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Method for preparing fosaprepitant dimeglumine intermediates

A technology of chloromethyl and step 2, which is applied in the fields of chemical instruments and methods, compounds of group 5/15 elements of the periodic table, organic chemistry, etc., which can solve the problems of unsuitable for industrial production, high price of aprepitant, and increased processing Difficulty and other issues, to achieve the effect of high implementation value, simple and efficient post-processing, and stable physical and chemical properties

Active Publication Date: 2015-05-27
SHANDONG NEWTIME PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The aprepitant used in this method is expensive, and the conditions for the phosphorylation reaction using aprepitant as a raw material are harsh, impurities are easily introduced, and the yield is low, which increases the difficulty of handling the reaction and is not suitable for industrial production.

Method used

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  • Method for preparing fosaprepitant dimeglumine intermediates
  • Method for preparing fosaprepitant dimeglumine intermediates
  • Method for preparing fosaprepitant dimeglumine intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Add 13.35g (100mmol) 3-chloromethyl-1,2,4-triazolin-5-one and 50ml THF into the reaction flask, stir well, add 220ml of 1mol / L sodium hexamethyldisilazane The tetrahydrofuran solution was cooled to -5°C, and a tetrahydrofuran solution of dibenzylphosphoryl chloride (32.6g of dibenzylphosphoryl chloride dissolved in 50ml of tetrahydrofuran) was slowly added dropwise. After the dripping was complete, the stirring reaction was continued, and the reaction endpoint was monitored by TLC. Add 300ml of saturated aqueous sodium bicarbonate solution and 300ml of isopropyl ether to the reaction solution, stir for 15min, separate the liquids, wash the organic phase with saturated brine until neutral, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and dry in vacuo to obtain a white solid 35.84g, yield 91%.

[0033] The resulting 35.84g product, 42.64g (90mmol) [2R-2α(R), 3α]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-( Add 4-fluorophenyl)-3-morp...

Embodiment 2

[0038] Add 13.35g (100mmol) 3-chloromethyl-1,2,4-triazolin-5-one, 64.62g (120mmol) tetrabenzyl pyrophosphate and 50mlTHF into the reaction flask, stir well, and cool down to - At 5°C, 220 ml of 1 mol / L sodium hexamethyldisilazane tetrahydrofuran solution was added dropwise. After the drop was completed, the stirring reaction was continued, and the reaction end point was monitored by TLC. Add 300ml of saturated aqueous sodium bicarbonate solution and 300ml of isopropyl ether to the reaction solution, stir for 15min, separate the liquids, wash the organic phase with saturated brine until neutral, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and dry in vacuo to obtain a white solid 34.25g, yield 87%.

[0039]The resulting 34.25g product, 40.75g (86mmol) [2R-2α(R), 3α]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxyl]-3-( Add 4-fluorophenyl)-3-morpholine hydrochloride and 100ml methanol into the reaction flask, stir to dissolve. Control the reactio...

Embodiment 3

[0041] Add 13.35g (100mmol) 3-chloromethyl-1,2,4-triazolin-5-one, 64.62g (120mmol) tetrabenzyl pyrophosphate and 50mlTHF into the reaction flask, stir well, and cool down to - At 5°C, 24.69 g (220 mmol) of potassium tert-butoxide was added. After the addition was complete, the stirring reaction was continued, and the end point of the reaction was monitored by TLC. Add 300ml of saturated aqueous sodium bicarbonate solution and 300ml of isopropyl ether to the reaction solution, stir for 15min, separate the liquids, wash the organic phase with saturated brine until neutral, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and dry in vacuo to obtain a white solid 33.86g, yield 86%.

[0042] The resulting 33.86g product, 40.27g (85mmol) [2R-2α(R), 3α]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxyl]-3-( Add 4-fluorophenyl)-3-morpholine hydrochloride and 100ml methanol into the reaction flask, stir to dissolve. Control the reaction temperature at 0°C, a...

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Abstract

The invention belongs to the technical field of pharmaceutical production, and relates to a preparation method of fosaprepitant dimeglumine intermediates. The technical scheme of the preparation method is particularly as follows: 3-chloromethyl-1,2,4-triazolin-5-one and a phosphine acylating reagent are subjected to a phosphine acylation reaction under the catalysis of alkali; and under the action of alkali, a product of the phosphine acylation reaction is reacted with [2R-2 alpha (R), 3 alpha]-2-[1-(3,5-di(trifluoromethyl) phenyl] ethoxy]-3-(4-fluorophenyl)-3-morpholine hydrochloride so as to generate a target compound. The phosphine acylation reaction in the technical scheme is simple in operation, mild in reaction condition, high in yield, good in product purity, and simple and efficient in post-processing; and the selected raw materials are stable in physical and chemical properties, convenient to control, low in price and easy to obtain, therefore, the method has a large implementation value, and is suitable for industrialized mass production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical production, and relates to a [3-[(2R)-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S) -(4-fluorophenyl)morpholin-4-yl]methyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl]phosphonic acid dibenzyl A new preparation method of the ester, the compound is an important pharmaceutical intermediate for the preparation of the antiemetic fosaprepitant dimeglumine. Background technique [0002] Fosaprepitant dimeglumine (Fosaprepitant dimeglumine, trade name Emend), developed by Merck, is used to treat acute and delayed nausea and vomiting caused by chemotherapy. CAS number: 265121-04-8, the structural formula is as follows: [0003] [0004] The key intermediate of fosaprepitant dimeglumine, namely [3-[(2R)-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3( S)-(4-fluorophenyl)morpholin-4-yl]methyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl]phosphonic acid Dibenzyl ester (Formula III) [0005] ...

Claims

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Application Information

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IPC IPC(8): C07F9/6558
Inventor 赵志全白文钦王友国孙秀玲代少刚
Owner SHANDONG NEWTIME PHARMA
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