A kind of synthetic method of chiral 3,3-disubstituted indol-2-one derivatives

A synthetic method and a disubstitution technique, which are applied in the field of synthesis of chiral 3,3-disubstituted indol-2-one derivatives, can solve the problems of insufficient universality of substrates and insufficient enantioselectivity. Achieve the effects of cheap and easy-to-obtain reaction reagents, high enantioselectivity, and wide adaptability

Active Publication Date: 2021-10-08
SHANGHAI UNIV OF ENG SCI
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Problems solved by technology

The common point of these three methods is that indol-2-one is used as the acceptor of nucleophilic reaction, some substrates are not universal enough, and some enantioselectivity is not high enough

Method used

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  • A kind of synthetic method of chiral 3,3-disubstituted indol-2-one derivatives
  • A kind of synthetic method of chiral 3,3-disubstituted indol-2-one derivatives
  • A kind of synthetic method of chiral 3,3-disubstituted indol-2-one derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1

[0032]

[0033] Add catalyst V-a (9.56 mg, 0.04 mmol), trichloroacetic acid (6.56 mg, 0.04 mmol), 3-methylindol-2-one I-a (29.4 mg, 0.2 mmol), trans -2-butenal II-a (42mg, 0.6mmol), toluene (0.4mL), stirred at room temperature for 18h, quenched with water, extracted 3 times with dichloromethane, washed with saturated brine, and dried the organic layer with anhydrous sodium sulfate , after concentration, add 0.8mL methanol, add NaBH in batches under ice-cooling 4 (15.2mg, 0.4mmol), reacted for 30min, added 1mL saturated ammonium chloride solution, extracted 3 times with ethyl acetate, washed with saturated sodium chloride, dried the organic layer with anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography Product 1, IV-a (39.0 mg, 89%) was obtained, 1 HNMR (400MHz, CDCl3) δ8.60 (s, 1H), 7.24-7.14 (m, 2H), 7.02 (t, J = 8.0Hz, 1H), 6.91.

[0034] (d,J=8.0Hz,1H),3.72(m,1H),3.59(m,1H),2.15–2.03(m,1H),1.90–1.82 (...

Embodiment 2

[0050]

[0051] The difference from Example 1 is that the substrate used to replace trans-2-butenal is trans-2-hexenal II-b (0.6mmol, 59mg), other reaction conditions and operating steps and examples 1, the white solid product IV-b (33.1 mg, 67%) was obtained, 1 H NMR (400MHz, CDCl3) δ8.15(s, 1H), 7.21(t, J=8.0Hz, 2H), 7.02(t, J=8.0Hz, 1H), 6.89(d, J=4.0Hz, 1H ),3.70–3.65(m,1H),3.61–3.54(m,1H),1.93-1.89(m,2H),1.60–1.50(m,1H),1.42(s,3H),1.32-1.26(m ,3H), 1.11-1.04(m,1H),0.81(t,J=4.0Hz,3H).13C NMR(100MHz,CDCl3)δ182.9,140.3,134.3,127.7,123.6,122.4,109.6,62.4,52.0, 41.5, 33.9, 33.6, 22.5, 21.7, 14.4. HPLC analysis conditions: Daicel CHIRALPAK ICcolumn, 254nm, n-hexane / i-PrOH=85 / 15, 1.0 ml / min, 10.4min(minor), 18.8min(major) , 82% ee.

Embodiment 3

[0053]

[0054] The difference from Example 1 is that the substrate used to replace 3-methylindolin-2-one is 3-benzylindolin-2-one I-b (0.2mmol, 44.6mg), and other reactions The conditions and operating steps were the same as in Example 1, and the white solid product IV-d (44.9 mg, 76%) was obtained, 1H NMR (400MHz, CDCl3) δ7.46 (s, 1H), 7.30 (d, J=8.0Hz, 1H),7.14-7.09(m,1H),7.04(dd,J=8.0,4.0Hz,1H),7.02–6.96 (m,3H),6.82(dd,J=8.0,4.0Hz,2H),6.60 (d,J=8.0Hz,1H),3.79-3.73(m,1H), 3.67-3.61(m,1H),3.21(q,J=12.0Hz,2H),2.31-2.20(m,1H), 2.02–1.93(m,1H), 1.55-1.46(m,1H),0.92(d,J=8.0Hz,3H).13C NMR(100MHz,CDCl 3 )δ180.4, 141.0, 136.1, 130.8, 129.9, 127.8, 127.5, 126.2, 124.4, 121.9, 109.1, 61.2, 58.3, 41.4, 36.9, 34.2, 14.4. PrOH=82 / 18, 1.0ml / min, 7.5min(minor), 15.0min(major), 86%ee.

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Abstract

The invention relates to a synthesis method of a chiral 3,3-disubstituted indole-2-one derivative, comprising the following steps: mixing an organic small molecule catalyst chiral camphorsulfonyl hydrazide, an organic acid and an organic solvent, and stirring evenly Then, add α, β-unsaturated aldehyde and 3-substituted indole-2-ketone successively, react while stirring until the reaction is completed, then quench and extract successively to obtain the crude product, add sodium borohydride for reduction, and then silica gel Purify by column chromatography to obtain the chiral 3,3-disubstituted indol-2-one derivative. Compared with the prior art, the present invention uses simple and easy-to-obtain chiral camphorsulfonyl hydrazide and organic acid as a catalyst, and in the presence of an organic solvent, 3-substituted indole-2-ketone reacts with α, β-unsaturated aldehyde compound by Michael The addition reaction forms the corresponding 3,3 disubstituted indole-2-one compounds, the reaction conditions are mild, the environment is friendly, the reaction reagent is cheap and easy to obtain, the reaction substrate range is wide, and the enantioselectivity is high.

Description

technical field [0001] The invention relates to the technical field of organic chemical pharmaceutical intermediates, in particular to a synthesis method of chiral 3,3-disubstituted indol-2-one derivatives. Background technique [0002] Asymmetric catalysis is one of the hottest fields in organic synthesis today, because it is the most important means and the most challenging synthetic method to obtain monochiral products. Asymmetric catalysis mainly includes three aspects: organic small molecule catalysis, metal-organic ligand catalysis and biological enzyme catalysis. In recent years, organic small molecule catalysis has become an important pillar in asymmetric catalysis with its own advantages. [0003] 3,3-disubstituted indol-2-one derivatives widely exist in many natural products and drug molecules, and have good biological activity. Therefore, the synthesis of 3,3-disubstituted indol-2-one derivatives is of great significance in many chemical fields such as organic s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/34
CPCC07D209/34
Inventor 陈玲艳程文富徐方方
Owner SHANGHAI UNIV OF ENG SCI
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