Preparation method of pemetrexed disodium

A technology of trifluoropyrimidine and trifluoromethyl, which is applied in the field of preparation of trifluoropyrimidine, can solve the problems of long reaction process, low reaction yield, and difficult wastewater treatment, and achieve the goal of increasing yield and shortening the reaction process Effect

Active Publication Date: 2020-08-28
JIANGXI AGRICULTURAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the existing trifluoropyrimidine synthesis process, due to the cumbersome process of ester hydrolysis and generation of active ester, the reaction process is long, resulting in low overall reaction yield, and the wastewater generated by the hydrolysis reaction is difficult to treat, which is not conducive to industrial production.

Method used

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  • Preparation method of pemetrexed disodium
  • Preparation method of pemetrexed disodium

Examples

Experimental program
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Effect test

Embodiment 1

[0030] A preparation method of trifluoropyrim, comprising the following steps:

[0031] (1) Take 2-(3-(trifluoromethyl)phenyl)malonate 30.43g and N-(pyridin-5-ylmethyl)pyridin-2-amine 18.62g, dissolve the two in 0.5 In the N-methylimidazole of L, add 28.06g of tetramethyl chlorourea hexafluorophosphate as catalyst, seal and stir reaction under microwave condition, obtain crude product;

[0032] (2) Remove N-methylimidazole from the crude product under reduced pressure, then add ethyl acetate and stir evenly, and use silica gel column chromatography to obtain the trifluoropyrimidine.

[0033] The synthetic route of the present embodiment is shown in the following formula:

[0034]

[0035] The present invention has the advantage of utilizing 2-(3-(trifluoromethyl)phenyl)malonate and N-(pyridin-5-ylmethyl)pyridin-2-amine to react directly under catalyst and microwave conditions , the reaction process is only one step, which greatly shortens the reaction process and improves...

Embodiment 2

[0041] A preparation method of trifluoropyrim, comprising the following steps:

[0042] (1) Take 2-(3-(trifluoromethyl)phenyl)malonate 30.56g and N-(pyridin-5-ylmethyl)pyridin-2-amine 18.07g, dissolve the two in 0.5 In 1 L of toluene, 28.12 g of tetramethyl chlorourea hexafluorophosphate was added as a catalyst, and the reaction was sealed and stirred under microwave conditions to obtain a crude product;

[0043] (2) Remove the toluene from the crude product under reduced pressure, then add ethyl acetate and stir evenly, and use silica gel column chromatography to obtain the trifluoropyrimidine.

[0044] In this example, the 2-(3-(trifluoromethyl)phenyl)malonate is diethyl 2-(3-(trifluoromethyl)phenyl)malonate, and the solvent is toluene.

[0045] Specifically, the microwave condition is a microwave environment of 4 GHz, the stirring is continued at 300 r / min for 30 min, the column chromatography uses 100 g of silica gel, and the mobile phase used is ethyl acetate chloroform...

Embodiment 3

[0048] This embodiment is basically the same as Embodiment 2, the difference is:

[0049] In the process of removing the solvent under reduced pressure, the environmental vacuum starts from 50mmHg, and increases the environmental vacuum at a rate of 1mmHg / min until the environmental vacuum reaches 100mmHg, and the total duration is 60min .

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PUM

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Abstract

A preparation method of pemetrexed disodium is disclosed. The preparation method comprises the following steps: (1) dissolving 30-35 parts of 2-(3-(trifluoromethyl)phenyl) malonate and 15-20 parts ofN-(pyridin-5-yl methyl) pyridine-2-amine in a solvent, adding a catalyst, and carrying out a sealed stirring reaction under a microwave condition to obtain a crude product; and (2) removing the solvent from the crude product under reduced pressure, adding ethyl acetate, uniformly stirring, and carrying out silica gel column chromatography to obtain the pemetrexed disodium. According to the method,the 2-(3-(trifluoromethyl)phenyl) malonate and the N-(pyridin-5-yl methyl) pyridine-2-amine directly react under the conditions of the catalyst and microwaves, the reaction process is only one step,the reaction process is greatly shortened, and the yield of pemetrexed disodium is increased.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a preparation method of trifluoropyrimidine. Background technique [0002] Trifluoropyrimidine (Pemetrexed disodium), the chemical name is 3,4-dihydro-2,4-dioxo-1-(pyrimidin-5-ylmethyl)-3-(α,α,α-trifluoro m-tolyl)-2H-pyrido[1,2-α]pyrimidin-1-ium-3-salt, its structural formula is shown in formula 1 below: [0003] [0004] Trifluoropyrimidine is developed by DuPont Company of the United States to control rice planthoppers and acts on insect nicotinic acetylcholine receptors. [0005] At present, trifluoropyrimidine generally uses m-iodobenzotrifluorotoluene and diethyl malonate as raw materials, undergoes Ullmann reaction and ester hydrolysis to synthesize active ester, and cyclizes with substituted 2-aminopyridine to generate mesoionic compound 1, Its synthetic route is shown in the following formula: [0006] [0007] In the existing trifluoropyrimidine synth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04C07B2200/13
Inventor 彭大勇李保同史云莲石绪根汤丽梅彭文文
Owner JIANGXI AGRICULTURAL UNIVERSITY
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