Initial Scale-Up and Process Improvements for the Preparation of a Lead Antibacterial Macrolone Compound

Abstract

Macrolones are a novel class of potent antimicrobial agents that consist of a macrolide scaffold to which a quinolone unit is tethered by various linkers to the 4′′-O-position of the cladinose sugar. In this paper is described a modified 13-step route to a lead compound in the series. Critical reaction steps in the medicinal chemistry route were modified for an initial scale-up process, and as a result, a synthetic procedure suitable for preparation of multihundred gram quantities of the final product, with 98% purity, has been developed. The new procedure does not require any purification by column chromatography for any of the reaction steps. The overall yield was increased from 5−8% in the medicinal chemistry route to 27% in the improved procedure.

Od vitamina do antibiotika – sjećanja jednog kemičara II. dio

“…s dva dušika u veznom lancu, 19 dok su se kasnije pokazali bolji s jednim ili više kisika. 20,21,22,23 S kolegama iz Verone smo objavili još neke zaostale rezultate.…”

“…Velik dio praktičnih savjeta u svezi s poboljšanjem uvjeta reakcija publiciran je u radu objavljenom u Organic Process Research and Development, koji je napisao Vlado Štimac, 21 glavni nositelj uspješnog uvećanja postupka na univerzalni kemijski reaktor obujma 5 litara.…”

An Efficient and Scalable Synthesis of Quinolone 006

“…Moreover, because many quinolone candidates have been tested in the clinic, the effective syntheses of these compounds has become the focus of process chemistry initiatives. [1][2][3][4][5] While crystallization from solution is an established technique for the separation and purification of organic compounds, challenges arising from the complex interactions of variables including polymorphism, crystal nucleation and growth, and impurity profile are common. 6) For drug substances, understanding and controlling the polymorphism, particle size, morphology, and crystal habit have become fundamental steps in pharmaceutical development programs.…”

Synthesis and Antibacterial Evaluation of a Series of 11,12-Cyclic Carbonate Azithromycin-3-O-descladinosyl-3-O-carbamoyl Glycosyl Derivatives

“…Additionally, 9a- N substituted 15-membered azalides with amide and amine functionalities also had marked advantages over azithromycin in terms of high selectivity for the bacteria and moderate oral bioavailability in vivo [ 9 , 14 , 15 , 16 ]. Besides, with intensive research of azithromycin, a novel modified measure of the 4″-position of the cladinose was potent against emergence of drug resistance [ 17 , 18 , 19 , 20 , 21 ]. To resolve these therapeutic problems of tolerance, we investigated and found that the 3- O -acylerythromycin derivatives, which were named ‘acylides’, not only recovered the abolished antibacterial activity but also enhanced pharmacological activity against resistant pathogens [ 22 ].…”