A new process for synthesizing vilanterol

A synthesis method and technology of synthesis route, which are applied in the preparation of organic compounds, preparation of aminohydroxy compounds, organic chemistry and other directions, can solve the problems of restricting industrial scale-up of vilanterol, complicated preparation, long steps and the like, and achieve short reaction steps, The effect of easy availability of raw materials and mild reaction conditions

Active Publication Date: 2016-08-31
成都伊诺达博医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

And the preparation of raw material compound 5 is very loaded down with trivial details, take p-hydroxyacetophenone or 2-hydroxyl-4-bromo-benzaldehyde as raw material preparation, need to go through 7-8 step reaction and just can make, not only step is long, and yield is low, Reagents that are not suitable for industrial scale-up, such as bromine, butyllithium, and sodium hydride, need to be used
These all restrict the industrial scale-up of vilanterol

Method used

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  • A new process for synthesizing vilanterol
  • A new process for synthesizing vilanterol
  • A new process for synthesizing vilanterol

Examples

Experimental program
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Effect test

Embodiment 1

[0023] (2R)-Hydroxy-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-N-3-[6-[2-[(2,6- Preparation of dichlorophenyl)methoxy]ethoxy]hexyl]-ethylamine

[0024] Add 300ml of methanol to a 500ml three-necked flask, and then add 31.9g of 2-({2-[(5-formyl-hexyloxy)]-ethoxy}methyl)-1,3-dichlorobenzene With 22.3g of (2R)-hydroxyl-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-ethylamine, stirred at room temperature for about 5h, and the reaction was completed by TLC monitoring. Slowly add 4.2 g of sodium borohydride in batches, and control the internal temperature not to exceed 30°C. After the addition was complete, 5ml of water was slowly added dropwise to quench the reaction. Stir and add the reaction solution to 900ml of water, stir for 30min, add isopropyl ether to extract 3 times, wash with saturated brine 3 times, dry over anhydrous sodium sulfate, dry and concentrate under reduced pressure, the residue is purified by column chromatography to obtain (2R)- Hydroxy-2-(2,2-dimethyl-4H-1,3-ben...

Embodiment 2

[0026] 4-{(1R)-2-[(6-{2-[(2,6-dichlorophenyl)methoxy]ethoxy}hexyl)amine]-1-hydroxyethyl}-2- ( Preparation of hydroxymethyl)phenol (vilanterol)

[0027] (2R)-Hydroxy-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-N-3-[6-[2-[(2,6 Add 46.4 g of -dichlorophenyl)methoxy]ethoxy]hexyl]-ethylamine to 200ml of acetic acid, then add 100ml of water, stir at room temperature for 7-8h, and monitor the completion of the reaction by TLC. Concentrate under reduced pressure, add 400ml of dichloromethane to the residue, adjust the pH to 7-8 with saturated sodium bicarbonate, separate the layers, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Chromatographic purification afforded 39.5 g of vilanterol with a yield of about 92.1%.

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Abstract

The present invention discloses a new method for synthesizing vilanterol. The present invention provides a completely-new vilanterol synthesis method, wherein the easily available starting raw material is adopted so as to effectively avoid disadvantages of harsh reaction conditions (such as anhydrous reaction), expensive reagents and the like of the existing process, and the method has characteristics of short route, high yield, and market competitiveness.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis technology, and in particular relates to a new synthesis method of Vilanterol. Background technique [0002] Chronic obstructive pulmonary disease (COPD) is characterized by incomplete airflow limitation and progressive aggravation, and has become the fifth leading cause of death in patients. Actively controlling symptoms and improving lung function are the mainstays of treatment for this disease. important goal. At present, the main drugs used to relieve the symptoms of COPD patients are long-acting β2 receptor agonists such as formoterol and salmeterol. [0003] In mid-May 2013, the US FDA approved the compound dry powder inhaler Breo Ellipta (adrenal cortex hormone fluticasone 100ug + long-acting β2 receptor agonist vilanterol 25ug) jointly developed by GlaxoSmithKline and Theravance. Once a day for chronic obstructive pulmonary disease (COPD), including long-term maintenance...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/08C07C213/00
Inventor 付清泉岳利剑林强邹涛周平赵茂先秦艳
Owner 成都伊诺达博医药科技有限公司
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