27367-90-4

Nopron,Carrion,France,1976

Niaprazine comprises norepinephrine reuptake inhibitors (NRIs), non-myorelaxing hypnotic agents and 5-HT2A inverse agonists or antagonists for treating sleep apnea.

ChEBI: Niaprazine is a member of piperazines.

1st Stage: 10 ml of concentrated (10 N) hydrochloric acid and 240 ml of acetone were added to a solution of 217.5 g (1 mol) of 1-(4- fluorophenyl)piperazine dihydrochloride in 400 ml of 96% ethanol. 50 g of powdered trioxymethylene were then added and the mixture was then slowly heated to reflux, which was maintained for 1 hour. A further 60 g of trioxymethylene were then added and heating to reflux was continued for a further 6 hours.
The mixture was then cooled, the precipitate formed was filtered off, washed with acetone and recrystallized from 96% ethanol.
The base was liberated from its salt by taking up the product in an aqueous solution of sodium bicarbonate. The precipitate of the base thus obtained was recrystallized from petroleum ether to give 160 g of the desired product; melting point 46°C; yield 64%.
2nd Stage: 45.5 g (0.65 mol) of hydroxylamine hydrochloride were added to a solution of 128 g (0.5 mol) of the amino-ketone obtained in the preceding stage in 100 ml of ethanol and 40 ml of water. The mixture was allowed to react for 15 minutes at room temperature and was then heated to reflux for ? hour. A part of the solvent was then distilled off and the product was then allowed to crystallize on cooling. After recrystallization from 96% ethanol, 117 g of the desired product were obtained; melting point 170°C; yield 77%.
3rd Stage: 93 g (0.35 mol) of the oxime obtained in the preceding stage, in the form of the base, were added in portions to a suspension of 17 g (0.45 mol) of lithium aluminum hydride in 400 ml of anhydrous ether. The mixture was then heated to reflux for 15 hours.
10 ml of ethyl acetate and then 50 ml of dilute caustic soda were added slowly with the usual precautions to the mixture. The organic phase was separated, dried over anhydrous Na2SO4, the solvent was distilled off and the residue obtained was distilled under reduced pressure to give 51 g of a thick oil; boiling point (2 mm Hg), 142°C to 143°C; yield 58%.
4th Stage: 10 ml of triethylamine were added in a solution of 25.2 g (0.1 mol) of the amine obtained in the preceding stage in 100 ml of anhydrous chloroform and the mixture was cooled to 2°C to 3°C. While maintaining this temperature, 17 g (0.12 mol) of nicotinic acid chloride were added with vigorous agitation.
After evaporation of the solvent, the residue was washed with water, the product taking the form of a mass. After recrystallization from ethyl acetate, a constant melting point of 131°C was obtained.

Antihistaminic

Store at -20°C