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Chiral spiro-oxindole constructed by three-step relay catalysis, as well as synthesizing method and application thereof

A technology of spiro-epoxy indole and synthesis method, which is applied in organic chemistry, drug combination, anti-infective drugs, etc., can solve the problems that chiral spiro-epoxindole has not been realized and has not been reported in any literature, and achieves high Yield enantioselectivity, high yield and enantioselectivity, simple and convenient operation

Active Publication Date: 2016-04-13
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the construction of chiral spirooxindole through this synthetic strategy has not been realized, nor has any literature report

Method used

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  • Chiral spiro-oxindole constructed by three-step relay catalysis, as well as synthesizing method and application thereof
  • Chiral spiro-oxindole constructed by three-step relay catalysis, as well as synthesizing method and application thereof
  • Chiral spiro-oxindole constructed by three-step relay catalysis, as well as synthesizing method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051]

[0052] Add 10% Pd / C (8.4mg, 10wt%), nitro compound 1a (84.4mg, 0.3mmol) and Et in the 5.0mL reaction flask successively 2 O (1mL), then stirred at room temperature under hydrogen atmosphere for 3h, then added p-TsOH (2.1mg, 4mol%), isatin 2a (58.0mg, 1.2eq) and additive MS (100mg, 120wt%), then stirred at 60°C for 6h, cooled to room temperature, first added Et 2 O (2mL), followed by chiral catalyst IC 1 (17.8mg, 10mol%), followed by stirring at 40°C for 2d, and finally direct column chromatography with eluent (petroleum ether / acetone=6:1). The target compound 3a was obtained as 100.6 mg of white solid with a yield of 85%. [α] 25 D =-90.3 (c=1.0, CHCl 3 ); 92% ee. (Chiralcel AS column, 85:15 n-hexane:isopropanol). 1 HNMR (400MHz, CDCl 3 ): δ7.63(d, J=7.6Hz, 1H), 7.34(td, J=7.6Hz, J1.2Hz, 1H), 7.23-7.17(m, 2H), 6.98-6.91(m, 2H), 6.85(d, J=7.6Hz, 1H), 6.78(d, J=8.0Hz, 1H), 4.24-4.09(m, 4H), 4.01-3.97(m, 1H), 3.19(s, 3H), 1.22 (t, J=7.2Hz, 3H), 1.03(t, J=7.2...

Embodiment 2

[0054]

[0055] Add Na to the 5.0mL reaction flask in sequence 2 S (4.7mg, 20mol%), nitro compound 1b (76.0mg, 0.3mmol) and toluene (1mL), then stirred at room temperature under hydrogen atmosphere for 3h, then added p-TsOH (2.1mg, 4mol%), isatin 2a (58.0mg, 1.2eq) and additive P 2 o 5 (100mg, 120wt%), then stirred at 40°C for 6h, cooled to room temperature, first added toluene (2mL), then added the chiral catalyst IC 4 (16.4mg, 10mol%), followed by stirring at 40°C for 2d, and finally direct column chromatography with eluent (petroleum ether / acetone=6:1). The target compound 3b was obtained as 83.5 mg of white solid with a yield of 76%. [α] 25 D =-95.3 (c=1.0, CHCl 3 ); 92% ee. (Chiralcel AD column, 80:20 n-hexane:isopropanol). 1 HNMR (400MHz, CDCl 3 ): δ7.60(d, J=7.6Hz, 1H), 7.35(td, J=7.6Hz, J=1.2Hz, 1H), 7.22(td, J=7.6Hz, J=1.2Hz, 1H), 7.13(d, J=7.6Hz, 1H), 7.00-6.92(m, 2H), 6.87(d, J=8.0Hz, 1H), 6.80(d, J=8.0Hz, 1H), 4.19(s, 1H ), 3.76(s, 3H), 3.59(s, 3H), 3...

Embodiment 3

[0057]

[0058] Add 10% Pd / C (8.4mg, 10wt%), nitro compound 1a (84.4mg, 0.3mmol) and CH 2 Cl 2 (1mL), then stirred at room temperature under hydrogen atmosphere for 3h, then added HOAc (1.8mg, 10mol%), isatin 2b (64.5mg, 1.2eq) and additive MgSO 4 (100mg, 120wt%), then stirred at 80°C for 3h, cooled to room temperature, added CH 2 Cl 2 (2mL), after adding the chiral catalyst IC 2 (18.0mg, 10mol%), followed by stirring at 40°C for 2d, and finally direct column chromatography with eluent (petroleum ether / acetone=6:1). The target compound 3c was obtained as 100.2 mg of white solid with a yield of 81%. [α] 25 D =-133.6 (c=1.0, CHCl 3 ); 92% ee. (Chiralcel AD column, 80:20 n-hexane:isopropanol). 1 HNMR (400MHz, CDCl 3 ): δ7.62(d, J=7.6Hz, 1H), 7.22(td, J=7.6Hz, J=0.8Hz, 1H), 7.05(td, J=8.4Hz, J=2.4Hz, 1H), 6.99(dd, J=8.4Hz, J=2.4Hz, 1H), 6.94(t, J=7.2Hz, 1H), 6.80-6.76(m, 2H), 4.24-4.14(m, 4H), 4.09-4.05 (m, 1H), 3.18(s, 3H), 1.23(t, J=7.2Hz, 3H), 1.09(t, J=7.2Hz, 3H...

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Abstract

The invention relates to a method for synthesizing chiral spiro-oxindole constructed by three-step relay catalysis. The target product chiral spiro-oxindole is synthesized by sequentially conducting a catalyst IA catalyzed nitro-reduction reaction, a catalyst IB catalyzed imine formation reaction and a catalyst IC catalyzed asymmetric catalysis reaction by using a nitro-compound as a raw material. The method adopts a reaction system of one-pot method and three-step relay catalysis which are serially connected, and starts from simple raw materials by means of simple operations, so that separation purification of intermediate can be avoided, and thus the chiral spiro-oxindole compound with high yield and high enantioselectivity is synthesized. The chiral spiro-oxindole has a structure as shown in a formula (3), and has excellent anti-malarial drug activity.

Description

technical field [0001] The invention belongs to the technical field of organic compound process application, and specifically relates to a three-step relay catalytic construction of chiral spiro-epoxy indole and its synthesis method and application. Background technique [0002] An important international frontier research field of organic chemistry is to explore the conversion of simple and cheap raw materials into target compounds in a high-yield and high-selectivity manner under environmentally friendly conditions, in an atomic economics manner, and to minimize waste emissions. In order to realize the greening of chemical reactions, chemists have proposed a variety of catalyst-promoted synthesis strategies for cascade reactions, which stand out for their unique advantages and become a rapidly developing research field. The advantages of this strategy for organic synthesis are mainly manifested in: (1) The intermediates do not need to be separated and can be directly used ...

Claims

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Application Information

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IPC IPC(8): C07D487/10C07D471/20A61P33/06
Inventor 周剑尹小平
Owner EAST CHINA NORMAL UNIV
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