CN105237603B - A kind of method with stigmasterol as Material synthesis cholesterol - Google Patents
A kind of method with stigmasterol as Material synthesis cholesterol Download PDFInfo
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- CN105237603B CN105237603B CN201510713730.0A CN201510713730A CN105237603B CN 105237603 B CN105237603 B CN 105237603B CN 201510713730 A CN201510713730 A CN 201510713730A CN 105237603 B CN105237603 B CN 105237603B
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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 43
- 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 28
- 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 28
- 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 28
- 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 28
- 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 28
- 235000016831 stigmasterol Nutrition 0.000 title claims abstract description 28
- 229940032091 stigmasterol Drugs 0.000 title claims abstract description 28
- 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 28
- 238000000034 method Methods 0.000 title claims abstract description 25
- 235000012000 cholesterol Nutrition 0.000 title claims abstract description 21
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 18
- 239000000463 material Substances 0.000 title claims abstract description 17
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 92
- 238000006243 chemical reaction Methods 0.000 claims abstract description 80
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims abstract description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 27
- 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 26
- -1 sulphonic acid ester Chemical class 0.000 claims abstract description 18
- 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
- 235000011056 potassium acetate Nutrition 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 13
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims abstract description 12
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000001475 halogen functional group Chemical group 0.000 claims abstract description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 17
- 238000010438 heat treatment Methods 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 10
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 7
- 239000001632 sodium acetate Substances 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
- 239000007788 liquid Substances 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 238000009413 insulation Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 125000000532 dioxanyl group Chemical group 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 3
- 239000005864 Sulphur Substances 0.000 claims 3
- 125000001340 2-chloroethyl group Chemical class [H]C([H])(Cl)C([H])([H])* 0.000 claims 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 claims 1
- 244000046052 Phaseolus vulgaris Species 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 150000003431 steroids Chemical class 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 239000000376 reactant Substances 0.000 abstract description 4
- 230000009471 action Effects 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 abstract 2
- 238000007239 Wittig reaction Methods 0.000 abstract 1
- 230000007613 environmental effect Effects 0.000 abstract 1
- 230000000977 initiatory effect Effects 0.000 abstract 1
- 238000004519 manufacturing process Methods 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
- 241001465754 Metazoa Species 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000282898 Sus scrofa Species 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000001273 butane Substances 0.000 description 2
- 238000006073 displacement reaction Methods 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
- 230000007246 mechanism Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 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
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-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
- 241000894006 Bacteria Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- 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 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
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 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
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- UQXKXGWGFRWILX-UHFFFAOYSA-N ethylene glycol dinitrate Chemical compound O=N(=O)OCCON(=O)=O UQXKXGWGFRWILX-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 208000006278 hypochromic anemia Diseases 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
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 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
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Abstract
A kind of method with stigmasterol as Material synthesis cholesterol, specially：(1) stigmasterol generates sulphonic acid ester with benzene sulfonyl chloride reaction, and sulphonic acid ester adds potassium acetate back flow reaction to obtain compound 03 in methyl alcohol；(2) there is oxidation reaction in compound 03 and ozone, gained reactant liquor again with zinc powder, glacial acetic acid reacts, and obtains compound 04；(3) triphenylphosphine and 1 halo, 3 methybutane react to obtain 3 methyl butyl triphenyl phosphonium halides phosphines；3 methyl butyl triphenyl phosphonium halides phosphines generate wittig reagents with highly basic reaction, and wittig reagents occur wittig reactions with compound 04, obtain compound 05；(4) there is hydrogenation in compound 05 under catalyst action, obtain compound 06；(5) there is hydrolysis in compound 06, obtain cholesterol 01, and the method is with stigmasterol as initiation material, cheap and easy to get, process is simple, and consumption supplementary material is few, and high income, low cost, environmental protection are easy to industrialized production.
Description
Technical field
A kind of the present invention relates to cholesterol biosynthesis technical field, more particularly to side with stigmasterol as Material synthesis cholesterol
Method.
Background technology
It is Material synthesis cholesterol also known as cholesterine, a kind of derivative of cyclopentanoperhy drophenanthrene with stigmasterol.Early in 18 generation
Discipline people have been found that from cholelith with stigmasterol as Material synthesis cholesterol, and chemist in 1816 is by this tool lipid nature
Material is named as with stigmasterol as Material synthesis cholesterol.Animal body is widely present in as Material synthesis cholesterol with stigmasterol
Interior, especially enriched in brain and nerve fiber the most, in kidney, spleen, skin, liver and bile, content is also high.With stigmasterol as raw material
Synthetic cholesterol is the indispensable important substance of institute of animal tissue cell, and it is not only involved in forming cell membrane, and is synthesis
The raw material of bile acid, vitamin D and steroid hormone.
At present, cholesterol is mainly and extracts from the brain and vertebra of the animals such as pig, ox, sheep, due to rabid ox disease and pig hammer
The appearance that bacterium catches, people generate suspection to the safety in utilization for coming from animal cholesterol, need a kind of safer
Synthetic cholesterol synthetic method.
Content of the invention
It is an object of the invention to provide a kind of method with stigmasterol as Material synthesis cholesterol, the reaction mechanism mechanism of reaction is：
Specifically include following steps：
(1) stigmasterol 02 generates sulphonic acid ester with benzene sulfonyl chloride or paratoluensulfonyl chloride reaction, and the sulphonic acid ester is in methyl alcohol
Plus potassium acetate or sodium acetate back flow reaction, compound 03 is purified to obtain after reaction completely；
(2) there is oxidation reaction with ozone in the compound 03, and gained reactant liquor is reacted with reducing agent again, after reaction completely
Purify to obtain compound 04；
(3) triphenylphosphine reacts to obtain 3- methyl butyl triphenyl phosphonium halides phosphines with 1- halo -3- methybutanes；The 3- methyl
Butyl triphenyl phosphonium halides phosphine generates wittig reagents with highly basic reaction, and it is anti-that the wittig reagents occur wittig with compound 04
Should, compound 05 is obtained after reaction completely after purification；
(4) there is hydrogenation in the compound 05 under catalyst action, through purifying to obtain compound 06 after reaction completely；
(5) there is hydrolysis in the compound 06, purify to obtain cholesterol 01 after reaction completely.
Preferably, the concrete operations of step (1) are：The concrete operations of step (1) are：With molar ratio computing, stigmasterol 02：Benzene
Sulfonic acid chloride or paratoluensulfonyl chloride：Potassium acetate or sodium acetate=1：(1.1-1.3)：(3-5), by stigmasterol 02, benzene sulfonyl chloride or
Paratoluensulfonyl chloride, pyridine react at room temperature, obtain sulphonic acid ester, the sulphonic acid ester is dissolved in methyl alcohol after reaction completely, add
Potassium acetate or sodium acetate, to reacting completely, concentration crystallizes to obtain compound 03 to heating reflux reaction.Wherein, potassium acetate or sodium acetate
Can not only neutralization reaction generate sulfonic acid, play acid-base buffer agent, additionally with certain catalyst effect.
Preferably, the concrete operations of step (2) are：With molar ratio computing, compound 03：Reducing agent=1：(6-8), by chemical combination
Thing 03 is dissolved in solvent, is cooled to -50～-80 DEG C, is passed through ozone reaction, after reaction completely, by reacting liquid temperature recover to
Room temperature, addition reducing agent continue reaction, obtain compound 04 after reaction completely.
It is further preferred that the solvent is dichloromethane, and acetone, one or more in dichloroethanes, further
Preferably dichloromethane.
The reducing agent is reducing agent commonly used in the art, such as zinc powder or dimethyl sulphide, more preferably zinc powder.More
Further, in order to improve the reducing activity of zinc powder, the reaction system of reduction reaction will keep acid, for this purpose, can be to reaction
Acid solution is added in liquid, and the acid solution is acid solution commonly used in the art, such as hydrochloric acid, sulfuric acid, glacial acetic acid, the one kind or many in phosphoric acid
Plant, preferably glacial acetic acid, more preferably, compound 03 is 1g with the mass volume ratio of glacial acetic acid：1mL.
Preferably, the concrete operations of step (3) are：With molar ratio computing, compound 04：Triphenylphosphine：1- halo -3- methyl
Butane：Highly basic=1：(1.5-3.0)：(1.5-3.0)：(1.8-3.6), triphenylphosphine is added in anhydrous aprotic solvent, plus
Enter 1- halo -3- methybutanes, heating reflux reaction under oxygen free condition is cooled to less than 20 DEG C after reaction completely, adds highly basic,
Compound 04, under oxygen free condition, heating reflux reaction is complete to reaction；Less than 10 DEG C are finally cooled to, and pH are adjusted to neutrality, are removed
Solvent is removed, compound 05 is obtained.
It is further preferred that the solvent is toluene, and tetrahydrofuran, one or more in glycol dimethyl ether, preferably
For toluene.
It is further preferred that the 1- halos -3- methybutanes are 1- bromo -3- methybutanes or 1- chloro -3- methyl
One or two in butane, preferably 1- chloros -3- methybutanes.
It is further preferred that the highly basic is potassium tert-butoxide, and sodium tert-butoxide, one or more in butyl lithium, preferably
Potassium tert-butoxide.
It is further preferred that adjusting pH value using industrial concentrated hydrochloric acid or the concentrated sulfuric acid.
Preferably, in step (4), the catalyst is palladium-carbon catalyst, and concrete operations are：With molar ratio computing, compound
05:Palladium=1：(0.01-0.03), in solvent, palladium-carbon catalyst and compound 05 is added, under oxygen free condition, is passed through hydrogen,
React under the conditions of 40-60 DEG C to reaction completely, concentrated, crystallize to obtain compound 06.
It is further preferred that the solvent is ethanol, and glacial acetic acid, dichloromethane, toluene, tetrahydrofuran, glycol dinitrate
One or more in ether, preferably ethanol.
It is further preferred that the palladium-carbon catalyst adopt palladium content for 5% wet palladium carbon, 5% refer to palladium-carbon catalyst in
Metal Palladium accounts for the percentage by weight of whole palladium-carbon catalyst.
Preferably, the concrete operations of step (5) are：Compound 06 is dissolved in solvent, under the conditions of 45-55 DEG C, is added dropwise
98% concentrated sulfuric acid, insulation reaction after completion of dropwise addition, after reaction completely, remove solvent and obtain compound 01, wherein, compound 06 with
The mass volume ratio of 98% concentrated sulfuric acid is：100g：(3-8)mL.
It is further preferred that the solvent be dioxane, glacial acetic acid, ethanol, in tetrahydrofuran one or more with
The mixed solvent of water composition, the mixed solvent for still more preferably constituting for dioxane and water, most preferably, for raising
The solute effect of compound, is conducive to that reacted fully to carry out, and solvent is dioxane and water with 3:The mixing of 2 volume ratio composition
Solvent.
Most preferably scheme of the invention, a kind of with stigmasterol as the method for Material synthesis cholesterol, comprise the steps：
(1) with molar ratio computing, stigmasterol 02：Benzene sulfonyl chloride or paratoluensulfonyl chloride：Potassium acetate=1：(1.1-1.3)：(3-
5), by stigmasterol 02, benzene sulfonyl chloride or paratoluensulfonyl chloride, pyridine react at room temperature, reaction completely sulphonic acid ester, will be described
Sulphonic acid ester is dissolved in methyl alcohol, adds potassium acetate, and to reacting completely, concentration crystallizes to obtain compound 03 to heating reflux reaction；
(2) with molar ratio computing, compound 03：Zinc powder=1：(6-8), compound 03 is dissolved in dichloromethane, is lowered the temperature
To -50～-80 DEG C, ozone reaction is passed through, after reaction completely, reacting liquid temperature is recovered to room temperature, zinc powder and glacial acetic acid is added,
React under room temperature condition, after reaction completely, remove zinc powder, obtain compound 04, wherein, the quality volume of compound 03 and glacial acetic acid
Than for 1g：1mL.
(3) with molar ratio computing, compound 04：Triphenylphosphine：1- chloro -3- methybutanes：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, 1- chloro -3- methyl is added
Butane, heating reflux reaction under oxygen free condition are cooled to less than 20 DEG C after reaction completely, add potassium tert-butoxide or sodium tert-butoxide,
Compound 04, heating reflux reaction under oxygen free condition, after reaction completely, are cooled to less than 10 DEG C, adjust pH to neutrality, remove molten
Agent, obtains compound 05；
(4) with molar ratio computing, compound 05:5% palladium carbon=1：(0.01-0.03), in ethanol, 5% palladium carbon is added to urge
Agent and compound 05, under oxygen free condition, are passed through hydrogen up to 2-4 atmospheric pressure, react under the conditions of 40-60 DEG C, and reaction is completely
Afterwards, concentrated, crystallize to obtain compound 06；
(5) compound 06 is dissolved in the mixed solvent of dioxane and water composition, under the conditions of 45-55 DEG C, is added dropwise 98%
The concentrated sulfuric acid, insulation reaction after completion of dropwise addition, after reaction completely, remove solvent and obtain compound 01, wherein, compound 06 plus and 98%
The mass volume ratio of the concentrated sulfuric acid is 100g：3-8mL 98%.
Specific embodiment
Following examples are used for the present invention to be described, but are not limited to the scope of the present invention.
Embodiment 1
A kind of with stigmasterol as the method for Material synthesis cholesterol, comprise the steps：
(1) add pyridine 500mL in the reaction bulb of 1000mL, 02 100g of stigmasterol, paratoluensulfonyl chloride 47g are stirred at room temperature
Reaction 24 hours, reactant liquor is poured in a large amount of frozen water, separates out a large amount of solids, is filtered, is washed with clear water, drain to obtain intermediate sulfonic acid
Ester, sulphonic acid ester wet product is dissolved in the methyl alcohol of 1000mL, plus potassium acetate 72g, and reactant liquor is heated to reflux 2 hours, is evaporated to
200ml methyl alcohol is about remained, and freezing and crystallizing obtains 03 96.87g of compound, molar yield 93.69%；
(2) 03 20g of compound is dissolved in the dichloromethane of 1000mL, is cooled to -70 DEG C, is slowly passed through ozone and (is used
Ozone machine produces ozone), reaction end is monitored with HPLC or TLC, and reaction completely, makes reacting liquid temperature recover to room temperature, plus
, in room temperature reaction (25 DEG C) 3 hours, reaction is completed, and is filtered to remove zinc powder, and filtrate is washed 2 times for 18.4g zinc powders and 20mL glacial acetic acid,
Dense dry to obtain 04 14.12g of compound, molar yield 87.43%.
(3) in 2000mL glass reaction bottles, plus toluene 1200mL, stirring, plus triphenylphosphine 63g, it is heated to backflow and steams
The moisture gone out in toluene.Stop heating, nitrogen protection is cooled to less than 40 DEG C, plus the chloro- 3- methybutanes 26g of 1-, after adding, then
Heating reflux reaction 2 hours；
Stop heating, nitrogen protection is cooled to less than 20 DEG C, is incubated gradation plus potassium tert-butoxide 32g, after stirring 30 minutes, plus
04 54g of compound, after adding, reheats back flow reaction 4 hours.TLC monitors reaction end, and after reaction completely, ice-water bath is lowered the temperature
To less than 10 DEG C, it is slowly added to, in the acid solution of ice-water bath cooling (running water 500ml, the industrial concentrated hydrochloric acid 39g for plus 30%), adjust
PH is stirred 30 minutes to neutrality, and normal pressure is concentrated into solvent-free smell, is cooled to less than 40 DEG C, is filtered, is washed to neutrality, drains,
Dry, obtain 05 57.31g of compound, molar yield 91.73%.
(4) in the stainless steel hydrogenation reaction cauldron of 3000mL, palladium-carbon catalyst 2g, 05 200g of compound and the second of plus 5%
Alcohol 2000mL, nitrogen displacement 3 times lead to hydrogen up to 3 atmospheric pressure, react 12 hours at 50 DEG C, after completion of the reaction, stop insulation,
Row's hydrogen, with nitrogen displacement, filters, then is washed with a small amount of ethanol, filtrate reduced in volume to small size, freezing and crystallizing, filter, then
Washed with ethanol, drained, obtain compound (06) 185.27g, molar yield 92.17%.
(5) in the reaction bulb of 1000mL, plus dioxane 300ml, water 200ml, stirring, 98% concentrated sulfuric acid 5ml is added dropwise,
Plus 05 100g of compound, 50 DEG C are reacted 3 hours, and decompression steams dioxane, and add water 500ml, filters, washs, drains, obtains courage
01 94.32g of sterol, molar yield 97.74%.
Embodiment 2
A kind of method with stigmasterol as Material synthesis cholesterol, with embodiment 1, which differs only in synthetic method：
In step (1), benzene sulfonyl chloride, the consumption of potassium acetate are respectively 52g and 95g, obtain 03 96.64g of compound, mole
Yield 93.46%.
In step (2), the consumption of zinc powder is 21.5g, obtains 04 14.25g of compound, molar yield 88.23%.
In step (3), triphenylphosphine, the chloro- 3- methybutanes of 1-, potassium tert-butoxide, the consumption difference of 30% industrial concentrated hydrochloric acid
For 94g, 39g, 48g, 58g, compound 05 57.66%, molar yield 92.29% is obtained.
In step (4), 5% palladium-carbon catalyst consumption is 4g, obtains 06 185.92g of compound, molar yield 92.50%.
In step (5), solvent dioxane is substituted for glacial acetic acid, obtains 01 94.55g of compound, molar yield 97.98%.
Embodiment 3
A kind of method with stigmasterol as Material synthesis cholesterol, with embodiment 1, which differs only in synthetic method：
In step (1), benzene sulfonyl chloride, the consumption of potassium acetate are respectively 56g and 119g, obtain 03 96.02g of compound, mole
Yield 92.86%.
In step (2), the consumption of zinc powder is 24.5g, obtains 04 14.28g of compound, molar yield 88.42%.
In step (3), triphenylphosphine, the chloro- 3- methybutanes of 1-, the consumption of potassium tert-butoxide are respectively 125g, 58g,
42.5g, the concentrated sulfuric acid that 30% industrial concentrated hydrochloric acid is substituted for 32g 98%, obtains 05 57.51g of compound, molar yield
92.05%.
In step (4), 5% palladium-carbon catalyst consumption is 6g, obtains 06 186.12g of compound, molar yield 92.59%.
In step (5), solvent dioxane is substituted for tetrahydrofuran, obtains 01 94.41g of compound, molar yield
97.83%.
Embodiment 4
A kind of method with stigmasterol as Material synthesis cholesterol, with embodiment 1, which differs only in synthetic method：Step
Suddenly in (4), dioxane is substituted for ethanol, obtains 01 93.94g of compound, molar yield 97.35%.
Although, general explanation, specific embodiment and test has above been used, the present invention has been made to retouch in detail
State, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to claimed
Scope.
Claims (13)
1. a kind of method with stigmasterol as Material synthesis cholesterol, it is characterised in that synthesis equation is：
Specifically include following steps：
(1) stigmasterol 02 generates sulphonic acid ester with benzene sulfonyl chloride or paratoluensulfonyl chloride reaction, and the sulphonic acid ester is dissolved in methyl alcohol and adding
Potassium acetate or sodium acetate back flow reaction, purify to obtain compound 03 after reaction completely；
(2) with molar ratio computing, compound 03：Reducing agent=1：(6-8), compound 03 is dissolved in solvent, -50 are cooled to
～-80 DEG C, ozone reaction is passed through, after reaction completely, reacting liquid temperature is recovered to room temperature, add reducing agent to continue reaction, instead
Compound 04 is obtained after answering completely；The reducing agent is zinc powder or dimethyl sulphide；
(3) with molar ratio computing, compound 04：Triphenylphosphine：1- halo -3- methybutanes：Highly basic=1：(1.5-3.0)：(1.5-
3.0)：(1.8-3.6), triphenylphosphine is added in anhydrous aprotic solvent, 1- halo -3- methybutanes, oxygen free condition is added
Lower heating reflux reaction, is cooled to less than 20 DEG C after reaction completely, adds highly basic, compound 04 to be heated to reflux under oxygen free condition
React to reaction completely；Less than 10 DEG C are finally cooled to, and pH are adjusted to neutrality, are removed solvent, obtain compound 05；
(4) there is hydrogenation in the compound 05 under palladium-carbon catalyst effect, through purifying to obtain compound 06 after reaction completely；
(5) compound 06 is dissolved in solvent, under the conditions of 45-55 DEG C, 98% concentrated sulfuric acid of dropwise addition, insulation reaction after completion of dropwise addition,
After reaction completely, remove solvent and obtain compound 01, wherein, compound 06 with the mass volume ratio of 98% concentrated sulfuric acid is：100g：
(3-8)mL.
2. method according to claim 1, it is characterised in that：The concrete operations of step (1) are：With molar ratio computing, beans steroid
Alcohol 02：Benzene sulfonyl chloride or paratoluensulfonyl chloride：Potassium acetate or sodium acetate=1：(1.1-1.3)：(3-5), by stigmasterol 02, benzene sulphur
Acyl chlorides or paratoluensulfonyl chloride, pyridine react at room temperature, obtain sulphonic acid ester, the sulphonic acid ester is dissolved in methyl alcohol after reaction completely
In, potassium acetate or sodium acetate is added, to reacting completely, concentration crystallizes to obtain compound 03 to heating reflux reaction.
3. method according to claim 1, it is characterised in that：In step (2), the solvent be dichloromethane, acetone, two
One or more in chloroethanes.
4. method according to claim 3, it is characterised in that：The solvent is dichloromethane.
5. the method according to any one of claim 1-3, it is characterised in that：In step (2), the reducing agent is zinc powder.
6. method according to claim 1, it is characterised in that：In step (3), the solvent be toluene, tetrahydrofuran, second
One or more in glycol dimethyl ether；1- halos -3- the methybutanes are 1- bromo -3- methybutanes or 1- chloro -3-
One or two in methybutane, and/or, the highly basic is potassium tert-butoxide, sodium tert-butoxide, the one kind or many in butyl lithium
Kind.
7. method according to claim 6, it is characterised in that：The solvent is toluene.
8. method according to claim 1, it is characterised in that：The concrete operations of step (4) are：With molar ratio computing, chemical combination
Thing 05:Palladium=1：(0.01-0.03), in solvent, palladium-carbon catalyst and compound 05 is added, under oxygen free condition, is passed through hydrogen,
React under the conditions of 40-60 DEG C to reaction completely, concentrated, crystallize to obtain compound 06.
9. method according to claim 8, it is characterised in that：The solvent be ethanol, glacial acetic acid, dichloromethane, toluene,
Tetrahydrofuran, one or more in glycol dimethyl ether；And/or, the palladium-carbon catalyst is 5% palladium-carbon catalyst.
10. method according to claim 9, it is characterised in that：The solvent is ethanol.
11. methods according to claim 1, it is characterised in that：In step (5), the solvent is dioxane, ice vinegar
Acid, ethanol, one or more mixed solvents with water composition in tetrahydrofuran.
12. methods according to claim 11, it is characterised in that：The solvent is the mixed solvent of dioxane and water.
13. methods according to claim 1, it is characterised in that comprise the steps：
(1) with molar ratio computing, stigmasterol 02：Benzene sulfonyl chloride or paratoluensulfonyl chloride：Potassium acetate=1：(1.1-1.3)：(3-5),
Stigmasterol 02, benzene sulfonyl chloride or paratoluensulfonyl chloride, pyridine are reacted at room temperature, reaction obtains sulphonic acid ester completely, by the sulphur
Acid esters is dissolved in methyl alcohol, adds potassium acetate, and to reacting completely, concentration crystallizes to obtain compound 03 to heating reflux reaction；
(2) with molar ratio computing, compound 03：Zinc powder=1：(6-8), compound 03 is dissolved in dichloromethane, -50 are cooled to
～-80 DEG C, ozone reaction is passed through, after reaction completely, reacting liquid temperature is recovered to room temperature, zinc powder and glacial acetic acid, room temperature is added
Under the conditions of react, after reaction completely, remove zinc powder, obtain compound 04, wherein, the mass volume ratio of compound 03 and glacial acetic acid
For：1g：1mL；
(3) with molar ratio computing, compound 04：Triphenylphosphine：1- chloro -3- methybutanes：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, 1- chloro -3- methybutanes are added,
Heating reflux reaction under oxygen free condition, is cooled to less than 20 DEG C after reaction completely, adds potassium tert-butoxide or sodium tert-butoxide, compound
04, heating reflux reaction under oxygen free condition, after reaction completely, is cooled to less than 10 DEG C, adjusts pH to neutrality, removes solvent, obtain
Compound 05；
(4) with molar ratio computing, compound 05:5% palladium carbon=1：(0.01-0.03), 5% palladium-carbon catalyst is added in ethanol
With compound 05, under oxygen free condition, hydrogen is passed through up to 2-4 atmospheric pressure, is reacted under the conditions of 40-60 DEG C, after reaction completely, warp
Concentration, crystallizes to obtain compound 06；
(5) compound 06 is dissolved in the mixed solvent of dioxane and water composition, under the conditions of 45-55 DEG C, 98% dense sulphur is added dropwise
Acid, insulation reaction after completion of dropwise addition, after reaction completely, remove solvent and obtain compound 01, wherein, compound 06 plus and 98% dense sulphur
The mass volume ratio of acid is 100g：3-8mL.
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| 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 |
| CN111320664B (en) * | 2018-12-13 | 2023-01-24 | 上海医药工业研究院 | A kind of preparation method of ethyl 24-choleenoic acid |
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| WO2021005618A1 (en) * | 2019-07-09 | 2021-01-14 | Fermenta Biotech Limited | Synthesis of cholesterol and vitamin d3 from phytosterols |
| WO2021120127A1 (en) | 2019-12-19 | 2021-06-24 | 湖南科瑞生物制药股份有限公司 | Method for preparing cholesterol, derivative and analogue thereof |
| 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 |
| CN114524856B (en) | 2022-01-27 | 2024-03-15 | 华东师范大学 | Synthesis method of high-purity plant-derived cholesterol |
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| CN115555034B (en) * | 2022-10-17 | 2023-08-18 | 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 synthesis of cholesterol by composite catalyst |
| CN116102610B (en) * | 2022-11-11 | 2025-06-06 | 长沙钰腾新材料有限公司 | Method for preparing 3,5-ring,6-ether structure steroid compound from sterol compound |
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