Practical Synthesis of 2-Pyridone Core: Ethyl 8-Chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizinone-3-carboxylate

A practical synthesis of the fluoropyridone core (2), an important intermediate to ABT-719 and other 2-pyridones, from the commercially available 3-chlorotetrafluoropyridine in 10 to 11 linear transformations with 10.26% overall yield is described.2-pyridonesl are a class of newly discovered and potent broad-spectrum antibacterial agents which exert their activity by inhibiting bacterial DNA gyrase.ABT-719 (1)' is the first compound of this class which is, among other things, efficacious against resistant organisms such as methicillin-resistant Staphylococcus aurew (MRSA) and vancomycin-resistant enterococci (VRE).Interest in this area has been increasing rapidly2 due to the alarming frequency of bacterial resistance.'One very impoltant intermediate to ABT-719 and other fluoropyridones is the fluoropyridone core (2).Our original 13 step approach to 2 was cost prohibitive, and involved procedures such as hydrazination, thermal cyclization in Dowtherm A, and multiple chromatography steps, making the approach impractical for large scale synthesis.Therefore, there was a need for a more practical and efficient preparation of 2. We describe here a concise and practical synthesis of ethyl 8-chloro-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-cboxyate (2).The synthesis of 2 is illustrated in Scheme 1. Commercially available regioisomerically impure 3chlorotetrafluoropyridine (3) (70% pure, the remainder is 4-chlorotetrafluoropyridine)3 was reacted with