WO2016004704A1 - Gastrodin production process - Google Patents
Gastrodin production process Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- gastrodin
- stirring
- reaction
- crystal
- acetoxymethylphenol
- Prior art date
Links
Images
Classifications
-
- 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%.
Landscapes
- 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
Disclosed is a gastrodin production process comprising the preparation of acetoxymethyl phenol, the preparation of pentacetyl gastrodin, and the preparation and refining of gastrodin, including: stirring hydroxybenzyl alcohol, glacial acetic acid and ethyl acetate to react to obtain a wet acetyloxymethylphenol product; stirring pentacetyl glucose, acetoxymethyl phenol and acetonitrile to react, and then stabilizing for layering; drying an organic phase via anhydrous sodium sulfate to obtain the pentacetyl gastrodin; and finally stirring the pentacetyl gastrodin and methyl alcohol to react, decolorizing, cooling for crystallizing, spin-drying and vacuum drying to obtain gastrodin. The present invention provides a stable process, and enables preparation of a gastrodin pharmaceutical agent satisfying the requirements of each index of the Chinese Pharmacopoeia.
Description
本发明涉及药物合成领域，特别是涉及一种天麻素的生产工艺。The invention relates to the field of pharmaceutical synthesis, in particular to a production process of gastrodin.
天麻素(Gastrodin)，本品为4-羟甲基苯-β-D-吡喃葡萄糖苷半水合物，分子式为(C13H18O7)·1/2H2O，分子量为295.38，结构式为
本品为白色结晶性粉末，无臭、味苦，在水、甲醇中易溶，在乙醇中溶解，在氯仿中不溶，熔点为153～156℃。Gastrodin, this product is 4-hydroxymethylbenzene-β-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.
中国专利201210450047.9公开了一种高纯度、高稳定性天麻素的半合成方法，以四乙酰为原料进行反应得到乙酰天麻素，在乙酰天麻素中加入醇溶剂回流反应，再加入非极性溶剂，固形物干燥后即得到天麻素粗品，而后再将天麻素粗品进行精制得到天麻素精品。此发明制备的乙酰天麻素较稳定，可以直接用于原料药，也可以作为中间体来合成高纯度的天麻素，对于满足临床上对于天麻素和乙酰天麻素需要是非常有利的。但是，此发明需运用催化剂，工艺路线复杂，在生产过程中会产生污染物，反应过程中杂质较多，提纯不便。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. However, 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.
发明内容Summary of the invention
本发明主要解决的技术问题是提供一种天麻素的生产工艺，工艺稳定，能够制备出符合中国药典中各项指标要求的天麻素药剂。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.
为解决上述技术问题，本发明采用的一个技术方案是：In order to solve the above technical problem, a technical solution adopted by the present invention is:
提供一种天麻素的生产工艺，包括对乙酰氧甲基苯酚的制备、五乙酰天麻素的制备和天麻素的制备及精制；Providing a process for producing gastrodin, comprising preparation of p-acetoxymethylphenol, preparation of pentaacetyl gastrodin, and preparation and purification of gastrodin;
(1)对乙酰氧甲基苯酚的制备，将对羟基苯甲醇、冰醋酸和乙酸乙酯一起搅拌反应8～9h，再将得到的反应液减压浓缩，浓缩得到的残余物用纯化水洗涤再用
乙醇重结晶，形成含对乙酰氧甲基苯酚结晶的结晶液，而后抽滤，对乙酰氧甲基苯酚结晶滤饼用乙醇洗涤，最后抽干，形成对乙酰氧甲基苯酚湿品；(1) Preparation of p-acetoxymethylphenol, the reaction mixture is stirred for 8 to 9 hours with p-hydroxybenzyl alcohol, glacial acetic acid and ethyl acetate, and the obtained reaction liquid is concentrated under reduced pressure, and the obtained residue is washed with purified water. Reuse
Recrystallization of ethanol to form a crystal solution containing crystals of p-acetoxymethylphenol, followed by suction filtration, washing the acetoxymethylphenol crystal filter cake with ethanol, and finally draining to form a wet product of p-acetoxymethylphenol;
(2)五乙酰天麻素的制备，将五乙酰葡萄糖、对乙酰氧甲基苯酚和乙腈进行搅拌反应，搅拌过程中加入三氟化硼-乙腈，后再搅拌反应5～8h；反应结束后加入适量纯化水，搅拌后静置分层，分离两相，再用纯化水洗涤分离出的有机相，然后第二次静置分层、分离两相，将第二次分离出的有机相用无水硫酸钠干燥，蒸干后得到残余物用乙醇进行重结晶，形成含五乙酰天麻素结晶的结晶液，后进行抽滤得到五乙酰天麻素结晶；(2) Preparation of pentaacetyl gastrodin, stirring reaction of pentaacetylglucose, p-acetoxymethylphenol and acetonitrile, adding boron trifluoride-acetonitrile during stirring, and then stirring the reaction for 5-8 hours; Appropriate amount of purified water, stirring, standing layering, separating the two phases, and then washing the separated organic phase with purified water, then standing still for the second time, separating the two phases, and separating the organic phase separated for the second time. Drying with sodium sulfate and evaporation to dryness, the residue is recrystallized from ethanol to form a crystal solution containing pentaacetyl gastrodin crystals, followed by suction filtration to obtain pentaacetyl gastrodin crystals;
(3)天麻素的制备及精制，将五乙酰天麻素和甲醇一并搅拌反应，后加入甲醇钠溶液于40.0℃保温搅拌反应1～2h；停止搅拌后加入药用炭混悬液脱色，形成脱色液，后将脱色液压入结晶罐中，开启结晶罐夹套冷冻盐水，温度降至0℃以后搅拌析晶，最后离心甩干后真空干燥得到天麻素。(3) Preparation and purification of gastrodin, stirring the reaction of pentaacetyl gastrodin and methanol together, then adding sodium methoxide solution and stirring at 40.0 ° C for 1 to 2 hours; after stirring, adding medicinal carbon suspension to decolorize, forming After decolorizing the liquid, the decolorizing hydraulic pressure is introduced into the crystallizing tank, and the crystallization tank jacket is opened to freeze the brine. After the temperature is lowered to 0 ° C, the crystal is stirred and finally centrifuged, dried, and vacuum dried to obtain gastrodin.
在本发明一个较佳实施例中，所述步骤(1)中对乙酰氧甲基苯酚的制备，具体包括下述步骤：In a preferred embodiment of the present invention, the preparation of the para-acetoxymethylphenol in the step (1) specifically includes the following steps:
(11)酯化反应，将对羟基苯甲醇、冰醋酸和乙酸乙酯一并加入第一反应罐中，在30℃的温度下搅拌反应8h；所述对羟基苯甲醇、冰醋酸和乙酸乙酯的质量份数比为1:1.11:5.00；(11) 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;
(12)重结晶，将步骤(11)得到的反应液减压浓缩，浓缩得到的残余物用纯化水洗涤，再用乙醇进行重结晶，升温至65℃搅拌溶解，降温至0～5℃结晶，而后保温结晶110～120min，形成含对乙酰氧甲基苯酚结晶的结晶液；(12) Recrystallization, 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;
(13)抽滤洗涤，将含对乙酰氧甲基苯酚结晶的结晶液放入抽滤器中抽滤，得到对乙酰氧甲基酚结晶滤饼，后用0～5℃的乙醇洗涤，再抽干，得到对乙酰氧甲基苯酚结晶湿品。(13) Washing by suction filtration, the crystal solution containing crystals of p-acetoxymethylphenol is placed in a suction filter and suction-filtered to obtain a para-acetoxymethylphenol crystal filter cake, which is then washed with 0 to 5 ° C of ethanol, and then pumped. Dry to obtain a crystalline wet product of p-acetoxymethylphenol.
在本发明一个较佳实施例中，所述步骤(2)中五乙酰天麻素的制备具体包括下述步骤：In a preferred embodiment of the present invention, the preparation of the pentaacetyl gastrodin in the step (2) specifically comprises the following steps:
(21)缩合反应，将五乙酰葡萄糖、对乙酰氧甲基苯酚和乙腈一并放入第二反应罐中，开启搅拌，搅拌下加入三氟化硼-乙腈，加完后控制料液温度在30℃，搅拌反应6h；其中，五乙酰葡萄糖、对乙酰氧甲基苯酚、乙腈和三氟化硼-乙腈的质量份数比为2.35:1:7.52:3.52；
(21) Condensation reaction, putting pentaacetylglucose, p-acetoxymethylphenol and acetonitrile into a second reaction tank, stirring is started, boron trifluoride-acetonitrile is added under stirring, and the temperature of the feed liquid is controlled after the addition. The reaction was stirred at 30 ° C for 6 h; wherein the mass fraction ratio of pentaacetylglucose, p-acetoxymethylphenol, acetonitrile and boron trifluoride-acetonitrile was 2.35:1:7.52:3.52;
(22)分离，将纯化水加入第二反应罐搅拌10分钟后静置分层，分离两相，再用纯化水洗涤分离出的有机相，然后第二次静置分层、分离两相，将第二次分离出的有机相用无水硫酸钠干燥，减压蒸干后得残余物；(22) Separation, adding purified water to the second reaction tank and stirring for 10 minutes, then standing to separate the layers, separating the two phases, and then washing the separated organic phase with purified water, then standing still for two times, separating the two phases, The organic phase separated a second time is dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure;
(23)重结晶，将乙醇加入第二反应罐中，通过调节温度来进行重结晶，升温至65℃后搅拌溶解，再降温至0～5℃结晶，保温结晶2h，形成含五乙酰天麻素结晶的结晶液；(23) Recrystallization, adding ethanol to the second reaction tank, recrystallization by adjusting the temperature, heating to 65 ° C, stirring and dissolving, then cooling to 0 ~ 5 ° C crystallization, heat crystallization for 2 h, forming pentane acetylephrine Crystallized crystal solution;
(24)抽滤洗涤，将含五乙酰天麻素结晶的结晶液放入抽滤器中抽滤，得到五乙酰天麻素结晶滤饼，用0～5℃的乙醇洗涤，再抽干，得到五乙酰天麻素湿品。(24) Washing by suction filtration, and crystallization liquid containing pentaacetyl gastrodin crystals is filtered in a suction filter to obtain a pentaacetyl gastrodin crystal filter cake, washed with 0 to 5 ° C ethanol, and then drained to obtain pentaacetyl. Gastrodin wet product.
在本发明一个较佳实施例中，在所述步骤(22)中，加压蒸干的条件是气压为-0.09Mpa、温度为82℃。In a preferred embodiment of the present invention, in the step (22), the conditions of the pressure evaporation are: a gas pressure of -0.09 MPa and a temperature of 82 °C.
在本发明一个较佳实施例中，在所述步骤(3)中天麻素的制备及精制，具体包括下述步骤：In a preferred embodiment of the present invention, the preparation and purification of gastrodin in the step (3) specifically includes the following steps:
(31)备料，将0.06kg甲醇溶于8kg纯化水中配置成0.2mol/L的甲醇钠溶液；将1.5kg药用炭加入到5kg甲醇中，配制成药用炭混悬液；将甲醇抽入洗涤液储罐，开启夹套冷冻盐水，将甲醇温度冷却至0℃；(31) Preparation, dissolving 0.06 kg of methanol in 8 kg of purified water to prepare a 0.2 mol/L sodium methoxide solution; adding 1.5 kg of medicinal charcoal to 5 kg of methanol to prepare a medicinal carbon suspension; Liquid storage tank, open the jacketed frozen brine, and cool the methanol temperature to 0 ° C;
(32)成盐，将五乙酰天麻素和甲醇一起加入第三反应罐中，搅拌升温至40℃，后将步骤(31)配制好的甲醇钠溶液加入第三反应罐中，于40℃下保温搅拌反应1.5h；(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;
(33)脱色，在第三反应罐中加入药用炭混悬液，在40℃下保温搅拌脱色30min，形成脱色液；(33) Decolorization, adding a medicinal carbon suspension in the third reaction tank, and decolorizing at 40 ° C for 30 min to form a decolorizing liquid;
(34)压滤，将脱色液从第三反应罐压入结晶罐，而后再用甲醇冲洗第三反应罐，洗液一并压入结晶罐内；(34) pressure filtration, press the decoloring liquid from the third reaction tank into the crystallization tank, and then rinse the third reaction tank with methanol, and the washing liquid is pressed into the crystallizing tank;
(35)冷却结晶，开启结晶罐夹套冷冻盐水并开启搅拌，将其中料液温度降至0℃进行析晶，保温析晶1.5h，形成含天麻素晶体的结晶液；(35) cooling the crystal, opening the crystallization tank jacket frozen brine and opening the stirring, the temperature of the liquid solution is lowered to 0 ° C for crystallization, and the crystallization is performed for 1.5 h to form a crystal liquid containing gastrodin crystals;
(36)离心洗涤，将含天麻素晶体的结晶液放入离心机中甩滤，甩干后用甲醇洗涤，然后甩干，形成天麻素结晶湿品；(36) Centrifugal washing, the crystal solution containing gastrodin crystals is placed in a centrifuge, filtered, dried, washed with methanol, and then dried to form a gastrodin crystal wet product;
(37)真空干燥，将天麻素结晶湿品放入打粉机中打粉后分装到干燥盘中干燥6～8h，得到天麻素结晶；(37) vacuum drying, 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;
(38)粉碎内包，将天麻素结晶放入打粉机中粉碎，而后包装。
(38) The inner package is pulverized, and the gastrodin crystal is pulverized in a powdering machine and then packaged.
在本发明一个较佳实施例中，在步骤(37)中，天麻素结晶湿品分装到干燥盘中之后，在68～72℃、-0.085MPa的真空度下进行干燥。In a preferred embodiment of the present invention, in step (37), the gastrodin crystal wet product is dried in a drying tray at a vacuum of 68 to 72 ° C and -0.085 MPa.
本发明的有益效果是：本发明一种天麻素的生产工艺，将天麻素的生产分成三个大的步骤，反应条件温和、工艺稳定、原料价格低廉，各工序分别进行质量控制，使最终天麻素的成品具有较高的品质和较高的收率，药用性能、经济性能良好。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.
图1是本发明一较佳实施例中天麻素的生产工艺流程图。BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a flow chart showing the production process of gastrodin in a preferred embodiment of the present invention.
下面结合附图对本发明的较佳实施例进行详细阐述，以使本发明的优点和特征能更易于被本领域技术人员理解，从而对本发明的保护范围做出更为清楚明确的界定。The preferred embodiments of the present invention are described in detail below with reference to the accompanying drawings, in which the advantages and features of the invention can be more readily understood by those skilled in the art.
一种天麻素的生产工艺，包括对乙酰氧甲基苯酚的制备、五乙酰天麻素的制备和天麻素的制备及精制，具体步骤如下所示。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.
(1)对乙酰氧甲基苯酚的制备，其化学反应方程式如下：(1) For the preparation of p-acetoxymethylphenol, the chemical reaction equation is as follows:
步骤(1)中所用的物料使用情况一览表如下所示：The list of materials used in step (1) is as follows:
| 原料名称raw material name | 规格specification | 数量(kg)Quantity (kg) | 重量比weight ratio | 其他用量(kg)Other dosage (kg) | 备注Remarks |
| 对羟基苯甲醇P-hydroxybenzyl alcohol | 工业含量≥90.0％Industrial content ≥90.0% | 1818 | 11 | -- | |
| 冰醋酸glacial acetic acid | 工业品Industrial products | 2020 | 1.111.11 | -- | |
| 乙酸乙醋Ethyl acetate | 工业品Industrial products | 9090 | 5.005.00 | -- | |
| 乙醇Ethanol | 工业品Industrial products | 8080 | 4.444.44 | 1010 | 洗涤washing |
| 纯化水purified water | -- | -- | 4040 | 洗涤washing |
| 原料名称raw material name | 规格specification | 数量(kg)Quantity (kg) | 重量比weight ratio | 其他用量(kg)Other dosage (kg) | 备注Remarks |
| 对羟基苯甲醇P-hydroxybenzyl alcohol | 工业含量≥90.0％Industrial content ≥90.0% | 1818 | 11 | -- | |
| 冰醋酸glacial acetic acid | 工业品Industrial products | 2020 | 1.111.11 | -- | |
| 乙酸乙酯Ethyl acetate | 工业品Industrial products | 9090 | 5.005.00 | -- | |
| 乙醇Ethanol | 工业品Industrial products | 8080 | 4.444.44 | 1010 | 洗涤washing |
| 纯化水purified water | -- | -- | 4040 | 洗涤washing |
(11)酯化反应，称取对羟基苯甲醇18kg、冰醋酸19.5kg和乙酸乙酯90kg，一并加入第一反应罐中，在30℃的温度下搅拌反应8h；(11) 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;
(12)重结晶，将步骤(11)得到的反应液减压浓缩，浓缩得到的残余物用纯化水洗涤2次，每次使用纯水20kg，再用80kg乙醇进行重结晶，升温至65℃搅拌溶解，降温至0～5℃结晶，而后保温结晶110min，形成含对乙酰氧甲基苯酚结晶的结晶液；(12) Recrystallization, the reaction liquid obtained in the step (11) was concentrated under reduced pressure, and the obtained residue was washed twice with purified water, 20 kg of purified water each time, and then recrystallized with 80 kg of ethanol, and the temperature was raised to 65 ° C. Stirring and dissolving, cooling to 0 ~ 5 ° C crystallization, and then crystallization for 110 min, forming a crystal solution containing para-acetoxymethylphenol crystals;
(13)抽滤洗涤，将含对乙酰氧甲基苯酚结晶的结晶液放入抽滤器中抽滤，得到对乙酰氧甲基酚结晶滤饼，后用10kg0～5℃的乙醇洗涤，再抽干。(13) Washing by suction filtration, the crystal solution containing crystals of p-acetoxymethylphenol is placed in a suction filter and suction-filtered to obtain a para-acetoxymethylphenol crystal filter cake, which is then washed with 10 kg of 0 to 5 ° C ethanol, and then pumped. dry.
步骤(1)得到对乙酰氧甲基苯酚结晶湿品≥17.03kg，收率≥57.8％。Step (1) gives p-acetoxymethylphenol crystal wet product ≥ 17.03 kg, yield ≥ 57.8%.
(2)五乙酰天麻素，其化学反应方程式如下：(2) Pentaacetyl gastrodin, the chemical reaction equation is as follows:
步骤(2)中所用的物料使用情况一览表如下所示：The list of material usage used in step (2) is as follows:
| 原料名称raw material name | 规格specification | 数量(kg)Quantity (kg) | 重量比weight ratio | 其他用量(kg)Other dosage (kg) | 备注Remarks |
| 对乙酰氧甲基苯酚Acetoxymethylphenol | 步骤(1)所制Step (1) | 17.0317.03 | 11 | -- | |
| 五乙酰葡萄糖Pentaacetylglucose | 工业品Industrial products | 4040 | 2.352.35 | -- | |
| 乙腈Acetonitrile | 工业品Industrial products | 128128 | 7.527.52 | -- |
| 三氟化硼-乙腈Boron trifluoride-acetonitrile | 工业品Industrial products | 6060 | 3.523.52 | -- | |
| 纯化水purified water | 8080 | 4.704.70 | 4040 | 洗涤washing | |
| 无水硫酸钠Anhydrous sodium sulfate | 工业品Industrial products | 1010 | 0.590.59 | -- | |
| 乙醇Ethanol | 工业品Industrial products | 120120 | 7.087.08 | 23twenty three | 洗涤washing |
中抽滤，得到五乙酰天麻素结晶滤饼，用23kg0～5℃的乙醇洗涤，再抽干。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.
步骤(2)得到五乙酰天麻素湿品≥40.91kg，收率≥79.3％。In step (2), the wet product of pentaacetyl gastrodin is ≥40.91 kg, and the yield is ≥79.3%.
(3)天麻素的制备及精制，其化学反应方程式如下：(21)缩合反应，将称量好的五乙酰葡萄糖40kg、对乙酰氧甲基苯酚17.03kg和乙腈125kg一并放入第二反应罐中，开启搅拌，搅拌下加入三氟化硼-乙腈60kg，加完后控制料液温度在30℃，搅拌反应6h；(3) Preparation and purification of gastrodin, the chemical reaction equation is as follows: (21) condensation reaction, weighing 40 kg of weighed pentaacetylglucose, 17.03 kg of p-acetoxymethylphenol and 125 kg of acetonitrile into the second reaction In the tank, the stirring was started, and 60 kg of boron trifluoride-acetonitrile was added under stirring. After the addition, the temperature of the feed liquid was controlled at 30 ° C, and the reaction was stirred for 6 hours;
(22)分离，缩合反应结束后，将80kg纯化水加入第二反应罐中，搅拌10分钟后静置分层，分离两相，再用40kg纯化水洗涤分离出的有机相，然后第二次静置分层、分离两相，将第二次分离出的有机相用10kg无水硫酸钠干燥，于-0.090MPa、82℃的条件下减压蒸干后，得残余物；(22) Separation, after the condensation reaction is completed, 80 kg of purified water is added to the second reaction tank, stirred for 10 minutes, then allowed to stand for separation, the two phases are separated, and the separated organic phase is washed with 40 kg of purified water, and then the second time. The mixture was allowed to stand for separation and the two phases were separated, and the organic phase separated for the second time was dried with 10 kg of anhydrous sodium sulfate, and evaporated under reduced pressure at -0.090 MPa and 82 ° C to obtain a residue.
(23)重结晶，将已称量好的120kg乙醇加入第二反应罐中，通过调节温度来进行重结晶，升温至65℃后搅拌溶解，再降温至0～5℃结晶，保温结晶2h，形成含五乙酰天麻素结晶的结晶液；(23) Recrystallization, adding 120 kg of ethanol weighed into the second reaction tank, recrystallization by adjusting the temperature, heating to 65 ° C, stirring and dissolving, then cooling to 0 ~ 5 ° C crystallization, thermal crystallization for 2 h, Forming a crystal solution containing pentaacetyl gastrodin crystals;
(24)抽滤洗涤，将含五乙酰天麻素结晶的结晶液放入抽滤器(24) Washing by suction filtration, and crystallization liquid containing pentane gastrodin crystals is placed in a suction filter
步骤(3)中所用的物料使用情况一览表如下所示：
The list of materials used in step (3) is as follows:
| 原料名称raw material name | 规格specification | 数量(kg)Quantity (kg) | 重量比weight ratio | 其他用量(kg)Other dosage (kg) | 备注Remarks |
| 五乙酰天麻素Pentaacetyl gastrodin | 步骤(2)所制Step (2) | 40.9140.91 | 11 | -- | |
| 甲醇Methanol | 工业品Industrial products | 160160 | 5.005.00 | 4040 | 洗涤washing |
| 甲醇钠Sodium methoxide | 工业品Industrial products | 0.060.06 | 0.00150.0015 | -- | |
| 纯化水 purified water | 88 | 0.200.20 | -- | ||
| 药用炭Medicinal charcoal | 针剂injection | 1.51.5 | 0.0370.037 | -- |
(31)备料，将0.06kg甲醇溶于8kg纯化水中配置成0.2mol/L的甲醇钠溶液；将1.5kg药用炭加入到5kg甲醇中，配制成药用炭混悬液；将甲醇抽入洗涤液储罐，开启夹套冷冻盐水，将甲醇温度冷却至0℃，备用；(31) Preparation, dissolving 0.06 kg of methanol in 8 kg of purified water to prepare a 0.2 mol/L sodium methoxide solution; adding 1.5 kg of medicinal charcoal to 5 kg of methanol to prepare a medicinal carbon suspension; Liquid storage tank, open the jacketed frozen brine, and cool the methanol temperature to 0 ° C, standby;
(32)成盐，将40.91kg五乙酰天麻素和130kg甲醇一起加入第三反应罐中，搅拌升温至40℃，后将步骤(31)配制好的甲醇钠溶液加入第三反应罐中，于40℃下保温搅拌反应1.5h；(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;
(33)脱色，停止搅拌，在第三反应罐中加入药用炭混悬液，开启搅拌，在40℃下保温搅拌脱色30min，形成脱色液；(33) Decolorization, stirring was stopped, a medicinal carbon suspension was added to the third reaction tank, stirring was started, and the mixture was decolorized by stirring at 40 ° C for 30 min to form a decolorizing liquid;
(34)压滤，调节好第三反应罐和结晶罐之间的阀门，用0.1MPa的压缩空气，将脱色液从第三反应罐压入结晶罐，而后再用25kg甲醇冲洗第三反应罐，洗液一并压入结晶罐内；(34) Pressure filtration, adjusting the valve between the third reaction tank and the crystallization tank, pressing the decoloring liquid from the third reaction tank into the crystallization tank with 0.1 MPa of compressed air, and then rinsing the third reaction tank with 25 kg of methanol , the washing liquid is pressed into the crystallizing tank;
(35)冷却结晶，开启结晶罐夹套冷冻盐水并开启搅拌，将其中料液温度降至0℃进行析晶，有大量的晶体析出，在0℃的条件下保温析晶1.5h，形成含天麻素晶体的结晶液；(35) cooling the crystal, opening the crystallization tank jacket chilled brine and opening the stirring, and the temperature of the liquid solution is lowered to 0 ° C for crystallization, a large amount of crystals are precipitated, and the crystal is liquefied at 0 ° C for 1.5 h to form a Crystallization solution of gastrodin crystals;
(36)离心洗涤，将含天麻素晶体的结晶液放入离心机中甩滤，甩干后用冷的甲醇洗涤2次，每次使用20kg甲醇，然后甩干，形成天麻素结晶湿品；(36) Centrifugal washing, the crystal solution containing gastrodin crystals is placed in a centrifuge and filtered, dried, and washed twice with cold methanol, 20 kg of methanol each time, and then dried to form a gastrodiazein crystal wet product;
(37)真空干燥，将天麻素结晶湿品放入打粉机中打粉后分装到干燥盘中，于68～72℃、-0.085MPa真空度下干燥6h，得到天麻素结晶；(37) vacuum drying, 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;
(38)粉碎内包，将干燥好的天麻素结晶放入打粉机中粉碎，按10kg/桶的包装规格分装到全纸桶中。(38) 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.
步骤(3)得到天麻素白色结晶粉末≥19.60kg，收率≥96.3％。Step (3) gives a gastrodin white crystal powder ≥ 19.60 kg, and the yield is ≥ 96.3%.
以上所述仅为本发明的实施例，并非因此限制本发明的专利范围，凡是
利用本发明说明书及附图内容所作的等效结构或等效流程变换，或直接或间接运用在其他相关的技术领域，均同理包括在本发明的专利保护范围内。
The above description is only an embodiment of the present invention, and thus does not limit the scope of the patent of the present invention.
The equivalent structure or equivalent flow transformation made by the specification and the drawings of the present invention, or directly or indirectly applied to other related technical fields, are all included in the scope of patent protection of the present invention.
Claims (6)
- 一种天麻素的生产工艺，其特征在于，包括对乙酰氧甲基苯酚的制备、五乙酰天麻素的制备和天麻素的制备及精制；A process for producing gastrodin, which comprises the preparation of p-acetoxymethylphenol, the preparation of pentaacetyl gastrodin and the preparation and purification of gastrodin;(1)对乙酰氧甲基苯酚的制备，将对羟基苯甲醇、冰醋酸和乙酸乙酯一起搅拌反应8～9h，再将得到的反应液减压浓缩，浓缩得到的残余物用纯化水洗涤再用乙醇重结晶，形成含对乙酰氧甲基苯酚结晶的结晶液，而后抽滤，对乙酰氧甲基苯酚结晶滤饼用乙醇洗涤，最后抽干，形成对乙酰氧甲基苯酚湿品；(1) Preparation of p-acetoxymethylphenol, the reaction mixture is stirred for 8 to 9 hours with p-hydroxybenzyl alcohol, glacial acetic acid and ethyl acetate, and the obtained reaction liquid is concentrated under reduced pressure, and the obtained residue is washed with purified water. Recrystallization from ethanol to form a crystal solution containing crystals of p-acetoxymethylphenol, followed by suction filtration, washing the acetoxymethylphenol crystal filter cake with ethanol, and finally draining to form a wet product of p-acetoxymethylphenol;(2)五乙酰天麻素的制备，将五乙酰葡萄糖、对乙酰氧甲基苯酚和乙腈进行搅拌反应，搅拌过程中加入三氟化硼-乙腈，后再搅拌反应5～8h；反应结束后加入适量纯化水，搅拌后静置分层，分离两相，再用纯化水洗涤分离出的有机相，然后第二次静置分层、分离两相，将第二次分离出的有机相用无水硫酸钠干燥，蒸干后得到残余物用乙醇进行重结晶，形成含五乙酰天麻素结晶的结晶液，后进行抽滤得到五乙酰天麻素结晶；(2) Preparation of pentaacetyl gastrodin, stirring reaction of pentaacetylglucose, p-acetoxymethylphenol and acetonitrile, adding boron trifluoride-acetonitrile during stirring, and then stirring the reaction for 5-8 hours; Appropriate amount of purified water, stirring, standing layering, separating the two phases, and then washing the separated organic phase with purified water, then standing still for the second time, separating the two phases, and separating the organic phase separated for the second time. Drying with sodium sulfate and evaporation to dryness, the residue is recrystallized from ethanol to form a crystal solution containing pentaacetyl gastrodin crystals, followed by suction filtration to obtain pentaacetyl gastrodin crystals;(3)天麻素的制备及精制，将五乙酰天麻素和甲醇一并搅拌反应，后加入甲醇钠溶液于40.0℃保温搅拌反应1～2h；停止搅拌后加入药用炭混悬液脱色，形成脱色液，后将脱色液压入结晶罐中，开启结晶罐夹套冷冻盐水，温度降至0℃以后搅拌析晶，最后离心甩干后真空干燥得到天麻素。(3) Preparation and purification of gastrodin, stirring the reaction of pentaacetyl gastrodin and methanol together, then adding sodium methoxide solution and stirring at 40.0 ° C for 1 to 2 hours; after stirring, adding medicinal carbon suspension to decolorize, forming After decolorizing the liquid, the decolorizing hydraulic pressure is introduced into the crystallizing tank, and the crystallization tank jacket is opened to freeze the brine. After the temperature is lowered to 0 ° C, the crystal is stirred and finally centrifuged, dried, and vacuum dried to obtain gastrodin.
- 根据权利要求1所述的天麻素的生产工艺，其特征在于，所述步骤(1)中对乙酰氧甲基苯酚的制备，具体包括下述步骤：The process for producing gastrodin according to claim 1, wherein the preparation of the para-acetoxymethylphenol in the step (1) comprises the following steps:(11)酯化反应，将对羟基苯甲醇、冰醋酸和乙酸乙酯一并加入第一反应罐中，在30℃的温度下搅拌反应8h；所述对羟基苯甲醇、冰醋酸和乙酸乙酯的质量份数比为1:1.11:5.00；(11) 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;(12)重结晶，将步骤(11)得到的反应液减压浓缩，浓缩得到的残余物用纯化水洗涤，再用乙醇进行重结晶，升温至65℃搅拌溶解，降温至0～5℃结晶，而后保温结晶110～120min，形成含对乙酰氧甲基苯酚结晶的结晶液；(12) Recrystallization, 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;(13)抽滤洗涤，将含对乙酰氧甲基苯酚结晶的结晶液放入抽滤器中抽滤，得到对乙酰氧甲基酚结晶滤饼，后用0～5℃的乙醇洗涤，再抽干，得到对乙酰氧甲基苯酚结晶湿品。(13) Washing by suction filtration, the crystal solution containing crystals of p-acetoxymethylphenol is placed in a suction filter and suction-filtered to obtain a para-acetoxymethylphenol crystal filter cake, which is then washed with 0 to 5 ° C of ethanol, and then pumped. Dry to obtain a crystalline wet product of p-acetoxymethylphenol.
- 3、根据权利要求1所述的天麻素的生产工艺，其特征在于，所述步骤(2)中五乙酰天麻素的制备具体包括下述步骤： The process for producing gastrodin according to claim 1, wherein the preparation of the pentaacetyl gastrodin in the step (2) specifically comprises the following steps:(21)缩合反应，将五乙酰葡萄糖、对乙酰氧甲基苯酚和乙腈一并放入第二反应罐中，开启搅拌，搅拌下加入三氟化硼-乙腈，加完后控制料液温度在30℃，搅拌反应6h；其中，五乙酰葡萄糖、对乙酰氧甲基苯酚、乙腈和三氟化硼-乙腈的质量份数比为2.35:1:7.52:3.52；(21) Condensation reaction, putting pentaacetylglucose, p-acetoxymethylphenol and acetonitrile into a second reaction tank, stirring is started, boron trifluoride-acetonitrile is added under stirring, and the temperature of the feed liquid is controlled after the addition. The reaction was stirred at 30 ° C for 6 h; wherein the mass fraction ratio of pentaacetylglucose, p-acetoxymethylphenol, acetonitrile and boron trifluoride-acetonitrile was 2.35:1:7.52:3.52;(22)分离，将纯化水加入第二反应罐搅拌10分钟后静置分层，分离两相，再用纯化水洗涤分离出的有机相，然后第二次静置分层、分离两相，将第二次分离出的有机相用无水硫酸钠干燥，减压蒸干后得残余物；(22) Separation, adding purified water to the second reaction tank and stirring for 10 minutes, then standing to separate the layers, separating the two phases, and then washing the separated organic phase with purified water, then standing still for two times, separating the two phases, The organic phase separated a second time is dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure;(23)重结晶，将乙醇加入第二反应罐中，通过调节温度来进行重结晶，升温至65℃后搅拌溶解，再降温至0～5℃结晶，保温结晶2h，形成含五乙酰天麻素结晶的结晶液；(23) Recrystallization, adding ethanol to the second reaction tank, recrystallization by adjusting the temperature, heating to 65 ° C, stirring and dissolving, then cooling to 0 ~ 5 ° C crystallization, heat crystallization for 2 h, forming pentane acetylephrine Crystallized crystal solution;(24)抽滤洗涤，将含五乙酰天麻素结晶的结晶液放入抽滤器中抽滤，得到五乙酰天麻素结晶滤饼，用0～5℃的乙醇洗涤，再抽干，得到五乙酰天麻素湿品。(24) Washing by suction filtration, and crystallization liquid containing pentaacetyl gastrodin crystals is filtered in a suction filter to obtain a pentaacetyl gastrodin crystal filter cake, washed with 0 to 5 ° C ethanol, and then drained to obtain pentaacetyl. Gastrodin wet product.
- 根据权利要求3所述的天麻素的生产工艺，其特征在于，在所述步骤(22)中，加压蒸干的条件是气压为-0.09Mpa、温度为82℃。The process for producing gastrodin according to claim 3, characterized in that in the step (22), the conditions of pressurization and evaporation are a gas pressure of -0.09 MPa and a temperature of 82 °C.
- 根据权利要求1所述的天麻素的生产工艺，其特征在于，在所述步骤(3)中天麻素的制备及精制，具体包括下述步骤：The process for producing gastrodin according to claim 1, characterized in that the preparation and purification of gastrodin in the step (3) specifically comprises the following steps:(31)备料，将0.06kg甲醇溶于8kg纯化水中配置成0.2mol/L的甲醇钠溶液；将1.5kg药用炭加入到5kg甲醇中，配制成药用炭混悬液；将甲醇抽入洗涤液储罐，开启夹套冷冻盐水，将甲醇温度冷却至0℃；(31) Preparation, dissolving 0.06 kg of methanol in 8 kg of purified water to prepare a 0.2 mol/L sodium methoxide solution; adding 1.5 kg of medicinal charcoal to 5 kg of methanol to prepare a medicinal carbon suspension; Liquid storage tank, open the jacketed frozen brine, and cool the methanol temperature to 0 ° C;(32)成盐，将五乙酰天麻素和甲醇一起加入第三反应罐中，搅拌升温至40℃，后将步骤(31)配置好的甲醇钠溶液加入第三反应罐中，于40℃下保温搅拌反应1.5h；(32) salt formation, adding pentane 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;(33)脱色，在第三反应罐中加入药用炭混悬液，在40℃下保温搅拌脱色30min，形成脱色液；(33) Decolorization, adding a medicinal carbon suspension in the third reaction tank, and decolorizing at 40 ° C for 30 min to form a decolorizing liquid;(34)压滤，将脱色液从第三反应罐压入结晶罐，而后再用甲醇冲洗第三反应罐，洗液一并压入结晶罐内；(34) pressure filtration, press the decoloring liquid from the third reaction tank into the crystallization tank, and then rinse the third reaction tank with methanol, and the washing liquid is pressed into the crystallizing tank;(35)冷却结晶，开启结晶罐夹套冷冻盐水并开启搅拌，将其中料液温度降至0℃进行析晶，保温析晶1.5h，形成含天麻素晶体的结晶液；(35) cooling the crystal, opening the crystallization tank jacket frozen brine and opening the stirring, the temperature of the liquid solution is lowered to 0 ° C for crystallization, and the crystallization is performed for 1.5 h to form a crystal liquid containing gastrodin crystals;(36)离心洗涤，将含天麻素晶体的结晶液放入离心机中甩滤，甩干后用甲醇洗 涤，然后甩干，形成天麻素结晶湿品；(36) Centrifugal washing, the crystal solution containing gastrodin crystals is placed in a centrifuge, filtered, dried, and washed with methanol. Polyester, then dried to form a gastrodialysin wet product;(37)真空干燥，将天麻素结晶湿品放入打粉机中打粉后分装到干燥盘中干燥6～8h，得到天麻素结晶；(37) vacuum drying, 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;(38)粉碎内包，将天麻素结晶放入打粉机中粉碎，而后包装。(38) The inner package is pulverized, and the gastrodin crystal is pulverized in a powdering machine and then packaged.
- 根据权利要求5所述的天麻素的生产工艺，其特征在于，在步骤(37)中，天麻素结晶湿品分装到干燥盘中之后，在68～72℃、-0.085MPa的真空度下进行干燥。 The process for producing gastrodin according to claim 5, wherein in the step (37), the gastrodin crystal wet product is dispensed into the drying tray at a vacuum of 68 to 72 ° C and -0.085 MPa. Dry.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410329077.3A CN104072549B (en) | 2014-07-11 | 2014-07-11 | The production technique of Gastrodine |
| CN201410329077.3 | 2014-07-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2016004704A1 true WO2016004704A1 (en) | 2016-01-14 |
Family
ID=51594191
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2014/089422 WO2016004704A1 (en) | 2014-07-11 | 2014-10-24 | Gastrodin production process |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN104072549B (en) |
| WO (1) | WO2016004704A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109609434A (en) * | 2018-11-23 | 2019-04-12 | 湖南中医药大学 | The method and application of bioconversion synthetic gastrodin |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104072549B (en) * | 2014-07-11 | 2016-03-09 | 江苏汉斯通药业有限公司 | The production technique of Gastrodine |
| CN105997853A (en) * | 2016-05-23 | 2016-10-12 | 悦康药业集团有限公司 | Preparation method of gastrodin injection liquid |
| CN106279311B (en) * | 2016-08-23 | 2018-08-14 | 宜宾莱特医药化工有限公司 | A kind of 4- hydroxymethyl phenyl-β-D glucopyranoside synthetic methods |
| CN110903333A (en) * | 2019-12-30 | 2020-03-24 | 陕西岳达德馨生物制药有限公司 | Preparation method of glucoside and derivatives thereof |
| CN114573647A (en) * | 2020-11-30 | 2022-06-03 | 昆药集团股份有限公司 | Gastrodin anhydrous crystal form and preparation method thereof |
| CN114685575A (en) * | 2020-12-29 | 2022-07-01 | 昆药集团股份有限公司 | Gastrodin anhydrous crystal form and preparation method thereof |
| CN114685576A (en) * | 2020-12-29 | 2022-07-01 | 昆药集团股份有限公司 | High-purity gastrodin unstable crystal form, preparation method thereof and preparation method of gastrodin crystal form FormA |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977161A (en) * | 2012-12-17 | 2013-03-20 | 青岛农业大学 | Method for chemically synthesising gastrodin |
| CN104072549A (en) * | 2014-07-11 | 2014-10-01 | 江苏汉斯通药业有限公司 | Production process of gastrodin |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7622563B2 (en) * | 2002-07-11 | 2009-11-24 | Mitsui Chemicals, Inc. | Process for producing glycoside |
| CN103804438B (en) * | 2012-11-12 | 2016-09-07 | 昆药集团股份有限公司 | A kind of high-purity, the semisynthesis of high stability Gastrodin |
| CN103275146B (en) * | 2013-06-13 | 2015-07-29 | 青岛农业大学 | A kind of Gastrodine chemical synthesis process being suitable for industrialization |
-
2014
- 2014-07-11 CN CN201410329077.3A patent/CN104072549B/en active Active
- 2014-10-24 WO PCT/CN2014/089422 patent/WO2016004704A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977161A (en) * | 2012-12-17 | 2013-03-20 | 青岛农业大学 | Method for chemically synthesising gastrodin |
| CN104072549A (en) * | 2014-07-11 | 2014-10-01 | 江苏汉斯通药业有限公司 | Production process of gastrodin |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109609434A (en) * | 2018-11-23 | 2019-04-12 | 湖南中医药大学 | The method and application of bioconversion synthetic gastrodin |
| CN109609434B (en) * | 2018-11-23 | 2022-08-30 | 湖南中医药大学 | Method for synthesizing gastrodin through biotransformation and application |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104072549B (en) | 2016-03-09 |
| CN104072549A (en) | 2014-10-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2016004704A1 (en) | Gastrodin production process | |
| CN104447600B (en) | A kind of Preparation Method And Their Intermediate impurity of Parecoxib sodium compound, preparation method and application | |
| US9663550B2 (en) | Method for preparing abiraterone acetate | |
| CN105968093A (en) | Preparation method for trelagliptin succinate | |
| BR112016010788B1 (en) | PROCESS FOR THE LARGE-SCALE PRODUCTION OF 1-[(2-BROMOPHENYL)SULFONYL]-5-METHOXY-3-[(4-METHYL-1-PIPERAZINYL)METHYL]-1H-INDOLE | |
| CN110590587A (en) | Synthetic method of 3-chloro-L-alanine methyl ester hydrochloride | |
| WO2021212535A1 (en) | Method for refining benzhexol hydrochloride | |
| CN108017601B (en) | Method for refining ranitidine alkali | |
| CN116350618A (en) | Stable pharmaceutical composition containing non-steroidal anti-inflammatory drug derivative | |
| KR101737883B1 (en) | Crystal form of compound used as mineralocorticoid receptor antagonist and preparation method therefor | |
| CN112724191B (en) | Refining method of dienogest | |
| WO2023122868A1 (en) | Posaconazole impurity reference substance and preparation method therefor | |
| CN111978266B (en) | Parecoxib sodium, injection preparation and preparation method | |
| CN107879979A (en) | A kind of preparation method of Dexmedetomidine | |
| WO2017177781A1 (en) | Ahu377 crystal forms, and preparation method therefor and use thereof | |
| TWI662031B (en) | Crystals of 1- ｛2-fluoro-4- [5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl] -benzylpyrene-3-azetidinecarboxylic acid type | |
| CN102206185B (en) | Process for refining bendazac lysine and analogs thereof | |
| CN104098638A (en) | Dehydroepiandrosterone acetate preparation method | |
| CN102746178B (en) | The preparation method of flutamide | |
| CN108440324B (en) | Ornithine aspartate and crystallization method thereof | |
| CN110156860A (en) | A kind of purification process of high-purity Austria shellfish cholic acid | |
| CN108863946B (en) | Preparation method of dibazole impurity reference substance | |
| CN114920705B (en) | Preparation method and application of glipizide ester impurities | |
| EP2045244A1 (en) | Novel crystal of substituted phenylalkanoic acid and production process | |
| WO2014106419A1 (en) | Process for synthesizing 1-methyl-2-oxo-3,6,7-trioxabicyclo[2,2,2]octane |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14897112 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 14897112 Country of ref document: EP Kind code of ref document: A1 |