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Preparation method of anti-migraine drug almotriptan

A technology for almotriptan and migraine, which is applied in the field of preparation of anti-migraine drug almotriptan, can solve the problems of difficult industrial production, high cost of ligands, and small dosage, and achieve simple and easy-to-obtain raw materials and reagents, The effect of convenient purification and high overall yield

Active Publication Date: 2019-06-25
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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-)acetate formula (Ⅲ)

[0047] Under nitrogen protection, N-(2-iodo-4-((pyrrolidinyl-1-sulfonyl) methyl) phenyl)-4-methylbenzenesulfonamide (formula (I) (26g, 50mmol ), 4-acetoxyethyl crotonate formula (Ⅱ) (8.6g, 50mmol), palladium acetate (0.23g, 1mmol), tri(o-methylphenyl)phosphine (0.6g, 2mmol), diisopropyl Add anhydrous N,N-dimethylacetamide (125ml) into a 250ml three-neck flask containing ethylethylamine (15.5g, 0.12mol) and a rotor, stir overnight in an oil bath at 100°C, and cool to room temperature after the reaction , add water (25ml), let stand in ice bath for 2h, filter, filter cake is washed with water (50ml) and ethanol (50ml) successively, and ethyl acetate is beaten to give white solid (formula (Ⅲ)) (19g, 38mmol). 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,1H), 7.41-7.37(m,3H), 4.47(s,2H) ,4.09(q,2H),3.78(s,2H),...

Embodiment 2

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

[0051] Under nitrogen protection, N-(2-bromo-4-((pyrrolidinyl-1-sulfonyl) methyl) phenyl)-4-methylbenzenesulfonamide (formula (I)) (2.4g , 5mmol), ethyl 4-acetoxycrotonate (formula (II)) (860mg, 5mmol), palladium acetate (45mg, 0.2mmol), tris(o-methylphenyl)phosphine (122mg, 0.4mmol), Add anhydrous N,N-dimethylacetamide (15ml) into a 50ml three-neck flask containing diisopropylethylamine (1.6g, 12mmol) and a rotor, stir overnight in an oil bath at 120°C, and cool after the reaction To room temperature, add water (3ml), let it stand in an ice bath for 2h, filter, wash the filter cake with water (6ml) and ethanol (6ml) successively, and beat with ethyl acetate to obtain a white solid (formula (Ⅲ)) (2.07g, 4.1 mmol), the yield is 80%.

Embodiment 3

[0053] 2-(5-((pyrrolidinyl-1-sulfonyl) methyl)-1-p-toluenesulfonyl-1H-indolyl-3-) preparation of ethyl acetate formula (Ⅲ) under nitrogen protection, to Equipped with N-(2-iodo-4-((pyrrolidinyl-1-sulfonyl)methyl)phenyl)-4-methylbenzenesulfonamide (formula (I)) (2.6g, 5mmol), 4 -Acetoxyethyl crotonate (formula (II)) (860mg, 5mmol), tris(dibenzylideneacetone)dipalladium) (183mg, 0.2mmol), tris(o-methylphenyl)phosphine (122mg, 0.4mmol), diisopropylethylamine (1.6g, 12mmol) and the 50ml three-neck flask of the rotor were added anhydrous N,N-dimethylacetamide (15ml), stirred overnight in an oil bath at 100°C, After the reaction, cool to room temperature, add water (3ml), let stand in an ice bath for 2h, filter, wash the filter cake with water (6ml) and ethanol (6ml) successively, and beat with ethyl acetate to obtain a white solid (formula (Ⅲ)) ( 1.96g, 3.9mmol), the yield was 78%.

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Abstract

The invention discloses a preparation method of an anti-migraine drug almotriptan. The method comprises the following steps: (1) N-protected o-haloaniline represented by formula (I) and 4-acetoxycrotonate represented by formula (II), which are used as raw materials, undergo a cascade reaction under the action of the basic skeleton of a palladium catalyst and a phosphine ligand, and an almotriptanbasic skeleton represented by formula (III) is collected from the obtained reaction product; and (2) the almotriptan basic skeleton represented by formula (III) undergoes reduction, deprotection, hydroxyl group activation and amino group substitution to obtain the product almotriptan. The preparation method has the advantages of simple and easily available raw materials and reagents, simplicity inoperation of the preparation, no harsh conditions, convenience in purification of the intermediate and the product, and high overall yield. The reaction formula is shown in the description.

Description

technical field [0001] The invention relates to a method for preparing anti-migraine drug almotriptan Background technique [0002] The chemical name of Almotriptan (Almotriptan) is 3-[2-(dimethylamino)ethyl]-5-(pyrrolidin-1-ylsulfonylmethyl)-1H-indole. The drug developed by Luo Company for the treatment of migraine headache with or without aura, its structural formula is as follows: [0003] [0004] The drug was first launched in Spain in September 2000, and was approved by the FDA in May 2001 in the United States. In 2009, the United States FDA approved almotriptan for the acute treatment of migraine in adolescents (12-17 years old) (the only one approved at present) 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 of intermediate A. However, this method has problems such as hi...

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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