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Process for preparing pemetrexed

A technology of pemetrexed and compounds, applied in the field of pemetrexed, can solve the problems of long operation period and complex process, and achieve the effect of simple operation and favorable industrial production

Active Publication Date: 2006-10-04
QILU PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In these methods, the preparation of the compound of formula (4) needs to be carried out under anhydrous conditions, and the product needs to be purified by column chromatography and use toxic solvents such as dichloromethane. Obtain product formula (1) pemetrexed, therefore all there is the defective of long operating cycle, complex process

Method used

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  • Process for preparing pemetrexed
  • Process for preparing pemetrexed
  • Process for preparing pemetrexed

Examples

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Embodiment 1

[0030] Add 100ml of deionized water, 10.0g (68.0mmol) of L-glutamic acid, and 7.0g (69.0mmol) of N-methylmorpholine into the reaction flask, stir until completely dissolved, then add 200ml of dimethylformamide to obtain a clear solution.

[0031] Under a nitrogen atmosphere, 7.0 g (69.0 mmol) of N-methylmorpholine and 11.7 g (66.6 mmol) of 4-chloro-2,6-dimethoxytriazine were added to 4-[2-(2-amino -4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid (10.0g, 33.5mmol) in dimethylformamide (150ml ) solution, stirred at room temperature for 1 hour. The reaction solution was slowly dropped into the L-glutamic acid solution prepared above in about 0.5 hours to obtain a clear reaction solution, which was stirred at room temperature for 2 hours. Suction filtration, the filtrate was adjusted to pH 2.5-3.5 with 2N hydrochloric acid, the reaction solution was transferred to a 5L reaction flask, 4L deionized water was slowly added, stirred for 1 hour, and suction filtr...

reference example 1

[0034]Under a nitrogen atmosphere, 7.0 g (69.0 mmol) of N-methylmorpholine and 11.7 g (66.6 mmol) of 4-chloro-2,6-dimethoxytriazine were added to 4-[2-(2-amino -4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid (10.0g, 33.5mmol) in dimethylformamide (200ml ) solution. Stir at room temperature for 1 hour, add 7.0 g (69.0 mmol) of N-methylmorpholine and 10.0 g (41.7 mmol) of L-diethyl glutamate hydrochloride, and stir at room temperature for 2 hours. Add 400ml of deionized water and 200ml of dichloromethane to the reaction solution, wash the organic layer with 200ml of deionized water × 2, concentrate, purify by silica gel chromatography (eluent, methanol: dichloromethane 1: 4), combine the pure components, Concentration to give the product N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzene Formyl]-L-glutamic acid diethyl ester 6.7g (13.9mmol), yield 41.5%.

[0035] The above product N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrol...

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Abstract

The related preparation method in hydrosolvent for N-[4-]2-(2-amido-4, 7-dihydro-4-oxo-3H- pyrrolo[2, 3-d]pyrimidine-5-radical)ethyl]benzoyl]-L-glutacid (Pemetrexed) and its acceptable salt in pharmacy is to react the 4-[2-(2-amido-4, 7-dihydro-4-oxo-3H-pyrrolo[2, 3-d] pyrimidine- 5-radical)ethyl]benzoic acid with L-glutacid dissolved in organic solvent and water. This invention is more simple than prior art and fit to industrial production.

Description

technical field [0001] The present invention relates to pemetrexed, namely N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl ) A method for preparing ethyl]benzoyl]-L-glutamic acid and pharmaceutically acceptable salts thereof. Background technique [0002] Pemetrexed (see the following formula (1) for its structure, and its chemical name is N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3 -d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid) [0003] [0004] It is an antineoplastic drug that acts on folate-dependent pathways with multiple targets, and is a cell cycle-specific antimetabolite drug. Its main targets are thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycine Aminoamide nucleotide transformylase (GARFT) affects the synthesis of purine and pyrimidine through the inhibition of these key enzymes, thereby inhibiting DNA synthesis. Clinical studies have proved that its single drug is effective for a variety of tumors, including non-sm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P35/00C07D239/00C07D209/00
Inventor 范传文林栋单衍强郭可飞张芸刘洪艳
Owner QILU PHARMA CO LTD
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