Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems

Definitions

• the present invention relates to a novel method for producing a biotin derivative, and particularly to a method for producing a biotin derivative by reducing a hydroxybiotin derivative or a vinylbiotin derivative.
• Biotin is a useful compound that is used in various pharmaceuticals, food additives, feed additives, etc.
• a method for producing a biotin derivative a method for obtaining a biotin derivative by reducing a vinyl biotin derivative has been reported (see Non-Patent Document 1).
• Non-Patent Document 1 a biotin derivative is produced by reacting a hydroxybiotin derivative or a vinylbiotin derivative having a benzyl ester group at the end of a side chain with triethylsilane as a reducing agent in a solvent containing trifluoroacetic acid and dichloromethane. A method for doing so is disclosed.
• Non-Patent Document 1 a highly purified hydroxybiotin derivative or vinylbiotin derivative is used as a reaction substrate. In this way, since a step of once purifying the reaction substrate is included, there is room for improvement in terms of application to industrial production aimed at mass production.
• the present inventors surprisingly found that by using a solvent containing a predetermined proportion or more of a strong acid having an acid dissociation constant pKa of 1 or less, hydroxy
• a biotin derivative can be synthesized with a high conversion rate, leading to the completion of the present invention.
• R 1 and R 2 are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group, or a substituted an aryl group that may be
• R 4 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group, or an optionally substituted aryl group.
• a method for producing a biotin derivative comprising producing a biotin derivative represented by [2] The method for producing a biotin derivative according to [1], wherein the trialkylsilane compound is selected from trimethylsilane, triethylsilane, triisopropylsilane and trihexylsilane. [3] The method for producing a biotin derivative according to [1] or [2], wherein each of the at least one derivative has a purity of 95% or less as measured by liquid chromatography. [4] The method for producing a biotin derivative according to [1] or [3], wherein 0.1 to 20 mL of the solvent is used per 1 g of the at least one derivative. [5] The method for producing a biotin derivative according to [3], wherein 0.1 to 20 mL of the solvent is used per 1 g of the at least one derivative.
• a biotin derivative can be produced with a high conversion rate without using highly pure raw materials.
• a hydroxybiotin derivative (1) represented by formula (1) and a vinylbiotin derivative represented by formula (2) ( The present invention relates to a method for producing a biotin derivative (3) represented by formula (3) by contacting at least one derivative selected from the group consisting of 2) with a trialkylsilane compound. The details of the present invention will be described below.
• Halogeno group includes, for example, fluoro group, chloro group, bromo group, iodo group and the like.
• Alkyl group The number of carbon atoms in 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 is 1 or 2.
• Alkyl groups may be linear or branched. The straight-chain alkyl group has 1 or more carbon atoms, and the branched-chain alkyl group has 3 or more carbon atoms.
• Aryl Groups are, for example, monocyclic or polycyclic (eg bicyclic or tricyclic) aromatic hydrocarbon ring groups.
• the number of carbon atoms in the aryl group is, for example, 3-22, preferably 3-20, more preferably 4-14, more preferably 6-14, more preferably 6-10.
• Polycyclics are preferably fused rings. Examples of aryl groups include phenyl groups and naphthyl groups.
• Aryl groups are preferably phenyl groups.
• Aralkyl Group An aralkyl group is an alkyl group having one or more aryl groups, and the description of the alkyl group and the aryl group is as described above.
• the number of aryl groups contained in the aralkyl group is, for example, 1-3, preferably 1 or 2, more preferably 1.
• Examples of aralkyl groups include benzyl, phenylethyl, phenylpropyl, phenylbutyl, and naphthylmethyl groups.
• An aryl group contained in an aralkyl group is preferably a phenyl group.
• Aralkyl groups are preferably benzyl groups.
• Alkoxy Group An alkoxy group is a group represented by the formula: --O-alkyl group, and the description of the alkyl group is as described above.
• hydroxybiotin derivative (1) is a compound represented by the following formula (1).
• R 1 and R 2 each independently represent a hydrogen atom, an optionally substituted alkyl group (that is, an alkyl group or an alkyl group having a substituent), or a substituted an aralkyl group that may have a substituent (that is, an aralkyl group or an aralkyl group that has a substituent), or an aryl group that may have a substituent (that is, an aryl group or an aryl group that has a substituent).
• R 1 and R 2 may be the same functional group, or different types of functional groups.
• R 1 and/or R 2 are optionally substituted alkyl groups.
• Alkyl groups may be 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, more preferably 1 to 6, and 1 to 4. is more preferred, 1 to 3 is more preferred, 1 or 2 is more preferred, and 1 is particularly preferred.
• the alkyl group may have a substituent.
• substituents that the alkyl group may have include aryl groups having 3 to 22 carbon atoms (preferably 3 to 20 carbon atoms, more preferably 4 to 14 carbon atoms, more preferably 6 to 14 carbon atoms, more preferably 6 to 14 carbon atoms, and more preferably is an aryl group having 6 to 10 carbon atoms), an alkoxy group having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms), A halogeno group etc. are mentioned.
• the substituent that the alkyl group may have is preferably an aryl group having 6 to 14 carbon atoms, more preferably an aryl group having 6 to 10 carbon atoms, and particularly preferably a phenyl group.
• the number of substituents is preferably 1 to 5, more preferably 1 to 3, more preferably 1 or 2, particularly 1 preferable.
• R 1 and/or R 2 are optionally substituted aralkyl groups.
• aralkyl group an aralkyl group having 7 to 11 carbon atoms is preferred.
• suitable aralkyl groups include benzyl, phenylethyl, phenylpropyl, phenylbutyl and naphthylmethyl groups.
• the aralkyl group may have a substituent. Examples of substituents that the aralkyl group may have include alkoxy groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms).
• the number of substituents is preferably 1 to 5, more preferably 1 to 3, more preferably 1 or 2, particularly 1 preferable.
• R 1 and/or R 2 are optionally substituted aryl groups.
• Aryl groups include those that are monocyclic, bicyclic or tricyclic.
• the aryl group is preferably an aryl group having 6 to 14 carbon atoms, particularly preferably a phenyl group.
• the aryl group may have a substituent. Examples of substituents that the aryl group may have include alkoxy groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms). ), a carboxyl group, a halogeno group, and the like.
• the number of substituents is preferably 1 to 5, more preferably 1 to 3, more preferably 1 or 2, particularly 1 preferable.
• R 1 and R 2 are preferably an optionally substituted aralkyl group, more preferably an aralkyl group, considering that they are finally removed in the deprotection step.
• a benzyl group is particularly preferred.
• R 3 is a hydrogen atom, an optionally substituted alkyl group, a cyano group, or a monovalent functional group represented by —C( ⁇ O)OR 4
• R 4 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group, or an optionally substituted aryl group.
• An optionally substituted alkyl group for R 3 , an optionally substituted alkyl group, an optionally substituted aralkyl group, and an optionally substituted alkyl group for R 4 aryl group is as defined above.
• the above explanations regarding an optionally substituted alkyl group, an optionally substituted aralkyl group, and an optionally substituted aryl group also apply to R 3 and R 4 .
• the hydroxybiotin derivative (1) in the present invention is not particularly limited, and those produced by known methods can be used. For example, those produced by the method described in Non-Patent Document 1 and those purified can be used. Specifically, it can be produced according to the following reaction formula.
• the compound represented by formula (5) is a thiolactone derivative and can be produced by a known method.
• R 1 or R 2 has the same meaning as R 1 or R 2 in formula (1).
• the thiolactone derivative (5) represented by the formula (5) is reacted with an organometallic reagent represented by the formula: R 3 —(CH 2 ) 4 —MX to obtain the formula ( Hydroxybiotin derivative (1) represented by 1) can be produced.
• organometallic reagent represented by the formula: R 3 —(CH 2 ) 4 —MX, X is a halogen atom, M is a metal element selected from zinc or magnesium, and R 3 is represented by the formula ( It has the same meaning as R 3 in 1).
• the purity of the hydroxybiotin derivative (1) is not particularly limited, for example, the hydroxybiotin derivative (1) may have a purity of 80.0 to 99.9% as measured by liquid chromatography. .
• the purity measured by liquid chromatography is the value of area % when measured by liquid chromatography.
• the purity measured by liquid chromatography is preferably the purity measured by high performance liquid chromatography (HPLC). performed under the conditions described in In this specification, the purity measured by HPLC may be referred to as "HPLC purity".
• biotin derivative (3) can be produced with a high conversion rate even when hydroxybiotin derivative (1) with relatively low purity is used as a raw material. Therefore, from the viewpoint of shortening the number of production steps, it is preferable to use the crude hydroxybiotin derivative (1) as a raw material without going through a purification step.
• the hydroxybiotin derivative (1) used as a raw material in the method for producing a biotin derivative according to the present invention preferably has a purity of 95% or less as measured by liquid chromatography (preferably HPLC purity). can be used.
• the biotin derivative (3) finally obtained has a high purity
• the crude purity of hydroxybiotin derivative (1) can be relatively increased by producing hydroxybiotin derivative (1) by the method shown below.
• the purity of the biotin derivative (3) obtained by the method for producing a biotin derivative according to the present invention is also higher.
• a thiolactone derivative (5) represented by formula (5) and an organozinc reagent (R 3 —(CH 2 ) 4 — for introducing a desired side chain into the thiolactone derivative (5) ZnX) can be subjected to Fukuyama coupling reaction to produce hydroxybiotin derivative (1).
• organozinc reagent represented by the formula: R 3 —(CH 2 ) 4 —ZnX X represents a halogen atom, and examples of the halogen atom represented by X include chlorine, bromine, and iodine atoms. is mentioned. Among them, from the viewpoint of reactivity, bromine atom and iodine atom are preferable, and iodine atom is particularly preferable.
• Organozinc reagents can be prepared by contacting the corresponding organohalide (R 3 —(CH 2 ) 4 —X) with zinc in an organic solvent.
• Single zinc can be used as the zinc used, and its form is not limited. Examples of the form of zinc include powder, shavings, strips, and the like.
• the amount of zinc to be used may be appropriately determined according to the type of organic halide, and is, for example, 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of organic halide.
• the contact between the organic halide and zinc is preferably carried out in the presence of a zinc activator.
• Zinc activators include, for example, bromine, iodine, 1,2-dibromoethane, trimethylsilyl chloride and the like.
• the amount of zinc activator to be used is, for example, 0.01 to 1.5 mol, preferably 0.2 to 0.8 mol, per 1 mol of zinc.
• organic zinc reagent it is preferable to prepare the organic zinc reagent in an organic solvent.
• organic solvents include tetrahydrofuran, 2-methyltetrahydrofuran, toluene, cyclopentylmethylether, N,N-dimethylformamide, N,N-dimethylacetamide, tert-butylmethylether, diisopropylether, and diglyme.
• the organic solvents exemplified above can be used alone, or a mixture of two or more of them can be used.
• the amount of organic solvent used is not particularly limited, but is, for example, 0.5 to 20 mL, preferably 1 to 10 mL, per 1 g of zinc. When a mixture is used as the organic solvent, the amount used is based on the total amount of the mixture.
• the contact temperature between the organic halide and zinc is, for example, 20 to 120°C, preferably 30 to 100°C.
• the contact time between the organic halide and zinc is, for example, 0.1 to 10 hours, preferably 1 to 5 hours.
• the organic zinc reagent it is preferable to prepare the organic zinc reagent by the following method. First, after mixing an organic solvent and zinc, a zinc activator is added to activate the zinc. An organozinc reagent can then be prepared by adding an organohalide and mixing. The resulting zinc reagent can be used in the form of a solution for the production of hydroxybiotin derivative (1) without separation and purification.
• Hydroxybiotin derivative (1) can be obtained by subjecting thiolactone derivative (5) and an organic zinc reagent to Fukuyama coupling reaction in the presence of a palladium or nickel catalyst.
• Palladium catalysts include, for example, palladium carbon, palladium black, palladium acetate, palladium chloride, bistriphenylphosphine palladium chloride, and the like.
• Nickel catalysts include, for example, nickel acetylacetonate, nickel chloride, and the like. From the viewpoint of reactivity, palladium acetate, palladium carbon, and nickel acetylacetonate are preferred.
• the amount of palladium or nickel catalyst used is not particularly limited, but is, for example, 0.001 to 0.5 mol, preferably 0.005 to 0.05 mol, per 1 mol of the thiolactone derivative (5). is.
• the amount of the organic zinc reagent to be used is not particularly limited, but is, for example, 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of the thiolactone derivative (5).
• the organic solvent in the synthesis reaction of hydroxybiotin derivative (1) is not particularly limited as long as it does not inhibit the reaction, and may be used as needed.
• organic solvents include tetrahydrofuran, 2-methyltetrahydrofuran, toluene, cyclopentylmethylether, N,N-dimethylformamide, N,N-dimethylacetamide, tert-butylmethylether, diisopropylether, and diglyme.
• the organic solvents exemplified above can be used alone, or a mixture of two or more of them can be used.
• the amount of the organic solvent to be used is not particularly limited, but is, for example, 3 to 30 mL, preferably 5 to 20 mL, per 1 g of thiolactone derivative (5).
• the amount used is based on the total amount of the mixture.
• the total value (total amount) with the newly used organic solvent may be adjusted so as to be within the above range.
• the Fukuyama coupling reaction can be performed by mixing a palladium or nickel catalyst, a thiolactone derivative (5), an organic zinc reagent and an organic solvent, and the order of mixing these is not particularly limited, and can be performed by stirring and mixing. can.
• the temperature of the Fukuyama coupling reaction is not particularly limited, but in terms of the conversion rate of the reaction and the purity of the hydroxybiotin derivative (1), it is, for example, in the range of 20 to 100°C, preferably in the range of 25 to 80°C. is.
• the reaction time is not particularly limited, but is, for example, in the range of 1 to 48 hours, preferably in the range of 2 to 20 hours.
• the hydroxybiotin derivative (1) can be produced by reacting under the above conditions.
• a method for removing the hydroxybiotin derivative (1) from the reaction system is not particularly limited. Specifically, hydroxybiotin derivative (1) is dissolved in a solvent that is sparingly soluble in water such as ethyl acetate, toluene, chloroform, and dichloromethane, followed by washing with water, concentration, drying, etc. to obtain hydroxybiotin derivative (1). can be taken out. When a solvent that is sparingly soluble in water is used as the solvent, the solution can be washed with water as it is.
• the purity of hydroxybiotin derivative (1) obtained under the above conditions as measured by liquid chromatography is not particularly limited, but according to the preferred production method, A hydroxybiotin derivative (1) having a purity measured by liquid chromatography (preferably HPLC purity) of 90.0 to 95.0% can be obtained.
• a hydroxybiotin derivative (1) having such purity can be suitably used as a reaction substrate of the present invention.
• the reaction solution containing the hydroxybiotin derivative (1) can be directly converted to the vinylbiotin derivative (2).
• hydroxybiotin derivative (1) 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 following formula (1B) Hydroxybiotin derivatives (1B) are preferred.
• Hydroxybiotin derivative (1A) is a compound of hydroxybiotin derivative (1) in which both R 1 and R 2 are benzyl groups, and R 3 is —CO 2 Et (that is, R 4 is an ethyl group).
• Hydroxybiotin derivative (1B) is a compound in which R 1 and R 2 are both benzyl groups and R 3 is —CO 2 H (that is, R 4 is a hydrogen atom) in hydroxybiotin derivative (1).
• "Bn" in the formula represents a benzyl group
• "Et” represents an ethyl group.
• similar description may be omitted.
• the vinyl biotin derivative (2) is a compound represented by the following formula (2).
• R 1 , R 2 and R 3 have the same meanings as R 1 , R 2 and R 3 in formula (1).
• the purity of the vinyl biotin derivative (2) is not particularly limited, for example, the vinyl biotin derivative (2) may have a purity of 80.0 to 99.9% as measured by liquid chromatography. .
• the method for producing a biotin derivative according to the present invention even when vinyl biotin derivative (2) with relatively low purity is used as a raw material, biotin derivative (3) can be produced with a high conversion rate. Therefore, from the viewpoint of shortening the number of production steps, it is preferable to use the crude vinyl biotin derivative (2) as a raw material without going through a purification step.
• the vinyl biotin derivative (2) used as a raw material in the method for producing a biotin derivative according to the present invention preferably has a purity of 95% or less as measured by liquid chromatography (preferably HPLC purity). can be used.
• the biotin derivative (3) finally obtained has a high purity
• the vinyl biotin derivative (2) by the method shown below, the crude purity of the vinyl biotin derivative (2) can be relatively increased.
• the purity of the biotin derivative (3) obtained by the method for producing a biotin derivative according to the present invention is also higher.
• the vinyl biotin derivative (2) in the present invention is not particularly limited and can be produced by known methods. Specifically, as shown in the following reaction formula, it can be produced by subjecting hydroxybiotin derivative (1) to a dehydration reaction.
• Examples of dehydration methods for hydroxybiotin derivative (1) include acid treatment and heat treatment, but acid treatment is preferable in consideration of the purity of the product.
• Acid treatment involves contacting a solution of hydroxybiotin derivative (1) with an acid catalyst.
• Acid catalysts include, for example, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, mixtures thereof, and the like.
• the amount of acid to be used may be appropriately determined depending on the type of acid used, and is, for example, 1 to 1000 mol, preferably 20 to 200 mol, per 1 mol of hydroxybiotin derivative (1).
• the temperature for the acid treatment is not particularly limited, but is, for example, 10 to 100°C, preferably 20 to 70°C.
• the acid treatment time is, for example, 0.1 to 10 hours, preferably 1 to 7 hours.
• the method of bringing the solution of hydroxybiotin derivative (1) into contact with the acid catalyst is not particularly limited.
• a method of simultaneously mixing hydroxybiotin derivative (1), an acid catalyst, and a solvent capable of dissolving hydroxybiotin derivative (1); A method of preparing the obtained reaction solution), adding an acid catalyst to the solution and mixing them, or the like can be employed.
• the vinyl biotin derivative (2) can be easily produced by reacting under the above conditions.
• a method for removing the vinyl biotin derivative (2) from the reaction system is not particularly limited. Specifically, the vinyl biotin derivative (2) is dissolved in a water-sparing solvent such as ethyl acetate, toluene, chloroform, or dichloromethane, washed with water, concentrated, and dried to obtain the vinyl biotin derivative (2). can be taken out. When a solvent that is sparingly soluble in water is used as the solvent, the solution can be washed with water as it is.
• a water-sparing solvent such as ethyl acetate, toluene, chloroform, or dichloromethane
• the purity of the vinyl biotin derivative (2) obtained under the above conditions as measured by liquid chromatography is not particularly limited.
• a vinyl biotin derivative (2) with a purity measured by chromatography (preferably HPLC purity) of 90.0 to 95.0% can be obtained.
• a vinyl biotin derivative (2) having such purity can be suitably used as a reaction substrate of the present invention.
• vinyl biotin derivative (2A) represented by formula (2A) below and vinyl biotin derivative (2A) represented by formula (2B) below A vinyl biotin derivative (2B) is preferred.
• the vinyl biotin derivative (2A) is a compound obtained from the dehydration reaction of the hydroxybiotin derivative (1A) represented by formula (1A).
• the vinyl biotin derivative (2B) is a compound obtained from the dehydration reaction of the hydroxybiotin derivative (1B) represented by formula (1B).
• At least one derivative selected from the group consisting of hydroxybiotin derivative (1) and vinylbiotin derivative (2) is brought into contact with a trialkylsilane compound as a reducing agent to obtain biotin derivative (3). manufacture.
• any trialkylsilane compound available as an industrial raw material or reagent can be used without any limitation.
• the trialkylsilane compound is a compound represented by the formula: SiH-L 1 (-L 2 )(-L 3 ).
• 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.
• Alkyl groups may be linear or branched.
• the number of carbon atoms in the alkyl group is preferably 1-10, more preferably 1-8, more preferably 1-7, more preferably 1-6, more preferably 1-4, more preferably 1-3.
• As the trialkylsilane compound those having 3 to 21 carbon atoms are preferred.
• Preferred trialkylsilane compounds used in the present invention include, for example, trimethylsilane, triethylsilane, triisopropylsilane, trihexylsilane (eg, tri-n-hexylsilane), and the like.
• trimethylsilane triethylsilane
• triisopropylsilane trihexylsilane (eg, tri-n-hexylsilane)
• trihexylsilane eg, tri-n-hexylsilane
• the amount of the trialkylsilane compound used in the present invention is not particularly limited, but the desired reaction rate can be obtained while avoiding the complexity of the post-treatment operation due to the excessive amount of the trialkylsilane compound. Therefore, the range of 0.5 to 10.0 mol per 1 mol 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 and particularly preferably in the range of 1.0 to 5.0 mol.
• the amount of the reaction substrate in the present invention means the amount of the one derivative when one derivative is selected as the reaction substrate in the present invention, and two or more derivatives are selected as the reaction substrate in the present invention. When used, it means the total amount of the two or more derivatives (the same applies throughout the specification).
• the solvent used in the present invention contains 40% by volume or more of a strong acid having an acid dissociation constant pKa of 1 or less.
• the pKa used in the present invention refers to the acid dissociation constant (pKa) in an aqueous solution at 25°C.
• the "strong acid having a pKa of 1 or less" in the present invention is not limited to those in a liquid state at room temperature. Or it can be used by dissolving in other solvents. Among them, it is preferable to use one that is liquid at room temperature and also serves as a solvent.
• the solvent in the present invention contains 40% by volume or more of the above strong acid.
• the solvent in the present invention may contain 60% by volume or less of a solvent other than the strong acid.
• the amount of other solvents is preferably 30% by volume or less, particularly preferably 0% by volume. That is, the solvent preferably contains 70% by volume or more of the strong acid, particularly preferably 100% by volume.
• the content of 100% by volume of the strong acid (that is, the content of other solvents other than the strong acid is 0% by volume) means that in addition to the strong acid, it inevitably enters the solvent. Note that it does not completely eliminate contamination by impurities.
• the rate of conversion to the biotin derivative (3) is improved, and the reaction can be completed in a shorter time.
• 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. Specific examples include dichloromethane, chloroform, and toluene.
• the amount of the solvent containing 40% by volume or more of a strong acid with an acid dissociation constant pKa of 1 or less is not particularly limited. at least one derivative selected from the group consisting of hydroxybiotin derivative (1) and vinylbiotin derivative (2)), for example 0.1 to 20 mL, preferably 0.5 to 10 mL, more preferably 3 mL to 1 g 7 mL.
• the amount to be used is the total amount of the mixture.
• a reaction substrate at least one derivative selected from the group consisting of hydroxybiotin derivative (1) and vinylbiotin derivative (2) in the present invention 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 (3) can be produced by contacting with a trialkylsilane compound. At this time, it is sufficient to mix the components so that they can sufficiently come into 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 oxygen and air, but also in an inert gas atmosphere such as nitrogen, argon and carbon dioxide.
• a method for mixing each component is not particularly limited. For example, all ingredients may be added to the reactor at the same time and mixed. Alternatively, one component may be mixed in advance, and the remaining components may be added and mixed. Each component can also be diluted with a solvent and supplied to a reactor or the like. Above all, in order to further reduce by-products and increase the purity of the biotin derivative (3), at least one selected from the group consisting of the hydroxybiotin derivative (1) and the vinyl biotin derivative (2) under an inert gas atmosphere.
• a strong acid having a pKa of 1 or less or a solvent containing a strong acid having a pKa of 1 or less are mixed and stirred, and then, if necessary, a trialkylsilane compound diluted with a solvent is added and stirred (mixed). preferable.
• the reaction temperature (the temperature in the reaction system after all the components are mixed) is not particularly limited, but it can usually be carried out in the range of 0 to 100°C. Among them, it is particularly preferable to carry out the reaction at 10 to 70° C. in consideration of the reaction rate, the purity of the resulting biotin derivative (3), and the like. By carrying out the reaction within this range, the reaction substrate can be efficiently converted into the biotin derivative (3) in a short period of time. Also, the reaction time is not limited, and may be appropriately determined 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 refers to the time during which the reaction substrate in the present invention, the solvent containing a strong acid with a pKa of 1 or less, and the trialkylsilane compound are mixed at the set reaction temperature.
• the reaction solution obtained in the present invention may be post-treated as appropriate.
• the crude biotin derivative (3) can be obtained by removing the solvent from the reaction solution by distillation under reduced pressure or the like.
• the biotin derivative (3) obtained in the present invention is a compound represented by the following formula (3).
• R 1 , R 2 and R 3 have the same definitions as R 1 , R 2 and R 3 in formula (1).
• Biotin derivative (3A) is a biotin derivative (3) in which both R 1 and R 2 are benzyl groups, and R 3 is —CO 2 Et (that is, R 4 is ethyl group).
• Biotin derivative (3B) is biotin derivative (3) in which both R 1 and R 2 are benzyl groups, R 3 is —CO 2 H (that is, R 4 is a hydrogen atom), and a biotin derivative ( It is a compound that can be handled as 4).
• Biotin can be easily produced from biotin derivative (3B) through a step of removing benzyl groups corresponding to R 1 and R 2 by deprotection treatment.
• R 3 is —CO 2 R 4 '
• R 4 ' is an optionally substituted alkyl group, an optionally substituted aralkyl group, or a substituent It is an aryl group that may have.
• R 4 ' has the same definition as R 4 except when R 4 is a hydrogen atom, and in R 4 , an optionally substituted alkyl group, an optionally substituted aralkyl group, and The description regarding the optionally substituted aryl group also applies to R 4 ′.
• Biotin derivative (4) is useful as a biotin precursor, and biotin can be easily produced from biotin derivative (4). Specifically, biotin can be easily produced from biotin derivative (4) through a step of removing the functional groups represented by R 1 and R 2 by deprotection treatment. In this specification, the biotin derivative (4) may be referred to as "biotin precursor (4)".
• the biotin derivative (3) is brought into contact with hydrogen halide and a phosgene compound to obtain the biotin derivative.
• the biotin derivative (4) can be produced through the hydrolysis reaction and deprotection reaction of (3).
• Hydrogen bromide for example, may be used as the hydrogen halide.
• triphosgene may be used as the phosgene compound.
• HPLC measurement conditions The analysis conditions for HPLC analysis are as follows. Apparatus: high performance liquid chromatography (HPLC) Model: 2695-2489-2998 (manufactured by Waters) Detector: UV absorption photometer (measurement wavelength: 210 nm) Column: XBridge-C18, inner diameter 4.6 mm, length 15 cm (particle size: 5 ⁇ m) (manufactured by Waters) Column temperature: 30°C (constant) Sample temperature: 25°C (constant) Mobile phase A: acetonitrile Mobile phase B: 0.25% acetic acid aqueous solution Feeding 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. Flow rate: 0.6 mL/min Measurement time: 40 minutes
• the purities of the hydroxybiotin derivative (1A), the vinylbiotin derivative (2A), and the biotin derivative (3A) were each measured under the above conditions, and the area value of all peaks (derived from the solvent is the ratio (percentage) of the peak area values of hydroxybiotin derivative (1A), vinylbiotin derivative (2A), and biotin derivative (3A) to the total of the peak areas of hydroxybiotin derivative (1A), vinylbiotin derivative (2A), and biotin derivative (3A).
• the reaction conversion rate is the ratio of the peak area value of the biotin derivative (3A) produced, the peak area value of the hydroxybiotin derivative (1A) or vinyl biotin derivative (2A), and the peak area value of the biotin derivative (3A). It is a value calculated as a percentage of the total value.
• the reaction conversion rate of the biotin derivative (3A) is the peak area value of the biotin derivative (3A) produced, the peak of the hydroxybiotin derivative (1A) It is a value calculated as a percentage of the total value of the area value and the peak area value of the biotin derivative (3A). It is a value calculated as a percentage of the peak area value of the biotin derivative (3A) calculated as a percentage of the total value of the peak area values of the vinyl biotin derivative (2A) and the biotin derivative (3A).
• Example 3 A reaction was carried out in the same manner as in Example 2, except that the vinyl biotin derivative (2A) (98.82% purity) obtained in Production Example 3 was used. Table 2 shows the results. After stirring for 5 hours at 25° C., the reaction conversion of biotin derivative (3A) was 100%.
• Example 4 A reaction was carried out in the same manner as in Example 2, except that the amount of triethylsilane used was changed to 0.39 g (3.33 mmol). Table 2 shows the results. After stirring for 5 hours at 25° C., the reaction conversion of biotin derivative (3A) was 100%.
• Example 5 A reaction was carried out in the same manner as in Example 2, except that the amount of trifluoroacetic acid used was changed to 1 mL (13.07 mmol). Table 2 shows the results. After stirring at 25° C. for 5 hours, the reaction conversion of biotin derivative (3A) was 81.2%. After a total of 24 hours with continued stirring at 25° C., the reaction conversion of the biotin derivative (3A) was 100%.
• Example 7 A reaction was carried out in the same manner as in Example 2, except that the amounts of trifluoroacetic acid and triethylsilane used and the reaction temperature were changed as shown in Table 2. Table 2 shows the results.
• Example 7 after stirring at 25° C. for 5 hours, the reaction conversion of biotin derivative (3A) was 67.2%. After a total of 24 hours with continued stirring at 25° C., the reaction conversion of the biotin derivative (3A) was 90.4%.
• Example 8 after stirring at 40° C. for 5 hours, the reaction conversion of biotin derivative (3A) was 87.1%. After a total of 24 hours with continued stirring at 40° C., the reaction conversion of the biotin derivative (3A) was 100%.

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