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Preparation method of lorazepam intermediate

An intermediate, chlorophenyl technology, applied in the field of medicine and chemical industry, can solve the problems of limited reaction temperature, slow reaction rate, weakened oxidation, etc., to achieve the effect of reducing production cost, shortening process cycle, and improving the production site environment

Active Publication Date: 2021-03-16
HUAZHONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Technologists generally believe that the mass concentration of hydrogen peroxide used in the oxidation reaction should be in the range of 25% to 35%, lower than this concentration range will lead to weakened oxidation and slower reaction rate; higher than this concentration range will limit the reaction temperature, need Perform the reaction at room temperature or lower, otherwise the purpose of the oxidation reaction will not be achieved due to the rapid decomposition of hydrogen peroxide

Method used

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  • Preparation method of lorazepam intermediate
  • Preparation method of lorazepam intermediate
  • Preparation method of lorazepam intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Add 30g of 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one and 75ml of dimethylformazine to the reaction flask in turn Amide, stir to dissolve and heat up to 40°C, then add 30g of hydrogen peroxide dropwise at a temperature of 40°C to 55°C with a concentration of 50wt%. After the dropwise addition was completed, the reaction was maintained at 55°C to 65°C for 3 hours. After the heat preservation reaction is completed, control the temperature at 60°C to 65°C and add 10g of hydrogen peroxide with a concentration of 50% by mass dropwise again. Cool down to -5°C, add 30g of water dropwise, continue stirring at 0°C to -5°C for 0.5 hours, let stand for 2 hours, filter, and wash with water to obtain 7-chloro-2-oxo-5-(2-chloro Phenyl)-1,4-benzodiazepine-4-oxide crude. The crude product was added into a mixed solvent of 90ml of acetone and 30ml of water for beating and refining to obtain 27.2g of 7-chloro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4- Oxid...

Embodiment 2

[0039] Add 30g of 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one and 105ml of dimethylacetamide to the reaction flask in turn Amide, stir to dissolve and heat up to 40°C, then add 30g of 50% hydrogen peroxide dropwise at a controlled temperature of 40°C to 55°C. After the dropwise addition was completed, the reaction was maintained at 55°C to 65°C for 3 hours. At the end of the heat preservation reaction, control the temperature at 60°C to 65°C and add 10g of hydrogen peroxide with a concentration of 50% by mass dropwise again. After the addition is complete, continue the heat preservation reaction at 60°C to 65°C for 7 hours. Cool down to -5°C, add 50g of water dropwise, continue stirring at 0°C to -5°C for 0.5 hours, let stand for 2 hours, filter, and wash with water to obtain 7-chloro-2-oxo-5-(2-chloro Phenyl)-1,4-benzodiazepine-4-oxide crude. Add the crude product to a mixed solvent of 60ml of acetone and 15ml of water for beating and refining to obta...

Embodiment 3

[0041] Add 30g of 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one and 105ml of dimethylacetamide to the reaction flask in turn Amide, stir to dissolve and heat up to 40°C, then add 30g of 50% hydrogen peroxide dropwise at a controlled temperature of 40°C to 55°C. After the dropwise addition was completed, the reaction was maintained at 55°C to 65°C for 3 hours. After the heat preservation reaction is completed, control the temperature at 60°C to 65°C and add 15g of hydrogen peroxide with a concentration of 50% by mass dropwise again. After the dropwise addition, continue the heat preservation reaction at 60°C to 65°C for 6.5 hours. Cool down to -5°C, add 54g of water dropwise, continue stirring at 0°C to -5°C for 0.5 hours, let stand for 2 hours, filter, and wash with water to obtain 7-chloro-2-oxo-5-(2-chloro Phenyl)-1,4-benzodiazepine-4-oxide crude. Add the crude product to a mixed solvent of 60ml of acetone and 15ml of water to obtain 27.7g of 7-chloro-...

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Abstract

The invention discloses a preparation method of a lorazepam intermediate. The preparation method comprises the following steps: taking 7-chloro-5-(-2-chlorphenyl)-1, 3-dihydro-2H-1, 4-benzodiazepine-2-ketone as a raw material, carrying out oxidation reaction with hydrogen peroxide in an aprotic polar solvent without an acidic solvent, and after the reaction is finished, carrying out aftertreatmentto obtain the 7-chloro- dioxo-5-(2chlorphenyl) 1, 3-dihydro-2H-1, 4-benzodiazepine. The invention relates to a 4-benzodiazepine-4-oxide. According to the preparation method, expensive raw materials do not need to be used for catalysis in the reaction process, operations such as reaction quenching, solvent extraction and concentration distillation do not need to be carried out in the post-treatment process, operation steps are reduced, the production period is shortened, the production cost is reduced, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and specifically relates to a lorazepam intermediate 7-chloro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4- Oxide preparation method. 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. Lorazepam intermediate 7-chloro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide, CAS number: 2955-37-5, Its structural formula is: [0003] [0004] 7-chloro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide is an important intermediate for the preparation of lorazepam and chlormethazepam, while It is also the lorazepam impurity C specified in the European Pharmacopoeia EP8.0. [0005] The traditional preparation process of lorazepam intermediate 7-chloro-2-oxo-5-(2-...

Claims

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Application Information

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IPC IPC(8): C07D243/30
CPCC07D243/30
Inventor 付林廖俊代先朋朱小涛王定军李桂莲
Owner HUAZHONG PHARMA
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