CN105218439B - A kind of crystal of Rui Gefeini and preparation method thereof - Google Patents
A kind of crystal of Rui Gefeini and preparation method thereof Download PDFInfo
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- CN105218439B CN105218439B CN201410250111.8A CN201410250111A CN105218439B CN 105218439 B CN105218439 B CN 105218439B CN 201410250111 A CN201410250111 A CN 201410250111A CN 105218439 B CN105218439 B CN 105218439B
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Abstract
The present invention provides the crystal and preparation method thereof of Rui Gefeini a kind of, it is radiated using Cu-K α, it is in the X-ray powder diffraction pattern, it is about 7.20,13.34,14.46,14.72,15.57,16.44,17.17 in 2 θ, has diffraction maximum 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.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 mild, is suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of crystal of Rui Gefeini and preparation method thereof.
Background technique
Rui Gefeini (Regorafenib) has structure shown in formula (I), and chemical name is 4- [4- ({ [the chloro- 3- (three of 4-
Methyl fluoride) phenyl] carbamoyl } amino) -3- fluorophenoxy]-N- picoline -2- formamide.
Rui Gefeini is a kind of inhibitor for the VEGFR and Raf kinases double activity developed by Bayer AG, and
The stimulant of caspase-3 and -9, can be administered orally treatment solid tumor, including clear-cell carcinoma (RCC), colorectal cancer
(CRC) and hepatocellular carcinoma (HCC).
Rui Gefeini is first disclosed as WO2005009961, and the crystal obtained by triturated under ether is Rui Gefei in the patent application
The I type crystal of Buddhist nun.WO2008043446 discloses the monohydrate of Rui Gefeini, by the way that polymorphic I is dissolved in acetone or alcohol
In, elutriation crystalline substance is added and obtains, is suspended in acetonitrile/water, stirs to get in THF/ water.Rui Gefeini is disclosed in WO2008058644
II type crystal, obtained by crystallizing polymorphic I in ethyl acetate.The III of Rui Gefeini is disclosed in WO2008055629
Type crystal, by the way that the short time heats to obtain at 100 DEG C -110 DEG C by polymorphic I.
It is living with different fusing points, solubility, stability, biology that the variation of medicinal compound crystal form typically results in compound
Property etc., these are the key factors of difficulty or ease, storage stability, preparation difficulty or ease and bioavilability for influencing medicine preparation etc..
When compound is there are when polymorphic, macroscopic property and stability due to specific polymorph with specificity are being made
In standby process, the crystal form for understanding the compound applied in each dosage form is important, to guarantee that process application is identical
The drug of form.Thus it is guaranteed that the known mixture that compound is single crystal form or some crystal forms is necessary.
When it is preferred for judging which kind of polymorph, it is necessary to compare their many properties and preferred polymorphic
Object is made a choice based on many physical properties.Entirely possible be a kind of polymorphic in some aspects as the difficulty or ease of preparation,
Stability etc. be considered as it is critical under the conditions of be preferred.In other cases, different polymorphs may Yin Genggao
Solubility or excellent pharmacokinetics and it is preferred that.
The discovery of the new polymorph of medicinal compound provides the chance for improving drug physical characteristic, that is, extends object
Whole properties of matter, so as to preferably instruct the research of compound and its preparation, therefore Rui Gefeini provided by the invention
Polymorph it is commercially valuable in the manufacture and other application of drug.
Summary of the invention
One aspect of the present invention provides the crystal of Rui Gefeini a kind of, is radiated using Cu-K α, in X-ray powder diffraction
(XRD) in map, 2 θ be 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
With 34.92 degree at have diffraction maximum.
It is radiated using Cu-K α, the spectrogram of the typical XRD of Rui Gefeini crystal is as shown in Fig. 1, with following feature：
Another aspect of the present invention provides the preparation method of Rui Gefeini crystal, including：
(a) 4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamoyl } amino) -3- fluorophenoxy]-N- methyl
Pyridine-2-carboxamide is mixed with organic solvent, is heated to dissolving；
(b) by the solution cooling crystallization of (a), filtering is dried under reduced pressure.
Wherein, organic solvent is selected from C1-C4 alkylol, acetone, tetrahydrofuran, acetonitrile, ethyl acetate, 1 in step (a),
The mixture of 4- dioxane or above-mentioned solvent；It is preferred that one of acetone, methanol, ethyl alcohol or acetonitrile or acetone, methanol, second
Two kinds, three kinds or four kinds of mixture in alcohol, acetonitrile；Wherein, Rui Gefeini：Organic solvent=1：10-100 (quality/body
Product, g/mL), preferably 1：10-60；More preferable 1:15-40, in some embodiments, when Rui Gefeini is 1 gram, You Jirong
The amount of agent is 10-100mL.In some embodiments, step (a) is heated to flowing back.
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
℃；In a specific embodiment, the cooling crystallization temperature is 20 DEG C.
Wherein, it is dry in the case where being no more than 70 DEG C when step (b) is dry；It is preferred that dry in the case where being no more than 60 DEG C；Specific
In embodiment, at -0.09-0.1Mpa, in 60 DEG C of dryings.
Another aspect of the present invention provides the pharmaceutical composition containing above-mentioned crystal.The pharmaceutical composition also includes one
Kind or a variety of pharmaceutic adjuvants also may include optionally other therapeutic activity ingredients.It can also be with chemotherapy, radiotherapy, outer
Section perform the operation these therapies administering drug combinations.
The pharmaceutical composition is preferably with oral administration.Being suitble to oral pharmaceutical composition includes tablet, capsule
Agent, pulvis, granule, dripping pill, paste, powder, tincture etc., preferred tablet and capsule.Wherein tablet can be ordinary tablet
Agent, dispersible tablet, effervescent tablet, sustained release tablets, controlled release tablet or enteric coatel tablets, capsule can be conventional capsule, spansule, controlled release capsule
Or capsulae enterosolubilis.
Conventional pharmaceutical adjuvants well known in the art can be used to be made by conventional method for pharmaceutical composition of the invention.It is conventional
Pharmaceutic adjuvant include filler, absorbent, wetting agent, adhesive, disintegrating agent, lubricant etc..Filler includes starch, cream
Sugar, mannitol, microcrystalline cellulose etc.；Absorbent includes calcium sulfate, calcium monohydrogen phosphate, calcium carbonate, magnesia etc.；Wetting agent includes
Water, ethyl alcohol etc.；Adhesive includes hydroxypropyl methylcellulose, povidone, microcrystalline cellulose etc.；Disintegrating agent includes cross-linked carboxymethyl fiber
Plain sodium, crospovidone, surfactant, low-substituted hydroxypropyl cellulose etc.；Lubricant includes magnesium stearate, talcum powder, gathers
Ethylene glycol, Stepanol MG, superfine silica gel powder, talcum powder etc..Pharmaceutic adjuvant further includes colorant, sweetener etc..
In another aspect, the present invention provides above-mentioned crystal, pharmaceutical composition in preparation for treating in anti-tumor drug
Purposes.
Herein, according to 2010 editions Ⅸ F of annex of Chinese Pharmacopoeia, the X-ray powder diffraction spectrum of sample is under the following conditions
Measurement, instrument and its model：II X-ray powder diffraction instrument of D/Max-RA Japan RigakuXMiniFlex；Ray：Monochromatic Cu-
Ka rayScanning mode：The θ of θ/2, scanning range：0-40 °, voltage：30Kv, electric current 15mA；Detect environment item
Part：Temperature：23.9 DEG C, humidity：38.6%.
It should be noted that in X-ray powder diffraction spectrum (XRD), the diffraction spectrogram pair that is obtained by crystalline compounds
Often characteristic in specific crystal, wherein the relative intensity of bands of a spectrum may be because of crystal condition, partial size and other surveys
The difference of fixed condition and the advantage orientation effect that generates and change.Therefore, the relative intensity of diffraction maximum to targeted crystal simultaneously
It is non-be it is characteristic, judge whether with known crystal phase simultaneously, it should be noted that the relative position at peak rather than they
Relative intensity.In addition, there may be slight errors for the position at peak, this is in crystallography art for any given crystal
In be also well known.For example, the variation of temperature, sample movement or calibration of instrument etc. when due to analyzing sample, the position at peak can
With movement, the evaluated error of 2 θ values is about ± 0.2 ° sometimes.Therefore, when determining every kind of crystal structure, it should examine this error
Including worry.Peak position usually is indicated away from d with 2 angles θ or crystal face in XRD spectrum, and there is simple conversion relation between the two：d
=λ/2sin θ, wherein d represents crystal face away from λ represents the wavelength of incident X-rays, and θ is the angle of diffraction.
The Rui Gefeini crystal that the present invention is prepared, has that purity is high, crystallinity are high, stability is good, non-hygroscopic etc. excellent
Point；Meanwhile the preparation method of Rui Gefeini crystal provided by the invention is simple, high income, solvent is cheap and easy to get, crystallization condition temperature
With, be suitble to industrialized production, can preferably meet pharmacy industry demand.
Detailed description of the invention
The X-ray powder diffraction figure for the Rui Gefeini crystal that Fig. 1 embodiment is prepared
The DSC for the Rui Gefeini crystal that Fig. 2 embodiment is prepared schemes
Specific embodiment
Illustrate technical solution of the present invention with specific embodiment, but protection scope of the present invention is not limited to following implementation
Example range.Used reagent is commercial product.
The preparation of 1 Rui Gefeini crystal of embodiment
By 1g4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamoyl } amino) -3- fluorophenoxy]-N- methyl
Pyridine-2-carboxamide is added in the acetonitrile of 38mL, is heated to reflux to dissolution, naturally cools to 20 DEG C and continues to stir 1 hour crystallization.
The solid being precipitated is filtered, 60 DEG C are dried under reduced pressure 3h and obtain white solid 708mg, with X-ray powder diffraction figure shown in FIG. 1.
The preparation of 2 Rui Gefeini crystal of embodiment
By 1g4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamoyl } amino) -3- fluorophenoxy]-N- methyl
Pyridine-2-carboxamide is added in the ethyl alcohol of 25mL, is heated to reflux to dissolution, is naturally cooled to 20 DEG C and is continued to stir 1 hour crystallization.
The solid being precipitated is filtered, 60 DEG C are dried under reduced pressure 3h and obtain white solid 463mg, with X-ray powder diffraction figure shown in FIG. 1.
The preparation of 3 Rui Gefeini crystal of embodiment
By 1g4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamoyl } amino) -3- fluorophenoxy]-N- methyl
Pyridine-2-carboxamide is added in the methanol of 25mL, is heated to reflux to dissolution, is naturally cooled to 20 DEG C and is continued to stir 1 hour crystallization.
The solid being precipitated is filtered, 60 DEG C are dried under reduced pressure 3h and obtain white solid 489mg, with X-ray powder diffraction figure shown in FIG. 1.
The preparation of 4 Rui Gefeini crystal of embodiment
By 1g4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamoyl } amino) -3- fluorophenoxy]-N- methyl
Pyridine-2-carboxamide is added in the acetone of 16mL, is heated to reflux to dissolution, is naturally cooled to 20 DEG C and is continued to stir 1 hour crystallization.
The solid being precipitated is filtered, 60 DEG C are dried under reduced pressure 3h and obtain white solid 512mg, with X-ray powder diffraction figure shown in FIG. 1.
The stability of 5 Rui Gefeini crystal of embodiment
Stability experiment method referring to described in 2010 editions two annex XIX C of Chinese Pharmacopoeia of crystal herein carries out
Test.
1 stability test result of table
Can be seen that Rui Gefeini crystal of the invention from the long term test at high temperature, strong light and 25 DEG C is thermodynamics
Stable, and X-ray powder diffraction measurement display crystal does not change, is therefore particularly suitable for pharmaceutical preparation.
Claims (5)
1. the crystal of Rui Gefeini is radiated using Cu-K α, in the X-ray powder diffraction pattern, there is following feature,
The preparation method of the crystal, includes the following steps：(a) 4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl
Base } amino) -3- fluorophenoxy] and-N- picoline -2- formamide with selected from acetone, methanol, ethyl alcohol, acetonitrile organic solvent in
One or more mix, be heated to flowing back, dissolve；(b) by the solution of (a) at a temperature of -5 DEG C~40 DEG C cooling crystallization,
Filtering, is dried under reduced pressure.
2. the crystal of claim 1 has XRD spectrum substantially as shown in Fig. 1.
3. crystal described in claim 1, wherein the mass/volume of step (a) China and Sweden Ge Feini and organic solvent ratio is 1：10-
100。
4. crystal described in claim 1, wherein step (b) is dry in the case where being no more than 70 DEG C.
5. including the pharmaceutical composition of crystal as claimed in claim 1 or 2 and pharmaceutically acceptable carrier.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2081902A1 (en) * | 2006-11-09 | 2009-07-29 | 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 |
-
2014
- 2014-06-06 CN CN201410250111.8A patent/CN105218439B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
|---|
| 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32页反应路线和第33页右栏第2段 * |
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