Method for producing biotin intermediates

Abstract

This invention provides a method for efficiently obtaining biotin intermediates. [Solution] A method for producing a biotin intermediate, comprising contacting a saturated linear hydrocarbon-substituted thienoimidazole derivative with hydrogen bromide to obtain a mixed solution containing the biotin intermediate of formula (1), and then mixing it with a solvent containing an alcohol or water having 3 or more carbon atoms to precipitate the intermediate of formula (1). TIFF2026167474000013.tif59170 (R 1 , and R 2 Each of these is independently an optionally substituted alkyl group, an optionally substituted aralkyl group, or an optionally substituted aryl group.

Description

Technical Field

[0001] The present invention relates to a method for producing a biotin intermediate.

Background Art

[0002] Biotin represented below is considered a type of vitamin useful as an animal feed or pharmaceutical product.

[0003]

Chemical Formula

[0004] Various methods have been proposed as industrial production methods for biotin. For example, a method via a "biotin intermediate" represented by the following formula is known. Patent Document 1 introduces a synthesis method of the "biotin intermediate" as the prior art. Specifically, as shown below, first, a thiolactone compound (A) and a Grignard reagent are subjected to an addition reaction. Next, the compound (B) obtained by hydrolyzing the product is dehydrated to obtain a compound (C). Then, this compound (C) is hydrogenated to obtain a compound (D). Finally, it is known that a biotin intermediate is obtained by subjecting this compound (D) to a cyclization reaction using hydrobromic acid. Patent Document 2 describes a method for producing a biotin intermediate from the compound (D) using hydrobromic acid. In addition, "Bn" represents a benzyl group, and "Me" represents a methyl group.

[0005]

Chemical Formula

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Summary of Invention

[0007] As a method for producing a biotin intermediate, a method is disclosed in which the aforementioned compound (D) is brought into contact with hydrobromic acid, then the reaction solution is concentrated under reduced pressure, and subsequently 2-propanol is added to the residue for crystallization (Patent Document 1).

[0008] However, according to studies by the present inventors, in the method described in Patent Document 1, it is necessary to remove hydrobromic acid which is difficult to remove by concentration under reduced pressure, and improvements were required when large-scale industrial production is considered. Further, for the intended use of the finally obtained biotin, development of a method capable of obtaining a biotin intermediate with higher HPLC purity (hereinafter, references to purity and high purity shall mean HPLC purity) has been desired.

[0009] Further, Patent Document 2 describes a method of precipitating a biotin intermediate by adding methyl isobutyl ketone and water to the reaction solution, and adjusting the pH of the solution with an aqueous sodium hydroxide solution.

[0010] However, there are problems such as complicated post-treatment due to pH adjustment, risk of heat generation and explosion by mixing a strong acid with methyl isobutyl ketone at high temperature, and the high price of methyl isobutyl ketone itself, leaving room for improvement in view of industrial production.

[0011] Accordingly, an object of the present invention is to provide a method that can be easily implemented even on an industrial scale. In particular, it is an object of the present invention to provide a method for producing a biotin intermediate with high yield and high purity by a simple and low-cost process. MEANS FOR SOLVING THE PROBLEMS

[0012] According to one embodiment, a method for producing a biotin intermediate represented by the following formula (1) is provided. This production method includes a first step of contacting a saturated linear hydrocarbon-substituted thienoimidazole derivative represented by the following formula (2) with hydrogen bromide in a first solvent containing water to obtain a mixed solution containing the biotin intermediate represented by the following formula (1), and a second step of mixing the mixed solution with an alcohol having 3 or more carbon atoms or a second solvent containing water, and then precipitating the biotin intermediate represented by the following formula (1) in a mixture of the mixed solution and the second solvent.

[0013] Furthermore, in order to obtain a biotin intermediate of higher purity, the process includes a third step of washing with at least one solvent selected from the group consisting of alcohol solvents, ketone solvents, and water.

[0014] [ka]

[0015] In the above formula (1), R 1 , and R 2 Each of these is independently an optionally substituted alkyl group, an optionally substituted aralkyl group, or an optionally substituted aryl group.

[0016] [ka]

[0017] In the above equation (2), R 1 , and R 2 This is equivalent to the one in formula (1) above, R 3 This is an alkyl group which may have substituents. [Effects of the Invention]

[0018] The method of the present invention provides a method for producing biotin intermediates in high yield, which can be easily implemented even on an industrial scale. MODE FOR CARRYING OUT THE INVENTION

[0019] A production method according to one embodiment includes a first step of bringing a saturated linear hydrocarbon-substituted thienoimidazole derivative represented by the following formula (2) into contact with hydrogen bromide in a first solvent containing water to obtain a mixed solution containing a biotin intermediate represented by the following formula (1), and a second step of mixing the mixed solution with an alcohol having 3 or more carbon atoms or a second solvent containing water, and then precipitating the biotin intermediate represented by the following formula (1) in the mixed liquid of the mixed solution and the second solvent.

[0020] According to this method, the biotin intermediate represented by the following formula (1) can be obtained in a high yield. That is, after the saturated linear hydrocarbon-substituted thienoimidazole derivative is brought into contact with hydrobromic acid, the reaction solution is not concentrated under reduced pressure, so that the number of steps can be reduced, and the biotin intermediate with high yield and high purity can be obtained. Therefore, the biotin intermediate can be produced efficiently at low cost.

[0021] Hereinafter, the production method according to the embodiment will be described in detail.

[0022] <Biotin intermediate represented by formula (1)> The biotin intermediate is a compound represented by the following formula (1).

[0023] [Chemical Formula]

[0024] In the above formula (1), R 1 and R 2 are each independently 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 1 and R 2 may be the same functional group as each other, or may be different types of functional groups from each other. R 1 and R 2Each of these groups is preferably an alkyl group having a substituent, more preferably an alkyl group having a phenyl group, and even more preferably a benzyl group.

[0025] 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 is, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 8, even more preferably 1 to 6, even more preferably 1 to 4, even more preferably 1 to 3, even more preferably 1 or 2, and even more preferably 1.

[0026] R 1 or R 2 The alkyl group represented by may have substituents. 1 or R 2 Substituents that the alkyl group represented by may have include, for example, aryl groups having 3 to 20 carbon atoms (preferably 6 to 20, more preferably 6 to 14, and even more preferably 6 to 10), alkoxy groups having 1 to 6 carbon atoms (preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2), halogen atoms, etc. The aryl group may be a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon ring group. The aryl group is preferably a monocyclic ring with 3 to 8 members, and more preferably a phenyl group. The alkoxy group may be linear or branched. The halogen atom can be selected from fluorine, chlorine, bromine, and iodine atoms. 1 or R 2 The substituents that the alkyl group represented by may have are preferably aryl groups having 3 to 8 carbon atoms, and more preferably phenyl groups. 1 or R 2 When the alkyl group represented by has substituents, the number of substituents is, for example, 1 to 5, preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

[0027] 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 is preferably a monocyclic ring with 3 to 8 members. 1 or R 2 The number of carbon atoms in the aryl group represented by is, for example, 3 to 30, preferably 3 to 20, more preferably 6 to 20, even more preferably 6 to 14, and even more preferably 6 to 10. 1 or R 2 The aryl group represented is preferably a phenyl group.

[0028] R 1 or R 2 The aryl group represented by may have substituents. 1 or R 2 Substituents that the aryl group represented by can have include, for example, alkyl groups having 1 to 6 carbon atoms (preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2), alkoxy groups having 1 to 6 carbon atoms (preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2), carboxyl groups, halogen atoms, and the like. The alkyl groups and alkoxy groups may be linear or branched. The halogen atom can be selected from fluorine, chlorine, bromine, and iodine atoms. 1 or R 2 When the aryl group represented by has substituents, the number of substituents is, for example, 1 to 5, preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

[0029] <Saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (2)> Saturated linear hydrocarbon-substituted thienoimidazole derivatives are compounds represented by the following formula (2).

[0030] [ka]

[0031] In equation (2), R 1 , and R 2 This is equivalent to the one in formula (1) above, R 3 R is an alkyl group which may have substituents. 1 or R 2 The above description of alkyl groups that may have substituents, represented by R 3 This also applies to alkyl groups having substituents, represented by R. 3 The alkyl group that may have substituents, represented by R, is 1 and R 2 The same things as those listed above can be cited. 3 It is preferably an alkyl group having 1 to 6 carbon atoms, and more preferably a methyl group or an ethyl group.

[0032] The saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (2) is not particularly limited, but one with a purity of 80% or higher as determined by HPLC can be used. Even if a saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (2) with low purity as determined by HPLC is used, a high-purity biotin intermediate can be produced according to the present invention. Specifically, even if the purity as determined by HPLC is 80% or higher but less than 90%, it can be suitably handled.

[0033] <First step> In the first step, the contact between the saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (2) and hydrogen bromide is carried out in a first solvent containing water.

[0034] The first solvent may include a solvent other than water, such as an organic solvent. While not particularly limited, examples of organic solvents include methanol, ethanol, acetone, tetrahydrofuran (THF), toluene, and acetic acid. These may be included individually or in combination of two or more. Of the organic solvents, methanol and ethanol are preferred, with methanol being more preferred. These organic solvents may be organic solvents that inevitably remain after the production of the saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (2).

[0035] In particular, the first solvent is preferably substantially water, from the viewpoint of being inexpensive and being able to increase the hydrogen bromide concentration. Therefore, even if the first solvent contains an organic solvent, the amount of the organic solvent is preferably 5% by mass or less, more preferably 3% by mass or less, and preferably 1% by mass or less. The lower limit of the organic solvent is 0% by mass.

[0036] The amount of the first solvent containing water used is preferably 0.3 ml to 3 ml, and more preferably 0.5 ml to 1.5 ml, per 1 g of the saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (2). If the amount of the first solvent used is within the above range, the saturated linear hydrocarbon-substituted thienoimidazole derivative can be sufficiently dispersed in the first solvent.

[0037] In the present invention, a saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (2) is brought into contact with hydrogen bromide in the first solvent. Hydrogen bromide can be used by blowing hydrogen bromide gas into the first solvent. Alternatively, hydrobromic acid, which is an aqueous solution, may be used as at least a part of the first solvent. It is preferable to include hydrobromic acid in the first solvent or to use it as the first solvent because it is easy to handle. When using hydrobromic acid, the concentration of hydrogen bromide is usually 45% by mass or more and 60% by mass or less, and it may be used as is. Of course, hydrogen bromide gas and hydrobromic acid can be used individually, but they can also be used in combination.

[0038] The amount of hydrogen bromide used is preferably 1.5 moles to 11 moles, more preferably 2.0 moles to 10.0 moles, and particularly preferably 2.5 moles to 8.0 moles, per mole of the saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (2). The above amount of hydrogen bromide is particularly suitable when hydrobromic acid is used. When hydrogen bromide gas is used, the number of moles of hydrogen bromide refers to the total number of moles of hydrogen bromide supplied until the reaction is completed. When hydrobromic acid is used, it refers to the number of moles of hydrogen bromide contained in the hydrobromic acid used in the reaction. When both are used, it refers to the number of moles of hydrogen bromide present in the reaction system until the reaction is completed.

[0039] As described above, in order to simplify the procedure, it is preferable to use a solvent containing hydrobromic acid, and more preferably hydrobromic acid itself, as the first solvent. In this case, the resulting biotin intermediate represented by formula (1) dissolves in hydrobromic acid.

[0040] When using hydrobromic acid, the concentration of hydrobromic acid is preferably in the range of 1% by mass or more and 60% by mass or less. If the concentration of hydrobromic acid is too low, the amount of hydrobromic acid used for the saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (2) becomes too large, which tends to complicate solvent treatment and other processes. For this reason, it is preferably in the range of 20% by mass or more and 60% by mass or less, and more preferably in the range of 45% by mass or more and 60% by mass or less. If the concentration of hydrobromic acid is 45% by mass or more and 60% by mass or less, it is preferable to use 0.5 ml or more and 3.0 ml or less per 1 g of the saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (2), and more preferably 0.5 ml or more and 2.0 ml or less. By using amounts within this range, the biotin intermediate represented by formula (1) can be efficiently produced while reducing the amount of solvent.

[0041] In the first step, raw material compounds that are inevitably mixed into the saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (2) may be included, specifically compounds such as compounds (A), (B), and (C) described in the prior art. However, even if they are included, it is preferable that the amount of these raw material compounds is 0 parts by mass or more and 5 parts by mass or less, and more preferably 0 parts by mass or more and 2 parts by mass or less, when the amount of the biotin intermediate represented by formula (1) produced is 100 parts by mass. Even if an amount of raw material compounds of this magnitude is included, it does not affect the purification of the biotin intermediate represented by formula (1).

[0042] Known methods can be used to contact the saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (2) with hydrogen bromide. For example, one method can be used in which the saturated linear hydrocarbon-substituted thienoimidazole derivative is dispersed in a first solvent while stirring, and then hydrogen bromide gas is supplied to it. When using hydrobromic acid, the saturated linear hydrocarbon-substituted thienoimidazole derivative and hydrobromic acid (the same solvent as a first solvent containing water mixed with hydrogen bromide) can be mixed and stirred to bring the two into contact.

[0043] The temperature at which the saturated linear hydrocarbon-substituted thienoimidazole derivative is brought into contact with hydrogen bromide is not particularly limited. Considering operability and reaction time, the contact temperature is preferably 30°C or higher and below the reflux temperature, specifically 30°C to 110°C, and more preferably 60°C to 100°C. In particular, when a second solvent containing an alcohol with 3 or more carbon atoms is used in the second step, the contact temperature is more preferably 60°C to 90°C.

[0044] Furthermore, if a second solvent containing water is used in the second step described below, the contact temperature can be set to 80°C or higher and below the reflux temperature, specifically, 80°C or higher and 110°C or lower.

[0045] The temperature at contact can be determined by checking the temperature of the first solvent (mixed solution) in which each component is dissolved.

[0046] The contact time between the saturated linear hydrocarbon-substituted thienoimidazole derivative and hydrogen bromide should be determined while confirming the production ratio of the biotin intermediate represented by formula (1). Specifically, within the aforementioned temperature range, the contact time is 0.5 hours to 24 hours, preferably 0.5 hours to 16 hours, and more preferably 0.5 hours to 8 hours. This mixing time is the time from when all components have been mixed.

[0047] Under the conditions described above, a mixed solution containing the biotin intermediate represented by formula (1) can be produced by contacting a saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (2) with hydrogen bromide in a first solvent. Next, a second step of precipitating the biotin intermediate from this mixed solution will be described.

[0048] <Second process> In the present invention, the second step is to precipitate the biotin intermediate represented by formula (1) by mixing the mixed solution obtained in the first step with a second solvent containing an alcohol having 3 or more carbon atoms, or water. At this time, the mixed solution can be concentrated by reducing the pressure of the first solvent to the extent that the effects of the present invention are not hindered, but considering ease of operation, it is preferable to mix the second solvent without concentrating the first solvent of the mixed solution.

[0049] In this invention, the second step includes cases in which an alcohol having 3 or more carbon atoms is used, and cases in which water is used. Since the crystallization behavior and operability differ when using an alcohol having 3 or more carbon atoms and when using water, the optimal conditions differ depending on the purpose. This invention takes advantage of the advantages of both. Both methods can increase yield and purity compared to the conventional technique, but when operability is more important, it is preferable to use an alcohol having 3 or more carbon atoms as the second solvent. On the other hand, when an even greater improvement in yield is desired, it is preferable to use water as the second solvent.

[0050] In this second step, the optimal conditions differ depending on whether a second solvent containing an alcohol with 3 or more carbon atoms is used or water is used, as described above. These conditions are explained below.

[0051] First, we will explain the conditions under which a second solvent containing an alcohol with 3 or more carbon atoms is used.

[0052] <Second step: Method using a second solvent containing an alcohol with 3 or more carbon atoms> The second solvent to be mixed with the mixed solution is a solvent containing an alcohol with 3 or more carbon atoms. Using an alcohol with 2 or fewer carbon atoms is undesirable because it reduces the yield of the resulting biotin intermediate. As the alcohol with 3 or more carbon atoms, at least one selected from, for example, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, tert-butyl alcohol, etc., can be used. Among these, 2-propanol is preferred as the alcohol with 3 or more carbon atoms, considering the improvement of the yield of the resulting biotin intermediate and ease of handling.

[0053] The second solvent may contain alcohols with 3 or more carbon atoms, as well as other organic solvents, water, etc. In particular, considering the yield and purity of the biotin intermediate obtained, the amount of other organic solvents, water, etc. in the second solvent is preferably 5% by mass or less, more preferably 3% by mass or less, and even more preferably 1% by mass or less. Considering the yield, it is most preferable that the second solvent consists only of alcohols with 3 or more carbon atoms (100% by mass). Especially considering operability, when using alcohols with 3 or more carbon atoms as the second solvent, it is preferable to use only alcohols with 3 or more carbon atoms.

[0054] The amount of the second solvent containing an alcohol with 3 or more carbon atoms used is not particularly limited. In particular, considering the purity and yield of the resulting biotin intermediate, it is preferable to use 5 ml to 30 ml of the alcohol with 3 or more carbon atoms in the second solvent per 1 ml of water in the first solvent, more preferably 5 ml to 20 ml, and even more preferably 10 ml to 20 ml.

[0055] Furthermore, when using hydrobromic acid with a hydrogen bromide concentration of 45% by mass or more and 60% by mass or less in the first step, it is preferable to use 3 ml to 30 ml of the alcohol with 3 or more carbon atoms contained in the second solvent per 1 ml of hydrobromic acid, more preferably 5 ml to 20 ml, and even more preferably 7 ml to 15 ml. When using hydrobromic acid with a hydrogen bromide concentration of 45% by mass or more and 60% by mass or less, by using the amount of alcohol with 3 or more carbon atoms contained in the second solvent within the above range, an economical and highly pure biotin intermediate can be obtained.

[0056] The method for mixing the mixed solution obtained in the first step with the second solvent containing an alcohol with 3 or more carbon atoms is not particularly limited, and known methods can be used. To mix the mixed solution and the second solution in a container, for example, the second solvent may be added to the mixed solution and mixed, or vice versa. Alternatively, both may be added to the reaction vessel and mixed simultaneously. It is preferable to stir the mixture during mixing.

[0057] The mixing temperature of the mixed solution and the second solvent containing an alcohol with 3 or more carbon atoms is not particularly limited, but is preferably 0°C or higher and below the boiling temperature of the mixed solution (below the reflux temperature), more preferably 0°C to 90°C, even more preferably 20°C to 90°C, and particularly preferably 40°C to 85°C. Alternatively, the temperature at the time of mixing the mixed solution and the second solvent containing an alcohol with 3 or more carbon atoms can be reduced to the following cooling temperature while adding the second solvent to the mixed solution.

[0058] Furthermore, after mixing within the above temperature range, it is preferable to cool the resulting mixture (a mixture of the mixed solution and the second solvent) to the following temperature range. Specifically, it is preferable to precipitate the biotin intermediate represented by formula (1) in the mixture within a temperature range of 0°C to 60°C, preferably 0°C to 50°C, and even more preferably 0°C to 30°C. In addition, to facilitate operation, the biotin intermediate can also be precipitated within a temperature range of 20°C to 50°C. Furthermore, the biotin intermediate may be added as a seed crystal during precipitation.

[0059] It is preferable to stir the mixture obtained in this temperature range for 0.1 hours to 5 hours, preferably 0.5 hours to 5 hours, and more preferably 0.5 hours to 2 hours. After stirring for this time range, a highly pure biotin intermediate can be obtained by removing the precipitated solid.

[0060] <Second step: Method using a second solvent containing water> The second solvent mixed with the mixed solution is a water-containing solvent. By lowering the concentration of hydrobromic acid (hydrogen bromide) with water, the biotin intermediate can be precipitated and recovered in high yield. Furthermore, the biotin intermediate can be obtained in high purity while maintaining the yield through the post-treatment steps described below.

[0061] When using alcohols with 3 or more carbon atoms, dilution with a large amount of alcohol with 3 or more carbon atoms can improve operability and the yield of the biotin intermediate. Conversely, when using water as the second solvent, the yield of the biotin intermediate can be increased while maintaining the same ease of operation as when using alcohols with 3 or more carbon atoms, where the biotin intermediate is obtained by filtration.

[0062] The second solvent containing water may also contain alcohols having 3 or more carbon atoms and other organic solvents. In particular, considering the yield and purity of the resulting biotin intermediate, the amount of alcohols having 3 or more carbon atoms and other organic solvents in the second solvent containing water is preferably 20% by mass or less, more preferably 15% by mass or less, and even more preferably 10% by mass or less. Considering the yield and purity, it is most preferable that the second solvent be water only (100% by mass).

[0063] The amount of water used in the second solvent is not particularly limited. In particular, when using hydrobromic acid with a hydrogen bromide concentration of 45% to 60% by mass, it is preferable to use 0.5 ml to 5 ml of water contained in the second solvent per 1 ml of hydrobromic acid, more preferably 1 ml to 3 ml, and even more preferably 1.5 ml to 2 ml, considering the purity and yield of the resulting biotin intermediate. When using hydrobromic acid with a hydrogen bromide concentration of 45% to 60% by mass, using the amount of water contained in the second solvent within the above range makes it possible to obtain an economical and highly pure biotin intermediate.

[0064] The method for mixing the mixed solution obtained in the first step with the second solvent containing water is not particularly limited, and known methods can be used. Specifically, a method similar to the mixing method used when a second solvent containing an alcohol with 3 or more carbon atoms is used can be employed. A similar method can also be used as a preferred method.

[0065] The mixing temperature of the mixed solution and the second solvent containing water is not particularly limited, but is preferably 0°C or higher and below the boiling temperature of the mixed solution (below the reflux temperature), more preferably 0°C to 100°C, even more preferably 50°C to 100°C, and particularly preferably 80°C to 100°C. Furthermore, the temperature at the time of mixing the mixed solution and the second solvent containing water can be reduced to the following cooling temperature while adding the second solvent to the mixed solution.

[0066] Furthermore, after mixing within the above temperature range, it is preferable to cool the resulting mixture (a mixture of the mixed solution and the second solvent) to the following temperature range. Specifically, it is preferable to age the biotin intermediate represented by formula (1) in the mixture within a temperature range of 0°C to 60°C, preferably 0°C to 50°C, and even more preferably 0°C to 30°C. Furthermore, it is preferable to separate the biotin intermediate from the water as much as possible by filtration. For this reason, it is preferable to set the temperature when precipitating the biotin intermediate within a temperature range of 0°C to 2.5°C. The biotin intermediate may be added as a seed crystal when precipitating.

[0067] It is preferable to stir the mixture obtained in this temperature range for 0.1 hours to 5 hours, preferably 0.5 hours to 5 hours, and more preferably 0.5 hours to 2 hours. After stirring for this time range, a highly pure biotin intermediate can be obtained by removing the precipitated solid.

[0068] <Method for separating and processing biotin intermediates> The biotin intermediate precipitated in the mixture in the second step can be separated by known methods such as filtration and centrifugation. A preferred method is to set the temperature of the mixture to 0°C or higher and 10°C or lower, and separate the biotin intermediate crystals by filtration. A biotin intermediate of sufficiently high purity can be obtained even after this second step, but to obtain a biotin intermediate of even higher purity, it is preferable to carry out the third step detailed below.

[0069] The separated biotin intermediate can also be washed in a third step by contacting it with at least one solvent selected from the group consisting of alcohol solvents, ketone solvents, and water. Washing can further increase its purity.

[0070] <Third step> In the third step, the crystalline (solid) biotin intermediate can be washed by contacting it with at least one solvent selected from the group consisting of alcohol solvents, ketone solvents, and water. Specifically, the solvents used for this washing include methanol, ethanol, and the aforementioned alcohols having 3 or more carbon atoms as alcohol solvents. Examples of ketone solvents include acetone and methyl isobutyl ketone. These solvents can also be used in various combinations.

[0071] This washing should be continued until a biotin intermediate of the desired purity is obtained, and the number of washes, the duration, the amount of solvent used for washing, and the contact temperature should be determined accordingly.

[0072] In particular, considering ease of operation and cost-effectiveness, the amount of solvent used is preferably 0.5 ml to 10 ml per gram of biotin intermediate to be washed, and more preferably 1 ml to 5 ml.

[0073] The washing temperature (the temperature of the solvent at the time of contact between the solvent used for washing and the biotin intermediate) is not particularly limited, but it is preferably between 0°C and 30°C. The washing time (the contact time between the solvent and the biotin intermediate) is also not particularly limited and should be carried out within a range that is feasible for the operation, and is usually between 0.1 minutes and 5 hours, and preferably between 0.5 minutes and 5 hours. During this time, stirring may also be performed. The number of washes can be determined as appropriate, and is usually between 1 and 10 times.

[0074] <Third step: A combination of water washing and other solvent washing> To obtain a biotin intermediate in high yield and with high purity, it is preferable to first contact the biotin intermediate with water, and then wash the obtained biotin intermediate by contacting it with at least one solvent selected from the group consisting of alcohol solvents, ketone solvents, and water. In other words, it is preferable to first use water as the washing solution, and then contact it with at least one solvent selected from the group consisting of alcohol solvents, ketone solvents, and water. The number of washes, the duration, the amount of solvent used for washing, and the temperature at contact should be appropriately determined to obtain the desired biotin intermediate.

[0075] To improve operability and efficiently obtain a high-purity biotin intermediate in high yield, it is preferable to employ the following method.

[0076] Specifically, it is preferable to use 0.5 ml to 5 ml of water for washing per 1 g of the target biotin intermediate. It is preferable to keep the temperature during washing (the temperature of the water in contact with the biotin intermediate) between 0°C and 10°C, and allow the biotin intermediate to come into contact with the water for 0.1 minutes to 5 hours. The contact with water can be repeated. Stirring can also be done during contact.

[0077] Next, after filtering out the water, 1 g of the target biotin intermediate is washed by contacting it with at least one solvent selected from the group consisting of alcohol solvents, ketone solvents, and water. The at least one solvent selected from the group consisting of alcohol, ketone, and water may be a single solvent or a mixed solvent. When water is used, the process is the same as when washing multiple times with water. When a mixed solvent is used, the mixing ratio may be changed as appropriate depending on the impurities to be removed. In particular, it is preferable to use 0.5 ml to 5 ml of at least one solvent selected from the group consisting of alcohol solvents, ketone solvents, and water for washing per 1 g of the target biotin intermediate. It is preferable to keep the biotin intermediate in contact with the solvent for 0.5 minutes to 5 hours at a washing temperature (temperature of the solvent in contact with the biotin intermediate) of 0°C to 30°C. The contact with the solvent can be repeated. Stirring can also be performed during contact.

[0078] The biotin intermediate after the third step can be filtered to remove the solvent and dried by a known method.

[0079] The biotin intermediate obtained by the method of the present invention can have a high-performance liquid chromatography (HPLC) purity of 99% or higher, and a residual palladium (Pd) content of 0.2 ppm or less. However, to further increase the purity, purification by recrystallization can also be performed. [Examples]

[0080] The present invention will be described in detail below with reference to examples, but these are just examples and the present invention is not limited thereto.

[0081] <Manufacturing Example 1> As shown in the reaction equation below, the compound represented by saturated linear hydrocarbon-substituted thienoimidazole derivative (2') was obtained from the thiolactone derivative (I). Note that "Bn" represents a benzyl group and "Me" represents a methyl group.

[0082] [ka]

[0083] (Preparation of the first Grignard reagent) First, the first Grignard reagent was prepared using the following method: Magnesium (Mg) (0.76 g, 31.40 mmol, 1.42 equivalents) was mixed with THF (31 ml) and iodine (0.08 equivalents, 0.44 g) as the first reaction solvent. Then, 1-chloro-3-methoxypropane (3.13 g, 28.81 mmol, 1.30 equivalents) was slowly added dropwise, and the mixture was stirred at 70°C for 1 hour. In this way, the THF solution of the first Grignard reagent was prepared.

[0084] (Production of hydroxythienoimidazole derivatives) A second solution was prepared by adding thiolactone derivative (I) (7.5 g, 22.2 mmol) and copper(I) chloride (CuCl) (1.91 g, 19.3 mmol, 0.87 equivalents) prepared by a known method to THF (41 ml), which was the second reaction solvent. The THF solution of the first Grignard reagent obtained by the above method was added dropwise to the second solution at 0°C, and the mixture was stirred at 0°C for 1 hour. The resulting reaction solution was measured by high-performance liquid chromatography (HPLC) to confirm the completion of the reaction, and a reaction solution containing hydroxythienoimidazole derivative (II) was obtained.

[0085] The NMR results for the hydroxythienoimidazole derivative (II) were as follows.

[0086] 1 H NMR (400MHz, CDCl3, 25℃) 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).

[0087] (Manufacturing of vinyl sulfide derivatives) Formic acid (7.5 ml) was added to the reaction solution at 0°C, and the mixture was stirred at 60°C for 1 hour. Next, toluene (38 ml) and a 30% by mass aqueous solution of ammonium chloride (23 ml) were added, and the resulting insoluble matter was filtered out, after which the aqueous layer and organic layer were separated. The organic layer was further washed with a 10% by mass aqueous solution of HCl (23 ml) and a 10% by mass saline solution (23 ml), and concentrated to obtain vinyl sulfide derivative (III). The yield determined by liquid chromatography (HPLC) was 98%. The residual rate of the thiolactone derivative after the reaction was 2.5%.

[0088] The residual rate of the thiolactone derivative after the reaction is calculated by dividing the peak area value of the remaining thiolactone derivative in HPLC by the sum of the peak area values ​​of the thiolactone derivative (I) used as a starting material and the starting material and peak area values ​​of the hydroxythienoimidazole derivative (II), and multiplying the result by 100.

[0089] The residual rate of the thiolactone derivative after the reaction is determined by quantifying the weight of the remaining thiolactone derivative by HPLC and dividing it by the weight of the thiolactone derivative used in the reaction.

[0090] The NMR results for vinyl sulfide derivative (III) were as follows.

[0091] 1 H NMR (400MHz, CDCl3, 25℃) 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).

[0092] (Preparation of saturated linear hydrocarbon-substituted thienoimidazole derivatives (2')) A methanol solution of vinyl sulfide derivative (III) (29.65 g) was mixed with 50% by mass of hydrated palladium carbon (3 g) and heated at 110°C and 0.6 MPa. After the reaction was complete, the palladium carbon was filtered, and the filtrate was concentrated to obtain saturated linear hydrocarbon-substituted thienoimidazole derivative (2') as an oily compound (26.5 g, 90%).

[0093] The NMR analysis results for the saturated linear hydrocarbon-substituted thienoimidazole derivative (2') are as follows.

[0094] 1 H NMR (400 MHz, CDCl3, 25℃) 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 (100MHz, CDCl3, 30℃) δ 161.1,137.1,137.0,128.8,128.80,128.4,127.8,72.2,62.7,61.3,58.7,54.2,47.9,46.8,34.9,29.2,25.6; HRMS (FAB + ) m / z calcd. for C 23 H 29 N2O2S 397.1950 ([M+H] + ) Found 397.1946.

[0095] <Example 1> (Production of biotin intermediate (1')) To the saturated linear hydrocarbon-substituted thienoimidazole derivative (2') (15.0 g, 37.8 mmol, 1 equivalent) obtained by the above method, a 48% by mass HBr aqueous solution (hydrobromide) (23 ml (17.7 g water), 201.9 mmol, 5.3 equivalents of hydrogen bromide) was added, and the reaction was carried out for 2 hours while heating at 85°C.

[0096] After confirming the completion of the reaction by HPLC (completion of step one), 150 ml of 2-propanol was added to the mixture without concentrating it, while maintaining the temperature of the mixed solution at 80°C (step two). After adding 2-propanol, the temperature was cooled to room temperature (23°C), and a solid precipitated. The precipitated solid was collected, and the solid was washed by contacting it with 30 ml of 2-propanol at 20°C (2 ml of 2-propanol per 1 g of the target biotin intermediate (1')) for 0.5 minutes (step three). By drying the obtained solid, the biotin intermediate (1') was obtained as a white solid (13.6 g, 86%). The yield, purity, and residual Pd content of the obtained biotin intermediate (1') were summarized. The results are shown in Table 1.

[0097] [ka]

[0098] The NMR analysis results for the biotin intermediate (1') were as follows.

[0099] 1 H NMR (600 MHz, CD3OD,25℃) δ 7.36-7.22(m,10H),4.87(d,J=15.0Hz,1H),4.67(d,J=15.0Hz,1H),4.61(dt,J=7.8Hz,J=6.0Hz,1H),4.48(dd,J=8.1Hz,J=7.8Hz,1H),4.29(d,J= 15.0Hz,1H),4.23-4.20(m,1H),4.17(d,J=15.0Hz,1H),3.82(m,1H),3.5 9-3.52(m,2H),3.29-3.28(m,1H),2.31-2.19(m,2H),2.17-2.08(m,2H). <Example 2> In Example 1 described above, the first and second steps were carried out in the same manner as in Example 1, except that 5 g (12.6 mmol, 1 equivalent) of saturated linear hydrocarbon-substituted thienoimidazole derivative (2') was used, 10 ml of 48% HBr aqueous solution (7.7 g water, 87.8 mmol, 7 equivalents) was used, and 100 ml of 2-propanol was used. In addition, the same procedure as in Example 1 was performed using 10 ml of 2-propanol to obtain biotin intermediate (1') as a white solid. The results are shown in Table 1.

[0100] <Example 3> In Example 1 described above, the first and second steps were carried out in the same manner as in Example 1, except that 5 g (12.6 mmol, 1 equivalent) of saturated linear hydrocarbon-substituted thienoimidazole derivative (2') was used, 5 ml of 48% HBr aqueous solution (3.85 g of water, 43.9 mmol, 3.5 equivalents of hydrogen bromide) was used, and 50 ml of 2-propanol was used. In addition, the same procedure as in Example 1 was performed using 10 ml of 2-propanol to obtain biotin intermediate (1') as a white solid. The results are shown in Table 1.

[0101] <Example 4> In Example 1 described above, the first and second steps were carried out in the same manner as in Example 1, except that 5 g (12.6 mmol, 1 equivalent) of saturated linear hydrocarbon-substituted thienoimidazole derivative (2') was used, 7.5 ml of 48% HBr aqueous solution (5.77 ml of water, 65.9 mmol, 5.2 equivalents of hydrogen bromide) was used, and 100 ml of 2-propanol was used. In addition, the same procedure as in Example 1 was performed using 10 ml of 2-propanol to obtain biotin intermediate (1') as a white solid. The results are shown in Table 1.

[0102] <Comparative Example 1> In the first step of Example 1 described above, 5 g (12.6 mmol, 1 equivalent) of saturated linear hydrocarbon-substituted thienoimidazole derivative (2') was used, along with 10 ml of a 48% by mass HBr aqueous solution (7.7 g of water, 87.8 mmol, 7 equivalents of hydrogen bromide). Next, the resulting mixed solution was concentrated, and then 35 ml of 2-propanol was added to obtain biotin intermediate (1') as a white solid. The precipitated solid was collected, and the solid was washed by contacting it with 10 ml of 2-propanol at 20°C (2 ml of 2-propanol per 1 g of the target biotin intermediate (1')) for 0.5 minutes. The results for the obtained biotin intermediate (1') are shown in Table 1.

[0103] <Comparative Example 2> In the first step of Example 1 described above, 5 g (12.6 mmol, 1 equivalent) of saturated linear hydrocarbon-substituted thienoimidazole derivative (2') was used, and 10 ml of 48% by mass HBr aqueous solution (7.7 g water, 87.8 mmol hydrogen bromide, 7 equivalents) was used. Next, the resulting mixed solution was concentrated, and then 40 ml of 2-propanol and 4 ml of water were added to obtain biotin intermediate (1') as a white solid. The precipitated solid was collected, and the solid was washed by contacting it with 10 ml of 2-propanol at 20°C (10 ml of 2-propanol per 1 g of the target biotin intermediate (1')) for 0.5 minutes. The results for the obtained biotin intermediate (1') are shown in Table 1.

[0104] [Table 1]

[0105] As is clear from Table 1, Examples 1 to 4, in which the post-reaction concentration step was eliminated, showed yields and HPLC purity at or above the level of Comparative Examples 1 and 2. Reducing the number of steps and shortening the manufacturing time offers significant cost advantages.

[0106] Example 5 (An example in which a second solvent containing water was used, and washing with water was performed in the third step) To the saturated linear hydrocarbon thienoimidazole derivative (2') (2g, 4.4 mmol, 1 equivalent) prepared in the manufacturing example, 1.9 ml of 48% by mass HBr aqueous solution (hydrobromide acid) (1.5 g of water, 17 mmol, 3.4 equivalents of hydrogen bromide) was added, and the reaction was carried out for 2 hours while heating at 100°C.

[0107] After confirming the completion of the reaction by HPLC (completion of step one), water (4 ml) was added to the mixed solution without concentrating it, while maintaining the temperature of the mixed solution at 90°C, and a solid precipitated immediately (step two). The water temperature was cooled to 20°C, and after stirring overnight, the precipitated solid was filtered off.

[0108] Subsequently, as a third step, water (8 ml; 4 ml per 1 g of the target biotin intermediate (1')) was mixed with the mixture at a water temperature of 5°C for 0.5 minutes to wash the solid, thereby finally obtaining the biotin intermediate (1') as a white solid (1.9 g, yield 98%, HPLC purity 94%).

[0109] Example 5-1 (Third step: Water / acetone used) The biotin intermediate (1') obtained in Example 5 (HPLC purity 94%, 0.4 g, 0.88 mmol) was washed with 2 ml of acetone at 5°C for 2 hours. The HPLC purity of the biotin intermediate (1') after washing was 99.3%. The yield, purity, and residual Pd content of the final obtained biotin intermediate (1') were summarized. The results are shown in Table 2.

[0110] Example 5-2 (Third step: 10% by mass aqueous solution of water / acetone used) The biotin intermediate (1') obtained in Example 5 (HPLC purity 94%, 0.4 g, 0.88 mmol) was washed with a 10% by mass aqueous solution of acetone at 5°C for 2 hours. The HPLC purity of the biotin intermediate (1') after washing was 95.7%. The yield, purity, and residual Pd content of the final obtained biotin intermediate (1') were summarized. The results are shown in Table 2.

[0111] Example 5-3 (Third step: Water / 2-propanol used) The biotin intermediate (1') obtained in Example 5 (HPLC purity 94%, 0.4 g, 0.88 mmol) was washed with 2 ml of 2-propanol at 5°C for 2 hours. The HPLC purity of the biotin intermediate (1') after washing was 99.3%. The yield, purity, and residual Pd content of the final obtained biotin intermediate (1') were summarized. The results are shown in Table 2.

[0112] Example 6 (An example in which a second solvent containing water was used, and the third step involved sequential washing with water and 2-propanol) To the saturated linear hydrocarbon thienoimidazole derivative (2') (10 g, 22.7 mmol, 1 equivalent) prepared in the manufacturing example, 9 ml of 48% HBr aqueous solution (hydrobromide) (7.0 g water, 80 mmol, 3.2 equivalents of hydrogen bromide) was added, and the reaction was carried out for 2 hours while heating at 100°C.

[0113] After confirming the completion of the reaction by HPLC (completion of step one), water (20 ml) was added to the mixed solution without concentrating it, while maintaining the temperature of the mixed solution at 90°C, and a solid precipitated immediately (second step). The water temperature was cooled to 20°C, and after stirring overnight, the precipitated solid was collected to obtain the biotin intermediate (1') as a white solid.

[0114] Next, the biotin intermediate (1') was washed with 20 ml of water (2 ml of water per 1 g of the target biotin intermediate (1')) at a water temperature of 5°C for 0.5 minutes. Then, the target biotin intermediate (1') was washed with 30 ml of 2-propanol (3 ml of 2-propanol per 1 g of the target biotin intermediate (1')) at a 2-propanol temperature of 0°C for 0.5 minutes (third step).

[0115] The HPLC purity of the biotin intermediate (1') after washing was 99.7%. The yield, purity, and residual Pd content of the final biotin intermediate (1') were summarized. The results are shown in Table 2.

[0116] Example 7 (An example in which a second solvent containing water was used, and the third step involved sequential washing with water and acetone.) To the saturated linear hydrocarbon thienoimidazole derivative (2') (10 g, 22.7 mmol, 1 equivalent) prepared in the manufacturing example, 9 ml of 48% HBr aqueous solution (hydrobromide) (7.0 g water, 80 mmol, 3.2 equivalents of hydrogen bromide) was added, and the reaction was carried out for 2 hours while heating at 100°C.

[0117] After confirming the completion of the reaction by HPLC (completion of step one), water (20 ml) was added to the mixed solution without concentrating it, while maintaining the temperature of the mixed solution at 90°C, and a solid precipitated immediately (second step). The water temperature was cooled to 20°C, and after stirring overnight, the precipitated solid was collected to obtain the biotin intermediate (1') as a white solid.

[0118] Next, the biotin intermediate (1') was washed with 20 ml of water (2 ml of water per 1 g of the target biotin intermediate (1')) at a water temperature of 5°C for 0.5 minutes. The target biotin intermediate (1') was then washed with 30 ml of acetone (3 ml of acetone per 1 g of the target biotin intermediate (1')) at a acetone temperature of 0°C for 0.5 minutes.

[0119] The HPLC purity of the biotin intermediate (1') after washing was 99.3%. The yield, purity, and residual Pd content of the final biotin intermediate (1') were summarized. The results are shown in Table 2.

[0120] [Table 2]

Claims

1. A method for producing a biotin intermediate represented by the following formula (1), A first step involves contacting a saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (2) below with hydrogen bromide in a first solvent containing water to obtain a mixed solution containing a biotin intermediate represented by formula (1) below, and The second step involves mixing the aforementioned mixed solution with a second solvent containing an alcohol with 3 or more carbon atoms, or water, and then precipitating the biotin intermediate represented by the following formula (1) in the mixture of the mixed solution and the second solvent. A method for producing biotin intermediates containing; 【Chemistry 1】 In the above formula (1), R １ , and R ２ Each of these is independently an optionally substituted alkyl group, an optionally substituted aralkyl group, or an optionally substituted aryl group. 【Chemistry 2】 In the above formula (2), R １ , and R ２ This is equivalent to the one in formula (1) above, R ３ This is an alkyl group which may have substituents.

2. In the first step, a mixed solution containing a biotin intermediate represented by formula (1) is obtained by mixing a saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (2) with hydrobromic acid. For 1 g of the saturated linear hydrocarbon-substituted thienoimidazole derivative, use 0.5 ml to 3.0 ml of the hydrobromic acid. The method for producing a biotin intermediate according to claim 1, characterized in that, in the second step, the second solvent contains an alcohol having 3 or more carbon atoms, and 3 ml to 30 ml of the second solvent is used per 1 ml of hydrobromic acid.

3. In the first step, a mixed solution containing a biotin intermediate represented by formula (1) is obtained by mixing a saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (2) with hydrobromic acid. For 1 g of the saturated linear hydrocarbon-substituted thienoimidazole derivative, use 0.3 ml to 2.0 ml of the hydrobromic acid. The method for producing a biotin intermediate according to claim 1, characterized in that, in the second step, the second solvent contains water, and 0.5 ml to 3 ml of the second solvent is used per 1 ml of hydrobromic acid.

4. The method for producing a biotin intermediate according to claim 1, characterized in that in the first step, 1.5 moles or more and 11 moles or less of hydrogen bromide are used per mole of 1 mole of the saturated linear hydrocarbon-substituted thienoimidazole derivative represented by formula (2).

5. The biotin intermediate represented by formula (1) precipitated in the second step is separated by filtration, and the obtained biotin intermediate is used as follows: A method for producing a biotin intermediate according to claim 1, comprising a third step of washing the biotin intermediate by contacting it with at least one solvent selected from the group consisting of alcohol solvents, ketone solvents, and water.

6. The aforementioned third step is After washing the biotin intermediate obtained in the second step by contacting it with water, then, The method for producing a biotin intermediate according to claim 5, comprising the step of washing the obtained biotin intermediate by contacting it with at least one solvent selected from the group consisting of an alcohol solvent, a ketone solvent, and water.

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