Manufacturing Process
The reaction is performed under dry conditions. 2.1 g of lithium aluminum
hydride and 50 ml of dry tetrahydrofuran are placed in a flask. Then 13.2 g of
cinnamaldehyde in 50 ml of dry tetrahydrofuran are added while stirring and
keeping the temperature at 25°-35°C. The stirring is continued for another 30
min at room temperature. Then 26.9 g of 4-[2-(N,N-dimethylamino)-
ethoxy]benzophenone in 70 ml of dry tetrahydrofuran are added while
stirring. The temperature is kept at 35°-45°C during the addition. After
stirring for 2 h at 40°C the reaction mixture is poured into 150 ml of 25%
ammonium chloride solution, and aluminium hydroxide is precipitated and
filtered off. The filtrate is transferred to a separating funnel and the organic
layer is separated. The aqueous layer is once again extracted with 60 ml of
ethyl acetate. The organic layers are combined and dried over sodium sulfate.
The solvent is evaporated. The residue is recrystallized from toluene. The yield
is 27.5 g (68%) of 1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]-
butane-1,4-diol.
The reaction is performed under dry conditions. 40.5 g 1,2-diphenyl-1-[4-[2-
(N,N-dimethylamino)ethoxy]phenyl]butane-1,4-diol and 150 ml of acetic acid
anhydride are placed in a flask. The temperature is raised to 90°C, where it is
kept until the primary OH-group is completely acetylated. [4-Acetoxy-1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]butan-1-ol is obtained as
intermediate; melting point of the (RR, SS)-isomer pair is 97°-99°C. While
stirring the reaction mixture, 30 ml of acetyl chloride in 50 ml of acetic acid
anhydride are added at 90°C. The stirring is continued at this temperature for
2 h. The solvent is evaporated. Then 1 M sodium carbonate solution is added
in excess, after which the product is extracted in toluene. The solution is dried
over sodium sulfate, and the solvent is evaporated. The yield of the pure
isomer mixture (Z:E 2:1) of 4-acetoxy-1,2-diphenyl-1-[4-[2-(N,N_x0002_dimethylamino)ethoxy]-phenyl]-1-butene is quantitative.
The4-acetoxy-1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]-phenyl]-1-
butene are dissolved in 94% ethanol, after which water and 20% sodium
hydroxide solution are added. The mixture is refluxed for 1 h. The solution is
neutralized with 2 M hydrochloric acid, after wich the ethanol is evaporated.
Water is added into the residue. The product is extracted in ethyl acetate, the
ethyl acetate solution is dried and the solvent is avaporated. The product is
recrystallized from a mixture of water and methanol. The yield of the pure
mixture of the isomers (Z:E 2:1) of 1,2-diphenyl-1-[4-[2-(N,Ndimethylamino)ethoxy]phenyl]-1-buten-4-ol, melting point 93°-100°C, is
quantitative.
Isolation of the (Z)-isomer as a free base: the mixture of the isomers (Z:E
2:1) of 1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]-1-buten-4-ol
is recrystallized from toluene, and 15.9 g (41%) of the (Z)-isomer is obtained,
melting point 110°-112°C.
The reaction is performed under dry conditions. 42.4 g of (Z)-1,2-diphenyl-1-
[4-[2-(N,N-dimethylamino)ethoxy]phenyl]-1-buten-4-ol are dissolved in 250
ml of chloroform. Then 23.8 g of thionyl chloride are added dropwise. The
mixture is refluxed 3 h. The solvent is evaporated, after which the product is
recrystallized from ethyl acetate. The yield of the hydrochloride salt of 4-
chloro-1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]-phenyl]-1-butene
(Z) is 36.7 g (83%), melting point 194°-196°C.
The base can be liberated from the salt with 1 M sodium carbonate solution,
after which the base is extracted in toluene. The toluene solution is dried and
the solvent is evaporated. The free base, 4-chloro-1,2-diphenyl-1-[4-[2-(N,Ndimethylamino)ethoxy]-phenyl]-1-butene (Z), has melting point 108°-110°C
(from acetone).
In practice it is usually used as citrate salt (1:1).
