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Optically active indole derivative, synthetic method and application thereof

A technology of indole derivatives and optical activity, applied in the direction of organic active ingredients, chemical instruments and methods, drug combinations, etc., to achieve the effect of simple and safe operation, high yield, and efficient construction

Inactive Publication Date: 2012-08-01
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, there is no effective method for constructing such compounds with high enantioselectivity (Adv. Synth. Catal. 2011, 353, 2939 – 2944)

Method used

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  • Optically active indole derivative, synthetic method and application thereof
  • Optically active indole derivative, synthetic method and application thereof
  • Optically active indole derivative, synthetic method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] (2-1)

[0044] N-methylindole (0.3 mmol), Rh 2 (OAc) 4 (0.0025 mmol), the chiral small molecule catalyst PPA (0.005 mmol) and 4? molecular sieves (0.1 g) were dissolved in toluene (1 ml), and then, the (0.25mmol,) was added dropwise in the reaction system within 1 hour, and the reaction system was at 0°C. After the dropwise addition was completed, it was stirred for 1 hour, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, which had a structure such as formula (2 -1) as shown. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:100~1:40) to obtain a pure product. The yield was 96%, ee%=92%. nuclear magnetic resonance 1 H NMR, 13 C NMR spectrum as figure 1Shown, product 4a 1H NMR (400MHz, CDCl3) δ (ppm) 3.69 (s, 3H), 3.72 (s, 3H), 5.25 (s, 1H), 7.02-7.07 (m, 2H), 7.17-7.31 ( m, 5H), 7.40-7.45 (m, 3H); 13C NMR (400Hz, CDCl3) δ (ppm) 32.80, 48.87, 52.32, 109.40, 112.14, 119.09...

Embodiment 2

[0046] (2-2)

[0047] N-methylindole (0.3 mmol), (0.3 mmol), Rh 2 (OAc) 4 (0.0025 mmol), the chiral small molecule catalyst PPA (0.005 mmol) and 4? molecular sieves (0.1 g) were dissolved in toluene (1 ml), and then the p-methoxyphenyl Nitroacetic acid methyl ester (0.25mmol,) was added dropwise to the reaction system within 1 hour, and the reaction system was at 0°C. After the dropwise addition was completed, it was stirred for 1 hour, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product with the structure As shown in formula (2-2). The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:100~1:40) to obtain a pure product. The yield was 93%, ee%=89%. nuclear magnetic resonance 1 H NMR, 13 C NMR spectrum as figure 2 As shown, product 4b 1H NMR (400MHz, CDCl3) δ (ppm) 3.69 (s, 3H), 3.71 (s, 3H), 3.73 (s, 3H), 5.19 (s, 1H), 6.81-6.84 (m, 2H), 7.00-7.06 (m, 2H), 7.18 (t, J=7.2Hz, 1H), 7.19-...

Embodiment 3

[0049] (2-3)

[0050] N-methylindole (0.3 mmol), Rh 2 (OAc) 4 (0.0025 mmol), chiral small molecule catalyst PPA (0.005 mmol) and 4? molecular sieves (0.1 g) were dissolved in toluene (1 ml), then, 4-bromophenyldiazo Methyl acetate (0.25mmol,) was added dropwise in the reaction system within 1 hour, and the reaction system was at 0°C. After the dropwise addition was completed, it was stirred for 1 hour, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product whose structure was as follows: Formula (2-3) shows. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:100~1:40) to obtain a pure product. The yield was 95%, ee%=90%. nuclear magnetic resonance 1 H NMR, 13 C NMR spectrum as image 3 Shown, product 4c 1H NMR (400MHz, CDCl3) δ (ppm) 3.80 (s, 3H), 3.81 (s, 3H), 5.28 (s, 1H), 7.11-7.15 (m, 2H), 7.27-7.29 ( m, 1H), 7.34-7.37 (m, 3H), 7.46-7.50 (m, 3H); 13C NMR (400Hz, CDCl3) δ (ppm) 32.8...

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Abstract

The invention discloses a synthetic method for an optically active indole derivative. The method includes steps of choosing diazo compound and indole derivatives as raw materials, rhodium acetate and chiral phosphoric acid as catalyst, an organic solvent as a solvent and 4A molecular sieve as a water absorbent, and obtaining the optically active indole derivative after one-step reaction at the temperature of -10-50 DEG C. The synthetic method for the optically active indole derivative has the advantages of being efficient in atom economy, high in selectivity and yield, low in catalyst dosage, simple and safe to operate, and the like. The optically active indole derivative can be widely applied to the field of pharmaceutical chemicals as an active molecule precursor.

Description

technical field [0001] The invention belongs to the fields of synthetic medicine and chemical industry, and mainly relates to an optically active indole derivative and its synthesis method and application. Background technique [0002] Optically active indole derivatives widely exist in nature and are important skeleton structures for the construction of natural products and drugs. Optically active indole derivatives can also be used in the synthesis of numerous antitumor drugs, antibiotics, and antifungal drugs. Such as UK-350,926, UK-350,862 reported by Pfizer. Currently, there is no effective method for constructing such compounds with high enantioselectivity (Adv. Synth. Catal. 2011, 353, 2939 – 2944). [0003] The invention overcomes the shortcomings in the synthesis method of the prior art, and proposes an optically active indole derivative and its synthesis method and application. The method of the invention has the beneficial effects of simple and easy-to-obtain r...

Claims

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Application Information

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IPC IPC(8): C07D209/24C07D209/18C07D209/22C07D209/30C07D409/06C07F7/10A61K31/405A61K31/695A61P35/00A61P31/00A61P31/10
Inventor 胡文浩邱晃张丹翟昌伟马超群杨琍苹
Owner EAST CHINA NORMAL UNIV
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