Preparation method of 4-nitro-piperidine derivative

A derivative, piperidine technology, applied in the new synthesis field of 4-nitro-piperidine derivatives, can solve the problems of inability to realize process amplification, low synthesis process yield, easy explosion, etc., and achieve the effect of rapid preparation

Active Publication Date: 2014-12-10
武汉药明康德新药开发有限公司
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  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The purpose of the present invention is to develop a new method for preparing 4-nitro-piperidine derivatives, which mainly solves the technical problems such as low yield, easy explosion, inability to realize process amplification and difficult purification in the current synthesis process

Method used

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  • Preparation method of 4-nitro-piperidine derivative
  • Preparation method of 4-nitro-piperidine derivative
  • Preparation method of 4-nitro-piperidine derivative

Examples

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example 1

[0011] Example 1: At room temperature, mix 4-Boc-piperidone (200 g, 1.0 mol) and potassium carbonate (276.4 g, 2.0 mol) 3 Dissolve in ethanol (2000 mL), slowly add hydroxylamine hydrochloride (174.4 g, 2.5 mol), and react at 50°C for 0.5 hours. After the reaction, cool, filter, and spin dry the filtrate, then dissolve the solid in water (1000 mL), extract with ethyl acetate (600 mL×2), wash the organic phase with saturated brine, dry, and spin dry to obtain a white Solid product 2 (195 g, 90.6 %).

[0012] step 2

[0013]

[0014] Example 1: At 25°C, sodium cyanoborohydride (16.5 g, 0.263 mol) was slowly added to a solution of compound 2 (50 g, 0.233 mol) in anhydrous methanol (700 mL). 1N) The pH was maintained at 3. After the dropwise addition, react at room temperature for 3 hours until the end of the reaction. The reaction solution was adjusted to pH = 10 with saturated sodium bicarbonate, extracted with dichloromethane, the organic phase was washed with satur...

example 2

[0019] Example 2: Compound 3 (48.25 g, 0.225 mol), p-nitrobenzaldehyde (34 g, 0.225 mol) and calcium chloride (7.86 g) were dissolved in chloroform (492 mL), and stirred under reflux for 18 hours. After the reaction solution was cooled to room temperature, ethanol (196 mL) was added, filtered, and the filtrate was spin-dried to obtain an intermediate, which was directly used in the next reaction. Dissolve the intermediate obtained in the previous step reaction in methanol (1100mL) and dichloromethane (1100 mL), the concentration of the reaction solution is (35 g / L), cool to -78 ° C, and pass ozone into the reaction solution until it turns yellow The reaction solution turned blue in about 3 hours. Saturated sodium bisulfite was added to the reaction solution, concentrated and dissolved in ethyl acetate, washed with water, dried, concentrated and column chromatographed to obtain the nitro compound product (46 g, 86 %).

example 3

[0020] Example 3: Compound 3 (48.25 g, 0.225 mol), p-nitrobenzaldehyde (34 g, 0.225 mol) and calcium chloride (7.86 g) were dissolved in chloroform (492 mL), and stirred under reflux for 18 hours. After the reaction solution was cooled to room temperature, ethanol (196 mL) was added, filtered, and the filtrate was spin-dried to obtain an intermediate, which was directly used in the next reaction. Dissolve the intermediate obtained in the previous step reaction in methanol (1100mL) and dichloromethane (1100 mL), the concentration of the reaction solution is (55 g / L), cool to -78 °C, and pass ozone into the reaction solution until it turns yellow The reaction solution turned blue in about 6 hours. Saturated sodium bisulfite was added to the reaction solution, concentrated and dissolved in ethyl acetate, washed with water, dried, concentrated and column chromatographed to obtain the nitro compound product (42 g, 80 %).

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Abstract

The invention relates to a novel method for preparing a 4-nitro-piperidine derivative, mainly aiming at solving the technical problems of low yield, easy exploding, unavailability of realizing process amplification, difficulty in purifying and the like existing in the conventional synthesis process. According to the method, a nitro compound is obtained with an ozone oxidation method by taking 4-Boc-piperidone as a starting raw material. The method comprises the following steps of: I, reacting the 4-Boc-piperidone serving as the starting raw material with hydroxylamine hydrochloride by taking potassium carbonate as an alkali and taking ethanol as a solvent under a heating condition to obtain a 4-oximido-piperidine derivative; II, reacting the 4-oximido-piperidine derivative product obtained in the step I with sodium cyanoborohydride in a methanol solution at the room temperature to reduce oxime into hydroxy amine; and III, refluxing the hydroxyl amine obtained in the step II together with p-nitrobenzaldehyde and calcium chloride in chloroform to generate an intermediate, and introducing ozone at the temperature of 78 DEG C below zero by taking methanol and methylene dichloride as solvents till a reaction ends to obtain a target product. The 4-nitro-piperidine derivative obtained by utilizing the novel method disclosed by the invention is a useful intermediate or product for the synthesis of multiple medicaments and spirocyclic compounds.

Description

Technical field [0001] The invention involves a new synthesis method of 4-nitrine-pyrimidine derivatives. Background technique [0002] The snail ring compounds are widely used in pharmaceutical chemistry and organic synthesis, while 4-nitro-pyrine derivatives are important starting materials for synthetic snail ring compounds. It is of great significance to study its preparation methods and craftsmanship.At present, the synthesis method of this compound is reported less. It is mainly based on pyrine ketone as the starting raw material.In this method, the reaction income is low, the purification is difficult, and the response is prone to explosion, which is difficult to enlarge the process.The reaction type is as follows: [0003] [0004] Therefore, it is necessary to develop a method that is simpler, the response conditions and income are more stable, and the method can be enlarged by processing. Invention content [0005] The purpose of the present invention is to develop a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/38
Inventor 薛明明宋艳民马建义姜鲁勇马汝建陈曙辉
Owner 武汉药明康德新药开发有限公司
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