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Chiral spiro [3,2'] pyrrolidine oxoindole skeleton compound, preparation method and application thereof, intermediate and preparation method thereof

A technology of skeleton compound and indole oxide, applied in the field of medicine and chemical industry, can solve the problems of short synthesis route, high reaction yield, difficult to satisfy, etc., and achieve the effects of improving utilization rate and simple and efficient operation process

Active Publication Date: 2020-05-19
CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] In summary, no matter it is Method A, Method B or Method C, there are unique defects in the method itself, and it is difficult to meet the requirements of short synthetic route, cheap and easy-to-obtain raw materials, strong practicability, and high reaction yield, especially in the synthesis of synthetic methods. The method of epoxidizing indole with spiro[3,2']pyrrole is difficult to meet the above requirements

Method used

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  • Chiral spiro [3,2'] pyrrolidine oxoindole skeleton compound, preparation method and application thereof, intermediate and preparation method thereof
  • Chiral spiro [3,2'] pyrrolidine oxoindole skeleton compound, preparation method and application thereof, intermediate and preparation method thereof
  • Chiral spiro [3,2'] pyrrolidine oxoindole skeleton compound, preparation method and application thereof, intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] This example provides a 3-ketoiminooxindole derivative (1a) and its preparation method:

[0084]

[0085] The specific preparation process is called:

[0086] 1.5g (8.15mmol) white crystals of 3-aminoindole hydrochloride (5a R 1 , R 2 , R 3 =H) Place in a 100mL single-necked flask, add 30mL of dichloromethane, and slowly drop in 1.62g (8.97mmol) of benzophenone imine under the vigorous stirring of a magnet, and add it completely in about 10 minutes. After reacting overnight, the system turned reddish, and white solid ammonium chloride was formed. TLC detected that the raw material (5a) had reacted completely, and the ammonium chloride was removed by filtration under reduced pressure. The solvent was removed by rotary evaporation, a mixed solvent of ethyl acetate / petroleum ether=1:4 was added, and heated to reflux to remove excess benzophenone imine and a small amount of benzophenone. After the system was cooled, the light red solid obtained by direct filtration w...

Embodiment 2

[0089] This example provides a 3-ketoiminooxindole derivative (1b) and its preparation method:

[0090] The specific preparation method is: the R in the raw material 5a in the embodiment 1 1 Substrate 1b can be obtained by changing to benzyl and other conditions unchanged.

[0091] Substrate 1b 1 H NMR (400MHz, CDCl 3 ) spectra are: δ7.67(d,J=7.4Hz,2H), 7.61–7.42(m,6H),7.40(t,J=7.2Hz,1H),7.35–7.20(m,9H),7.17( t,J=7.7Hz,1H),7.11(d,J=7.2Hz,1H),7.00(t,J=7.5Hz,1H),6.72(d,J=7.8Hz,1H),5.21(s, 1H), 4.92(dd, J=97.9, 15.7Hz, 2H).13C NMR (101MHz, CDCl3) δ174.48(s), 174.01(s), 143.46(s), 139.39(s), 135.78(d, J=15.2Hz), 130.57(s), 129.10(d, J=9.4Hz), 128.74(dd, J=9.9, 6.2Hz), 128.38(s), 128.03(s), 127.49(d, J=19.3 Hz), 124.61(s), 122.67(s), 109.22(s), 77.28(d, J = 11.5Hz), 77.02(s), 76.70(s), 64.71(s), 44.09(s).)

Embodiment 3

[0093] Chiral spiro imine compound shown in formula (3) and preparation method thereof:

[0094]

[0095] The specific reaction process is:

[0096] Add benzophenone-protected 3-aminooxindole (1a)R to the reaction test tube 1 , R 2 , R 3 , R 4 , R 5 =H 327 mg (0.1 mmol), 20% cat1 and 1 mL of dichloromethane (solvent 1). Stir at room temperature for 5 min. Then 84 mg (0.15 mmol) of acrolein were added. After 12 h of reaction, TLC detected that the reaction was complete. Through column separation (PE / EA=4:1 silica gel column), the obtained product 2 was dissolved in 2mL THF, 0.5mL of 10% citric acid aqueous solution was stirred at room temperature for 1h, and the reaction of raw materials was detected to be completely separated through column separation with a yield of 71.3%. The chiral spiro imine compound 3a was obtained with 61.2% ee value.

[0097] Chiral imine intermediate 3a 1 H NMR (300MHz, DMSO) spectrum: δ10.48(s, 1H), 7.88(s, 1H), 7.84–6.44(m, 4H), 3.41(s,...

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Abstract

The invention provides a chiral spiro [3,2'] pyrrolidine oxoindole skeleton compound, and the chiral spiro [3,2'] pyrrolidine oxoindole skeleton compound has good anti-inflammatory, antibacterial andanti-tumor biological activity; meanwhile, the skeleton compound also contains a prolinamide skeleton structure, is easy to modify, and is a potential chiral ligand and chiral catalyst. The inventionalso provides a preparation method of the chiral spiro [3,2'] pyrrolidine oxoindole skeleton compound, wherein the method can simultaneously meet the requirements of short synthesis route, cheap and easily available raw materials, strong practicability, high reaction yield and the like, and has good popularization and application prospects. The invention further provides an intermediate for preparing the chiral spiro [3,2'] pyrrolidine oxoindole skeleton compound and application of the chiral spiro [3,2'] pyrrolidine oxoindole skeleton compound.

Description

technical field [0001] The present invention relates to the field of medicine and chemical industry, in particular to a chiral spiro 3,2'-pyrrolidinoxindole skeleton compound, a preparation method and application, an intermediate and a preparation method. Background technique [0002] In the early 21st century, in the field of medicinal chemistry, it was discovered that compounds with pyrrolidine spiroepoxidized indole skeleton structure (shown in the following formula a ~ formula e) have good anti-inflammatory, antibacterial and anti-tumor biological activities (New J.Chem ., 2018, 42, 20024). [0003] [0004] Physiologically active compounds of formula a to formula e containing pyrrolidine spiroepoxide indole skeleton [0005] The pyrrolidine spirooxindole skeleton is divided into two types: spiro[3,3’]pyrroleepoxindole and spiro[3,2’]pyrroleepoxindole. In the past ten years, medicinal chemists have extensively tested the physiological activity of compounds containin...

Claims

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Application Information

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IPC IPC(8): C07D487/10C07D209/40A61P29/00A61P31/00A61P35/00B01J31/22C07B53/00
CPCC07D209/40C07D487/10A61P29/00A61P31/00A61P35/00C07B53/00B01J31/2217B01J31/184C07B2200/07Y02P20/55
Inventor 王立新黄志诚田芳邹滢宋祥家
Owner CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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