Purification method of lorazepam

A purification method, the technology of lorazepam, applied in the field of medicine and chemical industry, can solve the problems such as difficult to meet the quality standards, and achieve the effect of reducing content, simple operation and controllable quality

Inactive Publication Date: 2020-02-18
HUAZHONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The existence of impurity Ⅱ in lorazepam makes it difficult to meet the quality standards stipulated in the British Pharmacopoeia 2017 and European Pharmacopoeia 9.0, although the quality of the API product meets the requirements of the Chinese Pharmacopoeia and the United States Pharmacopoeia
In the preparation process of lorazepam, it is difficult to control the impurity II within 0.1% and the total impurities within 0.2% by the existing purification methods

Method used

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  • Purification method of lorazepam
  • Purification method of lorazepam

Examples

Experimental program
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Effect test

Embodiment 1

[0022] The present invention proposes a method for purifying lorazepam, comprising the steps of:

[0023] Add 100ml of tetrahydrofuran into the reaction flask, raise the temperature to reflux, and maintain the reflux for degassing for 30 minutes. Under the protection of nitrogen, lower the temperature to 55°C-60°C, add 20g of lorazepam crude product under stirring, keep it at 55°C-60°C for 2 hours after feeding, add 1g of activated carbon and keep it at 55°C-60°C for 1 hour. Filtrate while it is hot, heat up the filtrate to 55°C-60°C, add 300ml of petroleum ether, control the speed of adding petroleum ether, the system temperature is 50°C-60°C during the process of adding petroleum ether, and keep stirring at 55°C-60°C for 30 Minutes, then first lower the temperature to 40°C-45°C and keep for 1 hour; then cool down to 20°C-25°C and keep for 1 hour; continue to cool down to -5°C-0°C to crystallize, crystallize for 2 hours, filter and dry 16.3 g of lorazepam product was obtaine...

Embodiment 2

[0025] The present invention proposes a method for purifying lorazepam, comprising the steps of:

[0026] Add 120ml of tetrahydrofuran into the reaction flask, raise the temperature to reflux, and maintain reflux for 30 minutes for degassing. Under the protection of argon, lower the temperature to 50°C-55°C, add 20g of lorazepam crude product under stirring, keep it at 50°C-55°C for 2 hours after feeding, add 1g of activated carbon and keep it at 50°C-55°C for 1 hour. Filtrate while it is hot, raise the temperature of the filtrate to 55°C-60°C, add 360ml of n-hexane, control the speed of adding n-hexane, the system temperature is 50°C-60°C during the process of adding n-hexane, and keep stirring at 55°C-60°C for 30 Minutes, then first lower the temperature to 40°C-45°C and keep for 1 hour; then cool down to 20°C-25°C and keep for 1 hour; continue to cool down to -5°C-0°C to crystallize, crystallize for 2 hours, filter and dry 15.7 g of lorazepam product was obtained, the HPLC...

Embodiment 3

[0028] The present invention proposes a method for purifying lorazepam, comprising the steps of:

[0029] Add 100ml of tetrahydrofuran into the reaction flask, raise the temperature to reflux, and maintain the reflux for degassing for 30 minutes. Under the protection of argon, lower the temperature to 55°C-60°C, add 20g of crude lorazepam under stirring, keep it at 55°C-60°C for 2 hours after feeding, add 1g of activated carbon and keep it at 55°C-60°C for 1 hour. Filtrate while it is hot, heat the filtrate to 55°C-60°C, add 250ml of n-hexane, control the speed of adding n-hexane, the system temperature is 50°C-60°C during the addition of n-hexane, and keep stirring at 55°C-60°C for 30 minutes, then lower the temperature to 40°C-45°C and keep for 1 hour; then lower the temperature to 20°C-25°C and keep for 1 hour; continue to cool down to 5°C-10°C to crystallize, crystallize for 2 hours, filter and dry to obtain 15g of lorazepam product, HPLC purity 99.93%, impurity 6-chloro-...

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Abstract

The invention discloses a purification method of lorazepam. The purification method specifically comprises the following steps: heating for refluxing a good solvent, cooling the refluxed solvent underthe protection of an inert gas, adding crude lorazepam, stirring for dissolving, adding activated carbon to decolorize, performing filtration, adding an inert solvent into the obtained filtrate, carrying out cooling crystallization, and performing filtration to obtain the lorazepam product. The purity of the lorazepam product is not less than 99.85%, and the content of an impurity 6-chloro-4-(2-chlorphenyl)quinazoline-2-carboxaldehyde in the lorazepam product does not exceed 0.05%. The method has the advantages of simplicity in operation, controllable quality, and suitability for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical engineering, in particular to a method for purifying lorazepam. Background technique [0002] Lorazepam (Lorazepam) belongs to benzodiazepine sedative-hypnotics, and is a benzodiazepine psychotropic drug developed by Wyeth Company of the United States. The drug of choice for anti-status epilepticus is a national essential drug. "Chinese Pharmacopoeia", "United States Pharmacopoeia", "British Pharmacopoeia", "European Pharmacopoeia" and "Japanese Pharmacopoeia" all recorded lorazepam raw materials, and the CHP2015 edition recorded two known impurities I (namely USP impurity B) and impurity II (ie USP impurity C). The structural formulas of impurity Ⅰ and impurity Ⅱ in Chinese Pharmacopoeia are as follows: [0003] [0004] The lorazepam impurity II recorded in the Chinese Pharmacopoeia is the most important process impurity and degradation impurity. In the literature "Research ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D243/24
CPCC07D243/24
Inventor 廖俊刘玉亭付林
Owner HUAZHONG PHARMA
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