Novel method for synthesis and purification of aclidinium bromide

A kind of technology of aclidinium bromide and new method, applied in the field of organic compound synthesis and purification, can solve problems such as difficult control, low yield, harsh reaction conditions and the like

Inactive Publication Date: 2018-11-13
FARMASINO PHARMA ANHUI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the reaction conditions are harsh, difficult to control and the yield is low

Method used

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  • Novel method for synthesis and purification of aclidinium bromide
  • Novel method for synthesis and purification of aclidinium bromide

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Embodiment 1

[0036] The invention provides a new method for the synthesis and purification of aclidinium bromide, the synthesis and purification method comprising the following steps:

[0037] Magnesium powder (30g, 1250mmol, 2.5eq), iodine (0.5g), THF (600mL) were added into a 1L three-necked flask, and 10mL of 2-bromothiophene (179g, 1100mmol, 2.2q) was added dropwise under heating and reflux conditions. THF (100 mL) mixed solution, and then bromoethane (1 mL) was added dropwise into a 1 L three-necked flask to control the reaction rhythm. Control the dropping rate, keep the reaction violently reflux, and reflux for about 1 hour after the addition to prepare the Grignard reagent;

[0038] Add dimethyl oxalate (59g, 500mmol, 1eq) and THF (360mL) into a 2L three-necked flask, cool in an ice-water bath to -5°C, add the above-mentioned Grignard reagent dropwise into a 2L three-necked flask, and mix in the temperature-controlled three-necked flask The solution was at -5°C, and the ice-water ...

Embodiment 2

[0040] The invention provides a new method for synthesizing and purifying aclidinium bromide, the preparation method comprising the following steps:

[0041] Magnesium powder (30g, 1250mmol, 2.5eq), iodine (0.5g), THF (600mL) were added into a 1L three-necked flask, and 10mL of 2-bromothiophene (179g, 1100mmol, 2.2q) was added dropwise under heating and reflux conditions. THF (100 mL) mixed solution, and then bromoethane (1 mL) was added dropwise into a 1 L three-necked flask to control the reaction rhythm. Control the dropping rate, keep the reaction violently reflux, and reflux for about 1 hour after the addition to prepare the Grignard reagent;

[0042] Add dimethyl oxalate (59g, 500mmol, 1eq) and THF (360mL) to a 2L three-necked flask, cool in an ice-water bath to -4°C, then add the above-mentioned Grignard reagent dropwise into a 2L three-necked flask, and mix in the temperature-controlled three-necked flask The solution was at -4°C, and the ice-water bath was removed afte...

Embodiment 3

[0044] The invention provides a new method for synthesizing and purifying aclidinium bromide, the preparation method comprising the following steps:

[0045] Magnesium powder (30g, 1250mmol, 2.5eq), iodine (0.5g), THF (600mL) were added into a 1L three-necked flask, and 10mL of 2-bromothiophene (179g, 1100mmol, 2.2q) was added dropwise under heating and reflux conditions. THF (100 mL) mixed solution, and then bromoethane (1 mL) was added dropwise into a 1 L three-necked flask to control the reaction rhythm. Control the dropping rate, keep the reaction violently reflux, and reflux for about 1 hour after the addition to prepare the Grignard reagent;

[0046] Add dimethyl oxalate (59g, 500mmol, 1eq) and THF (360mL) into a 2L three-necked flask, cool in an ice-water bath to -3°C, then add the above-mentioned Grignard reagent dropwise into a 2L three-necked flask, and mix in the temperature-controlled three-necked flask The solution was at -3°C, and the ice-water bath was removed ...

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Abstract

The invention discloses a novel method for synthesis and purification of aclidinium bromide. According to the method, tetrahydrofuran is used, haloalkane is used as an initiator, and a finished product is obtained through solvent extraction and recrystallization after acidification. The preparation process is mild in reaction conditions, simple and convenient to operate, high in yield and high infinished product purity, and breakthrough progress is made for the process in China.

Description

technical field [0001] The invention relates to the field of organic compound synthesis and purification, in particular to a new method for the synthesis and purification of aclidinium bromide. Background technique [0002] Aclidinium bromide is an antimuscarinic drug jointly developed by Almirall Pharmaceutical Company of Spain and Forest Laboratory of the United States. The drug was approved by the US FDA in July 2012 under the trade name tudorzapressair. Aclidinium bromide is used for the long-term maintenance treatment of bronchospasm caused by chronic obstructive pulmonary disease (copd), including chronic bronchitis and emphysema. [0003] The chemical name of aclidinium bromide is 3R-2-hydroxy-2,2-dithiophen-2-ylacetoxy-1-(3-phenoxypropyl)-1-azabicyclo[2.2.2]octane Alkyl bromide (shown as compound 3 in the accompanying drawings). [0004] The existing synthetic method of aclidinium bromide uses dimethyl oxalate and 2-thienylmagnesium bromide as raw materials to pre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor 燕立波燕立兵王丽
Owner FARMASINO PHARMA ANHUI
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