CN112479960A - Vitamin D3Purification method of (2) - Google Patents
Vitamin D3Purification method of (2) Download PDFInfo
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- CN112479960A CN112479960A CN202011453810.4A CN202011453810A CN112479960A CN 112479960 A CN112479960 A CN 112479960A CN 202011453810 A CN202011453810 A CN 202011453810A CN 112479960 A CN112479960 A CN 112479960A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Abstract
The application discloses a vitamin D3The purification method of (2), comprising the steps of: a1. organic amine, a first organic solvent and vitamin D3Mixing oil and aryl acyl chloride for reaction, and adding water to stop the reaction; a2. washing the obtained product in the step a1, drying, filtering, distilling under reduced pressure, dissolving, distilling under reduced pressure for the second time, cooling and crystallizing; b1. mixing vitamin D3Dissolving benzyl ester in methanol, and dropwise adding a strong base solution for reaction; b2. distilling the product obtained in the step b1 under reduced pressure, then separating liquid, washing an organic phase with water, drying, filtering, distilling under reduced pressure for the second time, dissolving, and cooling for recrystallization; c1. mixing vitamin D3Dissolving the crude product in a third organic solvent, and then stirring and decoloring; c2. c1, filtering, distilling the filtrate under reduced pressure, dissolving, cooling, recrystallizing, filtering, and drying to obtain vitamin D3. Vitamin D purified by the purification method of the present application3Has high purity, low content of harmful impurities and high stability.
Description
Technical Field
The application relates to the field of fine chemical engineering, in particular to vitamin D3The purification method of (1).
Background
Vitamin D3Also known as cholecalciferol, is vitamin DOne, only soluble in fat or fat solvent, resistant to high temperature and oxidation in neutral and alkaline solution, and capable of improving absorption of calcium and phosphorus by organism to make plasma calcium and plasma phosphorus levels reach saturation level. With international vitamin D pair3Extensive and intensive research into vitamin D3Is widely used for preparing medicaments for treating various diseases.
Vitamin D3The production method of (A) is generally that 7-dehydrocholesterol is dissolved in ethanol, then the ring opening is carried out by ultraviolet irradiation, the reaction solution is concentrated, frozen and filtered, nitrogen is introduced into the filtrate and the filtrate is decompressed and concentrated to be dry, thus obtaining vitamin D3And (3) oil. The vitamin D3The oil is vitamin D3A compound of a vitamin D-rich type3And other impurities, vitamin D3The content of (b) is generally 50-60%, and vitamin D with high purity can be obtained by purification3。
The inventors believe that the present purification method purifies vitamin D3The purity of the vitamin D is still to be improved, and the purified vitamin D3Also contains more harmful impurities which promote vitamin D3Degradation occurs under the conditions of high temperature, high humidity and strong light, and the vitamin D is reduced3The stability of the product is not beneficial to the later packaging, storage and transportation processes.
Disclosure of Invention
To increase vitamin D3Has reduced vitamin D content3The present application provides a vitamin D3The purification method of (1).
The application provides a vitamin D3The purification method adopts the following technical scheme:
vitamin D3The purification method of (2), comprising the steps of:
a. esterification reaction
a1. At the temperature of 25-35 ℃, organic amine, a first organic solvent and vitamin D are added3Mixing oil and aryl acyl chloride, reacting for 2-3 h, and adding water to stop the reaction; organic amine, first organic solvent and vitamin D3Oil, aryl acid chloride andthe weight ratio of the water is (1.97-1.98): (12.5-13.5): 1: (0.85-0.95): 1.8-2.2);
a2. washing the product obtained in the step a1 with water, drying the product with anhydrous sodium sulfate, filtering the product with neutral alumina, controlling the temperature below 35 ℃ and the vacuum degree below-0.06 MPa, carrying out reduced pressure distillation, and adding 11.5-12.5 times of vitamin D3Dissolving the oil in acetone, controlling the temperature below 40 ℃, performing secondary reduced pressure distillation under the vacuum degree below-0.06 MPa, cooling and crystallizing at the temperature of 0-5 ℃ for 2-3 h, and drying to obtain the vitamin D3Benzyl ester;
b. hydrolysis reaction
b1. Mixing vitamin D3Dissolving benzyl ester in methanol, dropwise adding a strong base solution, and reacting for 2-3 h at the temperature of 25-35 ℃; wherein, vitamin D3The weight ratio of the benzyl ester to the methanol to the strong alkali solution is 1 (4.6-5.4) to 5.0-5.6;
b2. distilling the product obtained in the step b1 at the temperature of below 35 ℃ under reduced pressure, adding dichloromethane and water, uniformly mixing, separating liquid, washing an organic phase with water, drying anhydrous sodium sulfate, filtering neutral alumina, distilling at the temperature of below 35 ℃ under reduced pressure twice, adding a second organic solvent, dissolving at the temperature of 30-40 ℃, cooling to 5-15 ℃ and recrystallizing to obtain vitamin D3A crude product; the dosage of the dichloromethane, the water and the second organic solvent is respectively vitamin D328-32 times, 5.7-6.3 times and 1.64-1.7 times of the dosage of the benzyl ester;
c. refining by decolorizing
c1. Mixing vitamin D3Dissolving the crude product in a third organic solvent, adding activated carbon, and stirring and decoloring at the temperature of 25-35 ℃ for 1-2 hours; wherein the third organic solvent and vitamin D3The weight ratio of the crude product is (4.5-5.5) to 1;
c2. filtering the product obtained in the step c1, distilling the filtrate at the temperature of below 35 ℃ under reduced pressure, and then adding 2.06-2.12 times of vitamin D3Dissolving a fourth organic solvent with the weight of the crude product at the temperature of 30-40 ℃, then cooling to 5-15 ℃ for recrystallization, filtering, and drying to obtain the vitamin D3。
By adopting the technical scheme, the vitamin D is firstly added into the vitamin D-containing food3Oil andaryl acyl chloride is subjected to esterification reaction in a first organic solvent to obtain vitamin D3Vitamin D in oil3More HCl is extracted, and HCl generated in the esterification reaction process is continuously absorbed by organic amine. The application controls the dosage of each reactant in the esterification reaction, and the organic amine, the first organic solvent and the vitamin D3The weight ratio of oil, aryl acyl chloride and water is preferably 1.975:13:1:0.9:2, which promotes the generation of the product and improves the yield. And then washing, drying, filtering, distilling under reduced pressure, dissolving, distilling for the second time, cooling, crystallizing, drying, and other post-treatment processes, controlling the conditions of the processes, and sufficiently removing harmful impurities to obtain high-purity vitamin D3Benzyl ester.
Then mixing vitamin D3The benzyl ester and the methanol are subjected to hydrolysis reaction in a strong alkaline environment to ensure that the vitamin D is generated3Conversion of benzyl ester to vitamin D3Crude product, by controlling the reaction conditions and the amount of reactants, and vitamin D3The weight ratio of the benzyl ester, the methanol and the strong alkali solution is preferably 1:5:5.3, so that the vitamin D is increased3Conversion of benzyl ester to give vitamin D3The yield of the crude product is improved. Then, through the steps of reduced pressure distillation, stirring, dissolving and separating liquid, washing an organic phase, drying anhydrous sodium sulfate, filtering, secondary distillation, redissolving, cooling, crystallizing and other multi-step post-treatment processes, harmful impurities are sufficiently removed, and the application further preferably selects the usage amounts of dichloromethane, water and a second organic solvent in the step b2 as vitamin D330 times, 6 times and 1.67 times of the dosage of the benzyl ester, and the vitamin D is greatly improved3The purity of the crude product.
Then adding vitamin D3The crude product is subjected to a decolorization refining process, wherein a third organic solvent and vitamin D3The weight ratio of the crude product is preferably 5:1, and then the crude product is subjected to multi-step post-treatment processes such as filtration, distillation, summarization, cooling crystallization, drying and the like, so that harmful impurities are sufficiently removed, and the vitamin D is improved3And in step c2, the fourth organic solvent is adopted to dissolve at a specific temperature and then the temperature is reduced for crystallization, and the method is further preferredThe usage amount of the fourth organic solvent is 2.09 times of that of the vitamin D3Crude product weight, so that vitamin D is obtained3The crystal form of the vitamin D is needle-shaped, the crystal of the product is better, and the vitamin D is improved3Stability of (2).
In summary, the present application will provide vitamin D3The oil is subjected to esterification, hydrolysis and decoloration refining processes, and the dosage and reaction conditions of reactants in each reaction process are controlled to fully react vitamin D3Vitamin D in oil3Extracting, and performing multiple post-treatment processes in each process to remove harmful impurities to a large extent and improve vitamin D3While reducing harmful impurities and promoting vitamin D3The possibility of degradation is increased, and the vitamin D is increased3Stability under high temperature, high humidity and high light conditions.
Preferably, in step a1, the organic amine is one of triethylamine and pyridine.
By adopting the technical scheme, one of triethylamine and pyridine is adopted to absorb vitamin D in the application3HCl generated in the esterification reaction process of oil and aryl acyl chloride improves the yield of the product, so that the vitamin D3Vitamin D in oil3More conversion to vitamin D3Benzyl ester, thereby increasing vitamin D3The yield of (A) was found.
Preferably, in step a1, the first organic solvent is one of dichloromethane, methanol and ethanol.
Preferably, in step a1, the aryl acyl chloride is one of benzoyl chloride and 3, 5-dinitrobenzoyl chloride.
By adopting the technical scheme, one of dichloromethane, methanol and ethanol is adopted as vitamin D in the vitamin D-vitamin C3The organic solvent for esterification reaction of oil and aryl acyl chloride adopts one of benzoyl chloride and 3, 5-dinitrobenzoyl chloride and vitamin D3Esterification of the oil to produce vitamin D3Vitamin D in oil3Is extracted sufficiently to increase vitamin D3Yield of the product.
Preferably, in the step a2, the acetone is dissolved under stirring at a temperature of 40-50 ℃ for 15-30 min.
By adopting the technical scheme, the vitamin D-containing water-soluble vitamin D-vitamin D compound is dissolved by using a specific amount of acetone3The weight of the oil is 12 times, the reaction conditions are controlled, and then the reduced pressure distillation is carried out, so that the vitamin D is improved3The purity of benzyl ester is improved, so as to improve vitamin D3The purity of (2).
Preferably, in the step a2 and the step c2, the drying condition is that the vacuum degree is controlled to be below-0.08 MPa at the temperature of 30-35 ℃, and N is introduced2And controlling the vacuum degree to be-0.07 to-0.08 MPa, and drying for 4 to 5 hours.
By adopting the technical scheme, the method controls the condition parameters of the drying process, and then N is introduced2The product is effectively protected, the possibility of contacting the product with air is reduced, and the purity of the product is improved.
Preferably, in the step b1, the alkali solution comprises methanol and sodium hydroxide in a weight ratio of (4.8-5.2): (0.2-0.4) or methanol and potassium hydroxide in a weight ratio of (4.8-5.2): (0.2-0.4).
By adopting the technical scheme, the alkaline environment is provided for the hydrolysis reaction process by adopting the sodium hydroxide alcoholic solution or the potassium hydroxide alcoholic solution, so that the vitamin D3The benzyl ester is hydrolyzed sufficiently, and vitamin D is increased3The conversion rate of the benzyl ester is improved, thereby improving the yield of the product.
Preferably, in the step b2, the second organic solvent includes methyl formate or methyl formate and acetone in a weight ratio of (0.84-0.88) (0.8-0.82) or ethyl acetate and acetonitrile in a weight ratio of (0.84-0.88) (0.8-0.82) or methyl formate and methanol in a weight ratio of (0.84-0.88) (0.8-0.82).
Preferably, in the step c2, the fourth organic solvent includes methyl formate or methyl formate and acetone in a weight ratio of (1.06-1.1): (1-1.02) or ethyl acetate and acetonitrile in a weight ratio of (1.06-1.1): (1-1.02) or methyl formate and methanol in a weight ratio of (1.06-1.1): 1-1.02).
By adopting the technical scheme, the second organic solvent and the fourth organic solvent are used as the organic solvent for recrystallization in the hydrolysis reaction and the decolorizing and refining process, so that the recrystallized crystal form is needle-shaped, the crystal form is good, the stability is higher, and the improvement of vitamin D is facilitated3Stability of (2).
Preferably, in step c1, the third organic solvent is one of acetone, ethyl acetate, dichloromethane, petroleum ether, methanol and ethanol.
By adopting the technical scheme, one of acetone, ethyl acetate, dichloromethane, petroleum ether, methanol and ethanol is adopted as vitamin D in the vitamin D vitamin C-vitamin D-vitamin C-vitamin3Decolorizing the crude product with organic solvent to obtain vitamin D3The crude product is fully dissolved in the organic solvent, and the yield of the product is improved.
In summary, the present application includes at least one of the following beneficial technical effects:
1. vitamin D purified by the purification method of the present application3Has high purity, low content of harmful impurities, and vitamin D3The stability of the composition is high, and the composition is not easy to degrade under the conditions of high temperature, high humidity and strong light;
2. the purification method has the advantages of simple and easy operation process, high product yield, mild reaction conditions, difficult decomposition of products in the purification process, high stability and suitability for large-scale industrial production.
Detailed Description
The present application will be described in further detail with reference to examples.
Vitamin D of the present application3Vitamin D in oil3The content of (A) is 60%;
the triethylamine of the application is purchased from Jinan chemical Co Ltd;
pyridine of the application is purchased from Jinan Cheng Rici chemical Co., Ltd;
the benzoyl chloride of the present application was purchased from Shandong Xuchen chemical science and technology Co., Ltd;
the 3, 5-dinitrobenzoyl chloride of the present application was purchased from Shanghai koji chemical Co., Ltd.
Example 1
Vitamin D3The purification method of (2), comprising the steps of:
a. esterification reaction
a1. Firstly, 15.8kg of triethylamine and 104kg of dichloromethane are mixed and stirred in a reaction kettle, and then 8kg of vitamin D is added3Controlling the temperature in the reaction kettle to be below 25 ℃, slowly adding 7.2kg of benzoyl chloride into the reaction kettle, then adjusting the temperature in the reaction kettle to be 30 ℃, preserving the temperature for reaction for 2.5h, then adding 16kg of pure water into the reaction kettle, stirring for 7.5min, standing for 12.5min, stopping the reaction, and transferring a lower organic phase;
a2. washing the organic phase with 48kg pure water for three times, adding 8kg anhydrous sodium sulfate, stirring, dehydrating and drying for 30min, filtering with 4kg neutral alumina, controlling the internal temperature below 35 ℃ and the vacuum degree below-0.06 MPa, distilling under reduced pressure until the mixture is nearly dry, adding 96kg acetone, heating to 45 ℃, stirring and dissolving for 22.5min, controlling the internal temperature below 40 ℃ and the vacuum degree below-0.06 MPa, distilling under reduced pressure for two times until a large amount of solids are separated out, cooling to 2.5 ℃, stirring for 2.5h at a constant temperature, standing for 13h, stirring for 30min, centrifuging, filtering, spin-drying for 12.5min, controlling the temperature at 32.5 ℃, adjusting the vacuum degree below-0.08 MPa, introducing N2, controlling the vacuum degree at-0.075 MPa, and drying for 4.5h to obtain the vitamin D3Benzyl ester;
b. hydrolysis reaction
b1. 32.5kg of methanol and 6.5kg of vitamin D3Mixing benzyl ester in a reaction kettle; mixing 32.5kg of methanol and 1.95kg of sodium hydroxide in a preparation kettle to obtain a strong alkali solution; controlling the internal temperature below 25 ℃, dropwise adding 34.45kg of strong base solution into the reaction kettle, after the dropwise adding is finished, heating to 30 ℃, and carrying out heat preservation reaction for 2.5 hours;
b2. distilling under reduced pressure at internal temperature below 35 deg.C and vacuum degree below-0.06 MPa to near dryness, adding 195kg dichloromethane and 97.5kg pure water, stirring to dissolve, standing for 12.5min, separating liquid, transferring organic phase, and purifying with 3Washing the organic phase with 9kg pure water for three times, adding 8kg anhydrous sodium sulfate, stirring, dehydrating and drying for 30min, filtering with 4kg neutral alumina, controlling the internal temperature below 35 ℃ and the vacuum degree below-0.06 MPa, distilling under reduced pressure to near dryness, adding 5.95kg methyl formate and 5.27kg acetone, heating to 35 ℃, stirring for dissolving, cooling to 10 ℃ for recrystallization, filtering, draining for 17.5min, collecting powder material to obtain vitamin D3A crude product;
c. refining by decolorizing
c1. Adding 4kg vitamin D3Dissolving the crude product in 20kg of acetone, adding 0.5kg of activated carbon, and stirring and decoloring at the temperature of 30 ℃ for 1.5 h;
c2. filtering the product obtained in the step c1, washing with 3kg of acetone, combining the filtrates, controlling the temperature below 35 ℃ and the vacuum degree below-0.06 MPa for reduced pressure distillation, then adding 4.32kg of methyl formate and 4.04kg of acetone for dissolution at the temperature of 35 ℃, then cooling to 10 ℃ for recrystallization, filtering, draining for 17.5min, then controlling the temperature at 32.5 ℃ and the vacuum degree below-0.08 MPa, introducing N2, controlling the vacuum degree at-0.075 MPa, drying for 4.5h, and obtaining the vitamin D with the purity of 99.95 percent3(yield 89.5%).
Example 2
Vitamin D3The purification method of (2), comprising the steps of:
a. esterification reaction
a1. Mixing and stirring 15.76kg of pyridine and 100kg of methanol in a reaction kettle, and then adding 8kg of vitamin D3Controlling the temperature in the reaction kettle to be below 25 ℃, slowly adding 6.8kg of 3, 5-dinitrobenzoyl chloride into the reaction kettle, then adjusting the temperature in the reaction kettle to be below 25 ℃, keeping the temperature for reaction for 2 hours, then adding 14.4kg of pure water into the reaction kettle, stirring for 5min, standing for 10min, terminating the reaction, and transferring a lower organic phase;
a2. washing the organic phase with 48kg pure water for three times, adding 8kg anhydrous sodium sulfate, stirring, dehydrating and drying for 35min, filtering with 4kg neutral alumina, distilling under reduced pressure at internal temperature below 35 deg.C and vacuum degree below-0.06 MPa, adding 92kg acetone, heating to 40 deg.C, stirring for dissolving for 15min, controlling internal temperature below 40 deg.C,distilling under reduced pressure below-0.06 MPa for the second time until a large amount of solid is separated out, cooling to 0 deg.C, stirring for 2h, standing for 2h, stirring for 30min, centrifuging, filtering, drying for 10min, controlling temperature at 30 deg.C, adjusting vacuum below-0.08 MPa, introducing N2, controlling vacuum at-0.07 MPa, and drying for 4h to obtain vitamin D3Benzyl ester;
b. hydrolysis reaction
b1. Adding 29.9kg of methanol and 6.5kg of vitamin D3Mixing benzyl ester in a reaction kettle; mixing 31.2kg of methanol and 1.3kg of potassium hydroxide in a preparation kettle to obtain a strong alkali solution; controlling the internal temperature below 25 ℃, dropwise adding 32.5kg of strong base solution into the reaction kettle, heating to 25 ℃ after dropwise adding, and carrying out heat preservation reaction for 2 hours;
b2. controlling the internal temperature below 35 ℃ and the vacuum degree below-0.06 MPa, carrying out reduced pressure distillation to be nearly dry, adding 182kg of dichloromethane and 96.2kg of pure water, stirring and dissolving to be clear, standing for 10min, then carrying out liquid separation and organic phase transfer, washing the organic phase by 39kg of pure water for three times, then adding 8kg of anhydrous sodium sulfate, stirring, dehydrating and drying for 35min, then filtering by 4kg of neutral alumina, controlling the internal temperature below 35 ℃ and the vacuum degree below-0.06 MPa, carrying out reduced pressure distillation to be nearly dry, then adding 10.66kg of methyl formate, heating to 30 ℃, stirring and dissolving, cooling to 5 ℃, recrystallizing, filtering, carrying out suction drying for 15min, and collecting powder materials to obtain the vitamin D3A crude product;
c. refining by decolorizing
c1. Adding 4kg vitamin D3Dissolving the crude product in 18kg of ethyl acetate, adding 0.5kg of activated carbon, and stirring and decoloring at the temperature of 25 ℃ for 1 h;
c2. filtering the product obtained in the step c1, washing with 3kg of acetone, combining the filtrates, controlling the temperature below 35 ℃ and the vacuum degree below-0.06 MPa for reduced pressure distillation, then adding 8.24kg of methyl formate to dissolve at the temperature of 30 ℃, then cooling to 5 ℃ for recrystallization, filtering, pumping for 15min, then controlling the temperature at 30 ℃, adjusting the vacuum degree below-0.08 MPa, introducing N2, controlling the vacuum degree at-0.07 MPa, drying for 4h to obtain the vitamin D with the purity of 99.67 percent3(yield 83.4%).
Example 3
Vitamin D3The purification method of (2), comprising the steps of:
a. esterification reaction
a1. Firstly, 15.84kg of triethylamine and 108kg of ethanol are mixed and stirred in a reaction kettle, and then 8kg of vitamin D is added3Controlling the temperature in the reaction kettle to be below 25 ℃, slowly adding 7.6kg of benzoyl chloride into the reaction kettle, then adjusting the temperature in the reaction kettle to be 35 ℃, preserving the temperature for reaction for 3 hours, then adding 17.6kg of pure water into the reaction kettle, stirring for 10min, standing for 15min, stopping the reaction, and transferring the lower organic phase;
a2. washing the organic phase with 48kg pure water for three times, adding 8kg anhydrous sodium sulfate, stirring, dehydrating and drying for 40min, filtering with 4kg neutral alumina, controlling the internal temperature below 35 ℃ and the vacuum degree below-0.06 MPa, distilling under reduced pressure until the mixture is nearly dry, adding 100kg acetone, heating to 50 ℃, stirring and dissolving for 30min, controlling the internal temperature below 40 ℃ and the vacuum degree below-0.06 MPa, distilling under reduced pressure for two times until a large amount of solids are separated out, cooling to 5 ℃, stirring for 3h under heat preservation, standing for 24h, stirring for 30min, centrifuging, spin-filtering, spin-drying for 15min, controlling the temperature below 35 ℃, adjusting the vacuum degree below-0.08 MPa, introducing N2, controlling the vacuum degree below-0.08 MPa, drying for 5h to obtain vitamin D3Benzyl ester;
b. hydrolysis reaction
b1. Adding 35.1kg of methanol and 6.5kg of vitamin D3Mixing benzyl ester in a reaction kettle; mixing 33.8kg of methanol and 2.6kg of sodium hydroxide in a preparation kettle to obtain a strong alkali solution; controlling the internal temperature below 25 ℃, dropwise adding 36.4kg of strong base solution into the reaction kettle, heating to 35 ℃ after dropwise adding, and carrying out heat preservation reaction for 3 hours;
b2. controlling the internal temperature below 35 ℃ and the vacuum degree below-0.06 MPa, distilling under reduced pressure till the mixture is nearly dry, adding 208kg of dichloromethane and 98.8kg of pure water, stirring to dissolve until the mixture is clear, standing for 15min, separating liquid, transferring the organic phase, washing the organic phase with 39kg of pure water for three times, adding 8kg of anhydrous sodium sulfate, stirring, dehydrating and drying for 40min, filtering with 4kg of neutral alumina, controlling the internal temperature below 35 ℃ and the vacuum degree below-0.06 MPa, distilling under reduced pressure till the mixture is nearly dry, adding 5.72kg of ethyl acetate and 5.33kg of acetone, heating till the mixture is nearly dryDissolving at 40 deg.C under stirring, cooling to 15 deg.C for recrystallization, filtering, draining for 20min, and collecting powder to obtain vitamin D3A crude product;
c. refining by decolorizing
c1. Adding 4kg vitamin D3Dissolving the crude product in 22kg of dichloromethane, adding 0.5kg of activated carbon, and stirring and decoloring at the temperature of 35 ℃ for 2 hours;
c2. filtering the product obtained in the step c1, washing with 3kg of acetone, combining the filtrates, controlling the temperature below 35 ℃ and the vacuum degree below-0.06 MPa for reduced pressure distillation, then adding 4.4kg of ethyl acetate and 4.08kg of acetone for dissolution at the temperature of 40 ℃, then cooling to 15 ℃ for recrystallization, filtering, pumping out for 20min, controlling the temperature below 35 ℃, adjusting the vacuum degree below-0.08 MPa, introducing N2, controlling the vacuum degree below-0.08 MPa, drying for 5h to obtain the vitamin D with the purity of 99.78%3(yield 86.3%).
Example 4
Vitamin D3The purification method of (2), comprising the steps of:
a. esterification reaction
a1. 15.776kg of pyridine and 102.4kg of dichloromethane are mixed and stirred in a reaction kettle, and then 8kg of vitamin D is added3Controlling the internal temperature of the reaction kettle to be below 25 ℃, slowly adding 7.04kg of benzoyl chloride into the reaction kettle, then adjusting the internal temperature to be 28 ℃, preserving the temperature and reacting for 2.3h, then adding 15.2kg of pure water into the reaction kettle, stirring for 6min, standing for 12min, stopping the reaction, and transferring the lower organic phase;
a2. washing the organic phase with 48kg pure water for three times, adding 8kg anhydrous sodium sulfate, stirring, dehydrating and drying for 45min, filtering with 4kg neutral alumina, controlling the internal temperature below 35 ℃ and the vacuum degree below-0.06 MPa, vacuum distilling to near dry, adding 94.4kg acetone, heating to 42 ℃, stirring and dissolving for 20min, controlling the internal temperature below 40 ℃ and the vacuum degree below-0.06 MPa, vacuum distilling for two times until a large amount of solid is separated out, cooling to 2 ℃, keeping the temperature and stirring for 2.3h, standing for 8h, stirring for 30min, centrifugally spin-filtering, spin-drying for 12min, controlling the temperature below 32 ℃, adjusting the vacuum degree below-0.08 MPa, introducing N2, controlling the vacuum degree below-0.08 MPa, drying for 4.2h,obtaining vitamin D3Benzyl ester;
b. hydrolysis reaction
b1. Adding 31.2kg of methanol and 6.5kg of vitamin D3Mixing benzyl ester in a reaction kettle; 31.85kg of methanol and 1.625kg of sodium hydroxide are mixed in a preparation kettle to obtain a strong base solution; controlling the internal temperature below 25 ℃, dropwise adding 33.475kg of strong base solution into the reaction kettle, heating to 28 ℃ after dropwise adding, and carrying out heat preservation reaction for 2.3 hours;
b2. controlling the internal temperature below 35 ℃ and the vacuum degree below-0.06 MPa, carrying out reduced pressure distillation to be nearly dry, adding 188.5kg of dichloromethane and 96.85kg of pure water, stirring and dissolving to be clear, standing for 12min, carrying out liquid separation and organic phase transfer, washing the organic phase by 39kg of pure water for three times, then adding 8kg of anhydrous sodium sulfate, stirring, dehydrating and drying for 45min, then filtering by 4kg of neutral alumina, controlling the internal temperature below 35 ℃ and the vacuum degree below-0.06 MPa, carrying out reduced pressure distillation to be nearly dry, then adding 5.525kg of ethyl acetate and 5.2325kg of acetonitrile, heating to 33 ℃, stirring and dissolving, cooling to 7 ℃, recrystallizing, filtering, draining for 16min, collecting powder, and obtaining the vitamin D3A crude product;
c. refining by decolorizing
c1. Adding 4kg vitamin D3Dissolving the crude product in 18.8kg of petroleum ether, adding 0.5kg of activated carbon, and stirring and decoloring at the temperature of 28 ℃ for 1.3 h;
c2. filtering the product obtained in the step c1, washing with 3kg of acetone, combining the filtrates, controlling the temperature below 35 ℃ and the vacuum degree below-0.06 MPa, carrying out reduced pressure distillation, then adding 4.28kg of ethyl acetate and 4.02kg of acetonitrile to dissolve at the temperature of 32 ℃, then cooling to 7 ℃ for recrystallization, filtering, pumping to dry for 16min, then controlling the temperature at 32 ℃, adjusting the vacuum degree below-0.08 MPa, introducing N2, controlling the vacuum degree at-0.08 MPa, and drying for 4.3h to obtain the vitamin D with the purity of 99.86 percent3(yield 88.5%).
Example 5
Vitamin D3The purification method of (2), comprising the steps of:
a. esterification reaction
a1. 15.824kg of triethylamine and 105.6kg of dichloromethane are firstly reactedMixing and stirring in a kettle, and then adding 8kg of vitamin D3Controlling the internal temperature of the reaction kettle to be below 25 ℃, slowly adding 7.36kg of benzoyl chloride into the reaction kettle, then adjusting the internal temperature to be 32 ℃, preserving the temperature and reacting for 2.7h, then adding 15.2kg of pure water into the reaction kettle, stirring for 8min, standing for 14min, terminating the reaction, and transferring the lower organic phase;
a2. washing the organic phase with 48kg pure water for three times, adding 8kg anhydrous sodium sulfate, stirring, dehydrating and drying for 50min, filtering with 4kg neutral alumina, controlling the internal temperature below 35 ℃ and the vacuum degree below-0.06 MPa, distilling under reduced pressure until the mixture is nearly dry, adding 98.4kg acetone, heating to 47 ℃, stirring and dissolving for 25min, controlling the internal temperature below 40 ℃ and the vacuum degree below-0.06 MPa, distilling under reduced pressure for two times until a large amount of solids are separated out, cooling to 4 ℃, keeping the temperature and stirring for 2.7h, standing for 18h, stirring for 30min, centrifugally filtering, spin-drying for 14min, controlling the temperature below 34 ℃, adjusting the vacuum degree below-0.08 MPa, introducing N2, controlling the vacuum degree below-0.08 MPa, drying for 4.7h to obtain vitamin D3Benzyl ester;
b. hydrolysis reaction
b1. Adding 33.8kg of methanol and 6.5kg of vitamin D3Mixing benzyl ester in a reaction kettle; 33.15kg of methanol and 2.275kg of sodium hydroxide are mixed in a preparation kettle to obtain strong alkali solution; controlling the internal temperature below 25 ℃, dropwise adding 35.425kg of strong base solution into the reaction kettle, heating to 33 ℃ after dropwise adding, and carrying out heat preservation reaction for 2.7 hours;
b2. controlling the internal temperature below 35 ℃ and the vacuum degree below-0.06 MPa, carrying out reduced pressure distillation to be nearly dry, adding 201.5kg of dichloromethane and 98.15kg of pure water, stirring and dissolving to be clear, standing for 14min, carrying out liquid separation and organic phase transfer, washing the organic phase by 39kg of pure water for three times, adding 8kg of anhydrous sodium sulfate, stirring, dehydrating and drying for 50min, filtering by 4kg of neutral alumina, controlling the internal temperature below 35 ℃ and the vacuum degree below-0.06 MPa, carrying out reduced pressure distillation to be nearly dry, adding 5.655kg of methyl formate and 5.2975kg of methanol, heating to 37 ℃, stirring and dissolving, cooling to 12 ℃, recrystallizing, filtering, carrying out suction drying for 18min, collecting powder, and obtaining the vitamin D3A crude product;
c. refining by decolorizing
c1. Adding 4kg vitamin D3Dissolving the crude product in 21.2kg ethanol, adding 0.5kg activated carbon, and stirring and decolorizing at 32 deg.C for 1.7 h;
c2. filtering the product obtained in the step c1, washing with 3kg of acetone, combining the filtrates, controlling the temperature below 35 ℃ and the vacuum degree below-0.06 MPa for reduced pressure distillation, then adding 4.36kg of methyl formate and 4.06kg of methanol to dissolve at the temperature of 38 ℃, then cooling to 13 ℃ for recrystallization, filtering, pumping out for 18min, then controlling the temperature at 34 ℃, adjusting the vacuum degree below-0.08 MPa, introducing N2, controlling the vacuum degree below-0.08 MPa, drying for 4.7h to obtain the vitamin D with the purity of 99.8 percent3(yield 87.1%).
Performance detection
Reference SOP-C011228-01 vitamin D3(CP 2015) examination of relevant content of Standard operating protocol for vitamin D prepared in examples 1 to 53Respectively detecting high temperature degradation (40 deg.C), high humidity degradation (relative humidity 90% RH + -5% RH) and strong light degradation (illuminance 4500 + -500 Lux) on 5 th and 10 th days, each group is vitamin D3Sample 100g, recording vitamin D separately3The purity of the environment exposed to the environment and the oxygen-isolated environment under different experimental conditions is shown in table 1.
TABLE 1 test results Table
| 5 days at 40 DEG C | Exposed to the environment | Isolating oxygen environment | 10 days at 40 DEG C | Is exposed to the environmentIn | Isolating oxygen environment |
| Example 1 | 99.88 | 99.90 | Example 1 | 99.85 | 99.88 |
| Example 2 | 99.62 | 99.65 | Example 2 | 99.61 | 99.65 |
| Example 3 | 99.69 | 99.73 | Example 3 | 99.67 | 99.70 |
| Example 4 | 99.81 | 99.83 | Example 4 | 99.79 | 99.80 |
| Example 5 | 99.73 | 99.75 | Example 5 | 99.71 | 99.73 |
| High humidity for 5 days | Exposed to the environment | Isolating oxygen environment | High humidity for 10 days | Exposed to the environment | Isolating oxygen environment |
| Example 1 | 99.90 | 99.92 | Example 1 | 99.87 | 99.90 |
| Example 2 | 99.61 | 99.63 | Example 2 | 99.60 | 99.61 |
| Example 3 | 99.73 | 99.75 | Example 3 | 99.71 | 99.72 |
| Example 4 | 99.82 | 99.83 | Example 4 | 99.78 | 99.81 |
| Example 5 | 99.75 | 99.78 | Example 5 | 99.72 | 99.74 |
| Strong light for 5 days | Exposed to the environment | Isolating oxygen environment | Strong light for 10 days | Exposed to the environment | Isolating oxygen environment |
| Example 1 | 99.90 | 99.92 | Example 1 | 99.88 | 99.89 |
| Example 2 | 99.63 | 99.65 | Example 2 | 99.60 | 99.62 |
| Example 3 | 99.71 | 99.73 | Example 3 | 99.70 | 99.72 |
| Example 4 | 99.81 | 99.84 | Example 4 | 99.80 | 99.82 |
| Example 5 | 99.75 | 99.77 | Example 5 | 99.73 | 77.76 |
As can be seen from Table 1, vitamin D produced in examples 1 to 5 of the present application3Placing the glass fiber at the temperature of 40 ℃ for 5 days, and exposing the glass fiber to the environment to ensure that the purity of the glass fiber is 99.62-99.88% and the purity of the isolated oxygen is 99.65-99.90%; placing the glass fiber at the temperature of 40 ℃ for 10 days, and exposing the glass fiber to the environment to ensure that the purity of the glass fiber is 99.61-99.90% and the purity of the isolated oxygen is 99.63-99.92%; the product is placed for 10 days under a high humidity condition, and the purity of the product exposed in the environment is 99.60-99.87%, and the purity of the isolated oxygen is 99.61-99.90%; placing the glass fiber for 5 days under the strong light condition, wherein the purity of the glass fiber exposed in the environment is 99.63-99.90%, and the purity of the isolated oxygen is 99.65-99.92%; the glass is placed for 10 days under the condition of strong light, the purity of the glass exposed in the environment is 99.60-99.88%, and the purity of the oxygen isolated is 99.62-99.89%; all prepared as described in examples 1-53Has a small difference in purity (99.67 to 99.95), and shows that vitamin D is produced in examples 1 to 5 of the present application3Has high purity, low content of harmful impurities, and good vitamin D tolerance3The generated influence is small, thereby leading to vitamin D3The product still maintains higher purity and higher stability in high temperature, high humidity and illumination environment.
The embodiments of the present invention are preferred embodiments of the present application, and the scope of protection of the present application is not limited by the embodiments, so: all equivalent changes made according to the structure, shape and principle of the present application shall be covered by the protection scope of the present application.
Claims (10)
1. Vitamin D3The purification method is characterized by comprising the following steps:
a. esterification reaction
a1. At the temperature of 25-35 ℃, organic amine, a first organic solvent and vitamin D are added3Mixing oil and aryl acyl chloride, reacting for 2-3 h, and adding water to stop the reaction; organic amine, first organic solvent and vitamin D3The weight ratio of the oil to the aryl acyl chloride to the water is (1.97-1.98): 12.5-13.5): 1: (0.85-0.95): 1.8-2.2);
a2. washing the product obtained in the step a1 with water, drying the product with anhydrous sodium sulfate, filtering the product with neutral alumina, controlling the temperature below 35 ℃ and the vacuum degree below-0.06 MPa, carrying out reduced pressure distillation, and adding 11.5-12.5 times of vitamin D3Dissolving the oil in acetone, controlling the temperature below 40 ℃, performing secondary reduced pressure distillation under the vacuum degree below-0.06 MPa, cooling and crystallizing at the temperature of 0-5 ℃ for 2-3 h, and drying to obtain the vitamin D3Benzyl ester;
b. hydrolysis reaction
b1. Mixing vitamin D3Dissolving benzyl ester in methanol, dropwise adding a strong base solution, and reacting for 2-3 h at the temperature of 25-35 ℃; wherein, vitamin D3The weight ratio of the benzyl ester to the methanol to the strong alkali solution is 1 (4.6-5.4) to 5.0-5.6;
b2. distilling the product obtained in the step b1 at the temperature of below 35 ℃ under reduced pressure, adding dichloromethane and water, uniformly mixing, separating liquid, washing an organic phase with water, drying anhydrous sodium sulfate, filtering neutral alumina, distilling at the temperature of below 35 ℃ under reduced pressure twice, adding a second organic solvent, dissolving at the temperature of 30-40 ℃, cooling to 5-15 ℃ and recrystallizing to obtain vitamin D3A crude product; the dosage of the dichloromethane, the water and the second organic solvent is respectively vitamin D328-32 times, 14.8-15.2 times and 1.64-1.7 times of the dosage of the benzyl ester;
c. refining by decolorizing
c1. Mixing vitamin D3Dissolving the crude product in a third organic solvent, adding activated carbon, and stirring and decoloring at the temperature of 25-35 ℃ for 1-2 hours; wherein the third organic solvent and vitamin D3The weight ratio of the crude product is (4.5-5.5) to 1;
c2. filtering the product obtained in the step c1, distilling the filtrate at the temperature of below 35 ℃ under reduced pressure, and then adding 2.06-2.12 times of vitamin D3Dissolving a fourth organic solvent with the weight of the crude product at the temperature of 30-40 ℃, then cooling to 5-15 ℃ for recrystallization, filtering, and drying to obtain the vitamin D3。
2. A vitamin D in accordance with claim 13The purification method of (2), characterized in that: in step a1, the organic amine is one of triethylamine and pyridine.
3. A vitamin D in accordance with claim 13The purification method of (2), characterized in that: in step a1, the first organic solvent is one of dichloromethane, methanol and ethanol.
4. A vitamin D in accordance with claim 13The purification method of (2), characterized in that: in the step a1, the aryl acyl chloride adopts one of benzoyl chloride and 3, 5-dinitrobenzoyl chloride.
5. A vitamin D in accordance with claim 13The purification method of (2), characterized in that: in the step a2, the acetone is dissolved under the condition of stirring for 15-30 min at the temperature of 40-50 ℃.
6. A vitamin D in accordance with claim 13The purification method of (2), characterized in that: in the step a2 and the step c2, the drying condition is that the vacuum degree is controlled to be below-0.08 MPa at the temperature of 30-35 ℃, and N is introduced2And controlling the vacuum degree to be-0.07 to-0.08 MPa, and drying for 4 to 5 hours.
7. A vitamin D in accordance with claim 13The purification method of (2), characterized in that: in the step b1, the strong alkaline solution comprises (4.8-5.2): (0.2-0.4) by weight of methanol and sodium hydroxide or (4.8-5.2): (0.2-0.4) by weight of methanol and potassium hydroxide.
8. A vitamin D in accordance with claim 13The purification method of (2), characterized in that: in the step b2, the second organic solvent comprises methyl formate or methyl formate and acetone in a weight ratio of (0.84-0.88): (0.8-0.82) or ethyl acetate and acetonitrile in a weight ratio of (0.84-0.88): (0.8-0.82) or methyl formate and methanol in a weight ratio of (0.84-0.88): (0.8-0.82).
9. A vitamin D in accordance with claim 13The purification method of (2), characterized in that: in the step c2, the fourth organic solvent comprises methyl formate or methyl formate and acetone in a weight ratio of (1.06-1.1) - (1-1.02) or ethyl acetate and acetonitrile in a weight ratio of (1.06-1.1) - (1-1.02) or methyl formate and methanol in a weight ratio of (1.06-1.1) - (1-1.02).
10. A vitamin D in accordance with claim 13The purification method of (2), characterized in that: in step c1, the third organic solvent is one of acetone, ethyl acetate, dichloromethane, petroleum ether and ethanol.
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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 |
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| 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 |
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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 |
| CN103772432A (en) * | 2014-01-03 | 2014-05-07 | 湖北瑞锶科技有限公司 | Production method of benfotiamine |
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| 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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