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Optically active 3-substituted indole derivatives as well as synthesis method and application thereof

A technology of indole derivatives and optical activity, applied in drug combination, organic chemistry, anti-tumor drugs, etc., can solve the difficulties in the preparation of chiral catalysts, the limited scope of substrate application, and the unfavorable application of 3-substituted indole derivatives Industrial synthesis and other issues, to achieve the effect of wide application range of substrates, efficient atom economy, and low cost

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

AI Technical Summary

Problems solved by technology

However, in the preparation method of synthesizing 3-substituted indole derivatives in the prior art, there are defects such as difficult preparation of chiral catalysts, simple structure of prepared 3-substituted indole derivatives, and limited scope of substrate application, which are not conducive to optical activity. -Application of substituted indole derivatives in organic synthesis and its industrial synthesis

Method used

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  • Optically active 3-substituted indole derivatives as well as synthesis method and application thereof
  • Optically active 3-substituted indole derivatives as well as synthesis method and application thereof
  • Optically active 3-substituted indole derivatives as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105]

[0106] Cinnamaldehyde (1.0mmol), 1,5-cyclooctadiene iridium chloride dimer (0.05mmol), chiral diphenylprolinol trimethylsilyl ether (0.2mmol), 3,5-bis Trifluoromethylbenzoic acid (0.4mmol) and Molecular sieves (200 mg) were dissolved in 1 mL of dichloromethane to prepare a mixed solution A, which was stirred at 0° C. for 1 hour; methyl phenyldiazoacetate (2.0 mmol), N-methyl-5-chloroindole ( 2.0 mmol) was dissolved in 1 mL of dichloromethane to prepare a mixed solution B; at 0°C, the mixed solution B was added to the aforementioned mixed solution A with a syringe pump, stirred, and reacted. After the diazo decomposition is complete, after the reaction is over, the crude product is subjected to column chromatography (using ethyl acetate:petroleum ether=1:100 as eluent) to obtain a pure product with structures such as formulas (1a) and (1b) As shown, (1a) is methyl (2S,3S-)2-(5-chloro-1-methyl-3-1H-indolyl)-5-oxo-2,3-diphenylpentanoate , (1b) is (2R,3S-)2-(5-chlor...

Embodiment 2

[0116]

[0117] Cinnamaldehyde (1.0mmol), 1,5-cyclooctadiene iridium chloride dimer (0.05mmol), chiral diphenylprolinol trimethylsilyl ether (0.2mmol), 3,5-bis Trifluoromethylbenzoic acid (0.4mmol) and Molecular sieves (200 mg) were dissolved in 1 mL of dichloromethane to prepare a mixed solution A, which was stirred at 0° C. for 1 hour; methyl phenyldiazoacetate (2.0 mmol), N-methyl-5-bromoindole ( 2.0 mmol) was dissolved in 1 mL of dichloromethane to prepare a mixed solution B; at 0°C, the mixed solution B was added to the aforementioned mixed solution A with a syringe pump, stirred, and reacted. After the diazo decomposition is complete, after the reaction is over, the crude product is subjected to column chromatography (using ethyl acetate:petroleum ether=1:100 as the eluent) to obtain a pure product whose structure is as shown in formulas (2a) and (2b) As shown, (2a) is (2S,3S-)2-(5-bromo-1-methyl-3-1H-indolyl)-5-oxo-2,3-diphenylpentanoic acid methyl ester , (2b) is...

Embodiment 3

[0127]

[0128] Cinnamaldehyde (1.0mmol), 1,5-cyclooctadiene iridium chloride dimer (0.05mmol), chiral diphenylprolinol trimethylsilyl ether (0.2mmol), 3,5-bis Trifluoromethylbenzoic acid (0.4mmol) and Molecular sieves (200 mg) were dissolved in 1 mL of dichloromethane to prepare a mixed solution A, which was stirred at 0°C for 1 hour; methyl 4-bromophenyldiazoacetate (2.0 mmol), N-methylindole (2.0 mmol) was dissolved in 1 mL of dichloromethane to prepare a mixed solution B; at 0° C., add the mixed solution B to the aforementioned mixed solution A with a syringe pump, stir and react. After the diazo decomposition is complete, after the reaction is over, the crude product is subjected to column chromatography (using ethyl acetate:petroleum ether=1:100 as the eluent) to obtain a pure product whose structure is as shown in formulas (3a) and (3b) As shown, (3a) is (2S,3S-)-2-(4-bromophenyl)-2-(1-methyl-3-1H-indolyl)-5-oxo-3-phenyl Methyl valerate, (3b) as (2R,3S-)-2-(4-brom...

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Abstract

The invention discloses optically active 3-substituted indole derivatives as well as a synthesis method and an application thereof. The optically active 3-substituted indole derivatives are with structures as shown in a formula (Ia) and a formula (Ib). The target products which are the optically active 3-substituted indole derivatives are prepared through one-step reaction at the temperature of 0-40 DEG C, wherein the raw materials include a diazo compound, an indole derivative and an alpha, beta-unsaturated aldehyde, the water absorbent is a 4-angstrom molecular sieve, the catalysts include a metal catalyst, chiral diaryl prolinol silicon ether and substituted benzoic acid, and the solvent is an organic solvent. The synthesis method disclosed by the invention has the advantages of high atom economy, high selectivity, high yield and mild reaction condition and is easy and safe to operate. The pair of optically active 3-substituted indole derivatives has high enantioselectivity and bioactivity and can be used for preparing antitumor medicines.

Description

technical field [0001] The invention belongs to the field of synthetic medicine and chemical industry, and mainly relates to an optically active 3-substituted indole derivative and its chemical synthesis method and application. Background technique [0002] At present, the research on indole chemistry is one of the most active fields in heterocyclic chemistry. Among the more than 3,000 known natural indole derivatives, more than 40 are therapeutic drugs. Among them, 3-substituted indole derivatives Occupy a certain proportion. Lysergic acid diethylammonium is the most powerful hallucinogen known; brazil is a phytoalexin that can be used as a defensive drug against microbial attack; vincristine is a bis-indole alkaloid that resists Tumor targets are microtubules, which are very useful in the treatment of tumors. At the same time, they are important structural units for the synthesis of many bioactive compounds and natural products, so the asymmetric synthesis of 3-substitut...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/24A61P35/00
CPCC07D209/24
Inventor 胡文浩李明凤金伟峰刘顺英
Owner 广东和博制药有限公司
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