CN1314642C - Art for synthesizing acetylide of coenzyme Q10 intermediate - Google Patents
Art for synthesizing acetylide of coenzyme Q10 intermediate Download PDFInfo
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- CN1314642C CN1314642C CNB2005101006148A CN200510100614A CN1314642C CN 1314642 C CN1314642 C CN 1314642C CN B2005101006148 A CNB2005101006148 A CN B2005101006148A CN 200510100614 A CN200510100614 A CN 200510100614A CN 1314642 C CN1314642 C CN 1314642C
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Abstract
The present invention relates to a synthesis technique for coenzyme Q10 intermediate acetylide. The aim of the present invention is to solve the defects of high cost of an ethynation technique, obvious safe problems, environment pollution, etc. existing in the prior art. The main point of the technical scheme is a synthesis technique that solanesyl acetone is introduced into ethinyl and ethynated to obtain 3-methyl-solanesyl butine-1-alcohol-3 in the process of preparing coenzyme Q10 by a semisynthesis method. The present invention is characterized in that: firstly, in the synthesis technique, an amount of sodium hydroxide or potassium hydroxide, an alcohol solution and toluene are added into a chemical reaction vessel; the sodium hydroxide or the potassium hydroxide, the alcohol solution and the toluene are heated and refluxed for sufficient reaction; water is separated; after reaction liquid is cooled, acetylene is fed to react with the reaction liquid so as to obtain acetylene reaction liquid; a solanesyl acetone solution is added into the acetylene reaction liquid and reacts with the acetylene reaction liquid; after the reaction, a right amount of water is added; an acid solution is added for neutralization after cooling to separate a water layer and an organic solution layer; water is used for washing an organic solution; organic solvent is heated and evaporated to dryness; finally, the 3-methyl-solanesyl butine-1-alcohol-3 is obtained.
Description
Technical field
The present invention relates to a kind of semi-synthesis method and produce ubiquinone
10The preparation method of the intermediate material in the technological process, particularly ubiquinone
10The synthesis technique of intermediate acetylide.
Background technology
Ubiquinone
10Be a kind of biological intravital fat-soluble quinones that extensively is present in, chemical name: 2,3-dimethoxy-5-methyl-6-prenyl in the last of the ten Heavenly stems-1, the 4-benzoquinones, chemical structural formula:
Studies show that ubiquinone
10In the human body respiration chain, play an important role in proton displacement and the electron transport, can be used as cellular metabolism and cellular respiration activator, or important antioxidants and nonspecific immunity strengthening agent, but the promotes oxidn phosphorylation reaction, protection biofilm structure integrity.Clinically, ubiquinone
10Can be used as congestive heart failure, coronary heart disease, hypertension, irregular pulse, the adjuvant therapy medicaments of primary, secondary aldosteronism, neck wound sequela, cerebrovascular disorder, hemorrhagic shock and hepatitis etc., current research is also found ubiquinone
10Parkinson's disease there is mitigation.At present, ubiquinone
10Be widely used in field of medicaments; Abroad also with ubiquinone
10Be applied to healthcare products and cosmetic field.
Ubiquinone
10Production method have three: biological extraction, fermentation and semi-synthetic, be mainly derived from present the fermentation and semi-synthetic.By chemical structural formula as can be known, ubiquinone
10Be that a benzoquinones parent nucleus (has another name called ubiquinone
0) and one ten polyisoprene side chain composition.The eggplant Buddhist nun alcohol that application is extracted from tobacco is the synthetic ten polyisoprene side chains of raw material, and then synthesizing coenzyme Q
10Method, the common name semi-synthesis method.Ubiquinone
0Chemical structural formula with eggplant Buddhist nun alcohol:
(ubiquinone
0) (eggplant Buddhist nun alcohol)
Shown in above-listed chemical structural formula, ubiquinone
10Side chain be ten prenyls, and eggplant Buddhist nun alcohol is the alcohol of nine isoprene, therefore selects an economy and easy method is introduced the method for a prenyl and become ubiquinone in eggplant Buddhist nun alcohol
10A ten minutes important content in the semi-synthesis method.Existing method has:
1, the synthetic route of De Guo Lv Aige people such as (R ü egg) proposition:
Wherein eggplant Buddhist nun alcohol (I) is with phosphorus tribromide (PBr
3) bromination gets eggplant Thessaloniki bromine compounds (II), then introduce acetonyl and obtain eggplant Thessaloniki acetone (III) through acetonization with the methyl aceto acetate reaction, on the ketone group of eggplant Thessaloniki acetone (III), introduce ethynyl and obtain 3-methyl-eggplant Thessaloniki butine-1-alcohol-3 (IV) through ethinylation with the method for liquefied ammonia-sodium Metal 99.5, use Lin Dela (Lindlar) catalyzer that three key selective reduction Cheng Shuanjian, hydrogenation are generated different ten isopolyprenols (V) again, the isomerization transposition obtains ten isopolyprenols (VI) then, last and ubiquinone
0Coupling and ubiquinone
10
2, U.S. Pat 2002/0156302A1 than method 1, is characterized in: the Grignard reagent single step reaction of above-mentioned eggplant Thessaloniki acetone (III) and vinyl bromide is made different ten isopolyprenols (V).
3, Ma Zhen changes the vinyl bromide in the method 2 into chloro ethene, obtains different ten isopolyprenols (V) too.
These three methods all are to introduce a prenyl in eggplant Buddhist nun alcohol, as ubiquinone
10Side chain.But it is that raw material, method 3 will be raw material with lower boiling chloro ethene equally that the United States Patent (USP) of method 2 needs with lower boiling vinyl bromide, has the inconvenience in storage, the transportation during extensive application, and large-scale industrialization is used and had difficulties.1 of method is a more satisfactory method of introducing a prenyl in eggplant Buddhist nun alcohol, but the problem that method 1 exists is: introduce and use liquefied ammonia and sodium Metal 99.5 when ethynyl carries out ethinylation, belong to hazardous substance, and require compressive reaction, not only the technology cost is higher but also use and have tangible safety problem; Can not all reclaim liquefied ammonia during aftertreatment, liquefied ammonia is easily overflowed, and can cause environmental pollution.
Summary of the invention
The purpose of this invention is to provide a kind of ubiquinone
10The synthesis technique of intermediate acetylide improves the ethinylation processing step of aforesaid method 1, the ethinylation technology cost of aforesaid method 1 is reduced, security is good, can not cause environmental pollution.
The technical solution adopted for the present invention to solve the technical problems is: a kind of ubiquinone
10The synthesis technique of intermediate acetylide is that semi-synthesis method is produced ubiquinone
10In the process, obtain the synthesis technique of 3-methyl-eggplant Thessaloniki butine-1-alcohol-3 through ethinylation through the introducing ethynyl by eggplant Thessaloniki acetone, it is characterized in that: described synthesis technique is earlier with proper amount of sodium hydroxide or potassium hydroxide, alcoholic solution and toluene place chemical reaction container, reflux makes it abundant reaction, separate and remove the water of generation, reaction solution cooling back feeds acetylene and its reaction, obtain acetylene reaction liquid, under agitation condition, eggplant Thessaloniki acetone soln is added in the acetylene reaction liquid and reacts, fully the reaction back adds an amount of water, the cooling back adds acid solution and neutralizes, divide water-yielding stratum and organic liquid layer, layer and wash organic liquor with water anhydrates, the organic solvent that is contained in the reheat evaporate to dryness organic liquor obtains 3-methyl-eggplant Thessaloniki butine-1-alcohol-3 at last.
Above-mentioned alcohol can adopt isopropylcarbinol, propyl carbinol etc.
Above-mentioned acid can be adopted sulfuric acid, hydrochloric acid etc.
The reaction process of above-mentioned synthesis technique all can be carried out under normal pressure.
The consumption of above-mentioned reactive material (weight): 0.5～1.5 times of the desirable eggplant Thessaloniki of sodium hydroxide or potassium hydroxide acetone; Alcohol 8～15 times of desirable eggplant Thessaloniki acetone; 10～25 times of the desirable eggplant Thessaloniki of toluene acetone.
Desirable 3～5 hours of the above-mentioned eggplant Thessaloniki acetone soln and the reaction times of acetylene reaction liquid.
The used organic solvent of above-mentioned eggplant Thessaloniki acetone soln can adopt toluene, benzene, ether, tetrahydrofuran (THF) or its mixed solvent.
Beneficial effect of the present invention: because reactive material sodium hydroxide that the ethinylation process is used or potassium hydroxide, pure and mild toluene, all are the stable industrial chemicals commonly used of chemical property, store easily, use and operate that security is better, chemical reaction can carry out under normal pressure, and the technology cost is lower; Reaction process does not have the waste gas effusion, can not cause environmental pollution.
Embodiment
For a more detailed description below in conjunction with embodiment to the present invention.Embodiment all is to a kind of giving an example of the present invention.
Embodiment one:
This ubiquinone
10The synthesis technique of intermediate acetylide is that semi-synthesis method is produced ubiquinone
10Obtain the synthesis technique of 3-methyl-eggplant Thessaloniki butine-1-alcohol-3 in the process, by eggplant Thessaloniki acetone through ethinylation through the introducing ethynyl, it is characterized in that: described synthesis technique be earlier 40 gram sodium hydroxide, 400 milliliters of isopropylcarbinols and 530 milliliters of toluene are placed be furnished with water trap, 2000 milliliters flask of agitator, being heated under stirring refluxes fully reacts it, separate to remove and generate about 18～20 milliliters of water, reaction solution cooling back feeds acetylene gas and its reaction, obtains acetylene reaction liquid behind about 2.5～3 liters of the absorption acetylene.100 ml solns that will be dissolved with 40 gram eggplant Thessaloniki acetone under room temperature, agitation condition are added drop-wise to and react after 5 hours in the acetylene reaction liquid, add 400 milliliters of frozen water, sulphuric acid soln with concentration 30% is neutralized to pH value 7～8 then, divide water-yielding stratum and organic liquid layer, the layer that anhydrates also washs organic liquor twice with 400 ml waters respectively, the organic solvent that is contained in the evaporate to dryness organic liquor obtains about 40 grams of 3-methyl-eggplant Thessaloniki butine-1-alcohol-3 then.
Embodiment two:
This ubiquinone
10The synthesis technique of intermediate acetylide is that semi-synthesis method is produced ubiquinone
10Obtain the synthesis technique of 3-methyl-eggplant Thessaloniki butine-1-alcohol-3 in the process, by eggplant Thessaloniki acetone through ethinylation through the introducing ethynyl, it is characterized in that: described synthesis technique is 150 gram potassium hydroxide, 1200 milliliters of butanols and 1200 milliliters of toluene to be placed to be furnished with water trap and agitator 3000 ml flasks earlier, being heated under stirring refluxes fully reacts it, separate to remove and generate about 60～64 milliliters of water, reaction solution cooling back feeds acetylene gas and its reaction, obtains acetylene reaction liquid behind about 8～10 liters of the absorption acetylene.250 ml solns that will be dissolved with 100 gram eggplant Thessaloniki acetone under room temperature, agitation condition are added drop-wise in the acetylene reaction liquid and reacted 5 hours, import then and fill in 5000 ml beakers of 1000 milliliters of frozen water, and be neutralized to pH value 7～8 with the sulphuric acid soln of concentration 30%, divide water-yielding stratum and organic liquid layer, the layer that anhydrates also washs organic liquor twice with 800 ml waters respectively, the organic solvent that is contained in the evaporate to dryness organic liquor obtains about 100 grams of 3-methyl-eggplant Thessaloniki butine-1-alcohol-3 then.
Embodiment three:
This ubiquinone
10The synthesis technique of intermediate acetylide is that semi-synthesis method is produced ubiquinone
10Obtain the synthesis technique of 3-methyl-eggplant Thessaloniki butine-1-alcohol-3 in the process, by eggplant Thessaloniki acetone through ethinylation through the introducing ethynyl, it is characterized in that: described synthesis technique is earlier 2.5 kilograms of potassium hydroxide, 25 liters of isopropylcarbinols and 58 liters of toluene to be placed the reactor of being furnished with water trap and agitator, reflux is fully reacted it, separate to remove and generate about 0.85～0.9 liter of water, reaction solution cooling back feeds acetylene gas and its reaction, obtains acetylene reaction liquid behind about 125～150 liters of the absorption acetylene.5 liters of solution that will be dissolved with 2 kilograms of eggplant Thessaloniki acetone under room temperature, agitation condition are added to and react after 3 hours in the acetylene reaction liquid, in reactor, add 20 liters of frozen water, and be neutralized to pH value 7～8 with the sulphuric acid soln of concentration 30%, divide water-yielding stratum and organic liquid layer, the layer that anhydrates also washs organic liquor twice with 15 premium on currency respectively, the organic solvent that is contained in the heating evaporate to dryness organic liquor obtains about 2 kilograms of 3-methyl-eggplant Thessaloniki butine-1-alcohol-3 at last.
Claims (10)
1, a kind of ubiquinone
10The synthesis technique of intermediate acetylide is that semi-synthesis method is produced ubiquinone
10In the process, obtain the synthesis technique of 3-methyl-eggplant Thessaloniki butine-1-alcohol-3 through ethinylation through the introducing ethynyl by eggplant Thessaloniki acetone, it is characterized in that: described synthesis technique is earlier with proper amount of sodium hydroxide or potassium hydroxide, alcoholic solution and toluene place chemical reaction container, reflux makes it abundant reaction, separate and remove the water of generation, reaction solution cooling back feeds acetylene and its reaction, obtain acetylene reaction liquid, under agitation condition, eggplant Thessaloniki acetone soln is added in the acetylene reaction liquid and reacts, fully the reaction back adds an amount of water, the cooling back adds acid solution and neutralizes, divide water-yielding stratum and organic liquid layer, layer and wash organic liquor with water anhydrates, the organic solvent that is contained in the reheat evaporate to dryness organic liquor obtains 3-methyl-eggplant Thessaloniki butine-1-alcohol-3 at last.
2, by the described ubiquinone of claim 1
10The synthesis technique of intermediate acetylide is characterized in that the reaction process of described synthesis technique is all carried out under normal pressure.
3, by claim 1 or 2 described ubiquinones
10The synthesis technique of intermediate acetylide is characterized in that the consumption of described reactive material, and by weight, sodium hydroxide or potassium hydroxide are got 0.5～1.5 times of eggplant Thessaloniki acetone, and alcohol is got 8～15 times of eggplant Thessaloniki acetone, and toluene is got 10～25 times of eggplant Thessaloniki acetone.
4, by claim 1 or 2 described ubiquinones
10The synthesis technique of intermediate acetylide is characterized in that the reaction times of described eggplant Thessaloniki acetone soln and acetylene reaction liquid got 3～5 hours.
5, by claim 1 or 2 described ubiquinones
10The synthesis technique of intermediate acetylide is characterized in that the used organic solvent of described eggplant Thessaloniki acetone soln adopts toluene, benzene, ether, tetrahydrofuran (THF) or its mixed solvent.
6, by claim 1 or 2 described ubiquinones
10The synthesis technique of intermediate acetylide is characterized in that described alcohol adopts isopropylcarbinol or propyl carbinol.
7, by claim 1 or 2 described ubiquinones
10The synthesis technique of intermediate acetylide is characterized in that described acid employing sulfuric acid or hydrochloric acid.
8, by claim 1 or 2 described ubiquinones
10The synthesis technique of intermediate acetylide, it is characterized in that described synthesis technique is earlier with 40 gram sodium hydroxide, 400 milliliters of isopropylcarbinols and 530 milliliters of toluene place is furnished with water trap, in 2000 milliliters the flask of agitator, being heated under stirring refluxes fully reacts it, separate to remove and generate about 18～20 milliliters of water, reaction solution cooling back feeds acetylene gas and its reaction, obtain acetylene reaction liquid after absorbing about 2.5～3 liters of acetylene, in room temperature, 100 ml solns that will be dissolved with 40 gram eggplant Thessaloniki acetone under the agitation condition are added drop-wise to and react after 5 hours in the acetylene reaction liquid, add 400 milliliters of frozen water, sulphuric acid soln with concentration 30% is neutralized to pH value 7～8 then, divide water-yielding stratum and organic liquid layer, the layer that anhydrates also washs organic liquor twice with 400 ml waters respectively, the organic solvent that is contained in the evaporate to dryness organic liquor obtains about 40 grams of 3-methyl-eggplant Thessaloniki butine-1-alcohol-3 then.
9, by claim 1 or 2 described ubiquinones
10The synthesis technique of intermediate acetylide, it is characterized in that described synthesis technique is earlier with 150 gram potassium hydroxide, 1200 milliliters of butanols and 1200 milliliters of toluene place is furnished with water trap and agitator 3000 ml flasks, being heated under stirring refluxes fully reacts it, separate to remove and generate about 60～64 milliliters of water, reaction solution cooling back feeds acetylene gas and its reaction, obtain acetylene reaction liquid after absorbing about 8～10 liters of acetylene, in room temperature, 250 ml solns that will be dissolved with 100 gram eggplant Thessaloniki acetone under the agitation condition are added drop-wise in the acetylene reaction liquid and reacted 5 hours, import then and fill in 5000 ml beakers of 1000 milliliters of frozen water, and be neutralized to pH value 7～8 with the sulphuric acid soln of concentration 30%, divide water-yielding stratum and organic liquid layer, the layer that anhydrates also washs organic liquor twice with 800 ml waters respectively, the organic solvent that is contained in the evaporate to dryness organic liquor obtains about 100 grams of 3-methyl-eggplant Thessaloniki butine-1-alcohol-3 then.
10, by claim 1 or 2 described ubiquinones
10The synthesis technique of intermediate acetylide, it is characterized in that described synthesis technique is earlier with 2.5 kilograms of potassium hydroxide, 25 liters of isopropylcarbinols and 58 liters of toluene place the reactor of being furnished with water trap and agitator, reflux is fully reacted it, separate to remove and generate about 0.85～0.9 liter of water, reaction solution cooling back feeds acetylene gas and its reaction, obtain acetylene reaction liquid after absorbing about 125～150 liters of acetylene, in room temperature, 5 liters of solution that will be dissolved with 2 kilograms of eggplant Thessaloniki acetone under the agitation condition are added to and react after 3 hours in the acetylene reaction liquid, in reactor, add 20 liters of frozen water, and be neutralized to pH value 7～8 with the sulphuric acid soln of concentration 30%, divide water-yielding stratum and organic liquid layer, the layer that anhydrates also washs organic liquor twice with 15 premium on currency respectively, the organic solvent that is contained in the heating evaporate to dryness organic liquor obtains about 2 kilograms of 3-methyl-eggplant Thessaloniki butine-1-alcohol-3 at last.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005101006148A CN1314642C (en) | 2005-10-20 | 2005-10-20 | Art for synthesizing acetylide of coenzyme Q10 intermediate |
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| CNB2005101006148A CN1314642C (en) | 2005-10-20 | 2005-10-20 | Art for synthesizing acetylide of coenzyme Q10 intermediate |
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| CN1757621A CN1757621A (en) | 2006-04-12 |
| CN1314642C true CN1314642C (en) | 2007-05-09 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5498707A (en) * | 1978-01-13 | 1979-08-03 | Kawaken Fine Chem Co Ltd | Preparation of ethynyl alcohol |
| US6686485B2 (en) * | 2001-04-19 | 2004-02-03 | Daniel David West | Synthesis of coenzyme Q10, ubiquinone |
| CN1546445A (en) * | 2003-12-05 | 2004-11-17 | 浙江大学 | Method for synthesizing deca-isoprene alcohol |
-
2005
- 2005-10-20 CN CNB2005101006148A patent/CN1314642C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5498707A (en) * | 1978-01-13 | 1979-08-03 | Kawaken Fine Chem Co Ltd | Preparation of ethynyl alcohol |
| US6686485B2 (en) * | 2001-04-19 | 2004-02-03 | Daniel David West | Synthesis of coenzyme Q10, ubiquinone |
| CN1546445A (en) * | 2003-12-05 | 2004-11-17 | 浙江大学 | Method for synthesizing deca-isoprene alcohol |
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| CN1757621A (en) | 2006-04-12 |
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