Aceclofenac preparation method

A technology of aceclofenac and acid hydrolysis, which is applied in the preparation of organic compounds, chemical instruments and methods, and preparation of cyanide reactions, etc., can solve the problems of poor purity of crude products, difficulty in controlling the degree of acid hydrolysis, and difficulty in obtaining it. Achieve the effect of high selectivity, high conversion rate and easy refining

Active Publication Date: 2013-05-08
HENAN DONGTAI PHARM
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AI Technical Summary

Problems solved by technology

Extremely difficult to remove, affecting the purity of the product
It can be seen from comprehensive existing literature that aceclofenac tert-butyl is easy to prepare and the yield is relatively high, but when the tert-butyl group is removed by acidification, it is difficult to obtain a purer product, sometimes even a mixture, vinegar Clofenac tert-butyl ester has poor specificity for removing tert-butyl group by acidification method, because aceclofenac tert-butyl ester has two alkoxy centers that can be broken, namely tert-butoxyl and ethoxyl. , in which the tert-butoxy group is easier to be broken by acid hydrolysis than the ethoxy group, and the obtained product is aceclofenac, but the ethoxy group can also be broken, and the obtained product is diclofenac
At the same time, aceclofenac can further undergo ethoxyl breakage to generate diclofenac as well. It has been proved by experiments that the acid hydrolysis reaction of aceclofenac tert-butyl ester is affected by the type of acid used, the concentration of the acid, the reaction temperature, and the acid hydrolysis reaction. Affected by factors such as time, the degree of acidolysis is difficult to control. As long as the intensity of acidolysis is large enough, under certain conditions, aceclofenac tert-butyl ester and aceclofenac will be completely acidolyzed, and the final products will all be diclofenac. Under the existing acid hydrolysis process conditions, the purity of the obtained crude product is very poor, which brings great difficulties to post-processing, especially aceclofenac and diclofenac have similar properties, and it is difficult to separate them by ordinary methods, and they often have to go through a complicated refining process. Obtain qualified product, therefore, select appropriate acidolysis agent, reasonable solvent system and reaction condition, be the key that solves the selectivity of acidolysis of aceclofenac tert-butyl ester, this is also the key that adopts aceclofenac tert-butyl ester acidolysis Decision steps for the quality and economy of the preparation of aceclofenac

Method used

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Examples

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Embodiment 1

[0010] Example 1: Preparation of tert-butyl 2-((2,6-dichlorophenyl)amino)phenylacetoxyacetate (tert-butyl aceclofenac)

[0011] Dissolve diclofenac sodium shown in formula II and tert-butyl haloacetate shown in formula III, represented by tert-butyl chloroacetate in the following formula, in hydrocarbon solvents, ketone solvents or ether solvents, and add phase transfer Catalyst, carry out esterification reaction, obtain the aceclofenac tert-butyl ester shown in formula IV through aftertreatment.

[0012]

preparation example

[0013] The tert-butyl haloacetate used can be tert-butyl chloroacetate or tert-butyl bromoacetate, and the phase transfer catalyst used is a quaternary ammonium compound, which can be such as benzyltriethylamine halide, tetrabutylammonium halide, The hydrocarbon solvent used can be alkane or aromatic hydrocarbon or halocarbon, the ketone solvent can be acetone or butanone, etc., and the ether solvent refers to ether or methyl tert-butyl ether. The specific preparation examples are as follows:

[0014] 85L of toluene was pumped into the reaction tank, and 40Kg of diclofenac sodium, 20Kg of tert-butyl chloroacetate, and 0.1Kg of benzyltriethylamine chloride were added. The temperature was raised to reflux, and the reaction was carried out for 6 hours. Cool down to 75°C, add 50Kg of water, and stir for 20 minutes. Let stand for 20 minutes. Separate the aqueous layer. Toluene was recovered under reduced pressure to dryness. Add 60L methanol to dissolve. Slowly cool down to ro...

example 2

[0015] Example 2: Preparation of Aceclofenac

[0016] Put 75kg of formic acid into the reaction tank, add 40Kg of tert-butyl aceclofenac, stir to dissolve, and feed hydrogen chloride until the content (w / w) of hydrogen chloride is 6%. Control the temperature at 60°C, continue to stir and react for 5 hours, lower the temperature to 20°C, let stand for 3 hours until crystallization is complete, top wash, drain, and dry at 80°C to obtain 32.9 Kg of aceclofenac with a yield of 95.32%. The crude product was dissolved in 120L of toluene and heated to above 90°C. Filter and cool to room temperature. Until the crystallization is complete, filter, wash with a small amount of toluene, and drain. Obtain 31.4 Kg of aceclofenac fine works. The refined yield is 92%. HPLC content 99.72%.

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Abstract

The invention relates to an aceclofenac preparation method and belongs to the chemical pharmaceutical field. The method comprises a step that acidolysis of aceclofenac tert-butyl ester is carried out in a mixed solution comprising a low-molecular-weight organic acid and hydrogen halide to obtain aceclofenac. The method which allows the acidolysis of aceclofenac tert-butyl ester to be carried out in the mixed solution comprising the low-molecular-weight organic acid and hydrogen halide has the advantages of high selectivity, reduction of the fracture of the ethoxy group in aceclofenac tert-butyl ester to a lowest limit, high acidolysis reaction conversion rate, extremely-low content of diclofenac in obtained aceclofenac, easy aceclofenac refining, and high aceclofenac purity.

Description

technical field [0001] The invention relates to a preparation method of an anti-inflammatory and analgesic drug, in particular to a preparation method of aceclofenac, which belongs to the field of chemical pharmacy. Background technique [0002] Aceclofenac, chemical name is 2-((2,6-dichlorophenyl)amino)phenylacetoxyacetic acid, English name: Aceclofenac, structural formula is: [0003] [0004] This product is a newly synthesized orally effective non-steroidal anti-inflammatory analgesic (NSAIDs), which belongs to the phenylacetic acid anti-inflammatory, antipyretic and analgesic drugs. In structure, it is similar to diclofenac, aclofenac and fenclofenac In clinical practice, compared with other non-steroidal drugs (NSAIDs) in its pharmacological effects, it has a wide range of anti-inflammatory effects, strong analgesic and antipyretic effects, and gastric Toxic effect is characteristic, and the preparation method of aceclofenac reported in the literature mostly uses d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/42C07C227/18
Inventor 苗青刘康宋晓星杨向阳李恒远
Owner HENAN DONGTAI PHARM
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