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Neratinib dimaleate crystal forms and preparation method thereof

A technology of maleic acid and crystal form, which is applied in the field of medicine and can solve problems such as inability to maintain stable crystal form

Inactive Publication Date: 2018-07-20
JIANGSU CHUANGUO PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It can be seen that the crystal form I and the crystal form II cannot keep the stability of the crystal form with the change of humidity

Method used

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  • Neratinib dimaleate crystal forms and preparation method thereof
  • Neratinib dimaleate crystal forms and preparation method thereof
  • Neratinib dimaleate crystal forms and preparation method thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0065] The preparation method of the crystal form V of the compound of formula (I) comprises the following steps:

[0066] (1) Adding Neratinib free base and maleic acid to the first solvent (an alcoholic organic solvent, preferably methanol) to obtain the first solution;

[0067] (2) drop the second solvent (being an ester organic solvent, preferably isopropyl acetate) into the first solution obtained in step (1), stir (as carried out at room temperature), filter, and vacuum-dry the filter cake, thereby Obtaining the crystal form V of the compound of formula (I);

[0068] The temperature of the vacuum drying is 30-50°C (preferably 40°C).

[0069] In another preferred example, the molar ratio of maleic acid to neratinib free base is 1.8-2.5, preferably 1.9-2.1.

[0070] In another preferred example, the volume ratio of the first solvent to the second solvent is 1:1˜1:3, preferably 1:2.

[0071] The new crystal form of the present invention is the crystal form IV of the comp...

Embodiment 1

[0108] Embodiment 1: Preparation of Form IV

[0109] Weigh 35.2 mg of neratinib free base, add 1 mL of methanol, add 15 mg of maleic acid, dissolve, add dropwise 2 mL of toluene, and evaporate the resulting solution to dryness at 45°C. The resulting solid is Form IV of the compound of formula (I).

[0110] Carry out XRPD test to the obtained solid, its X-ray powder diffraction data are as shown in table 1, and its X-ray powder diffraction figure is as follows figure 1 shown; the obtained solid was 1 H-NMR test, its spectrum is as follows image 3 Shown, show that the ratio of neratinib and maleic acid is 1:2; Gained solid is carried out TGA test, and its spectrogram is as follows figure 2 Shown, heating to 100 ℃, weight loss 0.8%, no weight loss platform, is anhydrous.

[0111] Table 1

[0112]

[0113]

Embodiment 2

[0114] Embodiment 2: Preparation of Form IV

[0115] Weigh 200mg of neratinib free base, add 5mL of methanol, add 80mg of maleic acid, dissolve, add dropwise 10mL of isopropyl acetate, add a small amount of the crystal form IV seed crystal of the above-mentioned Example 1, and leave it at room temperature overnight, a large amount of solid Precipitated, filtered, and vacuum dried at 25°C to obtain 208.1 mg of sample with a yield of 73.5%. The resulting solid is Form IV of the compound of formula (I).

[0116] Carry out XRPD test to the obtained sample, its X-ray diffraction pattern is basically as figure 1 Shown; Carry out TGA test to the obtained sample, its thermogravimetric analysis diagram is basically as figure 2 shown; the obtained samples were 1 H-NMR test, its 1 The H-NMR spectrum is basically as image 3 shown.

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Abstract

The invention relates to neratinib dimaleate crystal forms and a preparation method thereof. Particularly, the invention discloses three crystal forms of neratinib dimaleate, i.e., crystal forms IV, Vand VI respectively, which are all anhydrous substances of the neratinib dimaleate, wherein the crystal forms IV and V have better solubility than a known crystal form II, the crystal form V has lower hygroscopicity, and the crystal forms cannot be transformed by a relative moisture change. The invention further discloses proper medicine research of the three crystal forms and the preparation method in industrial production.

Description

field of invention [0001] The invention belongs to the field of medicine, in particular, the invention relates to a new crystal form of neratinib dimaleate and a preparation method thereof. Background of the invention [0002] Neratinib, an anti-breast cancer drug, was developed by Wyeth Pharmaceuticals, a subsidiary of Pfizer Pharmaceuticals in the United States, and Puma Biotechnology Company (Puma) obtained a development license from Pfizer. The drug is an oral, irreversible pan-tyrosine kinase inhibitor with activity against HER1, HER2, and HER4. The chemical name of neratinib is (E)-N-{4-[3-chloro-4-(2-pyridylmethoxy)anilino]-3-cyano-7-ethoxy-6- Quinolinyl}-4-(dimethylamino)-2-butenamide, shown in its molecular structural formula (II): [0003] [0004] WO2009052264 discloses that the maleate of neratinib can not only increase the solubility of the free base, but also reduce the diarrhea caused by the free base of neratinib. The patent discloses three monomaleate ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07C57/145C07C51/41A61K31/4709A61P35/00
CPCC07D401/12C07B2200/13
Inventor 李中华尚婷婷龚俊波张良蔡志刚
Owner JIANGSU CHUANGUO PHARMA CO LTD
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