Industrialized production method of high-purity pemetrexed disodium

Abstract

The invention provides an industrialized production method of high-purity pemetrexed disodium, comprising the following steps of: (1) adding crude pemetrexed disodium into a reactor, adding water and stirring to dissolve at a temperature of 10-30 DEG C; (2) adding tetrahydrofuran or acetonitrile serving as a dissolvent into the reaction solution of the step (1), dissolving out a part of solids, adding kieselguhr or silica gel and stirring for 5-30 minutes; and (3) filtering the reaction solution of the step (2), adding dissolvent same as the dissolvent added in the step (2) into filtrate, crystallizing for 0.5-10 hours at a temperature of 10-30 DEG C, isolating solids, and drying for 0.5-10 hours at a temperature of 20-40 DEG C to obtain the high-purity pemetrexed disodium. By means of the production method, the shortcomings that in the prior art column chromatography, purification and heating are needed, the product purity is low, the operation is cumbersome and the industrialized production is difficult to realize are overcome; the production method is simple and convenient for operation, is easy to realize the industrialized production and has the advantages of few consumptionof dissolvent, energy saving, environmental protection and low labor intensity; and the products have the advantages of white color, high purity, less than 0.05% of impurities in a single product andgood stability.

Description

Technical field [0001] The invention relates to an industrialized production method of high-purity pemetrexed disodium, which belongs to the technical field of medicinal chemistry. Background technique [0002] Pemetrexed disodium chemical name: N-{4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl) Ethyl]benzoyl}-L-glutamate disodium [0003] Its structural formula is: [0004] [0005] Pemetrexed disodium is a new multi-target folate blocker, which can block a variety of enzymes needed in the process of cancer cell division and proliferation, including thymidine synthase TS and dihydrofolate reductase (DHFR) And glycine ribonucleoside formyltransferase (GARFT), and even inhibit the activity of all folate-dependent enzymes in the biosynthesis of thymidine and purine nucleotides. Developed by Eli Lilly of the United States, it was first marketed in the United States in 2004 for the treatment of malignant pleural mesothelioma and non-small cell lung cancer. In February...

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Problems solved by technology

Wherein the product crystallization method used all is water dissolution, adds the method for direct crystallization such as ethanol, isopropanol, because the impurity gained in the synthetic process of pemetrexed disodium is dissolved in water the same as product under alkaline condition, Then add anti-solvents such as ethanol, isopropanol and other solvents, the impurities will be precipitated together, and the effect of removing impurities is basically not achieved

[0008] In addition, the purification method disclosed in Chinese patent CN200710092879.7 is to add saturated sodium salt, potassium salt, etc. to the pemetrexed disodium crude product solution to precipitate the product pemetrexed disodium, but the pemetrexed disodium dissolves in water The product is relatively large, adding saturated sodium salt, potassium salt, etc. generally precipitates few products, and the loss is very large; especially when the crude product of pemetrexed disodium is high in purity, the lower yield will greatly increase the cost of the product; In addition, the solid product separated out by this method is often wrapped with excessive salt, which makes the product content low and introduces inorganic impurities.

[0009] Chinese patent CN200810037024.9 discloses pemetrexed disodium amorphous polymorph and its preparation method. The method used is to add pemetrexed to an organic solvent and dissolve it, and add sodium hydroxide solution to crystallize to obtain the product ; This method at first pemetrexed solubility in organic solvent is very little, needs a large amount of solvent and heating to dissolve, then adding alkaline solution will certainly make product damage, impurity increase, can't reach the purpose of refining and removing impurity

[0011] The above known technologies cannot effectively remove impurities, and the color of the resulting product is off-white or light green, and the individual impurities are generally more than 0.2%; it is very difficult to continue to improve its purity on this basis, especially to control the single impurity within Below 0.1% is unattainable, it is difficult to meet the quality requirements of injection raw materials, and it also fails to meet the relevant technical requirements of ICH, the European Union's quality research technical guidelines

If the raw materials with high impurities are used to make injections, it is bound to bring high adverse reactions to patients

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