CN1445215A - Photochemical synthesis of vitamin D3Method (2) - Google Patents
Photochemical synthesis of vitamin D3Method (2) Download PDFInfo
- Publication number
- CN1445215A CN1445215A CN 02104444 CN02104444A CN1445215A CN 1445215 A CN1445215 A CN 1445215A CN 02104444 CN02104444 CN 02104444 CN 02104444 A CN02104444 A CN 02104444A CN 1445215 A CN1445215 A CN 1445215A
- Authority
- CN
- China
- Prior art keywords
- reaction
- polar solvent
- dehydrocholesterol
- vitamins
- oil
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 9
- 235000013343 vitamin Nutrition 0.000 title description 2
- 239000011782 vitamin Substances 0.000 title description 2
- 229940088594 vitamin Drugs 0.000 title description 2
- 229930003231 vitamin Natural products 0.000 title description 2
- 150000003722 vitamin derivatives Chemical class 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 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 abstract description 37
- 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 claims abstract description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000006552 photochemical reaction Methods 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 26
- 239000000047 product Substances 0.000 claims abstract description 20
- 239000000243 solution Substances 0.000 claims abstract description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 17
- 238000003756 stirring Methods 0.000 claims abstract description 16
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 13
- 239000002798 polar solvent Substances 0.000 claims abstract description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 12
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 9
- 239000007864 aqueous solution Substances 0.000 claims abstract description 8
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 3
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 3
- 239000011710 vitamin D Substances 0.000 claims description 41
- 239000003921 oil Substances 0.000 claims description 38
- 235000019166 vitamin D Nutrition 0.000 claims description 34
- 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 claims description 32
- 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 claims description 32
- 238000005286 illumination Methods 0.000 claims description 19
- 239000012071 phase Substances 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 13
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 claims description 12
- 229910052753 mercury Inorganic materials 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 11
- 239000012454 non-polar solvent Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 239000003112 inhibitor Substances 0.000 claims description 8
- 230000003647 oxidation Effects 0.000 claims description 8
- 238000007254 oxidation reaction Methods 0.000 claims description 8
- 239000008367 deionised water Substances 0.000 claims description 7
- 229910021641 deionized water Inorganic materials 0.000 claims description 7
- 238000007710 freezing Methods 0.000 claims description 7
- 230000008014 freezing Effects 0.000 claims description 7
- 238000006317 isomerization reaction Methods 0.000 claims description 7
- 231100000614 poison Toxicity 0.000 claims description 7
- 230000007096 poisonous effect Effects 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 6
- 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 claims description 6
- 229940046008 vitamin d Drugs 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 4
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 claims description 4
- 238000007670 refining Methods 0.000 claims description 4
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical group CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 2
- 240000008415 Lactuca sativa Species 0.000 claims description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- 235000012045 salad Nutrition 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 235000019198 oils Nutrition 0.000 claims 8
- 235000019483 Peanut oil Nutrition 0.000 claims 1
- 239000000312 peanut oil Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 239000011647 vitamin D3 Substances 0.000 abstract 4
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 238000001704 evaporation Methods 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- 239000002994 raw material Substances 0.000 description 9
- 239000006227 byproduct Substances 0.000 description 7
- 235000013305 food Nutrition 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000000654 additive Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- 229930182558 Sterol Natural products 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 150000003432 sterols Chemical class 0.000 description 3
- 235000003702 sterols Nutrition 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000003504 photosensitizing agent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- PGGZAZHZNVKDLG-UHFFFAOYSA-N 1,4-dioxane;hexane Chemical compound CCCCCC.C1COCCO1 PGGZAZHZNVKDLG-UHFFFAOYSA-N 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000010504 bond cleavage reaction Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000010517 secondary reaction Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000004148 unit process Methods 0.000 description 1
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of organic photochemical synthesis, and particularly relates to photochemical synthesis of vitamin D3The method of (1). Under the protection of nitrogen, dissolving 7-dehydrocholesterol in a nonpolar-polar solvent mixed system, adding an antioxidant, stirring uniformly, illuminating, and controlling the temperature of a photochemical reaction liquid at 23-30 ℃; evaporating the reaction solution to dryness, adding a polar solvent, and separating unreacted 7-dehydrocholesterol from the reaction product; adding maleic anhydride and 45-55 wt% KOH or NaOH aqueous solution into the reactor while stirring to obtain viscous product; determination of Previtamin D3And vitamin D3Dissolving in 8-10 times of refined oil, heating to 60-70 deg.C under vacuum, and removing vacuum to obtain clear high-quality vitamin D3And (4) oil preparation. The invention can convert vitamin D3The yield of the oil agent is improved to about 70 percent, and the production process is very simple and convenient.
Description
Technical field
The invention belongs to organic photochemistry synthetic field, particularly photochemistry synthesis of vitamin d
3Method.
Background technology
Vitamins D
3Be human health, domestic animal, poultry normal growth and breed one of requisite important VITAMIN, all need an amount of adding in food and the feed.Along with the raising of social development and people's living standard, vitamins D
3Reach at home and have market widely in the world, have only a few countries productions such as Germany, Switzerland at present in the world, cost an arm and a leg.China manufacturer once utilized tens of one kilowatt mercury lamp as light source, and ethanol is solvent, and the photochemical reaction temperature is more than 60 ℃, the concentration of reaction raw materials is no more than 2%, transformation efficiency is 100%, and by product is very many will finish the product purification with column chromatography, and productive rate has only about 30%.Because the photochemistry production technology does not pass a test, from China's vitamins D nineties
3Basic stopping production, required vitamins D
3Dependence on import.Photochemical reaction is unit process important in the medical pharmaceutical industry, and correlation technique also is the technological difficulties of some pharmaceutical production, solves vitamins D
3The photochemistry production technology also extend in the production of other drug, have great economy, social benefit.Vitamins D
3Synthetic be to be raw material with the 7-dehydrocholesterol, one step of illumination singlet state scission of link, thermal isomerization reaction and obtaining.But the secondary reaction of photoresponse is difficult to control, have at least 7 high pressure liquid chromatography that comprise raw material can detect isomer and generate, and one of them by product (tachysterol) is also poisonous, and purification of products is very difficult.Raw material in the product that obtains after people's illumination such as Eyley: tachysterol: product is 1: 2: 1.Adopt the way of column chromatography to separate (Eyley, S.C.; Willems, D.H.J.Chem.Soc., Chem.Commun., 1975,858).People such as Okabe adopt the method for twice illumination, and the light that adds spectral filter general＜340nm wavelength when second time illumination filters, and adding triplet state photosensitizers changes tachysterol into Previtamin D
3, productive rate has only 46% (Okabe, M.; Sun, R.-C.; Scalone, M.; Jibilian, C.H.; Hutchings, S.D.J.Org.Chem., 1995,60,767-771).Also have other method,, earlier after the UV-light illumination with 254 nano wave lengths, add photosensitizers again and carry out the illumination second time, make the tachysterol of the illumination generation first time change Previtamin D into the wavelength of 350 nanometers as adopting the UV-light of single wavelength
3, obtain about 50% productive rate.The illumination system complexity that these researchs relate to, the aftertreatment trouble is difficult to realize industrialization (Kobayashi, T.; Yasumura, M.J.Nutr.Sci.Vitaminol., 1973,19,123-128; Sato, T.; Yamauchi, H.; Ogata, Y., Kunii, T.; Kagei, K.; Katsui, G.; Toyoshima, S.; Yasumura, M.; Kobayashi, T. J.Nutr.Sci.Vitaminol., 1980,26,545-556; Dauben, W.G.; Phillips, R.B. J.Am.Chem.Soc., 1982,104,355-356; Dauben, W.G.; Phillips, R.B., J.Am.Chem.Soc., 1982,104,5780-5781).In addition, the 7-dehydrocholesterol has profit amphipathic, and its solubleness is no more than 1% under the room temperature in general solvent, gives high-volume to produce and causes difficulty.
Summary of the invention
The objective of the invention is at the problems referred to above, utilize inner-immersed type nitrogen bubbling photochemical reactor, optimize reaction conditions, the generation of control photochemical reaction by product, the screening reaction solvent provides a kind of photochemistry synthesis of vitamin d
3Method.
Utilize the photochemical reaction synthesis of vitamin d of 7-dehydrocholesterol at present
3As follows:
We have at first carried out the experiment of the reaction kinetics of photochemistry of 7-dehydrocholesterol, and its reaction kinetics as shown in Figure 1.HPLC before the photoresponse analyzes, referring to Fig. 2.
Obtaining as drawing a conclusion from Fig. 1 kinetic Process Analysis: the photochemical product that is generated the illumination reaction is pre--vitamins D
3Extinction generation secondary light chemical reaction generates bright sterol of by product and tachysterol again.If 7-dehydrocholesterol transformation efficiency is too high, bright sterol of by product and tachysterol that the secondary light chemical reaction generates will increase greatly, not only greatly reduce vitamins D
3Productive rate, and give to separate purify and to have caused very big difficulty.When the transformation efficiency of 7-dehydrocholesterol is no more than 30% (area percent of showing the 7-dehydrocholesterol in HPLC is no more than 55%), both can obtain higher photochemical product pre--vitamins D
3, the concentration of bright sterol of by product and tachysterol also can be controlled under the lower level simultaneously, obtains ratio best in the suitability for industrialized production.
Photochemistry synthesis of vitamin d of the present invention
3Method, carry out as follows:
(1) illumination reaction of 7-dehydrocholesterol
The 7-dehydrocholesterol is dissolved in the nonpolar-polar solvent mixed system, at room temperature be made into the solution that concentration is 4-6wt%, wherein the volume ratio of non-polar solvent and polar solvent is 2: 1-10: 1, add oxidation inhibitor, the mol ratio of 7-dehydrocholesterol and oxidation inhibitor is 500: 1-2,000: 1, mix, be made into photochemical reaction liquid.Pouring reaction solution into put 450W well high voltage mercury lamp also leads in the inner-immersed type photochemical reactor of nitrogen.Turn on light and carry out illumination, the temperature of control photochemical reaction liquid under 23-30 ℃ condition, illumination reaction 10-20 minute.
(2) reclaim the 7-dehydrocholesterol
After finishing according to above-mentioned photochemical reaction, termination reaction, after the reaction solution usefulness rotatory evaporator evaporated under reduced pressure with step (1), add a certain amount of polar solvent, be configured to the solution that concentration is 20-30wt%, under-20 to-15 ℃ condition freezing 4-6 hour, unreacted 7-dehydrocholesterol all will be precipitated out this moment.Then this suspension liquid is filtered fast, unreacted 7-dehydrocholesterol is separated with reaction product.
(3) remove the poisonous component tachysterol
It is 15-25wt% that step (2) filtrate filtered is evaporated to concentration with rotatory evaporator.Content with each reaction product of high-pressure liquid phase chromatograph measuring.At room temperature add a certain amount of non-polar solvent and oxidation inhibitor, the concentration that makes solution is 10-20wt%, and with each the reaction product content addition that determines, the mol ratio that makes total reaction product and oxidation inhibitor is 200: 1-1000: 1.Temperature is controlled at 7-12 ℃, and stirring the mol ratio that adds down with tachysterol is 1.5: 1-2: 1 maleic anhydride, restir 1-2 hour.Be cooled to 0-3 ℃, slowly adding concentration is the aqueous solution of KOH or the NaOH of 45-55wt%, and wherein, the mol ratio of KOH or NaOH and maleic anhydride is 3: 1 to 5: 1, continues to stir 1-2 hour, pours separating funnel into and leaves standstill phase-splitting in 15-30 minute.After the phase-splitting, the 0.8-1.2 non-polar solvent aqueous phase extracted doubly with the oil phase volume merges non-polar solvent after the extraction and oil phase.Then divide the washing oil phase 2-4 time with oil phase cumulative volume 2-3 times the deionized water and the mixed solvent of polar solvent, the volume ratio of deionized water and polar solvent is 1: 3-1: 9.Above-mentioned oil phase evaporate to dryness must be removed the thick product of tachysterol.
(4) thermal isomerization reaction system vitamins D
3Finish
The thick product of step (3) is weighed, use the high-pressure liquid phase chromatograph measuring Previtamin D
3And vitamins D
3Content after, be dissolved in Previtamin D
3And vitamins D
3In the treated oil of content 8-10 times weight, be heated to 60-70 ℃ under the vacuum, slowly vacuum tightness brought up to the 2-3mmHg post, kept 3-4 hour, slowly cool to 28-35 ℃ then, kept original vacuum tightness 8-10 hour.Feed nitrogen and remove vacuum, get limpid high-quality vitamins D
3Finish.Purity is more than 95%.Yield is about 70%.
Each above step all will be carried out under nitrogen protection.
The present invention considers light transmission, do not influence singlet state reaction, low cost, and selected non-polar solvent comprises that boiling point is that 30-60 ℃, boiling point are 60-90 ℃ aliphatic solvents such as sherwood oil, hexanaphthene, normal hexane, pentamethylene, pentane or iso-pentane.Selected polar solvent comprises aliphatic solvents such as acetonitrile, methyl alcohol, ethanol or dioxane.
Described antioxidant is 2,6-di-t-butyl-p-methyl phenol or 2,6-di-t-butyl-p methoxy phenol etc.
Described treated oil is refining salad oil or refining peanut wet goods refined edible oil.
The present invention adopt transformation efficiency that mixed solvent guarantees high density, control 7-dehydrocholesterol 30% below, utilize the solubleness effect to reclaim unreacted 7-dehydrocholesterol conduct photochemical reaction raw material next time, improved reactant concn greatly, removed the toxic byproduct tachysterol with chemical process, both guaranteed photochemically reactive quantity, productive rate is improved greatly, thereby with vitamins D
3The productive rate of finish is brought up to about 70%, and production process is very easy.
Description of drawings
Fig. 1 .7-dehydrocholesterol (5wt%) sherwood oil (30-60 ℃)-ethanol (6: 1, V/V)
(the isomer percentage contains photochemical reaction with the products distribution of light application time in the mixed solvent
Amount is in the HPLC area percentage)
Fig. 2. the HPLC spectrogram among the embodiment 1 before the photoresponse
Fig. 3. the HPLC spectrogram among the embodiment 1 after the photoresponse
Fig. 4. reclaim the HPLC spectrogram of 7-dehydrocholesterol among the embodiment 1
Fig. 5. reclaim the HPLC spectrogram of 7-dehydrocholesterol rear filtrate among the embodiment 1
Fig. 6. the HPLC spectrogram among the embodiment 1 behind the removal tachysterol
Fig. 7. vitamins D among the embodiment 1
3The HPLC spectrogram of finish
Specific embodiment
Utilize inner-immersed type nitrogen bubbling photochemical reactor and Beijing Electrooptic Source Inst's high voltage mercury lamp system.
(1) illumination reaction of .7-dehydrocholesterol
In flask at the bottom of 500 milliliters of gardens, with 16.5 gram 7-dehydrocholesterols be dissolved in 330 milliliters of sherwood oils (30-60 ℃)-ethanol (6: 1, V/V) in the mixed solvent, add 10 milligram 2,6-di-t-butyl-p methoxy phenol mixes with magnetic, the photochemical reaction liquid that is configured to.Reaction solution is inserted in the inner-immersed type photochemical reactor of putting 450 watts of high voltage mercury lamps (GGZ1000-1 of Beijing Electrooptic Source Inst) and logical nitrogen well.Regulate the flow of nitrogen, make bubble even.Start mercury lamp, and timing.Reaction unit is put into lighttight ventilating kitchen, and an electric fan, guarantees that the temperature of photochemical reaction liquid is no more than 28 ℃, to avoid generating vitamins D too early in photochemical reaction process
3With high pressure liquid chromatography (HPLC) method monitoring reaction (instrument: HitachiL-7100; Dalian Yi Lite Spher SiO
2Normal phase column, particle diameter 5 μ, the diameter=4.6mm of post, column length 250mm; Moving phase: normal hexane/amylalcohol=997/3, V/V; Flow velocity: 2 ml/min; 254nm detects.The retention time that contrasts each isomer with standard specimen is approximately: pre--vitamins D
3-7 minutes, bright sterol-10 minute, vitamins D
3-14 minutes, tachysterol-15 minute, 7-dehydrocholesterol-21 minute, retention time change with condition slightly change), reacted 15 minutes.
(2). reclaim the 7-dehydrocholesterol
After above-mentioned photochemical reaction finished, its HPLC analyzed and is shown in Fig. 3.Reaction solution poured at the bottom of 500 milliliters of gardens rotate evaporate to dryness in the flask, add 60 milliliters of ethanol then, insert-20 ℃ refrigerator and cooled and freeze and spend the night.Filter fast freezing back, gets solid 7-dehydrocholesterol 12.1 grams (can be used as next photoresponse raw material), and its HPLC analyzes and is shown in Fig. 4, substantially pure.The HPLC of filtrate analyzes and is shown in Fig. 5.
(3). remove the poisonous component tachysterol
With the content of high pressure liquid chromatograph detection tachysterol, see Fig. 5.The content that therefrom can calculate tachysterol is 0.79 gram, must remove.Filtrate is concentrated into 20 milliliters, adds 8 milliliters of sherwood oils and 5 milligram 2 again, 6-di-t-butyl-p methoxy phenol is controlled at 10 ℃ with temperature, stirs to add 0.40 gram maleic anhydride, restir 1 hour down.Be cooled to 1 ℃, slowly add 1.6 milliliter 50% the KOH aqueous solution, continue to stir 1 hour, pour separating funnel into and leave standstill layering in 20 minutes.After the layering, with 8 milliliters of petroleum ether extraction waters, sherwood oil after the extraction and oil phase being merged, is that (1/4, V/V) the mixed solvent washing oil is 3 times mutually for 36 ml deionized water/ethanol with total amount then.The HPLC of oil phase analyzes and is shown in Fig. 6, and tachysterol is removed substantially.Above-mentioned oil phase evaporate to dryness is got thick product 4.2 grams.
(4). thermal isomerization reaction system vitamins D
3Finish
The thick product of step (3) is dissolved in 27 gram treated oils, vacuumized (2mmHg) 4 hours under 70 ℃, slowly cool to 35 ℃ and took out again 8 hours.Remove vacuum, get limpid high-quality vitamins D
3Finish 30.2 grams are analyzed the gram into 412I.U/, total recovery 70.7%.Its HPLC analyzes and is shown in Fig. 7.Its pre--vitamins D
3And vitamins D
3(P+D) total content is higher than 95%, does not contain tachysterol substantially, can be used as food or fodder additives.
(1) illumination reaction of .7-dehydrocholesterol
In flask at the bottom of 500 milliliters of gardens, with 16.5 gram 7-dehydrocholesterols be dissolved in 330 milliliters of pentane-methyl alcohol (6: 1, V/V) in the mixed solvent, add 10 milligram 2,6-di-t-butyl-p methoxy phenol mixes with magnetic, the photochemical reaction liquid that is configured to.Reaction solution is inserted in the inner-immersed type photochemical reactor of putting 450 watts of high voltage mercury lamps (with embodiment 1) and logical nitrogen well.Regulate the flow of nitrogen, make bubble even.Start mercury lamp, and timing.Reaction unit is put into lighttight ventilating kitchen, and an electric fan, guarantees that the temperature of photochemical reaction liquid is no more than 28 ℃, to avoid generating vitamins D too early in photochemical reaction process
3With high pressure liquid chromatography (HPLC) method monitoring reaction (condition is with embodiment 1), reacted 15 minutes.
(2). reclaim the 7-dehydrocholesterol
After above-mentioned photochemical reaction finishes.Reaction solution poured at the bottom of 500 milliliters of gardens rotate evaporate to dryness in the flask, add 60 ml methanol then, insert-20 ℃ refrigerator and cooled and freeze and spend the night.Filter fast freezing back, gets solid 7-dehydrocholesterol 12.5 grams (can be used as next photoresponse raw material).
(3). remove the poisonous component tachysterol
With the content of high pressure liquid chromatograph detection tachysterol, the content that calculates tachysterol is 0.75 gram.Filtrate is concentrated into 20 milliliters, adds 8 milliliters of pentanes and 5 milligram 2 again, 6-di-t-butyl-p methoxy phenol is controlled at 10 ℃ with temperature, stirs to add 0.37 gram maleic anhydride, restir 1 hour down.Be cooled to 0 ℃, slowly add 1.6 milliliter 50% the KOH aqueous solution, continue to stir 1 hour, pour separating funnel into and leave standstill layering in 20 minutes.After the layering, with 8 milliliters of pentane aqueous phase extracted, pentane after the extraction and oil phase being merged, is that (1/4, V/V) the mixed solvent washing oil is 3 times mutually for 36 ml deionized water/methyl alcohol with total amount then.Above-mentioned oil phase evaporate to dryness is got thick product 3.9 grams.
(4). thermal isomerization reaction system vitamins D
3Finish
The thick product of step (3) is dissolved in 24 gram treated oils, and 70 ℃ of following vacuum (2mmHg) were taken out 4 hours, slowly cooled to 35 ℃ and took out 8 hours again.Remove vacuum, get limpid high-quality vitamins D
3Finish 26.9 grams, analysis are 421 I.U/ grams, total recovery 70.8%.Its pre--vitamins D
3And vitamins D
3(P+D) total content is higher than 95%, does not contain tachysterol substantially, can be used as food or fodder additives.
(1) illumination reaction of .7-dehydrocholesterol
In flask at the bottom of 500 milliliters of gardens, with 16.5 gram 7-dehydrocholesterols be dissolved in 330 milliliters of hexane-dioxane (6: 1, V/V) in the mixed solvent, add 10 milligram 2,6-di-t-butyl-p methoxy phenol mixes with magnetic, the photochemical reaction liquid that is configured to.Reaction solution is inserted in the inner-immersed type photochemical reactor of putting 450 watts of high voltage mercury lamps (with embodiment 1) and logical nitrogen well.Regulate the flow of nitrogen, make bubble even.Start mercury lamp, and timing.Reaction unit is put into lighttight ventilating kitchen, and an electric fan, guarantees that the temperature of photochemical reaction liquid is no more than 28 ℃, to avoid generating vitamins D too early in photochemical reaction process
3With high pressure liquid chromatography (HPLC) method monitoring reaction (condition is with embodiment 1), reacted 15 minutes.
(2). reclaim the 7-dehydrocholesterol
After above-mentioned photochemical reaction finishes.Reaction solution poured at the bottom of 500 milliliters of gardens rotates evaporate to dryness in the flask, after add 60 milliliters of dioxane, insert-20 ℃ refrigerator and cooled and freeze and spend the night.Filter fast freezing back, gets solid 7-dehydrocholesterol 11.7 grams (can be used as next photoresponse raw material).
(3). remove the poisonous component tachysterol
Detect the content of tachysterol with high pressure liquid chromatograph.The content that calculates tachysterol is 0.85 gram.Filtrate is concentrated into 20 milliliters, adds 8 milliliters of hexanes and 5 milligram 2 again, 6-di-t-butyl-p methoxy phenol is controlled at 10 ℃ with temperature, stirs to add 0.40 gram maleic anhydride, restir 1 hour down.Be cooled to 0 ℃, slowly add 1.6 milliliter 50% the KOH aqueous solution, continue to stir 1 hour, pour separating funnel into and leave standstill layering in 20 minutes.After the layering, with 8 milliliters of hexane extraction waters, hexane after the extraction and oil phase being merged, is that (1/4, V/V) the mixed solvent washing oil is 3 times mutually for 36 ml deionized water/dioxane with total amount then.Above-mentioned oil phase evaporate to dryness is got thick product 4.5 grams.
(4). thermal isomerization reaction system vitamins D
3Finish
The thick product of step (3) is dissolved in 27 gram treated oils, and 70 ℃ of following vacuum (2mmHg) were taken out 4 hours, slowly cooled to 35 ℃ and took out 8 hours again.Remove vacuum, get limpid high-quality vitamins D
3Finish 30.6 grams, analysis are 434 I.U/ grams, total recovery 69.2%.Its pre--vitamins D
3And vitamins D
3(P+D) total content is higher than 95%, does not contain tachysterol substantially, can be used as food or fodder additives.
(1) illumination reaction of 1.7-dehydrocholesterol
In flask at the bottom of 500 milliliters of gardens, with 16.5 gram 7-dehydrocholesterols be dissolved in 330 milliliters of hexanaphthene-acetonitriles (6: 1, V/V) in the mixed solvent, add 10 milligram 2,6-di-t-butyl-p methoxy phenol mixes with magnetic, the photochemical reaction liquid that is configured to.Reaction solution is inserted in the inner-immersed type photochemical reactor of putting 450 watts of high voltage mercury lamps (with embodiment 1) and logical nitrogen well.Regulate the flow of nitrogen, make bubble even.Start mercury lamp, and timing.Reaction unit is put into lighttight ventilating kitchen, and an electric fan, guarantees that the temperature of photochemical reaction liquid is no more than 28 ℃, to avoid generating vitamins D too early in photochemical reaction process
3With high pressure liquid chromatography (HPLC) method monitoring reaction (condition is with embodiment 1), reacted 15 minutes.
(2). reclaim the 7-dehydrocholesterol
After above-mentioned photochemical reaction finishes.Reaction solution poured at the bottom of 500 milliliters of gardens rotates evaporate to dryness in the flask, after add 60 milliliters of acetonitriles, insert-20 ℃ refrigerator and cooled and freeze and spend the night.Filter fast freezing back, gets solid 7-dehydrocholesterol 11.9 grams (can be used as next photoresponse raw material).
(3). remove the poisonous component tachysterol
Detect the content of tachysterol with high pressure liquid chromatograph.The content that calculates tachysterol is 0.82 gram.Filtrate is concentrated into 20 milliliters, adds 8 milliliters of hexanaphthenes and 5 milligram 2 again, 6-di-t-butyl-p methoxy phenol is controlled at 10 ℃ with temperature, stirs to add 0.40 gram maleic anhydride, restir 1 hour down.Be cooled to 0 ℃, slowly add 1.6 milliliter 50% the KOH aqueous solution, continue to stir 1 hour, pour separating funnel into and leave standstill layering in 20 minutes.After the layering, with 8 milliliters of hexanaphthene aqueous phase extracted, hexanaphthene after the extraction and oil phase being merged, is that (1/4, V/V) the mixed solvent washing oil is 3 times mutually for 36 ml deionized water/acetonitrile with total amount then.Above-mentioned oil phase evaporate to dryness is got thick product 4.4 grams.
(4). thermal isomerization reaction system vitamins D
3Finish
The thick product of step 3 is dissolved in 27 gram treated oils, and 70 ℃ of following vacuum (2mmHg) were taken out 4 hours, slowly cooled to 35 ℃ and took out 8 hours again.Remove vacuum, get limpid high-quality vitamins D
3Finish 30.4 grams are analyzed the gram into 425I.U/, total recovery 70.2%.Its pre--vitamins D
3And vitamins D
3(P+D) total content is higher than 95%, does not contain tachysterol substantially, can be used as food or fodder additives.
Claims (9)
1. photochemistry synthesis of vitamin d
3Method, it is characterized in that: this method is carried out as follows:
(1) illumination reaction of 7-dehydrocholesterol
The 7-dehydrocholesterol is dissolved in the nonpolar-polar solvent mixed system, at room temperature be made into the solution that concentration is 4-6wt%, wherein the volume ratio of non-polar solvent and polar solvent is 2: 1-10: 1, add oxidation inhibitor, the mol ratio of 7-dehydrocholesterol and oxidation inhibitor is 500: 1-2,000: 1, mix, be made into photochemical reaction liquid; Reaction solution is poured in the photochemical reactor that leads to nitrogen, carried out illumination, the temperature of control photochemical reaction liquid is at 23-30 ℃;
(2) reclaim the 7-dehydrocholesterol
Behind the reaction solution evaporate to dryness with step (1), add polar solvent, be made into the solution that concentration is 20-30wt%, freezing under-20 to-15 ℃ condition, this suspension liquid is filtered fast, unreacted 7-dehydrocholesterol is separated with reaction product;
(3) remove the poisonous component tachysterol
It is 15-25wt% that step (2) filtrate filtered is concentrated into concentration, measure the content of each reaction product, at room temperature add non-polar solvent and oxidation inhibitor, the concentration that makes solution is 10-20wt%, with each the reaction product content addition that determines, the mol ratio that makes total reaction product and oxidation inhibitor is 200: 1-1000: 1; Temperature is controlled at 7-12 ℃, stirring the mol ratio that adds down with tachysterol is 1.5: 1-2: 1 maleic anhydride, continue to stir, be cooled to 0-3 ℃, slowly adding concentration is the aqueous solution of KOH or the NaOH of 45-55wt%, and wherein, the mol ratio of KOH or NaOH and maleic anhydride is 3: 1 to 5: 1, continue to stir, pour separating funnel into and leave standstill the back phase-splitting; After the phase-splitting, use the non-polar solvent aqueous phase extracted, non-polar solvent after the extraction and oil phase are merged,, above-mentioned oil phase evaporate to dryness must be removed the thick product of tachysterol then with the mixed solvent washing oil phase of deionized water and polar solvent;
(4) thermal isomerization reaction system vitamins D
3Finish
The thick product of step (3) is weighed, measure Previtamin D
3And vitamins D
3Content after, be dissolved in Previtamin D
3And vitamins D
3In the treated oil of content 8-10 times weight, be heated to 60-70 ℃ under the vacuum, slowly vacuum tightness brought up to the 2-3mmHg post, kept 3-4 hour, slowly cool to 28-35 ℃ then, keep original vacuum tightness, feed nitrogen and remove vacuum, get limpid high-quality vitamins D
3Finish;
Each above step all will be carried out under nitrogen protection.
2. the method for claim 1, it is characterized in that: the light source in the described step (1) is the high voltage mercury lamp of 450W, illumination reaction 10-20 minute.
3. the method for claim 1 is characterized in that: described step (2) under-20 to-15 ℃ condition freezing 4-6 hour.
4. the method for claim 1 is characterized in that: stirred 1-2 hour behind described step (3) the adding maleic anhydride; The aqueous solution that adds KOH or NaOH continues to stir 1-2 hour.
5. the method for claim 1, it is characterized in that: described step (4) is brought up to the 2-3mmHg post with vacuum tightness, keeps 3-4 hour, cools to 28-35 ℃, keeps original vacuum tightness 8-10 hour.
6. the method for claim 1, it is characterized in that: described non-polar solvent comprises that boiling point is 30-60 ℃ sherwood oil, sherwood oil, hexanaphthene, normal hexane, pentamethylene, pentane or the iso-pentane that boiling point is 60-90 ℃.
7. the method for claim 1, it is characterized in that: described polar solvent comprises acetonitrile, methyl alcohol, ethanol or dioxane.
8. the method for claim 1, it is characterized in that: described antioxidant is 2,6-di-t-butyl-p-methyl phenol or 2,6-di-t-butyl-p methoxy phenol.
9. the method for claim 1 is characterized in that: described treated oil is refining salad oil or refining peanut oil.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02104444 CN1196677C (en) | 2002-03-18 | 2002-03-18 | Photochemical synthesis of vitamin D3Method (2) |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02104444 CN1196677C (en) | 2002-03-18 | 2002-03-18 | Photochemical synthesis of vitamin D3Method (2) |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1445215A true CN1445215A (en) | 2003-10-01 |
| CN1196677C CN1196677C (en) | 2005-04-13 |
Family
ID=27810883
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 02104444 Expired - Fee Related CN1196677C (en) | 2002-03-18 | 2002-03-18 | Photochemical synthesis of vitamin D3Method (2) |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1196677C (en) |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1307154C (en) * | 2004-08-10 | 2007-03-28 | 中国科学院理化技术研究所 | Photochemical synthesis of vitamin D2Method (2) |
| CN100582118C (en) * | 2006-08-04 | 2010-01-20 | 浙江新和成股份有限公司 | Method for preparing 7-dehydrogenation cholesterol |
| CN101085755B (en) * | 2007-06-22 | 2011-12-07 | 厦门金达威集团股份有限公司 | Actinic chemistry reaction device and method for synthesizing provitamin D3 |
| CN102276510A (en) * | 2011-05-30 | 2011-12-14 | 何德海 | Technological method for preparing vitamin D3 |
| CN101381336B (en) * | 2007-09-06 | 2012-07-04 | 浙江新和成股份有限公司 | Vitamin D3 preparation method and device |
| CN102850248A (en) * | 2012-09-29 | 2013-01-02 | 浙江花园生物高科股份有限公司 | Technology for preparing vitamin D3 |
| CN103044301A (en) * | 2011-10-17 | 2013-04-17 | 中国科学院理化技术研究所 | Photochemical synthesis of 25-hydroxy vitamin D3Method (2) |
| CN103553993A (en) * | 2013-11-12 | 2014-02-05 | 中国科学院理化技术研究所 | Synthesis of resinous vitamin D by using micro-flow photoreaction technology3Method and microfluidic photochemical reactor |
| CN109761867A (en) * | 2019-02-28 | 2019-05-17 | 四川健腾生物技术有限公司 | One kind producing vitamin D by raw material of lanolin3New industrial process |
| CN111960980A (en) * | 2019-05-20 | 2020-11-20 | 重庆桑禾动物药业有限公司 | Method for synthesizing pre-vitamin D3 by using LED ultraviolet lamp |
| CN112979738A (en) * | 2021-03-02 | 2021-06-18 | 浙江新和成股份有限公司 | Crystallization purification method of 7-dehydrocholesterol and application thereof in VD3 production |
| CN114380726A (en) * | 2021-12-31 | 2022-04-22 | 浙江花园生物高科股份有限公司 | Method for preparing vitamin D3 by recovering mother liquor obtained by separating and purifying crude vitamin D3 |
| CN114409579A (en) * | 2021-12-31 | 2022-04-29 | 杭州下沙生物科技有限公司 | Method for improving yield of vitamin D3 by using vitamin D3 byproduct |
| CN115746075A (en) * | 2022-10-14 | 2023-03-07 | 浙江新和成股份有限公司 | Method for recovering and purifying 7-dehydrocholesterol in high-impurity-content photochemical reaction liquid in vitamin D3 production process |
-
2002
- 2002-03-18 CN CN 02104444 patent/CN1196677C/en not_active Expired - Fee Related
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1307154C (en) * | 2004-08-10 | 2007-03-28 | 中国科学院理化技术研究所 | Photochemical synthesis of vitamin D2Method (2) |
| CN100582118C (en) * | 2006-08-04 | 2010-01-20 | 浙江新和成股份有限公司 | Method for preparing 7-dehydrogenation cholesterol |
| CN101085755B (en) * | 2007-06-22 | 2011-12-07 | 厦门金达威集团股份有限公司 | Actinic chemistry reaction device and method for synthesizing provitamin D3 |
| CN101381336B (en) * | 2007-09-06 | 2012-07-04 | 浙江新和成股份有限公司 | Vitamin D3 preparation method and device |
| CN102276510A (en) * | 2011-05-30 | 2011-12-14 | 何德海 | Technological method for preparing vitamin D3 |
| CN103044301B (en) * | 2011-10-17 | 2014-12-03 | 中国科学院理化技术研究所 | Photochemical synthesis of 25-hydroxy vitamin D3Method (2) |
| CN103044301A (en) * | 2011-10-17 | 2013-04-17 | 中国科学院理化技术研究所 | Photochemical synthesis of 25-hydroxy vitamin D3Method (2) |
| CN102850248A (en) * | 2012-09-29 | 2013-01-02 | 浙江花园生物高科股份有限公司 | Technology for preparing vitamin D3 |
| CN103553993A (en) * | 2013-11-12 | 2014-02-05 | 中国科学院理化技术研究所 | Synthesis of resinous vitamin D by using micro-flow photoreaction technology3Method and microfluidic photochemical reactor |
| CN103553993B (en) * | 2013-11-12 | 2015-05-20 | 中国科学院理化技术研究所 | Synthesis of resinous vitamin D by using micro-flow photoreaction technology3Method and microfluidic photochemical reactor |
| CN109761867A (en) * | 2019-02-28 | 2019-05-17 | 四川健腾生物技术有限公司 | One kind producing vitamin D by raw material of lanolin3New industrial process |
| CN111960980A (en) * | 2019-05-20 | 2020-11-20 | 重庆桑禾动物药业有限公司 | Method for synthesizing pre-vitamin D3 by using LED ultraviolet lamp |
| CN112979738A (en) * | 2021-03-02 | 2021-06-18 | 浙江新和成股份有限公司 | Crystallization purification method of 7-dehydrocholesterol and application thereof in VD3 production |
| CN112979738B (en) * | 2021-03-02 | 2022-04-05 | 浙江新和成股份有限公司 | Crystallization purification method of 7-dehydrocholesterol and application thereof in VD3 production |
| CN114380726A (en) * | 2021-12-31 | 2022-04-22 | 浙江花园生物高科股份有限公司 | Method for preparing vitamin D3 by recovering mother liquor obtained by separating and purifying crude vitamin D3 |
| CN114409579A (en) * | 2021-12-31 | 2022-04-29 | 杭州下沙生物科技有限公司 | Method for improving yield of vitamin D3 by using vitamin D3 byproduct |
| CN114380726B (en) * | 2021-12-31 | 2024-04-23 | 浙江花园生物医药股份有限公司 | Method for preparing vitamin D3 by recovering mother solution for separating and purifying vitamin D3 crude product |
| CN115746075A (en) * | 2022-10-14 | 2023-03-07 | 浙江新和成股份有限公司 | Method for recovering and purifying 7-dehydrocholesterol in high-impurity-content photochemical reaction liquid in vitamin D3 production process |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1196677C (en) | 2005-04-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1196677C (en) | Photochemical synthesis of vitamin D3Method (2) | |
| CN1031705C (en) | 24-homo-Vitamin-0-derivatives, process for preparing them, pharmaceutical preparation containing them and use as pharmaceuticals | |
| CN102850248A (en) | Technology for preparing vitamin D3 | |
| KR101634841B1 (en) | Preparation Method of Pimaric Acid Type Resin Acid | |
| CN103044301B (en) | Photochemical synthesis of 25-hydroxy vitamin D3Method (2) | |
| EP3912968A1 (en) | Continuous synthesis method for 1,1'-bicyclo[1.1.1]pentane-1,3-diethyl ketone organic matter | |
| Baldwin et al. | Free radical macrocyclisation via propiolate esters. | |
| CN111440260B (en) | 1, 4-dihydropyridine polymer and high-flux preparation method and application thereof | |
| CN1307154C (en) | Photochemical synthesis of vitamin D2Method (2) | |
| CN108774290B (en) | Resveratrol-carboxyalkyl cyclodextrin derivative and preparation method thereof | |
| CN1246306C (en) | New method for preparing brufen arginine salt | |
| TWI301483B (en) | ||
| CN114634434B (en) | Method for preparing vitamin D2 by double-filter technology | |
| CN114871443A (en) | Method for preparing gold nanocluster by solid-state grinding method | |
| CN1324042C (en) | Method of separating ergosterol | |
| CN114591499B (en) | Preparation method and application of poly (R) -3-hydroxybutyrate | |
| CN1030763C (en) | Method for obtaining a mixture of higher aliphatic alcohols from sugar cane wax | |
| JP6894945B2 (en) | Lubiprostone crystals and their preparation methods | |
| CN1082045C (en) | Synthetic method of a-benzoin oxime | |
| CN117088768B (en) | Method for extracting nervonic acid from acer truncatum seeds | |
| CN115650952B (en) | Microwave synthesis method of 5, 6-dihydro-cyclopenta [ B ] thiophene-4-ketone | |
| CN114805158A (en) | Method for preparing high-purity calcitriol | |
| RU2808483C2 (en) | Method of continuous synthesis of pharmaceutical intermediate | |
| CN1220674C (en) | Levodopa methyl ester hydrochloride purifying method | |
| JPS6130544A (en) | Preparation of 1,3,5-trialkyl-2,4,6-tris(3,5-dialkyl-4-hydroxybenzyl)benzene |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20050413 Termination date: 20120318 |