Novel crystal form of pemetrexed disodium and preparation method thereof

Abstract

The invention discloses a novel crystal form of pemetrexed disodium and a preparation method thereof. The novel crystal form of pemetrexed disodium is marked as a crystal form X for short, wherein X is hydrate of the pemetrexed disodium, and in an X-ray powder diffraction spectrogram, characteristic diffraction peaks emerge at 2 theta diffraction angles of 7.82 degrees, 9.20 degree, 12.84 degrees,18.70 degrees, 19.56 degrees, 24.60 degrees and 24.93 degrees; the test error is +/-0.2 degree. According to the novel crystal form of the pemetrexed disodium and the preparation method thereof, thenovel crystal form of the pemetrexed disodium is hydrate, has no toxic effect of solvent and low content of water so that filtration and drying can be easy, and has good thermal stability, high wet stability and especially excellent fluidity and compressibility; besides, the novel crystal form of the pemetrexed disodium can be made into tablets and other forms of oral preparations through pressing, and therefore great significance can be provided for the development of the subsequent preparations.

Description

technical field [0001] The invention relates to a new crystal form of pemetrexed diacid and a preparation method thereof, belonging to the technical field of medicinal chemistry. Background technique [0002] Pemetrexed diacid, its chemical name is: N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine- 5-yl) ethyl] benzoyl] -L-glutamic acid, the chemical structural formula is: [0003] This compound is an important precursor of Pemetrexed Disodium, a drug for treating tumors developed by Eli Lilly and Company of the United States. It was approved for marketing by the European Union on January 18, 2016. The dosage form of this drug is injection. [0004] Various crystal forms of pemetrexed diacid have been disclosed in the prior art, for example: US20080045711 discloses pemetrexed diacid crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, wherein: crystal form A and crystal form B are hydrates, crystal ...

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Problems solved by technology

[0004] Various crystal forms of pemetrexed diacid have been disclosed in the prior art, for example: US20080045711 discloses pemetrexed diacid crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, wherein: crystal form A and crystal form B are hydrates, crystal form C is dimethyl sulfoxide solvate, crystal form D and crystal form E are N,N-dimethyl Formamide solvate, crystal form F and crystal form G are anhydrous; international patent application WO2010031357 discloses pemetrexed dioic acid crystal form H, crystal form I and crystal form J, these three crystal forms are Hydrate; the international patent application WO2014185797 also discloses pemetrexed dioic acid crystal form 1 and crystal form 2, both of which are dimethyl sulfoxide solvates; studies have shown that: crystal form A The preparation yield is low (about 40%), filtration is difficult, the preparation cost is too high, and the preparation time of crystal form B is relatively long, and it takes about 18 hours to only crystallize, which is not conducive to scale-up production; crystal form C, crystal form D and Form E is a solvate with a high boiling point. In the process of further preparation of finished preparations, high boiling point solvents may be introduced into the finished product, resulting in excessive solvent residues in the finished product, resulting in solvent toxicity; Form F and Form G are obtained by drying at high temperature. Therefore, the stability is poor, and at the drying temperature, the product will be degraded to a certain extent, which is not conducive to the maintenance of product purity; the water content of crystal form H, crystal form I and crystal form J is too high (up to 80%), which is not conducive to Storage and transportation of samples; since both crystal form 1 and crystal form 2 are prepared from dimethyl sulfoxide, and dimethyl sulfoxide is a high-boiling solvent, the product contains more dimethyl sulfoxide solvent, which has a solvent Toxicity; the point is that the existing crystal forms of pemetrexed dioic acid have poor fluidity and poor compressibility, and cannot be compressed and prepared into oral preparations, so that they can only be used in the market as injections at present, and the production cost is relatively high. Defects such as inconvenient use

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