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Preparation method of 1-tert-butyloxycarbonylpiperidyl-4-formaldehyde

A technology of tert-butoxycarbonylpiperidine and tert-butoxycarbonyl, which is applied in the field of organic chemical synthesis, can solve the problems of unsuitability for large-scale industrial production, harsh reaction conditions, and low utilization of equipment, and achieve easy control and high utilization of equipment High, good effect

Active Publication Date: 2016-12-07
郑州本质医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the reaction to synthesize 1-tert-butoxycarbonylpiperidine-4-carbaldehyde needs to be carried out at -78°C, the reaction conditions are harsh, the equipment utilization rate is low, and it is not suitable for large-scale industrial production. Therefore, it is urgent to improve its preparation method

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The preparation method of 1-tert-butoxycarbonyl piperidine-4-carbaldehyde of the present embodiment comprises the following steps:

[0028] 1) Add 50g of 1-tert-butoxycarbonyl-4-piperidine methanol and 152g of dichloromethane in the reaction flask, add 65g of water after stirring, and mix to obtain mixture A; 1-tert-butoxycarbonyl-4-piperidine The mass ratio of methanol to dichloromethane and water is 1:3.04:1.3;

[0029] 2) Cool the mixture A obtained in step 1) to 0-5 °C, and sequentially add 4 g of 2,2,6,6-tetramethylpiperidine oxide (TEMPO, catalyst), 0.5 g of K 2 MnO 4 (cocatalyst) and 40 g of sodium bicarbonate (NaHCO 3 ) to obtain mixture B; 1-tert-butoxycarbonyl-4-piperidinemethanol and TEMPO, K 2 MnO 4 , the mass ratio of sodium bicarbonate is 1:0.08:0.010:0.8;

[0030] 3) Cool the obtained mixture B in step 2) to -5~0°C, add 250g (1-tert-butoxycarbonyl-4-piperidinemethanol) aqueous solution of sodium hypochlorite (NaClO, oxidant) with a mass concentration...

Embodiment 2

[0033] The preparation method of 1-tert-butoxycarbonyl piperidine-4-carbaldehyde of the present embodiment comprises the following steps:

[0034] 1) in the reactor, add 5kg of 1-tert-butoxycarbonyl-4-piperidine methanol and 20kg of toluene, add 10kg of water after stirring, and mix to obtain mixture A; 1-tert-butoxycarbonyl-4-piperidine methanol and The mass ratio of toluene and water is 1:4:2;

[0035] 2) Cool the mixture A obtained in step 1) to 0-5 °C, and sequentially add 450 g of 2,2,6,6-tetramethylpiperidine oxide (TEMPO, catalyst), 60 g of K 2 MnO 4 (cocatalyst) and 4.5 kg of sodium bicarbonate (NaHCO 3 ) to obtain mixture B; 1-tert-butoxycarbonyl-4-piperidinemethanol and TEMPO, K 2 MnO 4 , the mass ratio of sodium bicarbonate is 1:0.09:0.012:0.9;

[0036] 3) cooling the obtained mixture B in step 2) to -5~0°C, adding 21kg (1-tert-butoxycarbonyl-4-piperidinemethanol) aqueous solution of sodium hypochlorite (NaClO, oxidant) with a mass concentration of 10% using a ...

Embodiment 3

[0039] The preparation method of 1-tert-butoxycarbonyl piperidine-4-carbaldehyde of the present embodiment comprises the following steps:

[0040] 1) In the reaction flask, add 75g of 1-tert-butoxycarbonyl-4-piperidine methanol and 150g of dichloromethane, stir evenly, add 75g of water, and mix to obtain mixture A; 1-tert-butoxycarbonyl-4-piperidine The mass ratio of methanol to dichloromethane and water is 1:2:1;

[0041] 2) Cool the mixture A obtained in step 1) to 0-5 °C, and sequentially add 4.5 g of 2,2,6,6-tetramethylpiperidine oxide (TEMPO, catalyst), 0.6 g of K 2 MnO 4 (cocatalyst) and 45 g of sodium bicarbonate (NaHCO 3) to obtain mixture B; 1-tert-butoxycarbonyl-4-piperidinemethanol and TEMPO, K 2 MnO 4 , the mass ratio of sodium bicarbonate is 1:0.06:0.008:0.6;

[0042] 3) Cool the obtained mixture B in step 2) to -5~0°C, add 450g (1-tert-butoxycarbonyl-4-piperidinemethanol) aqueous solution of sodium hypochlorite (NaClO, oxidant) with a mass concentration of 1...

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Abstract

The invention discloses a preparation method of 1-tert-butyloxycarbonylpiperidyl-4-formaldehyde. The method comprises the following steps: 1) mixing 1-tert-butyloxycarbonyl-4-piperidylmethanol, an organic solvent and water to obtain a mixture A; 2) cooling the mixture A to 5 DEG C or below, and adding a catalyst, a cocatalyst and sodium bicarbonate to obtain a mixture B, wherein the catalyst is 2,2,6,6-tetramethyl piperidine oxide, and the cocatalyst is potassium manganate; and 3) cooling the mixture B to 0 DEG C or below, adding NaClO to carry out oxidation reaction, and carrying out separation and purification to obtain the 1-tert-butyloxycarbonylpiperidyl-4-formaldehyde. The TEMPO-K2MnO4 catalytic system used by the preparation method has the advantages of high catalytic activity, favorable effect and high product yield. The method is simple to operate and easy to control, has the advantages of mild reaction conditions, high equipment utilization rate and the like, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic chemical synthesis, in particular to a preparation method of 1-tert-butoxycarbonylpiperidine-4-carbaldehyde. Background technique [0002] Donepezil hydrochloride is an acetylcholinesterase inhibitor (AchEI) developed by Japan's Eisai Pharmaceutical Company. The main component is (±) 2,3-bishydroxy-5,6-bismethoxy-2-{1-(benzyl yl)-4-piperidinylmethyl}-1H-inden-1-one hydrochloride, first listed in the United States in 1997, this product is highly selective for neuronal acetylcholinesterase, has no liver toxicity, and is clinically used for Treat Alzheimer's disease. 1-tert-butoxycarbonylpiperidine-4-carbaldehyde is an important intermediate for the synthesis of donepezil hydrochloride, and its preparation and yield directly affect the production of donepezil hydrochloride. Therefore, in recent years, the preparation of 1-tert-butoxycarbonylpiperidine-4-carbaldehyde and research work has received m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/32B01J31/32
CPCC07D211/32B01J31/32B01J31/0244B01J23/34B01J35/19
Inventor 郝家金王建莉王妍赵萍萍杨勇胡孝伦张玉天
Owner 郑州本质医药科技有限公司