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

A technology for benzodiazepines and dihydropyrroles, applied in the field of synthesizing chiral dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepines, achieving reaction Complete, 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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  • Summary
  • Abstract
  • Description
  • 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]-benzodiazepines

Method used

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

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Embodiment 1

[0034] Embodiment 1: optimization of conditions

[0035] 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 the reaction flask of 1mL solvent benzene, stirred at room temperature for 10 minutes, then transferred the prepared catalyst to another reaction bottle containing raw material pyrrolo[2,1-c][1,4]-benzodiazepine A total of 3 mL of solvent benzene was used in the reaction flask of Zhuo 1a (25 mg, 0.125 mmol). The reaction bottle was placed in a stainless steel autoclave, hydrogen gas was introduced at a pressure of 50 atmospheres, and the reaction was carried out at room temperature for 20 hours. Slowly release hydrogen, remove the solvent with a rotary evaporator, and then directly column chromatography (the volume ratio of the eluent petroleum ether and ethyl acetate is 50:1-20:1) to separate the pure product, the reaction formula and the ligand str...

Embodiment 2

[0041] Example 2: Synthesis of various chiral dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepines by iridium-catalyzed asymmetric hydrogenation

[0042] 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 solvent benzene, stir at room temperature for 10 minutes, then transfer the prepared catalyst to another substrate pyrrolo[2,1-c][1,4 ]-Benzodiazepine 1 (0.125 mmol) in a reaction flask, a total of 3 mL of solvent benzene was used. The reaction bottle was placed in a stainless steel autoclave, hydrogen gas was introduced at a pressure of 50 atmospheres, and the reaction was carried out at room temperature for 20 hours. Slowly release hydrogen, remove the solvent with a rotary evaporator and then directly column chromatography (the volume ratio of eluent sherwood oil and ethyl acetate is 50:1-20:1) to separate and obtain pure product, the reaction formula...

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Abstract

The invention relates to a method for synthesizing chiral dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine by iridium-catalyzed asymmetric hydrogenation. The reaction conditions are as follows: the temperature is 20-50 DEG C; the solvent is benzene or toluene; the pressure is 13-50 atmospheric pressures; the ratio of the substrate to the catalyst is 50 / 1; and the catalyst is a complex of (1,5-cyclooctadiene)iridium chloride dimer and diphosphine ligand. Seven-element cyclic pyrrolo[2,1-c][1,4]-benzodiazepine 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 present invention relates to a highly enantioselective catalytic hydrogenation of pyrrolo[2,1-c][1,4]-benzodiazepines using a homogeneous system of iridium to synthesize chiral dihydro-pyrrolo[2, Process for 1-c][1,4]-benzodiazepines, specifically an iridium-catalyzed asymmetric hydrogenation to chiral dihydro-pyrrolo[2,1-c][1,4] - The benzodiazepine approach. Background technique [0002] Dihydro-pyrrolo[2,1-c][1,4]-benzodiazepines are a class of seven-membered heterocyclic compounds with unique structures, which usually have antidepressant, anticancer, antibacterial and other biological activities . Rivaptan (Lixivaptan) is an important drug for the treatment of hyponatremia, it is V 2 Antagonist of the receptor, V 2 The receptor is located in the distal renal collecting duct and is a G-protein-mediated receptor that balances the reabsorption and excretion of free water in the body. Aptazepine is a powerful alpha 2 Adrenergic receptor agoni...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07B53/00
Inventor 周永贵高凯吴波余长斌时磊
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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