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Chiral 2,3-dihydropyrrole[1,2-a] indole derivatives with biological activity and asymmetric synthesizing method thereof

A kind of indole derivatives, biological activity technology, applied in the field of chirality 2

Inactive Publication Date: 2013-03-13
HUAZHONG NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the one-step synthesis of chiral polycyclic indole compounds based on the tandem strategy of indole C2 and N1 nucleophilicity has not been reported in the literature.

Method used

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  • Chiral 2,3-dihydropyrrole[1,2-a] indole derivatives with biological activity and asymmetric synthesizing method thereof
  • Chiral 2,3-dihydropyrrole[1,2-a] indole derivatives with biological activity and asymmetric synthesizing method thereof
  • Chiral 2,3-dihydropyrrole[1,2-a] indole derivatives with biological activity and asymmetric synthesizing method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Compound I-1

[0020] preparation of

[0021] At room temperature, metal catalyst copper trifluoromethanesulfonate (7.23 mg, 0.02 mmol) and ligand IV (6.61 mg, 0.02 mmol) were stirred for 1 hour under nitrogen protection, and then unsaturated ketoester III-1 (R 3 = phenyl, R 4 = methyl) (76mg, 0.40mmol), after continuing to stir at room temperature for 10 minutes, the system was cooled in a reaction bath at 0°C for 20 minutes, and indole II-1 (R 1 = Hydrogen, R 2 =methyl) (55mg, 0.42mmol) was added to the reaction system, and the reaction mixture continued to react at 0°C until TLC detected that the reaction was complete. 石油醚 / V 乙酸乙酯 =15:1~7:1 column chromatography directly obtained 122 mg of the target product of formula I, with a yield of 95%.

[0022] 1 H NMR (400 MHz, CDCl 3 )δ (ppm) 7.48 (dd, J=5.2, 3.4 Hz, 1H), 7.36-7.33 (m, 3H), 7.30-7.26 (m, 3H), 7.16-7.11 (m, 2H), 4.69 (s, 1H), 4.61-4.57(m, 1H), 3.80(s, 3H), 3.50(dd, J=13.8, 9.0 Hz, 1H), 2.72(dd, J=13...

Embodiment 2

[0029] Compound I-2

[0030] preparation of

[0031] At room temperature, metal catalyst copper trifluoromethanesulfonate (7.23mg, 0.02mmol) and ligand IV (6.61mg, 0.02mmol) were stirred under nitrogen protection for one hour, and then unsaturated ketoester III-2 (R 3 = phenyl, R 4 =ethyl) (82mg, 0.40mmol), after continuing to stir at room temperature for 10 minutes, the system was cooled in a reaction bath at 0°C for 20 minutes, and indole II-1 (R 1 = Hydrogen, R 2 =methyl) (55mg, 0.42mmol) was added to the reaction system, and the reaction mixture continued to react at 0°C until TLC detected that the reaction was complete. 石油醚 / V 乙酸乙酯 =15:1~7:1 column chromatography directly obtained 125 mg of the target product of formula I, with a yield of 93%.

[0032] 1 H NMR (400 MHz, CDCl 3 )δ (ppm) 7.49-7.47 (m, 1H), 7.34-7.25 (m, 6H), 7.13-7.10 (m, 2H), 4.72 (s, 1H), 4.58 (t, J = 7.8 Hz, 1H) , 4.33-4.27(m, 1H), 4.25-4.18(m, 1H), 3.51(dd, J=13.7, 9.1 Hz, 1H), 2.70(dd, J=13.7...

Embodiment 3

[0039] Compound I-3

[0040] preparation of

[0041] At room temperature, metal catalyst copper trifluoromethanesulfonate (7.23mg, 0.02mmol) and ligand IV (6.61mg, 0.02mmol) were stirred for one hour under nitrogen protection, and then unsaturated ketoester III-3 (R 3 = phenyl, R 4 = benzyl) (107mg, 0.40mmol), after continuing to stir at room temperature for 10 minutes, the system was cooled in a reaction bath at 0°C for 20 minutes, and indole II-1 (R 1 = Hydrogen, R 2 =methyl) (55mg, 0.42mmol) was added to the reaction system, and the reaction mixture continued to react at 0°C until TLC detected that the reaction was complete. 石油醚 / V 乙酸乙酯 =15:1~7:1 column chromatography directly obtained 146 mg of the target product of formula I, with a yield of 92%.

[0042] 1 H NMR (400MHz, CDCl 3 )δ (ppm) 7.48 (d, J = 7.3 Hz, 1H), 7.34-7.32 (m, 4H), 7.28-7.24 (m, 5H), 7.14-7.05 (m, 4H), 5.26 (d, J = 12.2 Hz, 1H), 5.13(d, J=12.3Hz, 1H), 4.67(s, 1H), 4.58-4.54(m, 1H), 3.48(dd, J=13...

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Abstract

The invention relates to chiral 2,3-dihydropyrrole[1,2-a] indole derivatives with a biological activity and an asymmetric synthesizing method thereof. The derivatives have a structure of a general formula I, in which R1 is hydrogen, 6-methyl, 7-methyl, 8-methyl, 7-methoxyl, 6-fluorine, 6-chlorine, 7-fluorine, 7-chlorine, 7-bromine or 7-benzyloxyl; R2 is methyl, ethyl, isopropyl, cyclohexyl, phenyl, benzyl, dimethyl tertiary butyl siloxy ethyl, benzosuccinimide ethyl or CH2CO2Me; R3 is phenyl, 4-methyl phenyl, 4-methoxyl phenyl, 4-fluorophenyl, 4-chlorphenyl, 4-bromophenyl, 3-bromophenyl, 2-fluorophenyl, 2-thienyl, styryl, ester group or cyclohexyl; and R4 is methyl, ethyl, isopropyl or benzyl. The derivatives are synthesized by Michael-semiacetalation cascade reaction of 3-substituted indole and beta, gamma-unsaturated alpah-keto ester catalyzed by copper trifluoromethanesulfonate and oxazoline ligand.

Description

technical field [0001] The present invention relates to biologically active chiral 2,3-dihydropyrrole [1,2-a]indole derivatives and their asymmetric synthesis methods, as well as their pharmacological activity as protein tyrosine phosphatase inhibitors. Background technique [0002] Chiral 2,3-dihydropyrrole[1,2-a]indole derivatives have aroused the interest of more and more chemists due to their wide range of biological activities. Various substituted 2,3-dihydropyrrole [1,2-a]indole derivatives are widely distributed in organisms and have important biological activities. For example, Yuremamine is an important neuromodulator, and Flinderoles A-C have good antimalarial activity. Therefore, the development of effective general methods for the synthesis of chiral 2,3-dihydropyrrole [1,2-a] indole derivatives and the preparation of biologically active natural products and their derivatives have become the synthetic goals of many organic chemists. . [0003] One of the most ...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07F7/18A61K31/407A61K31/695A61P3/10A61P3/04
Inventor 肖文精程鸿刚陈加荣陆良秋汪涛
Owner HUAZHONG NORMAL UNIV
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