(Z)-4-[3-(2-chloro-9H-thioxanthen-9-ylidene)propyl]piperazine-1-ethanol dihydrochloride

Originator

Zuclopenthixol Hydrochloride,ZYF Pharm Chemical

Uses

Zuclopenthixol ((Z)-Clopenthixol) dihydrochloride is a thioxanthene derivative which acts as a mixed dopamine D1/D2 receptor antagonist. Zuclopenthixol dihydrochloride is used in the study of schizophrenia[1][2][3].

Manufacturing Process

288.0 g of 2-chloro-9-allylthiaxanthenol-(9), melting at 77-78°C, are prepared by adding 2-chloro-thiaxanthone to an ether solution of allyl magnesium bromide followed by hydrolysis.
The 2-chloro-9-allylthiaxanthenol-(9) is dissolved in 2 L of anhydrous ether, whereafter 360.0 g triethylamine are added. While stirring and cooling, 150.0 g thionyl chloride dissolved in 500 ml ether are added gradually, allowing the temperature to rise to a maximum of -10°C. After completion of addition, the ether solution is shaken 3 times with ice water, each time with 0.3 L, whereafter it is dried with potassium carbonate. Thereafter, the ether is evaporated in vacuum and the 2-chloro-9-(propene-3-ylidene-1)-thiaxanthene formed is obtained as a light yellow syrup.
2 methods of producing of 2-chloro-9-[3'-(N'-2-hydroxyethylpiperazino- N)propylidene]thiaxanthene from 2-chloro-9-(propene-3-ylidene-1) thiaxanthene:
1). 27.0 g of 2-chloro-9-(propene-3-ylidene-1)thiaxanthene, are mixed with 50.0 g anhydrous piperazine and 10 ml absolute ethanol and the mixture is heated for 12 h at 120°C under reflux. After cooling, the solidified reaction mixture is treated with 500 ml of water and the mixture extracted with ether. From the ether solution, the 2-chloro-9-(3'-N-piperazino)propylidene) thiaxanthene formed is extracted with dilute hydrochloric acid and precipitated as the base from the aqueous solution by rendering the solution alkaline. By extraction with ether, drying of the ether solution with potassium carbonate and evaporation of the ether, the free base 2-chloro-9-(3'-N-piperazino) propylidene)thiaxanthene is obtained as a colorless oil in a yield of 21.0 g.
35.0 g of the base 2-chloro-9-(3'-N-piperazino)propylidene)thiaxanthene are dissolved in 200 ml of methanol. 5.0 g ethylene oxide are added and the mixture is left standing at room temperature for 3 h. Thereafter, the reaction mixture is evaporated, dried and the 2-chloro-9-[3'-(N'-2- hydroxyethylpiperazino-N)propylidene]thiaxanthene is obtained.
2). 27.0 g of 2-chloro-9-(propene-3-ylidene-1)thiaxanthene, are mixed with 50.0 g anhydrous N-2-hydroxyethylpiperazine and 10 ml absolute ethanol and the mixture is heated for 12 h at 120°C under reflux. After cooling, the solidified reaction mixture is treated with 500 ml of water and the mixture extracted with chloroform. From the chloroform solution, the 2-chloro-9-[3'- (N'-2-hydroxyethylpiperazino-N)-propylidene]thiaxanthene formed is extracted with dilute hydrochloric acid and precipitated as the base from the aqueous solution by rendering the solution alkaline. By extraction with chloroform, drying of the organic solution with potassium carbonate and evaporation of the chloroform, the base 2-chloro-9-[3'-(N'-2-hydroxyethylpiperazino- N)propylidene]thiaxanthene is obtained as colorless syrup. By dissolving the base in petrol and leaving the solution to stand the trans form crystallize out as a white crystalline substance, from the mother liquor from the trans base, the corresponding cis base can be obtained as a white crystalline substance.
In practice it is usually used as dihydrochloride.

Therapeutic Function

Neuroleptic, Antipsychotic

in vivo

IC 50

D₂ Receptor

References

[1] Khalifa AE, et al. Pro-oxidant activity of zuclopenthixol in vivo: differential effect of the drug on brain oxidative status of scopolamine-treated rats. Hum Exp Toxicol. 2004 Aug;23(9):439-45. DOI:10.1191/0960327104ht470oa
[2] Manzaneque JM, et al. An ethopharmacological assessment of the effects of zuclopenthixol on agonistic interactions in male mice. Methods Find Exp Clin Pharmacol. 1999 Jan-Feb;21(1):11-5. DOI:10.1358/mf.1999.21.1.527012
[3] Bryan EJ, et al. Zuclopenthixol dihydrochloride for schizophrenia. Cochrane Database Syst Rev. 2017 Nov 16;11(11):CD005474. DOI:10.1002/14651858.CD005474.pub2