CN102731610B - 26 sulfo-s or seleno spirostanol saponin, its synthetic method and application - Google Patents

26 sulfo-s or seleno spirostanol saponin, its synthetic method and application Download PDF

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CN102731610B
CN102731610B CN201210241555.6A CN201210241555A CN102731610B CN 102731610 B CN102731610 B CN 102731610B CN 201210241555 A CN201210241555 A CN 201210241555A CN 102731610 B CN102731610 B CN 102731610B
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seleno
sulfo
acid
spirostanol saponin
spirostanol
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CN102731610A (en
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李明
陈朋伟
王鹏
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Ocean University of China
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Abstract

The present invention relates to a kind of 26 sulfo-s or seleno spirostanol saponin and chemical synthesis process thereof, the method comprises the steps: (1) 26 sulphonates of pseudo-spirostanol saponin unit and the nucleophilic reagent of sulphur or selenium react, and obtain 26 S or Se substitution products; (2) again with alkali, or reductive agent and acid-respons obtain 26 sulfo-s or seleno spirostanol saponin unit; (3) continue with acyl group, silica-based protection rhamnosyl three chlorimide ester to precursor reactant, obtain chacotriose sulphur glycosides, then through hydrolysis, with Trichloroacetonitrile react be converted into chacotriose three chlorimide esters to body; (4) react with the glycosyl donor of acyl group, alkyl and silica-based protection again, at the chacotriose that its 3 OH introduce full guard, obtain 26 sulfo-s of the full guard of α, β two kinds of configurations or the spirostanol saponin of seleno; (5) slough all protecting groups and obtain 26 sulfo-s or seleno spirostanol saponin.This compounds has stronger anti-tumor activity, can be used for the preparation of antitumor drug.

Description

26 sulfo-s or seleno spirostanol saponin, its synthetic method and application
Technical field
The invention belongs to pharmaceutical synthesis field, relate to a kind of sulfo-or seleno spirostanol saponin and chemical synthesis process thereof and the application at anti-tumor aspect.
Technical background
Spirostanol saponin distributes widely in plant, and it has multiple biological activity: the activity of antitumor, antiviral, antibacterial, antiphlogistic activity and immune stimulatory.Dioscin is one of representational spirostanol saponin of most, has now become the saponin(e [Viviane, the S.P. that are widely used in medical treatment most; Alemandre, T.C.; Taketa, G.G. j.Braz.Chem.Soc.2002, 13, 135 – 139].A large amount of experiments shows that the activity of spirostanol saponin is determined jointly by sugar chain and aglycon, on the steric configuration of the number size of sugar chain, the type of glycosyl, glycosidic link, position and glycosyl hydroxyl isomerization, to replace etc. and all can produce material impact to the activity of saponin(e.
Sulphur and selenium are as the classical bioisostere of oxygen, be often used in the composition optimizes of lead compound, in addition, organosulfur and selenium compound are because its good biological activity, be subject to everybody in recent years and more and more pay attention to [(a) Yang Zhannan, Yang your pupil guizhou Normal University's journal, 2004, 22, 104 – 112; (b) Hu, C.; Zhang, P.; Li, Y.; Liu, B. chemistry, 2002, 3, 162 – 166; (c) Govindasamy, M.; Wolf-Walther, M.; Helmut, S.; chem.Rev.2001, 101, 2125 – 2179].Although have report [(a) Uhle, the F.C. of the spirostanol saponin unit chemosynthesis replaced about sulphur or selenium; j.Org.Chem.1962, 27, 2797 – 2799; (b) Quan, H.J.; Koyanagi.J.; Ohmori, K.; Uesato, S.; Tsuchido, T.; Saito, S. eur.J.Med.Chem.2002, 37, 659 – 669], but also do not find at present about 26-position sulfo-or the synthesis of seleno spirostanol saponin and the report of application thereof.
Summary of the invention
An object of the present invention is to provide a kind of with pseudo-spirostane type sapogenin and chacotriose be Material synthesis 26 sulfo-s or seleno spirostanol saponin.
Another object of the present invention is to provide the chemical synthesis process of above-mentioned sulfo-or seleno spirostanol saponin, and it is in the application of anti-tumor aspect.
26 sulfo-s of the present invention or seleno spirostanol saponin structure as follows:
R 1-R 8for any one in hydrogen, acyl group or alkyl;
Chacotriose and derivative thereof are connected with aglycon α or β glycosidic link;
Described acyl group is C 2-C 6straight or branched aliphatic acyl radical or C 6-C 10aromaticacyl radical;
Described alkyl be methyl (Me), ethyl (Et), n-propyl ( n-Pr) or sec.-propyl ( i-Pr);
The absolute configuration of 22 carbon of described spirostanol saponin is r, the absolute configuration of 25 carbon is ror s.
The synthetic method of described 26 sulfo-s or seleno spirostanol saponin comprises the steps:
The synthesis of (1) 26 sulfo-or the pseudo-spirostanol saponin unit of seleno:
In a solvent or under phase-transfer catalyst exists, 26 sulphonates of pseudo-spirostanol saponin unit and the nucleophilic reagent of S or Se react, and obtain the product of corresponding 26 S or Se replacement;
The synthesis of (2) 26 sulfo-s or seleno spirostanol saponin unit:
Under 0-150 DEG C of condition, the pseudo-spirostanol saponin unit that 26 S or Se replace and alkali, or reductive agent and acid-respons obtain 26 sulfo-s or seleno spirostanol saponin unit;
(3) chacotriose is to the preparation of body:
In the presence of a dehydrating agent, with Lewis acid or protonic acid for promotor, 3, the rhamnosyl three chlorimide ester of 6-bis--oxygen-benzoyl-β-D-Glucose sulphur glycosides and acyl group, silica-based protection is to precursor reactant, obtain chacotriose sulphur glycosides, then through hydrolysis, with Trichloroacetonitrile react be converted into chacotriose three chlorimide esters to body;
The introducing of (4) 3 glycosyls:
In the presence of a dehydrating agent, with Lewis acid or protonic acid for promotor, 26 sulfo-s or seleno spirostanol saponin unit react with the glycosyl donor of acyl group or alkyl and silica-based protection, introduce the chacotriose of full guard at its 3 OH, obtain 26 sulfo-s of the full guard of α, β two kinds of configurations or the spirostanol saponin of seleno;
The synthesis of (5) 26 sulfo-s or seleno spirostanol saponin:
In the presence of a base, all protecting groups of sloughing the spirostanol saponin of full guard respectively obtain 26 sulfo-s or seleno spirostanol saponin or derivatives thereof.
Concrete each step is as follows:
The synthesis of (1) 26 sulfo-or the pseudo-spirostanol saponin unit of seleno:
In a solvent or under phase-transfer catalyst exists, the sulphonate of 26 pseudo-spirostanol saponin units and the nucleophilic reagent of sulphur or selenium react 1-10 hour under 0-150 DEG C of condition, obtain the product of 26 S or Se replacements; Wherein, the mol ratio of sulphonate and nucleophilic reagent is 1.0:(1.0-5.0);
Described solvent is organic solvent, water or their mixture;
Described organic solvent is C 1-C 6halohydrocarbon, 1,4 – dioxane, ether (Et 2o), acetonitrile (CH 3cN), 2,2,2 – trimethylacetonitriles ( t-BuCN), tetrahydrofuran (THF) (THF), n, n– dimethyl formamide (DMF), n, na kind of in – N,N-DIMETHYLACETAMIDE (DMA), hexamethylphosphoramide (HMPA), toluene or their mixture;
Described nucleophilic reagent is KSCOCH 3, Na 2s 2, Li 2s 2, Cs 2s 2, K 2s 2in any one or KSeCOCH 3, Na 2se 2, Li 2se 2, Cs 2se 2, K 2se 2in any one;
Described phase-transfer catalyst is the one in Tetrabutyl amonium bromide (TBAB), tetrabutylammonium iodide (TBAI), 4-butyl ammonium hydrogen sulfate (TBAH), 18-hat-6 (18-C-6), PEG-4000 (PEG-400).
The preparation of (2) 26 sulfo-s or seleno spirostanol saponin unit:
In a solvent with at 0-150 DEG C, the hydrolysis refluxing in an acidic solution under alkali effect of the pseudo-spirostanol saponin unit of the replacement of above-mentioned S or Se, or reduce with reductive agent under acetic acid exists and within 0.1-10 hour, obtain 26 sulfo-s or seleno spirostanol saponin is first; The mol ratio 1.0:(2.0-20.0 of described substitution product and alkali or reductive agent): (2.0-5.0);
Described alkali can be mineral alkali, as the one in sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate, salt of wormwood, cesium carbonate; Also can be the one in organic bases potassium tert.-butoxide, sodium methylate, sodium ethylate, magnesium methylate;
Described acidic solution is hydrochloric acid methanol or the ethanolic soln of 0.1-1mol/L.
(3) chacotriose is to the preparation of body:
In organic solvent with under the existence of dewatering agent, at-78-40 DEG C, with Lewis acid or protonic acid for promotor, 3, the rhamnosyl three chlorimide ester of 6-bis--oxygen-benzoyl-β-D-Glucose sulphur glycosides and acyl group, silica-based protection is to precursor reactant 1-10 hour, obtain chacotriose sulphur glycosides, then through hydrolysis, react be converted into trisaccharide three chlorimide ester to body with Trichloroacetonitrile;
3,6-, bis--oxygen-benzoyl-β-D-Glucose sulphur glycosides and rhamnosyl are 1.0:(1.0-5.0 to the mol ratio of body and promotor): (0.05-0.5); The weight ratio of 3,6-, bis--oxygen-benzoyl-β-D-Glucose sulphur glycosides and dewatering agent is 1.0:(3.0-10.0);
Described dewatering agent is a kind of in 3 molecular sieves (AW-3) of 3,4,5 molecular sieves or pickling or anhydrous sodium sulphate, anhydrous calciumsulphate, anhydrous cupric sulfate, anhydrous magnesium sulfate or their mixture;
Described Lewis acid is C 1-C 6one in trialkyl silyl triflate, boron trifluoride diethyl etherate, silver trifluoromethanesulfonate, copper trifluoromethanesulfcomposite, trifluoromethanesulfonic acid zinc, trifluoromethanesulfonic acid scandium, trifluoromethanesulfonic acid lanthanum, Ytterbiumtriflate, trifluoromethanesulfonic acid indium, trifluoromethanesulfonic acid, perchloric acid, Tetrafluoroboric acid, four (phenyl-pentafluoride base) boric acid or two (fluoroform sulphonyl) imines;
Described acyl group is C 1-C 8fatty acyl group, C 6-C 10aromaticacyl radical, C 7-C 10aromatic halohydrocarbons (as Benzyl Chloride, to methoxyl group benzyl chloride), silica-based be C 1-C 6trialkyl silyl.
The introducing of (4) 3 chacotrioses:
Under existing with dewatering agent in organic solvent, at-78-40 DEG C, with Lewis acid or protonic acid for promotor, 26 sulfo-s and seleno spirostanol saponin unit with acyl group or/and the potato three chlorimide ester of silica-based protection is to precursor reactant 1-10 hour, introduce the chacotriose of full guard at its 3 OH, obtain 26 sulfo-s or the seleno spirostanol saponin of the full guard of α and β two kinds of configurations;
26 described sulfo-s or seleno spirostanol saponin unit are 1.0:(1.0-5.0 with the mol ratio of glycosyl acceptor and promotor): (0.05-0.5); The weight ratio 1.0:(3.0-10.0 of 26 sulfo-s and seleno spirostanol saponin unit and dewatering agent);
Described dewatering agent is a kind of in 3 molecular sieves (AW-3) of 3,4,5 molecular sieves or pickling or anhydrous sodium sulphate, anhydrous calciumsulphate, anhydrous cupric sulfate, anhydrous magnesium sulfate or their mixture;
Described Lewis acid is C 1-C 6one in trialkyl silyl triflate, boron trifluoride diethyl etherate, silver trifluoromethanesulfonate, copper trifluoromethanesulfcomposite, trifluoromethanesulfonic acid zinc, trifluoromethanesulfonic acid scandium, trifluoromethanesulfonic acid lanthanum, Ytterbiumtriflate, trifluoromethanesulfonic acid indium, trifluoromethanesulfonic acid, perchloric acid, Tetrafluoroboric acid, four (phenyl-pentafluoride base) boric acid or two (fluoroform sulphonyl) imines;
Described glycosyl donor is C 1-C 8straight or branched aliphatic acyl radical, C 7-C 10aromaticacyl radical, silica-based be C 1-C 6trialkyl silyl is protected.
The synthesis of (5) 26 sulfo-s or seleno spirostanol saponin:
In a solvent, under-20-60 DEG C of condition, 26 sulfo-s of α and/or β two kinds of configurations of full guard or seleno spirostanol saponin respectively in the presence of a base, react and within 10-60 hour, slough 26 sulfo-s or the seleno spirostanol saponin that all protecting groups obtain α and/or β two kinds of configurations; Described alkali is inorganic or organic bases; The mol ratio of the spirostanol saponin of described full guard and alkali or hydrogenation catalyst is 1.0:(0.2-20);
Described alkali can be mineral alkali, as the one in sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate, salt of wormwood, cesium carbonate; Also can be the one in organic bases potassium tert.-butoxide, sodium methylate, sodium ethylate, magnesium methylate.
Method of the present invention is carried out, as argon gas, nitrogen etc. under being recommended in protection of inert gas.
26 sulfo-s described in the present invention or seleno spirostanol saponin are preparing the application in antitumor drug.
The invention provides the chemical process of a kind of easy, effective synthesis 26 sulfo-s or seleno spirostanol saponin and derivative thereof, this compounds has stronger anti-tumor activity, can be used for the preparation of antitumor drug.
Accompanying drawing explanation
Fig. 1 is the building-up process of 26 sulfo-s or seleno diosgenin.
Fig. 2 is 26 sulfo-s or seleno dioscin 13 β, the building-up process of 14 β and isomer 13 α and 14 α.
Embodiment
Below in conjunction with accompanying drawing, and with the preparation of 26 sulfo-s and seleno diosgenin and αisomer thereof be antitumorly applied as specific embodiment the present invention is described in detail, but the invention is not restricted to following content.
The synthesis of (1) 26 sulfo-or seleno diosgenin
As shown in Figure 1, the reagent in the building-up reactions of 26 sulfo-s or seleno diosgenin and condition are: (a) KSCOCH 3, DMF, 60 DEG C, 96%; (b) (i) KOH, MeOH, H 2o; (ii) HCl, EtOH, H 2o, reflux, 87%; (c) CsOHH 2o, Se, N 2h 4h 2o, DMF, 60 DEG C, 92%; (d) (i) Zn, CH 3cOOH, 150 oc; (ii) KOH, EtOH, H 2o, dioxane, 87%.
Specific experiment process and data as follows:
The synthesis of compound 2:
Under argon shield, by sulphonate 1 (369mg, 0.65mmol) [(a) Uhle, F.C. j.Org.Chem.1962, 97, 2797 – 2799; (b) Zha, X.; Sun, H.; Hao, J.; Zhang, Y. chem.Biodiv.2007, 4, 25 – 31] be dissolved in 5mLDMF, then add KSCOCH 3(222mg, 1.95mmol, 3.0equiv.).Reaction is after stirring at room temperature 10h, and TLC display reacts completely, concentrating under reduced pressure, CH 2cl 2wash through saturated NaCl after dilution, Na 2sO 4drying, filtration, the compound 2 (295mg, 0.62mmol, 96%) that concentrated, rapid column chromatography obtains 26 ethanethioyls replacements.
[α] =-22.8( c1.00,CHCl 3)；
1HNMR(600MHz,CDCl 3): δ5.32(d,1H, J=5.4Hz),4.73-4.69(m,1H),3.51-3.47(m,1H),2.91(dd,1H, J=13.2,5.4Hz),2.75(dd,1H, J=13.2,7.2Hz),2.44(d,1H, J=10.2Hz),2.30(s,3H),1.56(s,3H),1.00(s,3H),0.93(d,3H, J=6.6Hz),0.66(s,3H)。
13CNMR(150MHz,CDCl 3): δ195.9,151.3,140.8,121.3,103.7,84.2,71.5,64.1,54.9,50.0,43.2,42.2,39.4,37.2,36.5,35.6,34.0,33.2,32.8,32.1,31.5,31.2,30.6,23.2,20.9,19.3,18.9,13.9,11.6。
HRMS (ESI): [M+H] +, C 29h 45o 3s, calculated value: 473.3084; Measured value: C 29h 45o 3s473.3090.
The synthesis of compound 3:
Under argon shield, compound 2 (295mg, 0.62mmol) is dissolved in 20ml methyl alcohol, then adds the methanol/water (MeOH:H that 5mL contains KOH (70mg, 1.23mmol, 2.0equiv.) 2o=9:1) solution.Mixture is after stirring at room temperature reaction 15min, and TLC display reacts completely, and then adds 6mol/L aqueous hydrochloric acid (320 μ L, 1.87mmol, 3.0equiv.), and after stirring at room temperature 30min, preserves 12h, solid collected by filtration in 0 DEG C.This solid after drying, is dissolved in the ethanol/water (EtOH:H of 20mL under argon shield 2o=19:1) in mixing solutions, then add the dense HCl of 0.5mL37%, after reflux 5h, cool, to pour in frozen water, filter, collect solid, be further purified to obtain the spirostanol saponin unit 3 (209mg that replaces of 26 S through rapid column chromatography, 0.48mmol, 87%).
[α] =-162.7( c1.10,CHCl 3)；
1HNMR(600MHz,CDCl 3): δ5.34(d,1H, J=4,8Hz),4.62(dd,1H, J=15.0,7.2Hz),3.55-3.48(m,1H),2.52(t,1H, J=13.2Hz),2.28(d,2H, J=13.2Hz),2.22(t,1H, J=12.6Hz),1.01(s,3H),1.00(d,3H, J=8.4Hz),0.92(d,3H, J=6.6Hz),0.80(s,3H)。
13CNMR(150MHz,CDCl 3): δ140.8,121.4,97.5,81.6,71.7,62.8,56.6,50.0,44.4,42.2,40.3,39.7,38.5,37.2,36.6,33.3,32.1,32.0,31.7,31.6,31.41,31.38,22.4,20.8,19.4,16.5,16.2。
HRMS (ESI): [M+H] +, C 27h 43o 2s, calculated value: 431.2978; Measured value: C 27h 43o 2s431.2983.
The synthesis of compound 4:
Under argon shield, by CsOHH 2o (76mg, 0.45mmol), selenium powder (23.7mg, 0.30mmol) adds in 2mLDMF, drips N at room temperature condition 2h 4h 2o (55 μ l, 0.90mmol), after stirring reaction 2h, adds sulphonate 1 (171mg, 0.30mmol), is then warming up to 60 DEG C, after continuing to stir 4h, and concentrating under reduced pressure.Resistates CH 2cl 2after dilution, wash through saturated NaCl.Organic phase Na 2sO 4drying, filters, concentrated, Flash silica column chromatography obtains diselenide 4 (132mg, 0.14mmol, 92%).
[α] =34.2( c1.21,CHCl 3)；
1HNMR(600MHz,CDCl 3) δ5.34(d,2H, J=4.8Hz),4.75-4.70(m,2H),3.53-3.49(m,2H),3.02(dd,2H, J=12.0,5.4Hz),2.82(dd,2H, J=12.0,7.8Hz),2.45(d,2H, J=10.2Hz),2.30(m,4H),2.22(t,4H, J=10.8Hz)1.58(s,6H),1.01(s,6H),0.99(d,6H, J=6.6Hz),0.68(s,6H)。
13CNMR(150MHz,CDCl 3) δ151.5,140.8,121.3,103.7,84.3,71.6,64.2,55.0,50.0,43.2,42.2,39.5,39.1,37.2,36.6,34.1,33.9,33.8,32.2,31.6,31.2,23.4,21.0,19.5,19.4,14.0,11.7。
The synthesis of compound 5:
Under argon shield, in the mixture of diselenide 4 (286mg, 0.30mol) and zinc powder (59mg, 0.90mmol, 3.0eqiuv.), add 30mL acetic acid, after heating reflux reaction 24h, TLC display reacts completely.The resistates that concentrating under reduced pressure obtains, is dissolved in the dioxane of 25mL under argon shield, then adds the ethanol/water mixing solutions (EtOH:H of 20mL10%KOH 2o=1:1), in, after stirring at room temperature 24h, in reaction solution impouring frozen water, CH is used 2cl 2extraction.Organic phase is washed through saturated NaCl, Na 2sO 4dry, filter, concentrated, rapid column chromatography obtains compound 5 (250mg, 0.52mmol, 87%).
[α] =-192.8( c1.00,CHCl 3)；
1HNMR(600MHz,CDCl 3): δ5.34(d,1H, J=4.8Hz),4.64(dd,1H, J=15.6,7.8Hz),3.53-3.50(m,1H),2.58(t,1H, J=12.0Hz),2.37-2.34(m,1H),2.31-2.28(m,1H),2.25-2.20(m,2H),2.04-1.97(m,2H),1.02(d,3H, J=7.2Hz),1.01(s,3H),0.96(d,3H, J=6.6Hz),0.80(s,3H)。
13CNMR(150MHz,CDCl 3): δ140.8,121.4,97.9,82.7,71.7,62.9,56.6,50.0,45.4,42.2,40.4,40.1,39.7,37.2,36.6,34.0,32.6,32.0,31.6,31.4,31.1,24.8,23.7,20.8,19.4,17.7,16.6。
(2) chacotriose is to the synthesis of body, 26 sulfo-s or seleno dioscin and αisomer thereof
As shown in Figure 2, chacotriose is to body 10,26 sulfo-s or seleno dioscin 13 β, and the reagent in the building-up reactions of 14 β and isomer 13 α and 14 α and condition are: (a) TMSOTf, CH 2cl 2,-30 oc; (b) NBS, acetone-H 2o, 72%(2 walk reaction); (c) Cl 3cCN, DBU, CH 2cl 2, 91%; (d) 3 or 5,4 MS, TMSOTf, CH 2cl 2, 46%for11 α; 27%for11 β; , 32%for12 α; 46%for12 β; (e) CH 3oNa, CH 3oH:CH 2cl 2=1:1,99%for13 α; 95%for13 β; 90%for14 α; 78%for14 β.
The synthesis of compound 10:
Under argon shield, by compound 6 [Song, G.; Yang, S.; Zhang, W.; Cao, Y.; Wang, P.; Ding, N.; Zhang, Z.; Guo, Y.; Li, Y. j.Med.Chem.2009, 52, 7368 – 7371.] and (1.73g, 3.50mmol), 4 molecular sieves (2.30g) of new activation add anhydrous CH 2cl 2(30mL), in, after stirring 30min at-30 DEG C, TMSOTf(126 μ L, 0.70mmol is added), add compound 7 [(a) Kitagawa, I. after stirring 10min; Back, N.I.; Ohashi, K.; Sakagami, M.; Yoshikawa, M.; Shibuya, chem.Pharm.Bull.1989, 37, 1131 – 1133; (b) Cheng, M.S.; Wang, Q.L.; Tian, Q.; Song, H.Y.; Liu, Y.X.; Li, Q.; Xu, X.; Miao, H.D.; Yao, X.S.; Yang, Z. j.Org.Chem.2003, 68, 3658 – 3662.] and the CH of (4.56g, 10.49mmol) 2cl 2solution (5ml), at-30 DEG C, after stirring reaction 2h, TLC detection reaction is complete, adds Et 3n cancellation is reacted, and concentrating under reduced pressure, rapid column chromatography obtains the mixture of compound 8 and compound 7 different head position hydrolysate.
Under argon shield, upper step is reacted the product obtained and is dissolved in 30mL acetone/water (9:1), under ice bath, add NBS(1.16g, 6.50mmol), after stirring reaction 30min, TLC display reacts completely, and drips saturated NaHCO 3cancellation is reacted, concentrating under reduced pressure removing acetone, raffinate CH 2cl 2after dilution, separated and collected organic phase, then uses saturated NaHCO successively 3wash, through anhydrous Na SO with saturated NaCl 4dry, filter, concentrated, rapid column chromatography obtains compound 9 (2.34g, 2.51mmol, two step overall yields 72%).
Under argon shield, by compound 9(1.92g, 2.06mmol) be dissolved in CH 2cl 2(25mL), in, DBU(125 μ L, 0.82mmol under ice bath, is added), slowly drip Cl after stirring 5min 3cCN(2.06mL, 20.58mmol) rise to room temperature reaction 2h after, TLC display react completely, reaction solution is after concentrating under reduced pressure, and rapid column chromatography obtains compound 10 (2.02g, 1.87mmol, 91%).
[α] =103.2( c1.05,CHCl 3)；
1HNMR(600MHz,CDCl 3): δ8.74(s,1H),8.05(m,4H),7.59-7.54(m,2H),7.47-7.43(m,4H),6.48(d,1H, J=3.6Hz),5.89(t,1H, J=10.2Hz),5.20(dd,1H, J=9.6,3.0Hz),5.15(dd,1H, J=3.6,1.8Hz),5.11(dd,1H, J=9.6,3.6Hz),4.93-4.87(m,3H),4.83-4.80(m,2H),4.79(d,1H, J=1.2Hz),4.51(dd,1H, J=12.6,3.6Hz),4.33-4.30(m,1H),4.10(t,1H, J=9.6Hz),4.05(dd,1H, J=10.2,4.2Hz),3.90-3.87(m,1H),3.78-3.75(m,1H),2.00(s,3H),1.98(s,3H),1.95(s,3H),1.93(s,3H),1.86(s,3H),1.85(s,3H),1.13(d,3H, J=6.6Hz),0.69(d,3H, J=6.0Hz)。
13CNMR(150MHz,CDCl 3): δ169.92,169.88,169.86,169.82,169.2,169.0,165.7,165.1,161.2,133.2,133.1,129.9,129.7,129.6,129.2,128.3,99.4,99.1,94.1,90.6,76.3,72.3,71.5,70.8,70.5,69.9,69.3,68.4,68.1,67.5,67.2,62.0,60.3,20.65,20.61,20.45,20.38,17.2,16.8,14.1。
HRMS (ESI): C 46h 52nO 22cl 2 37cl, calculated value: 1077.2012; Measured value: 1077.1991.
Compound 11 α, the synthesis of 11 β:
Under argon shield, compound 3 (86mg, 0.20mmol) is dissolved in the anhydrous CH of 4mL 2cl 2in; add dry 4 molecular sieves (300mg) wherein; after-30 DEG C of stirring 30min; add the silica-based triflate of trifluoromethyl (TMSOTf) (7 μ L; 0.04mmol, 0.2equiv.), after continuing to stir 10min; add three saccharide donor 10 (280mg of ester group protection; 0.26mmol, 1.30equiv.), after-30 DEG C of stirring 4h, TLC display reacts completely; triethylamine cancellation is reacted; after filtration, concentrated, rapid column chromatography obtains white solid 11 α (125mg, 0.093mmol, 46%) and 11 β (73mg; 0.054mmol, 27%).
Compound 11 α:
[α] =76.6( c0.80,CHCl 3)；
1HNMR(600MHz,CDCl 3): δ8.05-8.03(m,4H),7.56-7.51(m,2H),7.43-7.39(m,4H),5.77(t,1H, J=9.6Hz),5.25(d,1H, J=4.2Hz),5.22(dd,1H, J=10.2,3.6Hz),5.17(dd,1H, J=10.2,3.6Hz),5.15-5.11(m,1H),5.05(d,1H, J=3.6Hz),4.90(t,1H, J=9.6Hz),4.89(t,1H, J=10.2Hz),4.85(d,1H, J=1.8Hz),4.77-4.72(m,3H),4.63(dd,1H, J=15.6,7.2Hz),4.52(dd,1H, J=12.6,5.4Hz),4.29-4.26(m,1H),3.91-3.86(m,2H),3.80-3.75(m,1H),3.72(dd,1H, J=9.6,3.0Hz),3.48-3.42(m,1H),2.53(t,1H, J=13.2Hz),2.47(d,2H, J=7.8Hz),2.28(d,1H, J=12.6Hz),2.01(s,3H),1.98(s,3H),1.95(s,3H),1.93(s,3H),1.87(s,3H),1.85(s,3H),1.12(d,3H, J=6.0Hz),1.05(s,3H),1.00(d,3H, J=7.2Hz),0.92(d,3H, J=6.6Hz),0.80(s,3H),0.69(d,3H, J=6.0Hz)。
13CNMR(150MHz,CDCl 3): δ170.0,169.90,169.87,169.2,165.9,165.2,140.1,132.99,132.96,129.83,129.77,129.71,129.6,128.3,128.2,121.9,99.4,99.0,97.5,96.2,81.6,79.1,78.7,77.8,72.4,71.1,70.6,70.1,69.5,68.8,68.5,68.3,67.4,66.8,62.8,56.6,49.9,44.3,40.3,40.0,39.7,38.4,37.0,36.7,33.2,32.0,31.7,31.4,31.3,27.8,22.4,20.73,20.67,20.5,19.3,17.4,16.8,16.5,16.2。
HRMS (ESI): [M+Na] +, C 71h 92o 23sNa, calculated value: 1367.5642; Measured value: 1367.5691.
Compound 11 β:
[α] =34.6( c0.80,CHCl 3)；
1HNMR(600MHz,CDCl 3): δ8.04-8.01(m,4H),7.55-7.52(m,2H),7.44-7.38(m,4H),5.60(t,1H, J=9.4Hz),5.33(d,1H, J=5.4Hz),5.14-5.11(m,2H),5.09(m,1H),4.95-4.93(m,1H),4.89(t,1H, J=10.4Hz),4.85(t,1H, J=10.2Hz),4.83(brs,1H),4.77(d,1H,J=11.52Hz),4.74(brs,1H),4.65(d,1H, J=7.68Hz),4.64-4.60(m,1H),4.49(dd,1H, J=12.0,5.4Hz),4.35-4.30(m,1H),3.94(t,1H, J=9.6Hz),3.85-3.81(m,1H),3.77(t,1H, J=7.2Hz),3.70-3.66(m,1H),3.58-3.53(m,1H),2.52(t,1H, J=11.4Hz),2.38(d,1H, J=10.8Hz),2.28(d,1H, J=11.4Hz),2.23(t,1H, J=12.6Hz),1.96(s,6H),1.92(s,3H),1.90(s,3H),1.86(s,3H),1.72(s,3H),1.13(d,3H, J=6.0Hz),1.00(d,3H, J=6.6Hz),0.93(s,3H),0.90(d,3H, J=6.0Hz),0.78(s,3H),0.66(d,3H, J=6.0Hz)。
13CNMR(150MHz,CDCl 3): δ169.93,169.88,169.80,169.6,168.8,165.7,164.9,140.0,133.2,132.9,132.3,130.8,130.0,129.8,129.7,129.0,128.8,128.34,128.31,121.9,99.4,98.9,98.0,97.4,81.5,79.4,77.3,76.1,75.9,72.9,71.7,71.0,70.4,70.0,69.1,68.7,68.4,67.5,66.4,62.7,56.5,49.8,44.3,40.2,39.6,38.45,38.36,36.8,36.7,33.2,32.02,31.99,31.7,31.3,29.6,27.6,22.4,20.73,20.68,20.65,20.62,20.5,20.2,19.1,17.1,16.8,16.5,16.1。
HRMS (ESI): [M+Na] +, C 71h 92o 23sNa, calculated value: 1367.5642; Measured value: 1367.5696.
Compound 12 α, the synthesis of 12 β:
Under argon shield, compound 5 (81mg, 0.17mmol) is dissolved in the anhydrous CH of 4mL 2cl 2in, add dry 4 molecular sieves (300mg) wherein, after-78 DEG C of stirring 30min; add the silica-based triflate of trifluoromethyl (TMSOTf) (6 μ L; 0.034mmol, 0.2equiv.), after continuing to stir 10min; add three saccharide donor 10 (238mg of ester group protection; 0.22mmol, 1.30equiv.) ,-78 DEG C are stirred 1h; after continuing stirring reaction 3h at-40 DEG C again, TLC display reacts completely.Reaction is with after triethylamine cancellation, and after filtration, concentrated, rapid column chromatography obtains white solid 12 α (76mg, 0.055mmol, 32%) and 12 β (110mg, 0.079mmol, 46%).
Compound 12 α:
[α] =-1.9( c1.40,CHCl 3)；
1HNMR(600MHz,CDCl 3): δ8.06(d,2H, J=4.2Hz),8.04(d,2H, J=4.2Hz),7.57-7.52(m,2H),7.44-7.40(dd,4H, J=13.8,7.8Hz),5.78(t,1H, J=9.6Hz),5.26(d,1H, J=4.2Hz),5.23(dd,1H, J=10.2,3.0Hz),5.18(dd,1H, J=9.6,3.6Hz),5.15-5.12(m,1H),5.06(d,1H, J=3.6Hz),4.93-4.88(m,2H),4.86(brs,1H),4.78-4.76(m,1H),4.74(d,1H, J=13.2Hz),4.66(dd,1H, J=15.6,7.2Hz),4.53(dd,1H, J=12.0,4.8Hz),4.32-4.26(m,1H),3.91-3.89(m,2H),3.80-3.77(m,1H),3.73(dd,1H, J=9.6,3.6Hz),3.48-3.43(m,1H),2.59(t,1H, J=12.0Hz),2.48(d,2H, J=7.8Hz),2.37(d,1H, J=11.4Hz),2.26-2.20(m,1H),2.02(s,3H),1.99(s,3H),1.96(s,3H),1.94(s,3H),1.88(s,3H),1.86(s,3H),1.13(d,3H, J=6.0Hz),1.06(s,3H),1.02(d,3H, J=7.2Hz),0.96(d,3H, J=6.6Hz),0.81(s,3H),0.69(d,3H, J=6.0Hz)。
13CNMR(150MHz,CDCl 3): δ170.05,169.93,169.90,169.2,166.0,165.2,140.1,133.02,132.99,129.88,129.80,129.76,129.6,128.34,128.28,121.9,99.4,99.0,97.9,96.2,82.7,79.2,78.7,77.8,72.5,71.1,70.7,70.2,69.5,68.9,68.6,68.4,67.4,66.9,62.9,56.6,49.9,45.4,40.4,40.1,39.7,37.0,36.7,34.0,32.6,32.0,31.3,31.1,27.9,24.8,23.7,20.8,20.5,19.3,17.7,17.4,16.8,16.6。
HRMS (ESI): [M+Na] +, C 71h 92o 23seNa, calculated value: 1415.5087; Measured value: 1415.5119.
Compound 12 β:
[α] =-44.5( c1.70,CHCl 3)；
1HNMR(600MHz,CDCl 3): δ8.03(d,2H, J=8.4Hz),8.01(d,2H, J=8.4Hz),7.57-7.52(m,2H),7.45-7.39(m,4H),5.60(t,1H, J=9.0Hz),5.33(d,1H, J=5.4Hz),5.15-5.12(m,2H),5.10-5.09(m,1H),4.95(dd,1H, J=3.6,1.8Hz),4.89(t,1H, J=9.6Hz),4.85(t,1H, J=9.6Hz),4.83(d,1H, J=1.8Hz),4.77(dd,1H, J=12.0,1.8Hz),4.74(d,1H, J=1.2Hz),4.65(d,1H, J=7.8Hz)4.64(dd,1H, J=12.4,7.8Hz),4.49(dd,1H, J=12.6,5.4Hz),4.34-4.31(m,1H),3.95(t,1H, J=9.6Hz),3.88-3.82(m,1H),3.77(t,1H, J=8.4Hz),3.71-3.67(m,1H),3.57-3.53(m,1H),2.57(t,1H, J=12.0Hz),2.39-2.34(m,2H),2.24-2.18(m,2H),1.96(s,6H),1.93(s,3H),1.90(m,3H),1.86(s,3H),1.72(s,3H),1.13(d,3H, J=6.6Hz),1.01(d,3H, J=6.6Hz),0.95(d,3H, J=7.8Hz)0.94(s,3H),0.78(s,3H),0.66(d,3H, J=6.6Hz)。
13CNMR(150MHz,CDCl 3): δ169.93,169.87,169.80,169.5,168.8,165.7,164.9,140.0,133.2,132.9,130.0,129.8,129.7,129.1,128.34,128.29,121.9,99.4,98.9,98.0,97.8,82.6,79.4,77.3,76.1,75.9,72.9,71.0,70.4,70.0,69.1,68.7,68.4,67.5,66.4,62.8,62.7,56.4,49.8,45.4,40.3,40.1,39.6,38.4,36.8,36.7,33.9,32.6,32.0,31.3,31.1,29.6,24.8,23.6,20.73,20.67,20.62,20.5,20.2,19.1,17.6,17.1,16.8,16.5。
HRMS (ESI): [M+Na] +, C 71h 92o 23seNa, calculated value: 1415.5087; Measured value: 1415.5144.
The synthesis of compound 13 α:
Under argon shield, compound 11 α (40mg, 0.0297mmol) is dissolved in by 2ml ethanol/methylene (MeOH:CH 2cl 2=1:1) mixed solvent, then add the methanol solution (230 μ L) of sodium methylate (24mg, 0.44mmol, 14.6equiv.), stirring at room temperature reaction 48h, TLC display react completely.React through acidic resins neutralization and solids removed by filtration, concentrating filter liquor and rapid column chromatography obtain white solid 13 α (26mg, 0.0294mmol, 99%).
[α] =-46.0 ( c0.09, CHCl 3: the MeOH=1:1 containing 8% water);
1HNMR(600MHz,pyridine- d 5 ): δ5.89(s,1H),5.81(s,1H),5.46(d,1H, J=3.0Hz),5.27(d,1H, J=3.6Hz),4.89-4.83(m,1H),4.81-4.76(m,2H),4.69-4.65(m,1H),4.62-4.55(m,2H),4.52-4.48(m,1H),4.42-4.37(m,2H),4.33-4.28(m,2H),4.26(d,1H, J=10.2Hz),4.21(d,1H, J=12.0Hz),4.14-4.11(m,2H),3.73-3.68(m,1H),2.64-2.55(m,2H),2.49-2.42(m,1H),2.29(d,1H, J=10.8Hz),1.66(d,3H, J=6.0Hz),1.64(d,3H, J=6.0Hz),1.07(d,3H, J=6.0Hz),0.82(m,6H),0.78(s,3H)。
13CNMR(150MHz,pyridine- d 5 ) δ140.8,121.3,103.9,102.7,97.9,97.5,81.7,79.3,78.9,78.4,73.6,72.6,72.45,72.40,72.3,72.0,70.2,70.0,63.1,61.2,56.4,49.9,44.4,40.5,40.2,39.5,38.7,37.0,36.6,33.3,32.1,32.0,31.9,31.4,31.3,28.4,22.4,20.8,19.0,18.4,18.3,16.3。
HRMS (ESI): [M+Na] +, C 45h 72o 15sNa, calculated value: 907.4484; Measured value: 907.4505.
The synthesis of compound 13 β:
According to the method that synthetic compound 13 α is identical, obtain white solid 13 β (25mg, 0.0282mmol, 95%) by compound 11 β (40mg, 0.0297mmol) through deprotection.
[α] =-97.4 ( c0.85, CHCl 3: the MeOH=1:1 containing 8% water);
1HNMR(600MHz,pyridine- d 5 ): δ6.36(s,1H),5.82(s,1H),5.27(s,1H),4.93-4.86(m,3H),4.79-4.75(m,2H),4.64(brs,1H),4.59-4.56(m,1H),4.51-4.48(m,1H),4.35-4.28(m,3H),4.19-4.17(m,3H),4.05(d,1H, J=12.6Hz),3.86-3.80(m,1H),3.60(d,1H, J=7.8Hz),2.74(d,1H, J=12.0Hz),2.68(t,1H, J=12.0Hz),2.60(t,1H, J=12.6Hz),2.30(d,1H, J=12.0Hz),1.72(d,3H, J=6.0Hz),1.58(d,3H, J=6.0Hz),1.07(d,3H, J=7.2Hz),1.01(s,3H),0.79(m,6H)。
13CNMR(150MHz,pyridine- d 5 ): δ140.5,121.5,102.6,101.8,100.0,97.5,81.7,78.2,77.8,77.7,77.5,76.7,73.8,73.6,72.6,72.4,72.2,70.1,69.2,63.1,61.0,56.4,50.0,44.4,40.2,40.2,39.5,38.7,37.2,36.8,33.3,32.1,32.0,31.9,31.45,31.39,29.9,22.4,20.8,19.1,18.4,18.2,16.3。
HRMS (ESI): [M+Na] +, C 45h 72o 15sNa, calculated value: 907.4484; Measured value: 907.4501.
The synthesis of compound 14 α:
According to the method that synthetic compound 13 α is identical, obtain white solid 14 α (24mg, 0.0258mmol, 90%) by compound 12 α (40mg, 0.0287mmol) through deprotection.
[α] =-87.4 ( c0.85, CHCl 3: the MeOH=1:1 containing 8% water);
1HNMR(600MHz,pyridine- d 5 ) δ5.92(s,1H),5.83(s,1H),5.48(d,1H, J=3.0Hz),5.27(d,1H, J=3.6Hz),4.91-4.85(m,1H),4.81-4.76(m,2H),4.68-4.65(m,1H),4.62-4.57(m,2H),4.52(dd,1H, J=9.0,3.0Hz),4.42-4.37(m,2H),4.33-4.28(m,2H),4.26(d,1H, J=10.2Hz),4.21(d,1H, J=12.0Hz),4.14-4.11(m,2H),3.73-3.68(m,1H),2.66-2.60(m,2H),2.48(t,1H, J=11.4Hz),2.35(d,1H, J=12.0Hz),2.26-2.22(m,1H),2.14(d,1H, J=12.0Hz),2.00-1.97(m,1H),1.93-1.89(m,2H),1.66(d,3H, J=6.0Hz),1.64(d,3H, J=6.0Hz),1.07(d,3H, J=6.0Hz),0.82(m,6H),0.78(s,3H)。
13CNMR(150MHz,Pyridine- d 5 ): δ140.8,121.3,103.9,102.7,98.0,97.9,82.8,79.3,79.0,78.4,73.6,72.6,72.5,72.4,72.3,72.0,70.2,70.1,63.2,61.2,56.4,49.9,45.4,40.5,40.3,39.5,37.0,36.7,34.0,32.8,32.0,31.3,31.1,28.4,24.7,23.6,20.8,19.0,18.4,18.3,17.7,16.4。
HRMS (ESI): [M+Na] +, C 45h 72o 15seNa, calculated value: 955.3929; Measured value: 955.3950.
The synthesis of compound 14 β:
According to the method that synthetic compound 13 α is identical, obtain white solid 14 β (21mg, 0.0225mmol, 78%) by compound 12 β (40mg, 0.0287mmol) through deprotection.
[α] =-148.7 ( c0.80, CHCl 3: the MeOH=1:1 containing 8% water);
1HNMR(600MHz,pyridine- d 5 ) δ6.40(s,1H),5.86(s,1H),5.28(d,1H, J=5.4Hz),4.97-4.92(m,3H),4.83-4.78(m,2H),4.67(brs,1H),4.62(dd,1H, J=9.0,3.6Hz),4.53(dd,1H, J=9.6,3.6Hz),4.41-4.30(m,3H),4.22-4.18(m,3H),4.07(dd,1H, J=12.6,3.6Hz),3.88-3.83(m,1H),3.62(d,1H, J=9.6Hz),2.80-2.75(m,1H),2.72-2.69(d,1H, J=11.4Hz),2.66(t,1H, J=10.8Hz),2.37(d,1H, J=11.4Hz),2.27-2.23(m,1H),2.04-2.00(m,2H),1.75(d,3H, J=6.0Hz),1.62(d,3H, J=6.6Hz),1.07(d,3H, J=6.6Hz),1.02(s,3H),0.83(d,3H, J=6.6Hz),0.79(s,3H)。
13CNMR(150MHz,pyridine- d 5 ) δ140.5,121.5,102.6,101.8,100.0,97.8,82.8,78.2,77.7,77.6,77.5,76.6,73.8,73.6,72.5,72.4,72.2,70.1,69.2,63.2,61.0,56.3,50.0,45.4,40.3,39.4,38.6,37.2,36.8,34.0,32.8,32.0,31.3,31.2,29.9,24.7,23.6,20.8,19.1,18.4,18.2,17.7,16.4。
HRMS (ESI): [M+H] +, C 45h 73o 15se, calculated value: 933.4109; Measured value: 933.4137.
(3) the anti-tumor activity test of compound
Adopt mtt assay, test compound 13 β, 13 α, 14 β and 14 α and dioscin [(a) Deng, S. respectively; Yu, B.; Hui, Y. tetrahedronLett.1998, 39, 6511 – 6514; (b) Tao, H.C.; Yu, B. tetrahedronLett.2001, 42, 2405 – 2407] and inhibit activities to tumor cell line A-549, Hela and K562, result is as shown in table 1.Compared with dioscin, the activity of 26 thip-analogues 13 β increases, but the activity of 26 seleno-analogue 14 β is a little less than dioscin, and the activity of 13 α and 14 α type isomer all significantly declines.This shows for spirostanol saponin compound, and 3 β type glycosidic links between sugar chain and aglycon play critical effect in its anti-tumor activity.
Table 1:13 α, 13 β, 14 α, the anti-tumor activity (IC50) of 14 β and dioscin
Compound A-549 Hela K562
Dioscin 4.02 7.86 5.12
13β 3.72 6.68 4.1
13α >10 >10 >10
14β 5.0 >10 4.96
14α >10 >10 >10

Claims (5)

1. 26 sulfo-s that general structure is as follows or a synthetic method for seleno spirostanol saponin,
Wherein,
5,6 is double bond (Δ 5); X=S or Se; Y=H and H;
R 1-R 8for hydrogen;
Chacotriose and derivative thereof are connected with β glycosidic link with aglycon;
The absolute configuration of 22,25 carbon is all r;
It is characterized in that the method comprises the steps:
The synthesis of (1) 26 sulfo-or the pseudo-spirostanol saponin unit of seleno:
In a solvent or phase-transfer catalyst exist under, 26 p-toluenesulfonic esters of pseudo-spirostanol saponin unit and the nucleophilic reagent of sulphur or selenium react 1-10 hour under 0-150 DEG C of condition, obtain correspondence sulphur or selenium substitution product; Wherein, the mol ratio of p-toluenesulfonic esters and nucleophilic reagent is 1:(1.0-5.0); Described nucleophilic reagent is KSCOCH 3, Na 2s 2, Li 2s 2, Cs 2s 2, K 2s 2in one or KSeCOCH 3, Na 2se 2, Li 2se 2, Cs 2se 2, K 2se 2in one; Described phase-transfer catalyst is the one in Tetrabutyl amonium bromide, tetrabutylammonium iodide, 4-butyl ammonium hydrogen sulfate, PEG-4000;
The preparation of (2) 26 sulfo-s or seleno spirostanol saponin unit:
In a solvent with at 0-150 DEG C, the pseudo-spirostanol saponin unit of 26 sulfo-s or seleno and alkali, or after react with reductive agent, then obtain 26 sulfo-s with acid-respons 0.1-10 hour or seleno spirostanol saponin is first; Described 26 sulfo-s or the pseudo-spirostanol saponin unit of seleno are 1.0:(2.0-20.0 with the mol ratio of alkali), described 26 sulfo-s or the pseudo-spirostanol saponin unit of seleno are 1.0:(2.0-5.0 with the mol ratio of reductive agent); Described alkali is organic bases or mineral alkali; Acid is organic acid or mineral acid;
(3) chacotriose is to the preparation of body:
In organic solvent with under the existence of dewatering agent, at-78-40 DEG C, with Lewis acid or protonic acid for promotor, 3, the rhamnosyl three chlorimide ester of 6-bis--oxygen-benzoyl-β-D-Glucose sulphur glycosides and acyl group, silica-based protection is to precursor reactant 1-10 hour, obtain chacotriose sulphur glycosides, then through hydrolysis, react be converted into trisaccharide three chlorimide ester to body with Trichloroacetonitrile; 3,6-, bis--oxygen-benzoyl-β-D-Glucose sulphur glycosides and rhamnosyl are 1.0:(1.0-5.0 to the mol ratio of body and promotor): (0.05-0.5); The weight ratio of 3,6-, bis--oxygen-benzoyl-β-D-Glucose sulphur glycosides and dewatering agent is 1.0:(3.0-10.0);
The introducing of (4) 3 glycosyls:
In organic solvent with under the existence of dewatering agent, at-78-40 DEG C, with Lewis acid or protonic acid for promotor, 1-10 hour reacts with the glycosyl donor of acyl group, silica-based protection in 26 sulfo-s or seleno spirostanol saponin unit, introduce the chacotriose of full guard at its 3 OH, obtain the spirostanol saponin of the full guard of beta comfiguration; Wherein, 26 sulfo-s or seleno spirostanol saponin unit are 1.0:(1.0-5.0 with the mol ratio of glycosyl donor and promotor): (0.05-0.5); The weight ratio 1.0:(3.0-10.0 of 26 sulfo-s or seleno spirostanol saponin unit and dewatering agent);
The synthesis of (5) 26 sulfo-s or seleno spirostanol saponin:
In a solvent ,-20-60 DEG C, the spirostanol saponin of the full guard of beta comfiguration respectively with alkali reaction 10-60 hour, slough 26 sulfo-s or seleno spirostanol saponin that all protecting groups obtain beta comfiguration; Described alkali is inorganic or organic bases; The spirostanol saponin of described full guard and alkali mol ratio are 1.0:(0.2-20);
Above-mentioned solvent is organic solvent, water or their mixture;
Above-mentioned organic solvent is C 1-C 6halohydrocarbon, 1,4 – dioxane, C 1-C 6alkyl alcohol, ether, acetonitrile, 2, a kind of in 2,2 – trimethylacetonitriles, tetrahydrofuran (THF), N, N – dimethyl formamide, N, N – N,N-DIMETHYLACETAMIDE, hexamethylphosphoramide, toluene, benzene or their mixture;
Described dewatering agent is a kind of in 3 molecular sieves of 3,4,5 molecular sieves or pickling or anhydrous sodium sulphate, anhydrous calciumsulphate, anhydrous cupric sulfate, anhydrous magnesium sulfate or their mixture;
Above-mentioned mineral alkali refers to the oxyhydroxide of monovalent metal, hydride or carbonate; Organic bases is potassium tert.-butoxide, sodium tert-butoxide, tert-butyl lithium, sodium methylate, sodium ethylate or magnesium methylate;
Above-mentioned mineral acid is HCl or H 2sO 4; Organic acid is acetic acid or formic acid;
Described pseudo-spiral shell sterioside unit is pseudo-diosgenin [△ 5, Y=H, H, 25 ( r)].
2. synthetic method as claimed in claim 1, is characterized in that described reductive agent is zinc/acetum or indium/acetic acid or indium/aqueous ammonium chloride solution.
3. synthetic method as claimed in claim 1, is characterized in that described Lewis acid is the one in trialkyl silyl triflate, boron trifluoride diethyl etherate, silver trifluoromethanesulfonate, copper trifluoromethanesulfcomposite, trifluoromethanesulfonic acid zinc, trifluoromethanesulfonic acid scandium, trifluoromethanesulfonic acid lanthanum, Ytterbiumtriflate, trifluoromethanesulfonic acid indium, trifluoromethanesulfonic acid, perchloric acid, Tetrafluoroboric acid, four (phenyl-pentafluoride base) boric acid or two (fluoroform sulphonyl) imines.
4. synthetic method as claimed in claim 1, is characterized in that described acyl group is C 2-C 8fatty acyl group or C 6-C 10aromaticacyl radical.
5. synthetic method as claimed in claim 3, is characterized in that described trialkyl silyl is C 1-C 6trialkyl silyl.
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Preparations of heterospirostanols and their pharmacological activities;Hang-Ji Quan et al;《Eur. J. Med. Chem.》;20021231;第37卷;第662页右栏倒数第1段，图2-4,第664-666页, *
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