Preparation method of 5-HT1F agonist compound

A compound and solvent technology, applied in the field of medicinal chemistry, can solve the problems of high raw material price, cumbersome process and high process condition requirements

Active Publication Date: 2019-10-29
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Both of the above two routes involve ultra-low temperature operation below -70°C, requiring high process conditions, cumbersome processes, and high raw material prices, which are not conducive to industrial production

Method used

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  • Preparation method of 5-HT1F agonist compound
  • Preparation method of 5-HT1F agonist compound
  • Preparation method of 5-HT1F agonist compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1: Preparation of 2-chloro-5,6-dioxo-n-heptanonitrile (Ⅲ1)

[0073] To a 500 ml four-neck flask connected with a stirring, thermometer, and reflux condenser, add 250 g of tetrahydrofuran, 43.0 g (0.5 mole) of 2,3-butanedione (II), 43.5 g (0.5 mole) of 2-chloropropene Nitrile, 0.6 g of lithium hydroxide, 50 to 55 ° C stirring reaction for 4 hours, cooled to 20 to 25 ° C, added 1.0 g of acetic acid, distillation recovery solvent, and then vacuum distillation to collect 90-105 ° C / 1-2mmHg fraction, to obtain 81.2 gram of 2-chloro-5,6-dioxo-n-heptanonitrile (Ⅲ1), the yield was 93.6%, and the gas phase purity was 99.5%.

Embodiment 2

[0074] Example 2: Preparation of 2-bromo-5,6-dioxo-n-heptanonitrile (Ⅲ2)

[0075] To a 500 ml four-neck flask connected with a stirring, thermometer, and reflux condenser, add 250 g of isopropyl ether, 43.0 g (0.5 mol) of 2,3-butanedione (II), 66.0 g (0.5 mol) of 2- Bromoacrylonitrile, 0.6 g of DBU, stirred at 60 to 65°C for 4 hours, recovered the solvent by distillation, and then collected 105-115°C / 1-2mmHg fractions by distillation under reduced pressure to obtain 103.2 g of 2-bromo-5,6-dioxo N-heptanonitrile (Ⅲ2), the yield is 94.7%, and the gas phase purity is 99.2%.

Embodiment 3

[0076] Example 3: Preparation of 2-dimethylmethyleneamino-6-acetylpyridine (V1)

[0077] To a 500 ml four-necked flask connected with stirring, thermometer, reflux condenser and dropping funnel, add 80 g of methanol, 40.0 g (0.4 moles) of 17% ammonia methanol solution, between 50 and 55 ° C, dropwise add 17.4 g (0.1 mole) The solution of 2-chloro-5,6-dioxo-n-heptanonitrile (III1) prepared in Example 1 and 80 g of methanol was added dropwise in about 2 hours, and then stirred at 55 to 60°C for 4 hours. Cool to 20 to 25°C, add the resulting reaction liquid to 200 grams of dichloromethane and 200 grams of ice water, separate layers, extract the water layer with dichloromethane 3 times, 20 grams each time, combine the organic phases, 10.0 grams of anhydrous Sodium sulfate was dried for 4 hours, filtered, and the resulting filtrate was transferred to a 500 ml four-neck flask connected with stirring, a thermometer, and a reflux condenser, and 20.0 grams (0.19 moles) of 2,2-dimethoxy...

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Abstract

The invention relates to a preparation method of a 5-HT1F agonist compound. The preparation method of the 5-HT1F agonist compound comprises the steps that 2,3-butanedione and 2-halogenated acrylonitrile are subjected to 1,4-addition reaction to obtain 2-halogenated-5,6-dioxo n-heptanoic nitrile, then the 2-halogenated-5,6-dioxo n-heptanoic nitrile and ammonia are subjected to pyridine cyclizationand amino protection to obtain 2-disubstituted methylamino-6-acetyl pyridine, then 2-disubstituted methylamino-6-(1-methyl piperidine-4-base)formyl group piperidine is prepared through hydroxyethylation, sulfonic acid esterification and methylamine condensation reaction, and then the 5-HT1F agonist compound Lasmiditan is obtained through deprotection reaction and 2,4,6-trifluoro-benzoyl chloride amidation. The raw materials of the preparation method of the 5-HT1F agonist compound are easy to get, ultralow temperature reaction is avoided, the operation is simple and convenient, the cost is low,and industrial production of Lasmiditan is easy.

Description

technical field [0001] The invention relates to a preparation method of a 5-HT1F agonist compound Lasmiditan, which belongs to the technical field of medicinal chemistry. Background technique [0002] Lasmiditan hydrochloride (Lasmiditan Hydrochloride (1:1)) is an oral serotonin 5-HT1F agonist drug jointly developed by Eli Lilly and Colucid Pharmaceuticals for the treatment of acute migraine, the latest clinical phase III study Excellent treatment results were shown. At the same time, clinical research has been carried out on other medicinal salts of Lasmiditan, so the preparation of its free base Lasmiditan (I) is of great significance for related medicinal research or marketing. [0003] Lasmiditan (I), the chemical name is N-[6-[(1-methyl-4-piperidinyl)carbonyl]pyridin-2-yl]-2,4,6-trifluorobenzamide, the relevant chemical structure As follows: [0004] [0005] Chinese patent document CN1642939A and document J.C.S.perkin T (24), 3597-3600 (1997) use 2-chloropyridine...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/06
CPCC07D401/06
Inventor 戚聿新刘月盛吕强三于大伟
Owner XINFA PHARMA
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