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Preparation method of quinine-3-yl R-2,2-di(2-thienyl)-2-glycolate

The technology of quinine and thienyl hydroxyacetate is applied in the field of preparation of R-2,2-di-2-hydroxyacetate quinine-3-yl ester, and can solve the problem that impurity a is unfavorable for industrialized production, unsuitable for industrialized production, It is easy to generate hydrogen and other problems, and achieves the effect of being suitable for industrial production, precise and easy operation, and improved yield.

Inactive Publication Date: 2018-05-22
YANGZHOU AORUITE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] In the above synthesis method, method one adopts sodium metal as the source of alkali, and method two uses sodium hydride as the source of alkali. Due to the poor stability of sodium metal, sodium hydride easily generates hydrogen when it meets water, and is prone to explosion. Therefore, method one and Method two is not suitable for industrialized production; although the yield in method three is high, it is easy to produce impurity a due to the use of dichloromethane extraction, which is not conducive to industrialized production

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  • Preparation method of quinine-3-yl R-2,2-di(2-thienyl)-2-glycolate

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Embodiment 1

[0025] Add methyl 2,2-dithienylglycolate (12.19g, 48mmol), R-(-)-3-quinine alcohol (5.08g, 40mmol) and sodium methoxide (1.08g, 20mmol) into a 500mL three-necked flask , then add 200ml of cyclohexane to dissolve, heat at 85°C for 1 hour, during which methanol is continuously separated, and cyclohexane is added at the same time. After the reaction, the reaction solution is poured into 100ml of dilute hydrochloric acid with a concentration of 2mol / L, and stirred After 10 minutes, the water layer was separated, and the pH of the water layer solution was adjusted to alkaline with potassium carbonate solution, filtered, and dried under reduced pressure at 50°C to obtain 11.20 g of white solid R-2,2-bis(2- Thienyl)-2-hydroxyacetic acid quinine-3-yl ester, the yield was 76.71%.

Embodiment 2

[0027] Add methyl 2,2-dithienylglycolate (12.19g, 48mmol), R-(-)-3-quinine alcohol (5.08g, 40mmol) and sodium methoxide (2.16g, 40mmol) into a 500mL three-necked flask , then add 200ml of cyclohexane to dissolve, heat at 95°C for 2 hours, during which methanol is continuously separated, and cyclohexane is added at the same time. After the reaction, the reaction solution is poured into 100ml of dilute acetic acid with a concentration of 2mol / L, and stirred After 10 minutes, separate the water layer, adjust the pH of the water layer solution to alkaline with potassium bicarbonate solution, filter and dry under reduced pressure to obtain 10.33 g of white solid R-2,2-bis(2-thienyl)- The yield of quinine-3-yl 2-hydroxyacetate is 70.75%.

Embodiment 3

[0029] Add methyl 2,2-dithienylglycolate (12.19g, 48mmol), R-(-)-3-quinine alcohol (5.08g, 40mmol) and sodium methoxide (3.24g, 60mmol) into a 500mL three-necked flask , then add 160ml of cyclohexane and 40ml of 2-methyltetrahydrofuran to dissolve, heat at 90°C for 3 hours, during which methanol is continuously separated, and at the same time, add the mixed solvent of the above ratio. After the reaction, pour the reaction solution into 100ml, the concentration is In 2mol / L dilute acetic acid, after stirring for 10min, separate the water layer, then adjust the pH of the water layer solution to alkaline with sodium carbonate solution, filter and dry under reduced pressure to obtain 11.77g of white solid R-2,2- Bis(2-thienyl)-2-hydroxyacetic acid quinine-3-yl ester, the yield is 80.50%.

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Abstract

The invention discloses a preparation method of quinine-3-yl R-2,2-di(2-thienyl)-2-glycolate, and belongs to the technical field of preparation and application of an anti-chronic obstructive pulmonarydisease drug aclidinium bromide intermediate. The preparation method comprises the following steps: adding methyl 2,2-dithienylglycolate, R-(-)-3-quinuclidinol and sodium methoxide into an organic solvent in an inert gas atmosphere, and carrying out a heating reaction; and adding the obtained reaction solution into a diluted acid solution after the reaction is finished, separating the obtained water layer, alkalizing the water layer, and filtering the alkalinized water layer to obtain the quinine-3-yl R-2,2-di(2-thienyl)-2-glycolate. The preparation method of the quinine-3-yl R-2,2-di(2-thienyl)-2-glycolate has the advantages of simplicity in operation, high yield, mild conditions, few three wastes, and easiness in industrial production.

Description

technical field [0001] The invention belongs to the technical field of preparation and application of aclidinium bromide intermediates for anti-chronic obstructive pulmonary disease, in particular, it relates to a kind of R-2,2-bis(2-thienyl)-2-hydroxyacetic acid quinolone Process for the preparation of nin-3-yl esters. Background technique [0002] Aclidinium bromide is an inhaled, long-acting, selective muscarinic receptor antagonist developed by American Forest Experiment Pharmaceuticals and Almirall, mainly used for the treatment of chronic obstructive pulmonary disease (COPD) . Aclidinium bromide is the third anticholinergic bronchodilator listed after ipratropium bromide and tiotropium bromide, due to its effect on M 3 The receptor is highly selective, safer than tiotropium bromide, and has fewer adverse reactions. Among them, R-2,2-bis(2-thienyl)-2-hydroxyacetic acid quinine-3-yl ester is an important intermediate for the synthesis of aclidinium bromide, and the ma...

Claims

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Application Information

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IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor 顾建辉王国平
Owner YANGZHOU AORUITE PHARMA CO LTD
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