CIS-THIOTHIXENE

Originator

Navane,Roerig,US,1967

Uses

Thiothixene is a modulator of human P-glycoprotein and is frequently used a an anti-psychotic.

Uses

Thiothixene displays a specific chemical and pharmacological similarity to piperazine derivatives of the phenothiazine series, and is used for treating psychotic disorders. The indications for using thiothixene are the same as for chlorprothixene.

Uses

antipsychotic

Definition

ChEBI: Thiothixene is a N-methylpiperazine. It has a role as an anticoronaviral agent.

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).

brand name

Tiotixene is INN, BAN and JAN.

Therapeutic Function

Tranquilizer

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.

Synthesis

Thiothixene, N,N-dimethyl-9-[3-(4-methyl-1-1piperazinyl)propyliden]-thioxanten-2-sulfonamide (6.2.14), is synthesized from 9H-thioxantene, which is reacted with chlorosulfonic acid to give 9H-thioxanten-2-sulfonic acid (6.2.8). This is transformed into 2-dimethylaminosulfonyl-9H-thioxantene (6.2.9) by reaction of 6.2.8 with thionyl chloride and dimethylamine. The reaction of 2-dimethylaminosulfonyl-9H-thioxantene (6.2.9) with butyllithium and then with methylacetate forms 9-acetyl-2-dimethylaminosulfonyl-9H-thioxantene (6.2.10). Aminomethylation of the resulting product with dimethylamine and formaldehyde gives 9-(2-dimethylamineopropionyl)-2-dimethylaminosulfonyl-9H-thioxantene (6.2.11). Reacting this with 1-N-methylpiperazine results in a substitution of the dimethylamine group in the acylic part of the molecule with a N-methylpiperazine group, giving the product (6.2.12). The carbonyl group of the product is reduced to a secondary hydroxyl group using sodium borohydride followed by the dehydration of the product (6.2.13) with the help of phosphorous oxychloride to give the desired thiothoxene (6.2.14) [37¨C40].