Synthesis of 4-(Aminomethyl)quinolin-2(1H)-ones

Key words

topisomerase IV inhibitor - DNA gyrase inhibitor - fluoroquinolones - Chan–Lam coupling - Suzuki coupling - Buchwald–Hartwig coupling

Significance

Compound O is one of a series of 4-(aminomethyl)quinolin-2(1H)-ones that inhibits bacterial DNA gyrase and topoisomerase IV, and displays potent activity against ciprofloxacin-resistant Gram-negative pathogens. Unfortunately, a number of in vitro safety issues were identified that, together with severe loss of antibacterial potency at pH 5.8, led to termination of the project.

Comment

Noteworthy steps in the synthesis of O are (1) the appendage of the cyclopropyl ring to the aniline via a Chan–Lam coupling; (2) construction of the quinolin-2(1H)-one core by base-mediated Claisen condensation (H → I); appendage of the aminomethyl group via Suzuki reaction (J → L); and Buchwald–Hartwig coupling of the pyrrolidine fragment M and enol triflate J.

Publication History

Article published online:
17 September 2020