Chlorination at the 8-Position of a Functionalized Quinolone and the Synthesis of Quinolone Antibiotic ABT-492

Abstract

The total synthesis of quinolone antibiotic ABT-492 has been achieved in 67% yield over nine steps from 2,4,5-trifluorobenzoic acid. The highlights of this synthesis include a novel chemoselective chlorination at the 8-position of a highly elaborated quinolone core. In addition, a Lewis acid promoted cyclization reaction to form the quinolone heterocycle was developed which was incorporated into a one-pot, three-step cyclization/coupling/protection sequence that proceeds in 93% yield.

Synthetic Approaches to the New Drugs Approved During 2017

“…The synthesis of delafloxacin is similar to that of other fluoroquinolone antibiotics but is unique in that the introduction of the chlorine to the C8 position of the quinolone occurred at a later stage of the synthetic sequence. Many routes have been published in the patent literature, and the multikilogram route disclosed by Abbott is described in Scheme . Ketoester 8 (whose synthesis is described in Scheme ) was condensed with triethylorthoformate to give ethoxymethylene ester 9 .…”

New Synthesis of 7‐(3‐chloropropoxy)‐4‐hydroxy‐6‐methoxyquinoline‐3‐carbonitrile, a Key Intermediate to Bosutinib

“…Treated with 1 equiv of sodium cyanide (NaCN) in EtOH/DMSO solution at room temperature , compound 22 was transferred to the 3‐oxo‐3‐phenylpropanenitrile intermediate 23 in 86% yield after recrystallization from hexane/EtOAc. Compound 23 was condensed with trimethyl orthoformate (CH(OMe)3) in acetic anhydride (Ac 2 O) to give the intermediate 24 , which was then substituted by ammonia (NH 3 ) in MeOH to give the 3‐amino‐2‐benzoylacrylonitrile compound 25 in 82% yield . The intramolecular cyclization of 25 was carried out in K 2 CO 3 /DMF condition to afford 3 , which was purified by heating and stirring in 1/1 (vol/vol) EtOH/EtOAc to give the final compound 3 in 73% overall yield and 98.71% purity (HPLC).…”

Use of bacteria for rapid, pH-neutral, hydrolysis of the model hydrophobic carboxylic acid esterp-nitrophenyl picolinate

“…This method gives high yields but is incompatible with alkenes, alkynes and ketones because it reduces these functional groups. Similarly, sodium hydroxide in ethanol or isopropanol is used to hydrolyze pivalate and isobutyrate esters (Barnes et al 2006; Ogilvie and Iwacha 1973). However, these basic conditions are incompatible with certain substrates such as methyl-(S)-2-methyl butyrate which is susceptible to racemization, and ethyl β-hydroxyhydrocinnamate which is prone to dehydration.…”