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Method for synthesizing vilanterol intermediate from tert-butyl carbamate

A technology of carbamic acid and tert-butyl ester, applied in organic chemistry, bulk chemical production, etc., can solve the problems of low total yield, long reaction steps, poor selectivity of Boc protecting group removal by trifluoroacetic acid, etc., and reduce production cost, avoiding poor selectivity, and shortening the effect of synthetic routes

Pending Publication Date: 2022-07-12
ANHUI DEXINJIA BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] This reaction route avoids the use of expensive two (tert-butoxycarbonyl) amines, and simultaneously avoids the problem of poor selectivity of trifluoroacetic acid to remove the Boc protecting group, but the reaction steps are too long to cause the overall yield to be on the low side

Method used

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  • Method for synthesizing vilanterol intermediate from tert-butyl carbamate
  • Method for synthesizing vilanterol intermediate from tert-butyl carbamate
  • Method for synthesizing vilanterol intermediate from tert-butyl carbamate

Examples

Experimental program
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Effect test

Embodiment 1

[0019] At room temperature, add tert-butyl carbamate (225g, 1.1eq) to a 5L three-necked flask, add 500mL of tetrahydrofuran, stir to dissolve, bring the system to -5-0°C, and slowly dropwise add LDA (960mL, 2mol / L, 1.1 eq) solution, keep stirring for 0.5h after adding, then slowly add 6-bromoacetyl-2,2-dimethyl-4H-benzo[1,3]dioxin (500g, 1.0eq) and 1L The solution prepared with tetrahydrofuran was added dropwise to the reaction system, and the reaction was incubated for 2h after the addition. The middle control reaction was completed, the reaction solution was concentrated, then saturated sodium bicarbonate solution (2L) and ethyl acetate (2L) were added, the residue was stirred and dispersed, and the layers were separated. The organic layer was water (2L) and saturated brine (2L) respectively. Washed, then dried with anhydrous sodium sulfate, filtered to remove magnesium sulfate, concentrated in vacuo to remove solvent, added isopropyl ether (1 L), stirred for crystallization...

Embodiment 2

[0021] To a 5L three-necked flask at room temperature, add tert-butyl carbamate (225g, 1.1eq), add tetrahydrofuran (500mL), stir to dissolve, bring the system to -5-0°C, slowly add potassium tert-butoxide (217g, 1.1eq) ) solution, keep stirring for 0.5h after adding, then slowly mix 6-bromoacetyl-2,2-dimethyl-4H-benzo[1,3]dioxin (500g, 1.0eq) and 1L tetrahydrofuran The prepared solution was added dropwise to the reaction system, and the reaction was incubated for 2h after the addition. The middle control reaction was completed, the reaction solution was concentrated, then saturated sodium bicarbonate solution (2L) and ethyl acetate (2L) were added, the residue was stirred and dispersed, and the layers were separated. The organic layer was water (2L) and saturated brine (2L) respectively. Washed, then dried with anhydrous sodium sulfate, filtered to remove magnesium sulfate, concentrated in vacuo to remove solvent, added isopropyl ether (1 L), stirred for crystallization at roo...

Embodiment 3

[0023] Add tert-butyl carbamate (225g, 1.1eq) to a 5L three-necked flask at room temperature, add tetrahydrofuran (500mL) and stir to dissolve. At room temperature, slowly add potassium tert-butoxide (217g, 1.1eq) solution, and stir after adding 0.5h, then slowly add the solution prepared by 6-bromoacetyl-2,2-dimethyl-4H-benzo[1,3]dioxin (500g, 1.0eq) and 1L tetrahydrofuran into the reaction system dropwise , and the reaction was incubated for 2h after the addition. The middle control reaction was completed, the reaction solution was concentrated, then saturated sodium bicarbonate solution (2L) and ethyl acetate (2L) were added, the residue was stirred and dispersed, and the layers were separated. The organic layer was water (2L) and saturated brine (2L) respectively. Washed, dried with anhydrous sodium sulfate, filtered to remove magnesium sulfate, concentrated in vacuo to remove solvent, added isopropyl ether (1 L), stirred for crystallization at room temperature, filtered t...

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Abstract

The invention discloses a method for synthesizing a vilanterol intermediate from tert-butyl carbamate, and belongs to the field of medicine synthesis. The method comprises the following steps: taking 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1, 3] dioxin as a raw material, and carrying out substitution reaction on the 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1, 3] dioxin and tert-butyl carbamate to obtain N-(2-(2, 2-dimethyl-4H-1, 3-benzdioxin-6-yl)-2-oxoethyl) tert-butyl carbamate. According to the vilanterol intermediate synthesis method provided by the invention, cheap and easily available tert-butyl carbamate is used as a raw material, the synthesis reaction conditions are mild, the operation is simple, the synthesis route is shortened by synthesizing vilanterol from the intermediate, the production cost is reduced, and the vilanterol intermediate synthesis method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and relates to a method for synthesizing a vilanterol intermediate from tert-butyl carbamate. Background technique [0002] Vilanterol trifenatate is a long-acting beta developed by GlaxoSmithKline (GSK) 2 receptor agonists. Its combination with fluticasone furoate and umeclidinium bromide were approved by the FDA in May and December 2013, respectively, for the treatment of obstructive pulmonary disease and asthma. Among them, tert-butyl N-(2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethyl)carbamate is a synthetic vilante Luo's key intermediate, CAS: 452339-71-8, molecular formula: C 17 H 23 NO 5 , molecular weight: 321.37. Structural formula of vilanterol and tert-butyl N-(2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethyl)carbamate As follows: [0003] [0004] At present, the synthesis of tert-butyl N-(2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethyl)carbamate mainly in...

Claims

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Application Information

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IPC IPC(8): C07D319/08
CPCC07D319/08Y02P20/55
Inventor 张启龙许坤张文成王红磊惠爱玲汪崇文
Owner ANHUI DEXINJIA BIOPHARM
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