A kind of choline M receptor antagonist aclidinium bromide and preparation method thereof

A technology of receptor antagonist and aclidinium bromide, which is applied in the field of respiratory system drug aclidinium bromide and its preparation, can solve the problems of high production cost, long reaction route and high production cost of aclidinium bromide, and achieve easy industrialization The production and reaction routes are short and the cost is low

Active Publication Date: 2017-08-01
DONGHUA UNIV +1
View PDF3 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In the above three synthetic methods, the first method is condensed in toluene by 2,2-bis(2-thienyl)-2-hydroxyacetic acid methyl ester (2) and R-3-quinine alcohol (3) to obtain 2,2-bis(2-thienyl)-2-hydroxyacetic acid-R-quinine-3-yl ester (4), the yield is only 40%, and the yield is low; method two: first mix oxalyl chloride with R- 3-quinine alcohol reaction to obtain di-R-quinine-3-yl oxalate (7), and then react with the Grignard reagent prepared by the reaction of 2-bromothiophene and magnesium powder to obtain 2,2-di Thienyl-2-hydroxyacetic acid-R-quinine-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
Method 3 also uses a large amount of expensive R-3-quinine alcohol, and the production cost is relatively high
[0012] 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • A kind of choline M receptor antagonist aclidinium bromide and preparation method thereof
  • A kind of choline M receptor antagonist aclidinium bromide and preparation method thereof
  • A kind of choline M receptor antagonist aclidinium bromide and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] 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, 0.03mol), 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: 173~175℃. IR: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

[0043] 2-Hydroxy-2,2-di(2-thiophene) acetic acid-3-quinyl ester (15.0 g, 0.043 mol), L-tartaric acid (6.45 g, 0.043 mol), 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 a white solid, with a yield of 39.1%. [α] D 25 =+116.1°(c=0.8g / 100mL, H 2 O). 1 H NMR (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).

[0044] Add tartrate prepared in the previous step and 5 mL of ethanol to a 50 mL eggplant-shaped bottle, add sodium hydroxide solution to adjust the pH to 7-8, stir at room temperature for 30 min, cool, and extract with chloroform. The solvent was removed to obtain 5.1 g of white solid R-2-hydroxy-2,2-bis(2-thienyl)acetic acid-3-quinyl ester, Mp: 175-178°C, the y...

Embodiment 3

[0046] Add 3-quinine alcohol (25.4g, 0.2mol) and 600mL anhydrous toluene to a 1000mL three-necked flask, add potassium tert-butoxide (23.5g, 0.21mol) in batches, stir at room temperature for 15min, then add 2-hydroxyl -2,2-bis(2-thienyl)acetic acid methyl ester (50.8g, 0.2mol), reflux reaction for 6h. After the reaction was completed, add 300 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 39.1 g of white solid quinine-3-yl 2,2-bis(2-thienyl)-2-hydroxyacetate, yield: 56.1%. Mp: 173~175℃. Prepared, yield 58.0%, mp: 172~175°C.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
melting pointaaaaaaaaaa
Login to View More

Abstract

The invention relates to choline M receptor antagonist aclidinium bromide and a preparation method thereof. According to the preparation method, 2,2-di(2-thienyl)-2-methyl glycolate reacts with 3-quinuclidinol to obtain 2-hydroxy-2,2-di(2-thienyl) acetic acid-3-quinine ester, split is performed with chiral acid, alkalization is performed in an alkaline solution to obtain R-2-hydroxy-2,2-di(2-thienyl) acetic acid-3-quinine ester, and lastly R-2-hydroxy-2,2-di(2-thienyl) acetic acid-3-quinine ester and 3-phenoxy propyl bromide are stirred for a reaction to obtain the aclidinium bromide. The prepared aclidinium bromide is simple in reaction operation, high in yield, low in price and short in reaction route, causes less waste water, waste gas and residues and facilitates industrial production.

Description

technical field [0001] The invention belongs to the field of respiratory system drug aclidinium bromide and its preparation, in particular to a choline M receptor antagonist aclidinium bromide 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 (Aclidinium bromide) was developed by American Forest Laboratory Pharmaceutical Company and Almirall Company. It was approved by the U.S. FDA in 2013. Its trade name is Tudorza Pressair. Aclidinium bromide inhalation powder is approved for use in chronic obstructive pulmonary disease ( Long-term maintenance treatment of bronchospasm caused by COPD). Tudorza is administered twice a day and is an inhaled long-acting anticholinergic drug. Its mechanism of action is to promot...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & AuthorityPatents(China)
IPC IPC(8): C07D453/02
CPCC07B2200/07C07D453/02
Inventor赵圣印安玉龙王明
OwnerDONGHUA UNIV