Synthesis method of intermediate of pemetrexed disodium impurity

A kind of technology of pemetrexed disodium and synthetic method, applied in the synthetic field of intermediate, can solve the problems such as synthetic method that have not been reported

Inactive Publication Date: 2015-02-11
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Its synthetic method has not been reported in existing patents and literatures

Method used

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  • Synthesis method of intermediate of pemetrexed disodium impurity
  • Synthesis method of intermediate of pemetrexed disodium impurity
  • Synthesis method of intermediate of pemetrexed disodium impurity

Examples

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example 1

[0022] Take 50g of compound II nitrile ethyl acetate, put it into a 1000ml three-necked flask, add 400ml of absolute ethanol, add 36.1g of sodium ethylate and 88g of compound I ethyl formate propionyl chloride under stirring, heat and reflux for 6 hours, and then evaporate to dryness under reduced pressure Solvent, then add 500ml of toluene and 300ml of purified water to the three-necked flask, stir for 30 minutes and separate the water layer, add 15g of magnesium sulfate to the toluene layer to dry for 2 hours, then filter, add 22g of compound IV guanidine to the filtrate, heat and reflux for 4 hours , and then the solvent was evaporated to dryness to obtain 90.5 g of oil, with a purity of 95.3% and a yield of 71.3%.

example 2

[0024] Take 50g of compound II nitrile ethyl acetate, put it into a 1000ml three-neck flask, add 400ml of anhydrous methanol, add 28.7g of sodium methoxide under stirring, compound I p-ethyl formate propionyl chloride 88g, heat and reflux for 5 hours, and then evaporate to dryness under reduced pressure Solvent, then add 500ml of toluene and 300ml of purified water to the three-necked flask, stir for 30 minutes and separate the water layer, add 15g of magnesium sulfate to the toluene layer to dry for 2 hours, then filter, add 22g of compound IV guanidine to the filtrate, heat and reflux for 4 hours , and then the solvent was evaporated to dryness to obtain 87.2 g of oily matter with a purity of 96.4% and a yield of 69.5%.

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Abstract

The invention discloses a synthesis method of an intermediate of a pemetrexed disodium impurity, belonging to the field of drug synthesis. A compound V ethyl N-4-[3-(2,6-diamido-1,4-dihydro-4-oxy-5-pyrimidyl)-3-carbonylpropyl]benzoate is the key intermediate of the pemetrexed disodium impurity N-[4-[3-(2,6-diamido-1,4-dihydro-4-oxy-5-pyrimidyl)-3-carbonylpropyl]benzoic]-L-glutamic acid. The synthesis method comprises the following steps: reacting a compound I ethyl p-formate propionyl chloride and a compound II ethyl cyanoacetate to obtain a compound III ethyl N-4-[2-cyanoacetic-ether-3-carbonylpropyl]benzoate, and reacting the compound III with a compound IV guanidine to obtain the ethyl N-4-[3-(2,6-diamido-1,4-dihydro-4-oxy-5-pyrimidyl)-3-carbonylpropyl]benzoate.

Description

technical field [0001] The invention relates to a synthesis method of an intermediate of pemetrexed disodium impurity. Background technique [0002] Pemetrexed disodium, chemical name N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5- Base) ethyl] benzoyl] -L-glutamic acid disodium salt is a multi-targeted antifolate agent developed by Eli Lilly Company of the United States, which is suitable for the combined treatment of inoperable malignant pleural mesothelioma with cisplatin. N-[4-[3-(2,6-diamino-1,4-dihydro-4-oxo-5-pyrimidine)-3-carbonylpropyl]benzoic acid]-L-glutamic acid is pemet The impurity of trecet disodium, ethyl N-4-[3-(2,6-diamino-1,4-dihydro-4-oxo-5-pyrimidine)-3-carbonylpropyl]benzoate is the Key intermediates for impurities. [0003] Its synthetic method has not been reported in existing patents and literatures. Contents of the invention [0004] The invention introduces a method for synthesizing the intermediate of the pemetrexed disodiu...

Claims

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Application Information

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IPC IPC(8): C07D239/48
CPCC07D239/48
Inventor赵孝杰刘远慧
OwnerSHANDONG BOYUAN PHARM CO LTD