CN105237603A - Method for synthesizing cholesterol from stigmasterol - Google Patents
Method for synthesizing cholesterol from stigmasterol Download PDFInfo
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- CN105237603A CN105237603A CN201510713730.0A CN201510713730A CN105237603A CN 105237603 A CN105237603 A CN 105237603A CN 201510713730 A CN201510713730 A CN 201510713730A CN 105237603 A CN105237603 A CN 105237603A
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- compound
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- reaction
- stigmasterol
- methylbutane
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 title claims abstract description 48
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 title claims abstract description 29
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 title claims abstract description 29
- HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 title claims abstract description 29
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 title claims abstract description 29
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 title claims abstract description 29
- 229940032091 stigmasterol Drugs 0.000 title claims abstract description 29
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 235000016831 stigmasterol Nutrition 0.000 title claims abstract description 29
- 235000012000 cholesterol Nutrition 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 99
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 28
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000463 material Substances 0.000 claims abstract description 16
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims abstract description 16
- 238000010992 reflux Methods 0.000 claims abstract description 15
- 229960000583 acetic acid Drugs 0.000 claims abstract description 14
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 14
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims abstract description 13
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 17
- 230000015572 biosynthetic process Effects 0.000 claims description 16
- 238000003786 synthesis reaction Methods 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 14
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- CZHLPWNZCJEPJB-UHFFFAOYSA-N 1-chloro-3-methylbutane Chemical compound CC(C)CCCl CZHLPWNZCJEPJB-UHFFFAOYSA-N 0.000 claims description 11
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 230000002829 reductive effect Effects 0.000 claims description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 7
- 239000012046 mixed solvent Substances 0.000 claims description 7
- 239000001632 sodium acetate Substances 0.000 claims description 7
- 229960004249 sodium acetate Drugs 0.000 claims description 7
- 235000017281 sodium acetate Nutrition 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 238000009413 insulation Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- QKMNVQGPFDVZTK-UHFFFAOYSA-N 3-methylbutyl(triphenyl)phosphanium Chemical compound C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCC(C)C)C1=CC=CC=C1 QKMNVQGPFDVZTK-UHFFFAOYSA-N 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- YXZFFTJAHVMMLF-UHFFFAOYSA-N 1-bromo-3-methylbutane Chemical compound CC(C)CCBr YXZFFTJAHVMMLF-UHFFFAOYSA-N 0.000 claims description 2
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- -1 3-methylbutyl triphenyl phosphonium halide Chemical class 0.000 abstract 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 abstract 2
- 238000007239 Wittig reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- 235000011056 potassium acetate Nutrition 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 0 C=CC[C@@](C1)C(CC2)C1(CC1)C2C2C1C(CCC(C1)*=C)C1=CC2 Chemical compound C=CC[C@@](C1)C(CC2)C1(CC1)C2C2C1C(CCC(C1)*=C)C1=CC2 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- IZVFFXVYBHFIHY-SKCNUYALSA-N 5alpha-cholest-7-en-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[C@H]21 IZVFFXVYBHFIHY-SKCNUYALSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- IUXWFWQWKZBGFL-ISNOEQTCSA-N CCC(C)CCC[C@@H](C)C(CC1)C(C)(CC2)C1C1C2C(C)(CCC(C2)O)C2=CC1 Chemical compound CCC(C)CCC[C@@H](C)C(CC1)C(C)(CC2)C1C1C2C(C)(CCC(C2)O)C2=CC1 IUXWFWQWKZBGFL-ISNOEQTCSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010061372 Streptococcal infection Diseases 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Abstract
The invention relates to a method for synthesizing cholesterol from stigmasterol. The method specifically comprises the following steps: (1) enabling stigmasterol to react with benzene sulfonyl chloride so as to produce sulfonate, adding potassium acetate into sulfonate in methanol, and carrying out reflux reaction, so as to obtain a compound 03; (2) enabling the compound 03 to be subjected to oxidation reaction with ozone, and then, enabling the obtained reaction solution to react with zinc powder and glacial acetic acid, so as to obtain a compound 04; (3) enabling triphenylphosphine to react with 1-halo-3-methylbutane so as to obtain 3-methylbutyl triphenyl phosphonium halide, enabling 3-methylbutyl triphenyl phosphonium halide to react with a strong base so as to produce a wittig reagent, and enabling the wittig reagent to be subjected to wittig reaction with the compound 04, so as to obtain a compound 05; (4) enabling the compound 05 to be subjected to hydrogenation reaction in the presence of a catalyst, so as to obtain a compound 06; and (5) enabling the compound 06 to be subjected to hydrolysis reaction, thereby obtaining the cholesterol 01. According to the method, stigmasterol serves as a starting raw material and is cheap and readily-available, the process is simple, the amount of consumed raw and auxiliary materials is small, the yield is high, the cost is low, and the method is environment-friendly, so that industrial production is facilitated.
Description
Technical field
The present invention relates to cholesterol biosynthesis technical field, particularly relating to a kind of take Stigmasterol as the method for Material synthesis cholesterol.
Background technology
With Stigmasterol be Material synthesis cholesterol also known as cholesterol, a kind of derivative of perhydrocyclopentanophenanthrene.From cholelith, found to take Stigmasterol as Material synthesis cholesterol as far back as 18th century people, the material called after of this tool lipid nature is Material synthesis cholesterol with Stigmasterol by chemist in 1816.Be that Material synthesis cholesterol is extensively present in animal body with Stigmasterol, especially with the abundantest in brain and nervous tissue, in kidney, spleen, skin, liver and bile, content is also high.With Stigmasterol by Material synthesis cholesterol is the indispensable important substance of animal tissue cell, it not only participates in forming cytolemma, and is synthetic bile acid, the raw material of vitamins D and steroid hormone.
At present, cholesterol is mainly extracted from the brain of the animals such as pig, ox, sheep and vertebra, due to the appearance of mad cow disease and streptococcus suis infection disease, people create suspection to the safety in utilization coming from animal cholesterol, need a kind of safer synthetic cholesterol synthetic method.
Summary of the invention
The object of this invention is to provide a kind of take Stigmasterol as the method for Material synthesis cholesterol, and reaction mechanism is:
Specifically comprise the steps:
(1) Stigmasterol 02 reacts with benzene sulfonyl chloride or Tosyl chloride and generates sulphonate, and described sulphonate adds Potassium ethanoate or sodium-acetate back flow reaction in methyl alcohol, compound 03 of purifying after reacting completely to obtain;
(2) described compound 03 and ozone generation oxidizing reaction, gained reaction solution reacts with reductive agent again, compound 04 of purifying after reacting completely to obtain;
(3) triphenylphosphine and 1-halo-3-methylbutane react to obtain 3-methyl butyl triphenyl phosphonium halides phosphine; Described 3-methyl butyl triphenyl phosphonium halides phosphine and highly basic react and generate wittig reagent, and described wittig reagent and compound 04 wittig occur and react, and obtain compound 05 after reacting completely after purifying;
(4) there is hydrogenation in described compound 05 under catalyst action, through compound 06 of purifying to obtain after reacting completely;
(5) there is hydrolysis reaction in described compound 06, cholesterol 01 of purifying after reacting completely to obtain.
Preferably, the concrete operations of step (1) are: the concrete operations of step (1) are: with molar ratio computing, Stigmasterol 02: benzene sulfonyl chloride or Tosyl chloride: Potassium ethanoate or sodium-acetate=1:(1.1-1.3): (3-5), by Stigmasterol 02, benzene sulfonyl chloride or Tosyl chloride, pyridine at room temperature reacts, sulphonate is obtained after reacting completely, described sulphonate is dissolved in methyl alcohol, add Potassium ethanoate or sodium-acetate, heating reflux reaction is to reacting completely, and concentrated, crystallization obtains compound 03.Wherein, Potassium ethanoate or sodium-acetate can not only the sulfonic acid that generate of neutralization reaction, play acid-base buffer agent, have the effect of certain catalyzer in addition.
Preferably, the concrete operations of step (2) are: with molar ratio computing, compound 03: reductive agent=1:(6-8), compound 03 is dissolved in solvent, is cooled to-50 ~-80 DEG C, passes into ozone reaction, after reacting completely, reacting liquid temperature is returned to room temperature, adds reductive agent and continue reaction, after reacting completely, obtain compound 04.
Further preferred, described solvent is methylene dichloride, acetone, one or more in ethylene dichloride, is further preferably methylene dichloride.
Described reductive agent is the reductive agent that this area is commonly used, such as zinc powder or dimethyl sulphide, more preferably zinc powder.Further, in order to improve the reducing activity of zinc powder, the reaction system of reduction reaction will keep acid, for this reason, can add acid solution in reaction solution, described acid solution is the acid solution that this area is commonly used, such as hydrochloric acid, sulfuric acid, Glacial acetic acid, one or more in phosphoric acid, are preferably Glacial acetic acid, be more preferably, compound 03 is 1g:1mL with the mass volume ratio of Glacial acetic acid.
Preferably, the concrete operations of step (3) are: with molar ratio computing, compound 04: triphenylphosphine: 1-halo-3-methylbutane: highly basic=1:(1.5-3.0): (1.5-3.0): (1.8-3.6), triphenylphosphine is added in anhydrous aprotic solvent, add 1-halo-3-methylbutane, heating reflux reaction under oxygen free condition, less than 20 DEG C are cooled to after reacting completely, add highly basic, compound 04, under oxygen free condition, heating reflux reaction is to reacting completely; Finally be cooled to less than 10 DEG C, regulate pH to neutral, except desolventizing, obtain compound 05.
Further preferred, described solvent is toluene, tetrahydrofuran (THF), one or more in glycol dimethyl ether, is preferably toluene.
Further preferred, described 1-halo-3-methylbutane is one or both in 1-bromo-3-methylbutane or 1-chloro-3-methylbutane, is preferably 1-chloro-3-methylbutane.
Further preferred, described highly basic is potassium tert.-butoxide, sodium tert-butoxide, one or more in butyllithium, is preferably potassium tert.-butoxide.
Preferred further, adjust ph uses industrial concentrated hydrochloric acid or the vitriol oil.
Preferably, in step (4), described catalyzer is palladium-carbon catalyst, and concrete operations are: with molar ratio computing, compound 05: palladium=1:(0.01-0.03), palladium-carbon catalyst and compound 05 is added in solvent, under oxygen free condition, passing into hydrogen, reacting to reacting completely under 40-60 DEG C of condition, through concentrated, crystallization obtains compound 06.
Further preferred, described solvent is ethanol, Glacial acetic acid, methylene dichloride, toluene, tetrahydrofuran (THF), one or more in glycol dimethyl ether, is preferably ethanol.
Preferred further, described palladium-carbon catalyst employing palladium content is the wet palladium carbon of 5%, and 5% refers to that in palladium-carbon catalyst, palladium metal accounts for the weight percent of whole palladium-carbon catalyst.
Preferably, the concrete operations of step (5) are: be dissolved in solvent by compound 06, under 45-55 DEG C of condition, drip 98% vitriol oil, dropping terminates rear insulation reaction, after reacting completely, except desolventizing obtains compound 01, wherein, the mass volume ratio of compound 06 and 98% vitriol oil is: 100g:(3-8) mL.
Preferred further, described solvent is the mixed solvent that one or more and water in dioxane, Glacial acetic acid, ethanol, tetrahydrofuran (THF) form, further be preferably the mixed solvent of dioxane and water composition, most preferred, in order to improve the solute effect of compound, be conducive to fully carrying out of reaction, solvent is the mixed solvent that dioxane and water form with the volume ratio of 3:2.
The most preferred scheme of the present invention, a kind of take Stigmasterol as the method for Material synthesis cholesterol, comprises the steps:
(1) with molar ratio computing, Stigmasterol 02: benzene sulfonyl chloride or Tosyl chloride: Potassium ethanoate=1:(1.1-1.3): (3-5), by Stigmasterol 02, benzene sulfonyl chloride or Tosyl chloride, pyridine at room temperature reacts, react completely to obtain sulphonate, be dissolved in methyl alcohol by described sulphonate, add Potassium ethanoate, heating reflux reaction is to reacting completely, concentrated, crystallization obtains compound 03;
(2) with molar ratio computing, compound 03: zinc powder=1:(6-8), compound 03 is dissolved in methylene dichloride, be cooled to-50 ~-80 DEG C, pass into ozone reaction, after reacting completely, reacting liquid temperature is returned to room temperature, add zinc powder and Glacial acetic acid, react under room temperature condition, after reacting completely, removing zinc powder, obtain compound 04, wherein, compound 03 is 1g:1mL with the mass volume ratio of Glacial acetic acid.
(3) with molar ratio computing, compound 04: triphenylphosphine: 1-chloro-3-methylbutane: potassium tert.-butoxide or sodium tert-butoxide=1:(1.5-3.0): (1.5-3.0): (1.8-3.6), triphenylphosphine is added in dry toluene, add 1-chloro-3-methylbutane, heating reflux reaction under oxygen free condition, less than 20 DEG C are cooled to after reacting completely, add potassium tert.-butoxide or sodium tert-butoxide, compound 04, heating reflux reaction under oxygen free condition, after reacting completely, be cooled to less than 10 DEG C, regulate pH to neutral, except desolventizing, obtain compound 05;
(4) with molar ratio computing, compound 05:5% palladium carbon=1:(0.01-0.03), palladium-carbon catalyst and the compound 05 of 5% is added in ethanol, under oxygen free condition, pass into hydrogen and reach 2-4 normal atmosphere, react under 40-60 DEG C of condition, after reacting completely, through concentrated, crystallization obtains compound 06;
(5) compound 06 is dissolved in the mixed solvent of dioxane and water composition, under 45-55 DEG C of condition, drip 98% vitriol oil, dropping terminates rear insulation reaction, after reacting completely, except desolventizing obtains compound 01, wherein, compound 06 adds with the mass volume ratio of 98% vitriol oil is 100g:3-8mL98%.
Embodiment
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
Take Stigmasterol as a method for Material synthesis cholesterol, comprise the steps:
(1) pyridine 500mL is added, Stigmasterol 02100g, Tosyl chloride 47g in the reaction flask of 1000mL, stirring at room temperature reacts 24 hours, in a large amount of frozen water of reaction solution impouring, separates out a large amount of solid, filter, with clear water washing, drain to obtain intermediate sulfonic acid ester, sulphonate wet product is dissolved in the methyl alcohol of 1000mL, add Potassium ethanoate 72g, reaction solution reflux 2 hours, be evaporated to about surplus 200ml methyl alcohol, freezing and crystallizing obtains compound 0396.87g, molar yield 93.69%;
(2) compound 0320g is dissolved in the methylene dichloride of 1000mL, be cooled to-70 DEG C, slowly pass into ozone (using ozone machine to produce ozone), reaction end HPLC or TLC monitors, react completely, make reacting liquid temperature return to room temperature, add 18.4g zinc powder and 20mL Glacial acetic acid in room temperature reaction (25 DEG C) 3 hours, reaction completes, cross and filter zinc powder, filtrate washes 2 times, densely dry to obtain compound 0414.12g, molar yield 87.43%.
(3) in 2000mL glass reaction bottle, add toluene 1200mL, stir, add triphenylphosphine 63g, be heated to reflux the moisture steamed in toluene.Stop heating, nitrogen protection is cooled to less than 40 DEG C, adds 1-chloro-3-methylbutane 26g, after adding, reheats back flow reaction 2 hours;
Stop heating, nitrogen protection is cooled to less than 20 DEG C, and insulation gradation adds potassium tert.-butoxide 32g, stirs after 30 minutes, adds compound 0454g, after adding, reheat back flow reaction 4 hours.TLC monitors reaction end, and after reacting completely, ice-water bath is cooled to less than 10 DEG C, slowly add in the acid solution of ice-water bath cooling (tap water 500ml adds the industrial concentrated hydrochloric acid 39g of 30%), adjust pH to neutral, stir 30 minutes, normal pressure is concentrated into solvent-free smell, is cooled to less than 40 DEG C, filter, be washed to neutrality, drain, dry, obtain compound 0557.31g, molar yield 91.73%.
(4) in the stainless steel hydrogenation reaction cauldron of 3000mL, the palladium-carbon catalyst 2g of 5%, compound 05200g and ethanol 2000mL is added, nitrogen replacement 3 times, logical hydrogen reaches 3 normal atmosphere, 50 DEG C of reactions 12 hours, after completion of the reaction, stop insulation, row's hydrogen, with nitrogen replacement, filter, then use a small amount of washing with alcohol, filtrate reduced in volume is to small volume, freezing and crystallizing, filters, then uses washing with alcohol, drain, obtain compound (06) 185.27g, molar yield 92.17%.
(5) in the reaction flask of 1000mL, add dioxane 300ml, water 200ml, stir, drip 98% vitriol oil 5ml, add compound 05100g, 50 DEG C are reacted 3 hours, and decompression steams dioxane, add water 500ml, filter, wash, drain, obtain cholesterol 0194.32g, molar yield 97.74%.
Embodiment 2
Take Stigmasterol as a method for Material synthesis cholesterol, synthetic method is with embodiment 1, and its difference is only:
In step (1), benzene sulfonyl chloride, the consumption of Potassium ethanoate is respectively 52g and 95g, obtains compound 0396.64g, molar yield 93.46%.
In step (2), the consumption of zinc powder is 21.5g, obtains compound 0414.25g, molar yield 88.23%.
In step (3), triphenylphosphine, the chloro-3-methylbutane of 1-, potassium tert.-butoxide, the consumption of 30% industrial concentrated hydrochloric acid is respectively 94g, 39g, 48g, 58g, obtains compound 0557.66%, molar yield 92.29%.
In step (4), 5% palladium-carbon catalyst consumption is 4g, obtains compound 06185.92g, molar yield 92.50%.
In step (5), solvent dioxane replaces to Glacial acetic acid, obtains compound 0194.55g, molar yield 97.98%.
Embodiment 3
Take Stigmasterol as a method for Material synthesis cholesterol, synthetic method is with embodiment 1, and its difference is only:
In step (1), benzene sulfonyl chloride, the consumption of Potassium ethanoate is respectively 56g and 119g, obtains compound 0396.02g, molar yield 92.86%.
In step (2), the consumption of zinc powder is 24.5g, obtains compound 0414.28g, molar yield 88.42%.
In step (3), triphenylphosphine, the chloro-3-methylbutane of 1-, the consumption of potassium tert.-butoxide is respectively 125g, 58g, 42.5g, 30% industrial concentrated hydrochloric acid is replaced to the vitriol oil of 32g98%, obtains compound 0557.51g, molar yield 92.05%.
In step (4), 5% palladium-carbon catalyst consumption is 6g, obtains compound 06186.12g, molar yield 92.59%.
In step (5), solvent dioxane replaces to tetrahydrofuran (THF), obtains compound 0194.41g, molar yield 97.83%.
Embodiment 4
Take Stigmasterol as a method for Material synthesis cholesterol, synthetic method is with embodiment 1, and its difference is only: in step (4), dioxane is replaced to ethanol, obtain compound 0193.94g, molar yield 97.35%.
Although above with general explanation, embodiment and test, the present invention is described in detail, and on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (10)
1. be a method for Material synthesis cholesterol with Stigmasterol, it is characterized in that, synthesis equation is:
Specifically comprise the steps:
(1) Stigmasterol 02 reacts with benzene sulfonyl chloride or Tosyl chloride and generates sulphonate, and described sulphonate is dissolved in methyl alcohol and adds Potassium ethanoate or sodium-acetate back flow reaction, compound 03 of purifying after reacting completely to obtain;
(2) described compound 03 and ozone generation oxidizing reaction, gained reaction solution reacts with reductive agent again, compound 04 of purifying after reacting completely to obtain;
(3) triphenylphosphine and 1-halo-3-methylbutane react to obtain 3-methyl butyl triphenyl phosphonium halides phosphine; Described 3-methyl butyl triphenyl phosphonium halides phosphine and highly basic react and generate wittig reagent, and described wittig reagent and compound 04 wittig occur and react, through compound 05 of purifying to obtain after reacting completely;
(4) there is hydrogenation in described compound 05 under catalyst action, through compound 06 of purifying to obtain after reacting completely;
(5) there is hydrolysis reaction in described compound 06, cholesterol 01 of purifying after reacting completely to obtain.
2. method according to claim 1, it is characterized in that: the concrete operations of step (1) are: with molar ratio computing, Stigmasterol 02: benzene sulfonyl chloride or Tosyl chloride: Potassium ethanoate or sodium-acetate=1:(1.1-1.3): (3-5), by Stigmasterol 02, benzene sulfonyl chloride or Tosyl chloride, pyridine at room temperature reacts, sulphonate is obtained after reacting completely, described sulphonate is dissolved in methyl alcohol, add Potassium ethanoate or sodium-acetate, heating reflux reaction is to reacting completely, and concentrated, crystallization obtains compound 03.
3. method according to claim 1, it is characterized in that: the concrete operations of step (2) are: with molar ratio computing, compound 03: reductive agent=1:(6-8), compound 03 is dissolved in solvent, is cooled to-50 ~-80 DEG C, passes into ozone reaction, after reacting completely, reacting liquid temperature is returned to room temperature, adds reductive agent and continue reaction, after reacting completely, obtain compound 04.
4. method according to claim 3, is characterized in that: described solvent is methylene dichloride, acetone, one or more in ethylene dichloride, is preferably methylene dichloride; Described reductive agent is zinc powder or dimethyl sulphide, is preferably zinc powder.
5. method according to claim 1, it is characterized in that: the concrete operations of step (3) are: with molar ratio computing, compound 04: triphenylphosphine: 1-halo-3-methylbutane: highly basic=1:(1.5-3.0): (1.5-3.0): (1.8-3.6), triphenylphosphine is added in anhydrous aprotic solvent, add 1-halo-3-methylbutane, heating reflux reaction under oxygen free condition, less than 20 DEG C are cooled to after reacting completely, add highly basic, compound 04, under oxygen free condition, heating reflux reaction is to reacting completely; Finally be cooled to less than 10 DEG C, regulate pH to neutral, except desolventizing, obtain compound 05.
6. method according to claim 5, is characterized in that; Described solvent is toluene, tetrahydrofuran (THF), one or more in glycol dimethyl ether, is preferably toluene; Described 1-halo-3-methylbutane is one or both in 1-bromo-3-methylbutane or 1-chloro-3-methylbutane, is preferably 1-chloro-3-methylbutane; And/or described highly basic is potassium tert.-butoxide, sodium tert-butoxide, one or more in butyllithium, are preferably potassium tert.-butoxide.
7. method according to claim 1, it is characterized in that: in step (4), described catalyzer is palladium-carbon catalyst, and concrete operations are: with molar ratio computing, compound 05: palladium=1:(0.01-0.03), palladium-carbon catalyst and compound 05 is added in solvent, under oxygen free condition, passing into hydrogen, reacting to reacting completely under 40-60 DEG C of condition, through concentrated, crystallization obtains compound 06.
8. method according to claim 7, is characterized in that: described solvent is ethanol, Glacial acetic acid, methylene dichloride, toluene, tetrahydrofuran (THF), one or more in glycol dimethyl ether, is preferably ethanol; And/or described palladium-carbon catalyst is 5% palladium-carbon catalyst.
9. method according to claim 1, it is characterized in that: the concrete operations of step (5) are: be dissolved in solvent by compound 06, under 45-55 DEG C of condition, drip 98% vitriol oil, dropping terminates rear insulation reaction, after reacting completely, except desolventizing obtains compound 01, wherein, the mass volume ratio of compound 06 and 98% vitriol oil is: 100g:(3-8) mL; Further, described solvent is the mixed solvent that one or more and water in dioxane, Glacial acetic acid, ethanol, tetrahydrofuran (THF) form, and further, described solvent is the mixed solvent of dioxane and water.
10. method according to claim 1, is characterized in that, comprises the steps:
(1) with molar ratio computing, Stigmasterol 02: benzene sulfonyl chloride or Tosyl chloride: Potassium ethanoate=1:(1.1-1.3): (3-5), by Stigmasterol 02, benzene sulfonyl chloride or Tosyl chloride, pyridine at room temperature reacts, react completely to obtain sulphonate, be dissolved in methyl alcohol by described sulphonate, add Potassium ethanoate, heating reflux reaction is to reacting completely, concentrated, crystallization obtains compound 03;
(2) with molar ratio computing, compound 03: zinc powder=1:(6-8), compound 03 is dissolved in methylene dichloride, be cooled to-50 ~-80 DEG C, pass into ozone reaction, after reacting completely, reacting liquid temperature is returned to room temperature, add zinc powder and Glacial acetic acid, react under room temperature condition, after reacting completely, removing zinc powder, obtain compound 04, wherein, compound 03 with the mass volume ratio of Glacial acetic acid is: 1g:1mL.
(3) with molar ratio computing, compound 04: triphenylphosphine: 1-chloro-3-methylbutane: potassium tert.-butoxide or sodium tert-butoxide=1:(1.5-3.0): (1.5-3.0): (1.8-3.6), triphenylphosphine is added in dry toluene, add 1-chloro-3-methylbutane, heating reflux reaction under oxygen free condition, less than 20 DEG C are cooled to after reacting completely, add potassium tert.-butoxide or sodium tert-butoxide, compound 04, heating reflux reaction under oxygen free condition, after reacting completely, be cooled to less than 10 DEG C, regulate pH to neutral, except desolventizing, obtain compound 05;
(4) with molar ratio computing, compound 05:5% palladium carbon=1:(0.01-0.03), palladium-carbon catalyst and the compound 05 of 5% is added in ethanol, under oxygen free condition, pass into hydrogen and reach 2-4 normal atmosphere, react under 40-60 DEG C of condition, after reacting completely, through concentrated, crystallization obtains compound 06;
(5) compound 06 is dissolved in the mixed solvent of dioxane and water composition, under 45-55 DEG C of condition, drip 98% vitriol oil, dropping terminates rear insulation reaction, after reacting completely, except desolventizing obtains compound 01, wherein, compound 06 adds with the mass volume ratio of 98% vitriol oil is 100g:3-8mL98%.
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| CN111320663A (en) * | 2018-12-13 | 2020-06-23 | 上海医药工业研究院 | Preparation method of 24-cholenenoic acid ethyl ester intermediate |
| CN111320664A (en) * | 2018-12-13 | 2020-06-23 | 上海医药工业研究院 | Preparation method of 24-cholenenoic acid ethyl ester |
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| CN106632565A (en) * | 2016-11-07 | 2017-05-10 | 湖南科瑞生物制药股份有限公司 | Novel method used for synthesizing cholesterol |
| CN109021059A (en) * | 2017-06-09 | 2018-12-18 | 郑州泰丰制药有限公司 | Ring cholane carboxylic ester derivative and its preparation method and application |
| CN111320663A (en) * | 2018-12-13 | 2020-06-23 | 上海医药工业研究院 | Preparation method of 24-cholenenoic acid ethyl ester intermediate |
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| CN111320663B (en) * | 2018-12-13 | 2023-01-24 | 上海医药工业研究院 | Preparation method of 24-cholenenoic acid ethyl ester intermediate |
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| CN112745253B (en) * | 2021-02-07 | 2023-03-14 | 成都健腾生物技术有限公司 | Preparation of vitamin D from stigmasterol 3 Is a new method for industrialization |
| CN115555034A (en) * | 2022-10-17 | 2023-01-03 | 湖南科瑞生物制药股份有限公司 | Composite catalyst for converting carbonyl into methylene and preparation method for efficiently catalyzing cholesterol synthesis by using composite catalyst |
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