(±)-7-[[(4-fluorophenyl)methyl]amino]-8-methylnonan-1-oic acid

Originator

Zafuleptine,ZYF Pharm Chemical

Manufacturing Process

295 g of cyclohexanone and 261 g of morpholine are dissolved in 800 ml of benzene. After the whole has been dissolved, 1.5 g of p-toluene sulfonic acid is added and the mixture is heated under reflux. The water formed is extracted continuously by azeotropic distillation. After 20 hours reflux, the remaining solvent is distilled off and the oily residue is recovered. 379 g of the enamine are so obtained, boiling at 115°C to 117°C/2mm. The yield amounts to 76%. The pure 1-morpholinocyclohex-1-ene has a refractive index of n D 22 =1.5122.
To solution of 16.7 g 1-morpholinocyclohex-1-ene in 45 ml chloroform, 10.1 g of triethylamine are added. Over a period of one hour a solution of 1 mole- equivalent of isobutyroyl chloride in 15 ml chloroform is added, with stirring. The mixture is stirred for two hours at room temperature and is thereafter heated at 60°C for 3 hours. It is kept aside for a night, then 150 ml hydrochloric acid are added. The mixture is shaken and is then allowed to settle. The chloroformic phase is discarded. The aqueous phase is partially neutralized with sodium carbonate until the pH value reaches 6 and is then extracted with chloroform three times. The organic phases are united, washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The crude residue is purified by distillation under reduced pressure to give 2- (isobutyroyl)cyclohexanone.
1 mole-equivalent of 2-(isobutyroyl)cyclohexanone is added to 70 ml of a 5% aqueous solution of sodium hydroxide. The mixture is heated under reflux for 2 hours. The aqueous solution is then made acidic with a 4 N solution of hydrochloric acid and is extracted with ether. The ethereous phase is separated, is washed with a saturated solution of sodium chloride, is dried on sodium sulfate, is filtered and is evaporated to dryness. The solid residue is left to stand at room temperature. The crystallization begins quickly. The crystals are recovered and are recrystallized from n-pentane to give 7-oxo-8- methylnonanoic acid.
A fresh solution of 1 mole-equivalent of p-fluorobenzylamine and 1 mole equivalent methylamine is added to a solution of 1 mole-equivalent 7-oxo-8- methylnonanoic acid in 20 ml ethanol. The mixture is warmed at 40°C for a night. 0.1 g of platinum oxide is then added and the mixture is hydrogenated under ordinary pressure at 40°C. After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off and the solvent is evaporated under reduced pressure. The oily residue crystallized quickly, at room temperature. The product is purified by recrystallizing it from ethyl acetate and is dried over phosphoric anhydride in a closed vessel. (+/-)-7-((p- Fluorobenzyl)amino)-8-methylnonanoic acid is a crystalline solid; MP: 88°- 89°C.

Therapeutic Function

Antidepressant