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Synthetic method of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidine-4-yl)-N'-(4-isobutoxybenzyl)urea

A technology of isobutoxybenzyl and isobutoxybenzylamine, which is applied in the preparation of amino hydroxyl compounds, preparation of carbamic acid derivatives, chemical instruments and methods, etc., can solve the problem of long production cycle, complicated post-processing, and poor safety and other issues, to achieve the effect of less three wastes, easy to obtain raw materials, and low cost

Active Publication Date: 2015-10-07
SHENYANG PHARMA UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The technical problem to be solved in the present invention is to propose a new N-(4-fluorobenzyl)-N-( A synthetic method for the tartrate of 1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea, the method has short preparation period, high yield, simple post-treatment and high safety high

Method used

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  • Synthetic method of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidine-4-yl)-N'-(4-isobutoxybenzyl)urea
  • Synthetic method of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidine-4-yl)-N'-(4-isobutoxybenzyl)urea
  • Synthetic method of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidine-4-yl)-N'-(4-isobutoxybenzyl)urea

Examples

Experimental program
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Effect test

Embodiment 1

[0049] Embodiment 1, with ethoxycarbonyl as protecting group

[0050] 1) N-(4-hydroxybenzyl) ethyl carbamate

[0051] 4-Hydroxybenzylamine (20 g) and sodium bicarbonate (16 g) were added to dichloromethane (100 ml) and stirred at room temperature, and ethyl chloroformate (19.4 g) was added dropwise to in suspension. After the addition was complete, the mixture was stirred at 20°C to 25°C for 2 hours, starting material remaining by TLC. After the reaction was completed, suction filtration was performed to remove excess sodium salt. The filter cake was washed with dichloromethane (50ml x 2). The filtrate was washed with 5% dilute hydrochloric acid (36ml×2), and then washed with water (75ml×2). After separating the layers, the aqueous layer was discarded, and the organic layer was dried. The solvent was recovered under reduced pressure at 30°C to 40°C to obtain a crude red solid (30g), which was washed with toluene (45ml×2). The product was filtered and dried under vacuum at...

Embodiment 2

[0062] Embodiment 2, with methoxycarbonyl as protecting group

[0063] 1) Methyl N-(4-hydroxybenzyl)carbamate

[0064]Add 4-hydroxybenzylamine (15g) and sodium bicarbonate (15g) into dichloromethane (90ml) at room temperature (25°C, the same below) and stir, and dichloroformate formaldehyde at -25°C to 0°C for 1 hour The ester (13.8 g) was added dropwise to the suspension. After the addition was complete, the mixture was stirred at -25°C for 2 hours and the remaining starting material was checked by TLC. After the reaction was completed, suction filtration was performed to remove excess sodium salt. The filter cake was washed with dichloromethane (50ml x 2). The filtrate was washed with 5% dilute hydrochloric acid (36ml×2), and then washed with water (75ml×2). After separating the layers, the aqueous layer was discarded, and the organic layer was dried. The solvent was recovered under reduced pressure at 40°C to obtain a red liquid, which was dried under vacuum at 50°C for...

Embodiment 3

[0075] Example 3, using tert-butoxycarbonyl as a protecting group

[0076] 1) N-(4-hydroxybenzyl)-tert-butyl carbamate

[0077] 4-Hydroxybenzylamine (20g) and potassium bicarbonate (22g) were added to tetrahydrofuran (60ml) and water (15ml) at room temperature and stirred, di-tert-butyl dicarbonate (46.1 g) dropwise into the suspension. After the addition was complete, the mixture was stirred at 20°C to 25°C for 24 hours, starting material remaining by TLC. After the reaction was complete, the solid was filtered with suction, the filter cake was washed with tetrahydrofuran (30ml×2), the solid was washed with 5% dilute hydrochloric acid (36ml×2), the solid was filtered, washed with water (50ml×2), and filtered with suction. The solid was dried under vacuum at 60°C for 5 hours to obtain 14.7g of off-white powder, yield: 72.1%, mp: 105~107°C, ESI-MS m / z: 224[M+H] + ,246[M+Na] +

[0078] 2) tert-butyl N-(4-isobutoxybenzyl)carbamate

[0079] Dissolve N-(4-hydroxybenzyl)-tert-...

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Abstract

The invention belongs to the technical field of medicine, and relates to a synthetic method of a tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidine-4-yl)-N'-(4-isobutoxybenzyl)urea. According to the synthetic method, 4-hydroxybenzylamine is taken as a raw material, and N-protecting group-4-isobutoxybenzylamine is obtained via amino protection and hydrocarbylation reaction; key intermediate 4-isobutoxybenzylamine is obtained via deprotection reaction; N-(4-isobutoxybenzyl)phenyl carbamate is obtained via reaction with phenyl chloroformate; N-(4-fluorobenzyl)-N-(1-methylpiperidine-4-yl)-N'-(4-isobutoxybenzyl)urea is prepared via ammonolysis reaction with another intermediate N-(4-fluorobenzyl)-1-methyl-4-piperidylamine; and the tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidine-4-yl)-N'-(4-isobutoxybenzyl)urea is obtained via salifying with tartaric acid. The raw materials are easily available; operation is simple and mild; production period is short; yield is high; safety is high; cost is low; and the synthetic method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a kind of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea The synthetic method of tartrate also relates to its intermediate N-protecting group-4-hydroxybenzylamine, N-protecting group-4-isobutoxybenzylamine, 4-isobutoxybenzylamine and N-(4- The synthetic method of isobutoxybenzyl) phenyl carbamate. Background technique [0002] Parkinson's syndrome (Parkinsonism) is a chronic degenerative disorder of the central nervous system, clinically characterized by certain movement disorders (rest tremor, muscle rigidity, bradykinesia and loss of postural reflexes). It can impair a patient's motor skills, speech, and other functions. Its etiology is still unknown, and it is speculated that it is related to the rapid degeneration of brain cells in the basal ganglia and substantia nigra of the brain, which cannot produce enough neuroguiding substance dopamine (DA) (...

Claims

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Application Information

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IPC IPC(8): C07D211/58C07C269/04C07C269/06C07C271/16C07C213/02C07C217/58C07C271/48
CPCY02P20/55C07D211/58C07C213/02C07C217/58C07C269/04C07C269/06C07C271/16C07C271/48
Inventor 王绍杰王瀚培赵龙山
Owner SHENYANG PHARMA UNIVERSITY
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