CN105218439A - Crystal of a kind of Rui Gefeini and preparation method thereof - Google Patents
Crystal of a kind of Rui Gefeini and preparation method thereof Download PDFInfo
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- CN105218439A CN105218439A CN201410250111.8A CN201410250111A CN105218439A CN 105218439 A CN105218439 A CN 105218439A CN 201410250111 A CN201410250111 A CN 201410250111A CN 105218439 A CN105218439 A CN 105218439A
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Abstract
The invention provides crystal of a kind of Rui Gefeini and preparation method thereof, use Cu-K α radiation, it is in X-ray powder diffraction, be about 7.20,13.34,14.46,14.72,15.57,16.44,17.17 at 2 θ, there is diffraction peak at 18.52,18.80,19.75,23.37,23.75,24.22,24.71,25.84,26.23,26.35,27.11,27.40,29.24,30.33,31.5 and 34.92 places.The preparation method of Rui Gefeini crystal provided by the invention is simple, and solvent is cheap and easy to get, and crystallization condition is gentle, is suitable for industrialized production.
Description
Technical field
The invention belongs to medical art, be specifically related to crystal of a kind of Rui Gefeini and preparation method thereof.
Background technology
Rui Gefeini (Regorafenib) has the structure shown in formula (I), and chemical name is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } is amino)-3-fluorophenoxy]-N-picoline-2-methane amide.
Rui Gefeini is the inhibitor of a kind of VEGFR and the Raf kinases double activity developed by Bayer AG, and the stimulant of caspase-3 and-9, by oral treatment solid tumor, comprise renal cell carcinoma (RCC), colorectal cancer (CRC) and hepatocellular carcinoma (HCC).
Rui Gefeini is first disclosed as WO2005009961, is the I N-type waferN of Rui Gefeini in this patent application by triturated under ether gained crystal.WO2008043446 discloses the monohydrate of Rui Gefeini, by being dissolved in acetone or alcohol by polymorphic I, adding elutriation crystalline substance and obtaining, and is suspended in acetonitrile/water, THF/ water to stir to obtain.II N-type waferN of Rui Gefeini is disclosed, by polymorphic I crystallization in ethyl acetate being obtained in WO2008058644.III N-type waferN of Rui Gefeini is disclosed, by polymorphic I short period of time heating at 100 DEG C-110 DEG C being obtained in WO2008055629.
The change of medicinal compound crystal formation causes compound to have different fusing points, solubleness, stability, biological activity etc. usually, and these are all the important factors affecting difficulty or ease, stability in storage, preparation difficulty or ease and bioavailability etc. prepared by medicine.When there is polymorphic in compound, because specific polymorphic form has specific thermodynamic property and stability, therefore, in the process of preparation, the crystal formation understanding the compound applied in each formulation is important, to ensure the medicine of process application same modality.Therefore, ensure that compound be single crystal formation or the known miscellany of some crystal formations is necessary.
When judging which kind of polymorphic form is preferred, their much character must be compared and preferred polymorphic form makes a choice based on many physical propertiess.Preferred under completely likely the difficulty or ease, stability etc. of a kind of polymorphic in some aspects as preparation are considered to critical condition.In other cases, different polymorphic form may the solubleness of Yin Genggao or excellent pharmacokinetics and preferably.
The discovery of the new polymorphic form of medicinal compound provides the chance improving medicine physical property, namely whole character of material are extended, thus the research of compound and preparation thereof can be instructed better, therefore the polymorphic form of Rui Gefeini provided by the invention has commercial value in the manufacture and other application of medicine.
Summary of the invention
One aspect of the present invention provides the crystal of a kind of Rui Gefeini, use Cu-K α radiation, it is in X-ray powder diffraction (XRD) collection of illustrative plates, and being about 7.20,13.34,14.46,14.72,15.57,16.44,17.17,18.52,18.80,19.75,23.37,23.75,24.22,24.71,25.84,26.23,26.35,27.11,27.40,29.24,30.33,31.5 and 34.92 degree of places at 2 θ has diffraction peak.
Use Cu-K α radiation, as shown in Figure 1, it has following feature to the spectrogram of the typical XRD of Rui Gefeini crystal:
The present invention on the other hand, provides the preparation method of Rui Gefeini crystal, comprising:
A () 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } is amino)-3-fluorophenoxy]-N-picoline-2-methane amide mixes with organic solvent, is heated to dissolve;
B (), by the solution cooling crystallization of (a), filters, drying under reduced pressure.
Wherein, in step (a), organic solvent is selected from the mixture of C1-C4 alkyl alcohol, acetone, tetrahydrofuran (THF), acetonitrile, ethyl acetate, Isosorbide-5-Nitrae-dioxane or above-mentioned solvent; One in preferred acetone, methyl alcohol, ethanol or acetonitrile, or acetone, methyl alcohol, ethanol, in acetonitrile two kinds, three kinds or four kinds mixture; Wherein, Rui Gefeini: organic solvent=1:10-100 (mass/volume, g/mL), preferred 1:10-60; More preferably 1:15-40, in some embodiments, when Rui Gefeini is 1 gram, the amount of organic solvent is 10-100mL.In some embodiments, step (a) is heated to backflow.
Wherein, the temperature of step (b) cooling crystallization is-5 DEG C ~ 40 DEG C, preferably 10 DEG C ~ 30 DEG C, more preferably 15 DEG C ~ 25 DEG C; In a specific embodiment, described cooling crystallization temperature is 20 DEG C.
Wherein, when step (b) is dry, be no more than drying at 70 DEG C; Preferably be no more than drying at 60 DEG C; In certain embodiments, under-0.09-0.1Mpa, 60 DEG C of dryings.
The present invention on the other hand, provides the pharmaceutical composition containing above-mentioned crystal.Described pharmaceutical composition also comprises one or more pharmaceutical excipients, optionally, also can comprise other therapeutic activity composition.Also can with chemotherapy, radiotherapy, these therapy Combined Preparation of surgical operation.
Described pharmaceutical composition is preferably with oral administration.Be applicable to oral pharmaceutical composition and comprise tablet, capsule, pulvis, granule, dripping pill, paste, powder, tincture etc., preferred tablet and capsule.Wherein tablet can be conventional tablet, dispersible tablet, effervescent tablet, slow releasing tablet, controlled release tablet or enteric coated tablet, and capsule can be conventional capsule, slow releasing capsule, controlled release capsule or enteric coated capsule.
Pharmaceutical composition of the present invention can use conventional pharmaceutical adjuvants well known in the art to be obtained by ordinary method.Conventional pharmaceutical excipient comprises weighting agent, absorption agent, wetting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent comprises starch, lactose, N.F,USP MANNITOL, Microcrystalline Cellulose etc.; Absorption agent comprises calcium sulfate, secondary calcium phosphate, calcium carbonate, magnesium oxide etc.; Wetting agent comprises water, ethanol etc.; Tackiness agent comprises hypromellose, polyvidone, Microcrystalline Cellulose etc.; Disintegrating agent comprises croscarmellose sodium, polyvinylpolypyrrolidone, tensio-active agent, low-substituted hydroxypropyl cellulose etc.; Lubricant comprises Magnesium Stearate, talcum powder, polyoxyethylene glycol, Stepanol MG, micropowder silica gel, talcum powder etc.Pharmaceutical excipient is also comprising toner, sweeting agent etc.
Again on the one hand, the invention provides above-mentioned crystal, pharmaceutical composition for the preparation of the purposes in treatment antitumor drug.
Herein, according to Chinese Pharmacopoeia 2010 editions annex Ⅸ F, the X-ray Powder Diffraction pattern of sample measures under the following conditions, instrument and model thereof: D/Max-RA Japan RigakuXMiniFlex II X-ray powder diffractometer; Ray: monochromatic Cu-Ka ray
scan mode: θ/2 θ, sweep limit: 0-40 °, voltage: 30Kv, electric current 15mA; Sense environmental conditions: temperature: 23.9 DEG C, humidity: 38.6%.
It should be noted that, in X-ray Powder Diffraction pattern (XRD), the diffraction spectrogram obtained by crystalline compounds is distinctive often for specific crystal, wherein the relative intensity of the bands of a spectrum advantage orientation effect that may produce because of the difference of crystal condition, particle diameter and other condition determination and changing.Therefore, the relative intensity of diffraction peak to for crystal be not distinctive, when judging whether identical with known crystal, should be noted that relative position instead of their relative intensity at peak.In addition, for any given crystal, may there is slight errors in the position at peak, and this is also known in crystallography art.Such as, because the change of temperature during analytic sample, sample move or the demarcation etc. of instrument, the position at peak can be moved, and the error at measurment of 2 θ values is about sometimes ± and 0.2 °.Therefore, when determining often kind of crystalline structure, this error should be taken into account.In XRD figure spectrum, usually represent peak position with 2 θ angles or crystal face apart from d, have simple conversion relation between the two: d=λ/2sin θ, wherein d represents crystal face distance, and λ represents the wavelength of incident X-rays, and θ is diffraction angle.
The Rui Gefeini crystal that the present invention prepares, has that purity is high, degree of crystallinity is high, good stability, an advantage such as non-hygroscopic; Meanwhile, the preparation method of Rui Gefeini crystal provided by the invention is simple, and yield is high, and solvent is cheap and easy to get, and crystallization condition is gentle, is applicable to suitability for industrialized production, can meets pharmacy industry demand better.
Accompanying drawing explanation
The X-ray powder diffraction pattern of the Rui Gefeini crystal that Fig. 1 embodiment prepares
The DSC figure of the Rui Gefeini crystal that Fig. 2 embodiment prepares
Embodiment
With specific embodiment, technical scheme of the present invention is described, but protection scope of the present invention is not limited to following scope of embodiments.The reagent adopted is commercially available prod.
The preparation of embodiment 1 Rui Gefeini crystal
1g4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } is amino)-3-fluorophenoxy]-N-picoline-2-methane amide is added in the acetonitrile of 38mL; reflux, to dissolving, naturally cools to 20 DEG C and continues stirring 1 hour crystallization.Filter the solid of separating out, 60 DEG C of drying under reduced pressure 3h obtain white solid 708mg, and it has the X-ray powder diffraction figure shown in Fig. 1.
The preparation of embodiment 2 Rui Gefeini crystal
1g4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } is amino)-3-fluorophenoxy]-N-picoline-2-methane amide is added in the ethanol of 25mL; reflux, to dissolving, naturally cools to 20 DEG C and continues stirring 1 hour crystallization.Filter the solid of separating out, 60 DEG C of drying under reduced pressure 3h obtain white solid 463mg, and it has the X-ray powder diffraction figure shown in Fig. 1.
The preparation of embodiment 3 Rui Gefeini crystal
1g4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } is amino)-3-fluorophenoxy]-N-picoline-2-methane amide is added in the methyl alcohol of 25mL; reflux, to dissolving, naturally cools to 20 DEG C and continues stirring 1 hour crystallization.Filter the solid of separating out, 60 DEG C of drying under reduced pressure 3h obtain white solid 489mg, and it has the X-ray powder diffraction figure shown in Fig. 1.
The preparation of embodiment 4 Rui Gefeini crystal
1g4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } is amino)-3-fluorophenoxy]-N-picoline-2-methane amide is added in the acetone of 16mL; reflux, to dissolving, naturally cools to 20 DEG C and continues stirring 1 hour crystallization.Filter the solid of separating out, 60 DEG C of drying under reduced pressure 3h obtain white solid 512mg, and it has the X-ray powder diffraction figure shown in Fig. 1.
The stability of embodiment 5 Rui Gefeini crystal
The stability experiment of crystal is tested with reference to the method described in Chinese Pharmacopoeia 2010 editions two annex XIXC herein.
Table 1 stability test result
Test of long duration at high temperature, high light and 25 DEG C, Rui Gefeini crystal of the present invention is thermodynamically stable, and X-ray powder diffraction measures display crystal does not change, and is therefore specially adapted to pharmaceutical preparation.
Claims (10)
1. the crystal of Rui Gefeini, use Cu-K α radiation, it is in X-ray powder diffraction, and being about 7.20,13.34,14.46,14.72,15.57,16.44,17.17,18.52,18.80,19.75,23.37,23.75,24.22,24.71,25.84,26.23,26.35,27.11,27.40,29.24,30.33,31.5 and 34.92 degree of places at 2 θ has diffraction peak.
2. the crystal of claim 1, its have substantially as shown in Figure 1 XRD figure spectrum.
3. the preparation method of crystal described in claim 1 or 2, comprises the following steps:
A () 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } is amino)-3-fluorophenoxy]-N-picoline-2-methane amide mixes with organic solvent, is heated to dissolve;
B (), by the solution cooling crystallization of (a), filters, drying under reduced pressure.
4. preparation method according to claim 3, wherein the organic solvent of step (a) is selected from the mixture of C1-C4 alkyl alcohol, acetone, tetrahydrofuran (THF), acetonitrile, ethyl acetate, Isosorbide-5-Nitrae-dioxane or above-mentioned solvent.
5. preparation method according to claim 3, wherein the organic solvent of step (a) is selected from the one in acetone, methyl alcohol, ethanol, acetonitrile, or the mixture of in acetone, methyl alcohol, ethanol and acetonitrile two kinds, three kinds or four kinds.
6. preparation method according to claim 3, wherein step (a) China and Sweden Ge Feini and the mass/volume of organic solvent are than being 1:10-100.
7. preparation method according to claim 3, wherein step (a) is heated to backflow.
8. preparation method according to claim 3, wherein the temperature of step (b) cooling crystallization is-5 DEG C ~ 40 DEG C.
9. preparation method according to claim 3, wherein step (b) is being no more than drying at 70 DEG C.
10. comprise the pharmaceutical composition of crystal described in claim 1 or 2 and pharmaceutically acceptable carrier.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100063112A1 (en) * | 2006-11-09 | 2010-03-11 | Bayer Schering Pharma Aktiengesellschaft | Polymorph iii of 4-[4-(amino)-3-fluorophenoxy]-n-methylpyridine-2-carboxamide |
| US20100113533A1 (en) * | 2006-11-14 | 2010-05-06 | Bayer Schering Pharma Aktiengesellschaft | Polymorph II of 4-[4-(Amino)-3- Fluorophenoxy]-N-Methylpyridine-2-Carboxamide |
| CN102947271A (en) * | 2010-04-15 | 2013-02-27 | 拜耳制药股份公司 | Process for the preparation of 4- {4-[({[4 -chloro-3 -(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-n-methylpyridine-2-carboxamide, its salts and monohydrate |
| CN103079567A (en) * | 2010-04-17 | 2013-05-01 | 拜尔健康护理有限责任公司 | Synthetic metabolites of fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention diseases and conditions |
-
2014
- 2014-06-06 CN CN201410250111.8A patent/CN105218439B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100063112A1 (en) * | 2006-11-09 | 2010-03-11 | Bayer Schering Pharma Aktiengesellschaft | Polymorph iii of 4-[4-(amino)-3-fluorophenoxy]-n-methylpyridine-2-carboxamide |
| US20100113533A1 (en) * | 2006-11-14 | 2010-05-06 | Bayer Schering Pharma Aktiengesellschaft | Polymorph II of 4-[4-(Amino)-3- Fluorophenoxy]-N-Methylpyridine-2-Carboxamide |
| CN102947271A (en) * | 2010-04-15 | 2013-02-27 | 拜耳制药股份公司 | Process for the preparation of 4- {4-[({[4 -chloro-3 -(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-n-methylpyridine-2-carboxamide, its salts and monohydrate |
| CN103079567A (en) * | 2010-04-17 | 2013-05-01 | 拜尔健康护理有限责任公司 | Synthetic metabolites of fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention diseases and conditions |
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》 * |
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