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Method for catalytically synthesizing N-arylated derivative of pyrimidine-2-amine

A technology of arylation and derivatives, applied in chemical instruments and methods, compounds containing elements of group 3/13 of the periodic table, chemical/physical processes, etc., can solve problems such as harsh reaction conditions and low catalyst conversion numbers, etc. Achieve the effects of mild reaction conditions, less by-products, and stable physical and chemical properties

Active Publication Date: 2022-04-12
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are some problems in the current catalytic process, such as the use of noble metals, high ligands, harsh reaction conditions, and low catalyst conversion numbers (J.Org.Chem.2017, 82, 12603; 2019, 84, 15079)

Method used

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  • Method for catalytically synthesizing N-arylated derivative of pyrimidine-2-amine
  • Method for catalytically synthesizing N-arylated derivative of pyrimidine-2-amine
  • Method for catalytically synthesizing N-arylated derivative of pyrimidine-2-amine

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preparation example Construction

[0031] The preparation method of the cuprous complex containing the meta-carborane ligand of N-coordination comprises the following steps:

[0032] 1) Add the n-BuLi solution to the m-carborane solution at -80°C to -75°C, stir and react at room temperature for 30-60min;

[0033] 2) Add 3-chloromethylpyridine and react at room temperature for 3-5h;

[0034] 3) Add CuI, react at room temperature for 2-5h, and obtain the cuprous complex after post-treatment.

[0035] In step 1), the n-BuLi solution is n-BuLi n-hexane solution, and the m-carborane solution is m-carborane tetrahydrofuran solution.

[0036] In step 3), the post-treatment process is: standing and filtering after the reaction, decompressing to dry the solvent to obtain the crude product, and then subjecting the crude product to column chromatography separation; during the column chromatography separation process, the eluent is petroleum ether and A mixed solvent of ethyl acetate, and the volume ratio of petroleum et...

Embodiment 1

[0039] Synthesis of N,N-Coordinated Cuprous Complex Cu Containing Meta-Carborane Ligands:

[0040]

[0041] At -78°C, n-BuLi (1.6M) in n-hexane (1.00 mL, 1.6 mmol) was slowly added dropwise to m-C containing m-carborane 2 B 10 h 10 (92.0mg, 0.64mmol) in tetrahydrofuran solution, stirred at this temperature for 30 minutes, slowly rose to room temperature and continued to react for 1 hour, then added 3-chloromethylpyridine (162.3mg, 1.28mmol), and continued to react at room temperature React for 5 hours. CuI (122.9 mg, 0.64 mmol) was then added to the reaction for another 2 hours. After the reaction, stand and filter, and dry the solvent under reduced pressure, the obtained crude product is separated by column chromatography (petroleum ether / ethyl acetate=8:1), and the brown target product cuprous complex Cu (257.8mg, Yield 78%).

[0042] 1 H NMR (400MHz, CDCl 3 ,25℃):δ=7.83(d,J=7.0Hz,2H),7.55(s,2H),7.43(d,J=6.5Hz,2H),7.35(t,J=6.5Hz,2H), 2.91(s,4H). Elemental analysis...

Embodiment 2

[0044] The cuprous complex catalyzes the coupling reaction, and the specific process is as follows:

[0045]

[0046] The cuprous complex Cu (0.01mmol) and iodobenzene (1.1mmol) dissolved in N-methylpyrimidin-2-amine (1mmol), cuprous complex Cu (0.01mmol) and iodobenzene (1.1mmol) were used as a catalyst as a catalyst. In 3mL toluene, react at room temperature for 6 hours. After the end, the concentrated reaction solution is directly separated by silica gel column chromatography, dried until the mass remains unchanged, and the corresponding product C is obtained. 11 h 11 N 3 (yield 91%), 1 H NMR (400MHz, CDCl 3 ,25°C): δ=8.35(d, J=7.0Hz, 2H), 7.45(t, J=7.0Hz, 2H), 7.33(d, J=7.0Hz, 2H), 7.27(t, J=7.5 Hz, 1H), 6.56(t, J=4.0Hz, 1H), 3.52(s, 3H). Elemental analysis: C 71.33, H 5.99, N 22.69 (theoretical); C 71.36, H 5.98, N 22.75 (actual).

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Abstract

The invention relates to a method for catalytically synthesizing an N-arylated derivative of pyrimidine-2-amine, which comprises the following steps: by taking an N, N-coordinated meta-carborane ligand-containing cuprous complex as a catalyst and taking pyrimidine-2-amine compounds and aryl halide compounds as raw materials, carrying out coupling reaction at room temperature to obtain the N-arylated derivative of pyrimidine-2-amine. The N-arylation derivative of the pyrimidine-2-amine is obtained. Compared with the prior art, the preparation method disclosed by the invention has the advantages that the N, N-coordinated cuprous complex containing the meta-carborane ligand is used as the catalyst, has higher catalytic activity under a mild condition, can be used for catalyzing Buchwald-Harwig coupling reaction of the pyrimidine-2-amine compound and the aryl halide compound to prepare the N-arylated derivative of pyrimidine-2-amine, is good in universality, and can be used for preparing the N-arylated derivative of pyrimidine-2-amine. The method has the advantages of mild reaction conditions, high catalytic efficiency, few byproducts, lower cost and easiness in separation of products.

Description

technical field [0001] The invention belongs to the technical field of synthetic chemistry, and relates to a method for catalytically synthesizing N-arylated derivatives of pyrimidin-2-amines by utilizing cuprous complexes. Background technique [0002] The Buchwald-Hartwig coupling reaction is an important method to directly construct C-N bonds to synthesize related nitrogen-containing compounds, which is widely used in the synthesis of natural products and pharmaceuticals. Among them, since pyrimidin-2-amine is a common structure in many antitumor drugs (such as imatinib base), the Buchwald-Hartwig coupling reaction of its derivatives is particularly important, which can realize the synthesis of pyrimidin-2-amine structure. The introduction, and can be applied to the modification of pyrimidin-2-amine, provides a powerful tool for drug synthesis. However, there are some problems in the current catalytic process, such as the use of noble metals, high ligand usage, harsh rea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42C07F5/05B01J31/22
CPCY02P20/584
Inventor 李苏阳孙迎新高永红卞明刘振江姚子健
Owner SHANGHAI INST OF TECH
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