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

Imported: 23 Feb '17 | Published: 22 Oct '02

John M. Gruber, A. Ray Bulls, John H. Grate

USPTO - Utility Patents

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.

Claims

1. A process for preparing a 2-oxindole, a N-hydroxy-2-oxindole, or mixtures thereof, comprising:

2. The process of claim 1, further comprising:

3. A process of claim 1, wherein the 2-nitroarylmalonate diester starting material is prepared by a process comprising:

4. The process of claim 3, further comprising:

5. A process of claim 1, wherein the 2-nitroarylmalonate diester starting material is prepared by a process comprising:

6. The process of claim 5, further comprising:

7. The process of claim 1,

2,

3,

4,

5, or

6 wherein the 2-oxindole is selected from the group consisting of 5-chloro-2-oxindole, 5-bromo-2-oxindole, 6-chloro-2-oxindole, 6-bromo-2-oxindole, and 6-methoxy-2-oxindole.

8. The process of claim 1,

2,

3,

4,

5, or

6 wherein the N-hydroxy-2-oxindole is selected from the group consisting of N-hydroxy-5-chloro-2-oxindole, N-hydroxy-5-bromo-2-oxindole, N-hydroxy-6-chloro-2-oxindole, N-hydroxy-6-bromo-2-oxindole, and N-hydroxy-6-methoxy-2-oxindole.

9. The process of claim 1,

2,

3,

4,

5, or

6 wherein the 2-nitroarylmalonate diester is a dimethyl 2-nitroarylmalonate.

10. The process of claim 1,

2,

3,

4,

5, or

6 wherein the hydrogenation catalyst is selected from the group consisting of palladium and platinum.

11. The process of claim 10 wherein the hydrogenation catalyst is supported on carbon.

12. The process of claim 1,

2,

3,

4,

5, or

6 wherein the process converting the 2-nitroarylmalonate diester to the 2-oxindole, a N-hydroxy-2-oxindole, or mixtures thereof is conducted at a temperature from 20 to 150° C. and at a hydrogen pressure from 1 to 20 atmospheres.

13. The process of claim 1,

2,

3,

4,

5, or

6 wherein the process converting the 2-nitroarylmalonate diester to the 2-oxindole, a N-hydroxy-2-oxindole, or mixtures thereof is conducted in a solvent comprising an alcohol, an ester, a carboxylic acid, or mixtures thereof.

14. The process of claim 13 wherein the solvent comprises ethanol, acetic acid, or mixtures thereof.

15. The process of claim 5 or 6 wherein the alcoholysis reaction comprises an acid catalyzed methanolysis reaction.

16. The process of claim 15 wherein the methanolysis reaction comprises:

17. The process of claim 5 or 6 wherein the 2-nitroaryl--cyanoacetate ester is methyl 2-nitroaryl--cyanoacetate.

18. The process of claim 5 or 6 wherein the cyanoacetate ester anion is provided by a process comprising:

19. The process of claim 3 or 4 wherein the malonate diester anion is provided by a process comprising: