Preparation method of 1-benzyl-4-piperidine formaldehyde

A technology of piperidine formaldehyde and piperidine carboxylic acid, which is applied in the field of preparation of donepezil hydrochloride, can solve the problems of unfriendly environment, harsh reaction conditions, and high production cost, and achieve the effects of good product purity, easy preparation, and simple operation

Inactive Publication Date: 2016-06-22
上海金树科技股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The DIBALH used in this method is more expensive, it is difficult to apply industrially, and the production cost is higher
And find in practice, this method also has some problems that Red-ALP-KTB reducing system exists
[0022] In summary, among the various methods for the preparation of 1-benzyl-4-piperidinecarbaldehyde that have been reported, there are problems such as unavailable reagents, harsh reaction conditions, low yield or unfriendly environment, which are not conducive to industrial production.

Method used

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  • Preparation method of 1-benzyl-4-piperidine formaldehyde
  • Preparation method of 1-benzyl-4-piperidine formaldehyde
  • Preparation method of 1-benzyl-4-piperidine formaldehyde

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The preparation of embodiment 11-benzyl-4-piperidinecarboxylic acid methyl ester

[0041] Add 1.62kg of 4-piperidinecarboxylic acid methyl ester hydrochloride, 1.08kg of benzyl chloride, 1.89kg of sodium bicarbonate and 4.3kg of absolute ethanol into a 20L reaction kettle, heat to reflux, keep the reflux reaction for 3 hours, and cool down to an internal temperature of 30 At about ℃, discharge, filter, wash the filter cake with 2.15kg of absolute ethanol, drain, concentrate the filtrate to obtain a paste, the residue is dispersed in 4.7kg of toluene and 6.0kg of pure water, stir and wash the organic layer, and separate the organic layer, and concentrated toluene to obtain 1.92 kg of methyl 1-benzyl-4-piperidinecarboxylate as a pale yellow oily liquid. Yield: 96.5% (calculated as benzyl chloride). HPLC: 99.12%

[0042] 1 H-NMR (400MHz, CDCl3) δppm: 7.21-7.32 (5H, m), 3.67 (3H, s), 3.48 (2H, s), 2.85 (2H, d), 2.29 (1H, tt), 2.02 (2H ,dt),1.89-1.84(2H,m),1.82-1.71(2H,m...

Embodiment 2

[0044] The preparation of embodiment 21-benzyl-4-piperidinecarboxylic acid ethyl ester

[0045]Add 18.4g of ethyl 4-piperidinecarboxylate hydrochloride, 12.7g of benzyl chloride, 21.0g of sodium bicarbonate and 40ml of absolute ethanol into a 100ml reaction flask, heat to reflux, keep the reflux reaction for 3h, and cool down to an internal temperature of 30°C Left and right, filter, wash the filter cake with 20ml of absolute ethanol, concentrate the filtrate to obtain a paste, add 40ml of toluene and 40ml of water, stir and disperse, separate the organic layer, concentrate toluene to obtain 1-benzyl-4-piperidinecarboxylic acid Ethyl ester 23.2g, is light yellow oily liquid. Yield: 93.8% (calculated as benzyl chloride). HPLC: 98.74%

[0046] 1 H-NMR (400MHz, CDCl3) δppm: 1.24(t, 3H), 1.69-1.82(m, 2H), 1.82-1.92(m, 2H), 1.96-2.10(m, 2H), 2.20-2.34(m, 1H),2.79-2.91(m,2H),3.48(s,2H),4.12(q,2H),7.20-7.32(m,5H)

[0047] ESI(+):248.17

Embodiment 3

[0048] The preparation of embodiment 3 red aluminum-morpholine complexes

[0049] Nitrogen gas was slowly introduced into a 10L dry jacketed reactor, and 2.6kg of toluene and 2.89kg of 70% red aluminum solution were added to the reactor, stirred, and cooled to an internal temperature of -5°C. Dissolve 0.96kg of morpholine in 0.85kg of toluene, drop it into the reactor, and control the reaction temperature to -5°C. After the dropwise addition was completed, the temperature was raised to 15°C, and the stirring reaction was continued for 8h to obtain the product.

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Abstract

The invention discloses a preparation method of 1-benzyl-4-piperidine formaldehyde. The preparation method comprises the following steps of carrying out a partial reduction reaction on 1-benzyl-4-piperidine methyl formate or 1-benzyl-4-piperidine ethyl formate and a vitride complex in a solvent; then collecting the 1-benzyl-4-piperidine formaldehyde from a reaction product. According to the preparation method of the 1-benzyl-4-piperidine formaldehyde, disclosed by the invention, 1-benzyl-4-piperidine formic acid esters are used as raw materials, the vitride complex is used as a reducing agent, the raw materials are easy to prepare, the operation is simple and convenient, the yield is high, the product purity is good, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of donepezil hydrochloride, in particular to a preparation method of a key intermediate used for the preparation of donepezil hydrochloride, in particular to a preparation method of 1-benzyl-4-piperidinecarbaldehyde. Background technique [0002] 1-benzyl-4-piperidinecarbaldehyde is an important intermediate for preparing the anti-senile dementia drug donepezil hydrochloride, and its structural formula is: [0003] [0004] Molecular formula: C 13 h 17 NO [0005] Molecular weight: 203.28 [0006] Donepezil hydrochloride is a long-acting symptomatic drug for Alzheimer's disease (AD). It was first listed in the United States in 1997. Compared with similar drugs, the incidence of adverse reactions is low. Among all drugs for the treatment of AD, the drug has the greatest effect Most obviously, it is the only new drug approved by the US FDA and the UK MCA for the symptomatic treatment of mild and modera...

Claims

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Application Information

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IPC IPC(8): C07D211/32
CPCC07D211/32
Inventor 朱犇
Owner 上海金树科技股份有限公司
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