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A kind of method of bidirectional enantioselective synthesis of chiral tetrahydroisoquinoline catalyzed by iridium

A technology of tetrahydroisoquinoline and enantioselectivity, applied in the direction of organic chemistry, etc., to achieve the effect of convenient and practical reaction operation, easy separation, and mild reaction conditions

Active Publication Date: 2020-09-01
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although good progress has been made in the asymmetric hydrogenation of isoquinoline imines, there is a method for the double enantioselective synthesis of chiral tetrahydroisoquinolines by using a single chiral source and adjusting the achiral additives. Not yet reported

Method used

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  • A kind of method of bidirectional enantioselective synthesis of chiral tetrahydroisoquinoline catalyzed by iridium
  • A kind of method of bidirectional enantioselective synthesis of chiral tetrahydroisoquinoline catalyzed by iridium
  • A kind of method of bidirectional enantioselective synthesis of chiral tetrahydroisoquinoline catalyzed by iridium

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Experimental program
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Effect test

Embodiment 1

[0035] Embodiment 1: optimization of conditions

[0036] In the glove box, drop 1,5-cyclooctadiene iridium chloride dimer (0.1mol%-2mol% of the amount of substrate in formula 1) and chiral phosphine ligand (substrate in formula 1) into the reaction bottle 0.22mol%-4.4mol% of the amount of substance used) and solvent (1mL), stirred at room temperature for 10 minutes; then the catalyst was transferred to a container containing substrate 1a (62.2 mg, 0.3 mmol), additive N-bromosuccinyl Amine (10mol%-150mol% of substrate consumption in formula 1) and alkali (0-75mol% of substrate consumption in formula 1) ampoule, and add solvent 2mL, then reaction bottle is transferred in the autoclave, Introduce hydrogen (500psi-1000psi), react at 0°C-80°C for 24-36 hours; release hydrogen, remove the solvent and directly separate the pure product by column chromatography. The reaction formula and ligand structure are as follows:

[0037]

[0038] The yield is the NMR yield, and the enantio...

Embodiment 2

[0042] Example 2: Synthesis of chiral tetrahydroisoquinoline 2 by iridium-catalyzed asymmetric hydrogenation

[0043] Condition A (condition A): in the glove box, drop into 1,5-cyclooctadiene iridium chloride dimer (2mol% of substrate consumption in formula 1) and (R)-BINAP (formula 1) in reaction bottle 4.4mol% of the amount of substrate in 1) and solvent 1,2-dichloroethane (1mL), stirred at room temperature for 10 minutes; succinimide (10mol% of the amount of substrate in formula 1) in an ampoule, and add 2mL of solvent, then transfer the reaction bottle to a high-pressure reactor, feed hydrogen (1000psi), and react at 0°C for 36 hours ; Release hydrogen, remove the solvent and obtain the pure product S configuration product (S)-2 directly by column chromatography.

[0044] Condition B (condition B): in the glove box, drop into 1,5-cyclooctadiene iridium chloride dimer (1mol% of the substrate consumption in formula 1) and (R)-BINAP (formula 1) in the reaction bottle 2.2mol...

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Abstract

An iridium-catalyzed two-way enantioselective synthesis method of chiral tetrahydroisoquinoline, the catalyst system used is a chiral bisphosphine complex of iridium. Using a single chiral source, the asymmetric hydrogenation of simple and easy-to-obtain 3,4-dihydroisoquinoline substrates was realized by adjusting the amount of achiral additive N-bromosuccinimide in the reaction system . The method utilizes a single chiral source to obtain two enantiomers of the corresponding chiral tetrahydroisoquinoline respectively, and the enantiomeric excess can reach 89% (S) and 98% (R), respectively. The invention is simple and practical in operation, simple and easy to obtain raw materials, commercially available catalyst, mild reaction conditions, high yield and high enantioselectivity. In addition, the two enantiomers of tetrahydroisoquinoline can be obtained only through the conditions of achiral additives, successfully avoiding the synthesis of two different configuration ligands.

Description

technical field [0001] The invention relates to a method for highly enantioselectively synthesizing two enantiomers of chiral tetrahydroisoquinoline by using an iridium homogeneous catalyst system and adjusting the amount of achiral additives. Background technique [0002] In the 1950s, the tragedy of thalidomide (thalidomide) in Europe caused the widespread attention and attention of pharmacists and chemists to the chirality of drug molecules (Reference 1: (a) Burley, D.M. ; Lenz, W. Lancet 1962, 279, 271-272. (b) Stephans, T.D. Teratology 1988, 38, 229-239.). In 1992, the U.S. Food and Drug Administration (FDA) stipulated that all marketed racemic drugs must provide the physiological activity and toxicological research data of their two enantiomers; and in 1997, supplementary regulations: early Marketed racemic drugs must be replaced by their corresponding chiral enantiomers. Therefore, the simultaneous synthesis of two enantiomers of a racemic compound is of great signi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/02C07D217/20C07D217/18
Inventor 周永贵时磊姬悦陈木旺孙蕾
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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