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Adamantane amine derivative as well as preparation method and application of derivative

A technology for amantadine and adamantanecarboxamide, applied in the field of amantadine derivatives and their preparation, can solve the problems of complex preparation method steps, single type of groups and the like, and achieve prevention and treatment of biological activity and cell death rate. The effect of reducing and protecting nerve cells

Inactive Publication Date: 2015-06-10
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The above three preparation methods have complex steps, and the types of groups introduced on the 2-position carbon atom are single, and it is impossible to construct structurally diverse amantadine molecules on the 2-position carbon atom

Method used

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  • Adamantane amine derivative as well as preparation method and application of derivative
  • Adamantane amine derivative as well as preparation method and application of derivative
  • Adamantane amine derivative as well as preparation method and application of derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: the synthesis of compound A-1

[0042] S1 Add 15 mL of thionyl chloride to 3,5-dimethyladamantane-1-carboxylic acid (28.8 mmol, 6 g), drop 3 drops of DMF into the solution, reflux at 80°C for 2 hours, and spin the reaction solution to dryness Remove excess thionyl chloride. The residue was dissolved in 50 mL of anhydrous toluene, 2,3,5,6-tetrafluoro-4-(trifluoromethyl)aniline (14 mmol, 3.4 g) was added, and the mixture was refluxed at 120° C. for 12 hours. Spin to dry the solvent of the reaction solution, and recrystallize from petroleum ether to obtain 3,5-dimethyl-N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-1-adamantane Formamide, white solid, yield 64% (based on aniline).

[0043]

[0044]3,5-Dimethyl-N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-1-adamantanecarboxamide

[0045] S2: 3,5-dimethyl-N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-1-adamantanecarboxamide (0.1mmol), Pd( TFA) 2 (0.01mmol), m-chloroiodobenzene (0.5mmol), PPh...

Embodiment 2

[0054] Embodiment 2: the synthesis of compound A-2

[0055] S1: Add 1-adamantanecarboxylic acid (40.8mmol, 7.4g) to 16ml of thionyl chloride solution, then drop 3 drops of DMF, reflux at 80°C for 2 hours, and spin the reaction solution to dry to remove excess dichloride. Thionyl chloride. The residue was dissolved in 50 mL of anhydrous toluene, 2,3,5,6-tetrafluoro-4-(trifluoromethyl)aniline (10 mmol, 2.4 g) was added, refluxed at 120 ° C for 12 hours, and the solvent of the reaction solution was spin-dried. Recrystallization from petroleum ether gave N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-1-adamantanecarboxamide, white solid, yield 73% (based on aniline) .

[0056]

[0057] N-(2,3,5,6-Tetrafluoro-4-(trifluoromethyl)phenyl)-1-adamantanecarboxamide

[0058] S2. Weigh the obtained in step S1. N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-1-adamantanecarboxamide (0.1mmol), Pd(TFA) 2 (0.01mmol), p-iodoanisole (0.5mmol), PPh 3 (0.05mmol), CsF (0.3mmol) and n-h...

Embodiment 3

[0066] Embodiment 3: the synthesis of compound A-3

[0067] The preparation method and steps were the same as in Example 2, except that the intermediate chloroiodobenzene (0.5 mmol) in the S2 step was replaced with iodoethane (0.5 mmol) to obtain the final product A-3, a white solid, with a yield of 55%.

[0068]

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Abstract

The invention provides a preparation method of an adamantane amine derivative. The preparation method comprises the following steps: performing an amidation reaction on an adamantane formic acid compound to generate an adamantane amide formate compound, and then reacting the adamantane amide formate compound with a heterocyclic aromatic halogenated substance, an aryl halogenated substance, an aliphatic alkyl halogenated substance, a halogen molecular, a metal or metalloid reagent or a high-valence iodide in the presence of additives under the catalytic action of a transitional metal catalyst, thereby generating an adamantane formamide C2 derivatization product; next, performing a hydrolysis reaction on the adamantane formamide C2 derivatization product to obtain an adamantane carboxylic acid derivative; and finally, performing a rearrangement reaction on the adamantane carboxylic acid derivative, thereby obtaining the adamantane amine derivative. The preparation method is capable of importing groups of rich types to two C atoms of the adamantane and also capable of constructing adamantane amine molecules diversified in structure on the two C atoms.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to an amantadine derivative and a preparation method and application thereof. Background technique [0002] In 1964, Davies, W.L. found that amantadine has antiviral effect and can be used for the prevention and treatment of type A influenza virus. Through decades of research on amantadine compounds and their derivatives, it has been shown that adamantyl-containing compounds have a wide range of physiological activities, such as anti-virus (influenza, herpes, hepatitis C, HIV), anti-diabetes, anti- Central system diseases (Parkinson's disease, Alzheimer's disease). For example, amantadine hydrochloride can be used for primary Parkinson's disease, Parkinson's syndrome after encephalitis, drug-induced extrapyramidal reaction, Parkinson's syndrome after carbon monoxide poisoning, and Parkinson's syndrome with cerebral arteriosclerosis in the elderly sign. It can also b...

Claims

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Application Information

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IPC IPC(8): C07C211/41C07C209/00C07C209/56C07C219/24C07C213/02C07C211/38C07C217/74A61P31/16A61P25/00
Inventor 王洪根劳业兴吴家强张尚师
Owner SUN YAT SEN UNIV
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