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Process for preparing 2-oxindoles and N-hydroxy-2-oxindoles

A technology of oxindole and hydroxyl, applied in the field of preparing 2-oxindole and N-hydroxy-2-oxindole, can solve the problem of many reaction steps and undisclosed methyl 4-chloro-2-nitrophenyl acetate Issues such as ester preparation and separation

Inactive Publication Date: 2002-01-30
CATALYTICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is that there are many reaction steps, the intermediate solid is separated, and the preparation and separation of the undisclosed 4-chloro-2-nitrophenylacetic acid methyl ester is also included

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Preparation of dimethyl 4-chloro-2-nitrophenylmalonate from 2,5-dichloronitrobenzene and dimethyl malonate

[0072] A solution of dimethyl malonate (30.25g, 0.229mol) and dimethylformamide (80ml) was heated to 45°C and treated with a solution of 25% sodium methoxide in methanol (50ml). Methanol was distilled off at a vacuum degree of 300 mmHg, and 54 mL of methanol was distilled off at a final temperature of 95°C. The resulting mixture of sodium dimethyl malonate in dimethylformamide was cooled to 80 °C, and 2,5-dichloronitrobenzene (20.0 g, 0.104 mol) in dimethylformamide was added thereto in 10 minutes. (20ml). The reaction mixture was heated at 95°C for 2 hours to complete the reaction to form sodium dimethyl 4-chloro-2-nitrophenylmalonate. 55 mL of dimethylformamide was distilled off under reduced pressure at a vacuum degree of 40 mmHg. The reaction mixture was cooled and partitioned between water (120 mL) and toluene (100 mL). 6N HCl (25 mL) was then added to p...

Embodiment 2

[0075] Preparation of 6-chloro-2-oxindole from dimethyl 4-chloro-2-nitrophenylmalonate

[0076] Dimethyl 4-chloro-2-nitrophenylmalonate (30g, 0.104mol, the oil obtained according to the method of Example 1), 5% Pt / C (0.15g), acetic acid (83mL) and water (3 mL) into the autoclave. The sealed reactor was purged with nitrogen and then fed with hydrogen to 75 psig. The reaction mixture was mixed with hydrogen with rapid stirring and heated to 65°C and reacted at this temperature under a hydrogen pressure of 75 psig until no hydrogen uptake was observed. The reaction mixture was heated to 100°C to effect the hydrolysis and decarboxylation of the intermediate 3-methoxyoxindole. The gas phase containing carbon dioxide was vented, hydrogen was added to reach 75 psig, and the hydrogenolysis of N-hydroxyoxindole to oxindole was completed by heating at 105°C and 75 psig hydrogen pressure for 3.5 hours. The reaction mixture was cooled to 60° C., the catalyst was filtered off, and filte...

Embodiment 3

[0079] Preparation of dimethyl 5-chloro-2-nitrophenylmalonate from 2,4-dichloronitrobenzene and dimethyl malonate

[0080] A solution of dimethyl malonate (30.25g, 0.229mol) and dimethylformamide (80ml) was heated to 40-50°C and treated with a solution of 25% sodium methoxide in methanol (50ml). Methanol was distilled off at a vacuum of 300mmHg, and the final reaction conditions were a temperature of 95°C and 200mmHg. The resulting mixture of sodium dimethyl malonate in dimethylformamide was placed in an oil bath at 70° C., and 2,4-dichloronitrobenzene (20.0 g, 0.104 mol) was added thereto within 30 minutes. A solution in dimethylformamide (20ml). The reaction mixture was slowly heated to 95°C (for 2.5 hours) to complete the reaction between 2,5-dichloronitrobenzene and sodium dimethyl malonate. Dimethylformamide (50 mL) was distilled off at a vacuum of 40 mmHg. The reaction mixture was partitioned between water (120 mL) and toluene (100 mL). 6N HCl (18 mL) was then added ...

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Abstract

The present invention provides a processes, having practical utility, for preparing 2-oxindoles, N-hydroxy-2-oxindoles, or mixtures thereof comprising: catalytically hydrogenating a 2-nitroarylmalonate diester to produce a 2-(N-hydroxyamino)arylmalonate diester, a 2-aminoarylmalonate diester, or mixtures thereof as a first reaction intermediate; cyclizing, by intramolecular aminolysis of one ester group, the first reaction intermediate to produce a N-hydroxy-2-oxindole-3-carboxylate ester, 2-oxindole-3-carboxylate ester, or mixtures thereof as a second reaction intermediate; and hydrolyzing and decarboxylating the remaining ester group of the second reaction intermediate to produce the N-hydroxy-2-oxindole, the 2-oxindole, or mixtures thereof, wherein the cyclization reaction and the hydrolysis and decarboxylation reaction are conducted in situ with the catalytic hydrogenation reaction without isolation of said reaction intermediates.

Description

field of invention [0001] The present invention relates to a process for the preparation of 2-oxindole and N-hydroxy-2-oxindole. 2-Oxindole is commonly referred to as 2-oxoindoline and indol-2(3H)-one, and oxindole as used herein refers to 2-oxindole. More particularly, the present invention relates to the reduction of 2-nitroaryl malonate diesters to prepare 2-oxindole and N-hydroxy-2-oxindole. It also relates to the preparation of 2-nitroarylmalonate diesters from 2-halogenated nitroarenes, followed by reduction to 2-oxindole or N-hydroxy-2-oxindole. [0002] 2-Oxindole is a valuable pharmaceutical agent and / or an intermediate used in the preparation of pharmaceutical agents, including analgesics and anti-inflammatory agents (U.S. Patent No. 4,721,712), anxiolytics (U.S. Patent No. 3,882,236) , and sleep-inducing agents (U.S. Patent No. 4,160,032). N-Hydroxy-2-oxindole is used as an intermediate in the preparation of certain 5-substituted-2-oxindole (U.S. Patent No. 5,210...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C201/12C07C205/56C07D209/34
CPCC07C205/56C07C253/30C07D209/34C07C201/12C07C255/41
Inventor D·J·M·格鲁斯R·A·布尔斯J·H·格雷斯
Owner CATALYTICA
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