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Method for preparing pemetrexed disodium 2.5 water crystal

A pemetrexed disodium and crystallization technology, which is applied in the field of preparation of 2.5 hydrate crystals, can solve the problems of difficult removal of solvent residues, increased production costs, and difficulty in obtaining pure 2.5 hydrate forms, etc.

Active Publication Date: 2011-05-11
SHANGHAI ACEBRIGHT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The inventors found that the pemetrexed disodium 2.5 hydrate crystal obtained according to the preparation method disclosed in WO0114379 has strong hygroscopicity, and it is difficult to control its moisture to 2.5 crystal water during the preparation process. In addition, it is difficult to obtain Pure 2.5-hydrate form with a little 7-hydrate mixed in its crystals
Although the hygroscopicity of the pemetrexed disodium of the 3 hydrate is slightly weaker than the hygroscopicity of the pemetrexed disodium of the 2.5 crystalline hydrate disclosed in WO0114379, there is still the problem that it is difficult to control the water of crystallization when drying, and the solvent in the product Residues are also difficult to remove
And although the pemetrexed disodium of 7 hydrates has no hygroscopicity, it is prone to dehydration to become a hydrate less than 7 in storage under higher temperature, lower humidity or vacuum conditions (existing in CN1778802 report), in addition, compared with the drying process of 2.5 crystal hydrate, the drying process of 7 hydrate also increases the process and corresponding equipment with wet nitrogen flow, which increases the production cost

Method used

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  • Method for preparing pemetrexed disodium 2.5 water crystal
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  • Method for preparing pemetrexed disodium 2.5 water crystal

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Under the protection of argon, add 10 g of pemetrexed disodium into 60 ml of water, stir and heat up until the system dissolves;

[0026] Then the aqueous solution was added dropwise to 480ml of absolute ethanol at room temperature for 30 minutes, and after the drop was completed, the temperature was lowered to 5° C. and kept for 30 minutes. After filtering, the filter cake was dried under reduced pressure at 50° C. to obtain 9.5 g of pemetrexed disodium 2.5 hydrate.

[0027] According to the method stipulated in the Chinese Pharmacopoeia, the obtained product was subjected to accelerated and long-term stability experiments, its water content was regularly measured and its crystal form was analyzed by X-ray powder diffraction. The specific data are shown in Table 1 and Table 2.

[0028] Table 1 Pemetrexed Disodium 2.5 Hydrate Stability Investigation Accelerated Experiment

[0029]

[0030] Table 2 Pemetrexed disodium 2.5 hydrate stability investigation long-term exp...

Embodiment 2

[0036] Add 10 g of pemetrexed disodium into 60 ml of water under argon protection, stir and heat up until the system dissolves;

[0037] Then the aqueous solution was added dropwise to 600ml of isopropanol at room temperature for 1 hour, and after the drop was completed, the temperature was lowered to 10° C. and kept for 1 hour. After filtering, the filter cake was dried under reduced pressure at 50° C. to obtain 9.3 g of pemetrexed disodium 2.5 hydrate.

[0038] Using the same method as in Example 1, the acceleration and long-term stability tests were carried out, and the results were basically the same as in Example 1.

Embodiment 3

[0040] Under the protection of argon, add 10g of pemetrexed disodium into 50ml of water, stir and heat up until the system dissolves; then add the aqueous solution dropwise to 650ml of acetone at room temperature, the dropping time is 1 hour, and cool down after dropping Incubate at 5°C for 1 hour. After filtering, the filter cake was dried under reduced pressure at 50° C. to obtain 9.0 g of pemetrexed disodium 2.5 hydrate. Using the same method as in Example 1, the acceleration and long-term stability tests were carried out, and the results were basically the same as in Example 1.

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Abstract

The invention provides a method for preparing a pemetrexed disodium 2.5 water crystal. The method comprises the following steps of: (1) dissolving a raw material, namely pemetrexed disodium in water; (2) dropwise adding the aqueous solution of the pemetrexed disodium into an organic solvent which can be miscible with the water, and crystallizing; and (3) filtering, collecting a filter cake, and drying to obtain a target product. The preparation method is high in controllability, easy and convenient to operate, high in repeatability, high in production yield, and stable in crystal form and industrial production is easy to implement, and special equipment is not required.

Description

technical field [0001] The invention relates to a preparation method of pemetrexed disodium crystals, in particular to a new preparation method of pemetrexed disodium 2.5 hydrate crystals. 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 disodium is 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. At present, it has been listed in more than 70 countries including the United States and the Eur...

Claims

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Application Information

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IPC IPC(8): C07D487/04
Inventor 刘蔚蔡志刚王锰
Owner SHANGHAI ACEBRIGHT PHARMA CO LTD
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