Phenol → HCID 66556492, compound

Participants

Reaction Steps

The first step involves the selective iodination of position 3 of the quinolone nucleus with iodine in the presence of n-butylamine in DMF to give 7-chloro-3-iodoquinolin-4-ol (B) according to the procedure of Hart (Hart, J Med Chem 49, 1101-1112 (2006) incorporated by reference herein), in approximately 59% yield. Without further purification, this material is converted cleanly to the corresponding 4,7-dichloro-3-iodoquinoline (C) in approximately 99% yield according to the procedure of Andersag (Andersag, Chem Ber 81, 499-507, (1948), incorporated by reference herein). The iodoquinoline is then treated in THF with potassium ethoxide in the presence of a catalytic amount of 18-crown-6 ether to give pure 7-chloro-4-ethoxy-3-iodoquinoline (D) in approximately 90% yield as shown, for example, by GC-MS and NMR. In the next step, Suzuki coupling conditions (Mphahlele, J Chem Res 2008, 437-440 (2008) incorporated by reference herein) may be used to react 4-(trifluoromethoxy)-phenyl)boronic acid with the iodoquinoline intermediate (D) in the presence of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) and 2M potassium carbonate in DMF. The reaction is allowed to proceed at 85° C. to give 7-chloro-4-ethoxy-3-(4-(trifluoromethoxy)phenyl)quinoline (E) in approximately 63% yield as white crystalline material after flash chromatography. Finally, the desired compound (Compound 1) is obtained by reacting the 4-ethoxy quinoline derivative (E) with N-tert-butyl propane 1,3 diamine in the presence of phenol according to the procedure of Andersag supra, in a Carius tube using 2 ethoxyethanol as a solvent at 180° C. for 4 days. The crude product is further purified by flash chromatography followed by crystallization in ethyl acetate to give Compound 1 as transparent white rectangular plates in approximately 59% yield.

Provenance & Evidence