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Continuous process for preparation of anticholinergic agents

A technology for anticholinergic drugs and drugs, which is applied in the continuous field of preparing anticholinergic drugs and can solve problems such as large-scale production and saving

Pending Publication Date: 2022-03-18
HOVIONE SCIENTIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Remarkably, even small improvements in reaction design can lead to significant savings in large-scale production

Method used

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  • Continuous process for preparation of anticholinergic agents
  • Continuous process for preparation of anticholinergic agents

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[0035] The methods for the preparation of anticholinergics / drugs disclosed herein may include the use of one or more flow programs to perform a continuous flow mode process.

[0036]The term "flow procedures" as used herein relates to procedures, for example, using certain devices and / or certain conditions required to enable chemical synthesis to run continuously. Flow procedures as used herein do not include traditional batch processes. Preferably, a continuous reactor is used to deliver the materials in a flowing stream, as will be understood by those skilled in the art.

[0037] A process may be defined as continuous in that it is characterized by the continuous feeding of reactants into the reactor while the continuous formation and withdrawal of a product stream.

[0038] The continuous process disclosed in this invention may be advantageous for a number of reasons including, but not limited to, improved purity and yield of product and reduced effluent; thus, the process...

Embodiment 1

[0063] Preparation of umeclidinium bromide

[0064] 1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.3g, 1.0mmol) and ((2-bromoethoxy)methyl)benzene (0.24mL, 1.5mmol) A solution in 1-propanol (30 mL) was injected into a stainless steel coil continuous flow reactor (2.1 mL) at a rate of 0.11 mL / min. The reactor temperature was 180°C. The reaction time was 20 minutes. The solution flowing out from the continuous flow reactor was collected (conversion by HPLC: 93.8%), and the volume was concentrated to 4 mL under reduced pressure. The resulting suspension was cooled to 5°C and stirred for 1 hour. The product was filtered, washed twice with methyl tert-butyl ether (MTBE), and dried under reduced pressure (white powder, 0.34 g, 80%). The product was analyzed by HPLC and a purity of 98.5% was obtained.

Embodiment 2

[0066] Preparation of umeclidinium bromide

[0067] 1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.34g, 1.2mmol) and ((2-bromoethoxy)methyl)benzene (0.27mL, 1.7mmol) A solution in 1-propanol (10 mL) was injected into a stainless steel coil continuous flow reactor (2.1 mL) at a rate of 0.42 mL / min. The reactor temperature was 180°C. The reaction time was 5 minutes. The solution flowing out from the continuous flow reactor (conversion by HPLC: 97.3%) was collected and concentrated to a volume of 4 mL under reduced pressure. The resulting suspension was cooled to 5°C and stirred for 1 hour. The product was filtered, washed twice with methyl tert-butyl ether (MTBE), and dried under reduced pressure (white powder, 0.36 g, 75%). The product was analyzed by HPLC and a purity of 98.9% was obtained.

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Abstract

The present invention relates to a novel process for the preparation of anticholinergic agents / drugs, such as umeclidinium bromide, tiotropium bromide, glycopyrronium bromide, aclidinium bromide, ipratropium bromide (V), in a continuous flow mode in the presence of one or more polar protic solvents. The anticholinergic agents are useful in the treatment of respiratory diseases, such as asthma or chronic obstructive pulmonary disease (COPD), in a form suitable for inhalation.

Description

[0001] field of invention [0002] The present invention generally relates to the preparation of anticholinergics / drugs such as umeclidinium bromide (I) (chemical name: 4-[hydroxy(diphenyl)methyl]-1-[2-(phenylmethyl) Oxy]ethyl]-1-nitrogen cation (azonia) bicyclo[2.2.2]octane bromide), tiotropium bromide (II) (chemical name: 1α, 2β, 4β, 7β)-7-[( Hydroxy-di-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azacation-tricyclo[3.3.1.0 2，4 ]nonane bromide), glycopyrronium bromide (III) (chemical name: 3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium bromide), aclidinium bromide (IV) (chemical name: 3(R)-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(3-phenoxypropyl )-1-nitrogen cationic bicyclo[2.2.2]octane bromide), ipratropium bromide (V) (chemical name: [8-methyl-8-(1-methylethyl)-8-nitrogen Novel process for cationic bicyclo[3.2.1]oct-3-yl]-3-hydroxy-2-phenyl-propionate), as well as medicaments thus prepared and their use in medicine. The anticholinergic drugs listed ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02A61K31/439A61K31/46A61P11/06C07D451/10
CPCC07D453/02C07D451/10A61K31/439A61P11/06A61K31/46A61K9/0073C07D471/00A61K31/40A61P11/00C07B2200/13
Inventor M·卡茨N·托雷斯洛伦索
Owner HOVIONE SCIENTIA
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