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Method for synthesizing chiral 3,4-dihydroquinazolinone through asymmetric hydrogenation of quinazolinone compound under catalysis of iridium

A dihydroquinazolinone, asymmetric technology, applied in organic chemistry methods, organic chemistry and other directions, can solve problems such as limited substrate scope, and achieve the effects of reducing aromaticity, convenient preparation and good reaction selectivity

Active Publication Date: 2020-02-11
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

But its substrate range is limited to trifluoromethyl, difluoromethyl substituted quinazolinone compounds (references two: Duan, Y.; Zhu, X.-Y.; Ma, J.-A.; Zhou , Y.-G.Tetrahedron Lett.2013, 54, 6161.)

Method used

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  • Method for synthesizing chiral 3,4-dihydroquinazolinone through asymmetric hydrogenation of quinazolinone compound under catalysis of iridium
  • Method for synthesizing chiral 3,4-dihydroquinazolinone through asymmetric hydrogenation of quinazolinone compound under catalysis of iridium
  • Method for synthesizing chiral 3,4-dihydroquinazolinone through asymmetric hydrogenation of quinazolinone compound under catalysis of iridium

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Experimental program
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Embodiment 1-13

[0035] Optimization of the Reaction Conditions for the Hydrogenation of 4-Substituted Quinazolinones

[0036] Put 1,5-cyclooctadiene iridium chloride dimer (0.5mol%-5mol% of substrate consumption) and chiral bisphosphine ligand (1.1mol%-11mol% of substrate consumption) in the reaction bottle ), add an organic solvent (1.0-4.0mL) after nitrogen replacement, and stir at room temperature for 10 minutes; 5 mol%-30mol% of the amount used), moved to the reaction kettle, introduced hydrogen (400psi-800psi), and reacted for 24 hours at 25-80 degrees Celsius; released hydrogen, and directly separated by column chromatography after removing the solvent to obtain For the target product, 13 different examples were obtained by changing the types of organic solvents, additives, and chiral bisphosphine ligands during the reaction, and the types of changes are shown in Table 1. The reaction formula and ligand structure are as follows:

[0037]

[0038] Note: In the formula [Ir(COD)Cl] 2...

Embodiment 14-28

[0043] Iridium-Catalyzed Asymmetric Hydrogenation of 4-Substituted Quinazolinones

[0044] Drop into 1,5-cyclooctadiene iridium chloride dimer (1.0mol% of substrate consumption) and (R)-SegPhos (2.2mol% of substrate consumption) in reaction bottle, add tetrahydrofuran (THF) after nitrogen replacement ( 1.0 mL), stirred at room temperature for 10 minutes; then this solution was transferred to an ampoule containing substrate 1 (0.3 mmol) and bromochlorohydantoin (10 mol%) with tetrahydrofuran (2.0 mL), and moved to the reaction kettle , pass into hydrogen (600psi), react 24 hours under 25 degrees centigrade; Release hydrogen, remove the direct column chromatography separation after solvent to obtain pure product, change the kind of substrate in the reaction process, obtain 15 different embodiments, change Please refer to Table 2 for details. The reaction formula is as follows:

[0045]

[0046] Note: In the formula [Ir(COD)Cl] 2 It is 1,5-cyclooctadiene iridium chloride di...

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Abstract

The invention provides a method for synthesizing chiral 3,4-dihydroquinazolinone through asymmetric hydrogenation of a quinazolinone compound under the catalysis of iridium, wherein in the formula defined in the specification, R is C1-6 alkyl or aryl containing a substituent group, R' is at least one selected from hydrogen, C1 alkyl, alkoxy and chlorine, and the substituent group is at least one selected from F, Cl, CF3, Ph, Me and MeO. According to the invention, with the method, the substrate range is wide, the synthesis of chiral 3,4-dihydroquinazolinone is diverse, and the enantiomeric excess can achieve 98%; and the method has characteristics of simple, convenient, practical and easily-performing operation, high yield, environmental protection, commercially available catalyst, mild reaction conditions and practical application value.

Description

technical field [0001] The invention relates to a method for synthesizing 3,4-dihydroquinazolone through the asymmetric hydrogenation of quinazolinone compounds with high enantioselectivity using an iridium catalyst system, and belongs to the field of chemical synthesis of chiral amine compounds. Background technique [0002] Compounds containing chiral 3,4-dihydroquinazolinones have important applications in the field of medicinal chemistry due to their broad-spectrum biological activities (Formula 1). For example, the second-generation AIDS non-nucleoside reverse transcriptase inhibitors DPC 083 and DPC 961 have shown encouraging biological activity in the treatment of AIDS; Disease efficacy. [0003] [0004] The asymmetric addition reaction of quinazolinones by nucleophiles is currently the most important method for the synthesis of chiral 3,4-dihydroquinazolones (Reference 1: (a) Yuan, H.N.; Wang, S .; Nie, J.; Meng, W.; Yao, Q.; Ma, J.A. Angew. Chem. Int. Ed. 2013...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/82C07D239/80
CPCC07B2200/07C07D239/80C07D239/82
Inventor 周永贵冯广收时磊孙蕾
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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