Manufacturing Process
There are some means to produce aliflurane:
1). 2.2 g (0.01 mol) of (2-dimethylaminoethyl)cyclohexylketone hydrochloride
(produced by Mannich reaction from 1-acetyl-1-cyclohexene with
formaldehyde and dimethylamine hydrochloride and subsequent
hydrogenation with Pd/C as catalyst) and 1.5 g (0.01 mol) of 1-norephedrine
were dissolved in 20 ml of warm isopropanol. The product crystallizing out in
the cooling was filtered off with suction and recrystallized from ethanol. Yield
of desired 1-propanone, 1-cyclohexyl-3-((2-hydroxy-1-methyl-2-
phenylethyl)amino)-, (R-(R*,S*) hydrochloride 24%, M.P: 219-221°C.
2). 13.8 g (0.1 mol) of cyclohexylvinyl ketone (obtainable by the splitting off
of HCl during the distillation of cyclohexyl-β-chloroethyl ketone) and 15.1 g
(0.1 mol) of 1-norephedrine were dissolved in 50 ml of isopropanol. The
desired compound crystallized out as the free base in the standing overnight.
The hydrochloride was made with isopropanolic hydrochloric acid. M.P. of the
hydrochloride: 219-221°C.
3). The oily cyclohexyl-β-chloroethyl ketone obtained from a solution of 200 g
(1.36 mol) of cyclohexanecarboxylic acid chloride in 500 ml of dried 1,2-
dichloroethane by portion-wise addition of 182 g (1.3 mol) of AlCl3 at -5°C,
then leading ethylene through, subsequent hydrolysis with 500 ml of water at
room temperature and concentration of the organic phase dried with Na2SO4
in a vacuum (analogous to U.S. Pat. No. 2,792,406) was added to a solution
of 164 g (1.09 mol) of 1-norephedrine in 1000 ml of dioxane. The desired
product crystallized out overnight, was filtered off with suction and
recrystallized from ethanol/water 1:1 (by volume). Yield: 67% (based on the
cyclohexane carboxylic acid chloride). M.P. of the hydrochloride: 219-221°C.
