotin derivative (3A) (yield=99.2%).

[0126] Example 10: Synthesis of vinylbiotin derivative As shown in the following reaction formula, a vinylbiotin derivative (4A) was synthesized by dehydrating a hydroxybiotin derivative represented by formula (3A), where "Bn" represents a benzyl group and "Et" represents an ethyl group.

[0127]

[0128] Into a 100 mL three-necked flask equipped with a 2.5 cm diameter stirrer piece, 7.15 g (15.37 mmol) of the hydroxybiotin derivative (3A) synthesized in Example 9 and 30 mL (475.79 mmol) of acetic acid were added, and the mixture was stirred at 50° C. for 5 hours. When confirmed by high performance liquid chromatography (HPLC), the reaction conversion was 100%.

[0129] The reaction mixture was filtered through Celite, and the resulting filtrate was concentrated under reduced pressure. 35 mL of ethyl acetate was added to the residue for extraction, followed by separation and washing with 30% aqueous ammonium chloride, 5% aqueous sodium bicarbonate, and 10% saline, in that order. The resulting organic layer was concentrated under reduced pressure to give 6.38 g of vinylbiotin derivative (4A) (yield: 92.1%).

[0130]

Claims

1. In the presence of a copper catalyst and an amine compound, a reaction of the following formula (1): [In the formula, R １ and R ２ and each independently represent a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent.] and a thiolactone derivative represented by the following formula (2): [wherein X represents a bromine atom or a chlorine atom; R ３ represents a direct bond or an alkylene group having 1 to 7 carbon atoms which may have a substituent, R ４ is -C(=O)OR ５ a monovalent group represented by -OR ５ or a cyano group, ５ represents a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent.] is contacted with a zinc reagent represented by the following formula (3): [In the formula, R １ and R ２ is the same as in formula (1), and R ３ and R ４ has the same meaning as the above formula (2).

2. The method for producing a hydroxybiotin derivative according to claim 1, wherein the amine compound is used in an amount of 0.1 moles or more and 5.0 moles or less per mole of the copper catalyst.

3. The method for producing a hydroxybiotin derivative according to claim 1, wherein the amine compound is at least one selected from the group consisting of polydentate aliphatic amines and tertiary aromatic amines.

4. The method for producing a hydroxybiotin derivative according to claim 1, wherein the thiolactone derivative, the zinc reagent and the amine compound are mixed together, and then the resulting mixture is mixed with the copper catalyst, thereby contacting the thiolactone derivative with the zinc reagent in the presence of the copper catalyst and the amine compound.

5. A method for producing a hydroxybiotin derivative according to claim 1, wherein the thiolactone derivative is contacted with the zinc reagent in the presence of the copper catalyst and the amine compound in a solvent containing a polar solvent having a dielectric constant of 15 or more at 25°C.

6. The method for producing a hydroxybiotin derivative according to claim 5, wherein the polar solvent is N,N-dimethylacetamide.

7. The method for producing a hydroxybiotin derivative according to claim 5, wherein the thiolactone derivative and the zinc reagent are contacted in the presence of the copper catalyst and the amine compound by mixing the thiolactone derivative, the amine compound and the copper catalyst in the solvent and then mixing the resulting mixture with the zinc reagent, or by mixing the thiolactone derivative, the amine compound and the zinc reagent in the solvent and then mixing the resulting mixture with the copper catalyst.

8. After producing a hydroxybiotin derivative represented by the formula (3) by the method according to any one of claims 1 to 7, the obtained hydroxybiotin derivative is dehydrated to give a hydroxybiotin derivative represented by the following formula (4): [In the formula, R １ and R ２ is the same as in formula (1), and R ３ and R ４ has the same meaning as the above formula (2).

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