Manufacturing Process
Sodium Thioxanthene-2-Sulfonate: A solution of thioxanthene (32.2 grams,
0.160 mol) in 160 ml of chloroform was cooled to 0°C and chlorosulfonic acid
(12.4 ml, 0.190 mol) added as rapidly as possible while maintaining the
internal temperature below 10°C. After the addition was complete, the
reaction mixture was allowed to approach room temperature during 30
minutes, then refluxed for an additional 20 minutes. The deep red solution
was poured onto 100 grams of crushed ice and to convert the sulfonic acid to
its sodium salt there was added 20 grams of sodium chloride. After filtering
the slurry through a sintered glass funnel, the filter cake was washed with 50
ml of chloroform and 50 ml of 20% sodium chloride solution.
The crude sulfonate product was digested in 1,500 ml of boiling water, and
filtered at the boiling point. Crystallization was allowed to proceed overnight
at 4°C and after filtration and vacuum drying at 100°C, 33.3 grams (69%) of
glistening, colorless plates were obtained.
2-Dimethylsulfamylthioxanthene: To a slurry of dry sodium thioxanthene-2-
sulfonate (33.3 grams, 0.111 mol) in 50 ml of N,N-dimethylformamide was
added thionyl chloride (14.3 grams, 0.122 mol) in divided portions. An
exothermic reaction ensued with complete dissolution being effected in
minutes. Treatment of the reaction mixture with crushed ice precipitated a
gum which crystallized after a short period of stirring. The sulfonyl chloride
was filtered, washed with water, and stirred with 100 ml of liquid
dimethylamine. After allowing the mixture to evaporate to dryness, water was
added and the sulfonamide filtered, washed with water, and dried in vacuo.
The crude product (32.5 grams, 96%) obtained melts at 163.5° to 165°C.
One crystallization from ethanol chloroform yielded an analytical sample, MP
164.5 to 166.5°C.
9-Acetyl-2-Dimethylsulfamylthioxanthene: A suspension of 2-
dimethylsulfamylthioxanthene (12.22 grams, 0.04 mol) in 60 ml of dimethoxymethane is cooled to 0°C and 17.2 ml of a 2.91 M solution of nbutyl
lithium in heptane is added slowly in a nitrogen atmosphere while the
temperature is maintained below 10°C. After an additional 10 minutes of
stirring, the cooling bath is removed and a solution of 2.96 grams of methyl
acetate in 20 ml of dimethoxyethane is added during 1/2 hour and then the
mixture is stirred at 25°C for an additional 3 hours. The reaction mixture is
then treated with 60 ml of ethyl acetate and with 60 ml of a 10% aqueous
ammonium chloride solution. The layers are separated and the ethyl acetate
layer is washed once with water (25 ml) and then the solvent is removed by
distillation.
The product is purified by the method of Teitelbaum, J. Org. Chem., 23, 646
(1958). The gummy residue is treated with 7.8 grams of Girard's "T" reagent, a
commercially available (carboxymethyl) trimethylammonium chloride hydrazide
which can be prepared by the method described by Girard in Organic
Syntheses, collective volume II, page 85 (1943). 0.2 grams of a methacryliccarboxylic
cation exchange resin of 20 to 50 mesh particle size, such as
Amberlite IRC-50 (Rohm & Haas Co.) and 20 ml of ethanol. The mixture is
refluxed for 1 hour, then is cooled to 25°C, is diluted with 80 ml of water and is
filtered. The filtrate is stirred for 16 hours with 20 ml of aqueous formaldehyde
and the product precipitates as a white solid, MP 118° to 123°C, net 5.6 grams,
yield, 40% of the theoretical.
9-(3-Dimethylaminopropionyl)-2-Dimethylsulfamylthioxanthene: To a mixture
of 9-acetyl-2-dimethylsulfamylthioxanthene (54.1 grams, 0.155 mol), 100 ml
isopropanol, 10.6 grams paraformaldehyde and 16.4 grams (0.200 mol)
dimethylamine hydrochloride, is added 1.0 milliliter of concentrated
hydrochloric acid. The mixture is refluxed in a nitrogen atmosphere for 24
hours, then is concentrated to one-half volume by distillation of part of the
solvent in vacuo. The concentrate is treated with 60 ml of ethyl acetate then
the mixture is cooled to 5°C whereupon the crystalline product precipitates.
This is removed by filtration and, after drying, weighs 47.8 grams, and melts
at 177° to 181°C. After two crystallizations from isopropanol the product is
obtained as the monohydrochloride addition salt, MP 187° to 189°C.
9-[3-(4-Methyl-1-Piperazinyl)-1-Hydroxypropyl]-2-
Dimethylsulfamylthioxanthene: A mixture of 9-(3-dimethylaminopropionyl)-2-
dimethylsulfamylthioxanthene hydrochloride (17 grams, 0.039 mol) and 20.0
grams (0.2 mol) 1-methylpiperazine in 40 ml of isopropanol is refluxed in a
nitrogen atmosphere for 3 hours. 200 ml ethyl acetate is then added and the
mixture is washed twice with 100 ml of water, the organic layer is separated
and dried with anhydrous sodium sulfate, then the solvent is removed by
distillation in vacuo. The 9-[3-(4-methyl-1-piperazinyl)propionyl]-2-
dimethylsulfamylthioxanthene which remains as a residue is treated with a
solution of 3.03 grams (0.08 mol) of sodium borohydride in 100 ml of ethanol.
The mixture is refluxed under nitrogen for 3 hours, is cooled and is treated
with an equal volume of water. The aminoalcohol is extracted 3 times with
equal volumes of ethyl acetate. The organic layer is separated and is dried
with anhydrous magnesium sulfate, then the solvent is removed by distillation
leaving the product as a white, amorphous solid.
9-[3-(4-Methyl-1-Piperazinyl)-Propylidene]-2-Dimethylsulfamylthioxanthene: A
solution of 12 grams of 9-[3-(4-methyl-1-piperazinyl)-1-hydroxypropyl]-2-
dimethylsulfamylthioxanthene in 20 ml of pyridine is cooled to 0°C in an ice bath and 18.4 ml of phosphorus oxychloride dissolved in 60 ml of pyridine is
added dropwise. The mixture is allowed to warm to 25°C during 30 minutes,
then is heated, immersed in an 80°C oil bath, for an additional 30 minutes.
The dark brown reaction mixture is cooled to 25°C then is poured onto 50
grams of ice. After the ice has melted, the aqueous solution is saturated with
potassium carbonate and the liberated oil is extracted with three 150 ml
portions of ethyl acetate. The solvents are removed from the separated
organic layer by distillation. The product, a light brown amorphous solid,
remains as a residue from the distillation. The free base is dissolved in 50 ml
of acetone, is treated with two stoichiometric equivalents of maleic acid in 50
ml of acetone and the white crystalline dimaleate salt is removed by filtration.
There is obtained 12.3 grams, 47% yield, MP 158° to 160.5°C (after
recrystallization from ethanol).
General Description
The thioxanthene system differsfrom the phenothiazine system by replacement of the N-Hmoiety with a carbon atom doubly bonded to the propylideneside chain. With the substituent in the 2-position, ZandE-isomers are produced. In accordance with the conceptthat the presently useful antipsychotics can be superimposedon DA, the Z-isomers are the more active antipsychotic isomers.The compounds of the group are very similar in pharmacologicalproperties to the corresponding phenothiazines.Thus, thiothixene (Z-N-dimethyl-9-[3-(4-methyl-1-piperazinyl)propylidene]thioxanthene-2-sulfonamide (Navane),displays properties similar to those of the piperazine subgroupof the phenothiazines.
