CN105985287A - Novel crystal form of regorafenib - Google Patents
Novel crystal form of regorafenib Download PDFInfo
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- CN105985287A CN105985287A CN201510076275.8A CN201510076275A CN105985287A CN 105985287 A CN105985287 A CN 105985287A CN 201510076275 A CN201510076275 A CN 201510076275A CN 105985287 A CN105985287 A CN 105985287A
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- rui gefeini
- crystal formation
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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
The present invention relates to drug crystal forms field, be specifically related to novel crystal forms of a kind of Rui Gefeini and preparation method thereof.
Background technology
The Chinese of Rui Gefeini (Regorafenib) is entitled: fluoro-(4-(2-(the N-methyl ammonia of N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-2-
Formoxyl)-4-pyridyloxy) phenyl) urea, it has the structure shown in Formulas I
This medicine is a kind of novel multi-kinase inhibitor, by suppressing multiple promotion tumor growth protein kinase, targeting
Generate in tumor, tumor vessel occurs and the maintenance of tumor microenvironment signal conduction.
Rui Gefeini has multiple crystal formation, such as crystal formation I, II (seeing PCT application WO2008058644), III (sees PCT
Application WO2008055629), and monohydrate crystal form (seeing CN101547903).It addition, in PCT application
The preparation method of the Rui Gefeini hydrate disclosed in WO2008043446, the method needs specific by Rui Gefeini free alkali
Crystal formation (Form I) is transformed by the stirring of long-time (1～2 week) in aqueous solvent (acetone, acetonitrile etc.), raw
The product cycle is long, poor repeatability, is unfavorable for realizing industrialized production.Rui Gefeini monohydrate less stable, hygroscopicity simultaneously
Greatly.The multiple crystal formation of Rui Gefeini is also disclosed, including crystal formation A, B, C in patent application CN104250227A.
Summary of the invention
One aspect of the present invention provides the novel crystal forms of a kind of Rui Gefeini, and this novel crystal forms is described as form D in the present invention.
Another aspect of the present invention provides the preparation method of a kind of Rui Gefeini form D.
In certain embodiments, the Rui Gefeini form D of the present invention, its X-ray powder diffraction at 2 θ about 19.02,21.47,
There is characteristic peak the position of 25.11 degree；Further, the Rui Gefeini form D of the present invention also 14.68,14.96,25.83,
There is characteristic peak the position of 27.41 degree；Further, the Rui Gefeini form D of the present invention also 9.25,12.06,12.88,
13.23, there is characteristic peak the position of 15.76,17.46,18.44,22.97,24.69,27.12,29.66 degree；Further, originally
The Rui Gefeini form D of invention, its X-ray powder diffraction has a following characteristic peak at 2 θ:
In certain embodiments, the Rui Gefeini form D of the present invention has XPRD collection of illustrative plates substantially as shown in；
In certain embodiments, the form D of Rui Gefeini of the present invention has DSC collection of illustrative plates as shown in Figure 2, its maximum heat absorption
Melt temperature is 203.7 DEG C.
Another aspect of the present invention provides the preparation method of described form D, and the method includes by formula III with Formula II in organic solvent
React, and direct crystallization obtains.In certain embodiments, described preparation method is to be dissolved in organic solvent by formula III, and is dissolved in
The Formula II of organic solvent is reacted, and direct crystallization obtains.In certain embodiments, described preparation method is that formula III is dissolved in third
In ketone, dichloromethane or its mixed solvent, be dissolved in acetone, the Formula II of dichloromethane is reacted, and direct crystallization obtains.As
Preferred embodiment, described method is to be dissolved in by formula III in the admixture solvent of acetone or acetone and dichloromethane, joins and is dissolved in
Acetone or acetone react in the Formula II of the mixed solvent of dichloromethane, and direct crystallization obtains.
It is simple that the Rui Gefeini form D of the present invention has preparation technology, and stability of crystal form is good, the Rui Gefeini form D of the present invention
Significantly it is better than the crystal formation that prior art has been reported.
Accompanying drawing explanation
The XRPD figure of Fig. 1 Rui Gefeini form D；
The DSC figure of Fig. 2 Rui Gefeini form D；
The TGA figure of Fig. 3 Rui Gefeini form D.
Detailed description of the invention
Should be appreciated that embodiments of the invention are only used for understanding the present invention, rather than limitation of the present invention.Do not make special declaration,
The term of the present invention has the conventional sense of this area, and agents useful for same is commercially available rear directly use.
Assay method:
X-ray powder diffraction is to be recorded by RigakuD/max2550VB-pc diffractometer, employing Cu/K-alphal (λ=
1.540598A) radiation, power: 40kV × 100mA gathers associated diffraction data, step width 0.02 ° in 0 ° of-60 ° of scope of 2 θ, sweeps
Retouch 6 °/min of speed.
DSC is by the resistance to DSC 200F3 detection of speeding of Germany, temperature range 30-350 DEG C, programming rate 10.0K/min, seals
Prick hole, nitrogen environment.
HPLC detection method:
Chromatographic column: Phenomenex luna 5 μ, 4.6mm × 250mm
Flow velocity: 1.0mL/min
Wavelength: DAD detector, main wavelength is with 268nm
Column temperature: 40 DEG C
Mobile phase A: 0.1% trifluoroacetic acid aqueous solution
Mobile phase B: acetonitrile
Gradient program such as following table:
| t/min | A/% | B/% |
| 0 | 80 | 20 |
| 30 | 10 | 90 |
| 40 | 10 | 90 |
Posttime:5min
With acetonitrile sample dissolution.
The preparation of embodiment 1 form D
By the temperature of 10 DEG C, the acetone soln (50mL) of formula III (4g) is instilled the acetone soln (35 of Formula II (3.7g)
ML) in.After dripping off, stir 24h, have solid to separate out.Filter, with Acetone rinse, drain, at 20 DEG C of drying under reduced pressure,
To the white solid of 5.0g, XPRD is detected as Rui Gefeini form D.HPLC:99.6%.MS (ESI): m/z=483
(M+H+)。
The preparation of embodiment 2 form D
Will be at 20 DEG C, by the mixed solution 50mL (dichloromethane: acetone=1:4) of the dichloromethane of formula III (4g) Yu acetone
Instill in the dichloromethane solution (35mL) of Formula II (3.7g).After dripping off, stir 24h, have solid to separate out.Filter, use
Acetone rinse, drains, and at 20 DEG C of drying under reduced pressure, obtains the white Rui Gefeini form D of 5.5g.HPLC:99.5%.
Embodiment 3 hygroscopicity and Stability Determination
Method of testing: with reference to 2010 editions two note on the use XIX C of Chinese Pharmacopoeia, weighs and is ground into the test sample of fine powder in weighing botle,
Spread out into thickness and be about the thick thin layer of 5mm, be placed in hermetic container, at high humidity (25 DEG C of temperature 90% humidity), high temperature (60 DEG C)
Under the conditions of illumination (4500Lx), respectively at sampling in the 5th day and the 10th day, and accurately weigh weight, measure the relevant thing of sample
Matter, content, measure X-ray diffraction and determine sample crystal formation, result such as following table.
| Outward appearance | Crystal formation | Weightening finish (%) | Content (%) | There is related substance (%) |
| 0 day | White crystalline powder | Form D | 0 | 99.48 | 0.51 |
| High humidity 5 days | White crystalline powder | Form D | 0.02 | 99.47 | 0.52 |
| High humidity 10 days | White crystalline powder | Form D | 0.02 | 99.46 | 0.53 |
| High temperature 5 days | White crystalline powder | Form D | 0 | 99.46 | 0.53 |
| High temperature 10 days | White crystalline powder | Form D | 0.1 | 99.46 | 0.54 |
| Illumination 5 days | White crystalline powder | Form D | 0 | 99.47 | 0.52 |
| Illumination 10 days | White crystalline powder | Form D | 0 | 99.47 | 0.53 |
Claims (6)
1. the form D of Yi Zhong Rui Gefeini, its X-ray powder diffraction about has the position of 19.02,21.47,25.11 degree at 2 θ
Characteristic peak.
2. the crystal formation described in claim 1, its X-ray powder diffraction 2 θ about 14.68,14.96,19.02,21.47,25.11,
25.83, there is characteristic peak the position of 27.41 degree.
3. the crystal formation described in claim 1, its X-ray powder diffraction 2 θ 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、29.66
There is characteristic peak the position of degree.
4. the crystal formation described in claim 1, its X-ray powder diffraction has a following characteristic peak at 2 θ:
5. the crystal formation described in claim 1, it has XPRD collection of illustrative plates substantially as shown in.
6. the crystal formation described in claim 1-5, it has DSC collection of illustrative plates as shown in Figure 2, and its maximum heat absorption melt temperature is
203.7℃。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510076275.8A CN105985287B (en) | 2015-02-13 | 2015-02-13 | A kind of Rui Gefeini novel crystal forms |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510076275.8A CN105985287B (en) | 2015-02-13 | 2015-02-13 | A kind of Rui Gefeini novel crystal forms |
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|---|---|
| CN105985287A true CN105985287A (en) | 2016-10-05 |
| CN105985287B CN105985287B (en) | 2018-07-17 |
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| CN201510076275.8A Expired - Fee Related CN105985287B (en) | 2015-02-13 | 2015-02-13 | A kind of Rui Gefeini novel crystal forms |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111995571A (en) * | 2020-08-07 | 2020-11-27 | 天津理工大学 | Eutectic crystal of regorafenib and maleic acid and preparation method thereof |
Citations (8)
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|---|---|---|---|---|
| WO2008055629A1 (en) * | 2006-11-09 | 2008-05-15 | Bayer Schering Pharma Aktiengesellschaft | Polymorph iii of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-n-methylpyridine-2-carboxamide |
| WO2008058644A1 (en) * | 2006-11-14 | 2008-05-22 | Bayer Schering Pharma Aktiengesellschaft | Polymorph ii of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-n-methylpyridine-2-carboxamide |
| CN101547903A (en) * | 2006-10-11 | 2009-09-30 | 拜耳先灵制药股份公司 | 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl)]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate |
| WO2012012404A1 (en) * | 2010-07-19 | 2012-01-26 | Bayer Healthcare Llc | Drug combinations with fluoro-substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions |
| CN103923001A (en) * | 2014-04-30 | 2014-07-16 | 药源药物化学（上海）有限公司 | Regorafenib salt, crystal thereof and preparation method of crystal |
| CN103923000A (en) * | 2014-01-29 | 2014-07-16 | 苏州晶云药物科技有限公司 | Several new crystal forms and preparation methods thereof |
| CN104250227A (en) * | 2013-06-29 | 2014-12-31 | 广东东阳光药业有限公司 | Novel crystal form of regorafenib and preparation method thereof |
| WO2015011659A1 (en) * | 2013-07-24 | 2015-01-29 | Dr. Reddys Laboratories Limited | Crystalline polymorphic forms of regorafenib and processes for the preparation of polymorph i of regorafenib |
-
2015
- 2015-02-13 CN CN201510076275.8A patent/CN105985287B/en not_active Expired - Fee Related
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101547903A (en) * | 2006-10-11 | 2009-09-30 | 拜耳先灵制药股份公司 | 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl)]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate |
| WO2008055629A1 (en) * | 2006-11-09 | 2008-05-15 | Bayer Schering Pharma Aktiengesellschaft | Polymorph iii of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-n-methylpyridine-2-carboxamide |
| WO2008058644A1 (en) * | 2006-11-14 | 2008-05-22 | Bayer Schering Pharma Aktiengesellschaft | Polymorph ii of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-n-methylpyridine-2-carboxamide |
| WO2012012404A1 (en) * | 2010-07-19 | 2012-01-26 | Bayer Healthcare Llc | Drug combinations with fluoro-substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions |
| CN104250227A (en) * | 2013-06-29 | 2014-12-31 | 广东东阳光药业有限公司 | Novel crystal form of regorafenib and preparation method thereof |
| WO2015011659A1 (en) * | 2013-07-24 | 2015-01-29 | Dr. Reddys Laboratories Limited | Crystalline polymorphic forms of regorafenib and processes for the preparation of polymorph i of regorafenib |
| CN103923000A (en) * | 2014-01-29 | 2014-07-16 | 苏州晶云药物科技有限公司 | Several new crystal forms and preparation methods thereof |
| CN103923001A (en) * | 2014-04-30 | 2014-07-16 | 药源药物化学（上海）有限公司 | Regorafenib salt, crystal thereof and preparation method of crystal |
Non-Patent Citations (1)
| Title |
|---|
| 刘亚方，等: "瑞格拉非尼（Regorafenib）的合成", 《精细化工中间体》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111995571A (en) * | 2020-08-07 | 2020-11-27 | 天津理工大学 | Eutectic crystal of regorafenib and maleic acid and preparation method thereof |
| CN111995571B (en) * | 2020-08-07 | 2021-12-03 | 天津理工大学 | Eutectic crystal of regorafenib and maleic acid and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN105985287B (en) | 2018-07-17 |
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