A Facile Two-Step Synthesis of 3-Fluoro-6-methoxyquinoline

Abstract

A facile two-step synthesis of 3-fluoro-6-methoxyquinoline is described. p-Anisidine was heated at reflux with 2-fluoromalonic acid in the presence of phosphorus oxychloride to produce 2,4-dichloro-3-fluoro-6-methoxyquinoline. This was followed by hydrogenolysis to produce 3-fluoro-6-methoxyquinoline.

Initial Route Scouting and Final Process Development for the Multi-Kg Production of 3-Fluoro-6-methoxyquinoline from p-Anisidine and 2-Fluoromalonic Acid

“…After double decarboxylation, the resulting fluoroketone 5 was envisioned to be converted into 1 via a series of formylation, nitro-reduction/cyclization, chlorination, and final hydrodechlorination. Finally, the construction of the quinoline core via condensation of p -anisidine ( 6 ) with 2-fluoromalonic acid ( 7 ) has been previously described (route C) . The attractiveness of this approach lies in its conciseness, as 1 can be synthesized in only two steps from the commercially available starting materials.…”

“…After the negative assessments of Route A and B, our attention shifted toward the development of the previously disclosed synthesis of 1 from p -anisidine ( 6 ) and 2-fluoromalonic acid ( 7 ) . The original process heated a mixture of 2-fluoromalonic acid ( 7 ) in POCl 3 (6 vol) to reflux and was held for 30 min.…”

“…To get a deeper understanding of chemistry, the process was reproduced on a laboratory scale and then on a 1 kg scale (Scheme ). The reactions behaved as described in the literature . There were three main observations: (1) an amide intermediate ( 9 ) was observed in the reaction mixture [aqueous quench for in-process control (IPC)].…”

“…Since the Raney nickel-catalyzed hydrogenolysis was very slow and the multiple additions of Raney nickel posed a severe safety hazard, it was decided to develop an improved hydrodechlorination system. Pd/C was reported to be effective in this reaction, but intermediate 8 had to be pretreated by stirring with 10% Pd/C (5% w/w) in MeOH to remove an unidentified catalyst poison . Therefore, it was decided to explore transfer hydrogenations since these conditions are often less sensitive to catalyst poisons (Table ).…”

Synthesis of 4-Halogenated 3-Fluoro-6-methoxyquinolines: Key Building Blocks for the Synthesis of Antibiotics

“…8f For both of these routes, only 1 g of final product was reported. However, a scalable route to 2,4-dichloro-3-fluoro-6-methoxyquinoline (5) was reported by Li and co-workers (Scheme 1), 9 and we envisioned that this compound would be a suitable starting material for the synthesis of 4-halogenated derivatives 6a and 6b. To facilitate downstream functionalization, we proposed that iodine could be introduced through regioselective hydrodechlorination at the 2-position of quinoline 5, 10,11 followed by substitution of chlorine with iodine at the 4-position.…”