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Synthesis method of N-benzyl-4-piperidyl formaldehgde

A synthetic method, benzyl technology, applied in the field of pharmaceuticals, can solve the problems of high price, difficulty in industrial production, complex products, etc., and achieve the effect of easy preparation, cheap price and wide source

Inactive Publication Date: 2004-12-22
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] There are certain defects in the above method: butyllithium is not only a flammable and explosive substance, but also expensive. At the same time, the reaction products of this synthesis route are complicated and need to be separated by column chromatography, and the reaction yield is very low. The step-by-step combined calculation is only 17.8%, so the method reported in U.S. Patent No. 5,100,901 has brought greater difficulty to industrial production.
[0006] Another document Tetrahedron, 2001: 2701-2710 reported that ethyl isonicotinate was used as a raw material, first undergoing N-benzylation, and then reducing it with diisobutylaluminum hydride (DIBAL-H) ​​under the catalysis of a tertiary amine The target compound is obtained, but the reducing agent diisobutylaluminum hydride (DIBAL-H) ​​used therein is complex to prepare, flammable, explosive, difficult to store, and also brings inconvenience to industrial production

Method used

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  • Synthesis method of N-benzyl-4-piperidyl formaldehgde
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  • Synthesis method of N-benzyl-4-piperidyl formaldehgde

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Experimental program
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Effect test

Embodiment 1

[0024] (1) Put 18.9g (0.10 moles) of N-benzyl-4-piperidone, 24.2g (0.11 moles) of trimethoxysulfonium iodide, and 180ml of toluene into a reaction flask, and add 50ml of 10% NaOH dropwise at room temperature After the addition of the solution, the temperature was slowly raised to 80° C., and the reaction was continued for 4 hours. Cool to room temperature, pour the reaction solution into a separatory funnel, separate the organic layer, extract the aqueous layer with toluene (50ml×3), combine the toluene layers, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, and recover under reduced pressure Toluene, the intermediate product 6-benzyl-1-oxa-6-azaspiro[2.5]octane 18.6g was obtained, and the yield was 91.6%;

[0025] 1 HNMR data: δ: 1.49-1.55 (m, 2H), 1.76-1.83 (m, 2H), 2.50-2.59 (m, 6H), 3.53 (s, 2H), 7.20-7.33 (m, 5H).

[0026] (2) Use 6.0ml (0.12 moles) of bromine, 5.76g of magnesium chips and 200ml of anhydrous ether to prepare magnesium bromide-eth...

Embodiment 2

[0029] (1) In a three-necked flask equipped with 4.4g (0.11 moles) of sodium hydride (60%) and 200ml of anhydrous tetrahydrofuran, add 24.2g (0.11 moles) of trimethoxysulfonium iodide in portions under ice-cooling, add After the reaction was completed, the reaction was continued for 30 minutes, and then a solution of 18.9 g (0.10 moles) of N-benzyl-4-piperidone and 30 ml of tetrahydrofuran was slowly added dropwise. After the addition, the temperature was gradually raised to reflux, and the reaction was continued for 5 hours. After cooling, recover the solvent, add 50ml of ice water and 200ml of ether, separate the ether layer, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, recover the ether to obtain the intermediate product 6-benzyl-1-oxa-6-aza Spiro[2.5]octane 17.5g, the yield is 86.2%;

[0030] (2) Using benzene instead of anhydrous ether as a solvent, the operation method is the same as the second step reaction in Example 1, and the yield...

Embodiment 3

[0032] (1) Operation is the same as in Example 1.

[0033] (2) Use benzene and anhydrous ether (1: 1) mixed solvent to replace anhydrous ether as solvent, other operating methods are the same as the second step reaction of Example 1, and the yield to obtain the target product is 74.8%

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Abstract

A process for synthesizing N-benzyl-4-piperidyl formaldehyde as the intermediate for preparing donepezil to treat senile dementia includes reacting between N-benzyl-4-piperidinone and Liuyelide to generate 6-benzyl-1-oxo-6-azaspiro[2,5] octane, and catalytic reforming with magnesium bromide-ether. Its advantage is high output rate.

Description

Technical field [0001] The invention belongs to the field of pharmacy and relates to a compound synthesis method, mainly relating to the synthesis method of N-benzyl-4-piperidinyl formaldehyde. Background technique [0002] N-benzyl-4-piperidinylcarbaldehyde is an important intermediate for the preparation of senile dementia drug Donepezil, and its structural formula is: [0003] [0004] U.S. Patent No. 5,100,901 has reported a method for preparing N-benzyl-4-piperidinyl formaldehyde. The method first reacts butyllithium with triphenylphosphonium chloride to generate methoxymethylene phosphorus ylide, and then React it with N-benzyl-4-piperidone to obtain the intermediate N-benzyl-4-methoxymethylene-piperidine, and finally hydrolyze it with dilute hydrochloric acid, and obtain the pure target compound after column chromatography . [0005] There are certain defects in the above method: butyllithium is not only a flammable and explosive substance, but also expensive. At...

Claims

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Application Information

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IPC IPC(8): C07D211/32C07D491/107
Inventor 盛荣胡永洲
Owner ZHEJIANG UNIV
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