A kind of preparation method of lorazepam intermediate

An intermediate and reaction technology, applied in the direction of organic chemistry, can solve the problems of weakened oxidation, slow reaction rate, and limited reaction temperature, so as to reduce production cost, shorten process cycle, and improve the production site environment.

Active Publication Date: 2022-06-03
HUAZHONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • A kind of preparation method of lorazepam intermediate
  • A kind of preparation method of lorazepam intermediate
  • A kind of preparation method of lorazepam intermediate

Examples

Experimental program
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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 dimethylformaldehyde to the reaction flask in turn amide, stir to dissolve and raise the temperature to 40°C, then control the temperature to 40°C to 55°C and add 30 g of hydrogen peroxide with a concentration of 50 wt% dropwise. After the dropwise addition was completed, the reaction was incubated at 55°C to 65°C for 3 hours. After the insulation reaction was completed, the temperature was controlled to be 60°C to 65°C, and 10 g of hydrogen peroxide with a concentration of 50% was added dropwise again. Cool to -5°C, add 30g of water dropwise, continue to stir at 0°C~-5°C for 0.5 hours, stand for 2 hours, filter, wash with water to obtain 7-chloro-2-oxo-5-(2-chloro Phenyl)-1,4-benzodiazepine-4-oxide crude. The crude product was added to a mixed solvent of 90ml of acetone and 30ml of water, beating and refining to obtain 27.2g of 7-chloro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepi...

Embodiment 2

[0039] 30g of 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one and 105ml of dimethyl ethyl acetate were added to the reaction flask successively. amide, stir to dissolve and heat up to 40°C, and then control the temperature to 40°C to 55°C and dropwise add 30 g of hydrogen peroxide with a concentration of 50% by mass. After the dropwise addition was completed, the reaction was incubated at 55°C to 65°C for 3 hours. After the insulation reaction is completed, the temperature is controlled to be 60°C to 65°C, and 10 g of hydrogen peroxide with a concentration of 50% by mass is added dropwise again. Cool to -5°C, add 50g of water dropwise, continue to stir at 0°C~-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 to a mixed solvent of 60ml of acetone and 15ml of water, beating and refining to obtain 27.5g of 7-chloro-2-oxo-5-(2-chloro...

Embodiment 3

[0041] 30g of 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one and 105ml of dimethyl ethyl acetate were added to the reaction flask successively. amide, stir to dissolve and heat up to 40°C, and then control the temperature to 40°C to 55°C and dropwise add 30 g of hydrogen peroxide with a concentration of 50% by mass. After the dropwise addition was completed, the reaction was incubated at 55°C to 65°C for 3 hours. After the insulation reaction is completed, 15 g of hydrogen peroxide with a mass percentage concentration of 50% is added dropwise again at a temperature of 60°C to 65°C, and the dropwise addition is completed, and the reaction is continued at 60°C to 65°C for 6.5 hours. Cool to -5°C, add 54g of water dropwise, continue to stir at 0°C~-5°C for 0.5 hours, stand for 2 hours, filter, wash with water to obtain 7-chloro-2-oxo-5-(2-chloro Phenyl)-1,4-benzodiazepine-4-oxide crude. The crude product was added to a mixed solvent of 60ml of acetone and 1...

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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-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ketone as raw material in the aprotic In a polar solvent, it does not need to be oxidized with hydrogen peroxide in an acidic solvent. After the reaction is completed, 7-chloro-2-oxo-5-(2-chlorophenyl)-1,4-benzo Diazepine‑4‑oxide. The reaction process of the preparation method of the present invention does not require the use of expensive raw materials for catalysis, and the post-treatment process does not require operations such as reaction quenching, solvent extraction, and concentrated distillation, which reduces operating steps, shortens the production cycle, and reduces production costs. It is suitable for Industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a lorazepam intermediate 7-chloro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4- Method for the preparation of oxides. Background technique [0002] Lorazepam is a benzodiazepine sedative-hypnotic drug. It is a benzodiazepine psychotropic drug developed by the American Wyeth Company. The drug of choice for anti-status epilepticus is the national essential drug. Lorazepam Intermediate 7-Chloro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide, CAS No: 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 chlorometazepam. It is also a lorazepam impurity C specified in the European Pharmacopoeia EP8.0. [0005] The traditional preparation process of lorazepam intermediate 7-chloro-2-oxo-5-(2-chlorophenyl)-1,4-be...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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