catalyzed with 4-bromopropiophenone the side chain ketone N-arylation intermediate was formed in 30 62 % yields.52, 53 Final cyclisation with oxazoline gave 31 – quinolones 32a-g in 35 57% yields. – Scheme 7. Synthesis of quinolones 32a-g.a Conditions and reagents: (a) EtMgBr, THF, 0 oC, 1h; (b) PCC, DCM, r.t., 2h; (c) 5mol% CuI, a 20mol% trans-N,N’-Dimethyl-1,2cyclohexanediamine, K3PO4, Toluene, 110oC, 24 h; (d) CF3SO3H, N2, 130 oC, 24 h. n-BuOH, 5. Yields for the Synthesis of Compounds 32a-g. Compound X Y R % 31 % yield 32 32a 5-F,7-F - 38 55 32b 5-F,7-F - 30 57 5-F,7-F - 46 35 32c 32d 5-F 62 32 - 32e 5-F,7-F - 62 30 32f 5-F,7-F 49 39 m-Cl 32g 5-F,7-F 52 39 o-F Using fluorine to block metabolism and improve oral absorptions was further explored. Research by Smith has shown that gem-difluorinated piperidine compounds exhibited a significant improvement in metabolic stability.54 This led to the design and synthesis of fluorinated quinolones 38a-f as well as the alcohol side chain quinolones 38g-i. The chemistry used in the synthesis of these compounds is shown in Scheme 8.
catalyzed N-arylation with 4-bromopropiophenone the side chain ketone intermediate 31 was formed in 30 – 62 % yields.52, 53 Final cyclisation with oxazoline gave quinolones 32a-g in 35 – 57% yields. Scheme 7. Synthesis of quinolones 32a-g.a a Conditions and reagents: (a) EtMgBr, THF, 0 oC, 1h; (b) PCC, DCM, r.t., 2h; (c) 5mol% CuI, 20mol% trans-N,N’-Dimethyl-1,2cyclohexanediamine, K3PO4, Toluene, 110oC, 24 h; (d) CF3SO3H, n-BuOH, N2, 130 oC, 24 h. 5. Yields for the Synthesis of Compounds 32a-g. Compound X Y R % 31 % yield 32 32a 5-F,7-F - 38 55 32b 5-F,7-F - 30 57 32c 5-F,7-F - 46 35 32d 5-F - 62 32 32e 5-F,7-F - 62 30 32f 5-F,7-F m-Cl 49 39 32g 5-F,7-F o-F 52 39 Using fluorine to block metabolism and improve oral absorptions was further explored. Research by Smith has shown that gem-difluorinated piperidine compounds exhibited a significant improvement in metabolic stability.54 This led to the design and synthesis of fluorinated quinolones 38a-f as well as the alcohol side chain quinolones 38g-i. The chemistry used in the synthesis of these compounds is shown in Scheme 8.
Quinolone%20J%20Med%20Chem%20-%20TB%20-%20final%20-%20revised.docx