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Neratinib hydrochloride crystal form and preparation method thereof

A technology of hydrochloride and dimethylaminocroton hydrochloride, applied in the field of medicine

Inactive Publication Date: 2019-10-22
JIANGSU CHUANGUO PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] WO2009052264 discloses acetic acid, fumaric acid, maleic acid, methanesulfonic acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonate of neratinib, but these salts are all looking for suitable neratinib medicinal No research on neratinib salt as a synthetic intermediate has been found so far

Method used

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  • Neratinib hydrochloride crystal form and preparation method thereof
  • Neratinib hydrochloride crystal form and preparation method thereof
  • Neratinib hydrochloride crystal form and preparation method thereof

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preparation example Construction

[0054] The present invention also provides a preparation method of the aforementioned crystal form I, the preparation method comprising the following steps:

[0055] (i) Dissolve trans-4-dimethylaminocrotonyl chloride hydrochloride in the first inert solvent, react with chlorinating reagent to obtain trans-4-dimethylaminocrotonyl chloride hydrochloride The solution;

[0056] (ii) The solution obtained in step (1) is mixed with 6-amino-4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7- Ethoxyquinoline is reacted, the reaction is completed, and the crystal form I of the compound hydrochloride of formula (I) is obtained through post-processing.

[0057] Wherein, the molar ratio of trans-4-dimethylamino croton hydrochloride to the chlorination reagent is 1:1-3; the chlorination reagent is selected from oxalyl chloride, phosphorus oxychloride or thionyl chloride ; 6-amino-4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinoline and trans-4 - The ...

Embodiment 1

[0089] Example 1 Preparation of Neratinib Hydrochloride Form I

[0090] (1) Add 10g trans-4-dimethylamino croton hydrochloride, 50ml N-methylpyrrolidone in a 250ml there-necked flask and stir at room temperature, add 9.26g phosphorus oxychloride dropwise to a constant pressure dropping funnel, After 1 hour of dropwise addition, the reaction temperature was controlled at -15 to -10°C. During the reaction, the solution gradually changed from white to light brown, monitored by HPLC. After 2 hours, the reaction was stopped, and the resulting reaction solution was used for later use;

[0091] (2) Add 18 g of 6-amino-4-[[3-chloro-4-[(pyridine-2- base) methoxy] phenyl] amino] -3-cyano-7-ethoxyquinoline in 70ml N-methylpyrrolidone solution, after 1h dropwise addition, the reaction temperature was controlled at -15~-10°C, Insulated for 2 hours, 10ml of methanol was added dropwise, filtered with suction, rinsed twice with 10ml of dichloromethane, and vacuum-dried to obtain 24.2g of ner...

Embodiment 2

[0093] Example 2 Preparation of Neratinib Hydrochloride Form I

[0094] (1) Add 10g of trans-4-dimethylaminocroton hydrochloride and 80ml of N,N-dimethylformamide into a 250ml three-neck flask, stir at room temperature, add 7.66g of grass Acyl chloride, 1h dropwise, the reaction temperature is controlled at -10~-5°C, the solution gradually changes from white to light brown during the reaction, HPLC monitors, stop the reaction after 2h, and the obtained reaction solution is ready for use;

[0095](2) Add 18 g of 6-amino-4-[[3-chloro-4-[(pyridine-2- base)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinoline in 70ml N,N-dimethylformamide solution, after 1h dropwise addition, the reaction temperature was controlled at -15~ -10°C, keep warm for 4 hours, add dropwise 10ml of methanol, filter with suction, rinse twice with 10ml of dichloromethane, and vacuum dry to obtain 23.1g of neratinib hydrochloride, with a yield of 90.84% ​​and a purity of 98.26%.

[0096] The X-ray powder diffract...

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Abstract

The invention relates to a neratinib hydrochloride new crystal form I and a preparation method thereof, and belongs to the technical field of medicines. An X-ray powder diffraction pattern of the neratinib hydrochloride crystal form I has characteristic absorption peaks when the reflection angle, namely 2*theta is 4.0+ / -0.2 degrees, 8.8+ / -0.2 degrees, 11.1+ / -0.2 degrees, 15.7+ / -0.2 degrees, 17.6+ / -0.2 degrees, 20.2+ / -0.2 degrees, 23.8+ / -0.2 degrees, 26.6+ / -0.2 degrees, 27.1+ / -0.2 degrees and 28.9+ / -0.2 degrees, and the crystal form I has the excellent stability and purity; and additionally, the preparation method of the crystal form I is simple, easy to operate, mild in reaction condition, small in type and using quantity of organic solvents and environmentally friendly, and facilitates industrialization innovation.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a crystal form of neratinib hydrochloride, namely (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy ]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide hydrochloride crystal form, and a preparation method thereof. Background technique [0002] Neratinib was developed by Wyeth Pharmaceutical Company of the United States, and in July 2009, a global phase III clinical trial of breast cancer was launched in patients who had previously received trastuzumab-based treatment. In October 2011, Wyeth Pharmaceutical Company licensed Puma Biomedical Company of the United States to develop neratinib, and then Puma started the research on neratinib in the third-line treatment of recurrent and metastatic breast cancer. In April 2014, it announced the development of neratinib. Positive data from a Phase II clinical study of Neratinib showed that Neratinib was superior to R...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12C07B2200/13
Inventor 周吴戴光福
Owner JIANGSU CHUANGUO PHARMA CO LTD
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