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Method for synthesizing chiral cyclic urea by asymmetric hydrogenation of 2-hydroxy pyrimidine compounds catalyzed by iridium

A hydroxypyrimidine and asymmetric technology, which is applied in the field of catalyzing the asymmetric hydrogenation of 2-hydroxypyrimidine compounds to synthesize chiral cyclic ureas, can solve the problems of poor enantioselectivity, achieve improved activity, reduce aromaticity, and mild reaction conditions Effect

Active Publication Date: 2019-05-31
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

[0003] In 2015, the Glorius group developed a ruthenium / N-heterocyclic carbene complex to catalyze the hydrogenation of pyridone substrates, which can obtain cyclic lactams in excellent yields, but its enantioselectivity is relatively poor (Reference 2 : Wysocki, J.; Schlepphorst, C.; Glorius. F. Synlett. 2015, 26, 1557.);

Method used

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  • Method for synthesizing chiral cyclic urea by asymmetric hydrogenation of 2-hydroxy pyrimidine compounds catalyzed by iridium
  • Method for synthesizing chiral cyclic urea by asymmetric hydrogenation of 2-hydroxy pyrimidine compounds catalyzed by iridium
  • Method for synthesizing chiral cyclic urea by asymmetric hydrogenation of 2-hydroxy pyrimidine compounds catalyzed by iridium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-13

[0030] Example 1-13 Optimization of hydrogenation reaction conditions for disubstituted substrates

[0031] 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 flask , add an organic solvent (1.0-4.0mL) after nitrogen replacement, and stir at room temperature for 10 minutes; 5mol%-30mol%) of the reaction flask, moved to the reactor, feed hydrogen (400psi-800psi), 40-80 degrees Celsius reaction for 24 hours; release hydrogen, remove the solvent directly after column chromatography to obtain the target product , the reaction formula and ligand structure are as follows:

[0032]

[0033] Note: In the formula [Ir(COD)Cl] 2 It is 1,5-cyclooctadiene iridium chloride dimer, chiral ligand is a chiral ligand, Additive is an additive, and Solvent is a solvent.

[0034] The yield is the conversion rate, and the enantiomeric excess of the product is determined ...

Embodiment 14-19

[0037] Example 14-19 Synthesis of chiral cyclic urea 2 by iridium-catalyzed asymmetric hydrogenation of disubstituted substrates

[0038] Put 1,5-cyclooctadiene iridium chloride dimer (1.0mol% of the substrate amount) and (S,S)-f-Binaphane (2.2mol% of the substrate amount) into the reaction flask, nitrogen replacement Then add organic solvent (1.0mL) and stir at room temperature for 10 minutes; then use organic solvent (2.0mL) to transfer this solution to an ampoule containing substrate 1 (0.3mmol) and trichloroisocyanuric acid (10mol%) in advance In, move in the reaction kettle, pass into hydrogen (800psi), react 24 hours under 40 degrees centigrade; Release hydrogen, remove the direct column chromatography separation after solvent to obtain pure product, reaction formula is as follows:

[0039]

[0040] Note: In the formula [Ir(COD)Cl] 2 It is 1,5-cyclooctadiene iridium chloride dimer, (S,S)-f-binaphane is a chiral ligand, TCCA is trichloroisocyanuric acid, and DCM is di...

Embodiment 3

[0044] Example 3: Synthesis of chiral cyclic urea by hydrogenation of monosubstituted substrate

[0045] Put 1,5-cyclooctadiene iridium chloride dimer (1.0mol% of the substrate amount) and (R)-C in the reaction bottle 1 -TunePhos (2.2mol% of the amount of substrate), add organic solvent (1.0mL) after nitrogen replacement, and stir at room temperature for 0.5 hours; ) and 1,3-dichloro-5,5-dimethylhydantoin (10mol%) in the ampoule, moved to the reactor, feed hydrogen (800psi), reacted 24 hours at 40 degrees Celsius; release hydrogen, After removing solvent, direct column chromatography separates and obtains pure product, and reaction formula is as follows:

[0046]

[0047] Note: In the formula [Ir(COD)Cl] 2 1,5-cyclooctadiene iridium chloride dimer, (R)-C 1 -TunePhos as the chiral ligand,

[0048] DCDMH is 1,3-dichloro-5,5-dimethylhydantoin and THF is tetrahydrofuran.

[0049] The yield is the isolated yield, and the enantiomeric excess of the product is determined by chi...

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Abstract

The invention provides a method for synthesizing chiral cyclic urea by asymmetric hydrogenation of 2-hydroxy pyrimidine compounds catalyzed by iridium. In the formula described below, R refers to alkyl or aryl of C1-C6; R' refers to aryl, heteroaryl or alkyl containing substituents, and the substituent contains at least one of F, Cl, CF3, Me and MeO, and the enantiomeric excess of the synthesizedchiral cyclic urea can reach 96%. The method is simple to operate and practical and easy to implement, high in the yield, environmental friendly, commercially available for catalysts and moderate in reaction condition and has potential practical application value.

Description

technical field [0001] The invention relates to a method for synthesizing chiral cyclic urea through the asymmetric hydrogenation of 2-hydroxypyrimidine compound catalyzed by an iridium catalytic system with high enantioselectivity. Background technique [0002] It is a very simple and effective method to obtain chiral amines by asymmetric hydrogenation of aromatic heterocyclic compounds. In recent years, asymmetric hydrogenation of aromatic heterocyclic compounds has made great progress. A variety of aromatic heterocyclic compounds, such as: isoquinoline, pyridine, quinoline, pyrazine, etc., can achieve high stereoselective hydrogenation reactions through asymmetric catalysis to obtain corresponding heterocyclic compounds (Reference 1: (a) Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G.Angew.Chem.Int.Ed.2006,45,2260.(b)Ye, Z-S.; Chen, M.-W.; Chen, Q.-A.; Shi, L.; Duan, Y.; Zhou, Y.-G.Angew.Chem.Int.Ed.2012,51,10181. (c) Wang, W.-B.; Lu, S-M.; Yang, P.-Y.; Han, X.-W.; Zhou...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/10
Inventor 时磊周永贵孙蕾冯广收
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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