Exploratory Process Development and Kilogram-Scale Synthesis of a Novel Oxazolidinone Antibacterial Candidate

Abstract

A concise, environmentally benign, and cost-effective route was developed for the large-scale preparation of 1, a novel oxazolidinone antibacterial candidate. The key intermediate 2-(1-(2-fluoro-4-nitrophenyl)-1H-pyrazol-4-yl)­pyridine 7 was prepared with high purity by mild deamination of the regioisomeric mixture 21. The mixture was prepared from a nucleophilic SNAr reaction by selective C–N coupling of the secondary amine functionality of 4-(pyridin-2-yl)-1H-pyrazol-3-amine 14 with 1,2-difluoro-4-nitrobenzene 10 in optimized conditions with the primary amine group remaining intact. The gaseous nitrogen release rate and reaction mixture temperature of the deamination step can be well controlled by altering the feeding manner, thereby providing safety guarantees. The optimized synthetic strategy of 1 with an overall yield of 27.6%, including seven sequential transformations by only five solid–liquid isolations, significantly improved the product separation workup. The strategy bypassed time-consuming and laborious procedures for any intermediate involved as well as for the final API. This study presents a process enabling the rapid delivery of a multikilogram quantity of API with high purity.

Discovery of a Teraryl Oxazolidinone Compound (S)-N-((3-(3-Fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide Phosphate as a Novel Antimicrobial Agent with Enhanced Safety Profile and Efficacies

“…were prepared in high yield as previously described 20 . Sandmeyer condition was used to introduce halogen atom to the pyrazoyl ring and produce chlorinated 36b 28 or brominated 36c 29 , whereas fluoroaromatic 36a was obtained through Balz-Schiemann reaction 30 .…”

“…Then, the nitro derivatives 15 were reduced with ion powder and NH 4 Cl complex in ethanol and then reacted with benzyl chloroformate to yield compound 16. According to a general in-house method, 20 After obtaining the most potent compound 10f, further attempts of structural refinement were carried out to seek more potent compounds. First, several malonaldehyde compounds were obtained using amide formation reaction 21 or esterification, 22 in which 5-carboxylpyridin-2-yl malonaldehyde was used as starting material (Scheme 4).…”

Deep eutectic solvent as solvent and catalyst: one-pot synthesis of 1,3-dinitropropanesviatandem Henry reaction/Michael addition

“…27 They have been also used as key building blocks for biologically active substances including a novel oxazolidinone antibacterial candidate. 28 Several examples for the synthesis of 1,3dinitroalkanes have been described in the literature. The conventional synthesis of 1,3-dinitroalkanes is performed in basic condition through the Michael addition of nitroalkanes to nitroolefins under basic catalysis, usually affording the products 30 KF-NaHCO3, 31 silica-alumina supported amines.…”

Synthesis and in vitro antibacterial activity of novel fluoroalkyl-substituted pyrazolyl oxazolidinones

“…5 However, bacterial resistance to linezolid has been found recently in Grampositive bacteria Staphylococcus aureus and Enterococcus faecium. [7][8][9][10][11] These studies have focused mainly on the modification of Aring (oxazolidinone), B-ring (phenyl), C-ring (morpholine), and the C-5 side chain on the A-ring substructure of linezolid. [7][8][9][10][11] These studies have focused mainly on the modification of Aring (oxazolidinone), B-ring (phenyl), C-ring (morpholine), and the C-5 side chain on the A-ring substructure of linezolid.…”

“…6 Hence, numerous researches on the synthesis and bioassay of various oxazolidinones have been developed. [7][8][9][10][11] These studies have focused mainly on the modication of Aring (oxazolidinone), B-ring (phenyl), C-ring (morpholine), and the C-5 side chain on the A-ring substructure of linezolid. Among them, series of oxazolidinones containing nitrogen heterocyclic structures as C-ring unit were reported and some analogues have good activity comparable or superior to linezolid against Gram-positive bacterial pathogens (Fig.…”