CN114456109A - Preparation method and application of high-purity cabozantinib malate - Google Patents

Preparation method and application of high-purity cabozantinib malate Download PDF

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CN114456109A
CN114456109A CN202011236189.6A CN202011236189A CN114456109A CN 114456109 A CN114456109 A CN 114456109A CN 202011236189 A CN202011236189 A CN 202011236189A CN 114456109 A CN114456109 A CN 114456109A
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cabozantinib
malate
organic solvent
stirring
cabozantinib malate
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黄辉
王宏
刚梁
刘保庆
邢孟磊
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Beijing Xuansheng Pharmaceutical Co Ltd
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Jilin Huikang Pharmaceutical Co ltd
Beijing Sihuan Pharmaceutical Co Ltd
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part

Abstract

The invention provides a preparation method of cabozantinib malate, which comprises the following steps: 1) adding a required amount of organic solvent into cabozantinib, and stirring at 70-78 ℃ to prepare a mixed solution; 2) adding an organic solvent aqueous solution of L-malic acid into the mixed solution obtained in the step 1), and stirring to obtain a reaction solution; 3) adding organic solvent suspension of the cabozantinib malate seed crystal into the reaction liquid prepared in the step 2), stirring, cooling, crystallizing, separating and drying to obtain the cabozantinib malate seed crystal. The cabozinib malate prepared by the preparation method of the invention has the advantages of high purity, less residual solvent, low genotoxic impurity content, simple and convenient operation, reduced waste liquid discharge, improved production efficiency, reduced production cost, suitability for industrial production and the like.

Description

Preparation method and application of high-purity cabozantinib malate
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method and application of high-purity cabozantinib malate.
Background
Cabozantinib (Cabozantinib, chemical name N- [4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] phenyl ] -N' - (4-fluorophenyl) -1, 1-cyclopropanedicarboxamide) suppresses tumor cell growth by inhibiting RET, c-Met and VEGFR2 signaling pathways.
Figure BDA0002766756550000011
CN102388024A discloses cabozantinib 1:1 malate, N-1 crystals thereof, N-2 crystals thereof and a preparation method thereof, wherein the preparation method of the cabozantinib L-malate N-2 crystals comprises the following steps of firstly preparing seed crystals of the N-2 crystals, taking methyl isobutyl ketone and tetrahydrofuran as mixed solvents, and carrying out multiple steps for more than 2 days to prepare the N-2 crystals of the cabozantinib L-malate. The method has the defects of long generation period, high cost, substandard solvent residue and the like.
CN103221035A and CN108341773A disclose a method for preparing cabozantinib L-malate by using water and methyl ethyl ketone as solvents, and the subsequent treatment adopts a large amount of methyl ethyl ketone for multiple azeotropic drying or vacuum distillation operations to gradually precipitate solids to obtain the product. The method has the defects of complex operation, more control parameters, more generated waste liquid, poor reproducibility and the like. Therefore, an improved method for preparing cabozantinib malate with high purity, low impurity content, standard solvent residue, simple operation and high safety is urgently needed.
Disclosure of Invention
One of the purposes of the invention is to provide a preparation method of cabozantinib malate, which comprises the following steps: 1) adding a required amount of organic solvent into cabozantinib, and stirring at 70-78 ℃ to prepare a mixed solution; 2) adding an organic solvent aqueous solution of L-malic acid into the mixed solution obtained in the step 1), and stirring to obtain a reaction solution; 3) adding organic solvent suspension of the cabozantinib malate seed crystal into the reaction liquid prepared in the step 2), stirring, cooling, crystallizing, separating and drying to obtain the cabozantinib malate seed crystal.
In a preferred embodiment of the present invention, the organic solvent in any one of the steps 1) to 3) is selected from linear C1-C5Alcohol, branched C1-C5Any one or combination of alcohol, aliphatic ketone, cyclic ether and ester, preferably any one or combination of methanol, ethanol, acetone, butanone, 1, 4-dioxane, tetrahydrofuran, ethyl acetate and 2-butanone.
In a preferred technical scheme of the invention, the mass-to-volume ratio (g/ml) of cabozantinib to organic solvent in step 1) is 1:5-30, preferably 1:10-20, and more preferably 1: 19.
In the preferred technical scheme of the invention, in the step 2), the cabozantinib: the molar ratio of malic acid is 1: 1.0 to 1.5, preferably 1: 1.0, 1: 1.1, 1:1.2, 1:1.3, 1:1.4, 1: 1.5.
In a preferred technical scheme of the invention, the mass-to-volume ratio (g/ml) of the malic acid to the organic solvent in the step 2) is 1:1-10, preferably 1:2-8, and more preferably 1: 3.1-5.
In a preferred technical scheme of the invention, the mass-to-volume ratio (g/ml) of malic acid to water in the step 2) is 1:1-10, preferably 1:1-5, and more preferably 1: 3.1.
In the preferable technical scheme of the invention, the adding amount of the cabozantinib malate seed crystal in the step 3) is 0.5-3.0 per mill of the weight of cabozantinib, and is preferably 1.0-2.0 per mill.
In the preferable technical scheme of the invention, the cabozantinib malate seed crystals are dispersed in the organic solvent in the step 3) to prepare a suspension.
In a preferred technical scheme of the invention, the organic solvent for preparing the cabozantinib malate seed suspension is selected from linear chain C1-C5Alcohol, branched C1-C5Any one or combination of alcohol, aliphatic ketone, cyclic ether and ester, preferably methanol, ethanol, acetone, butanone, 1, 4-dioxane, tetrahydrofuran, ethyl acetate, and 2-butanone, or any one or combination thereof.
In the preferred technical scheme of the invention, in the cabozantinib malate seed crystal suspension, the mass-to-volume ratio (g/ml) of the cabozantinib malate seed crystal to the organic solvent is 1:20-200, preferably 1: 50-150, more preferably 1: 80-100.
In a preferred technical scheme of the invention, the cooling mode is selected from any one of natural cooling and forced cooling or a combination thereof.
In the preferred technical scheme of the invention, the forced cooling adopts a cooling medium to realize forced cooling or programmed cooling on the crystallization system.
In a preferred embodiment of the present invention, the cooling medium is selected from water, brine ice, dry ice solvent or liquid nitrogen solvent, preferably any one of condensed water, ice water and brine ice or a combination thereof.
In the preferred technical scheme of the invention, the crystallization temperature is 0-30 ℃, preferably 0-20 ℃, and more preferably 0-10 ℃.
In a preferred embodiment of the present invention, the crystallization manner is selected from any one of standing crystallization and stirring crystallization or a combination thereof.
In the preferred technical scheme of the invention, the crystallization time is 1-24h, preferably 10-20h, and more preferably 12-16 h.
In a preferred embodiment of the present invention, the separation is selected from any one of centrifugation, filtration, and membrane treatment, or a combination thereof.
In the preferable technical scheme of the invention, the cabozantinib malate solid which is separated and collected is washed and dried to obtain the cabozantinib malate solid.
In a preferred embodiment of the present invention, the washing solvent is selected from linear C1-C5Alcohol, branched C1-C5Any one or combination of alcohol, aliphatic ketone, cyclic ether and ester, preferably any one or combination of methanol, ethanol, acetone, butanone, 1, 4-dioxane, tetrahydrofuran, ethyl acetate and 2-butanone.
In a preferred embodiment of the present invention, the drying is selected from any one of vacuum drying, reduced pressure drying, atmospheric drying, spray drying, and boiling drying, or a combination thereof.
In the preferred technical scheme of the invention, the drying temperature is 40-80 ℃, preferably 40-60 ℃, and more preferably 50 ℃.
In the preferable technical scheme of the invention, the purity of the prepared cabozantinib malate is not less than 99.5%, wherein the cabozantinib malate is cabozantinib 1.0(L) -malate.
In a preferred technical scheme of the invention, the purity of the prepared cabozantinib malate is not less than any one of 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.91%, 99.92%, 99.93%, 99.94%, 99.95%, 99.96%, 99.97%, 99.98%, 99.99% and 100%.
In the preferred technical scheme of the invention, the content of the L-malic acid in the prepared cabozantinib malate is 18.0% -25.0%, and the preferred content is 19.5% -22.5%.
In the preferred technical scheme of the invention, the content of single impurities in the prepared cabozantinib malate is not more than 0.1%, and the content of total impurities is not more than 0.5%.
In a preferred technical scheme of the invention, the content of genotoxic impurities in the prepared cabozantinib malate is not more than 98.6ppm, wherein the genotoxic impurities are selected from any one of impurities D [4- (6, 7-dimethoxyquinoline-4-oxy) -aniline ], impurities Id (4-fluoroaniline) and impurities IIb (4-aminophenol) or a combination thereof.
In the preferred technical scheme of the invention, the content of genotoxic impurities in the prepared cabozantinib malate is not more than 50 ppm.
In the preferred technical scheme of the invention, the content of genotoxic impurities in the prepared cabozantinib malate is not detected.
In a preferable technical scheme of the invention, the amount of the residual solvent in the prepared cabozantinib malate is not more than 0.5%, wherein the residual solvent is selected from any one of methanol, ethanol, acetonitrile, ethyl formate, dichloromethane, methyl ethyl ketone, tetrahydrofuran, triethylamine, N-dimethylformamide and N, N-dimethylacetamide or a combination thereof.
In the preferred technical scheme of the invention, the residual solvent content in the prepared cabozantinib malate is not more than 0.3%, and preferably not more than 0.109%.
In the preferred technical scheme of the invention, the amount of the methyl ethyl ketone in the prepared cabozantinib malate is not more than 0.05%, and preferably not more than 0.011%.
In the preferred technical scheme of the invention, the tetrahydrofuran content in the prepared cabozantinib malate is not over 0.072%, and is preferably not detected.
In a preferred embodiment of the present invention, the amount of the remaining solvent other than methyl ethyl ketone in the residual solvent in the prepared cabozantinib malate salt is not detected.
In the preferred technical scheme of the invention, the content of the N-2 crystal form of cabozantinib malate in the prepared cabozantinib malate is not less than 92%, and preferably not less than any one of 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%.
Another object of the present invention is to provide a highly pure cabozantinib malate salt having a purity of not less than 99.5%, wherein the cabozantinib malate salt is cabozantinib 1.0(L) -malate.
In a preferred technical scheme of the invention, the purity of the cabozantinib malate is not lower than 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.91%, 99.92%, 99.93%, 99.94%, 99.95%, 99.96%, 99.97%, 99.98%, 99.99%, 100%.
In the preferred technical scheme of the invention, the content of the L-malic acid in the prepared cabozantinib malate is 18.0% -25.0%, and the preferred content is 19.5% -22.5%.
In the preferred technical scheme of the invention, the content of single impurities in the prepared cabozantinib malate is not more than 0.1%, and the content of total impurities is not more than 0.5%.
In a preferred technical scheme of the invention, the content of genotoxic impurities in the prepared cabozantinib malate is not more than 98.6ppm, wherein the genotoxic impurities are selected from any one of impurities D, impurities IId and impurities IIb or the combination of the impurities D, the impurities IId and the impurities IIb.
In the preferred technical scheme of the invention, the content of genotoxic impurities in the prepared cabozantinib malate is not more than 50 ppm.
In the preferred technical scheme of the invention, the content of genotoxic impurities in the prepared cabozantinib malate is not detected.
In a preferable technical scheme of the invention, the amount of the residual solvent in the prepared cabozantinib malate is not more than 0.5%, wherein the residual solvent is selected from any one of methanol, ethanol, acetonitrile, ethyl formate, dichloromethane, methyl ethyl ketone, tetrahydrofuran, triethylamine, N-dimethylformamide and N, N-dimethylacetamide or the combination thereof.
In the preferred technical scheme of the invention, the residual solvent content in the prepared cabozantinib malate is not more than 0.3%, and preferably not more than 0.109%.
In the preferred technical scheme of the invention, the amount of the methyl ethyl ketone in the prepared cabozantinib malate is not more than 0.05%, and preferably not more than 0.011%.
In the preferred technical scheme of the invention, the tetrahydrofuran content in the prepared cabozantinib malate is not over 0.072%, and is preferably not detected.
In a preferred embodiment of the present invention, the amount of the remaining solvent other than methyl ethyl ketone in the residual solvent in the prepared cabozantinib malate salt is not detected.
In the preferred technical scheme of the invention, the content of the N-2 crystal form of cabozantinib malate in the prepared cabozantinib malate is not less than 92%, and preferably not less than any one of 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%.
Another object of the present invention is to provide the use of the highly pure cabozantinib malate salt for the preparation of a medicament for the treatment and/or prevention of cell proliferative diseases.
In a preferred embodiment of the present invention, the cell proliferative disease is any one or a complication selected from esophageal cancer, gastric cancer, renal cancer, thyroid cancer, liver cancer, bone cancer, skin cancer, lymph cancer, glioma, soft tissue sarcoma, non-small cell lung cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, intestinal cancer, squamous cell tumor, myeloid leukemia, hemangioma, melanoma, astrocytoma, hodgkin's disease, and non-hodgkin's lymphoma.
Another object of the present invention is to provide a pharmaceutical composition comprising the highly pure cabozantinib malate salt of the present invention and a pharmaceutically acceptable carrier.
In the preferred technical scheme of the invention, the weight percentage of the high-purity cabozantinib malate in the pharmaceutical composition is 30% -32%, and the preferred weight percentage is 31.68%.
It is another object of the present invention to provide a pharmaceutical pack comprising the high purity cabozantinib malate salt of the present invention and other pharmaceutical agents.
In a preferred embodiment of the present invention, the other drug is selected from nivolumetrizumab, palbociclumab, teriprizumab, certralizumab, caprolizumab, tirelinlizumab, atelizumab, duvacizumab, bevacizumab, pembrolizumab, trastuzumab, cetuximab, erlotinib, gefitinib, imatinib, nilotinib, sunitinib, lapatinib, afatinib, nilotinib, erlotinib, sorafenib, erlotinib, crizotinib, apatinib, or a combination thereof.
The present invention is tested in terms of purity of cabozantinib malate, related substances, detection of L-malic acid according to high performance liquid chromatography (chinese pharmacopoeia 2015 edition, four parts general regulation 0512) unless otherwise specified. The residual solvent was measured by the residual solvent assay method (0861 in the fourth pharmacopoeia 2015 edition). The purity detection method of the N-2 crystal form refers to Raman spectrum analysis described in CN 106083714B.
Unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.
Compared with the prior art, the invention has the following beneficial technical effects:
1. the cabozantinib malate prepared by the preparation method provided by the invention has the advantages of high purity, less residual solvent (such as methanol, ethanol, acetonitrile, ethyl formate, dichloromethane, tetrahydrofuran, triethylamine, N-dimethylformamide, N-dimethylacetamide, methyl ethyl ketone and the like), low content of genotoxic impurities [ such as 4- (6, 7-dimethoxyquinoline-4-oxy) -aniline, 4-fluoroaniline, 4-aminophenol and the like ], and the like, and the content of the N-2 crystal form of the cabozantinib malate is not less than 92%, so that the dissolution rate and bioavailability of a preparation are remarkably improved, and the effectiveness, safety and quality controllability of a medicine are guaranteed.
2. The preparation method of cabozinib malate simplifies the salt forming process, and has the advantages of simple and convenient operation, reduction of waste liquid discharge, improvement of production efficiency, reduction of production cost, suitability for industrial production and the like.
Drawings
FIG. 1 Experimental HPLC chromatogram of the crystalline compound obtained in example 1 at 25 ℃.
Figure 2 experimental XRPD pattern of the crystalline compound obtained in example 1 at 25 ℃.
Detailed Description
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples.
Example 1Preparation of cabozantinib malate
The preparation of cabozantinib malate comprises the following steps:
1) adding cabozantinib 100.00g (0.20moL, dry weight) into a 3L three-neck bottle filled with 1.89L 2-butanone under the conditions of nitrogen protection and stirring, heating to 70-78 ℃, and stirring until the cabozantinib is dissolved to prepare a mixed solution;
2) adding 200ml of 2-butanone aqueous solution in which 32.16g (0.24mol) of L-malic acid is dissolved into the mixed solution prepared in the step 1), and stirring for 1h at the temperature of 70-78 ℃ to prepare mixed solution, wherein 2-butanone in the 2-butanone aqueous solution: the volume ratio of water is 1: 1;
3) adding 10mL of 2-butanone suspension containing 0.10g (0.16mmol) of cabozantinib malate N-2 crystal form into the mixed solution prepared in the step 2) to prepare a mixed solution;
4) cooling the mixed solution prepared in the step 3) to 0-10 ℃, and crystallizing for 12 h;
5) and (3) carrying out suction filtration on the crystallization liquid prepared in the step 4), taking a filter cake, washing the filter cake with 300mL of 2-butanone, carrying out vacuum drying on the washed filter cake at 50 ℃ for 24h under the vacuum degree of 0.1MPa to obtain 108.40g of a solid with the purity of 99.99% (see figure 1-figure 2), wherein the impurity D, the impurity IId, the impurity IIb and other impurities are not detected, and residual solvents of methanol, ethanol, acetonitrile, ethyl formate, dichloromethane, tetrahydrofuran, triethylamine, N-dimethylformamide and N, N-dimethylacetamide are not detected, 0.009% of methyl ethyl ketone and 22.17% of L-malic acid.
Example 2 preparation of cabozantinib malate
1) Adding cabozantinib 100.00g (0.20mol, dry weight) into a 3L three-neck bottle filled with 1.90L 2-butanone under the protection of nitrogen and stirring, heating to 70-78 ℃, and stirring until the cabozantinib is dissolved to prepare a mixed solution;
2) adding 100ml of 2-butanone aqueous solution in which 26.80g (0.2mol) of L-malic acid is dissolved into the mixed solution prepared in the step 1), and stirring for 1h at the temperature of 70-78 ℃ to prepare mixed solution, wherein 2-butanone in the 2-butanone aqueous solution: the volume ratio of water is 1: 1;
3) adding 15mL of 2-butanone suspension containing 0.30g (0.48mmol) of cabozantinib malate N-2 crystal form into the mixed solution prepared in the step 2) to prepare a mixed solution;
4) cooling the mixed solution prepared in the step 3) to 20-30 ℃, and crystallizing for 12 h.
5) And (3) carrying out suction filtration on the crystallization liquid prepared in the step 4), taking a filter cake, washing the filter cake with 300mL of 2-butanone, carrying out vacuum drying on the washed filter cake at 45 ℃ for 24h under the vacuum degree of 0.1MPa to obtain 117.23g of solid, wherein the purity is 99.96%, the impurity D, the impurity IId, the impurity IIb and other impurities are not detected, residual solvents such as methanol, ethanol, acetonitrile, ethyl formate, dichloromethane, tetrahydrofuran, triethylamine, N-dimethylformamide and N, N-dimethylacetamide are not detected, methyl ethyl ketone is 0.011%, and L-malic acid is 19.5%.
Example 3 preparation of Cabozantinib malate
1) Adding cabozantinib 100.00g (0.20moL, dry weight) into a 3L three-neck bottle filled with 2.50L 2-butanone under the conditions of nitrogen protection and stirring, heating to 70-78 ℃, and stirring until the cabozantinib is dissolved to obtain a mixed solution;
2) adding 150ml of 2-butanone aqueous solution containing 40.20g (0.3mol) of L-malic acid into the mixed solution prepared in the step 1), and stirring for 1h at the temperature of 70-78 ℃ to prepare mixed solution, wherein the content of 2-butanone in the 2-butanone aqueous solution is as follows: the volume ratio of water is 1: 1;
3) adding 30mL of 2-butanone suspension containing 0.20g (0.32mmol) of cabozantinib malate N-2 crystal form into the mixed solution prepared in the step 2) to prepare a mixed solution;
4) cooling the mixed solution prepared in the step 3) to 5-15 ℃, and crystallizing for 18 h;
5) and (3) carrying out suction filtration on the crystallization liquid prepared in the step 4), taking a filter cake, washing the filter cake with 300mL of 2-butanone, carrying out vacuum drying on the washed filter cake at 55 ℃ for 24h under the vacuum degree of 0.1MPa to obtain 116.35g of solid, wherein the purity is 99.96%, the impurity D, the impurity IId, the impurity IIb and other impurities are not detected, residual solvents such as methanol, ethanol, acetonitrile, ethyl formate, dichloromethane, tetrahydrofuran, triethylamine, N-dimethylformamide, N-dimethylacetamide are not detected, methyl ethyl ketone is 0.011%, and L-malic acid is 19.5%.

Claims (10)

1. A preparation method of cabozantinib malate is characterized by comprising the following steps: 1) adding a required amount of organic solvent into cabozantinib, and stirring at 70-78 ℃ to prepare a mixed solution; 2) adding an organic solvent aqueous solution of L-malic acid into the mixed solution obtained in the step 1), and stirring to obtain a reaction solution; 3) adding organic solvent suspension of the cabozantinib malate seed crystal into the reaction liquid prepared in the step 2), stirring, cooling, crystallizing, separating and drying to obtain the cabozantinib malate seed crystal.
2. The method according to claim 1, wherein the organic solvent used in any one of the steps 1) to 3) is selected from linear C1-C5Alcohol, branched C1-C5Any one or combination of alcohol, aliphatic ketone, cyclic ether and ester, preferably any one or combination of methanol, ethanol, acetone, butanone, 1, 4-dioxane, tetrahydrofuran, ethyl acetate and 2-butanone.
3. The method according to claim 1, wherein the mass to volume ratio (g/ml) of cabozantinib to organic solvent in step 1) is 1:5 to 30, preferably 1:10 to 20, more preferably 1: 19.
4. The method according to claim 1, wherein in step 2) cabozantinib: the molar ratio of malic acid is 1: 1.0 to 1.5, preferably 1: 1.0, 1: 1.1, 1:1.2, 1:1.3, 1:1.4, 1: 1.5.
5. The method according to claim 1, wherein the mass-to-volume ratio (g/ml) of malic acid to organic solvent in step 2) is 1:1 to 10, preferably 1:2 to 8, more preferably 1:3.1 to 5.
6. The method according to claim 1, wherein the mass to volume ratio (g/ml) of malic acid to water in step 2) is 1:1 to 10, preferably 1:1 to 5, more preferably 1: 3.1.
7. The process according to claim 1, wherein the amount of cabozantinib malate seeds added in step 3) is 0.5-3.0%, preferably 1.0-2.0% by weight of cabozantinib.
8. The process of any one of claims 1 to 7, wherein the cabozantinib malate salt is obtained in a purity of not less than 99.5%, wherein the cabozantinib malate salt is cabozantinib-1.0 (L) -malate.
9. The process according to any one of claims 1 to 7, wherein the cabozantinib malate salt is obtained in a content of genotoxic impurities of not more than 98.6ppm, preferably not more than 50ppm, wherein said genotoxic impurities are selected from any one of the impurities D [4- (6, 7-dimethoxyquinolin-4-yloxy) -aniline ], impurity Id (4-fluoroaniline), impurity IIb (4-aminophenol) or a combination thereof.
10. The method according to any one of claims 1 to 7, wherein the cabozantinib malate salt is obtained with a content of the N-2 crystalline form of cabozantinib malate salt of not less than 92%, preferably not less than any one of 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%.
CN202011236189.6A 2020-11-09 2020-11-09 Preparation method and application of high-purity cabozantinib malate Pending CN114456109A (en)

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