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New method for preparing fosaprepitant intermediate

A new method and compound technology, applied in the chemical field, can solve the problems of complex purification process and unfavorable large-scale production, and achieve the effect of reducing cost and simplifying operation

Active Publication Date: 2012-09-19
北京华众恩康医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the raw material tetrabenzyl pyrophosphate used therein is complex in the preparation process, especially the purification process.
Not conducive to large-scale production

Method used

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  • New method for preparing fosaprepitant intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Preparation of Dibenzylphosphoryl Chloride

[0025]

[0026] Put a 100ml three-necked bottle, equipped with a thermometer, magnetic stirring, N 2 . in N 2 Under protection, 10 g (36 mmol) of dibenzyl phosphate and 25 ml of toluene were first added to the bottle. Control the temperature of the reaction mixture below 25°C, and slowly add 3.5ml (43mmol) of sulfuryl chloride dropwise. After all the addition was completed, the temperature was maintained and stirring was continued for 30 minutes. The reaction solution was transferred to a 100ml dry single-necked bottle, and the solvent was evaporated under reduced pressure. 10ml of toluene was added to the residue again, and then evaporated under reduced pressure. This process was repeated three times to ensure that the residue did not contain sulfonyl chloride. The residue was dissolved in 5ml of tetrahydrofuran and used directly in the next reaction.

[0027] [3-[(2R)-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]...

Embodiment 2

[0031] Preparation of Dibenzylphosphoryl Chloride

[0032] Put a 100ml three-necked bottle, equipped with a thermometer, magnetic stirring, N 2 . in N 2 Under protection, 10 g (36 mmol) of dibenzyl phosphate and 25 ml of toluene were first added to the bottle. Control the temperature of the reaction mixture below 25°C, and slowly add 3.5ml (43mmol) of sulfuryl chloride dropwise. After all the addition was completed, the temperature was maintained and stirring was continued for 30 minutes. The reaction solution was transferred to a 100ml dry single-necked bottle, and the solvent was evaporated under reduced pressure. 10ml of toluene was added to the residue again, and then evaporated under reduced pressure. This process was repeated three times to ensure that the residue did not contain sulfonyl chloride. The residue was dissolved in 5ml of tetrahydrofuran and used directly in the next reaction.

[0033] [3-[(2R)-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-flu...

Embodiment 3

[0036] Preparation of Dibenzylphosphoryl Chloride

[0037] Put a 100ml three-necked bottle, equipped with a thermometer, magnetic stirring, N 2 . in N 2 Under protection, 10 g (36 mmol) of dibenzyl phosphate and 25 ml of toluene were first added to the bottle. Control the temperature of the reaction mixture below 25°C, and slowly add 3.5ml (43mmol) of sulfuryl chloride dropwise. After all the addition was completed, the temperature was maintained and stirring was continued for 30 minutes. The reaction solution was transferred to a 100ml dry single-necked bottle, and the solvent was evaporated under reduced pressure. 10ml of toluene was added to the residue again, and then evaporated under reduced pressure. This process was repeated three times to ensure that the residue did not contain sulfonyl chloride. The residue was dissolved in 5ml of tetrahydrofuran and used directly in the next reaction.

[0038] [3-[(2R)-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-flu...

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Abstract

The invention relates to a new method for preparing fosaprepitant intermediate, namely, [3-[(2R)-[(1R)-1-(3, 5-bi (trifluoromethyl) phenyl] ethyoxyl]-3 (S)-(4-fluorophenyl) morpholine 4-group] methyl]-5-oxo-4, 5-dihydro-[1, 2, 4]-triazole-1-group] phosphonic acid-benzyl ester. The compound is an important medicine intermediate, and is used for preparing antiemetic drug fosaprepitant. The new method comprises the steps of: enabling newly prepared phosphorylation agent dibenzyl phosphorus oxychloride and aprepitant to have reaction in organic solvent under the action of steric hindrance alkali, treating the product with methyl alcohol to obtain the fosaprepitant intermediate. The method is simple in operation and low in cost, thus being more suitable for industrial production.

Description

technical field [0001] The present invention belongs to the field of chemistry. It relates to a preparation of [3-[(2R)-[(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] a new method of phosphonic acid monobenzyl ester, the The compound is an important pharmaceutical intermediate and is used for preparing the antiemetic drug fosaprepitant. Background technique [0002] The present invention relates to the preparation of [3-[(2R)-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl ) A new method for monobenzyl morpholin-4-yl]methyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl]phosphonic acid. [0003] [0004] The compound is an important pharmaceutical intermediate for preparing the antiemetic fosaprepitant. [0005] The preparation method of the compound has been disclosed in patents US5691336, US5780467 and US2007265442. The methods used in patents US5691336 and U...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6558
Inventor 张瑞华张金凤
Owner 北京华众恩康医药技术有限公司
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