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Preparation method and application of vilanterol EP impurity 2

An impurity and reaction technology, which is applied in the field of preparation of vilanterol impurities, can solve problems such as the inability to provide a basis for quality control of vilanterol, and achieve the effects of high yield, few steps and low cost

Pending Publication Date: 2022-04-12
广州佳途科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The object of the present invention is to provide a kind of preparation method of vilanterol EP impurity 2, to solve the problem of tert-butyl [2-[2,2-dimethyl-4H-benzo[d][1, 3] Dioxin-7-yl]-2-oxoethyl] carbamate preparation technology blank, can not provide a basis for the quality control of vilanterol

Method used

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  • Preparation method and application of vilanterol EP impurity 2
  • Preparation method and application of vilanterol EP impurity 2
  • Preparation method and application of vilanterol EP impurity 2

Examples

Experimental program
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Effect test

Embodiment 1

[0062] Get 1 equivalent of the structural compound shown in formula I, dissolve in the acetonitrile of 10 times the volume of the structural compound shown in the formula I, the concentration of the structural compound shown in the formula I is 0.05~0.7 mol / liter, add p-toluenesulfonic acid 0.1 equivalent, without 2 equivalents of sodium sulfate in water, 1.5 equivalents of 2,2-dimethoxypropane, heated to 75°C under stirring, reacted for 1 hour, monitored the completion of the reaction, terminated the reaction, rotary evaporated the organic solvent, purified by column chromatography, mobile phase Petroleum ether: ethyl acetate = 1:0.3 to obtain white crystals (yield 90%), which is the compound of formula II.

[0063] Take 1 equivalent of the structural compound shown in formula II, dissolve it in a tetrahydrofuran solution with 10 times the volume of the structural compound shown in formula II, the reaction concentration of the structural compound shown in formula II is 0.05-0....

Embodiment 2

[0066] Take 1 equivalent of the structural compound shown in formula I, dissolve it in acetone with 10 times the volume of the structural compound shown in formula I, the concentration of the structural compound shown in formula I is 0.05~0.7 mol / liter, add 0.1 equivalent of p-toluenesulfonic acid, no 2.5 equivalents of sodium sulfate water, 2 equivalents of 2,2-dimethoxypropane. Under stirring, the temperature was raised to 75°C, and the reaction was carried out for 1 hour. After monitoring the completion of the reaction, the reaction was terminated, the organic solvent was evaporated to dryness, and purified by column chromatography. The mobile phase was petroleum ether:ethyl acetate=1:0.3, and white crystals were obtained (yield 87%), which is the structure compound shown in formula II.

[0067] Take 1 equivalent of the structural compound shown in formula II, dissolve it in a tetrahydrofuran solution with 10 times the volume of the structural compound shown in formula II, ...

Embodiment 3

[0069] Take 1 equivalent of the structural compound shown in formula I and dissolve it in dioxane with 10 times the volume of the structural compound shown in formula I. The concentration of the structural compound shown in formula I is 0.05-0.7 mol / liter, and add 0.09 equivalent of p-toluenesulfonic acid , 3.5 equivalents of anhydrous sodium sulfate, 2.5 equivalents of 2,2-dimethoxypropane, heated to 75°C under stirring, reacted for 1 hour, and monitored the completion of the reaction, terminated the reaction, rotary evaporated the organic solvent, and purified by column chromatography. The mobile phase was petroleum ether: ethyl acetate = 1:0.3, and white crystals (yield 85%) were obtained, which were compounds of the formula II.

[0070] Take 1 equivalent of the structural compound shown in formula II, dissolve it in a tetrahydrofuran solution with 10 times the volume of the structural compound shown in formula II, the reaction concentration of the structural compound shown ...

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Abstract

The invention discloses a preparation method and application of a vilanterol EP impurity 2, and the preparation method comprises the following steps: dissolving a compound with a structure as shown in a formula I in a first organic solvent, adding acid and a dewatering agent, and reacting with 2, 2-dimethoxypropane under a heating condition to obtain a compound with a structure as shown in a formula II; dissolving the compound with the structure as shown in the formula II in a second organic solvent, adding N-t-butyloxycarboryl-glycine-N '-methoxyl-N'-methyl amide, adding n-butyllithium at low temperature, and reacting for 1 hour to obtain a compound with the structure as shown in the formula III, namely the vilanterol EP impurity 2. The method has the advantages of easily available raw materials, few steps, high yield and low cost, and fills the technical blank of preparation of the vilanterol EP impurity 2. A cheap and high-quality impurity reference substance can be provided for quality research of vilanterol, and the method has important significance on safe medication of vilanterol.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a preparation method of vilanterol impurities. Background technique [0002] Vilanterol is a new long-acting beta 2 The receptor agonist, its compound preparation with fluticasone furoate and the compound preparation of umeclidinium bromide were approved by FDA in May and December 2013, respectively, for the treatment of obstructive pulmonary disease and asthma. vilanterol vs beta 2 Receptor affinity is below nanomolar. In cAMP functional activity studies, vilanterol has an effect on β 2 Receptor selectivity and salmeterol for β 1 receptors and beta 3 Receptor selectivity was similar but significantly higher than that of formoterol and indacterol. The level of intrinsic efficacy of vilanterol was significantly higher than that of salmeterol. Vilanterol was more durable than formoterol in cellular cAMP production and tissue-based persistence and retolerance studi...

Claims

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Application Information

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IPC IPC(8): C07D319/08G01N1/28
Inventor 李慧敏刘泽华梁大成
Owner 广州佳途科技股份有限公司
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