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Pemetrexed quality control method, and preparation of pemetrexed impurity and salt thereof

A pemetrexed and impurity technology, applied in the field of medicinal chemistry, can solve the problems of lack of reliable basis for drug safety and effectiveness research, difficulty in ensuring product quality, etc., achieve high product purity, strengthen impurity control, and mild reaction conditions Effect

Active Publication Date: 2012-11-28
JIANGSU SENRAN CHEM +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are many impurities in pemetrexed, and the retention time of each impurity is very close, it is difficult to obtain a pure single impurity by column chromatography
Therefore, when studying the influence of impurities in the pemetrexed disodium drug on the stability and efficacy of the drug in the later stage, because there is no single impurity pure product with higher purity and better quality as a control, the safety and effectiveness of the drug is lacking. Reliable basis, difficult to guarantee product quality control

Method used

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  • Pemetrexed quality control method, and preparation of pemetrexed impurity and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Dissolve 7.8g of the compound represented by formula (6) in 100ml of dichloromethane solution, then add 4.8g of dicyclohexylcarbodiimide, 0.2g of 4-dimethylaminopyridine, 5ml of absolute ethanol, and stir at room temperature for reaction 4 Hours, the solvent was removed by suction filtration to obtain 8.3 g of the compound represented by formula (5). MS[M+1] + 366.

[0032] Dissolve 8.3 g of the compound represented by formula (5) in 60 ml of methanol, add 0.8 g of palladium carbon, hydrogenate at room temperature for 2 hours, remove the palladium carbon by suction filtration, and remove the solvent from the filtrate under reduced pressure to obtain 4.6 g of the compound represented by formula (4). compound. MS[M-1] - 274.

[0033] Dissolve 4.6g of the compound shown in formula (4) in 50ml of dichloromethane solution, add 7.8g of N,N-dicyclohexylcarbodiimide, 3.3g of hydroxybenzotriazole, 11.5g of diethyl glutamic acid Esters, reacted for 1 hour while stirring at 0...

Embodiment 2

[0044]Dissolve 8.2g of the compound represented by formula (6) in 100ml of ether solution, then add 4.5g of dicyclohexylcarbodiimide, 0.2g of 4-dimethylaminopyridine, 5ml of absolute ethanol, and stir at room temperature for 2 hours. The solvent was removed by suction filtration to obtain 8.3 g of the compound represented by formula (5). MS[M+1] + 366.

[0045] Dissolve 8.2 g of the compound represented by formula (5) in 60 ml of 2-propanol, add 0.8 g of palladium carbon, hydrogenate at room temperature for 1 hour, remove the palladium carbon by suction filtration, and remove the solvent from the filtrate under reduced pressure to obtain 4.5 g of formula (4) Compounds shown. MS[M-1] - 274.

[0046] Dissolve 4.5g of the compound shown in formula (4) in 50ml petroleum ether solution, add 7.8g N,N-dicyclohexylcarbodiimide, 3.3g hydroxybenzotriazole, 4.5g diethyl glutamate , reacted for 1 hour while stirring at 0°C, and reacted for 10 hours while stirring at room temperature,...

Embodiment 3

[0057] Dissolve 7.6g of the compound represented by formula (6) in 100ml of petroleum ether solution, then add 4.5g of dicyclohexylcarbodiimide, 0.2g of 4-dimethylaminopyridine, 5ml of absolute ethanol, and stir at room temperature for 6 hours , and the solvent was removed by suction filtration to obtain 8.3 g of the compound represented by formula (5). MS[M+1] + 366.

[0058] Dissolve 8.0 g of the compound represented by the formula (5) in 60 ml of isobutanol, add 0.8 g of palladium carbon, hydrogenate at room temperature for 3 hours, remove the palladium carbon by suction filtration, and remove the solvent from the filtrate under reduced pressure to obtain 4.5 g of the compound represented by the formula (4). the indicated compounds. MS[M-1] - 274.

[0059] Dissolve 4.5g of the compound shown in formula (4) in 50ml of ether solution, add 7.8g of N,N-dicyclohexylcarbodiimide, 3.3g of hydroxybenzotriazole, 4.5g of diethyl glutamate, React for 1 hour while stirring at 0°C,...

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Abstract

The invention provides a pemetrexed quality control method, and preparation of a pemetrexed impurity and salt thereof. The pemetrexed impurity is synthesized from the raw material N-tert-butoxycarbonyl-L-glutamic acid-5-benzyl ester. The pemetrexed quality control method mainly uses the pemetrexed impurity prepared by the technique as a standard control substance in detection and analysis. The method provided by the invention solves the problem that the pemetrexed impurity can only be separated and obtained in the preparation process of the pemetrexed and sodium salt thereof in the prior art, and the high-purity pemetrexed impurity can not be obtained. The method is simple to operate, and has the advantages of low facility request, mild reaction conditions, high product purity and high yield.

Description

Technical field [0001] The present invention involves the field of pharmaceutical chemistry, especially in the quality control method of Permeuscern and the preparation of Peimevzer's impurities and its salt. Background technique [0002] Pemeuscerus is a new multi -target folic acid stagnation, which can block multiple enzymes required for cancer cell division and hyperplasia. By destroying the normal metabolic process of intracellular folic acid dependence, inhibiting cell replication, thereby inhibitingTumor growth.Developed by the US ELI Lilly Company, it was first launched in the United States in 2004 to treat malignant pleural dermatoma and non -small cellular lung cancer. In February 2004, FDA was approved and used in cisplatin to treat malignant interstitial cortex. [0003] The medicinal form of Permeusus is usually salt, and the most common is its second sodium salt. Due to the synthesis process of Permeuscer's sodium, it is easy to produce impurities, and it is difficu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04G01N33/15
CPCY02P20/55
Inventor 袁建栋刘涛任晓岚
Owner JIANGSU SENRAN CHEM
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