Sertindole synthesis method

A synthesis method and technology of serindole, applied in the field of serindole synthesis, can solve problems such as high cost and long hydrogenation time, and achieve the effects of low cost, short reaction time and easy availability of raw materials

Inactive Publication Date: 2009-02-11
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Above method has following shortcoming: (1), all adopt expensive PtO 2 As a catalyst, the cost is high
(3) The hydrogenation time is longer, and it takes 10 to 24 hours to complete the reaction

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-5,6-dihydropiperidin-1(2H)-yl] —2-imidazolinone hydrochloride (3g, 0.0063mol) is placed in 50ml tetrahydrofuran, stir well, add NaBH 4 (1.44g, 0.038mol);

[0032] Then, at 30°C, 0.25ml of glacial acetic acid was added dropwise and stirred for 30min.

[0033] Then, at room temperature, 7.5 ml of HCl with a weight concentration of 37% was added dropwise to the reaction solution, and stirred for 30 min;

[0034] Then add 50ml of water to the reaction solution, evaporate tetrahydrofuran (THF), adjust the pH to 12 with a 30% NaOH solution by weight, extract 3 times with dichloromethane, combine the extracts, backwash once with saturated NaCl solution, with anhydrous Na 2 SO 4 Dry, filter, and evaporate to dryness to obtain 2.5 g of a white solid, which is the target product, with a yield of 89.9%, m.p.153-154°C. 1 HNMR (400MHz, CDCl3): δ1.87 (dt, 2H), 2.05 (broad d, 2H), 2.27 (t, 2H), 2.62 (t, 2H), 2.82 (tt, 1H), 3.13 ...

Embodiment 2

[0036] 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-5,6-dihydropiperidin-1(2H)-yl] —2-imidazolinone (1.25g, 0.0028mol) is placed in 15ml 2-methyltetrahydrofuran, stirred evenly, and NaBH is added at room temperature 4 (0.22g, 0.057mol), at 20°C, 0.5ml of glacial acetic acid (0.084mol) was added dropwise, and stirred at room temperature for 30min. Then, at room temperature, 4 ml of HCl with a weight concentration of 35% was added dropwise to the reaction solution, and stirred for 30 min. Alkalization with 20% NaOH solution by weight, and the others were the same as in Example 1 to obtain 0.66 g of white solid with a yield of 52.4%. Melting point and spectral data are the same as above.

Embodiment 3

[0038] The raw material 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-5,6-dihydropiperidin-1(2H)-yl ]—2-imidazolinone hydrochloride (0.3g, 0.63mmol) was placed in 8ml tetrahydrofuran, stirred evenly, and KBH was added at room temperature 4(0.21g, 3.79mmol), below 30°C, add 0.07ml of glacial acetic acid dropwise, and stir at room temperature for 30min. At room temperature, 0.8 ml of sulfuric acid with a weight concentration of 60% was slowly added dropwise to the reaction liquid, and stirred for 30 min. Others were the same as in Example 1, and evaporated to dryness to obtain a white solid, which was separated by column chromatography to obtain 120 mg of the product with a yield of 43.16%. Melting point and spectral data are the same as above.

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Abstract

The invention discloses a synthetic method of sertindole, which comprises the following steps: 1-(2-(4-(5-chlorine-1-(4-fluorophenyl)-1H-indole-3-base)-5, 6-dihydro piperidine(-1(2H)-base) -2-imidazolinone (IA) or salt thereof or 5-chlorine-1-(4-fluorophenyl)-3-(1, 2, 3, 6-tetrahydro pyridine-4-base) indole (IB) or salt thereof reacts with borohydride reagent / R<1>COOH to generate borane intermediate; then acid and alkaline are added to obtain sertindole (III). The method has high conversion, short reaction time, easily controllable reaction conditions, high product purity, easily available raw materials, relatively low cost, easy operation, good position selectivity, relatively high product purity without by-product of chlorination, is environmentally friendly and can be applied to industrialized production. The reaction general formula is shown as the above formula.

Description

technical field [0001] The invention relates to a method for synthesizing sertindole. Background technique [0002] Sertindole is an atypical antipsychotic drug, its English name is Sertindole, its trade name is Serdolect (Serlect), and its chemical name is: 1-[2-[4-[5-chloro-1-(4-fluorophenyl)- 1H-indol-3-yl]-1-piperidinyl]ethyl-2-imidazolidinone, the English name is: 5-Chloro-1-(4-fluorophenyl)-3-[1-(2-oxoimidazolidin -1-ylethyl)-4-piperidyl]-1H-indole or 1-[2-[4-[5-Chloro-1-(4-fl-uorophenyl)-1H-indol-3-y1]piperidinyl]ethyl] -2-imidazolidinone. [0003] The structural formula of sertindole is shown in (III): [0004] [0005] This compound is disclosed in US 4,710,500 and its antischizophrenic activity is disclosed in US 5,112,838. In vivo, sertindole acts on the central nervous system D 2 and 5-HT 2A Antagonist of the receptor, and has further shown therapeutic effects in models of anxiety, hypertension, drug abuse and cognitive impairment. There are currently t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/454A61P9/12A61P25/22A61P25/28
Inventor 李建其叶雪雁黄丽瑛翁志洁
Owner SHANGHAI INST OF PHARMA IND CO LTD
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