N-protected-3,5-disubstituted indole derivative and its preparation method and application

A technology of indole derivatives and disubstitution, applied to N-protection-3, which can solve the problems of harsh reaction conditions, expensive reagents, unfavorable large-scale production, etc., and achieve the effect of shortening the reaction steps, not easy to store, and easy to operate

Inactive Publication Date: 2015-11-18
SHANGHAI INST OF PHARMA IND CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The obtained indole-3-acetate is hydrolyzed to the corresponding acid, then the corresponding acid is converted to the acid chloride, and further converted to dimethylamide by reaction with dimethylamine in alkaline medium, and finally, the amide carbonyl The reduction of this route produces the desired compound. The total yield of this route is low, the reaction conditions are harsh, and the reagents used are expensive, which is also unfavorable for large-scale industrial production.

Method used

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  • N-protected-3,5-disubstituted indole derivative and its preparation method and application
  • N-protected-3,5-disubstituted indole derivative and its preparation method and application
  • N-protected-3,5-disubstituted indole derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] 2-[1-Benzyl-3-(2-dimethylaminoethyl)-5-indolyl]-2-sulfonylpyrrolidine]acetonitrile (III-1)

[0068] N 2 Under protection, add 2-(pyrrole-1-sulfonyl)acetonitrile (1.46g, 8.4mmo), toluene (7.2ml), ethylene glycol dimethyl ether (1.8ml) into a 25ml three-necked flask, and ice-bath to 0°C Add NaH (0.6g, 15mmol), stir at room temperature for 1h, ice-bath, add tetrakis(triphenylphosphinepalladium) (0.58g, 0.5mmol).

[0069] 2-[1-Benzyl-5-bromo-1H-indol-3-yl]-N,N-dimethylethylamine (2.4g, 6.72mmol) was dissolved in toluene and added dropwise to the above reaction solution , heated to 110°C, and reacted for 2h. Ice bath, add water and ethyl acetate to separate the liquid, dry the organic layer over anhydrous sodium sulfate, filter and concentrate, and separate through neutral alumina column (petroleum ether: ethyl acetate = 1:1, the same below) to obtain 2.73g of the product . Yield 90%.

[0070] 1 HNMR (400MHz, CDCl 3 ): 1.82(m, 4H), 2.03(s, 6H), 2.65(t, 2H), 2.93(t, 2H...

Embodiment 2

[0073] 2-[1-p-toluenesulfonyl-3-(2-dimethylaminoethyl)-5-indolyl]-2-sulfonylpyrrolidine]acetonitrile (III-2)

[0074] N 2 Under protection, add 2-(pyrrole-1-sulfonyl)acetonitrile (2g, 11.5mmo), toluene (24ml), ethylene glycol dimethyl ether (6ml) into a 100ml three-necked flask, ice-bath to about 0°C, add NaH (0.83g, 20.7mmol), stirred at room temperature for 1h, ice-bathed, added tetrakis(triphenylphosphine palladium) (0.8g, 0.69mmol).

[0075] 2-[1-p-toluenesulfonyl-5-bromo-1H-indol-3-yl]-N,N-dimethylethylamine (3.88g, 9.2mmol) was dissolved in toluene and added dropwise to the above reaction solution, heated to 80°C, reacted in an ice bath for 6 hours, added water and ethyl acetate to separate the layers, dried the organic layer over anhydrous sodium sulfate, concentrated by filtration, and separated by neutral alumina column to obtain 4.03 g of the product. Yield 85%.

[0076] 1 HNMR (400MHz, CDCl 3 ): 1.92(m, 4H), 2.26(s, 6H), 2.34(s, 3H), 2.55(t, 2H), 2.63(t, 2H), 2...

Embodiment 3

[0079] 2-[1-Trifluoroacetyl-3-(2-dimethylaminoethyl)-5-indolyl]-2-sulfonylpyrrolidine]acetonitrile (III-3)

[0080] N 2 For protection, add 2-(pyrrole-1-sulfonyl)acetonitrile (1.8g, 10.3mmo), nitrobenzene (18ml), ethylene glycol dimethyl ether (4.5ml) into a 50ml three-necked flask, and ice-bath to 0°C Add NaH (0.75g, 18.7mmol), stir at room temperature for 1h, ice-bath, add tetrakis(triphenylphosphine palladium) (0.7g, 0.6mmol).

[0081] 2-[1-Trifluoroacetyl-5-bromo-1H-indol-3-yl]-N,N-dimethylethylamine (3g, 8.2mmol) was dissolved in nitrobenzene and added dropwise to the above In the reaction solution, heated to 150°C, reacted for 0.5h, ice-bathed, added water and ethyl acetate to separate the liquid, the organic layer was dried over anhydrous sodium sulfate, concentrated by filtration, and separated by neutral alumina column to obtain 3.2g of the product. Yield 85%.

[0082] 1 HNMR (400MHz, CDCl 3 ): 1.92(m, 4H), 2.26(s, 6H), 2.51(t, 2H), 2.6(t, 2H), 2.83(m, 4H), 5.28(...

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Abstract

The invention provides an N-protection-3, 5-disubstituted indole derivative, its preparation method and application. The N-protection-3, 5-disubstituted indole derivative can be used for preparing the anti-migraine drug Almotriptan. Compared with reported literature, the preparation method provided in the invention has the advantages of: cheap and easily available raw materials, mild reaction conditions, simple operation, greatly shortened reaction steps, quality controllable and high purity product, less pollution of ''three wastes'', and easy industrial production. The N-protection-3, 5-disubstituted indole derivative is a free alkali or salt of the compound having a structural general formula (I).

Description

technical field [0001] The present invention relates to N-protected-3,5-disubstituted indole derivatives and their preparation methods and applications. Background technique [0002] Almotriptan (Almotriptan), the chemical name is 3-[2-(dimethylamino)ethyl]-5-(pyrrolidin-1-ylsulfonylmethyl)-1H-indole, which is Spanish Emero 5-HT developed by the company 1B / 1D Receptor agonists for the treatment of migraine with or without aura. In September 2000, the drug was launched in Spain for the first time. In May 2001, it was approved by the FDA for marketing in the United States. In 2009, the US FDA approved almotriptan for the acute treatment of migraine in adolescents (12-17 years old). [0003] The pathogenesis of migraine is still unclear, but it has been confirmed that the large intracranial blood vessels dilate during headache, and migraine may be mainly related to the stimulation of 5-HT 1B / 1D related to the receptor. Compounds such as ergotamines and 5-HT produce vasocons...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/12C07F7/10
Inventor 李建其于圆圆金华王伟
Owner SHANGHAI INST OF PHARMA IND CO LTD
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