Method for synthesizing chiral dihydro-6H-indolo[2,1-c][1,4]-benzodiazepine

A technology for benzodiazepines and indolines, applied in the field of synthesizing chiral dihydro-6H-indolo[2,1-c][1,4]-benzodiazepines, It can solve the problems of less research on synthetic methods, and achieve the effects of simple and practical reaction operation, chiral value-added, high reactivity and enantioselectivity

Inactive Publication Date: 2013-09-11
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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Problems solved by technology

[0003] Despite the strong biological activity of indolo[2,1-c][1,4]-benzodiazepine derivatives, less research has been done on the synthesis of such compounds
Especially for the synthesis of optically active dihydro-indolo[2,1-c][1,4]-benzodiazepines, there are few reports in the literature

Method used

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  • Method for synthesizing chiral dihydro-6H-indolo[2,1-c][1,4]-benzodiazepine
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  • Method for synthesizing chiral dihydro-6H-indolo[2,1-c][1,4]-benzodiazepine

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Embodiment 1

[0034] Example 1: Synthesis of various chiral dihydro-6H-indolo[2,1-c][1,4]-benzodiazepines by iridium-catalyzed asymmetric hydrogenation

[0035] In a nitrogen-filled glove box, (1,5-cyclooctadiene) iridium chloride dimer (0.0025 mmol, 1.7 mg) and chiral ligand (R)-C 4 -TunePhos (0.0055 mmol) in the reaction bottle, add 1mL of solvent benzene, stir at room temperature for 10 minutes, then transfer the prepared catalyst to another containing raw material indolo[2,1-c][1,4 ]-Benzodiazepine 1 (0.125 mmol) in the reaction bottle, shared 3mL solvent benzene. Put the reaction bottle into a stainless steel autoclave, feed hydrogen at 50 atmospheres, and react at room temperature for 20-24 hours. Slowly release the hydrogen, remove the solvent with a rotary evaporator and then separate the pure product by direct column chromatography (the volume ratio of eluent petroleum ether and ethyl acetate is 50:1-20:1), and the reaction formula is as follows:

[0036]

[0037] 12-methyl-11...

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Abstract

The invention relates to a method for synthesizing chiral dihydro-6H-indolo[2,1-c][1,4]-benzodiazepine by iridium-catalyzed asymmetric hydrogenation. The reaction conditions are as follows: the temperature is 0-50 DEG C; the solvent is benzene or toluene; the pressure is 13-60 atmospheric pressures; the ratio of the substrate to the catalyst is 50 / 1; and the catalyst is a complex of (1,6-cyclooctadiene)iridium chloride dimer and diphosphine ligand. Seven-element cyclic indolo[2,1-c][1,4]-benzodiazepine is hydrogenated to obtain the corresponding chiral dihydro product, and the enantiomeric excess can reach 89%. The invention is simple and practical to operate, and has the advantages of accessible raw materials, favorable selectivity for antipode, high yield, atomic economical efficiency for reaction, and environment friendliness.

Description

technical field [0001] The invention relates to a highly enantioselective catalytic hydrogenation of indolo[2,1-c][1,4]-benzodiazepines using a homogeneous system of iridium to synthesize chiral dihydro-indolo[ A process for 2,1-c][1,4]-benzodiazepines, specifically an iridium-catalyzed asymmetric hydrogenation to chiral dihydro-indolo[2,1-c][1 , 4]-benzodiazepine method. Background technique [0002] Indolo[2,1-c][1,4]-benzodiazepines are a class of seven-membered heterocyclic compounds with a wide range of physiological and pharmacological activities. It is an important class of pharmaceutical intermediates, which can be used to synthesize serotonin-2-receptor antagonists, and can also be used to develop clinical antipsychotic drugs. Over the years, the structure and biological activity research of this class of compounds has attracted the attention of the pharmaceutical community (document 1: (a) Insel, T.R.; Young, L.J.Nat.Rev.Neurosci.2001, 2, 129. (b) Frantz, M .-C....

Claims

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Application Information

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IPC IPC(8): C07D487/04
Inventor 周永贵高凯余长斌时磊
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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