Continuous flow production process for etoricoxib intermediate

Abstract

The invention discloses a continuous flow production process for an etoricoxib intermediate, belonging to the field of application technologies for bulk pharmaceutical chemical production in fine chemical engineering processes. The method for the etoricoxib intermediate comprises the following steps: step 1, synthesis of an intermediate in a continuous flow microreactor with non-nucleophilic organic strong base as a reagent; and step 2, performing of an oxidation process in the continuous flow microreactor by using a cheap inorganic oxidant under the action of a transition metal catalyst. Themethod comprises the following concrete reaction steps: with 4-(methylthio)phenylacetic acid and methyl 6-methylpyridine-3-carboxylate as starting materials, allowing the 4-(methylthio)phenylacetic acid and the methyl 6-methylpyridine-3-carboxylate to undergo a two-step reaction in the continuous flow microreactor so as to form 1-(6-methylpyridin-3-yl)-2-(4-methylsulfonylphenyl)ethanone. The method provided by the invention adopts novel reagents and catalyst and innovative equipment, has a yield of more than 70%, well controls generation of reaction heat and gas, and has the characteristics ofnovel catalysts, relatively mild reaction conditions, etc.

Description

Technical field: [0001] The invention relates to a continuous flow production process of an etoricoxib intermediate, belonging to the technical field of application of fine chemical processes in the production of raw materials. Background technique: [0002] Etoricoxib is an anti-arthritic drug developed by a pharmaceutical company in the United States, and its trade name is Ankangxin. Ketone is the most critical intermediate of this drug. [0003] [0004] At present, there are two main synthetic routes of this intermediate: [0005] [0006] The first process route is to oxidize sulfide to sulfone first, and then perform condensation. Since the second step of condensation needs to convert the carboxyl group into a carbanion, and the methyl group adjacent to the sulfone functional group also has strong acidity, many side reactions and low yield. [0007] The second process route is condensation followed by oxidation. This route is more selective. [0008] [0...

AI Technical Summary

Problems solved by technology

[0010] The first step uses relatively expensive strong bases such as lithium hexamethyldisilazide and lithium diisopropylamide, which are costly and dangerous, and because of the use of highly active reagents, the heat of reaction is very high, and the process safety is difficult. Assure

[0011] The second step uses oxidizing reagents such as potassium dichromate and m-chloroperoxybenzoic acid. The atom economy is low and the materials are relatively expensive.

And it also has the defect that the heat of reaction is very high and the safety of the process is difficult to guarantee

[0012] In summary, the processes for the synthesis of etoricoxib intermediates reported in the literature all have the disadvantages of high material cost and low process safety.

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