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Method for preparing migraine resistant medicine Almotriptan

A technology for almotriptan and migraine, which is applied in the field of preparing an anti-migraine drug almotriptan, and can solve the problems of unfavorable large-scale production, low total yield, harsh reaction conditions and the like

Inactive Publication Date: 2012-11-14
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • Method for preparing migraine resistant medicine Almotriptan
  • Method for preparing migraine resistant medicine Almotriptan
  • Method for preparing migraine resistant medicine Almotriptan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] The compound represented by formula (1) is: 2-[1-benzyl-3-(2-dimethylaminoethyl)-5-indolyl-2-sulfonylpyrrolidine]acetonitrile (III-1) , The preparation method is as follows:

[0083] 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℃ Around, add NaH (0.6g, 15mmol), stir at room temperature for 1h, ice bath, add tetrakis(triphenylphosphine palladium) (0.58g, 0.5mmol).

[0084] Dissolve 2-[1-benzyl-5-bromo-1H-indol-3-yl]-N,N-dimethylethylamine (2.4g, 6.72mmol) in toluene and add dropwise to the above reaction solution In, heat to 110°C, react for 2h. Ice bath, add water and ethyl acetate for liquid separation, the organic layer is dried over anhydrous sodium sulfate, filtered and concentrated, and separated by neutral alumina column (petroleum ether: ethyl acetate = 1:1, the same below) to obtain -[1 -Benzyl-3-(2-dimethylaminoethyl)-5-indolyl...

Embodiment 2

[0092] The compound represented by formula (1) is: 1-[1-benzyl-3-(2-dimethylaminoethyl)-5-indolyl]methanesulfonylpyrrolidine (IV-1), preparation method as follows:

[0093] N 2 For protection, add 1-methylsulfonylpyrrolidine (3g, 20mmo), toluene (30ml), ethylene glycol dimethyl ether (7.5ml) into a 100ml three-necked flask, ice bath to about 0℃, add NaH(1.44g , 36mmol), stirred at room temperature for 1h, ice bath, added tetrakis (triphenylphosphine palladium) (1.4g, 1.2mmol).

[0094] 2-[1-Benzyl-5-bromo-1H-indol-3-yl]-N,N-dimethylethylamine (5.72g, 16mmol) was dissolved in toluene and added dropwise to the above reaction solution, Heat to 110°C and react for 2h. Water and ethyl acetate were added for liquid separation, the organic layer was dried with anhydrous sodium sulfate, filtered and concentrated, and separated by neutral alumina column to obtain 5.79 g of product. The yield was 85%.

[0095] 1 HNMR(400MHz, CDCl 3 ): 1.92 (m, 4H), 2.26 (s, 6H), 2.55 (t, 2H) 2.63 (t, 2H), ...

Embodiment 3

[0100] The compound represented by formula (1) is: 2-[1-trimethylsilylethoxymethyl-3-(2-dimethylaminoethyl)-5-indolyl]-2-sulfonylpyrrolidine ] Acetonitrile (III-2), the preparation method is as follows:

[0101] N 2 For protection, add 2-(pyrrole-1-sulfonyl)acetonitrile (2.75g, 15.8mmo), toluene (30ml), ethylene glycol dimethyl ether (7.5ml) into a 100ml three-necked flask, and ice bath to about 0℃, Add NaH (1.14 g, 28.4 mmol), stir at room temperature for 1 h, ice bath, and add tetrakis (triphenylphosphine palladium) (1.2 g, 1 mmol).

[0102] 2-[1-Trimethylsilylethoxymethyl-5-bromo-1H-indol-3-yl]-N,N-dimethylethylamine (5g, 12.6mmol) was dissolved in toluene and added dropwise Into the above reaction liquid, heat to 110°C and react for 2h. In an ice bath, water and ethyl acetate were added for liquid separation, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and separated by a neutral alumina column to obtain 4.6 g of product. The yield wa...

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Abstract

The invention provides a method for preparing a migraine resistant medicine Almotriptan. The method comprises the following steps: respectively or simultaneously removing R1 and R2 from an N-protected-3,5-disubstituted indole derivative which is adopted as an initial raw material, and then collecting Almotriptan from a reaction system. The method has the advantages of safety, mild reaction conditions, easy operation, high yield, cheap and easily obtained raw material, easy treatment of three wastes, and convenient industrialized production. The chemical formula of the N-protected-3,5-disubstituted indole derivative is represented by formula (I) in the specification.

Description

Technical field [0001] The invention relates to a method for preparing the anti-migraine drug Almotriptan. Background technique [0002] Almotriptan (Almotriptan), the chemical name is 3-[2-(dimethylamine)ethyl]-5-(pyrrolidin-1-ylsulfonylmethyl)-1H-indole, which is the Spanish eimero 5-HT developed by the company 1B / 1D Receptor agonist, used to treat migraine with or without aura. The structural formula is as follows: [0003] [0004] In September 2000, the drug was first marketed in Spain. In May 2001, it was approved by the FDA for marketing in the United States. In 2009, the FDA approved amotriptan for the acute treatment of migraine in adolescents (12-17 years old). [0005] The pathogenesis of migraine is not clear, but it has been confirmed that the large blood vessels in the brain expand during headache, and migraine may be mainly related to agitation of 5-HT 1B / 1D Receptor related. Compounds such as ergotamines and 5-HT produce vasoconstriction by stimulating 5-HT1 rece...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07F7/10A61P25/06
CPCY02P20/55
Inventor 李建其于圆圆金华王伟
Owner SHANGHAI INST OF PHARMA IND
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