CN103923000A - Several new crystal forms and preparation methods thereof - Google Patents
Several new crystal forms and preparation methods thereof Download PDFInfo
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- CN103923000A CN103923000A CN201410043637.9A CN201410043637A CN103923000A CN 103923000 A CN103923000 A CN 103923000A CN 201410043637 A CN201410043637 A CN 201410043637A CN 103923000 A CN103923000 A CN 103923000A
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- fluorophenoxy
- trifluoromethyl
- chloro
- phenyl
- amino
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
Abstract
The invention provides crystal form A, crystal form B, crystal form C, crystal form D and crystal form II of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl)]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide, and preparation methods thereof. The above new crystal forms can be used for treating many diseases, especially the advanced rectal cancer.
Description
Affiliated technical field
The present invention relates to chemical field of medicaments, particularly relate to 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl)] formamyl } amino)-3-fluorophenoxy] several new crystal and preparation method thereof of-N-picoline-2-methane amide.
Background technology
4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] cancer therapy drug of-N-picoline-2-methane amide (compound shown in formula Ι) Shi You Bayer Group research and development; on September 27th, 2012, obtaining FDA approval and be used for the treatment of intestinal cancer in late period, is a kind of oral many kinase inhibitor.The structure of this drug molecule is as follows:
（Ι）
CN200780037680 discloses the resulting 4-[4-of the preparation method who describes in WO2005009961 ({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] polymorphic of-N-picoline-2-methane amide.Its polymorphic, called after crystal formation Ι, has fusing point at 186-206 ℃.
CN200780037680 also discloses 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] monohydrate crystal form of-N-picoline-2-methane amide, the compound shown in corresponding formula II:
（Ⅱ）
Formula II compound is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] monohydrate crystal form of-N-picoline-2-methane amide; its X-ray powder diffraction figure is that 21.2 places show maximum value in 2theta value, and the moisture amount of formula II compound is 3.6%(quality).
CN201210293490 discloses 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] the salt type of-N-picoline-2-methane amide, comprise hydrochloride, benzene sulfonate and mesylate and preparation method thereof.
Summary of the invention
The invention provides 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] five kinds of new crystal of-N-picoline-2-methane amide, respectively called after crystal form A, crystal form B, crystal C, crystal formation D, crystal form II.
On the one hand; 4-[4-provided by the invention ({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] crystal form A of-N-picoline-2-methane amide; it is characterized in that, its X-ray powder diffraction figure is 25.5 ° ± 0.2 °, 10.0 ° ± 0.2 °, 23.3 ° ± 0.2 °, 14.7 ° ± 0.2 °, 20.5 ° ± 0.2 °, 18.2 ° ± 0.2 °, 15.7 ° ± 0.2 °, 17.1 ° ± 0.2 °, 6.4 ° ± 0.2 °, 20.0 ° ± 0.2 ° in 2theta value and locates to have characteristic peak.Its X-ray powder diffraction figure as shown in Figure 1.
Further; 4-[4-disclosed by the invention ({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] crystal form A of-N-picoline-2-methane amide; when being heated to 145 ℃; have approximately 22.5% weight loss gradient, its thermogravimetric analysis figure (TGA) as shown in Figure 2.
Further; 4-[4-disclosed by the invention ({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] crystal form A of-N-picoline-2-methane amide; its dsc (DSC) is analyzed and to be started to occur endotherm(ic)peak being heated to 83.1 ℃, as shown in Figure 3.
Further, 4-[4-disclosed by the invention ({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] crystal form A of-N-picoline-2-methane amide is the solvate of methyl-2-pyrrolidone.
Described 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] crystal form A of-N-picoline-2-methane amide, its preparation method comprises the steps:
A. by 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] solid of-N-picoline-2-methane amide is dissolved in the mixed solvent of methyl-2-pyrrolidone and water, and the volume ratio of described methyl-2-pyrrolidone and the mixed solvent of water is between between 1:0.1 to 1:10;
B. the solution to 40 described in heating steps a ℃ is to 70 ℃, and constant 0.5 to 3 hour;
C. the solution that filtration step b obtains, is cooled to room temperature to there being solid to separate out by filtrate;
D. by solid described in the method separating step c filtering, obtain crystal form A.
On the other hand; the invention provides 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] the another kind of new crystal of-N-picoline-2-methane amide; called after crystal form B; it is characterized in that, its X-ray powder diffraction figure is 7.0 ° ± 0.2 °, 23.4 ° ± 0.2 °, 19.2 ° ± 0.2 °, 29.7 ° ± 0.2 °, 25.9 ° ± 0.2 °, 18.7 ° ± 0.2 °, 25.0 ° ± 0.2 °, 12.7 ° ± 0.2 °, 28.2 ° ± 0.2 °, 22.4 ° ± 0.2 ° in 2theta value and locates to have characteristic peak.Its X-ray powder diffraction figure as shown in Figure 4.
Further; 4-[4-disclosed by the invention ({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] crystal form B of-N-picoline-2-methane amide; when being heated to 150 ℃; have 16.2% weight loss gradient, its thermogravimetric analysis figure (TGA) as shown in Figure 5.
Further; 4-[4-disclosed by the invention ({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] crystal form B of-N-picoline-2-methane amide; its dsc (DSC) analysis starts to occur first endotherm(ic)peak when being heated to 54.3 ℃; while being heated to 96.7 ℃, start to occur second heat absorption cutting edge of a knife or a sword; while being heated to 106.7 ℃ of peak temperatures, start to occur the 3rd endotherm(ic)peak; while being heated to 199.3 ℃, start to occur the 4th endotherm(ic)peak;, as shown in Figure 6.
Further, 4-[4-disclosed by the invention ({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] crystal form B of-N-picoline-2-methane amide is the solvate of acetic acid.
Described 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] crystal form B of-N-picoline-2-methane amide, its preparation method comprises the steps:
A. by 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] solid of-N-picoline-2-methane amide is dissolved in the mixed solvent of acetic acid or acetic acid and water.
B. above-mentioned solution is cooled to-16 ℃, and keeps 1 week at-16 ℃, have solid to separate out;
C. the solid that filtration step b obtains, after testing, obtains crystal form B.
On the other hand; the invention provides 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] the another kind of new crystal of-N-picoline-2-methane amide; called after crystal C; it is characterized in that, its X-ray powder diffraction figure is 7.3 ° ± 0.2 °, 23.1 ° ± 0.2 °, 29.6 ° ± 0.2 °, 25.0 ° ± 0.2 °, 27.8 ° ± 0.2 °, 26.1 ° ± 0.2 °, 20.1 ° ± 0.2 °, 14.4 ° ± 0.2 °, 15.4 ° ± 0.2 °, 27.3 ° ± 0.2 ° in 2theta value and locates to have characteristic peak.Its X-ray powder diffraction figure as shown in Figure 7.
Further; 4-[4-disclosed by the invention ({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] crystal C of-N-picoline-2-methane amide; when being heated to 150 ℃; have 11.5% weight loss gradient, its thermogravimetric analysis figure (TGA) as shown in Figure 8.
Further; 4-[4-disclosed by the invention ({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] crystal C of-N-picoline-2-methane amide; when being heated to 104.8 ℃, there is first endotherm(ic)peak in its dsc (DSC) analysis; while being heated to 112.0 ℃ of peak temperatures, start to occur second endotherm(ic)peak; while being heated to 199.8 ℃, start to occur the 3rd endotherm(ic)peak, as shown in Figure 9.
Further, 4-[4-disclosed by the invention ({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] crystal C of-N-picoline-2-methane amide is the solvate of acetic acid.
Described 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] crystal C of-N-picoline-2-methane amide, its preparation method comprises the steps:
A. by 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] solid of-N-picoline-2-methane amide is dissolved in the mixed solvent of acetic acid and normal heptane, and the volume ratio of the mixed solvent of described acetic acid and normal heptane is between between 1:0.1 to 1:10;
B. the solution to 40 described in heating steps a ℃ is to 70 ℃, and constant 2 to 3 hours;
C. slow cooling to 5 ℃, separates out without solid;
D. further slow cooling is extremely-16 ℃, and steady temperature is to there being solid to separate out;
E, by solid described in the method separating step d filtering, obtains crystal C.
On the other hand; the invention provides 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] the another kind of new crystal of-N-picoline-2-methane amide; called after crystal formation D; it is characterized in that, its X-ray powder diffraction figure is 18.8 ° ± 0.2 °, 25.3 ° ± 0.2 °, 18.4 ° ± 0.2 °, 14.1 ° ± 0.2 °, 12.8 ° ± 0.2 °, 25.3 ° ± 0.2 °, 27.7 ° ± 0.2 °, 6.3 ° ± 0.2 °, 28.7 ° ± 0.2 °, 10.0 ° ± 0.2 ° in 2theta value and locates to have characteristic peak.Its X-ray powder diffraction figure as shown in figure 10.
Further; 4-[4-disclosed by the invention ({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] the crystal formation D of-N-picoline-2-methane amide; when being heated to 80 ℃; there is 11.0% weight loss gradient; continue to be heated to 150 ℃; occur 13.6% weight loss gradient, its thermogravimetric analysis figure (TGA) as shown in figure 11.
Further, 4-[4-disclosed by the invention ({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] the crystal formation D of-N-picoline-2-methane amide, its dsc (DSC) is analyzed as shown in figure 12.
Further, 4-[4-disclosed by the invention ({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] the crystal formation D of-N-picoline-2-methane amide is the solvate of DMF.
Described 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] the crystal formation D of-N-picoline-2-methane amide, its preparation method comprises the steps:
A. by 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] solid of-N-picoline-2-methane amide is dissolved in N, in the mixed solvent of dinethylformamide and water, the volume ratio of the mixed solvent of described DMF and water is between between 1:0.1 to 1:10;
B. in the solution described in step a, add ionic liquid [DMMIM] OAc;
C. slow cooling to 5 ℃, and steady temperature is to there being solid to separate out;
D. by solid described in the method separating step c filtering, obtain crystal formation D.
On the other hand; the invention provides 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] the another kind of new crystal of-N-picoline-2-methane amide; called after crystal form II; it is characterized in that, its X-ray powder diffraction figure is 25.4 ° ± 0.2 °, 10.0 ° ± 0.2 °, 18.0 ° ± 0.2 °, 20.6 ° ± 0.2 °, 19.3 ° ± 0.2 °, 26.9 ° ± 0.2 °, 19.0 ° ± 0.2 °, 14.7 ° ± 0.2 °, 22.4 ° ± 0.2 ° in 2theta value and locates to have characteristic peak.Its X-ray powder diffraction figure as shown in figure 13.
Further; 4-[4-disclosed by the invention ({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] crystal form II of-N-picoline-2-methane amide; when being heated to 125 ℃; have 0.2% weight loss gradient, its thermogravimetric analysis figure (TGA) as shown in figure 14.
Further; 4-[4-disclosed by the invention ({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] crystal form II of-N-picoline-2-methane amide; its dsc (DSC) is analyzed and to be started to occur endotherm(ic)peak being heated to 97.9 ℃, as shown in figure 15.
Further, 4-[4-disclosed by the invention ({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] crystal form II of-N-picoline-2-methane amide is without hydrate.
Described 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] crystal form II of-N-picoline-2-methane amide; be by heating crystal form A to 70 ℃ to 80 ℃, and after constant 20 to 30 minutes, be down to room temperature and prepare.
Accompanying drawing explanation
Fig. 1 is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] XRPD of-N-picoline-2-methane amide crystal formation A figure
Fig. 2 is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] TGA of-N-picoline-2-methane amide crystal formation A figure
Fig. 3 is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] DSC of-N-picoline-2-methane amide crystal formation A figure
Fig. 4 is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] XRPD of-N-picoline-2-methane amide crystal formation B figure.
Fig. 5 is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] TGA of-N-picoline-2-methane amide crystal formation B figure.
Fig. 6 is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] DSC of-N-picoline-2-methane amide crystal formation B figure.
Fig. 7 is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] XRPD of-N-picoline-2-methane amide crystal formation C figure.
Fig. 8 is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] TGA of-N-picoline-2-methane amide crystal formation C figure.
Fig. 9 is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] DSC of-N-picoline-2-methane amide crystal formation C figure.
Figure 10 is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] XRPD of-N-picoline-2-methane amide crystal formation D figure.
Figure 11 is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] TGA of-N-picoline-2-methane amide crystal formation D figure.
Figure 12 is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] DSC of-N-picoline-2-methane amide crystal formation D figure.
Figure 13 is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] XRPD of-N-picoline-2-methane amide crystal formation II figure
Figure 14 is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] TGA of-N-picoline-2-methane amide crystal formation II figure
Figure 15 is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] DSC of-N-picoline-2-methane amide crystal formation II figure
Embodiment
Below will further set forth the present invention by specific embodiment, but be not limited to protection scope of the present invention.Those skilled in the art can make improvements preparation method and use instrument within the scope of claim, and these improvement also should be considered as protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
In following embodiment, except as otherwise noted, described test method is implemented according to the condition of normal condition or manufacturer's suggestion conventionally; Shown raw material, reagent all can obtain by the mode of commercially available purchase.
X-ray powder diffraction figure of the present invention gathers on Panalytical Empyrean x-ray powder diffraction instrument.The method parameter of X-ray powder diffraction of the present invention is as follows:
X ray reflection parameter: CuKa
Kα1(
)：1.540598；Kα2(
)：1.544426
K α 2/K α 1 intensity: 0.50
Voltage: 45 KVs (kV)
Electric current: 40 milliampere(mA)s (mA)
Divergent slit: automatically
Scan pattern: continuously
Sweep limit: from 3.0 to 40.0 degree
Sampling step length: 0.013 degree
Every step Measuring Time: 17.85 seconds/step
Means of differential scanning calorimetry of the present invention (DSC) analysis chart gathers on TA Q2000.The method parameter that means of differential scanning calorimetry of the present invention (DSC) is analyzed is as follows:
Temperature range: room temperature-230 ℃
Scanning speed: 10 ℃/min
Shielding gas: nitrogen 50mL/min
Thermogravimetric analysis of the present invention (TGA) figure gathers on TA Q500.The method parameter of thermogravimetric analysis of the present invention (TGA) is as follows:
Temperature range: room temperature-300 ℃
Scanning speed: 10 ℃/min
Shielding gas: nitrogen 60mL/min
Embodiment 1:4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] preparation method of-N-picoline-2-methane amide crystal formation A
A. by 500mg4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] solid of-N-picoline-2-methane amide joins in the mixed solvent that 2.5mL methyl-2-pyrrolidone and water volume ratio are 3:1;
B. the solution to 50 ℃ described in heating steps a, and constant 30 minutes;
C. the solution that filtration step b obtains, naturally cools to room temperature to there being solid to separate out by filtrate;
D. by solid described in the method separating step c filtering, obtain crystal form A.
The crystal form A obtaining, its X-ray powder diffraction figure (XRPD) as shown in Figure 1, it is characterized in that, in 2theta value, be 25.5 ° ± 0.2 °, 10.0 ° ± 0.2 °, 23.3 ° ± 0.2 °, 14.7 ° ± 0.2 °, 20.5 ° ± 0.2 °, 18.2 ° ± 0.2 °, 15.7 ° ± 0.2 °, 17.1 ° ± 0.2 °, 6.4 ° ± 0.2 °, 20.0 ° ± 0.2 ° and locate to there is characteristic peak.
Embodiment 2:4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] preparation method of-N-picoline-2-methane amide crystal formation B
A. by 4.4mg4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] solid of-N-picoline-2-methane amide joins in 0.15mL acetic acid, and solution is completely molten clear;
B. the solution described in step a is cooled to-16 ℃, and at this temperature, stirs 1 week, have solid to separate out;
C. the solid in filtration step b, after testing, is crystal form B.
The crystal form B obtaining, its X-ray powder diffraction figure (XRPD) as shown in Figure 4, it is characterized in that, in 2theta value, be 7.0 °, 23.4 °, 19.2 °, 29.7 °, 25.9 °, 18.7 °, 25.0 °, 12.7 °, 28.2 °, 22.4 ° and locate to there is characteristic peak.
Embodiment 3:4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] preparation method of-N-picoline-2-methane amide crystal formation C
A. by 35mg4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] solid of-N-picoline-2-methane amide joins in the mixed solvent that 0.48mL acetic acid and normal heptane volume ratio are 1:1;
B. the solution to 50 ℃ in heating steps a, after constant 1 hour, molten clear;
C. the solution in step b is placed in biochemical cultivation case, with the speed of 0.075 ℃/min, solution is down to 5 ℃ from 50 ℃, and constant 16 hours, without solid, separate out;
D. the solution in step c is placed in the refrigerator of-16 ℃, after 16 hours, has solid to separate out;
E. the solid in filtration step d, and with the distilled water wash of 5.0mL, gained solid is crystal C.The crystal C obtaining, its X-ray powder diffraction figure (XRPD) as shown in Figure 7, it is characterized in that, in 2theta value, be 7.3 ° ± 0.2 °, 23.1 ° ± 0.2 °, 29.6 ° ± 0.2 °, 25.0 ° ± 0.2 °, 27.8 ° ± 0.2 °, 26.1 ° ± 0.2 °, 20.1 ° ± 0.2 °, 14.4 ° ± 0.2 °, 15.4 ° ± 0.2 °, 27.3 ° ± 0.2 ° and locate to there is characteristic peak.
Embodiment 4:4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] preparation method of-N-picoline-2-methane amide crystal formation D
A. by 30mg4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] solid of-N-picoline-2-methane amide is dissolved in the mixed solvent that DMF and water volume ratio are 4:1;
B. in the solution described in step a, add about 8mg ionic liquid [DMMIM] OAc;
C. heat above-mentioned solution to 50 ℃, and constant 12 hours;
D. by above-mentioned solution slow cooling to 5 ℃, without solid, separate out;
E. the solution in steps d is continued to be cooled to-20 ℃, place 3 days to there being solid to separate out;
D. by solid described in the method separating step e filtering, obtain crystal formation D.
The crystal formation D obtaining, its X-ray powder diffraction figure (XRPD) as shown in figure 10, it is characterized in that, in 2theta value, be 18.8 °, 25.3 °, 18.4 °, 14.1 °, 12.8 °, 25.3 °, 27.7 °, 6.3 °, 28.7 °, 10.0 ° and locate to there is characteristic peak.
Embodiment 5:4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] preparation method of-N-picoline-2-methane amide crystal formation II
By 15mg4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] formamyl } amino)-3-fluorophenoxy] the crystal form A solid of-N-picoline-2-methane amide is placed in TGA dish; under the nitrogen protection of 60mL/min, be heated to 80 ℃; and after constant approximately 30 minutes; under nitrogen protection, be cooled to room temperature, gained solid is crystal form II.
Described crystal form II, its X-ray powder diffraction figure (XRPD) as shown in figure 13, is characterized in that, is 25.4 °, 10.0 °, 18.0 °, 20.6 °, 19.3 °, 26.9 °, 19.0 °, 14.7 °, 22.4 ° locates to have characteristic peak in 2theta value.
Claims (15)
1. a 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl)] formamyl } amino)-3-fluorophenoxy] crystal form A of-N-picoline-2-methane amide; it is characterized in that, in its X-ray diffractogram, in 2theta value, be 25.5 ° ± 0.2 °, 10.0 ° ± 0.2 °, 23.3 ° ± 0.2 ° and locate to there is characteristic peak.
2. crystal form A according to claim 1, be further characterized in that, in its X-ray diffractogram, in 2theta value, be 20.6 ° ± 0.2 °, 19.3 ° ± 0.2 °, 26.9 ° ± 0.2 °, 19.0 ° ± 0.2 °, 14.7 ° ± 0.2 °, 22.4 ° ± 0.2 ° and locate to there is characteristic peak.
3. according to the crystal form A described in claim 1 and 2, it is characterized in that, its X-ray powder diffraction figure is substantially consistent with Fig. 1.
4. a 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl)] formamyl } amino)-3-fluorophenoxy] crystal form B of-N-picoline-2-methane amide; it is characterized in that, in its X-ray diffractogram, in 2theta value, be 7.0 ° ± 0.2 °, 23.4 ° ± 0.2 °, 19.2 ° ± 0.2 ° and locate to there is characteristic peak.
5. crystal form B according to claim 4, be further characterized in that, in its X-ray diffractogram, in 2theta value, be 29.7 ° ± 0.2 °, 25.9 ° ± 0.2 °, 18.7 ° ± 0.2 °, 25.0 ° ± 0.2 °, 12.7 ° ± 0.2 °, 28.2 ° ± 0.2 °, 22.4 ° ± 0.2 ° and locate to there is characteristic peak.
6. according to the crystal form B described in claim 4 and 5, it is characterized in that, its X-ray powder diffraction figure is substantially consistent with Fig. 4.
7. a 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl)] formamyl } amino)-3-fluorophenoxy] crystal C of-N-picoline-2-methane amide; it is characterized in that, in its X-ray diffractogram, in 2theta value, be 7.3 ° ± 0.2 °, 23.1 ° ± 0.2 °, 29.6 ° ± 0.2 ° and locate to there is characteristic peak.
8. crystal C according to claim 7, be further characterized in that, in its X-ray diffractogram, in 2theta value, be 25.0 ° ± 0.2 °, 27.8 ° ± 0.2 °, 26.1 ° ± 0.2 °, 20.1 ° ± 0.2 °, 14.4 ° ± 0.2 °, 15.4 ° ± 0.2 °, 27.3 ° ± 0.2 ° and locate to there is characteristic peak.
9. according to the crystal C described in claim 7 and 8, it is characterized in that, its X-ray powder diffraction figure is substantially consistent with Fig. 7.
10. a 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl)] formamyl } amino)-3-fluorophenoxy] the crystal formation D of-N-picoline-2-methane amide; it is characterized in that, in its X-ray diffractogram, in 2theta value, be 18.8 ° ± 0.2 °, 25.3 ° ± 0.2 °, 18.4 ° ± 0.2 ° and locate to there is characteristic peak.
11. crystal formation D according to claim 10, be further characterized in that, in its X-ray diffractogram, in 2theta value, be 14.1 ° ± 0.2 °, 12.8 ° ± 0.2 °, 25.3 ° ± 0.2 °, 27.7 ° ± 0.2 °, 6.3 ° ± 0.2 °, 28.7 ° ± 0.2 °, 10.0 ° ± 0.2 ° and locate to there is characteristic peak.
12. according to the crystal formation D described in claim 10 and 11, it is characterized in that, its X-ray powder diffraction figure is substantially consistent with Figure 10.
13. 1 kinds of 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl)] formamyl } amino)-3-fluorophenoxy] crystal form II of-N-picoline-2-methane amide; it is characterized in that, in its X-ray diffractogram, in 2theta value, be 25.4 ° ± 0.2 °, 10.0 °+0.2 °, 18.0 °+0.2 ° and locate to there is characteristic peak.
14. crystal form IIs according to claim 13, be further characterized in that, in its X-ray diffractogram, in 2theta value, be 19.0 °+0.2 °, 19.3 °+0.2 °, 20.6 °+0.2 °, 14.7 °+0.2 °, 22.4 °+0.2 °, 26.9 °+0.2 ° and locate to there is characteristic peak.
15. according to the crystal form II described in claim 13 and 14, it is characterized in that, its X-ray powder diffraction figure is substantially consistent with Figure 13.
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| CN105985287A (en) * | 2015-02-13 | 2016-10-05 | 上海京新生物医药有限公司 | Novel crystal form of regorafenib |
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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 |
| 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 |
| WO2013000917A1 (en) * | 2011-06-28 | 2013-01-03 | Bayer Intellectual Property Gmbh | Topical ophthalmological pharmaceutical composition containing regorafenib |
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| 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 |
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| CN105985287A (en) * | 2015-02-13 | 2016-10-05 | 上海京新生物医药有限公司 | Novel crystal form of regorafenib |
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