JP2018108978A - Method for producing biotin intermediate and method for producing biotin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a trione compound which is an intermediate of biotin via a specific amide. An amide compound represented by formula (3) is synthesized from a specific ureido anhydrous compound, a trione compound is synthesized from the amide compound, and then biotin is produced via a specific thiolactone compound. [R1 and R2 are each independently a protecting group for H or a ureylene group; R3 is an alkyl group, an aralkyl group, or an aryl group; R4 to R6 are each independently H, an alkyl group, an alkoxy group, or a halogen atom] None

Description

  The present invention relates to a novel method for producing a biotin intermediate, and also relates to a novel method for producing biotin using an intermediate obtained by the production method.

  Following formula (10)

The biotin represented by is a water-soluble vitamin used for pharmaceuticals that are expected to have a diabetes-preventing effect, feed additives, and the like.

The biotin has a very long production process. Therefore, even if it is an intermediate body, it is manufactured through many processes. For example, a typical intermediate of biotin,
Following formula (5)

(Where
R ¹ and R ² are each a hydrogen atom or a protecting group for a ureylene group,
R ⁴ , R ⁵ , and R ⁶ are each a hydrogen atom, an alkyl group, an alkoxy group, or a halogen atom. ) Is produced by the following method. In the following process, an example in which R ¹ and R ² are benzyl groups (Bn groups), R ⁴ , R ⁵ , and R ⁶ are hydrogen atoms and R ³ is a methyl group is shown.

  Biotin is produced from the trione compound through a reduction reaction, a cyclization reaction, and a reaction with a sulfurizing agent (see Patent Document 1).

  In Examples of Patent Document 1, first, 1,3-dibenzyl-2-imidazolidone-cis-4,5-dicarboxylic acid (ureido compound), and α-phenethylamine ((R)-(+)-1-methyl Benzylamine (optically active amine) is reacted in toluene at reflux temperature. Subsequently, 1,3-dibenzyl-5- (α-phenethyl) -hexahydropyrrolo [3,4-a] is maintained in a high temperature state of 220 to 240 ° C. or more in a solvent-free state in which toluene is distilled off. It has been shown that imidazole-2,4,6-trione can be produced.

  However, when the present inventors tried the above method, it was found that there was room for improvement in the following points. It is considered that the above method is generally carried out by stirring and mixing the inside of the reaction system under reflux. However, when the same experiment was performed a plurality of times, crystals precipitated during the reaction and the reaction system was In some cases, the inside could not be sufficiently stirred and mixed. Moreover, since it is necessary to hold the extracted crystal itself at a very high temperature of 220 to 240 ° C., there is room for improvement in that there is a possibility that a corresponding apparatus is required or the product is decomposed. . Furthermore, since there is no solvent, dehydration is not sufficiently performed, and the yield of the trione compound may be reduced.

U.S. Pat. No. 3,876,656

  Biotin is produced through numerous processes. Therefore, in order to reduce the production cost of biotin, the production method of each intermediate is also important.

  Accordingly, an object of the present invention is to provide a method capable of easily producing a trione compound which is an intermediate of biotin. Another object of the present invention is to provide a novel method for producing biotin using an intermediate such as the trione compound as a raw material.

  The present inventors have made extensive studies to solve the above problems. And the crystal | crystallization which precipitates in a reaction system in the conventional method was confirmed. Then, it was considered that the reaction of the trione compound proceeded as follows.

  In the above reaction, when the raw material (ureido compound or anhydrous compound) and α-phenethylamine ((R)-(+)-1-methylbenzylamine; optically active amine) are reacted, the amide compound represented by the above formula It was found that (I) and amide (II) were once generated, and this amide (I) and amide (II) were precipitated in the reaction system as crystals. And if this crystal was not precipitated in the reaction system and could be dehydrated at the same time, it was considered that the reaction could proceed in a uniform state and the operability could be further improved, and various studies were conducted. . As a result, by carrying out the reaction in a specific solvent, the mixture of the amide compound (I) and the amide compound (II) can be easily separated from the reaction system in a uniform state without precipitating crystals. Since water can be drained, the inventors have found that a trione compound can be easily produced, and have completed the present invention.

That is, the first aspect of the present invention is
Following formula (1)

(Where
R ¹ and R ² are each a hydrogen atom or a protecting group for a ureylene group. An anhydrous compound represented by
Following formula (2)

(Where
R ³ is an alkyl group, an aralkyl group, or an aryl group,
R ⁴ , R ⁵ , and R ⁶ are each a hydrogen atom, an alkyl group, an alkoxy group, or a halogen atom. And an optically active amine compound represented by
By reacting in a reaction solvent containing an aromatic hydrocarbon solvent having a boiling point of 140 ° C. or higher,
Following formula (3)

(Where
R ¹ and R ² have the same meaning as in the formula (1),
R ³ , R ⁴ , R ⁵ , and R ⁶ have the same meanings as those in formula (2). Amide compound (I) represented by the following formula (4)

(Where
R ¹ and R ² have the same meaning as in the formula (1),
R ³ , R ⁴ , R ⁵ , and R ⁶ have the same meanings as those in formula (2). ) Is a method for producing a mixture comprising the amide (II).

The second aspect of the present invention
A mixture comprising the amide compound (I) represented by the formula (3) and the amide compound (II) represented by the formula (4) obtained by the method according to the first aspect of the present invention, and a boiling point of 140 By dehydrating the mixture at a reflux temperature of the first reaction solution containing an aromatic hydrocarbon solvent at a temperature of ℃ or higher,
Following formula (5)

(Where
R ¹ and R ² have the same meaning as in the formula (1),
R ³ , R ⁴ , R ⁵ , and R ⁶ have the same meanings as those in formula (2). ) Is a method for producing a trione compound represented by

The third aspect of the present invention is
In a reaction solvent containing an aromatic hydrocarbon solvent having a boiling point of 140 ° C. or higher, as a reflux temperature,
Following formula (6)

(Where
R ¹ and R ² have the same meaning as in the formula (1). The anhydrous compound shown by said Formula (1) is manufactured by dehydrating the ureido compound shown by this.

The fourth aspect of the present invention is
A second reaction solution comprising an anhydrous compound represented by the formula (1) obtained by the method of the third aspect of the present invention, and a reaction solvent containing an aromatic hydrocarbon solvent having a boiling point of 140 ° C. or higher; By mixing the optically active amine compound represented by (2), a mixture comprising the amide (I) represented by the formula (3) and the amide (II) represented by the formula (4) is produced. Is the method.

The fifth aspect of the present invention is
After producing the trione compound represented by the formula (5) by the method of the second present invention, reducing the trione compound with a reducing agent,
Following formula (7)

(Where
R ¹ and R ² have the same meaning as in the formula (1),
R ³ , R ⁴ , R ⁵ , and R ⁶ have the same meanings as those in formula (2). Is a method of producing an amide alcohol compound represented by

The sixth invention relates to
After producing the amide alcohol compound represented by the above formula (7) by the method of the fifth invention, the amide alcohol compound is cyclized with an acid,
Following formula (8)

(Where
R ¹ and R ² have the same meaning as in the formula (1). Is a method for producing a lactone compound represented by

The seventh aspect of the present invention is
After producing the lactone compound represented by the above formula (8) by the method of the sixth invention, by reacting the lactone compound with a sulfurizing agent,
Following formula (9)

(Where
R ¹ and R ² have the same meaning as in the formula (1). Is a method for producing a thiolactone compound represented by

The eighth aspect of the present invention is
After producing the thiolactone compound represented by the formula (9) by the method of the seventh invention, using the thiolactone compound as a raw material,
Following formula (10)

Is a method for producing biotin represented by

  According to the method of the present invention, a mixture of amide (I) and amide (II), which are biotin intermediates, and a trione compound can be produced with good operability. As a result, according to the method of the present invention, biotin can be produced efficiently.

  In particular, the optically active amine compound is introduced into the reaction system by using an aromatic hydrocarbon solvent having a boiling point of 140 ° C. or higher from the previous stage where the ureido compound as a raw material is an anhydrous compound. A trione compound can be produced only by performing dehydration without taking out the product each time. In particular, biotin can be efficiently produced by using this method.

  In the present invention, the anhydrous compound represented by the formula (1) and the optically active amine compound represented by the formula (2) are reacted in a reaction solvent containing an aromatic hydrocarbon solvent having a boiling point of 140 ° C. or higher. To produce a mixture comprising the amide (I) represented by the formula (3) and the amide (II) represented by the formula (4). The use of the aromatic hydrocarbon solvent is the greatest feature of the present invention. In the following, description will be given in order.

(Anhydrous compound)
In the present invention,
Following formula (1)

(Where
R ¹ and R ² are each a hydrogen atom or a protecting group for a ureylene group. ) (Hereinafter sometimes simply referred to as “anhydrous compound”).

In the formula, R ¹ and R ² are each a hydrogen atom or a protecting group for a ureylene group, and may be the same or different groups. Examples of the protecting group for the imide group include an alkyl group, an aryl group, an aralkyl group, and an acyl group. Especially, a C1-C10 alkyl group, a C5-C10 aryl group, a C6-C11 aralkyl group, or a C1-C11 acyl group is mentioned. In particular, each is preferably a benzyl group.

  Here, the ureylene group is a group represented by -NHCONH-. A protecting group for a ureylene group is a group that is substituted with a ureido group and inactivated during a predetermined reaction. After the predetermined reaction, a ureylene group is formed by deprotection.

(Method for producing anhydrous compound)
The anhydrous compound is not particularly limited, but is preferably produced by the following method. That is, the following formula (6)

(Where
R ¹ and R ² have the same meaning as in the formula (1). The ureido compound represented by () (hereinafter sometimes simply referred to as “ureido compound”) is preferably produced by dehydration. This ureido compound is a known compound and is a compound exemplified in Patent Document 1.

  The anhydrous compound can be produced by dehydrating and cyclizing the ureido compound. The dehydration of the ureido compound is preferably carried out in an aromatic hydrocarbon solvent having a boiling point of 140 ° C. or higher. By using the aromatic hydrocarbon solvent, the ureido compound can be easily dehydrated.

  The aromatic hydrocarbon solvent is not particularly limited as long as the boiling point is 140 ° C. or higher. The boiling point of the aromatic hydrocarbon solvent is preferably 140 to 210 ° C, and preferably 160 to 190 ° C in consideration of industrial production, ease of removal, usefulness, etc. of the solvent itself. Further preferred.

(Anhydrous compound production method; aromatic hydrocarbon solvent)
A commercially available aromatic hydrocarbon solvent can be used without any limitation. Specifically, it is a solvent having a boiling point of 140 ° C. or higher and having benzene substituted with 1 to 6 alkyl groups having 1 to 3 carbon atoms, or a solvent having benzene substituted with 2 to 6 halogen atoms. Is preferred. Specific solvents include mesitylene (boiling point 165 ° C.), pseudocumene (boiling point 169 ° C.), hemimeridene (boiling point 176 ° C.), cumene (boiling point 152 ° C.), 1,2-dichlorobenzene (boiling point 180 ° C.), 1, Examples include 3-dichlorobenzene (boiling point 172 ° C.) and 1,4-dichlorobenzene (boiling point 174 ° C.). These solvents can be used singly or a plurality of kinds of mixed solvents can be used. Among these, mesitylene (boiling point 165 ° C.) is particularly preferable in consideration of easiness of dehydration, solubility of the anhydrous compound, operability in the next reaction, and the like.

  In order to dehydrate the ureido compound in the aromatic hydrocarbon solvent, the following method is preferably employed. That is, a solution in which the ureido compound is dissolved in the aromatic hydrocarbon solvent is prepared. Then, while maintaining this solution at the reflux temperature, water generated in the reaction system may be taken out of the system.

  The conditions for dehydrating the ureido compound are not particularly limited, but the following conditions are preferably employed.

  Specifically, in consideration of the post-process, ease of dehydration, etc., it is preferable to use 1 to 20 mL of the aromatic hydrocarbon solvent with respect to 1 g of the ureido compound, and further 2 to 6 mL. It is preferable to use it.

  Moreover, when performing a dehydration reaction, it is preferable to set it as the state in which the inside of a reaction system is mixed sufficiently, and stirring mixing is preferable. The temperature (reaction temperature) at the time of dehydration is preferably the reflux temperature of the reaction solution, specifically, preferably 140 to 210 ° C., more preferably 160 to 190 ° C. It is preferable. This dehydration reaction may be performed under any conditions of reduced pressure, normal pressure, and increased pressure. However, in order to perform sufficient dehydration, it is preferable to carry out in a range from reduced pressure to normal pressure. Among these, when the aromatic hydrocarbon solvent is used, it is easy to azeotrope with water, and the dehydration reaction proceeds easily.

  The reaction time is not particularly limited, and may be appropriately determined by confirming the production state of the anhydrous compound. That is, the progress of the reaction can be confirmed by confirming the amount of azeotropic water, and it may be carried out until no azeotropic water is produced. Usually 0.5 to 20 hours is sufficient. In addition, the reaction atmosphere is not particularly limited, and the reaction can be performed in an air atmosphere or an inert gas atmosphere such as nitrogen gas.

  The dehydration reaction as described above can be performed with a known facility. For example, it can be performed using an apparatus (for example, a Dean-Stark dehydrator) equipped with a cooler.

  In the present invention, when an aromatic hydrocarbon solvent having a boiling point of 140 ° C. or higher is used for the dehydration reaction of the ureido compound, after the dehydration reaction is completed, the anhydrous compound represented by the formula (1), And a second reaction solution containing a reaction solvent containing an aromatic hydrocarbon solvent having a boiling point of 140 ° C. or higher. In the present invention, the anhydrous compound can be once taken out from the reaction system. However, in order to further improve the operability, the second reaction solution is used as it is in the next step (with an optically active amine compound). (Reaction) is preferably used.

(Optically active amine compound)
In the present invention, the anhydrous compound and the following formula (2)

(Where
R ³ is an alkyl group, an aralkyl group, or an aryl group,
R ⁴ , R ⁵ , and R ⁶ are each a hydrogen atom, an alkyl group, an alkoxy group, or a halogen atom. R ³ is an alkyl group, an aralkyl group, or an aryl group, which is reacted with an optically active amine compound (hereinafter sometimes referred to simply as “optically active amine compound”). Among these, an alkyl group having 1 to 10 carbon atoms, an aralkyl group having 6 to 11 carbon atoms, or an aryl group having 5 to 10 carbon atoms is preferable. Among these, an alkyl group having 1 to 10 carbon atoms is preferable, and a methyl group is particularly preferable.

R ⁴ , R ⁵ , and R ⁶ are each a hydrogen atom, an alkyl group, an alkoxy group, or a halogen atom. Among these, a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or a halogen atom is preferable. Among them, it is preferable that all of R ⁴ , R ⁵ , and R ⁶ are hydrogen atoms.

(Reaction conditions for optically active amine compound and anhydrous compound)
A feature of the present invention is that the anhydrous compound and the optically active amine compound are reacted in a reaction solvent containing an aromatic hydrocarbon solvent having a boiling point of 140 ° C. or higher. Examples of the aromatic hydrocarbon solvent include the same solvents as those described above (an example of an anhydrous compound production method; examples of aromatic hydrocarbon solvents), and preferred solvents are also the same solvents for the same reason.

  In the present invention, the anhydrous compound can be once taken out from the reaction system and separately reacted with the optically active amine compound in an aromatic hydrocarbon solvent having a boiling point of 140 ° C. or higher. However, in order to further improve the operability, the optically active amine compound is mixed with the second reaction solution containing the anhydrous compound and the reaction solvent containing the aromatic hydrocarbon solvent having a boiling point of 140 ° C. or higher. The reaction is preferably allowed to proceed. The reaction solvent may contain water inevitably mixed.

According to the study by the present inventors, the following formula (3) obtained by this reaction is obtained.

(Where
R ¹ and R ² have the same meaning as in the formula (1),
R ³ , R ⁴ , R ⁵ , and R ⁶ have the same meanings as those in formula (2). ) (Hereinafter sometimes simply referred to as “amide (I)”), and the following formula (4)

(Where
R ¹ and R ² have the same meaning as in the formula (1),
R ³ , R ⁴ , R ⁵ , and R ⁶ have the same meanings as those in formula (2). It was found that the mixture consisting of the amide compound (II) represented by () (hereinafter sometimes simply referred to as “amide compound (II)”) is difficult to dissolve in a solvent such as toluene. For this reason, it was found that depending on the reaction conditions, crystals of the mixture may precipitate in toluene and hinder the stirring in the reaction system. In contrast, the aromatic hydrocarbon solvent having a boiling point of 140 ° C. or higher used in the present invention has high solubility of the mixture, so that the mixture is dehydrated under uniform conditions while suppressing the precipitation of the mixture. The reaction can proceed.

  In the present invention, 1 to 20 mL of the aromatic hydrocarbon solvent is preferably used with respect to 1 g of the anhydrous compound, and 2 to 6 mL is preferably used. By setting the amount of the aromatic hydrocarbon solvent used within the above range, precipitation of the mixture or the like can be suppressed. When the second reaction solution is used, the amount of the aromatic hydrocarbon solvent is sufficient. If not, the aromatic hydrocarbon solvent can be newly added.

  The optically active amine compound is not particularly limited, but is preferably used in an amount of 0.8 to 2.0 mol, and 0.9 to 1.2 mol, relative to 1 mol of the anhydrous compound. More preferably.

  The reaction temperature at the time of reacting the optical amine compound and the anhydrous compound is preferably a temperature at which a mixture containing the anhydrous compound as a raw material and the resulting amide (I) and amide (II) does not precipitate. Specifically, 140 ° C. or higher is preferable, and 160 ° C. or higher is more preferable. Further, the upper limit of the reaction temperature is the reflux temperature of the reaction solution, but specifically, it may be 210 ° C, more preferably 190 ° C.

  The reaction of the optical amine compound and the anhydrous compound reacts instantaneously by mixing both. Therefore, it is preferable to mix the optically active amine compound under the condition that the anhydrous compound does not precipitate in the reaction system. Mixing may be performed by stirring and mixing the inside of the reaction system. That is, in the second reaction solution from which water has been removed by azeotropic distillation, the optically active amine compound is added to the second reaction solution under a temperature condition such that the anhydrous compound does not precipitate. preferable.

  This reaction is preferably carried out at the reflux temperature of the solution when the optically active amine compound is blended in the reaction solution (preferably the second reaction solution). In this case, when the reaction is completed, the dehydration reaction of the mixture starts, and the trione compound can be obtained. Therefore, it is preferable to carry out the apparatus to be used with the same apparatus as the said anhydrous compound was manufactured. By using the same device, operability can be improved.

  As described above, this reaction is completed instantaneously when the anhydrous compound and the optically active amine compound come into contact with each other. Therefore, the reaction time may be appropriately determined by confirming the state of consumption of the anhydrous compound. Further, the reaction atmosphere is not particularly limited, and the reaction can be performed in an air atmosphere or an inert gas atmosphere such as nitrogen gas. Moreover, since this reaction is completed instantly, it may be carried out under any conditions of reduced pressure, normal pressure, and increased pressure. However, in order to immediately perform the subsequent dehydration reaction of the mixture, it is preferable to carry out under reduced pressure to normal pressure. Especially, since the said aromatic hydrocarbon type solvent is used, it is preferable to implement under a normal pressure.

  In the present invention, next, a mixture of the amide (I) and the amide (II) is dehydrated to produce a trione compound represented by the formula (5). Therefore, the first reaction solution containing the mixture of the amide body (I) and the amide body (II) obtained by the reaction and the aromatic hydrocarbon solvent having a boiling point of 140 ° C. or higher is used as it is at the reflux temperature. As such, the mixture can be dehydrated. Next, the dehydration reaction of the amide body (I) and the mixture comprising the amide body (II) will be described.

(Dehydration reaction of the mixture)
When the mixture, that is, the amide (I) and the amide (II) are dehydrated, both of them are represented by the following formula (5):

(Where
R ¹ and R ² have the same meaning as in the formula (1),
R ³ , R ⁴ , R ⁵ , and R ⁶ have the same meanings as those in formula (2). ) (Hereinafter sometimes simply referred to as “trione compound”).

  The mixture obtained by the above method can be once taken out from the reaction system and separately subjected to a dehydration reaction. However, in order to carry out this dehydration reaction under relatively mild conditions, for example, at a temperature (less than 220 ° C.) than known literature, it is preferable to employ a method of removing water from the solution in which the mixture is dissolved. In order to prepare this solution, it is preferable to use the same aromatic hydrocarbon solvent as described above (an anhydrous compound production method; exemplified by the aromatic hydrocarbon solvent). Among these, in order to improve the operability most, it is preferable to use the first reaction solution.

  In order to carry out the dehydration reaction of the mixture in a uniformly dissolved solution, the aromatic compound is added to 1 g of the mixture (the total of the amide compound (I) and the amide compound (II)). It is preferable to use 1 to 20 mL of a hydrocarbon solvent, and it is more preferable to use 2 to 6 mL. In the case of using the first reaction solution, when the amount of the aromatic hydrocarbon solvent is insufficient, the aromatic hydrocarbon solvent can be newly added.

  The dehydration reaction of the mixture is preferably in a state where the reaction system is sufficiently mixed, and is preferably stirred and mixed. The temperature at the time of dehydration (reaction temperature) is preferably the reflux temperature of the reaction solution, specifically, preferably in the range of 140 ° C. or higher and 210 ° C., more preferably in the range of 160 to 190 ° C. This dehydration reaction may be performed under any conditions of reduced pressure, normal pressure, and increased pressure. However, in order to perform sufficient dehydration, it is preferable to carry out in a range from reduced pressure to normal pressure. Above all, when the aromatic hydrocarbon solvent is used, it is easy to azeotrope with water, and the dehydration reaction proceeds easily.

  The reaction time is not particularly limited, and may be appropriately determined by confirming the production state of the trione compound. That is, the amount of water to be azeotroped is confirmed to confirm the progress of the reaction, and the process may be carried out until no water to be azeotroped is produced. Usually 0.5 to 20 hours is sufficient. Further, the reaction atmosphere is not particularly limited, and the reaction can be performed in an air atmosphere or an inert gas atmosphere such as nitrogen gas.

  In the present invention, in order to further improve the operability, it is preferable to use the first reaction solution as it is and dehydrate it from the solution. That is, the first reaction solution can be refluxed as it is, and water can be azeotroped with the aromatic hydrocarbon solvent to remove it from the reaction system to proceed with the dehydration reaction. Therefore, the apparatus to be used is preferably carried out in the same apparatus as the apparatus in which the anhydrous compound and the optically active amine compound are reacted. By using the same device, operability can be improved.

(Purification of trione compounds)
In the present invention, a trione compound can be produced by the above method. When the mixture, that is, the mixture containing the amide (I) and the amide (II) is dehydrated, both of them become a trione compound. The method for purifying the trione compound is not particularly limited, but the following method is preferably employed.

  Specifically, a solvent, for example, the aromatic hydrocarbon solvent is distilled off from the reaction solution. Thereafter, the residue is dissolved in a mixed solvent containing water and a hydrophilic solvent such as alcohol having 1 to 6 carbon atoms, glycol having 1 to 6 carbon atoms, alkylene glycol monoalkyl ether having 2 to 6 carbon atoms, and crystallized. It is preferable to deposit (trione compound). The mixed solvent is preferably 0.5 to 10 mL of hydrophilic solvent and 0.5 to 10 mL of water with respect to 1 g of the solid content of the residue, 2 to 6 mL of hydrophilic solvent, and 1 to 1 of water. It is preferable to use 3 mL. The temperature for crystallization and the like and the temperature for dissolving the residue are preferably determined appropriately depending on the amount of the mixed solvent used.

  The trione compound crystal taken out as described above can be purified again by a method such as crystallization, column separation, and washing. The trione compound can be used as a raw material for biotin. The method for producing biotin from the trione compound is not particularly limited, and a known method can be adopted.

  Among these, particularly preferable trione compounds are exemplified by cis-1,3-dibenzyl-5-[(R) -1-phenethyl] hexahydropyrrolo [3,4-d] imidazole-2,4,6. -Trions are mentioned.

(Production of biotin from trione compounds)
(Reduction of trione compounds)
In the present invention, by reducing the trione compound with a reducing agent,
Following formula (7)

(Where
R ¹ and R ² have the same meaning as in the formula (1),
R ³ , R ⁴ , R ⁵ , and R ⁶ have the same meanings as those in formula (2). ) (Hereinafter sometimes simply referred to as “amide alcohol compound”).

(Reducing agent, reduction reaction)
In the present invention, a known reducing agent can be used to reduce the trione compound. Specifically, the reducing agent to be used is not particularly limited, and a known reducing agent can be used. Specific examples include sodium bis (2-methoxyethoxy) aluminum hydride, sodium borohydride, or a combination thereof.

Further, (i) after reduction with NaAlH ₂ (OCH ₂ CH ₂ OCH ₃ ) ₂ (production of aminal and amido aldehydes), the aminal and amido aldehydes are further reduced with a borohydride metal salt to obtain an amide Alcohol compounds can also be produced.
In addition, (ii) a trione compound can be reduced with calcium borohydride to an amide alcohol compound. By reducing with calcium borohydride, it is possible to react at a lower temperature.

  What is necessary is just to mix both in order for the said trione compound and the said reducing agent to contact. In mixing, it is preferable to mix in a reaction solvent. As the reaction solvent, methanol, ethanol, isopropanol, 1,2-dimethoxyethane, THF, methylene chloride, toluene and the like can be used.

  The amount of the reducing agent to be used is not particularly limited, and usually 0.25 to 10 moles may be used per 1 mole of the trione compound. Further, the reaction temperature is not particularly limited, but it is preferable to carry out the reaction at −78 to 50 ° C.

Among them, the reaction temperature when reducing the trione compound with NaAlH ₂ (OCH ₂ CH ₂ OCH ₃ ) ₂ is preferably −100 ° C. or more and 10 ° C. or less from the viewpoint of allowing the reaction to proceed with high selectivity, 20 degreeC or more and 5 degrees C or less are preferable. _{Further, NaAlH 2 (OCH 2 CH 2} OCH 3) the aminal body obtained by reduction with ₂ and an amide aldehyde, the reaction temperature during the reduction with metal borohydride salt, -20 ° C. or higher 100 ° C. or less It is preferably 0 ° C. or higher and 60 ° C. or lower.

  Further, the reaction temperature at the time of contacting the trione compound with the calcium borohydride is not particularly limited, and is preferably −100 ° C. or higher and 100 ° C. or lower, more preferably −30 ° C. or higher and 50 ° C. or lower, It is more preferably −10 ° C. or higher and 50 ° C. or lower, and particularly preferably −10 ° C. or higher and 40 ° C. or lower.

  According to the method as described above, the amide alcohol compound can be produced. The obtained amide alcohol compound can be taken out from the reaction system by performing operations such as extraction, concentration, recrystallization, and drying with an appropriate solvent.

(Method for producing lactone compound)
The amide alcohol compound obtained by the above method can be converted into a lactone compound by a known method. Specifically, by cyclizing the amide alcohol compound with an acid,
Following formula (8)

(Where
R ¹ and R ² have the same meaning as in the formula (1). ) Can be produced.

  The acid to be used is not particularly limited, and a known acid can be used. Specific examples include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, phosphoric acid, and acetic acid.

  What is necessary is just to mix both in order for the said amide alcohol compound and the said acid to contact. In mixing, it is preferable to mix in a reaction solvent. As the reaction solvent, the solvents exemplified in the method for producing an aminol compound can be used.

  The amount of the acid to be used is not particularly limited, and usually 0.1 to 1000 mol may be used per 1 mol of the amide alcohol compound. Also, the reaction temperature is not particularly limited, but it is preferably carried out at -20 to 110 ° C.

  The lactone compound can be produced by the above method. However, in order to improve the yield of the lactone compound, facilitate the removal of the reaction solvent used in the reaction, and improve the operability of the post-treatment process, It is preferable to cyclize under such conditions. Specifically, after producing the amide alcohol compound, the amide alcohol compound is added in a solvent containing an alkylene glycol monoalkyl ether having 2 to 12 total carbon atoms in the molecule in the presence of hydrogen chloride. It is preferable to produce the lactone compound by cyclization.

  Hydrogen chloride to be used can be introduced into the reaction system in the form of hydrochloric acid containing water, or hydrogen chloride gas can be introduced into the reaction system. However, in consideration of productivity and simplification of the apparatus, it is preferable to use in the state of hydrochloric acid containing water. When hydrochloric acid is used, hydrochloric acid having 30 to 40% by mass of hydrogen chloride and 60 to 70% by mass of water (however, the total of water and hydrogen chloride is 100% by mass) can be used. Commercially available hydrogen chloride or hydrochloric acid can be used.

  The amount of hydrogen chloride to be used is not particularly limited, but is preferably 0.1 to 100 mol with respect to 1 mol of the amide alcohol compound in order to facilitate the post-treatment step and sufficiently advance the reaction. Furthermore, 1-10 mol is preferable.

  As the solvent containing an alkylene glycol monoalkyl ether having 2 to 12 total carbon atoms in the molecule, it is particularly preferable to use 2-methoxyethanol, 2-butoxyethanol, or 2-methoxy-1-propanol.

  According to the method as described above, the lactone compound can be produced. The obtained lactone compound can be taken out from the reaction system by performing operations such as extraction, concentration, recrystallization, and drying with an appropriate solvent.

(Method for producing thiolactone compound)
The lactone compound obtained by the above method can be converted into a thiolactone compound by a known method. Specifically, by reacting the lactone compound with a sulfurizing agent,
Following formula (5)

(Where
R ¹ and R ² have the same meaning as in the formula (1). ) Can be produced.

  The sulfurizing agent to be used is not particularly limited, and a known sulfurizing agent can be used. Specific examples include potassium thioacetate, potassium xanthate, sodium hydrate, thioacetamide, and the like.

  What is necessary is just to mix both in order for the said amide alcohol compound and the said sulfurizing agent to contact. In mixing, it is preferable to mix in a reaction solvent. As the reaction solvent, N, N-dimethylacetamide, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and the like can be used.

  The amount of the sulfiding agent to be used is not particularly limited, and usually 1 to 10 mol may be used with respect to 1 mol of the lactone compound. Also, the reaction temperature is not particularly limited, but it is preferably carried out at 50 to 200 ° C.

  According to the method as described above, the thiolactone compound can be produced. The obtained lactone compound can be taken out from the reaction system by performing operations such as extraction, concentration, recrystallization, and drying with an appropriate solvent.

(Biotin production method)
The thiolactone compound is used as a raw material,
Following formula (10)

Can be produced.

  A known method can be adopted as a method for producing biotin from the thiolactone compound. Specifically, it may be carried out according to the methods described in Patent Document 1, Japanese Patent Publication No. 53-35076, Japanese Patent Publication No. 55-16435, and Japanese Patent Laid-Open No. 2000-191665, which are family patents of the patent literature.

Specifically, side chains are introduced by Grignard reaction, dehydrated and hydrogenated. Next, the biotin can be produced by converting it to a sulfonium salt with hydrogen halide, reacting with diethyl malonate, hydrolytic decarboxylation, and removing the N ¹ , N ³ -substituent (Patent Document 1, (See Japanese Patent Publication No. 53-35076 and Japanese Patent Publication No. 55-16435.)

In addition, a zinc reagent corresponding to the side chain (zinc reagent: X—Zn—CH ₂ —QY, where X is a halogen atom, Q is a trimethylene group, Y is an ester group, for example), and the thiolactone compound. Then, it is hydrolyzed and dehydrated. Then, reduction, and optionally followed by deprotection reaction of ^{R 1,} and ^{R 2,} can be produced the biotin (see JP 2000-191665).

  Biotin can be produced by the method as described above. According to the present invention, since the yield of the amide alcohol compound, which is an intermediate of biotin, can be improved, biotin finally obtained can also be efficiently produced.

  EXAMPLES Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is specific examples, and the present invention is not limited thereto.

Example 1
It is an example at the time of manufacturing a trione compound in the same reaction container from the ureido compound shown by a following formula.

(Method for producing anhydrous compound from ureido compound; dehydration reaction)
In a three-necked eggplant flask, cis-1,3-dibenzyl-2-oxo-4,5-imidazolidinedicarboxylic acid (200.0 g, 564.4 mmol ureido compound), mesitylene (600.0 mL; boiling point 165 ° C., “Aromatic hydrocarbon solvent at 140 ° C. or higher”) was charged. A Dean-Stark tube and a cooling tube were attached to a three-necked eggplant flask, and nitrogen was exchanged by flowing nitrogen for 1 minute. Heated, refluxed and stirred at 185 ° C. The water accumulated in the Dean-Stark tube was removed timely. Heated for a total of 3 hours or more. Progress of the reaction is confirmed by HPLC (High Performance Liquid Chromatography) using a sample subjected to metallization treatment by extracting 0.1 to 0.2 mL of the reaction solution, adding 2 mL of methanol, and adding a few drops of 5M NaOMe methanol solution. (It was confirmed that an anhydrous compound was synthesized). By this dehydration reaction, a second reaction solution containing an aromatic hydrocarbon solvent having a boiling point of 140 ° C. or higher and the anhydrous compound was prepared. The second reaction solution contained 3 mL of mesitylene per 1 g of the anhydrous compound.

(Reaction of anhydrous compound with optically active amine compound)
A dropping funnel was attached to the three-necked eggplant flask, and (R)-(+)-1-methylbenzylamine (65.6 g, 536.2 mmol, 0.95 equivalent optically active amine compound) was added to the three-necked eggplant flask. Prepared. That is, the optically active amine compound was dropped into the second reaction solution over 2 hours and 30 minutes while the second reaction solution was heated to 185 ° C. and stirred. The reaction was completed instantly. It was confirmed by HPLC (high performance liquid chromatography) that the anhydrous compound was consumed (a mixture of the amide (I) and the amide (II) was formed). At this time, the mixture comprising the amide (I) and the amide (II) did not precipitate in the solution. By performing the above method, the first reaction solution containing the mixture and mesitylene was prepared. At this time, the first reaction solution contained 3 mL of mesitylene per 1 g of the mixture.

(Dehydration reaction of the mixture)
After completion of the dropwise addition of the optically active amine compound, the first reaction solution was heated for 3 hours and 30 minutes with stirring. And it confirmed that water did not accumulate further in a Dean-Stark pipe | tube. It was confirmed by HPLC (high performance liquid chromatography) that the mixture was consumed (a trione compound was produced).

(Tunion compound removal and purification)
Thereafter, a total of 200 mL of mesitylene was extracted from the Dean-Stark tube. The temperature in the reactor was lowered to 100 ° C. or lower. While stirring, 700 mL of isopropyl alcohol was added. While maintaining the temperature at 80 ° C., 280 mL of water was further added dropwise. Thereafter, seed crystals were added, and 220 mL of water was further added. Thereafter, the mixture was allowed to cool to 23 ° C. and stirred for 24 hours, and the obtained crystals were filtered.

The collected crystals were washed with a mixture of 75 mL of isopropyl alcohol and 25 mL of water cooled to 5 ° C. or lower. The washed crystals were vacuum-dried at 60 ° C. for 23 hours and 30 minutes to obtain 205.2 g of the desired trione compound (466.9 mmol, yield 87%). mp: 157 [deg.] C., IR (KBr): 1780, 1705, 1680 cm < ^-1 >.

Example 2 Reduction of Trione Compound (Synthesis of Amido Alcohol Compound)
The reaction represented by the following formula was carried out.

  The trione compound (65.5 g) obtained in Example 1 was dissolved in ethanol (500 mL), and sodium borohydride (23.3 g) was added at 25 ° C. or lower. The mixture was stirred at the same temperature for 15 hours. After completion of the reaction, acetic acid (35 mL) was added to the reaction solution, and the reaction solution was concentrated under reduced pressure. Water (200 mL) and ether (150 ml) were added to the concentrated residue, and the solid was filtered and dried to obtain 64.1 g of a crude amide alcohol compound. This was recrystallized with a mixed solution of isopropanol / water = 7: 2 to obtain a pure amide alcohol compound (32 g, 49%).

Example 3 Method for Producing Lactone Compound According to the reaction formula shown below, a lactone compound was produced under the following conditions.

  The amide alcohol compound (1.33 g) obtained in Example 2 was suspended in 1,4-dioxane (5 mL), concentrated hydrochloric acid (0.5 mL) was added, and the mixture was heated to reflux for 5 hours. After the reaction, the reaction solution was cooled to room temperature and then washed with water and concentrated to obtain a lactone compound (967 mg, quant.). mp 115-120 ° C.

Example 4 Production of Thiolactone Compound According to the following reaction formula, a thiolactone compound was produced under the following conditions.

  To a solution of the lactone compound (3.22 g) produced in Example 3 in N, N-dimethylacetamide (5 mL) was added potassium thioacetate (1.52 g), and the mixture was stirred and stirred at 150 ° C. for 1 hour. After completion of the reaction, water (17 mL) was added at 60 ° C., the mixture was gradually cooled to room temperature, and stirred and mixed at 10 ° C. or lower for 1 hour. The obtained solid was collected by filtration and recrystallized from methanol to obtain a thilactone compound (2.87 g, 85%). mp 126 ° C.

Example 5 Biotin Production Method Biotin was produced according to the following reaction formula under the following conditions.

  Bromine (5.8 g) was added to a suspension of zinc dust (9.3 g) in THF (18 mL) and toluene (12 ml) at 40 ° C. or lower. To this suspension, 5-iodopentanoic acid ethyl ester (18.6 g) was added over 1 hour. After stirring and mixing at the same temperature for 1 hour, the thiolactone compound prepared in Example 4 (17.6 g), toluene (36 mL), dimethylformamide DMF (4.4 ml), 10% by mass Pd / C (0.5 g) The mixture was stirred and mixed for 5 hours in the temperature range of 28 ° C to 40 ° C. After completion of the reaction, 18% by mass hydrochloric acid (34 mL) was added to the reaction solution, and the mixture was stirred and mixed at room temperature for 1 hour. The organic layer was separated, washed with water, dried and concentrated under reduced pressure.

The concentrated residue was dissolved in a mixture of methanol (160 ml) and water (44 mL), Pd (OH) ₂ / C (50 wt% wet, 1.6 g) was added, and the mixture was heated at 110 ° C. and hydrogen pressure 0.9 MPa for 12 hours. , Catalytic reduction. After completion of the reaction, the reaction solution was filtered, and 31 mass% NaOH aqueous solution (19 g) was added to the filtrate, followed by stirring and mixing at 40 ° C for 2 hours.

  After completion of the hydrogenation reaction, the reaction solution was adjusted to pH 1 by adding 10 mass% hydrochloric acid. Methanol was distilled off under reduced pressure, and the product was extracted with ethyl acetate, washed with water, and concentrated.

  Methanesulfonic acid (1.2 g) and mesitylene (1.2 mL) were added to the concentrated residue, and the mixture was stirred and mixed at 135 ° C. for 3 hours. The reaction solution is cooled to 85 ° C. and then separated, and the lower layer is poured into water (8 ml). The mixture was stirred and mixed at 10 ° C. or lower for 1 hour, and the precipitated crystals were filtered to obtain biotin (10.7 g, 85%). mp 231-232 ° C.

Comparative Example 1
A 3-neck eggplant flask was charged with Cis-1,3-dibenzyl-2-oxo-4,5-imidazolidine dicarboxylic acid (20.0 g, 56.4 mmol ureido compound) and toluene (80 mL). A Dean-Stark tube and a cooling tube were attached to a three-necked eggplant flask, and nitrogen was exchanged by flowing nitrogen for 1 minute. Heated, refluxed and stirred at 110 ° C. The water accumulated in the Dean-Stark tube was removed timely. Heated for a total of 10 hours or more. At this point, a large amount of the anhydrous compound precipitated, making stirring difficult.

Comparative Example 2
The following formula obtained in Comparative Example 1

And (R)-(+)-1-methylbenzylamine (optically active amine compound) were reacted under the following conditions. That is, the anhydrous compound (50 g) was suspended in toluene (20 mL), (R)-(+)-α-methylbenzylamine (18.9 g) was added, and reflux dehydration was performed at 110 ° C. using a Dean-Stark tube. . When 2 hours passed, crystals of a mixture consisting of amide (I) and amide (II) were precipitated in the reaction solution, making stirring difficult.

Example 6 Reduction of Trione Compound (Synthesis of Amido Alcohol Compound)
The reaction represented by the following formula was carried out.

  Calcium chloride (68.26 mmol, 7.97 g (purity 95%)) and ethanol (180 mL, purity 99.4%) were placed in an eggplant flask and dissolved using ultrasonic waves. The mixture was placed in an ice bath and stirred for 5 minutes or more. While cooled in an ice bath, sodium borohydride (136.51 mmol, 5.74 g (purity 90%)) was added. The mixture was stirred in an ice bath for 20 minutes to produce calcium borohydride.

  Subsequently, the trione compound (30.0 g, 68.26 mmol) manufactured by performing the same operation as Example 1 was prepared, and it stirred at room temperature (23 degreeC) for 16 hours. The temperature was raised to 50 ° C. and stirred for 2 hours. The obtained reaction solution was analyzed by HPLC. The conversion rate of the trione compound was 100%, the isomer ratio was 75/25, and the aminal form was 0.6%.

Water (270 mL) and acetic acid (15 mL) were added to the reaction solution. The reaction solution was filtered. The obtained solid was vacuum-dried at 60 ° C. for 6 hours or more. This product was recrystallized from aqueous methanol to obtain an amide alcohol compound (yield: 18.8 g, yield: 62%).
Example 7 (Production of lactone compound)
According to the reaction formula shown below, a lactone compound was produced under the following conditions.

  Amide alcohol compound produced by the same operation as in Example 6; 4.15 g, 9.4 mmol), 2-methoxy-1-propanol (8.3 mL) as an alkylene monoalkyl ether, and 36% by mass hydrochloric acid ( 2.07 g, hydrogen chloride 20.4 mmol 2.2 mol used per 1 mol of the amide alcohol compound) was charged into a three-necked flask.

  The three-necked eggplant flask was placed in a preheated oil bath and heated. The mixture was stirred at an internal temperature of 100 ° C. for 15 minutes. While stirring, the mixture was cooled to 30 ° C, water (83 mL) was slowly added over 5 minutes, and the mixture was stirred at room temperature (25 ° C) for 2 hours to precipitate crystals of the lactone compound represented by the above formula in the reaction solution. I let you.

  The reaction solution was filtered through a glass filter funnel to obtain crystals. Water (20 mL) was added to the obtained crystals, and the mixture was stirred and filtered. The obtained crystal was blown and dried at 60 ° C. for 17 hours. 2.96 g of the desired lactone compound was obtained (9.18 mmol, yield 98%).

The analytical value of the obtained lactone compound; mp: 100 to 101 ° C., IR (Nujol): 1775 cm ⁻¹ , confirming that it was the target lactone compound.

Claims (8)

Following formula (1)

(Where
R ¹ and R ² are each a hydrogen atom or a protecting group for a ureylene group. An anhydrous compound represented by
Following formula (2)

(Where
R ³ is an alkyl group, an aralkyl group, or an aryl group,
R ⁴ , R ⁵ , and R ⁶ are each a hydrogen atom, an alkyl group, an alkoxy group, or a halogen atom. And an optically active amine compound represented by
By reacting in a reaction solvent containing an aromatic hydrocarbon solvent having a boiling point of 140 ° C. or higher,
Following formula (3)

(Where
R ¹ and R ² have the same meaning as in the formula (1),
R ³ , R ⁴ , R ⁵ , and R ⁶ have the same meanings as those in formula (2). Amide compound (I) represented by the following formula (4)

(Where
R ¹ and R ² have the same meaning as in the formula (1),
R ³ , R ⁴ , R ⁵ , and R ⁶ have the same meanings as those in formula (2). A method for producing a mixture comprising an amide (II) represented by formula (II): A mixture comprising the amide (I) represented by the formula (3) and the amide (II) represented by the formula (4) obtained by the method according to claim 1, and a boiling point of 140 ° C or higher By dehydrating the mixture at a reflux temperature of the first reaction solution containing the aromatic hydrocarbon solvent of
Following formula (5)

(Where
R ¹ and R ² have the same meaning as in the formula (1),
R ³ , R ⁴ , R ⁵ , and R ⁶ have the same meanings as those in formula (2). The trione compound shown by this is manufactured. In a reaction solvent containing an aromatic hydrocarbon solvent having a boiling point of 140 ° C. or higher, as a reflux temperature,
Following formula (6)

(Where
R ¹ and R ² have the same meaning as in the formula (1). The method for producing the anhydrous compound represented by the formula (1) by dehydrating the ureido compound represented by formula (1).   A second reaction solution containing the anhydrous compound represented by the formula (1) obtained by the method according to claim 3 and a reaction solvent containing an aromatic hydrocarbon solvent having a boiling point of 140 ° C or higher, and the formula By mixing the optically active amino compound represented by (2), a mixture comprising the amide (I) represented by the formula (3) and the amide (II) represented by the formula (4) is produced. Method. After producing the trione compound represented by the formula (5) by the method according to claim 2, reducing the trione compound with a reducing agent,
Following formula (7)

(Where
R ¹ and R ² have the same meaning as in the formula (1),
R ³ , R ⁴ , R ⁵ , and R ⁶ have the same meanings as those in formula (2). The method of manufacturing the amide alcohol compound shown by this. After producing the amide alcohol compound represented by the formula (7) by the method according to claim 5, the amide alcohol compound is cyclized with an acid,
Following formula (8)

(Where
R ¹ and R ² have the same meaning as in the formula (1). A method for producing a lactone compound represented by After producing the lactone compound represented by the formula (8) by the method according to claim 6, by reacting the lactone compound and a sulfurizing agent,
Following formula (9)

(Where
R ¹ and R ² have the same meaning as in the formula (1). A method for producing a thiolactone compound represented by the formula: After producing the thiolactone compound represented by the formula (9) by the method according to claim 7, using the thiolactone compound as a raw material,
Following formula (10)

A method for producing biotin represented by