Separation and purification method of zuclopenthixol

A technology of zuclothixol and a purification method is applied in the field of improved separation of antipsychotic drug clothixol isomers, and purification of its α-isomer zuclothixol and its carboxylate esters to achieve high-yield Effect

Inactive Publication Date: 2013-07-24
ZHANG JIA GANG VINSCE BIO PHARM
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this paper, purer zuclothixol is obtained by fractionating the chlorthixanth base with an ether organic solvent, but it has been instructed that the purification of the chlorthixol through the crystallization of the chlorthixanth base will not give good results. Especially in the case of isomeric mixtures with large amounts of impurities present

Method used

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  • Separation and purification method of zuclopenthixol
  • Separation and purification method of zuclopenthixol
  • Separation and purification method of zuclopenthixol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: the preparation of chlorothixanthene base

[0038] 1) Preparation of 2-chloro-9-allyl-9-thioxanthol

[0039] Dissolve 100.00g (0.405mol) of 2-chloro-9-thioxanthone in 600mL of tetrahydrofuran, stir at 20°C-30°C, then add 26g of magnesium powder, 1g of iodine, and drop in 65g (0.855mol) of allyl chloride, React at 40°C-50°C for 2 hours, after cooling, add 1000ml of 20% sodium chloride aqueous solution dropwise to the reaction solution, stir for 10min, filter the insoluble matter, then extract twice with dichloromethane, 500ml each time, combine the organic phases, and water 500ml was washed, and the organic layer was separated, dried and filtered, and the filtrate was concentrated to remove the solvent to obtain 105.40g of 2-chloro-9-allyl-9-thioxanthol.

[0040] 2) Preparation of 2-chloro-9-(2-propenylene)thioxanthene

[0041] Dissolve 100.00g (0.346mol) of 2-chloro-9-allyl-9-thioxanthol in 100ml of toluene, heat the solution to 40°C, and dissolve 1.34g ...

Embodiment 2

[0044] Embodiment 2: Preparation of Zhuclothixol p-chlorobenzoate 2HCl

[0045] Dissolve 100.00g (0.250mol) of α / β-chlorothixanthene in 500ml of ethyl acetate, add dropwise 100ml of ethyl acetate dissolved in 52.48g (0.30mol) of p-chlorobenzoyl chloride at 40°C, drop After the addition was complete, the reaction was refluxed until the reaction was complete as monitored by TLC. 300ml of solvent was distilled off under reduced pressure, cooled to 4°C, and the precipitate was removed by filtration. The mother liquor was heated to 40°C, and 12.50g (0.125mol) of 37% concentrated hydrochloric acid aqueous solution was added dropwise. After reacting for about 1 hour, after cooling, a solid precipitated out, and 56.27g of cloclothixol p-chlorobenzoate·2HCl was obtained by filtration. Purity (HPLC as above) 97.11%, yield 36.82%.

Embodiment 3

[0046] Embodiment 3: the preparation of Zhuclothixol

[0047] Dissolve 45.25 g (0.074 mol) of chlorothixol p-chlorobenzoate·2HCl in 300 ml of 80% aqueous methanol, and then add 16.83 mol (0.30 mol) of potassium hydroxide. The mixture was heated to 50° C. and kept for 1 h. The solvent was distilled off under reduced pressure, extracted with toluene (200ml×2) and water, the organic phases were combined, concentrated under reduced pressure to remove the toluene; the obtained residue was recrystallized with cyclohexane to obtain 25.51 g of dry crystals. The purity was 99.7%, and the yield was 86.17%. 1 H NMR (CDCl 3 , 400MHz), δ: 7.10-7.46 (7H, m), 5.98 (1H, t), 3.41 (2H, t), 2.46-2.52 (14H, m).

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Abstract

The invention relates to an improved method for separating and purifying zuclopenthixol. The method comprises the specific following steps of: dissolving a mixture of an alpha-isomer (i.e. zuclopenthixol) and a beta isomer of 2-chloro-9-[3'-(N'-2-ethoxy piperazine-N)-allyl]-thiaxanthene into an organic solvent, adding an active benzoic acid derivative, and esterifying with the mixture so as to remove the beta-isomer; subsequently carrying out alkali hydrolysis on the residual substances so as to obtain relatively pure zuclopenthixol; and further recrystallizing by using organic solvent so as to obtain zuclopenthixol which meets the United States pharmacopeia standards. In addition, the invention further relates to preparation of a carboxylic ester and pharmaceutically acceptable acid salt of zuclopenthixol. The method has the advantages that the content of zuclopenthixol is improved by optimizing the reaction of different steps when the raw material, namely, alpha/beta-chlorine thiaxanthene, is prepared, a novel and effective method for purifying a single isomer is provided, and high-yield and high-purity zuclopenthixol is obtained by using the method.

Description

technical field [0001] The invention relates to an improved method for separating the isomers of the antipsychotic drug chlorthixol, in particular to a method for purifying the α-isomer zhuclothixol and its carboxylate, and belongs to the technical field of medicinal chemistry. Background technique [0002] Chlorothioxol (Clopenthixol), the chemical name is 2-chloro-9-[3'-(N'-2-hydroxyethylpiperazine-N)-allyl]-thioxanne, this product is a thia Anthracene derivatives have significant antipsychotic effects and specific sedative effects, and are especially suitable for schizophrenic patients. Its active ingredient is its α-isomer, i.e. Zuclothixol (for the structural formula see figure 1 ); It has the effect of anti-stereotype caused by methylphenidate, and has the effect of anti-apomorphine. This product can inhibit conditioned avoidance response and catalepsy, which is 10 times stronger than chlorpromazine. Anticholinergic effect is weak, while antihistamine effect is stron...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D335/20
Inventor 赵金召张梅彭学东
Owner ZHANG JIA GANG VINSCE BIO PHARM
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