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Synthesis method of bufotenin and quaternary ammonium salt thereof and application in preparation of analgesic and anti-inflammatory drugs

A technology of bufotryptamine and its synthesis method, which is applied in the application fields of analgesia, synthesis of bufotryptamine and its quaternary ammonium salt, and anti-inflammatory drugs, and can solve the problem of unsuitable industrial production, highly toxic reagents, and unsuitable In line with the concept of green chemistry and other issues, to achieve the effect of easy purification and separation, low cost and high purity of synthetic products

Active Publication Date: 2020-02-11
马宏跃
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The whole route realizes the synthesis of bufotryptamine with a theoretical total yield of 23.9%, but some reagents are highly toxic (hydrazine hydrate), which does not conform to the concept of green chemistry, so this synthetic route is not suitable for industrial production

Method used

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  • Synthesis method of bufotenin and quaternary ammonium salt thereof and application in preparation of analgesic and anti-inflammatory drugs
  • Synthesis method of bufotenin and quaternary ammonium salt thereof and application in preparation of analgesic and anti-inflammatory drugs
  • Synthesis method of bufotenin and quaternary ammonium salt thereof and application in preparation of analgesic and anti-inflammatory drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Preparation of 2-(5-(benzyloxy)-1H-indol-3-yl)-2-oxoacetyl chloride (S-1)

[0043] At room temperature, take a 100mL round-bottomed flask, add 2.7mL of anhydrous diethyl ether, oxalyl chloride (175μL, 2.0mmol) in sequence, and stir well, then add 5-benzyloxyindole (220mg, 1.0mmol) into the flask , after fully stirring for 30 minutes, the reaction solution was suction-filtered, and the filter cake was washed repeatedly with ether to obtain about 302.9 mg of a reddish-brown solid precipitate, which was the crude product of S-1, with a yield of 95%.

[0044]

[0045] Preparation of 2-(5-(benzyloxy)-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (S-2)

[0046] At room temperature, take a 100mL round bottom flask, add potassium hydroxide (360mg, 6.38mmol) and 4.15mL water and dimethylamine hydrochloride (350mg, 4.25mmol) in turn, mix well, take S-1 (310mg , 1.0mmol) was slowly added to the mixed solution, stirred for 40 minutes, suction filtered, washed with anhydrous ether ...

Embodiment 2

[0062] Preparation of 2-(5-(benzyloxy)-1H-indol-3-yl)-2-oxoacetyl chloride (S-1)

[0063]At room temperature, take a 100mL round-bottomed flask, add 2.7mL of anhydrous diethyl ether, oxalyl chloride (175μL, 2.0mmol) in sequence, and stir well, then add 5-benzyloxyindole (220mg, 1.0mmol) into the flask , after fully stirring for 30 minutes, the reaction solution was suction-filtered, and the filter cake was washed repeatedly with ether to obtain about 299.8 mg of a reddish-brown solid precipitate, which was the crude product of S-1, with a yield of 94%.

[0064]

[0065] Preparation of 2-(5-(benzyloxy)-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (S-2)

[0066] At room temperature, take a 100mL round-bottomed flask, add sodium hydroxide (170mg, 4.25mmol) and 4.15mL water and dimethylamine hydrochloride (350mg, 4.25mmol) in turn, mix well, take S-1 (310mg , 1.0mmol) was slowly added to the mixed solution, stirred for 40 minutes, suction filtered, washed with anhydrous ether to...

Embodiment 3

[0082] Preparation of 2-(5-(benzyloxy)-1H-indol-3-yl)-2-oxoacetyl chloride (S-1)

[0083] At room temperature, take a 100mL round-bottomed flask, add 2.7mL of anhydrous diethyl ether, oxalyl chloride (175μL, 2.0mmol) in sequence, and stir well, then add 5-benzyloxyindole (220mg, 1.0mmol) into the flask , after fully stirring for 40 minutes, the reaction solution was suction-filtered, and the filter cake was washed repeatedly with ether to obtain about 293.1 mg of a reddish-brown solid precipitate, which was the crude product of S-1, with a yield of 95%.

[0084]

[0085] Preparation of 2-(5-(benzyloxy)-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (S-2)

[0086] At room temperature, take a 100mL round-bottomed flask, add sodium hydroxide (255mg, 6.38mmol) and 4.15mL water and dimethylamine hydrochloride (350mg, 4.25mmol) in turn, mix well, take S-1 (310mg , 1.0mmol) was slowly added to the mixed solution, stirred for 40 minutes, suction filtered, washed with anhydrous ether t...

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Abstract

The invention relates to a synthesis method of bufotenin and quaternary ammonium salt thereof. The method has the characteristics of simple steps, safe and convenient operation, high reaction efficiency, easy purification and separation, mild conditions and low cost, the total reaction yields of bufotenin and quaternary ammonium salt thereof are respectively greater than 65% and 60%, the purity ofthe synthesized product is high (greater than 99.0%), and the synthesis method is suitable for industrial production. A large number of experiments are carried out for screening, and heat pain and mechanical pain behavioral evaluation and phospholipidomics evaluation are combined to compare the activity of several tryptamine components, and the result shows that the bufotenin quaternary ammoniumsalt has the optimal analgesic effect, and also has a synergistic effect with morphine.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular, the invention relates to a synthesis method of bufotryptamine and its quaternary ammonium salt, and the application of the preparation in analgesic and anti-inflammatory drugs. Background technique [0002] The N,N-methylated product of serotonin (bufotryptamine) has the structure of formula (1), and its quaternary ammonium salt has the structure of formula (2). [0003] [0004] Bufotryptamine, as the N,N-dimethylation product of serotonin, was originally found in toads, hence the name bufotryptamine, which exists in frogs and toad skins, mushrooms, advanced plants and mammals; It has also been reported in the brain, plasma and urine of patients with schizophrenia. There are bufotryptamine and its quaternary ammonium salts in Bufoni, because strong acids (such as trifluoroacetic acid) and alkaline solvents are often used in previous chromatographic separation and purification...

Claims

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Application Information

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IPC IPC(8): C07D209/14A61K31/4045A61P29/00
CPCA61P29/00C07D209/14
Inventor 马宏跃李念光段金廒周婧
Owner 马宏跃
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