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Polymorphic substance of pyridinium derivative used as M3 muscarinic receptor antagonist as well as preparation method and medicine composition of polymorphic substance

A technology of pyrrolidine and crystal forms, which is applied in the field of preparation of drugs for urinary system diseases or gastrointestinal diseases, 3R-1, to prevent or treat respiratory diseases, and can solve the problem of poor stability and fluidity of solid powders and difficulties in lung preparations Uncertainty, insufficient crystallization and other problems, to achieve good performance and suitable for industrial production

Active Publication Date: 2014-08-06
JIANGSU LIANHUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] For the compound of formula I, the solid powder product obtained according to the preparation method described in Chinese patent application 201310467219.8 has certain hygroscopicity, and insufficient crystallization, and the stability and fluidity of the solid powder are also poor, which is difficult for subsequent preparations. Inhaled pulmonary preparations pose great difficulties and uncertainties

Method used

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  • Polymorphic substance of pyridinium derivative used as M3 muscarinic receptor antagonist as well as preparation method and medicine composition of polymorphic substance
  • Polymorphic substance of pyridinium derivative used as M3 muscarinic receptor antagonist as well as preparation method and medicine composition of polymorphic substance
  • Polymorphic substance of pyridinium derivative used as M3 muscarinic receptor antagonist as well as preparation method and medicine composition of polymorphic substance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Form A of (R)-1,1-dimethyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)pyrrolidinium bromide (compound of formula I)

[0059] Dissolve (R)-1-methyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)pyrrolidine (1.0g, 3.1mmol) in 4mL butanone, under ice-cooling Methyl bromide (588mg, 6.2mmol) was added dropwise, and the temperature was slowly raised to room temperature. After reacting overnight, a solid precipitated out. The solid was filtered with suction, and the filter cake was washed with methyl ethyl ketone to obtain an off-white solid (0.98g), melting point: 224°C-227°C. 1 H NMR (DMSO, 500MHz) 67.51 (m, 2H), 7.48 (s, 1H), 7.13 (m, 2H), 7.00 (m, 2H), 5.52 (m, 1H), 3.93 (m, 1H), 3.73 (m, 2H), 3.63(m, 1H), 3.20(s, 3H), 3.03(s, 3H), 2.74(m, 1H), 2.16(m, 1H); 13 C NMR (DMSO, 125MHz) 6170.33, 146.63, 126.69, 126.24, 125.75, 125.70, 76.24, 73.85, 69.09, 63.94, 52.66, 51.91, 29.74; EI-MS m / z 338.1 [M-Br] + . The solid product was confirmed to be crystal form A of the compound of formu...

Embodiment 2

[0061] Form B of (R)-1,1-dimethyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)pyrrolidinium bromide (compound of formula I)

[0062] Dissolve (R)-1-methyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)pyrrolidine (200mg, 0.62mmol) in 0.4mL dichloromethane, ice bath Methyl bromide (118mg, 1.24mmol) was added dropwise, and the temperature was slowly raised to room temperature. After reacting overnight, a solid precipitated out. The solid was filtered with suction, and the filter cake was washed with dichloromethane to obtain an off-white solid (245mg, 94%). Melting point: 227°C ~230°C. The solid product is confirmed to be crystal form B of the compound of formula I through X-ray powder diffraction, infrared scanning, DSC scanning and TGA scanning.

Embodiment 3

[0064] Form B of (R)-1,1-dimethyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)pyrrolidinium bromide (compound of formula I)

[0065] Dissolve the crystalline form A (300mg) of the compound of formula I in 4mL of a mixed solvent of ethanol and water (19:1) at a temperature of 80°C under stirring, then slowly cool to 15°C and let it stand, a white color precipitates out of the solution crystals. After filtering, the filter cake was washed with a small amount of ethanol, and the collected crystals were dried under reduced pressure at 45°C to obtain 278 mg of white crystals, melting point: 226°C-229°C. The crystal is confirmed to be crystal form B of the compound of formula I through X-ray powder diffraction, infrared scanning, DSC scanning, TGA scanning and elemental analysis.

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Abstract

The invention relates to the field of pharmacy, particularly to a polymorphic substance of 3R-1,1-dimethyl-3-(2-hydroxyl-2,2-dithienyl-2-acetoxyl) pyrrolidine bromide, a preparation method of the polymorphic substance and applications of the polymorphic substance to preparation of medicines for preventing or treating respiratory system diseases, urinary system diseases or gastrointestinal tract diseases.

Description

technical field [0001] The present invention relates to the pharmaceutical field, in particular to polymorphs of 3R-1,1-dimethyl-3-(2-hydroxyl-2,2-dithiophen-2-ylacetoxy)pyrrolidine bromide, its The preparation method and its application in the preparation of medicines for preventing or treating respiratory system diseases, urinary system diseases or gastrointestinal diseases. [0002] This patent application requires a Chinese patent application (application number 201310046167.7, application date: February 06, 2013, name of invention: pyrrolidinium derivatives as M3 muscarinic receptor antagonists, polymorphs and drug combinations thereof ) priority. Background technique [0003] M receptors are mainly distributed in effector cells dominated by postganglionic fibers of parasympathetic nerves, including respiratory smooth muscle, gastrointestinal smooth muscle, bladder detrusor, pupillary sphincter, cardiac muscle, etc. Nervous system function. M receptors belong to G pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/14A61K31/4025A61P11/14A61P11/00A61P13/00A61P1/00A61P11/02A61P11/06A61P13/10A61P13/02A61P1/04
CPCC07D409/14
Inventor 孙宏斌向左娟温小安
Owner JIANGSU LIANHUAN PHARMA
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