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High-purity Pralatrexate solid and preparation method thereof

A high-purity, solid technology, applied in the field of medicine, can solve problems such as difficult to meet the production requirements of the pharmaceutical industry

Active Publication Date: 2016-01-27
LIANYUNGANG RUNZHONG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although WO2012061469 discloses three crystal forms A, B, and C of pralatrexate and corresponding preparation methods, the method used in this patent is a suspension beating method for crystal transformation, and the purity of the obtained products is all below 99.0%, which is difficult to meet Production requirements of the pharmaceutical industry

Method used

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  • High-purity Pralatrexate solid and preparation method thereof
  • High-purity Pralatrexate solid and preparation method thereof
  • High-purity Pralatrexate solid and preparation method thereof

Examples

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Effect test

Embodiment 1

[0051] Embodiment 1 Preparation of pralatrexate D crystal form

[0052] Pralatrexate was prepared according to the preparation method described in the document "Synthesis and Antitumor Activity of 10-Propargyl-10-deazaaminopterin" J.Med.Chem.1993,36:2228-2231 by DeGraw et al., with a purity of 97.01%.

[0053] 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 at room temperature at 25°C for 4 hours to continue the crystallization, filter , 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. DSC: 197.3°C.

Embodiment 2

[0054] Embodiment 2 Preparation of high-purity pralatrexate crystals

[0055] 1000mL reaction flask, add 500mL acetone aqueous solution (V 丙酮 :V 水 =3:2), heat up to 55-60°C, add 10.0g of pralatrexate D crystal form prepared in Example 1, stir until the solid dissolves, cool down naturally for 2 hours, and then cool down to 15±5°C Crystallize for 8 hours, filter, rinse the filter cake with 20 mL of ethanol, and vacuum-dry the filter cake at 60° C. for 30 hours to obtain 7.6 g of pralatrexate as a solid. DSC: 237.9°C.

Embodiment 3

[0056] Embodiment 3 Preparation of high-purity pralatrexate crystals

[0057] 1000mL reaction flask, add 500mL acetone aqueous solution (V 丙酮 :V 水 =3:1), heat up to 65-70°C, add 10.0g of pralatrexate D crystal form prepared in Example 1, stir until the solid dissolves, cool down naturally for 2 hours, and then cool down to 15±5°C Crystallize for 8 hours, filter, rinse the filter cake with 20 mL of acetonitrile, and vacuum-dry the filter cake at 60° C. for 30 hours to obtain 7.8 g of pralatrexate as a solid. DSC: 238.8°C.

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Abstract

The invention provides a high-purity Pralatrexate solid and its preparation method. The high-purity Pralatrexate solid provided by the invention is prepared by recrystallization of an aqueous solution of lower alkyl ketone and has advantages of high purity, low individual impurity content, good stability, high safety and the like. Meanwhile, the preparation method of the high-purity Pralatrexate solid provided by the invention can be adopted to effectively remove IN0222(2,4-diamido-6-chloromethylpteridine) or its analogue and raise safety of medicine. In addition, the preparation method of the high-purity Pralatrexate solid is simple, a solvent is cheap and easily available, and crystallization condition is mild. The preparation method is suitable for industrial production.

Description

technical field [0001] The invention relates to a high-purity pralatrexate solid and a preparation method thereof, belonging to the technical field of medicine. Background technique [0002] The trade name of pralatrexate is Folotyn, which has the structure shown in formula (I), and its chemical name is (2S)-2-[[4-[(1RS)-1-[(2,4-diaminopteridine- 6-yl)methyl]-3-butynyl]benzoyl]amino]glutaric acid is the first approved drug for the treatment of relapsed and refractory peripheral T lymphocytoma (PTCL). In the United States, about 9,500 patients suffer from disease every year, and it is determined to be a rare disease, and Folotyn has been designated as an orphan drug. The FDA approved the drug through the fast-track approval process for the treatment of patients with relapsed or refractory PTCL who have not responded to other chemotherapy. In addition, pralatrexate has other indications, including skin T-cell lymphoma (stage III), non-Hodgkin's lymphoma (NHL, stage I / II), co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D475/08A61K31/519A61P35/00
Inventor 周舟张爱明胡志张喜全朱雪焱袁哲东
Owner LIANYUNGANG RUNZHONG PHARMA CO LTD
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