Method of preparing fluorine-18 labeled Cabozantinib and its analogs

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

or pharmaceutically salt thereof wherein:

R 4 is 18 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:

2. The method of claim 1 , further comprising preparing a compound of Formula 9, wherein R 4 is 18 F 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

and

ii) reducing the compound of Formula 22a to generate a compound of Formula 9a:

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

or pharmaceutically salt thereof wherein:

R 4 is 18 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 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:

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:

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:

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

or pharmaceutically salt thereof wherein:

R 4 is 18 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 sodium hydroxide and a solvent to generate a compound of Formula 15, wherein the solvent is methanol, ethanol, isopropanol, water or a combination thereof:

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:

5. The method of claim 3 , further comprising preparing the compound of Formula 9 wherein R 4 is 18 F 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

and

ii) reducing the compound of Formula 22a to generate a compound of Formula 9a:

6. The method of claim 4 , further comprising preparing the compound of Formula 9 wherein R 4 is 18 F 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

and

ii) reducing the compound of Formula 22a to generate a compound of Formula 9a:

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-carbenium 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[ 18 F] 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® 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.