CN106928068B - A kind of tetracyclic diterpene class iso steviol compound and the preparation method and application thereof - Google Patents
A kind of tetracyclic diterpene class iso steviol compound and the preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a kind of tetracyclic diterpene class iso steviol compounds and the preparation method and application thereof, belong to field of medicinal chemistry.Such compound contains alpha-methylene cyclopentanone structure fragment, and structure is as shown in Equation 1, and quaternary ammonium salt is as shown in Equation 2.It has preferable activity in terms of inhibiting human esophagus cancer cell strain Ec109, the human gastric carcinoma cell line MGC803 and human prostate cancer cell line PC-3.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 actions, belong to pharmaceutical chemistry neck
Domain.
Background technique
Natural products is the lead compound of drug 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 side effect is strong, poor activity or bioavilability are low and limit its clinical application.Therefore, to natural products into
The effective structural modification of row introduces special pharmacophoric group, obtains new derivatives, to improve its activity and availability, reduce
Toxicity is to develop the effective scheme of new type natural drug.In nature in miscellaneous bioactive natural product, terpenoid
Object exists extensively, has the characteristics that structure is complicated, many kinds of, diverse biological activities, is the effective way for finding natural drug
Diameter, such as qinghaosu, taxol, andrographolide clinical commonly used drug are all the terpenoids that separation is extracted from plants.
Diterpene-kind compound is the various structures found in addition to sequiterpene, the most abundant terpene natural products of type.
Iso steviol (isosteviol, Isosteviol) is the Si Te obtained by natural products stevioside through acidic hydrolysis
Tie up the product that alcohol is reset.Research shows that its anticancer, antibacterial, myocardial damage reparation, it is antiviral and in terms of show
Certain bioactivity.Wherein, the research of anti-tumor 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 fragment1For acetoxyl group or hydroxyl, R2For
Ethyl, propyl, isopropyl, benzyl, normal-butyl, sec-butyl or isobutyl group), all esterified group R2For alkyl, aryl, esterification
There is no the introducing of polar group on substituent group.
Paper (Bioorganic&Medicinal Chemistry Letters 21 (1): 130-132) reports one kind
Containing α, alpha, beta-unsaturated ketone analog derivative (formula 6), active testing is the result shows that these transformations all greatly improve different Si Tewei
The anti-tumor activity of alcohol parent compound, however the research only has a kind of substituent group of benzyl ester.Kataev etc. is reported
(Pharmaceutical Chemistry Journal 44 (11): 597-600) introduces quaternary ammonium salt on iso steviol skeleton
Structure fragment (formula 5).Activity research discovery, which introduces quaternary ammonium salt structure, can significantly improve antibacterial activity, and effect is mould better than positive drug gram
Azoles and Ciprofloxacin, however ethylene quaternary ammonium salt ester has only been investigated in the research, and is free of alpha-methylene cyclopentanone structure, is not also had
There is investigation anti-tumor activity.
In view of the activity of iso steviol itself is lower, dissolubility is poor, so many researchs are improved by structure of modification
These factors are to improving activity.In the Diterpenes natural products having found, α, alpha, beta-unsaturated ketone is proved to be a kind of crucial
Pharmacophoric group, and having an effect with the sulfydryl enzyme in tumour cell have preferable cytotoxicity.In addition, polar group
Introducing will increase the dissolubility of hydrophobic tetracyclic diterpene compound and with the binding force of target molecule to improve biological benefit
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 to be of great significance.
Summary of the invention
The purpose of the present invention is by α, alpha, beta-unsaturated ketone segment is introduced on iso steviol D- ring, and passes through carboxyl and be transformed
Different esters is introduced for group, is synthesized containing α, alpha, beta-unsaturated ketone segment and halogenated alkyl and quaternary ammonium salt isopolarity segment
Novel iso steviol derivative another object is to provide the synthetic method of such compound and its in antitumor aspect of performance
Using.
To achieve 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 mild synthetic method, and have studied the antitumor of compound
Performance.
The technical solution adopted by the invention is as follows:
1. the present invention provides iso steviol compound shown in a kind of formula 1 and 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 iso steviol derivative, the reaction process is as follows:
The specific method is as follows:
(1) in organic solvent, iso steviol 1 and formaldehyde react under alkaline condition, are evaporated after reaction molten
Agent, system are acidified with acid after adding water, obtain -16 beta-hydroxy iso steviol 2 of 15 alpha-hydroxymethyl；
The organic solvent uses methanol, ethyl alcohol, isopropanol or the tert-butyl alcohol；Alkali selects sodium ethoxide, sodium methoxide, the tert-butyl alcohol
Potassium, sodium hydroxide, potassium hydroxide, 11 carbon -7- alkene (DBU) of 1,8- diazabicylo or 4-dimethylaminopyridine (DMAP)；
(2) compound 2 and paratoluensulfonyl chloride react in organic solvent, and DMAP obtains compound 3 as catalyst reaction；
The organic solvent selects methylene chloride, tetrahydrofuran (THF), acetonitrile, chloroform, toluene, 1,2- dichloroethanes；
The molar ratio of the compound 2 and paratoluensulfonyl chloride is 1:1.1~2.5, preferably 1:2；
(3) in organic solvent, compound 3 and oxidant react at room temperature, and it is miscellaneous to be filtered to remove solid after reaction
Matter, filtrate are evaporated, and column chromatographs to obtain compound 4；
The oxidant uses Pyridinium dichromate (PDC), pyridinium chloro-chromate (PCC), manganese dioxide, Dai Si-horse
Fourth oxidant (DMP) or dimethyl sulfoxide (DMSO)；Organic solvent selects methylene chloride, acetonitrile, dioxane or tetrahydrofuran；
(4) compound 4 flows back to obtain 15- methylene compound 5 in pyridine；
(5) in organic solvent, under alkaline condition, compound 5 is reacted with dibromoalkane, after complete reaction, boils off acetonitrile,
Water is added, extraction washs after merging organic phase, separates organic phase, be evaporated under reduced pressure after drying, filtering, obtain product compound 6；
The dibromoalkane is 1,2- Bromofume, 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, sodium hydroxide, potassium carbonate, sodium carbonate, pyridine, triethylamine, DMAP or diisopropylethylamine.
The molar ratio of compound 5 and dibromoalkane is 0.8~1:1~1.5, preferably 1:1；
(6) (4~10 is small for confined reaction under the conditions of 30~100 DEG C in organic solvent for bromo esterification products 6 and trimethylamine
When), obtain compound 7；It is preferred that 65 DEG C, preferably 8 hours.
The organic solvent selects acetonitrile, DMSO, DMF, dioxane, tetrahydrofuran, methylene chloride, methanol or ethyl alcohol.
The molar ratio of compound 6 and trimethylamine is 1:1.5~3, and preferably 1:2.3, trimethylamine is trimethylamine aqueous solution.
3. the present invention also provides the isosteviol compounds to inhibit 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 present invention has the advantage that
1. novel containing Alpha-Methyl cyclopentanone and bromo Arrcostab or quaternary ammonium salt isopolarity base the present invention provides a kind of
The new derivatives of group；
2. iso steviol compound tool provided by the invention well has anti-tumor activity, research base is provided for new medicament screen
Plinth and lead compound have preferable application prospect；
3. iso steviol compound preparation flow of the present invention is simple, raw material is cheap and easy to get, and reaction condition is mild, post-processing
Simply, high income, up to 79% or more, solvent recoverable is conducive to industrialization production.
Specific embodiment
In order to better implement the present invention, now for embodiment, the invention will be further described, but these embodiments are only
It is for illustrating the present invention, but embodiment is not limitation of the present invention.
The preparation of 1 compound 2 and 3 of embodiment
It takes 250mL dehydrated alcohol to be placed in 500mL reaction flask, the metallic sodium of 6.0g is added, after metallic sodium reacts completely,
9.8g compound 1 is added, magnetic agitation, system is warming up to 50 DEG C, adds 20mL formalin, the reaction was continued 3 hours extremely
TLC tracking reaction terminates.Reaction system is poured into 500mL distilled water, system dilute hydrochloric acid adjusts pH to 5, has in system big
White flock precipitate is measured, the crude product of dry 10g compound 2 is filtered, purifies without isolation, is directly used in and reacts in next step.It takes
2 crude product of 4.5g compound, is placed in 100mL reaction flask, and after adding 30mL pyridinium dissolution, tolysulfonyl is added under stirring
Chlorine 3.6g and DMAP 60mg reacts 3 hours at room temperature.After complete reaction, pyridine is boiled off, 50mL water is added, with quality percentage
Than 10% hydrochloric acid regulation system pH to 5-6.The extraction of 3 × 30mL ethyl acetate, merges organic phase, and saturated common salt water washing separates
Organic phase anhydrous sodium sulfate is evaporated under reduced pressure after drying, filtering, and obtains yellow oily liquid.Silica gel column chromatography (petrol ether/ethyl acetate
It 3:1) separates, obtains 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 2 compound 4 of embodiment
3.5g compound 3 is taken, is placed in 50mL reaction flask, 20mL methylene chloride is added to dissolve, stirs 10 minutes, adds under ice bath
Enter 1.88g PDC oxidant, reacts 3 hours at room temperature.TLC detection pads filtration system after completion of the reaction with diatom, and filter cake is used
The washing of 30mL methylene chloride, concentration filtrate obtain crude product.Silica gel column chromatography (petrol ether/ethyl acetate 3:1) separation, obtains 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 3 compound 5 of embodiment
Take 440mg compound 4, be placed in 25mL reaction flask, add 5mL pyridinium dissolution, then plus 80mg DMAP, be heated to reflux 3
Hour.Pyridine is boiled off after thin-layer chromatography detection fully reacting, 10mL water is added, with 10% hydrochloric acid regulation system pH of mass percent
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 evaporated under reduced pressure after drying, filtering, and obtains yellow oily liquid.Silica gel column chromatography (petrol ether/ethyl acetate 3:1) separation, obtains
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 4 compound 6a~6d of embodiment synthesis
5mmol compound 5 is taken, is placed in 50mL reaction flask, adds 30mL acetonitrile to dissolve, 8mmol is added under stirring
The dibromoalkane of 5mmol is then added in potassium carbonate, reacts 4 hours at room temperature.After complete reaction, acetonitrile is boiled off, 30mL is added
Water, 3 × 15mL ethyl acetate extraction, merges saturated common salt water washing after organic phase, separates organic phase, and anhydrous sodium sulfate is dry,
It is evaporated under reduced pressure after filtering, obtains white solid.Silica gel column chromatography (petrol ether/ethyl acetate 8:1) separation, obtains 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), 0.90 (d, J=16.9Hz, 3H), 0.86 (dd, J=12.6,4.3Hz, 1H), 0.54 (s, 3H)13C 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 5 compound 7 of embodiment
220mg compound 6b is taken, 15mL sealing reaction Rong Guanzhong is placed in, the dissolution of 5mL acetonitrile adds 1mL trimethylamine aqueous solution,
Enclosed system reacts 8 hours in 65 DEG C.After complete reaction, decompression boils off solvent, obtains yellow solid, silica gel column chromatography (dichloro
Methane/methanol 10:1) separation, 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 test of 6 cancer cells in vitro inhibitory activity of embodiment
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 ratio 10% fetal calf serum, 100kUL-1 Pen .- Strep, DMEM (Dulbecco's modified eagle
Medium) high glucose medium is at 37 DEG C, volume fraction 5%CO2Under the conditions of cultivate.Cell survival rate MTT Determination Staining.
Under living cells mitochondria dehydrogenation enzyme effect reduction reaction occurs for MTT, generates purple formazane crystallization, is dissolved in dimethyl sulfoxide
Hyacinthine is shown in (dimethyl sulfoxide, DMSO), there is larger light absorption A490 at 490nm.
The corresponding cell strain of logarithmic growth phase, is adjusted to 4 × 104mL for cell concentration respectively-1, 5 × 104mL-1, 3 ×
104mL-1With 4 × 104mL-1It is added in 96 orifice plates, every 200 μ L of hole, the test compounds of the various concentration of certain volume is then added
Object (compound 6a~6d and 7, DMSO hydrotropy, DMSO cultivating system final concentration less than 0.02%), positive controls are etc.
The 5-Fu of volume, negative control group are the fetal calf serum of the 0.02%DMSO containing mass percent in equal volume.Each concentration respectively sets 5
Parallel group.At 37 DEG C, volume fraction 5%CO2After being incubated for 72h in incubator, it is separately added into MTT 5gL-1, every 15 μ L of hole, after
Continuous culture 4h, discards supernatant liquid, is then added DMSO dissolution, then 150 μ L of every hole, 37 DEG C of constant-temperature incubation 10min exist
A490 is measured in SpectraMax i3 microplate reader.The measured A490 data of 19.0 software of SPSS processing, obtain each compound
IC50。
IC of 1 compound of table to cancer cell line50(μg/mL)
As can be seen from the table, the introducing of 15- methyl can improve the anti-tumor activity of iso steviol parent compound,
And the esterification of iso steviol carboxyl also has crucial effect to its bioactivity.Bromo monoester compound is shown preferably
Cytotoxic activity.Wherein compound 6d shows preferable inhibitory activity to three groups of cancer cell line, especially to PC-3 and
The inhibitory activity of MGc803 cell strain down to 1.826 and 11.894, is better than positive drug 5-Fu respectively.7 activity of quaternary ammonium salt derivative
It is weaker, certain inhibitory activity is only shown to Ec109.
Claims (2)
1. the preparation method of tetracyclic diterpene class iso steviol compound of the general formula as described in 7, which is characterized in that pass through following step
It is rapid to realize:
Wherein n=2,3,4,6；
(1) in organic solvent, iso steviol 1 and formaldehyde react under alkaline condition, after reaction solvent evaporated, body
It is acidified with acid after system plus water, obtains -16 beta-hydroxy iso steviol 2 of 15 alpha-hydroxymethyl；
The organic solvent uses methanol, ethyl alcohol, isopropanol or the tert-butyl alcohol；Alkali selects sodium ethoxide, sodium methoxide, potassium tert-butoxide, hydrogen
Sodium oxide molybdena, potassium hydroxide, 11 carbon -7- alkene of 1,8- diazabicylo or 4-dimethylaminopyridine；
(2) compound 2 and paratoluensulfonyl chloride react in organic solvent, and 4-dimethylaminopyridine is as catalyst reaction
Close object 3；
The organic solvent selects methylene chloride, tetrahydrofuran, acetonitrile, chloroform, toluene or 1,2- dichloroethanes；
(3) in organic solvent, compound 3 and oxidant react at room temperature, are filtered to remove solid impurity after reaction, filter
Liquid is evaporated, and column chromatographs to obtain compound 4；
The oxidant uses Pyridinium dichromate, pyridinium chloro-chromate, manganese dioxide, Dai Si-Martin's oxidant or diformazan
Base sulfoxide；Organic solvent selects methylene chloride, acetonitrile, dioxane or tetrahydrofuran；
(4) compound 4 flows back to obtain 15- methylene compound 5 in pyridine；
(5) in organic solvent, under alkaline condition, compound 5 is reacted with dibromoalkane, after complete reaction, boils off acetonitrile, is added
Water, extraction wash after merging organic phase, separate organic phase, be evaporated under reduced pressure after drying, filtering, obtain product compound 6；
The dibromoalkane is 1,2- Bromofume, 1,3- dibromopropane, Isosorbide-5-Nitrae-dibromobutane or 1,6- dibromo-hexane；
Organic solvent selects acetonitrile, DMSO, N,N-dimethylformamide, dioxane, tetrahydrofuran or methylene chloride；Alkali is selected
Potassium hydroxide, sodium hydroxide, 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, obtains compound 7；
The organic solvent selects acetonitrile, DMSO, DMF, dioxane, tetrahydrofuran, methylene chloride, methanol or ethyl alcohol.
2. the preparation method of tetracyclic diterpene class iso steviol compound according to claim 1, which is characterized in that described
The molar ratio of compound 2 and paratoluensulfonyl chloride is 1:1.1~2.5；The molar ratio of compound 5 and dibromoalkane is 0.8~1:1
~1.5.
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