Preparation of a quinolinyloxydiphenylcyclopropanedicarboxamide

1. A method comprising contacting a compound of formula I:

with a compound of formula II:

under such conditions to form a compound of formula III:

wherein the compound of formula I and compound of formula II are contacted in the presence of a base, a palladium catalyst a phosphine ligand, and a suitable solvent.

2. The method of claim 1 wherein the base is Na 2 CO 3 , K 2 CO 3 , K 3 PO 4 or potassium tert-butoxide; the palladium catalyst is Pd(OAc) 2 ; and the ligand is 1′-(di-tert-butylphosphino)-1,2,3,4,5-pentaphenylferrocene; 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino) ferrocene; 2-di-tert-butylphosphino-2′-(N,N-dimethylamino)biphenyl; di -tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine; racemic 2-[di(tert-butyl)phosphino]-1,1′-binaphthyl; 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl; 2-(di-tent-butylphosphino)-1-phenylindole; N-2-methoxyphenyl-2-di-tert-butylphosphino pyrrole; 1-phenyl-2-(di-tent-butyl-phosphino)-1H-pyrrole; 2-(di-t-butylphosphino) -2′-methylbiphenyl; 2-(di-tert-butylphosphino)biphenyl; or a combination thereof; and the solvent is toluene, NMP, DMPU, anisole, a combination of toluene and NMP, or a combination of toluene and DMPU.

3. The method claim 1 wherein the phosphine ligand is racemic-2-(di-tent-butylphosphino)-1,1′-binaphthyl.

4. The method claim 1 wherein the compound of formula I is prepared by contacting under suitable conditions a compound of formula IV:

with a p-aminophenol of formula V:

5. The method of claim 4 wherein the p-aminophenol is prepared by the reduction of a p-nitrophenol of formula VII:

6. The method of claim 5 wherein the reduction of the compound of formula VII is carried out in the presence of a Pd/C catalyst or a Pt/V catalyst.

7. A method comprising:

a) reducing 2-fluoro-4-nitrophenol to form 4-amino-2-fluorophenol;

b) contacting 1- {[(4-fluorophenyl)amino]carbonyl}cyclopropanecarbonyl chloride with 4-amino-2-fluorophenol in the presence of a base to form N 1 -(3-fluoro-4-hydroxyphenyl)-N 1 -(4-fluorophenyl)-1,1-cyclopropanedicarboxamide; and

c) contacting N 1 -(3-fluoro-4-hydroxyphenyl)-N 1 -(4-fluorophenyl)-1,1-cyclopropanedicarboxamide with a compound of formula IIa:

under such conditions to form N 1 -{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-morpholinyl)propyl]oxy}-4-quinolinyl)oxy]phenyl}-N 1 -(4-fluorophenyl)-1,1-cyclopropanedicarboxamide; wherein X is a leaving group.

8. The method of claim 7 wherein in step (a) the 2-fluoro-4-nitrophenol is reduced in the presence of a Pd/C catalyst.

9. The method of claim 7 wherein in step (a) the 2-fluoro-4-nitrophenol is reduced in the presence of a Pt/V catalyst.

10. The method of claim 7 wherein in step (c) N 1 -(3-fluoro-4-hydroxyphenyl) -N 1 -(4-fluorophenyl)-1,1-cyclopropanedicarboxamide is contacted with the compound of formula IIa in the presence of a base and a Pd catalyst.

11. The method of claim 7 wherein X is Cl.