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Synthesis method of pyridopyrimidine-2, 4, 5-triketone compound

A pyridopyrimidine and synthetic method technology, which is applied in the field of synthesis of pyridopyrimidine-triketone compounds, can solve the problems of rapid construction and singleness of unfavorable compound libraries, achieve reduced synthesis costs, simple and easy-to-obtain raw materials, and high yield Effect

Active Publication Date: 2021-05-14
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The substituent R on the nitrogen atom in this method 1 and R 2 It needs to be introduced before ring closure, relatively fixed and single, therefore, it is not conducive to the rapid construction of compound libraries

Method used

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  • Synthesis method of pyridopyrimidine-2, 4, 5-triketone compound
  • Synthesis method of pyridopyrimidine-2, 4, 5-triketone compound
  • Synthesis method of pyridopyrimidine-2, 4, 5-triketone compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] Preparation of 1-ethyl-3-benzylpyrido[4,3-d]pyrimidine-2,4,5(1H,3H,6H)-trione (II-1)

[0015]

[0016] 1-Ethyl-3-benzyl-5-methyl-2,4-dioxo-1,3,4,5,7,8-hexahydropyrido[4,3-d]pyrimidine-6 (2H)-tert-butyl carboxylate (I-1a) (0.20g, 0.50mmol) and cerium ammonium nitrate (1.37g, 2.50mmol) were dissolved in 7.40mL mixed solvent (acetonitrile: water=5:1-1:1 ), stirred at room temperature for 2 h, after TLC showed that the reaction was complete, the reaction was quenched by adding saturated aqueous sulfurous acid solution, concentrated under reduced pressure to evaporate the organic solvent, then extracted, dried, concentrated under reduced pressure, and finally purified by column chromatography to obtain a white solid ( 0.12g), yield: 80%. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.54 (s, 1H), 7.37–7.20 (m, 5H), 6.36 (d, J = 9.1Hz, 1H), 5.68 (d, J = 8.4Hz ,1H),5.02(s,2H),4.35–4.18(m,2H),1.17(t,J=7.0Hz,3H).MS(ESI)m / z:298.28[M+H] + .

[0017] 1,5-diethyl-3-benzyl-2,4-dioxo-1,3,...

Embodiment 2

[0020] Preparation of 1-ethyl-3-methylpyrido[4,3-d]pyrimidine-2,4,5(1H,3H,6H)-trione (II-2)

[0021]

[0022] Referring to the synthetic method of I-1, by 1-ethyl-3,5-dimethyl-2,4-dioxo-1,3,4,5,7,8-hexahydropyrido[4,3 -d] pyrimidine-6(2H)-tert-butyl carboxylate (I-2a) (0.16g, 0.50mmol) or 1,5-diethyl-3-methyl-2,4-dioxo-1 , tert-butyl 3,4,5,7,8-hexahydropyrido[4,3-d]pyrimidine-6(2H)-carboxylate (I-2b) (0.17g, 0.50mmol) and ammonium cerium nitrate (1.37g, 2.50mmol) was reacted to obtain a crude product, and then purified by column chromatography to obtain a pure white solid, yield: 75-78%. MS(ESI)m / z:222.12[M+H] + .

Embodiment 3

[0024] Preparation of 1,3-diethylpyrido[4,3-d]pyrimidine-2,4,5(1H,3H,6H)-trione (II-3)

[0025]

[0026] Referring to the synthetic method of I-1, by 1,3-diethyl-5-methyl-2,4-dioxo-1,3,4,5,7,8-hexahydropyrido[4,3 -d] pyrimidine-6(2H)-tert-butyl carboxylate (I-3a) (0.17g, 0.50mmol) or 13,5-triethyl-2,4-dioxo-1,3,4, 5,7,8-hexahydropyrido[4,3-d]pyrimidine-6(2H)-carboxylate tert-butyl ester (I-3b) (0.18g, 0.50mmol) and cerium ammonium nitrate (1.37g, 2.50 mmol) reacted to obtain a crude product, which was then purified by column chromatography to obtain a pure white solid with a yield of 73-76%. MS(ESI)m / z:236.15[M+H] + .

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Abstract

The invention discloses a synthesis method of a pyridopyrimidine-2, 4, 5-triketone compound, which comprises the following steps: dissolving a compound represented by a 1-equivalent formula I in a solvent, adding 1-10 equivalents of ceric ammonium nitrate in batches, and stirring to react after the ceric ammonium nitrate is added; after the reaction is completed, a quenching reaction is conducted, a solvent is removed through concentration and evaporation, then the compound represented by the formula II is obtained through extraction, drying, concentration, chromatography or recrystallization purification in sequence, and the method can efficiently construct a compound library containing a pyridopyrimidine-2, 4, 5-triketone skeleton and is applied to new drug research and development projects.

Description

technical field [0001] The invention relates to a synthesis method of pyridopyrimidine-trione compounds, in particular to a synthesis method of pyridopyrimidine-2,4,5-trione compounds. Background technique [0002] Pyridopyrimidine-2,4,5-trione is an important class of structural skeletons. Compounds containing this skeleton have a wide range of biological activities and can be applied to the research and development of innovative drugs. For example, a class of TRAP1 inhibitors developed by Kumar et al. for the treatment of acute and chronic pain contains a pyridopyrimidine-2,4,5-trione backbone (WO 2010125469). At present, there are relatively few methods for the synthesis of pyridopyrimidine-2,4,5-trione compounds reported in the literature. The main method is to construct pyrimidone through multi-step reactions from intermediates containing pyrimidinedione, such as: The intermediate containing ortho-methyl and nitrile groups is condensed with acetal, and then undergoes r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 孙海鹰马宗辉
Owner CHINA PHARM UNIV