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Preparation method of Raltitrexed

A technology of raltitrexed and methanol, which is applied in the field of preparation of raltitrexed, can solve the problems of exceeding the standard on ignition residue, and achieve the effects of improving quality, good quality and simple operation

Active Publication Date: 2014-07-30
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The inventor successfully invented a preparation method of raltitrexed through a large amount of research, successfully overcomes the deficiencies in the prior art, and solves the problem that the residue on ignition exceeds the standard

Method used

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  • Preparation method of Raltitrexed

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Embodiment 1 (reaction solvent is methanol and water)

[0026] 40g (0.07mol) N-[[5-[[(1,4-dihydro-2-methyl-4-oxo-6-quinazoline)methyl]methylamino]-2-thiophene]methanol Acyl]-L-glutamic acid diethyl ester, 1000ml of 1M NaOH solution, 142ml of methanol were added to the reaction flask, and the internal temperature was maintained at about 0°C, stirred for 2 hours, filtered, and the filtrate was extracted with dichloromethane (2×240ml), and water Layer with 4N hydrochloric acid to adjust the pH, when the pH is adjusted to 6, a small amount of viscous solids are precipitated, stop adding hydrochloric acid, keep stirring for 2 hours, continue to drop hydrochloric acid to adjust the pH to 2.5 after the viscous solid is completely solidified, Stir at this temperature for 10 hours. Filter, wash the solid with purified water until the filtrate is free of Cl- (detected by silver nitrate), and the crude product is obtained as a loose light yellow-green powder solid.

[0027] Put ...

Embodiment 2

[0028] Embodiment 2 (reaction solvent is ethanol and water)

[0029] 40g (0.07mol) N-[[5-[[(1,4-dihydro-2-methyl-4-oxo-6-quinazoline)methyl]methylamino]-2-thiophene]methanol Acyl]-L-glutamic acid diethyl ester, 1000ml of 1M NaOH solution, 142ml of ethanol were added to the reaction flask, and the internal temperature was maintained at about 0°C, stirred for 2 hours, filtered, and the filtrate was extracted with dichloromethane (2×240ml), and water Layer with 4N hydrochloric acid to adjust the pH, when the pH is adjusted to 6, a small amount of viscous solids are precipitated, stop adding hydrochloric acid, keep stirring for 2 hours, continue to drop hydrochloric acid to adjust the pH to 2.5 after the viscous solid is completely solidified, Stir at this temperature for 10 hours. Filter and wash the solid with purified water until the filtrate is free of Cl - (Silver nitrate detection), the crude product was obtained as a loose light yellow-green powder solid.

[0030] The re...

Embodiment 3

[0031] Embodiment 3 (reaction solvent is water, does not contain organic solvent)

[0032] 40g (0.07mol) N-[[5-[[(1,4-dihydro-2-methyl-4-oxo-6-quinazoline)methyl]methylamino]-2-thiophene]methanol Acyl]-L-glutamic acid diethyl ester, 1000ml 1M NaOH solution, keep the internal temperature at about 0°C, stir for 2 hours, filter, and extract the filtrate with dichloromethane (2×240ml), take the aqueous layer and adjust the pH with 4N hydrochloric acid, When the pH is adjusted to 6, a small amount of viscous solid precipitates, stop adding hydrochloric acid, keep stirring for 2 hours, the viscous solid does not solidify, continue to add hydrochloric acid until the pH is 2.5, the precipitated solid condenses into a strong viscous large Lumpy solids adhered to the stirring paddles, making it impossible to stir. After filtering, the product was washed with distilled water to obtain a viscous crude product.

[0033] The refining process of the crude product was the same as in Example ...

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Abstract

The invention discloses a preparation method of Raltitrexed. The method comprises steps of: carrying out alkaline hydrolysis on N-[[5-[(1,4- dihydro-2-methyl-4-oxygen-6quinazoline) methyl] formoxyl-]-2-thiophene] formyl]-L-glutamic acid diethyl ester with existence of a certain proportion of alcoholic solvent; filtering out insoluble substances after the reaction; then extracting with an organic solvent; adjusting a pH of a water layer to 6-7 during neutralization to precipitate a small amount of viscous solid and stirring for 1-3 h; After complete solidification of a product, adjusting a pH to 2-3 to precipitate all of the product; dissolving a crude product with an organic solvent; filtering an depriving insoluble substances; adding water and crystallizing to obtain a finished product. The preparation method of the present invention well solves a problem, which commonly exists in a technology, of severe exceeding of standard of residue on ignition, has simple operations, produces high-quality product with high yield and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular, the invention relates to a preparation method of raltitrexed, which successfully solves the problem that the residue on ignition of raltitrexed exceeds the standard. Background technique [0002] Raltitrexed (chemical name N-[[5-[[(1,4-dihydro-2-methyl-4-oxo-6-quinazoline)methyl]methylamino]-2-thiophene ]Formyl]-L-glutamic acid) is a quinazoline folate analogue and a new water-soluble inhibitor of thymidylate synthase. Can cause DNA fragmentation and cell death by inhibiting thymidylate synthase. Compared with 5-fluorouracil, it has stronger selectivity, and can replace fluorouracil in the treatment of advanced colorectal cancer, and has become the first-line drug for the treatment of advanced colorectal cancer. [0003] Raltitrexed was developed and created by the British Zeneca Pharmaceutical Company (US Patent US4992550), and it was first launched in the UK in 1996. The trade...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D409/12
Inventor 陈令武郭春红储结根梁慧兴何国正尹必喜
Owner YANGTZE RIVER PHARM GRP CO LTD
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