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Choline M receptor antagonist aclidinium bromide and preparation method thereof

A receptor antagonist, aclidinium bromide technology, applied to the choline M receptor antagonist aclidinium bromide and its preparation field, can solve the problems of high production cost, long reaction route and high production cost of aclidinium bromide , to achieve the effect of easy industrial production, short reaction route and low cost

Inactive Publication Date: 2015-04-01
DONGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In the above two synthetic methods, the first method is to condense methyl 2,2-dithienyl glycolate (2) and R-3-hydroxyquinine alcohol (3) in toluene to obtain 2,2-dithienyl -2-hydroxyacetic acid-R-quinine-3-yl ester (4), the yield is only 40%, and the yield is low; method two: first react oxalyl chloride with R-3-quinine alcohol to obtain oxalic acid di- R-quinine-3-yl ester (7), and then react with the Grignard reagent prepared by the reaction of 2-bromothiophene and magnesium powder to obtain 2,2-dithienyl-2-hydroxyacetic acid-R-quinone Nin-3-yl ester (4), used a large amount of expensive R-3-quinine alcohol in the reaction, resulting in high production cost of final drug aclidinium bromide
In summary, the above-mentioned method has the disadvantages of long reaction route, low yield and high production cost, and the cost is relatively high in large-scale production.

Method used

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  • Choline M receptor antagonist aclidinium bromide and preparation method thereof
  • Choline M receptor antagonist aclidinium bromide and preparation method thereof
  • Choline M receptor antagonist aclidinium bromide and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Take 63.5g (0.50mol) of 3-quinine alcohol, 60.5mL (0.75mol) of pyridine and 500mL of dichloromethane into a 1000mL round-bottomed flask, cool in an ice-water bath to 0-10°C, and add 67.1g of methyl oxalyl chloride dropwise (0.55mol), after dropping, heat, stir and reflux at 42°C for 8 hours. After the reaction is completed, add 200 mL of 2N hydrochloric acid to the reaction solution, stir for 10 minutes, separate the dichloromethane layer, and extract the water layer twice with dichloromethane. Dry with anhydrous sodium sulfate, wash with water to obtain an oily substance, add a hydrogen chloride-saturated ethanol solution to obtain 83.1 g of methyl oxalate hydrochloride as a white solid, yield 78.1%, mp: 162-164°C. 1 H NMR (400MHz, CDCl 3 )δ:1.90-2.25(m,5H),2.54(s,1H),3.36(brs,5H),3.84(s,1H),3.93(s,3H),12.48(s,1H); 13 C NMR (101MHz, CDCl 3 )δ: 157.24, 156.62, 77.44, 77.13, 76.81, 69.78, 53.91, 52.50, 46.36, 45.57, 24.04, 20.37, 17.01. ESI-MS: 240[M+H] + .

Embodiment 2

[0040] Take 500 mL of anhydrous tetrahydrofuran, 48.9 g (0.30 mol) of 2-bromothiophene, and 7.2 g (0.3 mol) of magnesium powder, first add a small amount of 2-bromothiophene to the reaction solution, and then add 2 grains of iodine to initiate the reaction. Then add 2-bromothiophene dropwise, drop it in 30 minutes, continue stirring at room temperature for 2 hours, add 37.4 g (0.15 mol) of methyl oxalate 3-quinine alcohol ester hydrochloride in batches under stirring, dropwise, and stir at room temperature React for 30 minutes, then heat, stir and reflux at 60°C for 6 hours. After the reaction is complete, add 200 mL of saturated ammonium chloride solution, stir for 10 minutes, extract with ethyl acetate, wash the ethyl acetate layer with water, and dry the ethyl acetate layer with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 30.2 g of white color, yield 57.7%, mp: 149-151°C. 1 H-NMR(400MHz,DMSO)δ:1.24(m,2H),1.54-1.58(m,3H),1.91(m,1H...

Embodiment 3

[0042] Take 63.5g (0.50mol) of R-3-quinine alcohol, 60.5mL (0.75mol) of pyridine and 500mL of dichloromethane into a 1000mL round bottom flask, cool in an ice-water bath to 0-10°C, and add methyl oxalyl chloride dropwise 67.1g (0.55mol), after dropping, heat, stir and reflux at 45°C for 8 hours. After the reaction is completed, add 200mL of 2N hydrochloric acid to the reaction solution, stir for 10 minutes, separate the dichloromethane layer, and extract the water layer twice with dichloromethane. The methane layer was dried with anhydrous sodium sulfate, washed with water to obtain an oily substance, and an ethanol solution saturated with hydrogen chloride was added to obtain a white solid methyl-R-3-quinine oxalate, yield 68.5%, mp: 176-178°C.

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Abstract

The invention relates to choline M receptor antagonist aclidinium bromide and a preparation method thereof. The chemical structural formula of the choline M receptor antagonist aclidinium bromide is as shown in the specification. The preparation method comprises the following steps: mixing R-quinine-3 alcohol, alkali and an organic solvent, dripping methyl oxalyl chloride, after the methyl oxalyl chloride is completely dripped, heating, performing heating reflux for 1-20 hours, and separating and purifying, thereby obtaining a substance A; adding iodine into a tetrahydrofuran solution of 2-bromothiophene and magnesium powder to initiate reaction for 1-5 hours, thereby preparing a Grignard reagent of 2-bromothiophene, adding the substance A, stirring to react for 10-30 minutes at the room temperature, performing heating reflux for 4-6 hours, separating and purifying, thereby preparing 2,2-dithienyl-2-glycolic acid-R-quinine-3-base ester, and performing quaterisation reaction with 3-phenoxypropyl bromine, thereby obtaining aclidinium bromide. The aclidinium bromide provided by the invention is simple in reaction operation, high in yield, low in price, short in reaction route, small in waste generation and easy in industrialization production.

Description

technical field [0001] The invention belongs to the field of choline M receptor antagonist drug for treating chronic obstructive pulmonary disease and its preparation, and particularly relates to aclidinium bromide, a choline M receptor antagonist, and a preparation method thereof. Background technique [0002] Chronic obstructive pulmonary disease (COPD) is a common respiratory disease, which is a preventable and treatable disease characterized by airflow limitation. Its airflow limitation is not fully reversible and develops progressively. Aclidinium bromide is administered twice a day and is an inhaled long-acting anti-M choline drug, which is a selective M 3 Receptor antagonists are indicated for long-term maintenance treatment of bronchospasm (narrowing of the airways in the lungs) associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Aclidinium bromide is the third listed anticholinergic bronchodilator after ipratro...

Claims

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Application Information

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IPC IPC(8): C07D453/02A61K31/439A61P11/00
CPCC07D453/02
Inventor 赵圣印王明向远辉
Owner DONGHUA UNIV
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