Synthesis method of tolfenamic acid

A synthetic method, the technology of tolfenamic acid, applied in the field of drug synthesis, can solve the problems of cumbersome refining process, low product yield, and difficult operation, and achieve the effects of high yield, convenient purification treatment, and simple operation

Inactive Publication Date: 2012-11-21
QINGDAO AGRI UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] This route uses relatively cheap reagents o-chlorobenzoic acid and 3-chloro-2-methylaniline as starting materials, but uses DMF as a solvent, which has a relatively high boiling point and high toxicity, and needs to be evaporated to dryness after the reaction The DMF solvent with a high boiling point is difficult to operate, and the method of evaporating the solvent to dryness does not separate impurities and products, resulting in cumbersome subsequent product refining processes and low product yields

Method used

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  • Synthesis method of tolfenamic acid
  • Synthesis method of tolfenamic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Step 1. Weigh 157g of o-chlorobenzoic acid and 40g of sodium hydroxide into 600mL of methyl isobutyl ketone, and heat to reflux for 0.5 h.

[0033] Step 2. Weigh 142 g of 3-chloro-2-methylaniline, 90 g of sodium acetate and 1 g of copper acetate into the reaction mixture obtained in the previous step, heat to reflux for 3 h, then cool, add 500 mL of water to extract , liquid separation, acidify the aqueous phase with concentrated hydrochloric acid to PH=2, continue to stir for 1h to crystallize, filter, the filter cake is the crude product of tolfenamic acid, and recrystallize the crude product of tolfenamic acid with ethanol / water mixed solvent to obtain tolfenamic acid Namic acid refined product 215g, yield 82%.

Embodiment 2

[0035] Step 1. Weigh 157g of o-chlorobenzoic acid and 40g of sodium hydroxide into 600mL of methyl isobutyl ketone, and heat to reflux for 0.5 h.

[0036] Step 2. Weigh 142 g of 3-chloro-2-methylaniline, 84 g of sodium bicarbonate and 1 g of copper powder and add them to the reaction mixture obtained in the previous step, heat to reflux for 4 h, then cool, and add 500 mL of water Extraction, liquid separation, acidify the aqueous phase with concentrated hydrochloric acid to PH = 2, continue to stir for 1h to crystallize, filter, the filter cake is the crude tolfenamic acid, recrystallize the crude tolfenamic acid with ethanol / water mixed solvent to obtain Fenamic acid refined product 209g, yield 80%.

Embodiment 3

[0038] Step 1. Weigh 157g of o-chlorobenzoic acid and 66g of potassium hydroxide into 600mL of methyl isobutyl ketone, and heat to reflux for 0.5 h.

[0039] Step 2. Weigh 156 g of 3-chloro-2-methylaniline, 118 g of potassium acetate and 1.5 g of cuprous bromide and add them to the reaction mixture obtained in the previous step reaction, heat and reflux for 3 h, then cool and add Extract with 500mL water, separate the liquids, acidify the aqueous phase with concentrated hydrochloric acid to PH=2, continue to stir for 1h to crystallize, filter, the filter cake is the crude tolfenamic acid, recrystallize the crude tolfenamic acid with methanol to obtain tolfenamic acid Acid refined product 191g, yield 73%.

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Abstract

The invention provides a synthesis method of tolfenamic acid, and belongs to the field of medicament synthesis. According to the technical scheme, the synthesis method comprises the following steps of: adding o-chlorobenzoic acid and alkali metal hydroxide into methyl isobutyl ketone; heating and raising temperature for reaction; adding 3-chloro-2-methylaniline, an acid-binding agent and a catalyst into mixture; heating to react; performing extraction, acidification and filtration to obtain a tolfenamic acid rough product; and recrystalizing the rough product to obtain the tolfenamic acid refined product. The method has the advantages of easiness in operation, easiness in implementation of industrial production, high yield, low cost, safety and environmental friendliness.

Description

[0001] technical field [0002] The invention belongs to the field of drug synthesis, in particular to a method for synthesizing tolfenamic acid. Background technique [0003] The English name of tolfenamic acid is Tolfenamic Acid, and its chemical name is 2-[(3-chloro-2-methylphenyl)amino]benzoic acid. Its structural formula is as follows: [0004] [0005] Tolfenamic acid was developed by Danish GEA Pharmaceutical Co., Ltd. and is a widely used non-steroidal anti-inflammatory drug. In May 1983, Japan's Dongling Pharmaceutical Industry launched Clotam as a human medicine for joint pain and migraine. At present, the main manufacturers in the foreign market are French and Canadian Vetoquinol companies. The products are tablets and injections, and the trade name is TOLFEDINE. Tolfenamic acid was listed by Vetoquinol in 1994 for veterinary clinical use. It is mainly used for anti-inflammatory, antipyretic and analgesic treatment of dogs and cats. Recently, there are also r...

Claims

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Application Information

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IPC IPC(8): C07C229/58C07C227/08
Inventor 郝智慧林扬贾德强姚德勇沈魏张瑞丽王艳玲
Owner QINGDAO AGRI UNIV
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