Phosphorus oxychloride → HCID 118699719, compound

Participants

Reaction Steps

A slurry of 2,3,4,6-tetrahydrobenzo[c]-2,7-naphthyridin-5(1H)-one (43.1 g, 215 mmol) in POCl3 (260 mL) was vigorously stirred at reflux under nitrogen in a 2 L three-necked, round-bottomed flask equipped with a heating/cooling bath, mechanical stirrer, condenser, thermocouple, and nitrogen inlet. An aqueous base scrubber set-up was used to capture acidic exhaust gas. After 5 hours, the batch was homogeneous (indicating formation of the intermediate). Heating was continued for an additional 1 hour; then the mixture was allowed to slowly cool to ambient temperature and was stirred for 16 hours. When the starting material had been consumed, a 1 L addition funnel was fitted to the reaction flask, and the batch was cooled (ice-water) and carefully quenched by drop-wise addition of chilled water (˜1 L). The quench addition was completed in ˜6 hours. The resulting dark solution was stirred at ambient temperature for 18 hours. The batch was transferred to a 22 L round-bottomed flask equipped with a mechanical stirrer; the transfer was completed with water (13 L) to forestall salt precipitation that otherwise interferes with extraction. The pH was adjusted to 8.5-9 with aqueous 2 N sodium hydroxide (˜3.9 L). Product was extracted with 17% (v/v) tetrahydrofuran in 2-methyltetrahydrofuran (4×2 L). All organic layers were combined and washed with saturated aqueous sodium chloride (2×150 mL) and dried over anhydrous sodium sulfate (300 g). After removal of the drying agent, solvent was removed under reduced pressure at 35-40° C. The crude solid was swished with 10% (v/v) t-butyl methyl ether in diethyl ether (220 mL) for 1 hour (to remove BHT) and collected on a filter using the filtrate to complete the transfer. The filter cake was rinsed with 10% (v/v) t-butyl methyl ether in diethyl ether (40 mL) and diethyl ether (30 mL), and dried in a vacuum oven to constant weight. In this fashion the title compound was obtained as a light yellow solid of (41.6 g, 87% yield) of 96 A % purity by HPLC assay.

Provenance & Evidence