CN118164908A - Novel crystal form of cabozantinib sulfate as well as preparation method and application thereof - Google Patents
Novel crystal form of cabozantinib sulfate as well as preparation method and application thereof Download PDFInfo
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- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 title claims abstract description 51
- 239000013078 crystal Substances 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 title description 4
- ONIQOQHATWINJY-UHFFFAOYSA-N cabozantinib Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 ONIQOQHATWINJY-UHFFFAOYSA-N 0.000 title description 4
- 229960001292 cabozantinib Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- 239000003814 drug Substances 0.000 claims abstract description 15
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 238000006482 condensation reaction Methods 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 16
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- 239000012074 organic phase Substances 0.000 claims description 12
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- 238000010009 beating Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 238000004537 pulping Methods 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000007821 HATU Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- 238000011282 treatment Methods 0.000 claims description 3
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 abstract description 6
- 208000007054 Medullary Carcinoma Diseases 0.000 abstract description 5
- 208000024770 Thyroid neoplasm Diseases 0.000 abstract description 5
- 230000001394 metastastic effect Effects 0.000 abstract description 5
- 206010061289 metastatic neoplasm Diseases 0.000 abstract description 5
- 230000000750 progressive effect Effects 0.000 abstract description 5
- 201000002510 thyroid cancer Diseases 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 description 9
- 239000012535 impurity Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000004321 preservation Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 230000004584 weight gain Effects 0.000 description 4
- 235000019786 weight gain Nutrition 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical class OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 2
- 229940049920 malate Drugs 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 2
- 150000004701 malic acid derivatives Chemical class 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 229910021653 sulphate ion Inorganic materials 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 1
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- -1 benzotriazol-N, N, N ', N' -tetramethyl urea hexafluorophosphate Chemical compound 0.000 description 1
- HFCFMRYTXDINDK-WNQIDUERSA-N cabozantinib malate Chemical compound OC(=O)[C@@H](O)CC(O)=O.C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 HFCFMRYTXDINDK-WNQIDUERSA-N 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940034568 cometriq Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a novel crystal form of cabotinib sulfate, a preparation method and application thereof, and relates to the technical field of pharmaceutical chemistry. The compound n sulfate of the formula (I) has the characteristics of excellent stability, high solubility and the like, can be used for preparing medicaments for treating tumors, especially for treating progressive and metastatic thyroid cancer medullary carcinoma, and has wide practical application value.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a novel crystal form of cabotinib sulfate, and a preparation method and application thereof.
Background
A compound of formula (I) is known under the chemical name N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide. The structural formula is as follows:
WO2005/030140 discloses that such molecules specifically inhibit, modulate and/or modulate the signal of kinases (including in particular e.g. Ret, c-Met and VEGFR 2) and may be used as a treatment or prophylaxis of conditions associated with abnormal cell proliferation and angiogenesis.
In patent WO2010/083414, exelixis discloses a 1:1 malate salt of a compound of formula (I). The malate was approved for sale by the FDA in the united states for month 11 of 2012 under the trade name COMETRIQ.
Patent WO2018218233 discloses various salts of the compounds of formula (I) and crystalline forms thereof.
In chinese patent CN104961681B, the scofflaw pharmaceutical sciences ltd discloses mucic acid salts of the compounds of formula (I) and their crystalline forms. The patent research shows that the solubility of the mucic acid salt of the compound shown in the formula (I) is higher than that of the malic acid salt, and the mucic acid salt has certain significance for improving the bioavailability, the curative effect and the safety of the medicine.
In order to better exert therapeutic effects of a drug, the particular form of the pharmaceutically active ingredient is important to the properties of the drug, including stability and/or effectiveness properties during processing, manufacturing, storage, transportation and use. The inventor discovers that the sulfate of the compound of the formula (I) prepared by the compound of the formula (I) and sulfuric acid in the research process has good stability and high solubility, and is beneficial to improving the bioavailability, the curative effect and the safety of the medicine.
Disclosure of Invention
In order to solve the problems, the invention provides a novel crystal form of cabotinib sulfate, and a preparation method and application thereof.
In a first aspect, the present invention provides a compound of formula (I) ·n sulfate form ii having an X-ray powder diffraction pattern with characteristic peaks at 2θ values of 14.94±0.2°, 16.28±0.2°, 16.68±0.2°, 20.02±0.2°, 20.52±0.2°, 23.20±0.2°, 26.04±0.2°;
the formula (I):
wherein n is 0.8-1.2.
Further, the X-ray powder diffraction pattern thereof has characteristic peaks at 2 theta values of 14.94±0.2°、16.28±0.2°、16.68±0.2°、20.02±0.2°、20.52±0.2°、23.20±0.2°、24.30±0.2°、26.04±0.2°、26.80±0.2°、27.66±0.2° and 30.36 + -0.2 deg..
Further, the X-ray powder diffraction pattern data thereof are shown in table 1; the relative intensity of the peak in the X-ray powder diffraction pattern at a derivative angle 2 theta of 20.52 is greater than 99%.
Further, n is 1.
Further, the compound of formula (I) ·n sulfate form ii is an anhydrous non-solvate.
In a second aspect, the present invention provides a process for the preparation of a compound of formula (I) ·n sulfate form ii according to any one of the first aspects, comprising the steps of:
Dissolving the intermediate 2 and the intermediate 3 in a solvent A, adding a condensing agent for condensation reaction, and obtaining a mixture after the reaction is finished;
Adding water and a solvent B into the mixture, stirring, standing and separating to obtain an organic phase;
Dripping dilute H 2SO4 into the organic phase, heating, pulping, cooling, crystallizing, filtering and drying to obtain the compound of the formula (I) n sulfate crystal form II;
Wherein the chemical structural formula of the intermediate 2 is shown as a formula (II), and the chemical structural formula of the intermediate 3 is shown as a formula (III);
The formula (II):
The formula (III):
Further, the condition parameters of the condensation reaction include: the mol ratio of the intermediate 2 to the intermediate 3 is (1.2-1.5) 1.0; the condensation reaction temperature is-10 to 50 ℃ and the condensation reaction time is 1 to 24 hours.
Further, the condensation reaction temperature is between-10 and 25 ℃, and the condensation reaction time is between 2 and 16 hours; the temperature of the heating beating is 40-80 ℃, and the temperature of the cooling crystallization is-10-20 ℃.
Further, the solvent A is selected from dichloromethane and tetrahydrofuran; the condensing agent comprises at least one of EDCI, DCC, CDI, HBTU and HATU; the solvent B is selected from methanol, acetonitrile and ethanol; the temperature of the heating beating is 55-80 ℃, and the temperature of the cooling crystallization is 5-30 ℃; the concentration of H 2SO4 is 10-50% by volume percentage, and the molar ratio of H 2SO4 to intermediate 3 is 1.2-2.0; the dropping speed of the H 2SO4 is 0.5-2.0H after the dropping is finished.
In a third aspect, the invention provides the use of a compound of formula (I) as defined in any one of the first aspects, form ii of n-sulphate, and/or a compound of formula (I) as defined in any one of the second aspects, form ii of n-sulphate, for the manufacture of a medicament for the treatment of tumours.
Compared with the prior art, the technical scheme provided by the embodiment of the invention has at least the following advantages:
The embodiment of the invention provides a novel crystal form of cabatinib sulfate, namely a compound shown in a formula (I) and an n sulfate crystal form II, wherein the compound shown in the formula (I) and the n sulfate have the characteristics of excellent stability, high solubility and the like, can be used for preparing medicines for treating tumors, especially for treating progressive and metastatic thyroid cancer medullary carcinoma, and has wide practical application value.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the invention and together with the description, serve to explain the principles of the invention.
In order to more clearly illustrate the embodiments of the invention or the technical solutions of the prior art, the drawings which are used in the description of the embodiments or the prior art will be briefly described, and it will be obvious to a person skilled in the art that other drawings can be obtained from these drawings without inventive effort.
Fig. 1 is a flowchart of a preparation method of a novel crystal form of cabozantinib sulfate provided in the embodiment of the invention.
FIG. 2 is an XRPD pattern for compound (I) n sulfate form II of example 1 of the present invention.
FIG. 3 is a DSC/TGA plot of compound of formula (I) ·n sulfate form II of example 1 of the present invention.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Unless otherwise specifically indicated, the various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or may be prepared by existing methods.
In a first aspect, the present invention provides a compound of formula (I) ·n sulfate form ii having an X-ray powder diffraction pattern with characteristic peaks at 2θ values of 14.94±0.2°, 16.28±0.2°, 16.68±0.2°, 20.02±0.2°, 20.52±0.2°, 23.20±0.2°, 26.04±0.2°;
the formula (I):
wherein n is 0.8-1.2.
The embodiment of the invention provides a novel crystal form of cabatinib sulfate, namely a compound shown in a formula (I) and an n sulfate crystal form II, wherein the compound shown in the formula (I) and the n sulfate have the characteristics of excellent stability, high solubility and the like, can be used for preparing medicines for treating tumors, especially for treating progressive and metastatic thyroid cancer medullary carcinoma, and has wide practical application value.
In some embodiments, a typical X-ray powder diffraction pattern is shown in fig. 2 and X-ray powder diffraction pattern data is shown in table 1.
TABLE 1
In some embodiments, the X-ray powder diffraction pattern has characteristic peaks at 2 theta values of 14.94±0.2°、16.28±0.2°、16.68±0.2°、20.02±0.2°、20.52±0.2°、23.20±0.2°、24.30±0.2°、26.04±0.2°、26.80±0.2°、27.66±0.2° and 30.36±0.2°.
In some embodiments, the X-ray powder diffraction pattern data is as shown in table 1; the relative intensity of the peak in the X-ray powder diffraction pattern at a derivative angle 2 theta of 20.52 is greater than 99%.
In some embodiments, n is 1.
In some embodiments, the compound of formula (I) ·n sulfate form ii is an anhydrous non-solvate.
In a second aspect, based on the same inventive concept, the present invention provides a method for preparing the compound of formula (I) ·n sulfate form ii according to any one of the first aspects, as shown in fig. 1, the method comprising the steps of:
Dissolving the intermediate 2 and the intermediate 3 in a solvent A, adding a condensing agent for condensation reaction, and obtaining a mixture after the reaction is finished;
Adding water and a solvent B into the mixture, stirring, standing and separating to obtain an organic phase;
Dripping dilute H 2SO4 into the organic phase, heating, pulping, cooling, crystallizing, filtering and drying to obtain the compound of the formula (I) n sulfate crystal form II;
Wherein the chemical structural formula of the intermediate 2 is shown as a formula (II), and the chemical structural formula of the intermediate 3 is shown as a formula (III);
The formula (II):
The formula (III):
in some embodiments, the condensation reaction condition parameters include: the mol ratio of the intermediate 2 to the intermediate 3 is (1.2-1.5) 1.0; the condensation reaction temperature is-10 to 50 ℃, preferably-10 to 25 ℃, most preferably-10 to 10 ℃; the condensation reaction time is 1 to24 hours, preferably 2 to 16 hours, more preferably 3 to 5 hours.
In some specific embodiments, the condensation reaction temperature is between-10 and 25 ℃, and the condensation reaction time is between 2 and 16 hours; the temperature of the heating beating is 40-80 ℃, preferably 55-80 ℃; the temperature of the cooling crystallization is-10-20 ℃, preferably 5-30 ℃.
In some embodiments, the solvent a is selected from dichloromethane, tetrahydrofuran, preferably dichloromethane; the condensing agent comprises at least one of EDCI, DCC, CDI, HBTU and HATU; the solvent B is selected from methanol, acetonitrile and ethanol, preferably methanol; the temperature of the heating beating is 55-80 ℃, and the temperature of the cooling crystallization is 5-30 ℃; the concentration of H 2SO4 is 10-50%, preferably 10-30% by volume percent; the molar ratio of H 2SO4 to intermediate 3 is 1.2 to 2.0eq, preferably 1.4 to 1.84eq; the dropping speed of the H 2SO4 is 0.5-2.0H after the dropping is finished.
In a third aspect, based on the same inventive concept, the present invention provides a compound of formula (I) · n sulfate form ii according to any one of the first aspects, and/or the use of a compound of formula (I) · n sulfate form ii obtained by the preparation method according to any one of the second aspects, in the preparation of a medicament for treating tumors, such as for treating progressive, metastatic thyroid cancer medullary carcinoma (MTC).
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which are not specified in the following examples, are generally determined according to national standards. If the corresponding national standard does not exist, the method is carried out according to the general international standard, the conventional condition or the condition recommended by the manufacturer.
In the following examples: the structure of the compounds was determined by Mass Spectrometry (MS) or nuclear magnetic resonance (1 HNMR). Nuclear magnetic resonance (1 HNMR) displacements (δ) are given in parts per million (ppm); nuclear magnetic resonance (1 HNMR) was measured using a Bruker AVANCE-400 nuclear magnetic instrument with a deuterated dimethyl sulfoxide (DMSO) internal standard Tetramethylsilane (TMS) as the solvent and chemical shifts were given in units of 10 -6 (ppm). The Mass Spectrum (MS) was measured using AGILENT LCMS-6110 (ESI) mass spectrometer.
Example 1
The example provides a novel crystal form of cabotinib sulfate, namely a compound of formula (I) & n sulfate crystal form II, and the preparation method comprises the following steps:
Into a 2L glass reaction flask was charged 750mL of methylene chloride, and 75.0g of intermediate 2 (336.02 mmol,1.5 eq) and 66.4g of intermediate 3 (224.07 mmol,1.0 eq) were added with stirring; cooling to-10-0 ℃, and adding 64.4g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 335.94mmol,1.5 eq); preserving heat and reacting for 4 hours; 750mL of water and 225mL of methanol are added, stirred for 10 to 15min, and the mixture is left to stand for liquid separation. The organic phase is dripped with 405.0g of 10% H 2SO4 (412.93 mmol,1.84 eq) and heated to 65+ -2deg.C after 58min, beaten for 2 h+ -10 min and cooled to 25+ -5deg.C; filtering, and drying the filter cake under reduced pressure at 60 ℃ to obtain 113.26g of finished product with the yield of 84.3% and the chromatographic purity: 99.85%.
Characterization data for the product obtained in this example are as follows:
1H-NMR(400MHz,DMSO-d6)：10.20(s,1H),10.08(s,1H),9.21(s,1H),8.28(d,1H),7.90(s,1H),7.74(d,2H),7.64(m,2H),7.48(s,1H),7.23(d,2H),7.15(m,2H),6.45(d,1H),3.97-3.94(m,6H),1.47(s,4H).
EIMS m/z＝502.2([M+H]+)。
in this example, the XRPD pattern for compound (I) & n sulfate form II is shown in FIG. 2 and the DSC/TGA pattern is shown in FIG. 3.
Example 2
The example provides a novel crystal form of cabotinib sulfate, namely a compound of formula (I) & n sulfate crystal form II, and the preparation method comprises the following steps:
to a 1L glass reactor was added 335mL of dichloromethane, and 26.78g of intermediate 2 (120.00 mmol,1.2 eq) and 29.63g of intermediate 3 (100.00 mmol,1.0 eq) were added with stirring. Cooling to 0-10 deg.c and adding 23.00g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 120.00mmol,1.2 eq). And (5) carrying out heat preservation reaction for 4 hours. 350mL of water and 100mL of acetonitrile are added, stirred for 10 to 15min, and the mixture is left to stand for liquid separation. 90.0g of 20% H 2SO4 (183.52 mmol,1.84 eq) was added dropwise to the organic phase, the temperature was raised to 75.+ -. 2 ℃ after 35min, the slurry was stirred for 2 h.+ -. 10min, and the temperature was lowered to 10.+ -. 5 ℃. Filtering, and drying the filter cake under reduced pressure at 60 ℃ to obtain 49.10g of finished product with the yield of 81.9% and the chromatographic purity: 99.78%.
Example 3
The example provides a novel crystal form of cabotinib sulfate, namely a compound of formula (I) & n sulfate crystal form II, and the preparation method comprises the following steps:
A1L glass reaction flask was charged with 335mL of tetrahydrofuran, and 33.48g of intermediate 2 (150.00 mmol,1.5 eq) and 29.63g of intermediate 3 (100.00 mmol,1.0 eq) were added with stirring. Cooling to 0-10 deg.c, adding 56.89g benzotriazol-N, N, N ', N' -tetramethyl urea hexafluorophosphate (HBTU, 150.00mmol,1.5 eq). And (5) carrying out heat preservation reaction for 3 hours. 350mL of water and 100mL of methanol are added, stirred for 10 to 15min, and the mixture is left to stand for liquid separation. 92.2g of 15% H 2SO4 (141.00 mmol,1.41 eq) was added dropwise to the organic phase, the temperature was raised to 55.+ -. 2 ℃ after 42min, the slurry was stirred for 2 h.+ -. 10min, and the temperature was lowered to 5.+ -. 5 ℃. Filtering, and drying the filter cake under reduced pressure at 60 ℃ to obtain 49.89g of finished product with the yield of 83.2% and the chromatographic purity: 99.63%.
Characterization data for the product obtained in this example are as follows:
1H-NMR(400MHz,DMSO-d6)：10.18(s,1H),10.04(s,1H),9.20(s,1H),8.34-8.32(d,1H),7.92(s,1H),7.74(d,2H),7.64(m,2H),7.48(s,1H),7.23(d,2H),7.15(m,2H),6.45(d,1H),3.98-3.95(m,6H),1.47(s,4H)
EIMS m/z＝502.3([M+H]+)。
example 4: comparative experiments
The example provides a novel crystal form of cabotinib sulfate, namely a compound of formula (I) & n sulfate crystal form II, and the preparation method comprises the following steps:
350mL of methylene chloride was added to a 1L glass reactor, and 33.48g of intermediate 2 (150.00 mmol,1.5 eq) and 29.63g of intermediate 3 (100.00 mmol,1.0 eq) were added with stirring. Cooling to 0-10 deg.c and adding 28.76g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (150.00 mmol,1.50 eq). And (5) carrying out heat preservation reaction for 4 hours. 350mL of water was added and the mixture was allowed to stand to separate. The organic phase is concentrated to dryness under reduced pressure, 130mL of methanol is added, the temperature is raised to 65+/-5 ℃ for dissolving, 180.0g of 10% H 2SO4 is dripped, the mixture is pulped for 2 hours+/-10 minutes, and the mixture is cooled to 25+/-5 ℃. Filtering, and drying the filter cake under reduced pressure at 50 ℃ to obtain 49.95g of finished product with the yield of 83.3 percent and the chromatographic purity: 99.40%.
Example 5
Based on example 1, this example conducted a condition screening experiment during the preparation of the compound of formula (I) ·n sulfate form ii, in which the impurities mainly involved RRT (relative retention time) =0.76 and rrt=0.97 were relatively difficult to purify.
1. Investigation of the condensation reaction temperature
Reference example 1 preparation method: 1.0eq of intermediate 2,1.5eq of intermediate 3 and 10V of dichloromethane are added into a reaction bottle, the temperature is controlled to the reaction temperature shown in the table below, 1.5eq of EDCI is added, the reaction is carried out for 4 hours under heat preservation, and the reaction liquid is sampled for detection, and the results are shown in the table 2 below.
TABLE 2
| Method of | Reaction temperature | RRT＝0.76 | RRT＝0.97 | Cabotinib |
| 1 | 25～30℃ | 0.28％ | 2.82％ | 87.52％ |
| 2 | 0～5℃ | 0.14％ | 2.66％ | 90.35％ |
| 3 | -10～-5℃ | \ | 1.70％ | 91.42％ |
In table 2: "/" means undetected, meaning in the following table; eq represents the molar equivalent, here the molar equivalent ratio to intermediate 2; 10V represents the volume ratio to intermediate 3. As can be seen from table 2 above, the lower the reaction temperature, the lower the rrt=0.76 and rrt=0.97 impurity content, the higher the main peak purity.
2. Investigation of beating solvent
Reference example 1 preparation method: 1.0eq of intermediate 2,1.5eq of intermediate 3 and 10V of dichloromethane are added into a reaction bottle, the temperature is controlled to the reaction temperature shown in the table below, 1.5eq of EDCI is added, and the reaction is carried out for 4 hours under heat preservation. 10V water and 3V solvent B are added, and the mixture is kept stand for liquid separation. The organic phase was added dropwise to 10% H 2SO4 (1.84 eq). Heating to 75 ℃, pulping for 2 hours, and cooling to 25 ℃. The mixture was filtered, and the cake was dried at 60℃under reduced pressure to obtain a solid, and the results were shown in Table 3 below.
TABLE 3 Table 3
| Method of | Solvent B | RRT＝0.76 | RRT＝0.97 | Cabotinib | Yield is good |
| 1 | Methanol | \ | 0.03％ | 99.87％ | 84.1％ |
| 2 | Acetonitrile | 0.05％ | 0.05％ | 99.76％ | 83.2％ |
| 3 | Ethanol | 0.35％ | 0.06％ | 98.88％ | 86.4 |
From the table, the methanol has the best impurity removal effect and the highest purity of the main peak; the ethanol has the worst impurity removing effect after acetonitrile, and the impurity with rrt=0.76 exceeds 0.1 percent, which does not meet the pharmacopoeia standard.
3. Investigation of beating temperature
Reference example 1 preparation method: 1.0eq of intermediate 2,1.5eq of intermediate 3 and 10V of dichloromethane are added into a reaction bottle, the temperature is controlled to the reaction temperature shown in the table below, 1.5eq of EDCI is added, and the reaction is carried out for 4 hours under heat preservation. 10V water and 3V methanol are added, and the mixture is kept stand for liquid separation. The organic phase was added dropwise to 10% H 2SO4 (1.84 eq). Heating to 45-80 ℃, pulping for 2h, and cooling to 25 ℃. The mixture was filtered, and the cake was dried at 60℃under reduced pressure to obtain a solid, and the results were shown in Table 4 below.
TABLE 4 Table 4
| Method of | Beating temperature | RRT＝0.76 | RRT＝0.97 | Cabotinib | Yield is good |
| 1 | 40℃ | 0.38％ | 0.23％ | 98.88％ | 85.33％ |
| 2 | 55℃ | 0.07％ | 0.01％ | 99.87％ | 84.67％ |
| 3 | 65℃ | 0.04％ | \ | 99.91％ | 84.36％ |
| 4 | 80℃ | 0.05％ | \ | 99.90％ | 84.52％ |
From the table, when the pulping temperature is 40 ℃, the impurity removal effect is poor, the impurity limits of rrt=0.76 and rrt=0.97 are all over 0.1 percent, and when the pulping temperature is more than 55 ℃, the impurity removal effect is good, and single impurity is less than 0.1 percent, so that the method meets the pharmacopoeia standard.
Test case
1. Solubility test
The original patent WO2018218233A1 provides 3 sulphate forms of the compound of formula (I), form 5, form 11 and form 21 respectively. The original preparation uses malate crystal form N-2. By comparing the solubility of several crystal forms at different pH values, the compound of formula (I) n sulfate crystal form II provided by the patent of the invention has better solubility, and the test results are shown in table 5, and the sulfate crystal form II in table 5 is prepared in example 1.
TABLE 5
2. Stability test
Samples of the crystalline form II of the compound of formula (I) n sulfate of the present invention were taken and placed in an open place under the conditions of high temperature test (60 ℃), high humidity test (25 ℃, relative humidity 90% + -5%) and intense light irradiation test (illuminance 4500+ -500 lx), and after 10 natural samples were taken, the measurement results are shown in Table 6 below, and the self-made samples in Table 6 were prepared as example 1.
TABLE 6
The table shows that the compound n sulfate crystal form II of the formula (I) has no obvious change in purity after being placed for 10 days under the conditions of high-temperature experiments, high-humidity experiments and strong light irradiation experiments, and is a crystal form suitable for medicines.
Taking the compound (I) n sulfate crystal form II of the invention, adopting four drug hygroscopicity index experimental guidelines of pharmacopoeia 2020 edition, and experimental conditions: the temperature of 25.+ -. 1 ℃ and the relative humidity of 80%.+ -. 2% were shown in Table 7 below, and the self-made samples in Table 7 were prepared as in example 1.
TABLE 7
Remarks: deliquescence: absorbing a sufficient amount of moisture to form a liquid.
The moisture absorption performance is very good: the weight gain of the wet-induced type is not less than 15 percent.
Moisture permeability: the weight gain of the wet-guiding type is less than 15 percent but not less than 2 percent.
Slightly hygroscopic: the weight gain by moisture absorption is less than 2 percent but not less than 0.2 percent.
No or little hygroscopicity: the weight gain caused by moisture is less than 0.2 percent.
The results show that: the product has almost no hygroscopicity, and is effective in preventing moisture absorption during preparation, transportation and storage, and improving stability.
Therefore, the compound n sulfate crystal form II of the formula (I) provided by the invention has good stability and high solubility, is a crystal form suitable for medicines, and can be used for preparing medicines for treating cancers.
In summary, the invention provides a novel crystal form of cabatinib sulfate, namely a compound shown in a formula (I) and an n sulfate crystal form II, wherein the compound shown in the formula (I) and the n sulfate have the characteristics of excellent stability, high solubility and the like, can be used for preparing medicines for treating tumors, especially for treating progressive and metastatic thyroid cancer medullary carcinoma, and has wide practical application value.
Various embodiments of the invention may exist in a range of forms; it should be understood that the description in a range format is merely for convenience and brevity and should not be construed as a rigid limitation on the scope of the invention; it is therefore to be understood that the range description has specifically disclosed all possible sub-ranges and individual values within that range. For example, it should be considered that a description of a range from 1 to 6 has specifically disclosed sub-ranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as single numbers within the range, such as 1,2,3, 4, 5, and 6, wherever applicable. In addition, whenever a numerical range is referred to herein, it is meant to include any reference number (fractional or integer) within the indicated range.
The foregoing is only a specific embodiment of the invention to enable those skilled in the art to understand or practice the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. Compound n sulfate form II of formula (I), characterized by an X-ray powder diffraction pattern having characteristic peaks at 2Θ values of 14.94±0.2°, 16.28±0.2°, 16.68±0.2°, 20.02±0.2°, 20.52±0.2°, 23.20±0.2°, 26.04±0.2°;
the formula (I):
wherein n is 0.8-1.2.
2. Compound n-sulphate form II according to claim 1 having an X-ray powder diffraction pattern with characteristic peaks at 20 values 14.94±0.2°、16.28±0.2°、16.68±0.2°、20.02±0.2°、20.52±0.2°、23.20±0.2°、24.30±0.2°、26.04±0.2°、26.80±0.2°、27.66±0.2° and 30.36±0.2°.
3. Compound of formula (I) · n sulfate form II according to claim 1, characterized in that its X-ray powder diffraction pattern data are shown in table 1; the relative intensity of the peak in the X-ray powder diffraction pattern at a derivative angle 2 theta of 20.52 is greater than 99%.
4. Compound of formula (I) ·n sulfate form II according to claim 1, characterized in that n is 1.
5. Compound n-sulphate form II according to claim 1, wherein the compound n-sulphate form II of formula (I) is an anhydrous non-solvate.
6. A process for the preparation of a compound of formula (I) · n sulfate form II according to any one of claims 1 to 5, characterized in that it comprises the following steps:
Dissolving the intermediate 2 and the intermediate 3 in a solvent A, adding a condensing agent for condensation reaction, and obtaining a mixture after the reaction is finished;
Adding water and a solvent B into the mixture, stirring, standing and separating to obtain an organic phase;
dripping dilute H 2SO4 into the organic phase, heating, pulping, cooling, crystallizing, filtering and drying to obtain the compound of the formula (I) n sulfate crystal form II;
Wherein the chemical structural formula of the intermediate 2 is shown as a formula (II), and the chemical structural formula of the intermediate 3 is shown as a formula (III);
The formula (II):
The formula (III):
7. The method of claim 6, wherein the condensation reaction condition parameters include: the mol ratio of the intermediate 2 to the intermediate 3 is (1.2-1.5) to 1.0; the condensation reaction temperature is-10 to 50 ℃ and the condensation reaction time is 1 to 24 hours.
8. The method according to claim 6, wherein the condensation reaction temperature is-10 to 25 ℃, and the condensation reaction time is 2 to 16 hours; the temperature of the heating beating is 40-80 ℃, and the temperature of the cooling crystallization is-10-20 ℃.
9. The preparation method according to claim 6, wherein the solvent A is selected from dichloromethane and tetrahydrofuran; the condensing agent comprises at least one of EDCI, DCC, CDI, HBTU and HATU; the solvent B is selected from methanol, acetonitrile and ethanol; the temperature of the heating beating is 55-80 ℃, and the temperature of the cooling crystallization is 5-30 ℃; the concentration of H 2SO4 is 10-50% by volume percent, and the molar ratio of H 2SO4 to intermediate 3 is 1.2-2.0.
10. Use of a compound of formula (I) as defined in any one of claims 1 to 9 in the manufacture of a medicament for the treatment of tumors.
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