Manufacturing Process
A solution of 4-chlorobenzyl cyanide and 1,3-dibromopropane in dry
dimethylsulfoxide was added dropwise under nitrogen to a stirred mixture of
sodium hydride dispersed in mineral oil and dimethylsulfoxide at a
temperature in the range 30° to 35°C. The mixture was stirred at room
temperature for 2 h and propan-2-ol and then water were added dropwise.
The mixture was filtered through a diatomaceous earth sold under the
Registered Trade Mark CELITE and the solid residue washed with ether. The
ether layer was separated, washed with water, dried and evaporated. 1-(4-
Chlorophenyl)-1-cyclobutanecarbonitrile was isolated by distillation.
1-(4-Chlorophenyl)-1-cyclobutanecarbonitrile (37.6 g) was added to a solution
of potassium hydroxide (32.4 g) in diethyleneglycol (370 ml) and the mixture
heated under reflux for three and a 0.5 h The reaction mixture was poured
into an ice/water mixture and the resulting solution was washed with ether.
The aqueous layer was added to a mixture of concentrated hydrochloric acid
(100 ml) and ice and the resulting precipitate of 1-(4-chlorophenyl)-1-
cyclobutanecarboxylic acid (melting point 86°-88°C) collected, washed with
water and dried.
1-(4-Chlorophenyl)-1-cyclobutane carboxylic acid (10.5 g) was heated under
reflux with thionyl chloride (20 ml) for 2.5 h. Excess thionyl chloride was
evaporated off and the acid chloride of the above acid distilled (boiling point
82°-96°C /0.2 mm Hg). A solution of the acid chloride in dry tetrahydrofuran
was added slowly to the product of the reaction of magnesium turnings and
ethyl bromide in dry tetrahydrofuran. Water was added followed by 5 N
hydrochloric acid with cooling. The reaction mixture was extracted with ether,
washed with water, sodium bicarbonate solution, dried. The solvent was
removed by evaporation and 1-isobutyl-1-(4-chlorophenyl)cyclobutane
obtained by distillation. The 1-isobutyl-1-(4-chlorophenyl)cyclobutane,
diethylene glycoldimethyl ether, water and concentrated hydrochloric acid
were mixed and heated under reflux. The mixture was poured into water
aqueous NaOH was added and the product extracted into ether. Evaporation
gave a dark oil. A sample of this oil, water and formic acid were mixed and
formaldehyde added. The mixture was heated under reflux and then
concentrated hydrochloric acid and propan-2-ol were added. Evaporation to dryness gave N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]isobutyl
hydrochloride as a white solid.
Biochem/physiol Actions
Sibutramine is a serotonin and noradrenaline reuptake inhibitor (SNRI). It is an antiobesity drug, which decreases calorie intake and increases energy expanditure. Sibutramine antagonizes MPTP-induced dopamine depletion in mouse brain.
