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Synthesis method of isatin derivatives

A synthesis method and a derivative technology are applied in the synthesis field of isatin derivatives, can solve problems such as being unsuitable for industrial production, and achieve the effects of low cost, simple process flow and high product purity

Inactive Publication Date: 2010-07-28
滨海康杰化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, a large amount of water is used as a solvent in the first step of synthesizing acetamide, and a large amount of water is used for quenching in the second step of concentrated sulfuric acid cyclization to produce a large amount of process wastewater, which is not suitable for industrial production
As another example, when synthesizing 7-fluoroisatin with the Sandmeyer method in U.S. Patent 20060247442, a large amount of water was used to quench the concentrated sulfuric acid equally, and its waste water and product ratio were 68.9: 1 (w / w), and in the quenched Ethyl acetate, acetone, glyoxal and other organic solvents were added to the water for multiple extractions. Although the ring-closing yield of 7-fluoroisatin was the best in the current literature, it was still only 47.4%.

Method used

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  • Synthesis method of isatin derivatives
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  • Synthesis method of isatin derivatives

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Experimental program
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Embodiment 1

[0035] Embodiment 1: Preparation of 7-fluoroisatin

[0036] In a 500ml four-neck flask, add 380.0g of water and 27.0g of chloral hydrate, stir and dissolve at room temperature, and then add 95.0g of anhydrous Na 2 SO 4 , heating up. The temperature was raised to 40°C, 23.0g of hydroxylamine hydrochloride, 32.0g of 30% HCl and 11.0g of 2-fluoroaniline were added, and the temperature was raised to 65°C with stirring. React at 65℃~73℃, the color of the system gradually becomes darker, Na 2 SO 4 gradually dissolved completely. After 1 hour, the reaction reached the end point, and the unreacted o-fluoroaniline was 2.6 Area%, so the reaction was stopped. Filter at 40-45°C, wash with water, and dry to obtain 17.2 g of a light brown solid with an HPLC content of 96.5%.

[0037] Put 50.0g polyphosphoric acid and 17.2g N-(2-fluorophenyl)-2-(hydroxyimino)acetamide into a 250ml four-necked bottle, stir, raise the temperature to 70-75°C, and maintain it at 70-75°C After 2 hours of r...

Embodiment 2

[0038] Embodiment 2: the preparation of 6-fluoroisatin

[0039] Add 71.6g of 3-fluoroaniline, 160.0g of hydroxylammonium hydrochloride and 350.0g of water into a 500ml four-necked flask, and stir at 60°C for 0.5 hours. Add 900.0g water, 120.0g chloral hydrate, 609.6g anhydrous Na to another 2L four-necked bottle 2 SO 4 , 80.0g of 30% HCl, stirred and heated to 50-55°C. After stirring at 50-55°C for 1 hour, slowly add the prepared mixed solution of 3-fluoroaniline and hydroxylamine hydrochloride dropwise. After the dropwise addition, react at 75-80°C for 2 hours, and the reaction of 3-fluoroaniline is complete. Reduce the temperature of the kettle to 45-50°C, filter under reduced pressure, wash with water, and dry to obtain 112.9 g of a light brown solid with an HPLC content of 97.5%. The filtrate was adjusted to pH 7 with 10% NaOH, and 10% of water was distilled off for further use.

[0040] 146.0 g of polyphosphoric acid was put into a 1 L four-necked bottle, and 45.0 g ...

Embodiment 3

[0041] Embodiment 3: the preparation of 5-fluoroisatin

[0042] Add 35.8g of 4-fluoroaniline, 80.0g of hydroxylammonium hydrochloride and 100.0g of water into a 250ml four-necked flask, and stir at 60°C for 0.5 hours. Add 400.0g water, 60.0g chloral hydrate, 200.0g anhydrous Na to another 1L four-necked bottle 2 SO 4 , 40.0g of 30% HCl, stirred and heated to 50-55°C. After stirring at 50-55°C for 1 hour, slowly add the prepared mixed solution of 4-fluoroaniline and hydroxylamine hydrochloride dropwise. After the dropwise addition, react at 75-80°C for 2 hours, and the reaction of 4-fluoroaniline is complete. Reduce the temperature of the kettle to 45-50°C, filter under reduced pressure, wash with water, and dry to obtain 56.2 g of a light brown solid with an HPLC content of 95.8%. The filtrate was adjusted to pH 7 with 10% NaOH, and 10% of water was distilled off for further use.

[0043] Put 50.0ml of boron trifluoride / tetrahydrofuran, 36.4g of N-(4-fluorophenyl)-2-(hydr...

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Abstract

The invention relates to a synthesis method of isatin derivatives, which comprises the following steps of: (1) under acidic conditions, reacting aniline derivatives with hydroxyl amine and trihalogen acetaldehyde at 30-90 DEG C to obtain N-(substituted phenyl)-2-(hydroxyl imino) acetamide; and (2) cyclizing the N-(substituted phenyl)-2-(hydroxyl imino) acetamide in the presence of strong acid orLewis acid as a catalyst to obtain the isatin derivatives. The invention has the advantages of high yield, less three wastes, simple technical processes, simple and convenient post-treatment, high product purity and low product cost.

Description

technical field [0001] The present invention relates to a synthetic method of isatin derivatives, in particular to a synthetic method of fluoroisatin. Background technique [0002] Isatin derivatives, especially fluoroisatin is an important pharmaceutical intermediate. For example, 7-fluoroisatin and 5,6-difluoroisatin are important drug intermediates. Isatin derivatives can be synthesized by Sandmeyer method, Stolle method, Martinet method, Gassman method and other methods. However, although the Sandmeyer method has good prospects for industrial application due to its cheap and easy-to-obtain raw materials, the yield of this method is low, which seriously affects the industrial application of this method. For example, the Sandmeyer synthesis method using 3,4-difluoroaniline as a raw material is reported in US Patent No. 4,833,270, and the total yield of the two steps of the method is only 39.8%. Moreover, a large amount of water is used as a solvent in the first step of ...

Claims

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Application Information

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IPC IPC(8): C07D209/38
Inventor 谈平忠杨亿
Owner 滨海康杰化学有限公司
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