Process for preparing sulindac

A technology of sulindac and indene acetic acid is applied in the preparation of organic compounds, chemical instruments and methods, organic chemistry and other directions, which can solve the problems of increased COD in wastewater, incomplete reaction, and generation of impurities, and achieves reduction in production cost and reaction time. Short, small amount of impurities produced

Inactive Publication Date: 2005-11-23
ZHEJIANG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is that the second step needs to use noble metal Pd to catalyze hydrogenation; the third step uses a large amount of polyphosphoric acid to form a ring, and water is added after the reaction, resulting in a large amount of phosphorus-containing wastewater, and the reaction is not complete, and impurities are generated, and the product is not good. Pure; the fifth step uses a large amount of methanol solution of sodium methoxide, and after the reaction is completed, it is added to water. A large amount of methanol cannot be reused, and the COD of the wastewater is greatly increased; the last step uses expensive sodium periodate as an oxidant, and the cost is high

Method used

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  • Process for preparing sulindac

Examples

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Embodiment 1

[0025] Preparation of 2-(4-fluorophenyl)-2-methylmalonic acid

[0026] Add 100g of industrial sodium methoxide solution into a 1000ml reaction bottle, then add 100g of anhydrous methanol, heat to reflux, slowly add 72.7g (0.417mol) diethyl methylmalonate dropwise, after the dropwise addition is complete, reflux for 45min, Add 59.8g (0.414mol) of p-fluorobenzyl chloride dropwise, and reflux for about 4.5 hours after dropping. The end point of the reaction is detected by TLC. After the reaction is completed, anhydrous methanol is recovered, and 220 g of 25% KOH solution is added to the above-mentioned reactor, and the reaction is refluxed for about 9 hours. Adjust the pH to 1 with concentrated hydrochloric acid, extract three times with dichloromethane, and concentrate to obtain 75.2 g of off-white solid, mp.138.5-139.5°C, two-step molar yield 80.6%.

[0027] Preparation of 3-(4-fluorophenyl)-2-methylpropionic acid

[0028] Put 75.2g of the off-white solid obtained in the previ...

Embodiment 2

[0041] Preparation of 2-(4-fluorophenyl)-2-methylmalonic acid

[0042] Industrial sodium ethoxide was used instead of sodium methoxide, 100 g of absolute ethanol was used instead of absolute methanol as the solvent, and the rest was the same as in Example 1 to obtain 75.3 g of an off-white solid with a two-step molar yield of 80.7%.

[0043] Preparation of 3-(4-fluorophenyl)-2-methylpropionic acid

[0044] Put 75.3 g of the off-white solid obtained in the previous step into a 250 ml four-necked bottle equipped with a reflux tube and a drying tube, stir and heat up to 145° C., react for 1.5 h, and the rest are the same as in Example 1.

[0045] Preparation of 6-fluoro-2-methylindanone

[0046] Replace 54.6g of anhydrous aluminum trichloride with 55.8g of anhydrous zinc chloride, all the other are the same as in embodiment 1, obtain off-white solid 40.2g, mp.34~34.5 ℃.

[0047] Preparation of 5-fluoro-2-methyl-3-indeneacetic acid

[0048] Example 1 After refluxing for 12 hour...

Embodiment 3

[0053] Preparation of 2-(4-fluorophenyl)-2-methylmalonic acid

[0054] Sodium tert-butoxide was used instead of sodium methoxide, 100 g of tert-butanol was used instead of anhydrous methanol as the solvent, and the rest were the same as in Example 1 to obtain 75.5 g of off-white solid with a two-step molar yield of 80.8%.

[0055] Preparation of 3-(4-fluorophenyl)-2-methylpropionic acid

[0056] Put 75.5 g of the off-white solid obtained in the previous step into a 250 ml four-necked bottle equipped with a reflux tube and a drying tube, stir and raise the temperature to 155° C., react for 1.0 h, and the rest are the same as in Example 1.

[0057] Preparation of 6-fluoro-2-methylindanone

[0058] Carbon disulfide was used instead of dichloromethane as the cyclization solvent, and the rest was the same as in Example 1 to obtain 40.8 g of off-white solid.

[0059] Preparation of 5-fluoro-2-methyl-3-indeneacetic acid

[0060] Embodiment 1 adds cyanoacetic acid and ammonium acet...

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Abstract

The invention discloses a process for preparing sulindac comprising the steps of, condensating 4-fluorobenzyl chloride and diethyl methylmalonate at the presence of organic base, obtaining 2-(4-fluorobenzyl)-2-diethyl methylmalonate, hydrolyzing in aqueous alkali to obtain 2-(4-fluorobenzyl)-2-methyl malonic acid, carrying out decarboxylation directly under high temperature to obtain 3-(4-fluorophenyl)-2-methylpropanoic acid, chlorinating with sulfoxide acyl chloride, then using aluminium trichloride or waterless zinc chloride as catalyst, carrying out F-C acylation to obtain 6-fluoro-2-methylindanone, condensing with cyanocetic acid, hydrolyzing to obtain 5-fluoro-methyl-3-indenes acetic acid, then condensing with p-methylthiobenzaldehyde to obtain 5-fluoro-2-methyl-1-(4-methylthiobenzal)-3-indenes acetic acid, finally using organic acid as solvent, peracid or hydroperoxide as oxidation agent to obtain the sulindac.

Description

technical field [0001] The invention relates to a preparation method of non-steroidal anti-inflammatory drug sulindac. Background technique [0002] The main preparation method of existing sulindac (world patent WO9747295, WO9747303, WO9603987, U.S. patent US5902827, US5776962, European patent EP508586 etc.) is: the first step is starting raw material with p-fluorobenzaldehyde, under alkaline condition and Propionic anhydride is condensed to obtain p-fluoro-α-methylcinnamic acid; the second step is to use 5% Pd / C catalytic hydrogenation of p-fluoro-α-methyl cinnamic acid in ethanol to obtain p-fluoro-α-methylhydrocinnamic acid; In the third step, fluoro-α-methylhydrocinnamic acid is formed into a ring in the presence of a large amount of polyphosphoric acid to obtain 6-fluoro-2-methylindanone; the fourth step is 6-fluoro-2-methylindanone and cyanide Condensation and hydrolysis of acetic acid to produce 5-fluoro-2-methyl-3-indene acetic acid; the fifth step is 5-fluoro-2-met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C317/44
Inventor 戴立言洪芳王晓钟陈英奇
Owner ZHEJIANG UNIV
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