One-pot series synthetic method of oxoindole

A technology of an indole oxide and a synthesis method, which is applied in the field of one-pot series synthesis of indole oxide, can solve the problems of difficulty in large-scale production, narrow substrate application range, narrow application substrate range and the like, and achieves convenient post-processing procedures. , Wide range of application, avoid the effect of solvents and reagents

Inactive Publication Date: 2013-09-18
EAST CHINA NORMAL UNIV
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Problems solved by technology

[0011] Starting from substituted chloroacetanilides: the method uses the reaction product of chloroacetyl chloride and substituted anilines as a substrate, and uses expensive palladium (II) acetate as a catalyst. Phenyldi-tert-butylphosphine is used as a ligand, and 1.5 equivalents of triethylamine needs to be added in addition. The reaction requires strict anhydrous and oxygen-free operation, and the operation is complicated. This method is only applicable to indoles with protective groups on nitrogen atoms. Synthesis of Indole (Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc., 2003, 125, 12084-12085.)
[0012] Starting from o-halogenated nitrobenzene: this method usually requires 2-4 steps, 2-3 column chromatography purifications, and expensive Palladium metal or difficult to handle Raney / Ni or toxic metal tin, complicated to handle (a, Simet, L. J. Org. Chem., 1963, 28, 3580 -3581. b, Quallich, G. J.; Morrissey, P. M. Synthesis 1993, 51. c, Sun, L.; Tran, N.; Tang, F.; App, H.; Hirth, P. ; McMahon, G.; Tang, C. J. Med. Chem. 1998,41, 2588-2603. d, Kraynack, E. A.; Dalgard, J. E.; Gaeta, F. C. A. Tetrahedron Lett.1998, 39, 7679-7682. e, Gurjar, M. K.; Murugaiah, A. M. S.; Reddy, D. S. Org. Proc. Res. Dev. 2003, 7, 309-312. f, Cao, J. R.; Gao, H.; Bemis, G.; Salituro, F.; Ledeboer, M.; Harrington, E.; Wilke, S.; Taslimi, P.; Pazhanisamy, S.; Xie, X. L.; Jacobs, M.; Green, J. Bioorg. Med. Chem. Lett.2009, 19, 2891-2895 .)
[0013]Oxindole is an important pharmaceutical and chemical intermediate with a wide range of uses, but the existing synthetic methods not only have cumbersome steps, difficult sources of raw materials, high production costs, and low The scope of application of materials is narrow, making large-scale production face many difficulties

Method used

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  • One-pot series synthetic method of oxoindole
  • One-pot series synthetic method of oxoindole
  • One-pot series synthetic method of oxoindole

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preparation example Construction

[0052] The specific steps of the one-pot tandem synthesis method of the present invention comprise successively:

[0053] 1) Aromatic nucleophilic substitution reaction: add malonate, base MB, and the first solvent in sequence in the reaction bottle, heat to 25°C~60°C and stir, cool to room temperature, add o-nitrohalide containing substituents After substituting benzene, reheat to 25°C~160°C and stir until the reaction raw materials are completely converted;

[0054] 2) Krapcho deesterification reaction: After the above step 1) the aromatic nucleophilic substitution reaction is complete, heat to 110-180°C to remove the ester group until the deesterification reaction is completed;

[0055] 3) After the deesterification reaction in the above step 2) is completed, cool to room temperature, then add a second solvent such as acetic acid and a reducing agent, and heat to 25°C~150°C to react until TLC shows that the reaction is complete;

[0056] 4) The target product, oxidindole, ...

Embodiment 1

[0070] Oxindole 1 Synthesis:

[0071]

[0072] Dimethyl malonate (2.64 g, 20 mmol) was added to a mixture of potassium carbonate (2.76 g, 20 mmol) and 2.0 mL of anhydrous N, N-dimethylformamide, heated to 60 °C, and reacted for 20 After 1 min, cool to room temperature and add 2.0 mL o-chloronitrobenzene, reheat to 80°C, react for 2 h, follow the reaction process by TLC, when the conversion of raw materials is basically complete, directly heat to 160°C, follow the reaction by TLC, react for 20 After cooling to room temperature for h, 20 mL of acetic acid and iron powder (1.12 g, 20 mmol) were added directly, and then heated to 90°C for 1 h, followed by TLC until the reaction was complete. Stop the reaction, remove excess acetic acid under reduced pressure, add 20 mL of ethyl acetate to dissolve, wash the filtrate with 2 × 20 mL of 10% aqueous hydrochloric acid, dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, perform silica gel column chromatogr...

Embodiment 2

[0074] 6-Chloroindole 2 Synthesis:

[0075]

[0076] Diethyl malonate (640 mg, 4.0 mmol) was added to a mixture of potassium carbonate (552 mg, 4.0 mmol) and 2.0 mL of anhydrous dimethyl sulfoxide, heated to 35 °C, reacted for 30 min and cooled to room temperature, then add 2, 5-dichloronitrobenzene (384 mg, 2.0 mmol), and then reheat to 45 ° C for 2 h, TLC to track the reaction progress, when the raw material is basically converted, directly heated to 120 ° C, TLC Follow the reaction, continue to react for 8 h, then cool to room temperature, then directly add 2.0 mL of hydrochloric acid aqueous solution (1.0 mol / L), zinc powder (130 mg, 2.0 mmol), reheat to 30 ° C for 1 h, TLC traces the reaction progress to The response is complete. Stop the reaction, add 20 mL of ethyl acetate to dissolve, wash the filtrate with 2 × 20 mL of 10% aqueous hydrochloric acid, dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and obtain the product by silica gel...

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Abstract

The invention discloses a one-pot series synthetic method of oxoindole, which comprises the following steps of: sequentially adding malonate, alkali, a first solvent, a reducing agent and a second solvent, carrying out aromatic nucleophilic substitution reaction, ester group removal reaction, reduction ring-closing reaction, and column chromatography separation on a raw material halogenated ortho-nitroaniline containing a substituent group in turn so as to obtain oxoindole, wherein a by-product metal salt of the aromatic nucleophilic substitution reaction is directly used as a promoter for the ester group removal reaction. The method disclosed by the invention has the advantages of good substrate universality, wide raw material sources, low cost, mild reaction conditions, is simple to operate, and is capable of avoiding environmental pollution, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic compound technology application and relates to a synthesis method of oxindole, in particular to a one-pot serial synthesis method of oxindole. Background technique [0002] Oxindole A, also known as 2-indolinone and 1,3-dihydro-indol-2-one, is a class of important pharmaceutical and chemical intermediates with high application value. Starting from such synthetic building blocks, some natural products and drug molecules with strong biological activity can be conveniently synthesized, such as Ropinirole, Tenidap, Ziprasidone, Wasalexin A , B, SU5416, SU6668, SU9516, SU11248, etc. [0003] [0004] Currently, oxindole can be synthesized by the following methods: [0005] Oxidation from indole: This method is only applicable to the synthesis of oxindole with substituents at C3, and it is easy to obtain oxindole with halogenated C3 (R. L. Hinman, C. P. Bauman. J. Org. Chem. , 1964, 29 , 1206-121...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/34
Inventor 周剑
Owner EAST CHINA NORMAL UNIV
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