Preparation method of 3-hydroxypiperidine, preparation method of derivative of 3-hydroxypiperidine, and intermediate of 3-hydroxypiperidine

A technology of hydroxypiperidine and hydroxypentylamine hydrohalide, which is applied in the field of preparation of 3-hydroxypiperidine and its derivatives and its intermediates, and can solve the problems of unavailable raw materials, harsh reaction conditions, and low production efficiency

Inactive Publication Date: 2017-02-22
SHANGHAI PUYI CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The technical problem to be solved by the present invention is to overcome defects such as unavailable raw materials, harsh reaction conditions, high cost, low preparation efficiency, and inapplicability t

Method used

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  • Preparation method of 3-hydroxypiperidine, preparation method of derivative of 3-hydroxypiperidine, and intermediate of 3-hydroxypiperidine
  • Preparation method of 3-hydroxypiperidine, preparation method of derivative of 3-hydroxypiperidine, and intermediate of 3-hydroxypiperidine
  • Preparation method of 3-hydroxypiperidine, preparation method of derivative of 3-hydroxypiperidine, and intermediate of 3-hydroxypiperidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] (1) Preparation of 5-chloro-2-hydroxypentylamine hydrochloride ((1-2)

[0055]

[0056] Add 100mL of concentrated hydrochloric acid dropwise to 150.0g of tetrahydrofurfurylamine (1-1), control the rate of addition so that the reaction temperature is lower than 35°C, then continue to feed hydrogen chloride gas under stirring, slowly raise the temperature, and finally the reaction temperature reaches 80°C °C, react for 10 hours. The introduction of hydrogen chloride gas was stopped, and after cooling to room temperature, the reaction solution was concentrated under reduced pressure to remove most of the water, and a large amount of white solids were precipitated. Desalting was carried out by filtration, washed with cold water, and the resulting mother liquor was further concentrated to dryness to obtain 224.0 g of white solid 5-chloro-2-hydroxypentylamine hydrochloride (1-2), with a purity greater than 95% and a yield of 87%. 1 H NMR (400MHz,D 2 O)δ3.77(ddd, J=12.7,8...

Embodiment 2

[0064] (1) Preparation of 5-bromo-2-hydroxypentylamine hydrobromide ((2-2)

[0065]

[0066] Add 40mL of concentrated hydrobromic acid dropwise to 60.0g of tetrahydrofurfurylamine (1-1), control the rate of addition so that the reaction temperature is lower than 30°C, then continue to feed hydrogen bromide gas under stirring, slowly raise the temperature, and finally The reaction temperature reached 80°C, and the reaction was carried out for 8 hours. The introduction of hydrogen bromide gas was stopped, and after cooling to room temperature, the reaction solution was concentrated under reduced pressure to remove most of the water, and a large amount of white solids were precipitated. Desalting by filtration, washing with cold water, and further concentrating the resulting mother liquor to dryness yielded 86.0 g of 5-bromo-2-hydroxypentylamine hydrobromide (2-1), with a purity greater than 90% and a yield of 83%. 1 H NMR (400MHz,D 2 O)δ3.82(m,1H),3.57(t,J=6.6Hz,2H),3.06(dd...

Embodiment 3

[0074] Preparation of N-benzyloxycarbonyl-3-hydroxypiperidine (3-1)

[0075]

[0076] Dissolve 20.0g of 5-chloro-2-hydroxypentylamine hydrochloride ((1-2) in 50mL of water, add dropwise a solution of 20.4g of sodium hydroxide in 20mL of water at 10-15°C, and drop it in about 1 hour After dropping, react at about 15°C for 2 hours. Then heat up to 40-50°C and react for 4 hours. Cool to room temperature after stopping the reaction, add 80mL of dichloromethane and 20mL of water containing 7.5g of sodium hydroxide solution, and then Add 20.0g benzyl chloroformate, naturally rise to room temperature and react overnight. TLC spot plate, reaction is complete, separate liquid, and aqueous phase is extracted once with 50mL dichloromethane. Merge organic phase, organic phase is washed with water successively, and saturated saline is washed, without Drying over sodium sulfate over water, suction filtration, concentrated to obtain 25.0g colorless oily matter.The crude product was recrys...

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Abstract

The invention discloses a preparation method of 3-hydroxypiperidine, a preparation method of a derivative of 3-hydroxypiperidine, and an intermediate of 3-hydroxypiperidine. The preparation method of 3-hydroxypiperidine (I) is characterized in that 5-halo-2-hydroxypentylamine halogen acid salt (III) undergoes a ring closure reaction in water under the action of an inorganic alkali to obtain the 3-hydroxypiperidine (I). The preparation method of N-protected 3-hydroxypiperidine (II) comprises the following steps: 1, 5-halo-2-hydroxypentylamine halogen acid salt (III) undergoes the ring closure reaction in water under the action of the inorganic alkali to obtain the 3-hydroxypiperidine (I); and 2, the 3-hydroxypiperidine (I) and a nitrogen protection reagent undergo an N-acylation reaction in an organic solvent under the action of the inorganic alkali to obtain the N-protected 3-hydroxypiperidine (II). The preparation methods have the advantages of simple operation, no expensive catalysts, low production cost, easily available raw materials, simplicity in operation, high reaction conversion rate, high selectivity, simple process, and suitableness for industrial production.

Description

technical field [0001] The invention relates to a preparation method of 3-hydroxypiperidine and its derivatives and intermediates thereof. Background technique [0002] Many piperidine derivatives have various pharmacological activities such as antibacterial, antitumor, treatment of senile dementia and anesthesia, and are also one of the important drugs for the treatment of viral infections (including AIDS) and diabetes. 3-Hydroxypiperidine or its derivatives are one of the important intermediates, which are widely used in the synthesis of pharmaceutical intermediates such as chiral 3-aminopiperidine. It is of great significance to develop a synthetic method suitable for industrial production. [0003] [0004] The preparation method of existing 3-hydroxypiperidine or derivatives thereof mainly contains the following methods: [0005] 1. Using 3-hydroxypyridine as a raw material, prepare 3-hydroxypiperidine by high-pressure hydrogenation. There are many documents report...

Claims

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Application Information

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IPC IPC(8): C07D211/42C07C215/08C07C213/00
CPCY02P20/55C07D211/42C07C213/00C07C215/08
Inventor 李可来王博
Owner SHANGHAI PUYI CHEM CO LTD
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