Synthetic method of spiro-oxoindole ethylene oxide derivative

A technology of indolinone oxirane and a synthesis method, applied in the direction of organic chemistry and the like, can solve problems such as poor adaptability of substrates, and achieve the effects of mild reaction conditions, simple operation and environmental friendliness

Active Publication Date: 2015-04-29
广东和博制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is that amides must be used to stabilize sulfur ylides during the reaction and improve reactivity.
In addition, in [Chem.Eur.J.2013, 19, 2961-2965], using isatin derivatives and Baylis-Hillman bromide as raw materials, spiro-indolinone was obtained in the presence of dimethyl sulfide and cesium carbonate Ethylene oxide derivatives, but one of the substrates must be limited to Baylis-Hillman bromine, and the configuration must be a Z-type reaction to occur, and the substrate adaptability is not strong

Method used

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  • Synthetic method of spiro-oxoindole ethylene oxide derivative
  • Synthetic method of spiro-oxoindole ethylene oxide derivative
  • Synthetic method of spiro-oxoindole ethylene oxide derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055]

[0056] Add N-methylisatin (0.255mmol), p-tolylcinnamyl sulfide (0.306mmol), CsF (0.383mmol) and 8mL of anhydrous acetonitrile solvent into the reaction flask, stir at 40°C for 5min, and then add Add o-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.765mmol) into the reaction flask, keep stirring at 40°C overnight, and remove the solvent by rotary evaporation at 40-45°C after the reaction to obtain the crude product, which is The pure product was obtained by column chromatography with a solvent with a volume ratio of ethyl acetate:petroleum ether=1:50-1:5, and the structure of the product was shown as cis-4aa and trans-4aa, and the nuclear magnetic resonance 1 H NMR, 13 The C NMR spectra are as follows Figure 4 , Figure 5 As shown, the total yield is 87%, cis / trans=44:56. The product cis-4aa: 1 H NMR (400MHz, CDCl 3 )δ7.49(dd, J=8.3, 2.0Hz, 1H), 7.47-7.42(m, 2H), 7.36-7.29(m, 3H), 7.27(d, J=2.0Hz, 2H), 6.92(d , J=16.2Hz, 1H), 6.80(dd, J=19.2, 8.4Hz, 2H), 4...

Embodiment 2

[0058]

[0059] Add 5-methyl-N-methyl isatin (0.255mmol), p-tolyl cinnamyl sulfide (0.306mmol), CsF (0.383mmol) and 8mL of anhydrous acetonitrile solvent into the reaction flask, at 40°C Stir for 5 minutes, then add o-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.765mmol) into the reaction flask, keep stirring at 40°C overnight, and remove the solvent by rotary evaporation at 40-45°C after the reaction, to obtain crude Product,, the crude product is carried out column chromatography with the solvent that volume ratio is ethyl acetate:petroleum ether=1:50-1:5 and obtains pure product, and product structure is as shown in cis-4ab and trans-4ab, nuclear magnetic resonance 1 HNMR, 13 The C NMR spectra are as follows Figure 6 , Figure 7 As shown, the total yield is 50%, cis / trans=54:46. The product cis-4ab: Yellowish solid. 1 H NMR (400MHz, CDCl 3 ): δppm7.46(d, J=7.2Hz, 2H), 7.34-7.26(m, 3H), 7.17(d, J=8.0Hz, 1H), 6.98(s, 1H), 6.92-6.82(m, 2H), 6.79(d, J=8.0Hz, 1H)...

Embodiment 3

[0061]

[0062] Add 5-methoxy-N-methyl isatin (0.255mmol), p-tolyl cinnamyl sulfide (0.306mmol), CsF (0.383mmol) and 8mL of anhydrous acetonitrile solvent into the reaction flask, at 40 °C Stirring at low temperature for 5min, then adding o-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.765mmol) into the reaction flask, keeping stirring at 40°C overnight, after the reaction was completed, the solvent was removed by rotary evaporation at 40-45°C to obtain The crude product, the crude product is subjected to column chromatography with a volume ratio of ethyl acetate:petroleum ether=1:50-1:5 to obtain pure product, the product structure is shown in cis-4ac and trans-4ac, NMR 1 H NMR, 13 The C NMR spectra are as follows Figure 8 , Figure 9As shown, the total yield is 32%, cis / trans=59:41. Product cis-4ac: 1H NMR (400MHz, CDCl3) δ7.46 (d, J=7.2Hz, 2H), 7.32 (dd, J=14.9 , 7.4Hz, 4H), 6.89(d, J=2.7Hz, 2H), 6.87-6.75(m, 2H), 4.17(d, J=7.6Hz, 1H), 3.81(s, 3H), 3.25(d , J=...

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Abstract

The invention discloses a spiro-indolone ethylene oxide derivative obtained with an o-trimethylsilylphenyl triflate, an N-methyl isatin derivative and aryl thioether as raw materials, CsF as an alkali and an organic solvent as a solvent and through a one-pot method, wherein an active intermediate benzyne is obtained by allowing o-trimethylsilylphenyl triflate to generate 1,2- elimination under fluorinion induction. In the synthetic method, the whole reaction adopts the one-pot method, reaction substrates are friendly to the environment, operations are simple, conditions are mild, product structures are diverse, and the product is widely applied in natural products and clinical medicines.

Description

technical field [0001] The invention belongs to the field of synthetic medicine and chemical industry, and mainly relates to a method for synthesizing potentially biologically active spiro-oxindole oxirane derivatives. Background technique [0002] The spiro-oxindole structure has been found in natural products and clinical drugs, and it has become an important target in organic synthesis due to its good biological activity. For example, spiro-oxindole oxirane derivatives are used as drugs such as diuretics, sedatives and anticonvulsants [(a) Chem.Abstr.1967, 67, 21850a.(b) Chem.Abstr.1969, 70, 47294j.]; It has antifungal, antituberculosis and leukemia cell growth inhibitory activities [(a) Pharmazie.2002, 57, 602. (b) J.Chem.Inf.Comput.Sci.2003, 43, 1652 .]. Synthesizing such molecules is of increasing interest to chemists. [0003] The current synthetic method of this type of compound includes: the addition of carbene or carbene body to ketone, as in [Synlett.2004,4,639...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/107
CPCC07D491/107
Inventor 胡文浩蔡茂强何维杰徐华栋张人伟
Owner 广东和博制药有限公司
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