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Method for synthesizing chiral dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepino-5-one

A technology of benzodiazepines and dihydropyrrole, applied in the synthesis of chiral dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine-5-one field, to achieve the effect of simple and practical reaction operation, convenient preparation, high reactivity and enantioselectivity

Inactive Publication Date: 2013-09-11
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

However, there are few reports on the synthesis of optically active dihydro-pyrrolo[2,1-c][1,4]-benzodiazepin-5-ones

Method used

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  • Method for synthesizing chiral dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepino-5-one
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  • Method for synthesizing chiral dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepino-5-one

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Embodiment 1

[0036] Embodiment 1: optimization of conditions

[0037]In a nitrogen-filled glove box, (1,5-cyclooctadiene) iridium chloride dimer (0.0025 mmol, 1.7 mg) and one of the chiral ligands in the following formula (0.0055 mmol ) into a reaction flask with 1 mL of mixed solvent (the volume ratio of dichloromethane and toluene is 1:2), stirred at room temperature for 10 minutes, and then transferred the prepared catalyst to another container containing the raw material pyrrolo[2,1 -c] [1,4]-benzodiazepin-5-one 1a (38 mg, 0.125 mmol) and morpholine trifluoroacetate (2.5 mg, 0.0125 mmol) in a reaction vial, shared 3mL of mixed solvent (the volume ratio of dichloromethane and toluene is 1:2). The reaction bottle was placed in a stainless steel autoclave, and hydrogen gas was introduced at a pressure of 50 atmospheres, and the reaction was carried out at room temperature for 24 hours. Slowly release hydrogen, remove the solvent with a rotary evaporator, and then directly column chromat...

Embodiment 2

[0043] Example 2: Synthesis of various chiral dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine-5-ones by iridium-catalyzed asymmetric hydrogenation 2

[0044] In a nitrogen-filled glove box, (1,5-cyclooctadiene) iridium chloride dimer (0.0025 mmol, 1.7 mg) and chiral ligand (S, S, R)-C 3 *-TunePhos (0.0055 mmol) in the reaction bottle, add 1mL mixed solvent (the volume ratio of methylene chloride and toluene is 1: 2), stir at room temperature for 10 minutes, then transfer the prepared catalyst to another container containing The substrate pyrrolo[2,1-c][1,4]-benzodiazepin-5-one 1 (0.125 mmol) and morpholine trifluoroacetate (2.5 mg, 0.0125 mmol) In the reaction flask, 3 mL of mixed solvent (the volume ratio of dichloromethane and toluene is 1:2) is shared. The reaction bottle was placed in a stainless steel autoclave, and hydrogen gas was introduced at a pressure of 50 atmospheres, and the reaction was carried out at room temperature for 24 hours. Slowly release hydrogen, remov...

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Abstract

The invention relates to a method for synthesizing chiral dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepino-5-one by iridium-catalyzed asymmetric hydrogenation. The reaction conditions are as follows: the temperature is 20-50 DEG C; the solvent is a dichloromethane-toluene mixed solvent (V / V=1:2); the pressure is 13-50 atmospheric pressures; the ratio of the substrate to the catalyst is 50 / 1; the catalyst is a complex of (1,5-cyclooctadiene)iridium chloride dimer and diphosphine ligand; and the additive is morpholine trifluoroacetate or piperidine hydrochloride. Seven-element cyclic pyrrolo[2,1-c][1,4]-benzodiazepino-5-one is hydrogenated to obtain the corresponding chiral dihydro product, and the enantiomeric excess can reach 96%. 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 pyrrolo[2,1-c][1,4]-benzodiazepine-5-one using iridium homogeneous system to synthesize chiral dihydro-pyrrole A method for [2,1-c][1,4]-benzodiazepine-5-one, specifically a kind of iridium-catalyzed asymmetric hydrogenation to synthesize chiral dihydro-5H-pyrrolo[2 , 1-c][1,4]-benzodiazepine-5-one method. technical background [0002] Pyrrolo[2,1-c][1,4]-benzodiazepine-5-one is a class of seven-membered heterocyclic compounds with a wide range of physiological and pharmacological activities. Many compounds have been used as clinical drugs, with High research value and application prospect. These compounds have a variety of potential pharmaceutical activities, such as: anti-cancer, anti-inflammatory, sedative, hypnotic and anti-nervous properties. Over the years, the research on the structure and biological activity of these compounds has attracted the attention of the pha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07B53/00
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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