CN110981798A - Antineoplastic drug cabozantinib impurity, preparation method and application thereof - Google Patents
Antineoplastic drug cabozantinib impurity, preparation method and application thereof Download PDFInfo
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Abstract
The application discloses an antitumor drug cabozantinib impurity, a preparation method and an application thereof, and belongs to the technical field of biological medicines, wherein the antitumor drug cabozantinib impurity has the following structural formula:
meanwhile, the invention also provides a synthesis method of the compound, which comprises the following steps: (1) dissolving cyclopropane carboxylic acid and an acid-binding agent in a solvent, activating by a condensing agent, adding p-aminophenol, and carrying out condensation reaction to obtain a compound c:
(2) dissolving the compound c in a solvent, adding alkali to form a salt with the compound c, and then adding a compound d to perform substitution reaction to obtain a target compound II:
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to an anti-tumor medicine cabozantinib impurity, and a preparation method and application thereof.
Background
The cabozantinib malate is a multi-target tyrosine kinase inhibitor and can effectively inhibit the tyrosine kinase activity of hepatocyte growth factor receptors, vascular endothelial growth factor receptors, stem cell growth factor receptors, tyrosine kinase receptors, FMS-like tyrosine, AXL and epithelial growth factor-like domain tyrosine kinase 2. The kinase receptors play an important role in the growth process of both normal cells and tumor cells. The abnormal expression of the receptor plays an important role in the occurrence and development processes of various tumors, including the inhibition of tumor cell apoptosis and the participation in pathological processes such as tumor angiogenesis and invasion. Cabozantinib exerts an anti-tumor effect by inhibiting the activity of the above kinases, can kill tumor cells, reduce metastasis and inhibit tumor angiogenesis, promote massive apoptosis of malignant cells, reduce invasion and metastasis of tumors, reduce proliferation of tumors and endothelial cells, slow down progression of bone metastasis foci, and inhibit angiogenesis of tumors.
Clinical test results show that the cabozantinib has higher disease control rate on various advanced cancers, can reduce or even eliminate bone metastasis focuses, and has obvious curative effect on metastatic Medullary Thyroid Cancer (MTC).
Since the FDA approved cabozantinib for the treatment of medullary thyroid cancer in 2012, the product has been on the expansion of indications until us FDA official approval of cabozantinib for second line treatment of advanced liver cancer patients No. 1-14 in 2019, both in capsule and tablet dosage forms.
The content of the active ingredients of the medicine is an important mark reflecting the purity of the medicine, impurities in the medicine can directly influence the content of the active ingredients in the medicine, inactive toxic and side effects can be caused, and the standard vertebra of medicine treatment has clear regulations on the purity of the active ingredients of the medicine and the limit of the impurities in order to ensure safe medication.
The inventor repeatedly observes that an unknown peak with the HPLC content being ultrahigh by 0.1 percent appears in the synthesis process of the compound, and after the unknown compound is separated, the ion peak of the impurity molecule is M + H by liquid mass analysis+= 687.3 nuclear magnetic submission H1-NMR(400M,DMSO-d6), δ: 1.512(s, 4H), 3.952(d, 12H), 6.458(d, 2H), 7.260(d, 2H),7.400(s, 2H), 7.519(s, 2H), 7.802(d, 2H), 8.492(d, 2H), 10.190(s,2H), molecular weight and reaction process are combined, and the compound is confirmed to be a disubstituted compound II of cyclopropyl dicarboxylic acid in the synthesis process of cabozantinib by further researching the synthetic route of cabozantinib malate and combining the confirmation information of the structure of the compound. The compound is a new compound molecule, has similar functional groups with a finished product, and has great influence on the quality research of the cabozantinib malate. Therefore, hybrid compound II needs to be prepared for effectively researching and controlling the quality of the raw material drug of cabozantinib malate and the preparation thereof.
Disclosure of Invention
The invention aims to provide an anti-tumor drug cabozantinib impurity, a preparation method and application thereof, and provides new help for quality control of a raw material drug of cabozantinib malate and a preparation thereof.
Based on the purpose, the invention adopts the following technical scheme:
an antitumor drug cabozantinib impurity, which has the following structural formula:
chinese name: n, N' -bis (4- (6, 7-dimethoxyquinoline-4-oxy) phenyl) cyclopropyl-1, 1-dicarboxamide is called compound II for short, and the compound is referred to as compound II.
Meanwhile, the invention also provides a synthesis method of the compound, which comprises the following steps:
(1) dissolving cyclopropane carboxylic acid and an acid-binding agent in a solvent, activating by a condensing agent, adding p-aminophenol, and carrying out condensation reaction to obtain a compound c:
(2) dissolving the compound c in a solvent, adding alkali to form a salt with the compound c, and then adding a compound d to perform substitution reaction to obtain a target compound II:
in the synthesis process:
in the step (1), the condensation reaction condensing agent of 1, 1-cyclopropyldicarboxylic acid and p-aminophenol is one selected from 6-chlorobenzotriazole-1, 1,3, 3-tetramethyluronium Hexafluorophosphate (HCTU), O-benzotriazol-tetramethyluronium Hexafluorophosphate (HBTU), 2- (7-azabenzotriazole) -N, N' -tetramethyluronium Hexafluorophosphate (HATU) and 1-hydroxybenzotriazole (HOBt), and is more preferably HCTU.
In the step (1), the selected solvent is tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane and other polar solvents, preferably tetrahydrofuran and dichloromethane, and more preferably tetrahydrofuran.
In the step (1), the acid-binding agent is selected from tertiary amine such as triethylamine, diisopropylethylamine and the like or inorganic base such as sodium carbonate, potassium carbonate and the like, and preferably Diisopropylethylamine (DIPEA).
In the step (1), the reaction temperature is 15-40 ℃, preferably 20-40 ℃, and more preferably 35-40 ℃.
In the step (1), the molar ratio of the condensing agent to the cyclopropane dicarboxylic acid, the diisopropylethylamine and the p-aminophenol is 1 (2-4): (3-5): 2-5, preferably 1:2.6:2.8: 2.4.
The solvent in the step (2) is one or a mixture of more than two of N, N-dimethylformamide, N, N-dimethylacetamide, dioxane and dimethyl sulfoxide in any proportion, and N, N-Dimethylacetamide (DMAC) is preferred.
In the step (2), the selected alkali is potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium carbonate and the like. Sodium tert-butoxide, potassium tert-butoxide; more preferably potassium tert-butoxide.
In the step (2), the molar ratio of the compound c, the alkali and the compound d is 1 (3-8) to (2-5), preferably 1:4.0: 2.4.
In the step (2), the reaction temperature is 80-150 ℃, preferably 90-110 ℃, and more preferably 90-100 ℃.
In the step (2), after the reaction is finished, adding purified water with the mass 1.5-2 times that of the solvent in the step (2) for crystallization for 8-16 h, filtering, adding a crude product of a target compound II, and refining the crude product to obtain a refined product of the target compound II, wherein the refining process comprises the following specific steps: adding tetrahydrofuran into the crude product of the compound II, heating to 35-55 ℃ for dissolving, preserving the heat for 20-40 minutes, adding activated carbon accounting for 5% of the mass of the crude product of the compound II, and continuing stirring for 20-40 minutes; cooling to room temperature, and dropwise adding purified water, wherein the mass ratio of the crude compound II, tetrahydrofuran and purified water is 1 (5-8) to 6-12; stirring at room temperature for crystallization for 5-8 hours, filtering, washing with a mixed solution of purified water and tetrahydrofuran in a mass ratio of 1:1, and drying (preferably blowing and drying at 50 ℃ for more than 10 hours) to obtain a refined product of the target compound II.
The antineoplastic medicine cabozantinib impurity is applied to the quality control of a malic acid cabozantinib raw material medicine and a preparation thereof.
The antineoplastic drug cabozantinib impurity is used in the impurity detection process of a malic acid cabozantinib raw material drug and a preparation thereof, the impurity detection process is to judge the content of the impurity in the malic acid cabozantinib raw material drug and the preparation thereof by detecting the relation between the impurity concentration and the integral area of a liquid chromatogram through the liquid chromatogram, wherein the detection condition of the liquid chromatogram in the liquid chromatogram detection process is as follows: a chromatographic column: agilent ZORBAX Eclipse C18, 4.6X 250mm, 5 μm; taking a mobile phase A which is 0.01mol/L ammonium bicarbonate solution and acetonitrile in a volume ratio of 98:2 and taking a mobile phase B which is acetonitrile and methanol in a volume ratio of 70: 30; the detection wavelength is 243 nm; the column temperature was 40 ℃; the flow rate is 1.2 ml/min; gradient elution was performed as in table 1.
The method prepares the unreported compound II for the first time with higher yield, the compound is an important component of an impurity spectrum of the antineoplastic drug cabozantinib, and effective basis is provided for the research of related substances of cabozantinib and the structure confirmation of unknown impurities. Through refining the compound II, the method can obtain a target compound with better purity, can amplify a proper amount, and can more accurately measure the content of the impurity in the cabozantinib after calibrating the content of the compound II.
Drawings
FIG. 1 shows the formula II1-NMR spectrum;
FIG. 2 is an LC-MS spectrum of compound II.
Detailed Description
To make the purpose, technology and advantages of the present invention clearer and more complete description of the technical solutions related to the present invention will be given below with reference to specific embodiments of the present invention, and it will be apparent to those skilled in the art that various modifications may be made without departing from the principles of the embodiments of the present invention, and these modifications are also considered as the scope of the embodiments of the present invention.
First, specific synthesis example of compound II:
example 1:
adding 1.0g of 1, 1-cyclopropyl dicarboxylic acid (7.68 mmol) into a reaction bottle, adding 20g of tetrahydrofuran and 3.1g of DIPEA, stirring to dissolve, adding 6.0g of HCTU, heating to 40 ℃, stirring to activate the 1, 1-cyclopropyl dicarboxylic acid for 1.5 hours, adding 2.4g (22 mmol) of p-aminophenol, reacting for 10-20 hours at 20-40 ℃, adding 5wt% of sodium carbonate solution to adjust the pH to 7-8 after the reaction is finished, adding 20g of purified water for crystallization, filtering and drying to obtain 1.6g of an intermediate compound c, wherein the yield is 73%.
Taking 1.5g (4.8 mmol) of the compound c, adding the compound c into 10g of DMAC, adding 2.2g (19.2 mmol) of potassium tert-butoxide under stirring, stirring until the temperature is stable, adding 2.6g (compound d, 11.52 mmol) of 4-chloro-6, 7-dimethoxyquinoline, heating to 90-100 ℃, reacting for 8-10 hours, stopping heating, adding 10g of purified water, naturally cooling to room temperature, and crystallizing overnight. The target compound II is obtained by filtration and washing, and the HPLC purity is 93.3%. The sample amount is small, the total yield is general, the sample cannot be used for calibrating the content, the compound II with good product quality is prepared after the solvent dosage of each step is adjusted, and the specific operation is shown in example 2.
Example 2
Adding 20g of 1, 1-cyclopropyl dicarboxylic acid (153.7 mmol) into a reaction bottle, adding 140g of tetrahydrofuran and 60g of DIPEA, stirring to dissolve, adding 101.8g of HCTU, heating to 40 ℃, stirring to activate the 1, 1-cyclopropyl dicarboxylic acid for 1.5 hours, adding 40g of p-aminophenol (366.5 mmol), reacting for 10-20 hours at 20-40 ℃, adding 5wt% of sodium carbonate solution to adjust the pH to 7-8 after the reaction is finished, adding 80g of purified water for crystallization, filtering and drying to obtain 40.1g of an intermediate compound c, wherein the yield is 83%.
And (3) adding 30g of the compound c into 200g of DMAC (dimethylacetamide), adding 32.3g of potassium tert-butoxide while stirring, adding 64.4g of 4-chloro-6, 7-dimethoxyquinoline (compound d) after stirring until the temperature is stable, heating to 90-100 ℃, reacting for 8-10 hours, stopping heating, dropwise adding 300g of purified water, naturally cooling to room temperature, crystallizing overnight, filtering and washing to obtain a crude product of the target compound II. And the consumption of the purified water during crystallization after optimization is that the mass ratio of DMAC to the purified water is 1: 1.5.
Adding tetrahydrofuran 6 times the mass of the crude product of the compound II, heating to about 40 ℃ for dissolution, preserving the temperature for 30 minutes, adding active carbon 5% of the mass of the crude product of the compound II, and continuing stirring for 30 minutes. Cooling to room temperature, and slowly dropwise adding purified water with the mass 1.5 times that of tetrahydrofuran, namely, when refining, the compound II: tetrahydrofuran: the mass ratio of the purified water is 1:6: 9. Stirring and crystallizing for 6 hours at room temperature, filtering, washing by using a mixed solution of purified water and tetrahydrofuran according to the mass ratio of 1:1, and drying by blowing at 50 ℃ for more than 10 hours to obtain the target compound, wherein the total yield is about 75 percent, the HPLC purity is 95.6 percent, the purity requirement of a reference substance is met, tetrahydrofuran is used as a refined solvent, and purified water is used as a poor solvent. H of Compound II1NMR spectrum and LC-MS spectrum are shown in FIG. 1 and FIG. 2, respectively, in FIG. 1H1-NMR(400M,DMSO-d6) δ: 1.512(s, 4H), 3.952(d, 12H), 6.458(d, 2H), 7.260(d, 2H),7.400(s, 2H), 7.519(s, 2H), 7.802(d, 2H), 8.492(d, 2H), 10.190(s, 2H); FIG. 2 shows the ion peak of the impurity molecule is M + H+= 687.3, 344.3 for its major fragment peaks.
Secondly, detecting the content of a compound II in cabozantinib:
blank solvent: methanol purified water =7:3 (volume ratio)
Test solution: precisely weighing about 25mg of cabozantinib, placing into a 100ml measuring flask, adding a proper amount of diluent [ methanol-water (70: 30) ], ultrasonically dissolving, cooling to room temperature, diluting with diluent to scale, and shaking uniformly to obtain a test solution;
control solution: taking a proper amount of the compound II, and adding a diluent to dilute the compound II into solutions each containing 0.25 microgram per 1 ml, wherein the solutions are used as reference substance solutions;
chromatographic conditions are as follows: the detection wavelength is 243nm, and the sample injection amount is 10 mu l. A chromatographic column: agilent ZORBAX Eclipse C18, 4.6X 250mm, 5 μm. Taking 0.01mol/L ammonium bicarbonate solution-acetonitrile (98: 2) as a mobile phase A, and taking acetonitrile-methanol (70: 30) as a mobile phase B; the column temperature was 40 ℃; the flow rate is 1.2 ml/min; gradient elution was performed as in table 1.
Table 1: gradient elution procedure
Table 2: the result of the detection
Table 3: selecting proper refining conditions according to the structure of the compound II, and refining the cabozantinib to obtain a detection result:
the detection results in tables 2 and 3 show that after the structure of the compound II is determined, the content of the compound II in a finished product can be obviously reduced by adjusting the cabozantinib refining method according to the structure, and the product quality is obviously improved.
Claims (10)
1. An antitumor drug cabozantinib impurity, which is characterized in that the structural formula is as follows:
2. the method for preparing the antineoplastic drug cabozantinib impurity of claim 1, wherein the impurity is obtained by the steps of:
(1) dissolving cyclopropane carboxylic acid and an acid-binding agent in a solvent, activating by a condensing agent, adding p-aminophenol, and carrying out condensation reaction to obtain a compound c:
(2) dissolving the compound c in a solvent, adding alkali to form a salt with the compound c, and then adding a compound d to perform substitution reaction to obtain a target compound II:
3. the method for preparing cabozantinib impurity as antitumor agent according to claim 2, wherein in step (1), the condensation reaction condensing agent of 1, 1-cyclopropyl dicarboxylic acid and p-aminophenol is selected from one of HCTU, HBTU, HATU and HOBt, the acid-binding agent is selected from triethylamine, diisopropylethylamine, sodium carbonate or potassium carbonate, and the selected solvent is one or a mixture of more than two of tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide and dichloromethane at any ratio.
4. The method for preparing cabozantinib impurities as an antitumor drug according to claim 2, wherein the reaction temperature is 15-40 ℃, and the molar ratio of the condensing agent to the cyclopropane dicarboxylic acid, the acid-binding agent and the p-aminophenol is 1 (2-4): 3-5): 2-5.
5. The method for preparing the impurities of the antineoplastic drug cabozantinib according to claim 4, wherein the reaction temperature is 35-40 ℃, and the molar ratio of the condensing agent to the cyclopropane dicarboxylic acid, the acid-binding agent and the p-aminophenol is 1:2.6:2.8: 2.4.
6. The method for preparing cabozantinib impurities as an antitumor drug according to claim 2, wherein in the step (2), the solvent is one or a mixture of two or more of N, N-dimethylformamide, N-dimethylacetamide, dioxane and dimethylsulfoxide in any proportion; the base is potassium tert-butoxide, sodium methoxide, sodium ethoxide or potassium carbonate.
7. The method for preparing cabozantinib impurities as an antitumor drug according to claim 2, wherein the molar ratio of the compound c, the alkali and the compound d in the preparation in the step (2) is 1 (3-8) to (2-5), and the reaction temperature is 80-150 ℃.
8. The method for preparing the impurities of the antineoplastic drug cabozantinib according to claim 7, wherein the molar ratio of the compound c, the alkali and the compound d in the preparation of the step (2) is 1:4:2.4, and the reaction temperature is 90-110 ℃.
9. The preparation method of the antineoplastic drug cabozantinib impurity according to claim 2, characterized in that in step (2), after the reaction is completed, purified water with 1.5-2 times of the solvent mass in step (2) is added for crystallization for 8-16 h, and then the obtained product is filtered to obtain a crude targeted compound II product, and the crude product is refined to obtain a refined targeted compound II product, wherein the refining process is as follows: adding tetrahydrofuran into the crude product of the compound II, heating to 35-55 ℃ for dissolving, preserving the heat for 20-40 minutes, adding activated carbon accounting for 5% of the mass of the crude product of the compound II, and continuing stirring for 20-40 minutes; cooling to room temperature, and dropwise adding purified water, wherein the mass ratio of the crude compound II, tetrahydrofuran and purified water is 1 (5-8) to 6-12; stirring and crystallizing at room temperature for 5-8 hours, filtering, washing by using a mixed solution of purified water and tetrahydrofuran in a mass ratio of 1:1, and drying to obtain a refined product of the target compound II.
10. The use of the antineoplastic drug cabozantinib impurity of claim 1 in the quality control of cabozantinib malate bulk drug and its formulations.
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