CN100357310C - Synthesis process of chlesterol and its intermediate - Google Patents
Synthesis process of chlesterol and its intermediate Download PDFInfo
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- CN100357310C CN100357310C CNB2005100947623A CN200510094762A CN100357310C CN 100357310 C CN100357310 C CN 100357310C CN B2005100947623 A CNB2005100947623 A CN B2005100947623A CN 200510094762 A CN200510094762 A CN 200510094762A CN 100357310 C CN100357310 C CN 100357310C
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Abstract
The present invention discloses a method for synthesizing cholesterol, which uses yam aglycone as raw materials to carry out the following processing steps of the protection of hydroxyl radicals, ring opening reactions, sulfonylation reactions, sulfonic acid ester reduction, the acetylation and saponification reactions of dimethyl ether radicals to obtain cholesterol. The present invention simultaneously discloses two kinds of intermediate bodies namely that 16, 26-dihydroxy cholesterol-3-methyl ether and 16, 26-dimethyl sulfonyl cholesterol-3-methyl ether, obtained by the method. The present invention uses yam aglycone as raw materials to successfully synthesize the cholesterol through six steps of reactions. The present invention has the advantages of simple reaction process and high yield, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of steroide, be specifically related to a kind of synthetic method of cholesterol, and the intermediate that in this synthetic method, obtains.
Background technology
Cholesterol has steroid backbone, is the important source material of synthesizing steroid compounds.Japan Ma Shi makes cholesterol degradation 4-etioallocholane-3 with mycobacterium, 17-diketone (4AD) and etioallocholane-1,4-diene-3,17-diketone (ADD) changes into Testosterone again, and etherone, estradiol, Norethisterone are produced sexual hormoue, are fattened hormone, childbirth auxiliary agent and oral contraceptive; Contain 2% cholesterol in the artificial Calculus Bovis composition; Cholesterol is as the auxiliary agent of emulsifying agent and pharmaceutical preparation in the pharmacy, because it can increase in the medicament medicinal greasy emulsification and blend, also is a kind of wetting ability and water-absorbing ointment bases, also can be used as solid support material manufacturing liposome in addition; Wetting Agent for Printing Inks in the makeup; The raw material of liquid crystal in the photoelectric material.Vitamins D in addition
3, Vit D3, taurine synthesis material also be cholesterol.
At present the source of cholesterol is an animal, mainly be brain and the saponification of vertebra tendon with pig, ox, sheep after, utilize organic solvent extraction.Because now all to be that zoochory is given human for the numerous disease of finding, especially last century Mo European mad cow disease discovery, and the streptococcus suis infection of the beginning of this century makes people throw doubt upon to the security of the cholesterol of traditional method for making.People need the big cholesterol of a kind of safety coefficient.
Therefore, people begin one's study, and employing is synthesized or semisynthetic method is come the production cholesterol.Because the molecular structure complexity of cholesterol is though people have just found cholesterol as far back as 1815, for synthesizing until breakthrough has just been arranged the fifties in last century of steroid compound.Nineteen fifty-one, Woodward (R.B Woodward) has been finished the complete synthesis of cholesterol, yet the method reaction path that it adopts is wanted 30 multisteps, and productive rate is very low, is not suitable for industrial production.
The Chinese yam aglycon can extract preparation from Dioscoreaceae plant (as Ningpo Yam Rhizome, Dioscorea panthaica Prain et Burkill, Rhizome of Peltate Yam etc.), studies show that the steroidal loop section is consistent with cholesterol in the structure of Chinese yam aglycon, and their difference is the former two ether rings of side chain on 17.Thereby the present inventor wishes that with the Chinese yam aglycon be raw material, obtains cholesterol by the synthetic method, to adapt to need of industrial production.
Summary of the invention
The object of the invention provides the synthetic method of the cholesterol that a kind of technology is simple, productive rate is higher, and the intermediate of this synthetic method is provided simultaneously.
For achieving the above object, the technical solution used in the present invention is: a kind of synthetic method of cholesterol is a raw material with the Chinese yam aglycon, carries out following processing:
(1) protection of hydroxyl: the Chinese yam aglycon is handled with sodium hydride or potassium hydride KH, obtained Chinese yam aglycon sodium alkoxide or Chinese yam aglycon potassium alcoholate, the reaction mol ratio is 1: 1.2～2.0; With the methyl-sulfate reaction, obtain Chinese yam aglycon-3-methyl ether again, the reaction mol ratio is 1: 1.0～2.0;
(2) ring-opening reaction: the Chinese yam aglycon-3-methyl ether that obtains is become 16 with hydrochloric acid-zinc reduction system open loop, 26-dihydroxyl cholesterol-3-methyl ether, the mol ratio of Chinese yam aglycon-3-methyl ether, hydrochloric acid and zinc is 1: 50～150: 50～150;
(3) sulfonylation: 16,26-dihydroxyl cholesterol-3-methyl ether is dissolved in pyridine or the triethylamine solvent, be cooled to below 5 ℃, slowly add methylsulfonyl chloride or methylsulfonic acid acid anhydride, reaction mol ratio 1: 2.5～5, stirred overnight at room temperature, extraction obtains 16,26-two mesyloxies cholesterol-3-methyl ether;
(4) sulphonate reduction: 16,26-two mesyloxies cholesterol-3-methyl ether is dissolved in the glycol dimethyl ether, with zinc-sodium iodide-aqueous systems heating reflux reaction 4～6 hours, temperature of reaction? reaction product obtains cholesterol-3-methyl ether through extraction, 16, the mol ratio of 26-two mesyloxies cholesterol-3-methyl ether, zinc and sodium iodide is 1: 2～8: 5～12;
(5) methyl ether base acetylize: the cholesterol-3-methyl ether of above-mentioned acquisition is carried out the acetylize of methyl ether base, obtain the Cholesteryl acetate ester;
(6) saponification reaction: with sodium hydroxide or potassium hydroxide treatment, the reaction mol ratio is 1: 5～8 to the Cholesteryl acetate ester, obtains cholesterol in methyl alcohol-tetrahydrofuran (THF) mixed solvent.
In the technique scheme, the protection of described step (1) hydroxyl and step (2) ring-opening reaction have report in the prior art, are mainly used in the research of preparation hormones compound; Step (5) methyl ether base acetylize and step (6) saponification reaction also have report; be investigator's some achievements in research of reporting when the conversion of research cholesterol; be to be that raw material transforms with the cholesterol; oppositely be converted into some research property reports of cholesterol again; because raw material can not obtain, above-mentioned research can not be used to prepare cholesterol.The present invention successfully links up said process by two intermediates, can extract the raw material that obtains based on nature, has prepared cholesterol.
Synthetic route in the technique scheme can be expressed as follows:
Just:
The first step: change the hydroxyl on 3 into methoxyl group, promptly generate Chinese yam aglycon methyl ether and carry out the protection of hydroxyl.
Second step: carry out ring-opening reaction, generate 16 and 26 compounds that respectively contain a hydroxyl.
The 3rd step: 16,26 hydroxyls are carried out sulfonylation, generate the disulfonate compound.
The 4th step: the disulfonate compound carries out reduction reaction, sloughs alkylsulfonyl, generates the cholesterol methyl ether.
The 5th step: the acetylization reaction of cholesterol methyl ether generates the Cholesteryl acetate ester.
The 6th step: the saponification reaction of Cholesteryl acetate ester generates cholesterol.
The present invention has provided two intermediates that produce in the above-mentioned synthetic method simultaneously, and one is 16,26-dihydroxyl cholesterol-3-methyl ether, and its structural formula is,
In the formula, Me is a methyl.
It two is 16,26-two mesyloxies cholesterol-3-methyl ether, and its structural formula is,
In the formula, Me is a methyl, and Ms is a methylsulfonyl.
Because the technique scheme utilization, the present invention compared with prior art has following advantage:
1. the present invention is protection, ring-opening reaction, sulfonylation, sulphonate reduction, methyl ether base acetylize and the ethanoyl hydrolysis of raw material through perhydroxyl radical with the Chinese yam aglycon, and six-step process successfully synthesizes target molecule 3-beta-hydroxy cholesterol.Reaction process is simple, the productive rate height, and overall yield is 60.6%.
2. the present invention selects methylsulfonyl chloride or methylsulfonic acid acid anhydride to carry out sulfonylation and reduction reaction, thereby can obtain the cholesterol methyl ether of high yield.
Embodiment
Below in conjunction with embodiment the present invention is further described:
Embodiment one: the synthetic method of cholesterol comprises the following steps:
[protection of hydroxyl]: the sodium hydride of 6.0 gram (0.15mol) 60% places the three-necked bottle of 1L; adding 500ml does not have the tetrahydrofuran (THF) of water treatment; stir down 41.6 gram (0.1mol) Chinese yam aglycons are added wherein in batches; add the back and continued stirring reaction 15 minutes; the methyl-sulfate that in mixed solution, adds 18.9 grams (0.15mol) then; the reactant room temperature stirs spends the night; in reaction system, drip the excessive sodium hydride of methanolysis; there is not the gas generation up to adding methyl alcohol; mixed solution is poured in the 2L water; cold filtration, thick product recrystallizing methanol gets white needle-like crystals 40.6 grams.Fusing point: 184.5-185.0 ℃, productive rate: 95.3%.
[ring-opening reaction]: 20 gram (0.046mol) Chinese yam aglycon 3-methyl ethers and 300 gram (4.6mol) high-quality zinc powders place the three-necked bottle of 2L, add the dehydrated alcohol of 1L, the suspension liquid reflux.In reaction system, drip the 380ml concentrated hydrochloric acid simultaneously, dripped off in about 1.5 hours, add the back and continued back flow reaction 30 minutes, remove unreacted zinc powder then while hot, filter residue small amount of ethanol rinsing, filtrate are poured in the 1.5L water and are cooled off, and separate out white solid, suction filtration, thick product methanol-water mixed solvent recrystallization.Get 18.05 grams 16,26-dihydroxyl cholesterol, fusing point: 150.8-151.5 ℃, productive rate: 92.2%.
[sulfonylation]: 20.05 gram (0.046mol) 16,26-dihydroxyl cholesterol places the 500ml round-bottomed flask, adds the dissolving of 300ml pyridine, is cooled to below 5 ℃, slowly adds methylsulfonyl chloride 22.91 (0.20mol) gram in system, stirred overnight at room temperature.The most pyridine of pressure reducing and steaming, with 1 of 600ml, 2-ethylene dichloride lysate, with 10% hydrochloric acid washed twice, water washing twice again, solution removes after with anhydrous sodium sulfate drying and desolvates, 16,26-two mesyloxy cholesterol oily liquids 27 grams.
[sulphonate reduction]: 27 gram (0.046mol) 16,26-two mesyloxy cholesterol are dissolved in the 500ml glycol dimethyl ether, add 34.5 gram (0.23mol) sodium iodides and 35 gram (0.54mol) high-quality zinc powders, add 30ml water again, mixture heating up back flow reaction 4-6 hour, the 2L isopropyl ether dilution of system cooling back, suction filtration, filtrate is respectively washed once with 500ml water, 500ml 15% hydrochloric acid, 500ml water, 500ml saturated sodium bicarbonate, 500ml 10% Sulfothiorine respectively, at last with twice of 300ml washing.Solution behind anhydrous sodium sulfate drying, remove desolvate a viscous liquid.Get tabular crystal 16.5 grams with acetone-methanol mixed solvent recrystallization.Fusing point: 83.2-83.4 ℃, productive rate 80.8%
[acetylize of cholesterol methyl ether]: the method that adopts reference (Bruce Ganem and Vernon R.Small, J.Org.Chem, 39 (25), 3728～3730 (1974)) to provide gets a white plates solid.Fusing point: 110.1-111.8 ℃, productive rate: 87.0%.
Specific operation process is: 6.0 gram (0.015mol) cholesterol methyl ethers place the 500ml round-bottomed flask, add the 50ml ethyl acetate, all add the equivalent diacetyl oxide again after the dissolving, add 0.5 gram (0.003mol) FERRIC CHLORIDE ANHYDROUS then, stirring at room 12 hours.In reaction system, add sherwood oil 500ml and be transferred to separating funnel water extraction 1 time, use 10% soda solution washed twice again, wash with water at last twice, remove behind the anhydrous sodium sulfate drying and desolvate, residuum is removed a small amount of low polarity thing with petroleum ether-ethyl acetate (10: 1) chromatography on silicagel column, gets white solid 5.8 grams.
[hydrolysis of Cholesteryl acetate ester]: 2.1 gram (0.005mol) Cholesteryl acetate esters place the 500ml round-bottomed flask, add 5mol/L sodium hydrate methanol solution 100ml and 200ml tetrahydrofuran (THF), stirring at room 12 hours.Add 150～200ml water in reaction system, divide three extractions with the 300ml methylene dichloride, washing back anhydrous sodium sulfate drying removes the back crude product ethyl alcohol recrystallization that desolvates on a small quantity, gets white needle-like crystals 1.9 grams.Fusing point: 148.3～148.9 ℃, productive rate: 98.1%.Final product is cholesterol.
Embodiment two: a kind of synthetic method of cholesterol is a raw material with the Chinese yam aglycon, carries out following processing:
(1) protection of hydroxyl: under the condition that organic solvent exists, the Chinese yam aglycon is handled with sodium hydride or potassium hydride KH, obtained Chinese yam aglycon sodium alkoxide or Chinese yam aglycon potassium alcoholate, the reaction mol ratio is 1: 1.2～2.0; With the methyl-sulfate reaction, the reaction mol ratio is 1: 1.0～2.0, removes excessive sodium hydride or potassium hydride KH with methyl alcohol again, cold filtration in water, and recrystallization obtains Chinese yam aglycon-3-methyl ether;
(2) ring-opening reaction: the Chinese yam aglycon-3-methyl ether that obtains is added in the dehydrated alcohol with zinc powder, the suspension liquid reflux, slowly drip concentrated hydrochloric acid, reaction product is behind suction filtration, recrystallization, obtain 16,26-dihydroxyl cholesterol-3-methyl ether, the mol ratio of Chinese yam aglycon-3-methyl ether, hydrochloric acid and zinc is 1: 50～150: 50～150;
(3) sulfonylation: 16,26-dihydroxyl cholesterol-3-methyl ether is dissolved in pyridine or the triethylamine solvent, be cooled to below 5 ℃, slowly add the methylsulfonic acid acid anhydride, reaction mol ratio 1: 2.5～5, stirred overnight at room temperature, the most of solvent of pressure reducing and steaming, with the ethylene dichloride extraction, obtain 16,26-two mesyloxies cholesterol-3-methyl ether with hydrochloric acid and water washing, dry back;
(4) sulphonate reduction: 16,26-two mesyloxies cholesterol-3-methyl ether is dissolved in the glycol dimethyl ether, with zinc-sodium iodide-aqueous systems heating reflux reaction 4～6 hours, the reaction product cooling is after repeatedly extract acquisition cholesterol-3-methyl ether, 16, the mol ratio of 26-two mesyloxies cholesterol-3-methyl ether, zinc and sodium iodide is 1: 2～8: 5～12;
(5) methyl ether base acetylize: the cholesterol-3-methyl ether of above-mentioned acquisition is carried out the acetylize of methyl ether base, obtain the Cholesteryl acetate ester;
(6) saponification reaction: with sodium hydroxide or potassium hydroxide treatment, the reaction mol ratio is 1: 5～8 to the Cholesteryl acetate ester, obtains cholesterol in methyl alcohol-tetrahydrofuran (THF) mixed solvent.
Claims (3)
1. the synthetic method of a cholesterol is characterized in that, is raw material with the Chinese yam aglycon, carries out following processing:
(1) protection of hydroxyl: the Chinese yam aglycon is handled with sodium hydride or potassium hydride KH, obtained Chinese yam aglycon sodium alkoxide or Chinese yam aglycon potassium alcoholate, the reaction mol ratio of Chinese yam aglycon and sodium hydride or potassium hydride KH is 1: 1.2～2.0; With the methyl-sulfate reaction, obtain Chinese yam aglycon-3-methyl ether again, the reaction mol ratio of Chinese yam aglycon and methyl-sulfate is 1: 1.0～2.0;
(2) ring-opening reaction: the Chinese yam aglycon-3-methyl ether that obtains is become 16 with hydrochloric acid-zinc reduction system open loop, 26-dihydroxyl cholesterol-3-methyl ether, the mol ratio of Chinese yam aglycon-3-methyl ether, hydrochloric acid and zinc is 1: 50～150: 50～150;
(3) sulfonylation: 16,26-dihydroxyl cholesterol-3-methyl ether is dissolved in pyridine or the triethylamine solvent, be cooled to below 5 ℃, slowly add methylsulfonyl chloride or methylsulfonic acid acid anhydride, reaction mol ratio 1: 2.5～5, stirred overnight at room temperature, extraction obtains 16,26-two mesyloxies cholesterol-3-methyl ether;
(4) sulphonate reduction: 16,26-two mesyloxies cholesterol-3-methyl ether is dissolved in the glycol dimethyl ether, with zinc-sodium iodide-aqueous systems heating reflux reaction 4～6 hours, reaction product obtains cholesterol-3-methyl ether through extraction, 16, the mol ratio of 26-two mesyloxies cholesterol-3-methyl ether, zinc and sodium iodide is 1: 2～8: 5～12;
(5) methyl ether base acetylize: the cholesterol-3-methyl ether of above-mentioned acquisition is carried out the acetylize of methyl ether base, obtain the Cholesteryl acetate ester;
(6) saponification reaction: the Cholesteryl acetate ester is handled with sodium hydroxide or oxygen potassium oxide in methyl alcohol-tetrahydrofuran (THF) mixed solvent, and the reaction mol ratio is 1: 5～8, obtains cholesterol.
2. the intermediate of claim 1 synthetic method is 16,26-dihydroxyl cholesterol-3-methyl ether, and its structural formula is,
In the formula, Me is a methyl.
3. the intermediate of claim 1 synthetic method is 16,26-two mesyloxies cholesterol-3-methyl ether, and its structural formula is,
In the formula, Me is a methyl, and Ms is a methylsulfonyl.
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| CN105218610B (en) * | 2015-10-28 | 2017-01-11 | 湖南科瑞生物制药股份有限公司 | Method for synthesizing cholesterol by using stigmasterol degradation products as raw materials |
| 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 |
| EP4089100A1 (en) * | 2021-05-14 | 2022-11-16 | CordenPharma International GmbH | Novel synthesis of cholesterol |
| CN113651866B (en) * | 2021-08-02 | 2023-07-04 | 王涛 | Novel method for synthesizing cholesterol by taking 21-hydroxy-20-methyl pregna-4-en-3-one as raw material |
| CN115521353A (en) * | 2021-11-15 | 2022-12-27 | 武汉桐语科技有限公司 | Method for preparing diosgenin derivative by adopting dimethyl carbonate |
| CN115260271A (en) * | 2022-08-31 | 2022-11-01 | 沈阳化工研究院有限公司 | Method for removing 16, 26-sulfonate group from steroid compound |
| CN115286676B (en) * | 2022-08-31 | 2023-07-07 | 沈阳化工研究院有限公司 | Synthesis method for preparing cholesterol methyl ether from diosgenin |
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| CN1338462A (en) * | 2000-08-15 | 2002-03-06 | 中国科学院生态环境研究中心 | Chemical synthesis of echinocystic saponin derivative |
| CN1583784A (en) * | 2004-06-04 | 2005-02-23 | 中国科学院上海有机化学研究所 | 17 alpha, 22-dicarboxy furo compound and its use |
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| CN1338462A (en) * | 2000-08-15 | 2002-03-06 | 中国科学院生态环境研究中心 | Chemical synthesis of echinocystic saponin derivative |
| CN1583784A (en) * | 2004-06-04 | 2005-02-23 | 中国科学院上海有机化学研究所 | 17 alpha, 22-dicarboxy furo compound and its use |
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