WO2016004704A1 - Procédé de production de gastrodine - Google Patents

Procédé de production de gastrodine Download PDF

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Publication number
WO2016004704A1
WO2016004704A1 PCT/CN2014/089422 CN2014089422W WO2016004704A1 WO 2016004704 A1 WO2016004704 A1 WO 2016004704A1 CN 2014089422 W CN2014089422 W CN 2014089422W WO 2016004704 A1 WO2016004704 A1 WO 2016004704A1
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WO
WIPO (PCT)
Prior art keywords
gastrodin
stirring
reaction
crystal
acetoxymethylphenol
Prior art date
Application number
PCT/CN2014/089422
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English (en)
Chinese (zh)
Inventor
王多平
Original Assignee
江苏汉斯通药业有限公司
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Publication date
Application filed by 江苏汉斯通药业有限公司 filed Critical 江苏汉斯通药业有限公司
Publication of WO2016004704A1 publication Critical patent/WO2016004704A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems

Definitions

  • the invention relates to the field of pharmaceutical synthesis, in particular to a production process of gastrodin.
  • Gastrodin this product is 4-hydroxymethylbenzene- ⁇ -D-glucopyranoside hemihydrate, the molecular formula is (C 13 H 18 O 7 ) ⁇ 1/2H 2 O, molecular weight is 295.38, structural formula for This product is a white crystalline powder, odorless, bitter, soluble in water, methanol, soluble in ethanol, insoluble in chloroform, melting point 153 ⁇ 156 °C.
  • Chinese Patent No. 201210450047.9 discloses a semi-synthesis method of high-purity and high-stability gastrodin, which is obtained by reacting tetraacetyl as a raw material to obtain acetyl gastrodin, adding an alcohol solvent to reflux reaction in acetyl gastrodin, and then adding a non-polar solvent. After the solid matter is dried, a crude gastrodin is obtained, and then the crude gastrodin is refined to obtain a gastrodin.
  • the acetyl gastrodin prepared by the invention is relatively stable and can be directly used as a raw material drug, and can also be used as an intermediate to synthesize high-purity gastrodin, which is very advantageous for satisfying clinical requirements for gastrodin and acetyl gastrodin.
  • this invention requires the use of a catalyst, and the process route is complicated, and pollutants are generated in the production process, and impurities are more in the reaction process, which is inconvenient to purify.
  • the technical problem mainly solved by the present invention is to provide a production process of gastrodin, which is stable in process and capable of preparing a gastrodin agent which meets the requirements of various indexes in the Chinese Pharmacopoeia.
  • Providing a process for producing gastrodin comprising preparation of p-acetoxymethylphenol, preparation of pentaacetyl gastrodin, and preparation and purification of gastrodin;
  • the preparation of the para-acetoxymethylphenol in the step (1) specifically includes the following steps:
  • esterification reaction adding p-hydroxybenzyl alcohol, glacial acetic acid and ethyl acetate to the first reaction tank, stirring the reaction at a temperature of 30 ° C for 8 h; the p-hydroxybenzyl alcohol, glacial acetic acid and acetic acid
  • the mass fraction ratio of the ester is 1:1.11:5.00;
  • the reaction liquid obtained in the step (11) is concentrated under reduced pressure, and the residue obtained by concentration is washed with purified water, then recrystallized from ethanol, heated to 65 ° C, stirred and dissolved, and cooled to 0 to 5 ° C. And then maintaining the crystal for 110 to 120 minutes to form a crystal solution containing crystals of p-acetoxymethylphenol;
  • the preparation of the pentaacetyl gastrodin in the step (2) specifically comprises the following steps:
  • the conditions of the pressure evaporation are: a gas pressure of -0.09 MPa and a temperature of 82 °C.
  • the preparation and purification of gastrodin in the step (3) specifically includes the following steps:
  • step (32) salt formation, adding pentaacetyl gastrodin and methanol together to the third reaction tank, stirring and heating to 40 ° C, and then adding the sodium methoxide solution prepared in step (31) to the third reaction tank, at 40 ° C Insulation stirring reaction for 1.5h;
  • the gastrodin crystal wet product is put into a powdering machine, powdered, and then packed into a drying tray and dried for 6-8 hours to obtain gastrodin crystals;
  • the inner package is pulverized, and the gastrodin crystal is pulverized in a powdering machine and then packaged.
  • the gastrodin crystal wet product is dried in a drying tray at a vacuum of 68 to 72 ° C and -0.085 MPa.
  • the invention has the beneficial effects that the production process of gastrodin is divided into three large steps, the reaction condition is mild, the process is stable, the raw material price is low, and the quality control of each process is respectively performed to make the final gastrodia elata.
  • the finished product has high quality and high yield, and has good medicinal properties and economic performance.
  • Figure 1 is a flow chart showing the production process of gastrodin in a preferred embodiment of the present invention.
  • a process for producing gastrodin comprising the preparation of p-acetoxymethylphenol, the preparation of pentaacetyl gastrodin and the preparation and purification of gastrodin.
  • the specific steps are as follows.
  • step (1) The list of materials used in step (1) is as follows:
  • raw material name specification Quantity (kg) weight ratio Other dosage (kg) Remarks P-hydroxybenzyl alcohol Industrial content ⁇ 90.0% 18 1 - glacial acetic acid Industrial products 20 1.11 - Ethyl acetate Industrial products 90 5.00 - Ethanol Industrial products 80 4.44 10 washing purified water - - 40 washing
  • raw material name specification Quantity (kg) weight ratio Other dosage (kg) Remarks P-hydroxybenzyl alcohol Industrial content ⁇ 90.0% 18 1 - glacial acetic acid Industrial products 20 1.11 - Ethyl acetate Industrial products 90 5.00 - Ethanol Industrial products 80 4.44 10 washing purified water - - 40 washing
  • esterification reaction weigh 18 kg of p-hydroxybenzyl alcohol, 19.5 kg of glacial acetic acid and 90 kg of ethyl acetate, and added to the first reaction tank, and stirred at a temperature of 30 ° C for 8 h;
  • Step (1) gives p-acetoxymethylphenol crystal wet product ⁇ 17.03 kg, yield ⁇ 57.8%.
  • step (2) The list of material usage used in step (2) is as follows:
  • the mixture was filtered under suction to obtain a pentaacetyl gastrodin crystal cake, which was washed with 23 kg of 0 to 5 ° C ethanol, and then drained.
  • step (2) the wet product of pentaacetyl gastrodin is ⁇ 40.91 kg, and the yield is ⁇ 79.3%.
  • step (3) The list of materials used in step (3) is as follows:
  • step (32) salt formation 40.91kg of pentaacetyl gastrodin and 130kg of methanol together into the third reaction tank, stirring and heating to 40 ° C, then the step (31) prepared sodium methoxide solution was added to the third reaction tank, Stirring reaction at 40 ° C for 1.5 h;
  • the gastrodin crystal wet product is put into a powdering machine, powdered, and then packed into a drying tray, and dried at 68-72 ° C, -0.085 MPa vacuum for 6 hours to obtain gastrodin crystal;
  • the inner package is pulverized, and the dried gastrodin crystal is pulverized in a powdering machine, and is packed into a full paper drum according to the packaging specification of 10 kg/barrel.
  • Step (3) gives a gastrodin white crystal powder ⁇ 19.60 kg, and the yield is ⁇ 96.3%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de production de gastrodine consistant à la préparation d'acétoxyméthylphénol, à la préparation de pentacetylgastrodine, et à la préparation et l'affinage de la gastrodine, comprenant les étapes consistant à : agiter de l'alcool hydroxybenzylique, de l'acide acétique glacial et de l'acétate d'éthyle afin qu'ils réagissent pour obtenir un produit humide d'acétyloxyméthylphénol; agiter du pentacétylglucose, de l'acétoxyméthylphénol et de l'acétonitrile afin qu'ils réagissent, et ensuite stabiliser pour la stratification; sécher une phase organique à l'aide de sulfate de sodium anhydre pour obtenir la pentacétylgastrodine; et enfin agiter la pentacétylgastrodine et de l'alcool méthylique afin qu'ils réagissent, refroidir pour cristalliser, décolorer, faire un essorage rotatif et sécher sous vide pour obtenir la gastrodine. La présente invention concerne un procédé stable, et permet la préparation d'un agent pharmaceutique de la gastrodine satisfaisant les exigences de chaque indice de la pharmacopée chinoise.
PCT/CN2014/089422 2014-07-11 2014-10-24 Procédé de production de gastrodine WO2016004704A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410329077.3A CN104072549B (zh) 2014-07-11 2014-07-11 天麻素的生产工艺
CN201410329077.3 2014-07-11

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WO2016004704A1 true WO2016004704A1 (fr) 2016-01-14

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CN (1) CN104072549B (fr)
WO (1) WO2016004704A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109609434A (zh) * 2018-11-23 2019-04-12 湖南中医药大学 生物转化合成天麻素的方法及应用

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104072549B (zh) * 2014-07-11 2016-03-09 江苏汉斯通药业有限公司 天麻素的生产工艺
CN105997853A (zh) * 2016-05-23 2016-10-12 悦康药业集团有限公司 一种天麻素注射液的制备方法
CN106279311B (zh) * 2016-08-23 2018-08-14 宜宾莱特医药化工有限公司 一种4-羟甲基苯基-β-D吡喃葡萄糖苷合成方法
CN110903333A (zh) * 2019-12-30 2020-03-24 陕西岳达德馨生物制药有限公司 一种糖苷及其衍生物的制备方法
CN114573647A (zh) * 2020-11-30 2022-06-03 昆药集团股份有限公司 天麻素无水晶型及其制备方法
CN114685575A (zh) * 2020-12-29 2022-07-01 昆药集团股份有限公司 天麻素无水晶型及其制备方法
CN114685576A (zh) * 2020-12-29 2022-07-01 昆药集团股份有限公司 高纯度天麻素不稳定晶型、其制备方法及天麻素晶型FormA的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102977161A (zh) * 2012-12-17 2013-03-20 青岛农业大学 一种化学合成天麻素的方法
CN104072549A (zh) * 2014-07-11 2014-10-01 江苏汉斯通药业有限公司 天麻素的生产工艺

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CN100351262C (zh) * 2002-07-11 2007-11-28 三井化学株式会社 配糖体的制造方法
CN103804438B (zh) * 2012-11-12 2016-09-07 昆药集团股份有限公司 一种高纯度、高稳定性天麻素的半合成方法
CN103275146B (zh) * 2013-06-13 2015-07-29 青岛农业大学 一种适合于产业化的天麻素化学合成方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102977161A (zh) * 2012-12-17 2013-03-20 青岛农业大学 一种化学合成天麻素的方法
CN104072549A (zh) * 2014-07-11 2014-10-01 江苏汉斯通药业有限公司 天麻素的生产工艺

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109609434A (zh) * 2018-11-23 2019-04-12 湖南中医药大学 生物转化合成天麻素的方法及应用
CN109609434B (zh) * 2018-11-23 2022-08-30 湖南中医药大学 生物转化合成天麻素的方法及应用

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CN104072549A (zh) 2014-10-01

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