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5-fluoroindole-2-one preparation method

A technology of fluoroindole and difluoronitrobenzene, which is applied in the field of preparation of indole derivatives, can solve the problems of expensive raw materials, harsh reaction conditions, unsatisfactory yields, etc., and achieve high yields and cheap and easy-to-obtain raw materials Effect

Inactive Publication Date: 2014-09-17
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Based on the analysis of the above documents, most of the raw materials used in these documents have the disadvantages of expensive raw materials, harsh reaction conditions and unsatisfactory yields.
The synthesis method using 2,4-difluoronitrobenzene as a raw material has some defects and cannot realize industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] (1) Preparation of 4-fluoro-2-(dimethylmalonate) nitrobenzene

[0022]

[0023] in N 2 Under the protective atmosphere, add 6.48g (120.0mmol) NaOCH in reaction bottle 3 and dried dimethyl sulfoxide (30mL), add 15.85g (120.0mmol) dimethyl malonate dropwise at room temperature (the dropping time is more than 10min) and stir, then cool to 8°C and slowly add dropwise 6.36g (40.0mmol) 2,4-difluoronitrobenzene (dropping time greater than 40min). Continue to react, TLC tracks the reaction, after the completion of the reaction, add 14mL (80.0mmol) of 6M hydrochloric acid solution under constant stirring to quench, then add ethyl acetate and water to extract, combine the organic layers and wash 2 times with saturated brine, no Dried over sodium sulfate, spin-dried, and separated by column chromatography (eluted with ethyl acetate:petroleum ether=10:1) to obtain 4-fluoro-2-(dimethylmalonate)nitrobenzene, the yield was 88%.

[0024] (2) Preparation of 5-fluoroindol-2-one (t...

Embodiment 2

[0028] (1) The preparation of 4-fluoro-2-(dimethylmalonate)nitrobenzene was the same as step (1) in Example 1.

[0029] (2) Preparation of 3-methoxycarbonyl-5-fluoroindol-2-one

[0030]

[0031] in N 2 Under the atmosphere, add 2.71g (10.0mmol) 4-fluoro-2-(dimethylmalonate base) nitrobenzene and 0.24g (10% pd, 55% H 2 (0) palladium carbon, after replacing the hydrogen, add 50mL of ethyl acetate, adjust the temperature to 20°C for reaction, TLC tracking, add diatomaceous earth to filter after the reaction is complete, directly concentrate, column chromatography separation, use ethyl acetate Ester: petroleum ether = 1:1 (V / V) elution, the compound 3-methoxycarbonyl-5-fluoroindol-2-one was obtained with a yield of 92%.

[0032] (3) Preparation of 5-fluoroindol-2-one (target object)

[0033] Add 2.09g (10.0mmol) of 3-methoxycarbonyl-5-fluoroindol-2-one and 50mL of methanol in the reaction flask, add 5mL (30.0mmol) of 6M hydrochloric acid, and turn to reflux for reaction, TLC...

Embodiment 3

[0035] (1) Preparation of 4-fluoro-2-(dimethylmalonate) nitrobenzene

[0036] in N 2 Under the protective atmosphere, add 6.48g (120.0mmol) NaOCH in reaction bottle 3 and dried dimethyl sulfoxide (30mL), add 13.21g (100.0mmol) dimethyl malonate dropwise at room temperature (dropping time is more than 10min) and stir, then cool to 15°C and slowly add dropwise 6.36g (40.0mmol) 2,4-difluoronitrobenzene (dropping time greater than 40min). Continue to react, TLC tracks the reaction, after the completion of the reaction, add 14mL (80.0mmol) of 6M hydrochloric acid solution under constant stirring to quench, then add ethyl acetate and water to extract, combine the organic layers and wash 2 times with saturated brine, no Dry over sodium sulfate, spin dry, and separate by column chromatography (eluted with ethyl acetate:petroleum ether=10:1 (V / V)) to obtain 4-fluoro-2-(dimethylmalonate) nitrate Base benzene, the yield is 80%.

[0037] (2) Preparation of 5-fluoroindol-2-one (target ...

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Abstract

The invention relates to a 5-fluoroindole-2-one preparation method. The method includes the steps of (1) reaction of 2, 4-difluornitrobenzene and dimethyl malonate to prepare 4-fluoro-2-(methyl malonate) nitrobenzene; and (2) reduction cyclization reaction of the 4-fluoro-2-(methyl malonate) nitrobenzene by iron powder to obtain target object 5-fluoroindole-2-one, or palladium / carbon reduction of the 4-fluoro-2-(methyl malonate) nitrobenzene to obtain target object 3-methoxycarbonyl-5-fluoroindole-2-one, and then hydrolysis reaction of the 3-methoxycarbonyl-5-fluoroindole-2-one to obtain the target object 5-fluoroindole-2-one. The method has the advantages of easily obtained raw materials, mild reaction conditions, high yield, less equipment investment, easy industrial production and the like.

Description

technical field [0001] The invention relates to a preparation method of indole derivatives, in particular to a preparation method of 5-fluoroindol-2-one. Background technique [0002] 5-fluoroindol-2-one is a very important pharmaceutical intermediate, widely used in the synthesis of analgesic and anti-inflammatory drugs. In recent years, it has also been used as a synthetic raw material for the synthesis of new multi-targeted oral drug Sunitinib and its derivatives for the treatment of tumors, which has gradually increased the market demand. At present, there is no supplier with mature production technology in China, so it is very necessary to synthesize and optimize it. [0003] At present, 5-fluoroisatin, 2-methyl-4-fluoroaniline, 4-fluoroaniline, 3-fluoro-6-nitrophenylacetic acid and 2,4-difluoronitrobenzene are mainly used in its synthetic methods. as raw materials ([1] Shen Xuequan et al., Chemical Times, 2012, 26(4): 29-32; [2] Chen Xiuquan et al., Applied Chemical ...

Claims

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Application Information

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IPC IPC(8): C07D209/34
CPCC07D209/34
Inventor 邓卫平张小换杨小清王晨浩
Owner EAST CHINA UNIV OF SCI & TECH
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