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Preparation method of aprepitant intermediate

A kind of aprepitant, intermediate technology, applied in the field of chemical synthesis, can solve problems such as unfavorable production amplification, achieve the effect of less impurities, avoid potential safety hazards, and high process stability

Pending Publication Date: 2020-04-14
MAXENMED GUANGZHOU
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In order to overcome the above-mentioned shortcomings and deficiencies of the prior art, the object of the present invention is to provide a preparation method of an aprepitant intermediate to solve the problem that the preparation of the key intermediate I requires strict anhydrous and anaerobic operations, which is not conducive to production scale-up. problems, and the preparation process does not require hydrogenation, the operation is safer and more convenient, the by-products in the reaction process are less, and the aprepitant prepared from the obtained key intermediate Ⅰ has higher purity and is suitable for industrial production

Method used

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  • Preparation method of aprepitant intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1: Preparation of Compound III

[0050] (1) Influence of catalyst types on the preparation of compound III

[0051] Set up experimental groups 1 to 4, respectively mix 42.2 g of compound II, 16 g of 4-fluorophenylboronic acid, 630 mL of saturated sodium carbonate aqueous solution and 1260 mL of toluene, and stir evenly, add 0.422 g of catalyst, and heat to 100 °C while stirring for 10 hours. After finishing, it was lowered to room temperature, the catalyst was recovered by filtration, the filtrate was left to stand for stratification, the upper organic phase was washed with 630 mL of saturated brine, and then liquid-separated, the organic liquid was obtained and then concentrated and recovered toluene to obtain a white blocky solid, which was the intermediate of Intermediate I. Free base——Compound Ⅲ, its high performance liquid chromatogram is as follows figure 2 shown. Table 1 shows the differences between the experimental groups 1 to 4 and the experimental ...

Embodiment 2

[0084] Example 2: Preparation of Intermediate I

[0085] (1) Influence of organic solvent types on the preparation of intermediate I

[0086] Set up experimental groups 35 to 38, respectively dissolve 44 g of compound III obtained in experimental group 1 in 660 mL of organic solvent, add hydrochloric acid with a mass concentration of 20%-38% to adjust the pH to 1-2, and then distill under reduced pressure until the volume is the original. 30%, then cooled to 0 °C to separate out a white solid, filtered and dried to obtain a white solid powder, which is Intermediate I, and its high-performance liquid chromatogram is as follows image 3 As shown, the hydrogen NMR spectrum is shown in Figure 4 shown. The differences between the experimental groups 36-39 and the experimental results are shown in Table 9.

[0087] The influence of table 9 organic solvent types on the preparation of intermediate I

[0088]

[0089] (2) the influence of methyl isobutyl ketone dosage on the pr...

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Abstract

The invention provides a preparation method of an aprepitant intermediate, and belongs to the technical field of chemical synthesis. According to the invention, (2R)-2-[(1R)-1-[3, 5-bis (trifluoromethyl) phenyl] ethyoxyl]-3-bromomorpholine is subjected to Suzuki coupling reaction to obtain (2R, 3S)-2-[(1R)-1-[3, 5-bis (trifluoromethyl) phenyl] ethyoxyl]-3-(4- fluorophenyl) morpholine; reacting (2R, 3S)-2-[(1R)-1-[3, 5-bis (trifluoromethyl) phenyl] ethyoxyl]-3-(4- fluorophenyl) morpholine with hydrochloric acid to obtain the aprepitant intermediate (2R, 3S)-2-[(1R)-1-[3, 5-bis (trifluoromethyl) phenyl] ethoxy]-3-(4-fluorophenyl) morpholine hydrochloride. In the preparation process, environmental humidity and oxygen content do not need to be controlled, hydrogenation is not needed, operation is safer, simpler and more convenient, industrial scale-up production is easy, few byproducts are produced in the reaction process, and the purity of aprepitant prepared from the obtained key intermediate I is higher.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of an NK-1 receptor blocker aprepitant intermediate. Background technique [0002] Aprepitant, the first NK-1 receptor blocker developed by Merck Drugs & Biotechnology in Germany, has selectivity and high affinity for NK-1 receptors in the brain, while 2 and NK-3 receptors have a very low affinity, and are mainly used for the treatment of nausea and vomiting caused by chemotherapy drugs. It was approved by the FDA on March 27, 2003, and is now available in North America, Europe, South Korea, Hong Kong, etc. Listed in countries and regions, and sales have grown rapidly year by year. [0003] The chemical name for aprepitant is 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4 -Fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one, its chemical s...

Claims

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Application Information

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IPC IPC(8): C07D265/32
CPCC07D265/32
Inventor 郭淑儿
Owner MAXENMED GUANGZHOU
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