Manufacturing Process
A mixture of 6.6 parts of γ-chloro-4-fluorobutyrophenone and 12.5 parts of 1-
(2-methoxyphenyl)piperazine, heated for 10 hours at a temperature of 110°C.
The reaction mixture is treated with 800 parts of ether and fiItered. The ether
layer is washed with water, dried over anhydrous potassium carbonate and
filtered, whereupon hydrogen chloride gas is introduced into the solution. The
precipitate is collected on a filter and dissolved in a mixture of 240 parts of 2-
propanol and 80 parts of acetone to yield 1-[γ-(4-fluorobenzoyl)propyl]-4-(2-
methoxyphenyl)piperazine hydrochloride. This monohydrochloride is collected
on a filter and dissolved in 240 parts of 2-propanol. Anhydrous, gaseous
hydrogen chloride is passed through the solution. On cooling, the 1-[γ-(4-
fluorobenzoyl)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride
precipitates.
A second crop of product is obtained by passing hydrogen chloride gas
through the solution of mother liquors. The pale-brown, amorphous powder is
collected on a filter and found to melt at about 205°-205.5°C. This salt is
dissolved in water and treated with sodium hydroxide. The precipitated base is
recovered by filtration and recrystallized from diisopropylether. The white
crystals melt about 67.5°-68.5°C.
By dissolving 4 parts of 1-[γ-(4-fluorobenzoyl)propyl]-4-(2-methoxyphenyl)
piperazine dihydrochloride in 800 parts of water, rendering alkaline, extracting
with 400 parts of ether, drying over calcium chloride, filtering, and
evaporating the resulting solution, the free base of 1-[γ-(4-fluorobenzoyl)
propyl]-4-(2-methoxyphenyl)piperazine is obtained. This product is dissolved
in 120 parts of absolute ethanol and 0.03 part of sodium borohydride is added
portionwise at 35°C. After decomposition with 150 parts of 1 N hydrochloric
acid, the mixture is diluted with 500 parts of water, made alkaline with 4 N
sodium hydroxide, and further diluted to a volume of 1,000 parts. Upon
cooling for 4 hours at 0°C the precipitate formed is filtered, dried, and
recrystallized from diisopropyl ether to yield 1-(4-fluorophenyl)-4-[4-(2-
methoxyphenyl)piperazine]-1-butanol (anisopirol). The white granular powder
of this compound has a melting point of about 105°-106°C.
