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A kind of oxindole spirocyclopropane derivative and its synthetic method

A technology of oxindole spirocyclopropane and its synthesis method, which is applied in the field of oxindole spirocyclopropane derivatives and their synthesis, can solve the problems of limited types of substituents, and achieve good stability, rich types, and easy-to-obtain raw materials Effect

Active Publication Date: 2016-06-29
TAIYUAN UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in this report, the types of substituents on the quaternary carbon atoms are very limited

Method used

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  • A kind of oxindole spirocyclopropane derivative and its synthetic method
  • A kind of oxindole spirocyclopropane derivative and its synthetic method
  • A kind of oxindole spirocyclopropane derivative and its synthetic method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Synthesis of oxindole spirocyclopropane derivatives, R in the general structural formula 1 = Ph, R 2 =OEt, R 3 = H, R 4 = Ph, R 5 =Bn.

[0036]

[0037] In a 25mL schlenk bottle with a magnetic stirring bar, add 1.5mL dichloromethane, α-ketoester (R 1 = Ph, R 2 =OEt) 36mg (0.20mmol) and α, β-unsaturated oxindole compound (R 3 = H, R 4 = Ph, R 5 =Bn) 71mg (0.21mmol), the resulting reaction mixture was placed at -78°C and stirred for 10 minutes, then 38μL (0.21mmol) of hexamethylphosphorous triamide diluted with 0.5mL of dichloromethane, the concentration was 0.42mol / L, added dropwise to the above reaction mixture within 5 minutes. After the dropwise addition, the reaction was slowly warmed up to room temperature and continued to stir for 22 hours. After the reaction was completed, the solvent was removed by rotary evaporation. The target compound of oxindole spirocyclopropane was obtained by analysis and purification, the eluent was petroleum ether (boiling ...

Embodiment 2

[0040] Synthesis of oxindole spirocyclopropane derivatives, R in the general structural formula 1 = Ph, R 2 =OEt, R 3 =5-Me,R 4 = Ph, R 5 =Bn.

[0041]

[0042] The synthetic steps are basically the same as in Example 1, and the difference is listed as follows:

[0043] The α,β-unsaturated oxindole compound R used 3 =5-Me,R 4 = Ph, R 5 =Bn, the dosage was 75 mg (0.21 mmol), the reaction time at room temperature was 24 hours, and 102 mg of pure light yellow solid was obtained with a yield of 99%.

[0044] 1 HNMR (400MHz, CDCl 3 )δ8.30(d, J=7.4Hz, 2H, ArH), 7.63(t, J=7.4Hz, 1H, ArH), 7.53(t, J=7.4Hz, 2H, ArH), 7.33-7.18(m ,8H,ArH),7.09(d,J=7.4Hz,2H,ArH),6.94(d,J=7.9Hz,1H,ArH),6.68(d,J=7.9Hz,1H,ArH),6.42( s,1H,ArH),5.12(d,J=15.8Hz,1H,1 / 2Ph CH 2 ), 4.91 (d, J=15.8Hz, 1H, 1 / 2Ph CH 2 ),4.50(s,1H,CH),4.26-4.12(m,2H,OCH 2 ),2.09(s,3H,CH 3 ), 1.23(t, J=7.1Hz, 3H, OCH 2 CH 3 ); HRMS-ESI([M+H] + )CalcdforC 34 h 30 NO 4 516.2169, found 516.2180.

Embodiment 3

[0046] Synthesis of oxindole spirocyclopropane derivatives, R in the general structural formula 1 = Ph, R 2 =OEt,R 3 =5-MeO, R 4 = Ph, R 5 =Bn.

[0047]

[0048] The synthetic steps are basically the same as in Example 1, and the difference is listed as follows:

[0049] The α,β-unsaturated oxindole compound R used 3 =5-MeO, R 4 = Ph, R 5 =Bn, the dosage is 77mg (0.21mmol), the reaction mixture was stirred at -70°C for 15 minutes, the phosphorus reagent was added dropwise within 15 minutes, and the reaction time at room temperature was 21 hours to obtain 102mg of white solid pure product, the yield was 96% .

[0050] 1 HNMR (400MHz, CDCl 3 )δ8.29(d, J=8.4Hz, 2H, ArH), 7.64(t, J=7.3Hz, 1H, ArH), 7.54(t, J=7.7Hz, 2H, ArH), 7.28-7.18(m ,8H,ArH),7.10(d,J=7.1Hz,2H,ArH),6.72-6.65(m,2H,ArH),6.26(brs,1H,ArH),5.11(d,J=15.8Hz,1H ,1 / 2Ph CH 2 ), 4.90 (d, J=15.8Hz, 1H, 1 / 2Ph CH 2 ),4.52(s,1H,CH),4.30-4.13(m,2H,OCH 2 ),3.46(s,3H,OCH 3 ), 1.24(t, J=7.1Hz, 3H, OCH 2 CH ...

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Abstract

The invention discloses an oxindole spiro-cyclopropane derivative and a synthetic method thereof and belongs to the technical field of organic synthesis. Alpha-keto ester and an alpha,beta-unsaturated oxindole compound react under the promotion of a phosphorus reagent to obtain the oxindole spiro-cyclopropane derivative. Used raw materials are simple, easy to obtain and good in stability; the synthetized oxindole spiro-cyclopropane derivative contains multiple quaternary carbon centers, and substituent groups on quaternary carbon atoms are rich in kind and can be transformed flexibly; the synthetized compound has the potential drug activity, and a candidate compound is provided for design, synthesis and development of novel drug molecules which contain oxindole spiro-cyclopropane structures.

Description

technical field [0001] The invention relates to an oxindole spirocyclopropane derivative and a synthesis method thereof, belonging to the technical field of organic synthesis. Background technique [0002] 3,3'-spirooxindole compounds widely exist in natural products and pharmaceuticals, and the efficient synthesis of these compounds has attracted strong research interest of organic chemists. Oxindole spirocyclopropane derivatives represent an important class of 3,3'-spirooxindole compounds that possess a wealth of pharmaceutical activities, such as anticancer activity (Sampson, P.B.; et al. U.S. Patent WO2010 / 115279A1, 2010; Pauls, H.W.; etal.U.S.PatentWO2012 / 048411A1, 2012), and has good curative effect on obesity and diabetes (Chen, L.; etal.U.S.PatentWO2011 / 070039A1, 2011), and can be used as HIV-1 non-nuclear Glycoside reverse transcriptase inhibitors (He, Y.; etal. Bioorg. Med. Chem. Lett. 2006, 16, 2105-2108; U.S. Patent WO2004 / 037247A1, 2004); in addition, this type...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/96C07D401/06
CPCC07D209/96C07D401/06
Inventor 周荣刘蓉芳孙文阳李瑞丰
Owner TAIYUAN UNIV OF TECH
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