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4-imidazolinone derivative and synthesis method and application of method

A technology of imidazolinone and synthesis method, which is applied in the direction of drug combination, organic chemistry, antineoplastic drugs, etc., can solve the problem of carboxylic acid preactivation, etc., and achieve the effect of short synthesis route, simple operation process and mild reaction

Inactive Publication Date: 2020-08-07
CHONGQING UNIV OF ARTS & SCI
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  • Abstract
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Problems solved by technology

Although these reports are open-ended, for the decarboxylation reaction, it is still necessary to preactivate the carboxylic acid

Method used

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  • 4-imidazolinone derivative and synthesis method and application of method
  • 4-imidazolinone derivative and synthesis method and application of method
  • 4-imidazolinone derivative and synthesis method and application of method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] The chemical structural formula of compound 8a is as follows:

[0071]

[0072] The preparation method of compound 8a is as follows:

[0073] Add 0.50mmol cyclohexanone and 0.50mmol 4-bromoaniline to 1mL methanol, and stir in a 5mL microwave bottle for 10 minutes at room temperature, then add 0.50mmol benzoylformic acid and 0.50mmol benzyl isonitrile successively, and mix the obtained The mixture was stirred overnight at room temperature. After the reaction was complete, the disappearance of the isonitrile was detected by TLC. The reaction mixture was concentrated in vacuo to give the crude product, which was then purified by silica gel chromatography (20% EA / Hex) to give 173 mg of compound 8a as a white solid in 67% calculated yield.

[0074] 1 H NMR (400MHz, CDCl 3 )δ7.78–7.69(m,2H),7.52(t,J=7.4Hz,1H),7.43–7.35(m,6H),7.31–7.26(m,5H),6.76(t,J=5.1Hz ,1H),4.62(d,J=5.6Hz,2H),2.27–2.20(m,2H),1.93–1.86(m,2H),1.53–1.52(m,4H),1.40–1.24(m,2H ). 13 C NMR (101MHz, CDCl...

Embodiment 2

[0076] The chemical structural formula of compound 9a is as follows:

[0077]

[0078] The synthesis of compound 9a in this example is carried out according to the synthetic route of 4-imidazolinone derivatives, wherein, R in compound amine 1 1 is bromine, R in compound ketone 7 2 Is cyclohexyl, Ar in compound oxo acid 3 is phenyl, R in compound isocyanide 4 3 is benzyl. The specific synthesis method, raw material formula and process conditions were carried out according to the synthesis method of the related compound 9, and finally the yellow solid compound 9a was obtained with a yield of 60%.

[0079] 1 H NMR (400MHz, CDCl 3 )δ7.60(d,J=7.6Hz,2H),7.38–7.28(m,8H),7.26–7.25(m,2H),7.14(d,J=8.7Hz,2H),5.08(s,1H ),4.68(s,2H),1.94–1.88(m,2H),1.79–1.70(m,2H),1.41–1.22(m,6H). 13 C NMR (100MHz, CDCl 3 )δ171.9, 145.2, 138.2, 137.8, 132.0, 129.3, 128.6, 128.4, 127.7, 127.3, 127.1, 127.0, 118.4, 81.3, 68.4, 44.5, 36.8, 32.5, 24.1, 22.7, 22.4. calcd for C 27 h 28 BrN 2 o + (...

Embodiment 3

[0081] The chemical structural formula of compound 9b is as follows:

[0082]

[0083] The synthesis of compound 9b in this example is carried out according to the synthetic route of 4-imidazolinone derivatives, wherein, R in compound amine 1 1 is methoxy, R in compound ketone 7 2 Is cyclohexyl, Ar in compound oxo acid 3 is phenyl, R in compound isocyanide 4 3 is benzyl. The specific synthesis method, raw material formula and process conditions were carried out according to the synthesis method of related compound 9, and finally brown oily compound 9b was obtained with a yield of 51%.

[0084] 1 H NMR (400MHz, CDCl 3 )δ7.68(d,J=7.5Hz,2H),7.34–7.30(m,6H),7.27–7.22(m,4H),6.77(d,J=8.8Hz,2H),5.06(s,1H ),4.71–4.54(m,2H),3.74(s,3H),1.82–1.54(m,8H),1.18–1.00(m,2H). 13C NMR (100MHz, CDCl 3 )δ172.9,157.7,139.9,138.6,130.8,128.6,128.2,127.4,127.2,127.0,113.9,81.5,69.9,55.3,44.3,37.6,32.6,24.5,22.5,22.1.HRMS(ESI)m / z calcd C 28 h 31 N 2 o 2 + (M+H) + 427.23800, found 427....

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Abstract

The invention relates to the technical field of organic synthesis, and in particular, relates to a 4-imidazolinone derivative and a synthesis method thereof and an application of the method. Accordingto the synthesis method of the 4-imidazolinone derivative, aldehyde, amine, carbonyl acid and isocyanide are taken as main raw materials, the 4-imidazolinone derivative is prepared through Ugi reaction under a microwave radiation condition, and the method can be used for synthesizing central skeleton spiro imidazolinone analogues in GSK2137305 and SCH900822 compound structures. According to the synthesis method, aldehyde, amine, carbonyl acid and isocyanide are used as the main raw materials, the Ugi reaction is utilized, the reaction is carried out under the microwave radiation condition, nocatalyst is used in the reaction process, the operation is simple, the reaction is mild, and the yield is relatively high. The 4-imidazolinone derivative disclosed by the invention has a certain inhibition effect on liver cancer, colon cancer, cervical cancer and glioma, has antitumor activity and can be used for preparing antitumor drugs.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to 4-imidazolidinone derivatives, their synthesis method and the application of the method. Background technique [0002] 4-Imidazolone derivatives are a very important class of pharmacologically active compounds, which exist in many natural products and drugs, such as (-)-phenylalanine PP, heptacillin, anticonvulsant active compounds, anticonvulsant Malaria drug and selective glucagon receptor antagonist SCH900822, glycine transporter type 1 inhibitor GSK2137305. [0003] [0004] The traditional preparation methods of 4-imidazolinone derivatives often rely on the condensation reaction of α-aminoacetamide derivatives with ketones or aldehydes to directly couple C-N bonds, such as the classic method Curtius rearrangement reaction, Buchwald–Hartwig coupling C(sp 3 )-N bond formation. For several years, decarboxylated C(sp 3 )-N cross-coupling reaction, which extends ...

Claims

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Application Information

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IPC IPC(8): C07D235/02C07D405/04C07D233/32A61P35/00
CPCA61P35/00C07D233/32C07D235/02C07D405/04
Inventor 宋桂廷屈川华丁勇王娟丽黄玖红徐志刚陈中祝
Owner CHONGQING UNIV OF ARTS & SCI
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