CN104649969B - A kind of salt and preparation method thereof for Buddhist nun's class drug - Google Patents
A kind of salt and preparation method thereof for Buddhist nun's class drug Download PDFInfo
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- CN104649969B CN104649969B CN201410676653.1A CN201410676653A CN104649969B CN 104649969 B CN104649969 B CN 104649969B CN 201410676653 A CN201410676653 A CN 201410676653A CN 104649969 B CN104649969 B CN 104649969B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
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Abstract
The present invention relates to anticancer drug N- (4- { [6, bis- (methoxyl group) quinolyl-4s of 7-] oxygroup } phenyl)-N'- (4- fluorophenyl) cyclopropane -1, L MALIC ACID salt and the novel crystal forms of hydrobromate of 1- diformamide and preparation method thereof, in the X-ray powder diffraction figure of the malate novel crystal forms 2 θ be 9.33, 11.75, 13.44, 15.16, 19.72, 23.14, there is peak in 25.92 degree of position, in the X-ray powder diffraction figure of the novel crystal forms of hydrobromate 2 θ be 8.68, 13.01, 17.45, 19.52, 20.05, 21.71, 23.29, there is peak in 26.28 degree of position；The novel crystal forms have preferable physicochemical property, are conducive to operate in production, can be used for pharmaceutical preparation.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of salt for Buddhist nun's class drug, crystal form and preparation method thereof.
Background technique
Cabozantinib (its Chinese name is translated into card cloth for Buddhist nun by the present invention), entitled N- (4- { [6, the 7- bis- (methoxies of chemistry
Base) quinolyl-4] oxygroup } phenyl)-N'- (4- fluorophenyl) cyclopropane -1,1- diformamide, shown in structure such as formula (01),
Shown in the structure of its L MALIC ACID salt such as formula (I)；In November, 2012, U.S. FDA approval card cloth is for Buddhist nun's L MALIC ACID salt for controlling
It treats progressive metastatic medullary thyroid carcinoma (MTC):
PCT application WO2005030140, which discloses card cloth, has adjusting signal transduction of kinases with it for the preparation method of Buddhist nun
Active function；The different crystal forms that card cloth replaces Buddhist nun's malate are disclosed in China application CN201080012656.5, prompt card cloth
Poor for the dissolubility of Buddhist nun, card cloth has different physicochemical properties for the different salt of Buddhist nun, and card cloth is for Buddhist nun's malate relative to enumerating
Other salt, have and be preferably used to prepare the property of pharmaceutical composition.Because polymorph in pharmaceuticals is common existing in drug research and development
As being an important factor for influencing drug quality.The different crystal forms of same drug are in appearance, mobility, solubility, storage stability
Etc. might have it is dramatically different, can the generations such as storage transfer, application, stability, bioavilability, curative effect to drug not
Same influence；There may be huge differences for physicochemical property of different salt and/or crystal form etc.；In order to obtain more effective salt and/or
Crystal form, it is still desirable to card cloth comprehensively be investigated for the salt and card cloth of Buddhist nun for the crystallization behavior of Buddhist nun's malate, to obtain
Meet the advantageous salt and/or crystal form of the production requirements such as preparation.
Summary of the invention
Summary of the invention
First aspect present invention provides the crystal form A1, A2 that card cloth replaces Buddhist nun's malate.
Second aspect of the present invention provides the hydrobromate that card cloth replaces Buddhist nun.
Third aspect present invention provides the card cloth novel crystal forms essentially pure for Buddhist nun's hydrobromate, and the present invention is named as crystalline substance
Type I.
Fourth aspect present invention provide the card cloth for Buddhist nun's malate crystal form A1, A2 and card cloth for Buddhist nun's hydrobromate and
The preparation method of hydrobromate crystal form I.
Term definition
" crystal form " refers to the unique ordered arrangement and/or conformation of molecule of the compound in lattice.
" essentially pure " refers to a kind of crystal form substantially free of another or a variety of crystal forms, the i.e. purity of crystal form extremely
Few 60%, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or extremely
Few 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least
99.9% or crystal form in contain other crystal forms, percentage of the other crystal forms in the total volume of crystal form or total weight is less than
20% or less than 10% or less than 5% or less than 3% or less than 1% or less than 0.5% or less than 0.1%, or less than
0.01%.
The one or more other crystal forms of substantially free refer to other crystal forms in the total volume of crystal form or total weight
Percentage is less than 20% or less than 10% or less than 5% or less than 4% or less than 3% or less than 2% or less than 1%,
Or less than 0.5% or less than 0.1% or less than 0.01%.
X-ray powder diffraction " substantially as shown in the figure " refers at least 50% in X-ray powder diffraction figure, or at least
60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% peak is shown in figure.
" relative intensity " refers to that the intensity at the last the first peak in all diffraction maximums of X-ray powder diffraction figure (XRPD) is
When 100%, the ratio of the intensity of the intensity and the last the first peak at other peaks.
When referring to spectrogram or/and appearing in the data in figure, what " peak " referred to that those skilled in the art can identify will not
Belong to a feature of background noise.
In the present invention, 2 θ values in X-ray powder diffraction figure are with degree (°) for unit.
In the present invention, the X-ray powder diffraction (XRPD) of the crystal form, 2 θ of X-ray powder diffraction collection or
The measurement of diffraction maximum has experimental error, between a machine and another machine and sample and another sample it
Between, 2 θ of X-ray powder diffraction collection or the measurement of diffraction maximum may slightly have difference, the number of the experimental error or difference
Value may be +/- 0.2 unit or +/- 0.1 unit, thus 2 θ or the numerical value of diffraction maximum cannot be considered as it is absolute.
In the present invention, the differential scanning calorimetry figure (DSC) of the crystal form has experimental error, in a machine and another
Between machine and between a sample and another sample, the position of endothermic peak and peak value may slightly have difference, and experiment misses
The numerical value of difference or difference may be +/- 5 units, +/- 4 units, +/- 3 units, +/- 2 units, +/- 1 unit,
+/- 0.5 unit or +/- 0.1 unit, therefore the peak position of the DSC endothermic peak or the numerical value of peak value cannot be considered as absolutely
's.
In the present invention, the thermogravimetric analysis (TGA) of the crystal form has experimental error, a machine and another machine it
Between and a sample and another sample between, weightless temperature and weightless amount may slightly have difference, experimental error or difference
Other numerical value may be +/- 0.2 unit or +/- 0.1 unit, therefore the weightless temperature and the numerical value of weightless amount are not
It can be considered as absolute.
Detailed description of the invention
In a first aspect, inventor, which passes through, has researched and developed crystal form A1, A2 that card cloth replaces Buddhist nun's malate.
Card cloth replace Buddhist nun's malate crystal form A1, have the property that in its X-ray powder diffraction figure 2 θ be 13.47
There is peak in the position of degree.
In some embodiments, card cloth for Buddhist nun's malate crystal form A1 X-ray powder diffraction figure in 2 θ be 13.47,
15.23,26.10 there is peak in the position of degree.
In some embodiments, card cloth for Buddhist nun's malate crystal form A1 X-ray powder diffraction figure in 2 θ be 9.44,
13.47,15.23,22.79,26.10,27.08 there is peak in the position of degree.
In some embodiments, card cloth for Buddhist nun's malate crystal form A1 X-ray powder diffraction figure in 2 θ be 9.44,
10.99,11.79,13.47,15.23,18.94,19.72,21.12,22.79,23.37,26 the position many places of .10,27.08 degree
There is peak.
In some embodiments, card cloth for Buddhist nun's malate crystal form A1 X-ray powder diffraction figure in 2 θ be 6.70,
7.79,9.44,10.99,11.79,13.47,15.23,17.30,18.94,19.72,21.12,22.79,23.37,26.10,
There are peak in many places of 27.08 degree of position.
The X-ray powder diffraction figure of crystal form A1 substantially as shown in, wherein 2 θ of the angle of diffraction be 13.47 degree peak phase
50% is greater than to intensity, is perhaps greater than 60% and is perhaps perhaps perhaps greater than 90% greater than 80% greater than 70% or is greater than
99%, or be 100%.
The differential scanning calorimetry measurement (DSC) of crystal form A1 has heat absorption at 120 DEG C -130 DEG C and at 170 DEG C -180 DEG C
Peak；In some embodiments, endothermic peak summit value is respectively in 127 DEG C and 176 DEG C；In some embodiments, DSC such as Fig. 2
It is shown.
The thermogravimetric analysis (TGA) of crystal form A1 has weightlessness, weightless 4%-5% between 35 DEG C -130 DEG C；In some embodiments,
Its TGA is as shown in figure 3, weightlessness 4.85%.
Crystal form A1 is dry for a long time by high temperature, can obtain crystal form A2.
Card cloth replace Buddhist nun's malate crystal form A2, have the property that in its X-ray powder diffraction figure 2 θ be 13.44
There is peak in the position of degree.
In some embodiments, card cloth for Buddhist nun's malate crystal form A2 X-ray powder diffraction figure in 2 θ be 13.44,
15.16,25.92 there is peak in the position of degree.
In some embodiments, card cloth for Buddhist nun's malate crystal form A2 X-ray powder diffraction figure in 2 θ be 9.33,
13.44,15.16,19.72,25.92 there is peak in the position of degree.
In some embodiments, card cloth for Buddhist nun's malate crystal form A2 X-ray powder diffraction figure in 2 θ be 9.33,
11.75,13.44,15.16,19.72,23.14,25.92 there is peak in the position of degree.
In some embodiments, card cloth for Buddhist nun's malate crystal form A2 X-ray powder diffraction figure in 2 θ be 6.70,
7.73,9.33,10.97,11.75,13.44,15.16,17.27,18.86,19.72,20.9 7,23.14,25.92,26.90 degree
The many places of position have peak.
In some embodiments, in the X-ray powder diffraction figure of crystal form A2 2 θ of the angle of diffraction be 13.44 degree peak it is opposite
Intensity is greater than 50%, is perhaps greater than 60% and is perhaps perhaps perhaps greater than 90% greater than 80% greater than 70% or is greater than
99%.
In some embodiments, the X-ray powder diffraction figure of crystal form A2 is substantially as shown in figure 4, wherein 2 θ of the angle of diffraction is
The relative intensity at 13.44 degree of peak is greater than 80%, is perhaps greater than 90% or greater than 99%.
The XRPD figure that crystal form A2 has and crystal form A1 is essentially identical, but its differential scanning calorimetry measurement (DSC) is only 120
There is endothermic peak at DEG C -130 DEG C；In some embodiments, endothermic peak summit value is at 123.8 DEG C；In some embodiments,
DSC is as shown in Figure 5.
It is detected immediately after 105 DEG C of drying to constant weights of crystal form A2 sample, water content 1.4%, replaces Buddhist nun for a molecule card cloth
The crystallization of malate and 0.5 molecular water；Crystal form A2 sample is placed in air, there is hygroscopicity；In some cases, it is put in air
Postpone detect its thermogravimetric analysis (TGA) have weightlessness, weightless 1.5%-2.5% between 35 DEG C -150 DEG C；In some cases,
TGA is as shown in fig. 6, weightlessness 2.39%.
Second aspect, the present invention provides the hydrobromates that card cloth replaces Buddhist nun, shown in structure such as formula (2)；Card cloth replaces Buddhist nun's hydrogen
Bromate and card cloth replace Buddhist nun's malate free base having the same, equally have and inhibit a variety of generations with tumour, progress,
The active effect of related kinases is shifted,
The third aspect, the present invention provides the card cloth novel crystal forms essentially pure for Buddhist nun's hydrobromate, the present invention is named as
Crystal form I.Card cloth replace Buddhist nun's hydrobromate essentially pure crystal form I, have the property that in its X-ray powder diffraction figure
2 θ are that 23.29 degree of position has peak.
In some embodiments, in X-ray powder diffraction figure of the card cloth for the essentially pure crystal form I of Buddhist nun's hydrobromate
There is peak in the position that 2 θ are 13.01,17.45,23.29,26.28 degree.
In some embodiments, in X-ray powder diffraction figure of the card cloth for the essentially pure crystal form I of Buddhist nun's hydrobromate
There is peak in the position that 2 θ are 8.68,13.01,17.45,19.52,20.05,21.71,23.29,26.28 degree.
In some embodiments, in X-ray powder diffraction figure of the card cloth for the essentially pure crystal form I of Buddhist nun's hydrobromate
It is 8.68,12.17,13.01,16.71,17.45,19.52,20.05,21.71,23.29,23. 86,24.52,26.28 in 2 θ,
27.49,29.95,32.13 there are peak in many places for the position spent.
In some embodiments, in X-ray powder diffraction figure of the card cloth for the essentially pure crystal form I of Buddhist nun's hydrobromate
2 θ be 6.48,8.68,9.33,11.89,12.17,13.01,13.55,16.28,16.71,17.45,19.13,19.52,
20.05,20.68,21.71,23.29,23.53,23.86,24.52,25.22,26.28,27.49,27.81,29.95,
31.00,32.13,32.85 there are peak in many places for the position spent.
In some embodiments, in X-ray powder diffraction figure of the card cloth for the essentially pure crystal form I of Buddhist nun's hydrobromate
2 θ be 6.48,8.68,9.33,11.89,12.17,13.01,13.55,16.28,16.71,17.45,19.13,19.52,
20.05,20.68,21.25,21.71,22.47,22.64,23.29,23.53,23.86,24.52,25.22,25.45,
26.28,27.21,27.49,27.81,29.69,29.95,30.25,30.76,31.00,31 the position of .36,32.13,32.85 degree
There are peak in many places set.
In some embodiments, 2 θ of the angle of diffraction is 23.29 degree in the X-ray powder diffraction figure of essentially pure crystal form I
Peak relative intensity be greater than 50%, perhaps be greater than 60% perhaps be greater than 70% perhaps be greater than 80% or be greater than 90%, or
Person is greater than 99%.
In some embodiments, the X-ray powder diffraction figure of essentially pure crystal form I substantially as shown in fig. 7, its
The relative intensity at the peak that middle 2 θ of the angle of diffraction is 23.29 degree is greater than 99%.
Essentially pure crystal form I can also be characterized otherwise, for example, in some embodiments, differential scanning
Calorimetry (DSC) has endothermic peak at 215 DEG C -240 DEG C；In some embodiments, differential scanning calorimetry measurement (DSC)
There is endothermic peak at 220 DEG C -235 DEG C；In some embodiments, endothermic peak summit value is at 235 DEG C；In some embodiments
In, DSC is as shown in Figure 8.
Essentially pure crystal form I can also be characterized otherwise, for example, in some embodiments, thermogravimetric analysis
(TGA) there are weightlessness, weightlessness 0.75% between 40 DEG C -150 DEG C；In some embodiments, TGA is as shown in Figure 9.
Essentially pure crystal form I can also be characterized otherwise, for example, in some embodiments, being taken using karr-
Not method (KF method) measures its moisture content, water content 0.81%.
Fourth aspect, the present invention also provides the card cloths to replace Buddhist nun's hydrobromate and hydrogen for Buddhist nun's malate crystal form and card cloth
The preparation method of bromate crystal form I.
A kind of method for preparing card cloth and replacing Buddhist nun's malate crystal form A1 or A2 or hydrobromate and its crystal form I, with second
Alcohol/water mixed solvent is recrystallized.
Card cloth includes: that card cloth is heated to temperature for Buddhist nun and ethanol water for the preparation method of Buddhist nun's malate crystal form A1, A2
T1 is spent, L MALIC ACID, heating reaction a period of time is added；Then it is slow cooling to temperature T2 and solid is precipitated；Stirring and crystallizing, removal
Solvent collects solid；Obtained solid is dried at a certain temperature, obtains crystal.
Card cloth includes: that card cloth is heated to temperature T1 for Buddhist nun and ethanol water for the preparation method of Buddhist nun's hydrobromate, is added
Hydrobromic acid, heating reaction a period of time；Then it is slow cooling to temperature T2 and solid is precipitated；Stirring and crystallizing removes solvent, collects solid
Body；Obtained solid is dried at a certain temperature, obtains crystal.
The temperature T1 is 50 DEG C to solvent reflux temperature, and in some embodiments, the temperature T1 is 50 DEG C -80
℃；In some embodiments, the temperature T1 is 55 DEG C -70 DEG C.
The time of the heating reaction is -3 hours 0.5 hour；In some embodiments, the reaction time is 0.5
- 1.5 hours hours.
The slow cooling, which refers to, is reduced to precipitation solid for system temperature whithin a period of time；In some embodiments
In, system temperature is reduced to precipitation solid in -4 hours 0.1 hour；In some embodiments, at -2 hours 0.5 hour
It is interior that system temperature is reduced to precipitation solid.
The temperature T2 that solid is precipitated is 30 DEG C -60 DEG C；In some embodiments, temperature T2 is 30 DEG C -50 DEG C；?
In some embodiments, temperature T2 is 30 DEG C -40 DEG C.
The temperature of the stirring and crystallizing is -10 DEG C -10 DEG C；In some embodiments, the temperature of the stirring and crystallizing be-
5℃-5℃；In some embodiments, the stirring and crystallizing temperature is 0 DEG C.
The time of the stirring and crystallizing is -3 hours 0.5 hour；In some embodiments, the time of the stirring and crystallizing
It is -2 hours 1 hour.
When preparing crystal of the card cloth for Buddhist nun's malate, the content of ethyl alcohol is no more than 85% (body in the ethanol water
Product ratio)；In some embodiments, the content of ethyl alcohol is no more than 80% (volume ratio) in the ethanol water.
When preparing crystal of the card cloth for Buddhist nun's hydrobromate, the content of ethyl alcohol is no more than 95% (body in the ethanol water
Product ratio)；In some embodiments, the content of ethyl alcohol is no more than 90% (volume ratio) in the ethanol water.
The drying temperature is 65 DEG C, when drying time is 24 hours, obtains crystal form A1.
The drying temperature is 90 DEG C or 105 DEG C, dry to constant weight, obtains crystal form A2；In some embodiments, it does
The dry time is 24 or 48 hours.
The drying temperature is 65 DEG C, and drying time is 24 hours, obtains crystal form I.
In some embodiments, the method for preparing crystal form A2 includes: card cloth for Buddhist nun, i.e. N- (4- { [6,7- bis- (methoxies
Base) quinolyl-4] oxygroup } phenyl)-N'- (4- fluorophenyl) cyclopropane -1,1- diformamide, 50 are heated to ethanol water
DEG C -80 DEG C, L MALIC ACID, heating reaction -1.5 hours 0.5 hour is added；Then cooled in -2 hours 0.5 hour 30 DEG C -
40 DEG C of precipitation solids；Then -5 DEG C -5 DEG C of stirring and crystallizings -2 hours 1 hour；Solvent is removed, solid is collected；Obtained solid is 90
DEG C or 105 DEG C of dryings to constant weight, obtain A2 crystal.
In some embodiments, the method for preparing hydrobromate crystal form I includes: card cloth for Buddhist nun, i.e. ({ [6,7- is bis- by 4- by N-
(methoxyl group) quinolyl-4] oxygroup phenyl)-N'- (4- fluorophenyl) cyclopropane -1,1- diformamide, with ethanol water plus
Hydrobromic acid, heating reaction -1.5 hours 0.5 hour is added to 50 DEG C -80 DEG C in heat；Then it is cooled in -2 hours 0.5 hour
30 DEG C of -40 DEG C of precipitation solids；Then -5 DEG C -5 DEG C of stirring and crystallizings -2 hours 1 hour；Solvent is removed, solid is collected；Gained is solid
Body is 24 hours dry at 65 DEG C, obtains I crystal.
Card cloth of the present invention for Buddhist nun's malate crystal form A2 and card cloth for Buddhist nun's hydrobromate crystal form I stability,
Dissolubility, mobility or bioavilability etc. are with good performance, are conducive to store, operate, have in production technology
It is advantageously used for being prepared into various salt, is used to prepare the drug of the diseases such as treatment progressive metastatic medullary thyroid carcinoma.
Card cloth of the present invention for Buddhist nun's malate crystal form A2 and card cloth for Buddhist nun's hydrobromate crystal form I can with extremely
A kind of few pharmaceutically acceptable inert excipient or carrier mixing, are prepared into the various solid dosage forms of oral medicine, including capsule,
Tablet etc.；Solid dispersions etc. can also be prepared into various excipient or carrier, then be prepared into various solid pharmaceutical preparations.
Detailed description of the invention
Fig. 1 shows card cloth for the X-ray powder diffraction figure (XRPD) of the crystal form A1 of Buddhist nun's malate；
Fig. 2 shows card cloth for the DSC figure of the crystal form A1 of Buddhist nun's malate；
Fig. 3 shows card cloth for the TGA figure of the crystal form A1 of Buddhist nun's malate；
Fig. 4 shows card cloth for the X-ray powder diffraction figure of the crystal form A2 of Buddhist nun's malate；
Fig. 5 shows card cloth for the DSC figure of the crystal form A2 of Buddhist nun's malate；
Fig. 6 shows card cloth for the TGA figure of the crystal form A2 of Buddhist nun's malate；
Fig. 7 shows card cloth for the X-ray powder diffraction figure of the crystal form I of Buddhist nun's hydrobromate；
Fig. 8 shows card cloth for the DSC figure of the crystal form I of Buddhist nun's hydrobromate；
Fig. 9 shows card cloth for the TGA figure of the crystal form I of Buddhist nun's hydrobromate.
Specific embodiment
In order to make those skilled in the art more fully understand technical solution of the present invention, disclose further below some non-
Limiting embodiment, the present invention is described in further detail.
Reagent used in the present invention is available on the market or can described method system through the invention
It is standby and obtain.
In the present invention, mmol expression mM, h indicates hour, g expression gram, and mL indicates milliliter.
In the present invention, X-ray powder diffraction testing conditions are as follows: Cu target k α, wavelengthIn X-ray powder diffraction figure
In, ordinate is the diffracted intensity indicated with (counts) is counted, and abscissa is 2 θ of the angle of diffraction that expenditure (°) indicates
(2Theta)。
The testing conditions of the differential scanning calorimetry measurement (DSC) of crystal form A1 are to be heated up under nitrogen atmosphere with 10 DEG C/min, temperature
Spending range is 40 DEG C -300 DEG C.
The testing conditions of the differential scanning calorimetry measurement (DSC) of crystal form A2 are to be heated up under nitrogen atmosphere with 10 DEG C/min, temperature
Spending range is 25 DEG C -300 DEG C.
The testing conditions of the differential scanning calorimetry measurement (DSC) of crystal form I are to be heated up under nitrogen atmosphere with 10 DEG C/min, temperature
Range is 25 DEG C -300 DEG C.
Thermogravimetric analysis (TGA) testing conditions are to be heated up under nitrogen atmosphere with 10 DEG C/min, and temperature range is room temperature to 300
℃。
The condition of karl-Fischer method (KF method) measurement moisture content are as follows: instrument and reagent: moisture teller, 100,000/
One balance, karl Fischer titrating solution (5mg/mL), anhydrous methanol (analysis is pure)；Measuring method: calibration karl Fischer titrating solution is dense
Degree: after the completion of instrument titrates in advance, being taken about 10 μ L of ultrapure water (being equivalent to 10 μ L standard water samples) with micro syringe, and precision claims
Weight injects in titration cup rapidly, and input weight (g) starts to demarcate, continuous three parts of calibration, averages and relative standard deviation
(1.0%) RSD must not exceed；Sample determination of moisture: being pumped into suitable anhydrous methanol into titration cup, floods electrode (about
50mL), test sample about 0.2g is taken, precise weighing is stirred to dissolve into titration cup, measures moisture according to aquametry；In parallel
Two parts of operation, using average value as moisture content result.
Embodiment 1
4.00g card cloth mixes for Buddhist nun with the ethyl alcohol of 60mL 70% (volume ratio), is heated to 75 DEG C, and 20mL is added and contains
70% ethanol water (volume ratio) of 1.6g L MALIC ACID, adds the ethyl alcohol of 20mL 70% after dripping off, heating, and reflux 1 is small
When, 40 DEG C of precipitation solids being slow cooling in 1 hour, then cool to 0 DEG C of insulated and stirred 2 hours, being filtered, 65 DEG C of obtained solid are true
Sky is 24 hours dry, obtains 3.71g solid；XRPD, DSC, TGA are detected, is crystal form A1；Gained crystal form A1 is continued at 105 DEG C
It is 24 hours dry, obtain crystal form A2.
Embodiment 2
4.00g card cloth mixes for Buddhist nun with the ethyl alcohol 60mL of 75% (volume ratio), is heated to 75 DEG C, and dissolved clarification is added 20mL and contains
There is the ethanol water of 75% (volume ratio) of 1.6g L MALIC ACID, heat, flows back 1 hour；It is slow cooling in 1.5 hours
38 DEG C, solid is precipitated；Cool to 0 DEG C of insulated and stirred again 2 hours, filter, 105 DEG C drying 24 hours, obtain 3.77g solid, inspection
XRPD, DSC, TGA are surveyed, is crystal form A2.
Embodiment 3
4.00g card cloth mixes for Buddhist nun with the ethyl alcohol of 100mL 80% (volume ratio), is heated to 80 DEG C, addition contains 1.6g
The ethanol water of 80% (volume ratio) of L MALIC ACID, is heated to reflux 1 hour, and 38 DEG C of precipitations are slow cooling in 1.5 hours
Solid, then cool to 0 DEG C of insulated and stirred 2 hours, it filters, 105 DEG C of obtained solid are dried in vacuo 24 hours, obtain 3.78g solid；
XRPD, DSC, TGA are detected, is crystal form A2.
Embodiment 4
4.00g card cloth mixes for Buddhist nun with the ethyl alcohol of 100mL 60% (volume ratio), is heated to 80 DEG C, addition contains 1.6g
The ethanol water of 60% (volume ratio) of L MALIC ACID, is heated to reflux 1.5 hours, and 35 DEG C of analysis are slow cooling in 1.5 hours
Solid out, then cool to -5 DEG C of -0 DEG C of insulated and stirreds 2.5 hours, it filters, 90 DEG C of obtained solid are dried in vacuo 48 hours, obtain
3.75g solid；XRPD, DSC, TGA are detected, is crystal form A2.
Embodiment 5
5.00g card cloth mixes for Buddhist nun with the ethyl alcohol 75mL of 95% (volume ratio), is heated to 78 DEG C, 40% hydrobromic acid is added
Aqueous solution 3.00g adds rear solid dissolved clarification, is heated to reflux 0.5 hour, 40 DEG C of precipitation solids is slow cooling in 2 hours, then
30 DEG C are cooled to, 25mL water is added, then cool to 0 DEG C of insulated and stirred 2 hours, is filtered, it is solid to obtain 5.05g for 65 DEG C of vacuum drying
Body；XRPD, DSC, TGA are detected, is crystal form I, KF method detection aqueous 0.81%.
6 solubility test of embodiment
Enough each crystal form samples are added in 1.5mL centrifuge tube, 37 DEG C of water-baths shake 24 hours, are then cooled to 25 DEG C,
It constant temperature 4 hours, is then centrifuged for 5 minutes, supernatant is taken to dilute, efficient liquid phase detection；The solubility results for measuring each crystal form are as follows:
| Crystal form samples | Solubility (ug/mL) |
| Crystal form A1 | 2.82 |
| Crystal form A2 | 43.58 |
| Crystal form N-1 | 10.58 |
| Hydrobromate crystal form I | 3.04 |
Crystal form N-1 refers to N-1 crystal form disclosed in patent application CN201080012656.5.
7 stability test of embodiment
Crystal form A2 and hydrobromate crystal form I sample monolayer polyethylene bag tying are encapsulated, X- is penetrated after being placed at room temperature for 3 months
The detection of line powder diffraction, discovery crystal form are unchanged.
Method of the invention is described by preferred embodiment, related personnel obviously can the content of present invention,
To method described herein and application is modified or appropriate changes and combinations in spirit and scope, carry out the implementation and application present invention
Technology.Those skilled in the art can use for reference present disclosure, be suitably modified realization of process parameters.In particular, it should be pointed out that institute
There are similar replacement and change apparent to those skilled in the art, they are considered as being included in the present invention
It is interior.
Claims (5)
1.N- (4- { [bis- (methoxyl group) quinolyl-4s of 6,7-] oxygroup } phenyl)-N'- (4- fluorophenyl) cyclopropane -1,1- diformazan
The crystal form A2 of amide L MALIC ACID salt；In the X-ray powder diffraction figure of the crystal form A2 2 θ be 9.33,11.75,13.44,
15.16,19.72,23.14,25.92 there is peak in the position of degree.
It in 2 θ is 6.70,7.73,9.33,10.97 in X-ray powder diffraction figure 2. crystal form A2 described in claim 1,
11.75,13.44,15.16,17.27,18.86,19.72,20.97,23.14,25.92,26 there is peak in the position of .90 degree.
3. crystal form A2 described in claim 1, substantially as shown in, wherein 2 θ of the angle of diffraction is X-ray powder diffraction figure
The relative intensity at 13.44 degree of peak is greater than 80%.
4. the preparation method of any crystal form A2 of claim 1-3, comprising: N- (4- { [6,7- bis- (methoxyl group) quinoline -4-
Base] oxygroup } phenyl)-N'- (4- fluorophenyl) cyclopropane -1,1- diformamide and ethanol water be heated to 50 DEG C -80 DEG C, add
Enter L MALIC ACID, heating reaction -1.5 hours 0.5 hour；Then 30 DEG C -40 DEG C are cooled in -2 hours 0.5 hour to be precipitated admittedly
Body；Then -5 DEG C -5 DEG C of stirring and crystallizings -2 hours 1 hour, remove solvent, collect solid；Obtained solid is at 90 DEG C or 105
It is DEG C dry to constant weight, obtain crystal.
5. preparation method as claimed in claim 4, the content of ethyl alcohol is no more than 85% in the ethanol water.
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| US11261160B2 (en) * | 2016-12-07 | 2022-03-01 | Msn Laboratories Private Limited, R&D Center | Process for the preparation of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1, 1-dicarboxamide, (2S)-hydroxybutanedioate and its polymorphs thereof |
| CA3060370A1 (en) | 2017-05-26 | 2018-11-29 | Exelixis, Inc. | Crystalline solid forms of salts of n-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-n'-(4-fluorphenyl) cyclopropane-1,1-dicarboxamide, processes for making, and methods of use |
| WO2020075196A1 (en) * | 2018-10-11 | 2020-04-16 | Cipla Limited | Polymorphs of n-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-n'-(4-fluorophenyl)cyclopropane-1, 1-dicarboxamide, (s)- malate, methods of production and pharmaceutical uses thereof |
| US11814356B1 (en) | 2023-03-29 | 2023-11-14 | Apotex Inc. | Salt of cabozantinib |
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| CN102388024A (en) * | 2009-01-16 | 2012-03-21 | 埃克塞里艾克西斯公司 | Malate salt of n- (4- { [ 6, 7-bis (methyloxy) quin0lin-4-yl] oxy}phenyl-n' - (4 -fluorophenyl) cyclopropane-1-dicarboxamide, and crystalline forms therof for the treatment of cancer |
| WO2013059788A1 (en) * | 2011-10-20 | 2013-04-25 | Exelixis, Inc. | Process for preparing quinoline derivatives |
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| CN103391773A (en) * | 2010-09-27 | 2013-11-13 | 埃克塞里艾克西斯公司 | Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases |
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| CN102388024A (en) * | 2009-01-16 | 2012-03-21 | 埃克塞里艾克西斯公司 | Malate salt of n- (4- { [ 6, 7-bis (methyloxy) quin0lin-4-yl] oxy}phenyl-n' - (4 -fluorophenyl) cyclopropane-1-dicarboxamide, and crystalline forms therof for the treatment of cancer |
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