Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Fosaprepitant dimeglumine preparation method

A technology of fosaprepitant dimeglumine and benzhydryl group is applied in the field of preparing neurokinin-1 receptor antagonist fosaprepitant dimeglumine, which can solve the problem of difficult purification and removal and poor reaction yield. Ideal and other problems, to achieve the effect of enhancing regional selectivity and

Active Publication Date: 2014-10-15
INST OF BIOPHARM OF SHANDONG PROVINCE
View PDF9 Cites 10 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The method for preparing fosaprepitant dimeglumine disclosed in the patent WO2011045817 is to replace the water-sensitive bis(trimethylsilyl) with alkalis that are not afraid of water such as lithium hydroxide, sodium hydroxide, potassium hydroxide, DBN, DBU, etc. Base) sodium amide, trying to get rid of the harsh conditions of anhydrous reaction, but the reaction yield of this method is not ideal, and the used dimethyl sulfoxide, N,N-dimethylformamide, N-methyl-2 -Pyrrolidone, etc. are high-boiling solvents, which are not easy to purify and remove

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Fosaprepitant dimeglumine preparation method
  • Fosaprepitant dimeglumine preparation method
  • Fosaprepitant dimeglumine preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Step 1: Preparation of bis(diphenylmethyl)phosphite (compound VI)

[0038]

[0039] Add 68.7g of phosphorus trichloride (0.5mol) and 400mL of anhydrous toluene into a 1L three-necked flask, and cool down to -5 in an ice-salt bath under nitrogen protection. o C, slowly drop the mixed solution of 101.2g triethylamine (1.0mol) and 184.2g benzhydryl alcohol (1.0mol) in 300mL toluene, keep the temperature at 15 oBelow C, remove the ice bath after the dropwise addition, naturally rise to room temperature, and continue to stir for 2h. 300mL of water was dropped into the reaction solution, stirred at room temperature for 30min, the organic layer was separated, washed once with water (2*250mL) and saturated brine (250mL), dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness in vacuo to obtain 201g of shallow Yellow oil.

[0040] Step 2: Preparation of bis(benzhydryl)phosphoryl chloride (compound III)

[0041]

[00...

Embodiment 2

[0055] Step 1: {3-[[2(R)-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorobenzene base) morpholin-4-yl] methyl] -5-oxo-4,5-dihydro-1,2,4-triazol-1-yl} phosphate di(diphenylmethyl) ester (compound IV ) preparation

[0056]

[0057] Under nitrogen protection, add 15.0 g of compound II (28.1 mmol) into a 500 mL three-neck flask, add 120 mL of dioxane to dissolve it, and cool down to -5 o C, dropwise add 67mL of 1M bis(trimethylsilyl) sodium amide (67.0mmol), the temperature is controlled at 5 o Below C, stir for 30min after the dropwise addition, and then drop 12.9g of compound III (28.7mmol) in dioxane solution (80mL) into the bottle at a temperature of 5 o Below C, remove the ice-salt bath after the dropwise addition, naturally rise to room temperature, and continue to stir for 1h. Cool down in an ice bath, add 400 mL of saturated aqueous ammonium chloride dropwise to quench the reaction, extract the mixture with 400 mL of methyl tert-butyl ether, wash the or...

Embodiment 3

[0066] Step 1: {3-[[2(R)-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorobenzene base) morpholin-4-yl] methyl] -5-oxo-4,5-dihydro-1,2,4-triazol-1-yl} phosphate di(diphenylmethyl) ester (compound IV ) preparation

[0067]

[0068] Under nitrogen protection, add 15.0 g of compound II (28.1 mmol) into a 500 mL three-neck flask, add 120 mL of tetrahydrofuran to dissolve it, and cool down to -5 o C, dropwise add 73mL of 1M bis(trimethylsilyl) sodium amide (73.0mmol), the temperature is controlled at 5 o Below C, stir for 30min after the dropwise addition, then drop 12.9g of compound III (28.7mmol) in tetrahydrofuran solution (80mL) into the bottle, the temperature is at 5 o Below C, remove the ice-salt bath after the dropwise addition, naturally rise to room temperature, and continue to stir for 1h. Cool down in an ice bath, add 400 mL of saturated aqueous ammonium chloride dropwise to quench the reaction, extract the mixture with 400 mL of methyl tert-butyl eth...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a fosaprepitant dimeglumine preparation method, fosaprepitant dimeglumine has a structure shown as the formula I, and the route of synthesis of the method comprises the following two steps: (1) reacting compound di(benzhydryl) phosphoryl chloride (shown as the formula III) with aprepitant (shown as the formula II) under the action of a steric hindrance strong alkali to produce a new phosphorylation product intermediate (shown as the IV); (2) removing protecting group diphenylmethane of the new compound by catalytic reduction to obtain fosaprepitant and simultaneously to obtain a target product by salifying with N-methyl-D - glucosamine. A phosphorylation reagent used by the method has two higher steric hindrance protecting groups, due to the space steric hindrance effect, the regional selectivity and intermediate stability of the first step reaction can be enhanced, the intermediate stability can be enhanced, and the reaction yield can be improved.

Description

technical field [0001] The invention relates to a new method for preparing neurokinin-1 (NK-1) receptor antagonist fosaprepitant dimeglumine. Background technique [0002] Fosaprepitant dimeglumine (Fosaprepitant dimeglumine, chemical name: {3-[2(R)-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy] -3(S)-(4-fluorophenyl)morpholin-4-yl]methyl]-5-oxo-4,5-dihydro-[1,2,4]-triazole-1- Base}phosphonic acid bis[N-methyl-(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy]hexammonium salt, trade name: Emend), developed by Merck A new type of chemotherapy-related antiemetic drug, which was first launched in the United States in 2008. The drug is the prodrug of Aprepitant, the first human kinin NK-1 receptor blocker also developed by Merck, which is rapidly converted into aprepitant after being injected into the body, and is used for Prevention and treatment of acute and delayed nausea and vomiting caused by moderate and severe emetic anticancer drugs during the initial or repeated administration o...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07F9/6558C07C215/10C07C213/08
CPCY02P20/55
Inventor 任文杰郑德强王长斌郭新艳毋立华刘文涛王勤
Owner INST OF BIOPHARM OF SHANDONG PROVINCE
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com