Method for preparing benzodiazepine compounds

A benzodiazepine and diazepine technology, which is applied in the field of preparation of benzodiazepine compounds, can solve the problems of high catalyst selectivity, high reaction temperature, large raw material damage, etc. Explosion risk, improved reaction yield, reduced hazard effects

Active Publication Date: 2014-05-21
李宏 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] This route requires a higher reaction temperature, which is more destructive to the raw material, and is harmful to MnO 2 The selectivity of the catalyst is high, and

Method used

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  • Method for preparing benzodiazepine compounds
  • Method for preparing benzodiazepine compounds
  • Method for preparing benzodiazepine compounds

Examples

Experimental program
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Embodiment 1～9

[0033]Add raw material I and triethyl orthoacetate in the ultrasonic reactor according to the amount shown in Table 1, set the ultrasonic power and ultrasonic time of the ultrasonic reactor, react at 20~30 ° C, adopt HPLC to track the reaction conversion rate, after the reaction is complete, from Release the reaction solution in the ultrasonic reactor, cool to below 20°C, stir for 3 hours to precipitate crystals, filter to obtain intermediate II, use hydrogen spectrum, carbon spectrum and other methods to detect intermediate II, confirm the structure of intermediate II, and calculate content and molar yield. The content is the amount of pure intermediate II in the obtained intermediate II, which is used to illustrate the amount of impurities. When the content is higher, the impurities are less. The molar feed ratio, ultrasonic power, ultrasonic time and yield of raw material I and triethyl orthoacetate are shown in Table 1.

[0034] Table 1 Preparation conditions and yield of...

Embodiment 19～45

[0081] Add intermediate II and enzyme-containing bacterial cells obtained from different dehydrogenase-producing bacteria into the buffer solution, and perform biocatalysis according to the reaction time of 20h, reaction temperature of 34°C, stirring rate of 180r / min, and buffer solution pH value of 7.0 Dehydrogenation, to obtain the reaction solution containing product III, HPLC tracking conversion rate, HPLC detection conditions with embodiment 10 ~ 18, after the reaction, using toluene to extract the reaction solution, extraction 3 times, each extraction of toluene and reaction solution The volume ratio of the toluene phase is 1:1, the toluene phase is combined, and the toluene phase is concentrated to obtain the crude product III. The crude product is recrystallized to obtain the product III. The product III is detected by hydrogen spectrum, carbon spectrum and other methods to confirm the structure of the product III , and calculate the content and molar yield. Examples 1...

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Abstract

The invention relates to a method for preparing benzodiazepine compounds, and discloses a method for preparing 8-R2-6-(2-R1-phenyl)-1-methyl-3a,4-dihydro-3H-imidazo[1,5-a][1,4] benzodiazepine (midbody II) and 8-R2-6-(2-R1-phenyl)-1-methyl-4H-imidazo[1,5-a][1,4] benzodiazepine (product III), wherein R is hydrogen, fluorine, chlorine, bromine or iodine; R2 is fluorine, chlorine, bromine or iodine. The midbody II is prepared from 7-R2-5-(2-R1-phenyl)-2-aminomethyl-2,3-dihydro-1H-[1,4] benzodiazepine and triethyl orthoacetate as raw materials through ultrasonic reaction; the product III is prepared by performing enzyme dehydrogenation on the midbody II. By adopting the technical scheme of the invention, the dehydrogenation reaction selectivity is improved, and the reaction yield is improved.

Description

technical field [0001] The invention relates to a preparation method of benzodiazepine compounds, in particular to a preparation method of 4H-imidazo[1,5-a][1,4]benzodiazepine compounds. Background technique [0002] Benzodiazepines are heterocyclic compounds formed by condensing a benzene ring and a seven-membered nitrogen-containing heteroatom ring. The activity of neurons in the limbic system attenuates its activation of the reticular formation. At the same time, the special effect on the limbic system can effectively reduce emotional activities, and has a good effect on anxiety and insomnia, and can produce approximate physiological sleep. These drugs have a high therapeutic index, little impact on breathing, and a wide range of safety. They have almost no effect on liver drug enzymes, and do not affect the metabolism of other drugs. Among them, 1,4-benzodiazepine and 1,3-imidazole ring are cyclized to generate 4H-imidazo[1,5-a][1,4]benzodiazepine compounds, which can ...

Claims

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Application Information

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IPC IPC(8): C07D487/04C12P17/18
CPCC07D487/04C12P17/182
Inventor 潘自国李宏岳昌林张金涛贾英华
Owner 李宏
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