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Preparation method of acemetacin impurity D

A technology of acemetacin and impurities, which is applied in the field of drug impurity synthesis, can solve the problems of no acemetacin impurity D, etc., and achieve the effect of shortening linear steps, short linear steps and simple operation

Pending Publication Date: 2022-04-12
BEIJING INSTITUTE OF CLOTHING TECHNOLOGY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there is no synthetic technique for preparing acemetacin impurity D by using this method in the literature

Method used

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  • Preparation method of acemetacin impurity D
  • Preparation method of acemetacin impurity D
  • Preparation method of acemetacin impurity D

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] A method for rapidly preparing acemetacin impurity D, using indomethacin as a raw material, and preparing acemetacin impurity D through 6 steps of reaction, the synthetic route is as follows figure 2 Shown, where PrBr (1-bromopropane), DMF (N, N-dimethylformamide), DMAP (4-dimethylaminopyridine).

[0040] The specific preparation method is as follows:

[0041] (1) Preparation of indomethacin propyl ester (intermediate 1):

[0042] In a 500ml three-necked bottle, add indomethacin 10.0g (28mmol), potassium carbonate (K 2 CO 3 ) 8.31g (58.2mmol), 200mL of solvent DMF, stirred evenly, then added 1.1 times the equivalent of 1-bromopropane 3.82g (31.3mmol), stirred and reacted at room temperature for 12h, TLC monitored that the reaction was complete, and there was an insoluble precipitate in the system, Remove the organic solvent DMF under reduced pressure, add 200mL of water, extract twice with 150ml ethyl acetate respectively, combine the organic phases, wash the organi...

Embodiment 2

[0063] Other contents are as in Example 1, wherein in step (1) indomethacin and 1.5 times equivalent of 1-bromopropane are used as raw materials, in the solvent DMF, under the condition of alkaline pH 12, the reaction is stirred at room temperature for 12 hours, and the preparation 3 -(2-propyl acetate) substituted indole intermediate product 1;

[0064] (2) Dissolve the intermediate 1 prepared in the previous step in the substrate, that is, DCM that is 15 times the mass of intermediate 1, add an organic alcohol, cool the mixture to 0°C, and then add the substrate, that is, intermediate 1 4-5 times the equivalent of the catalyst, the mixture was stirred, and reacted at 40°C for 18 hours, and the mixture was separated and purified by extraction to obtain a brown intermediate compound 2;

[0065] (3) Intermediate 2 with a tert-butyl group introduced at the 6-position was added to a THF aqueous solution, and the substrate, that is, 3 times the equivalent of LiOH of Intermediate 2...

Embodiment 3

[0069] Other contents are as in Example 1, wherein in step (1) indomethacin and 1.3.5 times the equivalent of 1-bromopropane are used as raw materials, in the solvent DMF, under the condition of alkaline pH 12, the reaction is stirred at room temperature for 12h, Preparation of 3-(2-propyl acetate) substituted indole intermediate product 1;

[0070] (2) Dissolve the intermediate 1 prepared in the previous step in the substrate, that is, DCM that is 14 times the mass of intermediate 1, add an organic alcohol, cool the mixture to 0°C, and then add the substrate, that is, intermediate 1 4-5 times the equivalent of the catalyst, the mixture was stirred, and reacted at 40°C for 17h, and the mixture was separated and purified by extraction to obtain a brown intermediate compound 2;

[0071] (3) Intermediate 2 with a tert-butyl group introduced at the 6-position was added to THF aqueous solution, that is, LiOH, which was 3 times the equivalent of Intermediate 2, was stirred and react...

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Abstract

The invention belongs to the technical field of drug impurity synthesis, and particularly relates to a preparation method of an acemetacin impurity D. The acemetacin impurity D is prepared by taking indometacin as a raw material through six-step reaction. The method has the advantages of easily available raw materials, simple operation, short linear route, few reaction steps, rapid preparation of acemetacin impurity D, and high purity; the preparation efficiency is improved, and the preparation cost is reduced.

Description

technical field [0001] The invention belongs to the technical field of drug impurity synthesis, and in particular relates to a preparation method of acemetacin impurity D. Background technique [0002] Acemetacin is a non-steroidal anti-inflammatory pain drug and the prodrug of indomethacin. After oral administration, indomethacin is metabolized into indomethacin to exert its drug effect. It is considered to improve anti-inflammatory It is one of the best choices for improving efficacy, improving tolerance and reducing gastrointestinal side effects of indomethacin. Acemetacin is mainly used in the treatment of rheumatoid arthritis, postoperative pain and infection. [0003] [0004] Adverse reactions in the clinical use of drugs are not only determined by the pharmacological activity of the drug itself, but also closely related to the impurities and content in the drug. Full research and control of drug impurities is a necessary link to ensure drug safety. European Pharm...

Claims

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Application Information

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IPC IPC(8): C07D209/28
Inventor 张焱于文雅聂锦梅李昕郑一平赵长家
Owner BEIJING INSTITUTE OF CLOTHING TECHNOLOGY
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