Method for preparing sertindole by using alkyl imidazole type ionic liquid as solvent

An ionic liquid solvent, alkyl imidazole type technology, applied in the field of preparation of serindole, can solve the problems of affecting product purity, consumption of large organic solvent, low reaction yield, etc., to avoid the use of volatile organic solvents, solve the Recovery and purification issues, effects of easy control of reaction conditions

Inactive Publication Date: 2010-12-01
ZHENGZHOU UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0006] (1) The reaction yield is low, and the yield is 74%;
[0007] (2) The reaction selectivity is not high, and a large amount of by-products are arranged to generate, which directly affects the purity of the product;
[0008] (3) A large amount of organic solvents need to be consumed during reaction and aftertreatment, and 12ml methyl isobutyl ketone is needed for every 1g of product; the safety performance of the used solvent methyl isobutyl ketone is poor, and its vapor forms an explosive mixture with a

Method used

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  • Method for preparing sertindole by using alkyl imidazole type ionic liquid as solvent
  • Method for preparing sertindole by using alkyl imidazole type ionic liquid as solvent
  • Method for preparing sertindole by using alkyl imidazole type ionic liquid as solvent

Examples

Experimental program
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Effect test

Embodiment 1

[0029] 5-Chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-1 hydrogen-indole hydrochloride (1g, 0.0028mol) and 1-(2-Chloroethyl)-2-imidazolidinone (0.5g, 0.0034mol) was placed in a 100mL three-necked flask, and the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate (6.7g , 0.03mol), and solid KOH (0.55g, 0.0098mol) were stirred evenly, and reacted at 110°C for 15h to obtain a dark yellow viscous liquid. Then add 10 mL of water to the reaction solution, stir for 5 min to obtain a light yellow liquid; use dichloromethane solvent to extract 3 times, wash the organic phase 2 times, dry over anhydrous sodium sulfate, filter, and evaporate to dryness to obtain 1.09 g of a light yellow solid, namely The purity of the target product is 99.5% (HPLC), and the yield is 89.1%. At the same time, the water phase after dichloromethane extraction is filtered to remove solid impurities, evaporated to remove water, filtered to remove inorganic salt impurities, and vacuum-dri...

Embodiment 2

[0031] 5-Chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-1 hydrogen-indole hydrochloride (1g, 0.0028mol) and 1-(2-Chloroethyl)-2-imidazolidinone (0.8g, 0.0056mol) was placed in a 100mL three-necked flask, and the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate (8.9g, 0.031mol), solid Na 2 CO 3 (0.6g, 0.01mol) was stirred evenly, and reacted at 120°C for 10h to obtain a dark yellow viscous liquid. Then add 10 mL of water to the reaction solution, stir for 5 min to obtain a light yellow liquid; use dichloromethane solvent to extract 3 times, wash the organic phase 2 times, dry over anhydrous sodium sulfate, filter, and evaporate to dryness to obtain 1.04 g of a light yellow solid, namely It is the target product with a purity of 99.6% (HPLC) and a yield of 85.1%. At the same time, the water phase extracted by dichloromethane is filtered to remove solid impurities, evaporated to remove water, filtered to remove inorganic salt impurities, vacuum-dried ...

Embodiment 3

[0033] 5-Chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-1 hydrogen-indole hydrochloride (2g, 0.0055mol) and 1-(2-Chloroethyl)-2-imidazolidinone (1.1g, 0.0072mol) was placed in a 100mL three-necked flask, and the ionic liquid hydroxide 1-butyl-3-methylimidazole (8.9g, 0.057mol ), solid NaOH (1.12g, 0.02mol) was stirred evenly, and reacted at 150°C for 24h to obtain a brown viscous liquid. Then add 15 mL of water to the reaction solution, stir for 5 min to obtain a light yellow liquid; use ethyl acetate solvent extraction 3 times, wash the organic phase 2 times, dry over anhydrous sodium sulfate, filter, and evaporate to dryness to obtain 2.05 g of a light yellow solid, namely The purity of the target product is 99.5% (HPLC), and the yield is 85.2%. At the same time, the aqueous phase after ethyl acetate extraction is filtered to remove solid impurities, evaporated to remove water, filtered to remove inorganic salt impurities, vacuum-dried to recover the ionic liq...

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Abstract

The invention discloses a method for preparing sertindole, which belongs to the technical field of organic synthesis. The method comprises the following steps of: using alkyl imidazole type ionic liquid as a solvent; and under the catalysis of a solid base, reacting 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (IA) or a salt thereof, or 5-chloro-1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indole (IB) or a salt thereof with 1-(2-chloroethyl)-2-imidazole azululanone (II) to generate 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1-H-indole-3-yl]-5,6-dihydro-piperidine-1(2H)-yl]ethyl]-2-imidazolidinone (IIIA) or 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1-H-indole-3-yl]-1-piperidinyl]ethyl]-2-imidazolidinone (IIIB, sertindole). The method can prepare the sertindole and a structuralanalog thereof with high selectivity and high yield, the purity of the prepared sertindole is over 99.5 percent, and the yield can reach 85 to 90 percent. The method is simple and convenient to operate, has an easily controllable reaction condition and high selectivity, is environment-friendly, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of sertindole, in particular to a method for preparing sertindole by using an alkylimidazole type ionic liquid as a solvent, and belongs to the technical field of organic synthesis. Background technique [0002] Sertindole (sertindole) is an atypical antipsychotic drug, its chemical name is: 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indole-3 -yl]-1-piperidinyl]ethyl-2-imidazolidinone, the English name is: 5-Chloro-1-(4-fl uorophenyl)-3-[1-(2-oxoimidazolidin-1-ylethyl) -4-piperidyl]-1H-indoe. The structural formula of sertindole is: [0003] [0004] The mechanism of action of sertindole is the dual blockade of 5-hydroxytryptamine (5-HT) and dopamine (DA) receptors, which is not only reflected in the treatment of patients with acute attacks, but also in the maintenance treatment to prevent relapse of psychosis , less side effects, no need to cooperate with anticholinergic drugs, better tolerance and comp...

Claims

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Application Information

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IPC IPC(8): C07D401/14
Inventor 李雯王宇樊璐露马晓青
Owner ZHENGZHOU UNIV
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