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A technology of reaction time and compound, applied in the direction of organic chemistry, etc., can solve the problems of cumbersome post-processing, cumbersome post-processing, low yield, etc., and achieve the effects of eliminating high-temperature and high-pressure reactions, cheap and easily available raw materials, and simple reaction conditions.
Active Publication Date: 2011-06-08
XUZHOU WANBANG JINQIAO PHARMA +1
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[0008] In the technology of above-mentioned preparation formula (I), formula (II), formula (III) compound, following shortcoming is arranged: (1) take polyphosphoric acid as solvent, it can produce polymerization and become viscous in reaction process, does not It is beneficial to stirring, and the yield is low, which is not conducive to industrial production; (2) by hydrogen sulfide as a raw material pressurized preparation process, because hydrogen sulfide high-pressure reaction is very dangerous, it is not conducive to industrial production; (3) using phoxim and p-cyanophenol Reaction and thioacetamide and p-cyanophenol react in HCl / DMF, and the reaction time is long, and aftertreatment is loaded down with trivial details, and yield is not high, and production cost is higher; (4) in the technique for preparing compound (I), with multiple Polyphosphoric acid is a solvent, which becomes viscous as the reaction proceeds at high temperature, which is unfavorable for stirring, and the yield is low, which is unfavorable for industrial production; (5) the yield of each compound is all low
This method uses HCl / DMF as the reaction solvent system, avoids the use of hydrogen sulfide, and the yield is greatly improved, but the reaction cycle is long, the post-treatment is cumbersome, and the recovery and treatment cost is high
Method used
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Embodiment 1
[0049] In a 3L reaction flask, add 1200ml of concentrated hydrochloric acid (concentration: 12mol / L), under stirring, add 92g of thioacetamide, wait until it is completely dissolved, then add 96g of p-cyanophenol, and react with stirring at 40°C for 0.5 hours, A large amount of light yellow solid precipitated, and the reaction was continued for 3 hours, the reaction was stopped, cooled, a large amount of solid precipitated, filtered, the filter cake was rinsed with a small amount of water, and 112.2 g of the product was obtained after drying. Yield: 91.0%.
Embodiment 2
[0051] In a 0.5L reaction flask, add 300ml of dilute hydrochloric acid (concentration: 6mol / L), under stirring, add 28g of thioacetamide, wait until it is completely dissolved, then add 24g of p-cyanophenol, and stir for 3 hours at 50°C. After stopping the reaction, cooling, a large amount of solids precipitated out, suction filtered, and the filter cake was washed with a small amount of water to obtain 41.8 g of the product with a water content of 35.1%. Yield: 88.3%.
Embodiment 3
[0053] In a 100ml reaction bottle, add 40ml of 50% concentrated sulfuric acid, under stirring, add 8.9g of thioacetamide, after the dissolution is complete, then add 9.6g of p-cyanophenol, stir and react at 60°C for 5 hours, stop the reaction, and cool , a large amount of solids were precipitated, filtered, the filter cake was rinsed with a small amount of water, filtered with suction, and dried to obtain 9.7 g of the product. HPLC: 98.9%, yield: 78.8%.
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Abstract
The invention relates to a preparation method of important intermediates, such as 2-(3-formaldehyde radical-4-hydroxyl phenyl)-4-methyl-5-thiazole ethyl formate, of Febuxostat. The method is as follows: reacting thioacetamide and 4-cyanol phenol which are used as raw materials in concentrated hydrochloric acid solution to obtain 4-hydroxythiobenzamide; reacting 4-hydroxythiobenzamide with 2-chloracetyl ethyl acetate to prepare 2-(4-hydroxyl phenyl)-4-methyl-5-thiazole ethyl formate; and reacting 2-(4-hydroxyl phenyl)-4-methyl-5-thiazole ethyl formate with hexamethylenetetramine in the presence of polyphosphoric acid and methanesulfonic acid to obtain 2-(3-formaldehyde radical-4-hydroxyl phenyl)-4-methyl-5-thiazole ethyl formate. In the invention, the operation is simple and convenient, the yield is high, the preparation process is stable, and the production cost is low, thus the preparation method is suitable for industrial production and application.
Description
Technical field: [0001] The invention relates to the field of medicinal chemistry, in particular to 4-hydroxythiobenzamide (III), 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester (II), 2-(3 - a preparation method of ethyl formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (I), which are all important intermediates for preparing the anti-hyperuricemia drug febuxostat. technical background: [0002] 4-Hydroxythiobenzamide (III), ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (II), 2-(3-formyl-4-hydroxyphenyl )-4-methyl-5-thiazole ethyl carboxylate (I) is an important intermediate in the process of synthesizing the anti-hyperuricemia drug febuxostat. [0003] [0004] There are many literatures and patents on the preparation methods of the compounds of formula (I), formula (II) and formula (III). [0005] Japanese Patent JP11060552 reported that compound (III) was prepared by reacting p-cyanophenol and thioacetamide in polyphosphoric a...
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