CN114369047A - Method for crystallizing vitamin D3 - Google Patents
Method for crystallizing vitamin D3 Download PDFInfo
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- CN114369047A CN114369047A CN202210101465.0A CN202210101465A CN114369047A CN 114369047 A CN114369047 A CN 114369047A CN 202210101465 A CN202210101465 A CN 202210101465A CN 114369047 A CN114369047 A CN 114369047A
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- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 title claims abstract description 219
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 title claims abstract description 199
- 235000005282 vitamin D3 Nutrition 0.000 title claims abstract description 197
- 239000011647 vitamin D3 Substances 0.000 title claims abstract description 197
- 229940021056 vitamin d3 Drugs 0.000 title claims abstract description 197
- 238000000034 method Methods 0.000 title claims abstract description 49
- 239000013078 crystal Substances 0.000 claims abstract description 99
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 58
- 238000001816 cooling Methods 0.000 claims abstract description 49
- 238000003756 stirring Methods 0.000 claims abstract description 39
- 238000002425 crystallisation Methods 0.000 claims abstract description 33
- 230000008025 crystallization Effects 0.000 claims abstract description 33
- 239000000706 filtrate Substances 0.000 claims abstract description 33
- 239000003960 organic solvent Substances 0.000 claims abstract description 31
- 238000000926 separation method Methods 0.000 claims abstract description 29
- 238000001914 filtration Methods 0.000 claims abstract description 22
- 238000001179 sorption measurement Methods 0.000 claims abstract description 15
- 238000001035 drying Methods 0.000 claims abstract description 13
- 239000007788 liquid Substances 0.000 claims abstract description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 239000002994 raw material Substances 0.000 claims description 26
- UCTLRSWJYQTBFZ-UHFFFAOYSA-N Dehydrocholesterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)CCCC(C)C)CCC33)C)C3=CC=C21 UCTLRSWJYQTBFZ-UHFFFAOYSA-N 0.000 claims description 24
- 239000012043 crude product Substances 0.000 claims description 17
- 238000006552 photochemical reaction Methods 0.000 claims description 13
- 238000004440 column chromatography Methods 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 10
- 230000002572 peristaltic effect Effects 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000004821 distillation Methods 0.000 claims description 9
- 239000012528 membrane Substances 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000000919 ceramic Substances 0.000 claims description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 6
- 239000011148 porous material Substances 0.000 claims description 6
- 239000000741 silica gel Substances 0.000 claims description 6
- 229910002027 silica gel Inorganic materials 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 5
- 239000003480 eluent Substances 0.000 claims description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- 239000001913 cellulose Substances 0.000 claims description 3
- 229920002678 cellulose Polymers 0.000 claims description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 3
- 230000008569 process Effects 0.000 abstract description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- YUGCAAVRZWBXEQ-UHFFFAOYSA-N Precholecalciferol Natural products C=1CCC2(C)C(C(C)CCCC(C)C)CCC2C=1C=CC1=C(C)CCC(O)C1 YUGCAAVRZWBXEQ-UHFFFAOYSA-N 0.000 description 13
- 238000004090 dissolution Methods 0.000 description 13
- YUGCAAVRZWBXEQ-WHTXLNIXSA-N previtamin D3 Chemical compound C=1([C@@H]2CC[C@@H]([C@]2(CCC=1)C)[C@H](C)CCCC(C)C)\C=C/C1=C(C)CC[C@H](O)C1 YUGCAAVRZWBXEQ-WHTXLNIXSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 238000007670 refining Methods 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 230000001681 protective effect Effects 0.000 description 8
- XQFJZHAVTPYDIQ-LETJEVNCSA-N (1s)-3-[(e)-2-[(1r,3ar,7ar)-1-[(e,2r,5r)-5,6-dimethylhept-3-en-2-yl]-7a-methyl-1,2,3,3a,6,7-hexahydroinden-4-yl]ethenyl]-4-methylcyclohex-3-en-1-ol Chemical compound C=1([C@@H]2CC[C@@H]([C@]2(CCC=1)C)[C@H](C)/C=C/[C@H](C)C(C)C)\C=C\C1=C(C)CC[C@H](O)C1 XQFJZHAVTPYDIQ-LETJEVNCSA-N 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 238000005286 illumination Methods 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- BUNBVCKYYMRTNS-UHFFFAOYSA-N tachysterol Natural products C=1CCC2(C)C(C(C)CCC(C)C(C)C)CCC2C=1C=CC1=C(C)CCC(O)C1 BUNBVCKYYMRTNS-UHFFFAOYSA-N 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 230000001276 controlling effect Effects 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000011347 resin Substances 0.000 description 5
- 229920005989 resin Polymers 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000006317 isomerization reaction Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 229940088594 vitamin Drugs 0.000 description 4
- 229930003231 vitamin Natural products 0.000 description 4
- 235000013343 vitamin Nutrition 0.000 description 4
- 239000011782 vitamin Substances 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000013375 chromatographic separation Methods 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000001307 helium Substances 0.000 description 3
- 229910052734 helium Inorganic materials 0.000 description 3
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 150000003722 vitamin derivatives Chemical class 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- 229930003316 Vitamin D Natural products 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- UCTLRSWJYQTBFZ-DDPQNLDTSA-N cholesta-5,7-dien-3beta-ol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@@H](CC[C@@]3([C@@H]([C@H](C)CCCC(C)C)CC[C@H]33)C)C3=CC=C21 UCTLRSWJYQTBFZ-DDPQNLDTSA-N 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000001678 irradiating effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 235000019166 vitamin D Nutrition 0.000 description 2
- 239000011710 vitamin D Substances 0.000 description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 description 2
- 229940046008 vitamin d Drugs 0.000 description 2
- VPSSPAXIFBTOHY-LURJTMIESA-N (2s)-2-amino-4-methylpentan-1-ol Chemical compound CC(C)C[C@H](N)CO VPSSPAXIFBTOHY-LURJTMIESA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 238000001782 photodegradation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Images
Classifications
-
- 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
-
- 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
-
- 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
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a method for crystallizing vitamin D3. The method provided by the invention comprises the following steps: a) dissolving resin-shaped vitamin D3 oil in an organic solvent, adding activated carbon for adsorption treatment, and filtering to obtain a filtrate; b) cooling the filtrate, adding vitamin D3 seed crystals, performing gradient cooling crystallization, and performing solid-liquid separation and drying to obtain needle-shaped vitamin D3 crystal; the gradient cooling crystallization comprises the following steps: firstly, cooling to 5-15 ℃ under the stirring condition, keeping stirring and crystallizing until needle crystals are precipitated, and stopping stirring; and then continuously cooling to-20-0 ℃, standing and crystallizing. The method provided by the invention can be used for preparing the resin-shaped vitamin D3 crystal into the needle-shaped crystal, and can simplify the process, reduce the pollution and ensure high yield and high purity.
Description
Technical Field
The invention relates to the field of organic materials, in particular to a method for crystallizing vitamin D3.
Background
The vitamin D3 as additive is mainly used for regulating the metabolism of calcium and phosphorus of human body and animals, promoting the absorption of calcium and phosphorus in intestinal tract, controlling the excretion of calcium and phosphorus and the storage and transformation in bones, and is an essential vitamin for the normal growth of human body and animals.
The synthesis of vitamin D3 mainly comprises photochemical synthesis, and in recent decades, many scientists at home and abroad have made full-scale research in the field of organic photochemistry, including the development of 7-dehydrocholesterol, which is a raw material for photochemically synthesizing vitamin D3, the selection of a photochemical reaction light source, the conditions of photochemical reaction, and the design of a photochemical reaction device. Wherein, the vitamin D3 is prepared by irradiating 7-dehydrocholesterol with ultraviolet rays, generating a ring opening reaction to generate pre-vitamin D3 (pre-vitamin D3 is heated and isomerized into vitamin D3), further irradiating to generate by-products of leucinol and tachysterol, and if the pre-vitamin D3 is excessively irradiated, generating toxic bone alcohol, thus reducing the yield of the vitamin D3 and causing great difficulty in separation and purification. Among these, the UV wavelength plays a decisive role in the photoproduct distribution of 7-dehydrocholesterol in the photochemical synthesis of previtamin D3. The optimal wavelength for generating the pre-vitamin D3 by isomerizing the 7-dehydrocholesterol is 295nm, and the content of the pre-vitamin D3 is 70% after the irradiation of ultraviolet wavelength of 295 nm. A single wavelength of uv light increases the yield of pre-vitamin D3.
In general, the specific preparation process is as follows: dissolving 7-dehydrocholesterol in solvent, performing light irradiation reaction, and removing solvent and unconverted 7-dehydrocholesterol to obtain resin-like vitamin D converted oil (also called vitamin D3 light oil). Then, the crude product of the resinoid vitamin D converted oil is separated and purified to obtain the vitamin D3.
For example, CN1709869A proposes column chromatography to separate vitamin D3 photochemical oil, but vitamin D3 photochemical oil usually contains tachysterol, and the content of tachysterol can be 17% -20%, because vitamin D3 and tachysterol are similar in nature, it is difficult to separate them by this column chromatography, and the separation yield is low, and the average yield is not more than 30%.
For another example, CN1445215A discloses a method for photochemical synthesis of vitamin D3, which comprises, first, carrying out photochemical reaction on 7-dehydrocholesterol to generate vitamin P3, removing toxic by-product tachysterol by chemical method, and then carrying out thermal isomerization reaction to obtain vitamin D3 oil solution, wherein tachysterol is removed by DA reaction, but this process can only obtain high content of resin oil, which is used for feed-grade vitamin D3 oil and feed-grade vitamin D3 particles, and does not obtain medicinal vitamin D3 crystals.
In the prior art, the synthesis of vitamin D3 is mostly performed by the steps of carrying out light reaction on 7-dehydrocholesterol, removing tachysterol and 7-dehydrocholesterol, then carrying out thermal isomerization, and then extracting and concentrating by chemical methods such as esterification and alkalization hydrolysis to obtain the resin-shaped vitamin D3. Regardless of which method is used to isolate vitamin D3 from the reaction mixture, the final product is a resinous vitamin D3.
However, as it is known that the resinous vitamin D3 requires further processing to convert it into needle-like crystals, which is very difficult, it is reported in U.S. Pat. No. 3,3334118 that the direct crystallization of the resinous vitamin D3 isolated from the reaction mixture into needle-like crystalline vitamin D3 has a great limitation, and that the method using direct crystallization is not preferable and applicable because it is difficult to precipitate needle-like crystals, and the crystallization process is continued for several days and does not necessarily occur crystals. Furthermore, the direct crystallization process is not satisfactory because the crystallization process has the presence of colloid or floc formation, which inhibits the formation of crystalline vitamins.
Disclosure of Invention
In view of the above, the present invention provides a method for crystallizing vitamin D3, which can crystallize resinous vitamin D3 to form needle-like crystals, and which can simplify the process, reduce pollution, and ensure high yield and high purity.
The invention provides a method for crystallizing vitamin D3, which comprises the following steps:
a) dissolving resin-shaped vitamin D3 oil in an organic solvent, adding activated carbon for adsorption treatment, and filtering to obtain a filtrate;
b) cooling the filtrate, adding vitamin D3 seed crystals, performing gradient cooling crystallization, and performing solid-liquid separation and drying to obtain needle-shaped vitamin D3 crystal;
the gradient cooling crystallization comprises the following steps: firstly, cooling to 5-15 ℃ under the stirring condition, keeping stirring and crystallizing until needle crystals are precipitated, and stopping stirring; and then continuously cooling to-20-0 ℃, standing and crystallizing.
Preferably, the gradient cooling crystallization comprises: firstly, cooling to 5 ℃ under the stirring condition, keeping stirring and crystallizing until needle crystals are separated out, and stopping stirring; then continuously cooling to-20 ℃, standing and crystallizing.
Preferably, in the step b), the temperature of the filtrate is reduced to 10-15 ℃;
and standing and crystallizing for 3-10 hours.
Preferably, in the step b), the addition amount of the vitamin D3 seed crystals is 0.01-0.5 wt% of the mass of the resinous vitamin D3 oil.
Preferably, in the step a), the amount of the activated carbon is 0.5 wt% to 5 wt% of the mass of the resinous vitamin D3 oil;
the specifications of the activated carbon are as follows: bulk density of 200 to 500kg/m3The specific surface area is 1000-1500 m2(ii)/g, the average particle diameter is 20 to 80 μm.
Preferably, in the step a), the filter used for filtering is a ceramic membrane with the pore diameter of 20-200 nm;
after dissolving the resinoid vitamin D3 photochemical oil in the organic solvent, adding a filter aid;
the filter aid is cellulose and/or diatomite.
Preferably, in the step a), the temperature for dissolving the resin-shaped vitamin D3 oil in the organic solvent is less than or equal to 30 ℃;
the organic solvent is selected from one or more of methyl formate, ethyl formate, methyl acetate, ethyl acetate, acetonitrile, acetone and methanol.
The dosage ratio of the resin-shaped vitamin D3 oil to the organic solvent is (10-25) g to (55-75) mL.
Preferably, in the step a), the resinous vitamin D3 oil is prepared by the following preparation method:
s1, dissolving 7-dehydrocholesterol in an organic solvent to obtain a raw material solution;
s2, conveying the raw material solution to a photochemical reactor for photochemical reaction under the irradiation condition of an LED single-light-source ultraviolet lamp to obtain vitamin D3 photochemical oil;
s3, carrying out heat treatment on the vitamin D3 photochemical oil, and then carrying out reduced pressure distillation and concentration to obtain a resin-shaped vitamin D3 crude product converted oil; then, column chromatography separation and concentration are carried out to obtain the resin-shaped vitamin D3 oil.
Preferably, in step S2:
delivering the feedstock solution to a photochemical reactor by a peristaltic pump;
controlling the flow rate of the raw material solution to be 0.5-10 mL/min, and enabling the irradiation time of the raw material solution by the LED single-light-source ultraviolet lamp to be 30-60 min;
the temperature of the photochemical reactor is kept at 20-30 ℃;
in step S3, the heat treatment conditions are: the temperature is 40-60 ℃, the pressure is-0.095-0.08 MPa, and the temperature is kept for 1-3 h;
preferably, in step S3, the column chromatography separation and concentration process includes:
dissolving the resin-shaped vitamin D3 crude product converted oil in an adsorption solvent, injecting into a chromatographic column filled with chromatographic silica gel, eluting with an eluent until vitamin D3 is completely eluted, and concentrating the collected vitamin D3 under reduced pressure to obtain the resin-shaped vitamin D3 oil.
In the method for preparing the needle-shaped vitamin D3 crystal, firstly, resinous vitamin D3 oil is dissolved in an organic solvent, then activated carbon is added for adsorption treatment, and then filtration is carried out to obtain filtrate; and then cooling the filtrate, adding vitamin D3 seed crystals, performing gradient cooling crystallization, and performing solid-liquid separation and drying to obtain needle-shaped vitamin D3 crystals. Firstly, in the process of preparing the resin-shaped vitamin D3 oil, the flow rate is adjusted according to the power of a light source, the balance point of photochemical reaction is controlled, and the chromatographic separation efficiency is improved; and moreover, ultraviolet light with the wavelength of 295nm is adopted, the photoreaction conversion efficiency is higher, and the purity of the obtained vitamin D3 oil is better. In the process of obtaining crystals by using vitamin D3 oil crystals, the active carbon and the filter membrane are firstly used for filtering to mainly remove chemical and biological impurities and factors influencing the crystals; under the initiation of the seed crystal, floccules or powdery solids are prevented from being separated out through different temperature gradients, so that the needle-shaped crystal is ensured to be separated out. Compared with the prior art, the method provided by the invention simplifies the process, improves the separation efficiency and refining yield of column chromatography, separates out medicinal needle crystals, reduces pollution, and ensures high yield and high purity.
Test results show that the method provided by the invention can obtain needle-shaped vitamin D3 crystal products, the refining yield of the crystal reaches more than 85%, the purity of the crystal reaches more than 99%, and the obtained crystal meets the medicinal requirements. Wherein, in the preparation of the preorder resin-shaped vitamin D3 oil, the HPLC content of previtamin D3 in the vitamin D3 polished oil can reach more than 80 percent, and the separation yield of the resin-shaped vitamin D3 oil is higher and reaches more than 43 percent.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 is an HPLC chromatogram of needle-shaped vitamin D3 crystals obtained in example 1;
fig. 2 is an appearance diagram of needle-shaped vitamin D3 crystals obtained in example 1.
Detailed Description
The invention provides a method for crystallizing vitamin D3, which comprises the following steps:
a) dissolving resin-shaped vitamin D3 oil in an organic solvent, adding activated carbon for adsorption treatment, and filtering to obtain a filtrate;
b) cooling the filtrate, adding vitamin D3 seed crystals, performing gradient cooling crystallization, and performing solid-liquid separation and drying to obtain needle-shaped vitamin D3 crystal;
the gradient cooling crystallization comprises the following steps: firstly, cooling to 5-15 ℃ under the stirring condition, keeping stirring and crystallizing until needle crystals are precipitated, and stopping stirring; and then continuously cooling to-20-0 ℃, standing and crystallizing.
Concerning step a)：
Dissolving resin-like vitamin D3 oil in organic solvent, adding activated carbon for adsorption treatment, and filtering to obtain filtrate.
According to the present invention, a resinous vitamin D3 oil is first provided. In the present invention, the resinous vitamin D3 oil is preferably prepared by the following preparation method:
s1, dissolving 7-dehydrocholesterol in an organic solvent to obtain a raw material solution;
s2, conveying the raw material solution to a photochemical reactor for photochemical reaction under the irradiation condition of an LED single-light-source ultraviolet lamp to obtain vitamin D3 photochemical oil;
s3, carrying out heat treatment on the vitamin D3 photochemical oil, and then carrying out reduced pressure distillation and concentration to obtain a resin-shaped vitamin D3 crude product converted oil; then, column chromatography separation and concentration are carried out to obtain the resin-shaped vitamin D3 oil.
In the step S1:
the organic solvent is preferably one or more of tetrahydrofuran, methyl tert-butyl ether and methanol. The dosage ratio of the 7-dehydrocholesterol to the organic solvent is preferably (22-37) g to (935-1585) mL, and in some embodiments of the invention, the dosage ratio is 22.1g to 938mL, 33.5g to 1138mL, 37g to 1581 mL. In the present invention, the preferable dissolution temperature of 7-dehydrocholesterol in the organic solvent is 20 to 25 ℃, specifically 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃ and 25 ℃. In the present invention, the above dissolution is preferably carried out in a protective atmosphere; the type of gas for providing the protective atmosphere is not particularly limited in the present invention, and may be any inert gas conventionally used in the art, such as nitrogen, helium, argon, and the like. After the above dissolution, a raw material solution is obtained. The raw material solution is kept at the above temperature and fed into the next step.
In the step S2:
the power of the LED single-light-source ultraviolet lamp is preferably 100-500W, and specifically can be 100W, 150W, 200W, 250W, 300W, 350W, 400W, 450W and 500W. The wavelength of the irradiation of the LED single-light-source ultraviolet lamp is 295 nm. In the present invention, the raw material solution is preferably fed to the photochemical reactor by a peristaltic pump. In the conveying process, the flow rate of the raw material solution is preferably controlled to be 0.5-10 mL/min, so that the irradiation time of the raw material solution by the LED single-light-source ultraviolet lamp is 30-60 min; the flow rate may specifically be 0.5mL/min, 1.0mL/min, 1.5mL/min, 1.8mL/min, 2.0mL/min, 2.1mL/min, 2.5mL/min, 3.0mL/min, 3.5mL/min, 4.0mL/min, 4.5mL/min, 5.0mL/min, 5.5mL/min, 6.0mL/min, 6.5mL/min, 7.0mL/min, 7.5mL/min, 8.0mL/min, 8.5mL/min, 9.5mL/min, 10.0 mL/min. The temperature of the photochemical reactor is kept at 20-30 ℃, and specifically, the temperature can be 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃ and 30 ℃. After the above-mentioned light reaction, collecting reaction liquor, namely vitamin D3 light oil. The invention selects the LED single light source with specific wavelength, controls the time of the illumination reaction by adjusting the flow rate by a peristaltic pump, can lead the PHLC content of the main product previtamin D3 to reach more than 80 percent, and then carries out subsequent isomerization reaction and chromatographic separation; by controlling the content of main products in photochemical reaction, the separation efficiency and refining yield of subsequent column chromatography are improved, medicinal needle crystals are more easily separated out, pollution is reduced, and high yield and high purity are ensured.
In the step S3:
the conditions of the heat treatment are preferably: the temperature is 40-60 ℃, the pressure is-0.095-0.08 MPa, and the heat is preserved for 1-3 h. Wherein the temperature is 40 deg.C, 41 deg.C, 42 deg.C, 43 deg.C, 44 deg.C, 45 deg.C, 46 deg.C, 47 deg.C, 48 deg.C, 49 deg.C, 50 deg.C, 51 deg.C, 52 deg.C, 53 deg.C, 54 deg.C, 55 deg.C, 56 deg.C, 57 deg.C, 58 deg.C, 59 deg.C, 60 deg.C. The pressure can be specifically-0.095 MPa, -0.090MPa, -0.085MPa and-0.080 MPa. The heat preservation time can be 1h, 1.5h, 2h, 2.5h and 3 h. Isomerization reaction occurs by the above heat treatment to form an isomerized oil.
After the above heat treatment, the organic solvent was removed by distillation and concentration under reduced pressure. The conditions for the concentration by reduced pressure distillation are preferably as follows: the temperature is 40-60 ℃, and the pressure is-0.095 to-0.08 MPa; wherein the temperature is specifically 40 deg.C, 41 deg.C, 42 deg.C, 43 deg.C, 44 deg.C, 45 deg.C, 46 deg.C, 47 deg.C, 48 deg.C, 49 deg.C, 50 deg.C, 51 deg.C, 52 deg.C, 53 deg.C, 54 deg.C, 55 deg.C, 56 deg.C, 57 deg.C, 58 deg.C, 59 deg.C, 60 deg.C; the pressure can be specifically-0.095 MPa, -0.090MPa, -0.085MPa and-0.080 MPa.
Distilling under reduced pressure until the organic solvent is dried (namely, the organic solvent is fully removed), and then adding the organic solvent for dissolving. Wherein, the organic solvent is preferably one or more of methanol, ethanol, tetrahydrofuran and n-hexane. The dosage ratio of the organic solvent to the dissolved substance is preferably (90-150) mL to (20-50) g. After dissolution, the dissolution liquid is rapidly cooled. In the present invention, the temperature is preferably lowered to-10 to-30 ℃, specifically-30 ℃, -25 ℃, -20 ℃, -15 ℃, -10 ℃. After the temperature is reduced, the unconverted 7-dehydrocholesterol is removed by filtration to obtain a filtrate.
After the filtrate is obtained by the above filtration, the concentration is carried out again by reduced pressure distillation. In the present invention, the concentration by distillation under reduced pressure is preferably carried out under a protective atmosphere, and the kind of the gas for providing the protective atmosphere is not particularly limited, and may be any inert gas conventionally used in the art, such as nitrogen, helium, argon, or the like. The specific operation is as follows: protective gas is introduced into the filtrate, and reduced pressure distillation and concentration are carried out. The conditions for the concentration by reduced pressure distillation are preferably as follows: the temperature is 40-60 ℃, and the pressure is-0.095 to-0.08 MPa; wherein the temperature is specifically 40 deg.C, 41 deg.C, 42 deg.C, 43 deg.C, 44 deg.C, 45 deg.C, 46 deg.C, 47 deg.C, 48 deg.C, 49 deg.C, 50 deg.C, 51 deg.C, 52 deg.C, 53 deg.C, 54 deg.C, 55 deg.C, 56 deg.C, 57 deg.C, 58 deg.C, 59 deg.C, 60 deg.C; the pressure can be specifically-0.095 MPa, -0.090MPa, -0.085MPa and-0.080 MPa. After the above treatment, the resin-like vitamin D3 crude product converted oil is obtained.
After the resin-shaped vitamin D3 crude product is obtained by the treatment, the oil is converted, and then column chromatography separation is carried out. In the present invention, the process of column chromatography separation and concentration preferably comprises: dissolving the resin-shaped vitamin D3 crude product converted oil in an adsorption solvent, injecting into a chromatographic column filled with chromatographic silica gel, eluting with an eluent until vitamin D3 is completely eluted, and concentrating the collected vitamin D3 under reduced pressure to obtain the resin-shaped vitamin D3 oil.
Wherein: the adsorption solvent is preferably one or more of ethyl acetate, dichloromethane and n-hexane, and more preferably ethyl acetate. The volume ratio of the resin-shaped vitamin D3 crude product converted oil to the adsorption solvent is 1: 2-8, and specifically can be 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7 and 1: 8. The eluent is preferably one or more of ethyl acetate, dichloromethane and n-hexane. During the elution, vitamin D3 was collected in fractions and followed by thin layer analysis until vitamin D3 was completely eluted. The conditions for the concentration under reduced pressure are preferably: the temperature is 40-60 ℃, and the pressure is-0.095 to-0.08 MPa; wherein the temperature is specifically 40 deg.C, 41 deg.C, 42 deg.C, 43 deg.C, 44 deg.C, 45 deg.C, 46 deg.C, 47 deg.C, 48 deg.C, 49 deg.C, 50 deg.C, 51 deg.C, 52 deg.C, 53 deg.C, 54 deg.C, 55 deg.C, 56 deg.C, 57 deg.C, 58 deg.C, 59 deg.C, 60 deg.C; the pressure can be specifically-0.095 MPa, -0.090MPa, -0.085MPa and-0.080 MPa. The concentration under reduced pressure preferably comprises two stages of concentration under reduced pressure: the first stage is decompression concentrating to eliminate solvent and the second stage is decompression concentrating with protective gas. The type of the protective gas is not particularly limited, and may be any inert gas that is conventional in the art, such as nitrogen, helium, argon, or the like. The second stage is depressurized after introducing a protective gas so that the system pressure is still maintained within the above-mentioned pressure range and the temperature is also maintained within the above-mentioned temperature range. After the treatment, the resin-shaped vitamin D3 crude product chromatographic oil, namely the resin-shaped vitamin D3 oil, is obtained. The content of the obtained chromatographic oil is 2000-3000 IU.
The method for preparing the resin-shaped vitamin D3 oil can ensure that the separation yield of the vitamin D3 reaches more than 43 percent.
According to the present invention, after obtaining the resinous vitamin D3 oil, it is dissolved in an organic solvent. In the invention, the organic solvent is preferably one or more of methyl formate, ethyl formate, methyl acetate, ethyl acetate, acetonitrile, acetone and methanol, and more preferably methyl formate. In the invention, the dosage ratio of the resin-shaped vitamin D3 oil to the organic solvent is preferably (10-25) g to (55-75) mL; in some embodiments of the invention, the ratio is 11.3 g: 56.2mL, 14.6 g: 58.4mL, 24.6 g: 73.8 mL. In the present invention, the temperature of dissolving the resin-like vitamin D3 photochemical oil in the organic solvent is preferably controlled to be not more than 30 ℃, specifically 5 ℃, 6 ℃, 7 ℃, 8 ℃, 9 ℃, 10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃, 15 ℃, 16 ℃, 17 ℃, 18 ℃, 19 ℃, 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃, 30 ℃, more preferably 5 to 30 ℃, and most preferably 15 to 25 ℃. In the present invention, the dissolution process is preferably a stirring dissolution. The time for dissolution can be reduced by raising the temperature or enhancing the degree of mixing, and the time for the whole dissolution process is less than or equal to 30 min. After the above dissolution, a dissolution solution is obtained.
According to the invention, after the dissolution has been carried out as described above, activated carbon is added for the adsorption treatment, on which the impurities present in dissolved form can be adsorbed. In the present invention, the specification of the activated carbon is preferably: bulk density of 200 to 500kg/m3The specific surface area is 1000-1500 m2(ii)/g, the average particle diameter is 20 to 80 μm. Wherein the bulk density may be 200kg/m3、300kg/m3、400kg/m3、500kg/m3More preferably 300kg/m3(ii) a The specific surface area may be specifically 1000m2/g、1100m2/g、1200m2/g、1300m2/g、1400m2/g、1500m2(iv)/g, more preferably 1300kg/m3(ii) a The average particle diameter may be specifically 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, or 80 μm. The activated carbon is preferably Nuonat activated carbon, and can be better used for adsorbing biological impurities and separating chemical substances. In the present invention, the amount of the activated carbon is preferably 0.5 to 5 wt%, specifically 0.5 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, more preferably 2.5 wt% of the mass of the resinous vitamin D3 oil. After the activated carbon is put into the solution, the activated carbon adsorbs dissolved impurities from the solution. In the invention, the activated carbon is preferably added and then stirred and mixed, and the stirring speed is preferably 100-200 rpm, specifically 100rpm, 120rpm, 150rpm and 200 rpm. The time for the activated carbon to be placed in the dissolving solution for adsorption depends on impurities and is not limitedMore than 12 hours, specifically 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, preferably 0.5-1 hour.
In the present invention, a filter aid may be added in addition to the activated carbon. In the present invention, the filter aid is preferably cellulose and/or diatomaceous earth. In the present invention, the amount of the filter aid is preferably 2 to 10 wt%, specifically 2, 3, 4, 5, 6, 7, 8, 9, 10 wt% based on the mass of the resinous vitamin D3 oil.
In the present invention, the filtration is carried out after the adsorption with the activated carbon and the treatment with the filter aid. The activated carbon, any filter aids present and undissolved impurities can be removed by filtration. In the invention, the filter used for filtering is a ceramic membrane with the aperture of 20-200 nm; the pore size of the ceramic membrane is more preferably 30-60 nm, and in some embodiments is 55 nm. Filtration was carried out to obtain a filtrate.
Concerning step b)：
And cooling the filtrate, adding vitamin D3 seed crystals, performing gradient cooling crystallization, performing solid-liquid separation and drying to obtain needle-shaped vitamin D3 crystals.
According to the invention, the filtrate obtained in step a) is first cooled. In the present invention, the temperature reduction is preferably reduced to 10-15 ℃, specifically 10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃ and 15 ℃.
According to the invention, after the temperature is reduced, the vitamin D3 seed crystal is added. The vitamin D3 seed crystal is not particularly limited in the invention, and the seed crystal is a conventional seed crystal used in crystallization in the field. In the present invention, the amount of the vitamin D3 seed is preferably 0.01 wt% to 0.5 wt%, specifically 0.01 wt%, 0.03 wt%, 0.05 wt%, 0.07 wt%, 0.10 wt%, 0.12 wt%, 0.14 wt%, 0.16 wt%, 0.18 wt%, 0.20 wt%, 0.25 wt%, 0.30 wt%, 0.40 wt%, 0.50 wt%, preferably 0.07 wt%, based on the mass of the resinous vitamin D3 oil.
According to the invention, after the vitamin D3 seed crystal is added, gradient cooling crystallization is carried out. In the invention, the gradient cooling crystallization comprises: firstly, cooling to 5-15 ℃ under the stirring condition, keeping stirring and crystallizing until needle crystals are precipitated, and stopping stirring; and then continuously cooling to-20-0 ℃, standing and crystallizing. Wherein the stirring speed is preferably 50-150 rpm, and specifically can be 50rpm, 90rpm, 100rpm, 120rpm and 150 rpm. The temperature of the first cooling is 5-15 deg.C, specifically 5 deg.C, 6 deg.C, 7 deg.C, 8 deg.C, 9 deg.C, 10 deg.C, 11 deg.C, 12 deg.C, 13 deg.C, 14 deg.C, 15 deg.C, preferably 5 deg.C. Stirring and crystallizing after first cooling until needle crystals are precipitated, stopping stirring, then continuously cooling to-20-0 ℃, specifically-20 ℃, 19 ℃, 18 ℃, 17 ℃, 16 ℃, 15 ℃, 14 ℃, 13 ℃, 12 ℃, 11 ℃, 10 ℃, 9 ℃, 8 ℃, 7 ℃, 6 ℃, 5 ℃, 4 ℃, 3 ℃, 2 ℃, 1 ℃ and 0 ℃, preferably-20 ℃. And cooling to the temperature for standing crystallization, wherein the standing crystallization time is preferably 3-10 h, and specifically can be 3h, 4h, 5h, 6h, 7h, 8h, 9h and 10 h. After standing and crystallizing, a large amount of needle-shaped vitamin D3 crystals are formed. The invention adopts the crystallization mode of gradient cooling crystallization, can effectively separate out needle-shaped vitamin D3 crystal, and obtain high purity, if the needle-shaped vitamin D3 crystal is directly cooled and crystallized at one time, the invention has great limitation on the conversion into needle-shaped crystal, the needle-shaped crystal is difficult to separate out, colloid or floccule is easy to generate when the temperature is reduced below 5 ℃ without separating out the needle-shaped crystal, and the needle-shaped crystal can inhibit the formation of the crystal vitamin, thereby obtaining powdery solid.
According to the present invention, after the above-mentioned crystallization, solid-liquid separation and drying are carried out. Wherein, the solid-liquid separation mode is not specially limited, and the solid-liquid separation mode can be a separation mode which is conventional in the field, such as filtration or centrifugal separation. The drying temperature is preferably 30-50 ℃. Drying to obtain needle-shaped vitamin D3 crystal.
In the method for preparing the needle-shaped vitamin D3 crystal, firstly, resinous vitamin D3 oil is dissolved in an organic solvent, then activated carbon is added for adsorption treatment, and then filtration is carried out to obtain filtrate; and then cooling the filtrate, adding vitamin D3 seed crystals, performing gradient cooling crystallization, and performing solid-liquid separation and drying to obtain needle-shaped vitamin D3 crystals. Firstly, in the process of preparing the resin-shaped vitamin D3 oil, the flow rate is adjusted according to the power of a light source, the balance point of photochemical reaction is controlled, and the chromatographic separation efficiency is improved; and moreover, ultraviolet light with the wavelength of 295nm is adopted, the photoreaction conversion efficiency is higher, and the purity of the obtained vitamin D3 oil is better. In the process of obtaining crystals by using vitamin D3 oil crystals, the active carbon and the filter membrane are firstly used for filtering to mainly remove chemical and biological impurities and factors influencing the crystals; under the initiation of the seed crystal, floccules or powdery solids are prevented from being separated out through different temperature gradients, so that the needle-shaped crystal is ensured to be separated out. Compared with the prior art, the method provided by the invention simplifies the process, improves the separation efficiency and refining yield of column chromatography, separates out medicinal needle crystals, reduces pollution, and ensures high yield and high purity.
Test results show that the method provided by the invention can obtain needle-shaped vitamin D3 crystal products, the refining yield of the crystal reaches more than 85%, the purity of the crystal reaches more than 99%, and the obtained crystal meets the medicinal requirements. Wherein, in the preparation of the preorder resin-shaped vitamin D3 oil, the HPLC content of previtamin D3 in the vitamin D3 polished oil can reach more than 80 percent, and the separation yield of the resin-shaped vitamin D3 oil is higher and reaches more than 43 percent.
For a further understanding of the invention, reference will now be made to the preferred embodiments of the invention by way of example, and it is to be understood that the description is intended to further illustrate features and advantages of the invention, and not to limit the scope of the claims. In the following examples, the specifications of the activated carbon used are as described above.
Example 1
1. Preparation of resinous vitamin D3 oil
S1, photochemical reaction:
introducing nitrogen for protection, dissolving 37g of 7-dehydrocholesterol in 1581mL of tetrahydrofuran, keeping the temperature at 23 ℃, and stirring for 1 hour to obtain a raw material solution.
Controlling the temperature of the photochemical reactor to be kept at 25 ℃, starting an LED ultraviolet lamp single light source with the wavelength of 295nm, enabling the power of the light source to be 100W, conveying the raw material solution into the photochemical reactor by using a peristaltic pump, adjusting the flow of the raw material solution by 2mL/min through the peristaltic pump, carrying out illumination reaction under the irradiation of the LED ultraviolet lamp, converting the illumination time into 90min, and collecting reaction liquid, namely the vitamin D3 photodegradation oil. (the content of previtamin D3 in the obtained polished oil is 83.8% by HPLC).
Heat treating the vitamin D3 photochemical oil under the conditions of: the temperature is 50 ℃, the pressure is-0.09 MPa, and the temperature is kept for 2 h. Then, concentrating under reduced pressure (at 50 deg.C under-0.08 MPa) to dry, and removing tetrahydrofuran; then, 150mL of methanol is added to dissolve the mixture, the temperature is rapidly reduced to-20 ℃, and unconverted 7-dehydrocholesterol is filtered out to obtain filtrate. Introducing nitrogen into the obtained filtrate, and continuously concentrating (at 50 deg.C under-0.08 MPa for 4 hr) to obtain crude resin vitamin D3 converted oil.
S2 chromatography
Dissolving the crude resin vitamin D3 converted oil in 25.8g of ethyl acetate (the volume ratio of the converted oil to the ethyl acetate is 1: 4), injecting into a chromatographic column filled with chromatographic silica gel, eluting with ethyl acetate, collecting vitamin D3 in sections, tracking by a thin layer analysis method until vitamin D3 is completely eluted, concentrating all the collected vitamin D3 under reduced pressure (the conditions are that the temperature is 50 ℃ and the pressure is-0.09 MPa) to remove ethyl acetate, and introducing nitrogen to continue concentrating under reduced pressure (the conditions are that the temperature is 50 ℃ and the pressure is-0.09 MPa) to obtain 11.3g of crude resin vitamin D3 chromatographic oil, namely the crude resin vitamin D3 oil. The isolated yield of vitamin D3 was 43.8%.
2. Preparation of needle-like vitamin D3 crystals
K1, 11.3g of resinous vitamin D3 oil was dissolved in 56.2mL of methyl formate at 22 ℃ under stirring for 15min to obtain a solution. Then, 0.3g of activated carbon was added to the solution, and the mixture was stirred at 150rpm for 4 hours, and then the mixture was filtered through a ceramic membrane having a pore size of 55nm to obtain a filtrate.
K2, cooling the filtrate to 12 ℃, adding 0.02g of vitamin D3 seed crystal (the addition amount of the seed crystal is 0.18 wt% of the mass of the resin-shaped vitamin D3 oil) while stirring at 90rpm, continuously stirring and cooling to 5 ℃ for crystallization, stopping stirring until needle crystals are separated out, and continuously cooling to-20 ℃ for standing and crystallization for 10 hours. Then filtering, and drying at 40 ℃ for 12h to obtain 9.13g of needle-shaped vitamin D3 crystals. The calculated refining yield after depuration is 86.9 percent, and the purity is 99.3 percent. FIG. 1 is an HPLC chromatogram of needle-shaped vitamin D3 crystals obtained in example 1. Fig. 2 is an appearance diagram of the needle-shaped vitamin D3 crystals obtained in example 1, and it can be seen that the obtained crystals are needle-shaped.
Example 2
1. Preparation of resinous vitamin D3 oil
S1, photochemical reaction:
22.1g of 7-dehydrocholesterol was dissolved in 938mL of methyl tert-butyl ether under nitrogen, and the mixture was stirred at 20 ℃ for 1 hour to obtain a raw material solution.
Controlling the temperature of a photochemical reactor to be kept at 20 ℃, starting an LED ultraviolet lamp single light source with the wavelength of 295nm, enabling the power of the light source to be 100W, conveying the raw material solution into the photochemical reactor by using a peristaltic pump, adjusting the flow of the raw material solution by using the peristaltic pump to be 1.8mL/min, carrying out illumination reaction under the irradiation of the LED ultraviolet lamp, converting the illumination time into 100min, and collecting reaction liquid, namely the vitamin D3 photochemical oil (the content of previtamin D3 in the obtained photochemical oil is 85.1% by HPLC detection).
Heat treating the vitamin D3 photochemical oil under the conditions of: the temperature is 40 ℃, the pressure is-0.095 MPa, and the heat preservation is carried out for 3 hours. Then, concentrating under reduced pressure (the temperature is 40 ℃, the pressure is-0.09 MPa) to dryness, and removing the methyl tert-butyl ether; then, 150mL of methanol is added to dissolve the mixture, the temperature is rapidly reduced to-20 ℃, and unconverted 7-dehydrocholesterol is filtered out to obtain filtrate. And introducing nitrogen into the obtained filtrate to continuously concentrate (the conditions are that the temperature is 40 ℃, the pressure is-0.095 MPa, and the time is 4 hours), so as to obtain the resin-like vitamin D3 crude product converted oil.
S2 chromatography
Dissolving the resin-shaped vitamin D3 crude product converted oil in n-hexane (the volume ratio of the converted oil to the n-hexane is 1: 2), injecting into a chromatographic column filled with chromatographic silica gel, eluting with the n-hexane, collecting vitamin D3 in sections, tracking by a thin layer analysis method until vitamin D3 is completely eluted, concentrating all collected vitamin D3 under reduced pressure (the conditions are that the temperature is 40 ℃ and the pressure is-0.095 MPa) to remove the n-hexane, introducing nitrogen gas, and continuously concentrating under reduced pressure (the conditions are that the temperature is 40 ℃ and the pressure is-0.095 MPa) to obtain resin-shaped vitamin D3 crude product chromatographic oil, namely the resin-shaped vitamin D3 oil. The isolated yield of vitamin D3 was 44%.
2. Preparation of needle-like vitamin D3 crystals
K1, 14.6g of resinous vitamin D3 oil was dissolved in 58.4mL of ethyl acetate at 22 ℃ with stirring for 15min to obtain a solution. Then, 0.4g of activated carbon was added to the solution, and the mixture was stirred at 150rpm for 4 hours, and then the mixture was filtered through a ceramic membrane having a pore size of 55nm to obtain a filtrate.
K2, cooling the filtrate to 11 ℃, adding vitamin D3 seed crystals (the addition of the seed crystals is 0.2 wt% of the mass of the resin-shaped vitamin D3 oil) while stirring at 100rpm, continuously stirring and cooling to 5 ℃ for crystallization, stopping stirring until needle crystals are separated out, and continuously cooling to-20 ℃ for standing and crystallization for 10 hours. Then filtering, and drying at 40 ℃ for 12h to obtain 11.3g of needle-shaped vitamin D3 crystals. The refining yield after depuration is 85.4%, and the purity is 99.4%.
Example 3
1. Preparation of resinous vitamin D3 oil
S1, photochemical reaction:
under nitrogen protection, 33.5g of 7-dehydrocholesterol was dissolved in 1138mL of methanol, and the mixture was stirred at 25 ℃ for 1 hour to obtain a raw material solution.
Controlling the temperature of a photochemical reactor to be kept at 30 ℃, starting an LED ultraviolet lamp single light source with the wavelength of 295nm, enabling the power of the light source to be 100W, conveying the raw material solution into the photochemical reactor by using a peristaltic pump, adjusting the flow of the raw material solution by using the peristaltic pump to be 2.1mL/min, carrying out illumination reaction under the irradiation of the LED ultraviolet lamp, converting the illumination time into 85min, and collecting the reaction liquid, namely the vitamin D3 photodefinated oil (the content of the provitamin D3 in the obtained photodefinable oil is 84.4% by HPLC detection).
Heat treating the vitamin D3 photochemical oil under the conditions of: the temperature is 60 ℃, the pressure is-0.08 MPa, and the heat preservation is carried out for 1 h. Then, concentrating under reduced pressure (at 60 deg.C under-0.08 MPa) to dry, and removing methanol; then, 150mL of methanol is added to dissolve the mixture, the temperature is rapidly reduced to-20 ℃, and unconverted 7-dehydrocholesterol is filtered out to obtain filtrate. And introducing nitrogen into the obtained filtrate to continuously concentrate (the conditions are that the temperature is 60 ℃, the pressure is-0.08 MPa, and the time is 4 hours), so as to obtain the resin-like vitamin D3 crude product converted oil.
S2 chromatography
Dissolving the resin-shaped vitamin D3 crude product converted oil in ethyl acetate (the volume ratio of the converted oil to the ethyl acetate is 1: 6), injecting into a chromatographic column filled with chromatographic silica gel, eluting with ethyl acetate-n-hexane (the volume ratio of the ethyl acetate to the ethyl acetate is 1: 5), collecting vitamin D3 in sections, tracking by a thin layer analysis method until vitamin D3 is completely eluted, concentrating all the collected vitamin D3 under reduced pressure (the conditions are that the temperature is 60 ℃ and the pressure is-0.08 MPa) to remove the ethyl acetate-n-hexane, and introducing nitrogen to continue concentrating under reduced pressure (the conditions are that the temperature is 60 ℃ and the pressure is-0.08 MPa) to obtain resin-shaped vitamin D3 crude product layer separated oil, namely resin-shaped vitamin D3 oil. The isolated yield of vitamin D3 was 45%.
2. Preparation of needle-like vitamin D3 crystals
K1, dissolving 24.6g of resinous vitamin D3 oil in 73.8mL of acetone at 22 ℃ under stirring for 15min to obtain a solution. Then, 0.4g of activated carbon was added to the solution, and the mixture was stirred at 150rpm for 4 hours, and then the mixture was filtered through a ceramic membrane having a pore size of 55nm to obtain a filtrate.
K2, cooling the filtrate to 11 ℃, adding vitamin D3 seed crystals (the addition of the seed crystals is 0.25 wt% of the mass of the resin-shaped vitamin D3 oil) while stirring at 120rpm, continuously stirring and cooling to 5 ℃ for crystallization, stopping stirring until needle crystals are separated out, and continuously cooling to-20 ℃ for standing and crystallization for 10 hours. Then filtering, and drying at 40 ℃ for 12h to obtain 19.4g of needle-shaped vitamin D3 crystals. The refining yield after depuration is 85.7%, and the purity is 99.6%.
Comparative example 1
1. Preparing resin-like vitamin D3 oil:
performed as in example 1, except that: in step S1, the temperature for dissolving 7-dehydrocholesterol was 35 ℃, the flow rate of the raw material solution was controlled to 0.1mL/min, and the temperature of the photochemical reactor was maintained at 40 ℃.
2. Preparing vitamin D3 crystal: the same as in example 1.
Comparative example 2
1. Preparing resin-like vitamin D3 oil: the same as in example 1.
2. Preparing vitamin D3 crystal:
performed as in example 1, except that: in step K1, after dissolution, no activated carbon was added and no filtration was performed.
Comparative example 3
1. Preparing resin-like vitamin D3 oil: the same as in example 1.
2. Preparing vitamin D3 crystal:
performed as in example 1, except that: in the step K2, after seed crystals are added, the temperature is directly reduced to-20 ℃ for crystallization.
The effects of the intermediates and crystals of examples 1-3 and comparative examples 1-3 are shown in Table 1.
TABLE 1 Effect of intermediates and crystals of examples 1 to 3 and comparative examples 1 to 3
The test results in table 1 show that in examples 1 to 3 of the present invention, the content of previtamin D3 in the vitamin D3 polished oil reaches more than 80% by HPLC, and the separation yield of the resin-like vitamin D3 oil is high and reaches more than 43%; simultaneously, needle-shaped vitamin D3 crystal products can be obtained, the refining yield of the crystal reaches more than 85 percent, the purity reaches more than 99 percent, and the obtained crystal meets the medicinal requirements. In comparative example 1, the HPLC content of provitamin D3 in the vitamin D3 polished oil and the separation yield of the resin-like vitamin D3 oil are both low, and the yield and purity of the finally obtained crystals are also low; the products obtained in comparative examples 2-3 were a mixture of needle-like and powder-like crystals that were not completely obtained and were significantly reduced in yield and purity.
The foregoing examples are provided to facilitate an understanding of the principles of the invention and their core concepts, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention. The scope of the invention is defined by the claims and may include other embodiments that occur to those skilled in the art. Such other embodiments are intended to be within the scope of the claims if they have structural elements that approximate the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.
Claims (10)
1. A method of crystallizing vitamin D3, comprising the steps of:
a) dissolving resin-shaped vitamin D3 oil in an organic solvent, adding activated carbon for adsorption treatment, and filtering to obtain a filtrate;
b) cooling the filtrate, adding vitamin D3 seed crystals, performing gradient cooling crystallization, and performing solid-liquid separation and drying to obtain needle-shaped vitamin D3 crystal;
the gradient cooling crystallization comprises the following steps: firstly, cooling to 5-15 ℃ under the stirring condition, keeping stirring and crystallizing until needle crystals are precipitated, and stopping stirring; and then continuously cooling to-20-0 ℃, standing and crystallizing.
2. The method of claim 1, wherein the gradient temperature-decreasing crystallization comprises: firstly, cooling to 5 ℃ under the stirring condition, keeping stirring and crystallizing until needle crystals are separated out, and stopping stirring; then continuously cooling to-20 ℃, standing and crystallizing.
3. The method according to claim 1, wherein in the step b), the temperature of the filtrate is reduced to 10-15 ℃;
and standing and crystallizing for 3-10 hours.
4. The method according to claim 1, wherein in step b), the vitamin D3 seed crystals are added in an amount of 0.01 wt% to 0.5 wt% based on the mass of the resinous vitamin D3 oil.
5. The method as claimed in claim 1, wherein in the step a), the amount of the activated carbon is 0.5-5 wt% of the mass of the resinous vitamin D3 oil;
the specifications of the activated carbon are as follows: bulk density of 200 to 500kg/m3The specific surface area is 1000-1500 m2(ii)/g, the average particle diameter is 20 to 80 μm.
6. The method according to claim 1, wherein in the step a), the filter used for the filtration is a ceramic membrane with a pore size of 20-200 nm;
after dissolving the resinoid vitamin D3 photochemical oil in the organic solvent, adding a filter aid;
the filter aid is cellulose and/or diatomite.
7. The method as claimed in claim 1, wherein in step a), the resinous vitamin D3 oil is dissolved in the organic solvent at a temperature of 30 ℃ or less;
the organic solvent is selected from one or more of methyl formate, ethyl formate, methyl acetate, ethyl acetate, acetonitrile, acetone and methanol.
The dosage ratio of the resin-shaped vitamin D3 oil to the organic solvent is (10-25) g to (55-75) mL.
8. The method according to claim 1, wherein in step a), the resinous vitamin D3 oil is prepared by the following preparation method:
s1, dissolving 7-dehydrocholesterol in an organic solvent to obtain a raw material solution;
s2, conveying the raw material solution to a photochemical reactor for photochemical reaction under the irradiation condition of an LED single-light-source ultraviolet lamp to obtain vitamin D3 photochemical oil;
s3, carrying out heat treatment on the vitamin D3 photochemical oil, and then carrying out reduced pressure distillation and concentration to obtain a resin-shaped vitamin D3 crude product converted oil; then, column chromatography separation and concentration are carried out to obtain the resin-shaped vitamin D3 oil.
9. The method according to claim 8, wherein in step S2:
delivering the feedstock solution to a photochemical reactor by a peristaltic pump;
controlling the flow rate of the raw material solution to be 0.5-10 mL/min, and enabling the irradiation time of the raw material solution by the LED single-light-source ultraviolet lamp to be 30-60 min;
the temperature of the photochemical reactor is kept at 20-30 ℃;
in step S3, the heat treatment conditions are: the temperature is 40-60 ℃, the pressure is-0.095-0.08 MPa, and the heat is preserved for 1-3 h.
10. The method as claimed in claim 8, wherein in step S3, the step of column chromatography separation and concentration comprises:
dissolving the resin-shaped vitamin D3 crude product converted oil in an adsorption solvent, injecting into a chromatographic column filled with chromatographic silica gel, eluting with an eluent until vitamin D3 is completely eluted, and concentrating the collected vitamin D3 under reduced pressure to obtain the resin-shaped vitamin D3 oil.
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