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Preparation process of lorazepam impurity C

A lorazepam preparation technology, applied in the field of preparation of chemical drug lorazepam impurity C, to achieve high purity, improve preparation efficiency, and shorten the preparation cycle

Inactive Publication Date: 2020-10-02
HUAZHONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is no relevant literature report to announce the preparation method of 6-chloro-4-(2-chlorophenyl)quinazoline-2-carbaldehyde (USP impurity C), therefore, it is necessary to carry out in-depth research on the synthesis process of this impurity

Method used

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  • Preparation process of lorazepam impurity C
  • Preparation process of lorazepam impurity C
  • Preparation process of lorazepam impurity C

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add 500ml of toluene, 10g of lorazepam, 0.8g of p-toluenesulfonic acid, and 0.5ml of triethylamine into the reaction bottle, stir and heat up, and keep the reaction at 65°C for 8 hours. The temperature was lowered to 25° C., and the crude product solution of lorazepam impurity C was obtained by filtration, and the HPLC purity of the crude product was analyzed to be 97.13%.

[0031] The crude product of lorazepam impurity C was analyzed by HPLC. The injection conditions were as follows: Agilent ZORBAX Extend C18 column (250mm×4.6mm, 5 μm) chromatographic column was used, with 0.02mol L -1 Dipotassium hydrogen phosphate solution (1mol L -1 Sodium hydroxide adjusted the pH to 10.5)-acetonitrile (60:40) as mobile phase, flow rate 1.0mL min -1 , the column temperature was 35° C., the detection wavelength was 235 nm, and the injection volume was 10 μL.

[0032] The crude product HPLC spectrum of lorazepam impurity C is as follows figure 2 As shown, the information of each...

Embodiment 2

[0043] Add 200ml of ethyl acetate, 10g of lorazepam, 0.8g of p-toluenesulfonic acid, and 0.5ml of triethylamine into the reaction bottle, stir and heat up, and keep the reaction at 50°C for 11 hours. Cool down to 22°C, wash with 150ml×3 saturated brine until neutral, dry over anhydrous sodium sulfate, filter out sodium sulfate, concentrate the filtrate under reduced pressure, replace with 10ml×2 ethanol, add 15ml of isopropyl ether, freeze and filter , drying to obtain 5.5g lorazepam impurity C, HPLC purity 99.47%.

Embodiment 3

[0045] Add 200ml of ethyl acetate, 10g of lorazepam, 0.8g of p-toluenesulfonic acid, and 0.5ml of triethylamine into the reaction flask, stir and heat up, and keep the reaction at 70°C for 9 hours. Cool down to 20°C, wash with 150ml×3 saturated brine until neutral, dry over anhydrous sodium sulfate, filter out sodium sulfate, concentrate the filtrate under reduced pressure, replace with 10ml×2 methanol, add 15ml of isopropyl ether, freeze and filter , drying to obtain 5.2g lorazepam impurity C, HPLC purity 99.51%.

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Abstract

The invention provides a preparation process of a lorazepam impurity C. According to the process, lorazepam is taken as a raw material, a catalyst and a buffer reagent are added into an aprotic solvent, a heat preservation reaction is performed, and after the reaction is finished, the lorazepam impurity C is obtained through post-treatment. The method has the following advantages: the reaction andpost-treatment process is simple; separation and purification are performed without using a thin-layer chromatography (PTLC) technology or a liquid-phase preparative column technology; and the prepared lorazepam impurity C has higher purity and the like, and can be used for qualitative and quantitative analysis of impurities in lorazepam production, so that the quality standard of lorazepam is improved, and important guiding significance is provided for safe medication.

Description

【Technical field】 [0001] The invention belongs to the field of chemical pharmacy and relates to a preparation process of impurity C of chemical drug lorazepam. 【Background technique】 [0002] Lorazepam is a benzodiazepine sedative-hypnotics that has central nervous system sedative, hypnotic, anti-anxiety, and anti-epileptic effects. It can be used as the first-line anti-status epileptic drug and is a national essential drug. The quality research of lorazepam impurities has important and far-reaching significance for the research of raw materials and preparations. [0003] With the gradual expansion of the generic drug market and the consistency evaluation of domestic generic drugs, the demand for impurity reference substances in pharmaceutical companies has grown rapidly. The related substance test items of the United States Pharmacopoeia lorazepam API stipulate 5 known impurities, among which the chemical name of USP impurity C is: 6-chloro-4-(2-chlorophenyl)quinazoline-2-...

Claims

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Application Information

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IPC IPC(8): C07D239/74
CPCC07D239/74
Inventor 廖俊赵成安付林代先朋曾建华邹谨霜王运波
Owner HUAZHONG PHARMA
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