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Preparation method of high purity 2-benzyloxy bromoethane

A benzyloxyethanol, high-purity technology is applied in the field of preparation of umeclidinium bromide intermediate 2-benzyloxybromoethane, can solve the problems of harsh reaction conditions, low yield, difficult purification and the like, and achieves short steps , the effect of easy operation

Inactive Publication Date: 2019-06-18
SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The technical problem to be solved by the present invention is that in the existing 2-benzyloxybromoethane preparation process, the reaction conditions are harsh, the product purity is low, the purification is difficult, the yield is low, and it is not suitable for industrialized production.

Method used

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  • Preparation method of high purity 2-benzyloxy bromoethane
  • Preparation method of high purity 2-benzyloxy bromoethane
  • Preparation method of high purity 2-benzyloxy bromoethane

Examples

Experimental program
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Effect test

Embodiment 1

[0036] Preparation of crude product of 2-benzyloxy ethyl p-toluenesulfonate

[0037] 30.44g 2-benzyloxyethanol (0.2mol), 26.37gN,N-diisopropylethylamine (0.204mol), 1.22gN,N-dimethylaminopyridine (0.01mol), 38.89g p-toluenesulfonyl chloride ( 0.204mol) and 152mL of chloroform were sequentially added to a 500mL four-neck flask, kept at 20°C-30°C for 5h, TLC monitored the completion of the reaction, the reaction solution was washed with 0.1% malic acid aqueous solution, 0.1% sodium bicarbonate aqueous solution, distilled water After washing, the reaction solution was evaporated to dryness to obtain 60.0 g of yellow semi-solid oil (0.196 mol), yield 98.0%; HPLC purity 85.2%.

Embodiment 2

[0039] Purification of crude product of ethyl 2-benzyloxy p-toluenesulfonate

[0040] Add 30mL of absolute ethanol to 60.0g of 2-benzyloxy ethyl p-toluenesulfonate, heat until dissolved, add 60mL of petroleum ether dropwise, keep stirring at 30-50°C for 0.5-1h, cool down to 10°C, suction filter, filter cake Wash with 10 mL of petroleum ether to obtain 54.2 g of white crystalline powder, yield 90.3%; HPLC purity 98.6%.

Embodiment 3

[0042] Preparation of 2-Benzyloxybromoethane

[0043] Add 54.2g of refined ethyl 2-benzyloxy-p-toluenesulfonate (0.1769mol), 23.05g of lithium bromide (0.2654mol), and 271mL of acetone into a 1000mL four-neck flask, keep warm at 20°C-30°C for 5h, TLC Monitor the completion of the reaction, add 300mL of water, extract the reaction solution 3 times with 200mL of ethyl acetate, combine the organic phases, wash once with 200mL of water, and evaporate the organic phase to obtain 35.6g of colorless and transparent oily substance, yield 93.5%; HPLC purity 98.5% %, GC purity 99.1%.

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Abstract

The invention relates to a preparation method of an important intermediate 2-benzyloxy bromoethane (formula I) of umeclidinium bromide. The conditions of the preparation method are mild and controllable; post-treatment is simple; yield is high; and the purity of prepared 2-benzyloxy bromoethane is high.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a preparation method of umeclidinium bromide intermediate 2-benzyloxybromoethane. Background technique [0002] Uclidinium bromide (UMEC) is a long-acting cholinergic drug developed and launched by GlaxoSmithKline (GSK). M3 receptors show bronchodilator effect. In December 2013, the FDA approved Anoro Ellipta (a combined inhalation powder of umeclidinium bromide and vilanterol) for the maintenance treatment of COPD, including those with chronic bronchitis and / or emphysema. In May 2014, it was approved for marketing by the European Union, and in July 2014, it was approved for marketing by Japan. According to estimates by Thomson Reuters analysts, sales of Anoro Ellipta are expected to exceed $2 billion in 2019. In addition, umeclidinium bromide has also been approved as a separate drug by the United States, the European Union, and Japan. Approved by countries...

Claims

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Application Information

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IPC IPC(8): C07C41/22C07C43/174
Inventor 邓玉晓孙晋瑞段崇刚牛炳坤林治秘陈华来李丹张雯樊志萍边玲赵思太张宁张宗磊任业明马新成冯光玲
Owner SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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