WO2021036384A1 - Procédé de purification de vitamine d3 - Google Patents

Procédé de purification de vitamine d3 Download PDF

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Publication number
WO2021036384A1
WO2021036384A1 PCT/CN2020/093960 CN2020093960W WO2021036384A1 WO 2021036384 A1 WO2021036384 A1 WO 2021036384A1 CN 2020093960 W CN2020093960 W CN 2020093960W WO 2021036384 A1 WO2021036384 A1 WO 2021036384A1
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vitamin
purifying
lipase
ester
column
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PCT/CN2020/093960
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English (en)
Chinese (zh)
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蔡育森
余曦
何剑洋
王志强
许德兴
魏高宁
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厦门金达威维生素有限公司
厦门金达威集团股份有限公司
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Publication of WO2021036384A1 publication Critical patent/WO2021036384A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group

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  • the present invention relates to the field of vitamins, particularly to a method for the purification of vitamin D 3.
  • Vitamin D 3 also known as cholecalciferol, has the physiological functions of promoting intestinal calcium absorption, regulating calcium and phosphorus metabolism, and inducing bone calcium and phosphorus deposition. It can promote bone growth and prevent rickets. Large doses are also used for skin tuberculosis. , Skin and mucous membranes of various types of lupus erythematosus, etc.
  • Vitamin D 3 synthesized by photochemical reaction contains tachysterol, photosterol and residual raw material 7-dehydrocholesterol produced by side reactions. Generally, only 20-30 million IU/g of vitamin D 3 can be obtained. These by-products are similar in structure. Similar in nature, it is difficult to further separate and purify.
  • vitamin D 3 purification methods mainly include chemical methods and column chromatography, and there is also a supercritical CO 2 column separation method.
  • the chemical method such as US3157678A, is based on the principle that the illuminated product is made into the corresponding ester, and the difference in solubility in the solvent caused by the difference in the structure of the substance after esterification is used to separate impurities through multiple crystallizations, and then saponified into vitamin D 3 , and then Further crystallization and purification to obtain food-grade vitamin D 3 , the esterification reactant is mainly various acid chlorides.
  • the esterification raw materials such as benzoyl chloride or butyryl chloride are highly toxic and produce more difficult-to-treat waste water and waste residue.
  • the chemical synthesis process is relatively violent, and the yield is also low.
  • the method described in US3157678A is the highest yield of the chemical method recorded in the literature, and the yield of the vitamin D 3 butyl ester crystallization step is 72%.
  • Column chromatography such as US3367950A, requires separation by a chromatographic column, eluting with a large amount of solvent to obtain the main section, and then concentrating and replacing the solvent for crystallization to obtain high-unit vitamin D 3 .
  • Supercritical CO 2 column separation method for example, the supercritical method mentioned in CN1240209A is to use supercritical or liquid carbon dioxide through a chromatographic column, select a modified solvent as the mobile phase, and a modified silica gel as a stationary phase for separation.
  • the equipment pressure is 7.0 ⁇ 15.0MPa.
  • the supercritical column separation method requires the use of high-pressure equipment above 7MPa, the equipment safety requirements are high, and the more expensive modified silica gel is required, the industrialization cost is high, and it is difficult to industrialize the application.
  • the purpose of the present invention is to provide a method for purifying vitamin D3 with high yield, low cost, and environmental friendliness.
  • the present invention provides a method for purifying vitamin D3, which is characterized in that it comprises the following steps:
  • the saponification reaction is carried out through the lipase column B to obtain a saponification liquid; the saponification liquid is extracted with water, and the separated organic acid enters the water layer, and the organic layer is heavy Return to the lipase column B to saponify and hydrolyze the remaining vitamin D 3 ester again, and repeat the cycle of saponification-hydrolysis step 2 to 5 times until the residual vitamin D 3 ester in the organic phase is less than 1wt%, then stop the circulation;
  • the crystallization mother liquor is used as the substrate of step S1 after being concentrated and thermally isomerized.
  • the content of the crude vitamin D 3 in the step S1 is 1500-3500 IU/g;
  • the weight-volume ratio of the substrate to the non-aqueous phase solvent in the S1 step is 1 g: (5-30) ml, preferably 1 g: 8 ml.
  • the non-aqueous solvent is each independently an alkane, a halogenated hydrocarbon or an aromatic hydrocarbon; preferably, the alkane is selected from n-hexane, pentane, heptane, At least one of cyclohexane and petroleum ether.
  • the molar ratio of the substrate to the weak organic acid is 1:(1.0-10); preferably, the molar ratio of the substrate to the weak organic acid is 1:1.1;
  • the weak organic acid is butyric acid, valeric acid or lauric acid.
  • the acid anhydride is n-butyric anhydride, succinic anhydride or valeric anhydride;
  • the molar ratio of the substrate to the acid anhydride is 1:(0.5-5); preferably, the molar ratio of the substrate to the acid anhydride is 1:0.55;
  • the temperature of the esterification reaction is 20-50°C, preferably 35°C;
  • the residence time of the material in the column when passing through the lipase column A is 0.5-5 hours, preferably, 1 hour.
  • the extractant is water or aqueous methanol; preferably, the volume content of methanol in the aqueous methanol is 0-98%, and more preferably, the volume content of methanol in the aqueous methanol is 95%;
  • the feed volume ratio of the extractant to the esterification liquid containing vitamin D 3 ester is (0.2 ⁇ 3):1; preferably, the ratio of the extractant to the esterification liquid containing vitamin D 3 ester The feed volume ratio is 0.8:1.
  • the extraction operations in the S2 step and the S4 step are performed in an extraction tower.
  • the crystallization solvent is a ketone or alcohol solvent; preferably, the crystallization solvent is acetone;
  • the crystallization temperature is -5 to -30°C, preferably, the crystallization temperature is -20°C;
  • the ratio of the concentrated vitamin D 3 ester to the crystallization solvent is 1 g: (0.7-5) ml, preferably 1 g: 1 ml.
  • the mass-volume ratio of the vitamin D 3 ester crystal to the non-aqueous solvent is 1 g: (2-30) ml, preferably 1 g: 5 ml;
  • the temperature of the saponification reaction is 20-50°C, preferably 35°C.
  • the solvent of the crystallization is methyl formate or ethyl acetate, optionally, the temperature of the crystallization is 0-10°C, and the temperature is kept for more than 3 hours;
  • the mass-volume ratio of the concentrate obtained by concentrating the organic layer to the crystallization solvent is 1 g: (4-20) ml, preferably 1 g: 6 ml.
  • the lipase in the lipase column A and the lipase column B is an immobilized Candida antarctica lipase B, preferably, each independently is Novozymes 435 immobilized lipase, or Candida Antarctica lipase B treated by the immobilization method disclosed in CN105462952A;
  • the mass ratio of the substrate to the lipase in the lipase column A is 1:(0.2-30), preferably 1:(0.5-2);
  • the mass ratio of the vitamin D 3 ester crystal to the lipase in the lipase column B is 1:(0.2-30), preferably 1:(0.5-2).
  • the substrate material that can be processed in the present invention can be selected in the range of 1500-3500 IU/g. If the content is too low, the effect of esterification and crystallization is poor, and the enzyme activity is likely to decrease quickly, which affects the number of times of lipase application. If the content is too high, esterification may not be required, and it can be purified directly by crystallization.
  • the present invention improves on the problems of the current chemical synthesis method with relatively low industrialization cost, innovatively adopts the enzyme acylation method to carry out the vitamin D 3 esterification reaction, and then obtains the higher purity vitamin D 3 ester through crystallization and purification, and then Utilizing the reversibility of the enzyme acylation reaction, the vitamin D 3 ester crystal is saponified into vitamin D 3 by enzyme, and finally high unit vitamin D 3 is obtained by crystallization.
  • the invention uses enzymatic method for esterification and saponification, no more toxic raw materials, enzymes can be reused, some raw materials can be recovered, recycled, no solid waste is discharged, conform to the concept of green chemistry, and the enzyme acylation reaction is more gentle , The yield is improved compared with chemical method, and the cost of industrial application is lower.
  • the crystallization yield of vitamin D 3 in the whole process is 50-75.3%, plus the vitamin D 3 in each crystallization mother liquor, the recovery rate of pure vitamin D 3 is 90-97%, that is, the loss of vitamin D 3 in the whole process is 3-10%.
  • the lipase column A and lipase column B are stainless steel or other solvent-resistant material pipe processing cylindrical columns, the shape is shown in Figure 1 but the size is not limited to the drawings, filter paper and defatted cotton are placed at the inlet and outlet to prevent enzymes from being solution
  • the lipase used is immobilized Candida antarctica lipase B, for example, it can be Novozymes 435 immobilized lipase (Novozym R 435), or the Antarctic pseudolipase treated with the immobilization method disclosed in CN105462952A Silk Lipase B. Lipase is applied more than 40 times.
  • the vitamin D 3 crystal detection is based on the 2015 edition of the "Chinese Pharmacopoeia” method to detect specific rotation and absorption coefficient, and the product content is determined based on the “Chinese Pharmacopoeia” general rule 0722 Vitamin D determination method.
  • the present invention uses lipase catalysts for esterification of vitamin D 3, vitamin D 3 or a weak organic acid with an excess of the raw material mixed acid anhydride, an esterification reaction using a lipase in a non-aqueous solvent.
  • the invention uses an extraction tower to extract and remove excess acid from the reaction. After separation, the excess acid can continue to be used for esterification.
  • the invention utilizes the reversibility of the enzyme esterification reaction, uses lipase in the non-aqueous phase solvent to saponify and hydrolyze vitamin D 3 ester, and combines the extraction tower to extract the acid produced by the hydrolysis, and the organic phase circulates through the lipase column to promote the reversible reaction Proceed in the direction of hydrolysis, and finally the hydrolysis rate will reach 99% or more. After separation, the extracted organic acid can be applied to the esterification reaction to achieve recycling utilization.
  • the present invention creatively adopts the lipase method instead of the original chemical method to esterify the raw material vitamin D 3 , avoiding the use of highly toxic and corrosive benzoyl chloride, butyryl chloride and other raw materials.
  • the reaction adopts lipase esterification and saponification, the process is milder than the chemical method, and the yield is obviously improved. Only the esterification and crystallization step has increased by more than 8% compared with the highest 72% in the chemical method.
  • the acid in the water layer of the reaction extraction can be separated and recycled. Compared with the chemical method, there are no difficult-to-treat waste residues and more harmful waste water discharge. Lipase can be recycled many times, which meets the needs of green and environmental protection new industries.
  • the unit of the vitamin D 3 crystal product produced by the present invention exceeds 39 million IU/g, and the detection index meets the requirements of the Chinese Pharmacopoeia.
  • the present invention compared with the chemical method with the lowest industrialization cost, the present invention has higher yield, no high-toxic raw materials, and most of the raw materials can be recycled, avoiding the discharge of waste residues and difficult-to-treat wastewater, and is a greener and more environmentally friendly method. , A lower cost and more economical method for purification of vitamin D 3.
  • Fig. 1 is a schematic diagram of the structure of a lipase column A and a lipase column B according to a specific embodiment of the present invention.
  • Fig. 2 is a schematic flowchart of a specific embodiment of the present invention.
  • the extraction tower becomes the organic phase, which enters and exits from the top, and the water phase enters and exits from the bottom.
  • Vitamin D 3 ester 12.79g was dissolved in 64ml n-hexane and passed through a DN10 ⁇ 500 lipase column B containing 20g Novozymes 435 at a flow rate of 1ml/min. The column temperature was 35°C. After the column was passed, the pump was pumped into the extraction tower B with water Extraction separation; after extraction, the organic phase passes through lipase column B again at a flow rate of 1ml/min, and the column temperature is 35°C. After the column is passed, the pump is pumped into extraction tower B for extraction and separation with water; after this cycle 3 times, take a sample to detect vitamin D 3 After the residual ester is less than 1wt%, stop passing the column.
  • Vitamin D 3 was dissolved in 69ml of ethyl acetate, filtered through a clean filter, and then slowly cooled and crystallized. After cooling to 5°C, the temperature was kept for 3 hours, filtered, washed with cold ethyl acetate, dried and crystallized to obtain 9.61g of vitamins. D 3 crystal product, unit 39.95 million IU/g, specific rotation +110°, absorption coefficient 471.
  • Vitamin D 3 ester 12.50g is dissolved in 63ml n-hexane and passed through a DN10 ⁇ 500 lipase column B containing 20g Novozymes 435 at a flow rate of 1ml/min. The column temperature is 35°C.
  • the pump is pumped into the extraction tower B with water Extraction separation; after extraction, the organic phase passes through lipase column B again at a flow rate of 1ml/min, and the column temperature is 35°C.
  • the pump is pumped into extraction tower B for extraction and separation with water; after this cycle 3 times, take a sample to detect vitamin D 3 After the residual ester ⁇ wt 1%, stop passing the column, extract the remaining solution to obtain the organic phase.
  • Vitamin D 3 was dissolved by adding 68ml ethyl acetate, filtered through a clean filter, and then slowly cooled to crystallize. After cooling to 5°C, keep it for 3 hours, filter, wash with cold ethyl acetate, dry and crystallize to obtain 9.48g vitamins D 3 crystal product, unit 39.42 million IU/g, specific rotation +111°, absorption coefficient 473.
  • 12.8g vitamin D 3 ester is dissolved in 64ml n-hexane and passed through the DN10 ⁇ 500 lipase column B containing 20g Novozymes 435 at a flow rate of 1ml/min.
  • the column temperature is 35°C.
  • the pump is pumped into the extraction tower B with water Extraction separation; after extraction, the organic phase passes through lipase column B again at a flow rate of 1ml/min, and the column temperature is 35°C.
  • the pump is pumped into extraction tower B for extraction and separation with water; after this cycle 3 times, take a sample to detect vitamin D 3 After the residual ester is ⁇ wt 1%, stop passing the column.
  • Vitamin D 3 was dissolved in 69ml of ethyl acetate, filtered through a clean filter, and then slowly cooled and crystallized. After cooling to 5°C, the temperature was kept for 3 hours, filtered, washed with cold ethyl acetate, dried and crystallized to obtain 9.62g vitamins D 3 crystal product, unit 39.7 million IU/g, specific rotation +111°, absorption coefficient 477.
  • Vitamin D 3 ester 12.51g was dissolved in 63ml n-hexane and passed through a DN10 ⁇ 500 lipase column B containing 20g Novozymes 435 at a flow rate of 1ml/min. The column temperature was 35°C.
  • the pump was pumped into the extraction tower B with water Extraction separation; after extraction, the organic phase passes through lipase column B again at a flow rate of 1ml/min, and the column temperature is 35°C.
  • the pump is pumped into extraction tower B for extraction and separation with water; after this cycle 3 times, take a sample to detect vitamin D 3 After the residual ester ⁇ wt 1%, stop passing the column, extract the remaining solution to obtain the organic phase.
  • Vitamin D 3 was dissolved by adding 68ml ethyl acetate. After filtering through a clean filter, it began to slowly cool down and crystallize. After cooling to 5°C, keep it for 3 hours, filter, wash with cold ethyl acetate, dry and crystallize to obtain 9.23g vitamins D 3 crystal product, unit 39.35 million IU/g, specific rotation +110°, absorption coefficient 474.
  • the coefficient is 480.
  • the total yield of crystallization is 73.3%, and the total recovery of vitamin D 3 is 93.9%.
  • the butyric acid used for esterification was changed to 5.84g (0.057mol) of valeric acid, and the rest was the same as in Example 1.
  • the esterification yielded 12.03g of 98.8% vitamin D 3 amyl ester, and finally 8.34g of vitamin D 3 crystals, with a unit of 39.62 million IU/ g, specific rotation +108°, absorption coefficient 469.
  • the total yield of crystallization is 64.8%, and the total recovery of vitamin D 3 is 91.9%.
  • the column temperature was changed to 45°C, and the rest was the same as in Example 1.
  • the total yield of crystallization is 71.3%, and the total recovery of vitamin D 3 is 91.5%.
  • the dosage of lipase was changed to 10g, and the rest was the same as in Example 1.
  • the esterification conversion rate was 98.5%, and 12.36g of 99.1% vitamin D 3 butyl ester was obtained; after the saponification and hydrolysis step was cycled 4 times, the test was qualified and finally 9.30g of vitamin D 3 crystal was obtained.
  • the unit is 39.79 million IU/g, the specific rotation is +110°, and the absorption coefficient is 483.
  • the total yield of crystallization is 72.5%, and the total recovery of vitamin D 3 is 93.48%.
  • the dosage of lipase was changed to 10g, and the rest was the same as in Example 3.
  • the esterification conversion rate was 98.8% compared with Example 1, and 12.61g of 99.2% vitamin D 3 butyl ester was obtained.
  • the saponification and hydrolysis step was repeated 4 times, the test was qualified and finally vitamin D 3 was obtained.
  • the crystal is 9.51g, the unit is 39.8 million IU/g, the specific rotation is +109°, and the absorption coefficient is 479.
  • the total yield of crystallization is 74.2%, and the total recovery of vitamin D 3 is 95.19%.
  • lipase column A and lipase column B are DN10 ⁇ 500 columns processed with DN10 stainless steel pipes. Filter paper and cotton are placed at the entrance and exit of the column to prevent enzymes from being carried out.
  • the enzyme used is Novozymes 435 lipase and the enzyme activity is 10000 U/g.
  • the enzyme application experiment was performed 40 times in the scheme of Example 1, and the enzyme still had a high efficiency.
  • Lipase column A detected enzyme activity 7230 U/g
  • lipase column B detected enzyme activity 8243 U/g.
  • the water-washing extraction tower is constructed by laboratory glass tower section and wire mesh packing, and the other steps of filtration and concentration are all commonly used instruments in the laboratory.

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Abstract

L'invention concerne un procédé de purification de la vitamine D3, le procédé consistant à mélanger la vitamine D3 brute en tant que substrat avec un acide ou un anhydride organique faible dans un solvant non aqueux, à la soumettre à une estérification avec une colonne de lipase A et à l'extraire avec un agent d'extraction, à concentrer la couche organique obtenue, puis à ajouter un solvant de cristallisation pour la dissoudre, puis à réduire la température pour la cristallisation, et à la filtrer et à la sécher pour obtenir un cristal d'ester de vitamine D3; à la redissoudre, à la soumettre à une saponification avec une colonne de lipase B et à une extraction, à renvoyer la couche organique obtenue vers la colonne de lipase B pour sa saponification et son extraction, et à poursuivre le cycle jusqu'à ce que le résidu d'ester de vitamine D3 dans la couche organique soit inférieur à 1 % en poids; à soumettre enfin la couche organique à une concentration, une cristallisation et un séchage pour obtenir un cristal de vitamine D3 fin; et à traiter la liqueur mère de cristallisation pour une réutilisation en tant que substrat.
PCT/CN2020/093960 2019-08-30 2020-06-02 Procédé de purification de vitamine d3 WO2021036384A1 (fr)

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CN110527700B (zh) * 2019-08-30 2021-07-16 厦门金达威维生素有限公司 一种维生素d3的提纯方法
CN112479960B (zh) * 2020-12-12 2023-02-21 弘健制药(上海)有限公司 一种维生素d3的提纯方法
CN114369047A (zh) * 2022-01-27 2022-04-19 重庆迈德凯医药有限公司 一种结晶维生素d3的方法

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US3157678A (en) * 1959-08-04 1964-11-17 Philips Corp Method of producing a crystalline ester of vitamin d3 and crystalline vitamin d3 which may be obtained therefrom
CN1223639A (zh) * 1996-07-01 1999-07-21 中外制药株式会社 维生素d衍生物结晶及其制备方法
CN1240209A (zh) * 1998-06-23 2000-01-05 弗·哈夫曼-拉罗切有限公司 维生素d3的分离方法
CN110527700A (zh) * 2019-08-30 2019-12-03 厦门金达威维生素有限公司 一种维生素d3的提纯方法

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NL6516485A (fr) * 1964-12-19 1966-06-20
CN1167677C (zh) * 2000-10-18 2004-09-22 浙江新和成股份有限公司 维生素d3的提纯工艺
CN100347156C (zh) * 2005-05-31 2007-11-07 台州市海盛化工有限公司 维生素d分离提纯和结晶方法
CN102276510A (zh) * 2011-05-30 2011-12-14 何德海 一种制备维生素d3的工艺方法
CN106478479B (zh) * 2016-08-31 2018-08-07 四川省玉鑫药业有限公司 一种维生素d3的生产工艺

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3157678A (en) * 1959-08-04 1964-11-17 Philips Corp Method of producing a crystalline ester of vitamin d3 and crystalline vitamin d3 which may be obtained therefrom
CN1223639A (zh) * 1996-07-01 1999-07-21 中外制药株式会社 维生素d衍生物结晶及其制备方法
CN1240209A (zh) * 1998-06-23 2000-01-05 弗·哈夫曼-拉罗切有限公司 维生素d3的分离方法
CN110527700A (zh) * 2019-08-30 2019-12-03 厦门金达威维生素有限公司 一种维生素d3的提纯方法

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