WO2020129591A1 - Procédé de production d'un composé d'alcool amide - Google Patents

Procédé de production d'un composé d'alcool amide Download PDF

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Publication number
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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WIPO (PCT)
Prior art keywords
amide alcohol
alcohol compound
compound
water
formula
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PCT/JP2019/047033
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English (en)
Japanese (ja)
Inventor
雅彦 関
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株式会社トクヤマ
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Application filed by 株式会社トクヤマ filed Critical 株式会社トクヤマ
Publication of WO2020129591A1 publication Critical patent/WO2020129591A1/fr

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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de production d'un composé d'alcool amide, qui comprend : une étape de réduction consistant à réduire un composé de trione représenté par la formule (1) à l'aide de calcium de bore hydrogéné pour obtenir une solution contenant un composé d'alcool amide représenté par la formule (2) ; et une étape de contact consistant à amener la solution en contact avec de l'eau et avec un acide organique, la quantité d'eau à mettre en contact dans l'étape de contact étant de 1,0 à 3,0 mL par gramme du composé de trione, et la quantité de l'acide organique à mettre en contact dans l'étape de contact est de 0,5 à 10 moles par mole du composé de trione. Dans les formules, R1 et R2 représentent chacun indépendamment un groupe benzyle substitué ou non substitué, et R3 représente un groupe phényle substitué ou non substitué.
PCT/JP2019/047033 2018-12-19 2019-12-02 Procédé de production d'un composé d'alcool amide WO2020129591A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2018236883A JP2022028990A (ja) 2018-12-19 2018-12-19 アミドアルコール化合物の製造方法
JP2018-236883 2018-12-19

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WO2020129591A1 true WO2020129591A1 (fr) 2020-06-25

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4920196A (fr) * 1972-06-22 1974-02-22
JPS49117467A (fr) * 1973-03-23 1974-11-09
JPS49127994A (fr) * 1973-04-20 1974-12-07
WO2018025722A1 (fr) * 2016-08-04 2018-02-08 株式会社トクヤマ Procédé de production d'un intermédiaire de la biotine et procédé de production de biotine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4920196A (fr) * 1972-06-22 1974-02-22
JPS49117467A (fr) * 1973-03-23 1974-11-09
JPS49127994A (fr) * 1973-04-20 1974-12-07
WO2018025722A1 (fr) * 2016-08-04 2018-02-08 株式会社トクヤマ Procédé de production d'un intermédiaire de la biotine et procédé de production de biotine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
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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