Method for producing biotin derivative

Abstract

To provide a method for producing a biotin derivative applicable to industrial production intended for large-scale production.SOLUTION: A method for producing a biotin derivative includes producing a biotin derivative represented by a formula (3A) by bringing a hydroxybiotin derivative represented by a formula (1A) into contact with a trialkylsilane compound and a Lewis acid, as illustrated by the reaction scheme below.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a novel method for producing a biotin derivative, and particularly to a method for producing a biotin derivative by a reduction reaction of a hydroxybiotin derivative or a vinylbiotin derivative.

Background Art

[0002] Biotin is a useful compound used in various pharmaceuticals, food additives, or feed additives. As a method for producing a biotin derivative, a method of reducing a vinylbiotin derivative to obtain a biotin derivative has been reported (see Non-Patent Document 1). Non-Patent Document 1 discloses a method for producing a biotin derivative by reacting a hydroxybiotin derivative having a benzyl ester group at the end of the side chain or a vinylbiotin derivative with triethylsilane as a reducing agent in a solvent containing trifluoroacetic acid and dichloromethane.

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] However, according to the method described in Non-Patent Document 1, as a result of the study by the present inventor, the following formula (4)

[0005]

Chemical Formula

[0006] It has been revealed that a large amount of optical isomers (epimers) shown by are by-produced during the reaction. Further, since the epimer impurity has a structure similar to that of the desired target product, it is difficult to separate and purify, and it has been necessary to repeatedly perform purification operations to remove it. Therefore, there has been room for improvement in terms of applying it to industrial production aimed at mass production.

Means for Solving the Problems

[0007] As a result of intensive studies to solve the above problems, the present inventors surprisingly found that in a solvent containing a strong acid having an acid dissociation constant pKa of 1 or less in a predetermined ratio or more, a high-purity biotin derivative with reduced epimer impurities can be synthesized by contacting a hydroxybiotin derivative and / or a vinylbiotin derivative with a trialkylsilane compound and a Lewis acid, and thus completed the present invention.

[0008] That is, the present invention includes the following inventions. [1] In a solvent containing 40% by volume or more of a strong acid having an acid dissociation constant pKa of 1 or less,

[0009] The following formula (1):

[0010] [Chemical formula]

[0011] [In the above 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, R 3 is a hydrogen atom, an alkyl group which may have a substituent, a cyano group, or a monovalent group represented by -C(=O)OR 4 , R 4 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.] A hydroxybiotin derivative represented by the following formula and the following formula (2):

[0012] [Chemical formula]

[0013] [In the formula (2), R 1 , R 2 and R 3 are the same as R 1 , R 2 and R 3 in the formula (1), respectively.] At least one derivative selected from the group consisting of vinylbiotin derivatives represented by the following formula and a trialkylsilane compound and a Lewis acid and are brought into contact to obtain the following formula (3):

[0014] [Chemical formula]

[0015] [In the formula (3), R 1 , R 2 and R 3 are the same as R 1 , R 2 and R 3 in the formula (1), respectively.] A method for producing a biotin derivative, which includes producing a biotin derivative represented by the following formula.

[0016] [2] The method for producing a biotin derivative according to [1], wherein the Lewis acid is selected from boron trifluoride diethyl ether complex, boron trifluoride tetrahydrofuran complex, and boron trifluoride dimethanol complex.

[0017] [3] The method for producing a biotin derivative according to [1] or [2], wherein the trialkylsilane compound is selected from triisopropylsilane, tripropylsilane, tributylsilane, and t-butyldimethylsilane.

[0018] [4] The method for producing a biotin derivative according to [1] or [2], wherein the strong acid is selected from trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid. [Advantages of the Invention]

[0019] According to the method for producing a biotin derivative of the present invention, a biotin derivative with a higher purity and reduced epimer impurities can be produced. [Embodiments for Carrying Out the Invention]

[0020] The present invention relates to a method for producing a biotin derivative represented by formula (3) by contacting at least one derivative selected from the group consisting of a hydroxybiotin derivative (1) represented by formula (1) and a vinylbiotin derivative (2) represented by formula (2) with a trialkylsilane compound and a Lewis acid in a solvent containing 40% by volume or more of a strong acid having an acid dissociation constant pKa of 1 or less. Hereinafter, the details of the present invention will be described.

[0021] [Explanation of Terms] Hereinafter, the terms used in this specification will be explained. The following explanations apply throughout this specification unless otherwise specified. Note that the expression "value A to value B" means value A or more and value B or less unless otherwise specified.

[0022] Halogeno group Examples of the halogeno group include a fluoro group, a chloro group, a bromo group, an iodo group, and the like.

[0023] Alkyl group The number of carbon atoms of the alkyl group is, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 8, more preferably 1 to 6, more preferably 1 to 4, more preferably 1 to 3, more preferably 1 or 2. The alkyl group may be linear or branched. The number of carbon atoms of the linear alkyl group is 1 or more, and the number of carbon atoms of the branched alkyl group is 3 or more.

[0024] Aryl group The aryl group is, for example, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic hydrocarbon ring group. The number of carbon atoms in the aryl group is, for example, 3 to 22, preferably 3 to 20, more preferably 4 to 14, still more preferably 6 to 14, and even more preferably 6 to 10. The polycyclic is preferably a condensed ring type. Examples of the aryl group include a phenyl group, a naphthyl group, etc. The aryl group is preferably a phenyl group.

[0025] Aralkyl group The aralkyl group is an alkyl group having one or more aryl groups, and the descriptions of the alkyl group and the aryl group are as described above. The number of aryl groups contained in the aralkyl group is, for example, 1 to 3, preferably 1 or 2, and more preferably 1. Examples of the aralkyl group include a benzyl group, a phenylethyl group, a phenylpropyl group, a phenylbutyl group, a naphthylmethyl group, etc. The aryl group contained in the aralkyl group is preferably a phenyl group. The aralkyl group is preferably a benzyl group.

[0026] Alkoxy group The alkoxy group is a group represented by the formula: -O-alkyl group, and the description of the alkyl group is as described above.

[0027] <Hydroxybiotin derivative> In the present invention, the hydroxybiotin derivative (1) is a compound represented by the following formula (1).

[0028]

Chemical formula

[0029] (R 1 and R 2 ) In formula (1), R 1 and R 2is, independently of one another, a hydrogen atom, an alkyl group which may have a substituent (i.e., an alkyl group or an alkyl group having a substituent), an aralkyl group which may have a substituent (i.e., an aralkyl group or an aralkyl group having a substituent), or an aryl group which may have a substituent (i.e., an aryl group or an aryl group having a substituent). R 1 and R 2 may be the same functional group as each other or may be different types of functional groups from each other.

[0030] Hereinafter, 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 will be described.

[0031] Alkyl group which may have a substituent In one embodiment, R 1 and / or R 2 is an alkyl group which may have a substituent. The alkyl group may be linear 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 8, still more preferably 1 to 6, still more preferably 1 to 4, still more preferably 1 to 3, still more preferably 1 or 2, and particularly preferably 1. The alkyl group may have a substituent. Examples of the substituent that the alkyl group may have include an aryl group having 3 to 22 carbon atoms (preferably having 3 to 20 carbon atoms, more preferably having 4 to 14 carbon atoms, still more preferably having 6 to 14 carbon atoms, still more preferably having 6 to 10 carbon atoms), an alkoxy group having 1 to 6 carbon atoms (preferably having 1 to 4 carbon atoms, more preferably having 1 to 3 carbon atoms, still more preferably having 1 or 2 carbon atoms), a halogeno group, and the like. As the substituent that the alkyl group may have, an aryl group having 6 to 14 carbon atoms is preferable, an aryl group having 6 to 10 carbon atoms is more preferable, and a phenyl group is particularly preferable. When the alkyl group has a substituent, the number of substituents is preferably 1 to 5, more preferably 1 to 3, still more preferably 1 or 2, and particularly preferably 1.

[0032] Aralkyl group which may have a substituent In one embodiment, R 1 and / or R 2 is an aralkyl group which may have a substituent. As the aralkyl group, an aralkyl group having 7 to 11 carbon atoms is preferable. Examples of suitable aralkyl groups include benzyl group, phenylethyl group, phenylpropyl group, phenylbutyl group, and naphthylmethyl group. The aralkyl group may have a substituent. Examples of the substituent that the aralkyl group may have include an alkoxy group having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms, still more preferably 1 or 2 carbon atoms), a carboxyl group, a halogeno group, and the like. When the aralkyl group has a substituent, the number of substituents is preferably 1 to 5, more preferably 1 to 3, still more preferably 1 or 2, and particularly preferably 1.

[0033] Aryl group which may have a substituent In one embodiment, R 1 and / or R 2 is an aryl group which may have a substituent. As the aryl group, monocyclic, bicyclic or tricyclic aryl groups can be mentioned. The aryl group is preferably an aryl group having 6 to 14 carbon atoms, and particularly preferably a phenyl group. The aryl group may have a substituent. Examples of the substituent that the aryl group may have include an alkoxy group having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms, still more preferably 1 or 2 carbon atoms), a carboxyl group, a halogeno group, and the like. When the aryl group has a substituent, the number of substituents is preferably 1 to 5, more preferably 1 to 3, still more preferably 1 or 2, and particularly preferably 1.

[0034] Note that, considering that R 1 and R 2 are finally removed by a deprotection step or the like, it is preferably an aralkyl group which may have a substituent, more preferably an aralkyl group, and particularly preferably a benzyl group. (R 3 )

[0035] In formula (1), R 3 is a hydrogen atom, an alkyl group which may have a substituent, a cyano group, or a monovalent functional group represented by -C(=O)OR 4 , and R 4 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. The alkyl group which may have a substituent in R 3 , and 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 4 are synonymous with those described above. The above description 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 is also applicable to R 3 and R 4 .

[0036] R 3 is preferably a cyano group, a carboxylic acid (R 4 = hydrogen atom), or an ester (R 4 = an alkyl group which may have a substituent) from the viewpoint of reactivity and ease of conversion to biotin, and particularly preferably a carboxylic acid (R 4 = hydrogen atom) or an ester (R 4 = an alkyl group which may have a substituent).

[0037] (Hydroxybiotin derivative) According to the method for producing a biotin derivative of the present invention, even when using a hydroxybiotin derivative (1) with relatively low purity as a raw material, the biotin derivative (3) can be produced with a high conversion rate. Therefore, from the perspective of shortening the number of manufacturing steps, it is preferable to use the crude hydroxybiotin derivative (1) as the raw material without undergoing a purification process. Specifically, as the hydroxybiotin derivative (1) used as a raw material in the method for producing a biotin derivative according to the present invention, those with a purity (preferably HPLC purity) of 95% or less measured by liquid chromatography can also be suitably used.

[0038] However, since the finally obtained biotin derivative (3) preferably has a high purity, it is preferable to use a hydroxybiotin derivative (1) with a high purity as a raw material. For example, by producing the hydroxybiotin derivative (1) by the method shown below, the crude purity of the hydroxybiotin derivative (1) can be relatively increased. By using such a hydroxybiotin derivative (1) with a high purity as a raw material, the purity of the biotin derivative (3) obtained in the method for producing a biotin derivative according to the present invention also becomes higher.

[0039] (Suitable hydroxybiotin derivative) Considering its usefulness, the hydroxybiotin derivative (1) represented by the formula (1) preferably includes the hydroxybiotin derivative (1A) represented by the following formula (1A) and the hydroxybiotin derivative (1B) represented by the following formula (1B). The hydroxybiotin derivative (1A) is a compound in which R 1 and R 2 are both benzyl groups, and R 3 is -CO2Et (that is, R 4 is an ethyl group). Further, the hydroxybiotin derivative (1B) is a compound in which R 1 and R 2 are both benzyl groups, and R 3 is -CO2H (that is, R 4It is a compound in which (where the hydrogen atom is). In the formula, "Bn" represents a benzyl group and "Et" represents an ethyl group. Hereinafter, similar explanations may be omitted.

[0040] [Chemical formula]

[0041] [Chemical formula]

[0042] <Vinyl biotin derivative> In the present invention, the vinyl biotin derivative (2) is a compound represented by the following formula (2).

[0043] [Chemical formula]

[0044] In formula (2), R 1 , R 2 and R 3 are respectively synonymous with R 1 , R 2 and R 3 in formula (1).

[0045] The purity of the vinyl biotin derivative (2) is not particularly limited. For example, the vinyl biotin derivative (2) having a purity measured by liquid chromatography of 80.0 to 99.9% may be used.

[0046] According to the method for producing a biotin derivative according to the present invention, even when a vinyl biotin derivative (2) with relatively low purity is used as a raw material, the biotin derivative (3) can be produced with a high conversion rate. Therefore, from the perspective of shortening the number of manufacturing steps, it is preferable to use the vinyl biotin derivative (2) as a raw material in its crude form without undergoing a purification process. Specifically, as the vinyl biotin derivative (2) used as a raw material in the method for producing a biotin derivative according to the present invention, those with a purity (preferably HPLC purity) measured by liquid chromatography of 95% or less can also be suitably used. However, since the finally obtained biotin derivative (3) preferably has a higher purity, it is preferable to use a vinyl biotin derivative (2) with a high purity as a raw material. For example, by producing the vinyl biotin derivative (2) by the method shown below, the crude purity of the vinyl biotin derivative (2) can be relatively increased. By using such a vinyl biotin derivative (2) with a high purity as a raw material, the purity of the biotin derivative (3) obtained in the method for producing a biotin derivative according to the present invention will also be higher.

[0047] (Preferred vinyl biotin derivative) Considering its usefulness, as the vinyl biotin derivative (2) represented by formula (2), the vinyl biotin derivative (2A) represented by the following formula (2A) and the vinyl biotin derivative (2B) represented by the following formula (2B) are preferably mentioned. The vinyl biotin derivative (2A) is a compound obtained from the dehydration reaction of the hydroxy biotin derivative (1A) represented by formula (1A). The vinyl biotin derivative (2B) is a compound obtained from the dehydration reaction of the hydroxy biotin derivative (1B) represented by formula (1B).

[0048] [Chemical formula]

[0049] [Chemical formula]

[0050] <Reducing agent> In the present invention, at least one derivative selected from the group consisting of a hydroxybiotin derivative (1) and a vinylbiotin derivative (2) is contacted with a Lewis acid and a trialkylsilane compound as a reducing agent to produce a biotin derivative (3).

[0051] As the reducing agent used in the present invention, a trialkylsilane compound that is available as an industrial raw material or a reagent can be used without any limitation.

[0052] The trialkylsilane compound has the formula: SiH-L 1 (-L 2 )(-L 3 ) and is a compound represented by. L 1 , L 2 and L 3 are each independently an alkyl group. L 1 , L 2 and L 3 may be the same alkyl group or different alkyl groups. The alkyl group may be linear or branched. The number of carbon atoms in the alkyl group is preferably 1 to 10, more preferably 2 to 8, and particularly preferably 3 to 6. As the trialkylsilane compound, those having 9 to 21 carbon atoms are preferred. Preferred trialkylsilane compounds used in the present invention include, for example, triisopropylsilane, tripropylsilane, tributylsilane, t-tributyldimethylsilane, trihexylsilane (e.g., tri-n-hexylsilane), and the like. Among these trialkylsilane compounds, considering the amount of by-products of optical isomers such as epimer impurities, it is particularly preferred to use triisopropylsilane, tripropylsilane, tributylsilane, and t-tributyldimethylsilane. By using such a relatively sterically bulky trialkylsilane, it is possible to enhance the stereoselectivity of the reaction and reduce the amount of epimer impurities.

[0053] The amount of the trialkylsilane compound used in the present invention is not particularly limited. However, in order to obtain a desired reaction rate and avoid the complexity of the post-treatment operation due to an excessive amount of the trialkylsilane compound, it is preferably in the range of 0.5 to 10.0 moles, more preferably in the range of 1.0 to 5.0 moles, per mole of the reaction substrate (at least one derivative selected from the group consisting of the hydroxybiotin derivative (1) and the vinylbiotin derivative (2)) in the present invention. The amount of the reaction substrate in the present invention means the amount of one kind of derivative when one kind of derivative is selected as the reaction substrate in the present invention, and means the total amount of two or more kinds of derivatives when two or more kinds of derivatives are selected as the reaction substrate in the present invention (the same applies throughout this specification).

[0054] <Lewis acid> In the production method of the present invention, it is characterized in that a Lewis acid is used as a reaction assistant. By using a Lewis acid, the desired reaction preferentially proceeds, and it is possible to reduce the amount of by-produced optical isomers (epimers).

[0055] The Lewis acid used in the present invention is not particularly restricted, and ordinary commercially available ones can be used. Examples of the Lewis acid include boron trichloride, boron tribromide, boron trifluoride diethyl ether complex, boron trifluoride dibutyl ether complex, boron trifluoride tetrahydrofuran complex, boron trifluoride dimethanol complex, boron trifluoride acetic acid complex, boron trifluoride ethylamine complex, boron trifluoride phenol complex, boron trifluoride acetonitrile complex, boron trifluoride piperidinium, titanium tetrachloride, titanium isopropoxide, aluminum chloride, aluminum isopropoxide, zinc chloride, iron chloride, etc. Considering the reactivity and stereoselectivity, the Lewis acid is preferably a boron compound, and among them, boron trifluoride diethyl ether complex, boron trifluoride tetrahydrofuran complex, and boron trifluoride dimethanol complex, which are inexpensive and easily available, are particularly preferred.

[0056] The amount of the Lewis acid used in the present invention is not particularly limited. However, in order to obtain a desired reaction rate and avoid the complexity of post-treatment operations, it is preferably in the range of 0.1 to 10 moles, more preferably in the range of 0.3 to 5.0 moles, and particularly preferably 0.5 to 3.0 moles, per mole of the reaction substrate (at least one derivative selected from the group consisting of the hydroxybiotin derivative (1) and the vinylbiotin derivative (2)) in the present invention. <Solvent> As the solvent in the present invention, a solvent containing 40% by volume or more of a strong acid having an acid dissociation constant pKa of 1 or less is used. The pKa used in the present invention refers to the acid dissociation constant (pKa) in an aqueous solution at 25°C. The "strong acid with pKa of 1 or less" in the present invention is not limited to those in a liquid state at normal temperature. Even those in a solid state at normal temperature such as trichloroacetic acid can be used at a temperature above the melting point or by dissolving in other solvents. Among them, those in a liquid state at normal temperature are preferably used as the solvent at the same time. Examples of such strong acids include trifluoroacetic acid (pKa = -0.3), methanesulfonic acid (pKa = -2.6), trifluoromethanesulfonic acid (pKa = -14), etc. Among them, trifluoroacetic acid and methanesulfonic acid are preferred from the viewpoint of reactivity, and trifluoroacetic acid is particularly preferred.

[0057] The solvent in the present invention contains 40% by volume or more of the above-mentioned strong acid. In other words, the solvent in the present invention may contain other solvents other than the above-mentioned strong acid at a ratio of 60% by volume or less. Also, considering the reaction rate, other solvents are preferably 30% by volume or less, and particularly preferably 0% by volume. That is, the solvent preferably contains 70% by volume or more of the above-mentioned strong acid, and particularly preferably 100% by volume. It should be noted that the fact of containing 100% by volume of the above-mentioned strong acid (that is, the content rate of other solvents other than the above-mentioned strong acid is 0% by volume) does not completely exclude the mixing of impurities inevitably entering the solvent in addition to the above-mentioned strong acid.

[0058] By increasing the proportion of strong acids with a pKa of 1 or less in the reaction solvent of the present invention, the conversion rate to the biotin derivative (3) is improved, and the reaction can be completed in a shorter time. Further, other solvents are not particularly limited as long as they are stable in the presence of strong acids and do not affect the reaction of the present invention. Specifically, dichloromethane, chloroform, toluene and the like can be mentioned.

[0059] In the present invention, the amount of the solvent containing 40% by volume or more of a strong acid having an acid dissociation constant pKa of 1 or less is not particularly limited, but considering the post-treatment of the reaction and the like, at least one selected from the group consisting of the reaction substrates (hydroxybiotin derivative (1) and vinylbiotin derivative (2)) in the present invention For 1 g of the derivative), for example, it is 0.1 to 20 mL, preferably 0.5 to 10 mL, more preferably 1 mL to 7 mL. When using a mixture containing the above-mentioned strong acid and other solvents as the solvent, the reference for the amount used is the total amount of the mixture.

[0060] <Method for producing biotin derivative> In a solvent containing 40% by volume or more of a strong acid with an acid dissociation constant pKa of 1 or less, at least one derivative selected from the group consisting of the reaction substrates (hydroxybiotin derivative (1) and vinylbiotin derivative (2)) in the present invention, a trialkylsilane compound, and a Lewis acid are brought into contact to produce a biotin derivative (3). At this time, it is sufficient to mix them so that each component can be sufficiently contacted. The method of the present invention can be carried out under any state of normal pressure, reduced pressure, or increased pressure. Further, the method of the present invention can be carried out not only in the presence of oxygen such as oxygen and air, but also in an inert gas atmosphere such as nitrogen, argon, and carbon dioxide. The mixing method of each component is not particularly limited. For example, all components may be simultaneously charged into a reaction apparatus and mixed. Alternatively, one component may be premixed, and the remaining components may be sequentially added and mixed. Each component can also be diluted with a solvent and supplied to a reaction apparatus or the like. Among them, in order to further reduce by-products and increase the purity of the biotin derivative (3), at least one derivative selected from the group consisting of the hydroxybiotin derivative (1) and the vinylbiotin derivative (2) and a strong acid with a pKa of 1 or less or a solvent containing a strong acid with a pKa of 1 or less are mixed and stirred under an inert gas atmosphere, and then a Lewis acid and a trialkylsilane compound are added in this order and stirred (mixed). Further, these components can also be diluted with a solvent as necessary.

[0061] In the present invention, the reaction temperature (the temperature in the reaction system after all components are mixed) is not particularly limited, but it can usually be carried out in the range of -10 to 100 °C. Among them, considering the reaction rate, the amount of by-produced epimer impurities, etc., it is preferable to carry out the reaction at -10 to 70 °C, and particularly preferably at -10 to 50 °C. If the reaction temperature is too high, although the reaction rate increases, the amount of by-produced epimer impurities also tends to increase, and by carrying out the reaction within the said range, it can be efficiently converted into the biotin derivative (3). Also, the reaction time is not limited either, and it may be appropriately determined while confirming the reaction conversion rate described in the following examples. However, under the said reaction conditions, the reaction time is 1 to 72 hours, and preferably 1 to 24 hours. Here, the reaction time refers to the time for mixing the reaction substrate, the solvent containing a strong acid with a pKa of 1 or less, the trialkylsilane compound, and the Lewis acid at the set reaction temperature.

[0062] Appropriate post-treatment may be carried out on the reaction solution obtained in the present invention. Specifically, the crude form of the biotin derivative (3) can be obtained by removing the solvent from the reaction solution by distillation under reduced pressure or the like.

[0063] <Biotin derivative> The biotin derivative (3) obtained in the present invention is a compound represented by the following formula (3).

[0064]

Chemical formula

[0065] In formula (3), R 1 , R 2 and R 3 are respectively synonymous with R 1 , R 2 and R 3 in formula (1).

[0066] (Preferred biotin derivative) When using a hydroxybiotin derivative (1A) or a vinylbiotin derivative (2A), which are suitable raw material compounds, or a hydroxybiotin derivative (1B) or a vinylbiotin derivative (2B) as a substrate, as the biotin derivative (3) represented by the formula (3), a biotin derivative represented by the following formula (3A) or (3B) can be obtained respectively. In the biotin derivative (3A), in the biotin derivative (3), R 1 and R 2 are both benzyl groups, and R 3 is -CO2Et (that is, R 4 is an ethyl group). The biotin derivative (3B) is a compound in which, in the biotin derivative (3), R 1 and R 2 are both benzyl groups, R 3 is -CO2H (that is, R 4 is a hydrogen atom), and it is a compound that can be treated as the biotin derivative (4) described later.

[0067]

Chemical formula

[0068]

Chemical formula

[0069] Through the process of removing the benzyl groups corresponding to R 1 and R 2 from the biotin derivative (3B) by deprotection treatment, biotin can be easily produced.

[0070] Among the biotin derivatives (3), in particular, the biotin derivative in which R 3 is -CO2R 4 ’ (R 4 ’ is an alkyl group that may have a substituent, an aralkyl group that may have a substituent, or an aryl group that may have a substituent.) can be easily converted into the biotin derivative (6) represented by the following formula (6) by subjecting it to an alkali hydrolysis reaction. R 4' is R 4 except when R 4 is a hydrogen atom, is synonymous with R 4 and the descriptions of the optionally substituted alkyl group, optionally substituted aralkyl group, and optionally substituted aryl group in R 4 ' also apply. The biotin derivative (6) is useful as a biotin precursor, and biotin can be easily produced from the biotin derivative (6). Specifically, biotin can be easily produced from the biotin derivative (6) through a step of removing the functional groups represented by R 1 and R 2 by a deprotection treatment. In this specification, the biotin derivative (6) may sometimes be referred to as the "biotin precursor (6)".

[0071]

Chemical formula

[0072] Among the biotin derivatives (3), particularly for the biotin derivative in which R 3 is a cyano group, for example, by contacting the biotin derivative (3) with hydrogen halide and a phosgene compound, the biotin derivative (6) can be produced through the hydrolysis reaction and deprotection reaction of the biotin derivative (3). As the hydrogen halide, for example, hydrogen bromide may be used. As the phosgene compound, for example, triphosgene may be used.

Examples

[0073] Hereinafter, the present invention will be described in detail with reference to examples, but these are specific examples and the present invention is not limited thereto. The calculation of the reaction conversion rate and the purity evaluation in the examples and comparative examples were performed by the following method using high performance liquid chromatography (HPLC).

[0074] <Measurement conditions of HPLC> The analysis conditions for HPLC analysis are as follows. Apparatus: High Performance Liquid Chromatography (HPLC) Model: 2695 - 2489 - 2998 (manufactured by Waters) Detector: Ultraviolet Absorption Photometer (measurement wavelength: 210 nm) Column: XBridge - C18, inner diameter 4.6 mm, length 15 cm (particle size: 5 μm) (manufactured by Waters) Column Temperature: 30 °C (constant) Sample Temperature: 25 °C (constant) Mobile Phase A: Acetonitrile Mobile Phase B: 0.25% Aqueous Acetic Acid Solution Delivery of Mobile Phase: The concentration gradient is controlled by changing the mixing ratio of Mobile Phase A and Mobile Phase B as shown in Table 1 below.

[0075]

Table 1

[0076] Under the above HPLC measurement conditions, hydroxybiotin derivative (1A) (R 1 , R 2 = Bn, R 3 = -CO2Et) is about 25.5 minutes, vinylbiotin derivative (2A) (R 1 , R 2 = Bn, R 3 = -CO2Et) is about 28.5 minutes, biotin derivative (3A) (R 1 , R 2 = Bn, R 3 = -CO2Et) is about 28.3 minutes, the corresponding optical isomer (epimer) is about 28.0 minutes, biotin precursor (6) (R 1 , R 2 = Bn, R 3The peak of (-CO2H) is confirmed at about 19.9 minutes, and the peak of the corresponding optical isomer (epimer) is confirmed at about 18.9 minutes. In the examples and comparative examples, the purity of each of the hydroxybiotin derivative (1A), vinylbiotin derivative (2A), and biotin derivative (3A) is the ratio (percentage) of the peak area value of the hydroxybiotin derivative (1A), vinylbiotin derivative (2A), and biotin derivative (3A) to the total of the area values of all peaks measured under the above conditions (excluding the peak derived from the solvent).

[0077] <Calculation method of reaction conversion rate> The reaction conversion rate is a value calculated as the percentage of the peak area value of the generated biotin derivative (3A) with respect to the total value of the peak area value of the hydroxybiotin derivative (1A) or vinylbiotin derivative (2A) and the peak area value of the biotin derivative (3A). Specifically, when using the hydroxybiotin derivative (1A) as a raw material, the reaction conversion rate of the biotin derivative (3A) is a value calculated as the percentage of the peak area value of the generated biotin derivative (3A) with respect to the total value of the peak area value of the hydroxybiotin derivative (1A) and the peak area value of the biotin derivative (3A). When using the vinylbiotin derivative (2A) as a raw material, the reaction conversion rate of the biotin derivative (3A) is a value calculated as the percentage of the peak area value of the generated biotin derivative (3A) with respect to the total value of the peak area value of the vinylbiotin derivative (2A) and the peak area value of the biotin derivative (3A).

[0078] <Calculation method of optical isomer ratio> The optical isomer ratio is a method for calculating and evaluating the amount of optical isomers contained in the biotin derivative (3A) or biotin precursor (6), and is calculated as follows. Specifically, the isomer ratio contained in the biotin derivative (3A) is a value calculated as the percentage of the peak area value of the optical isomer (epimer) corresponding to the biotin derivative (3A) with respect to the total value of the peak area value of the biotin derivative (3A) and the peak area value of the corresponding optical isomer (epimer).

[0079] [Example 1] As shown in the following reaction formula, a biotin derivative (3A) represented by the formula (3A) was synthesized from a hydroxybiotin derivative (1A) represented by the formula (1A). In the formula, "Bn" represents a benzyl group and "Et" represents an ethyl group.

[0080]

Chemical formula

[0081] 1 g (2.13 mmol) of the hydroxybiotin derivative (1A) was weighed into a 50 mL four-necked flask equipped with a stirrer piece with a diameter of 2.5 cm, 1.5 mL (19.60 mmol) of trifluoroacetic acid (pKa = -0.3, 25 °C) was added, and the mixture was cooled to 0 °C. After sequentially adding 0.61 g (4.27 mmol) of boron trifluoride diethyl ether complex and 0.51 g (3.20 mmol) of triisopropylsilane at 10 °C or lower, the temperature was raised to 25 °C and the mixture was stirred at the same temperature for 12 hours. When confirmed by high performance liquid chromatography (HPLC), the reaction conversion rate of the biotin derivative (3A) after stirring at 25 °C for 12 hours was 99.8%, and the ratio of the optical isomer (epimer) corresponding to the biotin derivative (3A) was 1.3%.

[0082] 〔Example 2〕 As shown in the following reaction formula, a biotin derivative (3A) represented by the formula (3A) was synthesized from a vinylbiotin derivative (2A) represented by the formula (2A). In the formula, "Bn" represents a benzyl group and "Et" represents an ethyl group.

[0083]

Chemical formula

[0084] A 50 mL four-necked flask equipped with a stirrer piece with a diameter of 2.5 cm was weighed with 1 g (2.22 mmol) of vinyl biotin derivative (2A), 1.5 mL (19.60 mmol) of trifluoroacetic acid (pKa = -0.3, 25 °C) was added, and it was cooled to 0 °C. After sequentially adding 0.63 g (4.44 mmol) of boron trifluoride diethyl ether complex and 0.53 g (3.33 mmol) of triisopropylsilane at 10 °C or lower, the temperature was raised to 25 °C and stirred at the same temperature for 12 hours. When confirmed by high performance liquid chromatography (HPLC), the reaction conversion rate of biotin derivative (3A) after stirring at 25 °C for 12 hours was 99.8%, and the ratio of the optical isomer (epimer) corresponding to biotin derivative (3A) was 1.1%.

[0085] [Example 3] In Example 2, the reaction was carried out in the same manner except that boron trifluoride tetrahydrofuran complex was used instead of boron trifluoride diethyl ether complex. The results are shown in Table 2. The reaction conversion rate of biotin derivative (3A) after stirring at 25 °C for 12 hours was 99.1%, and the ratio of the optical isomer (epimer) corresponding to biotin derivative (3A) was 1.6%.

[0086] [Examples 4 - 5] In Example 2, the reaction was carried out in the same manner except that the reaction temperature was changed as shown in Table 2. The results are shown in Table 2. The reaction conversion rate of biotin derivative (3A) after stirring at 40 °C for 12 hours was 99.8%, and the ratio of the optical isomer (epimer) corresponding to biotin derivative (3A) was 1.7% (Example 4). Also, the reaction conversion rate of biotin derivative (3A) after stirring at 60 °C for 12 hours was 99.7%, and the ratio of the optical isomer (epimer) corresponding to biotin derivative (3A) was 4.2% (Example 5).

[0087] [Example 6] In Example 2, the reaction was carried out in the same manner except that methanesulfonic acid (pKa = -2.6, 25 °C) was used instead of trifluoroacetic acid (pKa = -0.3). The results are shown in Table 2. After stirring at 25 °C for 12 hours, the reaction conversion rate of the biotin derivative (3A) was 98.7%, and the ratio of the optical isomer (epimer) corresponding to the biotin derivative (3A) was 2.1%.

[0088] [Comparative Example 1] 1 g (2.22 mmol) of vinyl biotin derivative (2A) was weighed into a 50 mL four-necked flask equipped with a stirrer piece with a diameter of 2.5 cm, 1.5 mL (19.60 mmol) of trifluoroacetic acid (pKa = -0.3, 25 °C) was added, and the mixture was cooled to 0 °C. After adding 0.39 g (3.33 mmol) of triethylsilane at 10 °C or lower, the temperature was raised to 25 °C, and the mixture was stirred at the same temperature for 24 hours. When confirmed by high performance liquid chromatography (HPLC), after stirring at 25 °C for 24 hours, the reaction conversion rate of the biotin derivative (3A) was 99.7%, and the ratio of the optical isomer (epimer) corresponding to the biotin derivative (3A) was 11.4%.

[0089] [Comparative Example 2] 1 g (2.22 mmol) of vinyl biotin derivative (2A) was weighed into a 50 mL four-necked flask equipped with a stirrer piece with a diameter of 2.5 cm, 1.5 mL (19.60 mmol) of trifluoroacetic acid (pKa = -0.3, 25 °C) was added, and the mixture was cooled to 0 °C. After adding 0.53 g (3.33 mmol) of triisopropylsilane at 10 °C or lower, the temperature was raised to 25 °C, and the mixture was stirred at the same temperature for 24 hours. When confirmed by high performance liquid chromatography (HPLC), after stirring at 25 °C for 24 hours, the reaction conversion rate of the biotin derivative (3A) was 9.9%, and the ratio of the optical isomer (epimer) corresponding to the biotin derivative (3A) was 1.8%. Further, after continuing stirring at 25 °C for a total of 72 hours, the reaction conversion rate of the biotin derivative (3A) was 46.0%, and the ratio of the optical isomer (epimer) corresponding to the biotin derivative (3A) was 5.1%.

[0090]

Table 2

Claims

1. In a solvent containing 40% by volume or more of a strong acid with an acid dissociation constant pKa of 1 or less, the following formula (1): 【Chemical 1】 In the above formula (1), R １ and R ２ each independently 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, R ３ is a monovalent group represented by a hydrogen atom, an alkyl group which may have a substituent, a cyano group, or -C(=O)OR ４ and is R ４ 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. a hydroxybiotin derivative represented by and at least one derivative selected from the group consisting of the following formula (2): 【Chemical 2】 [In the formula (2), R １ , R ２ and R ３ are respectively synonymous with R １ , R ２ and R ３ in the formula (1).] a vinylbiotin derivative represented by, a trialkylsilane compound, a Lewis acid, are brought into contact to produce a biotin derivative represented by the following formula (3): [Chemical Formula 3] [In the formula (3), R １ , R ２ and R ３ are synonymous with R １ , R ２ and R ３ in the formula (1).] A method for producing a biotin derivative, comprising the step of producing the biotin derivative.

2. The method for producing a biotin derivative according to claim 1, wherein the Lewis acid is selected from boron trifluoride diethyl ether complex, boron trifluoride tetrahydrofuran complex, and boron trifluoride dimethanol complex.

3. The method for producing a biotin derivative according to claim 1 or 2, wherein the trialkylsilane compound is selected from triisopropylsilane, tripropylsilane, tributylsilane, and t-butyldimethylsilane.

4. The method for producing a biotin derivative according to claim 1 or 2, wherein the strong acid is selected from trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid.

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