1-Butanol → Mono-2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl)piperazinium-1-yl]ethoxy)ethanol trans-butenedioate

Participants

Reaction Steps

A 2 liter round bottom flask equipped with stirring rod, thermo pocket, reflux condenser and nitrogen inlet was charged with 50 gm (0.2 moles) of 11-chlorodibenzo[b,f][1,4]-thiazepine and 500 cc n-butanol and the mixture was stirred for 15 min. at room temperature. The resulting solution was combined with 39 gm (0.22 mole) of 1-(2-hydroxyethoxy)ethylpiperazine, 56.2 gm (0.40 mole) of potassium carbonate and 16.89 gm (0.10 mole) of potassium iodide. The reaction mixture was heated at gentle reflux for 12 hrs and a sample of the reaction mixture was analyzed by HPLC. The analysis revealed that starting material remains less than 1%. The reaction mixture was cooled to room temperature and treated with 1000 cc 1N hydrochloric acid solution to get a pH in between 1 to 2. The layers (aqueous and nonaqueous reaction solvent) were separated and the aqueous layer was extracted with 500 cc toluene and pH was adjusted to about 8 to 9 by addition of sodium carbonate. The layer s were separated and aqueous layer was again extracted with 500 cc toluene. The organic layers (n-butanol and toluene) were combined and washed with 2×500 cc of water. The solvent was distilled under vacuum at 70 to 80° C. to obtain an oil. To this oil 50 to 75 cc. toluene was added with 750 to 1000 cc absolute ethanol and activated carbon 5 to 6 gm, and heated to reflux for 90 min. The mixture was cooled to 55 to 60° C. and filtered. The filtrate was further cooled to 25 to 30° C. and fumaric acid 7 to 7.5 gm was added with stirring. The mixture was heated to reflux for 120 min, cooled slowly to 25 to 30° C., maintained for 120 min, filtered, and washed with 125 to 150 cc. of absolute ethanol. The wet material obtained was dried under vacuum at 50 to 60° C. to produce quetiapine fumarate (40 to 45 gm).

Provenance & Evidence