CN106928068A - A kind of tetracyclic diterpene class iso steviol compound and preparation method and application - Google Patents
A kind of tetracyclic diterpene class iso steviol compound and preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of tetracyclic diterpene class iso steviol compound and preparation method and application, belong to medicinal chemistry art.Such compound contains α methylene cyclopentanone structure fragments, and as shown in Equation 1, its quaternary ammonium salt is as shown in Equation 2 for structure.It is suppressing human esophagus cancer cell strain Ec109, the human gastric carcinoma cell line MGC803 and the aspects of human prostate cancer cell line PC 3 with preferably activity.In formula, n=1 6.
Description
Technical field
The present invention relates to a kind of iso steviol derivative and preparation method thereof and antitumor action, category pharmaceutical chemistry neck
Domain.
Background technology
Natural products is the lead compound of medicine and the important sources of functional organic molecule, is filtered out from natural products
Lead compound is always the effective way of new drug development.Although many natural products have certain bioactivity, so
And because toxic and side effect is strong, poor activity or bioavilability are low and limit its clinical practice.Therefore, natural products is entered
The effective structural modification of row introduces special pharmacophoric group, obtains new derivatives, so as to improve its activity and availability, reduce
Toxicity is to develop the effective scheme of new type natural medicine.In miscellaneous bioactive natural product in nature, terpenoid
Thing exists extensive, is the effective way for finding natural drug the features such as with complex structure, various species, diverse biological activities
Footpath, such as qinghaosu, taxol, andrographolide clinical commonly used drug are all the terpenoids that separation is extracted from plant.
Diterpene-kind compound is the most abundant terpene natural products of various structures, the type found in addition to sequiterpene.
Iso steviol (isosteviol, Isosteviol) is the Si Te obtained through acidic hydrolysis by natural products stevioside
The product that dimension alcohol is reset.Research shows that it shows at the aspect such as anticancer, antibacterial, myocardial damage reparation, antiviral and hypoglycemic
Certain bioactivity.Wherein, the research of its antitumor activity is the most active.Patent CN102718657 (formula 4) report containing
Iso steviol derivative (the R of alpha, beta-unsaturated ketone (alpha-methylene cyclopentanone) structure fragment1It is acetoxyl group or hydroxyl, R2For
Ethyl, propyl group, isopropyl, benzyl, normal-butyl, sec-butyl or isobutyl group), all of esterified group R2It is alkyl, aryl, esterification
There is no the introducing of polar group on substitution base.
Paper (Bioorganic＆Medicinal Chemistry Letters 21 (1):130-132) report one kind
Containing α, alpha, beta-unsaturated ketone analog derivative (formula 6), active testing result shows that these transformations all greatly improve different Si Tewei
The antitumor activity of alcohol parent compound, but the research only has a kind of substitution base of benzyl ester.Kataev etc. is reported
(Pharmaceutical Chemistry Journal 44(11):597-600) quaternary ammonium salt is introduced on iso steviol skeleton
Structure fragment (formula 5).Activity research finds that introducing quaternary ammonium salt structure can significantly improve antibacterial activity, and effect is mould better than positive drug gram
Azoles and Ciprofloxacin, but ethylene quaternary ammonium salt ester has only been investigated in the research, and without alpha-methylene cyclopentanone structure, also do not have
There is investigation antitumor activity.
In view of iso steviol active relatively low in itself, dissolubility is poor, so many researchs are improved by structure of modification
These factors are to improve activity.In the Diterpenes natural products having found, α, it is crucial that alpha, beta-unsaturated ketone is proved to be a class
Pharmacophoric group, have an effect and there is preferable cytotoxicity by with the sulfydryl enzyme in tumour cell.In addition, polar group
Introducing can increase the dissolubility of hydrophobic tetracyclic diterpene compound and with the adhesion of target molecule so as to improve biological profit
Expenditure and bioactivity.Therefore, structure of modification is carried out to iso steviol, and is provided by anti tumor activity in vitro test screen
There is guide's molecule of application value significant.
The content of the invention
The purpose of the present invention is that, by α, alpha, beta-unsaturated ketone fragment is incorporated on iso steviol D- rings, and is transformed by carboxyl
Different esters are introduced for group, is synthesized containing α, alpha, beta-unsaturated ketone fragment and haloalkyl and quaternary ammonium salt isopolarity fragment
New iso steviol derivative another object is to provide the synthetic method of such compound and its in antitumor aspect of performance
Using.
To realize the purpose of the present invention, the present invention prepares target compound by raw material of iso steviol, in concrete operations
Reaction substrate, catalyst, solvent, reagent, reaction time and purification process etc. are tested and optimized in step, is found
Easy to operate, yield is higher, selectivity preferably, reaction condition gentle synthetic method, and have studied the antitumor of compound
Performance.
The technical solution adopted by the present invention is as follows：
1. the present invention provides a kind of formula 1 and the iso steviol compound shown in formula 2.
N=1-6.
Further, the iso steviol compound is preferably one of following：
2. the present invention provides a kind of synthetic method of the iso steviol derivative, and the course of reaction is as follows：
Specific method is as follows：
(1) in organic solvent, iso steviol 1 and formaldehyde react in the basic conditions, and reaction is evaporated molten after terminating
Agent, system is acidified with acid after adding water, and obtains the beta-hydroxy iso steviol 2 of 15 alpha-hydroxymethyl -16；
The organic solvent uses methyl alcohol, ethanol, isopropanol or the tert-butyl alcohol；Alkali selects caustic alcohol, sodium methoxide, the tert-butyl alcohol
Potassium, NaOH, potassium hydroxide, carbon -7- alkene (DBU) of 1,8- diazabicylos 11 or DMAP (DMAP)；
(2) compound 2 and paratoluensulfonyl chloride react in organic solvent, and DMAP obtains compound 3 as catalyst reaction；
Described organic solvent selects dichloromethane, tetrahydrofuran (THF), acetonitrile, chloroform, toluene, 1,2- dichloroethanes；
The compound 2 is 1 with the mol ratio of paratoluensulfonyl chloride:1.1~2.5, preferably 1:2；
(3) in organic solvent, compound 3 and oxidant react at room temperature, and it is miscellaneous that reaction is filtered to remove solid after terminating
Matter, filtrate is evaporated, and column chromatography obtains compound 4；
The oxidant uses Pyridinium dichromate (PDC), pyridinium chloro-chromate (PCC), manganese dioxide, Dai Si-horse
Fourth oxidant (DMP) or dimethyl sulfoxide (DMSO) (DMSO)；Organic solvent selects dichloromethane, acetonitrile, dioxane or tetrahydrofuran；
(4) compound 4 flows back to obtain 15- methylene compounds 5 in pyridine；
(5) in organic solvent, under alkalescence condition, compound 5 reacts with dibromoalkane, after question response is complete, boils off acetonitrile,
Water is added, extraction is washed after merging organic phase, separates organic phase, is dried, and vacuum distillation after filtering obtains product compound 6；
The dibromoalkane is 1,2- Bromofumes, 1,3- dibromopropane, Isosorbide-5-Nitrae-dibromobutane or 1,6- dibromo-hexane；
Organic solvent selects acetonitrile, DMSO, N,N-dimethylformamide (DMF), dioxane, tetrahydrofuran or dichloromethane
Alkane；Alkali selects potassium hydroxide, NaOH, potassium carbonate, sodium carbonate, pyridine, triethylamine, DMAP or diisopropylethylamine.
Compound 5 is 0.8~1 with the mol ratio of dibromoalkane:1~1.5, preferably 1:1；
(6) bromo esterification products 6 and trimethylamine in organic solvent under the conditions of 30~100 DEG C confined reaction (4~10 is small
When), obtain compound 7；It is preferred that 65 DEG C, preferably 8 hours.
The organic solvent selects acetonitrile, DMSO, DMF, dioxane, tetrahydrofuran, dichloromethane, methyl alcohol or ethanol.
Compound 6 is 1 with the mol ratio of trimethylamine:1.5~3, preferably 1:2.3, trimethylamine is trimethylamine aqueous solution.
3. the present invention also provides described isosteviol compound to suppress human esophagus cancer cell strain Ec109, human gastric cancer thin
Application in born of the same parents' strain MGC803 and human prostate cancer cell line PC-3 activity.
Compared with prior art the invention has the advantages that：
1. the invention provides a kind of new Alpha-Methyl cyclopentanone and bromo Arrcostab or quaternary ammonium salt isopolarity base are contained
The new derivatives of group；
2. the iso steviol compound tool that the present invention is provided well has antitumor activity, for new medicament screen provides research base
Plinth and lead compound, with preferable application prospect；
3. iso steviol compound preparation flow of the present invention is simple, and raw material is cheap and easy to get, and reaction condition is gentle, post processing
Simply, high income, up to more than 79%, solvent recoverable, beneficial to industrialization production.
Specific embodiment
In order to preferably implement the present invention, now for embodiment, the invention will be further described, but these embodiments are only
It is that, for illustrating the present invention, but embodiment is not limitation of the present invention.
The preparation of the compound 2 and 3 of embodiment 1
Take 250mL absolute ethyl alcohols to be placed in 500mL reaction bulbs, add the metallic sodium of 6.0g, after metallic sodium reacts completely,
9.8g compounds 1 are added, magnetic agitation, system is warming up to 50 DEG C, add 20mL formalins, continue to react 3 hours extremely
TLC tracking reactions terminate.Reaction system is poured into 500mL distilled water, system adjusts pH to 5 with watery hydrochloric acid, there is big in system
Amount white flock precipitate, suction filtration it is dry 10g compounds 2 crude product, purify without isolation, be directly used in next step reaction.Take
The crude product of 4.5g compounds 2, is placed in 100mL reaction bulbs, plus after 30mL pyridinium dissolutions, tolysulfonyl is added under stirring
Chlorine 3.6g and DMAP 60mg, reacts 3 hours at room temperature.After question response is complete, pyridine is boiled off, add 50mL water, use quality percentage
Than 10% hydrochloric acid regulation system pH to 5-6.3 × 30mL ethyl acetate is extracted, and merges organic phase, and saturated common salt water washing is separated
Organic phase anhydrous sodium sulfate drying, vacuum distillation after filtering, obtains yellow oily liquid.Silica gel column chromatography (petrol ether/ethyl acetate
3:1) separate, obtain white solid 3.Yield：84%.1H NMR(400MHz,CDCl3, ppm) and δ 7.70 (d, J=8.3Hz, 2H),
7.35 (d, J=8.1Hz, 2H), 4.21 (dd, J=9.6,4.5Hz, 1H), 4.15 (dd, J=9.6,2.3Hz, 1H), 2.12
(dd, J=31.8,14.0Hz, 2H), 1.93-1.86 (m, 1H), 1.83 (dd, J=11.9,2.3Hz, 1H), 1.80-1.75 (m,
1H), 1.74-1.56 (m, 4H), 1.49-1.37 (m, 3H), 1.35-1.18 (m, 9H), 1.12 (ddd, J=17.4,13.4,
4.5Hz, 2H), 0.96 (d, J=6.6Hz, 1H), 0.92 (s, 3H), 0.86 (ddd, J=12.0,9.1,6.0Hz, 1H), 0.74
(s,3H).13C NMR(101MHz,CDCl3,ppm)δ184.15,145.00,132.62,129.96,129.96,128.00,
128.00,83.84,72.25,57.33,56.78,53.82,47.85,43.46,42.99,40.79,39.25,38.33,
37.58,34.47,32.93,28.69,24.85,21.79,21.64,19.53,18.67,12.65.。
The preparation of the compound 4 of embodiment 2
3.5g compounds 3 are taken, is placed in 50mL reaction bulbs, plus the dissolving of 20mL dichloromethane, stirred 10 minutes under ice bath, plus
Enter 1.88g PDC oxidants, react 3 hours at room temperature.After completion of the reaction with diatom pad filtration system, filter cake is used for TLC detections
30mL dichloromethane is washed, and concentration filtrate obtains crude product.Silica gel column chromatography (petrol ether/ethyl acetate 3:1) separate, obtain white powder
Shape solid.Yield：76%.
1H NMR (400MHz, CDCl3, ppm) 1H NMR (400MHz, CDCl3, ppm) δ 7.70 (d, J=8.3Hz, 2H),
7.35 (d, J=8.1Hz, 2H), 4.21 (dd, J=9.6,4.5Hz, 1H), 4.15 (dd, J=9.6,2.3Hz, 1H), 2.45 (s,
3H), 2.12 (dd, J=31.8,14.0Hz, 2H), 1.89 (d, J=13.9Hz, 1H), 1.83 (dd, J=11.9,2.3Hz,
1H), 1.78 (dd, J=11.2,2.8Hz, 1H), 1.73-1.56 (m, 5H), 1.46 (d, J=14.4Hz, 1H), 1.41-1.33
(m,1H),1.30(s,3H),1.28-1.19(m,4H),1.18-1.05(m,2H),0.92(s,3H),0.90-0.84(m,1H),
0.74(s,3H).13C NMR(101MHz,CDCl3,ppm)δ220.62,183.70,144.96,132.22,129.85,
129.85,128.06,128.06,60.43,56.99,56.87,52.82,51.18,48.05,43.62,40.50,39.55,
38.39,37.60,37.11,34.97,28.92,21.69,21.41,19.59,19.51,18.73,13.20.
The preparation of the compound 5 of embodiment 3
440mg compounds 4 are taken, is placed in 25mL reaction bulbs, plus 5mL pyridinium dissolutions, then add 80mg DMAP, it is heated to reflux 3
Hour.Pyridine is boiled off after thin-layer chromatography detection reaction completely, 10mL water is added, with the hydrochloric acid regulation system pH of mass percent 10%
To 5-6, the extraction of 3 × 10mL ethyl acetate merges saturated common salt water washing organic phase after organic phase, separates organic phase, anhydrous sulphur
Sour sodium is dried, and vacuum distillation after filtering obtains yellow oily liquid.Silica gel column chromatography (petrol ether/ethyl acetate 3:1) separate, obtain
White solid.Yield：77%.
1H NMR(400MHz,CDCl3,ppm)δ6.06(s,1H),5.48(s,1H),2.20-2.06(m,2H),1.97
(d, J=3.3Hz, 1H), 1.94 (dd, J=6.0,2.8Hz, 1H), 1.78 (dd, J=17.4,3.4Hz, 1H), 1.70 (dd, J
=7.9,3.0Hz, 2H), 1.67 (d, J=3.6Hz, 1H), 1.49 (ddd, J=13.8,7.3,4.0Hz, 2H), 1.43-1.37
(m, 2H), 1.31-1.12 (m, 7H), 1.04 (dd, J=13.5,4.0Hz, 1H), 1.00 (s, 3H), 0.86 (td, J=13.1,
3.9Hz,1H),0.67(s,3H).13C NMR(101MHz,CDCl3,ppm)δ39.42,18.63,37.44,43.92,56.42,
38.02,30.22,54.23,20.77,36.56,49.70,60.65,152.91,208.81,28.01,183.20,114.32.
The universal method of the compound 6a of embodiment 4~6d synthesis
5mmol compounds 5 are taken, is placed in 50mL reaction bulbs, plus the dissolving of 30mL acetonitriles, add 8mmol under stirring
Potassium carbonate, is subsequently added the dibromoalkane of 5mmol, reacts 4 hours at room temperature.After question response is complete, acetonitrile is boiled off, add 30mL
Water, 3 × 15mL ethyl acetate extraction, merges saturated common salt water washing after organic phase, separates organic phase, anhydrous sodium sulfate drying,
Vacuum distillation after filtering, obtains white solid.Silica gel column chromatography (petrol ether/ethyl acetate 8:1) separate, obtain white solid.
Compound 6a：Yield：81%.1H NMR(400MHz,CDCl3,ppm)δ6.04(s,1H),5.51(s,1H),
4.44-4.30 (m, 2H), 3.52 (t, J=5.7Hz, 2H), 2.19 (dd, J=13.2,1.2Hz, 1H), 2.17-2.08 (m,
1H),2.03-1.90(m,2H),1.82-1.57(m,3H),1.54-1.37(m,5H),1.34-1.28(m,1H),1.31-1.20
(m, 1H), 1.29-1.14 (m, 3H), 1.17 (ddd, J=18.7,12.8,7.5Hz, 2H), 1.09-0.98 (m, 1H), 1.02
(s, Hz, 3H), 0.86 (td, J=13.3,4.3Hz, 1H), 0.62 (s, 3H)13C NMR(101MHz,CDCl3,ppm)δ
210.83,177.12,154.45,116.20,64.12,57.00,56.77,53.54,46.85,44.16,43.86,40.49,
38.80,38.23,38.16,37.93,29.22,29.12,21.95,21.12,20.23,19.03,12.59.HRMS(ESI,m/
z)calcd.For C23H33BrNaO3,[M+Na]+459.1511,found 459.1511.
Compound 6b：Yield：80%.1H NMR(400MHz,CDCl3,ppm)δ6.04(s,1H),5.44(s,1H),
4.23-4.10 (m, 2H), 3.48 (t, J=6.5Hz, 2H), 2.20-2.13 (m, 3H), 2.11-1.91 (m, 3H), 1.81-1.62
(m, 5H), 1.55-1.48 (m, 1H), 1.47 (dd, J=8.6,2.7Hz, 1H), 1.45-1.39 (m, 3H), 1.29 (dd, J=
12.8,3.7Hz, 1H), 1.21 (s, 3H), 1.18-1.14 (m, 1H), 1.05 (dd, J=13.5,4.0Hz, 1H), 1.00 (s,
3H), 0.85 (td, J=12.8,3.5Hz, 1H), 0.60 (s, 3H)13C NMR(101MHz,CDCl3,ppm)δ210.77,
177.18,154.53,116.05,61.98,56.96,56.75,53.51,46.86,44.08,43.86,40.49,38.77,
38.20,38.12,37.93,31.60,29.70,29.15,21.96,21.11,20.23,19.12,12.56.HRMS(ESI,m/
z)calcd.For C24H35BrNaO3,[M+Na]+473.1667,found 473.1666.
Compound 6c：Yield：80%.1H NMR(400MHz,DMSO,ppm)δ5.90(s,1H),5.37(s,1H),
4.00-3.90 (m, 2H), 3.52 (t, J=6.6Hz, 2H), 2.08-1.97 (m, 2H), 1.89 (dd, J=18.3,7.5Hz,
2H),1.83-1.75(m,2H),1.67-1.60(m,2H),1.61-1.55(m,3H),1.53-1.48(m,2H),1.38(d,J
=3.5Hz, 2H), 1.36 (s, 1H), 1.34 (d, J=2.4Hz, 1H), 1.33 (d, J=5.2Hz, 1H), 1.24 (dd, J=
11.9,1.9Hz, 1H), 1.16 (s, 3H), 1.02 (td, J=13.7,4.6Hz, 2H), 0.92 (s, 3H), 0.85 (dd, J=
13.2,3.6Hz,1H),0.54(s,3H).13C NMR(101MHz,DMSO,ppm)δ209.82,176.97,155.04,
115.43,64.16,56.19,55.90,52.79,46.57,43.81,43.75,38.60,37.93,37.56,35.49,
32.56,28.93,28.33,27.56,25.33,21.93,21.05,20.42,19.04,12.48.HRMS(ESI,m/z)
calcd.For C25H37BrNaO3,[M+Na]+487.1824,found487.1822.
Compound 6d：Yield：79%.1H NMR(400MHz,DMSO,ppm)δ5.90(s,1H),5.40(s,1H),
4.05-3.96 (m, 2H), 3.57 (t, J=6.6Hz, 2H), 2.03 (dd, J=22.9,8.5Hz, 2H), 1.97-1.90 (m,
2H), 1.86 (d, J=6.4Hz, 2H), 1.69 (ddd, J=13.7,11.0,5.1Hz, 6H), 1.64-1.54 (m, 4H), 1.55-
1.46 (m, 3H), 1.40-1.30 (m, 3H), 1.25 (dd, J=12.0,2.3Hz, 1H), 1.17 (s, 3H), 1.10-0.97 (m,
2H), (s, the 3H) of 0.90 (d, J=16.9Hz, 3H), 0.86 (dd, J=12.6,4.3Hz, 1H), 0.5413C NMR(101MHz,
DMSO,ppm)δ209.82,176.93,154.95,115.62,63.57,56.19,55.88,52.80,46.56,43.81,
43.74,38.60,37.96,37.92,37.56,35.09,32.56,29.73,28.91,28.31,27.33,25.35,
21.94,21.05,20.43,19.04,12.47.HRMS(ESI,m/z)calcd.For C27H41BrNaO3,[M+Na]+
515.2137,found 515.2133.
The synthesis of the compound 7 of embodiment 5
220mg compound 6b are taken, 15mL sealing reaction Rong Guanzhong, the dissolving of 5mL acetonitriles, plus 1mL trimethylamine aqueous solutions is placed in,
Enclosed system reacts 8 hours in 65 DEG C.After question response is complete, decompression boils off solvent, obtains yellow solid, silica gel column chromatography (dichloro
Methane/methyl alcohol 10:1) separate, obtain white crystals.Yield：85%.
1H NMR (400MHz, MeOD, ppm) δ 6.02 (s, 1H), 5.52 (s, 1H), 4.84 (s, 4H), 4.16 (dd, J=
17.5,11.3,6.2Hz, 2H), 3.29 (d, J=51.1Hz, 9H), 2.31-2.15 (m, 3H), 2.10 (dd, J=19.0,
5.3Hz, 2H), 1.99 (dt, J=13.5,3.1Hz, 1H), 1.74 (d, J=4.3Hz, 1H), 1.69 (d, J=6.6Hz, 2H),
1.55 (d, J=11.2Hz, 2H), 1.44-1.37 (m, 3H), 1.31 (dd, J=11.4,3.5Hz, 2H), 1.27 (s, 3H),
1.23-1.06(m,2H),0.98(s,3H),0.65(s,3H).13C NMR(101MHz,MeOD,ppm)δ212.70,178.50,
156.38,116.61,65.15,62.09,57.76,57.62,54.30,53.80,53.76,53.72,47.87,45.11,
45.06,41.33,39.76,s39.07,38.89,38.86,29.40,23.81,23.12,22.14,20.47,20.14,
13.18.HRMS(ESI,m/z)calcd.For C27H43NO3,[M-Br]+430.3237,found430.3239.。
The cancer cells in vitro inhibitory activity of embodiment 6 is tested
Human esophagus cancer cell Eca109, prostate gland cancer cell PC-3, the human gastric carcinoma cell line MGC803 are respectively with containing quality hundred
Divide than 10% hyclone, 100kUL-1 Pen .- Streps, DMEM (Dulbecco's modified eagle
Medium) high glucose medium is in 37 DEG C, volume fraction 5%CO2Under the conditions of cultivate.Cell survival rate MTT Determination Stainings.
There is reduction reaction in MTT, the formazane crystallizations of generation purple are dissolved in dimethyl sulfoxide under living cells mitochondria dehydrogenation enzyme effect
Show hyacinthine in (dimethyl sulfoxide, DMSO), there is larger light absorbs A490 at 490nm.
Take the logarithm the corresponding cell line in growth period, cell concentration is adjusted to 4 × 104mL respectively-1, 5 × 104mL-1, 3 ×
104mL-1With 4 × 104mL-1Add in 96 orifice plates, per the μ L of hole 200, be subsequently adding the test compounds of the various concentrations of certain volume
(0.02%) compound 6a~6d and 7, DMSO hydrotropy, DMSO be less than thing in the final concentration of cultivating system, and positive controls are etc.
The 5-Fu of volume, negative control group is the hyclone for containing mass percent 0.02%DMSO in equal volume.Each concentration respectively sets 5
Parallel group.In 37 DEG C, volume fraction 5%CO2After being incubated 72h in incubator, MTT 5gL are separately added into-1, per the μ L of hole 15, after
Continuous culture 4h, abandoning supernatant is subsequently adding DMSO dissolvings, per hole 150 μ L, 37 DEG C of constant-temperature incubations 10min, Ran Hou
A490 is measured on SpectraMax i3 ELIASAs.A490 data measured by the software processings of SPSS 19.0, obtain each compound
IC50。
IC of the compound of table 1 to JEG-350(μg/mL)
As can be seen from the table, the introducing of 15- methyl can improve the antitumor activity of iso steviol parent compound,
And the esterification of iso steviol carboxyl also has crucial effect to its bioactivity.Bromo monoester compound shows preferably
Cytotoxic activity.Wherein compound 6d shows preferable inhibitory activity to three groups of JEG-3s, especially to PC-3 and
The inhibitory activity of MGc803 cell lines is low up to 1.826 and 11.894 respectively, better than positive drug 5-Fu.The activity of quaternary ammonium salt derivative 7
It is weaker, certain inhibitory activity is only shown to Ec109.
Claims (6)
1. a kind of iso steviol compound of tetracyclic diterpene class, it is characterised in that：With structure shown in formula 1,
Wherein n=1-6.
2. the iso steviol compound of tetracyclic diterpene class as claimed in claim 1, it is characterised in that：N=2,3,4,6.
3. a kind of iso steviol compound of tetracyclic diterpene class, it is characterised in that：With structure shown in formula 2,
Wherein n=1-6.
4. the iso steviol compound of tetracyclic diterpene class as claimed in claim 3, it is characterised in that：Choosing such as following chemical combination
Thing:
5. the method for preparing the tetracyclic diterpene class iso steviol compound as described in claim 1 or 3, it is characterised in that pass through
Following steps are realized：(1) in organic solvent, iso steviol 1 and formaldehyde are reacted in the basic conditions, and reaction is steamed after terminating
Dry solvent, system is acidified with acid after adding water, and obtains the beta-hydroxy iso steviol 2 of 15 alpha-hydroxymethyl -16；
The organic solvent uses methyl alcohol, ethanol, isopropanol or the tert-butyl alcohol；Alkali selects caustic alcohol, sodium methoxide, potassium tert-butoxide, hydrogen
Sodium oxide molybdena, potassium hydroxide, the carbon -7- alkene of 1,8- diazabicylos 11 or DMAP；
(2) compound 2 and paratoluensulfonyl chloride react in organic solvent, and DMAP is as catalyst reaction
Compound 3；
Described organic solvent selects dichloromethane, tetrahydrofuran, acetonitrile, chloroform, toluene or 1,2- dichloroethanes；
(3) in organic solvent, compound 3 and oxidant react at room temperature, and reaction is filtered to remove solid impurity after terminating, and filter
Liquid is evaporated, and column chromatography obtains compound 4；
The oxidant uses Pyridinium dichromate, pyridinium chloro-chromate, manganese dioxide, Dai Si-Martin's oxidant or diformazan
Base sulfoxide；Organic solvent selects dichloromethane, acetonitrile, dioxane or tetrahydrofuran；
(4) compound 4 flows back to obtain 15- methylene compounds 5 in pyridine；
(5) in organic solvent, under alkalescence condition, compound 5 reacts with dibromoalkane, after question response is complete, boils off acetonitrile, adds
Water, extraction is washed after merging organic phase, separates organic phase, is dried, and vacuum distillation after filtering obtains product compound 6；
The dibromoalkane is 1,2- Bromofumes, 1,3- dibromopropane, Isosorbide-5-Nitrae-dibromobutane or 1,6- dibromo-hexane；
Organic solvent selects acetonitrile, DMSO, N,N-dimethylformamide, dioxane, tetrahydrofuran or dichloromethane；Alkali is selected
Potassium hydroxide, NaOH, potassium carbonate, sodium carbonate, pyridine, triethylamine, DMAP or diisopropylethylamine.
(6) bromo esterification products 6 and the trimethylamine confined reaction under the conditions of 30~100 DEG C in organic solvent, obtain compound 7；
The organic solvent selects acetonitrile, DMSO, DMF, dioxane, tetrahydrofuran, dichloromethane, methyl alcohol or ethanol；
6. the preparation method of tetracyclic diterpene class iso steviol compound according to claim 5, it is characterised in that described
Compound 2 is 1 with the mol ratio of paratoluensulfonyl chloride:1.1~2.5；Compound 5 is 0.8~1 with the mol ratio of dibromoalkane:1
~1.5.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108456240A (en) * | 2018-02-02 | 2018-08-28 | 山东大学 | Isosteviol derivant and its preparation and application |
| CN110642740A (en) * | 2019-09-04 | 2020-01-03 | 郑州工程技术学院 | Isostaviolamide derivative and preparation method thereof |
| CN110681875A (en) * | 2019-11-12 | 2020-01-14 | 新乡医学院 | Isosteviol metal gel and preparation method and application thereof |
| CN114933554A (en) * | 2022-06-01 | 2022-08-23 | 新乡医学院 | Injectable supramolecular hydrogel based on isosteviol and preparation method and application thereof |
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| CN102718658A (en) * | 2012-06-08 | 2012-10-10 | 浙江工业大学 | Isosteviol derivative as well as preparation method and application thereof |
| CN102718657A (en) * | 2012-06-08 | 2012-10-10 | 浙江工业大学 | Isosteviol compound as well as preparation method and application thereof |
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| CN102718657A (en) * | 2012-06-08 | 2012-10-10 | 浙江工业大学 | Isosteviol compound as well as preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108456240A (en) * | 2018-02-02 | 2018-08-28 | 山东大学 | Isosteviol derivant and its preparation and application |
| CN110642740A (en) * | 2019-09-04 | 2020-01-03 | 郑州工程技术学院 | Isostaviolamide derivative and preparation method thereof |
| CN110642740B (en) * | 2019-09-04 | 2022-06-14 | 郑州工程技术学院 | Isostaviolamide derivative and preparation method thereof |
| CN110681875A (en) * | 2019-11-12 | 2020-01-14 | 新乡医学院 | Isosteviol metal gel and preparation method and application thereof |
| CN110681875B (en) * | 2019-11-12 | 2022-05-17 | 新乡医学院 | Isosteviol metal gel and preparation method and application thereof |
| CN114933554A (en) * | 2022-06-01 | 2022-08-23 | 新乡医学院 | Injectable supramolecular hydrogel based on isosteviol and preparation method and application thereof |
| CN114933554B (en) * | 2022-06-01 | 2023-09-29 | 新乡医学院 | Isotevelol-based injectable supermolecular hydrogel and preparation method and application thereof |
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