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Preparation method of 3-amino-4-alkoxyimino piperidine

A technology of alkoxyiminopiperidine and alkoxyamine hydrochloride, applied in the preparation of 3-amino-4-alkoxyiminopiperidine, 3-amino-4-alkoxyiminopiperidine and In the field of salt, it can solve the problems of being unsuitable for industrial production, odorous dimethyl sulfide, and polluting the environment, and achieve the effects of being suitable for large-scale production, less reaction steps, and reducing production costs.

Inactive Publication Date: 2013-05-08
浙江宏康医药化工股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But this preparation method exists: 1) the alkali (ammonia) catalyzed ring-opening reaction of epoxy compound causes this step yield very low because of non-selectivity, must go through column layer after protecting amino group with tert-butoxycarbonyl (Boc) subsequently separation and purification
In addition, after the reaction of methylation, removal of Boc protection group and salt formation reaction is completed, it also needs to be separated and purified by column chromatography; 2) using pyridine-SO 3 - DMSO system oxidizes hydroxyl, produces foul-smelling dimethyl sulfide, and seriously pollutes the environment, so it is not suitable for industrial production

Method used

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  • Preparation method of 3-amino-4-alkoxyimino piperidine
  • Preparation method of 3-amino-4-alkoxyimino piperidine
  • Preparation method of 3-amino-4-alkoxyimino piperidine

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Example 1, 1-N-tert-butoxycarbonyl-3-cyano-4-piperidone

[0031] Add ethyl 3-alanine propionate hydrochloride (153.5g, 1mol) and ethanol (850mL) into a 2000mL three-necked flask, stir it mechanically at room temperature to dissolve, add sodium hydroxide (41.5g, 1mol), and stir at room temperature for 0.5 hours . Heat to 50°C (internal temperature, the same below), and add a solution of acrylonitrile (66 mL, 1 mol) in ethanol (150 mL) dropwise. After dropping (1 hour), the stirring was continued at the same temperature, and the reaction was followed by TLC for about 4 hours.

[0032] After the reaction mixture obtained above was slightly cooled (~40°C), a solution of di-tert-butyl dicarbonate (218.25g, 1mol) in ethanol (150mL) was added dropwise thereto (temperature ≤50°C during the period), and the dropwise completion (~1 Hours), continued stirring at 40-45°C, and TLC followed the reaction to end in about 3 hours. After cooling down to room temperature, the insoluble...

Embodiment 2

[0034] Example 2, 1-N-tert-butoxycarbonyl-3-carbamoyl-4-methoxyiminopiperidine

[0035] Add methoxylamine hydrochloride (50.1g, 0.6mol) and methanol (400mL) to a 2000mL three-necked reaction flask, stir at room temperature to dissolve, add sodium hydroxide (25g, 0.6mol), stir at room temperature for 0.5 hours, add 1- tert-butoxycarbonyl-3-cyano-4-piperidone (112 g, 0.5 mol) in methanol (400 mL) was heated to 50° C. and stirred, and the reaction was followed by TLC for about 3 hours. Cool down to room temperature, filter out the insoluble matter (sodium chloride), concentrate the filtrate under reduced pressure, add distilled water (250mL) to the residue, stir well, extract with ethyl acetate (200mL×3), combine the extracts, and wash with saturated NaCl Washed with aqueous solution (250mL), anhydrous Na 2 SO 4 dry. Filtration, the filtrate was concentrated under reduced pressure, and under full stirring, the resulting residue was slowly poured into diethyl ether (1000 mL), a...

Embodiment 3

[0038] Example 3, N-tert-butoxycarbonyl-3-amino-4-methoxyiminopiperidine

[0039] Add 1-N-tert-butoxycarbonyl-3-carbamoyl-4-methoxyiminopiperidine (27.1g, 0.1mol) and acetonitrile (600mL) into a 1000mL three-necked flask, mechanically stir at room temperature to dissolve, and cool in an ice-water bath To about 0-5 ℃, add the freshly prepared sodium hypobromite solution (253 mL, 0.18mol) dropwise, after the dropwise completion (about 1 hour), stir the reaction at room temperature overnight, and follow the completion of the reaction by TLC. Leave to stand for stratification, and separate the water layer (lower layer). The upper layer (acetonitrile layer) was adjusted to pH 6.5 with acetic acid, concentrated under reduced pressure, distilled water (50 mL) was added to the obtained oily residue, and the pH was adjusted to 3 with 6N HCl solution. Combined, adjust pH9 with 6N NaOH solution, extract with ethyl acetate (150mLx6) and combine extracts, wash with saturated NaCl aqueous ...

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Abstract

The invention relates to a preparation method of 3-amino-4-alkoxyimino piperidine. More particularly, the preparation method provided by the invention comprises the following steps: performing nucleophilic addition reaction on ethyl 3-aminopropionate hydrochloride and acrylonitrile in the presence of alkali; treating with di-tert-butyl dicarbonate to obtain ethyl N-tert-butoxycarbonyl-3-(2-cyanoethyl)aminopropionate; performing cyclization in the presence of strong alkali to obtain 1-N-tert-butoxycarbonyl-3-cyano-4-piperidone, and performing oximation to obtain 1-N-tert-butoxycarbonyl-3-cyano-4-alkoxyimino piperidine; sequentially performing cyano hydrolysis and Hofmann degradation reaction on the latter to obtain 1-N-tert-butoxycarbonyl-3-amino-4-alkoxyimino piperidine; and finally, performing deprotection to obtain the 3-amino-4-alkoxyimino piperidine and salt thereof.

Description

technical field [0001] The invention belongs to the field of pharmaceutical and chemical production, and relates to a preparation method of 3-amino-4-alkoxyiminopiperidine. Specifically, the present invention uses 3-aminopropionic acid ethyl ester hydrochloride and acrylonitrile as starting materials, and successively undergoes 7 steps of reaction such as nucleophilic addition reaction to obtain 3-amino-4-alkoxyiminopiperidine Pyridine and its salts. Background technique [0002] 3-amino-4-alkoxyiminopiperidine is an important class of pharmaceutical and chemical intermediates that have emerged in recent years, and is mainly used to synthesize new quinolone antibacterial and anti-tuberculosis candidate compounds (ZL 200710145608.3; PCT / CN 2008 / 001526; ZL 201010156815.0). The literature so far has disclosed two laboratory synthesis methods of such intermediates. Among them, the literature method one uses ethyl 1-benzyl-4-oxopiperidine-3-carboxylate as the starting material...

Claims

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Application Information

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IPC IPC(8): C07D211/72
Inventor 郭慧元刘明亮刘秉全魏增泉刘开湘李素杰
Owner 浙江宏康医药化工股份有限公司
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