Improved preparation method of ketorolac intermediate

Abstract

The invention discloses an improved preparation method of a ketorolac intermediate. The intermediate is (5-Benzoyl-1H-pyrrol-2-yl)methanetricarboxylic acid triethyl ester (M-1). The method comprises the following steps: subjecting 2-benzoylpyrrole, methane tricarboxylic acid triethyl ester, manganese acetate dihydrate (trivalent), sodium acetate and acetic anhydride to reacting in an organic solvent; adding an aqueous sodium hydrogen sulfite solution for extraction and liquid separation; and conducting vacuum concentration on an organic phase and pulping the an organic phase with an alcohol solvent. According to the method, post-treatment problems caused by the existence of a large amount of manganese ion compounds and a large amount of solvent acetic acid are effectively solved; meanwhile, the problems of high energy consumption, long period, high cost and the like caused by later concentration are reduced; and the obtained intermediate has the advantages of high purity, high yield and the like and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for preparing an improved ketorolac intermediate 5-benzoylpyrrole-2-methanetricarboxylic acid triethyl ester. Background technique [0002] Ketorolac tromethamine is a new type of non-steroidal powerful analgesic and moderate anti-inflammatory antipyretic that can be injected. Its mechanism of action is to inhibit the production of prostaglandins (PG) in the periphery and central To reduce PG in the peripheral and central, the chemical structure of its main component, ketorolac, is as follows: [0003] [0004] At present, due to the mild conditions and fast reaction speed of the free radical reaction induced by trivalent manganese, the main route of synthesizing ketorolac trometamol is catalyzed by trivalent manganese ions, through 2-benzoylpyrrole and methane three Triethyl carboxylate undergoes free radical reaction, and then undergoes oxidative cond...

AI Technical Summary

Problems solved by technology

In the synthesis process, due to the limitation of the solvent used in the preparation of the trivalent manganese acetate compound, almost all the free radical reactions involving the synthesis of this intermediate use acetic acid as the solvent, so it is inevitable to encounter a large amount of Manganese ions and acetic acid exist in the system, resulting in difficult liquid separation and extraction and difficult removal of high boiling point acetic acid solvent

In addition, in order to remove a large amount of manganese ion compounds and impurities, the patent US5082950 has to adopt column chromatography, but this method is obviously not suitable for the requirements of large-scale industrial production

Although Zhu Ju etc. (Chinese Journal of Medicinal Chemistry, 1995,5(3):223-225) optimized the post-treatment process, quenched with water, and then extracted with toluene, although the literature did not clearly point out that the separation and extraction encountered However, it is undeniable that the reaction still has the problems of difficult liquid separation and extraction and a large amount of high-boiling acetic acid solvent is difficult to remove in the subsequent concentrated organic phase

[0007] The inventor repeated the experiments of the above-mentioned documents, and found that the whole reaction system appeared black due to the use of a large amount of manganese compounds in the actual test. Solvent and water all have a large amount of acetic acid of certain miscibility as solvent, the volume of adopting acetic acid can be as high as 20~30 mass volume times of 2-benzoylpyrrole (mass), emulsification is comparatively serious during liquid separation, and the liquid separation extraction Extremely difficult and cumbersome to operate

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