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Preparation method of compound for treating migraine

The technology of a compound and a catalyst is applied in the field of preparation of a migraine drug lasmiditant, and can solve the problems of low yield, high product cost, harsh conditions and the like

Pending Publication Date: 2022-06-03
SHANGHAI TIANCI INT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The synthetic methods reported in the existing patents have harsh conditions or use dangerous lithium reagents, which makes industrial production difficult and the yield is not high, resulting in high product costs

Method used

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  • Preparation method of compound for treating migraine
  • Preparation method of compound for treating migraine
  • Preparation method of compound for treating migraine

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Experimental program
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preparation example Construction

[0067] Preparation of compounds of formula III

[0068] The invention provides a preparation method of the compound of formula III, comprising the steps:

[0069] (i) Friedel-Crafts reaction between N-methyl-4-piperidinecarbonyl chloride and pyridine to obtain the compound of formula III.

[0070]

[0071] Specifically, it includes (i) Friedel-Crafts reaction between N-methyl-4-piperidinecarbonyl chloride and pyridine in the presence of a catalyst in an inert solvent to obtain the compound of formula III.

[0072] In another preferred embodiment, step (i) has one or more features selected from the following group:

[0073] (1) the catalyst of described reaction is selected from the following group: anhydrous aluminum trichloride, anhydrous zinc chloride, iron trichloride, titanium tetrachloride, or its combination, preferably, anhydrous aluminum trichloride , ferric chloride, or a combination thereof; more preferably, anhydrous aluminum trichloride;

[0074] (2) The mola...

Embodiment 1

[0118]

[0119] Dichloromethane (100ml) was added to the reaction flask, the compound of formula I (10.0g, 0.062mol) was added to the reaction flask, stirred to dissolve, anhydrous aluminum trichloride (12.4g, 0.093mol) was added, and the exhaust pipe was connected, Do a good job of exhaust gas absorption, stir evenly, add pyridine (5.9g, 0.0744mol) dropwise, raise the temperature to 40 °C for reaction for 2 hours, check the progress of the reaction by spotting, the reaction is completed, cool down to 20 °C, cool down to 0 °C in an ice bath, and dropwise purify Water (100ml), temperature control between 15-20°C, stirring for 20min, standing for stratification, taking the organic phase, drying over anhydrous sodium sulfate, and rotary evaporation to remove the solvent to obtain an off-white solid (10.8g), yield: 86.2 % (relative to formula I). MS(ESI): [M+1] + = 205.27.

Embodiment 2

[0121]

[0122] The compound of formula III (15.0g, 0.073mol) was added to sulfuric acid (80ml), stirred evenly, the ice salt was cooled to 0°C, and kept stirring to prepare a 1:1 solution of nitric acid (9.4ml, 0.146mol) / sulfuric acid (9.4ml) (Concentrated nitric acid (68%), concentrated sulfuric acid (98%)), added dropwise to the reaction solution at a temperature of 0 °C, kept at 0 °C for reaction for 1 h, poured the reaction solution into ice cubes to quench, added dichloromethane for extraction, and collected The organic phase was washed once with purified water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off to obtain the compound of formula IV (17.1 g), yield: 93.7% (relative to formula III). MS(ESI): [M+1] + = 250.27.

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Abstract

The invention provides a preparation method of a compound for treating migraine. Specifically, the method comprises the following steps: carrying out Friedel-Crafts reaction on N-methyl-4-piperidinecarbonyl chloride serving as a raw material and pyridine to obtain a compound shown in a formula III, carrying out nitration reaction on the compound shown in the formula III and nitric acid to obtain a compound shown in a formula IV, aminating the compound shown in the formula IV to obtain a compound shown in a formula V, and reacting the compound shown in the formula V with a compound shown in a formula VI (2, 4, 5, 6-tetramethyl-4-piperidinecarbonyl chloride). 2, 4, 6-trifluorobenzoyl chloride) is reacted to obtain a target compound as shown in a formula VII. The method disclosed by the invention is high in yield, simple and convenient to operate and easy for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of a migraine drug lasmiditant Background technique [0002] Lasmidetan is a central nervous system penetrating, selective, oral preparation of serotonin 1F (5-HT1F) agonist, and lasmiditant is the first drug in the ditan class to be used. A drug for the acute treatment of migraine in adults that is structurally and mechanistically different from approved migraine drugs and lacks vasoconstrictor activity; if approved, it would represent a major innovation in migraine treatment. On November 16, 2018, Eli Lilly submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for Lasmiditan for the acute treatment of migraine with or without aura in adult patients. [0003] In the currently reported patents for synthesizing lasmiditane, basically all of them are required to synthesize the key intermediate compound of formula V...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/06
CPCC07D401/06
Inventor 李函璞李勇刚丁正杰
Owner SHANGHAI TIANCI INT PHARMA