Hydrobromide of benzodiazepine derivative and multiple crystal forms thereof, and preparation method for multiple crystal forms

A technology of hydrobromide and hydrobromic acid, applied in the field of hydrobromide and its polymorphs and their preparation, can solve problems such as hidden dangers of drug safety, ethanol residue, etc., and achieves low solvent residue, low cost, potential Low toxicity effect

Active Publication Date: 2017-02-08
CHENGDU BRILLIANT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In view of the Velacet (nelfinavir mesylate) incident, during the storage of the drug by Roche, due to the large amount of ethanol remaining in the cleaning storage tank, it reacted with methanesulfonic acid and produced a seriously excessive amount of mesylate , which eventually led to a safety hazard of the drug and was mandated by EMEA to recall

Method used

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  • Hydrobromide of benzodiazepine derivative and multiple crystal forms thereof, and preparation method for multiple crystal forms
  • Hydrobromide of benzodiazepine derivative and multiple crystal forms thereof, and preparation method for multiple crystal forms
  • Hydrobromide of benzodiazepine derivative and multiple crystal forms thereof, and preparation method for multiple crystal forms

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1: the preparation of the hydrobromide I crystal form of formula (I) compound

[0040] Accurately weigh 44 mg (0.10 mmol) of the compound of formula (I) in a 10 mL single-necked bottle, add 0.4 mL of ethyl acetate and stir to make it all dissolve, the reaction temperature is down to 4 ° C, and then 1.1 mL of hydrobromic acid methanol solution (1mol / L, 0.11mmol) was added dropwise to the ethyl acetate solution of the compound of formula (I), stirred and crystallized, filtered with suction, rinsed with ethyl acetate, and dried under reduced pressure at 30°C to obtain the hydrobromide of the compound of formula (I) , white solid 42mg, yield 81%.

[0041] The X-ray diffraction spectrum figure of this crystal is shown in the attached figure 1 , with characteristic peaks at about 8.05, 10.24, 12.59, 13.47, 14.99, 17.44, 20.70, 22.69, 23.15, 24.01, 24.45, 25.25, 26.09, 26.45, 27.74, 28.20, 30.41, 31.34, 33.46, 36.395, 40.2 , see the attached DSC spectrum figure 2...

Embodiment 2

[0042] Embodiment 2: the preparation of the hydrobromide I crystal form of formula (I) compound

[0043] Accurately weigh 44 mg (0.10 mmol) of the compound of formula (I) in a 10 mL single-necked bottle, add 0.4 mL of acetone and stir to make it completely dissolved, and the reaction temperature is lowered to 4 ° C, then 1.1 mL of methanolic hydrobromic acid (1 mol / L , 0.11mmol) was added dropwise to the acetone solution of the compound of formula (I), stirred and crystallized, filtered by suction, washed with acetone, and dried under reduced pressure at 30°C to obtain the hydrobromide of the compound of formula (I), 37mg of white solid, yield 71%.

[0044] The X-ray diffraction spectrogram and the DSC spectrogram of the crystalline sample are studied and compared, and it is determined that the product is the hydrobromide I crystal form of the compound of formula (I).

Embodiment 3

[0045] Embodiment 3: the preparation of the hydrobromide II crystal form of formula (I) compound

[0046] Accurately weigh 22.26 mg of the compound of formula (I) in a 1 mL centrifuge tube, add 100 μL of acetone and stir to make it completely dissolved, then dissolve 10 mg of 47% aqueous hydrobromic acid in 75 μL of acetone, and add dropwise to the compound of formula (I) in acetone solution, stirred and crystallized, centrifuged, and dried under reduced pressure at 30° C. to obtain the hydrobromide salt of the compound of formula (I), 20 mg of white solid, with a yield of 76%.

[0047] The X-ray diffraction spectrum figure of this crystal is shown in the attached Figure 4 , at about 7.14, 8.78, 13.69, 14.34, 15.43, 17.26, 17.89, 18.22, 18.77, 19.69, 20.07, 20.49, 22.30, 22.89, 23.75, 25.03, 25.51, 26.51, 27.47, 230.70, 28.20.83 , 33.23, 33.92, 36.03, and 38.38 have characteristic peaks, and the DSC spectrum is attached Figure 5 , there are characteristic absorption peaks ...

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Abstract

The invention discloses hydrobromide of benzodiazepine derivative and multiple crystal forms thereof, and a preparation method for the multiple crystal forms. The preparation method comprises the following steps: heating and dissolving hydrobromide of the crystal form or amorphous form of a compound as shown in a formula (I) which is defined in the specification or the compound as shown in the formula (I) and a hydrobromic acid solution in a crystallization solvent; carrying out cooling and crystallization; and then carrying out washing and drying so as to prepare hydrobromide of the compound as shown in the formula (I) or the crystal forms thereof. The prepared hydrobromide of the compound as shown in the formula (I) has good stability, high purity and no toxicity and can be better applied to clinical treatment.

Description

technical field [0001] The invention belongs to the field of chemical drug preparation, in particular to benzodiazepines Hydrobromide salts of derivatives and polymorphic forms thereof and processes for their preparation. 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] This compound contains carboxylates and benzodiazepines The structure of CNS is a short-acting central nervous system (CNS, Central Nervous System) inhibitor, specifically manifested in sedative hypnotic, anxiolytic, muscle relaxation and anticonvulsant effects. The compound is also useful 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; administration of other anesthetics and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07B2200/13C07D487/04
Inventor 黄浩喜卓国清商国宁陈翠翠罗鸣李英富苏忠海
Owner CHENGDU BRILLIANT PHARMA CO LTD
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