Method of asymmetric hydrogenation synthesis of chiral lactam by catalyzing 2-hydroxypyrazine compound with palladium

A hydroxypyrazine and asymmetric technology, which is applied in the field of chemical synthesis of chiral cyclic amines, can solve the problems of cumbersome steps and limited substrate range, and achieve good enantioselectivity, good air stability and high yield Effect

Active Publication Date: 2020-03-10
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

Although relatively good enantioselectivity can be obtained, the steps are cumbersome and the scope of substrates is limited to pyrazine-2-carboxylic acid derivatives [K.Rossen, S.A.Weissman, J.Sager, R.A.Reamer, D.Askin, R.P. Volante, P.J. Reider, Tetrahedron Lett. 1995, 36, 6419]

Method used

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  • Method of asymmetric hydrogenation synthesis of chiral lactam by catalyzing 2-hydroxypyrazine compound with palladium
  • Method of asymmetric hydrogenation synthesis of chiral lactam by catalyzing 2-hydroxypyrazine compound with palladium
  • Method of asymmetric hydrogenation synthesis of chiral lactam by catalyzing 2-hydroxypyrazine compound with palladium

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Experimental program
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Effect test

Embodiment 1-12

[0030] Optimization of Hydrogenation Conditions of 5,6-Disubstituted-2-Hydroxypyrazine

[0031] Drop into palladium trifluoroacetate (1mol%-5mol% of substrate consumption) and chiral bisphosphine ligand (1.1mol%-5.5mol% of substrate consumption) in reaction flask, add organic solvent acetone (1.0mol%) after nitrogen displacement -4.0mL), stirred at room temperature for 30 minutes, and removed the organic solvent under reduced pressure; then, in the glove box, this catalyst was transferred to pre-placed substrate 1a (0.2mmol) and additive ( 10mol%-100mol% of the amount of substrate) in a reaction flask, moved to a reaction kettle, introduced hydrogen (400psi-1200psi), and reacted at 40-100 degrees Celsius for 24 hours; released hydrogen, and directly separated by column chromatography after removing the solvent To obtain the target product, change the types of organic solvents, additives, and chiral bisphosphine ligands in the reaction process, and obtain 12 different examples....

Embodiment 13-24

[0038] Synthesis of Chiral Lactams by Palladium-Catalyzed Asymmetric Hydrogenation of 5,6-Disubstituted-2-Hydroxypyrazines

[0039]Put palladium trifluoroacetate (3.0 mol% of the substrate amount) and (R)-TolBINAP (3.3 mol% of the substrate amount) into the reaction flask, add organic solvent acetone (1.0mL) after nitrogen replacement, and stir at room temperature for 30 minutes , and the solvent was removed under reduced pressure. Then, in the glove box, this solution was transferred to an ampoule containing substrate 1 (0.3 mmol) and p-toluenesulfonic acid monohydrate (100 mol%) with dichloromethane and benzene (1.5 mL / 1.5 mL). , moved to the reaction kettle, feed hydrogen (1000psi), and reacted for 24 hours at 80 degrees Celsius; release hydrogen, remove the solvent and separate directly to obtain pure products by column chromatography, change the type of substrate in the reaction process, and obtain 12 Different embodiments, the types of changes are shown in Table 2. The...

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Abstract

The invention provides a method of asymmetric hydrogenation synthesis of chiral lactam by catalyzing 2-hydroxypyrazine compound with palladium. In the formula, R is a C1-C6 alkyl group or an aryl group containing a substituent group being at least one of F, Cl, Br, CF3, Me, MeO, Et and nPr. The method employs feasible raw materials and is high in enantioselectivity of product and high in yield, wherein the enantiomeric excess can reach 90%. The catalyst is low-cost and feasible and is good in air stability, so that the method is a route with good atom economy and environment-friendly effect for the asymmetric hydrogenation synthesis of the chiral lactam from the 2-hydroxypyrazine compound. Meanwhile, the method is simple in operation, is practicable and easy, is high in yield, is environment-friendly and green, is gentle in reaction conditions, and has a potential practical application value.

Description

technical field [0001] The invention relates to a method for synthesizing chiral lactams through the asymmetric hydrogenation of 2-hydroxypyrazine compounds by highly enantioselectively catalyzing a palladium catalyst system, which belongs to the field of chemical synthesis of chiral cyclic amines. Background technique [0002] Chiral piperazinone structures widely exist in natural products and active pharmaceutical molecules. Although there are many methods to construct chiral piperazinone structures, most of these methods start from chiral amino acids and go through steps such as ring closure, so there are disadvantages such as expensive raw materials and cumbersome steps [(a) Dinsmore, C.J.; Beshore, D.C.Org.Prep.Proced.Int.2002, 34, 367; (b) Crestey, F.; Witt, M.; Jaroszewski, J.W.; Franzyk, H.J.Org.Chem.2009, 74, 5652; P.; B. Org. Lett. 2008, 10, 1473; (d) Kwon, S.H.; Lee, S.M.; Byun, S.M.; Chin, J.; S.K.; Panda, G. RSC Adv. 2013, 3, 18332;]. Using asymmetric hydro...

Claims

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Application Information

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IPC IPC(8): C07D241/08
CPCC07B2200/07C07D241/08
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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