Method for producing biotin derivative

Abstract

The present invention relates to a method for producing a biotin derivative. The purpose of the present invention is to provide a method for producing a biotin derivative with which it is possible to produce a biotin derivative at a high conversion rate while reducing the proportion of optical isomers. The method comprises the following steps: contacting at least one derivative selected from the group consisting of a hydroxy biotin derivative represented by formula (1) and a vinyl biotin derivative represented by formula (2), 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; a biotin derivative represented by formula (3) is produced. [Chemical Formula 1] # imgabs0 # [Chemical Formula 2] # imgabs1 # [Chemical Formula 3] # imgabs2 #

Description

Technical Field

[0001] The present invention relates to a novel method for producing biotin derivatives, and particularly to a method for producing biotin derivatives 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, feed additives, etc. As a method for producing biotin derivatives, a method of reducing a vinylbiotin derivative to obtain a biotin derivative has been reported (see Non-Patent Document 1).

[0003] Non-Patent Document 1 discloses the following method: In a solvent containing trifluoroacetic acid and dichloromethane, a hydroxybiotin derivative having a benzyl ester group at the end of the side chain or a vinylbiotin derivative is reacted with triethylsilane as a reducing agent to produce a biotin derivative.

[0004] Prior Art Documents

[0005] Non-Patent Documents

[0006] Non-Patent Document 1: Tetrahedon Assymmetry 19 2008, 1436-1443 Summary of the Invention

[0007] Problems to be Solved by the Invention

[0008] However, through the research of the inventors of the present application, it has been found that according to the method described in Non-Patent Document 1, since a large amount of optical isomers (epimers) represented by the following formula (4) are generated as side reactions in the reaction, and the epimer impurities are similar in structure to the desired target product, it is difficult to separate them. In order to separate them, purification operations need to be repeated. Therefore, the method described in Non-Patent Document 1 has room for improvement in industrial production for mass production purposes.

[0009] [Chemical Formula 1]

[0010]

[0011] Means for Solving the Problems

[0012] The inventors of the present application conducted in-depth research to solve the above problems, and surprisingly found that by contacting a hydroxybiotin derivative and / or a vinylbiotin derivative, a trialkylsilane compound, and a Lewis acid in a solvent containing a strong acid having an acid dissociation constant pKa of 1 or less in a specified proportion or more, a high-purity biotin derivative with reduced epimer impurities compared to the prior art can be synthesized, thereby completing the present invention.

[0013] That is, the present invention includes the following inventions.

[0014] [1] A method for producing a biotin derivative, comprising: contacting at least one derivative selected from the group consisting of a hydroxybiotin derivative represented by the following formula (1) and a vinylbiotin derivative represented by the following formula (2), 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 to produce a biotin derivative represented by the following formula (3).

[0015] [Chemical formula 2]

[0016]

[0017] [In the foregoing 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.

[0018] 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 .

[0019] 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. ]]

[0020] [Chemical formula 3]

[0021]

[0022] [In the foregoing formula (2), R 1 , R 2 and R 3 are respectively the same as R 1 , R 2 and R 3 in the foregoing formula (1). ]]

[0023] [Chemical formula 4]

[0024]

[0025] [In the foregoing formula (3), R 1 , R 2 and R 3 are the same as R 1 , R 2 and R 3 in the foregoing formula (1). ]]

[0026] [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.

[0027] [3] The method for producing a biotin derivative according to [1] or [2], wherein the trialkylsilane compound is selected from triisopropylsilane, tripropylsilane, tributylsilane, and tert-butyldimethylsilane.

[0028] [4] The method for producing a biotin derivative according to any one of [1] to [3], wherein the strong acid is selected from trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid.

[0029] Advantages of the Invention

[0030] According to the method for producing a biotin derivative of the present invention, a biotin derivative with higher purity in which the epimer impurity is reduced can be produced. Detailed Description of the Invention

[0031] The present invention relates to the following method: in a solvent containing 40% by volume or more of a strong acid having an acid dissociation constant pKa of 1 or less, 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), a trialkylsilane compound, and a Lewis acid are brought into contact to produce a biotin derivative (3) represented by formula (3). Hereinafter, the details of the present invention will be described.

[0032] [Explanation of Terms]

[0033] Hereinafter, the terms used in this specification will be explained. The following explanations apply to the entire specification unless otherwise specified. It should be noted that the expression "value A to value B" means value A or more and value B or less unless otherwise specified.

[0034] Halogen group

[0035] Examples of the halogen group include a fluorine group, a chlorine group, a bromine group, and an iodine group.

[0036] Alkyl

[0037] 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.

[0038] Aryl

[0039] An aryl group is an aromatic hydrocarbon ring group that is monocyclic or polycyclic (e.g., bicyclic or tricyclic). 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 group is preferably a fused ring type. Examples of the aryl group include a phenyl group and a naphthyl group. The aryl group is preferably a phenyl group.

[0040] Aralkyl

[0041] An 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, and a naphthylmethyl group. The aryl group contained in the aralkyl group is preferably a phenyl group. The aralkyl group is preferably a benzyl group.

[0042] Alkoxy

[0043] An alkoxy group is a group represented by the formula: -O-alkyl, and the description of the alkyl group is as described above.

[0044] <Hydroxybiotin derivative>

[0045] In the present invention, the hydroxybiotin derivative (1) is a compound represented by the following formula (1).

[0046] [Chemical formula 5]

[0047]

[0048] (R 1 and R 2 )

[0049] In formula (1), R 1 and R 2 are each independently 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 different types of functional groups from each other.

[0050] Hereinafter, 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.

[0051] Alkyl which may have substituents

[0052] In one embodiment, R 1 and / or R2 is an alkyl group which may have substituents. 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 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 substituents. Examples of the substituents that the alkyl group may have include aryl groups having 3 to 22 carbon atoms (preferably aryl groups having 3 to 20 carbon atoms, more preferably aryl groups having 4 to 14 carbon atoms, still more preferably aryl groups having 6 to 14 carbon atoms, still more preferably aryl groups having 6 to 10 carbon atoms), alkoxy groups having 1 to 6 carbon atoms (preferably alkoxy groups having 1 to 4 carbon atoms, more preferably alkoxy groups having 1 to 3 carbon atoms, still more preferably alkoxy groups having 1 or 2 carbon atoms), halogen groups, etc. As the substituents that the alkyl group may have, aryl groups having 6 to 14 carbon atoms are preferred, aryl groups having 6 to 10 carbon atoms are more preferred, and phenyl groups are particularly preferred. When the alkyl group has substituents, the number of substituents is preferably 1 to 5, more preferably 1 to 3, still more preferably 1 or 2, and particularly preferably 1.

[0053] Aralkyl which may have substituents

[0054] In one embodiment, R 1 and / or R 2 is an aralkyl group which may have substituents. As the aralkyl group, an aralkyl group having 7 to 11 carbon atoms is preferred. Examples of suitable aralkyl groups include benzyl, phenylethyl, phenylpropyl, phenylbutyl, and naphthylmethyl. The aralkyl group may have substituents. Examples of the substituents that the aralkyl group may have include alkoxy groups having 1 to 6 carbon atoms (preferably alkoxy groups having 1 to 4 carbon atoms, more preferably alkoxy groups having 1 to 3 carbon atoms, still more preferably alkoxy groups having 1 or 2 carbon atoms), carboxyl groups, halogen groups, etc. When the aralkyl group has substituents, the number of substituents is preferably 1 to 5, more preferably 1 to 3, still more preferably 1 or 2, and particularly preferably 1.

[0055] Aryl which may have substituents

[0056] In one embodiment, R 1 and / or R 2 is an aryl group which may have substituents. As the aryl group, monocyclic, bicyclic or tricyclic aryl groups can be cited. 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 substituents. Examples of the substituents that the aryl group may have include alkoxy groups having 1 to 6 carbon atoms (preferably alkoxy groups having 1 to 4 carbon atoms, more preferably alkoxy groups having 1 to 3 carbon atoms, still more preferably alkoxy groups having 1 or 2 carbon atoms), carboxyl groups, halogen groups, etc. When the aryl group has substituents, the number of substituents is preferably 1 to 5, more preferably 1 to 3, still more preferably 1 or 2, and particularly preferably 1.

[0057] It should be noted that for R1 and R 2 , if it is considered that it is removed by a deprotection process in the end, etc., it is preferably an aralkyl group that may have a substituent, more preferably an aralkyl group, and particularly preferably a benzyl group.

[0058] (R 3 )

[0059] In formula (1), R 3 is a hydrogen atom, an alkyl group that 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 that may have a substituent, an aralkyl group that may have a substituent, or an aryl group that may have a substituent. The alkyl group that may have a substituent in R 3 , and the alkyl group that may have a substituent, the aralkyl group that may have a substituent, and the aryl group that may have a substituent in R 4 have the same meanings as described above. The above descriptions of the alkyl group that may have a substituent, the aralkyl group that may have a substituent, and the aryl group that may have a substituent are also applicable to R 3 and R 4 .

[0060] Considering the reactivity and the ease of conversion to biotin, R 3 is preferably a cyano group, a carboxylic acid (R 4 = hydrogen atom), an ester (R 4 = an alkyl group that may have a substituent), and particularly preferably a carboxylic acid (R 4 = hydrogen atom) or an ester (R 4 = an alkyl group that may have a substituent).

[0061] (Hydroxybiotin derivative)

[0062] According to the method for producing a biotin derivative of the present invention, even when using a hydroxybiotin derivative (1) with a relatively low purity as a raw material, the biotin derivative (3) can be produced with a high conversion rate. Therefore, from the viewpoint of shortening the number of manufacturing steps, it is preferable that the hydroxybiotin derivative (1) as the raw material does not go through a purification process, but the crude product is directly used as the raw material. Specifically, for the hydroxybiotin derivative (1) used as the raw material in the method for producing a biotin derivative of the present invention, a substance with a purity (preferably HPLC purity) of 95% or less measured by liquid chromatography can also be suitably used.

[0063] However, considering the aspect that 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 using the method described in International Publication No. WO2023 / 120712A1 to produce the hydroxybiotin derivative (1), the crude purity of the hydroxybiotin derivative (1) can be relatively increased. By using the 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 is also higher.

[0064] (Suitable hydroxybiotin derivative)

[0065] As the hydroxybiotin derivative (1) represented by the formula (1), considering its usefulness, the hydroxybiotin derivative (1A) represented by the following formula (1A) and the hydroxybiotin derivative (1B) represented by the following formula (1B) can be cited as preferred examples. The hydroxybiotin derivative (1A) is a compound in which R 1 and R 2 are both benzyl and R 3 is -CO2Et (i.e., R 4 is ethyl). In addition, the hydroxybiotin derivative (1B) is a compound in which R 1 and R 2 are both benzyl and R 3 is -CO2H (i.e., R 4 is a hydrogen atom). It should be noted that "Bn" in the formula represents benzyl and "Et" represents ethyl. Hereinafter, the same explanation may be omitted.

[0066] [Chemical formula 6]

[0067]

[0068] [Chemical formula 7]

[0069]

[0070] [Vinyl biotin derivative]

[0071] In the present invention, the vinyl biotin derivative (2) is a compound represented by the following formula (2).

[0072] [Chemical formula 8]

[0073]

[0074] In the formula (2), R 1 , R 2 and R 3 correspond to R in the formula (1) respectively1 , R 2 and R 3 have the same meaning.

[0075] There is no particular limitation on the purity of the vinyl biotin derivative (2). For example, it may be a vinyl biotin derivative (2) having a purity of 80.0 to 99.9% as determined by liquid chromatography.

[0076] According to the method for producing a biotin derivative of the present invention, even when using a vinyl biotin derivative (2) with a relatively low purity as a raw material, the biotin derivative (3) can be produced with a high conversion rate. Therefore, from the viewpoint of shortening the number of manufacturing steps, it is preferable that the vinyl biotin derivative (2) as a raw material does not go through a purification process, but the crude product is directly used as a raw material. Specifically, for the vinyl biotin derivative (2) used as a raw material in the method for producing a biotin derivative of the present invention, a substance having a purity (preferably HPLC purity) of 95% or less as determined by liquid chromatography can also be suitably used.

[0077] However, considering that the finally obtained biotin derivative (3) preferably has a high purity, it is preferable to use a vinyl biotin derivative (2) with a high purity as a raw material. For example, by using the method described in International Publication No. WO2023 / 120712A1 to produce the vinyl biotin derivative (2), the crude purity of the vinyl biotin derivative (2) can be relatively increased. By using the 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 of the present invention is also higher.

[0078] (Suitable vinyl biotin derivative)

[0079] As the vinyl biotin derivative (2) represented by the formula (2), considering its usefulness, the vinyl biotin derivative (2A) represented by the following formula (2A) and the vinyl biotin derivative (2B) represented by the following formula (2B) can be cited as preferred examples. The vinyl biotin derivative (2A) is a compound obtained by a dehydration reaction of the hydroxy biotin derivative (1A) represented by the formula (1A). The vinyl biotin derivative (2B) is a compound obtained by a dehydration reaction of the hydroxy biotin derivative (1B) represented by the formula (1B).

[0080] [Chemical formula 9]

[0081]

[0082] [Chemical formula 10]

[0083]

[0084] <Reducing agent>

[0085] In the present invention, at least one derivative selected from the group consisting of a hydroxybiotin derivative (1) and a vinylbiotin derivative (2), a Lewis acid, and a trialkylsilane compound as a reducing agent are brought into contact to produce a biotin derivative (3).

[0086] As the reducing agent used in the present invention, a trialkylsilane compound that can be obtained as an industrial raw material or a reagent can be used without any limitation.

[0087] 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 of the alkyl group is preferably 1 to 10, more preferably 2 to 8, and particularly preferably 3 to 6. As the trialkylsilane compound, a trialkylsilane compound having 9 to 21 carbon atoms is preferred. As the preferred trialkylsilane compound used in the present invention, for example, triisopropylsilane, tripropylsilane, tributylsilane, tert-butyldimethylsilane, trihexylsilane (e.g., tri-n-hexylsilane), etc. can be cited. Among these trialkylsilane compounds, considering the by-production of optical isomers such as epimer impurities, triisopropylsilane, tripropylsilane, tributylsilane, and tert-butyldimethylsilane are particularly preferably used. By using such a sterically bulky trialkylsilane, the stereoselectivity of the reaction can be improved and the amount of epimer impurities can be reduced.

[0088] The amount of the trialkylsilane compound used in the present invention is not particularly limited. In order to obtain a desired reaction rate and avoid the complexity of post-treatment operations caused by an excessive amount of the trialkylsilane compound, it is preferably in the range of 0.5 to 10.0 moles, particularly preferably in the range of 1.0 to 5.0 moles, per 1 mole of the reaction substrate (at least one derivative selected from the group consisting of a hydroxybiotin derivative (1) and a vinylbiotin derivative (2)) in the present invention. The amount of the reaction substrate in the present invention refers to the amount of the one derivative when one derivative is selected as the reaction substrate in the present invention, and refers to the total amount of the two or more derivatives when two or more derivatives are selected as the reaction substrate in the present invention (the same applies throughout this specification).

[0089] <Lewis acid>

[0090] In the manufacturing 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 is preferentially carried out, and the by-production of optical isomers (epimers) can also be reduced.

[0091] The Lewis acid used in the present invention is not particularly limited, and a commonly commercially available Lewis acid 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 reactivity and stereoselectivity, as the Lewis acid, boron compounds are preferred, 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.

[0092] The amount of the Lewis acid used in the present invention is not particularly limited. In order to obtain a desired reaction rate and avoid the complexity of post-treatment operations, relative to 1 mole of the reaction substrate (at least one derivative selected from the group consisting of hydroxybiotin derivative (1) and vinylbiotin derivative (2)) in the present invention, 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 in the range of 0.5 to 3.0 moles.

[0093] <Solvent>

[0094] Regarding the solvent in the present invention, a solvent containing a strong acid with an acid dissociation constant pKa of 1 or less at 40% by volume or more is used.

[0095] 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 a strong acid that is liquid at room temperature. It can be a strong acid such as trichloroacetic acid that is solid at room temperature, and it can be used at a temperature above the melting point or by dissolving it in other solvents. Among them, it is preferred to use a strong acid that is liquid at room temperature as the solvent. Examples of such strong acids include trifluoroacetic acid (pKa = -0.3), methanesulfonic acid (pKa = -2.6), trifluoromethanesulfonic acid (pKa = -14), etc. Among them, from the aspect of reactivity, trifluoroacetic acid and methanesulfonic acid are preferred, and trifluoroacetic acid is particularly preferred.

[0096] 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 aforementioned strong acid in a proportion of 60% by volume or less. Additionally, considering the reaction rate, other solvents are preferably 30% by volume or less, and particularly preferably 0% by volume. That is, as the solvent, a solvent containing 70% by volume or more of the aforementioned strong acid is preferred, and a solvent containing 100% by volume of the aforementioned strong acid is particularly preferred. It should be noted that for a solvent containing 100% by volume of the aforementioned strong acid (i.e., the content rate of other solvents other than the aforementioned strong acid is 0% by volume), the mixing of impurities inevitably entering the solvent other than the aforementioned strong acid is not completely excluded, and this point needs to be noted.

[0097] By increasing the proportion of the strong acid with a pKa of 1 or less in the reaction solvent of the present invention, the conversion rate to the biotin derivative (3) is increased, and the reaction can be completed in a shorter time. Additionally, there is no particular limitation on other solvents as long as they are stable in the presence of the strong acid and do not affect the reaction of the present invention. Specifically, dichloromethane, chloroform, toluene, etc. can be cited.

[0098] In the present invention, the usage amount of the solvent containing 40% by volume or more of the strong acid with an acid dissociation constant pKa of 1 or less is not particularly limited. Considering the post-treatment of the reaction, etc., for 1 g 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, it is, for example, 0.1 to 20 mL, preferably 0.5 to 10 mL, and more preferably 1 mL to 7 mL. When using a mixture containing the aforementioned strong acid and other solvents as the solvent, the benchmark for the usage amount is based on the total amount of the mixture.

[0099] <Method for manufacturing biotin derivative>

[0100] In a solvent containing a strong acid with an acid dissociation constant pKa of 1 or less and a content of 40% by volume or more, by bringing the reaction substrate in the present invention (at least one derivative selected from the group consisting of hydroxybiotin derivatives (1) and vinylbiotin derivatives (2)), a trialkylsilane compound, and a Lewis acid into contact, a biotin derivative (3) can be produced. At this time, it is sufficient to perform mixing so that each component can be sufficiently contacted. The method of the present invention can be carried out under any of normal pressure, reduced pressure, and increased pressure. In addition, 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. There is no particular limitation on the method of mixing each component. For example, all components can be simultaneously charged into a reaction apparatus and mixed. In addition, one component can be pre-mixed, and the remaining components can 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 improve the purity of the biotin derivative (3), it is preferable to mix and stir at least one derivative selected from the group consisting of hydroxybiotin derivatives (1) and vinylbiotin derivatives (2) with a strong acid having a pKa of 1 or less or a solvent containing a strong acid having a pKa of 1 or less in an inert gas atmosphere, and then add and stir (mix) in the order of the Lewis acid and the trialkylsilane compound. In addition, these components can also be diluted with a solvent as needed.

[0101] In the present invention, the reaction temperature (the temperature in the reaction system after mixing all components) is not particularly limited, and generally can be carried out in the range of -10 to 100 °C. Among them, considering the reaction rate, the by-production amount of 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, the reaction rate increases, but on the other hand, there is a tendency that the by-production amount of epimer impurities also increases. By carrying out the reaction within this range, the reaction substrate can be efficiently converted into the biotin derivative (3). In addition, the reaction time is not limited, and it can be appropriately determined while confirming the reaction conversion rate described in the following examples. Among them, when the reaction conditions are as described above, the reaction time is 1 to 72 hours, preferably 1 to 24 hours. It should be noted that the reaction time here 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 in the present invention.

[0102] The reaction solution obtained in the present invention can be appropriately post-treated. Specifically, the solvent can be removed from the reaction solution by distillation under reduced pressure or the like, thereby obtaining a crude biotin derivative (3).

[0103] <Biotin derivative>

[0104] The biotin derivative (3) obtained in the present invention is a compound represented by the following formula (3).

[0105] [Chemical formula 11]

[0106]

[0107] In formula (3), R 1 , R 2 and R 3 are the same as R 1 , R 2 and R 3 in formula (1), respectively.

[0108] (Suitable biotin derivative)

[0109] When the hydroxybiotin derivative (1A) or vinylbiotin derivative (2A), or hydroxybiotin derivative (1B) or vinylbiotin derivative (2B) as suitable starting compounds is used as the substrate, the biotin derivatives represented by the following formula (3A) or (3B) can be obtained as the biotin derivative (3) represented by formula (3), respectively. Biotin derivative (3A) is a compound in which both R 1 and R 2 are benzyl, and R 3 is -CO2Et (i.e., R 4 is ethyl). Biotin derivative (3B) is a compound in which both R 1 and R 2 are benzyl, R 3 is -CO2H (i.e., R 4 is a hydrogen atom), and can be processed into the biotin derivative (6) described below.

[0110] [Chemical formula 12]

[0111]

[0112] [Chemical formula 13]

[0113]

[0114] By a process of removing the benzyl groups corresponding to R 1 and R 2 from the biotin derivative (3B) by deprotection treatment, biotin can be simply produced.

[0115] Among the biotin derivatives (3), especially when R 3 is -CO2R 4 '(R 4’ is 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 biotin derivative of ) can be easily converted into the biotin derivative (6) shown in the following formula (6) by carrying out an alkali hydrolysis reaction. For R 4 ’, except for the case where R 4 is a hydrogen atom, it has the same meaning as R 4 . The description of 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 also applies to R 4 ’. The biotin derivative (6) is useful as a biotin precursor, and biotin can be simply produced from the biotin derivative (6). Specifically, biotin can be simply produced via a step of removing the functional groups represented by R 1 and R 2 from the biotin derivative (6) by a deprotection treatment. It should be noted that in this specification, the biotin derivative (6) is sometimes referred to as “biotin precursor (6)”.

[0116] [Chemical formula 14]

[0117]

[0118] It should be noted that among the biotin derivatives (3), particularly for the biotin derivative in which R 3 is a cyano group, for example, by bringing this biotin derivative (3) into contact with a hydrogen halide and a phosgene compound, the biotin derivative (6) can be produced through the hydrolysis reaction and deprotection reaction of this biotin derivative (3). As the hydrogen halide, for example, hydrogen bromide can be used. As the phosgene compound, for example, triphosgene can be used.

[0119] Examples

[0120] Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited by these specific examples. It should be noted that the calculation of the reaction conversion rate and the purity evaluation in the examples and comparative examples are carried out by the following method using high performance liquid chromatography (HPLC).

[0121] <HPLC measurement conditions>

[0122] The analysis conditions for HPLC analysis are as follows.

[0123] Apparatus: High performance liquid chromatography (HPLC)

[0124] Model: 2695 - 2489 - 2998 (manufactured by Waters)

[0125] Detector: Ultraviolet spectrophotometer (measurement wavelength: 210 nm)

[0126] Column: XBridge-C18, inner diameter 4.6 mm, length 15 cm (particle size: 5 μm) (manufactured by Waters)

[0127] Column temperature: 30 °C (constant)

[0128] Sample temperature: 25 °C (constant)

[0129] Mobile phase A: Acetonitrile

[0130] Mobile phase B: 0.25% aqueous acetic acid solution

[0131] Delivery of the mobile phase: Control the concentration gradient by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 1 below.

[0132] [Table 1]

[0133] Table 1

[0134]

[0135] Flow rate: 0.6 mL / min

[0136] Measurement time: 40 minutes

[0137] Under the above HPLC measurement conditions, the hydroxybiotin derivative (1A) (R 1 , R 2 = Bn, R 3 = -CO2Et) shows a peak at about 25.5 minutes, the vinylbiotin derivative (2A) (R 1 , R 2 = Bn, R 3 = -CO2Et) shows a peak at about 28.5 minutes, the biotin derivative (3A) (R 1 , R 2 = Bn, R 3 = -CO2Et) shows a peak at about 28.3 minutes, the optical isomer (epimer) corresponding to the biotin derivative (3A) shows a peak at about 28.0 minutes, and the biotin precursor (6) (R 1 , R 2 = Bn, R 3The peak of (-CO2H) was confirmed at about 19.9 minutes, and the peak of the optical isomer (epimer) corresponding to the biotin precursor (6) was confirmed at about 18.9 minutes. It should be noted that 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) measured under the above conditions to the total area value of all peaks (excluding the peaks derived from the solvent).

[0138] <Calculation method of reaction conversion rate>

[0139] The reaction conversion rate is a value calculated in the form of a percentage of the peak area value of the generated biotin derivative (3A) 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 the hydroxybiotin derivative (1A) is used as a raw material, the reaction conversion rate of the biotin derivative (3A) is calculated in the form of a percentage of the peak area value of the generated biotin derivative (3A) 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 the vinylbiotin derivative (2A) is used as a raw material, the reaction conversion rate of the biotin derivative (3A) is calculated in the form of a percentage of the peak area value of the generated biotin derivative (3A) to the total value of the peak area value of the vinylbiotin derivative (2A) and the peak area value of the biotin derivative (3A).

[0140] <Calculation method of proportion of optical isomers>

[0141] The proportion of optical isomers is an index for evaluating the amount of optical isomers contained in the biotin derivative (3A) and is calculated as follows. Specifically, the proportion of optical isomers contained in the biotin derivative (3A) is calculated in the form of a percentage of the peak area value of the optical isomer (epimer) corresponding to the biotin derivative (3A) to the total value of the peak area value of the biotin derivative (3A) and the peak area value of the optical isomer (epimer) corresponding to the biotin derivative (3A).

[0142] 〔Example 1〕

[0143] As shown in the following reaction formula, the biotin derivative (3A) represented by the formula (3A) was synthesized from the hydroxybiotin derivative (1A) represented by the formula (1A). It should be noted that "Bn" in the formula represents benzyl, and "Et" represents ethyl.

[0144] [Chemical Formula 15]

[0145]

[0146] In a 50 mL four-necked flask equipped with a magnetic stir bar with a diameter of 2.5 cm, 1 g (2.13 mmol) of a hydroxybiotin derivative (1A) was measured, 1.5 mL (19.60 mmol) of trifluoroacetic acid (pKa = -0.3, 25 °C) was added, and the mixture was cooled to 0 °C. Below 10 °C, 0.61 g (4.27 mmol) of boron trifluoride diethyl ether complex and 0.51 g (3.20 mmol) of triisopropylsilane were sequentially added, and then the temperature was raised to 25 °C, and the mixture was stirred at this temperature for 12 hours. Confirmation was carried out by high performance liquid chromatography (HPLC). As a result, 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) after stirring at 25 °C for 12 hours was 1.3%.

[0147] [Example 2]

[0148] As shown in the following reaction formula, the biotin derivative (3A) represented by the formula (3A) was synthesized from the vinyl biotin derivative (2A) represented by the formula (2A). It should be noted that "Bn" in the formula represents benzyl, and "Et" represents ethyl.

[0149] [Chemical Formula 16]

[0150]

[0151] In a 50 mL four-necked flask equipped with a magnetic stir bar with a diameter of 2.5 cm, 1 g (2.22 mmol) of a vinyl biotin derivative (2A) was measured, 1.5 mL (19.60 mmol) of trifluoroacetic acid (pKa = -0.3, 25 °C) was added, and the mixture was cooled to 0 °C. Below 10 °C, 0.63 g (4.44 mmol) of boron trifluoride diethyl ether complex and 0.53 g (3.33 mmol) of triisopropylsilane were sequentially added, and then the temperature was raised to 25 °C, and the mixture was stirred at this temperature for 12 hours. Confirmation was carried out by high performance liquid chromatography (HPLC). As a result, 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) after stirring at 25 °C for 12 hours was 1.1%.

[0152] [Example 3]

[0153] In Example 2, boron trifluoride tetrahydrofuran complex was used instead of boron trifluoride diethyl ether complex, and the reaction was carried out in the same manner otherwise. 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) after stirring at 25 °C for 12 hours was 1.6%.

[0154] 〔Examples 4 - 5〕

[0155] In Example 2, the reaction temperature was changed as shown in Table 2, and the reaction was carried out in the same manner otherwise. 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) after stirring at 40 °C for 12 hours was 1.7% (Example 4). In addition, 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) after stirring at 60 °C for 12 hours was 4.2% (Example 5).

[0156] 〔Example 6〕

[0157] In Example 2, methanesulfonic acid (pKa = -2.6, 25 °C) was used instead of trifluoroacetic acid (pKa = -0.3, 25 °C), and the reaction was carried out in the same manner otherwise. The results are shown in Table 2. The reaction conversion rate of biotin derivative (3A) after stirring at 25 °C for 12 hours was 98.7%, and the ratio of the optical isomer (epimer) corresponding to biotin derivative (3A) after stirring at 25 °C for 12 hours was 2.1%.

[0158] 〔Comparative Example 1〕

[0159] In a 50 mL four-necked flask equipped with a stir bar with a diameter of 2.5 cm, 1 g (2.22 mmol) of vinyl biotin derivative (2A) was measured, 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 this temperature for 24 hours. Confirmation was carried out using high performance liquid chromatography (HPLC). As a result, the reaction conversion rate of biotin derivative (3A) after stirring at 25 °C for 24 hours was 99.7%, and the ratio of the optical isomer (epimer) corresponding to biotin derivative (3A) after stirring at 25 °C for 24 hours was 11.4%.

[0160] 〔Comparative Example 2〕

[0161] In a 50 mL four-necked flask equipped with a magnetic stir bar having a diameter of 2.5 cm, 1 g (2.22 mmol) of a vinyl biotin derivative (2A) was measured, 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 this temperature for 24 hours. Confirmation was carried out by high performance liquid chromatography (HPLC). As a result, the reaction conversion rate of the biotin derivative (3A) after stirring at 25 °C for 24 hours was 9.9%, and the ratio of the optical isomer (epimer) corresponding to the biotin derivative (3A) after stirring at 25 °C for 24 hours was 1.8%. In addition, the reaction conversion rate of the biotin derivative (3A) after further stirring at 25 °C for a total of 72 hours was 46.0%, and the ratio of the optical isomer (epimer) corresponding to the biotin derivative (3A) was 5.1%.

[0162] [Table 2]

[0163]

Claims

1. A method for producing a biotin derivative, comprising: In a solvent containing 40% by volume or more of a strong acid having an acid dissociation constant pKa of 1 or less, at least one derivative selected from the group consisting of a hydroxybiotin derivative represented by the following formula (1) and a vinylbiotin derivative represented by the following formula (2), a trialkylsilane compound, and a Lewis acid are contacted to produce a biotin derivative represented by the following formula (3). [Chemical formula 1] In the 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 hydrogen atom, an alkyl group which may have a substituent, a cyano group, or -C(=O)OR 4 a monovalent group as shown 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, [Chemical formula 2] In the formula (2), R 1 , R 2 and R 3 are respectively the same in meaning as R 1 , R 2 and R 3 in the formula (1). [Chemical formula 3] In the formula (3), R 1 , R 2 and R 3 have the same meanings as R 1 , R 2 and R 3 in the formula (1).

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 tert-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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