Refining method of aprepitant key intermediate

A refining method and a key technology, applied in the refining of neurokinin-1 receptor antagonist aprepitant intermediates, the refining of pharmaceutical intermediates, can solve the problem of increased side reactions, decreased compound stability, and difficult to remove and other problems, to achieve the effect of reducing the formation of defluorination impurities, reducing side reactions and increasing stability

Active Publication Date: 2015-02-04
SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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.

Method used

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  • Refining method of aprepitant key intermediate
  • Refining method of aprepitant key intermediate
  • Refining method of aprepitant key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Preparation of intermediate (I):

[0035] 1.40kg compound (II) dissolved in 0.8L tetrahydrofuran and 4.0L 4-fluorophenylmagnesium bromide tetrahydrofuran solution (1.0M) were subjected to Grignard addition reaction to generate intermediate (I) reaction solution, poured into the stirred In the mixed solution of 10L methyl tert-butyl ether and 10L saturated aqueous ammonium chloride solution, the temperature did not rise significantly. After stirring for 10 minutes, let it stand for stratification, separate the organic phase, and wash it with 6L water and 6L saturated saline successively. Then it was concentrated to dryness under reduced pressure at 25°C to obtain 1.55 kg of white solid. Yield 91.0%. HPLC purity: 99.1%.

Embodiment 2

[0037] Preparation of intermediate (I):

[0038] 1.40kg compound (II) dissolved in 0.8L tetrahydrofuran and 4.0L 4-fluorophenylmagnesium bromide tetrahydrofuran solution (1.0M) were subjected to Grignard addition reaction to generate intermediate (I) reaction solution, poured into the stirred In the mixed solution of 20L methyl tert-butyl ether and 15L saturated aqueous ammonium chloride solution, the temperature did not rise significantly. After stirring for 10 minutes, let it stand for stratification, separate the organic phase, and wash it with 10L water and 10L saturated brine successively. Then it was concentrated to dryness under reduced pressure at 25°C to obtain 1.59kg of white solid. Yield 93.5%. HPLC purity: 98.8%.

Embodiment 3

[0040] Preparation of intermediate (I):

[0041]1.40kg compound (II) dissolved in 0.8L tetrahydrofuran and 4.0L 4-fluorophenylmagnesium bromide tetrahydrofuran solution (1.0M) were subjected to Grignard addition reaction to generate intermediate (I) reaction solution, poured into the stirred In the mixed solution of 10L methyl tert-butyl ether and 10L saturated aqueous ammonium chloride solution, the temperature did not rise significantly. After stirring for 10 minutes, let it stand for stratification, separate the organic phase, and wash it with 6L water and 6L saturated saline successively. Then it was concentrated to dryness under reduced pressure at 20°C to obtain 1.56 kg of white solid. Yield 91.7%. HPLC purity: 98.2%.

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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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/32
CPCC07D265/32
Inventor 任文杰郑德强张利剑孙利民刘文涛张岱州王勤
Owner SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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