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Crystal form of Peimeiqusai disodium and its preparation

A technology of pemetrexed disodium and glutamic acid disodium salt, which is applied to medical preparations containing active ingredients, pharmaceutical formulations, organic active ingredients, etc. and other problems, to achieve the effect of simple operation, strong controllability and good reproducibility

Active Publication Date: 2008-01-30
重庆凯林制药有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The 2.5-hydrate pemetrexed disodium is extremely hygroscopic, and it is difficult to control its moisture to 2.5 crystal water in the actual preparation process; in addition, in the actual storage and use process, this product often causes measurement errors due to moisture absorption
Although pemetrexed disodium heptahydrate is non-hygroscopic, it will lose water and become a hydrate with crystal water number less than 7 at higher temperature, lower humidity and / or vacuum; in addition, the hydrate Compared with the 2.5 hydrate, the preparation process also increases the process of treating with wet nitrogen flow and the corresponding equipment, which increases the production cost

Method used

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  • Crystal form of Peimeiqusai disodium and its preparation
  • Crystal form of Peimeiqusai disodium and its preparation
  • Crystal form of Peimeiqusai disodium and its preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Preparation of Pemetrexed Disodium Trihydrate

[0050] In a 3L reaction flask, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl Base] benzoyl]-L-glutamic acid (pemetrexed) 230.0g (0.538mol) was dissolved in 1.3L of 1mol / L sodium hydroxide solution, and then adjusted the pH of the mixture to 8 with 1mol / L hydrochloric acid solution Left and right, filter, and measure the volume of the filtrate to about 1.8L. Heat the filtrate to 45-50°C in a 20L reaction bottle, add ethanol, and adjust the feeding speed so that the temperature of the mixture is not lower than 40°C. When about 7L of ethanol is added, a black gum will precipitate in the system. Remove the precipitate by filtration; then add 2 L of ethanol to the filtrate, stir and cool, during which a large amount of off-white solids are precipitated; when the system cools down to room temperature, collect the solids by filtration and wash with ethanol. Measured by HPLC: 98.25%, further purificati...

Embodiment 2

[0053] Preparation of freeze-dried powder injection with pemetrexed disodium trihydrate

[0054] Pemetrexed Disodium Trihydrate 90.0g

[0055] Mannitol 90.0g

[0056] Water for injection 2000ml

[0057] Weigh 90.0 g of pemetrexed disodium trihydrate and 90.0 g of mannitol, add 2000 ml of water for injection, stir well to dissolve completely, measure the pH of the solution after cooling, adjust the pH of the solution to 7.0 with hydrochloric acid or sodium hydroxide if necessary ~8.5, then set the volume to 2250ml; add 0.05% activated carbon, stir for 10 minutes, filter, and then carry out sterilizing filtration to the filtrate; fill it into a freeze-drying bottle with 12.5ml / bottle, and freeze-dry; Enter the sterile filtered nitrogen, press the stopper, and press the aluminum cap.

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Abstract

A crystal form of folic acid antagonistic N-(4-(2-(2-amino-4,7-methyl-4-oxo-1H-pyrrolo(2,3-d)pyrimidine-5-radical)ethyl)benzoyl)-L-glutamic acid disodium salt and its production are disclosed.

Description

technical field [0001] The present invention relates to the fields of organic chemistry and pharmacy. The present invention provides folic acid antagonist N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl A new hydrate crystal form of ]benzoyl]-L-glutamic acid disodium salt (compound of formula I, common name Pemetrexed disodium, pemetrexed disodium) and a preparation method thereof. [0002] Background technique [0003] Pemetrexed disodium is a potent inhibitor of several folate-dependent enzymes including thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT) Drug, clinical trials have shown that it is effective for a variety of solid tumors. At present, pemetrexed disodium has been listed in the United States, the European Union and other countries for the first-line treatment of malignant pleural mesothelioma and the second-line treatment of locally advanced and metastatic non-small ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/519A61K9/08A61P35/00C07D239/00C07D209/00
Inventor 叶文润罗杰张道林邓杰周永春
Owner 重庆凯林制药有限公司
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