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, can solve the problems of high cost of ligands, small feeding amount, large dosage and the like, and achieves convenient purification, high overall yield, The effect of simple operation in the preparation process

Active Publication Date: 2022-07-22
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method uses the strict anhydrous and oxygen-free Schlenk operation technology, which leads to a relatively small amount of feed, which brings certain difficulties to industrial production. At the same time, the cost of the phosphine ligand used is expensive and the amount used is large, and the halogen-containing indole fragment also needs to be prepared separately. preparation

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

[0046] Preparation of ethyl 2-(5-((pyrrolidinyl-1-sulfonyl)methyl)-1-p-toluenesulfonyl-1H-indolyl-3-) ethyl acetate formula (III)

[0047] Under nitrogen protection, charged with N-(2-iodo-4-((pyrrolidinyl-1-sulfonyl)methyl)phenyl)-4-methylbenzenesulfonamide (formula (I) (26 g, 50 mmol) ), ethyl 4-acetoxycrotonate formula (II) (8.6g, 50mmol), palladium acetate (0.23g, 1mmol), tris(o-methylphenyl)phosphine (0.6g, 2mmol), diisopropyl Anhydrous N,N-dimethylacetamide (125ml) was added to a 250ml three-necked flask of ethyl ethylamine (15.5g, 0.12mol) and a rotor, stirred overnight in an oil bath at 100°C, and cooled to room temperature after the reaction was completed. , add water (25ml), let stand under ice bath for 2h, filter, wash the filter cake with water (50ml) and ethanol (50ml) successively, beat with ethyl acetate to obtain a white solid (formula (III)) (19g, 38mmol), collect The rate is 76%.

[0048] H 1 NMR (400MHz, DMSO): 7.92(d,1H), 7.84(d,2H), 7.76(s,1H), 7.56(s,1...

Embodiment 2

[0050] Preparation of ethyl 2-(5-((pyrrolidinyl-1-sulfonyl)methyl)-1-p-toluenesulfonyl-1H-indolyl-3-) ethyl acetate formula (III)

[0051] Under nitrogen protection, charged with N-(2-bromo-4-((pyrrolidinyl-1-sulfonyl)methyl)phenyl)-4-methylbenzenesulfonamide (formula (I)) (2.4 g , 5mmol), ethyl 4-acetoxycrotonate (formula (II)) (860mg, 5mmol), palladium acetate (45mg, 0.2mmol), tris(o-methylphenyl)phosphine (122mg, 0.4mmol), Anhydrous N,N-dimethylacetamide (15ml) was added to a 50ml three-necked flask of diisopropylethylamine (1.6g, 12mmol) and a rotor, stirred overnight in an oil bath at 120°C, and cooled after the reaction was completed. After reaching room temperature, additional water (3ml) was added, and it was allowed to stand for 2h in an ice bath, filtered, and the filter cake was washed with water (6ml) and ethanol (6ml) in turn, and ethyl acetate was slurried to obtain a white solid (formula (III)) (2.07g, 4.1 mmol), the yield was 80%.

Embodiment 3

[0053] Preparation of ethyl 2-(5-((pyrrolidinyl-1-sulfonyl)methyl)-1-p-toluenesulfonyl-1H-indolyl-3-)acetate formula (III) Loaded with N-(2-iodo-4-((pyrrolidinyl-1-sulfonyl)methyl)phenyl)-4-methylbenzenesulfonamide (formula (I)) (2.6 g, 5 mmol), 4 - Ethyl acetoxycrotonate (formula (II)) (860 mg, 5 mmol), tris(dibenzylideneacetone)dipalladium) (183 mg, 0.2 mmol), tris(o-methylphenyl)phosphine (122 mg, 0.4mmol), diisopropylethylamine (1.6g, 12mmol) and a 50ml three-necked flask of the rotor were added anhydrous N,N-dimethylacetamide (15ml), stirred overnight in an oil bath at 100°C, After the reaction was completed, it was cooled to room temperature, water (3ml) was added, left standing for 2h in an ice bath, filtered, the filter cake was washed with water (6ml) and ethanol (6ml) successively, and ethyl acetate was beaten to obtain a white solid (formula (III)) ( 1.96 g, 3.9 mmol) in 78% yield.

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Abstract

The invention discloses a preparation method of an anti-migraine drug almotriptan, comprising the following steps: (1) N-protected o-haloaniline represented by formula (I) and 4-haloaniline represented by formula (II) Acetoxycrotonate is used as raw material, and under the action of palladium catalyst and phosphine ligand, the almotriptan basic skeleton represented by formula (III) is collected from the reaction product through series reaction; (2) formula (III) The shown basic skeleton of almotriptan is subjected to reduction, deprotection, hydroxyl activation and amino group substitution to obtain the product almotriptan; the raw materials and reagents used in the present invention are simple and easy to obtain, the preparation process is simple to operate, no harsh conditions, intermediate The purification of the body and the product is convenient and the overall yield is high. The general reaction formula is as follows:

Description

technical field [0001] The present invention relates to a method for preparing anti-migraine drug almotriptan Background technique [0002] The chemical name of Almotriptan is 3-[2-(dimethylamino)ethyl]-5-(pyrrolidin-1-ylsulfonylmethyl)-1H-indole, which is produced by the Spanish Emerald The drug developed by Luo Company for the treatment of headache during migraine attacks with or without aura has the following structural formula: [0003] [0004] The drug was first marketed in Spain in September 2000, and was approved by the FDA in May 2001 in the United States. In 2009, the US FDA approved almotriptan for the acute treatment of migraine in adolescents (12 to 17 years old) U.S. FDA-approved migraine treatment for adolescents). [0005] In the prior art, US5565447 first discloses a new preparation method, which uses copper oxide as a catalyst and quinoline as a solvent to prepare almotriptan through decarboxylation reaction of intermediate A. However, this method has...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/14
CPCY02P20/55
Inventor 李建其陈东升马志龙刘育陈园园孟凯
Owner SHANGHAI INST OF PHARMA IND CO LTD
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