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Novel crystal form of regorafenib

A technology of regorafenib and crystal form, applied in organic chemistry and other directions, can solve the problems of long production cycle, poor stability, high hygroscopicity, etc., and achieve the effect of simple preparation process and good crystal form stability

Inactive Publication Date: 2016-10-05
SHANGHAI JINGXIN BIOLOGICAL MEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the preparation method of regorafenib hydrate disclosed in PCT application WO2008043446 requires the specific crystal form (Form I) of regorafenib free base to pass a long time in an aqueous solvent (acetone, acetonitrile, etc.) (1 to 2 weeks) stirring conversion, long production cycle, poor repeatability, not conducive to the realization of industrial production
At the same time, regorafenib monohydrate has poor stability and high hygroscopicity

Method used

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  • Novel crystal form of regorafenib
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  • Novel crystal form of regorafenib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1 Preparation of D crystal form

[0035] The acetone solution (50 mL) of formula III (4 g) was dropped into the acetone solution (35 mL) of formula II (3.7 g) at a temperature of 10°C. After dripping, stirred for 24h, solid precipitated out. Filtered, rinsed with acetone, sucked dry, and dried under reduced pressure at 20°C to obtain 5.0 g of a white solid, which was detected by XPRD as crystal form D of regorafenib. HPLC: 99.6%. MS (ESI): m / z=483 (M+H + ).

Embodiment 2

[0036] Embodiment 2 Preparation of D crystal form

[0037] At 20°C, 50 mL of a mixed solution of methylene chloride and acetone of formula III (4g) (dichloromethane: acetone=1:4) was dropped into methylene chloride solution (35 mL) of formula II (3.7 g) . After dripping, stirred for 24h, solid precipitated out. Filter, rinse with acetone, suck dry, and dry under reduced pressure at 20°C to obtain 5.5 g of white crystalline form D of regorafenib. HPLC: 99.5%.

Embodiment 3

[0038] Example 3 Determination of hygroscopicity and stability

[0039] Test method: refer to the general example XIX C of the second part of the Chinese Pharmacopoeia 2010 edition, weigh the test product that has been ground into a fine powder in a weighing bottle, spread it into a thin layer with a thickness of about 5mm, place it in an airtight container, and place it in a high-humidity (25°C temperature and 90% humidity), high temperature (60°C) and light (4500Lx) conditions, samples were taken on the 5th and 10th days respectively, and the weight was accurately weighed to determine the related substances and contents of the samples, and to determine the X-ray diffraction Determine the crystal form of the sample, and the results are shown in the following table.

[0040]

[0041] 0 days

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Abstract

The invention provides a novel crystal form of regorafenib. Characteristic peaks occur in the X-ray powder diffraction pattern of the crystal form when 2theta is about 9.25, 12.06, 12.88, 13.23, 14.68, 14.96, 15.76, 17.46, 18.44, 19.02, 21.47, 22.97, 24.69, 25.11, 25.83, 27.12, 27.41 and 29.66. The crystal form of regorafenib has good stability.

Description

technical field [0001] The invention relates to the field of pharmaceutical crystal forms, in particular to a new crystal form of regorafenib and a preparation method thereof. Background technique [0002] The Chinese name of Regorafenib is: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-2-fluoro-(4-(2-(N-methylammonia) Formyl)-4-pyridyloxy)phenyl)urea, which has the structure shown in formula I [0003] [0004] The drug is a novel multi-kinase inhibitor that targets tumorigenesis, tumor angiogenesis and maintenance of tumor microenvironmental signaling by inhibiting multiple tumor growth-promoting protein kinases. [0005] Regorafenib has various crystal forms, such as crystal forms I, II (see PCT application WO2008058644), III (see PCT application WO2008055629), and monohydrate crystal form (see CN101547903). In addition, the preparation method of regorafenib hydrate disclosed in PCT application WO2008043446 requires the specific crystal form (Form I) of regorafenib free ...

Claims

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Application Information

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IPC IPC(8): C07D213/81
Inventor 戴向前沈金王成伟
Owner SHANGHAI JINGXIN BIOLOGICAL MEDICAL
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