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Preparation method of anti-migraine drug 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, expensive reagents and the like

Inactive Publication Date: 2012-11-14
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • 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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  • Preparation method of anti-migraine drug Almotriptan
  • Preparation method of anti-migraine drug Almotriptan
  • Preparation method of anti-migraine drug Almotriptan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Preparation of 1-[1-benzyl-3-(2-dimethylaminoethyl)-5-indolyl]methylsulfonylpyrrolidine (III-1)

[0093] N 2 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°C, add NaH (1.44g , 36mmol), stirred at room temperature for 1h, ice-bathed, 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, Heated to 110°C and reacted for 2h. Water and ethyl acetate were added for liquid separation, the organic layer was dried over anhydrous sodium sulfate, concentrated by filtration, and separated by neutral alumina column (petroleum ether: ethyl acetate = 1:1, the same below) to obtain 5.79 g of the product. Yield 85%.

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

Embodiment 2

[0100] The preparation of 1-[1-benzyl-3-(2-dimethylaminoethyl)-5-indolyl]methanesulfonylpyrrolidine (III-1) is the same as in Example 1.

[0101] Calcium (0.19g, 4.7mmol) was added to 4ml of solvent THF, the temperature was lowered to -40°C, liquid ammonia (4ml) was added, and stirred at -40°C for 15min to obtain a reaction solution, which was set aside;

[0102] Dissolve 1-[1-benzyl-3-(2-dimethylaminoethyl)-5-indolyl]methanesulfonylpyrrolidine (III-1) (1 g, 2.35 mmol) in solvent 2.5 ml THF , added dropwise to the above reaction solution, maintained at -40°C, stirred for 30 minutes, added dropwise saturated ammonium chloride aqueous solution, the silver gray reaction solution rose to room temperature, added water, stirred the white suspension for 15 minutes, suction filtered, and the solid was dissolved in In 5N HCl (15ml), the orange solution was extracted with ethyl acetate. The pH of the aqueous layer was adjusted to 10 with 10N NaOH, resulting in precipitation, which was ...

Embodiment 3

[0104] Preparation of 1-[1--allyl-3-(2-dimethylaminoethyl)-5-indolyl]methylsulfonylpyrrolidine (III-2)

[0105] N 2 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°C, add NaH (1.44g , 36mmol), stirred at room temperature for 1h, ice-bathed, added tetrakis(triphenylphosphine palladium) (1.4g, 1.2mmol).

[0106] 2-[1-allyl-5-bromo-1H-indol-3-yl]-N,N-dimethylethylamine (4.92g, 16mmol) was dissolved in toluene and added dropwise to the above reaction solution , heated to 110°C, and reacted for 2h. Ice-bathed, 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 5.12 g of the product. Yield 80%.

[0107] 1 HNMR (400MHz, CDCl 3 ): 1.92(m, 4H), 2.26(s, 6H), 2.54(t, 2H), 2.62(t, 2H), 3.27(m, 4H), 4.32(s, 2H), 5.22(m, 1H) , 5.25(s, ...

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Abstract

The invention provides a preparation method of an anti-migraine drug Almotriptan. The method includes the following steps of: taking an N-protection-3, 5-disubstituted indole derivative as a starting material, removing the N-protection group in a solvent and in the presence of a catalyst, and then collecting Almotriptan from the reaction system. The method provided in the invention for preparing Almotriptan has the advantages of safety, mild reaction condition, easy operation, high yield, cheap and easily available raw materials, easy ''three wastes'' treatment, and convenient industrial implementation. The N-protection-3, 5-disubstituted indole derivative has a chemical structural formula as shown in formula (I).

Description

technical field [0001] The invention relates to a method for preparing anti-migraine drug almotriptan. 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. The structural formula is as follows: [0003] [0004] 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). [0005] 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 produc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/14
CPCY02P20/55
Inventor 李建其于圆圆金华王伟
Owner SHANGHAI INST OF PHARMA IND CO LTD
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