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Method for constructing bisindole substituted dihydropyrrole derivative based on oxime ester and indole

A technology of dihydropyrrolidone and derivatives, applied in the direction of organic chemistry, etc., can solve the problems of harsh conditions, many reaction steps, difficult post-processing, etc., and achieves the effects of easy fracture, wide applicability, and broad application prospects.

Inactive Publication Date: 2019-03-29
CHANGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Although the raw materials of this method are easy to obtain, there are too many reaction steps and the conditions are relatively harsh, and there may be post-processing problems in the zinc chloride and aluminum trichloride used.

Method used

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  • Method for constructing bisindole substituted dihydropyrrole derivative based on oxime ester and indole
  • Method for constructing bisindole substituted dihydropyrrole derivative based on oxime ester and indole
  • Method for constructing bisindole substituted dihydropyrrole derivative based on oxime ester and indole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Acetophenone oxime acetate substituted with indole and diethyl malonate is raw material, according to indole: oxime acetate: copper acetate molar ratio is 1.6:1:2, oxime acetate 0.2mmol, solvent The amount of acetonitrile is 4mL, in N 2 Heated to 80°C under protective conditions, and TLC detected that the reaction was progressing. After all the raw materials were completely reacted, they were extracted, spin-dried, and dissolved in THF to dissolve the final product 3aa washed with ethyl acetate, with a yield of 85%.

[0052]

[0053] The obtained product is tested, and the instruments used for the test are: AVANCE 300MHz nuclear magnetic resonance instrument (Bruker company, TMS is the internal standard); SGW X-4 micro melting point instrument (the thermometer is not calibrated). The test method of the following examples is the same as that of this example.

[0054] 3aa: brown powdery solid, mp 295.4-296.7℃. 1 H NMR (300MHz, d 6 -DMSO) δ11.60(d, J=2.4Hz, 1H), 11.1...

Embodiment 2

[0056] With 5-methoxyindole, the acetophenone oxime acetate substituted by diethyl malonate as raw material, according to 5-methoxyindole: oxime acetate: copper acetate molar ratio is 1.6:1: 2, Oxime acetate 0.2mmol, the amount of solvent acetonitrile is 4mL, in N 2 Heated to 80°C under protective conditions, and TLC detected that the reaction was progressing. After all the raw materials were completely reacted, they were extracted with ethyl acetate and water, dried and spin-dried, and recrystallized from 3 mL of ethyl acetate to obtain the pure product 3ab with a yield of 78%.

[0057]

[0058] 3ab: yellow solid, mp 220-223℃. 1 H NMR (300MHz, d 6 -DMSO)δ11.27(d,J=2.6Hz,1H),10.96(d,J=2.4Hz,1H),9.42(s,1H),7.27-7.38(m,7H),6.85(d,J =2.3Hz,1H),6.77(td,J=8.4Hz,2.5Hz,2H),6.69(d,J=2.3Hz,1H),6.66(d,J=2.6Hz,1H),6.27(d, J=2.9Hz, 1H), 4.00(q, J=7.1Hz, 2H), 3.66(s, 3H), 3.57(s, 3H), 0.84(t, J=7.1Hz, 3H); 13 C NMR (75MHz, d 6 -DMSO) δ168.4, 165.1, 159.6, 154.7, 153.5, 140.7, 132.1...

Embodiment 3

[0060] With 7-methylindole, the acetophenone oxime acetate substituted by diethyl malonate as raw material, according to 7-methylindole: oxime acetate: copper acetate mol ratio is 1.6:1:2, Oxime acetate 0.2mmol, solvent acetonitrile consumption is 4mL, in N 2 Heated to 80°C under protective conditions, and TLC detected that the reaction was progressing. After all the raw materials were completely reacted, they were extracted with ethyl acetate and water, dried and spin-dried, dissolved in methanol, and washed with ethyl acetate to obtain the pure product 3ac with a yield of 82%.

[0061]

[0062] 3ac: Yellow-green solid, mp 203.4-204.2℃. 1 H NMR (300MHz, d 6 -DMSO) δ11.39(d, J=2.6Hz, 1H), 11.08(d, J=2.3Hz, 1H), 9.43(s, 1H), 7.27-7.40(m, 5H), 7.11-7.20(m ,2H),6.81-7.02(m,4H),6.65(d,J=2.6Hz,1H),6.16(d,J=2.9Hz,1H),4.00(q,J=7.1Hz,2H),2.44 (s,3H),2.40(s,3H),0.89(t,J=7.1Hz,3H); 13 C NMR (75MHz, d 6 -DMSO) δ168.4, 164.8, 159.8, 140.8, 136.5, 135.6, 128.6, 128.4, 128.2, 125.9,...

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Abstract

The invention belongs to the field of organic chemical industry, and particularly relates to a method for constructing a bisindole substituted dihydropyrrole derivative based on oxime ester and indole. The method comprises the steps that diethyl malonate substituted ketoxime acid ester, an indole compound and an oxidizing agent serve as raw materials and are heated to 60-100 DEG C under the protection condition of N2, and reaction is carried out so as to obtain the bisindole substituted dihydropyrrolidone derivative. According to the method, the indole compound, the diethyl malonate substituted ketoxime acid ester and the oxidizing agent are selected, the raw materials are cheap and easy to obtain, substrates are wide in range, the compatibility of functional groups is good, and the finalpyrrolidone derivative can be obtained with relatively high yield through various substituted indole and the diethyl malonate substituted ketoxime acid ester. The method has the advantages that the synthesis route is short, the toxicity of the reaction raw materials is low, separation and purification are convenient, reaction liquid can be obtained through recrystallization only, and the method issuitable for large-scale industrial production and has an important practical application value in a method for synthesis of the dihydropyrone derivative.

Description

technical field [0001] The invention belongs to the field of organic chemical industry, in particular to a method for constructing bisindole-substituted dihydropyrrolone based on oxime ester and indole. Background technique [0002] Bisindole substituted dihydropyrrolone compounds are a class of protease inhibitors with strong activity, which are widely used in anti-cancer and other frontier medical fields. The structure of the compound involved in the method has not been reported yet, and there are only a few reports on the synthesis method of the dihydropyrrolidone skeleton of the compound. [0003] Method 1, [J.Org.Chem.1999,64,4697-4704.] through 3-(2-nitro-(E)-1-vinyl)-1H-indole and 3-(2-methyl Butyl acetate)-indole reacts under the conditions of lithium diisopropylamide and tetrahydrofuran to obtain intermediate 4, and intermediate 4 obtains intermediate 5 through nickel-catalyzed hydrogenation and toluene heating conditions, and intermediate 5 uses DDQ is dehydroaro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14
CPCC07D405/14
Inventor 杨海涛毛鹏飞滕巧巧姜艳何光裕孟启缪春宝
Owner CHANGZHOU UNIV
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