Synthesis of Ketamine

1-Hydroxycyclopentyl-(o-chlorophenyl)-ketone N-methylimine

To the grignard reagent prepared from 119.0 g of cyclopentyl bromide and 19.4 g of magnesium is added 55.2 g of o-chlorobenzonitrile. The reaction mixture is stirred for three days and thereafter hydrolyzed in the usual manner. From the hydrolysis there is obtained o-chlorophenylcyclopentylketone, bp 96-97°C (0.3 mmHg). To 21.0 g of the ketone is added 10.0 g of bromine in 80 ml of CCl4. 1-bromocyclopentyl-(o-chlorophenyl)-ketone, bp 111-114°C (0.1 mmHg) is isolated in the usual manner. Since it is unstable, it must be used immediately. The bromoketone (29.0g) is dissolved in 50 ml of liquid methylamine freebase. After one hour, the excess liquid methylamine is allowed to evaporate. The organic residue is dissolved in pentane, and upon evaporation of the solvent, 1-hydroxy-cyclopentyl-(o-chlorophenyl)-ketone N-methylimine is isolated, mp 62°C.

2-Methylamino-2-(o-chlorophenyl)-cyclohexanone (Ketamine)

1-hydroxycyclopentyl-(o-chlorophenyl)-ketone N-methylimine (2.0 g) is dissolved in 15 ml of decalin and refluxed for 2.5 h. After evaporation of the decalin under reduced pressure, the residue is extracted with dilute hydrochloric acid, the solution treated with decolorizing charcoal, and the resulting acidic solution is made basic. The liberated product, 2-methylamino-2-(o-chlorophenyl)-cyclohexanone (Ketamine), after recrystallization from pentane-ether, has a mp of 92-93°C. The hydrochloride has a mp of 262-263°C.

Reference: C. L. Stevens, US Pat 3,254,124, and Goldenthalin, Toxical. Appl. Pharmacol. 18, 185 (1971).