Method of Preparing Fluorine-18 Labeled Cabozantinib and Its Analogs

1 . A method for preparing a compound of Formula I:

or pharmaceutically acceptable salt thereof wherein:

each of R 1 and R 2 is independently alkoxy or haloalkoxy;

R 3 is H, F, Cl, I, or Br; and

R 4 is F, 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 a tertiary amine base and an aprotic polar solvent to generate a compound of Formula I

2 . The method of claim 1 , wherein 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-carbenium hexafluorophosphate (COMU), or a combination thereof.

3 . The method of claim 2 , wherein the coupling reagent is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP).

4 . The method of claim 3 , wherein the tertiary amine base is selected from the group consisting of diisopropylethyl amine (DIPEA), triethyl amine (TEA), N-methyl imidazole, pyridine, 4-(dimethylamino)pyridine (DMAP), 3,4-lutidine, 4-methoxypyridine, N-methylmorpholine (NMO), 1,4-diazabicycle[2.2.2]octane (DABCO), and 1,8-diazacycloundec-7-ene (DBU), or a combination thereof.

5 . (canceled)

6 . The method of claim 1 , wherein the tertiary amine base is diisopropylethyl amine (DIPEA).

7 . The method of claim 1 , wherein the aprotic polar solvent is selected from the group consisting of acetonitrile, diethyl ether, diisopropyl ether, 2-methoxyethyl ether, 1,2-dimethoxyethane, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, α,α,α-trifluorotolune, cyclohexane, methylcyclohexane carbon tetrachloride, methylene chloride, N,N-dimethylformamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone or a combination thereof.

8 . (canceled)

9 . The method of claim 7 , wherein the aprotic solvent is N,N-dimethylformamide, dimethyl sulfoxide or a combination thereof.

10 . The method of claim 9 , wherein the reaction is heated with about 10 Watts to about 50 Watts of microwave radiation.

11 . (canceled)

12 . The method of claim 10 , wherein the reaction is heated with about 10 Watts to about 20 Watts of microwave radiation.

13 . The method of claim 12 , wherein the reaction is heated to about 20° C. to about 100° C.

14 . The method of claim 13 , wherein the reaction is heated to about 85° C.

15 . A method for preparing a compound of Formula I:

or pharmaceutically acceptable salt thereof wherein:

each of R 1 and R 2 is independently alkoxy or haloalkoxy;

R 3 is H, F, Cl, Br, or I; and

R 4 is F, Cl, Br, or I;

comprising:

i) reacting the compound of Formula 8 with a chlorinating or brominating agent and a base to generate compound of Formula 8a, wherein X is chloro or bromo:

and

ii) reacting the compound of Formula 8a with a compound of Formula 9 in the presence of a base to generate the compound of Formula I:

16 . The method of claim 15 , wherein the chlorinating or brominating agent comprises thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus pentachloride or phosphorus trichloride.

17 . The method of claim 16 , wherein the chlorinating agent is oxalyl chloride.

18 . The method of claim 17 , wherein the base is selected from the group consisting of 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 a combination thereof.

19 . (canceled)

20 . The method of claim 18 , wherein the base is potassium carbonate.

21 . The method of claim 20 , wherein the reaction is maintained at a temperature ranging from about 20° C. to about 40° C.

22 . The method of claim 21 , wherein the reaction is maintained at a temperature ranging from about 20° C. to about 25° C.

23 - 42 . (canceled)

43 . A method for preparing a compound of Formula 1a:

or pharmaceutically salt thereof wherein:

R 4 is F;

the method comprising:

i) reacting a compound of Formula 10 with a chlorinating agent to generate a compound of Formula 11:

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:

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:

iv) saponifying the compound of Formula 14 in the presence of a base to generate a compound of Formula 15:

v) reacting the compound of Formula 15 with a halogenating reagent to generate a compound of Formula 15a:

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:

44 . (canceled)