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Synthesis method of probucol

A synthetic method, the technology of probucol, which is applied in the field of synthesis of raw material probucol, can solve the problems of low yield, low product purity, insufficient purity, etc., and achieve reduced product cost, high product purity, and improved yield Effect

Active Publication Date: 2014-03-19
山东安弘制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction mechanism of this method is similar to method 1, and there are also situations where the yield is not high and the purity is insufficient
Although it is mentioned in CN10142348A that the yield can reach 90%, the yield data is not accurate because it is prepared by "one pot method", and there is no yield and purity of the product in its examples
According to the experimental verification, the yield of this step is actually only about 70% and the purity of the product obtained according to this method is low

Method used

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  • Synthesis method of probucol
  • Synthesis method of probucol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Raw material 2, 47.7g (0.2mol) of 6-di-tert-butyl-4-mercaptophenol solid (I) was added to a 0.5L autoclave, then 76g of methanol and 21.6g of sodium methoxide (0.40mol) were added, heated Stir to 50°C to dissolve, continue to heat to 60°C, pass through propyne to maintain a pressure of 1MPa, stir and react for 3 hours, then release the pressure, transfer the material liquid into a 500ml five-necked flask, add 2,6-di-tert Butyl-4-mercaptophenol 47.7g (0.2mol), add 35% hydrochloric acid under stirring to make the pH ≤ 1, heat to 60-65°C, keep warm for 1h, cool down to 5-15°C, stir for 4-6h, filter with suction , the crude probucol was obtained, washed with water, refined with 95% ethanol, and vacuum-dried to obtain 96.9 g of pure probucol, with a total yield of 93.8% and an HPLC purity of 99.90%. mp 125-126°C.

[0031] Product elemental analysis (%): The measured value C is 71.96, H is 9.44, and S is 12.36; the theoretical value C is 72.04, H is 9.36, and S is 12.41. IR ...

Embodiment 2

[0033] As described in Example 1, the difference is that the volume of the reaction vessel used is doubled, and the influence of the amount of alkyne on the reaction is investigated.

[0034] Add 47.7g (0.2mol) of 2,6-di-tert-butyl-4-mercaptophenol into a 1.0L autoclave, add 76g of methanol and 21.6g (0.4mol) of sodium methoxide, heat to 50°C and stir to dissolve the raw materials , continue heating to 60°C, pass in propyne, and maintain a pressure of 1MPa, release the pressure after stirring for 3 hours, transfer it to a 500ml five-necked flask, and then add 2,6-di-tert-butyl-4-mercaptophenol 47.7 g (0.2mol), heat to 60°C and stir to dissolve, add 35% hydrochloric acid to adjust pH=0.8, continue to heat to 60-65°C, keep warm for 1h, cool down to 5-15°C and stir for 4-6h, suction filter, wash with water After refining with 95% ethanol and vacuum drying, 97.6g of probucol was obtained, with a total yield of 94.5% and a purity of 99.93% by HPLC.

Embodiment 3

[0036] As described in Example 2, the difference is: replace the 76g methanol in Example 2 with 110g ethanol, and replace the sodium methylate in Example 2 with 26.4g (0.4mol) sodium ethylate. Finally, 94.0 g of probucol was obtained, the total yield was 90.9%, and the HPLC purity was 99.93%.

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Abstract

The invention relates to a synthesis method of probucol. The method comprises the following steps of: reacting 2,6-di-tert-butyl-4-mercaptophenol used as a starting material with allylene through pressurization under the catalysis of alkaline conditions, and then reacting the obtained olefin intermediate with 2,6-di-tert-butyl-4-mercaptophenol under the catalysis of a strong acid so as to obtain a product probucol. The method disclosed by the invention is simple in operation, high in product yield and good in purity.

Description

technical field [0001] The invention relates to a synthesis method of raw material probucol and belongs to the technical field of medicinal chemistry. Background technique [0002] Probucol (C 31 h 48 o 2 S 2 ) has the functions of regulating blood fat, preventing atherosclerosis and anti-lipid peroxidation, and its blood fat-lowering and anti-oxidation effects are remarkable, with little toxic and side effects. [0003] At present, the synthetic method of probucol mainly contains following two kinds: [0004] Method 1, using 2,6-di-tert-butyl-4-mercaptophenol as a raw material, using methanol as a solvent to condense with acetone under the catalysis of hydrochloric acid; The yield of the method is only 70%, and the highest yield reported in US2008119672 and EP1849768 is only 82%. [0005] Method 2. Probucol is prepared by condensation of 2,6-di-tert-butyl-4-mercaptophenol and 2,2-dimethoxypropane under acidic conditions, see CN10142348A. The reaction mechanism of thi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C323/20C07C319/18
Inventor 杨英英汤沸刘朝建冯宪东赵卫良
Owner 山东安弘制药有限公司