CN107556238A - It is a kind of to block the rich synthetic method for Buddhist nun - Google Patents
It is a kind of to block the rich synthetic method for Buddhist nun Download PDFInfo
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- CN107556238A CN107556238A CN201610505245.9A CN201610505245A CN107556238A CN 107556238 A CN107556238 A CN 107556238A CN 201610505245 A CN201610505245 A CN 201610505245A CN 107556238 A CN107556238 A CN 107556238A
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- buddhist nun
- condensing agent
- dimethoxy
- cyclopropyl
- quinoline
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Abstract
The present invention provides a kind of synthetic method blocked and won for Buddhist nun; this method is with 1; 1 cyclopropyl dicarboxylic acids is initiation material; with 4 [(6 after acylation; the quinoline of 7 dimethoxy 4) epoxide] aniline condensation, then be further condensed to be made to block to win in the case where polypeptide condensing agent acts on 4 fluoroanilines and replace Buddhist nun, this method reaction condition is gentle; an only step uses chlorination reagent, is adapted to industrialized production.
Description
Technical field
The invention belongs to field of antineoplastic medicaments, and in particular to one kind is applied to the original for the treatment of medullary carcinoma of thyroid gland (MTC)
Expect the rich preparation method for Buddhist nun of medicine card.
Background technology
Card is rich to replace Buddhist nun's (Cabozantinib) chemical name N- [4- [6,7- dimethoxy-4 's-quinolyl] epoxide] phenyl]-N-
(4- fluorophenyls) -1,1- cyclopropane diformamides, it is by the junket of Exelixis drugmakers of U.S. research and development that malic acid card, which is won for Buddhist nun,
Histidine kinase inhibitor, listed in 2012 in the U.S., trade name20mg and 80mg capsule preparations.It is clinical
It is mainly used in treatment of advanced, the medullary carcinoma of thyroid gland of transfer.The country there is no malic acid card is rich to be listed for Buddhist nun at present.
Malic acid card is rich as follows for Buddhist nun's structural formula：
The rich medullary carcinoma of thyroid gland (MTC) for being applied to treatment of advanced for Buddhist nun, shifting of card, is a kind of receptor tyrosine kinase
Mutiple Targets inhibitor, pass through targeted inhibition proto-oncogene encoded protein products (MET), vascular endothelial growth factor receptor
(VEGFR) and EGFR-TK receptoroid (RET) signal path and play antitumor action, so as to suppress tumour growth, turn
Move.The medicine to prostate cancer, malignant tumour and can not surgery excision pernicious Locally Advanced or metastatic medullary thyroid sample
Cancer (MTC) has fast explicit, significant clinical efficacy and preferable security.
Most early in the rich synthetic method for Buddhist nun's free alkali of report card in patent document WO2005030140A2, this method synthesis
Route is as follows：
This method with 6,7- dimethoxy-4 's-oxyquinoline and 1,1- cyclopropyl dicarboxylic acids for initiation material, by 6,7- bis-
Methoxyl group -4- oxyquinolines obtain esterification products with trifluoromethanesulfchloride chloride, in addition, two carboxyls by 1,1- cyclopropyl dicarboxylic acids
Priority and the amide product of 4- fluoroanilines and 4- hydroxyanilines, by esterification products and amide product under 165 DEG C of high-temperature heating
Condensation, which is made to block to win, replaces Buddhist nun's free alkali.This method need to use 165 DEG C of high temperature, and process conditions are harsh, under hot conditions accessory substance compared with
More, purifying difficulty is big, it is difficult to obtains the product of high quality, is not easy to industrialized production.
Patent document CN201080012656.5 reports the rich synthetic route for Buddhist nun of malic acid card, this method equally with 6,
7- dimethoxy-4 's-oxyquinoline and 1,1- cyclopropyl dicarboxylic acids are initiation material, but synthesize the rich centre for Buddhist nun's free alkali of card
Step is different.This method, which first substitutes 6,7- dimethoxy-4 's-oxyquinoline through POCl3 chlorination, is made 6,7- bis-
Methoxyl group -4- chloroquinolines (intermediate 1), then be condensed with 4- nitrophenols and intermediate 6,7- dimethoxy-4 's-(4- nitrobenzene is made
Epoxide) quinoline (intermediate 2), then it is reduced to 4- [(6,7- dimethoxy-4 's-quinoline) epoxide] aniline under palladium chtalyst effect
(intermediate 3).Meanwhile by another initiation material 1,1- (4- fluorine is condensed to obtain with 4- fluoroanilines after 1- cyclopropyl dicarboxylic acid chlorideizations
Aniline carbonyl) cyclopropyl -1- carboxylic acids (intermediate 4), it is condensed after oxalyl chloride is acylated and acyl chlorides (intermediate 5) is made with intermediate 3
It is made that card is rich replace Buddhist nun's free alkali, finally obtains target compound malic acid card into salt with L MALIC ACID and win and replace Buddhist nun.Its reaction equation is as follows：
The multiple step of this method is good for using corrosive chloride reagents such as thionyl chloride and oxalyl chlorides to environment and human body
Kang Buli,
It is unfavorable for industrialized production.
The content of the invention
The present invention provide it is a kind of block the rich synthetic method for Buddhist nun, this method with 1,1- cyclopropyl dicarboxylic acids for initiation material,
After acylation with 4- [(6,7- dimethoxy-4 's-quinoline) epoxide] aniline condensation, then with 4- fluoroanilines polypeptide condensing agent effect under
Further condensation, which is made to block to win, replaces Buddhist nun, and this method reaction condition is gentle, and an only step uses chlorination reagent, is adapted to industrialized production.
The rich synthetic method for Buddhist nun of card provided by the invention, it is characterised in that comprise the steps of：Step 1) 1,1- rings third
Base dicarboxylic acids carries out chlorination reaction with chlorination reagent and obtains the intermediate of formula II, the intermediate of formula II and 4- [(6,7- dimethoxy-4 's-quinoline
Quinoline) epoxide] aniline condensation obtains the i.e. N- of the intermediate of formula III { 4- [(6,7- dimethoxy-4 's-quinolyl) epoxide] phenyl } -1- first
Acid amides-cyclopropyl -1- carboxylic acids：
The intermediate of step 2) formula III and 4- fluoroanilines are condensed to yield card under condensing agent and alkali effect to be won and replaces Buddhist nun：
Wherein, step 1) is first activated 1,1- cyclopropyl dicarboxylic acids with triethylamine, and triethylamine dosage is worked as 0.5~5
Amount, preferably 1~2 equivalent, is stirred at room temperature 10 minutes~2 hours, preferably 0.5~1 hour, wherein the preferred chlorination of the chlorination reagent
Sulfoxide, the preferably equivalent of dosage 0.5~2,0.9~1.1 equivalent, is stirred at room temperature reaction 0.5~5 hour, preferably 1~3 hour；Solvent
Selected from tetrahydrofuran, acetone, ethyl acetate, dichloromethane, preferably tetrahydrofuran.
After completion of the reaction, add 4- [(6,7- dimethoxy-4 's-quinoline) epoxide] aniline and continue stirring reaction, dosage is
0.5~2 equivalent, preferably 0.9~1.5 equivalent, the preferred triethylamine of base reagent, the preferred tetrahydrofuran of solvent.After reaction completely,
Reaction solution adds organic solvent diluting, and the organic solvent includes ethers, esters, substitution hydro carbons, arene, ketone, acid amides
Class and nitrile etc., preferably tetrahydrofuran, acetone, ethyl acetate, dichloromethane, more preferably ethyl acetate, then add hydroxide
Sodium solution crystallization, filtering, gained filtration cakes torrefaction, obtains the compound N of formula III-{ 4- [(6,7- dimethoxy-4 's-quinolyl) epoxide] benzene
Base } -1- formamides-cyclopropyl -1- carboxylic acids.
Step 2) the condensing agent may be selected from polypeptide condensing agent, including carbodiimide type activation condensing agent such as N, N- diisopropyls
Base carbodiimide (DIC), N, N- dicyclohexylcarbodiimides (DCC), 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochloride
Salt (EDCI), phosphorus ionic condensing agent such as PyAOP, BrOP, PyClOP, PyBrOP, PyBOP etc., urea ionic condensing agent
As HOBt, HOAt, HOOBt, HOPyU, HBTU, TBTU, HBPyU, HBPipU, HBMDU, HATU, HAPyU, HAMDU, TAPipU,
HDTU, HPyOPfp, HPySPfp, HAPyTU, TOTU, HAPipU and other condensing agents such as BOP-Cl, FDP, FDPP, DEPBT,
EDQ etc..In order to avoid chloride reagent is used for multiple times, the present invention uses the reactive mode of carboxylic acid and amino direct polycondensation, to upper
State polypeptide condensing agent and carry out experiment screening, as a result find that HATU, HBTU, HOBt in urea ionic condensing agent are alone or share
Compared to other condensing agents, the yield and purity of product are more excellent, therefore at least one of condensing agent preferred HATU, HBTU, HOBt,
More preferably HBTU and HOBt combination, and HBTU and HOBt mol ratio is 1:1~2, preferably 1：1.5；The base reagent is selected from
Triethylamine, N, N- diisopropylamines, N, N- diisopropylethylamine are at least one；Reaction dissolvent is selected from N, accelerine, N,
Dinethylformamide, tetrahydrofuran are at least one.
Block the rich synthetic method for Buddhist nun the invention provides a kind of, this method is former for starting with 1,1- cyclopropyl dicarboxylic acids
Material, carboxyl carry out chloride again with after 4- [(6,7- dimethoxy-4 's-quinoline) epoxide] aniline condensation, another carboxyl
It is condensed using polypeptide condensing agent and 4- fluoroanilines, products obtained therefrom purity and yield are good, avoid reuse corrosivity
Chloride reagent, and reaction condition is gentle, more conducively industrialized production.
With reference to the embodiment of embodiment, the present invention will be further described.
Embodiment
Embodiment 1N- { 4- [(6,7- dimethoxy-4 's-quinolyl) epoxide] phenyl } -1- formamides-cyclopropyl -1- carboxylic acids
Preparation
Triethylamine is added into tetrahydrofuran (350ml) solution of 1,1- cyclopropyl dicarboxylic acids (44.9g, 0.345mol)
(48.5mL, 0.345mol), after solution is stirred at room temperature 40 minutes under nitrogen protection, addition thionyl chloride (25mL,
0.344mol), LC/MS monitoring reaction, conversion ratio (reaction solution monitoring monocarboxylic acid first after processing is quenched in methanol of single acyl chlorides is monitored
Ester), after being stirred at room temperature 3 hours, successively add 4- [(6,7- dimethoxy-4 's-quinoline) epoxide] aniline (102g, 0.344mol)
With tetrahydrofuran (150ml), continue to be stirred at room temperature 16 hours, after reaction slurry magma adds ethyl acetate (1000ml) dilution, use
1N sodium hydroxide solutions extract.By two-phase slurry magma filtering, aqueous phase filters after hydrochloric acid adjusts pH to 6, merges filter cake, through acetic acid second
After ester washing, it is dried under reduced pressure, obtains product 1- [4- (6,7- dimethoxy-quinoline -4- epoxides) carbanilino]-cyclopropyl -1- carboxylics
Acid (98.1g, yield 70.1%, purity 98%) MS：m/z 408[M+H]+).IR：3427cm-1, 3144~3029cm-1、
2972cm-1、2940cm-1、2840cm-1、1678cm-1、1625cm-1、1597cm-1、1552cm-1、1506cm-1、1480cm-1、
1455cm-1、1438cm-1、1266cm-1、1233cm-1、998cm-1、838cm-1、821cm-1.NMR：1H-NMR(DMSO-d6,
8223.7Hz)δ8.29(1H,d),
7.52(2H,AA′BB′),7.40(1H,s),7.21(1H,s),7.08(2H,AA′BB′),6.43(1H,d),3.85
(3H,s),3.81(3H,s),1.28(4H,m)。13C-NMR(DMSO-d6,24038.5Hz)δ177.98(1C,s),173.40
(1C,s),162.02(1C,s),
153.89(1C,s),150.94(1C,s),150.38(1C,s),150.11(1C,d),146.75(1C,s),
136.88(1C,s),123.15(2C,d),122.81(2C,d),116.88(1C,s),107.84(1C,d),104.79(1C,
d),100.78(1C,d),57.16(1C,q),57.09(1C,q),29.24(1C,s),20.03(2C,t)。
The rich preparation (2~embodiment of embodiment 6) for Buddhist nun's alkali of card
Embodiment 2
1- [4- (6,7- dimethoxy-quinoline -4- epoxides) carbanilino]-cyclopropyl -1- carboxylic acids are added into reaction bulb
(4.08g, 10m mol), add DMF dissolving, add I-hydroxybenzotriazole (HOBt, 2.43g,
18mmol), HB TU (4.55g, 12mmol) and DIPEA (1.55g, 12mmol), after stirring, 4- is added
Fluoroaniline (1.11g, 10mmol), reaction is stirred at room temperature overnight to reacting complete, adds water (800ml) dilution, stirring and crystallizing, mistake
Filter, filter cake is respectively through 1N hydrochloric acid tetrahydrofuran solution (800ml), 1N sodium hydroxides tetrahydrofuran solution (800ml) and tetrahydrochysene furan
After the aqueous solution of muttering (800ml) washes and starches crystallization, filter, dry, get Ka Bo replaces Buddhist nun alkali 4.6g, yield 91.8%, purity 99.1%.
MS：m/z 501[M+H]+.IR：3442cm-1、3244cm-1、3071cm-1、3021cm-1、2959cm-1、2836cm-1、1672cm-1、1642cm-1、1618cm-1、1589cm-1、1567cm-1、1541cm-1、1508cm-1、1480cm-1、1432cm-1、1408cm-1、
1350cm-1、1250cm-1、1217cm-1、1167cm-1、1176cm-1、851cm-1、829cm-1.NMR：1H-NMR(DMSO-d6,
8223.7Hz)δ15.0(4H,s),δ10.18(1H,brs),10.05(1H,brs),8.47(1H,d),7.76(2H,AA′BB′),
7.65(2H,m),7.51(1H,s),7.40(1H,s),7.23(2H,AA′BB′),7.15(2H,m),6.44(1H,d),3.95
(3H,s),3.94(3H,s)。13C-NMR(DMSO-d6,24038.5Hz)δ168.17(1C,s),168.12(1C,s),159.88
(1C,s),158.26(1C,d,1JCF=240.1Hz), 152.53 (1C, s), 149.54 (1C, s), 149.30 (1C, s),
148.74(1C,d),146.43(1C,s),136.28(1C,s),135.10(1C,s),122.40(2C,d,3JCF=7.7H z),
122.17(2C,d),121.04(2C,d),115.14(1C,s),114.95(2C,d,2JCF=22.2Hz), 107.83 (1C, d),
103.05(1C,d),99.08(1C,d),55.64(2C,q),31.40(1C,s),15.40(2C,t)。19F-NMR(DMSO-d6,
75000.0Hz)δF-118.40(1F,m)。
Embodiment 3
1- [4- (6,7- dimethoxy-quinoline -4- epoxides) carbanilino]-cyclopropyl -1- carboxylic acids are added into reaction bulb
(4.08g, 10mmol), add DMF dissolving, add I-hydroxybenzotriazole (HOBt, 2.43g,
18mmol), 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU, 4.56g, 12mmol)
With DIPEA (1.55g, 12mmol), after stirring, 4- fluoroanilines (1.11g, 10mmol) are added, room temperature is stirred
Reaction is mixed overnight to reacting complete, adds water (800ml) dilution, stirring and crystallizing, filtering, filter cake is respectively through 1N hydrochloric acid tetrahydrofurans
After solution (800ml), 1N sodium hydroxides tetrahydrofuran solution (800ml) and tetrahydrofuran aqueous solution (800ml) wash and starch crystallization, mistake
Filter, is dried, and get Ka Bo replaces Buddhist nun alkali 4.3g, yield 85.8%, purity 99.0%.
Embodiment 4
To fill 1- [4- (6,7- dimethoxy-quinoline -4- epoxides) carbanilino]-cyclopropyl -1- carboxylic acids (7.4g,
18.2mmol), 4- fluoroanilines (2.4g, 21.9mmol), N, N- diisopropylamines (9.0mL, 54.4mmol) and dimethylaniline
2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters are added in the reaction bulb of (100.0ml) solution
(HATU, 20.3g, 53.4mmol), after reaction solution is stirred at room temperature 1 hour, stirs and instill water (1000ml) down, at turbid solution ultrasound
Reason, filtering, 1N hydrochloric acid tetrahydrofuran solution (1000ml), 1N sodium hydroxides tetrahydrofuran solution (1000ml) and tetrahydrofuran water
After solution (1000ml) washes and starches crystallization, filter, dry, get Ka Bo replaces Buddhist nun alkali 7.5g, yield 82.5%, purity 98.5%.
Embodiment 5
1- [4- (6,7- dimethoxy-quinoline -4- epoxides) carbanilino]-cyclopropyl -1- carboxylic acids are added into reaction bulb
(4.08g, 1m mol), add DMF dissolving, add I-hydroxybenzotriazole (HOBt, 2.43g,
18mmol), 1H- BTAs -1- bases oxygen tripyrrole alkyl hexafluorophosphate (PyBOP, 6.24g, 1.2mmol), N, N- bis- are different
Propyl group carbodiimide (DIC, 1.51g, 1.2mmol) and DIPEA (1.55g, 1.2mmol), after stirring,
4- fluoroanilines (1.11g, 1mmol) are added, reaction is stirred at room temperature overnight to reacting complete, adds water (800ml) dilution, stirring analysis
Crystalline substance, filtering, filter cake is respectively through 1N hydrochloric acid tetrahydrofuran solution (800ml), 1N sodium hydroxides tetrahydrofuran solution (800ml) and four
After the hydrogen furans aqueous solution (800ml) washes and starches crystallization, filter, dry, get Ka Bo replaces Buddhist nun alkali 1.5g, yield 29.9%, purity
94.1%.
Embodiment 6
1- [4- (6,7- dimethoxy-quinoline -4- epoxides) carbanilino]-cyclopropyl -1- carboxylic acids are added into reaction bulb
(4.08g, 1mmol), add tetrahydrofuran and stir, add I-hydroxybenzotriazole (HOBt, 2.43g, 18mmol), two
Carbodicyclo hexylimide (DCC, 2.47g, 1.2mmol) and triethylamine (1.2g, 1.2mmol), stir lower addition 4- fluoroanilines
(1.11g, 1mmol), reaction is stirred at room temperature overnight to reacting complete, adds water (800ml) dilution, stirring and crystallizing, filtering, filter cake
Respectively through 1N hydrochloric acid tetrahydrofuran solution (800ml), 1N sodium hydroxides tetrahydrofuran solution (800ml) and tetrahydrofuran aqueous solution
After (800ml) washes and starches crystallization, filter, dry, get Ka Bo replaces Buddhist nun's alkali.(1.4g, yield 27.9%, purity 89.0%).
Claims (10)
1. a kind of block the rich synthetic method for Buddhist nun, it is characterised in that comprises the steps of：
Step 1) 1,1- cyclopropyl dicarboxylic acids carry out chlorination reaction with chlorination reagent and obtain the intermediate of formula II, the intermediate of formula II and 4-
[(6,7- dimethoxy-4 's-quinoline) epoxide] aniline condensation obtains the i.e. N- of the intermediate of formula III { 4- [(6,7- dimethoxy-4 's-quinoline
Base) epoxide] phenyl } -1- formamides-cyclopropyl -1- carboxylic acids：
The intermediate of step 2) formula III and 4- fluoroanilines are condensed to yield card under condensing agent and alkali effect to be won and replaces Buddhist nun：
2. according to the method for claim 1, it is characterised in that the step 1) chlorination reagent is thionyl chloride, and dosage is
0.5~2 equivalent, the chlorination reaction solvent are tetrahydrofuran.
3. according to the method for claim 1, it is characterised in that base reagent triethylamine is used in the step 1) chlorination reaction
Carry out 1,1- cyclopropyl dicarboxyl acid activations.
4. according to the method for claim 1, it is characterised in that the step 1) 4- [(6,7- dimethoxy-4 's-quinoline) oxygen
Base] dosage of aniline is 0.5~2 equivalent.
5. according to the method for claim 1, it is characterised in that the dosage of step 2) the 4- fluoroanilines is worked as 0.8~2.0
Amount.
6. according to the method for claim 1, it is characterised in that the step 2) condensing agent be HATU, HBTU, HOBt in extremely
Few one kind.
7. according to the method for claim 1, it is characterised in that the step 2) condensing agent is HBTU and HOBt combination.
8. according to the method for claim 1, it is characterised in that step 2) the condensing agent HBTU and HOBt mol ratio is
1:1~2.
9. according to the method for claim 8, it is characterised in that step 2) the condensing agent HBTU and HOBt mol ratio is
1:1.5。
10. according to the method for claim 1, it is characterised in that step 2) reaction dissolvent be selected from DMF,
At least one of DMA, tetrahydrofuran, the base reagent are selected from triethylamine, N, N- diisopropylamines, N, N- bis-
At least one of wopropyl ethyl amine.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108264482A (en) * | 2018-02-05 | 2018-07-10 | 南京法恩化学有限公司 | It is a kind of to block the rich preparation method for Buddhist nun |
| CN110240563A (en) * | 2019-05-09 | 2019-09-17 | 南京法恩化学有限公司 | A kind of rich preparation method for Buddhist nun of card |
| CN110981798A (en) * | 2019-12-20 | 2020-04-10 | 乐普药业股份有限公司 | Antineoplastic drug cabozantinib impurity, preparation method and application thereof |
| WO2024114710A1 (en) * | 2022-12-01 | 2024-06-06 | 江苏奥赛康药业有限公司 | Method for preparing cabozantinib and intermediate thereof |
| WO2024163400A1 (en) * | 2023-01-31 | 2024-08-08 | Handa Oncology, Llc | Improved cabozantinib compositions and methods of use |
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| EP2392565A1 (en) * | 2003-09-26 | 2011-12-07 | Exelixis Inc. | c-Met modulators and methods of use |
| CN103664776A (en) * | 2012-09-26 | 2014-03-26 | 正大天晴药业集团股份有限公司 | Preparation method for tyrosine kinase inhibitor and midbody thereof |
| CN105121412A (en) * | 2013-03-15 | 2015-12-02 | 埃克塞里艾克西斯公司 | Metabolites of n-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-n'-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide |
| WO2016019285A1 (en) * | 2014-07-31 | 2016-02-04 | Exelixis, Inc. | Method of preparing fluorine-18 labeled cabozantinib and its analogs |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2392565A1 (en) * | 2003-09-26 | 2011-12-07 | Exelixis Inc. | c-Met modulators and methods of use |
| CN103664776A (en) * | 2012-09-26 | 2014-03-26 | 正大天晴药业集团股份有限公司 | Preparation method for tyrosine kinase inhibitor and midbody thereof |
| CN105121412A (en) * | 2013-03-15 | 2015-12-02 | 埃克塞里艾克西斯公司 | Metabolites of n-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-n'-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide |
| WO2016019285A1 (en) * | 2014-07-31 | 2016-02-04 | Exelixis, Inc. | Method of preparing fluorine-18 labeled cabozantinib and its analogs |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108264482A (en) * | 2018-02-05 | 2018-07-10 | 南京法恩化学有限公司 | It is a kind of to block the rich preparation method for Buddhist nun |
| CN110240563A (en) * | 2019-05-09 | 2019-09-17 | 南京法恩化学有限公司 | A kind of rich preparation method for Buddhist nun of card |
| CN110981798A (en) * | 2019-12-20 | 2020-04-10 | 乐普药业股份有限公司 | Antineoplastic drug cabozantinib impurity, preparation method and application thereof |
| WO2024114710A1 (en) * | 2022-12-01 | 2024-06-06 | 江苏奥赛康药业有限公司 | Method for preparing cabozantinib and intermediate thereof |
| WO2024163400A1 (en) * | 2023-01-31 | 2024-08-08 | Handa Oncology, Llc | Improved cabozantinib compositions and methods of use |
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