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Improvement of preparation of Naratriptan

A technology of methyl methanesulfonamide and ethiamine, applied in the direction of organic chemistry, etc., can solve the problems of non-commercial supply preparation, difficulty, and high operating costs

Active Publication Date: 2007-05-16
上海生通生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the synthesis route of this method is relatively simple, the main raw material of the Heck reaction—vinylmethylsulfonamide is not commercially available and difficult to prepare. In addition, the two-step reaction requires a considerable amount of noble metal as a catalyst, resulting in high operating costs.

Method used

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  • Improvement of preparation of Naratriptan
  • Improvement of preparation of Naratriptan
  • Improvement of preparation of Naratriptan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] (1) Synthesis of 5-cyanindole [compound (3)]:

[0018]

[0019] A mixture of 4g (0.021mol) of compound (2), 3g (0.033mol) of CuCN, and 20ml of NMP (N-methylpyrrolidone) was placed in a 200W microwave oven to react for 30min, then the reactant was cooled to room temperature and diluted with 50ml of ice water ,filter. The obtained solid was washed with 3×10 ml of ammonia water, extracted with 50 ml of chloroform Soxhlet, and then recrystallized with ethanol to obtain 2.5 g of compound (3) as light brown powder with a yield of 80%. Melting point: 104-106°C.

[0020] (2) Synthesis of indole 5-carbaldehyde [compound (4)]:

[0021]

[0022] Mix 15g (0.106mol) of compound (3), 30g (0.283mol) of sodium hypophosphite, 100ml of water, 100ml of glacial acetic acid, and 200ml of pyridine, add 10g of Raney nickel while stirring, and react the mixture at 45°C for 2h, then cool. The reactant was filtered, the filtrate was extracted with 3×20ml ethyl acetate, the organic phase...

Embodiment 2

[0048] Except changing the reaction condition of compound (4) and compound (5), other steps are identical with embodiment 1

[0049]

[0050] A solution of 1g (0.004mol) of compound (5a) in 25ml of anhydrous tetrahydrofuran was cooled to -78°C under nitrogen protection, 1.08g (0.01mol) of n-BuOK was added with stirring, and reacted at -78°C for 1 hour, A solution of 1 g (0.004 mol) of compound (4a) in 15 ml of anhydrous tetrahydrofuran was added dropwise. After the addition was complete, THF was refluxed for 12 hours. After the end, add 20ml of ethyl acetate and 20ml of saturated ammonium chloride solution respectively, separate layers, extract the aqueous phase with 10ml of ethyl acetate, combine the organic phases, and wash with water. After washing with saturated brine, it was dried and evaporated to remove the solvent. The residue was separated by column chromatography, mobile phase: ethyl acetate:petroleum ether=1:2. The solvent was distilled off to obtain 0.54 g of ...

Embodiment 3

[0053] Except changing the reaction condition of compound (4) and compound (5), other steps are identical with embodiment 1

[0054]

[0055] Cool the solution of 3ml (0.022mol) of diisopropylamine and 16ml of anhydrous tetrahydrofuran to -78°C, add dropwise 8ml of 1.6M n-hexane solution of butyllithium (0.01mol) under the protection of nitrogen, and stir. After the temperature naturally rose to 0°C, the reactant was cooled to -78°C again, and a solution of 0.5g (0.005mol) of compound (5) in 16ml of anhydrous tetrahydrofuran was added dropwise. After the dropwise addition was completed, the reactant slowly rose to -30°C. React for 1 hour. Then the reactant was cooled to -78°C, and a solution of 0.8 (0.003 mol) compound (4a) in 8 ml of anhydrous tetrahydrofuran was added dropwise. After the addition was complete, the reaction was carried out at room temperature for 12 hours. After the end, cool the reactant to 0°C, add 50ml of 5% HCl to stir, stand to separate the layers, ...

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Abstract

The invention discloses a method for preparing Naratriptan [N-methyl-3- (1-methyl-4-piperidine)-1,4-indole-5-ethyl thiamine], employing 5-halogenated indole as start raw material, through cyanation, reduction, condensation with N-methyl methanesulfonamide, hydrogenation for reduction, condensation with N-methyprylone, and again hydrogenation for reduction to get the target compound. The invention is characterized by the designation of the synthetic Naratriptan course of easy-to-get raw amterial and low operating cost, overcoming the shortcomings of hard preparation of raw material and high operating cost in current technology.

Description

technical field [0001] The invention relates to a preparation method of N-methyl-3-(1-methyl-4-piperidinyl)-1,4-indole-5-ethanethiamine (Naratriptan). Background technique [0002] Naratriptan (aka Amerge, Naramig, GR-85548), chemical name N-methyl-3-(1-methyl-4-piperidinyl)-1,4-indole-5-ethanethiamine, is A second-generation triptan anti-migraine drug developed by Glaxo Wellcome. Its structure is as follows: [0003] [0004] Since Glaxo Wellcome’s triptan migraine treatment drug sumatriptan (sumatriptan) was launched in 1991, it has changed the past symptomatic treatment to cause-based treatment, and the curative effect is obvious. Triptans have advanced therapeutic mechanisms It has become the research direction of anti-migraine drugs. [0005] As the second generation anti-migraine new drug, Naratriptan has few reported synthetic methods due to its structural specificity, so far only the Heck reaction that is reported by Glaxo Company is N-methyl-3-(1, 2,3,4-tetra...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04C07D211/26C07D209/14
Inventor 蔡良珍陶晓春林健刘昕沈晶伟
Owner 上海生通生物科技有限公司
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