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Method for synthesizing 6-chlorhydroxyl indole

A technology of looxindole and its synthesis method, which is applied in the direction of organic chemistry, can solve the problems of no patent publications and process characteristics that cannot meet industrial production, so as to improve safety and operation controllability, and reduce post-processing procedures , mild effect

Inactive Publication Date: 2015-07-01
天津维智精细化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In China, there are few manufacturers of its intermediate 6-chlorooxindole. Although there are quite a lot of reports about the synthesis process of 6-chlorooxindole, it is limited to safety production control and cost factors, and most of them are in the laboratory stage at present. Process characteristics cannot meet industrial production
[0004] Through search and technical comparison, no patent publications related to the patent application of the present invention were found

Method used

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  • Method for synthesizing 6-chlorhydroxyl indole
  • Method for synthesizing 6-chlorhydroxyl indole
  • Method for synthesizing 6-chlorhydroxyl indole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] A kind of synthetic method of 6-chlorooxindole, the steps are as follows:

[0036] (1) Preparation of 2,5-dichloronitrobenzene

[0037] Add 157ml of concentrated sulfuric acid into a 1000ml three-necked bottle, add 196g of p-dichlorobenzene under stirring, add dropwise a mixed acid prepared from 60ml of concentrated sulfuric acid and 75ml of nitric acid under water cooling, after the dropwise addition, slowly heat up to 80-100°C, and keep warm for 2- After 4 hours, after the reaction, cool down to about 60°C, add 392g of cold water, stir for 1 hour, and suction filter to obtain a yellow solid. Melt the yellow solid with 249.5g of hot water at 80°C, stir and wash until neutral, and cool to 15°C , the yellow solid was obtained by suction filtration, that is, 2,5-dichloronitrobenzene.

[0038] Dry 244g, content: greater than 99%, yield 95%.

[0039] (2) Preparation of 2-(4-chloro-2-nitrophenyl) dimethyl malonate

[0040] Add 3000ml dimethyl sulfoxide and 280g dimethyl m...

Embodiment 2

[0046] A kind of synthetic method of 6-chlorooxindole, the steps are as follows:

[0047] (1) Preparation of 2,5-dichloronitrobenzene

[0048] Add 156.7ml of concentrated sulfuric acid into a 1000ml three-necked flask, add 196g of p-dichlorobenzene under stirring, and dropwise add a mixed acid prepared by 58.8ml of concentrated sulfuric acid and 70ml of fuming nitric acid under water cooling. -95°C, heat preservation reaction for 2 hours, after the reaction, cool down to about 60°C, add 392g of cold water, stir for 1 hour, and suction filter to get a yellow solid, melt the yellow solid with 257g of hot water at 80°C, stir and wash until neutral , cooled to 15°C, suction filtered to obtain a yellow solid, namely 2,5-dichloronitrobenzene. Dry 251.2g, content: 99.7%, yield 97.6%.

[0049] (2) Preparation of 2-(4-chloro-2-nitrophenyl) dimethyl malonate

[0050] Add 3000ml dimethyl sulfoxide and 326g dimethyl malonate into a 5000ml three-necked flask, add 251.2g of 2,5-dichloron...

Embodiment 3

[0056] A kind of synthetic method of 6-chlorooxindole, the steps are as follows:

[0057] (1) Preparation of 2,5-dichloronitrobenzene

[0058] Add 178ml of concentrated sulfuric acid into a 1000ml three-necked bottle, add 196g of p-dichlorobenzene under stirring, add dropwise a mixed acid prepared from 68ml of concentrated sulfuric acid and 95ml of nitric acid under water cooling, after the dropwise addition, slowly heat up to 80-100°C, and keep warm for 2- After 4 hours, cool down to about 60°C after the reaction, add 450g of cold water, stir for 1 hour, and filter to obtain a yellow solid. Melt the yellow solid with 250g of hot water at 80°C, stir and wash until neutral, and cool to 15°C , Suction filtration to obtain a yellow solid, namely 2,5-dichloronitrobenzene. Dry 239g, content: greater than 99%, yield 92.9%.

[0059] (2) Preparation of 2-(4-chloro-2-nitrophenyl) dimethyl malonate

[0060] Add 3000ml dimethyl sulfoxide and 370g dimethyl malonate into a 5000ml three-...

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Abstract

The invention relates to a method for synthesizing 6-chlorhydroxyl indole. The synthesizing steps are as follows: (1) preparing 2, 5-dichloronitrobenzene through paradichlorobenzene nitration; (2) synthesizing 2-(4-chlorine-2-nitrobenzophenone) dimethyl malonate by 2, 5-dichloronitrobenzene; (3) synthesizing 4-chlorine-2-nitrophenyl acetic acid by 2, 5-dichloronitrobenzene; and (4) preparing 6-chlorhydroxyl indole by 4-chlorine-2-nitrophenyl acetic acid. By adopting the method, the whole reaction process is mild in condition and easy to control; the safety in the reaction process is increased, the operation is simple and the industrial production can be realized; and the raw materials are simple and easy to obtain, the production cost is reduced, the yield is obviously increased and a foundation for the industrial production is laid.

Description

technical field [0001] The invention relates to a preparation method of a drug intermediate, in particular to a method for synthesizing the intermediate 6-chlorooxindole of the drug ziprasidone hydrochloride. Background technique [0002] Ziprasidone hydrochloride (Ziprasidone) is the latest atypical broad-spectrum antipsychotic drug developed for the treatment of schizophrenia. This product is a 5-hydroxytryptamine and dopamine receptor antagonist, especially for 5-HTA2 / DAD2 receptors with strong affinity. The oral dosage form and intramuscular injection dosage form of the drug were launched in Sweden in September 1998 and 2000, respectively. It has a good curative effect on acute or chronic, initial or recurrent schizophrenia; it is effective on schizophrenia-related symptoms (including audiovisual hallucinations, delusions, lack of motivation and social evasion). Compared with traditional antipsychotic drugs, the drug can not only improve positive symptoms, but also neg...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/34
CPCC07D209/34
Inventor 焦学宏
Owner 天津维智精细化工有限公司
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