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Industrialization preparation method for 4-fluoroisatin and product thereby

A technology of fluoroisatin and products, which is applied in the field of preparation of heterocyclic compounds, and achieves the effects of low energy consumption, low cost, and convenient quality control and post-processing

Active Publication Date: 2013-09-25
WUHAN LUOHUA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, further research and experiments have shown that the above method is only applicable when R=Cl, Br, I; and when R=F, only a single 6-fluoroisatin can be obtained instead of 4-fluoroisatin

Method used

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  • Industrialization preparation method for 4-fluoroisatin and product thereby
  • Industrialization preparation method for 4-fluoroisatin and product thereby
  • Industrialization preparation method for 4-fluoroisatin and product thereby

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The first step: Oxime formation reaction

[0031] Chloral hydrate (95.7 grams, 0.58 moles) and sodium sulfate (448.5 grams, 3.15 moles) were dissolved in 2.2 liters of water, heated to 30-35 degrees, reacted for 15 minutes, and then added m-fluoroaniline (58.8 grams, 0.53 moles) , 57 ml concentrated hydrochloric acid, 200 ml aqueous solution of hydroxylamine hydrochloride (109.7 g, 1.58 mol). After the addition, heat to 80-90 degrees to react for 2 hours, then cool to 50 degrees to filter, wash the filter cake with water, and dry to obtain 86 grams of product (yield 89.5%).

[0032] Step 2: Ring Closing Reaction

[0033] Heat 430 milliliters of concentrated sulfuric acid to 50-60 degrees, add 8.6 grams of TEBBE reagent, add product 2 (86 g, 0.47 moles) in batches, the temperature cannot exceed 65 degrees, after the addition is completed, heat up to 80-85 degrees for 15 minutes, and then Cool down to room temperature, pour into 1.2 liters of ice water, an orange-red pr...

Embodiment 2

[0035] The first step: Oxime formation reaction

[0036] Chloral hydrate (287 grams, 1.74 moles) and sodium sulfate (1.34 kilograms, 9.45 moles) were dissolved in 6.6 liters of water, heated to 30-35 degrees, reacted for 15 minutes, and then added m-fluoroaniline (176.4 grams, 1.59 moles) successively, For example, 171 milliliters of concentrated hydrochloric acid with a mass fraction of more than 37%, 600 milliliters of an aqueous solution of hydroxylamine hydrochloride (329.4 grams, 4.74 moles). After the addition, heat to 80-90 degrees to react for 2 hours, then cool down to 50 degrees to filter, wash the filter cake with water, and dry to obtain 272 grams of product (yield 93.9%).

[0037] Step 2: Ring Closing Reaction

[0038] Heat 1.4 liters of concentrated sulfuric acid with a mass percentage concentration of, for example, 85% or more to 50-60 degrees, add 27 grams of TEBBE reagent, and add product 2 (272 g, 1.5 moles) in batches. The temperature cannot exceed 65 degre...

Embodiment 3

[0040] The first step: Oxime formation reaction

[0041] Chloral hydrate (2.8 kg, 17.4 moles) and sodium sulfate (18 kg, 127.2 moles) were dissolved in 66 liters of water, heated to 30-35 degrees, reacted for 15 minutes, and then added m-fluoroaniline (1.76 kg, 15.9 moles) , 1.91 liters of concentrated hydrochloric acid, 6 liters of aqueous solution of hydroxylamine hydrochloride (3.3 kg, 47.4 moles). After the feeding is completed, heat to 80-90 degrees to react for 2 hours, then cool down to 50 degrees to filter, wash the filter cake with water, and dry to obtain 2.84 kg of product (yield 98.1%).

[0042] Step 2: Ring Closing Reaction

[0043] Heat 14 liters of concentrated sulfuric acid to 50-60 degrees, add 142 grams of TEBBE reagent in batches, add product 2 (2.84 kg, 15.6 moles) in batches, the temperature cannot exceed 65 degrees, and heat up to 80 degrees for 15 minutes after the addition. Cool down to room temperature, pour into ice water, an orange-red precipitate ...

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Abstract

An industrialization preparation method for 4-fluoroisatin is disclosed by the invention, and comprises: (a) dissolving chloral hydrate and sodium sulfate in water, heating to 30 DEG C-35 DEG C, then successively adding m-fluoroaniline, concentrated hydrochloric acid and an aqueous solution of hydroxylamine hydrochloride, heating to 80 DEG C-90 DEG C for continually reaction, after a complete reaction, air-pump filtering and washing the filter cake with water, and obtaining the intermediate; and (b) heating concentrated sulfuric acid to 50 DEG C-60 DEG C, successively adding TEBBE reagent and the intermediate obtained in step (a), then continually heating to 80 DEG C-85 DEG C and reacting, after a complete reaction, cooling and precipitating an orange red precipitate, and therefore obtaining the 4-fluoroisatin product. The invention also discloses the corresponding 4-fluoroisatin product. The industrialization preparation method can help to obtain the product with a simple process, a high yield and low cost, and is convenient to control quality and applicable in industrialization production in a large scale.

Description

technical field [0001] The invention belongs to the technical field of preparation of heterocyclic compounds, and more specifically relates to an industrial preparation method of 4-fluoroisatin and its products. Background technique [0002] Isatin is an endogenous active substance present in mammalian tissues and body fluids. Studies have shown that it is a selective inhibitor of monoamine oxidase-B, which can increase the levels of acetylcholine and dopamine in the striatum of mice with Parkinson's disease, improve Bradykinesia symptoms. In addition, it can also be used in various drug synthesis. As one of the important derivatives of isatin, 4-fluoroisatin (also known as 4-fluoroindolequinone, 4-fluoro-2,3-indoledione,) is a commonly used intermediate, widely used in Drugs and dyes and other fields. [0003] In order to obtain 4-fluoroisatin products, some preparation principles and methods have been proposed in the prior art (see J.Med.Chem.2004,47,935-946; J.Med.Chem...

Claims

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Application Information

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IPC IPC(8): C07D209/38
Inventor 姫长鹏张宝徽高中洪覃宇胡信波李维龙
Owner WUHAN LUOHUA TECH
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