New crystal form of pemetrexed diacid and method for preparing same

Abstract

The invention relates to organic chemistry and pharmacy field, and provides a new crystal form of a folic acid antagonist N-[4-[2-(2-amino-4, 7-dihydro-4-oxo-1H- pyrido[2, 3-d] pyrimidine-5-group) ethyl] benzoyl]-L-glutamate (pemetrexed diacid) and a method for preparing same. The method for preparing the new crystal form is simple and easy for the industrial production.

Description

technical field [0001] The present invention relates to the fields of organic chemistry and pharmacy, in particular to folic acid antagonist N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d ]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (compound of formula I, ie Pemetrexed diacid, a new crystal form of pemetrexed diacid) and a preparation method thereof. [0002] Background technique [0003] Pemetrexed dioic acid and its derivatives, as multi-target folate antagonists, can potently inhibit multiple folate-dependent enzymes, including thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycine Amide ribonucleotide formyltransferase (GARFT), etc., have excellent antitumor activity. At present, its disodium salt, Pemetrexed disodium (Pemetrexed disodium) has been listed in the United States, the European Union, Canada, China, Japan and other countries, and is used for the first-line treatment of malignant pleural mesothelioma and the first-line and second-lin...

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Problems solved by technology

Among these crystal forms, the solvents in the solvate crystal form C, crystal form D, and crystal form E have a higher boiling point (the boiling point of dimethyl sulfoxide is 189°C, and the boiling point of N,N-dimethylformamide is 156°C ), when used to further prepare pemetrexed disodium, these high-boiling point solvents may be introduced into the final product, increasing the burden on the control of organic residues in the final product; 160~200°C), and at such a temperature, pemetrexed diacid will be degraded to a certain extent, which is not conducive to the maintenance of product purity; although hydrate crystal forms A and B overcome the shortcomings of the previous crystal forms, However, the preparation yield of crystal form A is low (about 40%), and the practical value is not high; the preparation time of crystal form B is relatively long, and only crystallization takes about 18 hours, which is not conducive to the improvement of production efficiency

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