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A kind of neurokinin (nk-1) receptor antagonist crystal form preparation method

A technology of titanate crystal form and pitant crystal form, applied in the field of medicine and chemical industry, can solve the problems of lack of affinity and the like, and achieve the effects of low production cost, high yield and simple operation.

Active Publication Date: 2014-10-15
SHANGHAI BOCIMED PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This product is clinically used as a tablet to prevent acute and delayed nausea and vomiting caused by highly emetogenic anti-tumor chemotherapy drugs (including high-dose cisplatin therapy), which can pass through the blood-brain barrier and communicate with the brain Selective binding of NK-1 receptors exerts antiemetic effects, but has little affinity for 5-HT3, dopamine and glucocorticoid receptors

Method used

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  • A kind of neurokinin (nk-1) receptor antagonist crystal form preparation method
  • A kind of neurokinin (nk-1) receptor antagonist crystal form preparation method
  • A kind of neurokinin (nk-1) receptor antagonist crystal form preparation method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Starting material (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-morpholine Hydrochloride (5g 10.56mmoL), acetonitrile 50mL was added, 5-chloromethyl-2,4-dihydro[1,2,4]triazol-3-one (2.8g 21.12mmoL), potassium carbonate (0.97g 6.33moL), reacted at room temperature for 8 hours, the reaction solution was added dropwise to water, and the precipitated solid was aprepitant.

[0034] Dissolve 1.65 g of aprepitant obtained above in a mixed solution of tetrahydrofuran and water (tetrahydrofuran / water 6.6mL / 9.9mL), stir, heat up to 60°C, react for 2 hours, lower to room temperature and stir, filter and pump after 30min Drying, vacuum drying at 45°C for 8 hours to obtain the crystal form of aprepitant, yield: 90%.

Embodiment 2

[0036] Starting material (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-morpholine Hydrochloride (6g 12.67mmoL), DMSO 50mL was added, potassium carbonate (3.49g 25.32moL), 5-chloromethyl-2,4-dihydro[1,2,4]triazol-3-one (2.19g 16.47mmoL) at room temperature for 4 hours, the reaction solution was added dropwise to water, and the precipitated solid was aprepitant.

[0037] Dissolve 1 g of aprepitant obtained above in a mixed solution of tetrahydrofuran and water (tetrahydrofuran / water 6.6mL / 13.4mL), stir, heat up to 60°C, react for 2 hours, lower to room temperature and stir, filter and drain after 30min , dried under vacuum at 45°C for 8 hours to obtain the crystal form of aprepitant, yield: 90%.

Embodiment 3

[0039] Starting material (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-morpholine Hydrochloride (5g 10.56mmoL), acetonitrile 50mL was added, 2-(2-chloro-1-ethylene) hydrazide methyl carboxylate (2.8g 21.12mmoL), potassium carbonate (0.97g 6.33moL), react at room temperature After 6 hours, it was heated to 70° C. for reaction, then lowered to room temperature and stirred, and the reaction solution was added dropwise to water, and the precipitated solid was aprepitant.

[0040] Dissolve 3.3 g of aprepitant obtained above in a mixed solution of tetrahydrofuran and water (tetrahydrofuran / water 26.6 mL / 106.4 mL), stir, heat up to 80 ° C, react for 2 hours, lower to room temperature and stir, filter and pump after 30 min Drying, vacuum drying at 45°C for 8 hours to obtain the crystal form of aprepitant, yield: 91%.

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Abstract

The invention provides a new neurokinin (NK-1) receptor antagonist aprepitant crystal form V. The new aprepitant crystal form V powder has characteristic X diffraction ray peaks at the wavelengths of 12.08 degrees + / -0.2, 15.31 degrees + / -0.2, 17.61 degrees + / -0.2, 20.62 degrees + / -0.2 and 24.76 degrees + / -0.2 2 theta in an X-ray diffraction pattern. The invention also provides a preparation method of the aprepitant new crystal form V.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a method for preparing a neurokinin (NK-1) receptor antagonist aprepitant crystal form. Background technique [0002] Aprepitant (aprepitant), the chemical name is 5-[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)- (4-fluorophenyl)morpholin-4-ylmethyl]-3,4-dihydro-2H-1,2,4-triazol-3-one, the structure is shown in the figure below: [0003] [0004] Aprepitant is a neurokinin-1 (NK-1) receptor antagonist developed by Merck & Co of the United States. It was approved by the FDA in 2003, and its trade name is Emend. This product is clinically used as a tablet to prevent acute and delayed nausea and vomiting caused by highly emetogenic anti-tumor chemotherapy drugs (including high-dose cisplatin therapy), which can pass through the blood-brain barrier and communicate with the brain NK-1 receptors selectively bind to play an antiemetic effect, but...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/06A61P1/08
Inventor 吴水长冯保珍
Owner SHANGHAI BOCIMED PHARMA CO LTD