Preparation process of lorazepam impurity D

A technology of lorazepam and preparation process is applied in the field of preparation of lorazepam impurity D, and achieves the effects of shortening preparation period, simple operation and reducing preparation cost

Inactive Publication Date: 2020-02-14
HUAZHONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, there is no relevant literature report to publish (5RS)-7-chloro-5-(2-chlorophenyl)-4,5-dihydro-1hydro-1,4-benzodiazepine-2,3-dione (British Pharmacopoeia 2013 lorazepam impurity D), 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 D
  • Preparation process of lorazepam impurity D
  • Preparation process of lorazepam impurity D

Examples

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Embodiment 1

[0022] The present invention proposes a kind of preparation technology of lorazepam impurity D, comprises the steps:

[0023] Add 350ml of methanol and 100ml of water into the reaction flask, and add 5g of potassium hydroxide under stirring until dissolved. Then add 20 g of 7-chloro-5-(2-chlorophenyl)-3-acetoxy-1,3-dihydro-2H-1,4-benzodiazepine-2-one, at 40 ℃ ~ 45 ℃ heat preservation reaction for 3 hours. Cool down to 0°C-5°C, add dropwise an aqueous solution of glacial acetic acid to neutralize to pH 6-7. Extract with 400ml×2 dichloromethane, wash neutral with water, dry over anhydrous sodium sulfate, filter out sodium sulfate, add 5g column chromatography silica gel to the filtrate and stir for 1 hour, filter column chromatography silica gel again, concentrate the filtrate under reduced pressure, Add 100ml of petroleum ether, freeze, filter, and dry to obtain 16.2g of lorazepam impurity D, with an HPLC purity of 99.89%.

Embodiment 2

[0025] The present invention proposes a kind of preparation technology of lorazepam impurity D, comprises the steps:

[0026] Add 400ml of ethanol and 100ml of water into the reaction flask, and add 5g of potassium hydroxide under stirring until dissolved. Then add 20 g of 7-chloro-5-(2-chlorophenyl)-3-acetoxy-1,3-dihydro-2H-1,4-benzodiazepine-2-one, at 55 ℃ ~ 60 ℃ heat preservation reaction for 2 hours. Cool down to 0°C-5°C, add dropwise an aqueous solution of glacial acetic acid to neutralize to pH 6-7. Extract with 400ml×2 dichloromethane, wash neutral with water, dry over anhydrous sodium sulfate, filter out sodium sulfate, add 5g column chromatography silica gel to the filtrate and stir for 1 hour, filter column chromatography silica gel again, concentrate the filtrate under reduced pressure, Add 120ml of petroleum ether, freeze, filter, and dry to obtain 16.4g of lorazepam impurity D, with an HPLC purity of 99.80%.

Embodiment 3

[0028] The present invention proposes a kind of preparation technology of lorazepam impurity D, comprises the steps:

[0029] Add 400ml of ethanol and 100ml of water into the reaction flask, and add 5g of potassium hydroxide under stirring until dissolved. Then add 20 g of 7-chloro-5-(2-chlorophenyl)-3-acetoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one at 50 ℃ ~ 55 ℃ heat preservation reaction for 2 hours. Cool down to 0°C-5°C, add dropwise an aqueous solution of glacial acetic acid to neutralize to pH 6-7. Extract with 400ml×2 ethyl acetate, wash neutral with water, dry over anhydrous sodium sulfate, filter out sodium sulfate, add 5g column chromatography silica gel to the filtrate and stir for 1 hour, filter column chromatography silica gel again, concentrate the filtrate under reduced pressure, Add 100ml of petroleum ether, freeze, filter, and dry to obtain 16.6g of lorazepam impurity D, with an HPLC purity of 99.75%.

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Abstract

The invention discloses a preparation process of a lorazepam impurity D. The preparation process comprises the following steps: adding an alkaline reagent into a mixed solvent, performing stirring anddissolving, adding 7-chloro-5-(2-chlorophenyl)-3-acetoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one, performing a heat preservation reaction, and performing aftertreatment after the reaction is finished,so as to obtain the lorazepam impurity D. According to the method, the compound 7-chloro-5-(2-chlorophenyl)-3-acetoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one is used as a raw material, the reaction and aftertreatment process are simple, a liquid phase preparation column is not needed for separation and purification, the preparation period can be greatly shortened, and the preparation cost is reduced. The preparation process has the advantages that the raw materials are easy to obtain, the process flow is simple, and the purity of the prepared lorazepam impurity D is relatively high.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a preparation process of lorazepam impurity D. 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 British Pharmacopoeia 2013 quality standard for lorazepam specifies 5 impurities, and impurity D is one of the important impurities, and its structural formula is as follows: [0004] [0005] (5RS)-7-c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D243/26
CPCC07D243/26
Inventor 廖俊赵成安付林代先朋邬德琦李桂莲田玉林
Owner HUAZHONG PHARMA
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