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Preparation method of 4-methylpiperidine salt

A technology of methylene piperidine and methyl tert-butyl ether is applied in the field of preparation of 4-methylene piperidine salt, and achieves the effects of simple operation, recyclable solvent and high product recovery rate.

Inactive Publication Date: 2018-08-24
LIVZON GROUP CHANGZHOU KONY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • Preparation method of 4-methylpiperidine salt
  • Preparation method of 4-methylpiperidine salt

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Embodiment 1

[0027] Put 150ml of methyl tert-butyl ether and 40g of methyl triphenylphosphine bromide into a 250ml three-necked bottle, and lower the temperature to 0-10°C under nitrogen protection. After cooling down, stir for 30 minutes, and add 15g of tert-butanol in batches Potassium, after the addition, stir at 0-10°C for 2-3 hours. After stirring, dilute 24g of 1,5-dibromo-3-pentanone with 50ml of methyl tert-butyl ether, and slowly add it dropwise into the reaction system after dilution. After the dropwise addition, stir and react at 0-10°C for 8-10 hours. After the reaction is completed, filter and wash the filtrate three times with 100ml of water. Concentrate the organic phase to dryness to obtain an oily compound for later use.

[0028] Add 100ml of 15% ammonia water to a 250ml three-necked bottle, and add the prepared oil dropwise while keeping the temperature at 15-25°C. Add 145ml of ethyl acetate to the reaction system and stir for 10 minutes to separate the phases. The orga...

Embodiment 2

[0030] Put 100ml of tetrahydrofuran and 38g of methyltriphenylphosphine bromide into a 250ml three-necked flask, and lower the temperature to 0-10°C under nitrogen protection. Stir at 0-10°C for 2-3 hours. After stirring, dilute 15g of 1,5-dichloro-3-pentanone with 50ml of tetrahydrofuran, and slowly add it dropwise into the reaction system after dilution. After the dropwise addition, stir and react at 0-10°C for 8-10 hours. After the reaction is completed, filter and wash the filtrate three times with 100ml of water. Concentrate the organic phase to dryness to obtain an oily compound for later use.

[0031] Add 80ml of 20% ammonia water to a 250ml three-necked bottle, add the prepared oil dropwise while keeping the temperature at 15-25°C, after the dropwise addition, keep stirring at 15-25°C for 3-4 hours, and keep the temperature at 15-25°C for 3-4 hours. Add 100ml of ethyl acetate to the reaction system and stir for 10 minutes to separate the phases. The organic phase was...

Embodiment 3

[0033] Put 150ml of methyl tert-butyl ether and 45g of methyl triphenylphosphine bromide into a 250ml three-necked bottle, and lower the temperature to 0-10°C under nitrogen protection. After cooling down, stir for 30 minutes, then add 20g of tert-butanol in batches Potassium, after the addition, stir at 0-10°C for 2-3 hours. After stirring, dilute 20g of 1,5-dibromo-3-pentanone with 50ml of methyl tert-butyl ether, and slowly add it dropwise into the reaction system after dilution. After the dropwise addition, stir and react at 0-10°C for 8-10 hours. After the reaction is completed, filter and wash the filtrate three times with 100ml of water. Concentrate the organic phase to dryness to obtain an oily compound for later use.

[0034] Add 120ml of 10% ammonia water to a 250ml three-necked bottle, and add the prepared oil dropwise while keeping the temperature at 15-25°C. Add 100ml of dichloromethane to the reaction system and stir for 10 minutes to separate the phases. The o...

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Abstract

The invention relates to a preparation method of 4-methylpiperidine salt. According to the invention, 1,5-dihalide-3-pentanone is used as an initial raw material, through a wittig reaction, halogenated amine hydrolysis, salt forming with acid, the 4-methylpiperidine salt is obtained with high efficiency. The preparation method has the beneficial effects that the raw material source is wide, cost is low, operation is simple, a solvent is recycled and reused, the waste liquid discharge capacity is less, the product recovery rate is high, and industrialization is easily realized.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis and relates to a preparation method of 4-methylene piperidinium salt. Background technique [0002] Efinaconazole (efinaconazole) is the first external triazole antifungal drug, developed by Canadian DOW Pharmaceutical Company, and was approved by the US FDA on June 6, 2014, under the trade name Jublia. The medicine is a solution with a mass fraction of 10%, which is applied locally and is mainly used for treating moss on the hands and feet (namely onychomycosis) caused by Trichophyton rubrum and Trichophyton gypsum. [0003] 4-methylenepiperidinium salt is the key intermediate of efluconazole, and its molecular formula is C 6 h 12 ClN, the molecular weight is 133.62. Its structural formula is: [0004] [0005] In the reported patent and literature process, the patent uses BOC-methylene piperidine as raw material to prepare methylene piperidine hydrochloride in CN106565672A,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/72
CPCC07D211/72
Inventor 刘可可陈争一朱玲陈敖
Owner LIVZON GROUP CHANGZHOU KONY PHARMA