Preparation method and application of 1,4-benzodiazepine-N-nitrosamine intermediate

A technology of sodium nitrite and methylamine, applied in directions such as organic chemistry, can solve problems such as unfavorable large-scale production and environmental pollution

Inactive Publication Date: 2013-05-08
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The method prepares the yield of intermediate (II) as 62%, but will use highly toxic P 2 S 5 , and cause environmental pollution; and expensive acetonitrile is used as a solvent, which is not conducive to large-scale production

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  • Preparation method and application of 1,4-benzodiazepine-N-nitrosamine intermediate

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[0042] Specifically, the preparation method of the compound provided by the invention with the structure shown in formula I comprises the following steps:

[0043] (a) Mix the compound shown in formula IV or formula V with an organic solvent until completely dissolved, and feed methylamine gas at 0-250°C (preferably 30-150°C) to saturation;

[0044] (b) Keep the temperature at which methylamine gas is introduced in step (a), add a mixed solution of titanium tetrachloride and the same solvent as step (a), then heat up to 0-250 ° C, and stir for 20 minutes to 20 minutes Hour (preferably reaction temperature is 1 to 10 hours), obtains reaction solution 1;

[0045] (c) mixing reaction solution 1 and sodium nitrite in the presence of organic acid or inorganic acid to obtain reaction solution 2; and

[0046] (d) Mix the reaction solution 2 and water with the same solvent as step (a), extract the aqueous layer 1-4 times with the same solvent as step (a), and obtain the compound show...

Embodiment 1

[0080] Preparation of 1,4-benzodiazepine-N-nitrosamine intermediate (II)

[0081] 1.1 Methylamination reaction

[0082] Drop into 40.5g (0.14mol) 7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepine-2 ketone (IV), 270ml toluene and 60mlDMF in 1L reaction bottle, room temperature Stir until completely dissolved. The temperature of the ice-salt bath was lowered to below 5°C, and methylamine gas was slowly introduced to saturation. After completion of the process, slowly add a mixture of 23ml (0.21mol) of titanium tetrachloride and 40ml of toluene dropwise while keeping the temperature below 5°C, and the temperature during the dropping process does not exceed 10°C. Then the temperature was raised to 75°C and the reaction was stirred. Timing about 3h, the reaction is complete. The reaction solution was lowered to room temperature and suction filtered, the filter cake was washed with 60ml of toluene and 30ml of DMF respectively, and the combined filtrate and washings were transfer...

Embodiment 2

[0086] Preparation of 1,4-benzodiazepine-N-nitrosamine intermediate (III)

[0087] 2.1 Methylamination reaction

[0088] Add 37.8g (0.14mol) 7-chloro-5-(2-phenyl)-3H-1,4-benzodiazepine-2-ketone (V), 270ml toluene and 60ml tetrahydrofuran into the 1L reaction flask, room temperature Stir until completely dissolved. Cool the ice-salt bath to an internal temperature below 10°C, and slowly inject methylamine gas to saturation. After completion of the process, slowly add a mixture of 23ml (0.21mol) of titanium tetrachloride and 40ml of toluene dropwise while keeping the temperature below 10°C, and the temperature during the dropping process does not exceed 15°C. Then the temperature was raised to 75°C and the reaction was stirred. Timing about 3h, the reaction is complete. The reaction solution was lowered to room temperature and suction-filtered, the filter cake was washed with 60ml of toluene respectively, and the combined filtrate and washings were transferred to a 1L reacti...

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Abstract

The invention discloses a preparation method and an application of a 1,4-benzodiazepine-N-nitrosamine intermediate. The preparation method comprises the steps that: (1) a compound with a structure shown by a formula IV or a formula V is mixed with an organic solvent; and methylamine gas is delivered in; (2) a mixed solution of titanium tetrachloride and toluene is added; the mixture is heated to a temperature of 0-250 DEG C, and a reaction is carried out for 20min to 20h, such that a reaction liquid 1 is obtained; (3) the reaction liquid 1 and sodium nitrite is mixed under the existence of an organic acid or an inorganic acid, such that a reaction liquid 2 is obtained; and (4) the reaction liquid 2 is mixed with water and toluene, such that a compound represented by a structural formula I is obtained in an organic layer. The invention also discloses a method for synthesizing other benzodiazepine derivatives by using the intermediate 1,4-benzodiazepine-N-nitrosamine.

Description

technical field [0001] The present invention relates to chemical synthesis, in particular to a method for preparing a 1,4-benzodiazepine-N-nitrosamine intermediate with the structure shown in formula I and its application in midazolam synthesis. Background technique [0002] Benzodiazepines are a class of compounds with a wide range of physiological activities, such as sedative, hypnotic, anxiolytic, muscle relaxant, and anticonvulsant effects. Some of these compounds have been developed into drugs for the treatment of insomnia, anxiety and other diseases. Midazolam is a third-generation central nervous system depressant drug, first launched in Europe in 1982, for sedative hypnosis and anti-anxiety. It is favored for its short duration of action and strong sedative effect. Recent studies have shown that midazolam has obvious antiepileptic effects. [0003] There are many methods for synthesizing midazolam, and the synthetic routes are different due to different starting m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D243/20C07D487/04
Inventor 郭俊峰陈旭东单晓燕时惠麟
Owner SHANGHAI INST OF PHARMA IND CO LTD
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