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Large-steric-hindrance N-heterocyclic carbene palladium complex, preparation method and application thereof, and synthesis method of Sonidegib based on large-steric-hindrance N-heterocyclic carbene palladium complex

A complex and nitrogen heterocycle technology is applied in the preparation of amino compounds, the preparation of organic compounds, organic compounds/hydrides/coordination complex catalysts, etc. Fewer synthesis steps, avoiding palladium-carbon hydrogenation process, and efficient C-N coupling

Active Publication Date: 2021-12-14
SUN YAT SEN UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0015] In order to overcome the low reactivity of carbene palladium complexes in the above-mentioned prior art, the shortcomings and shortcomings of being unable to efficiently catalyze reactions at room temperature, the primary purpose of the present invention is to provide a large sterically hindered nitrogen heterocyclic carbene palladium complex

Method used

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  • Large-steric-hindrance N-heterocyclic carbene palladium complex, preparation method and application thereof, and synthesis method of Sonidegib based on large-steric-hindrance N-heterocyclic carbene palladium complex
  • Large-steric-hindrance N-heterocyclic carbene palladium complex, preparation method and application thereof, and synthesis method of Sonidegib based on large-steric-hindrance N-heterocyclic carbene palladium complex
  • Large-steric-hindrance N-heterocyclic carbene palladium complex, preparation method and application thereof, and synthesis method of Sonidegib based on large-steric-hindrance N-heterocyclic carbene palladium complex

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Embodiment approach

[0064] One embodiment, a large sterically hindered nitrogen heterocyclic carbene palladium complex (NHC-Pd complex), the structural formula is as follows:

[0065]

[0066] Another embodiment, a large sterically hindered nitrogen heterocyclic carbene palladium complex (NHC-Pd complex), the structural formula is as follows:

[0067]

[0068] Yet another embodiment, a large sterically hindered nitrogen heterocyclic carbene palladium complex (NHC-Pd complex), the structural formula is as follows:

[0069]

[0070] It should be noted that the large sterically hindered nitrogen heterocyclic carbene palladium complex structure of the present invention uses diphenylimidazole as the main ligand skeleton and functionalized allyl as auxiliary ligand. As an auxiliary ligand, the allyl group is not very tightly combined with the metal center, so it is easily activated into zero-valent palladium at room temperature, inserting into the C-Cl bond of the aromatic heterocyclic chloride,...

Embodiment 1

[0077] Embodiment 1: the synthesis of nitrogen heterocyclic carbene palladium complex Pd-NHC-1

[0078]

[0079] (1) Synthesis of diamine compound 2a:

[0080]

[0081] 5mmol of (1S,2S)-(-)-1,2-diphenylethylenediamine, 18mmol of tBuONa, 15mmol of 2,6-diisopropylbromobenzene, 1.5mmol of IPrMe·HCl, 0.5mmol Pd(dba) 2 Mix, add 20mL of anhydrous toluene, and react at 110°C for 24h under nitrogen atmosphere. After the reaction was completed, dilute with water, extract 3 times with ethyl acetate, anhydrous Na 2 SO 4 dry. The solvent was spin-dried under reduced pressure, and the crude product was subjected to silica gel column chromatography to obtain a white solid (eluent: petroleum ether / dichloromethane=10:1). Product yield: 1.70 g, yield: 65%. 1 H NMR (400MHz, CDCl 3 )δ7.06-6.99(m,16H),4.58(s,2H),4.24(s,2H),3.29(dt,J=13.1,6.4Hz,4H),1.23(d,J=6.6Hz,12H ),0.91(d,J=6.5Hz,12H). 13 C NMR (101MHz, CDCl 3 ) δ 143.1, 141.3, 140.2, 128.4, 127.8, 127.0, 123.7, 123.4, 69.1, 27...

Embodiment 2

[0092] Embodiment 2: the synthesis of nitrogen heterocyclic carbene palladium complex Pd-NHC-2

[0093]

[0094] (1) Synthesis of diamine compound 2b:

[0095]

[0096] 5mmol of (1S,2S)-(-)-1,2-diphenylethylenediamine, 18mmol of tBuONa, 15mmol of 2,4,6-triisopropylbromobenzene, 1.5mmol of IPrMe·HCl, 0.5mmol of Pd(dba) 2 Mix, add 20mL of anhydrous toluene, and react at 110°C for 24h under nitrogen atmosphere. After the reaction was completed, dilute with water, extract 3 times with ethyl acetate, anhydrous Na 2 SO 4 dry. The solvent was spin-dried under reduced pressure, and the crude product was subjected to silica gel column chromatography to obtain a white solid (eluent: petroleum ether / dichloromethane=10:1). Product yield: 2.15 g, yield: 70%. 1 H NMR (400MHz, CDCl 3 )δ7.10–6.94(m,10H),6.86(s,4H),4.57(d,J=4.3Hz,2H),4.18(s,2H),3.45–3.13(m,4H),2.95–2.63 (m,2H),1.33–1.12(m,24H),0.87(d,J=6.8Hz,12H). 13 C NMR (101MHz, CDCl 3 ) δ 143.7, 143.0, 140.5, 139.0, 128.5, ...

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Abstract

The invention belongs to the technical field of organic synthesis and chemical catalysis, and discloses a large-steric-hindrance N-heterocyclic carbene palladium complex, a preparation method thereof, application of the large-steric-hindrance N-heterocyclic carbene palladium complex to efficient catalysis of C-N coupling reaction at room temperature, and a synthesis method of Sonidegib based on the large-steric-hindrance N-heterocyclic carbene palladium complex. According to the structure of the large-steric-hindrance nitrogen heterocyclic carbene palladium complex, diphenyl imidazole serves as a main ligand framework, functionalized allyl serves as an auxiliary ligand, and the functionalized allyl is introduced beside a metal center of a catalyst to serve as the auxiliary ligand, so that the large-steric-hindrance nitrogen heterocyclic carbene palladium complex has remarkably improved catalytic activity and stability and can be applied to efficient catalysis of C-N coupling reaction; and especially, the catalyst can efficiently catalyze C-N coupling reaction at room temperature, and the yield can reach 99%. The invention also provides a three-step method for synthesizing the Sonidegib at room temperature by taking aryl / aliphatic amine and aryl chloride as reactants under the catalysis of a palladium catalytic system, the synthesis method provided by the invention has few steps, and the total yield can be up to 74.5%.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis and chemical catalysis, in particular to a large sterically hindered nitrogen-heterocyclic carbene palladium complex and its preparation method and its application in efficiently catalyzing C-N coupling reactions at room temperature, and Sony Gibbs based on it synthetic method. Background technique [0002] Phosphine ligands and nitrogen heterocyclic carbene (NHC) ligands are strong electron-donating ligands, and their palladium complexes can efficiently catalyze the rate-determining step of oxidative addition, but they have great differences in their three-dimensional structures. . In 1991, Arduengo successfully separated the nitrogen heterocyclic free carbene for the first time; in 1997, Tolman et al. carried out in-depth research on the three-dimensional structure of the phosphine ligand, and believed that the three-dimensional structure of the phosphine ligand was conical, and the l...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F15/00B01J31/22C07D413/04C07C209/10C07C211/54C07C211/48C07D295/033C07D295/023C07D213/74C07D417/12C07D471/04C07D405/14C07D401/12C07D405/12C07D409/12
CPCC07F15/006B01J31/2273C07D413/04C07C209/10C07D295/033C07D295/023C07D213/74C07D417/12C07D471/04C07D405/14C07D401/12C07D405/12C07D409/12B01J2231/4283B01J2531/824C07C211/54C07C211/48
Inventor 邱立勤欧阳嘉盛
Owner SUN YAT SEN UNIV
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