CN101863740B - Preparation method of decanisoprenol - Google Patents
Preparation method of decanisoprenol Download PDFInfo
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- CN101863740B CN101863740B CN 201010215575 CN201010215575A CN101863740B CN 101863740 B CN101863740 B CN 101863740B CN 201010215575 CN201010215575 CN 201010215575 CN 201010215575 A CN201010215575 A CN 201010215575A CN 101863740 B CN101863740 B CN 101863740B
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- big flowers
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Abstract
The invention discloses a preparation method of decanisoprenol. The method comprises the following steps: in a system of tetrahydrofuran and toluene solvents, using available acetoxyethlydiethyl phosphate or triethyl phosphate and taking sodium hydroxide or sodium ethylate, solane-copper to produce acetic decanisodialyklene ester or decanisodienoicacid ethyl ester; hydrolyzing by using sodium hydroxide or reducing by using lithium aluminium hydride/aluminum chloride; and hydrolyzing to obtain the product decanisoprenol. The invention has the advantages of easily bought raw materials, simple manufacture and mild reaction. Severe conditions of synthetic route of decanisoprenol desulfonylation and mercury toxicity pollution caused by using Na/Hg for reduction are avoided, and expensive and hard available diisopropyl lithium aluminium or dissobutyl lithium aluminium as a reductant is also avoided from utilization so that the synthesis becomes simple and feasible, the yield is high, the cost is low and industrial production is facilitated.
Description
Technical field
A kind of preparation method of the open certain herbaceous plants with big flowers isoprene alcohol of the present invention particularly relates to synthesizing coenzyme Q
10The preparation method of certain herbaceous plants with big flowers isoprene alcohol of important source material, field of biological pharmacy.
Background technology
Certain herbaceous plants with big flowers isoprene alcohol (E, E, E, E, E, E, E, E, E, E)-3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38 four ten carbon ten alkene-1-alcohol are a kind of straight chain diterpene-kind compounds, its molecular structural formula is:
The certain herbaceous plants with big flowers isoprene alcohol is synthesizing coenzyme Q
10Important source material, contain this kind material in the natural phant very few, contain in a small amount of plant but content is lower, be difficult to form Industrial raw material.
The research of synthetic certain herbaceous plants with big flowers isoprene alcohol becomes the chemist Main Topics, its research situation mainly contains: (one) is take Salanesol as starting raw material, make eggplant Thessaloniki ketone through halo, methyl aceto acetate addition reaction, eggplant Thessaloniki ketone is with sodium carbide or the addition of bromo vinyl magnesium, synthesize first different certain herbaceous plants with big flowers isoprene alcohol (tertiary alcohol) through phosphorus tribromide reaction, hydrolysis and get the certain herbaceous plants with big flowers isoprene alcohol, known synthetic route has two kinds:
A, R.Ruegg etc. (Helv.Chim.Acta2616-2621) (1959) synthetic route:
Above-mentioned two synthetic routes all are to make eggplant Thessaloniki ketone take Salanesol as starting raw material, obtain different certain herbaceous plants with big flowers isoprene alcohol (tertiary alcohol) through sodium carbide or bromo vinyl magnesium Ge Shi addition route, then through PBr
3Bromo, hydrolysis obtain the purpose product, and product is the mixture of cis-trans isomerism, and cis-structure is higher though transconfiguration is occupied an leading position, to ubiquinone
10Synthesize, separate, purify and bring difficulty, directly affect yield, make ubiquinone
10Cost occupies high, can't market competition.
(2) Wang Chaojie, Chen Bingzhi etc. (fine chemistry industry 9:549-551 (2000)) synthetic route is as raw material take Salanesol, through bromination, the benzene sulfinic acid reaction obtains eggplant Thessaloniki sulfone and reacts with 3-methyl-4-bromo-2-butylene-1-alcohol acetic ester, obtain object through taking off the sulfone processing, its reaction formula is as follows:
This route reaction step is simple and direct, can protect the stereo formation of product, and all there is better yield in each step; but 3-methyl-4-bromo-2-butylene-1-alcohol acetic ester source difficulty, and reductive agent Na/Hg takes off sulfone, the mercury residual hazard; very unfavorable to pharmaceutical production, be unfavorable for suitability for industrialized production.
(3) people (ZL200310109175.8) synthetic route such as Tang Feiyu, its reaction equation is as follows:
The route that this route and Wang Chaojie, Chen Bingzhi etc. study is similar all to be take Salanesol as raw material, through the synthetic eggplant Thessaloniki sulfone that obtains.Difference is to adopt 3-methyl-4-chloro-2-butylene-1-alcohol acetic ester condensation to make 5-sulfuryl certain herbaceous plants with big flowers isoprene alcohol without 3-methyl-4-bromo-2-butylene-1-alcohol acetic ester short chain as intermediate, obtain identical object through taking off sulfone again, the employed short chain latter has certain industrial value than the former steady sources.Taking off in the selection of sulfone reagent, the latter is lithium-methylamine reductive agent, and taking off the sulfone temperature is-78 ℃～-60 ℃, and the former Na/Hg reduces.Though people's routes such as Tang Feiyu have many saving graces, but the employed sulfone lithium-methylamine solvent that takes off of this route, the sulfone condition of taking off about-70 ℃, comparatively difficult in suitability for industrialized production, and the isomery of taking off sulfone Aim of Process product is restive, also bring separation, purifying, crystallization difficulty in Coenzyme Q10 99.0 is synthetic, affects yield, cost still occupies high.
Summary of the invention
The objective of the invention is the method improvement to the synthetic certain herbaceous plants with big flowers isoprene alcohol of forefathers' proposition, a kind of preparation method of invention certain herbaceous plants with big flowers isoprene alcohol, the present invention is that it uses key intermediate, solvent, reductive agent, reaction conditions to have its feature, and its advantage is that reactions steps is short, mild condition, raw material are easy to get, yield is high, cost is low, be beneficial to suitability for industrialized production.
A kind of preparation method of certain herbaceous plants with big flowers isoprene alcohol is characterized in that concrete steps are as follows:
(1), in the reaction solvent, one of them makes alkaline reagents with sodium hydride, sodium ethylate, potassium tert.-butoxide, under 25～61 ℃ of conditions, add acetoxyl group ethyl phosphonic acid diethyl ester or triethyl phosphate and eggplant Thessaloniki ketone back flow reaction under basic catalyst, through washing, extraction, dry, concentrated acetic acid certain herbaceous plants with big flowers isoprene ester or the certain herbaceous plants with big flowers isoprene acetic ester of making;
(2) above-mentioned reaction gained acetic acid certain herbaceous plants with big flowers isoprene ester is dissolved in toluene or the tetrahydrofuran (THF), adds at normal temperatures the hydrolysis of 10%NaOH alcoholic solution, through extraction, washing, drying, the concentrated target product certain herbaceous plants with big flowers isoprene alcohol that to get.Or certain herbaceous plants with big flowers isoprene acetic ester be dissolved in steam a part of solvent in toluene or the tetrahydrofuran (THF), be cooled to-20～0 ℃, once or gradation add lithium aluminum hydride/aluminum chloride reduction, through hydrolysis, extraction, dry, the concentrated target product certain herbaceous plants with big flowers isoprene alcohol that makes.
Its reaction equation is as follows:
Described reaction solvent is ethers, alkanes or arene, and wherein the ethers reaction solvent is ether, isopropyl ether, tetrahydrofuran (THF), dioxane or N.N. dimethyl formamide; The alkanes reaction solvent is hexane, octane or sherwood oil; Aromatic hydrocarbon solvent is benzene, toluene or dimethylbenzene.
The mol ratio of described acetoxyl group ethyl phosphonic acid diethyl ester or triethyl phosphate and eggplant Thessaloniki acetone is 1.79-2.36: 1.
The hydrolysis of described acetic acid certain herbaceous plants with big flowers isoprene ester is carried out at normal temperatures, and described certain herbaceous plants with big flowers isoprene acetoacetic ester reduction temperature is at-20-0 ℃.
The mol ratio of described basic catalyst and eggplant Thessaloniki ketone is 1.87-2.4: 1, and wherein react the alkaline catalysts that uses and be NaH, C
2H
5ONa or potassium tert.-butoxide.
Described acetic acid certain herbaceous plants with big flowers isoprene ester and 10%NaOH alcoholic solution hydrolysis consumption volume ratio are 5: 1, the mol ratio of lithium aluminum hydride/aluminum chloride reductive agent and certain herbaceous plants with big flowers isoprene acetoacetic ester is 0.075～0.077: 1, and the mol ratio of reductive agent lithium aluminum hydride and aluminum chloride is 3: 1.
The cmy vector of described hydrolysis or reduzate certain herbaceous plants with big flowers isoprene alcohol is Al
2O
3, silica gel, Na
2SO
4, white bole or diatomite.
The hydrolytic reagent of acetic acid certain herbaceous plants with big flowers isoprene ester is the 10%NaOH alcoholic solution among the present invention.Certain herbaceous plants with big flowers isoprene acetoacetic ester reductive agent is lithium aluminum hydride and aluminum chloride.Because the lithium aluminum hydride reactive behavior is too high, when the reduction of certain herbaceous plants with big flowers isoprene acetoacetic ester is carried out at low temperatures for carboxylicesters when reduction carbon-carbon double bond is not destroyed, the present invention adds 1-3 hydrogen atom in a certain amount of aluminum chloride replacement lithium aluminum hydride when using lithium aluminum hydride, make it be converted into aluminium alkane or alkoxyl group lithium aluminum hydride, with its reducing power of suitable reduction, thus the selectivity of raising reduction reaction.
The present invention uses acetoxyl group ethyl phosphonic acid diethyl ester or the triethyl phosphate that is easy to get, the mercury toxic pollutant of having avoided the certain herbaceous plants with big flowers isoprene alcohol to take off the severe condition of sulfone synthetic route and use the Na/Hg reduction to cause, also avoided the employing costliness again un-come-at-able di-isopropyl aluminium lithium or diisobutyl aluminum lithium as reductive agent.Make and synthetic become simple, yield is high, cost is low, be beneficial to suitability for industrialized production.Have industrial value, commodity are easily purchased, and make the characteristics such as simple.
Embodiment
The below further specifies flesh and blood of the present invention with example, but content of the present invention is not limited to this.
Method steps is as follows:
(1). in tetrahydrofuran (THF) and the toluene solvant, one of them makes alkaline reagents with sodium hydride, sodium ethylate, potassium tert.-butoxide, under 25-61 ℃ of condition, add acetoxyl group ethyl phosphonic acid diethyl ester or triethyl phosphate and eggplant Thessaloniki reactive ketone, through washing, extraction, dry, concentrated acetic acid certain herbaceous plants with big flowers isoprene ester or the certain herbaceous plants with big flowers isoprene acetic ester of making.
(2). above-mentioned reaction gained acetic acid certain herbaceous plants with big flowers isoprene ester is dissolved in toluene or the tetrahydrofuran (THF), adds at normal temperatures the hydrolysis of 10%NaOH alcoholic solution, through extraction, washing, drying, the concentrated target product certain herbaceous plants with big flowers isoprene alcohol that to get.Or certain herbaceous plants with big flowers isoprene acetic ester be dissolved in steam a part of solvent in toluene or the tetrahydrofuran (THF), lower the temperature-20～0 ℃, once or gradation add LiAlH
4/ AlCl
3Reduction is through hydrolysis, extraction, dry, the concentrated target product certain herbaceous plants with big flowers isoprene alcohol that makes.
Embodiment 1
Measuring the 100ml tetrahydrofuran (THF) adds in the there-necked flask, add 32g (0.177mol) acetoxyl group ethyl phosphonic acid diethyl ester, add again 4.32g (0.18mol) NaH, reaction 30min, add the eggplant Thessaloniki ketone with 30ml hexane dissolving 50g (0.075mol), temperature of reaction is controlled at 50 ℃, backflow 8h, and the silica gel G thin layer chromatography (tlc) checks, react complete, add the aqueous ammonium chloride solution washing, merge organic layer, add Na
2SO
4Drying, concentrating under reduced pressure get acetic acid certain herbaceous plants with big flowers isoprene ester 54g, 98% yield.
54g acetic acid certain herbaceous plants with big flowers isoprene ester with the dissolving of 200ml toluene, in the there-necked flask of distillation is housed, after heating steams a part of toluene, is cooled to normal temperature, and disposable adding 270ml NaOH alcoholic solution is hydrolyzed 3h at normal temperatures.The silica gel G thin layer chromatography (tlc) checks, reacts complete, and petroleum ether extraction merges organic layer, NaCl solution washing, Na
2SO
4Drying, concentrating under reduced pressure is flung to solvent, and residuum gets certain herbaceous plants with big flowers isoprene alcohol 45.5g with silica gel column chromatography, yield 91% (in eggplant Buddhist nun ketone quality).
Embodiment 2
Measure 150ml toluene and add in the there-necked flask, add 32g (0.177mol) acetoxyl group ethyl phosphonic acid diethyl ester, add again 12.24g (0.18mol) C
2H
5ONa, reaction 40min adds 50g (0.075mol) the eggplant Thessaloniki ketone solution with the dissolving of 30ml hexane, at normal temperatures reaction (about 25 ℃) 14h, the silica gel G thin layer chromatography (tlc) checks, reacts complete, adds the aqueous ammonium chloride solution washing, petroleum ether extraction merges organic layer, Na
2SO
4Drying, concentrating under reduced pressure get acetic acid certain herbaceous plants with big flowers isoprene ester 51g, 92.5% yield.
51g acetic acid certain herbaceous plants with big flowers isoprene ester with the dissolving of 250ml benzene, in the there-necked flask of distillation is housed, after heating steams a part of benzene, is cooled to normal temperature, and disposable adding 255ml NaOH alcoholic solution is hydrolyzed 3h at normal temperatures.The silica gel G thin layer chromatography (tlc) checks, reacts complete, and petroleum ether extraction merges organic layer, NaCl solution washing, Na
2SO
4Drying, concentrating under reduced pressure is flung to solvent, and residuum gets certain herbaceous plants with big flowers isoprene alcohol 44.5g with silica gel column chromatography, yield 89% (in eggplant Buddhist nun ketone quality).
Embodiment 3
Measure the 100ml tetrahydrofuran (THF) and add in the there-necked flask, add 30g (0.134mol) triethyl phosphate, add again 15.7g (0.14mol) potassium tert.-butoxide, reaction 30min, add with 30ml hexane dissolving 50g (0.075mol) eggplant Thessaloniki ketone solution, temperature of reaction is controlled at 61 ℃, backflow 8h, the silica gel G thin layer chromatography (tlc) checks, react complete, add the washing of chlorination aqueous ammonium, petroleum ether extraction, merge organic layer, add Na
2SO
4Drying, concentrating under reduced pressure get certain herbaceous plants with big flowers isoprene acetoacetic ester 56g, yield 99%.
56g certain herbaceous plants with big flowers isoprene acetoacetic ester with the dissolving of 200ml toluene, in the there-necked flask of distillation is housed, after heating steams a part of toluene, is cooled to-20 ℃, minute 2 adding 2.85g (0.075mol) LiAlH
4/ AlCl
3Reaction 4h, silica gel G thin layer chromatography (tlc) check, react complete, add water and extinguish, and add 3 times of water dilutions of 56g ammonium chloride and are the 168ml solution washing, and petroleum ether extraction merges organic layer, adds Na
2SO
4Drying, concentrating under reduced pressure is flung to solvent, and residuum gets certain herbaceous plants with big flowers isoprene alcohol 45g with silica gel column chromatography, yield 90% (in eggplant Buddhist nun ketone quality).
Claims (8)
1. a kind of preparation method of certain herbaceous plants with big flowers isoprene alcohol is characterized in that concrete steps are as follows:
(1), in the reaction solvent, one of them makes alkaline reagents with sodium hydride, sodium ethylate, potassium tert.-butoxide, under 25～61 ℃ of conditions, add acetoxyl group ethyl phosphonic acid diethyl ester or ethoxycarbonylmethyl group diethyl phosphoric acid and eggplant Thessaloniki acetone back flow reaction under basic catalyst, through washing, extraction, dry, concentrated acetic acid certain herbaceous plants with big flowers isoprene ester or the certain herbaceous plants with big flowers isoprene acetoacetic ester of making;
(2) above-mentioned reaction gained acetic acid certain herbaceous plants with big flowers isoprene ester is dissolved in toluene or the tetrahydrofuran (THF), adds at normal temperatures the alcoholysis of 10%NaOH alcoholic solution, through extraction, washing, drying, the concentrated target product certain herbaceous plants with big flowers isoprene alcohol that to get; Or certain herbaceous plants with big flowers isoprene acetoacetic ester is dissolved in steams a part of solvent in toluene or the tetrahydrofuran (THF), be cooled to-20～0 ℃; Once or gradation add lithium aluminum hydride/aluminum chloride reduction, through hydrolysis, extraction, dry, concentratedly make target product certain herbaceous plants with big flowers isoprene alcohol, its reaction equation is as follows:
2. a kind of preparation method of certain herbaceous plants with big flowers isoprene alcohol according to claim 1, it is characterized in that: described reaction solvent is ethers, alkanes or arene, wherein the ethers reaction solvent is ether, isopropyl ether, tetrahydrofuran (THF) or dioxane; The alkanes reaction solvent is hexane, octane, sherwood oil; Aromatic hydrocarbon solvent is benzene, toluene or dimethylbenzene.
3. a kind of preparation method of certain herbaceous plants with big flowers isoprene alcohol according to claim 1, it is characterized in that: the mol ratio of described acetoxyl group ethyl phosphonic acid diethyl ester or ethoxycarbonylmethyl group diethyl phosphoric acid and eggplant Thessaloniki acetone is 1.79-2.36: 1.
4. a kind of Preparation Method of the system of certain herbaceous plants with big flowers isoprene alcohol according to claim 1, it is characterized in that: described acetic acid certain herbaceous plants with big flowers isoprene ester carries out alcoholysis at normal temperatures, and described certain herbaceous plants with big flowers isoprene acetoacetic ester reduction temperature is at-20-0 ℃.
5. a kind of preparation method of certain herbaceous plants with big flowers isoprene alcohol according to claim 1, it is characterized in that: the mol ratio of described alkaline reagents and eggplant Thessaloniki acetone is 1.87-2.4: 1, wherein the alkaline reagents that uses of reaction is NaH, C
2H
5ONa or potassium tert.-butoxide.
6. a kind of preparation method of certain herbaceous plants with big flowers isoprene alcohol according to claim 1, it is characterized in that: described acetic acid certain herbaceous plants with big flowers isoprene ester and 10%NaOH alcoholic solution consumption volume ratio are 5: 1; The mol ratio of lithium aluminum hydride/aluminum chloride reductive agent and certain herbaceous plants with big flowers isoprene acetoacetic ester is 0.075～0.077: 1, and the mol ratio of lithium aluminum hydride and aluminum chloride is 3: 1 in the reductive agent.
7. a kind of preparation method of certain herbaceous plants with big flowers isoprene alcohol according to claim 1, it is characterized in that: the cmy vector of described hydrolysis or reduzate certain herbaceous plants with big flowers isoprene alcohol is Al
2O
3, silica gel, Na
2SO
4, white bole or diatomite.
8. a kind of preparation method of certain herbaceous plants with big flowers isoprene alcohol according to claim 1, it is characterized in that: described reaction solvent is DMF.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1629115A (en) * | 2004-08-06 | 2005-06-22 | 昆明韬辉生物工贸有限责任公司 | Method for extraction of high purity solanocupsin and synthesis of isodecyl dienol and isoprenol |
| CN1762942A (en) * | 2005-07-21 | 2006-04-26 | 昆明通发实业有限公司 | A kind of preparation method for isodeca-deca-isoprene-yl alcohol |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1629115A (en) * | 2004-08-06 | 2005-06-22 | 昆明韬辉生物工贸有限责任公司 | Method for extraction of high purity solanocupsin and synthesis of isodecyl dienol and isoprenol |
| CN1762942A (en) * | 2005-07-21 | 2006-04-26 | 昆明通发实业有限公司 | A kind of preparation method for isodeca-deca-isoprene-yl alcohol |
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