Method of Preparing Fluorine-18 Labeled Cabozantinib and Its Analogs

Abstract

The present invention relates to a method of preparing Cabozantinib (Cyclopropane-1,1-dicarboxylic acid [4-(6,7-di-methoxy-quinolin-4-vloxy)-phenyl]amide (4-fluoro-phenyl)amide) and 18 F labeled Cabozantinib.

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)