Refining method of aprepitant key intermediate

Abstract

The invention provides a refining and purifying method of aprepitant key intermediate (I); a product (I)-containing reaction liquid is obtained by Grignard addition reaction of a compound (II), the product (I)-containing reaction liquid is added into a mixture of an inorganic acid water solution and an organic solvent insoluble in water, after standing and layering, organic phase is washed successively with water and saturated salt water, and a white solid product is obtained by vacuum concentration to dry at a certain temperature. The refining method has low requirement to equipment, is in no need of control of the temperature in the quenching process, and is afe and convenient in operation, and the obtained intermediates (I) can be used for the preparation of aprepitant with higher purity, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a method for refining a drug intermediate, in particular to a method for refining a neurokinin-1 (NK-1) receptor antagonist aprepitant intermediate, belonging to the field of chemical pharmacy. Background technique [0002] Aprepitant chemical name: 3-[[(2R,3S)-2-[(R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3 -(4-fluorophenyl)morpholin-4-yl]methyl]-1H-1,2,4-triazol-5(4H)-one, the chemical structural formula is as follows: [0003] [0004] Aprepitant is the first NK-1 receptor blocker developed by Merk Company. It was approved by the FDA on March 27, 2003. It is also listed in Sweden, Czech Republic, Portugal and the United Kingdom. Its trade name in the United States is Emend, whose trade name is Ivemend in Sweden, the Czech Republic, Portugal and the United Kingdom, is suitable for use in combination with other antiemetics in the prevention and treatment of acute and severe emesis caused by initial and repeated administ...

AI Technical Summary

Problems solved by technology

But in actual operation, this method has the following disadvantages: (1) when the Grignard addition reaction is quenched with methanol, the reaction is violently exothermic, and the temperature needs to be strictly controlled for slow dropwise addition. During large-scale production, the reaction system needs to be cooled, and the operation process is time-consuming , increased cost and potential safety hazards

(3) In the reaction mixture quenched with methanol, there are magnesium salts, etherified intermediates (I), organic acids and other components, and the presence of these substances reduces the stability of compound (I)

(4) The intermediate (I) with complex composition increases side reactions during the synthesis of intermediate (III), especially in the scale-up test, the proportion of defluorinated impurities generated in intermediate (III) increases. During the process of fosaprepitant dimeglumine, the impurity will generate the corresponding defluorinated impurity by-product, and it is difficult to remove

(5) The residue obtained by filtering and concentrating the hydrogenation reaction solution has complex solid components and hard properties. It dissolves slowly when treated with an aqueous solution of methyl isobutyl ketone, sodium citrate and sodium bicarbonate, which is time-consuming and labor-intensive.

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