CN101423484A - A kind of preparation method of probucol raw material medicine - Google Patents
A kind of preparation method of probucol raw material medicine Download PDFInfo
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- CN101423484A CN101423484A CNA2008101477991A CN200810147799A CN101423484A CN 101423484 A CN101423484 A CN 101423484A CN A2008101477991 A CNA2008101477991 A CN A2008101477991A CN 200810147799 A CN200810147799 A CN 200810147799A CN 101423484 A CN101423484 A CN 101423484A
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Abstract
The present invention relates to a kind of preparation method of probucol raw material medicine, specifically by 2, the method for the synthetic probucol of 6-di-t-butyl-4-mercapto-phenol.It comprises following processing step: (1) through 2 of the reduction gained, 6-di-t-butyl-4-mercapto-phenol toluene liquid is not treated to be directly used in next step reaction; (2) in toluene liquid, add 2,2-Propanal dimethyl acetal and solid acid catalyst, insulation reaction; (3) reaction is used sodium hydrogen carbonate solution and saturated common salt water washing successively with reaction solution after finishing, and boils off solvent after the drying and promptly gets the probucol crude product; (4) the probucol crude product is made with extra care the pure product of probucol that obtain with 95% ethanol.The present invention compared with prior art, this step condensation reaction can coexist with first two steps reactions and carry out in the toluene, operates simplyr, equipment requirements still less.Adopt 2 simultaneously, the 2-Propanal dimethyl acetal is as ketal reagent and use the solid acid as catalyst, and the yield of this reaction is brought up to more than 90%.
Description
[technical field]
That the present invention relates to is the preparation method of probucol raw material medicine, is specifically synthesized the method for probucol by 2,6-di-t-butyl-4-mercapto-phenol.
[background technology]
Probucol (Probucol, C
31H
48O
2S
2) be a kind of hypolipidemic commonly used, with promoting the cholesterol decomposition blood cholesterol and low-density lipoprotein (LDL) are reduced by reducing cholesterol is synthetic.Though it can make the concentration of high density lipoprotein cholesterol (HDL) reduce, and has powerful study of anti-atherogenic effect, can suppress the formation of foam cell, delays the formation of atherosclerotic plaque, established atherosclerotic plaque disappears.Simultaneously it also has effects such as powerful anti-oxidant, anti-ageing, treatment of vascular shaping postoperative restenosis.
The preparation method of probucol substantially is to be raw material with 2,6-DI-tert-butylphenol compounds, gets this product with the condensation of ketal reagent again after making intermediate 2,6-di-t-butyl-4-mercapto-phenol.Synthetic about intermediate 2,6-di-t-butyl-4-mercapto-phenol, the method for description such as US5401883, EP0468581 is former thereby be difficult to mass production owing to relating to pressure hydration or complex operation etc.US3479407 provides a kind of and has obtained two (3,5-di-tert-butyl-hydroxy phenyl) disulphide by 2,6-DI-tert-butylphenol compounds and the condensation of sulfur monochloride elder generation, be the method for 2,6-di-t-butyl-4-mercapto-phenol again with zinc powder reduction, this method reactions steps is few, mild condition, with low cost.Patent CN1228419 and WO2006082950 make the probucol finished product with condensation of acetone after adopting this method to make 2,6-di-t-butyl-4-mercapto-phenol again under the katalysis of concentrated hydrochloric acid.Because this condensation reaction is a balanced reaction, add that the catalyzer concentrated hydrochloric acid also can be with a spot of water to enter reaction system, this makes that the yield of this step reaction is not high enough, is 70% as the yield of CN1228419 report, the highest yield that W02006082950 reports is 82%.Two in addition (3,5-di-tert-butyl-hydroxy phenyl) disulphide toluene mutually in by zinc powder reduction after gained 2,6-di-t-butyl-4-mercapto-phenol toluene liquid also must could be dissolved in another kind of solvent methanol again and carry out next step condensation reaction after washing, drying, distillation obtain solid crude product, operate more loaded down with trivial detailsly, the production cycle is longer.
[summary of the invention]
Purpose of the present invention is exactly that a kind of easy and simple to handle, mild condition, the method for preparing probucol that yield is higher will be provided, and it is characterized in that comprising following processing step:
(1) two (3,5-di-tert-butyl-hydroxy phenyl) disulphide toluene mutually in by zinc powder reduction after gained 2, the toluene liquid of 6-di-t-butyl-4-mercapto-phenol is separated with sour water in the reaction, and the oil phase that obtains is not treated to be directly used in next step reaction;
(2) in toluene liquid, add 2,2-Propanal dimethyl acetal and solid acid catalyst, insulation reaction;
(3) reaction is used sodium hydrogen carbonate solution and saturated common salt water washing successively with reaction solution after finishing, and boils off solvent after the siccative drying and promptly obtains the probucol crude product;
(4) the probucol crude product is made with extra care the pure product of probucol that obtain with 95% ethanol.
Described chemical equation is as follows:
Above-mentioned preparation technology's temperature of reaction is 25～70 ℃, and the best is 40～60 ℃.
Described solid acid catalyst comprises tosic acid and oxalic acid.
Described reactant 2,6-di-t-butyl-4-mercapto-phenol: 2, the 2-Propanal dimethyl acetal: the ratio of the amount of substance of acid catalyst is 1:(0.5～4.0): (0.01～1), best ratio is 1:(0.7～1.5): (0.05～0.2).
The concentration of described sodium hydrogen carbonate solution is 5%～10%.
The present invention compared with prior art, the condensation reaction in this step can coexist with the condensation of first two steps and reduction reaction and carry out in the toluene solvant, has realized " treating different things alike ", operate simpler, equipment requirements still less, the production cycle is shorter.In condensation one step, adopt 2, the 2-Propanal dimethyl acetal as ketal reagent and with solid acid as catalyzer, make yield that this step reacts by the highest 82% the bringing up to more than 90% of document.
[embodiment]
Example 1
Through reduction reaction make 2,6-di-t-butyl-4-mercapto-phenol toluene liquid 150mL (contains 2,6-di-t-butyl-4-mercapto-phenol 51.1g) add 2 in, 2-Propanal dimethyl acetal 32.0mL, tosic acid 3.0g edge up after the stirring and dissolving under the room temperature to 60 ℃ of reactions.Thin-layer chromatography shows feedstock conversion back stopped reaction fully.Reaction solution is chilled to sodium hydrogen carbonate solution and the saturated common salt water washing of using 50mL5% after the room temperature successively, pressure reducing and steaming toluene promptly gets the probucol crude product behind the anhydrous sodium sulfate drying, obtain the pure product of probucol, yield 90%, m.p.121-124 ℃ with 95% ethyl alcohol recrystallization.
Example 2
Through reduction reaction make 2,6-di-t-butyl-4-mercapto-phenol toluene liquid 4.0L (contains 2,6-di-t-butyl-4-mercapto-phenol 1.36kg) adds toluene 2.0L in, add 2 behind the stirring and evenly mixing, 2-Propanal dimethyl acetal 190.0mL and tosic acid 20.0g edge up after the stirring and dissolving under the room temperature to 60 ℃ of reactions.Thin-layer chromatography shows feedstock conversion back stopped reaction fully.Reaction solution is chilled to sodium hydrogen carbonate solution and the saturated common salt water washing of using 1.5L 5% after the room temperature successively, pressure reducing and steaming toluene promptly gets the probucol crude product behind the anhydrous sodium sulfate drying, obtain the pure product of probucol, yield 90%, m.p.121-124 ℃ with 95% ethyl alcohol recrystallization.
Example 3
Through reduction reaction make 2,6-di-t-butyl-4-mercapto-phenol toluene liquid 100mL (contains 2,6-di-t-butyl-4-mercapto-phenol 34.0g) add 2 in, 2-Propanal dimethyl acetal 20.0mL, oxalic acid 1.5g edge up after the stirring and dissolving under the room temperature to 60 ℃ of reactions.Thin-layer chromatography shows feedstock conversion back stopped reaction fully.Reaction solution is chilled to sodium hydrogen carbonate solution and the saturated common salt water washing of using 30mL5% after the room temperature successively, pressure reducing and steaming toluene promptly gets the probucol crude product behind the anhydrous sodium sulfate drying, obtain the pure product of probucol, yield 90%, m.p.121-124 ℃ with 95% ethyl alcohol recrystallization.
Claims (7)
1, a kind of preparation method of probucol raw material medicine is characterized in that comprising following processing step:
(1) two (3,5-di-tert-butyl-hydroxy phenyl) disulphide toluene mutually in by zinc powder reduction after the toluene liquid of 2,6-di-t-butyl-4-mercapto-phenol of gained and the sour water of reaction be separated, the oil phase that obtains is not treated to be directly used in down-to go on foot reaction; (2) in toluene liquid, add 2,2-Propanal dimethyl acetal and solid acid catalyst, insulation reaction; (3) reaction is used sodium hydrogen carbonate solution and saturated common salt water washing successively with reaction solution after finishing, and boils off solvent after the siccative drying and promptly gets the probucol crude product; (4) the probucol crude product is made with extra care the pure product of probucol that obtain with 95% ethanol.
2, the preparation method of probucol raw material medicine according to claim 1 is characterized in that the used solvent of this step condensation reaction is a toluene, and go up the crude product oil phase of step reduction reaction gained can be not treated and be directly used in this step and react.
3, the preparation method of probucol raw material medicine according to claim 1 is characterized in that described ketal reagent is 2, the 2-Propanal dimethyl acetal.
4, the preparation method of probucol raw material medicine according to claim 1 is characterized in that described solid acid catalyst is tosic acid or oxalic acid.
5, the preparation method of probucol raw material medicine according to claim 1, it is characterized in that the reaction in 2,6-di-t-butyl-4-mercapto-phenol: 2, the 2-Propanal dimethyl acetal: the ratio of the amount of substance of acid catalyst is 1:(0.5～4.0): (0.01～1), best ratio is 1:(0.7～1.5): (0.05～0.2).
6, the preparation method of probucol raw material medicine according to claim 1, the temperature that it is characterized in that condensation reaction is 25～70 ℃, the best is 40～60 ℃.
7, the preparation method of probucol raw material medicine according to claim 1, the concentration that it is characterized in that used sodium hydrogen carbonate solution is 5%～10%.
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| CNA2008101477991A CN101423484A (en) | 2008-12-09 | 2008-12-09 | A kind of preparation method of probucol raw material medicine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103145595A (en) * | 2013-04-01 | 2013-06-12 | 齐鲁安替（临邑）制药有限公司 | Synthesis method of probucol |
| CN105001129A (en) * | 2015-08-18 | 2015-10-28 | 齐鲁安替（临邑）制药有限公司 | High-yield probucol refining crystallization method |
-
2008
- 2008-12-09 CN CNA2008101477991A patent/CN101423484A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103145595A (en) * | 2013-04-01 | 2013-06-12 | 齐鲁安替（临邑）制药有限公司 | Synthesis method of probucol |
| CN105001129A (en) * | 2015-08-18 | 2015-10-28 | 齐鲁安替（临邑）制药有限公司 | High-yield probucol refining crystallization method |
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