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Preparation method of ziprasidone intermediate

A technology of chiprasidone and intermediates, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of unfavorable industrial promotion, long synthetic route, dangerous operation, etc., and achieve simple and easy process, mild deacidification process, and safe production Effect

Inactive Publication Date: 2016-07-13
ZHEJIANG MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesis route is long, the operation is dangerous, the pollution is large, the yield is low, and the cost is high. It is only suitable for scientific research and is not conducive to industrial promotion.

Method used

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  • Preparation method of ziprasidone intermediate
  • Preparation method of ziprasidone intermediate
  • Preparation method of ziprasidone intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] In the present embodiment, the preparation method of 6-chloro-2-indolinone, an intermediate of ziprasidone, comprises the following steps:

[0042] (1) Add 2500mL of acetone to the three-necked flask, add 200g of dimethyl malonate, 240g of 2,5-dichloronitrobenzene, 420g of potassium carbonate powder, and 10g of tetrabutylammonium bromide under the action of stirring. React at ~60°C for 20 hours, and TLC (PE:EA=3:1) detects that the raw materials disappear; cool down to room temperature, filter off the solid acid-binding agent, and recover acetone under reduced pressure to obtain the oily 2-(4-chloro-2-nitrate dimethylphenyl)malonate;

[0043] (2) Add 1000 mL of ethanol and 1000 g of 2N NaOH to the product of step (1) under stirring, react at 70 to 80° C. for 6 hours, until the raw materials are detected by TLC (PE:EA=3:1), and 2-(4- Chloro-2-nitrophenyl) malonate disodium salt;

[0044] (3) The reaction system of step (2) is cooled to 0-40 DEG C, and concentrated hydr...

Embodiment 2

[0049]In the present embodiment, the preparation method of 6-chloro-2-indolinone, an intermediate of ziprasidone, comprises the following steps:

[0050] (1) Add 2500mL butanone into the three-necked flask, add 200g of dimethyl malonate, 240g of 2,5-dichloronitrobenzene, 380g of anhydrous sodium carbonate powder, benzyl triethyl chloride under stirring Ammonium 10g, react in a water bath at 55-60°C for 20h, TLC (PE:EA=3:1) detects that the raw materials disappear; cool down to room temperature, filter off the solid acid-binding agent, recover butanone under reduced pressure, and obtain the oily 2-(4 -Dimethyl chloro-2-nitrophenyl) malonate;

[0051] (2) Add 1500 mL of ethanol and 1200 g of 2N KOH to the product of step (1) under stirring, and react at 70 to 80° C. for 6 hours. TLC (PE:EA=3:1) detects that the raw materials disappear, and 2-(4- Chloro-2-nitrophenyl) malonate dipotassium salt;

[0052] (3) The reaction system of step (2) is cooled to 0-40 DEG C, and concentrat...

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Abstract

The invention relates to a preparation method of a ziprasidone intermediate.The preparation method is a method to prepare 6-chloro-2-indolone by one-pot process, an alkali liquid and phase-transfer catalyst low in price are used in the preparation process to substitute the prior art sodium hydride necessary to use and high in price, recyclable low-grade aliphatic ketone and low-grade fatty alcohol are used to substitute DMF (dimethyl formamide) and DMSO (dimethylsulfoxide) difficult to recycle, the cost is reduced greatly, the materials used herein are cheap and easy to obtain, the process is simple and feasible, posttreatment steps are simplified, particularly the step (1) requires no washing, extracting and purifying operation, one step may be performed directly, the whole operating step needs no use of column chromatography for purification, the whole preparation process is simplified, and the method is convenient to industrialize; in the synthetic process of formula III compound, a deacidifying process is mild and safe; in the synthesis of formula II compound, low-valence sulfur-containing compound is used in reduction, generation of mass waste acid liquid is avoided, production is safe and environment-friendly, and the preparation process is simple and easy.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a preparation method of 6-chloro-2-indolinone, a ziprasidone intermediate. Background technique [0002] Ziprasidone hydrochloride (Ziprasidone) is an atypical broad-spectrum antipsychotic drug developed by Pfizer for the treatment of schizophrenia. Strong synergy. Ziprasidone hydrochloride has a good curative effect on acute or chronic, first-episode or relapse schizophrenia, and is effective on schizophrenia-related symptoms (including audiovisual hallucinations, delusions, lack of motivation, and social avoidance). Compared with traditional antipsychotic drugs, the drug can not only improve positive symptoms, but also improve negative symptoms, improve cognitive function, greatly reduce adverse reactions, especially extrapyramidal symptoms, and significantly improve acceptability. [0003] The chemical name of ziprasidone hydrochloride is 5-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/34
CPCC07D209/34
Inventor 刘雄
Owner ZHEJIANG MENOVO PHARMA
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