CN105985287B - A kind of Rui Gefeini novel crystal forms - Google Patents
A kind of Rui Gefeini novel crystal forms Download PDFInfo
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- CN105985287B CN105985287B CN201510076275.8A CN201510076275A CN105985287B CN 105985287 B CN105985287 B CN 105985287B CN 201510076275 A CN201510076275 A CN 201510076275A CN 105985287 B CN105985287 B CN 105985287B
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- rui gefeini
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Abstract
The present invention provides a kind of Rui Gefeini novel crystal forms, and X ray powder diffractions about have characteristic peak in 2 θ 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 degree of position.The Rui Gefeini crystal forms of the present invention have preferable stability.
Description
Technical field
The present invention relates to drug crystal forms fields, and in particular to a kind of novel crystal forms of Rui Gefeini and preparation method thereof.
Background technology
The Chinese of Rui Gefeini (Regorafenib) is entitled：N- (4- chloro- 3- (trifluoromethyl) phenyl) fluoro- (4- of-N ' -2-
(2- (N- methylcarbamoyls) -4- pyridines oxygroup) phenyl) urea, with structure shown in Formulas I
The drug is a kind of novel multi-kinase inhibitor, by inhibiting a variety of promotion tumour growth protein kinases, target
To acting on, tumour generates, tumor vessel occurs and the maintenance of tumor microenvironment signal transduction.
There are many crystal forms by Rui Gefeini, if crystal form I, II (referring to PCT application WO2008058644), III are (referring to PCT application
) and monohydrate crystal form WO2008055629 (referring to CN101547903).In addition, public in PCT application WO2008043446
The preparation method for the Rui Gefeini hydrates opened, this method need by Rui Gefeini free alkalis specific crystal formation (Form I) containing
It is transformed by the stirring of (1~2 week) for a long time in aqueous solvent (acetone, acetonitrile etc.), the production cycle is long, poor repeatability, no
Conducive to realization industrialized production.Rui Gefeini monohydrate stability is poor simultaneously, hygroscopicity is big.In patent application
A variety of crystal forms of Rui Gefeini, including crystal form A, B, C are also disclosed in CN104250227A.
Invention content
One aspect of the present invention provides a kind of novel crystal forms of Rui Gefeini, which is described as form D in the present invention.
Another aspect of the present invention provides a kind of preparation method of Rui Gefeini form Ds.
In certain embodiments, Rui Gefeini form Ds of the invention, X-ray powder diffraction in 2 θ about 19.02,
21.47, there is characteristic peak in 25.11 degree of position；Further, Rui Gefeini form Ds of the invention also 14.68,14.96,
25.83, there is characteristic peak in 27.41 degree of position；Further, Rui Gefeini form Ds of the invention also 9.25,12.06,
12.88, there is characteristic peak in 13.23,15.76,17.46,18.44,22.97,24.69,27.12,29.66 degree of position；Further
, Rui Gefeini form Ds of the invention, X-ray powder diffraction has following characteristic peak in 2 θ：
In certain embodiments, Rui Gefeini form Ds of the invention have 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, maximum heat absorption
Melting temperature is 203.7 DEG C.
Another aspect of the present invention provides the preparation method of the form D, and this method includes with Formula II by formula III organic molten
It is reacted in agent, and direct crystallization obtains.In certain embodiments, the preparation method is that formula III is dissolved in organic solvent, with
It is dissolved in the Formula II reaction of organic solvent, and direct crystallization obtains.In certain embodiments, the preparation method is that formula III is molten
In acetone, dichloromethane or its in the mixed solvent, reacted with the Formula II for being dissolved in acetone, dichloromethane, and direct crystallization obtains.It does
For preferred embodiment, the method is dissolved in formula III in the admixture solvent of acetone or acetone and dichloromethane, is added to
It is dissolved in acetone or acetone to react with the Formula II of the mixed solvent of dichloromethane, and direct crystallization obtains.
The Rui Gefeini form Ds of the present invention have preparation process simple, and stability of crystal form is good, Rui Gefeini D of the invention
Crystal form is significantly better than the crystal form that the prior art has been reported.
Description of the drawings
The XRPD of Fig. 1 Rui Gefeini form Ds schemes；
The DSC of Fig. 2 Rui Gefeini form Ds schemes；
The TGA of Fig. 3 Rui Gefeini form Ds schemes.
Specific implementation mode
It should be appreciated that the embodiment of the present invention is only used for understanding the present invention rather than limitation of the present invention.Special sound is not made
Bright, it is commercially available rear directly use that term of the invention, which has the conventional sense of this field, agents useful for same,.
Assay method：
X-ray powder diffraction is measured by RigakuD/max2550VB-pc diffractometers, using Cu/K-alphal (λ=
1.540598A) radiation, power：40kV × 100mA acquires associated diffraction data, 0.02 ° of step width, scanning in 2 θ, 0 ° of -60 ° of range
6 °/min of speed.
DSC is by the resistance to DSC 200F3 detections of speeding of Germany, 30-350 DEG C of temperature range, heating rate 10.0K/min, sealing
Prick hole, nitrogen environment.
HPLC detection methods：
Chromatographic column：Phenomenex luna 5 μ, 4.6mm × 250mm
Flow velocity：1.0mL/min
Wavelength：DAD detectors, main wavelength is with 268nm
Column temperature：40℃
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 1 form D of embodiment
By in 10 DEG C of temperature, by the acetone soln of acetone soln (50mL) the dropping type II (3.7g) of formula III (4g)
In (35mL).After dripping off, stirring for 24 hours, there is solid precipitation.Filtering, with Acetone rinse, drains, is dried under reduced pressure, obtains at 20 DEG C
The white solid of 5.0g, XPRD are detected as Rui Gefeini form Ds.HPLC：99.6%.MS(ESI)：M/z=483 (M+H+)。
The preparation of 2 form D of embodiment
It will be at 20 DEG C, by the mixed solution 50mL (dichloromethane of the dichloromethane of formula III (4g) and acetone：Acetone=
1:4) in the dichloromethane solution (35mL) of dropping type II (3.7g).After dripping off, stirring for 24 hours, there is solid precipitation.Filtering, with third
Ketone rinses, and drains, is dried under reduced pressure at 20 DEG C, obtains the white Rui Gefeini form Ds of 5.5g.HPLC：99.5%.
3 hygroscopicity of embodiment and Stability Determination
Test method：With reference to 2010 editions two note on the use XIX C of Chinese Pharmacopoeia, the test sample for being ground into fine powder is weighed in measuring cup
In, spread out at thickness be about 5mm thickness thin layer, be placed in closed container, in high humidity (25 DEG C of 90% humidity of temperature), high temperature (60 DEG C)
Under the conditions of illumination (4500Lx), sampled respectively at the 5th day and the 10th day, and accurately weigh weight, the related substance of determination sample,
Content measures X-ray diffraction and determines sample crystal form, as a result such as following table.
| Appearance | Crystal form | It increases weight (%) | Content (%) | 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 (5)
1. a kind of form D of Rui Gefeini, which is characterized in that 2 θ of its X-ray powder diffraction about 14.68,14.96,
19.02, there is characteristic peak in 21.47,25.11,25.83,27.41 degree of position.
2. crystal form described in claim 1, which is characterized in that 2 θ of its X-ray powder diffraction 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, there is characteristic peak in 27.12,27.41,29.66 degree of position.
3. crystal form described in claim 1, which is characterized in that its X-ray powder diffraction has following characteristic peak in 2 θ：
4. crystal form described in claim 1, which is characterized in that it has XPRD collection of illustrative plates substantially as shown in, the D brilliant
Type is made by following preparation methods：Formula III is reacted in organic solvent with Formula II, and direct crystallization obtains；
The organic solvent is the mixed solvent of acetone or acetone and dichloromethane.
5. claim 1-4 any one of them crystal forms, which is characterized in that it is maximum with DSC collection of illustrative plates as shown in Figure 2
Melting temperature of absorbing heat is 203.7 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510076275.8A CN105985287B (en) | 2015-02-13 | 2015-02-13 | A kind of Rui Gefeini novel crystal forms |
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| CN201510076275.8A CN105985287B (en) | 2015-02-13 | 2015-02-13 | A kind of Rui Gefeini novel crystal forms |
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| CN105985287A CN105985287A (en) | 2016-10-05 |
| CN105985287B true CN105985287B (en) | 2018-07-17 |
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| 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 |
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 |
|---|
| 瑞格拉非尼（Regorafenib）的合成;刘亚方，等;《精细化工中间体》;20121231;第42卷(第6期);第31-34页 * |
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