Method for producing thiophenium salt derivative

Abstract

To provide a method for producing a thiophenium salt derivative, useful as a synthetic intermediate of biotin, enabling reduction of a ratio of stereoisomers and allowing production of a biotin derivative with a high conversion rate.SOLUTION: A method for producing a thiophenium salt derivative, comprises a step of bringing at least one derivative selected from the group consisting of a hydroxybiotin derivative and a vinylbiotin derivative into contact with a trialkylsilane compound in a solvent containing a strong acid having an acid dissociation constant pKa of 1 or less, at a temperature range of 0°C or more and 80°C or less, thereby obtaining a thiophenium salt derivative represented by the following formula (3) [where R1 and R2 are each independently H, an alkyl group optionally having a substituent, an aralkyl group optionally having a substituent, or an aryl group optionally having a substituent].SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a novel method for producing thiophanium salt derivatives which are useful as synthetic intermediates for biotin. [Background technology]

[0002] Biotin is a useful compound used in various pharmaceuticals, food additives, feed additives, etc. Biotin is synthesized, for example, by the following method (see Patent Document 1).

[0003] [ka]

[0004] That is, the thiolactone derivative shown in formula (I) is reacted with 3-methoxypropyl magnesium chloride (Grignard reagent) to synthesize the hydroxybiotin derivative shown in formula (1A). The hydroxybiotin derivative is then dehydrated and converted to the vinylbiotin derivative shown in formula (2A). The resulting vinylbiotin derivative is then subjected to a hydrogenation reaction using a palladium or Raney nickel catalyst to synthesize the biotin derivative shown in formula (5A). The biotin derivative is then subjected to a cyclization reaction to synthesize the thiophanium salt derivative shown in formula (3A). Finally, the thiophanium salt derivative undergoes coupling with a malonic acid ester and deprotection steps to produce biotin. In the formulas, "Bn" represents a benzyl group, and "Me" represents a methyl group. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 53-027279 Summary of the Invention [Problem to be solved by the invention]

[0006] As described above, the production of biotin from thiolactone derivatives requires a multi-step reaction process, and there has been a strong demand for improving the efficiency of the reaction and shortening the reaction process. Furthermore, expensive noble metal catalysts are required.

[0007] Therefore, an object of the present invention is to provide a method for more efficiently producing thiophanium salt derivatives that are useful as synthetic intermediates for biotin. [Means for solving the problem]

[0008] As a result of intensive research aimed at solving the above-mentioned problems, the present inventors surprisingly discovered that by contacting a hydroxybiotin derivative and / or a vinylbiotin derivative with a trialkylsilane compound at a temperature ranging from 0°C to 80°C in a solvent containing a strong acid with an acid dissociation constant pKa of 1 or less, a reduction reaction and a cyclization reaction proceed simultaneously, enabling the synthesis of a thiophanium salt derivative in a single step, leading to the completion of the present invention. Furthermore, this method not only shortens the reaction steps, but also makes it possible to obtain a highly pure thiophanium salt derivative with a sufficiently reduced amount of stereoisomers.

[0009] That is, the present invention includes the following inventions.

[0010] [1] In a solvent containing a strong acid with an acid dissociation constant pKa of 1 or less, The following formula (1): [ka] [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 -OR 4 is a monovalent alkoxy group or halogeno group represented by R 4represents a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent. and hydroxybiotin derivatives represented by the following formula (2): [ka] [In the formula (2), R 1 , R 2 and R 3 are R in the formula (1), respectively. 1 , R 2 and R 3 is equivalent to.] and a trialkylsilane compound at a temperature in the range of 0° C. to 80° C. to obtain a compound represented by the following formula (3): [ka] [In the formula (2), R 1 , R 2 and R 3 are R in the formula (1), respectively. 1 , R 2 and R 3 is equivalent to.] A method for producing a thiophanium salt derivative, comprising the step of obtaining a thiophanium salt derivative represented by the formula:

[0011] [2] When the hydroxybiotin derivative represented by the formula (1) and the vinylbiotin derivative represented by the formula (2) are contacted with a trialkylsilane compound, a Lewis acid is further contacted therewith. A method for producing the thiophanium salt derivative described in [1].

[0012] [3] the Lewis acid is selected from boron trifluoride diethyl ether complex, boron trifluoride tetrahydrofuran complex, and boron trifluoride dimethanol complex; A method for producing the thiophanium salt derivative according to [1] or [2].

[0013] [4] The method for producing a thiophanium salt derivative according to any one of [1] to [3], wherein the trialkylsilane compound is selected from triisopropylsilane, tripropylsilane, tributylsilane, and t-butyldimethylsilane.

[0014] [5] The method for producing a thiophanium salt derivative according to any one of [1] to [4], wherein the strong acid is selected from trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid.

[0015] [6] At least one derivative selected from the group consisting of the hydroxybiotin derivative represented by the formula (1) and the vinylbiotin derivative represented by the formula (2) is contacted with the trialkylsilane compound at a temperature in the range of 0°C to 40°C to obtain a compound represented by the following formula (5): [ka] After obtaining the biotin derivative represented by the formula: The method for producing a thiophanium salt derivative according to any one of [1] to [5], further comprising maintaining the temperature in the range of 50°C or higher and 80°C or lower to cyclize the biotin derivative represented by formula (5) and obtain the thiophanium salt derivative represented by formula (3). [Effects of the Invention]

[0016] According to the method for producing a thiophanium salt derivative of the present invention, the reduction reaction and the cyclization reaction proceed simultaneously, enabling the production of a highly pure biotin derivative in a short process.Furthermore, a highly pure thiophanium salt derivative with a sufficiently reduced amount of stereoisomers can be obtained. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention relates to a method for producing a thiophanium salt derivative (3) represented by formula (3), which comprises 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 at a temperature ranging from 0°C to 80°C in a solvent containing 40% by volume or more of a strong acid having an acid dissociation constant pKa of 1 or less. The details of the present invention are described below.

[0018] [Terminology] The terms used in this specification are explained below. The following explanations apply throughout this specification unless otherwise specified. The expression "value A to value B" means value A or more and value B or less unless otherwise specified.

[0019] Alkyl group The alkyl group has, for example, 1 to 20 carbon atoms, preferably 1 to 10, more preferably 1 to 8, more preferably 1 to 6, more preferably 1 to 4, more preferably 1 to 3, and more preferably 1 or 2. The alkyl group may be linear or branched. A linear alkyl group has 1 or more carbon atoms, and a branched alkyl group has 3 or more carbon atoms.

[0020] alkoxy group The alkoxy group is a group represented by the formula: -O-alkyl group, and the explanation regarding the alkyl group is as above.

[0021] 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, more preferably 6 to 14, and more preferably 6 to 10. The polycyclic group is preferably a fused ring group. Examples of the aryl group include a phenyl group and a naphthyl group. The aryl group is preferably a phenyl group.

[0022] Aralkyl groups An aralkyl group is an alkyl group having one or more aryl groups, and the alkyl group and 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.

[0023] Halogeno group Examples of the halogeno group include a fluoro group, a chloro group, a bromo group, and an iodo group.

[0024] <Hydroxybiotin derivative> In the present invention, the hydroxybiotin derivative (1) is a compound represented by the following formula (1).

[0025] [ka]

[0026] (R 1 and R 2 ) 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 which has a substituent), an aralkyl group which may have a substituent (i.e., an aralkyl group or an aralkyl group which has a substituent), or an aryl group which may have a substituent (i.e., an aryl group or an aryl group which has a substituent). 1 and R 2 may be the same functional group or different types of functional groups.

[0027] The alkyl group which may have a substituent, the aralkyl group which may have a substituent, and the aryl group which may have a substituent will be described below.

[0028] an 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 either linear or branched. The alkyl group has, for example, 1 to 20 carbon atoms, 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, 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 an aryl group having 3 to 20 carbon atoms, more preferably an aryl group having 4 to 14 carbon atoms, more preferably an aryl group having 6 to 14 carbon atoms, more preferably an aryl group having 6 to 10 carbon atoms), an alkoxy group having 1 to 6 carbon atoms (preferably an alkoxy group having 1 to 4 carbon atoms, more preferably an alkoxy group having 1 to 3 carbon atoms, more preferably an alkoxy group having 1 or 2 carbon atoms), a halogeno group, and the like. Examples of the substituent that the alkyl group may have include an aryl group having 6 to 14 carbon atoms, more preferably an aryl group having 6 to 10 carbon atoms, and particularly preferably a phenyl group. When the alkyl group has a substituent, the number of the substituents is preferably 1 to 5, more preferably 1 to 3, still more preferably 1 or 2, and particularly preferably 1.

[0029] an aralkyl group which may have a substituent; In one embodiment, R 1 and / or R 2is an aralkyl group which may have a substituent. The aralkyl group is preferably an aralkyl group having 7 to 11 carbon atoms. Examples of suitable aralkyl groups include a benzyl group, a phenylethyl group, a phenylpropyl group, a phenylbutyl group, and a 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 an alkoxy group having 1 to 4 carbon atoms, more preferably an alkoxy group having 1 to 3 carbon atoms, and more preferably an alkoxy group having 1 or 2 carbon atoms), a carboxyl group, a halogeno group, etc. When the aralkyl group has a substituent, the number of the substituent is preferably 1 to 5, more preferably 1 to 3, more preferably 1 or 2, and particularly preferably 1.

[0030] an optionally substituted aryl group; In one embodiment, R 1 and / or R 2 is an aryl group which may have a substituent. Examples of the aryl group include monocyclic, bicyclic, and tricyclic groups. 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 an alkoxy group having 1 to 4 carbon atoms, more preferably an alkoxy group having 1 to 3 carbon atoms, and more preferably an alkoxy group having 1 or 2 carbon atoms), a carboxyl group, a halogeno group, and the like. When the aryl group has a substituent, the number of the substituent is preferably 1 to 5, more preferably 1 to 3, more preferably 1 or 2, and particularly preferably 1.

[0031] In addition, R 1 and R 2 In consideration of the fact that it will ultimately be removed in a deprotection step, it is preferably an aralkyl group which may have a substituent, more preferably an aralkyl group, and particularly preferably a benzyl group.

[0032] (R 3 ) In formula (1), R3 -OR 4 is a monovalent alkoxy group or halogeno group represented by 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, and R 4 R 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. 3 The halogeno group and R 4 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 the above formula have the same meanings as above. The above explanations regarding the alkyl group which may have a substituent, the aralkyl group which may have a substituent, and the aryl group which may have a substituent are the same as above. 3 and R 4 also applies to

[0033] R 3 is selected as -OR due to its reactivity and ease of conversion to biotin. 4 Specifically, a methoxy group, an ethoxy group, or a propoxy group is preferred, and a methoxy group is particularly preferred.

[0034] (hydroxybiotin derivative) According to the method for producing a biotin derivative of the present invention, even when a relatively low-purity hydroxybiotin derivative (1) is used as a starting material, a thiophanium salt derivative (3) can be produced with a high conversion rate. Therefore, from the viewpoint of reducing the number of production steps, it is preferable to use the raw hydroxybiotin derivative (1) as a crude starting material without a purification step. Specifically, the hydroxybiotin derivative (1) used as a starting material in the method for producing a biotin derivative of the present invention can be suitably one having a purity of 95% or less as measured by liquid chromatography (preferably HPLC purity).

[0035] However, since the purity of the finally obtained thiophanium salt derivative (3) is preferably high, it is preferable to use a highly pure hydroxybiotin derivative (1) as a starting 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 highly pure hydroxybiotin derivative (1) as a starting material, the purity of the thiophanium salt derivative (3) obtained by the method for producing a biotin derivative according to the present invention can also be increased.

[0036] (Suitable Hydroxybiotin Derivatives) Considering their usefulness, the hydroxybiotin derivative (1) represented by formula (1) is preferably a hydroxybiotin derivative (1A) represented by the following formula (1A) and a hydroxybiotin derivative (1B) represented by the following formula (1B). The hydroxybiotin derivative (1A) is a hydroxybiotin derivative (1) having R 1 and R 2 are both benzyl groups, and R 3 is -OMe (i.e., R 4 is a methyl group). Hydroxybiotin derivative (1B) is a compound in which R 1 and R 2 are both benzyl groups, and R 3 is -OEt (i.e., R 4 is an ethyl group). In the formula, "Bn" represents a benzyl group, "Me" represents a methyl group, and "Et" represents an ethyl group. Hereinafter, similar explanations may be omitted.

[0037] [ka]

[0038] [ka]

[0039] <Vinylbiotin derivatives> In the present invention, the vinylbiotin derivative (2) is a compound represented by the following formula (2).

[0040] [ka]

[0041] In formula (2), R 1 , R 2 and R 3 are R in equation (1), respectively. 1 , R 2 and R 3 is synonymous with.

[0042] The purity of the vinylbiotin derivative (2) is not particularly limited, but may be, for example, a vinylbiotin derivative (2) having a purity of 80.0 to 99.9% as measured by liquid chromatography.

[0043] According to the method for producing a biotin derivative of the present invention, even when a vinylbiotin derivative (2) with a relatively low purity is used as a raw material, a thiophanium salt derivative (3) can be produced with a high conversion rate. Therefore, from the viewpoint of reducing the number of production steps, it is preferable to use the vinylbiotin derivative (2) as a raw material in its crude form without undergoing a purification step. Specifically, as the vinylbiotin derivative (2) used as a raw material in the method for producing a biotin derivative of the present invention, even one with a purity of 95% or less as measured by liquid chromatography (preferably HPLC purity) can be suitably used.

[0044] However, since the final thiophanium salt derivative (3) preferably has a high purity, it is preferable to use a highly pure vinylbiotin derivative (2) as a starting material. For example, by producing the vinylbiotin derivative (2) by the method shown below, the crude purity of the vinylbiotin derivative (2) can be relatively increased. By using such a highly pure vinylbiotin derivative (2) as a starting material, the purity of the thiophanium salt derivative (3) obtained by the method for producing a biotin derivative according to the present invention can also be increased.

[0045] (Suitable vinylbiotin derivatives) Considering their usefulness, vinylbiotin derivative (2) represented by formula (2) preferably includes hydroxybiotin derivative (2A) represented by formula (2A) below and vinylbiotin derivative (2B) represented by formula (2B) below. Vinylbiotin derivative (2A) is a compound obtained by dehydration of hydroxybiotin derivative (1A) represented by formula (1A). Vinylbiotin derivative (2B) is a compound obtained by dehydration of hydroxybiotin derivative (1B) represented by formula (1B).

[0046] [ka]

[0047] [ka]

[0048] <Reducing agent> In the present invention, at least one derivative selected from the group consisting of hydroxybiotin derivatives (1) and vinylbiotin derivatives (2) is contacted with a trialkylsilane compound as a reducing agent to produce a thiophanium salt derivative (3).

[0049] As the reducing agent used in the present invention, any trialkylsilane compound available as an industrial raw material or reagent can be used without any limitation.

[0050] The trialkylsilane compound has the formula: HSi-L 1 (-L 2 )(-L 3 ) is a compound represented by L 1 , L 2 and L 3 are each independently an alkyl group. 1 , L 2 and L 3 The alkyl groups may be the same or different. 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. The trialkylsilane compound preferably has 9 to 21 carbon atoms. Examples of preferred trialkylsilane compounds used in the present invention include triethylsilane, triisopropylsilane, tripropylsilane, tributylsilane, t-tributyldimethylsilane, and trihexylsilane (e.g., tri-n-hexylsilane). Among these trialkylsilane compounds, triisopropylsilane, tripropylsilane, tributylsilane, and t-tributyldimethylsilane are particularly preferred, considering the amount of by-product stereoisomers such as epimeric impurities. The use of such relatively sterically bulky trialkylsilanes increases the stereoselectivity of the reaction and reduces the amount of stereoisomeric impurities in the resulting biotin derivative or thiophanium salt derivative.

[0051] The amount of the trialkylsilane compound used in the present invention is not particularly limited, but in order to obtain the desired reaction rate while avoiding the complication of post-treatment operations due to an excessive amount of trialkylsilane compound, it is preferably in the range of 0.5 to 10.0 moles, and particularly preferably in the range of 1.0 to 5.0 moles, per mole of the reaction substrate in the present invention (at least one derivative selected from the group consisting of hydroxybiotin derivative (1) and vinylbiotin derivative (2)). When one type of derivative is selected as the reaction substrate in the present invention, the amount of the reaction substrate in the present invention refers to the amount of the one type of derivative, and when two or more types of derivatives are selected as the reaction substrate in the present invention, it refers to the total amount of the two or more types of derivatives (the same applies throughout the present specification).

[0052] <Lewis acid> In the production method of the present invention, a Lewis acid may be further used as a reaction aid. The use of a Lewis acid allows the desired reaction to proceed preferentially, and also makes it possible to reduce the amount of stereoisomers (epimers) produced as by-products.

[0053] The Lewis acid used in the present invention is not particularly limited, and can be a commercially available one. Examples of Lewis acids include boron trichloride, boron tribromide, boron trifluoride diethyl ether complex (BFOEt), 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, boron compounds are preferred as Lewis acids, 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.

[0054] The amount of Lewis acid used in the present invention is not particularly limited, but in order to obtain a desired reaction rate while avoiding complicated post-treatment procedures, it is preferably in the range of 0.1 to 10 mol, more preferably in the range of 0.3 to 5.0 mol, and particularly preferably in the range of 0.5 to 3.0 mol, per mol of the reaction substrate in the present invention (at least one derivative selected from the group consisting of hydroxybiotin derivative (1) and vinylbiotin derivative (2)).

[0055] <Solvent> The solvent used in the present invention contains a strong acid having an acid dissociation constant pKa of 1 or less.

[0056] 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 a pKa of 1 or less" in the present invention is not limited to those that are liquid at room temperature. Even those that are solid at room temperature, such as trichloroacetic acid, can be used by using them at a temperature above their melting point or by dissolving them in another solvent. Among these, it is preferable to use those that are liquid at room temperature as solvents. Examples of such strong acids include trifluoroacetic acid (pKa = -0.3), methanesulfonic acid (pKa = -2.6), and trifluoromethanesulfonic acid (pKa = -14). Among these, trifluoroacetic acid and methanesulfonic acid are preferred from the standpoint of reactivity, and trifluoroacetic acid is particularly preferred.

[0057] The solvent in the present invention preferably contains, for example, 40% by volume or more of the strong acid. In other words, the solvent in the present invention preferably contains 60% by volume or less of other solvents other than the strong acid. Furthermore, in consideration of the reaction rate, the other solvents are more preferably 30% by volume or less, and particularly preferably 0% by volume. That is, the solvent more preferably contains 70% by volume or more of the strong acid, and particularly preferably 100% by volume. It should be noted that containing 100% by volume of the strong acid (i.e., the content of other solvents other than the strong acid is 0% by volume) does not completely eliminate the inclusion of impurities that inevitably enter the solvent in addition to the strong acid.

[0058] Increasing the proportion of a strong acid with a pKa of 1 or less in the reaction solvent of the present invention improves the conversion rate to biotin derivative (3), allowing the reaction to be completed in a shorter time. Furthermore, the other solvent is not particularly limited, and any solvent that is stable in the presence of a strong acid and does not affect the reaction of the present invention may be used. Specific examples include dichloromethane, chloroform, and toluene.

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

[0060] <Method for producing biotin derivatives> The thiophanium salt derivative (3) can be produced by contacting the reaction substrate of the present invention (at least one derivative selected from the group consisting of hydroxybiotin derivative (1) and vinylbiotin derivative (2)) with a trialkylsilane compound at a temperature of 0°C to 80°C in a solvent containing a strong acid with an acid dissociation constant pKa of 1 or less. The components are mixed so that they are in sufficient contact with each other. The method of the present invention can be carried out under normal pressure, reduced pressure, or increased pressure. The method of the present invention can be carried out not only in the presence of oxygen, such as air, but also in an inert gas atmosphere, such as nitrogen, argon, or carbon dioxide. The method of mixing the components is not particularly limited. For example, all components may be simultaneously charged into a reaction apparatus and mixed. Alternatively, one component may be mixed in advance, and the remaining components may be added sequentially and mixed. The components may also be diluted with a solvent and supplied to a reaction apparatus or the like. In particular, to further reduce by-products and increase the purity of the thiophanium salt derivative (3), it is preferable to mix and stir at least one derivative selected from the group consisting of hydroxybiotin derivative (1) and vinylbiotin derivative (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 under an inert gas atmosphere, and then add a Lewis acid and a trialkylsilane compound in that order and stir (mix) them. These components can also be diluted with a solvent as needed.

[0061] In the present invention, the reaction temperature (the temperature in the reaction system after all components are mixed) is in the range of 0 to 80°C. Considering the reaction rate and the amount of by-product epimeric impurities, the reaction is preferably carried out at 0 to 70°C, and particularly preferably at 0 to 40°C. A too high reaction temperature increases the reaction rate but also tends to increase the amount of by-product epimeric impurities. By carrying out the reaction within this range, efficient conversion to the thiophanium salt derivative (3) is possible. The reaction time is also not limited and can be determined appropriately while checking the reaction conversion rate described in the Examples below. However, under the above reaction conditions, the reaction time is 1 to 72 hours, preferably 1 to 24 hours. The reaction time here refers to the time during which the reaction substrate, a solvent containing a strong acid with a pKa of 1 or less, a trialkylsilane compound, and a Lewis acid are mixed at the set reaction temperature.

[0062] In the present invention, after the reduction reaction has progressed, a biotin derivative (5) may be produced that has not yet progressed to the cyclization reaction. Specifically, when at least one selected from the group consisting of hydroxybiotin derivative (1) and vinylbiotin derivative (2) is contacted with a trialkylsilane compound at a temperature of 0°C or higher and 40°C or lower, a biotin derivative (5) represented by the following formula (5) may be produced.

[0063] [ka]

[0064] The biotin derivative (5A) is a compound obtained by the reduction reaction of the hydroxybiotin derivative (2A) represented by formula (2A) and the vinylbiotin derivative (1B) represented by formula (2B).

[0065] [ka]

[0066] In the present invention, after the reduction reaction has progressed, the cyclization reaction can be accelerated by heating. Generally, the reduction reaction is preferably carried out at a temperature within the aforementioned range to avoid the by-production of epimeric impurities, but the cyclization reaction can be carried out at any temperature within the range of 0 to 100°C. The temperatures for the reduction reaction and the cyclization reaction may be the same or different. The cyclization reaction is preferably carried out at a temperature maintained within the range of 50 to 80°C.

[0067] The reaction mixture obtained in the present invention may be subjected to appropriate post-treatment. Specifically, the solvent may be removed from the reaction mixture by distillation under reduced pressure or the like to obtain a crude thiophanium salt derivative (3).

[0068] <Thiophanium salt derivatives> The thiophanium salt derivative (3) obtained in the present invention is a compound represented by the following formula (3).

[0069] [ka]

[0070] In formula (3), R 1 , R 2 and R 3 are R in Eq. (1), respectively. 1 , R 2 and R 3 is synonymous with.

[0071] (Suitable Thiophanium Salt Derivatives) When the hydroxybiotin derivative (1A) or the vinylbiotin derivative (2A), or the hydroxybiotin derivative (1B) or the vinylbiotin derivative (2B), which are suitable starting compounds, are used as substrates, the biotin derivatives represented by the following formula (3A) can be obtained as the thiophanium salt derivative (3) represented by formula (3). The thiophanium salt derivative (3A) is the thiophanium salt derivative (3) in which R 1 and R 2 are both benzyl groups.

[0072]

Chem.

[0073] The thiophanium salt derivative obtained in the present invention can be converted into known salts such as bromide salts. For example, according to the method described in Patent Document 1, 48% aqueous HBr is added, the solution is concentrated, and then recrystallized to obtain thiophanium salt bromide (6).

[0074]

Chem.

[0075] From thiophanium salt bromide, according to the method described in Patent Document 1, through a carbon chain elongation reaction with malonic ester and a step of removing the benzyl group corresponding to R 1 and R 2 by deprotection treatment, biotin can be easily produced.

Examples

[0076] Hereinafter, the present invention will be described in detail with reference to examples, which 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 ultra-high performance liquid chromatography (UPLC).

[0077] <Measurement Conditions of UPLC> The analysis conditions for UPLC analysis are as follows. Apparatus: Ultra-high performance liquid chromatography (UPLC) Model: 1290 infinity II LC system (manufactured by Agilent Technologies) Detector: Ultraviolet absorption photometer (measurement wavelength: 210 nm) Column: ACQUITY UPLC BEH C18 Column, inner diameter 2.1 mm, length 5 cm (particle size: 1.7 μm) (manufactured by Waters) Column temperature: 40 °C (constant) Sample temperature: 25℃ (constant) Mobile phase A: 0.1% formic acid in water Mobile phase B: 0.1% formic acid in acetonitrile Delivery of mobile phase: The mixing ratio of mobile phase A and mobile phase B is changed as shown in Table 1 below to control the concentration gradient.

[0078] [Table 1]

[0079] Under the above UPLC measurement conditions, vinylbiotin derivative (2A) (R 1 , R 2 =Bn, R 3 =-OMe) at approximately 7.75 min, the biotin derivative (5A) at 7.57 min, its corresponding stereoisomer (epimer) at approximately 7.47 min, and the thiophanium salt derivative (3A) (R 1 , R 2 =Bn) peaks are observed at approximately 4.0 minutes.

[0080] <Calculation method of reaction conversion rate> The reaction conversion rate of the thiophanium salt derivative (3A) is calculated as a percentage of the peak area of ​​the produced thiophanium salt derivative (3A) relative to the sum of the peak area of ​​the hydroxybiotin derivative (1A) or the vinylbiotin derivative (2A) and the peak area of ​​the biotin derivative (5A) and the thiophanium salt derivative (3A). The reaction conversion rate of the biotin derivative (5A) is calculated as a percentage of the peak area of ​​the produced biotin derivative (5A) relative to the sum of the peak area of ​​the hydroxybiotin derivative (1A) or the vinylbiotin derivative (2A) and the peak area of ​​the biotin derivative (5A) and the thiophanium salt derivative (3A).

[0081] <Calculation method for stereoisomer ratio> The stereoisomer ratio is a method for calculating and evaluating the amount of stereoisomers contained in the thiophanium salt derivative (3A) or biotin derivative (5A), and is calculated as follows: Specifically, the isomer ratio contained in the thiophanium salt derivative (3A) is calculated as a percentage of the peak area value of the stereoisomer (epimer) corresponding to the thiophanium salt derivative (3A) relative to the sum of the peak area value of the thiophanium salt derivative (3A) and the peak area value of the corresponding stereoisomer (epimer).

[0082] Example 1 As shown in the following reaction scheme, a thiophanium salt derivative (3A) represented by formula (3A) was synthesized from a vinylbiotin derivative (2A) represented by formula (2A) via a biotin derivative (5A). In the formula, "Bn" represents a benzyl group, and "Me" represents a methyl group.

[0083] [ka]

[0084] 2.39 g (6.06 mmol) of the vinyl biotin derivative (2A) was weighed into a 50 mL four-neck flask equipped with a 2.5 cm diameter stirrer, and 7.15 mL of trifluoroacetic acid (pKa = -0.3, 25 °C) was added. The mixture was then cooled to 0 °C. 1.43 g (9.09 mmol) of triisopropylsilane was added, and the mixture was heated to 25 °C and stirred at that temperature for 21 hours. High-performance liquid chromatography (HPLC) confirmed that the conversion of the thiophanium salt derivative (3A) was 1.6% and the conversion of the biotin derivative (5A) was 70.2% after stirring at 25 °C for 21 hours. The proportion of the stereoisomer (epimer) corresponding to the biotin derivative (5A) was 1.7%.

[0085] Example 2 As shown in the following reaction scheme, a thiophanium salt derivative (3A) represented by formula (3A) was synthesized from a vinylbiotin derivative (2A) represented by formula (2A). In the formula, "Bn" represents a benzyl group, and "Me" represents a methyl group.

[0086] [ka]

[0087] 2.39 g (6.06 mmol) of the vinyl biotin derivative (2A) was weighed into a 50 mL four-neck flask equipped with a 2.5 cm diameter stirrer, and 7.15 mL of trifluoroacetic acid (pKa = -0.3, 25 °C) was added. The mixture was cooled to 0 °C. 0.86 g (9.09 mmol) of boron trifluoride diethyl ether complex and 1.43 g (9.09 mmol) of triisopropylsilane were added sequentially. The mixture was then heated to 25 °C and stirred at that temperature for 21 hours. High-performance liquid chromatography (HPLC) confirmed that the conversion of the thiophanium salt derivative (3A) was 56.9% and the conversion of the biotin derivative (5A) was 42.9% after stirring at 25 °C for 21 hours. The proportion of the stereoisomer (epimer) corresponding to the biotin derivative (5A) was 1.7%.

[0088] After further stirring at 40°C for 6 hours, the reaction conversion of the thiophanium salt derivative (3A) was 82.4%, and the reaction conversion of the biotin derivative (5A) was 17.6%.

[0089] Example 3 The reaction was carried out in the same manner as in Example 2, except that boron trifluoride tetrahydrofuran complex was used instead of boron trifluoride diethyl ether complex. The results are shown in Table 2. After stirring at 25°C for 21 hours, the reaction conversion of the thiophanium salt derivative (3A) was 57.6%, and the reaction conversion of the biotin derivative (5A) was 42.4%. The proportion of the stereoisomer (epimer) corresponding to the biotin derivative (5A) was 1.4%. After further stirring at 60°C for 2 hours, the reaction conversion rate of the thiophanium salt derivative (3A) was 99.8%, and the reaction conversion rate (residual rate) of the biotin derivative (5A) was 0.2%.

[0090] Example 4 The reaction was carried out in the same manner as in Example 1, except that triethylsilane was used instead of triisopropylsilane. The results are shown in Table 2. After stirring for 21 hours at 25°C, the reaction conversion of the thiophanium salt derivative (3A) was 3.0%, and the reaction conversion of the biotin derivative (5A) was 97.0%. The proportion of the stereoisomer (epimer) corresponding to the biotin derivative (5A) was 11.0%.

[0091] Example 5 The reaction was carried out in the same manner as in Example 1, except that the reaction temperature was 50°C. The results are shown in Table 2. After stirring at 50°C for 21 hours, the reaction conversion of the thiophanium salt derivative (3A) was 51.4%, and the reaction conversion of the biotin derivative (5A) was 48.6%. The proportion of the stereoisomer (epimer) corresponding to the biotin derivative (5A) was 4.1%.

[0092] Example 6 The reaction was carried out in the same manner as in Example 5, except that triethylsilane was used instead of triisopropylsilane. The results are shown in Table 2. After stirring at 50°C for 21 hours, the reaction conversion of the thiophanium salt derivative (3A) was 57.7%, and the reaction conversion of the biotin derivative (5A) was 42.3%. The proportion of the stereoisomer (epimer) corresponding to the biotin derivative (5A) was 9.7%.

[0093] Example 7 The reaction was carried out in the same manner as in Example 3. The results are shown in Table 2. After stirring at 25°C for 72 hours, the reaction conversion rate of the thiophanium salt derivative (3A) was 95.0%, and the reaction conversion rate of the biotin derivative (5A) was 5.0%. The proportion of the stereoisomer (epimer) corresponding to the biotin derivative (5A) was 1.6%.

[0094] [Table 2]

Claims

1. In a solvent containing a strong acid having an acid dissociation constant pKa of 1 or less, The following formula (1): 【Chemistry 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 -OR ４ is a monovalent alkoxy group or halogeno group represented by the formula: R ４ 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. and a hydroxybiotin derivative represented by the following formula (2): 【Chemistry 2】 [In the formula (2), R １ , R ２ and R ３ are R in the formula (1), respectively. １ , R ２ and R ３ is equivalent to the above.] and at least one derivative selected from the group consisting of vinyl biotin derivatives represented by the formula: and a trialkylsilane compound at a temperature in the range of 0° C. to 80° C. to form a compound represented by the following formula (3): 【Transformation 3】 [In the formula (2), R １ , R ２ and R ３ are R in the formula (1), respectively. １ , R ２ and R ３ is equivalent to the above.] A method for producing a thiophanium salt derivative, comprising the step of obtaining a thiophanium salt derivative represented by the formula:

2. When the hydroxybiotin derivative represented by the formula (1) and the vinylbiotin derivative represented by the formula (2) are contacted with a trialkylsilane compound, a Lewis acid is further contacted therewith. A method for producing the thiophanium salt derivative according to claim 1.

3. the Lewis acid is selected from boron trifluoride diethyl ether complex, boron trifluoride tetrahydrofuran complex, and boron trifluoride dimethanol complex; A method for producing the thiophanium salt derivative according to claim 1 or 2.

4. 3. The method for producing a thiophanium salt derivative according to claim 1, wherein the trialkylsilane compound is selected from the group consisting of triisopropylsilane, tripropylsilane, tributylsilane, and t-butyldimethylsilane.

5. 3. The method for producing a thiophanium salt derivative according to claim 1, wherein the strong acid is selected from the group consisting of trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid.

6. At least one derivative selected from the group consisting of the hydroxybiotin derivative represented by the formula (1) and the vinylbiotin derivative represented by the formula (2) is contacted with the trialkylsilane compound at a temperature in the range of 0° C. to 40° C. to obtain a compound represented by the following formula (5): 【Chemistry 4】 After obtaining the biotin derivative represented by the formula: Further, by keeping the temperature in the range of 50°C or more and 80°C or less, the biotin derivative represented by formula (5) is cyclized to obtain the thiophanium salt derivative represented by formula (3). A method for producing the thiophanium salt derivative according to claim 1 or 2.

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