Synthesis of Eticyclidine

N-(cyclohexylidene)ethylamine [1]

A mixture const. of 100 g. anhydrous ethylamine and 220 g of cyclohexanone is allowed to stand for 16 hrs. Then the reaction mixture was shaken thoroughly with solid potassium hydroxide and the oil layer removed by decantation. Distillation of the oil layer in vacuo yields the desired N-cyclohexylidene ethyl amine;bp 68-75°C at 22 mmHg.

(1-phenylcyclohexyl)ethylamine (Eticyclidine) [1]

A soln of phenyllithium prepared from 11.2 g Li and 76 ml of PhBr in 500 ml of ether is added dropwise at 0C to a soln of 51 g of N-cyclohexylideneethylamine at 500 ml of ether. After the addition has been completed, the reaction mixture is stirred for one hour and then decomposed by addition of water. The ether layer was removed, washed with water and dried. The ether was evaporated and the residue distilled in vacuo to obtain the desired (1-phenylcyclohexyl)ethylamine; bp 104-108 (2.5 mm Hg).

The hydrochloride salt was prepared by dissolving the free base in excess of IPA soln hydrogen chloride, precipitating the salt with ether and recryst. the product obtained from ether-IPA mixture. mp 236-237°C.

Synthesis of Rolicyclidine

Cyclohexanone cyanhydrin [2]

A soln of 65 g (1mole) of KCN in 125 ml of water was added dropwise with stirring to a mixture of 94 ml (102 g, 1.00 mole) Ac2O and 52 ml (49 g, 0.50 mole) of cyclohexanone in 1 l flask fitted with a mech stirrer a dropping funnel and a reflux condensor. During the addition the system was cooled in ice-bath. Stirring was continued for 14 hrs ar RT, after which the reaction mixture was homogeneous. Saturated aqueous Na2CO3 was added until the mixture was alkaline to litmus. A red oil separated during this time, it was removed, and then water layer was extracted with three 50-ml portions of benzene. The extract and oil were combined, washed with three 50 ml portions of 30% soln NaHSO3, dried over MgSO4 and the benzene removed at 15 mm pressure. The resudue oil cryst. when a spot on the flask was cooled with dry ice. It was purified by rapid distillation at 91-95C (2mm) from a Claisen flask to yield 47.7g (76%) of colorless liquid, nd 1.4643, which crystallized on chilling, mp 35°C.

Note by Assholium: Don't do this foolish "rapid distillation" - this product readily decomposes back to HCN and cyclohexanone (if your distillation not fast enough!). Use crude orange-red cyanohydrin.

1-(1-pyrrolidino)cyclohexane carbonitrile [3]

A mixture consist. of 62,5 g of cyclohexanone cyanohydrin, 50 ml of pyrrolidine and 500 ml of benzene is subjected to azeotropic distillation until evolution of water ceases to be evolved. The mixture was subj. to distillation in vacuo to obtain the desired 1-(1-pirrolidino)cyclohexane carbonitrile; bp 96-98°C at 0.3 mmHg.

1-(1-phenylcyclohexyl)pyrrolidine (Rolicyclidine) [3]

A soln. of 19.2g of 1(1-pyrrolidino)cyclohexane carbonitrile in 100 ml of ether is added to 39g of PhMgBr in 80 ml of benzene and 200 ml of ether. Upon completion of the addition the mixture is heated under reflux for 3 hrs. The reaction mixture was cooled and decomposed with conc. ammonium hydroxide and saturated NH4Cl soln taking are not to precipitate the magnesium salts. The ether layer is separated and the aq. layer extracted with ether. The etheral extracts combined, dried and the ether removed by distillation. Dist. of the residue in vacuo yields the desired 1-(1-phenylcyclohexyl)pyrrolidine - bp 114-123°C at 0.14 mm. After recrystallization from isooctane product melts at 44-45°C, and the hydrochloride salt at 235-237°C.


[1] US Pat. 3,097,136 Process for producing depressant-like effect on the CNS
[2] JACS 71:3839 (1949)
[3] Heterocyclic amine compounds Brit. pat. 836,083