Preparation method and application of a copper-catalyzed tetrahydropyrroloquinoline derivative

A technology of tetrahydropyrrole and derivatives, which can be used in organic chemistry, drug combination, antitumor drugs, etc., can solve the problems of long reaction time, limited substrate range, expensive catalyst, etc., and achieves low cost, high yield and time. quick effect

Active Publication Date: 2018-06-08
HANGZHOU FIRST PEOPLES HOSPITAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The use of gold to catalyze the intramolecular hydroamination of amino alkynes to generate enamine intermediates, and further coupling reactions with alkynes and intramolecular cyclization reactions have been reported, but the catalysts used in this reaction are relatively expensive and the reaction time is relatively high. In addition, the substrate of the reaction must be a terminal alkyne, which greatly limits the scope of the substrate. The reaction formula is as follows:

Method used

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  • Preparation method and application of a copper-catalyzed tetrahydropyrroloquinoline derivative
  • Preparation method and application of a copper-catalyzed tetrahydropyrroloquinoline derivative
  • Preparation method and application of a copper-catalyzed tetrahydropyrroloquinoline derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1 preparation of aminoalkyne compound

[0037]

[0038] Add 3-butyn-1-ol (5.0 g, 72 mmol), imidazole (6.8 g, 100 mmol) into a one-necked bottle. Add dichloromethane to dissolve. Add tert-butyldimethylsilyl chloride (12.9 g, 86 mmol) under ice-bath conditions, stir at room temperature for 30 minutes, and check the completion of the reaction by thin-layer chromatography, extract with dichloromethane, wash with water, and dry. Column chromatography (petroleum ether / ethyl acetate=50:1) yielded 13.2 g of a colorless oily liquid.

[0039] Weigh the TBS (tert-butyldimethylsilyl)-protected acetylenic alcohol (15mmol) obtained in the previous step and add it to an anhydrous three-neck reaction flask, add anhydrous tetrahydrofuran (20mL) under the protection of argon, and put the reaction at -78°C With stirring at ambient, n-butyllithium (2.5M, 8 mL) was slowly added thereto. Stir at -78°C for 1 hour, then add iodomethane (45 mmol), and react overnight at room te...

Embodiment 2

[0043] To a microwave tube equipped with a magneton was added cuprous chloride (2 mg, 0.02 mmol) under nitrogen, followed by 5 mL of anhydrous DMF by syringe, and finally, aminoalkyne (31.8 mg, 0.2 mmol) was added under nitrogen , phenylacetylene (61.2mg, 0.6mmol) under microwave irradiation, reacted at 150°C for 30 minutes, after TLC detected that the reaction was complete, added ethyl acetate, water layer, washed 3 times with ethyl acetate, washed 5 times with water, combined the organic layer, Dry over anhydrous sodium sulfate. Pass through the column (eluent: petroleum ether / ethyl acetate=50 / 1) to obtain 47 mg of a yellow solid. of the resulting product 1 HNMR spectrum, 13 CNMR spectrum, see figure 1 , figure 2 .

[0044]

[0045] The physical properties and spectral data of the product are as follows: yellow solid; 1 H NMR (500MHz, CDCl 3 )δ7.50–7.33(m,5H),7.16(t,J=7.5Hz,1H),6.97(d,J=7.5Hz,1H),6.57(t,J=7.5Hz,1H),6.52( d,J=7.5Hz,1H),5.67(s,1H),3.59–3.42(m,2H),2...

Embodiment 3

[0047] To a microwave tube equipped with a magnet was added cuprous chloride (2mg, 0.02mmol) under nitrogen atmosphere, then 5mL of anhydrous DMF was added by syringe, and finally, aminoalkyne (38.6mg, 0.2mmol) was added under nitrogen atmosphere , phenylacetylene (61.2mg, 0.6mmol) under microwave irradiation, reacted at 150°C for 30 minutes, after TLC (thin layer chromatography) detected that the reaction was complete, add ethyl acetate, water layer, wash with ethyl acetate 3 times, wash with water 5 times, the combined organic layers were dried over anhydrous sodium sulfate. Pass through the column (eluent: petroleum ether / ethyl acetate=50 / 1) to obtain 42 mg of yellow solid. of the resulting product 1 HNMR spectrum, 13 CNMR spectrum, see image 3 , Figure 4 .

[0048]

[0049] The physical properties and spectral data of the product are as follows: yellow solid; 1 H NMR (500MHz, CDCl 3 )δ7.44–7.37(m,3H),7.35–7.31(m,2H),7.07(dd,J=8.5,2.5Hz,1H),6.90(d,J=2.5Hz,1H),6....

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Abstract

The invention discloses a preparation method of a tetrahydropyrroloquinoline derivative. The preparation method comprises the following steps: cuprous chloride, aminoalkyne and alkyne are added in a reaction flask, a solvent DMF (dimethyl formamide) is added to the reaction flask, an obtained mixture is subjected to a reaction for 30 min at the temperature of 150 DEG C under microwave irradiation, and a target product is obtained. According to the method, the yield is high, the time is short, the cost is low, a used substrate is not limited by terminal alkyne, good applicability to terminal alkyne and non-terminal alkyne is realized, and the defect of gold catalysis for the reaction is overcome; cell viability tests indicate that part of compounds prepared with the method have inhibitory activity on tumor cell proliferation, so that the method has potential application value in antitumor drug discovery.

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to a preparation method and application of copper-catalyzed tetrahydropyrroloquinoline derivatives. Background technique [0002] Nitrogen-containing heterocyclic compounds, especially tetrahydropyrroloquinoline derivatives, widely exist in natural products and bioactive molecules. The use of gold to catalyze the intramolecular hydroamination of amino alkynes to generate enamine intermediates, and further coupling reactions with alkynes and intramolecular cyclization reactions have been reported, but the catalysts used in this reaction are relatively expensive and the reaction time is relatively high. In addition, the substrate of the reaction must be a terminal alkyne, which greatly limits the scope of the substrate. The reaction formula is as follows: [0003] Contents of the invention [0004] In order to solve the above technical problems, the present invention provides a ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61P35/00
CPCC07D471/04
Inventor 张博董晓武林能明姚停停赵金浩
Owner HANGZHOU FIRST PEOPLES HOSPITAL
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