Preparation method and application of 21-methyl-subditine

A technology of strychnine and methyl, which is applied in the field of chemical drug synthesis, can solve the problems of difficult chemical synthesis and chemical synthesis without subditine, and achieve the effect of strong practical value, strong superiority, and short synthetic route

Inactive Publication Date: 2019-08-30
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] As a new type of alkaloid of the genus Ebony, because Subditine has certain advantages in biological activity, this compound has greater druggability, and has a wider range of medicinal and commercial prospects. It is a double-substituted structure, which is a relatively difficult challenge in chemical synthesis. There is no related report on the chemical synthesis of Subditine.

Method used

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  • Preparation method and application of 21-methyl-subditine
  • Preparation method and application of 21-methyl-subditine
  • Preparation method and application of 21-methyl-subditine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Embodiment 1: the preparation of formula 1 compound

[0060]

[0061] Put the compound of formula 3 (15.2mg, 0.042mmol) and bis(triphenylphosphine) palladium dichloride (4.8mg, 0.042mmol) in a branched reaction flask, and after three gas changes, the system was placed in a nitrogen atmosphere , add a 1:1 mixed solution of toluene and N,N-dimethylformamide (1.50ml) and tributylvinyltin (13ul, 0.046mmol) to the system successively, and put it at 100°C for 3 hours to react. Completely, cool the system to room temperature, after suction filtration, dilute with ethyl acetate solution, wash the organic phase with distilled water and saturated brine successively, dry the organic phase with anhydrous sodium sulfate, spin off the solvent, and wash the concentrate with 50% ethyl acetate / dichloromethane eluent carries out column chromatography and obtains solid product formula 1 (6.8g, 79%), R f = 0.28 (5% methanol / dichloromethane).

[0062] Tested: 1 H NMR (500MHz, DMSO-d ...

Embodiment 2

[0064] Embodiment 2: the preparation of formula 6 compound

[0065]

[0066] Dissolve the compound of formula 5 (500 mg, 2.15 mmol) in dichloromethane (15 ml) solution, add triethylamine (6 ml), stir at room temperature for 1 hour, and dissolve the compound of formula 4 (250 mg, 1.34 mmol) in the above system, Put it at 45°C to start the reaction, react for 2 hours, the reaction is complete, spin off the solvent, and the concentrate is separated by column chromatography with 25% ethyl acetate / petroleum ether eluent to obtain the compound of formula 6 (250mg, yield 49%) , R f =0.63 (30% ethyl acetate / petroleum ether).

Embodiment 3

[0067] Embodiment 3: the preparation of formula 7 compound

[0068]

[0069] Put the compound of formula 6 (250mg, 0.65mmol) in a round-bottomed flask, heat up to 190°C under vacuum, react for 30 minutes, the reaction is complete, cool to room temperature, concentrate with 50% ethyl acetate / dichloromethane The eluent was separated by column chromatography to obtain the compound of formula 7 (120mg, yield 48%), R f = 0.65 (10% methanol / dichloromethane).

[0070] 1 H NMR (500MHz, Chloroform-d) δ9.40(s, 1H), 7.65(d, J=7.9Hz, 1H), 7.49(d, J=8.2 Hz, 1H), 7.37(ddd, J=8.2, 7.0, 1.1Hz, 1H), 7.23(t, J=7.5Hz, 4H), 6.87(s, 1H), 4.54(t, J=6.7Hz, 2H), 3.20(t, J=6.7Hz, 2H) , 2.83(s, 3H).

[0071] 13 C NMR(126MHz,Chloroform-d)δ161.41,159.48,149.34,141.59,138.48,137.42, 127.23,125.92,125.53,120.99,119.88,119.12,117.19,116.79,111.78,96.15,40.64, 26.11,19.79ppm. HRMS (ESI, m / s): [M+H] + calcd.for C 19 h 15 N 3 OBr, 380.0398; found 380.0393.

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Abstract

The invention discloses a preparation method of a natural product Subditine shown as a formula 1, 21-methyl-subditine shown as a formula 2 and preparation methods thereof. The natural product Subditine and the 21-methyl-subditine are prepared from a higher intermediate through a coupling reaction between bromine atoms and a coupling reagent. The invention achieves full synthesis of the natural product Subditine, and achieves chemical synthesis of the 21-methyl-subditine for the first time. The natural product Subditine can be prepared through a simple oxidation reaction of the 21-methyl-subditine, and an important practical value for the first chemical synthesis of the natural product Subditine is achieved.

Description

technical field [0001] The invention belongs to the technical field of chemical drug synthesis, and relates to a preparation method of natural product strychnine, 21-methyl-sychnine and a preparation method thereof. Background technique [0002] The natural product strychnine is an indole alkaloid of the genus Echinacea (Au, T.Y.; Cheung, H.T.; Sternhell, S.; J.Chern.Soc.W. Perkin Trans.I.1973, 13-16.), alkaloids of the genus Ebony have anti-cell proliferation, anti-microbial, anti-inflammatory and other activities. Its chemical structure is shown in the following formula (1): [0003] [0004] The prior art (Repke, D B.; Clark, R.D.; Nelson, J.T.Tetrahedron.1989, 45, 2541-2550.) is that in the early stage of the reaction, the brominated pyridine compound is obtained through a coupling reaction to the pyridine compound containing the vinyl group , and then carry out a subsequent multi-step reaction to obtain the target compound; the preparation of raw materials requires...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/22
CPCC07D471/22
Inventor 杜珊何海兵高栓虎
Owner EAST CHINA NORMAL UNIV
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