Synthetic method of pyridine alkaloid compounds and applications of these compounds

A pyridine alkaloid and synthesis method technology, which is applied in the field of synthesis of pyridine alkaloid compounds, can solve problems such as difficult structure-activity research, low content of PenipyridoneB, etc., and achieve significant lipid-lowering activity and good development and application prospects

Inactive Publication Date: 2019-05-03
OCEAN UNIV OF CHINA
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  • Abstract
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Problems solved by technology

(Haibo Zhou, Liyuan Li, et al. Penipyridones A-F, Pyridone Alkaloids from Penicillium funiculosum. J. Nat. Prod., 2016, 79, 1783-1790), wherein Penipyridone B has significant lipid-lowering activity, and the patent of this compound has been published (CN104370806); But the content of Penipyridone B in the microbial fermentation product is low, and it is difficult to obtain a large amount of follow-up structure-activity research

Method used

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  • Synthetic method of pyridine alkaloid compounds and applications of these compounds
  • Synthetic method of pyridine alkaloid compounds and applications of these compounds
  • Synthetic method of pyridine alkaloid compounds and applications of these compounds

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0012] Embodiment 1: the chemical synthesis of compound B

[0013]

[0014] A (293.1mg, 1.2mmol), condensing agent EDCI (276.1mg, 1.44mmol), catalyst DMAP (29.3mg, 0.24mmol) were sequentially added to the reaction flask, vacuum decompression, nitrogen protection, 10ml of anhydrous dichloromethane was added, Stir at 0°C, then add glacial acetic acid (137ul, 2.4mmol), keep the reaction at low temperature for 1 hour, no material A is detected by thin-layer chromatography, transfer to room temperature, add a small amount of dilute hydrochloric acid, extract and dry, and concentrate under reduced pressure Afterwards, the target product B was obtained as a yellow oil by column chromatography (eluent: dichloromethane:methanol=30:1). Yield 78%.

[0015] Product B is analyzed and the results are as follows: 1 H NMR (500MHz, DMSO) δ12.43(s,1H),9.40(s,1H),8.37(s,1H),7.41(ddd,J=20.4,16.5,7.0Hz,5H),6.64(s, 1H), 6.39(s, 1H), 2.18(s, 3H)ppm. 13 C NMR(125MHz,DMSO)δ177.74,169.76,165.51,...

Embodiment 2

[0016] Embodiment 2: the chemical synthesis of compound D1

[0017]

[0018] Add B (200mg, 0.7mmol) and potassium carbonate (193.5mg, 1.4mmol) to the pressure tube in turn, reduce the pressure under vacuum, protect with nitrogen, add 5ml of anhydrous acetone, then add C1 (248ul, 3.5mmol), at 75 degrees Stir under the conditions for 36 hours, no material B was detected by thin-layer chromatography, cooled to room temperature, extracted and dried, concentrated under vacuum and reduced pressure, and the target product was obtained by column chromatography (eluent: ethyl acetate:petroleum ether=10:1) D1, white solid. Yield 52%.

[0019] Product D1 is analyzed, and the results are as follows: 1 H NMR (500MHz, DMSO) δ8.71(s, 1H), 7.72(s, 1H), 7.60(s, 1H), 7.46(d, J=7.3Hz, 2H), 7.32(tt, J=14.6, 7.2Hz, 4H), 6.66 (s, 1H), 5.16(t, J=5.3Hz, 1H), 4.28(t, J=4.3Hz, 2H), 3.77(dd, J=9.2, 4.9 Hz, 2H) ,2.18(s,3H)ppm. 13 CNMR (125MHz, DMSO) δ170.06, 165.09, 163.67, 163.61, 152.03, 139.01...

Embodiment 3

[0020] Embodiment 3: the chemical synthesis of compound D2

[0021]

[0022] Add B (200mg, 0.7mmol) and potassium carbonate (193.5mg, 1.4mmol) to the pressure tube in turn, reduce the pressure under vacuum, protect with nitrogen, add 5ml of anhydrous acetone, then add C2 (181.7ul, 2.1mmol), at 75 Stir under the condition of 12 hours, thin-layer chromatography monitors that there is no raw material B, cool to room temperature, extract and dry, concentrate under vacuum and reduce pressure, and obtain the target product by column chromatography (eluent is dichloromethane:methanol=50:1) D2, white solid. Yield 33%.

[0023] Product D2 is analyzed, and the results are as follows: 1 H NMR (500MHz,DMSO)δ8.60(s,1H),7.66(s,1H),7.57(s,1H),7.47–7.43(m,2H),7.37–7.32(m,2H),7.32– 7.28(m,1H), 7.26(s,1H),6.65(s,1H),6.06(ddt,J=17.2,10.6,5.4Hz,1H),5.45(dd,J=17.3,1.6Hz,1H) ,5.32(dd,J=10.6,1.4Hz,1H),4.84(d,J=5.3Hz,2H),2.18 (s,3H)ppm. 13 C NMR(125MHz,DMSO)δ169.57,165.03,162.70,162.38,150.74...

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Abstract

The invention relates to a synthetic method of pyridine alkaloid compounds and applications of these compounds. The compounds have the structural general formula as the specification, wherein R is selected from one of ethanol, allyl group, bromoethane, dimethyl aminoethane, benzyl group and N-(2-ethyl)pyrrolidine. The synthetic method of the skeleton structure includes: 1) synthesis of an intermediate compound: performing a reaction at 0 DEG C, wherein a compound A (Penipyridone A) and glacial acetic acid are reactants, EDCI is a condensating agent, DMAP is a catalyst and anhydrous dichloromethane is a solvent; 2) synthesis of a target compound: performing a reaction on the intermediate compound with halogenated hydrocarbon with K2CO3 being an alkali and anhydrous acetone being a solvent,wherein pyridone is subjected to isomerization, thus preparing the target compound. The synthetic method employs accessible raw materials, is simple in operation and is simplified in synthetic route,and is an effective synthesis route for synthesizing the pyridine compounds. Besides, the compounds D1 and D6 have excellent development and application prospect as lipid lowering drugs.

Description

Technical field: [0001] The present invention relates to a synthetic method of pyridine alkaloid compounds, and the present invention also relates to the application of two such compounds in lipid-lowering aspects, belonging to the field of medicinal chemistry. Background technique: [0002] Our research group discovered pyridone alkaloids with lipid-lowering activity from Penicillium funiculosum GWT2-24, a moss sample collected near the Great Wall Station in Antarctica. (Haibo Zhou, Liyuan Li, et al. Penipyridones A-F, Pyridone Alkaloids from Penicillium funiculosum. J. Nat. Prod., 2016, 79, 1783-1790), wherein Penipyridone B has significant lipid-lowering activity, and the patent of this compound has been published (CN104370806); However, the content of Penipyridone B in microbial fermentation products is low, and it is difficult to obtain a large amount for subsequent structure-activity research. The present invention aims to provide a synthetic method of pyridine alkalo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/82A61P3/06
Inventor 朱天骄段忠伟刘延凯车茜李德海顾谦群
Owner OCEAN UNIV OF CHINA
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