WO2020129591A1 - Production method for amide alcohol compound - Google Patents
Production method for amide alcohol compound Download PDFInfo
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- WO2020129591A1 WO2020129591A1 PCT/JP2019/047033 JP2019047033W WO2020129591A1 WO 2020129591 A1 WO2020129591 A1 WO 2020129591A1 JP 2019047033 W JP2019047033 W JP 2019047033W WO 2020129591 A1 WO2020129591 A1 WO 2020129591A1
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- amide alcohol
- alcohol compound
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- 0 *C1(CN*([C@]([C@](CO)N2*)N(*)C2=O)=O)CC1 Chemical compound *C1(CN*([C@]([C@](CO)N2*)N(*)C2=O)=O)CC1 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/30—Oxygen or sulfur atoms
- C07D233/32—One oxygen atom
Definitions
- the present invention relates to a novel method for producing an amide alcohol compound, which is a typical synthetic intermediate of biotin.
- Biotin is a water-soluble vitamin used in pharmaceutical products that are expected to have diabetes prevention effects and as feed additives.
- Biotin is manufactured through a great many processes, and even its synthetic intermediate is manufactured through a large number of processes.
- a biotin synthetic intermediate is a thiolactone derivative represented by the following formula (3).
- R 1 and R 2 each independently represent a substituted or unsubstituted benzyl group.
- This thiolactone derivative is also produced through a number of steps as shown in, for example, the following synthetic scheme (see Patent Document 1).
- the following synthetic scheme shows an example in which R 1 and R 2 in the above formula (3) are benzyl groups (Bn groups).
- Patent Document 1 first, 1,3-dibenzyl-2-imidazolidone-cis-4,5-dicarboxylic acid is reacted with ⁇ -phenethylamine ((R)-(+)-1-methylbenzylamine). Then, 1,3-dibenzyl-5-( ⁇ -phenethyl)-hexahydropyrrolo[3,4-d]imidazol-2,4,6-trione is obtained (step 1). Then, a thiolactone compound having a benzyl group is obtained through a reduction reaction (step 2), an acid hydrolysis reaction (step 3), and a sulfurization reaction (step 4). In the example of Patent Document 1, biotin, which is the final target product, is obtained from this thiolactone compound through 7 additional steps.
- biotin is manufactured through numerous processes. Therefore, in order to reduce the production cost of biotin, it is also important to reduce the production cost of the synthetic intermediate in each step, that is, to improve the yield of each synthetic intermediate.
- the optical isomer is generated as an impurity in addition to the amide alcohol compound which can finally become biotin, and the yield of the amide alcohol compound is reduced.
- the product obtained by the reduction reaction (step 2) is recrystallized with a mixed solvent of water and isopropanol, and the yield of the amide alcohol compound finally obtained is about 50%. Has become.
- the yield of amide alcohol compound can be improved, the yield of biotin finally obtained can also be improved.
- the present inventors have found that the yield of the amide alcohol compound can be improved by using a specific reducing agent when producing the amide alcohol compound (see Patent Document 2).
- Patent Document 2 a amide alcohol compound of high purity is obtained by isolating the amide alcohol compound as a crude product and then recrystallizing it in water-containing methanol.
- the isolated yield was only 62%, and there was room for improvement in efficiently producing the amide alcohol compound.
- there is a problem in the fluidity of the crystals during recrystallization and it takes a relatively long time to filter the precipitated crystals. Therefore, there is room for improvement in terms of operability.
- An object of the present invention is to provide a production method capable of efficiently obtaining an amide alcohol compound with high purity.
- the production method of the present invention it is possible to efficiently obtain a high-purity amide alcohol compound having a small content of optical isomers as a by-product.
- the operation of isolating the crude amide alcohol compound and then purifying it by recrystallization is not necessary, and therefore the amide alcohol compound can be produced industrially and efficiently.
- crystals of an amide alcohol compound having excellent fluidity can be obtained.
- a trione compound represented by the following formula (1) (hereinafter, also simply referred to as “trione compound”) is reduced with calcium borohydride to give a formula (1) 2) a contacting step including a reducing step of obtaining a solution containing an amide alcohol compound (hereinafter, also simply referred to as “amide alcohol compound”) and a contacting step of contacting the solution with water and an organic acid.
- the amount of water to be contacted with is 1.0 to 3.0 mL per 1 g of the trione compound, and the amount of organic acid to be contacted in the contacting step is 0.5 to 10 mol per mol of the trione compound.
- R 1 and R 2 each independently represent a substituted or unsubstituted benzyl group, and R 3 represents a substituted or unsubstituted phenyl group.
- R 1 and R 2 each independently represent a substituted or unsubstituted benzyl group.
- the position of the substituent in the substituted benzyl group is not particularly limited, and may be the benzene ring portion, the methylene group portion, or both. Further, the number of substituents in the substituted benzyl group is not particularly limited, and may be 1 or 2 or more. When the benzyl group has two or more substituents, those substituents may be the same or different from each other. Examples of the substituent of the benzyl group include a methyl group, a methoxy group, a nitro group, an amino group and a halogen atom.
- R 3 represents a substituted or unsubstituted phenyl group.
- the number of substituents in the substituted phenyl group is not particularly limited, and may be 1 or 2 or more. When the phenyl group has two or more substituents, those substituents may be the same or different from each other. Examples of the substituent of the phenyl group include a methyl group, a methoxy group, a nitro group, an amino group and a halogen atom.
- the trione compound is reduced with calcium borohydride to obtain a solution containing the amide alcohol compound.
- Calcium borohydride is a substance similar to sodium borohydride used in Patent Document 1 etc., but by using this calcium borohydride, the content of optical isomers as impurities is reduced. be able to. The reason is not clear, but it is considered that calcium borohydride reacts at a lower temperature than sodium borohydride.
- calcium borohydride for example, calcium halide is reacted with a monovalent metal salt of borohydride (sodium borohydride, potassium borohydride, etc.) in a solvent such as an alcohol having 1 to 4 carbon atoms. Can be manufactured by.
- a monovalent metal salt of borohydride sodium borohydride, potassium borohydride, etc.
- 2 mol of “monovalent metal salt of borohydride” may be used per mol of calcium halide.
- 1 mol of calcium borohydride can be obtained by reacting 2 mol of sodium borohydride with 1 mol of calcium chloride.
- Calcium borohydride obtained may be purified and used after isolation. However, since calcium borohydride is an unstable compound, it is preferable to use it as it is without isolation.
- the trione compound and calcium borohydride may be brought into contact with each other.
- the amount of calcium borohydride used is not particularly limited as long as it can reduce the trione compound sufficiently. Considering the yield of the amide alcohol compound, the ease of post-treatment, and the like, the amount of calcium borohydride used is preferably 1 to 10 mol, and more preferably 1 to 3 mol, per 1 mol of the trione compound. ..
- the amount of calcium borohydride used is preferably 1 to 10 mol, and more preferably 1 to 3 mol, per 1 mol of the trione compound. ..
- the amount of calcium borohydride used is preferably 1 to 10 mol, and more preferably 1 to 3 mol, per 1 mol of the trione compound. ..
- the amount of calcium borohydride used is preferably 1 to 10 mol, and more preferably 1 to 3 mol, per 1 mol of the trione compound. ..
- the number of moles of calcium borohydride used in the reduction step should be determined based on the number of moles of calcium halide used in the
- the reaction between the trione compound and calcium borohydride is preferably carried out in a reaction solvent.
- the reaction solvent is preferably a solvent capable of accelerating the reduction reaction, and specific examples thereof include methanol, ethanol, 1-propanol, 2-propanol, butanol, ethylene glycol, ethylene glycol monomethyl ether (2-methoxyethanol), 1-methoxy.
- Preferred are alcohols having 1 to 6 carbon atoms such as -2-propanol and 1-methyl-2-butanol; ethers such as 1,2-dimethoxyethane; These reaction solvents may be used alone or in combination of two or more. Among these reaction solvents, ethanol and 2-propanol are more preferable. In addition, inevitably contained water may be present in these reaction solvents.
- the amount of the reaction solvent used is not particularly limited, and for example, it is preferably 1 to 100 mL per 1 g of the trione compound, and more preferably 5 to 20 mL per 1 g of the trione compound.
- the amount of this reaction solvent may include the solvent used for producing calcium borohydride.
- the reaction temperature and reaction time for contacting the trione compound and calcium borohydride are not particularly limited.
- the reaction temperature is, for example, preferably ⁇ 30° C. to 80° C., more preferably ⁇ 10° C. to 60° C.
- the reaction time may be appropriately determined by checking the consumption amount of the trione compound and the production amount of the amide alcohol compound.
- a solution containing an amide alcohol compound is contacted with water and an organic acid. Crystals of the amide alcohol compound can be deposited by this contacting step.
- the organic acid serves as a solvent for precipitating the amide alcohol compound and also has a function of decomposing calcium borohydride used excessively in the reduction step.
- the organic acid is not particularly limited, and examples thereof include acetic acid, propionic acid, citric acid, trifluoroacetic acid, methanesulfonic acid and the like.
- acetic acid is preferable in terms of industrial availability and purity and yield of the resulting amide alcohol compound.
- the method of contacting the solution containing the amide alcohol compound with water or an organic acid is not particularly limited.
- water and an organic acid may be sequentially added after obtaining a solution containing an amide alcohol compound by reducing a trione compound, or a mixed solution of water and an organic acid may be prepared in advance, and the amide alcohol may be added to the solution.
- a solution containing the compound may be added.
- the amount of water contacted with the solution containing the amide alcohol compound is 1.0 to 3.0 mL per 1 g of the trione compound, and preferably 1.5 to 2.5 mL per 1 g of the trione compound.
- the amount of the organic acid to be brought into contact with the solution containing the amide alcohol compound is 0.5 to 10 mol per mol of the trione compound, and preferably 3 to 5 mol per mol of the trione compound.
- a high-purity amide alcohol compound can be efficiently obtained by adjusting the amounts of water and organic acid to be brought into contact with the solution containing the amide alcohol compound as described above.
- the temperature and time of the contacting process are not particularly limited as long as the temperature and time are sufficient for precipitating crystals of the amide alcohol compound.
- the temperature of the contacting step is usually 0°C to 80°C, preferably 40°C to 60°C.
- the time of the contacting step is usually 1 to 10 hours, preferably 3 to 5 hours.
- the precipitated amide alcohol compound can be isolated by a known solid-liquid separation operation such as pressure filtration, vacuum filtration, and centrifugation.
- the isolated crystal of the amide alcohol compound may be washed with a solvent to replace the solution attached to the crystal.
- the solvent used for washing is preferably hydrous ethanol from the viewpoint of the isolation yield of the amide alcohol compound.
- the amount of hydrous ethanol used for washing may be appropriately determined according to the type and size of the solid-liquid separator.
- a dried product can be obtained by drying the washed amide alcohol compound by a known drying operation.
- the amide alcohol compound obtained by the production method according to this embodiment has high optical purity and chemical purity, and can be suitably used for production of biotin.
- Example 2 Ethanol (16 mL) added with calcium chloride (0.53 g, 4.78 mmol) was stirred at room temperature for 30 minutes, cooled to 10° C., and sodium borohydride (0.39 g, 10.3 mmol) was added to the mixture to give 10 The mixture was stirred at a temperature of not higher than 0°C for 5 minutes. IMD (2.00 g, 4.55 mmol) was added to the stirred solution at 10°C, and the mixture was stirred at 30°C for 24 hours and then at 50°C for 2 hours.
- Table 1 below shows the type and amount of acid added to the reaction solution in Example 2, the method of adding acid and water, and the yield of ALC crystals, yield, and isomer ratio.
- Example 3 Comparative Examples 2 to 4> ALC crystals were obtained in the same manner as in Example 2 except that the type and amount of acid added to the reaction solution and the method of adding acid and water were changed as shown in Table 1 below. The yield, yield, and isomer ratio of the obtained ALC crystals are shown in Table 1 below.
- a high-purity amide alcohol compound could be efficiently obtained by contacting the reaction solution with a predetermined amount of water and an organic acid.
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Abstract
Provided is a production method that is for an amide alcohol compound, and that comprises: a reduction step for reducing a trione compound represented by formula (1) using hydrogenated boron calcium to obtain a solution containing an amide alcohol compound represented by formula (2); and a contact step for bringing the solution into contact with water and with an organic acid, wherein the amount of water to be brought in contact in the contact step is 1.0-3.0 mL per gram of the trione compound, and the amount of the organic acid to be brought in contact in the contact step is 0.5-10 mol per mole of the trione compound. In the formulas, R1 and R2 each independently represent a substituted or unsubstituted benzyl group, and R3 represents a substituted or unsubstituted phenyl group.
Description
本発明は、ビオチンの代表的な合成中間体であるアミドアルコール化合物の新規な製造方法に関する。
The present invention relates to a novel method for producing an amide alcohol compound, which is a typical synthetic intermediate of biotin.
ビオチンは、糖尿病予防効果等が期待される医薬品や、飼料添加剤等に使用される水溶性ビタミンである。
Biotin is a water-soluble vitamin used in pharmaceutical products that are expected to have diabetes prevention effects and as feed additives.
ビオチンは、非常に多くの工程を経て製造されており、その合成中間体であっても多くの工程を経て製造されている。例えば、ビオチンの合成中間体として、下記式（３）で表されるチオラクトン誘導体がある。
Biotin is manufactured through a great many processes, and even its synthetic intermediate is manufactured through a large number of processes. For example, a biotin synthetic intermediate is a thiolactone derivative represented by the following formula (3).
このチオラクトン誘導体についても、例えば下記の合成スキームに示すように、多くの工程を経て製造されている（特許文献１参照）。下記の合成スキームは、上記式（３）中のＲ１及びＲ２がベンジル基（Ｂｎ基）である場合の例を示したものである。
This thiolactone derivative is also produced through a number of steps as shown in, for example, the following synthetic scheme (see Patent Document 1). The following synthetic scheme shows an example in which R 1 and R 2 in the above formula (3) are benzyl groups (Bn groups).
特許文献１の実施例では、まず、１，３－ジベンジル－２－イミダゾリドン－シス－４，５－ジカルボン酸とα－フェネチルアミン（（Ｒ）－（＋）－１－メチルベンジルアミン）とを反応させて、１，３－ジベンジル－５－（α－フェネチル）－ヘキサヒドロピロロ［３，４－ｄ］イミダゾール－２，４，６－トリオンを得る（ｓｔｅｐ１）。次いで、還元反応（ｓｔｅｐ２）、酸加水分解反応（ｓｔｅｐ３）、及び硫化反応（ｓｔｅｐ４）を経て、ベンジル基を有するチオラクトン化合物を得る。特許文献１の実施例では、このチオラクトン化合物からさらに７工程を経て、最終目的物であるビオチンを得ている。
In the example of Patent Document 1, first, 1,3-dibenzyl-2-imidazolidone-cis-4,5-dicarboxylic acid is reacted with α-phenethylamine ((R)-(+)-1-methylbenzylamine). Then, 1,3-dibenzyl-5-(α-phenethyl)-hexahydropyrrolo[3,4-d]imidazol-2,4,6-trione is obtained (step 1). Then, a thiolactone compound having a benzyl group is obtained through a reduction reaction (step 2), an acid hydrolysis reaction (step 3), and a sulfurization reaction (step 4). In the example of Patent Document 1, biotin, which is the final target product, is obtained from this thiolactone compound through 7 additional steps.
以上のように、ビオチンは、非常に多くの工程を経て製造される。そのため、ビオチンの製造コストを低減するためには、各工程における合成中間体の製造コストを低減すること、すなわち各合成中間体の収率を向上することも重要になる。
As mentioned above, biotin is manufactured through numerous processes. Therefore, in order to reduce the production cost of biotin, it is also important to reduce the production cost of the synthetic intermediate in each step, that is, to improve the yield of each synthetic intermediate.
ここで、上記の合成スキームの還元反応（ｓｔｅｐ２）については、最終的にビオチンになり得るアミドアルコール化合物以外にその光学異性体が不純物として生成し、アミドアルコール化合物の収率が低下することが知られている。例えば、特許文献１の実施例３では、還元反応（ｓｔｅｐ２）により得られる生成物を水及びイソプロパノールの混合溶媒で再結晶しており、最終的に得られるアミドアルコール化合物の収率は約５０％となっている。
Here, regarding the reduction reaction (step 2) of the above-mentioned synthetic scheme, it is known that the optical isomer is generated as an impurity in addition to the amide alcohol compound which can finally become biotin, and the yield of the amide alcohol compound is reduced. Has been. For example, in Example 3 of Patent Document 1, the product obtained by the reduction reaction (step 2) is recrystallized with a mixed solvent of water and isopropanol, and the yield of the amide alcohol compound finally obtained is about 50%. Has become.
アミドアルコール化合物の収率を改善することができれば、最終的に得られるビオチンの収率も改善することができる。本件発明者らは、鋭意検討の結果、アミドアルコール化合物を製造する際に特定の還元剤を使用することにより、アミドアルコール化合物の収率を改善できることを見出した（特許文献２参考）。
If the yield of amide alcohol compound can be improved, the yield of biotin finally obtained can also be improved. As a result of earnest studies, the present inventors have found that the yield of the amide alcohol compound can be improved by using a specific reducing agent when producing the amide alcohol compound (see Patent Document 2).
特許文献２では、アミドアルコール化合物を粗体として単離した後、含水メタノール中での再結晶により、高純度のアミドアルコール化合物を得ている。しかし、単離収率は６２％に留まっており、効率良くアミドアルコール化合物を製造する点で改善の余地があった。また、再結晶時の結晶の流動性に難があり、析出晶の濾過に比較的長い時間を要するため、操作性の点でも改善の余地があった。
In Patent Document 2, a amide alcohol compound of high purity is obtained by isolating the amide alcohol compound as a crude product and then recrystallizing it in water-containing methanol. However, the isolated yield was only 62%, and there was room for improvement in efficiently producing the amide alcohol compound. Further, there is a problem in the fluidity of the crystals during recrystallization, and it takes a relatively long time to filter the precipitated crystals. Therefore, there is room for improvement in terms of operability.
本発明は、アミドアルコール化合物を高純度で効率的に得ることが可能な製造方法を提供することを課題とする。
An object of the present invention is to provide a production method capable of efficiently obtaining an amide alcohol compound with high purity.
上記課題を解決するための具体的な手段には、以下の実施態様が含まれる。
＜１＞ 下記式（１）：
（式中、Ｒ１及びＲ２はそれぞれ独立に置換又は非置換のベンジル基を示し、Ｒ３は置換又は非置換のフェニル基を示す。）
で表されるトリオン化合物を水素化ホウ素カルシウムで還元することにより、下記式（２）：
（式中、Ｒ１、Ｒ２、及びＲ３は前記式（１）と同義である。）
で表されるアミドアルコール化合物を含む溶液を得る還元工程と、
前記アミドアルコール化合物を含む溶液と水及び有機酸とを接触させる接触工程とを含み、
前記接触工程で接触させる水の量が前記トリオン化合物１ｇ当たり１．０～３．０ｍＬであり、前記接触工程で接触させる有機酸の量が前記トリオン化合物１モル当たり０．５～１０モルであるアミドアルコール化合物の製造方法。 Specific means for solving the above problems include the following embodiments.
<1> The following formula (1):
(In the formula, R 1 and R 2 each independently represent a substituted or unsubstituted benzyl group, and R 3 represents a substituted or unsubstituted phenyl group.)
By reducing the trione compound represented by the formula (2) with calcium borohydride:
(In the formula, R 1 , R 2 , and R 3 have the same meanings as in the formula (1).)
A reduction step for obtaining a solution containing an amide alcohol compound represented by:
A contact step of contacting a solution containing the amide alcohol compound and water and an organic acid,
The amount of water contacted in the contacting step is 1.0 to 3.0 mL per 1 g of the trione compound, and the amount of organic acid contacted in the contacting step is 0.5 to 10 mol per 1 mol of the trione compound. Method for producing amide alcohol compound.
＜１＞ 下記式（１）：
で表されるトリオン化合物を水素化ホウ素カルシウムで還元することにより、下記式（２）：
で表されるアミドアルコール化合物を含む溶液を得る還元工程と、
前記アミドアルコール化合物を含む溶液と水及び有機酸とを接触させる接触工程とを含み、
前記接触工程で接触させる水の量が前記トリオン化合物１ｇ当たり１．０～３．０ｍＬであり、前記接触工程で接触させる有機酸の量が前記トリオン化合物１モル当たり０．５～１０モルであるアミドアルコール化合物の製造方法。 Specific means for solving the above problems include the following embodiments.
<1> The following formula (1):
By reducing the trione compound represented by the formula (2) with calcium borohydride:
A reduction step for obtaining a solution containing an amide alcohol compound represented by:
A contact step of contacting a solution containing the amide alcohol compound and water and an organic acid,
The amount of water contacted in the contacting step is 1.0 to 3.0 mL per 1 g of the trione compound, and the amount of organic acid contacted in the contacting step is 0.5 to 10 mol per 1 mol of the trione compound. Method for producing amide alcohol compound.
＜２＞ 前記接触工程を０℃～８０℃で行う＜１＞に記載のアミドアルコール化合物の製造方法。
<2> The method for producing an amide alcohol compound according to <1>, wherein the contacting step is performed at 0°C to 80°C.
本発明に係る製造方法によれば、副生する光学異性体の含有量が少ない高純度のアミドアルコール化合物を効率的に得ることができる。特に、本発明に係る製造方法では、アミドアルコール化合物の粗体を単離してから再結晶により精製する操作が不要となるため、工業的にも効率的にアミドアルコール化合物を製造することができる。また、本発明に係る製造方法によれば、流動性に優れたアミドアルコール化合物の結晶を得ることができる。
According to the production method of the present invention, it is possible to efficiently obtain a high-purity amide alcohol compound having a small content of optical isomers as a by-product. In particular, in the production method according to the present invention, the operation of isolating the crude amide alcohol compound and then purifying it by recrystallization is not necessary, and therefore the amide alcohol compound can be produced industrially and efficiently. Further, according to the production method of the present invention, crystals of an amide alcohol compound having excellent fluidity can be obtained.
以下、本発明の実施形態について詳細に説明する。ただし、本発明は以下の実施形態に限定されるものではない。
本明細書においては特に断らない限り、数値Ａ及びＢを用いた「Ａ～Ｂ」という表記は「Ａ以上Ｂ以下」を意味するものとする。かかる表記において数値Ｂのみに単位を付した場合には、当該単位が数値Ａにも適用されるものとする。 Hereinafter, embodiments of the present invention will be described in detail. However, the present invention is not limited to the following embodiments.
In the present specification, the notation “A to B” using the numerical values A and B means “above A and below B” unless otherwise specified. In this notation, when a unit is attached only to the numerical value B, the unit is also applied to the numerical value A.
本明細書においては特に断らない限り、数値Ａ及びＢを用いた「Ａ～Ｂ」という表記は「Ａ以上Ｂ以下」を意味するものとする。かかる表記において数値Ｂのみに単位を付した場合には、当該単位が数値Ａにも適用されるものとする。 Hereinafter, embodiments of the present invention will be described in detail. However, the present invention is not limited to the following embodiments.
In the present specification, the notation “A to B” using the numerical values A and B means “above A and below B” unless otherwise specified. In this notation, when a unit is attached only to the numerical value B, the unit is also applied to the numerical value A.
本実施形態に係るアミドアルコール化合物の製造方法は、下記式（１）で表されるトリオン化合物（以下、単に「トリオン化合物」ともいう。）を水素化ホウ素カルシウムで還元することにより、下記式（２）で表されるアミドアルコール化合物（以下、単に「アミドアルコール化合物」ともいう。）を含む溶液を得る還元工程と、該溶液と水及び有機酸とを接触させる接触工程とを含み、接触工程で接触させる水の量がトリオン化合物１ｇ当たり１．０～３．０ｍＬであり、接触工程で接触させる有機酸の量がトリオン化合物１モル当たり０．５～１０モルである。
In the method for producing an amide alcohol compound according to the present embodiment, a trione compound represented by the following formula (1) (hereinafter, also simply referred to as “trione compound”) is reduced with calcium borohydride to give a formula (1) 2) a contacting step including a reducing step of obtaining a solution containing an amide alcohol compound (hereinafter, also simply referred to as “amide alcohol compound”) and a contacting step of contacting the solution with water and an organic acid. The amount of water to be contacted with is 1.0 to 3.0 mL per 1 g of the trione compound, and the amount of organic acid to be contacted in the contacting step is 0.5 to 10 mol per mol of the trione compound.
＜トリオン化合物＞
本実施形態に係る製造方法では、上記式（１）で示されるトリオン化合物を用いる。 <Trione compound>
In the manufacturing method according to the present embodiment, the trione compound represented by the above formula (1) is used.
本実施形態に係る製造方法では、上記式（１）で示されるトリオン化合物を用いる。 <Trione compound>
In the manufacturing method according to the present embodiment, the trione compound represented by the above formula (1) is used.
上記式（１）中、Ｒ１及びＲ２はそれぞれ独立に、置換又は非置換のベンジル基を示す。置換のベンジル基における置換基の位置は特に制限されず、ベンゼン環部分であってもメチレン基部分であってもその両方であってもよい。また、置換のベンジル基における置換基の数は特に制限されず、１個であっても２個以上であってもよい。ベンジル基が２個以上の置換基を有する場合、それらの置換基は互いに同一であっても異なっていてもよい。ベンジル基の置換基としては、メチル基、メトキシ基、ニトロ基、アミノ基、ハロゲン原子等が挙げられる。
In the above formula (1), R 1 and R 2 each independently represent a substituted or unsubstituted benzyl group. The position of the substituent in the substituted benzyl group is not particularly limited, and may be the benzene ring portion, the methylene group portion, or both. Further, the number of substituents in the substituted benzyl group is not particularly limited, and may be 1 or 2 or more. When the benzyl group has two or more substituents, those substituents may be the same or different from each other. Examples of the substituent of the benzyl group include a methyl group, a methoxy group, a nitro group, an amino group and a halogen atom.
上記式（１）中、Ｒ３は、置換又は非置換のフェニル基を示す。置換のフェニル基における置換基の数は特に制限されず、１個であっても２個以上であってもよい。フェニル基が２個以上の置換基を有する場合、それらの置換基は互いに同一であっても異なっていてもよい。フェニル基の置換基としては、メチル基、メトキシ基、ニトロ基、アミノ基、ハロゲン原子等が挙げられる。
In the above formula (1), R 3 represents a substituted or unsubstituted phenyl group. The number of substituents in the substituted phenyl group is not particularly limited, and may be 1 or 2 or more. When the phenyl group has two or more substituents, those substituents may be the same or different from each other. Examples of the substituent of the phenyl group include a methyl group, a methoxy group, a nitro group, an amino group and a halogen atom.
＜還元工程＞
還元工程では、トリオン化合物を水素化ホウ素カルシウムで還元することにより、アミドアルコール化合物を含む溶液を得る。水素化ホウ素カルシウムは、特許文献１等で使用されている水素化ホウ素ナトリウムと類似した物質であるが、この水素化ホウ素カルシウムを使用することにより、不純物としての光学異性体の含有量を低減することができる。その理由は明確ではないが、水素化ホウ素ナトリウムよりも水素化ホウ素カルシウムの方が低温で反応するためと考えられる。 <Reduction process>
In the reduction step, the trione compound is reduced with calcium borohydride to obtain a solution containing the amide alcohol compound. Calcium borohydride is a substance similar to sodium borohydride used in Patent Document 1 etc., but by using this calcium borohydride, the content of optical isomers as impurities is reduced. be able to. The reason is not clear, but it is considered that calcium borohydride reacts at a lower temperature than sodium borohydride.
還元工程では、トリオン化合物を水素化ホウ素カルシウムで還元することにより、アミドアルコール化合物を含む溶液を得る。水素化ホウ素カルシウムは、特許文献１等で使用されている水素化ホウ素ナトリウムと類似した物質であるが、この水素化ホウ素カルシウムを使用することにより、不純物としての光学異性体の含有量を低減することができる。その理由は明確ではないが、水素化ホウ素ナトリウムよりも水素化ホウ素カルシウムの方が低温で反応するためと考えられる。 <Reduction process>
In the reduction step, the trione compound is reduced with calcium borohydride to obtain a solution containing the amide alcohol compound. Calcium borohydride is a substance similar to sodium borohydride used in Patent Document 1 etc., but by using this calcium borohydride, the content of optical isomers as impurities is reduced. be able to. The reason is not clear, but it is considered that calcium borohydride reacts at a lower temperature than sodium borohydride.
水素化ホウ素カルシウムは、例えば、ハロゲン化カルシウムと水素化ホウ素の１価金属塩（水素化ホウ素ナトリウム、水素化ホウ素カリウム等）とを炭素数１～４のアルコール類等の溶媒中で反応させることにより製造することができる。該反応には、ハロゲン化カルシウム１モル当たり２モルの「水素化ホウ素の１価の金属塩」を使用すればよい。例えば、塩化カルシウム１モルに対して２モルの水素化ホウ素ナトリウムを反応させることにより、１モルの水素化ホウ素カルシウムを得ることができる。
For calcium borohydride, for example, calcium halide is reacted with a monovalent metal salt of borohydride (sodium borohydride, potassium borohydride, etc.) in a solvent such as an alcohol having 1 to 4 carbon atoms. Can be manufactured by. In the reaction, 2 mol of “monovalent metal salt of borohydride” may be used per mol of calcium halide. For example, 1 mol of calcium borohydride can be obtained by reacting 2 mol of sodium borohydride with 1 mol of calcium chloride.
得られた水素化ホウ素カルシウムは、単離後に精製して使用してもよい。ただし、水素化ホウ素カルシウムは不安定な化合物であるため、単離することなく、そのまま使用することが好ましい。
Calcium borohydride obtained may be purified and used after isolation. However, since calcium borohydride is an unstable compound, it is preferable to use it as it is without isolation.
トリオン化合物を還元するためには、トリオン化合物と水素化ホウ素カルシウムとを接触させればよい。
To reduce the trione compound, the trione compound and calcium borohydride may be brought into contact with each other.
水素化ホウ素カルシウムの使用量は、トリオン化合物を十分に還元できる量であれば特に制限されない。アミドアルコール化合物の収率、後処理の容易さ等を考慮すると、水素化ホウ素カルシウムの使用量は、トリオン化合物１モル当たり１～１０モルであることが好ましく、より好ましくは１～３モルである。なお、上記のように、ハロゲン化カルシウムと水素化ホウ素の１価金属塩とを反応させて水素化ホウ素カルシウムを製造する場合、反応に使用したハロゲン化カルシウムと同じモル数の水素化ホウ素カルシウムが生成する。そのため、得られた水素化ホウ素カルシウムを単離せずに使用する場合には、反応に使用したハロゲン化カルシウムのモル数を基準にして、還元工程で使用する水素化ホウ素カルシウムのモル数を決定すればよい。
The amount of calcium borohydride used is not particularly limited as long as it can reduce the trione compound sufficiently. Considering the yield of the amide alcohol compound, the ease of post-treatment, and the like, the amount of calcium borohydride used is preferably 1 to 10 mol, and more preferably 1 to 3 mol, per 1 mol of the trione compound. .. As described above, when calcium borohydride is reacted with a monovalent metal salt of borohydride to produce calcium borohydride, the same number of moles of calcium borohydride as the calcium halide used in the reaction is used. To generate. Therefore, when using the obtained calcium borohydride without isolation, the number of moles of calcium borohydride used in the reduction step should be determined based on the number of moles of calcium halide used in the reaction. Good.
トリオン化合物と水素化ホウ素カルシウムとの反応は、反応溶媒中で実施することが好ましい。反応溶媒としては、還元反応を促進できる溶媒が好ましく、具体的には、メタノール、エタノール、１－プロパノール、２－プロパノール、ブタノール、エチレングリコール、エチレングリコールモノメチルエーテル（２－メトキシエタノール）、１－メトキシ－２－プロパノール、１－メチル－２－ブタノール等の炭素数１～６のアルコール類；１，２－ジメトキシエタン等のエーテル類；などが好ましい。これらの反応溶媒は、１種を単独で用いてもよく、２種以上を併用してもよい。これらの反応溶媒の中でも、エタノール及び２－プロパノールがより好ましい。なお、これらの反応溶媒中には、不可避的に含まれる水が存在していてもよい。
The reaction between the trione compound and calcium borohydride is preferably carried out in a reaction solvent. The reaction solvent is preferably a solvent capable of accelerating the reduction reaction, and specific examples thereof include methanol, ethanol, 1-propanol, 2-propanol, butanol, ethylene glycol, ethylene glycol monomethyl ether (2-methoxyethanol), 1-methoxy. Preferred are alcohols having 1 to 6 carbon atoms such as -2-propanol and 1-methyl-2-butanol; ethers such as 1,2-dimethoxyethane; These reaction solvents may be used alone or in combination of two or more. Among these reaction solvents, ethanol and 2-propanol are more preferable. In addition, inevitably contained water may be present in these reaction solvents.
反応溶媒の使用量は特に制限されず、例えば、トリオン化合物１ｇ当たり１～１００ｍＬであることが好ましく、トリオン化合物１ｇ当たり５～２０ｍＬであることがより好ましい。なお、この反応溶媒の量には、水素化ホウ素カルシウムを製造した際の溶媒が含まれていてもよい。
The amount of the reaction solvent used is not particularly limited, and for example, it is preferably 1 to 100 mL per 1 g of the trione compound, and more preferably 5 to 20 mL per 1 g of the trione compound. The amount of this reaction solvent may include the solvent used for producing calcium borohydride.
トリオン化合物と水素化ホウ素カルシウムとを接触させる際の反応温度及び反応時間は特に制限されない。反応温度は、例えば、－３０℃～８０℃であることが好ましく、－１０℃～６０℃であることがより好ましい。反応時間は、トリオン化合物の消費量やアミドアルコール化合物の生成量を確認し、適宜決定すればよい。
The reaction temperature and reaction time for contacting the trione compound and calcium borohydride are not particularly limited. The reaction temperature is, for example, preferably −30° C. to 80° C., more preferably −10° C. to 60° C. The reaction time may be appropriately determined by checking the consumption amount of the trione compound and the production amount of the amide alcohol compound.
＜接触工程＞
接触工程では、アミドアルコール化合物を含む溶液と水及び有機酸とを接触させる。この接触工程により、アミドアルコール化合物の結晶を析出させることができる。なお、有機酸は、アミドアルコール化合物の析出溶媒となるほか、還元工程において過剰に用いられた水素化ホウ素カルシウムを分解する作用も示す。 <Contact process>
In the contacting step, a solution containing an amide alcohol compound is contacted with water and an organic acid. Crystals of the amide alcohol compound can be deposited by this contacting step. The organic acid serves as a solvent for precipitating the amide alcohol compound and also has a function of decomposing calcium borohydride used excessively in the reduction step.
接触工程では、アミドアルコール化合物を含む溶液と水及び有機酸とを接触させる。この接触工程により、アミドアルコール化合物の結晶を析出させることができる。なお、有機酸は、アミドアルコール化合物の析出溶媒となるほか、還元工程において過剰に用いられた水素化ホウ素カルシウムを分解する作用も示す。 <Contact process>
In the contacting step, a solution containing an amide alcohol compound is contacted with water and an organic acid. Crystals of the amide alcohol compound can be deposited by this contacting step. The organic acid serves as a solvent for precipitating the amide alcohol compound and also has a function of decomposing calcium borohydride used excessively in the reduction step.
有機酸としては特に制限されず、酢酸、プロピオン酸、クエン酸、トリフルオロ酢酸、メタンスルホン酸等が挙げられる。これらの有機酸の中でも、工業的な入手容易性、並びに得られるアミドアルコール化合物の純度及び収率の点から、酢酸が好ましい。
The organic acid is not particularly limited, and examples thereof include acetic acid, propionic acid, citric acid, trifluoroacetic acid, methanesulfonic acid and the like. Among these organic acids, acetic acid is preferable in terms of industrial availability and purity and yield of the resulting amide alcohol compound.
アミドアルコール化合物を含む溶液と水及び有機酸との接触方法は特に制限されない。例えば、トリオン化合物を還元することによりアミドアルコール化合物を含む溶液を得た後、水及び有機酸を順次添加してもよいし、予め水と有機酸との混合溶液を用意し、これにアミドアルコール化合物を含む溶液を添加してもよい。
The method of contacting the solution containing the amide alcohol compound with water or an organic acid is not particularly limited. For example, water and an organic acid may be sequentially added after obtaining a solution containing an amide alcohol compound by reducing a trione compound, or a mixed solution of water and an organic acid may be prepared in advance, and the amide alcohol may be added to the solution. A solution containing the compound may be added.
アミドアルコール化合物を含む溶液と接触させる水の量は、トリオン化合物１ｇ当たり１．０～３．０ｍＬであり、好ましくはトリオン化合物１ｇ当たり１．５～２．５ｍＬである。
The amount of water contacted with the solution containing the amide alcohol compound is 1.0 to 3.0 mL per 1 g of the trione compound, and preferably 1.5 to 2.5 mL per 1 g of the trione compound.
また、アミドアルコール化合物を含む溶液と接触させる有機酸の量は、トリオン化合物１モル当たり０．５～１０モルであり、好ましくはトリオン化合物１モル当たり３～５モルである。
Further, the amount of the organic acid to be brought into contact with the solution containing the amide alcohol compound is 0.5 to 10 mol per mol of the trione compound, and preferably 3 to 5 mol per mol of the trione compound.
アミドアルコール化合物を含む溶液と接触させる水及び有機酸の量を上記のように調整することにより、高純度のアミドアルコール化合物を効率的に得ることができる。
A high-purity amide alcohol compound can be efficiently obtained by adjusting the amounts of water and organic acid to be brought into contact with the solution containing the amide alcohol compound as described above.
接触工程の温度及び時間は、アミドアルコール化合物の結晶が析出するのに十分な温度及び時間であれば特に制限されない。接触工程の温度は、通常０℃～８０℃であり、好ましくは４０℃～６０℃である。また、接触工程の時間は、通常１～１０時間であり、好ましくは３～５時間である。
The temperature and time of the contacting process are not particularly limited as long as the temperature and time are sufficient for precipitating crystals of the amide alcohol compound. The temperature of the contacting step is usually 0°C to 80°C, preferably 40°C to 60°C. Moreover, the time of the contacting step is usually 1 to 10 hours, preferably 3 to 5 hours.
析出したアミドアルコール化合物は、加圧濾過、減圧濾過、遠心分離等の公知の固液分離操作によって単離することができる。単離したアミドアルコール化合物の結晶は、溶媒を用いて洗浄し、結晶に付着する溶液を置換してもよい。洗浄の際に用いる溶媒としては、アミドアルコール化合物の単離収率の観点から、含水エタノールが好ましい。含水エタノール中のエタノールと水との混合比は、例えば、容量比でエタノール：水＝５：５～８：２の範囲とすることができる。洗浄に用いる含水エタノールの量は、固液分離装置の種類、大きさ等に応じて適宜決定すればよい。
The precipitated amide alcohol compound can be isolated by a known solid-liquid separation operation such as pressure filtration, vacuum filtration, and centrifugation. The isolated crystal of the amide alcohol compound may be washed with a solvent to replace the solution attached to the crystal. The solvent used for washing is preferably hydrous ethanol from the viewpoint of the isolation yield of the amide alcohol compound. The mixing ratio of ethanol and water in the water-containing ethanol can be, for example, ethanol:water=5:5 to 8:2 by volume ratio. The amount of hydrous ethanol used for washing may be appropriately determined according to the type and size of the solid-liquid separator.
洗浄後のアミドアルコール化合物を公知の乾燥操作で乾燥することにより、乾燥体を得ることができる。本実施形態に係る製造方法で得られるアミドアルコール化合物は、光学純度及び化学純度が高く、ビオチンの製造に好適に用いることができる。
A dried product can be obtained by drying the washed amide alcohol compound by a known drying operation. The amide alcohol compound obtained by the production method according to this embodiment has high optical purity and chemical purity, and can be suitably used for production of biotin.
以下、本発明の実施例について説明するが、本発明はこれら実施例に限定されるものではない。
Hereinafter, examples of the present invention will be described, but the present invention is not limited to these examples.
＜実施例１＞
下記の反応式に示すように、トリオン化合物（ＩＭＤ）からアミドアルコール化合物（ＡＬＣ）を合成した。 <Example 1>
As shown in the following reaction formula, an amide alcohol compound (ALC) was synthesized from a trione compound (IMD).
下記の反応式に示すように、トリオン化合物（ＩＭＤ）からアミドアルコール化合物（ＡＬＣ）を合成した。 <Example 1>
As shown in the following reaction formula, an amide alcohol compound (ALC) was synthesized from a trione compound (IMD).
塩化カルシウム（２．６６ｇ、２３．９７ｍｍｏｌ）を添加したエタノール（１００ｍＬ）を室温で溶解確認まで撹拌し、７℃まで冷却した後、水素化ホウ素ナトリウム（１．９２ｇ、３７．８３ｍｍｏｌ）を加えて３０分間撹拌した。同温でＩＭＤ（１０ｇ、２２．８０ｍｍｏｌ）を加え、７℃で２時間、次いで室温で１８時間、次いで５０℃で２時間撹拌した。撹拌後の反応液について、高速液体クロマトグラフィー（ＨＰＬＣ）により下記測定条件にて各成分の面積割合を確認した。その結果、ＩＭＤの転化率（反応にかかわった割合）は９５％であった。また、ＡＬＣと下記式（４）で表されるＡＬＣの光学異性体との比（ＡＬＣ／ＡＬＣの光学異性体；以下、単に「異性体比」という。）は７５／２５であった。
Ethanol (100 mL) added with calcium chloride (2.66 g, 23.97 mmol) was stirred at room temperature until dissolution was confirmed, and after cooling to 7° C., sodium borohydride (1.92 g, 37.83 mmol) was added. Stir for 30 minutes. IMD (10 g, 22.80 mmol) was added at the same temperature, and the mixture was stirred at 7°C for 2 hours, then at room temperature for 18 hours, and then at 50°C for 2 hours. With respect to the reaction liquid after stirring, the area ratio of each component was confirmed under the following measurement conditions by high performance liquid chromatography (HPLC). As a result, the conversion rate of IMD (the rate involved in the reaction) was 95%. The ratio of ALC to the optical isomer of ALC represented by the following formula (4) (ALC/optical isomer of ALC; hereinafter simply referred to as “isomer ratio”) was 75/25.
反応液に、５０℃で、酢酸（５ｍＬ、ＩＭＤ１モル当たり３．５モル）及び水（２０ｍＬ、ＩＭＤ１ｇ当たり２ｍＬ）の混合溶液を１５分間かけて滴下した。その後、室温まで徐々に冷却し、同温で４時間撹拌した後、析出晶を濾過した。析出晶の濾過性は良好であり、比較的短時間で濾過が完了した。得られた結晶を含水エタノール（エタノール：水＝７：３、２０ｍＬ）で洗浄した後、５５℃で６時間、減圧乾燥することにより、ＡＬＣの結晶（７．０１ｇ、収率７０％）を得た。本品をＨＰＬＣにより下記測定条件にて分析したところ、異性体比は１００／０であった。
A mixed solution of acetic acid (5 mL, 3.5 mol per 1 mol of IMD) and water (20 mL, 2 mL per 1 g of IMD) was added dropwise to the reaction solution at 50° C. over 15 minutes. Then, the mixture was gradually cooled to room temperature, stirred at the same temperature for 4 hours, and then the precipitated crystals were filtered. The filterability of the precipitated crystals was good, and the filtration was completed in a relatively short time. The obtained crystals were washed with hydrous ethanol (ethanol:water=7:3, 20 mL) and dried under reduced pressure at 55° C. for 6 hours to obtain ALC crystals (7.01 g, yield 70%). It was When this product was analyzed by HPLC under the following measurement conditions, the isomer ratio was 100/0.
（ＨＰＬＣ条件）
測定波長：２５４ｎｍ
流速：１．０ｍＬ／ｍｉｎ
移動相：アセトニトリル／（酢酸／水＝１／４００）＝４０／６０（０ｍｉｎ）→２０／８０（２０ｍｉｎ）→１００／０（３０ｍｉｎ）
カラム：Ｘ Ｂｒｉｄｇｅ Ｃ１８（Ｗａｔｅｒｓ社製）、粒子径５μｍ、４．８ｍｍ×１５０ｍｍ
カラム温度：３０℃
保持時間：ＡＬＣ １０．８ｍｉｎ；ＡＬＣの光学異性体 １１．１ｍｉｎ (HPLC conditions)
Measurement wavelength: 254 nm
Flow rate: 1.0 mL/min
Mobile phase: acetonitrile/(acetic acid/water=1/400)=40/60 (0 min)→20/80 (20 min)→100/0 (30 min)
Column: X Bridge C18 (manufactured by Waters), particle size 5 μm, 4.8 mm×150 mm
Column temperature: 30°C
Retention time: ALC 10.8 min; ALC optical isomer 11.1 min
測定波長：２５４ｎｍ
流速：１．０ｍＬ／ｍｉｎ
移動相：アセトニトリル／（酢酸／水＝１／４００）＝４０／６０（０ｍｉｎ）→２０／８０（２０ｍｉｎ）→１００／０（３０ｍｉｎ）
カラム：Ｘ Ｂｒｉｄｇｅ Ｃ１８（Ｗａｔｅｒｓ社製）、粒子径５μｍ、４．８ｍｍ×１５０ｍｍ
カラム温度：３０℃
保持時間：ＡＬＣ １０．８ｍｉｎ；ＡＬＣの光学異性体 １１．１ｍｉｎ (HPLC conditions)
Measurement wavelength: 254 nm
Flow rate: 1.0 mL/min
Mobile phase: acetonitrile/(acetic acid/water=1/400)=40/60 (0 min)→20/80 (20 min)→100/0 (30 min)
Column: X Bridge C18 (manufactured by Waters), particle size 5 μm, 4.8 mm×150 mm
Column temperature: 30°C
Retention time: ALC 10.8 min; ALC optical isomer 11.1 min
＜比較例１＞
ＡＬＣ（０．３ｇ）と上記式（４）で表されるＡＬＣの光学異性体（０．１ｇ）との混合物にエタノール（４．３ｍＬ）及び水（３．０ｍＬ）を加え、５０℃で１時間撹拌した後、析出晶を濾過した。析出晶の濾過性は悪く、濾過に比較的長時間を要した。得られた結晶を含水エタノール（エタノール：水＝７：３、２０ｍＬ）で洗浄した後、５５℃で６時間、減圧乾燥することにより、ＡＬＣの結晶（０．１９ｇ、収率４７．５％）を得た。本品をＨＰＬＣにより上記測定条件にて分析したところ、異性体比は８９／１１であった。 <Comparative Example 1>
Ethanol (4.3 mL) and water (3.0 mL) were added to a mixture of ALC (0.3 g) and the ALC optical isomer represented by the above formula (4) (0.1 g), and the mixture was added at 50° C. for 1 hour. After stirring for hours, the precipitated crystals were filtered. The filterability of the precipitated crystals was poor and the filtration took a relatively long time. The obtained crystals were washed with hydrous ethanol (ethanol:water=7:3, 20 mL) and dried under reduced pressure at 55° C. for 6 hours to give ALC crystals (0.19 g, yield 47.5%). Got When this product was analyzed by HPLC under the above-mentioned measurement conditions, the isomer ratio was 89/11.
ＡＬＣ（０．３ｇ）と上記式（４）で表されるＡＬＣの光学異性体（０．１ｇ）との混合物にエタノール（４．３ｍＬ）及び水（３．０ｍＬ）を加え、５０℃で１時間撹拌した後、析出晶を濾過した。析出晶の濾過性は悪く、濾過に比較的長時間を要した。得られた結晶を含水エタノール（エタノール：水＝７：３、２０ｍＬ）で洗浄した後、５５℃で６時間、減圧乾燥することにより、ＡＬＣの結晶（０．１９ｇ、収率４７．５％）を得た。本品をＨＰＬＣにより上記測定条件にて分析したところ、異性体比は８９／１１であった。 <Comparative Example 1>
Ethanol (4.3 mL) and water (3.0 mL) were added to a mixture of ALC (0.3 g) and the ALC optical isomer represented by the above formula (4) (0.1 g), and the mixture was added at 50° C. for 1 hour. After stirring for hours, the precipitated crystals were filtered. The filterability of the precipitated crystals was poor and the filtration took a relatively long time. The obtained crystals were washed with hydrous ethanol (ethanol:water=7:3, 20 mL) and dried under reduced pressure at 55° C. for 6 hours to give ALC crystals (0.19 g, yield 47.5%). Got When this product was analyzed by HPLC under the above-mentioned measurement conditions, the isomer ratio was 89/11.
＜実施例２＞
塩化カルシウム（０．５３ｇ、４．７８ｍｍｏｌ）を添加したエタノール（１６ｍＬ）を室温で３０分間撹拌し、１０℃まで冷却した後、水素化ホウ素ナトリウム（０．３９ｇ、１０．３ｍｍｏｌ）を加えて１０℃以下で５分間撹拌した。撹拌液に１０℃でＩＭＤ（２．００ｇ、４．５５ｍｍｏｌ）を加え、３０℃で２４時間、次いで５０℃で２時間撹拌した。 <Example 2>
Ethanol (16 mL) added with calcium chloride (0.53 g, 4.78 mmol) was stirred at room temperature for 30 minutes, cooled to 10° C., and sodium borohydride (0.39 g, 10.3 mmol) was added to the mixture to give 10 The mixture was stirred at a temperature of not higher than 0°C for 5 minutes. IMD (2.00 g, 4.55 mmol) was added to the stirred solution at 10°C, and the mixture was stirred at 30°C for 24 hours and then at 50°C for 2 hours.
塩化カルシウム（０．５３ｇ、４．７８ｍｍｏｌ）を添加したエタノール（１６ｍＬ）を室温で３０分間撹拌し、１０℃まで冷却した後、水素化ホウ素ナトリウム（０．３９ｇ、１０．３ｍｍｏｌ）を加えて１０℃以下で５分間撹拌した。撹拌液に１０℃でＩＭＤ（２．００ｇ、４．５５ｍｍｏｌ）を加え、３０℃で２４時間、次いで５０℃で２時間撹拌した。 <Example 2>
Ethanol (16 mL) added with calcium chloride (0.53 g, 4.78 mmol) was stirred at room temperature for 30 minutes, cooled to 10° C., and sodium borohydride (0.39 g, 10.3 mmol) was added to the mixture to give 10 The mixture was stirred at a temperature of not higher than 0°C for 5 minutes. IMD (2.00 g, 4.55 mmol) was added to the stirred solution at 10°C, and the mixture was stirred at 30°C for 24 hours and then at 50°C for 2 hours.
反応液に、酢酸（１．０１ｇ、１６．８ｍｍｏｌ、ＩＭＤ１モル当たり３．７モル）及び水（４ｍＬ、ＩＭＤ１ｇ当たり２ｍＬ）の混合溶液を５分間かけて滴下した。その後、４０℃まで冷却し、同温で１８時間撹拌した後、析出晶を濾過した。析出晶の濾過性は良好であり、比較的短時間で濾過が完了した。得られた結晶をメタノール１．６ｍＬと水０．４ｍＬとの混合溶媒で洗浄した後、水２ｍＬで洗浄し、乾燥することにより、ＡＬＣの結晶（１．４２ｇ、収率７０．３％）を得た。本品をＨＰＬＣにより上記測定条件にて分析したところ、異性体比は１００／０であった。
A mixed solution of acetic acid (1.01 g, 16.8 mmol, 3.7 mol per 1 mol of IMD) and water (4 mL, 2 mL per 1 g of IMD) was added dropwise to the reaction solution over 5 minutes. Then, the mixture was cooled to 40° C., stirred at the same temperature for 18 hours, and then the precipitated crystals were filtered. The filterability of the precipitated crystals was good, and the filtration was completed in a relatively short time. The obtained crystals were washed with a mixed solvent of 1.6 mL of methanol and 0.4 mL of water, then washed with 2 mL of water, and dried to give ALC crystals (1.42 g, yield 70.3%). Obtained. When this product was analyzed by HPLC under the above-mentioned measurement conditions, the isomer ratio was 100/0.
実施例２において反応液に添加した酸の種類及び添加量、酸及び水の添加方法、並びにＡＬＣの結晶の収量、収率、異性体比を下記表１に示す。
Table 1 below shows the type and amount of acid added to the reaction solution in Example 2, the method of adding acid and water, and the yield of ALC crystals, yield, and isomer ratio.
＜実施例３、比較例２～４＞
反応液に添加する酸の種類及び添加量、並びに酸及び水の添加方法を下記表１のように変更した以外は実施例２と同様にして、ＡＬＣの結晶を得た。得られたＡＬＣの結晶の収量、収率、異性体比を下記表１に示す。 <Example 3, Comparative Examples 2 to 4>
ALC crystals were obtained in the same manner as in Example 2 except that the type and amount of acid added to the reaction solution and the method of adding acid and water were changed as shown in Table 1 below. The yield, yield, and isomer ratio of the obtained ALC crystals are shown in Table 1 below.
反応液に添加する酸の種類及び添加量、並びに酸及び水の添加方法を下記表１のように変更した以外は実施例２と同様にして、ＡＬＣの結晶を得た。得られたＡＬＣの結晶の収量、収率、異性体比を下記表１に示す。 <Example 3, Comparative Examples 2 to 4>
ALC crystals were obtained in the same manner as in Example 2 except that the type and amount of acid added to the reaction solution and the method of adding acid and water were changed as shown in Table 1 below. The yield, yield, and isomer ratio of the obtained ALC crystals are shown in Table 1 below.
表１に示すとおり、反応液に所定量の水及び有機酸を接触させることにより、高純度のアミドアルコール化合物を効率的に得ることができた。
As shown in Table 1, a high-purity amide alcohol compound could be efficiently obtained by contacting the reaction solution with a predetermined amount of water and an organic acid.
＜比較例５＞
塩化カルシウム（７．９７ｇ、６８．２６ｍｍｏｌ）を添加したエタノール（１８０ｍＬ）を室温で溶解確認まで撹拌し、氷浴につけて５分間以上撹拌した。氷浴につけたまま水素化ホウ素ナトリウム（５．７４ｇ、１３６．５１ｍｍｏｌ）を加えて２０分間撹拌した。同温でＩＭＤ（３０．０ｇ、６８．２６ｍｍｏｌ）を加え、室温で１６時間、次いで５０℃で２時間撹拌した。撹拌後の反応液について、ＨＰＬＣにより上記測定条件にて分析したところ、ＩＭＤの転化率は１００％であり、異性体比は１００／０であった。 <Comparative Example 5>
Ethanol (180 mL) added with calcium chloride (7.97 g, 68.26 mmol) was stirred at room temperature until dissolution was confirmed, and the mixture was placed in an ice bath and stirred for 5 minutes or more. Sodium borohydride (5.74 g, 136.51 mmol) was added while the ice bath was kept, and the mixture was stirred for 20 minutes. IMD (30.0 g, 68.26 mmol) was added at the same temperature, and the mixture was stirred at room temperature for 16 hours and then at 50° C. for 2 hours. When the reaction solution after stirring was analyzed by HPLC under the above measurement conditions, the conversion rate of IMD was 100% and the isomer ratio was 100/0.
塩化カルシウム（７．９７ｇ、６８．２６ｍｍｏｌ）を添加したエタノール（１８０ｍＬ）を室温で溶解確認まで撹拌し、氷浴につけて５分間以上撹拌した。氷浴につけたまま水素化ホウ素ナトリウム（５．７４ｇ、１３６．５１ｍｍｏｌ）を加えて２０分間撹拌した。同温でＩＭＤ（３０．０ｇ、６８．２６ｍｍｏｌ）を加え、室温で１６時間、次いで５０℃で２時間撹拌した。撹拌後の反応液について、ＨＰＬＣにより上記測定条件にて分析したところ、ＩＭＤの転化率は１００％であり、異性体比は１００／０であった。 <Comparative Example 5>
Ethanol (180 mL) added with calcium chloride (7.97 g, 68.26 mmol) was stirred at room temperature until dissolution was confirmed, and the mixture was placed in an ice bath and stirred for 5 minutes or more. Sodium borohydride (5.74 g, 136.51 mmol) was added while the ice bath was kept, and the mixture was stirred for 20 minutes. IMD (30.0 g, 68.26 mmol) was added at the same temperature, and the mixture was stirred at room temperature for 16 hours and then at 50° C. for 2 hours. When the reaction solution after stirring was analyzed by HPLC under the above measurement conditions, the conversion rate of IMD was 100% and the isomer ratio was 100/0.
反応液に、酢酸（１５ｍＬ、ＩＭＤ１モル当たり３．５モル）及び水（２７０ｍＬ、ＩＭＤ１ｇ当たり９ｍＬ）の混合溶液を滴下して撹拌した後、析出晶を濾過した。析出晶の濾過性は悪く、濾過に比較的長時間を要した。得られた結晶を含水エタノールで洗浄した後、減圧乾燥することにより、ＡＬＣの結晶（１８．８ｇ、収率６２％）を得た。本品をＨＰＬＣにより上記測定条件にて分析したところ、異性体比は１００／０であった。
A mixed solution of acetic acid (15 mL, 3.5 mol per 1 mol of IMD) and water (270 mL, 9 mL per 1 g of IMD) was added dropwise to the reaction mixture, and the mixture was stirred, and then the precipitated crystals were filtered. The filterability of the precipitated crystals was poor and the filtration took a relatively long time. The obtained crystals were washed with hydrous ethanol and dried under reduced pressure to give ALC crystals (18.8 g, yield 62%). When this product was analyzed by HPLC under the above-mentioned measurement conditions, the isomer ratio was 100/0.
＜比較例６＞
塩化カルシウム（３３．１ｇ、２９８ｍｍｏｌ）を添加したエタノール（８００ｍＬ）を、窒素雰囲気下、室温で１０分間撹拌した後、氷水にて８℃まで冷却した。撹拌液に水素化ホウ素ナトリウム（２３．６ｇ、６２４ｍｍｏｌ）を加え、１０℃以下で３０分間撹拌した。撹拌液にＩＭＤ（１２４．４ｇ、２８４ｍｍｏｌ）を１０℃以下で１５分間かけて分割添加し、１０℃以下で１時間、次いで室温で１８時間、次いで５０℃で２時間撹拌した。撹拌後の反応液について、ＨＰＬＣにより上記測定条件にて分析したところ、ＩＭＤの転化率は９５％であり、異性体比は７０／３０であった。 <Comparative example 6>
Ethanol (800 mL) added with calcium chloride (33.1 g, 298 mmol) was stirred at room temperature for 10 minutes under a nitrogen atmosphere, and then cooled to 8° C. with ice water. Sodium borohydride (23.6 g, 624 mmol) was added to the stirring liquid, and the mixture was stirred at 10°C or lower for 30 minutes. IMD (124.4 g, 284 mmol) was added portionwise to the stirring solution at 10°C or lower over 15 minutes, and the mixture was stirred at 10°C or lower for 1 hour, then at room temperature for 18 hours, and then at 50°C for 2 hours. When the reaction solution after stirring was analyzed by HPLC under the above measurement conditions, the conversion rate of IMD was 95% and the isomer ratio was 70/30.
塩化カルシウム（３３．１ｇ、２９８ｍｍｏｌ）を添加したエタノール（８００ｍＬ）を、窒素雰囲気下、室温で１０分間撹拌した後、氷水にて８℃まで冷却した。撹拌液に水素化ホウ素ナトリウム（２３．６ｇ、６２４ｍｍｏｌ）を加え、１０℃以下で３０分間撹拌した。撹拌液にＩＭＤ（１２４．４ｇ、２８４ｍｍｏｌ）を１０℃以下で１５分間かけて分割添加し、１０℃以下で１時間、次いで室温で１８時間、次いで５０℃で２時間撹拌した。撹拌後の反応液について、ＨＰＬＣにより上記測定条件にて分析したところ、ＩＭＤの転化率は９５％であり、異性体比は７０／３０であった。 <Comparative example 6>
Ethanol (800 mL) added with calcium chloride (33.1 g, 298 mmol) was stirred at room temperature for 10 minutes under a nitrogen atmosphere, and then cooled to 8° C. with ice water. Sodium borohydride (23.6 g, 624 mmol) was added to the stirring liquid, and the mixture was stirred at 10°C or lower for 30 minutes. IMD (124.4 g, 284 mmol) was added portionwise to the stirring solution at 10°C or lower over 15 minutes, and the mixture was stirred at 10°C or lower for 1 hour, then at room temperature for 18 hours, and then at 50°C for 2 hours. When the reaction solution after stirring was analyzed by HPLC under the above measurement conditions, the conversion rate of IMD was 95% and the isomer ratio was 70/30.
反応液を３０℃以下に冷却した後、酢酸（６８．３ｇ、１．１ｍｏｌ、ＩＭＤ１モル当たり４．０モル）を１５分間かけて滴下した。次いで、室温で２０分間撹拌した後、同温で水（１１７０ｍＬ、ＩＭＤ１ｇ当たり９．４ｍＬ）を１０分間かけて滴下した。室温で２時間撹拌した後、濾過した。このとき、濾過性は非常に悪く、濾過に長時間を要した。得られた固体を水３００ｍＬで洗浄した後、６５℃の送風乾燥を１８時間行ったが、十分に乾燥できず、湿体（２８１ｇ）を得た。本品をＨＰＬＣにより上記測定条件にて分析したところ、異性体比は７１／２９であった。
After cooling the reaction solution to 30° C. or lower, acetic acid (68.3 g, 1.1 mol, 4.0 mol per 1 mol of IMD) was added dropwise over 15 minutes. Then, after stirring at room temperature for 20 minutes, water (1170 mL, 9.4 mL per 1 g of IMD) was added dropwise at the same temperature over 10 minutes. After stirring at room temperature for 2 hours, it was filtered. At this time, the filterability was very poor and the filtration took a long time. The obtained solid was washed with 300 mL of water and then air-dried at 65° C. for 18 hours, but it could not be sufficiently dried to obtain a wet body (281 g). When this product was analyzed by HPLC under the above-mentioned measurement conditions, the isomer ratio was 71/29.
Claims (2)
- 下記式（１）：
で表されるトリオン化合物を水素化ホウ素カルシウムで還元することにより、下記式（２）：
で表されるアミドアルコール化合物を含む溶液を得る還元工程と、
前記アミドアルコール化合物を含む溶液と水及び有機酸とを接触させる接触工程とを含み、
前記接触工程で接触させる水の量が前記トリオン化合物１ｇ当たり１．０～３．０ｍＬであり、前記接触工程で接触させる有機酸の量が前記トリオン化合物１モル当たり０．５～１０モルであるアミドアルコール化合物の製造方法。 The following formula (1):
By reducing the trione compound represented by the formula (2) with calcium borohydride:
A reduction step for obtaining a solution containing an amide alcohol compound represented by:
A contact step of contacting a solution containing the amide alcohol compound and water and an organic acid,
The amount of water contacted in the contacting step is 1.0 to 3.0 mL per 1 g of the trione compound, and the amount of organic acid contacted in the contacting step is 0.5 to 10 mol per 1 mol of the trione compound. Method for producing amide alcohol compound. - 前記接触工程を０℃～８０℃で行う請求項１に記載のアミドアルコール化合物の製造方法。 The method for producing an amide alcohol compound according to claim 1, wherein the contacting step is performed at 0°C to 80°C.
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Citations (4)
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|---|---|---|---|---|
| JPS4920196A (en) * | 1972-06-22 | 1974-02-22 | ||
| JPS49117467A (en) * | 1973-03-23 | 1974-11-09 | ||
| JPS49127994A (en) * | 1973-04-20 | 1974-12-07 | ||
| WO2018025722A1 (en) * | 2016-08-04 | 2018-02-08 | 株式会社トクヤマ | Method for producing intermediate of biotin and method for producing biotin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4920196A (en) * | 1972-06-22 | 1974-02-22 | ||
| JPS49117467A (en) * | 1973-03-23 | 1974-11-09 | ||
| JPS49127994A (en) * | 1973-04-20 | 1974-12-07 | ||
| WO2018025722A1 (en) * | 2016-08-04 | 2018-02-08 | 株式会社トクヤマ | Method for producing intermediate of biotin and method for producing biotin |
Non-Patent Citations (1)
| Title |
|---|
| SHIMIZU, M. ET AL.: "Stereocontrol in the reduction of meso-imides using oxazaborolidine, leading to a facile synthesis of (+)-deoxybiotin", TETRAHEDRON LETTERS, vol. 40, 1999, pages 8873 - 8876, XP004184083, DOI: 10.1016/S0040-4039(99)01864-X * |
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