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Building IP: EXEL Patent Grant re "Method of preparing fluorine-18 labeled Cabozantinib and its analogs"
Method of preparing fluorine-18 labeled Cabozantinib and its analogs The present invention relates to a method of preparing Cabozantinib (Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylo]amide(4-fluoro-phenyl)amide) and .sup.18F labeled Cabozantinib.
Primary Examiner: Seaman; D Margaret M Attorney, Agent or Firm: CROSS-REFERENCE TO RELATED APPLICATIONS This application is a United States National Phase filing of PCT/US2015/043195, filed Jul. 31, 2015, which claims the benefit of U.S. Provisional Application No. 62/031,471, filed Jul. 31, 2014, the entire contents of which are incorporated herein by reference. The invention claimed is: 1. A method for preparing a compound of Formula 1a: ##STR00049## or pharmaceutically salt thereof wherein: R.sup.4 is .sup.18F; the method comprising: i) reacting a compound of Formula 10 with a chlorinating agent to generate a compound of Formula 11: ##STR00050## ii) coupling the compound of Formula 11 with a compound of Formula 23 in the presence of a base to generate a compound of Formula 12: ##STR00051## iii) coupling the compound of Formula 12 with a compound of Formula 13 in the presence of a coupling agent to generate a compound of Formula 14: ##STR00052## iv) saponifying the compound of Formula 14 in the presence of a base to generate a compound of Formula 15: ##STR00053## v) reacting the compound of Formula 15 with a halogenating reagent to generate a compound of Formula 15a: ##STR00054## wherein X is chloro or bromo; and vi) reacting the compound of Formula 15a with a compound of Formula 9 to generate a compound of Formula 1a: ##STR00055## 2. The method of claim 1, further comprising preparing a compound of Formula 9, wherein R.sup.4 is .sup.18F and the compound of Formula 9 is a compound of Formula 9a, which comprises: i) reacting a compound of Formula 18 with a fluorinating reagent to generate a compound of Formula 22a; and ##STR00056## and ii) reducing the compound of Formula 22a to generate a compound of Formula 9a: ##STR00057## 3. A method for preparing a compound of Formula 1a: ##STR00058## or pharmaceutically salt thereof wherein: R.sup.4 is .sup.18F; the method comprising: i) reacting a compound of Formula 10 with a chlorinating agent to generate a compound of Formula 11: ##STR00059## ii) coupling the compound of Formula 11 with a compound of Formula 23 in the presence of a base to generate a compound of Formula 12: ##STR00060## iii) coupling of the compound of Formula 12 with a compound of Formula 13 in the presence of a coupling reagent to generate a compound of Formula 14: ##STR00061## iv) saponifying the compound of Formula 14 in the presence of sodium hydroxide to generate a compound of Formula 15, wherein a solvent is used which is methanol, ethanol, isopropanol, water or a combination thereof: ##STR00062## and v) coupling the compound of Formula 15 with a compound of Formula 9 in the presence of a coupling reagent to generate a compound of Formula 1a: ##STR00063## 4. A method for preparing a compound of Formula 1a: ##STR00064## or pharmaceutically salt thereof wherein: R.sup.4 is .sup.18F; the method comprising: i) reacting a compound of Formula 10 with a chlorinating agent to generate a compound of Formula 11: ##STR00065## ii) coupling the compound of Formula 11 with a compound of Formula 23 in the presence of a base to generate a compound of Formula 12: ##STR00066## iii) coupling the compound of Formula 12 with a compound of Formula 13 in the presence of a coupling agent to generate a compound of Formula 14: ##STR00067## iv) saponifying the compound of Formula 14 in the presence of sodium hydroxide and a solvent to generate a compound of Formula 15, wherein the solvent is methanol, ethanol, isopropanol, water or a combination thereof: ##STR00068## v) reacting the compound of Formula 15 with a halogenating reagent to generate a compound of Formula 15a: ##STR00069## wherein X is chloro or bromo; and vi) reacting the compound of Formula 15a with a compound of Formula 9 to generate a compound of Formula 1a: ##STR00070## 5. The method of claim 3, further comprising preparing the compound of Formula 9 wherein R.sup.4 is .sup.18F and the compound of Formula 9 is a compound of Formula 9a, which comprises: i) reacting a compound of Formula 18 with a fluorinating reagent to generate a compound of Formula 22a; and ##STR00071## and ii) reducing the compound of Formula 22a to generate a compound of Formula 9a: ##STR00072## 6. The method of claim 4, further comprising preparing the compound of Formula 9 wherein R.sup.4 is .sup.18F and the compound of Formula 9 is a compound of Formula 9a, which comprises: i) reacting a compound of Formula 18 with a fluorinating reagent to generate a compound of Formula 22a; and ##STR00073## and ii) reducing the compound of Formula 22a to generate a compound of Formula 9a: ##STR00074## 7. The method of claim 1, wherein the chlorinating agent is selected from thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus pentachloride and phosphorus trichloride. 8. The method of claim 1, wherein the base in step ii) is sodium hydroxide, potassium hydroxide, lithium diisopropylamide, lithium tetramethylpiperidide, sodium tert-butoxide, potassium tert-butoxide or sodium-pentoxide. 9. The method of claim 8, wherein the base is sodium t-butoxide. 10. The method of claim 1, wherein the coupling agent in step iii) is N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (BOP reagent) benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N'N'-tetramethyluronium tetrafluoroborate (TBTU), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate (HBTU), O-[(ethoxycarbonyl)cyanomethylenamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), or (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeni- um hexafluorophosphate (COMU). 11. The method of claim 10, wherein the coupling agent is N,N'-diisopropylcarbodiimide. 12. The method of claim 1, wherein the base in step iv) is selected from sodium hydroxide, lithium hydroxide, caesium hydroxide, and potassium hydroxide. 13. The method of claim 12, wherein the base is sodium hydroxide. 14. The method of claim 1, wherein the halogenating agent is thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus pentachloride or phosphorus trichloride. 15. The method of claim 14, wherein the halogenating agent is thionyl chloride or oxalyl chloride. 16. The method of claim 1, wherein step vi) is carried out in the presence of a base. 17. The method of claim 16, wherein the base is potassium carbonate, sodium carbonate, sodium bicarbonate, triethyl amine (TEA), diisopropyl ethyl amine (DIPEA), pyridine, N,N-dimethylamino-4-pyridine (DMAP) or N-methylmorpholine (NMO). 18. The method of claim 16, wherein the base is diisopropyl ethyl amine. 19. The method of claim 2, wherein the fluorinating reagent is K[.sup.18F] bound to a cryptand, wherein cryptand is 1,10-diaza-4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (Kryptofix.RTM. 2.2.2. or Kryptofix 2.2.2 or Kryptofix 222). 20. The method of claim 2, wherein the reducing is carried out in the presence of a metal catalyst, an acid and hydrogen. 21. The method of claim 19, wherein the reducing is carried out in the presence of palladium, palladium black, platinum, rhodium, or nickel catalyst. FIELD OF THE INVENTION The present invention relates to a method of preparing Cabozantinib (Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylo]amide(4-fluoro-phenyl)amide) and .sup.18F-labeled Cabozantinib. BACKGROUND OF THE INVENTION Molecular imaging provides a non-invasive assessment of biological and biochemical processes in living subjects. The use of positron emission tomography (PET) has the potential to enhance the understanding of a potential drug during preclinical and clinical drug development. This information would be especially important in determining whether a potential drug reaches its target tissue in challenging environments such as glioblastoma multiforme (GBM) brain tumors. Cabozantinib (Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylo]amide(4-fluoro-phenyl)amide, (1) is a multitargeted kinase inhibitor with inhibitory activity against vascular endothelial growth factor receptor-2 (VEGFR-2) (IC.sub.50 of 0.035 nM), tyrosine kinase MET (IC.sub.50 of 1.3 nM), receptor tyrosine kinase encoded by rearranged during transfection (RET) proto-oncogene (IC.sub.50 4 nM), and c-KIT (stem-cell factor) (IC.sub.50 of -4.6 nM). ##STR00001## In cellular assays, Cabozantinib inhibits phosphorylation of receptors VEGFR-2, RET, and MET, as well as c-KIT, with IC.sub.50 values of 1.9, 7.8, 5.0, and 42 nM, respectively. Cabozantinib inhibits MET and VEGFR-2 phosphorylation in tumor models in vivo and demonstrates potent antimetastatic, antitumor, and antiangiogenic activity in preclinical models. The vascular endothelial growth factor (VEGF) and the hepatocyte growth factor (HGF) are potent mediators of angiogenesis. Angiogenesis is the formation of new blood vessels and is one of the key requirements of tumor growth during cancer progression. Recent studies suggest that activation of VEGF through the VEFGR-2 and the HGF receptor kinase MET, play synergistic roles in tumor progression. In 2012, the FDA approved Cabozantinib as the L-malate salt (COMETRIQ.RTM., Exelixis, Inc.) for the treatment of patients with progressive metastatic medullary thyroid cancer (MTC) and is currently being evaluated in patients with glioblastoma multiforme. Over expression of MET and VEGFR-2 have shown to correlate with poor prognosis in GBM, one of the most common and aggressive brain tumors. The synthesis of Cabozantinib (1) has been previously described in International Patent Application publication No. WO 2005/030140 filed Sep. 9, 2004, the contents of which are incorporated herein by reference in its entirety. There remains a need for new processes for synthesizing Cabozantinib and isotopically labeled Cabozantinib, [.sup.18F]-Cabozantinib, in a minimum number of steps and concomitant high yields. SUMMARY OF THE INVENTION These and other needs are met by the present invention which is directed to a method for synthesizing Cabozantinib by incorporating the fluoroaniline moiety as the last step of the synthesis. In some embodiments, 1-(4-(6,7-dimethoxyquinolin-3-yloxy)phenylcarbamoyl)cyclopropanecarboxyli- c acid is coupled with 4-fluoroaniline or [.sup.18]-fluoroaniline. Thus, in one aspect, the present invention provides a method for generating a compound of Formula I: ##STR00002## or a pharmaceutically acceptable salt thereof, wherein each of R.sup.1 and R.sup.2 is independently alkoxy or haloalkoxy; R.sup.3 is H, F, Cl, I or Br; and R.sup.4 is F, .sup.18F, Cl, I or Br; comprising: i) reacting a compound of Formula 8 with a compound of Formula 9 in the presence of a coupling reagent to generate a compound of Formula I: ##STR00003## In some implementations, the coupling reagent is selected from the group consisting of N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (BOP reagent), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N'N'-tetramethyluronium tetrafluoroborate (TBTU), N,N,N',N'-Tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate (HBTU), O-[(ethoxycarbonyl)cyanomethylenamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), and (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeni- um hexafluorophosphate (COMU) or a combination thereof. Another aspect of the present invention provides a method for generating a compound of Formula I or a pharmaceutically acceptable salt thereof wherein each of R.sup.1 and R.sup.2 is independently alkoxy or haloalkoxy; R.sup.3 is H, F, Cl, I or Br; and R.sup.4 is F, .sup.18F, Cl, I or Br; comprising: i) reacting a compound of Formula 8 with a compound of Formula 9 in the presence of a coupling reagent and heating the reaction with microwave radiation to generate a compound of Formula I: ##STR00004## In some embodiments, heating the reaction during the coupling reaction using microwave radiation results in shorter reaction times compared to the coupling reaction without microwave heating. In some embodiments, microwave radiation can be applied to the coupling reaction in an amount ranging from about 10 watts to about 20 watts, thereby generating a higher yield of a compound of Formula I as compared to the yield of a compound of Formula I in the absence of microwave heating. Another aspect of the present invention provides a method for synthesizing a compound of Formula I, the method comprising: i) reacting a compound of Formula 8 with a halogenating agent to generate an acid halide compound of Formula 8a, followed by reacting the acid halide compound of Formula 8a with a compound of Formula 9 in the presence of a base to generate the compound of Formula I: ##STR00005## In some implementations, the base can include: potassium carbonate, sodium carbonate, sodium bicarbonate, triethyl amine (TEA), diisopropyl ethyl amine (DIPEA), pyridine, N,N-dimethylamino-4-pyridine (DMAP), and N-methylmorpholine (NMO), or combination thereof. In another aspect, the present invention provides a method for generating a compound of Formula 9a, wherein R.sup.4 is .sup.18F, the method comprising: i) reacting a compound of Formula 18 with a fluorinating reagent to generate a compound of Formula 22a: ##STR00006## and ii) reducing the compound of Formula 22a to generate a compound of Formula 9a: ##STR00007## In some implementations, the fluorinating reagent is K[.sup.18F] bound to a cryptand. In some embodiments, suitable cryptand compounds can include: 1,10-diaza-4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (Kryptofix.RTM. 2.2.2. or Kryptofix 2.2.2 or Kryptofix 222). In some implementations, an exemplary fluorinating reagent is Kryptofix 2.2.2/K.sup.18[F]. |
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