Development of an Efficient Synthesis of the Pyrrolquinolone PHA-529311

Abstract

An efficient synthesis of N-(4-chlorobenzyl)-2-(2-hydroxyethyl)-8-(morpholin-4-ylmethyl)-6-oxo-6H-pyrrol[3.2.1-ij]quinoline-5carboxamide (5) was developed. The route was chosen due to its reasonable length (seven steps), solubility of intermediates, and capabilities of the pilot and production facilities. The critical transformations in this route were the selective iodination of an aniline, formation of the quinolone, and Sonogashira coupling/pyrrole formation. In addition, removal of residual palladium and copper from the penultimate and final products, which was of lower concern during the discovery phase of development, became a difficult process chemistry issue on scale-up.

The methods of synthesis, modification, and biological activity of 4-quinolones (review)

“…The cyclization of the enamines 16 is realized by the action of heat in high-boiling solvents such as biphenyl [44], biphenyl ether [1, 26,32,34,36,37,41,42,[45][46][47], Dowtherm A [35,38,39,48,49], and mineral oil [1] or by using effective cyclization agents such as polyphosphoric acid or its esters [1, 2], the halogen derivatives of phosphorus [1], ZnCl 2 [1], conc. sulfuric acid in mixture with acetic anhydride [1], and Eaton's reagent (a mixture of phosphorus(V) oxide and methanesulfonic acid) [37,40].…”

“…sulfuric acid in mixture with acetic anhydride [1], and Eaton's reagent (a mixture of phosphorus(V) oxide and methanesulfonic acid) [37,40]. With the latter it is possible to reduce the cyclization temperature from 140°C (if polyphosphoric acid is used as cyclization agent) to 50°C (!)…”

“…In addition, active researches have been carried out on other types of biological activity in 4-quinolones. The following types of activity have been observed in a series of papers: Antiviral with respect to hepatitis B, C, and HIV viruses [3,4,24] and herpes viruses [3,37], antiallergic [3], antimalarial [68,109], antitubercular [36,39,110], immunomodulating [38], antihypoxic [25], antidiabetic [46]. 4-Quinolones have antithrombocytic [111] and positive cardiotonic activity [24].…”

“…The analogous reaction of 3-ethoxycarbonyl-4-oxo-1,4-dihydroquinolines with 4-chlorobenzylamine can take place in ethylene glycol [37]. The "retro-amides" 54a (R 2 = NHCOR 3 ) were obtained from the acids 53 by the Curtius reaction in the presence of diphenylphosphoryl azide (DPPA).…”

Separation of Reaction Product and Palladium Catalyst after a Heck Coupling Reaction by means of Organic Solvent Nanofiltration

“…To accomplish an acceptable residual Pd level, [8] classical purification methods often call for repeated purification cycles or a combination of several methods. When several purification cycles or steps are needed, the operating cost of the overall process increases at the same time as the throughput and yield decreases.…”