CN1709869A - Vitamin D separating, purifying and crystallizing method - Google Patents
Vitamin D separating, purifying and crystallizing method Download PDFInfo
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- CN1709869A CN1709869A CN 200510040330 CN200510040330A CN1709869A CN 1709869 A CN1709869 A CN 1709869A CN 200510040330 CN200510040330 CN 200510040330 CN 200510040330 A CN200510040330 A CN 200510040330A CN 1709869 A CN1709869 A CN 1709869A
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Abstract
This invention involves the separating purification and crystallization method to vitamin D2, D3, D4. Dissolve the actinic oil of vitamin D in absorption solvent by weight ratio of 0.3-3, feed it into chromatography column which has installed alumina inside; Elute separating by elution solvents, collect by subsection, track the part of pure vitamin D with the folium analytical approach, until vitamin D is totally washed out; The pure vitamin D component that has been collected decompresses to remove solvents, put into the crystal solvent, when -5 to -10 deg. C, freeze and crystal, filter after 10-16 hours, vacuum getting dry vitamin D crystallisation. This invention improves accepting rate and purity, the craft is simple, lower costs and has reduced the environmental pollution.
Description
Technical field
The invention belongs to photochemistry synthesis of vitamin d field, particularly vitamins D
2, D
3, D
4Purify and separate and the crystalline method.
Background technology
Vitamins D is human health, domestic animal, poultry normal growth and breeds one of requisite important VITAMIN, there are impurity and remaining 7-dehydrocholesterols such as a large amount of tachysterols, lumisterol in the product of photochemical synthesis of vitamin d, these byproducts are because structural similitude, character is close, have a strong impact on the separation purification and the crystallization of vitamins D, wherein tachysterol still is malicious byproduct, therefore must separate and remove.The classical way of removing these impurity is to adopt 3,5 dinitrobenzoylchloride or butyryl chloride esterification Crystallization Separation method of purification, and this method technical process is long, and toxicity is big, and three waste discharge is many.Owing to be fractionation, so the vitamins D loss is many, also have not carboxylate fully simultaneously, so yield is low.And the chromatography rule adopts benzene to make solvent, and toxicity is big.Chinese patent 99108675.9 is introduced and is used overcritical column chromatography, owing to need the high pressure with 7.5-15Mpa, device security requires high, is difficult to industrialization, and needs the more expensive modified silica-gel of price.
Summary of the invention
At above problem, the purpose of this invention is to provide the vitamins D that a kind of technological process is simple, treatment capacity is big, toxicity is low, environmental pollution is little, yield is high and separate purification and crystallization method novel method.
Technical scheme of the present invention is: adopt column chromatography, earlier by 1: the weight ratio of 0.3-3 fully is dissolved in the photochemical oil of vitamins D in the adsorption solvent, the chromatography column of dress aluminum oxide in injecting; Carry out wash-out with eluting solvent and separate, Fractional Collections is followed the tracks of with thin layer chromatography, washes out fully until vitamins D; With the pure vitamin D component removal of solvent under reduced pressure of collecting, add recrystallisation solvent, freezing and crystallizing under-5-10 ° temperature, through 10-16 hour after-filtration, vacuum-drying got the vitamins D crystallization.
Evenly add the fine particulate alumina adsorbant with porous plate to chromatography column.
Above-mentioned adsorption solvent is: alkane, as sherwood oil; Naphthenic hydrocarbon is as hexanaphthene, pentamethylene, normal hexane; The ester class is as methyl acetate, ethyl formate, ethyl acetate, N-BUTYL ACETATE etc.; Alcohols is as methyl alcohol, ethanol; Preferred sherwood oil, normal hexane, ethyl acetate.
Above-mentioned eluting solvent is: alkane, as sherwood oil, normal hexane; Naphthenic hydrocarbon is as hexanaphthene, pentamethylene; Halohydrocarbon, as methylene dichloride, the ester class is as methyl acetate, ethyl formate, ethyl acetate, N-BUTYL ACETATE; Alcohols: as methyl alcohol, ethanol, or have the mixture of the above solvent of close polarity and washing effect, preferred methylene dichloride and ethyl acetate.
Above-mentioned recrystallisation solvent is: ketone, as acetone; The ester class is as methyl-formiate, methyl acetate, ethyl formate, ethyl acetate, acetic acid, butyl ester; Alcohols: as methyl alcohol and ethanol; Or non-proton property polar solvent, as oxo solvent, nitrogen-containing solvent and other their mixtures; Preferable formic acid methyl esters, methyl alcohol or ethyl acetate.
Above-mentioned recrystallisation solvent is 0.5-3 with the weight ratio of the pure vitamin D component of collecting: 1.
The present invention adopts column chromatography, selects high-efficiency aluminum oxide sorbent material and special dress post method, suitable solvent systems, improved yield, purity reaches more than 99.7%, and technology is simple, reduce cost, reduced environmental pollution, reached the purpose of green chemical industry process basically.
Embodiment
1, the selection of sorbent material
Sorbent material is most important to column chromatography for separation.Sorbent material commonly used has silica gel, aluminum oxide etc., because the alumina adsorption capacity is big, cheap and easy to get, and good separating effect, therefore preferred aluminum oxide is as the column chromatography stationary phase.
2, dress post method
Separator column evenly whether directly influence separating effect, so sorbent material must be adorned very evenly.The present invention adopts the charging process of even porous plate, can obviously improve the separating effect of post.
3, chromatography solvent systems
The chromatography solvent systems is extremely important to the separation fully of each component.Earlier photochemical oil is dissolved in the adsorption solvent, adds in the post and adsorb.Separate washing out again with eluting solvent, follow the tracks of with thin layer chromatography, Fractional Collections is to reach complete isolating purpose.These solvents can be alkane such as sherwood oil etc.; Naphthenic hydrocarbon such as hexanaphthene, pentamethylene etc.; Halohydrocarbon such as methylene dichloride etc.; Ester class such as methyl acetate, ethyl formate, ethyl acetate, N-BUTYL ACETATE etc.; Alcohols such as methyl alcohol, ethanol etc.; Or have the mixture of the above solvent of close polarity and washing effect, to reach the separation fully of each component.
4, recrystallisation solvent system
The chromatographic solution of Fractional Collections is not complete single composition, also contains some impurity, must carry out crystallization, just can obtain pure vitamins D with further separating impurity.Therefore the selection of recrystallisation solvent is extremely important.These solvents are ketone such as acetone; Ester class such as methyl-formiate, methyl acetate, ethyl formate, ethyl acetate, N-BUTYL ACETATE; Alcohols such as methyl alcohol and ethanol.The present invention is preferred crystallization solvent system has obtained the vitamins D crystallization that crystalline form is good, purity is very high.
Below example specifies above process by experiment.
Embodiment 1
Press 0.4-0.6: 1 weight ratio, or with 50 the gram 2,386 ten thousand IU vitamins D
3Photochemical oil (crude product) is dissolved in the 100 gram sherwood oils, evenly joins 4 centimetres of internal diameters by porous plate, and is high 1 meter, in adorn in the chromatography column of 1 kilogram of aluminum oxide, wait to have flowed the back and carry out wash-out separation with ethyl acetate, Fractional Collections, is followed the tracks of with thin plate by 5 liters every part.With the pure vitamin D that collects
3The component evaporated under reduced pressure adds the recrystallisation solvent ethyl acetate, and freezing and crystallizing filtered 12 hours, and vacuum-drying again gets the needle-like vitamins D
3Crystallization 8.2 grams, purity is 99.7%, 111.0 ° of optically-actives meet the vitamins D that pharmacopeia is stipulated
3
Embodiment 2
With 400 grams, 2,452 ten thousand IU vitamins Ds
3Photochemical oil (crude product) is dissolved in 800 ml n-hexanes, joins 10 centimetres of internal diameters, and is high 2 meters, in adorn in the chromatography column of 10 kilograms of aluminum oxide, wait to have flowed the back and carry out wash-out with methylene dichloride and separate, Fractional Collections, is followed the tracks of with thin plate by 500 milliliters every part.Pure vitamin D component evaporated under reduced pressure with collecting adds recrystallisation solvent methyl esters methyl esters 200ml, and freezing and crystallizing filters, and vacuum-drying gets the needle-like vitamins D
3Crystallization 65.5 grams.Purity is 100.1%, and 111.9 ° of optically-actives meet the vitamins D that pharmacopeia is stipulated
3
Embodiment 3
Vitamins D with 50 grams, 1,800 ten thousand IU
2Photochemical oil is dissolved in 100 milliliters of ethyl acetate, joins in the alumina adsorption post as embodiment 1, and presses embodiment 1 process operations.With the vitamins D of collecting
2The component methanol crystallization gets the acicular vitamins D that meets the pharmacopeia requirement of 6.5 grams
2Crystallization.
Claims (7)
1, a kind of vitamins D separates purification and crystallization method, and it is characterized in that earlier by 1: the weight ratio of 0.3-3 fully is dissolved in the photochemical oil of vitamins D in the adsorption solvent, the chromatography column of dress aluminum oxide in injecting; Carry out wash-out with eluting solvent and separate, Fractional Collections is followed the tracks of pure vitamin D component with thin layer chromatography, washes out fully until vitamins D; With the pure vitamin D component removal of solvent under reduced pressure of collecting, add recrystallisation solvent, freezing and crystallizing under-5-10 ° temperature, after filtering in 10-16 hour, vacuum-drying gets the vitamins D crystallization.
2, vitamins D according to claim 1 separates purification and crystallization method, it is characterized in that evenly adding the fine particulate alumina adsorbant with porous plate to chromatography column.
3, vitamins D according to claim 2 separates purification and crystallization method, and it is characterized in that by 0.4-0.6: 1 weight ratio is with vitamins D
3Photochemical oil fully is dissolved in adsorption solvent.
4, vitamins D according to claim 1 separates purification and crystallization method, it is characterized in that adsorption solvent is: alkane, as sherwood oil, normal hexane; Naphthenic hydrocarbon is as hexanaphthene, pentamethylene; The ester class is as methyl acetate, ethyl formate, ethyl acetate, N-BUTYL ACETATE; Alcohols is as methyl alcohol, ethanol; Preferred sherwood oil, normal hexane, ethyl acetate.
5, vitamins D according to claim 1 separates purification and crystallization method, it is characterized in that eluting solvent is: alkane, as sherwood oil, normal hexane; Naphthenic hydrocarbon is as hexanaphthene, pentamethylene; Halohydrocarbon is as methylene dichloride; The ester class is as methyl acetate, ethyl formate, ethyl acetate, N-BUTYL ACETATE; Alcohols is as methyl alcohol, ethanol; Or have a mixture of the above solvent of close polarity and washing effect, preferred methylene dichloride and ethyl acetate.
6, vitamins D according to claim 1 separates purification and crystallization method, it is characterized in that recrystallisation solvent is: ketone, as acetone; The ester class is as methyl-formiate, methyl acetate, ethyl formate, ethyl acetate, N-BUTYL ACETATE; Alcohols is as methyl alcohol and ethanol; Or non-proton property polar solvent, as oxo solvent, nitrogen-containing solvent and other their mixtures; Preferred acetone, methyl-formiate, ethyl acetate, methyl alcohol.
7, vitamins D according to claim 1 separates purification and crystallization method, it is characterized in that the recrystallisation solvent and the weight ratio of the pure vitamin D component of collecting are 0.5-3: 1.
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| CNB2005100403304A CN100347156C (en) | 2005-05-31 | 2005-05-31 | Vitamin D separating, purifying and crystallizing method |
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| CN101863809A (en) * | 2010-05-12 | 2010-10-20 | 重庆泰濠制药有限公司 | Method for purifying doxercalciferol |
| CN101998949A (en) * | 2008-03-12 | 2011-03-30 | 赛特克罗公司 | Stabilized 1,25-dihydroxyvitamin D2 and method of making same |
| CN102850248A (en) * | 2012-09-29 | 2013-01-02 | 浙江花园生物高科股份有限公司 | Technology for preparing vitamin D3 |
| CN103073469A (en) * | 2013-01-16 | 2013-05-01 | 青岛正大海尔制药有限公司 | Preparation method for alfacalcidol |
| CN103191134A (en) * | 2013-04-26 | 2013-07-10 | 四川省惠达药业有限公司 | Pharmaceutical composition of lipid-soluble vitamin and preparation method thereof |
| CN107151178A (en) * | 2017-06-26 | 2017-09-12 | 徐州市贾汪区恒之盛农业发展有限公司 | A kind of composite nutrient-fluid of vegetables in day-light greenhouse |
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| CN107744064A (en) * | 2017-09-08 | 2018-03-02 | 芜湖永昌生物科技有限公司 | A kind of Elaphe Carinatas feed formula and preparation method thereof |
| CN108017126A (en) * | 2017-10-30 | 2018-05-11 | 周爱民 | A kind of improver of water quality used for aquiculture |
| CN108094703A (en) * | 2018-01-08 | 2018-06-01 | 菏泽学院 | A kind of alimentation composition of animal and preparation method thereof |
| CN108918848A (en) * | 2018-05-22 | 2018-11-30 | 德康润生物科技（北京）有限公司 | Vitamin D releasing reagent and the preparation method and application thereof |
| CN110527700A (en) * | 2019-08-30 | 2019-12-03 | 厦门金达威维生素有限公司 | A kind of vitamin D3Method of purification |
| CN114369047A (en) * | 2022-01-27 | 2022-04-19 | 重庆迈德凯医药有限公司 | Method for crystallizing vitamin D3 |
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| WO2014085486A2 (en) | 2012-11-30 | 2014-06-05 | Waters Technologies Corporation | Methods and apparatus for the analysis of vitamin d metabolites |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| EP0969001A3 (en) * | 1998-06-23 | 2005-09-14 | DSM IP Assets B.V. | Process for the preparation of vitamin D3 and provitamin D3 |
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2005
- 2005-05-31 CN CNB2005100403304A patent/CN100347156C/en active Active
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| CN101998949A (en) * | 2008-03-12 | 2011-03-30 | 赛特克罗公司 | Stabilized 1,25-dihydroxyvitamin D2 and method of making same |
| CN101998949B (en) * | 2008-03-12 | 2015-11-25 | 赛特克罗公司 | 1,25-dihydroxyvitamin D 2 and its preparation method of stabilization |
| CN101863809B (en) * | 2010-05-12 | 2013-11-13 | 重庆泰濠制药有限公司 | Method for purifying doxercalciferol |
| CN101863809A (en) * | 2010-05-12 | 2010-10-20 | 重庆泰濠制药有限公司 | Method for purifying doxercalciferol |
| CN102850248A (en) * | 2012-09-29 | 2013-01-02 | 浙江花园生物高科股份有限公司 | Technology for preparing vitamin D3 |
| CN103073469A (en) * | 2013-01-16 | 2013-05-01 | 青岛正大海尔制药有限公司 | Preparation method for alfacalcidol |
| CN103191134A (en) * | 2013-04-26 | 2013-07-10 | 四川省惠达药业有限公司 | Pharmaceutical composition of lipid-soluble vitamin and preparation method thereof |
| CN103191134B (en) * | 2013-04-26 | 2014-02-12 | 四川省惠达药业有限公司 | Pharmaceutical composition of lipid-soluble vitamin and preparation method thereof |
| CN107151178A (en) * | 2017-06-26 | 2017-09-12 | 徐州市贾汪区恒之盛农业发展有限公司 | A kind of composite nutrient-fluid of vegetables in day-light greenhouse |
| CN107744064A (en) * | 2017-09-08 | 2018-03-02 | 芜湖永昌生物科技有限公司 | A kind of Elaphe Carinatas feed formula and preparation method thereof |
| CN107691828A (en) * | 2017-09-08 | 2018-02-16 | 芜湖永昌生物科技有限公司 | One kind promotees digestion Elaphe Carinatas feed and preparation method thereof |
| CN108017126A (en) * | 2017-10-30 | 2018-05-11 | 周爱民 | A kind of improver of water quality used for aquiculture |
| CN108094703A (en) * | 2018-01-08 | 2018-06-01 | 菏泽学院 | A kind of alimentation composition of animal and preparation method thereof |
| CN108918848A (en) * | 2018-05-22 | 2018-11-30 | 德康润生物科技（北京）有限公司 | Vitamin D releasing reagent and the preparation method and application thereof |
| CN110527700A (en) * | 2019-08-30 | 2019-12-03 | 厦门金达威维生素有限公司 | A kind of vitamin D3Method of purification |
| CN110527700B (en) * | 2019-08-30 | 2021-07-16 | 厦门金达威维生素有限公司 | Vitamin D3Purification method of (2) |
| CN114369047A (en) * | 2022-01-27 | 2022-04-19 | 重庆迈德凯医药有限公司 | Method for crystallizing vitamin D3 |
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| CN100347156C (en) | 2007-11-07 |
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Address after: 317016 Zhejiang city of Taizhou province chemical raw materials base of Coastal Park Nanyang Road No. 22 Taizhou Haisheng Pharmaceutical Co. Ltd. Patentee after: Taizhou Hisound Pharmaceutical Co., Ltd. Address before: 317016 Zhejiang 317000 Duqiao Chemical Industry Park Haisheng Chemical Co. Ltd. Patentee before: Taizhou Hisound Chemical Company Ltd |
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Address after: 317016 Zhejiang Zhejiang 317000 chemical raw materials base of Coastal Park Nanyang Road No. 22 Taizhou Haisheng Pharmaceutical Co. Ltd. Patentee after: Taizhou Hisound Pharmaceutical Co., Ltd. Address before: 317016 Zhejiang city of Taizhou province chemical raw materials base of Coastal Park Nanyang Road No. 22 Taizhou Haisheng Pharmaceutical Co. Ltd. Patentee before: Taizhou Hisound Pharmaceutical Co., Ltd. |