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A kind of crystal form of pralatrexate and preparation method thereof

A technology of pralatrexate and its crystal form, which is applied in the field of medicine, can solve problems such as low crystallinity of the crystal form and difficulty in meeting the production requirements of the pharmaceutical industry, and achieve the effects of high crystallinity, simple preparation method, and mild crystallization conditions

Active Publication Date: 2018-08-21
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] WO2012061469 discloses three crystal forms A, B, and C of pralatrexate and corresponding preparation methods. Since the method used in this patent is the suspension beating method for crystallization, the crystallinity of the obtained crystal form is not high, and the purity of the product is uniform. Below 99.0%, it is difficult to meet the production requirements of the pharmaceutical industry

Method used

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  • A kind of crystal form of pralatrexate and preparation method thereof
  • A kind of crystal form of pralatrexate and preparation method thereof
  • A kind of crystal form of pralatrexate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1 Preparation of pralatrexate D crystal form

[0037] Pralatrexate was prepared according to the preparation method described in the document "Synthesis and Antitumor Activity of 10-Propargyl-10-deazaaminopterin" J.MedChem.1993, 36:2228-2231 by DeGraw et al., with a purity of 97.01%.

[0038] Take 15.0g of pralatrexate, add 100mL of N,N-dimethylformamide, raise the temperature to 50°C, stir for 10 minutes, add 50mL of acetonitrile dropwise, cool and crystallize naturally, keep warm at room temperature for 4 hours to continue the crystallization, After filtering, the filter cake was rinsed with 30 mL of acetonitrile, and the filter cake was vacuum-dried at 50° C. to obtain 12.1 g of pralatrexate Form D with a purity of 98.6%. it has figure 1 X-ray powder diffraction pattern shown.

Embodiment 2

[0039] Embodiment 2 Preparation of pralatrexate E crystal form

[0040] 1000mL reaction bottle, add 500mL ethanol aqueous solution (V 乙醇 :V 水 =3:2), heat up to 50°C, add 10.0g of pralatrexate crystal form D prepared in Example 1, stir until the solid dissolves, cool and crystallize naturally, keep warm at 25°C for 6 hours to continue the crystallization , filtered, the filter cake was rinsed with 20 mL of ethanol, and the filter cake was vacuum-dried at 60° C. for 30 hours to obtain 7.8 g of pralatrexate Form E.

Embodiment 3

[0041] Embodiment 3 Preparation of pralatrexate E crystal form

[0042] 500mL reaction bottle, add 250mL ethanol aqueous solution (V 乙醇 :V 水 =3:2), heat up to 80°C, add 10.0g of pralatrexate crystal form D prepared in Example 1, stir until the solid dissolves, cool down and crystallize naturally, and keep warm at 25°C for 6 hours to continue the crystallization , filtered, the filter cake was rinsed with 20 mL of ethanol, and the filter cake was vacuum-dried at 60° C. for 30 hours to obtain 8.6 g of pralatrexate E crystal form.

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Abstract

The invention provides a pralatrexate crystal form and a preparation method thereof, and concretely relates to a pralatrexate E crystal form, a preparation method thereof, a crystallized composition containing the pralatrexate E crystal form, and a medicinal composition containing the pralatrexate E crystal form. The pralatrexate E crystal form prepared in the invention has the advantages of high purity, high degree of crystallization, and good stability; and the preparation method of the pralatrexate E crystal form has the advantages of simplicity, cheap and easily available solvent, mild crystallization conditions, and suitableness for industrial production.

Description

technical field [0001] The invention relates to a crystal form of pralatrexate and a preparation method thereof, belonging to the technical field of medicine. Background technique [0002] In small molecule pharmaceutical compounds, the polymorphism of solid structure usually manifests as the diversity of crystal forms, which is a characteristic of some molecules and molecular complexes. A single molecule, such as: pralatrexate can form polymorphic complexes, with different crystal forms and physical properties, such as: melting point, solubility, thermogravimetric analysis, differential thermal analysis, X-ray diffraction powder pattern and solid NMR Different features appear in the resonance spectrum. Any one or more of these methods can be used to identify different crystal forms. [0003] A variety of crystal forms and solvates can obtain ideal processing properties, such as: easy to obtain, easy to prepare, storage stability, easy to purify or easy to convert into ide...

Claims

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Application Information

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IPC IPC(8): C07D475/08A61K31/519A61P35/00
CPCC07D475/08
Inventor 周舟张爱明张喜全胡志朱雪焱袁哲东
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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