Technology for preparing aclidinium bromide employing one-pot process

A kind of aclidinium bromide, process technology, applied in the field of one-pot preparation of aclidinium bromide, can solve the problems of cumbersome operation, complicated post-processing, long reaction time, etc.

Inactive Publication Date: 2014-04-30
AVENTIS PHARMA HAINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] This method obtains target product (I) through two-step reaction, and operation is loaded down with trivial details, and reaction time is long and post-processing is more complicated.

Method used

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  • Technology for preparing aclidinium bromide employing one-pot process
  • Technology for preparing aclidinium bromide employing one-pot process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Add 50mL of toluene into a 100mL three-necked flask, and then add (R)-3-quinuclidinol (1.52g, 12mmol), sodium hydride (0.60g, 15mmol), methyl 2,2-dithienyl glycolate (2.54 g, 10mmol), N 2 Under protection, heat to reflux for 4 hours, cool to room temperature; then add 3-phenoxypropyl bromide (2.15 g, 10 mmol) into the same reactor, heat and stir the reaction, and control the reaction temperature at 60-65°C, TLC tracking, until the thin-layer plate shows that the component point of the intermediate product disappears, cool to room temperature, add 10 mL of water to quench, separate the liquid, and distill the organic phase under reduced pressure. The residue is pulped with petroleum ether, and a white solid is obtained by suction filtration. Crystallized to obtain 1.9 g of white powder with a yield of 33.7%. m.p.227.5-230.0℃; 1 H NMR (400 MHz, DMSO) δppm 1.67(m, 2H), 1.97(m, 2H), 2.11(m, 2H), 2.32(m, 1H), 3.21(m, 1H), 3.45(m, 6H), 4.01(m, 3H), 5.16(m, 1H), 6.92(m, 3...

Embodiment 2

[0017] Add 50mL xylene into a 100mL three-necked flask, and then add (R)-3-quinuclidinol (1.52g, 12mmol), sodium hydride (0.60g, 15mmol), methyl 2,2-dithienyl glycolate ( 2.54g, 10mmol), N 2 Under protection, heat to reflux for 4 hours, cool to room temperature; then add 3-phenoxypropyl bromide (2.15g, 10mmol) into the same reactor, heat and stir the reaction, control the reaction temperature at 60-65°C, TLC Track until the thin-layer plate shows that the component point of the intermediate product disappears, cool to room temperature, add 10 mL of water to quench, separate the liquid, distill the organic phase under reduced pressure, beat the residue with petroleum ether, filter with suction to obtain a white solid, and recrystallize from methanol , to obtain white powder 2.0g, productive rate 35.5%. m.p. 226.5-229.0°C.

Embodiment 3

[0019] Add 50mL of ethylene glycol dimethyl ether into a 100mL three-necked flask, and then add (R)-3-quinuclidinol (1.52g, 12mmol), sodium hydride (0.60g, 15mmol), and 2,2-dithienyl ethanol Acid methyl ester (2.54g, 10mmol), N 2 Under protection, heat to reflux for 4 hours, cool to room temperature; then add 3-phenoxypropyl bromide (2.15g, 10mmol) into the same reactor, heat and stir the reaction, control the reaction temperature at 60-65°C, TLC Track until the thin-layer plate shows that the component point of the intermediate product disappears, cool to room temperature, add 10 mL of water to quench, separate the liquid, distill the organic phase under reduced pressure, beat the residue with petroleum ether, filter with suction to obtain a white solid, and recrystallize from methanol , to obtain 2.4 g of white powder, yield 42.4%. m.p. 228.0-229.5°C.

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Abstract

The invention belongs to the field of medicinal chemistry, and discloses a technology for preparing aclidinium bromide. By adopting the technology, (R)-3-quinuclidinol, (C1)methyl-2,2-dithienyl glycolate and 3-phenoxy propyl bromide are taken as raw materials, and the aclidinium bromide is prepared by adopting a one-pot process. The method is simple to operate, and convenient for post-treatment, and has good application value.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a process for preparing aclidinium bromide in one pot. Background technique [0002] Aclidinium bromide is a selective muscarinic cholinergic receptor antagonist that can relax the muscles around the large airways of the lungs, thereby improving ventilation; it is mainly used to treat bronchospasm caused by chronic obstructive pulmonary disease. The drug is the third anticholinergic bronchodilator on the market after ipratropium bromide and tiotropium bromide. Its onset speed is faster than tiotropium bromide, and it is safe and well tolerated. few. [0003] At present, only one preparation method of aclidinium bromide (WO 01 / 04118A2) is disclosed, and the reaction route is as follows: [0004] [0005] The method obtains the target product (I) through a two-step reaction, and the operation is cumbersome, the reaction time is long and the post-treatment is relatively comp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor 徐艳王涛苟远诚黄莉莎王绪堃侯春马苏峰
Owner AVENTIS PHARMA HAINAN
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