Benzodiazepine derivatives tosylate salts, their polymorphic forms, preparation methods and uses thereof

A technology of tosidic acid salt and citric acid, which is applied in the preparation of sulfonate salts, medical preparations containing active ingredients, drug combinations, etc., and can solve problems such as unsatisfactory chemical and optical purity and affecting the stability of compounds

Active Publication Date: 2014-08-27
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Existing patent applications CN101,501,019 and US20,100,075,955 have respectively reported benzenesulfonate and ethanesulfonate of the compound of formula (I), but the chemical and optical purity of the formed salt is not very ideal, and the recrystallization process has not Significantly improve its chemical and optical purity, because the chemical and optical purity of the compound directly affects whether the compound can be used as a drug and the stability of the drug, so develop a compound of formula (I) with higher chemical and optical purity The salt is very necessary

Method used

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  • Benzodiazepine derivatives tosylate salts, their polymorphic forms, preparation methods and uses thereof
  • Benzodiazepine derivatives tosylate salts, their polymorphic forms, preparation methods and uses thereof
  • Benzodiazepine derivatives tosylate salts, their polymorphic forms, preparation methods and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: Synthesis of salt:

[0047] Take 1g of compound base of formula (I) (prepared according to patent US200,700,934,75A) and dissolve 1g in 6ml ethyl acetate, then dissolve 0.39g tosidic acid (equal molar ratio) in 1ml methanol, and add dropwise to formula ( I) In the ethyl acetate solution of the compound base, stirred for crystallization, suction filtration, and dried under reduced pressure to obtain the tosidate of the compound of formula (I), 0.94 g of white solid, and the yield was 75.0%. HPLC: 99.18%, optical purity: 99.87%.

Embodiment 2

[0049] Add 1.0 g of tosidate of the compound of formula (I) obtained in Example 1 into a 50 ml round bottom flask, add 20 ml of water, and heat to reflux for 10 minutes to completely dissolve the solid, stop heating, filter while hot, and cool to crystallize The resultant product was dried under reduced pressure at 45° C. overnight to obtain 0.64 g of a white solid with a yield of 64%. The X-ray diffraction spectrum of the crystalline sample is shown in figure 1 . The crystals are about 6.05 (14.61), 7.18 (12.30), 8.02 (11.02), 12.25 (7.22), 14.00 (6.32), 14.50 (6.10), 15.71 (5.64), 16.68 (5.31), 17.62 (5.03), 18.60 (4.77), 19.69 (4.50), 21.25 (4.18), 24.23 (3.67), 25.22 (3.53) and 27.22 (3.27) have characteristic peaks, see the DSC spectrum figure 2 , There are characteristic absorption peaks at about 152.02°C, 195.05°C and 204.49°C, defining this crystal form as I crystal form.

Embodiment 3

[0051] Add 1.0g of the tosidate of the compound of formula (I) obtained in Example 1 into a 10ml round bottom flask, add 50% isopropanol aqueous solution to 5.0ml, heat to reflux to completely dissolve the solid, stop heating, and cool After crystallization, the obtained product was dried under reduced pressure at 45° C. overnight to obtain 0.72 g of white solid with a yield of 72%. The X-ray diffraction and DSC spectra of the crystalline sample were studied and compared, and it was determined that the product was crystal form I.

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Abstract

Disclosed are tosylate salts of benzodiazepine derivatives, their polymorphic forms, preparation methods and uses thereof, in particular to a tosylate salt of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]propionic acid methyl ester of formula (I), which is a crystalline polymorph, its preparation method and use. The crystalline polymorph of tosylate salt of the compound of formula (I) has a low solvent residue and good stability, and can be used for the clinical treatment.

Description

Technical field [0001] The present invention relates to 3-[(4s)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazole[1,2-a][1,4]benzodiazepine -4-yl] methyl propionate tosidate polymorph and preparation method and application thereof. Background technique [0002] The chemical name of the compound of formula (I) is 3-[(4s)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazole[1,2-a][1,4]benzene Diaza -4-yl]methyl propionate, [0003] [0004] Because it contains carboxylic acid ester and benzodiazepine The structure of the patent EP1,183,243 reported that these compounds are short-acting central nervous system (CNS, Central Nervous System) inhibitors, with sedative hypnosis, anti-anxiety, muscle relaxation and anticonvulsant effects. They can be used for intravenous administration in the following clinical treatment programs: such as preoperative sedation, anti-anxiety and amnesia during surgery; conscious sedation during short-term diagnosis, surgery or endoscopic procedures; in the administrati...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D401/04C07C309/30C07C303/32A61K31/5517A61P25/20A61P25/22A61P25/08A61P21/02
CPCC07D401/04C07C309/30A61P21/02A61P25/08A61P25/20A61P25/22
Inventor 孙飘扬武乖利高晓晖张全良陈永江
Owner JIANGSU HENGRUI MEDICINE CO LTD
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