Preparation method of pyrimidine dione compounds

A technology of pyrimidine diketones and compounds, which is applied in the field of preparation of pyrimidine diketones, can solve the problems of single types of pyrimidine diketones, incapability of large-scale industrial production, and difficulty in adding functional groups, etc., to achieve superior performance and benefit The effect of large-scale industrial production and less harsh storage conditions

Active Publication Date: 2017-11-03
ARMY MEDICAL UNIV
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  • Abstract
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Problems solved by technology

[0007] The above two synthetic methods are to add functional groups to the molecular formula of urea by chemical reaction to obtain pyrimidine diketone compounds. However, it is difficult to add functional groups to the molecular formula of urea, which leads to low synthetic efficiency of these two synthetic methods. In addition, us

Method used

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  • Preparation method of pyrimidine dione compounds
  • Preparation method of pyrimidine dione compounds
  • Preparation method of pyrimidine dione compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029]

[0030] Take a 10ml reaction tube, add 1,4-dioxane (2mL) as a solvent, weigh oxime ester compound 1a (0.2mmol), isocyanide compound 2a (0.3mmol), silver oxide (0.01mmol ), pyridine (0.2mmol), under inert gas protection, were added to the reaction tube, and the reaction tube was sealed. Stir and react in an oil bath at 80°C for 6 hours, TLC detection, after the reaction is completed, cool down to room temperature, filter with diatomaceous earth to obtain the filtrate, and rinse the filtered solid particles with ethyl acetate several times, and combine the rinses in the filtrate , and then distilled by a rotary evaporator to remove 1,4-dioxane and ethyl acetate to obtain a crude product of 3aa. The crude product of 3aa was purified by flash column chromatography to obtain a pure product of 3aa with a yield of 92%. 1 H NMR (600MHz, CDCl 3 ): δ9.97(s, 1H), 7.65(d, J=7.6Hz, 2H), 7.56(t, J=7.2Hz, 1H), 7.51(t, J=7.5Hz, 2H), 6.06(d ,J=1.4Hz,1H),4.69(s,2H),4.21(q,J=7.1Hz,2...

Embodiment 2

[0032]

[0033] Take a 10ml reaction tube, add acetone (2mL) as solvent, weigh oxime ester compound 1a (0.2mmol), isocyanide compound 2a (0.6mmol), AgNO 3 (0.01mmol), triethylamine (0.2mmol), under the protection of an inert gas, were added to the reaction tube, and the reaction tube was sealed. Stir and react in an oil bath at 60°C for 6 hours, TLC detection, after the reaction is completed, cool down to room temperature, filter with diatomaceous earth to obtain the filtrate, and rinse the filtered solid particles with ethyl acetate several times, and combine the rinses into the filtrate , and then distilled by a rotary evaporator to remove acetone and ethyl acetate to obtain a crude product of 3aa, and the crude product of 3aa was purified by flash column chromatography to obtain a pure product of 3aa with a yield of 79%. 1 H NMR (600MHz, CDCl 3 ):δ9.41(s,1H),7.60–7.56(m,2H),7.03–6.99(m,2H),5.99(d,J=1.5Hz,1H),4.70(s,2H),4.22( d, J=7.1Hz, 2H), 3.88(s, 3H), 1.28(t, J=7.1H...

Embodiment 3

[0035]

[0036] Take a 10ml reaction tube, add tetrahydrofuran (2mL) as a solvent, weigh oxime ester compound 1a (0.2mmol), isocyanide compound 2a (0.3mmol), AgF (0.01mmol), pyridine (0.2mmol), Under the protection of inert gas, add to the reaction tube respectively, and seal the reaction tube. Stir and react in an oil bath at 100°C for 6 hours, TLC detection, after the reaction, cool down to room temperature, filter with diatomaceous earth to obtain the filtrate, and rinse the filtered solid particles with ethyl acetate several times, and combine the rinses into the filtrate , and then distilled by a rotary evaporator to remove tetrahydrofuran and ethyl acetate to obtain a crude product of 3aa. The crude product of 3aa was purified by flash column chromatography to obtain a pure product of 3aa with a yield of 65%. 1 H NMR (600MHz, d 6 -DMSO): δ11.74(s,1H),7.93(d,J=8.2Hz,2H),7.84(d,J=8.3Hz,2H),6.10(s,1H),4.52(s,2H) ,4.11(q,J=7.1Hz,2H),1.17(t,J=7.1Hz,3H).; 13 C NMR (150MHz,...

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Abstract

The invention relates to a preparation method of pyrimidine dione compounds. According to the preparation method, the pyrimidine dione compounds are efficiently synthesized in a solvent by taking cyclic oxime ester compounds and isocyan compounds as reaction raw materials under the protection of inert gases and the catalytic action of univalent silver compounds. The preparation method provided by the invention has the advantages of low price of the raw materials, easy obtaining of the raw materials, short steps, high atom economy (100%) and mild reaction conditions, and can realize large-scale industrial application; by using cyclic oxime ester N-O bond cleavage, the pyrimidine dione compounds are efficiently constructed in one step. The breakthrough progress in chemical synthesis of a system is realized, and the deep expansion of pharmaceutical chemistry studies related to the system is promoted.

Description

technical field [0001] The invention relates to the field of organic compound synthesis, in particular to a preparation method of pyrimidinedione compounds. Background technique [0002] The pyrimidinedione structure widely exists in natural compounds, such as the unique base uracil of RNA. In addition, the pyrimidinedione structure is also the core skeleton of a variety of drug molecules and has unique biological activities, such as anti-metabolism and anti-tumor activity. Drugs - 5-fluorouracil, and zidovudine, the world's first anti-AIDS drug approved by the US FDA. The pyrimidinedione structure is also an important intermediate in organic synthesis, which can be used to synthesize many other organic compounds. [0003] At present, the synthesis methods of pyrimidine diketones mainly include the following two methods: (1) β-ketone esters react with urea under reflux to generate pyrimidine diketones (U.S.PatAppl.Publ.20070048752); [0004] (2) The β-keto ester compound r...

Claims

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Application Information

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IPC IPC(8): C07D239/54C07D239/70C07D403/04C07D405/04C07D409/04C07F9/6512
Inventor 魏晔梁洪文
Owner ARMY MEDICAL UNIV
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