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Crystal forms and preparation method of neratinib free alkali

A technology of crystal form and polymorph, applied in the field of new crystal form of neratinib free base and its preparation, can solve problems such as easy wrapping of mother liquor and difficulty in filtration

Inactive Publication Date: 2018-08-07
JIANGSU CHUANGUO PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

During the experiment, it was found that the crystal form I particles were very fine needle-shaped, difficult to filter and easy to wrap the mother liquor

Method used

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  • Crystal forms and preparation method of neratinib free alkali
  • Crystal forms and preparation method of neratinib free alkali
  • Crystal forms and preparation method of neratinib free alkali

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0147] Embodiment 1: the preparation of crystal form II

[0148] Weigh 1 g of the maleate salt of the compound of formula (I) and suspend it in 10 mL of methanol, add dropwise 2.5 ml of 5% NaOH, concentrate to about 5 times the amount, add 10 mL of isopropanol, concentrate to about 8 times the amount, and filter with suction , the filter cake was vacuum-dried at 25° C. to obtain 710 mg of solid, the yield was 88.7%, and the moisture content was 3.95%. The resulting solid is Form II of the compound of formula (I).

[0149] Carry out XRPD test to the obtained solid, its X-ray powder diffraction data are as shown in table 2, and its X-ray powder diffraction pattern is as follows Figure 4 Shown; Carry out TGA test to gained solid, its spectrogram is as Figure 5 As shown, there is about 2.9% weight loss when heated to 80°C, which is a hydrate; the spectra of the resulting solid under a 400-fold microscope are Image 6 shown.

[0150] Table 2

[0151]

[0152]

Embodiment 2

[0153] Embodiment 2: the preparation of crystal form III

[0154] Weigh 1g of the maleate salt of the compound of formula (I) and suspend it in 10mL of methanol, add dropwise 2.5ml of 5% NaOH, add the crystal form II in Example 1, concentrate to about 5 times the amount, add 10mL of isopropanol , concentrated to about 8 times the amount, suction filtered, and the filter cake was vacuum-dried at 40° C. to obtain 861.3 mg of solid with a yield of 91.7% and a moisture content of 5.45%. The resulting solid is Form III of the compound of formula (I).

[0155] Carry out XRPD test to the obtained solid, its X-ray powder diffraction data are as shown in table 3, and its X-ray powder diffraction pattern is as follows Figure 7 Shown; Carry out TGA test to gained solid, its spectrogram is as Figure 8 As shown, it has about 5.0% weight loss when heated to 140°C, which is a hydrate; the spectrum of the resulting solid under a microscope at 400 times is as Figure 9 shown.

[0156] ta...

Embodiment 3

[0158] Embodiment 3: the preparation of crystal form III

[0159] Weigh 1g of the maleate salt of the compound of formula (I) and suspend it in 10mL of methanol, add dropwise 2.5ml of 5% NaOH, add the crystal form III in Example 2, concentrate to about 5 times the amount, add dropwise 10mL of water, pump Filter, rinse with 2 times the amount of water, and dry the filter cake under vacuum at 40°C to obtain 867.9 mg of solid with a yield of 92.4%. The resulting solid is Form III of the compound of formula (I).

[0160] Carry out XRPD test to the obtained solid, its X-ray powder diffraction pattern is basically as Figure 7 Shown; Carry out TGA test to gained solid, its spectrogram is basically as Figure 8 shown.

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PUM

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Abstract

The invention relates to crystal forms and a preparation method of neratinib free alkali. Specifically, the invention discloses new crystal forms of a compound shown in a formula (I) or a solvate thereof, namely a crystal form III, a crystal form IV, a crystal form V and a crystal form VI respectively. The new crystal forms disclosed by the invention are beneficial to separation and purification of a compound free alkali shown in the formula (I), and process efficiency and chemical quality of a product are greatly improved. (The formula (I) is as shown in the description.).

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 free base 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 (I): [0003] [0004] There is currently no report on the free base crystal form of the compound of formula (I). In WO2006127207, the hydrochloride of the compound of formula (I) was decomposed in 10% methanol solution of potassium carbo...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/4709A61P35/00
CPCC07D401/12A61P35/00C07B2200/13
Inventor 张良尚婷婷范成明
Owner JIANGSU CHUANGUO PHARMA CO LTD
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