Tosilate of benzodiazepine derivative, its crystal forms, their preparation method and application

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

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

CN102964349AInactive Publication Date: 2013-03-13JIANGSU HENGRUI MEDICINE CO LTD
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  • Tosilate of benzodiazepine derivative, its crystal forms, their preparation method and application
  • Tosilate of benzodiazepine derivative, its crystal forms, their preparation method and application
  • Tosilate of benzodiazepine derivative, its crystal forms, their preparation method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1: the synthesis of salt:

[0047] Get formula (I) compound base (according to patent US200,700,934,75A preparation) 1g is dissolved in 6ml ethyl acetate, then 0.39g Toxic acid (equal molar ratio) is dissolved in 1ml methyl alcohol, and is added dropwise to formula ( I) in the ethyl acetate solution of the compound base, stirred and crystallized, suction filtered, and dried under reduced pressure to obtain the toxic acid salt 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 the toxic acid salt of the compound of formula (I) obtained in Example 1 into a 50 ml round-bottomed flask, add 20 ml of water, and heat to reflux for 10 min to completely dissolve the solid, stop heating, filter while hot, and cool to crystallize , the obtained 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 figure of this crystalline sample is shown in figure 1 . The crystallization at 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] Toxinate 1.0g of the compound of formula (I) obtained in Example 1 is added in a 10ml round-bottomed flask, added in 5.0ml of 50% isopropanol aqueous solution, heated to reflux to make the solid dissolve completely, stop heating, and cool After crystallization, the obtained product was dried under reduced pressure at 45° C. overnight to obtain 0.72 g of a white solid, with a yield of 72%. The X-ray diffraction and DSC spectrograms of the crystalline sample are studied and compared, and it is determined that the product is the I crystal form.

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Abstract

The invention relates to a tosilate of a benzodiazepine derivative, its crystal forms, their preparation method and application, especially to the crystal forms of a 3-[(4S)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazole[1, 2-a][1, 4]benzodiazepine-4-yl)methyl propionate (I) tosilate, their preparation method and application. The obtained crystals of the tosilate of a compound as shown in formula (I) has low solvent residual and good stability, and can be better used in clinical treatment.

Description

technical field [0001] The present invention relates to 3-[(4s)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine Toxic acid salt polymorph of -4-yl] propionate methyl ester and its preparation method and use. Background technique [0002] The chemical name of the compound of formula (I) is 3-[(4s)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzene and diazepines -4-yl] propionate methyl ester, [0003] [0004] Due to the presence of carboxylates and benzodiazepines The structure of the compound is reported in the patent EP1,183,243 as a short-acting central nervous system (CNS, Central Nervous System) inhibitor, and has effects including sedative hypnosis, anxiolytic, muscle relaxation and anticonvulsant. They can be used for intravenous administration in clinical regimens such as: preoperative sedation, anxiolytic and amnestic use during surgery; conscious sedation during short-term diagnostic, surgical or endoscopic procedures; admin...

Claims

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Application Information

Patent Timeline
13 Mar 2013
Publication
CN102964349A
IPC
C07D487/04; C07C309/30; C07C303/32; A61K31/5517; A61P25/20; A61P25/22; A61P25/08; A61P21/02
CPC
A61K31/00; C07C309/30; C07D401/04; A61P21/02; A61P25/08; A61P25/20; A61P25/22
Inventors
孙飘扬; 武乖利