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R-2,2-di(2-thienyl)-2-glycolic acid quinine-3-ester and preparation and application thereof

A technology of quinine glycolate and methyl glycolate, which is applied in the field of R-2,2-di-2-hydroxyacetate quinine-3-yl ester, can solve the problem of high production cost, long reaction route and low yield and other problems, to achieve the effect of low cost, short reaction route and high yield

Active Publication Date: 2016-02-24
DONGHUA UNIV +1
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0009] In the above three synthetic methods, the first method is condensed in toluene by 2,2-two (2-thienyl) methyl glycolate (2) and R-3-hydroxyquinine alcohol (3) to obtain 2, 2-two (2-thienyl)-2-hydroxyacetic acid-R-quinine-3-yl ester (1), the yield is only 40%, and the yield is low; Method two and the third method used in the reaction Large, expensive R-3-quinine alcohol, resulting in high production costs of 2,2-bis(2-thienyl)-2-hydroxyacetic acid-R-quinine-3-yl ester (1)
[0010] 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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  • R-2,2-di(2-thienyl)-2-glycolic acid quinine-3-ester and preparation and application thereof
  • R-2,2-di(2-thienyl)-2-glycolic acid quinine-3-ester and preparation and application thereof
  • R-2,2-di(2-thienyl)-2-glycolic acid quinine-3-ester and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Add 3-quinine alcohol (38.1g, 0.3mol) and 600mL anhydrous toluene into a 1000mL three-necked flask, add 60% sodium hydride (13.2g, 0.33mol) in batches, stir at room temperature for 15min, then add 2-hydroxyl -2,2-bis(2-thienyl)acetic acid methyl ester (76.2g, 0.3mol), reflux reaction for 6h. After the reaction is complete, add 250 mL of water and stir for 20 min, separate the toluene layer, dry over anhydrous sodium sulfate and spin off the solvent to obtain the crude product. Ethanol was recrystallized to obtain 54.5 g of white solid, yield: 52.1%. Mp: 175~177℃. IR(KBr):3435,3075,2946,2876,2735,1732,1637,1566,1423,1354,1320,1232,1132,1085,997,837,784,689. 1 H-NMR (400MHz, DMSO-d 6 )δ:1.24(m,2H),1.54-1.58(m,3H),1.91(m,1H),2.45(m,1H),2.58-2.60(m,3H),3.07-3.36(m,1H) ,4.80-4.82(m,1H),6.69-7.02(m,2H),7.11-7.12(m,2H),7.36(m,1H),7.49-7.51(m,2H).

Embodiment 2

[0039] Add 2,2-bis(2-thienyl)-2-hydroxy-acetic acid-3-quinine ester (15.0g, 0.043mol), L-tartaric acid (6.45g, 0.043mol), 180mL of absolute ethanol was heated to reflux for 30min, and the reaction solution was clarified. After cooling to room temperature, a white solid precipitated out. Suction filtration yielded 8.4 g of white solid, with a yield of 39.1%. [α] D 25 =+116.1°(c=0.8g / 100mL, H 2 O). 1 HNMR (400MHz, DMSO-d 6 )δ: 1.08(d, J=6.4Hz, 2H), 1.65(dd, J=66.5, 27.4Hz, 4H), 2.13(s, 1H), 2.93(t, J=33.3Hz, 5H), 3.41( dd,J=19.3,12.0Hz,2H),4.06(s,2H),5.04(s,1H),7.01(s,2H),7.14(s,2H),7.50(s,2H),7.73(s ,2H).

[0040] Add 2,2-bis(2-thienyl)-2-hydroxy-acetic acid-3-quinine ester-L-tartrate prepared in the previous step to a 100mL eggplant-shaped bottle, 50mL of ethanol, and add sodium hydroxide solution to adjust the pH to 7-8, stirred at room temperature for 30 minutes, cooled, and extracted with chloroform. The solvent was removed to obtain 5.1 g of white solid R-2-hydro...

Embodiment 3

[0042] Add 3-quinine alcohol (25.4g, 0.2mol) and 500mL of anhydrous toluene into a 1000mL three-neck flask, add sodium methoxide (11.9g, 0.22mol) in batches, stir at room temperature for 15min, then add 2,2-dimethoxide in batches (2-Thienyl)methyl 2-hydroxyacetate (53.5g, 0.21mol) was refluxed for 8h. After the reaction was completed, add 250 mL of water and stir for 20 min, separate the toluene layer, dry over anhydrous sodium sulfate, evaporate the solvent to obtain a crude product. Recrystallization from ethanol gave 35.1 g of white solid 2,2-bis(2-thienyl)-2-hydroxy-acetic acid-3-quinine ester, yield 48.1%, mp: 176-178°C.

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Abstract

The invention relates to R-2,2-di(2-thienyl)-2-glycolic acid quinine-3-ester and preparation and application thereof. A structural formula of the compound is shown in the specification, a reaction is conducted on 2,2-di(2-thienyl)-2-methyl glycolate and 3-quinuclidinol, and 2-hydroxy-2,2-di(2-thienyl) acetic acid-3-quinine ester is obtained; then separation is conducted through chiral acid, alkalization is conducted in an alkali solution, and the R-2,2-di(2-thienyl)-2-glycolic acid quinine-3-ester is obtained. The R-2,2-di(2-thienyl)-2-glycolic acid quinine-3-ester and the preparation and application thereof have the advantages of being simple in reaction operation, high in yield, low in price, short in reaction route, few in three wastes and prone to industrial production.

Description

technical field [0001] The invention belongs to the field of preparation and application of aclidinium bromide intermediates for anti-chronic obstructive pulmonary disease, in particular to a kind of R-2,2-di(2-thienyl)-2-hydroxyacetic acid quinine-3-yl ester and Its preparation and application. Background technique [0002] Aclidinium bromide (Aclidinium bromide) is developed by American Forest Laboratory Pharmaceutical Company and Almirall Company. It was approved by the US FDA in 2013. It is an effective drug for the treatment of chronic obstructive pulmonary disease (Chronic obstructive pulmonary disease, COPD). The trade name is Tudorza Pressair. Aclidinium bromide inhalation powder is currently approved as a long-term maintenance treatment of bronchospasm caused by chronic obstructive pulmonary disease (COPD). This product is administered twice a day and is an inhaled long-acting anticholinergic drug. Its mechanism of action is to promote bronchodilation by inhibiting...

Claims

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Application Information

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IPC IPC(8): C07D453/02A61K31/439A61P11/00
CPCA61K31/439C07D453/02
Inventor 赵圣印安玉龙王明
Owner DONGHUA UNIV
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