Preparation method of vilanterol and salt thereof

A compound and mixture technology, applied in the field of preparation of vilanterol and its salts, can solve the problems of high cost, low yield, low purity, etc.

Active Publication Date: 2020-10-23
SHANGHAI ANOVENT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The technical problem to be solved in the present invention is to provide a new vilanterol and its salt in order to overcome the defects of high cost, low yield and low purity of the preparation method of vilanterol and its salt in the prior art preparation method

Method used

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  • Preparation method of vilanterol and salt thereof
  • Preparation method of vilanterol and salt thereof
  • Preparation method of vilanterol and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Add (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidine-2 to a 1L reaction flask - Ketone (15.0 g, S isomer content 0.5%) and N, N- dimethylformamide 150 ml, stirred and dissolved, cooled to 5 ° C in an ice bath, added potassium tert-butoxide (10.1 g), stirred at room temperature for 1 hour, then added 2-[2-(6-bromo-hexyloxy)-ethoxymethyl]-1,3-dichloro-benzene (27.6g) to the solution, stirred at room temperature for 24 hours, TLC The detection response is complete. Join H 3 PO 4 / KH 2 PO 4 Buffer solution, adjust the pH to about 7, stir for 10 minutes, extract 3 times with ethyl acetate, combine the organic phases, wash 2 times with water, and concentrate the organic phases under reduced pressure to obtain a crude product of pale yellow oil.

[0051] At room temperature, tetrahydrofuran (300ml) was added to the crude oil, followed by potassium trimethylsiliconate (23.1g), heated to reflux, stirred for 3h, and the reaction was complete by TLC. The reactio...

Embodiment 2

[0057] Add (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidine-2 to a 1L reaction flask - Ketone (15.0 g, S isomer content 0.5%) and N, N- dimethylformamide 150 ml, stirred and dissolved, cooled to 5 ° C in an ice bath, added potassium tert-butoxide (10.1 g), stirred at room temperature for 1 hour, then added 2-[2-(6-bromo-hexyloxy)-ethoxymethyl]-1,3-dichloro-benzene (34.5g) to the solution, stirred at room temperature for 24 hours, TLC The detection response is complete. Join H 3 PO 4 / KH 2 PO 4 Buffer solution, adjust the pH to about 7, stir for 10 minutes, extract 3 times with ethyl acetate, combine the organic phases, wash 2 times with water, and concentrate the organic phases under reduced pressure to obtain a crude product of pale yellow oil.

[0058] At room temperature, tetrahydrofuran (300ml) was added to the crude oily product, followed by potassium trimethylsiliconate (38.5), heated to reflux, stirred and reacted for 3h, and the reaction was complete ...

Embodiment 3

[0060] Add (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidine-2 to a 1L reaction flask - Ketone (15.0 g, S isomer content 0.5%) and N, N- dimethylformamide 150 ml, stirred and dissolved, cooled to 5 ° C in an ice bath, added potassium tert-butoxide (10.1 g), stirred at room temperature for 1 hour, then added 2-[2-(6-bromo-hexyloxy)-ethoxymethyl]-1,3-dichloro-benzene (25.3g) to the solution, stirred at room temperature for 24 hours, TLC The detection response is complete. Join H 3 PO 4 / KH 2 PO 4 Buffer solution, adjust the pH to about 7, stir for 10 minutes, extract 3 times with ethyl acetate, combine the organic phases, wash 2 times with water, and concentrate the organic phases under reduced pressure to obtain a crude product of pale yellow oil.

[0061] At room temperature, tetrahydrofuran (300ml) was added to the crude oily product, followed by potassium trimethylsiliconate (7.7g), heated to reflux, stirred and reacted for 6h, and the reaction was complete ...

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PUM

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Abstract

The invention relates to a preparation method of vilanterol and a salt thereof. The preparation method comprises the following steps: in a solvent, reacting a mixture containing a compound shown as aformula I with succinic acid to obtain a compound shown as a formula II-1; and subjecting the obtained compound shown as the formula II-1 to reacting and conversion to obtain vilanterol and the salt thereof. The preparation method of the vilanterol and the salt thereof has the advantages of higher yield, high purity, easiness in refining, simplicity and convenience in operation and suitability forindustrialization.

Description

technical field [0001] The present invention specifically relates to a preparation method of vilanterol and a salt thereof. Background technique [0002] long-acting beta 2 - The adrenergic agonist drug Vilanterol Trifenatate, which has the chemical name 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy Base]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol triphenylacetate, molecular formula: C 24 h 33 Cl 2 NO 5 ·C 20 h 16 o 2 , Molecular weight: 774.8, developed by GlaxoSmithKline, the indication is the maintenance treatment of adult patients with chronic obstructive pulmonary disease (COPD), the structural formula is as follows: [0003] [0004] The synthesis process of vilanterol triphenylacetic acid is disclosed in the prior art, such as patents CN200910208840, WO2004 / 041565 and US2015 / 0239862 which disclose the use of (5R)-5-(2,2-dimethyl-4H-1, 3-Benzodioxin-6-yl)-1,3-oxazolidin-2-one and 2-[2-(6-bromo-hexyloxy)-ethoxymethyl]- 1,3-dichloro-benzene is us...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/00C07C217/28
CPCC07C213/00C07D317/46C07D413/04C07C217/28
Inventor 黄才古孙辉徐天祥
Owner SHANGHAI ANOVENT PHARMA CO LTD
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