Synthesis of diphenhydramine hydrochloride

The reactor module was charged manually with magnesium grit and dried by heating to 150°C under a stream of argon for 15 min. After cooling to room temperature (~25°C), diethyl ether and 2 ml of bromobenzene were added to the magnesium, and the mixture was heated to reflux for 20 min. After cooling below 25°C, 8.65 ml of bromobenzene was added at a rate of 1 ml/min, and the mixture was again heated to reflux for 20 min. Subsequently, a solution of benzaldehyde in diethyl ether was added at 1 ml/min, and the mixture was held at reflux for 5 hours. After quenching of the reaction with dilute HCl, the layers were separated, and the organic layer was washed with water and evaporated to dryness, yielding crude diphenylmethanol. After automatic cleaning of the system, the reactor was charged with acetyl bromide, and the crude diphenylmethanol was transferred from the rotary evaporator to the reactor with three portions of toluene. The mixture was heated to reflux for 4 hours and subsequently evaporated to dryness, yielding crude bromodiphenylmethane. The system was automatically cleaned once more, the reactor was charged with 2-(dimethylamino)ethanol and 10 ml of toluene, and the bromodiphenylmethane was transferred to the reactor with three portions of toluene. The mixture was heated to reflux for 20 hours. After cooling below 30°C, the reaction was quenched with aqueous sodium hydroxide. The layers were separated, and the organic layer was extracted with 2 M aqueous hydrochloric acid three times. Equimolar aqueous sodium hydroxide was added to the combined aqueous layers, and the mixture was extracted with diethyl ether three times. The combined etheric layers were evaporated to dryness, yielding crude diphenhydramine free base. The jacketed filter module was then charged with etheric hydrochloric acid, and the crude free base was slowly transferred to the filter with three portions of diethyl ether. The precipitate formed was collected by filtration, dried under a stream of argon, and recrystallized from isopropanol, yielding pure diphenhydramine hydrochloride as white crystalline powder.