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Method for preparing 7-halo-6-nitro-1,4-dihydroquinoline-4-one-3-carbonitrile

A technology of dihydroquinoline and carbonitrile, which is applied in the field of organic chemical synthesis, can solve the problems of difficult production scale-up, low process safety, and harsh reaction conditions, and achieve low cost, low equipment requirements, and relatively mild reaction conditions. Effect

Inactive Publication Date: 2018-03-09
RAFFLES PHAMRMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In order to improve the preparation of 7-halo-6-nitro-1,4-dihydroquinolin-4-one-3-carbonitrile for the deficiencies of the existing technology, the reaction conditions are harsh, the process safety is low, and it is difficult to produce and scale up. Problem, the present invention provides a preparation method of 7-halo-6-nitro-1,4-dihydroquinolin-4-one-3-carbonitrile

Method used

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  • Method for preparing 7-halo-6-nitro-1,4-dihydroquinoline-4-one-3-carbonitrile

Examples

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Embodiment 1

[0037] 1, Synthesis of 2-amino-4-chlorobenzoic acid methyl ester

[0038] Add 10g of 2-amino-4-chlorobenzoic acid and 150ml of methanol to the one-mouth bottle, cool to 0-5°C, and add 10.4g of thionyl chloride dropwise while keeping warm. After the dropwise addition was completed, the temperature was raised to reflux and reacted for 24hrs. Cool down to room temperature, and concentrate under reduced pressure to remove methanol. Add 100ml of ethyl acetate and 100ml of 5% sodium carbonate solution, stir, let stand, separate the water layer, wash the organic layer with 100ml of water, dry over anhydrous sodium sulfate and concentrate under reduced pressure to obtain 2-amino-4-chlorobenzoic acid methyl ester 8.9 g, yield 82%.

[0039] 2, Synthesis of 4-chloro-2-((2-cyanovinyl) amino) methyl benzoate

[0040] Add 10g of 2-amino-4-chlorobenzoic acid methyl ester, 80ml of ethyl acetate, 10ml of trifluoroacetic acid into the single-necked bottle, then dropwise add 6.2g of 3-dimethy...

Embodiment 2

[0047] 1, Synthesis of 2-amino-4-bromobenzoic acid methyl ester

[0048] Add 10g of 2-amino-4-bromobenzoic acid, 150ml of methanol, and 10ml of concentrated sulfuric acid into the single-necked bottle, and heat to reflux for 24hrs. Cool down to room temperature, and concentrate under reduced pressure to remove methanol. Add 100ml of ethyl acetate, 100ml of 5% sodium carbonate solution, stir for 5mins and then let stand to separate layers, separate the water layer, wash the organic layer with 100ml of water, dry over anhydrous sodium sulfate and concentrate under reduced pressure to obtain 2-amino-4-bromobenzoic acid Methyl ester 9.16g, yield 86%.

[0049] 2. Synthesis of 4-bromo-2-((2-cyanovinyl) amino) methyl benzoate

[0050] Add 10g methyl 2-amino-4-bromobenzoate, 60ml ethyl acetate, then dropwise add 6.0g 3-dimethylaminoacrylonitrile, react at room temperature for 3-4hrs, add dropwise 60ml of water, then stir at room temperature for 2hrs , filtered, washed with a small ...

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Abstract

The invention discloses a method for preparing 7-halo-6-nitro-1,4-dihydroquinoline-4-one-3-carbonitrile. The method comprises the following steps of: S1, adopting 2-amino-4-halo benzoic acid as a starting material, and performing esterification on simple fatty alcohol under the action of a catalyst so as to produce 4-halo-2-aminobenzoate; S2, performing a reaction between 4-halo-2-aminobenzoate and 3-dimethylaminoacrylonitrile under the action of an acidic catalyst so as to produce 4-halo-2-((2-cyanovinyl)amino) benzoate; S3, performing cyclization on 4-halo-2-((2-cyanovinyl)amino) benzoate under the action of strong base so as to produce 7-halo-1,4-dihydroquinoline-4-one-3-carbonitrile; and S4, performing nitrification on 7-halo-1,4-dihydroquinoline-4-one-3-carbonitrile in the presence ofa mixture of strong acid and nitric acid to obtain 7-halo-6-nitro-1,4-dihydroquinoline-4-one-3-carbonitrile. According to the method for preparing 7-halo-6-nitro-1,4-dihydroquinoline-4-one-3-carbonitrile, the process route is novel, the novel intermediates are obtained, and the total yield is more than 35%; the method has the advantages of a novel process route, mild reaction conditions and the like.

Description

technical field [0001] The present invention relates to the field of organic chemical synthesis, more specifically, to a preparation method of 7-halo-6-nitro-1,4-dihydroquinolin-4-one-3-carbonitrile. Background technique [0002] There are a variety of preclinical, clinical and marketed new drugs containing 6,7-disubstituted-4-substituted-3-carbonitrile fragments. The three types of drug molecules shown below, as well as marketed drugs such as Neratinib and Phase II clinical drug Pelitinib, all contain this important structural fragment. [0003] [0004] At present, there are two main synthetic routes for this structural sheet, among which the high-temperature ring-closing route is shown below. The main defect of this route is that the ring-closing reaction requires a high temperature of about 250 degrees, which is difficult for general pharmaceutical equipment to achieve, and it is also difficult to safely produce and scale up: [0005] [0006] Another synthetic m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/56
CPCC07D215/56
Inventor 周章涛叶伟平费安杰黄志宁樊彤彤吴桂宝肖诗华
Owner RAFFLES PHAMRMATECH CO LTD
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