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Synthetic method of BRONUCK intermediate 7-(p-bromobenzoyl)indole-2-one

A bromobenzoyl and synthetic method technology, applied in the field of organic chemical synthesis, can solve problems such as difficult to accept metal species addition, difficult to realize cyano addition reaction, increase of electron cloud density of benzene ring, etc., and achieve significant economic value and the effect of application potential

Active Publication Date: 2019-04-12
WENZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] A. Coordination problem: Since the imino group is easy to coordinate with the transition metal catalyst, the catalyst is deactivated, and it is difficult to realize the addition reaction to the cyano group;
[0019] B. Electronic effect problem: Since the imino group belongs to the strong first type of positioning group, the electron cloud density of the benzene ring increases, making the carbon atom of the cyano group difficult to accept the addition of metal species, thus making the reaction difficult to proceed
[0020] In summary, there are many problems in the existing synthesis process of the key intermediate of the non-steroidal anti-inflammatory analgesic drug Pronacol, such as cumbersome reaction steps, harsh reaction conditions, and low yield, which need to be solved urgently. The synthesis of the inflammatory drug analgesic pronaac has important theoretical and research value

Method used

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  • Synthetic method of BRONUCK intermediate 7-(p-bromobenzoyl)indole-2-one
  • Synthetic method of BRONUCK intermediate 7-(p-bromobenzoyl)indole-2-one
  • Synthetic method of BRONUCK intermediate 7-(p-bromobenzoyl)indole-2-one

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] The reaction formula is as above, and the concrete reaction process is as follows:

[0053] At room temperature, add 100mmol 7-cyanoindol-2-one, 200mmol p-bromophenylboronic acid, 15mmol nickel catalyst Ni(dppe)Cl to an appropriate amount of solvent (2-methyltetrahydrofuran) in the reaction vessel 2 And 400mmol trifluoromethanesulfonic acid, then stirred and warmed up to 70 ° C, and stirred at this temperature for 24 hours.

[0054] After the reaction was completed, the reaction mixture was rotary evaporated to dryness, then a sufficient amount of ethyl acetate was added to dissolve it, and then an appropriate amount of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride was added for washing, and the organic layer and the aqueous solution were separated. Aqueous layer, after the aqueous layer was extracted 3 times with ethyl acetate, the organic layer was combined (that is, the organic layer obtained by combining the organic layer washed with the...

Embodiment 2

[0056] The reaction formula is as above, and the concrete reaction process is as follows:

[0057] At room temperature, add 100mmol 7-cyanoindol-2-one, 400mmol p-bromophenylboronic acid, 5mmol nickel catalyst Ni(dppe)Cl to an appropriate amount of mixed solvent (2-methyltetrahydrofuran) in the reaction vessel 2 and 500 mmol trifluoromethanesulfonic acid, then stirred and heated to 100 ° C, and stirred at this temperature for 12 hours.

[0058] After the reaction was completed, the reaction mixture was rotary evaporated to dryness, then a sufficient amount of ethyl acetate was added to dissolve it, and then an appropriate amount of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride was added for washing, and the organic layer and the aqueous solution were separated. Aqueous layer, after the aqueous layer was extracted 3 times with ethyl acetate, the organic layer was combined (that is, the organic layer obtained by combining the organic layer washed with...

Embodiment 3

[0060] The reaction formula is as above, and the concrete reaction process is as follows:

[0061] At room temperature, add 100mmol 7-cyanoindol-2-one, 300mmol p-bromophenylboronic acid, 10mmol nickel catalyst Ni(dppe)Cl to an appropriate amount of mixed solvent (2-methyltetrahydrofuran) in the reaction vessel 2 And 450mmol trifluoromethanesulfonic acid, then stirred and warmed up to 80 ° C, and stirred at this temperature for 18 hours.

[0062] After the reaction was completed, the reaction mixture was rotary evaporated to dryness, then a sufficient amount of ethyl acetate was added to dissolve it, and then an appropriate amount of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride was added for washing, and the organic layer and the aqueous solution were separated. Aqueous layer, after the aqueous layer was extracted 3 times with ethyl acetate, the organic layer was combined (that is, the organic layer obtained by combining the organic layer washed wi...

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Abstract

The invention relates to a synthetic method of BRONUCK intermediate 7-(p-bromobenzoyl)indole-2-one. The method comprises the following step: performing a reaction on 7-cyanooxindole-2-one and p-bromophenylboronic acid in a solvent in the presence of a nickel catalyst and an acid accelerant to obtain the 7-(p-bromobenzoyl)indole-2-one. The method provided by the invention overcomes a plurality of defects existing in the prior art by comprehensive selection of a suitable reaction system, the target product can be obtained in a high yield, so that an easily-available raw material is provided forsynthesis of BRONUCK, an the BRONUCK intermediate has significant economic value and application potentiality in the field of pharmaceutical synthesis of the BRONUCK.

Description

technical field [0001] The present invention relates to a kind of synthetic method of pronacol intermediate, more specifically relate to a kind of synthetic method of 7-(p-bromobenzoyl) indol-2-one (the key intermediate of synthesizing pronacor) , belonging to the field of organic chemical synthesis. Background technique [0002] Pronaque ( Bromfenac Sodium Hydrate Eye Drops) is a non-steroidal anti-inflammatory analgesic ophthalmic drug jointly developed by Senju Company of Japan and Wyeth-Ayerst Company of the United States. Blepharitis, conjunctivitis and postoperative inflammation. Its active ingredient is Bromfenac sodium (Bromfenac sodium), the chemical name is 2-amino-3-(4-bromobenzoyl) sodium phenylacetate, and its structural formula is as follows: [0003] [0004] 7-(p-bromobenzoyl) indol-2-one itself is a very important nitrogen-containing heterocyclic compound, which can be widely used in drug synthesis, for example, it is the key intermediate for the synt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/34
CPCC07D209/34
Inventor 陈久喜邵银林程天行甄茜茜戚林军李国兴
Owner WENZHOU UNIVERSITY
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