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Preparation method of Raltitrexed

A technology of raltitrexed and methanol, applied in the field of preparation of raltitrexed, can solve problems such as excessive ignition residue, and achieve the effects of improving quality, high product yield and good quality

Active Publication Date: 2012-04-25
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
Comparison scheme
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]formyl-]-2-thiophene]formyl ]-L-diethyl glutamate, 1000ml 1M NaOH solution, 142ml methanol was 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 - (Detected by silver nitrate), the crude product was obtained as a loose light yellow-green powder solid.

[0027] Put the crude product in a 100...

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]formyl-]-2-thiophene]formyl ]-L-diethyl glutamate, 1000ml 1M NaOH solution, 142ml 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 - (Detected by silver nitrate), the crude product was obtained as a loose light yellow-green powder solid.

[0030] The refining process of the cru...

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]formyl-]-2-thiophene]formyl ]-L-diethyl glutamate, 1000ml 1M NaOH solution, keep the inner temperature at about 0°C, stir for 2 hours, filter, 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 is the same as in Example 1, the residue on ignition is...

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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]formyl-]-2-thiophene] Formyl]-L-glutamic acid) is a quinazoline folate analog 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 listed in the UK in 1996. Its trade name is ...

Claims

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Application Information

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Patent Type & Authority Applications(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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