CN101434579A - Fuziline esterification derivative, synthetic method and use - Google Patents
Fuziline esterification derivative, synthetic method and use Download PDFInfo
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- CN101434579A CN101434579A CN 200810147988 CN200810147988A CN101434579A CN 101434579 A CN101434579 A CN 101434579A CN 200810147988 CN200810147988 CN 200810147988 CN 200810147988 A CN200810147988 A CN 200810147988A CN 101434579 A CN101434579 A CN 101434579A
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- senbusine
- benzoyl
- derivative
- propionyl
- fatty acyl
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Abstract
The invention discloses a preparation method of a derivative (with a compound structure shown as the picture) of fuziline in a natural diterpenoid alkaloid of aconitum plants and an application thereof, pertaining to the technical field of medical and pesticide synthesis. The preparation method of the compound derivate comprises the steps that the fuziline is dissolved in a dry pyridine and subjected to alkaline treatment, chloroform extraction and steaming and concentration after being added with a sulfate reagent for a chemical reaction, thus obtaining the sulfated derivative; and a crude product can be purified by the method of recrystallization or column chromatography. The synthesizing method is simple and convenient and has relatively low cost and high transformation rate. The compound synthesized has relatively high biological activity and can be used for developing new products such as medicines, pesticides, etc. In the formula, R1 refers to alkanoyl, fatty acyl or aromaticacyl radical such as acetyl, propionyl, benzoyl, caproyl, p-chlorobenzene formyl, and the like; R2 refers to hydrogen atoms or alkanoyl, fatty acyl or aromaticacyl radical such as acetyl, propionyl, benzoyl, caproyl, p-chlorobenzene formyl, and the like; and R3 refers to hydrogen atoms or alkanoyl, fatty acyl or aromaticacyl radical such as acetyl, propionyl, benzoyl, caproyl, p-chlorobenzene formyl, and the like.
Description
(1) technical field
The present invention relates to the synthetic method and the application thereof of Senbusine C esterified derivative, belong to medicine, agricultural chemicals technical field of medicine synthesis
(2) technical background
Senbusine C is a kind of C-19 type diterpene alkaloid that extraction separation obtains in the sub-root of the Ranunculaceae aconitum plant rhizome of Chinese monkshood (Chinese medicine monkshood), and its structural formula is shown in figure (I).The medicinal history of the existing two thousand years of Chinese medicine monkshood, its effect mainly contains rheumatism, analgesia, cardiac stimulant, recuperating deplered YANG and rescuing the patient from collapse etc.In recent years, along with the rise that the plant insecticide of environmental protection is studied, alkaloidal insecticidal activity is found and attention by increasing people in the Aconitum class plant.Liu Lindong has applied for patent " rheumatism capsule " with the rhizome of Chinese monkshood as one of compound; Hou Deshan is that one of compound has been invented the dispel method of pain liniment of system cervical vertebra hyperplasia with the rhizome of Chinese monkshood and radix aconiti agrestis; Zhao Tao has invented a kind of Chinese herbal granules that is used for the treatment of heart failure.
Diterpene alkaloid is the main medical active effective constituent in the rhizome of Chinese monkshood plant, has the potentiality that exploitation becomes medical product innovation.In the anticancer analgetic agent of Jiang Lifu invention, lappaconitine kills and wounds cancer cells to leurocristine and has once quick property.Diterpene alkaloid is carried out structural modification (or structure of modification) research carried out for many years,, can make alkaloidal activity obtain changing by structural modification (or structure of modification).As HuaXi college of pharmacy, SiChuan University Wang Feng roc seminar discovery, structure of modification and the pharmacologically actives such as antitumor and analgesia thereof of diterpene alkaloid have been carried out comparatively deep research.Wherein, Wang Jianli is to N atom, the C of lappaconitine and bulleyaconitine A
8Position and C
14Structural modification has been carried out in the position, has inquired into C
19The chemical reaction method of diterpene alkaloid structural modification and rule.The king of pharmaceutical chemistry research department of China Medicine University such as refined etc. pays first element derivative to the pass of the plain acidylate modification of pass pair first back discovery its acetylize, propionylization and adjacent chlorobenzoylization has significant protective effect to the rat ventricular that napelline brings out.The bulleyaconitine A analogue of preparations such as Zhang Hongbin has stronger analgesic activity, and littler than napelline toxicity.Village's pediment hero has been invented new aconitine type compound and analgesic, analgesia, antiphlogiston, and compound can also reduce the consumption of morphine with morphine and time spent.
Find after deliberation that in addition the rhizome of Chinese monkshood has insecticidal effect preferably to the multiple kinds of crops insect.Ethanol, the ether extract of the discovery rhizome of Chinese monkshoods such as Ding Wei have certain preventive effect to mythimna separata.Discovery Root of Nakedstamen Monkshood methanol extracts such as Wang Haili are about 72% to the antifeedant activity of Autographa spp.Yu Dagang has also applied for the rhizome of Chinese monkshood liquid patent of composite herbal medicine agricultural chemicals as one of prescription.Liu Jingxiang has developed desinsection, has killed mite dual-purpose agricultural chemicals as one of compound with Radix Aconiti extract 2-10%.
Diterpene alkaloid is the insecticidal activity position of the rhizome of Chinese monkshood.Discovery Methyllycaconitines (Methyllycaconitine) such as Jennings KR have stronger insecticidal activity, and it can combine with the cholinocepter of insect is efficient.Hispanic ReinaM and Gonza ' lez-Coloma A etc. have carried out comparatively detailed research aspect the insecticidal activity of natural diterpene alkaloid.They find that the diterpene alkaloid of different structure shows different insecticidal activities, C to different insects
19Fall diterpene alkaloid and compare C
20Diterpene alkaloid has stronger activity.
Senbusine C is as a kind of C-19 type diterpene alkaloid, in close relations between its structure and the biological activity, and the substituting group kind is different with number, the difference of substituting group position etc. all can cause their activity change.
As seen, diterpene alkaloid component has preferably and eases pain, protects heart, medical active such as antitumor, with its be raw material institute synthetic compound also exist medicinal aspect multiple bioactive may, have the potentiality of the medicinal product innovation of exploitation.In addition, diterpene alkaloid has insecticidal effect preferably to the multiple kinds of crops insect, Senbusine C should be the natural plant active component that an agricultural chemicals lead compound structure innovation and a class of optimizing research got a good chance of, had the symptom of a trend, and the Biocidal agricultural chemicals that can be used as new and effective low toxicity is researched and developed.
(3) summary of the invention:
1, goal of the invention: the synthetic method that the purpose of this invention is to provide a kind of Senbusine C esterified derivative of biologically active.
2, technical scheme: realize that the means that invention is adopted are that Senbusine C is dissolved in pyridine, add esterifying reagent, under ice bath or room temperature condition, react, can synthesize esterified derivative.
The present invention is dissolved in pyridine with Senbusine C, can generate esterified derivative in 6～30 hours with the reaction of the esterifying reagent of 1～5 times of molar weight.The esterifying reagent that uses has acid anhydrides or acyl chlorides such as diacetyl oxide, propionic anhydride, o-chlorobenzoyl chloride, parachlorobenzoyl chloride, Benzoyl chloride, positive caproyl chloride.Quaternization system pH to 8～10.The extracting process that adopts is all transferred to alkaloid in the little polar solvent, layer.Solvent reclaims with Rotary Evaporators by the mode of underpressure distillation.The product that obtains may be the simplification compound, only need carry out simple purification process, as recrystallization; Product also may be the alkaloid mixture of multiple esterification, should carry out column chromatography for separation to it according to polar difference.All alkaloids utilize wave spectrums such as infrared chromatography, electron impact ionization mass spectrometry, nucleus magnetic resonance to unite and characterize and analyze.
(4) concrete enforcement:
Embodiment 1:
Senbusine C 108.1mg joins in the 2mL dry pyridine, adds the Benzoyl chloride 0.5mL that heavily steamed, room temperature reaction 20h behind the 20min under condition of ice bath.Slowly drip saturated sodium carbonate, until pH9.5, chloroform extraction three times, each 10mL.The combined chloroform extraction liquid, rotary evaporation reclaims chloroform and obtains thick product 154.7mg.Carry out column chromatography for separation with silica gel 12g, obtain pure orange amorphous powder Senbusine C benzoylation modified derivative.
If adopt pickling process to measure the insecticidal activity of compound to aphis craccivora: the broad bean blade is cut off two ends, and the back side is placed on the fritter cotton up, places in the plastic culture dish, adds less water, connects aphis craccivora and becomes aphid to produce aphid.Remove into aphid behind the 24h, continue behind the cultivation 2d blade behind the abundant 5s of infiltration, to be placed on the cotton natural airing again in soup.Check result behind the 24h.The mesaconitine derivative of the chlorobenzoyl modification aphis craccivora to 3 ages when the 500mg/L had cytotoxicity preferably.
Product records molten point: 74～76 ℃ of Mp;
Product structure confirms with mass spectrometric detection, EI-Ms m/z:766.0 (M
+);
Nuclear-magnetism detects,
1H-NMR (CDCl
3600MHz) δ (ppm): 8.11 (4H, d, J=7.98Hz, Ar-H), 8.08 (2H, d, J=7.02Hz, Ar-H), 7.60 (2H, ddd, J
1=7.44Hz, J
2=14.82Hz, J
3=28.44Hz, Ar-H), 7.51 (5H, dd, J
1=7.62Hz, J
2=15.18Hz, Ar-H), 7.42 (2H, dd, J
1=7.86Hz, J
2=15.42Hz, Ar-H), 3.31 (3H, s, OCH
3), 3.30 (1H, s) 3.29 (3H, s OCH
3), 3.27 (3H, s, OCH
3), 0.96 (3H, dd, J
1=7.02Hz, J
2=14.22Hz, N-CH
2CH
3)
Embodiment 2:
Senbusine C 61.0mg joins in the 1.0mL pyridine, adds diacetyl oxide 1.0mL, and the back quaternization liquid that reacts completely is until pH 9.8, chloroform extraction three times, each 10mL.The combined chloroform extraction liquid concentrates with Rotary Evaporators and to obtain thick product 65.3mg.Carry out column chromatography for separation with silica gel 3mg, obtain pure white thick material Senbusine C acetylation modification derivative.
If adopt pickling process to measure the insecticidal activity of compound to aphis craccivora: the broad bean blade is cut off two ends, and the back side is placed on the fritter cotton up, places in the plastic culture dish, adds less water, connects aphis craccivora and becomes aphid to produce aphid.Remove into aphid behind the 24h, continue behind the cultivation 2d blade behind the abundant 5s of infiltration, to be placed on the cotton natural airing again in soup.Check result behind the 24h.Aphis craccivora to 3 ages during compound 500mg/L has better cytotoxicity.
Product structure detects with nuclear-magnetism and confirms,
1HNMR (CDCl
3600MHz) δ (ppm): 4.85 (1H, dd, J
1=6.78Hz, J
2=9.72Hz, H-15 β), 4.12 (1H, d, J=9.54Hz, H-14 β), 3.59 (1H, d, J=8.58Hz, H-1 β), 3.36 (3H, s, OCH
3), 3.28 (6H, d, J=1.56Hz, 2 * OCH
3), 2.20 (3H, s, OAc), 2.05 (6H, d, J=11.28Hz, 2 * OAc), 1.14 (3H, t, J=7.14Hz, N-CH
2CH
3)
Claims (5)
1, Senbusine C esterified derivative is the compound shown in the following molecular formula general formula:
In the formula: R
1For ethanoyl, propionyl, benzoyl, positive caproyl, to alkyloyls such as chlorobenzene formacyl, fatty acyl group or aromaticacyl radical; R2 is hydrogen atom or ethanoyl, propionyl, benzoyl, positive caproyl, to alkyloyls such as chlorobenzene formacyl, fatty acyl group or aromaticacyl radical; R
3For hydrogen atom or ethanoyl, propionyl, benzoyl, positive caproyl, to alkyloyls such as chlorobenzene formacyl, fatty acyl group or aromaticacyl radical.
2, the synthetic method of the esterified derivative of Senbusine C as claimed in claim 1 is characterized in that the esterifying reagent with the Senbusine C of separation and Extraction in the aconitum plant and mol ratio 1:1～1:5 reacts the esterified derivative of 6～30 hours synthetic Senbusine Cs in the pyridine of room temperature or ice bath.With saturated aqueous sodium carbonate quaternization liquid to pH value is 8～10, after alkaloid is transferred in the chloroform, chloroform is recycled in the mode of underpressure distillation, obtains the alkaloid mixture.The mixture that obtains is purified by methods such as recrystallization or column chromatographies again, obtains Senbusine C esterified derivative compound.
3, the esterified derivative synthetic method of Senbusine C as claimed in claim 2 is characterized in that described esterifying reagent is acid anhydrides or acyl chlorides such as diacetyl oxide, propionic anhydride, o-chlorobenzoyl chloride, parachlorobenzoyl chloride, Benzoyl chloride, positive caproyl chloride.
4, as the purposes of claims 1 described Senbusine C esterification modified derivative, it is characterized in that the application aspect insecticidal materials.
5,, it is characterized in that the application aspect analgesia, anti-arrhythmia, antitumor drug as the purposes of claims 1 described Senbusine C esterification modified derivative.
Priority Applications (1)
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| CN 200810147988 CN101434579A (en) | 2008-12-24 | 2008-12-24 | Fuziline esterification derivative, synthetic method and use |
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|---|---|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102697777A (en) * | 2011-11-28 | 2012-10-03 | 雅安三九药业有限公司 | Preparation method and new application of fuziline |
| CN103120691A (en) * | 2012-04-10 | 2013-05-29 | 雅安三九药业有限公司 | Application of fuziline in preparation of medicine for preventing and treating shock |
| CN111187210A (en) * | 2020-01-08 | 2020-05-22 | 成都中医药大学 | Pyrolytic diterpenoid alkaloid compound and preparation method and application thereof |
-
2008
- 2008-12-24 CN CN 200810147988 patent/CN101434579A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102697777A (en) * | 2011-11-28 | 2012-10-03 | 雅安三九药业有限公司 | Preparation method and new application of fuziline |
| CN103120691A (en) * | 2012-04-10 | 2013-05-29 | 雅安三九药业有限公司 | Application of fuziline in preparation of medicine for preventing and treating shock |
| CN103120691B (en) * | 2012-04-10 | 2015-04-29 | 雅安三九药业有限公司 | Application of fuziline in preparation of medicine for preventing and treating shock |
| CN111187210A (en) * | 2020-01-08 | 2020-05-22 | 成都中医药大学 | Pyrolytic diterpenoid alkaloid compound and preparation method and application thereof |
| CN111187210B (en) * | 2020-01-08 | 2022-05-03 | 成都中医药大学 | Pyrolytic diterpenoid alkaloid compound and preparation method and application thereof |
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Open date: 20090520 |