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Iridium catalytic method for asymmetric hydrogenation to synthesize piperazine derivatives

An asymmetric and derivative technology, applied in organic chemistry methods, organic chemistry, etc., can solve problems such as cumbersome steps and limited substrate range, and achieve simple preparation process, convenient separation, high reactivity and enantioselectivity Effect

Inactive Publication Date: 2017-08-01
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 good enantioselectivity can be obtained, the steps are cumbersome, and the substrate scope is also 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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  • Iridium catalytic method for asymmetric hydrogenation to synthesize piperazine derivatives
  • Iridium catalytic method for asymmetric hydrogenation to synthesize piperazine derivatives
  • Iridium catalytic method for asymmetric hydrogenation to synthesize piperazine derivatives

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Embodiment 1: optimization of conditions

[0033] In a nitrogen-filled glove box, add (1,5-cyclooctadiene) iridium chloride dimer (0.002 mmol, 1.3 mg) and bisphosphine ligand (0.0044 mmol) to the reaction vial Add 1.0 ml of toluene solvent, stir at room temperature for 10-15 minutes, then transfer the prepared catalyst to another reaction flask containing raw material 3-phenylpyridinium salt 1a (0.20 mmol, 65.4 mg), 2.0 ml Wash the bottle with toluene, transfer the residual catalyst, and share 3 ml of solvent. The reaction bottle was put into a stainless steel autoclave, hydrogen gas was introduced at 600 psi, and the reaction was carried out at 30° C. for 36 hours. Slowly release hydrogen, filter the reaction solution, remove the solvent with a rotary evaporator, and then direct column chromatography (the volume ratio of the eluent dichloromethane and methanol is 20:1), and the pure product can be isolated. The reaction formula and formula The body is as follows:

...

Embodiment 2

[0038] Example 2: Synthesis of 3-substituted piperazine derivatives by homogeneous iridium-catalyzed asymmetric hydrogenation

[0039] In a nitrogen-filled glove box, (1,5-cyclooctadiene) iridium chloride dimer (0.002 mmol, 1.3 mg) and (R,S p )- t Bu-JosiPhos (0.0044 mmol, 2.4 mg) was added into a reaction flask containing 1.0 ml of solvent toluene, stirred at room temperature for 10-15 minutes, and then the prepared catalyst was transferred to another container containing raw material 3-substituted pyrazine salt 1 (0.20 mmol) in the reaction flask, 0.5 ml of toluene and 1.5 ml of 1,4-dioxane solvent wash the bottle, transfer the residual catalyst, and share 3 ml of solvent. The reaction bottle was put into a stainless steel autoclave, hydrogen gas was introduced at 1200 psi, and the reaction was carried out at -20°C for 36 hours. The autoclave was taken out from the low temperature reactor, slowly raised to room temperature, and then hydrogen was released. Add excess sodium ...

Embodiment 3

[0058] Example 3: Synthesis of 3,5-disubstituted piperazine derivatives by homogeneous iridium-catalyzed asymmetric hydrogenation

[0059] In a nitrogen-filled glove box, (1,5-cyclooctadiene) iridium chloride dimer (0.002 mmol, 1.3 mg) and (R)-SegPhos (0.0044 mmol, 2.7 mg) Add 1.0 milliliters of solvent toluene to the reaction bottle, stir at room temperature for 10-15 minutes, then transfer the prepared catalyst to another reaction bottle containing raw material 3,5-disubstituted pyrazine salt 3 (0.20 mmol) 0.5 ml of toluene and 1.5 ml of 1,2-dichloroethane solvent to wash the bottle, transfer the residual catalyst, and share 3 ml of solvent. The reaction bottle was put into a stainless steel autoclave, hydrogen gas was introduced at 600psi, and the reaction was carried out at -20°C for 24 hours. The autoclave was taken out from the low temperature reactor, slowly raised to room temperature, and then hydrogen was released. Add excess sodium carbonate powder to the reaction ...

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Abstract

In an iridium catalytic method for asymmetric hydrogenation to synthesize piperazine derivatives, an iridium chiral diphosphine complex is used as a catalyst. The reaction is carried out in the following condition that the temperature is in a range of -20 to 70 DEG C, the solvent is toluene, tetrahydrofuran and ethyl acetate, the pressure is 10-80 times of atmospheric pressure, the ratio of a substrate to the catalyst is 50 / 1, and the catalyst is a complex of (1,5-cyclo-octadiene) iridium chloride dimer and chiral diphosphine. 3-substitued, 3,5-disubstitued, and 2,3-disubstitued pyrazine salt can all be well hydrogenated to obtain corresponding chiral piperazine derivatives, with the highest enantiomeric excess reaching 96%. The method is simple to operate, available in raw materials, high in enantioselectivity, and good in yield, and an atom-economic eco-friendly route is provided for synthesizing 3-substitued, 3,5-disubstitued, and 2,3-disubstitued piperazine derivatives.

Description

technical field [0001] The invention relates to a method for synthesizing chiral piperazine derivatives with high yield and high enantioselectivity through iridium-catalyzed hydrogenation of pyrazine salts. Background technique [0002] Chiral piperazine structures widely exist in natural products and pharmaceutically active molecules (Formula 1). Although there are many methods to construct chiral piperazine structures, most of these methods start from chiral amino acids and undergo steps such as ring closure and carbonyl reduction. Therefore, there are disadvantages such as expensive raw materials, long synthetic routes, and cumbersome steps. Chiral centers readily racemize upon reduction [(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; (c) Maity, 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,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/04
CPCC07D241/04C07B2200/07
Inventor 周永贵黄文学柳莲今吴波孙蕾
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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