Continuous-Flow Synthesis of Nitro-o-xylenes: Process Optimization, Impurity Study and Extension to Analogues.

An efficient continuous-flow nitration process of o-xylene at pilot scale was demonstrated. The effects of parameters such as temperature, ratio of H2SO4 to HNO3, H2SO4 concentration, flow rate, and residence time on the reaction were studied. Under the optimal conditions, the yield of products reached 94.1%, with a product throughput of 800 g/h. The main impurities of this continuous-flow nitration process were also studied in detail. Compared with batch process, phenolic impurity decreased from 2% to 0.1%, which enabled the omission of the alkaline solution washing step and thus reduced the wastewater emission. The method was also successfully applied to the nitrification of p-xylene, toluene, and chlorobenzene with good yields.

One-Pot Route from Halogenated Amides to Piperidines and Pyrrolidines.

Piperidine and pyrrolidine derivatives are important nitrogen heterocyclic structures with a wide range of biological activities. However, reported methods for their construction often face problems of requiring the use of expensive metal catalysts, highly toxic reaction reagents or hazardous reaction conditions. Herein, an efficient route from halogenated amides to piperidines and pyrrolidines was disclosed. In this method, amide activation, reduction of nitrile ions, and intramolecular nucleophilic substitution were integrated in a one-pot reaction. The reaction conditions were mild and no metal catalysts were used. The synthesis of a variety of N-substituted and some C-substituted piperidines and pyrrolidines became convenient, and good yields were obtained.

Development of a novel nitric oxide (NO) production inhibitor with potential therapeutic effect on chronic inflammation.

Inflammation is a complex biological response to stimuli. Activated macrophages induced excessively release of pro-inflammatory cytokines and mediators such as endogenous radical nitric oxide (NO) play a significant role in the progression of multiple inflammatory diseases. Both natural and synthetic chalcones possess a wide range of bioactivities. In this work, thirty-nine chalcones and three related compounds, including several novel ones, based on bioactive kava chalcones were designed, synthesized and their inhibitory effects on NO production in RAW 264.7 cells were evaluated. The novel compound (E)-1-(2'-hydroxy-4',6'-dimethoxyphenyl)-3-(3-methoxy-4-(3-morpholinopropoxy)phenyl)prop-2-en-1-one (53) exhibited a better inhibitory activity (84.0%) on NO production at 10 µM (IC50 = 6.4 µM) with the lowest cytotoxicity (IC50 > 80 µM) among the tested compounds. Besides, western blot analysis indicated that compound 53 was a potent down-regulator of inducible nitric oxide synthase (iNOS) protein. Docking study revealed that compound 53 also can dock into the active site of iNOS. Furthermore, at the dose of 10 mg/kg/day, compound 53 could both significantly suppress the progression of inflammation on collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) models. In addition, the structure-activity relationship (SAR) of the kava chalcones based analogs was also depicted.