Hydroxybiotin derivative and method for producing vinyl biotin derivative

Abstract

The present invention addresses the problem of providing a method for producing a hydroxy biotin derivative and a method for producing a vinyl biotin derivative, whereby a coupling reaction between a thiolactone derivative and a zinc reagent containing a halogen atom other than iodine can be smoothly and efficiently performed using an inexpensive metal catalyst, and provides a method for producing a hydroxy biotin derivative. Comprising a step of bringing a thiolactone derivative represented by formula (1) into contact with a zinc reagent represented by formula (2) to obtain a hydroxybiotin derivative represented by formula (3). # imgabs0 # X-Zn-R3-R4 (2) # imgabs1 #

Description

Technical Field

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

[0002] Biotin is a useful compound that can be used in various pharmaceuticals, food additives, feed additives, etc. Biotin is synthesized by the following production method.

[0003] [Chemical formula 1]

[0004]

[0005] That is, first, (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione represented by the above formula (1A) (hereinafter, sometimes referred to as "thiolactone derivative") and (5-ethoxy-5-oxopentyl)zinc halide represented by the above formula (2A) (hereinafter, sometimes referred to as "zinc reagent") 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 the above formula (3A) (hereinafter, sometimes referred to as "hydroxybiotin derivative"). In addition, in the above formula (2A), X is a halogen atom. Next, the hydroxybiotin derivative is dehydrated to derive into ethyl 5-[(3aS,6aR)-1,3-dibenzyl-2-oxohexahydro-4H-thieno[3,4-d]imidazol-4-yl]pentanoate (hereinafter sometimes referred to as "vinylbiotin derivative") represented by the above formula (4A). Then, reduction, deprotection and hydrolysis reactions are carried out to produce biotin.

[0006] In this production method, hydroxybiotin derivatives are important synthetic intermediates of biotin, and many studies have been conducted on their synthetic methods.

[0007] For example, Non-Patent Document 1 describes a method in which a hydroxybiotin derivative is synthesized by reacting a thiolactone derivative with a zinc reagent in which X is composed of iodine in the presence of a bis(triphenylphosphine)palladium dichloride catalyst. However, this production method requires an expensive iodine-containing reagent as the zinc reagent and requires expensive palladium as the metal catalyst, so there is room for improvement in terms of cost.

[0008] Therefore, research on a production method that avoids the use of expensive iodine-containing zinc reagents is also actively being conducted. Non-patent documents 2 and 3 describe a method for synthesizing a hydroxybiotin derivative by reacting a thiolactone derivative with a zinc reagent in which X is composed of bromine in the presence of a palladium catalyst.

[0009] Prior art literature

[0010] Non-patent literature

[0011] Non-patent document 1: Tetrahedron Letters 41, 2000, 5099-5101

[0012] Non-patent document 2: Advanced Synthesis and Catalysis 2008, 350, 1635-1641 Non-patent document 3: Tetrahedron Asymmetry 21, 2010, 665-669 Summary of the invention

[0013] Problems to be solved by the invention

[0014] However, it is known that the conventional techniques disclosed in Non-Patent Documents 2 and 3 have room for improvement in the following aspects when a hydroxybiotin derivative is produced using a zinc reagent in which X is composed of bromine.

[0015] Non-patent document 3 describes a method for producing a hydroxybiotin derivative by reacting at 30° C. for 30 hours in the presence of a palladium-carbon catalyst. However, in this method, although 2.8 equivalents of zinc reagent are used relative to the thiolactone derivative, the yield of the hydroxybiotin derivative after the reaction is as low as 75%.

[0016] In contrast, non-patent document 2 records that a hydroxybiotin derivative is obtained with a yield of 85% by using 2.0 equivalents of a zinc reagent and reacting at 35° C. for 10 hours. However, this reaction requires a special nano palladium catalyst prepared independently, and there are many problems in industrial utilization. In addition, the methods described in non-patent documents 2 and 3 all require expensive palladium, and it is desired to develop a reaction using a cheaper metal catalyst.

[0017] Therefore, the present invention aims to smoothly carry out the coupling reaction of a thiolactone derivative with a zinc reagent containing a halogen atom other than iodine (e.g., bromine) using an inexpensive metal catalyst. In addition, the present invention provides a method for efficiently producing a hydroxybiotin derivative and a vinylbiotin derivative.

[0018] Means for solving problems

[0019] The inventors of the present application have conducted intensive studies to solve the above problems and surprisingly found that a hydroxybiotin derivative can be synthesized at a high conversion rate by contacting a thiolactone derivative with a zinc reagent in the presence of a copper catalyst, thereby completing the present invention.

[0020] That is, the first aspect of the present invention relates to a method for producing a hydroxybiotin derivative, comprising the step of contacting a thiolactone derivative represented by the following formula (1) with a zinc reagent represented by the following formula (2) in the presence of a copper catalyst to obtain a hydroxybiotin derivative represented by the following formula (3):

[0021] [Chemical formula 2]

[0022]

[0023] In formula (1), R 1 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,

[0024] [Chemical formula 3]

[0025] X-Zn—R 3 —R 4 (2)

[0026] In formula (2), X is a bromine atom or a chlorine atom, and R 3 is an alkylene group having 1 to 8 carbon atoms which may have a substituent, R 4 -C(=O)OR 5 A monovalent group or a cyano group, R 5 is 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,

[0027] [Chemical formula 4]

[0028]

[0029] In formula (3), R 1 and R 2 Same as the meaning of the above formula (1), R 3 and R 4 This has the same meaning as in the above formula (2).

[0030] The second aspect of the present invention relates to a method for producing a vinyl biotin derivative, comprising the steps of producing a hydroxy biotin derivative represented by the above formula (3) by the method according to the first aspect of the present invention, and then dehydrating the obtained hydroxy biotin derivative to obtain a vinyl biotin derivative represented by the following formula (4):

[0031] [Chemical formula 5]

[0032]

[0033] In formula (4), R 1 and R 2Same as the meaning of the above formula (1), R 3 and R 4 This has the same meaning as in the above formula (2).

[0034] Effects of the Invention

[0035] According to the method involved in the first embodiment of the present invention, a hydroxybiotin derivative can be produced at a high conversion rate using a copper catalyst which is a cheaper metal. According to the method involved in the second embodiment of the present invention, after producing a hydroxybiotin derivative using the method involved in the first embodiment of the present invention, the obtained hydroxybiotin derivative is subjected to a dehydration treatment, thereby being able to be simply and efficiently converted into a vinylbiotin derivative. DETAILED DESCRIPTION

[0036] <<First aspect of the present invention>>

[0037] A first aspect of the present invention relates to a method for producing a hydroxybiotin derivative by contacting a thiolactone derivative with a zinc reagent in the presence of a copper catalyst.

[0038] Hereinafter, one embodiment of the first aspect of the present invention (hereinafter also referred to as “this embodiment”) will be described in detail one by one.

[0039] <Thiolactone derivatives>

[0040] In the present embodiment, the thiolactone derivative used is a compound represented by the following formula (1).

[0041] [Chemical formula 6]

[0042]

[0043] In the above formula (1), R 1 and R 2 Each is 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 The functional groups may be the same as each other or different types of functional groups may be used.

[0044] (R 1 and R 2 )

[0045] Below, for R 1 or R 2 The case where each of them is independently an alkyl group will be described.

[0046] The alkyl group may be straight-chain or branched. The number of carbon atoms of the alkyl group is, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 6, further preferably 1 to 3, and particularly preferably 1 or 2. The alkyl group may have a substituent. As a substituent that the alkyl group may have, for example, 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 halogen group, and the like may be cited. The aryl group may be monocyclic or polycyclic (for example, bicyclic or tricyclic). The polycyclic group may be a condensed ring type. The aryl group is particularly preferably a phenyl group. The alkoxy group may be straight-chain or branched. As a halogen group, for example, a fluoro group, a chloro group, a bromo group, an iodo group, and the like may be cited. As a substituent that the alkyl group may have, an aryl group having 6 to 14 carbon atoms is preferred, an aryl group having 6 to 10 carbon atoms is more preferred, and a phenyl group is particularly preferred. When the alkyl 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.

[0047] Below, for R 1 and R 2 The case where each of them is independently an aralkyl group will be described.

[0048] Aralkyl refers to an alkyl group having one aryl group. That is, an aralkyl group is a group in which one hydrogen atom of an alkyl group is replaced by an aryl group. The alkyl group may be straight-chain or branched. The number of carbon atoms of the alkyl group is, for example, 1 to 10, preferably 1 to 6, more preferably 1 to 3, and further preferably 1 or 2. The number of carbon atoms of the aryl group is, for example, 6 to 22, preferably 6 to 14, and more preferably 6 to 10. The aryl group may be monocyclic or polycyclic (for example, bicyclic or tricyclic). The polycyclic group may be a condensed ring type. The aryl group is particularly preferably a phenyl group. As an aralkyl group, an aralkyl group having 7 to 11 carbon atoms is preferred. Examples of suitable aralkyl groups include benzyl, phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl, etc. The aralkyl group may have a substituent. As the substituent that the aralkyl group may have, for example, 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 can be mentioned. The alkyl group and the alkoxy group can each be either linear or branched. As the halogen group, for example, a fluoro group, a chloro group, a bromo group, an iodo group, and the like can be mentioned. When the aralkyl group has a substituent, the number of the substituent is preferably 1 to 5, more preferably 1 to 3, and particularly preferably 1. When the aralkyl group has a substituent, either the alkyl part or the aryl part of the aralkyl group may have a substituent, or both may have a substituent, and preferably at least the aryl part has a substituent.

[0049] Below, for R 1 or R 2The case where each is independently an aryl group is described below.

[0050] The aryl group may be a monocyclic or polycyclic group (for example, a bicyclic or tricyclic group). The polycyclic group may be a condensed ring group. The number of carbon atoms of the aryl group is, for example, 6 to 22, preferably 6 to 14, and more preferably 6 to 10. The aryl group is particularly preferably a phenyl group. The aryl group may have a substituent. As substituents that the aryl group may have, for example, 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 may be cited. Each of the alkyl group and the alkoxy group may be any of a straight chain or a branched chain. As a halogen group, for example, a fluoro group, a chloro group, a bromo group, an iodo group, and the like may be cited. 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.

[0051] It should be noted that if the final deprotection is taken into consideration, R 1 and R 2 An aralkyl group is preferred, and a benzyl group is particularly preferred.

[0052] Suitable thiolactone derivatives

[0053] As the thiolactone derivative represented by the above formula (1), in consideration of its usefulness, a thiolactone derivative represented by the following formula (1A) ((3aS, 6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione) can be cited as a suitable compound. In the following formula (1A), "Bn" represents a benzyl group. The thiolactone derivative represented by the following formula (1A) is a thiolactone derivative represented by the above formula (1) in which R 1 and R 2 All are benzyl compounds.

[0054] [Chemical formula 7]

[0055]

[0056] <Zinc reagent>

[0057] In this embodiment, the zinc reagent used is a compound represented by the following formula (2).

[0058] [Chemical formula 8]

[0059] X-Zn-R 3 -R 4 (2)

[0060] In the above formula (2), X is a chlorine atom or a bromine atom, and R 3 is an alkylene group having 1 to 8 carbon atoms which may have a substituent, R 4-C(=O)OR 5 A monovalent group or a cyano group, R 5 is 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. 5 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 are respectively the same as the above R 1 and R 2 The groups described in are the same as those described in , and detailed descriptions thereof are omitted here.

[0061] (R 3 )

[0062] R 3 It has -ZnX and -R at both ends. 4 The number of carbon atoms of the alkylene group is preferably 1 to 8, and particularly preferably 2 to 6. The alkylene group may have a substituent. As substituents that the alkylene group may have, for example, an aryl group having 6 to 22 carbon atoms (preferably 6 to 14, and more preferably 6 to 10), an alkoxy group having 1 to 6 carbon atoms (preferably 1 to 3, and more preferably 1 or 2), a halogen group, and the like may be mentioned. The aryl group may be a monocyclic or polycyclic group (for example, a bicyclic or tricyclic group). The polycyclic group may be a condensed ring group. The aryl group is particularly preferably a phenyl group. The alkoxy group may be straight-chain or branched. As halogen groups, for example, a fluoro group, a chloro group, a bromo group, an iodo group, and the like may be mentioned. 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. Among them, R in the present embodiment 3 An alkylene group having no substituent is most preferred.

[0063] (R 4 and R 5 )

[0064] Considering the reactivity and the ease of conversion to biotin, R 4 Preferably, it is a cyano group or a carboxyl group (R 5 = hydrogen atom) or ester group (R 5 = an alkyl group which may have a substituent), among which a carboxyl group (R 5 = hydrogen atom), or an ester group (R 5 = an alkyl group which may have a substituent).

[0065] Suitable zinc reagents

[0066] As the zinc reagent represented by the above formula (2), the zinc reagent represented by the following formula (2A) ((5-ethoxy-5-oxopentyl) zinc halide) is suitable. It should be noted that "Et" in the following formula (2A) represents an ethyl group. Hereinafter, the same description is sometimes omitted. X has the same meaning as in the above formula (2). The zinc reagent represented by the following formula (2A) is R in the zinc reagent represented by the above formula (2). 3 is an unsubstituted alkylene group having 4 carbon atoms (i.e., n-butylene group), R 4 is an ester group (R 5 is an ethyl) compound.

[0067] [Chemical formula 9]

[0068]

[0069] Among the zinc reagents represented by the above formula (2A), the zinc reagent represented by the following formula (2Aa) ((5-ethoxy-5-oxopentyl)zinc bromide) or the zinc reagent represented by the following formula (2Ab) ((5-ethoxy-5-oxopentyl)zinc chloride) is more suitable, and the zinc reagent represented by the following formula (2Aa) is particularly suitable. The zinc reagent represented by the following formula (2Aa) is a compound in which X is a bromine atom in the zinc reagent represented by the above formula (2A), and the zinc reagent represented by the following formula (2Ab) is a compound in which X is a chlorine atom in the zinc reagent represented by the above formula (2A).

[0070] [Chemical formula 10]

[0071]

[0072] The amount of the zinc reagent used in this embodiment is not particularly limited. In order to avoid the complexity of subsequent processing operations, it is preferably in the range of 1.0 to 2.0 moles, and particularly preferably in the range of 1.2 to 1.8 moles relative to 1 mole of the thiolactone derivative. In this embodiment, the reaction efficiency is greatly improved, and the reaction is fully carried out even with the zinc reagent within the aforementioned range.

[0073] <Method for producing zinc reagent>

[0074] The zinc reagent in this embodiment is not particularly limited, and a zinc reagent manufactured by a known method can be used. For example, a zinc reagent manufactured by the method described in Non-Patent Documents 2 and 3, and a purified zinc reagent can be used. Specifically, it can be manufactured according to the following reaction formula.

[0075] [Chemical formula 11]

[0076]

[0077] That is, the zinc reagent can be easily prepared by contacting the corresponding halide (2') with zinc. 3 and R 4 respectively with X, R described in the description of the above zinc reagent 3 and R 4 same.

[0078] (Zinc powder)

[0079] The zinc used in the above reaction is simple zinc, which can be in the form of powder, chips, strips, etc., and its form is not limited. The amount of the above zinc used can be appropriately determined according to the type of the above halide, for example, 1 to 5 moles are used relative to 1 mole of the above halide, preferably 1 to 3 moles are used.

[0080] (Activator)

[0081] The contact between the halide and zinc is preferably carried out in the presence of an activator. If the activator of zinc is exemplified, bromine, iodine, 1,2-dibromoethane, trimethylchlorosilane, 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), cesium iodide (CsI), etc. Among them, if the reactivity is taken into account, the activator is preferably selected from quaternary ammonium salts such as TBAI and TMAI and alkali metal iodide salts such as NaI and KI. If safety, price, etc. are further taken into account, the activator is particularly preferably selected from NaI and KI. The activator is used, for example, in an amount of 0.01 to 1.5 moles relative to 1 mole of the zinc, preferably 0.05 to 0.8 moles.

[0082] (Solvent)

[0083] The preparation of the above-mentioned zinc reagent is preferably carried out in an organic solvent. As organic solvents, 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), diethylene glycol dimethyl ether, etc. Among them, if the progress of the reaction, the influence on the subsequent process, etc. are taken into consideration, a polar solvent with a relative dielectric constant of 15 or more at 25°C is particularly preferred. Specifically, N,N-dimethylacetamide (DMAC) (relative dielectric constant = 37.78), N,N-dimethylformamide (DMF) (relative dielectric constant = 36.71), N,N-dimethylimidazolidinone (DMI) (relative dielectric constant = 37.6), etc. meet the requirements. The organic solvents exemplified above can be used alone or as a mixture of two or more.

[0084] The amount of the organic solvent used is not particularly limited, but is 0.1 to 20 mL, preferably 0.5 to 10 mL, based on 1 g of the halide. When a mixture is used as the organic solvent, the amount used is based on the total amount of the mixture.

[0085] (Contact method of halide and zinc)

[0086] The contact temperature of the halide and zinc may be appropriately determined depending on the 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.

[0087] The preparation of the above-mentioned zinc reagent is preferably carried out by the following method. First, after the above-mentioned solvent is mixed with zinc, an activator is added to activate the zinc. Then, the above-mentioned halide is added and mixed, so that the zinc reagent can be prepared. It should be noted that the obtained zinc reagent can be used in the manufacture of hydroxybiotin derivatives in the state of solution without separation and purification. Of course, in order to improve the purity, the separated and purified zinc reagent can also be used.

[0088] By reacting under the above conditions, the aforementioned zinc reagent can be prepared efficiently and simply. It should be noted that the zinc reagent obtained in the aforementioned reaction is not particularly limited and can be a zinc reagent with a purity of 80.0 to 95.0%. In addition, the subsequent coupling reaction can also be carried out without subsequent treatment of the solution containing excess zinc after the reaction.

[0089] The reaction atmosphere is not particularly limited, and the reaction can be carried out in an atmosphere of an inert gas such as nitrogen or argon.

[0090] <Copper Catalyst>

[0091] The greatest feature of the present invention is that the thiolactone derivative represented by formula (1) is brought into contact with the zinc reagent represented by formula (2) in the presence of a copper catalyst. By bringing the thiolactone derivative into contact with the zinc reagent in the presence of a copper catalyst, a coupling reaction can be smoothly performed, and the hydroxybiotin derivative can be efficiently converted.

[0092] The copper catalyst used in the present embodiment is not particularly limited, and any copper compound in 1valence and 2valence can be used as a copper catalyst. If a specific copper catalyst is exemplified, copper chloride (I), copper chloride (II), copper bromide (I), copper bromide (II), copper cyanide (I), 3-methylsalicylic acid copper (I), mesitylene copper (I), isopropoxide copper (I), copper iodide (I), copper iodide (II), copper acetate (I), copper acetate (II), copper sulfate (II), copper oxide (I), copper oxide (II), copper pivalate (I), copper pivalate (II), etc. The copper catalyst in this reaction is preferably a univalent copper compound, more preferably a univalent copper halide containing a halogen atom.

[0093] The amount of the copper catalyst used may be appropriately determined, and is preferably 0.01 to 10 mol, more preferably 0.1 to 8 mol, and particularly preferably 1.0 to 5 mol relative to the thiolactone derivative. Of course, the copper catalyst may be added later depending on the progress of the reaction, or may be added in batches while confirming the progress of the reaction.

[0094] <Reaction solvent>

[0095] The contact of the thiolactone derivative represented by formula (1) with the zinc reagent represented by formula (2) is preferably carried out in a solvent. The solvent used in the reaction of the thiolactone derivative with the zinc reagent is not particularly limited and can be appropriately selected from solvents that do not hinder the reaction. Specifically, non-polar solvents such as toluene, benzene, ether, chloroform, dichloromethane, tetrahydrofuran, acetonitrile, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylimidazolidinone, dimethyl sulfoxide and other non-protonic polar solvents can be cited. Among them, it is preferred to use a solvent containing a polar solvent having a relative dielectric constant of 15 or more at 25°C as the reaction solvent in this embodiment. The so-called relative dielectric constant is a parameter indicating the approximate polarity of an organic solvent. In other words, it can be said that it is preferred to react in a highly polar solvent. The reason is still uncertain, and it is believed that the coupling reaction is accelerated due to the increased solubility of the zinc reagent and the copper catalyst used in the reaction. If polar solvents with a relative dielectric constant of 15 or more at 25°C are exemplified, N,N-dimethylacetamide (DMAC) (relative dielectric constant = 37.78), N,N-dimethylformamide (DMF) (relative dielectric constant = 36.71), N,N-dimethylimidazolidinone (DMI) (relative dielectric constant = 37.6), acetonitrile (relative dielectric constant = 37.5), N-methylpyrrolidone (NMP) (relative dielectric constant = 32.0), dimethyl sulfoxide (DMSO) (relative dielectric constant = 48.9), sulfolane (relative dielectric constant = 43.3) and the like can be cited. Among them, from the aspect of reaction speed, it is preferred to use a solvent selected from DMAC, DMF and DMI, and DMAC is most preferred. In other words, as the solvent used in the reaction, it is preferred to use a solvent with a relative dielectric constant of 35 or more and 40 or less at 25°C. It should be noted that the solvents exemplified above can be used alone or as a mixture of two or more.

[0096] Wherein, when using a mixture of two or more, it is more preferred that the volume ratio of the aforementioned polar solvent in the aforementioned solvent is 15% or more. By increasing the ratio of the polar solvent in the reaction solvent, the reaction is carried out more efficiently and effectively, and the reaction can be completed in a short time. If the reaction rate is taken into consideration, the volume ratio of the aforementioned polar solvent is preferably 30% or more, more preferably 50% or more, and most preferably 100%. It should be noted that making the volume ratio of the aforementioned polar solvent 100% does not mean that the mixing of impurities that inevitably enter the solvent other than the aforementioned polar solvent is completely excluded.

[0097] In this embodiment, the amount of the solvent used is not particularly limited. Considering the post-treatment of the reaction, 0.1 to 20 mL, preferably 0.5 to 10 mL, and more preferably 1 to 7 mL are used relative to 1 g of the aforementioned thiolactone derivative. When a mixture of the aforementioned polar solvent and a solvent other than the aforementioned polar solvent is used as the solvent, the amount used is based on the total amount of the mixture.

[0098] It should be noted that the solvent is preferably the same as the solvent used in the preparation of the zinc reagent. By using the same solvent, the operation associated with solvent replacement can be omitted.

[0099] <Method for producing hydroxybiotin derivative>

[0100] In this embodiment, in the presence of a copper catalyst, a thiolactone derivative is contacted with a zinc reagent and reacted to produce a hydroxybiotin derivative. At this time, it is sufficient to mix the components in such a way that they can be fully contacted. The method involved in this embodiment can also be implemented under any state of normal pressure, reduced pressure, and pressurized pressure. The method involved in this embodiment can be implemented not only in the presence of oxygen such as oxygen and atmosphere, but also in an inert gas atmosphere such as nitrogen, argon, and carbon dioxide. There is no particular limitation on the mixing method of the components. For example, all components can be put into a reaction device at the same time and mixed. It is also possible to mix one component in advance, and add the remaining components in sequence and mix them. The components can also be diluted with a solvent and supplied to a reaction device, etc. Among them, in order to further reduce by-products and improve the purity of the hydroxybiotin derivative, it is preferred to adopt: a method of mixing a zinc reagent after dispersing a thiolactone derivative and a copper catalyst in a solvent; or a method of mixing a copper catalyst after dispersing a thiolactone derivative and a zinc reagent in a solvent. By adopting this method, the violent decomposition of the zinc reagent can be suppressed, and the reaction can proceed smoothly. This method can be carried out under an inert gas atmosphere.

[0101] In the present embodiment, the reaction temperature (here, "reaction temperature" refers to the temperature in the reaction system after all the components are mixed) is not particularly limited and can be implemented in the range of -10 to 50°C. Among them, if the reaction rate, the purity of the obtained biotin derivative, etc. are taken into consideration, it is preferably reacted at -5 to 35°C. By reacting within this range, it is possible to efficiently convert into a hydroxybiotin derivative in a short time. In addition, the reaction time is also not limited, and it can be appropriately determined while confirming the reaction conversion rate described in the following embodiments. Among them, if it is the aforementioned reaction conditions, the reaction time is preferably 1 to 30 hours, more preferably 1 to 20 hours. It should be noted that the reaction time refers to the time for mixing the aforementioned thiolactone derivatives at a set reaction temperature in the presence of a zinc reagent and a copper catalyst in a solvent added as needed.

[0102] <Hydroxybiotin derivatives>

[0103] In this embodiment, the obtained hydroxybiotin derivative is a compound represented by the following formula (3).

[0104] [Chemical formula 12]

[0105]

[0106] It should be noted that in the above formula (3), R 1 and R 2 Same as the meaning of the above formula (1), R 3 and R 4 This has the same meaning as in the above formula (2).

[0107] <<Second embodiment of the present invention>>

[0108] The second aspect of the present invention relates to a method for producing a vinyl biotin derivative, which comprises the following steps: after producing a hydroxybiotin derivative represented by the above-mentioned formula (3) by the method involved in the first aspect of the present invention, dehydrating the obtained hydroxybiotin derivative to produce a vinyl biotin derivative represented by the following formula (4).

[0109] [Chemical formula 13]

[0110]

[0111] It should be noted that in the above formula (4), R 1 and R 2 Same as the meaning of the above formula (1), R 3 and R 4 This has the same meaning as in the above formula (2).

[0112] As a method for dehydrating the hydroxybiotin derivative, for example, acid treatment or heat treatment can be cited. If the purity of the product is taken into consideration, it is preferably carried out by acid treatment. The acid treatment includes contacting the hydroxybiotin derivative with an acid catalyst. It should be noted that the hydroxybiotin derivative used can also be directly used as the reaction solution obtained by the above method. As an acid catalyst, for example, any acid in an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, or an organic acid such as formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid can be used.

[0113] These acid catalysts can be used alone or in combination. When using multiple acids, the amount of the acid used as a reference is the total amount of the multiple acids. The amount of the acid used can be appropriately determined according to the type of acid used, for example, 1 to 1000 moles, preferably 20 to 200 moles, relative to 1 mole of the hydroxybiotin derivative. The temperature during the acid treatment is not particularly limited, and is usually 0 to 100° C., preferably 10 to 60° C. In addition, the reaction time is, for example, about 0.1 to 15 hours, preferably 1 to 10 hours.

[0114] Example

[0115] Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these specific examples. It should be noted that the purity evaluation and concentration calculation of the zinc reagent in the preparation examples and examples were performed by using the following gas chromatography (GC) method, and the calculation of the reaction conversion rate and purity evaluation in the examples were performed by using the following high performance liquid chromatography (HPLC) method.

[0116] <GC measurement conditions>

[0117] As for the purity of the zinc reagent (2Aa), a portion of the reaction solution was dissolved in chloroform, and a 10% hydrochloric acid aqueous solution was added to completely convert the zinc reagent (2Aa) into ethyl valerate, and then the liquid was separated, and the purity of ethyl valerate in the obtained organic layer was analyzed by gas chromatography. The conversion of the zinc reagent (2Aa) to ethyl valerate was considered to be 100%. It should be noted that under the following conditions, the peak of the halide (2A') was confirmed at about 15.7 minutes, and the peak of ethyl valerate was confirmed at about 10.0 minutes.

[0118] Device: Gas Chromatography (GC)

[0119] Equipment model: 7820A (made by Agilent Technologies)

[0120] Detector: Flame ionization detector (FID)

[0121] Column: HP-5, inner diameter 0.32 mm, length 30 m, membrane thickness 0.25 μm (manufactured by Agilent Technologies)

[0122] Column temperature: After injection at a constant temperature of approximately 50°C, the temperature was maintained for 5 minutes, and then the temperature was increased to 150°C at 10°C / min. Then, the temperature was increased to 250°C at 20°C / min, and then maintained at 250°C for 5 minutes.

[0123] Inlet temperature: 300℃

[0124] Detector temperature: 300°C

[0125] Carrier gas: Helium

[0126] Column pressure: 5.35 psi

[0127] <HPLC measurement conditions>

[0128] The analysis conditions of HPLC analysis are as follows.

[0129] Apparatus: High Performance Liquid Chromatography (HPLC)

[0130] Equipment model: 2695-2489-2998 (made by Waters)

[0131] Detector: UV spectrophotometer (measurement wavelength: 210nm)

[0132] Column: XBridge-C18, inner diameter 4.6 mm, length 15 cm (particle size: 5 μm) (manufactured by Waters)

[0133] Column temperature: 30°C constant

[0134] Sample temperature: 25°C constant

[0135] Mobile phase A: acetonitrile

[0136] Mobile phase B: 0.25% acetic acid in water

[0137] Mobile phase feeding: The mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 1 below to control the concentration gradient.

[0138] Flow rate: 0.6mL / min

[0139] Measurement time: 40 minutes

[0140] [Table 1]

[0141] Table 1

[0142]

[0143] Under the above HPLC measurement conditions, the thiolactone derivative (1A) (R 1 , R 2 =Bn) peak, and a hydroxybiotin derivative (3A) (R 1 , R 2 =Bn,R 3 =CH 2 CH 2 CH 2 CH 2 , R 3 =CO 2Et) peak, and the vinyl biotin derivative (4A) (R 1 , R 2 =Bn,R 3 =CHCH 2 CH 2 CH 2 , R 4 =-CO 2 Et). It should be noted that, in the examples, the purity of each hydroxybiotin derivative (3A) and vinylbiotin derivative (4A) is the ratio of the peak area value of the hydroxybiotin derivative (3A) and vinylbiotin derivative (4A) measured under the above conditions to the total area value of all peaks (excluding the peak from the solvent). In addition, the reaction conversion rate refers to the value calculated as the percentage of the HPLC area value of the generated hydroxybiotin derivative (3A) or vinylbiotin derivative (4A) relative to the total value of the HPLC area value of the thiolactone derivative (1A) and the hydroxybiotin derivative (3A) or vinylbiotin derivative (4A).

[0144] <Production Example 1: Synthesis of zinc reagent 1>

[0145] As shown in the following reaction formula, the zinc reagent represented by the formula (2Aa) is synthesized from the halide represented by the formula (2A'). It should be noted that "Et" in the formula represents an ethyl group.

[0146] [Chemical formula 14]

[0147]

[0148] In a 100 mL three-necked flask equipped with a stirrer with a diameter of 2.5 cm, 23.5 g (358.71 mmol) of zinc powder, 37.5 mL of tetrahydrofuran, and 12.5 mL of N,N-dimethylacetamide were added under a nitrogen atmosphere, and mixed and stirred at 25°C. While maintaining the temperature below 30°C, 5.4 g (35.87 mmol) of sodium iodide was added, and the temperature was raised to 80°C. Next, 50 g (239.14 mmol) of ethyl 5-bromopentanoate (2A') 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 the remaining zinc and the like were removed by diatomaceous earth filtration, thereby obtaining a solution of zinc reagent (2Aa). A portion of the reaction solution was taken and analyzed by GC, which confirmed that the purity was 89.3% and the concentration of the zinc reagent (2Aa) solution was 4.27 mol / L (volume ratio of solvent = tetrahydrofuran:N,N-dimethylacetamide = 3:1).

[0149] <Example 1: Synthesis of Hydroxybiotin Derivatives>

[0150] As shown in the following reaction formula, the hydroxybiotin derivative represented by formula (3A) is synthesized from the thiolactone derivative represented by formula (1A) and the zinc reagent represented by formula (2Aa). It should be noted that "Bn" in the formula represents a benzyl group, and "Et" represents an ethyl group.

[0151] [Chemical formula 15]

[0152]

[0153] In a 50 mL three-necked flask equipped with a stirrer of 2.5 cm in diameter, 2.5 g (7.39 mmol) of thiolactone derivative (1A) and 6 mL of N,N-dimethylacetamide were added under a nitrogen atmosphere, and dissolved while stirring at 25°C. Next, 2.9 mL (12.56 mmol) of zinc reagent (2Aa) prepared in Preparation Example 1 (4.27 mol / L solution) was added, and the mixture was cooled to 0°C. After adding 1.83 g (18.47 mmol) of copper (I) chloride, the mixture was stirred at 0°C for 10 hours. After confirmation by the above-mentioned high performance liquid chromatography (HPLC), the reaction conversion rate was 98.2%. It should be noted that the composition ratio of the reaction solvent was tetrahydrofuran:N,N-dimethylacetamide = 2.2:6.7, and the volume ratio of N,N-dimethylacetamide (relative dielectric constant = 37.78) as a polar solvent in the reaction solvent was 75.3%.

[0154] <Example 2>

[0155] The reaction was carried out in the same manner as in Example 1 except that the reaction temperature was changed from 0°C to 30°C. The results are shown in Table 2.

[0156] <Example 3>

[0157] The reaction was carried out in the same manner as in Example 1 except that copper (I) cyanide was used instead of copper (I) chloride.

[0158] <Examples 4 and 5>

[0159] The reaction was carried out in the same manner as in Example 1 except that the amount of the solvent used and the ratio of the polar solvent in the solvent were changed as shown in Table 2. The results are shown in Table 2.

[0160] <Example 6>

[0161] The reaction was carried out in the same manner as in Example 1 except that the amount of copper chloride was changed as shown in Table 2. The results are shown in Table 2.

[0162] <Example 7: Synthesis of Hydroxybiotin Derivatives>

[0163] As shown in the following reaction formula, after synthesizing the zinc reagent (2Aa), the thiolactone derivative represented by formula (1A) is added for coupling reaction, thereby synthesizing the hydroxybiotin derivative represented by formula (3A). It should be noted that "Bn" in the formula represents a benzyl group, and "Et" represents an ethyl group.

[0164] [Chemical formula 16]

[0165]

[0166] In a 100mL three-necked flask with a stirrer having a diameter of 2.5cm, 2.35g (35.87mmol) of zinc powder and 5mL of N,N-dimethylacetamide were added under a nitrogen atmosphere, and mixed and stirred at 25°C. While maintaining below 30°C, 0.54g (3.59mmol) of sodium iodide was added, and the temperature was raised to 50°C. Then, 5g (23.91mmol) of ethyl 5-bromopentanoate (2A') was added dropwise over 0.5 hours, and stirred at this temperature for 6 hours. The reaction solution was cooled to 30°C to obtain a solution of zinc reagent (2Aa). It should be noted that a portion of the reaction solution was taken and analyzed by GC, and the result confirmed that the purity was 90.8% and the concentration of the solution of zinc reagent (2Aa) was 4.34 mol / L.

[0167] To the N,N-dimethylacetamide solution (21.71 mmol; 4.34 mol / L) of the zinc reagent (2Aa), 4.28 g (12.66 mmol) of the thiolactone derivative (1A) and 10 mL of N,N-dimethylacetamide were added, and the mixture was stirred at 0°C. Then, 3.10 g (31.30 mmol) of copper (I) chloride was added, and the mixture was stirred at 0°C for 10 hours. The reaction conversion rate was confirmed by the high performance liquid chromatography (HPLC) described above to be 99.0%. It should be noted that the volume ratio of N,N-dimethylacetamide (relative dielectric constant = 37.78) as a polar solvent in the reaction solvent was 100%.

[0168] The reaction solution was filtered through celite to remove excess metal, and the obtained filtrate was concentrated under reduced pressure to obtain 5.9 g of a hydroxybiotin derivative (3A) (yield = 100%).

[0169] <Example 8: Synthesis of Vinylbiotin Derivatives>

[0170] As shown in the following reaction formula, the hydroxybiotin derivative represented by formula (3A) is dehydrated to synthesize the vinylbiotin derivative (4A). In the formula, "Bn" represents a benzyl group, and "Et" represents an ethyl group.

[0171] [Chemical formula 17]

[0172]

[0173] In a 100 mL three-necked flask equipped with a stirring bar of 2.5 cm in diameter, 5.9 g (12.66 mmol) of the hydroxybiotin derivative (3A) synthesized in Example 7 and 30 mL (475.79 mmol) of acetic acid were added and stirred at 50° C. for 5 hours. The reaction conversion rate was confirmed to be 100% by the above-mentioned high performance liquid chromatography (HPLC).

[0174] The reaction solution was filtered through celite, and the obtained filtrate was concentrated under reduced pressure. 42 mL of ethyl acetate was added to the residue, and after extraction, 30% aqueous ammonium chloride solution, 5% aqueous sodium bicarbonate solution, and 10% saline solution were used for separation and washing. The obtained organic layer was concentrated under reduced pressure to obtain 5.14 g of vinyl biotin derivative (4A) (yield = 90.1%).

[0175] [Table 2]

[0176]

Claims

1. A method for producing a hydroxybiotin derivative, comprising the step of contacting a thiolactone derivative represented by the following formula (1) with a zinc reagent represented by the following formula (2) in the presence of a copper catalyst to obtain a hydroxybiotin derivative represented by the following formula (3). [Chemical formula 1] In formula (1), R 1 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, [Chemical formula 2] X-Zn-R 3 -R 4 (2) In formula (2), X is a bromine atom or a chlorine atom, R 3 is an alkylene group having 1 to 8 carbon atoms which may have a substituent, R 4 -C(=O)OR 5 A monovalent group or a cyano group represented by R 5 is 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, [Chemical formula 3] In formula (3), R 1 and R 2 Same as the meaning of formula (1), R 3 and R 4 This has the same meaning as in the above formula (2).

2. The method for producing a hydroxybiotin derivative according to claim 1, wherein The thiolactone derivative represented by the formula (1) is brought into contact with the zinc reagent represented by the formula (2) in a solvent containing a polar solvent having a relative dielectric constant of 15 or more at 25°C.

3. The method for producing a hydroxybiotin derivative according to claim 2, wherein: The volume ratio of the polar solvent in the solvent is 15% or more.

4. The method for producing a hydroxybiotin derivative according to claim 2 or 3, wherein The polar solvent is N,N-dimethylacetamide.

5. The method for producing a hydroxybiotin derivative according to claim 2 or 3, characterized in that: The zinc reagent represented by the formula (2) is further mixed after the thiolactone derivative represented by the formula (1) and the copper catalyst are dispersed in the solvent, or the copper catalyst is further mixed after the thiolactone derivative represented by the formula (1) and the zinc reagent represented by the formula (2) are dispersed in the solvent.

6. The method for producing a hydroxybiotin derivative according to any one of claims 1 to 3, wherein The copper catalyst is a monovalent copper compound.

7. The method for producing a hydroxybiotin derivative according to claim 6, wherein The monovalent copper compound is a copper halide containing a halogen atom.

8. The method for producing a hydroxybiotin derivative according to any one of claims 1 to 3, characterized in that: The copper catalyst is used in an amount of 0.01 mol to 10 mol based on 1 mol of the thiolactone derivative represented by the formula (1).

9. The method for producing a hydroxybiotin derivative according to any one of claims 1 to 3, characterized in that: The zinc reagent represented by the formula (2) is used in an amount of 1.0 mol to 2.0 mol per 1 mol of the thiolactone derivative represented by the formula (1).

10. The method for producing a hydroxybiotin derivative according to any one of claims 1 to 3, characterized in that: The thiolactone derivative represented by the formula (1) is brought into contact with the zinc reagent represented by the formula (2) at a temperature ranging from -10°C to 50°C.

11. A method for producing a vinyl biotin derivative, comprising producing the hydroxy biotin derivative represented by the formula (3) by the method according to any one of claims 1 to 3, and then dehydrating the obtained hydroxy biotin derivative to obtain a vinyl biotin derivative represented by the following formula (4): [Chemical formula 4] In formula (4), R 1 and R 2 Same as the meaning of formula (1), R 3 and R 4 This has the same meaning as in the above formula (2).

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