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Amorphous polymorph for pemetrexed disodium and preparation method thereof

A technology for pemetrexed disodium and polymorphic form, which is applied to the amorphous polymorphic form of pemetrexed disodium and its preparation field, and can solve the problems of unstable quality, large solvent residue, and difficulty in controlling crystal water. and other problems, to achieve the effect of simple drying and low production cost

Inactive Publication Date: 2009-11-11
SHANGHAI ACEBRIGHT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In experiments, we found that the quality of 2.5 hydrates was unstable (this has been reported in CN1183135C); although the stability of 3 hydrates is better than the former, it has the problem that it is difficult to control the water of crystallization when it is dry, that is to say, in In production, it is easy to dry to 2.5 crystalline water, and the solvent residue in the product is also relatively large; the quality of the 7 hydrate is very stable, but it is very easy to lose water when stored under high temperature, low humidity or vacuum conditions. A hydrate with crystal water number less than 7 (this has been reported in CN1778802A), in addition, the drying process of this hydrate is compared with the drying process of 2.5 crystal hydrates, and the process of treating with wet nitrogen flow and corresponding equipment, which increases production costs

Method used

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  • Amorphous polymorph for pemetrexed disodium and preparation method thereof
  • Amorphous polymorph for pemetrexed disodium and preparation method thereof
  • Amorphous polymorph for pemetrexed disodium and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Add 3.3g (7.7mmol) of pemetrexed to 50ml of methanol, heat to 40°C under nitrogen atmosphere, then dropwise add 30ml of methanol solution of sodium hydroxide (0.65g, 16.2mmol), react for 1h, and cool down to Crystallize at 5°C, filter, and dry the filter cake under reduced pressure at 50°C to obtain 3.2 g of powder, which is amorphous as detected by XRD.

Embodiment 2

[0054] Add 50g (117.0mmol) of pemetrexed to 1500ml of ethanol, under nitrogen atmosphere, heat to 30°C, then dropwise add 200ml of ethanol solution of sodium hydroxide (9.64g, 241.0mmol), react for 2h, cool to 10 °C, crystallized, filtered, and the filter cake was dried under reduced pressure at 50 °C to obtain 52.5 g of powder, which was detected as amorphous by XRD.

Embodiment 3

[0056] Add 20kg (46.8mol) of pemetrexed to 400L of methanol, under a nitrogen atmosphere, the temperature is controlled at 15°C, and then 50L of methanol solution of sodium hydroxide (3.8kg, 95.4mol) is added dropwise, and the reaction is kept at 25°C for 3h , part of the solvent was evaporated and the temperature was lowered to 5° C., crystallized, filtered, and the filter cake was dried to dryness under reduced pressure at 50° C. to obtain 21.6 kg of powder, which was detected as amorphous by XRD.

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Abstract

The invention discloses an amorphous polymorph for pemetrexed disodium and a preparation method thereof. An X-ray powder diffraction pattern of the amorphous polymorph does not contain an identifiable diffraction peak form. For not containing crystal water, the amorphous polymorph for the pemetrexed disodium is simple to dry on production, does not need special equipment, has low production cost, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a crystal form of pemetrexed disodium and a preparation method thereof, in particular to a new amorphous polymorph of pemetrexed disodium and a preparation method thereof. Background technique [0002] Pemetrexed disodium chemical name: N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidine-5- Base) ethyl] benzoyl] -L-glutamic acid disodium salt, its structural formula is as follows: [0003] [0004] Pemetrexed is disodium, a multi-target anti-metabolite drug, which is a variety of folate-dependent enzymes including thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycyl amino ribonucleoside It is a powerful inhibitor of acid formyltransferase (GARFT) and also has a certain inhibitory effect on aminoimidazole carboxamide nucleoside formyltransferase (AICARFI). Clinical trials have shown that it is effective for a variety of solid tumors. [0005] Currently disclosed pemetrexed disodium crystal forms i...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P35/00
Inventor 李金亮蔡志刚王锰
Owner SHANGHAI ACEBRIGHT PHARMA CO LTD
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