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Method for synthesizing vilanterol intermediate and salt thereof

An intermediate and system technology, applied in the field of pharmaceutical chemical synthesis, can solve problems such as high production cost and environmental pollution, and achieve the effects of reducing costs, reducing environmental pollution, and cheap and easy-to-obtain reagents

Active Publication Date: 2014-07-16
SHANGHAI DINGYA PHARM CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Although the synthesis process replaces sodium hydride with potassium tert-butoxide, which reduces the potential safety hazards in industrial production, highly toxic chiral oxazoborolane is still used as a catalyst in the process of preparing the key intermediate compound X, causing environmental pollution problems and The problem of high production costs remains unresolved

Method used

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  • Method for synthesizing vilanterol intermediate and salt thereof
  • Method for synthesizing vilanterol intermediate and salt thereof
  • Method for synthesizing vilanterol intermediate and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] (R)-1-(2,2-Dimethyl-4H-benzo[d][1,3]dioxan-6-yl)-2-((S)-1-phenylethyl Preparation steps of amino)ethanol and its salts 1): Preparation of 2,2-dimethyl-6-oxirane-4H-benzo[d][1,3]dioxane (compound of formula IV)

[0024] Add 12.8 grams of 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxine-6-yl)ethanone (compound of formula II) in the three-neck round bottom flask and 100 milliliters of methanol, stirred to dissolve and then cooled to -10°C, then slowly added 2.4 grams of sodium borohydride, and reacted at room temperature for 90 minutes after the addition was complete. Add 50 milliliters of ammonium chloride aqueous solution to the reaction solution to quench, stir for 10 minutes and concentrate to remove most of the methanol, then add 50 milliliters of dichloromethane for extraction, the aqueous phase is extracted 3 times with 50 milliliters of dichloromethane, and the organic phases are combined . The organic phase was washed once with 20 ml of distilled water and once with ...

Embodiment 2

[0034] (R)-1-(2,2-Dimethyl-4H-benzo[d][1,3]dioxan-6-yl)-2-((S)-2-methoxy- Preparation of 1-phenylethylamino)ethanol and its salts

[0035] Step 1): (R)-1-(2,2-Dimethyl-4H-benzo[d][1,3]dioxan-6-yl)-2-((S)-2- Preparation of methoxy-1-phenylethylamino)ethanol

[0036] The preparation method of compound IV is the same as step 1) of Example 1.

[0037]Add 8.24 grams of epoxy compound IV to 50 milliliters of acetonitrile solvent, stir to dissolve it, then slowly add 9.06 grams of S-2-methoxyl-1-phenylethylamine, stir and react at 80°C for 6 hours, and use TLC method After monitoring the completion of the reaction, the reaction solution was concentrated. Add 30 mL of saturated aqueous sodium bicarbonate, extract with ethyl acetate (3 x 30 mL), and dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to give (R)-1-(2,2-dimethyl- 4H-benzo[d][1,3]dioxane-6-yl)-2-((S)-2-methoxy-1-phenylethylamino)ethanol crude product 9.8 grams, yield The rate is 68%. The cr...

Embodiment 3

[0045] (R)-2-(Benzyl((S)-1-phenylethyl)amino)-1-(2,2-dimethyl-4H-benzo[d][1,3]dioxahexa Preparation of cyclo-6-yl)ethanol and its salts

[0046] Step 1): (R)-2-(Benzyl((S)-1-phenylethyl)amino)-1-(2,2-dimethyl-4H-benzo[d][1,3 ] the preparation of dioxane-6-yl) ethanol

[0047] The preparation method of compound IV is the same as step 1) of Example 1.

[0048] Add 8.24 grams of epoxy compound IV to 50 milliliters of tetrahydrofuran solvent, stir to dissolve it, then slowly add 10.97 grams of S-(-)-N-benzyl-1-phenethylamine, reflux for 4 hours, and monitor the reaction with TLC completely. After the reaction solution is cooled, add 30 milliliters of saturated ammonium chloride aqueous solution, stir at room temperature for 10 minutes, then add 3 grams of sodium chloride, continue to stir for 30 minutes, and leave to stand for layering, and the aqueous phase is extracted with ethyl acetate (3 × 30 ml), the organic phase was dried over anhydrous sodium sulfate, filtered, and co...

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PUM

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Abstract

The invention provides a method for preparing a vilanterol intermediate (formula V) and a salt (formula VII) thereof, belonging to the field of chemical drug synthesis. The method comprises the steps of carrying out ring opening reaction on an epoxy compound 2,2-dimethyl-6-ethylene oxide-4H-benzo[d][1,3]dioxane and an amine chiral auxiliary to prepare a chiral compound V; then, separating the compound V from a mixture in a way of forming a crystal salt with an acid. A reagent used in the method provided by the invention is cheap and easily available, and hypertoxic chiral oxazaborolidine is prevented from being used, so that the cost is reduced, and the environment pollution is reduced.

Description

Technical field: [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation method of a vilanterol intermediate and a salt thereof. Background technique: [0002] beta 2 - Adrenergic receptor agonists are the most widely used drugs in the treatment of asthma and chronic obstructive pulmonary disease. Beta currently available in the market 2 - Adrenoceptor agonists have a maximum duration of action of 12 hours, which results in the need for twice-daily dosing. In the past ten years, we have developed β with high potency, high selectivity, fast onset, long duration of action, and once-a-day administration. 2 -Adrenergic receptor agonists have attracted great attention from the pharmaceutical industry. Vilanterol trifluoromethanesulfonate is a new type of ultra-long-acting beta 2 -Adrenergic receptor agonist, which was approved by the US FDA on December 18, 2013, and its drug name is Anoro Ellipta. [0003] The chemical ...

Claims

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Application Information

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IPC IPC(8): C07D319/08
CPCC07D319/08
Inventor 阮诗文严海艳严恭超徐丽萍阮晓娜
Owner SHANGHAI DINGYA PHARM CHEM CO LTD
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