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Preparation method and application of glycopyrronium bromide chiral antipode

A technology of glycopyrronium bromide and enantiomers, which is applied in the field of medicine and can solve problems such as sales increase

Inactive Publication Date: 2013-04-03
SHENYANG PHARMA UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the development of a single enantiomer drug on the basis of a racemic drug is more time-saving and cost-effective than developing a brand new drug, and a single enantiomer drug may have better efficacy, higher safety, and fewer toxic and side effects, Potential to greatly increase sales

Method used

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  • Preparation method and application of glycopyrronium bromide chiral antipode
  • Preparation method and application of glycopyrronium bromide chiral antipode
  • Preparation method and application of glycopyrronium bromide chiral antipode

Examples

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Embodiment 1

[0053] Illustrate with respect to summary of the invention below, summary of the invention includes cited example but not limited to following example:

[0054] Preparation of (S)-N-benzyl-3-hydroxysuccinimide

[0055] 33.50 g of L-malic acid was suspended in 300 mL of toluene, 26.80 g of benzylamine was added dropwise, and heated to reflux for reaction. After the reaction, the toluene was evaporated under reduced pressure, and 40.82 g of white crystals were obtained by recrystallization with 50 mL of dichloromethane (yield 79 %), mp 104~106 ℃; MS (m / z): 228 (M+H + ); 1 H NMR (CD 3 OD) δ: 2.48 (dd, 1H), 3.05 (dd, 1H), 6.13 (d, 1H), 7.25 (d, 3H), 7.32 (t, 2H).

[0056] Preparation of (S)-N-benzylpyrrolidin-3-ol

[0057] Suspend 7.10 g of lithium aluminum hydride in 250 mL of anhydrous tetrahydrofuran, add dropwise a solution of 15.00 g of (S)-N-benzyl-3-hydroxysuccinimide in 150 mL of anhydrous tetrahydrofuran, and heat to reflux after the addition is complete. After the r...

Embodiment 2

[0089] The M receptor agonist acetylcholine (Ach) stimulates the M choline receptors on the smooth muscle to produce a smooth muscle contraction effect. In this study, the cecum and trachea of ​​guinea pigs were selected as objects to study the competitive antagonism of glycopyrronium bromide chiral enantiomers in vitro against acetylcholine ( Ach) agonistic effect on smooth muscle muscarinic receptors, and commercially available glycopyrronium bromide and racemic glycopyrrolate bromide were used as control drugs. Commercially available glycopyrronium bromide is a mixture of (3R, 2′S) and (3S, 2′R), and the racemic drugs are (3S, 2′S), (3R, 2′S), (3R, 2′R ) and (3S, 2′R) mixtures.

[0090] In this study, the above muscarinic receptor antagonistic drug screening system was used to initially screen out the chiral enantiomer of glycopyrronium bromide with the strongest cholinergic antagonistic effect. The specific implementation plan is as follows:

[0091] (1). Anticholinergic...

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Abstract

The invention belongs to the technical field of medicine, and discloses a preparation method of (3S,2'S), (3S,2'R), (3R,2'R) and (3R,2'S) four type chiral monomers of muscarine receptor antagonist racemic medicine glycopyrronium bromide. The method comprises the following steps: resolving racemic alpha-cyclopentylmandelic acid by a chemical resolution method by using L-Tyrosine methyl ester and (R)-alpha-phenylethylamine as resolution reagents to respectively prepare (S)-alpha-cyclopentylmandelic acid and (R)-alpha-cyclopentylmandelic acid; and carrying out esterification reaction to respectively obtain chiral intermediates (S) / (R)-alpha-cyclopentylmethyl mandelate. L / D-malic acid used as the raw material is subjected to four reaction steps, including condensation, carbonyl reduction, catalytic hydrogenation or transfer hydrogenation reduction debenzylation, and reduction alkylation or alkylogen alkylation, in a chiral synthesis mode to obtain another important chiral intermediate (S) / (R)-N-methyl-3-hydroxypyrrolidine. The chiral intermediate is subjected to ester exchange and quaterisation to respectively obtain the four (3S,2'S), (3S,2'R), (3R,2'R) and (3R,2'S) type glycopyrronium bromide chiral monomers. The result indicates that the (3R,2'S)-glycopyrronium bromide has the strongest cholinergic antagonistic action.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to the preparation of four chiral enantiomers of racemic drug muscarinic receptor antagonist glycopyrronium bromide and the research on their antagonistic effect on muscarinic receptors. Background technique [0002] Glycopyrronium Bromide (G1ycopyrronium Bromide) is a quaternary ammonium anticholinergic drug, a species recorded in the United States Pharmacopoeia, and a muscarinic receptor (M receptor) antagonist. M receptor antagonists, also known as M receptor blockers, can block the choline receptors on the effectors innervated by postganglionic cholinergic nerves, competitively antagonize the central and peripheral M receptors, by blocking Block acetylcholine or choline receptor agonist and receptor binding to produce antagonism. The pharmacological effects of M receptor antagonists mainly act on major organs such as the heart, eyes, glands, gastrointestinal tract, respiratory t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/12A61K31/40A61P1/04
Inventor 王钝于航毕璟璐陶润红毕洪书
Owner SHENYANG PHARMA UNIVERSITY
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