Synthetic process of eletriptan

A technology for eletriptan and a synthesis method is applied in the synthesis field of 5-hydroxytryptophan receptor inhibitor eletriptan, and achieves the effects of green environmental protection production procedure, great economic and social benefits, and simple equipment

Active Publication Date: 2016-05-04
ZHANG JIA GANG VINSCE BIO PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The core problem to be solved in the present invention is to overcome the shortcomings of the existing eletriptan preparation process, and to establish an industrial production process of eletriptan that is environmentally friendly, has high atom economy, lower cost, and better quality

Method used

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  • Synthetic process of eletriptan

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Experimental program
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Effect test

Embodiment 15-

[0016] The synthesis of embodiment 15-[2-(benzenesulfonyl) vinyl]-1H-indole

[0017] In a 300L enamel reaction kettle, add 150L of N,N-dimethylformamide, 20kg of benzenesulfonylethylene and 25kg of 5-bromoindole as the reaction raw materials, and the catalyst PdCO 3 Add 0.5kg at one time, 6kg of catalyst triphenylphosphine, 25kg of acid-binding agent triethylamine, stir and heat to 100°C for 6h, and monitor the complete reaction of 5-bromoindole by TLC. The reaction system was naturally lowered to room temperature, and about 100L of dichloromethane was added to dilute and filtered. The filtrate was extracted twice with 50L of brine, and the organic phase was dried overnight with anhydrous sodium sulfate. The organic phase was collected and concentrated to dryness under reduced pressure. The solid product was then crystallized with a mixed solvent of acetone-petroleum ether=1:1 to obtain the product intermediate 5-[2-(benzenesulfonyl)vinyl]-1H-indole.

Embodiment 2

[0018] Example 2 Synthesis of intermediate 3-(N-CBZ-2-pyrrolidinyl)formyl-5-(2-benzenesulfonyl-vinyl-1-yl)-1H-indole

[0019] Add 25kg of the intermediate 5-[2-(benzenesulfonyl)vinyl]-1H-indole to a 300L enamel reaction kettle, dissolve 100L in dried dichloromethane, then control the temperature within 10°C, and add N- The complex synthesized by CBZ-D-prolyl chloride and anhydrous aluminum trichloride in methylene chloride at a low temperature below 5°C is 50L, in which N-CBZ-D-prolyl chloride and anhydrous aluminum trichloride The ratio is 1:1.5, containing 20kg of N-CBZ-D-prolyl chloride. After adding the complex, continue to react at room temperature for 5h, and the intermediate raw material point disappears as monitored by TLC, indicating that the reaction is complete. Control the temperature at 10°C, first add 50L of ice water to hydrolyze, wash and extract once, then adjust the pH to about 7 with saturated sodium carbonate solution, extract once, and finally extract with...

Embodiment 3

[0020] The synthesis of embodiment 3 eletriptan

[0021] Add intermediate 3-(N-CBZ-2-pyrrolidinyl)formyl-5-(2-benzenesulfonyl-vinyl-1-yl)-1H-indole 25kg in 300L enamel reaction kettle, 75L of solvent was dissolved, and 15kg of reducing agent SnCl was added 2 and catalyst 25% ammonium chloride aqueous solution 75L, reflux reaction for 4h, thin-layer chromatography monitors that the intermediate raw material point disappears, and the reaction is completed. Adjust the pH value to about 8 with saturated sodium carbonate solution, add 50 L of dichloromethane for extraction twice, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to dryness under reduced pressure to obtain crude eletriptan.

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Abstract

The invention provides a novel synthetic process of Eletriptan. The process is as below: benzenesulfonyl ethylene acyl and 5-bromoindole are subjected to condensation to obtain an intermediate 5-[2-(benzenesulfonyl) ethylene acyl]-1H-indole, which is subjected to a Friedel-Crafts acylation reaction with N-CBZ-prolyl chlorine to obtain 3-(N-CBZ-2-pyrrolidinyl) formyl-5-(2-benzenesulfonyl-vinyl-1- radical)-1H-indole, which is subjected to a one-step reduction to obtain the product (R)-3-[(1-methyl-2- pyrrolidinyl) methyl]-5-[2-(benzenesulfonyl) ethyl ]-1H-indole; and finally the product is subjected to ethanol crystallization refining, suction filtration and two-cone drying, so as to obtain a qualified Eletriptan product. The process has advantages of conciseness and simple operations, and is suitable for industrialized production.

Description

technical field [0001] The present invention relates to the synthesis of a 5-hydroxytryptamine receptor inhibitor, eletriptan, in particular to the synthesis of benzenesulfonylethylene, 5-bromoindole and N-CBZ-prolyl chloride as raw materials, which are condensed, acyl The eletriptan with high purity and high content was obtained through chemical reaction, reduction reaction and separation and purification. Background technique [0002] Eletriptan hydrobromide, (R)-3-[(1-methyl-2-pyrrolidinyl)methyl]-5-[2-(phenylsulfonyl)ethyl]-1H-indole Hydrobromide, a tryptophan derivative, is a potent vascular selective 5-HT1B and neuronal 5-HT1D receptor agonist, clinically used in the treatment of acute migraine attacks in adults with or without aura. [0003] Eletriptan hydrobromide is obtained by salting the free alkaloid eletriptan and hydrobromic acid in an organic solvent. Therefore, to prepare eletriptan hydrobromide, the most important step is to prepare the precursor eletripta...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/06
Inventor 彭学东张梅赵金召闫勇义
Owner ZHANG JIA GANG VINSCE BIO PHARM
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