Parecoxib preparation method

Abstract

A parecoxib preparation method comprises the following steps: reacting diacetophenone oxime with ethyl acetate in a lithium diisopropylamide / tetrahydrofuran system to generate 4,5-dihydro-5-methyl-5-hydroxy-3,4-dibenzylisoxzzole; reacting 4,5-dihydro-5-methyl-5-hydroxy-3,4-dibenzylisoxzzole with halogenated sulfonic acid, and ammonolyzing to obtain valdecoxib; and reacting valdecoxib with propionic anhydride to obtain parecoxib. Compared with the prior art, the preparation method disclosed in the invention has the advantages of low initial raw material cost, simple and feasible technological process, low equipment requirement, and suitableness for the industrialized large-scale production.

Description

technical field [0001] The present application relates to a method for preparing parecoxib. Background technique [0002] Parecoxib is a specific inhibitor of cyclooxygenase-2 (COX-2), a prodrug of valdecoxib, and belongs to the coxib analgesics in anti-arthritis drugs. Parecoxib is used for the short-term treatment of pain after surgery. The sodium salt of parecoxib is clinically used as an injection. [0003] At present, the preparation methods of parecoxib can be divided into the following two categories according to the different starting materials: the preparation method using 1,2-benzophenone as the starting material and the method using 1-phenylacetone as the starting material method of preparation. [0004] Wherein, there are three kinds of preparation methods using 1,2-benzophenone as the starting material: [0005] Method 1: (WO2003029230) using 1,2-benzophenone as the starting material, reacting with hydroxylamine hydrochloride to form benzophenone oxime, cond...

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Problems solved by technology

[0007] Its main disadvantages are: butyllithium has high chemical reactivity and high safety requirements for the reaction, which is not conducive to industrial production, and fluoride is more serious to the environment, which increases the difficulty of three wastes treatment

[0010] The main disadvantage of this method is: the reaction requires the use of more expensive reagents, such as chloroacetylation requires the use of expensive 2,6-lutidine as an acidic agent, and the reaction time is relatively long, requiring 24 hours, the reaction system It is acidic, requires high equipment, and increases production costs. At the same time, this process uses trifluoroacetic acid as a dehydration medium, which will also be affected by fluoride

[0013] The disadvantage of this method is that the reagents used are more expensive, and the multi-step reaction uses strong corrosive reagents, such as chlorosulfonic acid, thionyl chloride, and propionic acid, which have high requirements for equipment and production personnel, which is not conducive to industrial production.

The raw material of this method is more expensive, and the source of benzonitrile N oxide is limited, so this method is not suitable for industrialized production

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