Method for producing hydroxythienoimidazole derivative, vinyl sulfide derivative, and saturated straight-chain hydrocarbon-substituted thienoimidazole derivative

Abstract

To provide a method for producing a hydroxythienoimidazole derivative in a high yield.SOLUTION: A thiolactone derivative, a grignard reagent and a copper salt are mixed under the presence of an amide compound to obtain a compound represented by formula (II) (wherein, R1 and R2 are each an aryl group or the like; and R3 is an alkyl group or the like). The method for producing the hydroxythienoimidazole derivative includes a step of obtaining the hydroxythienoimidazole derivative represented by general formula (1).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing hydroxythienoimidazole derivatives, vinyl sulfide derivatives, and saturated linear hydrocarbon-substituted thienoimidazole derivatives. [Background technology]

[0002] Biotin, shown below, is considered a vitamin useful in animal feed and medicine.

[0003] [ka]

[0004] Patent Document 1 introduces a prior art method for synthesizing biotin using the Grignard reagent ClMg(CH2)3OMe. Specifically, as shown below, it describes the process of adding a thiolactone compound (A) with the Grignard reagent, then hydrolyzing the resulting product to obtain intermediate (B), which is then dehydrated to obtain compound (C), which is then hydrogenated to obtain compound (D), and finally, biotin is obtained by coupling compound (D) with a malonic acid ester and deprotecting it. Note that "Bn" represents a benzyl group, and "Me" represents a methyl group.

[0005] [ka] [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2022 / 260168 Summary of the Invention [Problem to be solved by the invention]

[0007] The present inventors have proposed the following method as a method for producing hydroxythienoimidazole derivatives, which are intermediates in the production of biotin, in high yield (see Patent Document 1). Specifically, this method produces hydroxythienoimidazole derivatives by reacting a thiolactone derivative with a Grignard reagent in the presence of a copper salt. This method allows for the production of hydroxythienoimidazole derivatives in high yield. As a result, vinyl sulfide derivatives and saturated linear hydrocarbon-substituted thienoimidazole derivatives can also be produced in high yield.

[0008] However, according to the investigations of the present inventors, it has been found that in the method described in Patent Document 1, depending on the conditions, a solid content may be generated during the reaction, resulting in a decrease in yield.

[0009] Therefore, an object of the present invention is to provide a method for producing hydroxythienoimidazole derivatives, vinyl sulfide derivatives, and saturated linear hydrocarbon-substituted thienoimidazole derivatives in higher yields. [Means for solving the problem]

[0010] According to one embodiment, there is provided a method for producing a hydroxythienoimidazole derivative represented by the following formula (II), which comprises the step of mixing a thiolactone derivative represented by the following formula (I), a Grignard reagent represented by the following formula (1), and a copper salt in the presence of an amide compound to obtain the hydroxythienoimidazole derivative represented by the following formula (II).

[0011] [ka]

[0012] In formula (I), R 1 and R 2 are each independently an alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group.

[0013] [ka]

[0014] In formula (1), R 3 is an alkyl group, an alkyl group having a substituent, an aryl group, or an aryl group having a substituent. 1 is a halogen atom.

[0015] [ka]

[0016] In formula (II), R 1 and R 2 has the same meaning as in formula (I). 3 has the same meaning as in formula (1).

[0017] According to another embodiment, there is provided a method for producing a vinyl sulfide derivative represented by the following formula (III): This production method includes a step of obtaining a hydroxythienoimidazole derivative represented by the above formula (II) by the method according to the above embodiment, and a step of dehydrating the obtained hydroxythienoimidazole derivative to obtain a vinyl sulfide derivative represented by the following formula (III).

[0018] [ka]

[0019] In formula (III), R 1 and R 2 has the same meaning as in formula (I). 3 has the same meaning as in formula (1).

[0020] According to another embodiment, there is provided a method for producing a saturated linear hydrocarbon-substituted thienoimidazole derivative represented by the following formula (VI): This production method includes the steps of obtaining a vinyl sulfide derivative represented by the above formula (III) by the method according to the above embodiment, and contacting the obtained vinyl sulfide derivative with hydrogen in the presence of a catalyst to obtain the saturated linear hydrocarbon-substituted thienoimidazole derivative represented by the following formula (VI).

[0021] [ka]

[0022] In formula (VI), R 1 and R 2 has the same meaning as in formula (I). 3 has the same meaning as in formula (1). [Effects of the Invention]

[0023] According to the present invention, there is provided a method for producing hydroxythienoimidazole derivatives, vinyl sulfide derivatives, and saturated linear hydrocarbon-substituted thienoimidazole derivatives in higher yields. DETAILED DESCRIPTION OF THE INVENTION

[0024] A production method according to one embodiment includes a step of mixing a thiolactone derivative represented by the above formula (I), a Grignard reagent represented by the above formula (1), and a copper salt in the presence of an amide compound to obtain a hydroxythienoimidazole derivative represented by the above formula (II). The hydroxythienoimidazole derivative can be used, for example, as an intermediate for the synthesis of biotin and biotin derivatives.

[0025] This method allows for the production of hydroxythienoimidazole derivatives in high yield. Copper (Cu) has a high affinity for sulfur (S). Therefore, Cu in the copper salt readily coordinates with the S atom of the thiolactone derivative, thereby activating the S atom site of the thiolactone derivative. This is thought to facilitate the reaction of the Grignard reagent with the carbon atom bearing a carbonyl group adjacent to the S atom of the thiolactone derivative. This production method, compared to conventional methods that do not add copper salts, uses the minimum amount of Grignard reagent necessary, completes the reaction at low temperature and in a short time, and produces hydroxythienoimidazole derivatives in high yield without the use of expensive catalysts such as palladium catalysts. Therefore, biotin can be produced efficiently and at low cost.

[0026] In addition to mixing the copper salts described above, the present invention is characterized by mixing the components in the presence of an amide compound. The inventors' investigations revealed that, although the reason is unclear, conventional methods can sometimes produce solids during the reaction. In particular, considering industrial production, it is advantageous to increase the raw material concentration, but it was found that in such cases, solids are more likely to be produced. It was believed that these solids absorb the raw material thiolactone derivative, making it difficult to react the combined raw materials.

[0027] The present inventors have considered that if this solid content is not produced, or if it is produced, if it is dissolved, a sufficient amount of raw materials can be supplied to the reaction, and the yield can be improved. As a result, it has been found that the presence of an amide compound in the reaction system can suppress the by-production of solid content or can dissolve the solid content. Therefore, according to the present invention, the yield of the hydroxythienoimidazole derivative can be improved.

[0028] The manufacturing method according to the embodiment will be described in detail below. <Thiolactone derivative represented by formula (I)> The thiolactone derivative is represented by the following formula (I): The thiolactone derivative can be used as an intermediate for the synthesis of biotin as described above.

[0029] [ka]

[0030] In formula (I), R 1 and R 2 are each independently an alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group. 1 and R 2 R may be the same functional group or different functional groups. 1 and R 2 are each independently preferably an alkyl group having a substituent, more preferably an alkyl group having a phenyl group, and even more preferably a benzyl group.

[0031] R 1 or R 2 The alkyl group represented by R may be linear or branched. 1 or R 2 The number of carbon atoms in the alkyl group represented by the formula (I) is, for example, 1 or more and 20 or less, preferably 1 or more and 10 or less, more preferably 1 or more and 8 or less, even more preferably 1 or more and 6 or less, even more preferably 1 or more and 4 or less, even more preferably 1 or more and 3 or less, even more preferably 1 or 2, and even more preferably 1.

[0032] R 1 or R 2 The alkyl group represented by the formula (R) may have a substituent. 1 or R 2Examples of substituents that the alkyl group represented by the formula (I) may have include an aryl group having 3 to 20 carbon atoms (preferably 6 to 20, more preferably 6 to 14, and even more preferably 6 to 10), an alkoxy group having 1 to 6 carbon atoms (preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2), and a halogen atom. The aryl group may be a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon ring group. The aryl group is preferably a monocyclic group having 3 to 8 members, more preferably a phenyl group. The alkoxy group may be linear or branched. The halogen atom may be selected from a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. R 1 or R 2 The substituent that the alkyl group represented by the formula (R) may have is preferably an aryl group having 3 to 8 carbon atoms, more preferably a phenyl group. 1 or R 2 When the alkyl group represented by the formula (I) has a substituent, the number of the substituents is, for example, 1 or more and 5 or less, preferably 1 or more and 3 or less, more preferably 1 or 2, and even more preferably 1.

[0033] R 1 or R 2 The aryl group represented by R can be a monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring group. 1 or R 2 The aryl group represented by the formula (R) is preferably a monocyclic group having 3 to 8 members. 1 or R 2 The number of carbon atoms in the aryl group represented by R is, for example, 3 or more and 30 or less, preferably 3 or more and 20 or less, more preferably 6 or more and 20 or less, even more preferably 6 or more and 14 or less, and even more preferably 6 or more and 10 or less. 1 or R 2 The aryl group represented by the formula (I) is preferably a phenyl group.

[0034] R 1 or R 2 The aryl group represented by R may have a substituent. 1 or R 2Examples of the substituent that the aryl group represented by the formula (I) may have include an alkyl group having 1 to 6 carbon atoms (preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2), an alkoxy group having 1 to 6 carbon atoms (preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2), a carboxyl group, a halogen atom, and the like. The alkyl group and the alkoxy group may be linear or branched. The halogen atom may be selected from a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. R 1 or R 2 When the aryl group represented by the formula (I) has a substituent, the number of the substituents is, for example, 1 or more and 5 or less, preferably 1 or more and 3 or less, more preferably 1 or 2, and even more preferably 1. <First Grignard Reagent> The first Grignard reagent is represented by the following formula (1).

[0035] [ka]

[0036] In formula (1), R 3 R is an alkyl group, an alkyl group having a substituent, an aryl group, or an aryl group having a substituent. 1 or R 2 The above explanations regarding the alkyl group, the alkyl group having a substituent, the aryl group, and the aryl group having a substituent, represented by R 3 This also applies to alkyl groups, alkyl groups having a substituent, aryl groups, and aryl groups having a substituent, represented by the formula: R 3 Examples of the alkyl group, the alkyl group having a substituent, the aryl group, and the aryl group having a substituent, represented by the formula: 1 and R 2 The same as those listed in R 3 is preferably an alkyl group having 1 to 6 carbon atoms, and more preferably a methyl group or an ethyl group.

[0037] X 1is a halogen atom. The halogen atom can be selected from a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and is preferably a chlorine atom or a bromine atom.

[0038] The first Grignard reagent can be obtained, for example, by contacting an organic halogen derivative represented by the following formula (1a) with magnesium.

[0039] [ka]

[0040] In the above formula (1a), R 3 and X 1 has the same meaning as in formula (1).

[0041] As the magnesium, elemental magnesium is used, and the magnesium may be in the form of a powder or strips.

[0042] The contact temperature between the organic halogen derivative represented by the formula (1a) and magnesium is, for example, 40° C. or higher and 150° C. or lower, preferably 60° C. or higher and 100° C. The contact time between the organic halogen derivative represented by the formula (1a) and magnesium is, for example, 10 minutes or higher and 10 hours or lower, preferably 30 minutes or higher and 5 hours or lower, and more preferably 1 hour or higher and 5 hours or lower.

[0043] The amount of the organic halogen derivative represented by formula (1a) relative to 1 mole of magnesium is, for example, 0.1 mole or more and 2 moles or less, preferably 0.5 mole or more and 1.5 moles or less.

[0044] The contact of the organic halogen derivative represented by the formula (1a) with magnesium is preferably carried out in the presence of a magnesium activator. For example, at least one selected from the group consisting of 1,2-dibromoethane, bromine, iodine, and trimethylsilyl chloride can be used as the magnesium activator. The amount of the magnesium activator per mole of magnesium is, for example, 0.01 to 1.5 moles, preferably 0.02 to 0.8 moles, more preferably 0.02 to 0.5 moles, and even more preferably 0.2 to 0.5 moles.

[0045] The contact of the organic halogen derivative represented by formula (1a) with magnesium is preferably carried out in the presence of a first reaction solvent. Examples of the first reaction solvent include acetonitrile, propionitrile, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, diisopropyl ether, dimethyloxyethane, diglyme, acetone, methyl ethyl ketone, diethyl ketone, methyl acetate, ethyl acetate, butyl acetate, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, toluene, xylene, hexane, and heptane. Among these, it is preferable to use at least one solvent selected from the group consisting of THF, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, diisopropyl ether, dimethyloxyethane, and diglyme. Furthermore, it is more preferable to use at least one selected from the group consisting of THF, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, and diisopropyl ether.

[0046] The amount of the first reaction solvent used in the production of the first Grignard reagent is, for example, 0.001 mL or more and 10 mL or less, and preferably 0.01 mL or more and 1 mL or less, relative to 1 mg of magnesium.

[0047] When using the first reaction solvent, it is preferable to prepare the first Grignard reagent by the following method. First, an organohalogen derivative represented by formula (1a) is mixed with half of the first reaction solvent to prepare an organohalogen derivative solution. Next, magnesium, a magnesium activator, and half of the first reaction solvent are mixed to obtain a first mixture. The organohalogen derivative solution is added dropwise to this first mixture to obtain a second mixture. The second mixture is heated to the above-mentioned contact temperature and then stirred for the above-mentioned contact time to obtain the first Grignard reagent.

[0048] <Copper salts> The valence of the copper atom contained in the copper salt is preferably monovalent or divalent, and more preferably monovalent. As the copper salt, for example, at least one selected from copper chloride (I) (CuCl), copper chloride (II) (CuCl2), copper bromide (I) (CuBr), copper bromide (II) (CuBr2), copper cyanide (I) (CuCN), copper 3-methylsalicylate (I), mesitylene copper (I) (MesCu), isopropoxy copper (I) (iPrOCu), copper iodide (I) (CuI), copper iodide (II) (CuI2), copper acetate (I) (CuOAc), copper acetate (II) (Cu(OAc)2), copper sulfate (II) (CuSO4), copper oxide (I) (Cu2O), copper oxide (II) (CuO), copper pivalate (CuOPiv), copper pivalate (II) (Cu(OPiv)2), and sulfur-containing copper salts can be used. As the sulfur-containing copper salt, copper(I) thiophene-2-carboxylate is preferably used. Among copper salts in which the copper atom has a valence of one, CuCl, CuI, or CuBr is particularly preferred.

[0049] <Amide compounds> The greatest feature of the present invention is that a hydroxythienoimidazole derivative represented by the above formula (II) is produced by mixing a thiolactone derivative represented by the above formula (I), a Grignard reagent represented by the above formula (1), and a copper salt in the presence of an amide compound.

[0050] The amide compound is a compound having an amide bond (-(C=O)-N=). There are no particular limitations on the amide compound, and any amide compound may be used as long as it does not adversely affect the production of a hydroxythienoimidazole derivative. Among them, it is preferable to use at least one selected from dimethylformamide (DMF), dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), N,N'-dimethylpropyleneurea (DMPU), and hexaphosphoric acid triamide (HMPA). It is even more preferable to use at least one selected from dimethylformamide (DMF), dimethylacetamide (DMA), and N-methyl-2-pyrrolidone (NMP). These amide compounds are in the form of a solution and are easy to handle.

[0051] <Method for producing a hydroxythienoimidazole derivative represented by formula (II)> A method for producing a hydroxythienoimidazole derivative represented by formula (II) comprises the step of mixing a thiolactone derivative represented by formula (I), a first Grignard reagent, and a copper salt in the presence of an amide compound.

[0052] When a thiolactone derivative represented by formula (I) and a Grignard reagent represented by formula (1) are mixed in the presence of a copper salt, an addition reaction proceeds to produce an intermediate represented by formula (Ia). The presence of an amide compound in this reaction can suppress the production of solid by-products. Even if solids are produced, they can be dissolved, preventing them from forming lumps.

[0053] [ka]

[0054] Next, the intermediate represented by formula (Ia) is hydrolyzed to obtain the hydroxythienoimidazole derivative represented by formula (II). This hydrolysis reaction can be carried out by treating with water or an acid. Examples of the acid include at least one selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, paratoluenesulfonic acid, formic acid, acetic acid, propionic acid, ammonium chloride, silica gel, and the like. Liquid acids such as formic acid, acetic acid, sulfuric acid, and phosphoric acid, or aqueous solutions thereof, are preferred. The amount of water or acid used is not particularly limited, as long as it is sufficient to promote hydrolysis. Specifically, considering operability and the like, the amount of acid or aqueous acid used relative to the thiolactone derivative is preferably 0.1 to 20 moles per mole of the thiolactone derivative. When an acid is used, the preferred amount is the amount of the acid itself. For example, when an aqueous solution of hydrochloric acid is used, the amount is the amount of hydrogen chloride itself. When 10% by mass of hydrochloric acid is used, the amount of hydrogen chloride contained is preferably 0.1 mole or more and 20 moles or less per mole of the thiolactone derivative.

[0055] The hydrolysis of this intermediate can be advanced to a dehydration reaction by adding an excess amount of acid, and can also be converted into a vinyl sulfide derivative represented by the above formula (III).

[0056] The amount of copper salt used is preferably 0.05 mol or more and 1 mol or less relative to 1 mol of the first Grignard reagent, more preferably 0.5 mol or more and 0.8 mol or less, and even more preferably 0.6 mol or more and 0.72 mol or less relative to 1 mol of the first Grignard reagent.

[0057] The amount of copper salt used is usually 0.1 to 10 moles, preferably 0.5 to 5 moles, more preferably 0.5 to 2 moles, per mole of the thiolactone derivative.

[0058] The amount of the first Grignard reagent used is usually 0.5 to 10 moles, preferably 1.0 to 5 moles, more preferably 1.0 to 2.0 moles, per mole of the thiolactone derivative.

[0059] The amount of the amide compound used is preferably 0.10 mL to 2 mL, more preferably 0.15 mL to 1.5 mL, per 1 g of the thiolactone derivative. By satisfying this range, the generation of solids can be more effectively suppressed or the solids can be more effectively dissolved.

[0060] The mixing of the thiolactone derivative, the first Grignard reagent, and the copper salt in the presence of the amide compound may be carried out in the presence of a second reaction solvent. The second reaction solvent may be, for example, at least one selected from tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, diglyme, methylene chloride, toluene, xylene, hexane, heptane, etc. The second reaction solvent may be used alone or in combination with two or more solvents to form a mixed solvent. The second reaction solvent is preferably THF, toluene, or a mixed solvent thereof.

[0061] The amount of the second reaction solvent used is, for example, 1 mL to 100 mL, preferably 2 mL to 50 mL, per 1 g of the thiolactone derivative. In particular, in the present invention, the amount of the second reaction solvent used is preferably 2 mL to 35 mL, more preferably 2 mL to 30 mL, and even more preferably 2 mL to 20 mL. A smaller amount of reaction solvent is often advantageous in industrial production. According to the inventors' investigations, although the reason is unclear, it has been found that as the concentration of the thiolactone derivative increases, the reaction system tends to become cloudy and ultimately form clumps of solid matter. It is believed that the amide compound acts to suppress the generation of such solid matter or dissolve the solid matter. Therefore, the production method of the present invention is more suitable for industrial production.

[0062] The temperature at which the thiolactone derivative, the first Grignard reagent, and the copper salt are mixed in the presence of the amide compound is, for example, within a range of −40° C. to 100° C. The temperature at which the mixture is mixed is preferably within a range of −20° C. to 40° C., more preferably within a range of −10° C. to 20° C. Within this temperature range, the yield of the hydroxythienoimidazole derivative tends to be higher.

[0063] The time for mixing the thiolactone derivative, the first Grignard reagent, and the copper salt in the presence of the amide compound is usually from 0.5 hours to 72 hours, preferably from 0.5 hours to 48 hours, and more preferably from 1 hour to 48 hours. This mixing time is the time after all of the components have been mixed.

[0064] The method for making the amide compound present is not particularly limited, as long as it is present when the thiolactone derivative, the first Grignard reagent, and the copper salt are mixed. For example, the amide compound, the thiolactone derivative, the first Grignard reagent, and the copper salt may be simultaneously fed into a reaction apparatus and mixed. Alternatively, the thiolactone derivative, the first Grignard reagent, and the copper salt may be mixed in advance, and then the amide compound may be mixed. Furthermore, the thiolactone derivative and the amide compound may be mixed in advance, and then the first Grignard reagent and the copper salt may be mixed with the mixture.

[0065] <Mixing and contacting methods for efficient use of copper salts> As described above, the method for mixing the thiolactone derivative, the first Grignard reagent, and the copper salt in the presence of the amide compound is not particularly limited. In particular, when it is desired to ensure that the copper salt acts in the reaction, the method is preferably as follows.

[0066] First, a first Grignard reagent and a copper salt are mixed to obtain an organocopper reagent. The first Grignard reagent may be a first Grignard reagent solution prepared by dissolving the first Grignard reagent in the first or second reaction solvent. The copper salt may be a copper salt solution prepared by dissolving a copper salt in the second reaction solvent. The mixing temperature of the first Grignard reagent and the copper salt may be within the range of the mixing temperatures of the thiolactone derivative, the first Grignard reagent, and the copper salt. The mixing time of the first Grignard reagent and the copper salt is, for example, from 1 minute to 1 hour.

[0067] In this organocopper reagent, the first Grignard reagent and the copper salt are thought to form a copper complex represented by the following formula (3).

[0068] [ka]

[0069] In equation (3), R 3 and X 1has the same meaning as in formula (1). Y represents an anion of a copper salt. m and n are each an integer of 1 or more and 3 or less.

[0070] Next, this organocopper reagent is contacted with the thiolactone derivative represented by formula (I). Preparing the organocopper reagent in advance allows for efficient use of copper salts. In the present invention, the amide compound may be present when the organocopper reagent is contacted with the thiolactone derivative represented by formula (I).

[0071] The thiolactone derivative represented by formula (I) may be used as a solution of the thiolactone derivative dissolved in the second reaction solvent. Furthermore, in order to minimize the generation of solids, it is preferable to add an amide compound to the second reaction solution in which the thiolactone derivative is dissolved.

[0072] The contact temperature of the organocopper reagent and the thiolactone derivative in the presence of the amide compound may be within the range of the mixing temperature of the thiolactone derivative, the first Grignard reagent, and the copper salt. The contact time of the organocopper reagent and the thiolactone derivative in the presence of the amide compound may be within the range of the mixing time of the thiolactone derivative, the first Grignard reagent, and the copper salt. <Mixing and contacting method to simplify the process> In the present invention, the presence of an amide compound in the reaction system allows the concentration of the thiolactone derivative to be relatively high. The presence of the amide compound can suppress or eliminate the generation of solids during the reaction, which is thought to enable more uniform mixing within the reaction system. Therefore, the following mixing and contacting methods can be employed.

[0073] Specifically, this method involves mixing a first Grignard reagent with a mixture of a thiolactone derivative, a copper salt, and an amide compound. The procedure for premixing the three components of the thiolactone derivative, the copper salt, and the amide compound is not particularly limited, and the three components may be mixed simultaneously, or two components may be premixed and then the other component may be added.

[0074] By preliminarily allowing the thiolactone derivative, copper salt, and amide compound to coexist, it is believed that the generation of solids can be suppressed from the initial stage when the first Grignard reagent is mixed, allowing the reaction to proceed in a more uniform state. Therefore, it is believed that the effect of the copper salt can be fully exerted even without first forming the organocopper reagent before mixing with the thiolactone derivative. In other words, by proceeding with the reaction in the presence of the amide compound, it is believed that the reaction can proceed sufficiently even without handling the organocopper salt reagent in a formed state. In this respect, the process can be simplified. However, as described above, it is assumed that the reaction is driven by the organocopper salt reagent.

[0075] When a thiolactone derivative, an amide compound, and a copper salt are present together, the temperature at which this mixture is mixed with the first Grignard reagent and the copper salt may be within the range of the mixing temperatures for the thiolactone derivative, the first Grignard reagent, and the copper salt. The contact time may also be within the range of the mixing time for the thiolactone derivative, the first Grignard reagent, and the copper salt. This contact / mixing time is measured after all components have been mixed.

[0076] <Hydroxythienoimidazole derivative represented by formula (II)> The hydroxythienoimidazole derivative is represented by the following formula (II): The hydroxythienoimidazole derivative can be used as an intermediate for the synthesis of biotin as described above.

[0077] [ka]

[0078] In formula (II), R 1 and R 2 has the same meaning as in formula (I). 3 has the same meaning as in formula (1).

[0079] The hydroxythienoimidazole derivative is derivatized to biotin by a known method.

[0080] For example, first, a hydroxythienoimidazole derivative represented by formula (II) is dehydrated to obtain a vinyl sulfide derivative represented by the following formula (III).

[0081] [ka]

[0082] In formula (III), R 1 and R 2 has the same meaning as in formula (I). 3 has the same meaning as in formula (1).

[0083] Examples of methods for dehydrating a hydroxythienoimidazole derivative include acid treatment and heat treatment. This dehydration method can be carried out by temporarily removing the hydroxythienoimidazole derivative from the reaction system. To simplify the process, it is preferable to carry out the acid treatment or heat treatment without removing the hydroxythienoimidazole derivative from the reaction system.

[0084] The acid treatment involves contacting the hydroxythienoimidazole derivative represented by formula (II) with an acid. Examples of the acid catalyst include formic acid, acetic acid, sulfuric acid, hydrochloric acid, and mixtures thereof. The amount of acid is preferably 0.1 to 20 moles, more preferably 0.1 to 10 moles, per mole of the thiolactone derivative.

[0085] The temperature of the heat treatment is, for example, from −20° C. to 120° C., preferably from 0° C. to 70° C., and more preferably from 20° C. to 70° C. The acid treatment and the heat treatment may be combined.

[0086] Next, the vinyl sulfide derivative represented by formula (III) is hydrogenated, for example, in the presence of a Pd catalyst, to obtain a compound represented by formula (VI). The resulting compound represented by formula (VI) is reacted with hydrogen bromide to obtain a compound represented by formula (VIII). The resulting compound is then reacted with diethyl malonate to obtain a compound represented by formula (XI). The resulting compound is debenzylated and then treated with, for example, hydrogen bromide to obtain biotin. Note that "Et" represents an ethyl group.

[0087] [ka]

[0088] <Saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (VI)> The saturated straight-chain hydrocarbon-substituted thienoimidazole derivative is represented by the following formula (VI): The saturated straight-chain hydrocarbon-substituted thienoimidazole derivative can be used as an intermediate for the synthesis of biotin as described above.

[0089] [ka]

[0090] In formula (VI), R 1 and R 2 has the same meaning as in formula (I). 3 has the same meaning as in formula (1).

[0091] This saturated linear hydrocarbon-substituted thienoimidazole derivative can be obtained, for example, by contacting the vinyl sulfide derivative represented by formula (III) obtained by the method according to the above embodiment with hydrogen (H) in the presence of a catalyst.

[0092] Examples of the catalyst that can be used include platinum catalysts such as platinum on carbon and platinum oxide; palladium catalysts such as palladium black, palladium on carbon, palladium acetate, palladium chloride and palladium oxide; nickel catalysts such as Raney nickel, cobalt catalysts such as Raney cobalt, ruthenium catalysts such as ruthenium chloride, iridium catalysts such as iridium chloride, and iron catalysts such as iron powder. At least one of Raney nickel and palladium on carbon is preferred.

[0093] The amount of the catalyst is, for example, 0.001 mol % or more and 1000 mol % or less, and preferably 0.1 mol % or more and 800 mol % or less, relative to the vinyl sulfide derivative as the substrate.

[0094] When the vinyl sulfide derivative represented by formula (III) is contacted with hydrogen in the presence of a catalyst, the hydrogen pressure is, for example, from 1 to 150 atmospheres, and preferably from 1 to 50 atmospheres.

[0095] When the vinyl sulfide derivative represented by formula (III) is contacted with hydrogen in the presence of a catalyst, the contact temperature is, for example, 10°C or higher and 200°C or lower, and preferably 25°C or higher and 150°C or lower.

[0096] When the vinyl sulfide derivative represented by formula (III) is contacted with hydrogen in the presence of a catalyst, the contact time is, for example, from 0.5 hours to 100 hours, and preferably from 1 hour to 72 hours.

[0097] The contact of the vinyl sulfide derivative represented by formula (III) with hydrogen in the presence of a catalyst may be carried out in the presence of a solvent. Examples of the solvent that can be used include methanol, ethanol, isopropanol, butanol, 2-butanol, ethylene glycol, 1,2-dimethoxyethane, methyl cellosolve, ethyl acetate, methyl acetate, THF, cyclopentyl methyl ether, 1,4-dioxane, acetic acid, water, and mixtures thereof. Preferably, methanol or a mixture of methanol and water is used.

[0098] The amount of solvent used is, for example, 1 mL or more and 200 mL or less, and preferably 3 mL or more and 100 mL or less, per 1 g of the vinyl sulfide derivative as the substrate. [Example]

[0099] The present invention will be described in detail below with reference to examples, but these are merely specific examples and the present invention is not limited to these examples. <Reference example 1> As shown in the following reaction scheme, a compound represented by formula (III') was obtained from a compound represented by formula (I'), where "Bn" represents a benzyl group and "Me" represents a methyl group.

[0100] [ka]

[0101] (Preparation of the first Grignard reagent) First, the first Grignard reagent was prepared as follows: Under a nitrogen atmosphere, the first reaction solvent THF (31 mL) and iodine (0.08 equivalents, 0.44 g) were added to Mg (0.76 g, 31.40 mmol, 1.42 equivalents), and then 1-chloro-3-methoxypropane (3.13 g, 28.81 mmol, 1.30 equivalents) was slowly added dropwise thereto, followed by stirring at 70°C for 1 hour.

[0102] (Production of hydroxythienoimidazole derivatives) Under a nitrogen atmosphere, the THF solution of the first Grignard reagent obtained above was added dropwise to a solution of the thiolactone derivative (I') (7.5 g, 22.2 mmol) and CuCl (1.91 g, 19.3 mmol, 0.87 equivalents) in the second reaction solvent THF (41 mL) at 0°C, followed by stirring at 0°C for 1 hour. The reaction solution was analyzed by high-performance liquid chromatography (HPLC) to confirm the completion of the reaction (the compound represented by formula (II') was produced). Note that a white mass was observed in the resulting reaction solution.

[0103] The NMR results of the compound represented by formula (II') (hydroxythienoimidazole derivative (II')) were as follows. 1 H NMR (400MHz, CDCl3, 30℃) δ 7.35-7.22(m,10H),5.16-5.10(m,1H),4.86-4.78(m,1H),4.43(s,1H),4.17-3.96(m,3H),3.67(d d,J=15.7,9.3Hz,1H),3.61-3.32(m,5H),3.04-2.77(m,2H),2.38-2.31(m,1H),2.01-1.67(m,3H).

[0104] (Production of vinyl sulfide derivatives) Under a nitrogen atmosphere, formic acid (7.5 mL, 1 v / w) was added to the reaction solution at 0°C, and the mixture was stirred at 60°C for 1 hour. Toluene (38 mL, 5 v / w) and 30 wt% aqueous ammonium chloride solution (23 mL, 3 v / w) were then added, and the resulting insoluble matter was filtered off, after which the aqueous and organic layers were separated. The organic layer was further washed with 10 wt% aqueous HCl solution (23 mL, 3 v / w) and 10 wt% saline solution (23 mL, 3 v / w), and concentrated to obtain the vinyl sulfide derivative (III'). The yield determined by high-performance liquid chromatography (HPLC) was 98%. The residual percentage of the thiolactone derivative after the reaction was 2.5%. The residual rate of the thiolactone derivative after the reaction is calculated by dividing the peak area of ​​the remaining thiolactone derivative in HPLC by the sum of the peak area of ​​the thiolactone derivative (I') used as the raw material and the peak area of ​​the hydroxythienoimidazole derivative (II') used as the raw material, and multiplying the result by 100.

[0105] The residual ratio of the thiolactone derivative after the reaction is determined by quantifying the weight of the remaining thiolactone derivative by HPLC and dividing the weight by the weight of the thiolactone derivative used in the reaction.

[0106] The NMR results of the compound represented by formula (III') (vinyl sulfide derivative (III')) were as follows. 1 H NMR (400MHz, CDCl3, 30℃) δ 7.36-7.27(m,10H),5.51(t,J=7.0Hz,1H),4.93(d,J=15.6Hz,1H),4.79(d,J=15.3Hz,1H),4.30(d,J=7.7Hz,1H),4.23 (d,J=15.3Hz,1H),4.10-4.04(m,2H),3.36(dt,J=12.9,2.1Hz,2H),3.32(s,3H),3.00-2.92(m,2H),2.41-2.23(m,2H).

[0107] Example 1 The same procedure as in Reference Example 1 (production of hydroxythienoimidazole derivative) was carried out, except that NMP (10 mL) was added to a THF solution of thiolactone derivative (I') and CuCl to carry out the reaction.

[0108] In the production of the hydroxythienoimidazole derivative, no white lumps were observed in the final reaction solution. The NMR results of the obtained hydroxythienoimidazole derivative (II') were the same as those of Reference Example 1.

[0109] After the production of the vinyl sulfide derivative (III'), the residual ratio of the thiolactone derivative was 0.25%. The yield determined by liquid chromatography (HPLC) was 99%. The results are shown in Table 1. The NMR results of the obtained vinyl sulfide derivative (III') were the same as those of Reference Example 1.

[0110] <Example 2> The same procedure as in Reference Example 1 (production of hydroxythienoimidazole derivative) was carried out, except that DMA (10 mL) was added to a THF solution of thiolactone derivative (I') and CuCl to carry out the reaction.

[0111] In the production of the hydroxythienoimidazole derivative, the reaction solution finally obtained was slightly cloudy. NMR results of the obtained hydroxythienoimidazole derivative (II') were the same as those of Reference Example 1.

[0112] After the production of the vinyl sulfide derivative (III'), the residual ratio of the thiolactone derivative was 0.96%. The yield determined by liquid chromatography (HPLC) was 98%. The results are shown in Table 1. The NMR results of the obtained vinyl sulfide derivative (III') were the same as those of Reference Example 1.

[0113] Example 3 The same procedure as in Reference Example 1 (production of hydroxythienoimidazole derivative) was carried out, except that DMA (5 mL) was added to a THF solution of thiolactone derivative (I') and CuCl to carry out the reaction.

[0114] In the production of the hydroxythienoimidazole derivative, no white lumps were observed in the final reaction solution. The NMR results of the obtained hydroxythienoimidazole derivative (II') were the same as those of Reference Example 1.

[0115] After the production of the vinyl sulfide derivative (III'), the residual ratio of the thiolactone derivative was 0.36%. The yield determined by liquid chromatography (HPLC) was 99%. The results are shown in Table 1. The NMR results of the obtained vinyl sulfide derivative (III') were the same as those of Reference Example 1.

[0116] Example 4 The same procedure as in Reference Example 1 (production of hydroxythienoimidazole derivative) was carried out, except that DMA (2.5 mL) was added to a THF solution of thiolactone derivative (I') and CuCl to carry out the reaction.

[0117] In the production of the hydroxythienoimidazole derivative, no white lumps were observed in the final reaction solution. The NMR results of the obtained hydroxythienoimidazole derivative (II') were the same as those of Reference Example 1.

[0118] After the production of the vinyl sulfide derivative (III'), the residual ratio of the thiolactone derivative was 0.40%. The yield determined by liquid chromatography (HPLC) was 99%. The results are shown in Table 1. The NMR results of the obtained vinyl sulfide derivative (III') were the same as those of Reference Example 1.

[0119] [Table 1]

[0120] <Example 5> As shown in the reaction formula below, a compound represented by formula (VI') was obtained from a compound represented by formula (III'). Note that "Bn" represents a benzyl group, and "Me" represents a methyl group. The reaction was carried out using the vinyl sulfide derivative (III') obtained in Example 1.

[0121] [ka]

[0122] Raney nickel (92.5% by mass in water, 100 mg, 1.58 mmol, 6.7 equivalents) was quickly weighed into an autoclave glass test tube and methanol (5.00 mL) was added. A methanol solution (5.00 mL) of the compound represented by formula (III') (92.6 mg, 0.235 mmol, 1.0 equivalent) was added, and the mixture was stirred at 40°C under 20 atm of hydrogen pressure for 20 hours. The reaction mixture was analyzed by thin-layer chromatography (TLC) to confirm the completion of the reaction. A 1:1 volumetric mixture of ethyl acetate and n-hexane was used as the developing solvent. The Rf value of the compound represented by formula (VI') was 0.51. After cooling with ice and opening to the atmosphere, the Raney nickel was removed by Celite filtration (ethyl acetate, 5 mL x 4), taking care not to dry it out. The organic layer was washed with 1 M aqueous HCl (20 mL x 3) and brine (5 mL x 1) and then dried over Na2SO4. The solvent was distilled off to obtain the compound represented by formula (VI') in an amount of 90.8 mg and a yield of 97%. Only a trace amount of the compound represented by formula (III') was contained. The NMR analysis results of the compound represented by formula (VI') were as follows: 1 H NMR (400 MHz, CDCl3, 30°C) δ 7.34-7.24(m,10H),5.10(d,J=15.2Hz,1H),4.75(d,J=15.1Hz,1H),4.14(d,J=15.2Hz,1H),3.99-3.95(m,2H),3.87(dd,J=9.5,5.6Hz ,1H),3.43-3.35(m,2H),3.34(s,3H),3.335-3.25(m,1H),3.17-3.11(m,1H),2.77-2.66(m,1H),1.90-1.74(m,2H),1.61-1.45(m,2H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 HRMS (FAB + ) m / z calcd. for C 23 H 29N2O2S 397.1950 ([M+H] + ) found 397.1946。

Claims

1. In the presence of an amide compound, The following formula (I): 【Chemistry 1】 [In the formula, R １ and R ２ are each independently an alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group. a thiolactone derivative represented by The following formula (1): 【Chemistry 2】 [In the formula, R ３ is an alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group, and X １ is a halogen atom. Grignard reagents represented by Copper salts to mix the compounds of the following formula (II): 【Transformation 3】 [In the formula, R １ and R ２ has the same meaning as in formula (I), and R ３ has the same meaning as in the formula (1). A method for producing a hydroxythienoimidazole derivative, comprising the step of obtaining a hydroxythienoimidazole derivative represented by the formula:

2. 2. The method for producing a hydroxythienoimidazole derivative according to claim 1, wherein the amide compound is at least one selected from the group consisting of dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, N,N'-dimethylpropyleneurea, and hexaphosphoric acid triamide.

3. 3. The method for producing a hydroxythienoimidazole derivative according to claim 1, wherein the amount of the amide compound used is 0.15 mL to 1.5 mL relative to the amount of the thiolactone derivative.

4. 3. The method for producing a hydroxythienoimidazole derivative according to claim 1, wherein the amount of the copper salt relative to 1 mole of the Grignard reagent represented by formula (1) is 0.05 moles or more and 1 mole or less.

5. Obtaining the hydroxythienoimidazole derivative by the method according to claim 1 or 2; The hydroxythienoimidazole derivative is dehydrated to obtain a compound of the following formula (III): 【Chemistry 4】 [In the formula, R １ and R ２ has the same meaning as in formula (I), and R ３ has the same meaning as in formula (1). and obtaining a vinyl sulfide derivative represented by A method for producing a vinyl sulfide derivative, comprising:

6. Obtaining the vinyl sulfide derivative by the method of claim 5; The vinyl sulfide derivative is contacted with hydrogen in the presence of a catalyst to produce a compound represented by the following formula (VI): 【Transformation 5】 [In the formula, R １ and R ２ has the same meaning as in formula (I), and R ３ has the same meaning as in formula (1). and obtaining a saturated linear hydrocarbon-substituted thienoimidazole derivative represented by A method for producing a saturated linear hydrocarbon-substituted thienoimidazole derivative, comprising:

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