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Preparation method of 2-bromoindolizine derivative

The technology of a derivative, brominzine, is applied in the field of preparation of 2-bromoinzine derivatives, which can solve the problems of increasing the use of reagents and solvents, cumbersome operation steps, and long time consumption, so as to avoid the loss of resources and energy, and the boiling point High, reduce time consumption effect

Inactive Publication Date: 2020-06-02
HUAIYIN TEACHERS COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The reaction needs to be carried out step by step, and the pyrrole-substituted cinnamonitrile derivative needs to be separated and purified, which increases the use of reagents and solvents, and the operation steps are cumbersome and time-consuming

Method used

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  • Preparation method of 2-bromoindolizine derivative
  • Preparation method of 2-bromoindolizine derivative
  • Preparation method of 2-bromoindolizine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1: The preparation method of 2-bromoindolizine derivatives.

[0030] Step 1) In a 25mL round bottom flask, add brominated acetophenonyl-4-cyanopyridine quaternary ammonium salt (2.0mmol), 1-bromoethynyl-4-methylbenzene (1.0mmol), tetramethylpiperidine Pyridine nitrogen oxide (2.0 mmol), potassium carbonate (3.0 mmol) and 2 mL of dimethyl sulfoxide were reacted at 90°C for 2 hours;

[0031] Step 2) After the reaction is over, the resulting mixture is poured into water, extracted, dried, and separated by column chromatography to obtain pure product 3-benzoyl-2-bromo-1-(4-methylphenyl)indazine-7 - Nitrile, structural formula is as follows:

[0032]

[0033] The yield of pure 2-bromoindolizine derivative is 82%, and the product is a yellow solid.

[0034] Such as figure 1 Shown, is the proton nuclear magnetic resonance spectrogram of the 2-bromoinzine derivative pure product that makes in this embodiment: (DMSO-d 6 , 400MHz) (δ, ppm): 9.31(d, J=7.6Hz, 1H),...

Embodiment 2

[0035] Embodiment 2: The preparation method of 2-bromoindolizine derivatives.

[0036] Step 1) In a 25mL round bottom flask, add acetophenonyl bromide-4-cyanopyridinium quaternary ammonium salt (2.0mmol), bromoethynylbenzene (1.0mmol), tetramethylpiperidine nitrogen oxide (2.0mmol ), potassium carbonate (3.0mmol) and dimethyl sulfoxide 2mL, reacted at 90°C for 2 hours;

[0037] Step 2) After the reaction is finished, the resulting mixture is poured into water, extracted, dried, and separated by column chromatography to obtain pure product 3-benzoyl-2-bromo-1-phenylindazine-7-carbonitrile, the structural formula is as follows:

[0038]

[0039] The yield of pure 2-bromoindolizine derivatives prepared by this method is 82%, and the product is a yellow solid.

[0040] Such as figure 2 Shown, it is the 2-bromoinzine derivative pure product proton nuclear magnetic resonance spectrogram that makes in this embodiment: (DMSO-d 6 , 400MHz) (δ, ppm): 9.31(d, J=6.8Hz, 1H), 7.89(s,...

Embodiment 3

[0041] Embodiment 3: A kind of preparation method of 2-bromoindolizine derivative.

[0042] Step 1) In a 25mL round bottom flask, add 4-methoxyacetophenonyl-4-cyanopyridine quaternary ammonium bromide (2.0mmol), bromoethynylbenzene (1.0mmol), tetramethylpiperidine nitrogen Oxide (2.0mmol), potassium carbonate (3.0mmol) and 2mL of dimethyl sulfoxide were reacted at 90°C for 2 hours;

[0043] Step 2) After the reaction, the resulting mixture is poured into water, extracted, dried, and separated by column chromatography to obtain pure product 3-(4-methoxybenzoyl)-2-bromo-1-phenylindazine- 7-Nitrile, the structural formula is as follows:

[0044]

[0045] The yield of pure 2-bromoindolizine derivatives obtained by this method is 68%, and the product is a yellow solid.

[0046] Such as image 3 Shown, it is the 2-bromoinzine derivative pure product proton nuclear magnetic resonance spectrogram that makes in this embodiment: (DMSO-d 6 , 400MHz) (δ, ppm): 9.08(d, J=7.6Hz, 1H),...

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Abstract

The invention discloses a preparation method of a 2-bromoindolizine derivative. The preparation method comprises the following steps: putting bromoacetophenone-4-cyanopyridine quaternary ammonium salt, bromoethynylbenzene, tetramethyl-1-piperidinyloxy, potassium carbonate and a solvent into a reactor, and reacting at 90 DEG C; and after the reaction is finished, pouring the obtained mixture into water, and carrying out extraction, drying and column chromatography separation to obtain the pure 2-bromoindazine derivative. The used raw materials can be directly purchased, are easy to obtain and are low in price. The used solvent has high boiling point, is non-volatilize and is safe to operate and use. The synthesis method is wide in substrate application range, and synthesis of the target product with various structures is easy to realize. The target product can be obtained by the only one-step reaction in the technological process, and the reaction is completed within 2 h. The method avoids resource and energy loss caused by separation of intermediates and tedious operation caused by the step-by-step reaction, reduces time consumption, and greatly improves the synthesis efficiency.

Description

technical field [0001] The invention relates to a preparation method of 2-bromoindolizine derivatives, belonging to the technical field of organic compound synthesis. Background technique [0002] Indolizines are an important class of organic synthesis intermediates with broad-spectrum physiological and pharmacological activities (Organic Letters, 2015, 17, 1822). Among them, 2-bromoindolizine can be used to synthesize epidermal growth factor receptor variant inhibitors (Bioorganic & Medicinal Chemistry, 2017, 25, 6563). The development of simple and efficient methods to synthesize such compounds is of great significance to the development and research of new drugs. [0003] At present, the preparation method of the 2-bromoindolizine derivative of bibliography mainly contains following two kinds: [0004] 1) With 4-bromopyrrole-2-formaldehyde and 1,2-dicyanoethylene as raw materials, tetrahydrofuran as a solvent, under the action of triethylphosphine, react for 8 hours to ...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 王翔胡华友张载超支三军陈平陶晓晨姬心悦
Owner HUAIYIN TEACHERS COLLEGE
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