CN103193858B - The synthetic method of spiranostan glycoalkaloid - Google Patents

The synthetic method of spiranostan glycoalkaloid Download PDF

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CN103193858B
CN103193858B CN201310126415.9A CN201310126415A CN103193858B CN 103193858 B CN103193858 B CN 103193858B CN 201310126415 A CN201310126415 A CN 201310126415A CN 103193858 B CN103193858 B CN 103193858B
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compound
rhap
acid
glcp
spiranostan
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CN103193858A (en
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李明
王鹏
彭雁南
陈朋伟
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Ocean University of China
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The invention discloses a kind of spiranostan glycoalkaloid convergence type chemical synthesis process, the method comprises the steps: that 3 hydroxyls are converted into corresponding 16 acetoxyl groups 22 carbonyl 26 hydroxyl cholestane (III) with silica-based or acyl group protection spirostanol saponin unit (II) by (a)；The preparation (IV) of b 16 acetoxyl group 22 carbonyl 26 sulphonic acid ester cholestane that () 3 hydroxyls are protected with silica-based or acyl group；The preparation (V) of c 16 acetoxyl group 22 carbonyl 26 azido cholestane that () 3 hydroxyls are protected with silica-based or acyl group；The preparation of (d) spiranostan sapogenin (VI)；The preparation (VII) of (e) acyl group protection spiranostan glycoalkaloid；The preparation of (f) spiranostan glycoalkaloid (I).The preparation method technique of the present invention is simple, and yield is high, has stronger practical value.

Description

The synthetic method of spiranostan glycoalkaloid
Technical field
The invention belongs to pharmaceutical synthesis field, relate to the convergence type chemical synthesis process of a kind of spiral shell steroid glycoalkaloid.
Technical background
Spiranostan glycoalkaloid is the Secondary metabolites that a class is important, is mainly distributed on the Solanum of Solanaceae With Fructus Lycopersici esculenti belong to plant such as Herba Solani Nigri, Fructus Solani melongenae, Fructus Lycopersici esculenti and Rhizoma Solani tuber osi etc. in.Spiranostan glycoalkaloid is by having oxygen-nitrogen spiral shell The C of the E/F ring of decane27Spiranostan sapogenin (such as solasodine, tomatidine and tomatidenol etc.) and oligonucleotide chain are (such as Ma Ling Potato trisaccharide, solatriose etc.) composition.Solasonine, solamargine and tomatidine etc. are the allusion quotations of spiranostan glycoalkaloid Type represents (Lee, K.-R.；Kozukue, N.；Han, J.-S.；Park, J.-H.；Chang, E.-Y.；Baek, E.-J.； Friedman, M.J.Agric.Food Chem.2004,52,2832-2839).
Pernicious skin can be effectively treated from solasonine and the solamargine of Solunum sodomaeum isolated General edema with abdominal distension tumor, including basal cell carcinoma and squamous cell carcinoma (SCC) (Cham, B.E.；Gilliver, M.；Wilson, L.Planta Med.1987,53,34-36).1991, with solasonine and solamargine, the ointment-Curaderm as main component was in Australia Big Leah goes through to list.Research show this medicine respectively can with 83.3%, 83.3% and 100% efficiency suppression basal cell carcinoma, Squamous cell carcinoma and solar keratosis, and the patient cured not recurrence (Cham, B.E. within ensuing 5 years； Daunter, B.；Evans, R.Cancer Lett.1991,59,183-192.).It is made up of solasodine and solamargine Coramsine, at tumor cell experiment in vitro, Integral animal experiment and with tumor patient, all demonstrates that antitumor is made With, by GASAS approval be used for treating patient with advanced cancer, be Solbec company leading antitumor product (Millward, M.；Powell, A.；Tyson, S.；Daly, P.；Ferguson, R.；Carter, S.J.Clin.Oncol.2005,23, 218s.).Tomatidine, as a kind of Saponin adjuvant, has been used for preventing tularemia and research (Morrow, the W.J.W. of anticancer aspect； Yang, Y.-W.；Sheikh, N.A.Vaccine2004,22,2380-2384.).Solasonine, solamargine and tomatidine Also there is activity (Chataing, the B. of antiviral；Concepcion, J.L.；De Cristancho, N.B.；Usubillaga, A.Rev.Facul.Farm.1999,32,18-25).
Currently used glycoalkaloid is mainly obtained by the degraded of separation and Extraction or natural product.But, due to In plant, the attendant phenomenon of glycoalkaloid and the similarity of structure, make their isolated and purified difficulty, and content be low.Therefore, Need badly develop the economy, efficient spiranostan glycoalkaloid preparation method, the compound clear and definite to obtain structure, thus right It carries out the research and development of deep study on mechanism and newtype drug.Chemosynthesis solves the preferred means of this predicament beyond doubt One of.
Although the synthesis of solasodine and other spiranostan sapogenin is reported by domestic and international multiple group [(a) Uhle, F.C.J.Am.Chem.Soc.1961,83,1461-1472；(b) Kessar, S.V.；Gupta, Y.P.；Singh, M.；Mahajan, R.K.Tetrahydron1971,27,2869-2875；(c) Zha, X.；Sun, H.；Hao, J.；Zhang, Y.Chem.Biodiv.2007,4,25-31；(d) Zha, X.；Hou, Y.；Sun, H.；Zhang, Y.Chem.Biodiv.2007, 4,1557-1564；(e) Tang little Mei, Xu Qihai, Wang Jing, Lin Jingrong, gold handsome looks, the big biochemical journal 2007,65,2315-in field 2319；(f) Tian Weisheng, Tang little Mei, Xu Qihai, Chinese invention patent, 200710039217.3；(g) Koag, M.；Lee, S.Org.Lett.2011,13,4766-4769；(h) Zhang, G.-P.；Shen, S.-D.；Lei, M.；Hu, L.- H.Tetrahedron2011,67,5894-5896], but the synthesis of its glucosides report is the most few.Paczkowski utilizes Koenigs-Knorr method, has synthesized solasodine monoglycosides (Paczkowski, C.；Wojciechowski, Z.A.Phytochemistry1994,35,1429-1434).Lou Hongxiang etc. are prepared for 3 rhamnoside (Lou Hong of solasodine Auspicious, Jiang Gao, Wang Yanyan, Li Xia, Xue Xia Chinese invention patent, 201010286853.8)；2003, Lawson etc. was by sulfoxide Glycosides and the glycosidation of bromine glycosides, using solasodine as receptor, complete synthesis (Lawson, the C. of solasonine；John, W.-W.；Alexander, C.2005, WO Patent005449).European patent [WO/2003/018604] is to solamargine Synthesis reported.Recently, group of cuckoo state use sulfur glycosides and bromine glycosides glycosidation synthesized solamargine (Wei, G.；Wang, J.；Du, Y.Bioorg.Med.Chem.Lett.2011,21,2930-2933；Wei, G.；Wei, D.；Du, Y.Sin.China.Chem.2012,55,1247-1251；China of Wei state, cuckoo state Chinese invention patent, 201010608498.1 Hes 201110088831.5).Heavy metal silver salt (such as silver trifluoromethanesulfonate) is used as the accelerator of glycosylation reaction and to use effect The progressively synthesis strategy that rate is low is the deficiency of these methods.Therefore, develop efficient synthetic method and there is important using value, The present invention provide a kind of succinct, efficiently, stereo selectivity prepare the convergence type synthetic method that spiranostan glucosides is biological.
Summary of the invention
An object of the present invention is to provide closes with spiranostan sapogenin and multiple oligosaccharide three chlorimide ester for raw material The method becoming spiranostan glycoalkaloid.
Spiranostan glycoalkaloid structure synthesized by the present invention is as follows:
Wherein,
Dotted line represents 5, is singly-bound or double bond (Δ between 65), when it is singly-bound, 5 hydrogen atoms are α or beta comfiguration；
Curve represents that 27 methyl are in equatorial bond or axial bond；
X1=NH, X2=CH2Time, the absolute configuration of 25 carbon is R；Or
X1=CH2, X2During=NH, the absolute configuration of 25 carbon is S；
R1It is by β-D-Glucopyranose. (β-D-Glcp), β-D-galactopyranose (β-D-Galp), β-D-pyrans manna Sugar (β-D-Manp), α-D-mannopyranose (α-D-Manp), β-L-mannopyranose (β-L-Manp), α-L-pyrans are sweet Dew sugar (α-L-Manp), β-D-xylopyranose (β-D-Xylp), β-D-pyrans glucosamine (β-D-GlcNACp), α- L-rhamnopyranose (α-L-Rhap), α-D-rhamnopyranose (α-D-Rhap), β-D-pyrans/arabinofuranose (β-D- Araf/p), α-D-pyrans/arabinofuranose (α-D-Araf/p), α-L-pyrans/arabinofuranose (α-L-Araf/p), β-L-pyrans/arabinofuranose (β-L-Araf/p), α-L-pyrans fucose (α-L-Fucp), β-D-glucopyra alditol Acid the monosaccharide such as (β-D-GlcAp), β-D-galactopyranosyluronic (β-D-GalAp) composition the chain that the degree of polymerization is 2-8 or The oligosaccharide of ramiform；
Wherein it is preferred that
α-L-Rhap-(1→4)-[α-L-Rhap-(1→2)]-β-D-Glcp；
β-D-Glcp-(1→3)-[α-L-Rhap-(1→2)]-β-D-Galp；
α-L-Araf-(1→4)-[α-L-Rhap-(1→2)]-β-D-Glcp；
α-L-Arap-(1→4)-[α-L-Rhap-(1→2)]-β-D-Glcp；
β-D-Xylp-(1→4)-[α-L-Rhap-(1→2)]-β-D-Glcp；
α-D-Manp-(1→4)-[α-D-Manp-(1→2)]-β-D-Glcp；
α-D-Rhap-(1→4)-[α-D-Rhap-(1→2)]-β-D-Glcp；
α-L-Manp-(1→4)-[α-L-Manp-(1→2)]-β-D-Glcp；
{α-L-[α-L-Rhap-(1→4)]-Rhap-(1→4)}-[α-L-Rhap-(1→2)]-β-D-Glcp；
{α-L-[β-D-Xylp-(1→4)]-Rhap-(1→4)}-[α-L-Rhap-(1→2)]-β-D-Glcp；
{β-D-Xylp-(1→3)-[α-L-Rhap-(1→2)]-β-D-Glcp}-(1→4)-β-D-Galp；
α-L-Rhap-(1→2)-β-D-Glcp；[α-D-Manp-(1→2)]-β-D-Glcp；
[α-D-Rhap-(1→2)]-β-D-Glcp；[α-L-Manp-(1→2)]-β-D-Glcp；
It is characterized in that the method comprises the steps:
The preparation of (a) compound (III)
In a solvent, spirostanol saponin unit (II) under lewis acid or Bronsted acid promote with acetic anhydride-78-50 DEG C of condition Lower reaction 0.1-2 hour, obtains corresponding 16-acetoxyl group-22-carbonyl-26-hydroxyl cholestane (III)；Wherein, R2It is silicon Base or acyl group；Spirostanol saponin unit (II) is 1 with the mol ratio of Louis acid and acetic anhydride: (1.0-10.0): (3.0-10.0)；
Described solvent C1-C6Monohaloalkyl or polyhalo alkane, Isosorbide-5-Nitrae-dioxane, ether, acetonitrile, 2,2,2-front threes Base acetonitrile, oxolane, DMF, N,N-dimethylacetamide, hexamethyl phosphoramide, N-methylpyrrolidin- The C such as 2-ketone, toluene, benzotrifluoride, pyridine, methanol, ethanol, isopropanol1-C6Alkyl alcohols, a kind of in water or theirs is mixed Compound；
Preferably solvent is CH2Cl2、CHCl3、ClCH2CH2Cl；
Described acyl group is C2-C6Straight or branched aliphatic acyl radical or C6-C10Aromaticacyl radical；
Preferably acyl group be acetyl group, chloracetyl, pivaloyl group, 4-carbonyl valeryl, 2-chloro-2-methyl-propiono, Benzoyl, adjacent azido-methyl benzoyl, 2-(2-nitrobenzophenone)-acetyl group, tribromo-acetyl base；
Described silica-based three replacements constituted for methyl, ethyl, isopropyl, the tert-butyl group, phenyl etc. are silica-based；
The most silica-based is that t-Butyldimethylsilyl, tert-butyl diphenyl are silica-based；
Described spirostanol saponin unit is diosgenin [△5, Y=H, H, 25 (R)], refined nurse sapogenin [△5, Y=H, H, 25 (S)], Tigogenin [5 α-H, Y=H, H, 25 (R)], Neotigogenin [5 α-H, Y=H, H, 25 (S)], sea Ke's saponin Unit [5 α-H, Y=O, 25 (R)], new hecogenin [5 α-H, Y=O, 25 (S)], Chinaroot Greenbier Rhizome sapogenin [5 β-H, Y=H, H, 25 (R)], the one in Sarsasapogenin [5 β H, Y=H, H, 25 (S)]；
Described lewis acid or Bronsted acid are trimethylsilyl trifluoromethanesulfonate, the silica-based trifluoromethanesulfonic acid of triethyl group Ester, t-Butyldimethylsilyl triflate, boron trifluoride diethyl etherate, silver trifluoromethanesulfonate, copper trifluoromethanesulfcomposite, fluoroform Sulfonic acid zinc, trifluoromethanesulfonic acid scandium, trifluoromethanesulfonic acid lanthanum, Ytterbiumtriflate, trifluoromethanesulfonic acid indium, trifluoromethanesulfonic acid, perchloric acid, Tetrafluoroboric acid, four (phenyl-pentafluoride base) boric acid, two (fluoroform sulphonyl) imines, SiO2-H2SO4、SiO2-HClO4、SiO2-HOTf In a kind of or their mixture.
The preparation of (b) compound (IV)
Compound (III) in a solvent and in the presence of a base with sulfonylation agent-78-150 DEG C of reaction, obtain compound (IV), wherein, compound (III) is 1.0 with the mol ratio of sulfonylation agent: (1.0-3.0)；R3For sulfonyl；
Described alkali can be inorganic base, such as sodium hydroxide, potassium hydroxide, Lithium hydrate, Cesium hydrate., sodium carbonate, carbon One in acid potassium, cesium carbonate；Can also be organic base potassium tert-butoxide, Feldalat NM, Sodium ethylate, magnesium methoxide, triethylamine, pyrrole Pyridine, 4-N, N-lutidines, 2,6-lutidines, 2，4，6-trimethylpyridine, diisopropyl ethyl amine, the tetrabutyl are fluorinated One in ammonium；
Preferably alkali is pyridine, 4-N, N-lutidines, 2,6-lutidines, 2，4，6-trimethylpyridine, four fourths Base ammonium fluoride；
Described solvent is as defined above；
Preferably solvent is pyridine, oxolane, CH2Cl2、CHCl3、ClCH2CH2Cl；
Described sulfonylation agent is mesyl chloride, methanesulfonic acid acid anhydride, paratoluensulfonyl chloride, p-toluenesulfonic anhydride, fluoroform One or more in sulphonic acid anhydride, imidazoles sulfonic acid chloride.
The preparation of (c) compound (V)
Compound (IV) the most again with Azide reagent-78-150 DEG C of reaction, obtain compound (V)；Compound (IV) mol ratio with Hydrazoic acid,sodium salt is 1.0: (1.0-3.0)；
Described solvent is as defined above；
Preferably solvent be oxolane, DMF, N,N-dimethylacetamide, hexamethyl phosphoramide, NMP, CH2Cl2、CHCl3、ClCH2CH2Cl；
Described Azide reagent is Hydrazoic acid,sodium salt (NaN3), Lithium Azide (LiN3), trimethyl silica-based nitrine (TMSN3)、 Tributyl tinbase nitrine (Bu3SnN3One or more in).
Prepared by (d) compound (VI)
In the presence of a base, proton kind solvent removes under the conditions of-78-150 DEG C R in compound (V)2Protect with acetyl group Protect base, then with under the conditions of reducing agent or catalytic hydrogen reduction, in 0-100 DEG C, nitrine is reduced under 1-100 air pressure, formed Oxygen-nitrogen spiral shell decane structure obtains compound (VI)；Alkali is (0.1-5.0) with the mol ratio of compound (V): 1.0；Reducing agent and change The mol ratio of compound (V) is (0.1-10.0): 1.0；Catalyst needed for catalytic hydrogenation with the weight ratio of compound (V) is (0.1-100.0)∶1.0；
Described alkali and solvent are as defined above；
Preferably alkali is sodium hydroxide, potassium hydroxide, Lithium hydrate, potassium carbonate, Feldalat NM, tetrabutyl ammonium fluoride；Alkali with The mol ratio of 16-acetoxyl group-22-carbonyl-26-azido cholestane is (0.1-5.0): 1.0；
Preferably solvent is the C such as methanol, ethanol, isopropanol1-C6Alkyl alcohols, water or their mixture；
Described reducing agent is the trivalent phosphine compound of the compositions such as methyl, ethyl, isopropyl, the tert-butyl group, phenyl；Trivalent phosphine Compound is (1.0-10.0) with the mol ratio of compound (V): 1.0；
Preferably trivalent phosphine compound is trimethyl-phosphine, triphenylphosphine；
Described catalytic hydrogen reduction condition is by 5-10%Pd/C or 20%Pd (OH)2/ C or Lindlar catalyst or Raney-Ni and H2Or ammonium formate composition, catalyst is (0.1-100.0) with the weight ratio of compound (V): 1.0.
The preparation of (e) compound (VII)
In a solvent with dehydrant in the presence of, in-78-150 DEG C, with lewis acid or Bronsted acid as accelerator, chemical combination The oligosaccharide three chlorimide ester of thing (VI) and acyl group protection, to precursor reactant 1-48 hour, obtains compound (VII)；Wherein, compound (V) It is 1.0 with the mol ratio of oligosaccharide three chlorimide ester donor and accelerator: (1.0-5.0): (0.05-3.0)；Compound (VI) with The weight ratio 1.0 of dehydrant: (3.0-10.0)；
Described solvent is as defined above；
Preferably solvent is CH2Cl2、CHCl3、ClCH2CH2Cl, acetonitrile (CH3CN), 2,2,2-trimethylacetonitrile (t- BuCN), benzotrifluoride a kind of or their mixture；
Described lewis acid or Bronsted acid are as defined above；
Described dehydrant isMolecular sieve or AW-300 molecular sieve or anhydrous sodium sulfate, anhydrous slufuric acid A kind of in calcium, anhydrous cupric sulfate, anhydrous magnesium sulfate or their mixture；
The definition of described oligosaccharide such as R1Shown in；
Described acyl group is as defined above.
The synthesis of (f) compound (I)
In a solvent, remove the acyl protecting groups in compound (VII) in-78-150 DEG C with alkali, obtain spiranostan sugar Glycosides alkaloid；Wherein alkali is (0.1-100.0) with the mol ratio of compound (VII): 1.0；
Described alkali and solvent are as defined above；
The method of the present invention recommends to carry out under inert gas shielding, such as argon, nitrogen etc..
The invention provides a kind of spiranostan glycoalkaloid convergence type synthetic method easy, efficient (with chemical combination Thing II is raw material, linear 8 steps reactions, obtains glycoalkaloid with the productivity of 10-30%), also provide simultaneously a kind of simple, The practical method that spirostanol saponin unit is converted into spiranostan sapogenin.
Accompanying drawing explanation
Fig. 1 is the synthetic method of solasodine: (a) BF3·OEt2, Ac2O, CH2Cl2, 0 DEG C, 20min, 64% (b) TsCl, Pyridine, 0 DEG C, 16h, 92% (c) NaN3, DMF, 60 DEG C, 2h, 95% (d) K2CO3, CH3OH, 65 DEG C, 10h, 95% (e) Lindlar catalyst, H2, ethanol, THF, 30 DEG C, 4h, 91% (f) TBAF, THF, 70 DEG C, 18h, 88%；
Fig. 2 is the synthetic method of solasonine (solasodine): (a) HB (C6F5)4, H2SO4-SiO2, BTF, t-BuCN, CH2Cl2,Rt, 4h, 82%；(b)CH2Cl2, CH3OH, 1N NaOH, 70 DEG C, 10h, 45%；
Fig. 3 is the synthetic method of solamargine (solamargine): (a) HB (C6F5)4, H2SO4-SiO2, BTF, t- BuCN, CH2Cl2,Rt, 4h, 72%；(b)CH2Cl2, CH3OH, 1N NaOH, 70 DEG C, 10h, 70%.
Detailed description of the invention
Below in conjunction with the accompanying drawings, and specifically real with solamargine (solamargine) and solasonine (solasodine) The present invention is described in detail to execute example, but the invention is not restricted to herein below.
The preparation of compound 2 and data
The diosgenin 1 (3.0g, 4.60mmol) of the silica-based protection of tert-butyl diphenyl it is sequentially added in single port bottle, two Chloromethanes (30mL), glacial acetic acid (3.3mL, 32.2mmol), after stirring 20min in ice bath under argon shield, it is slowly added dropwise BF3·OEt2, in 25min, dropping is complete, product is proceeded to immediately in frozen water, and stirring is allowed to be sufficiently mixed；Then dichloro is used Methane extracts, and collects and merges organic facies, then with saturated sodium bicarbonate, saturated common salt washing, is dried also through anhydrous sodium sulfate Filter, silica gel column chromatography (CH after concentrating filter liquor2Cl2: ethyl acetate=12: 1-9: 1-6: 1) whitely isolated and purified Solid 2, productivity 64%.Its data are as follows:
1H NMR (600MHz, CDCl3) δ 7.66 (m, 4H), 7.43-7.33 (m, 6H), 5.10 (d, 1H, J=5.5Hz), 4.95 (m, 1H), 3.52 (m, 1H), 3.41 (d, 2H, J=6.1Hz), 1.95 (s, 3H), 1.12 (d, 3H, J=7.1Hz), 1.05 (s, 9H), 0.98 (s, 3H), 0.90 (d, 3H, J=7.1Hz), 0.84 (s, 3H)；
13C NMR (150MHz, CDCl3) δ 213.7,141.1,135.64,134.59,129.4,129.3,127.4, 127.3,120.7,75.6,73.0,67.4,54.9,53.9,49.7,43.4,42.3,41.8,39.5,38.4,37.0,36.3, 35.3,34.7,31.7,31.5,31.1,26.9,26.1,21.0,20.6,19.3,19.0,16.7,16.5,13.1；
HRMS-ESI TOF:m/z [M+Na]+calcd for C45H64O5NaSi:735.4415；Found:735.4412.
The preparation of compound 3 and data
By compound 2 (6.44g, 9.04mmol), TsCl (3.45g, 18.09mmol) is sequentially added into equipped with magnetic agitation In single port bottle, it is subsequently adding the pyridine (50mL) of new steaming, under argon shield, after 0 DEG C of reaction 24h；Concentrating under reduced pressure, then uses acetic acid Ethyl ester dissolves, successively with 1mol/L hydrochloric acid, saturated common salt washing；Organic facies is dried through anhydrous sodium sulfate, filters, concentrates, silica gel Column chromatography (petroleum ether: ethyl acetate=8: 1) obtains compound 3, productivity 92%.Its data are as follows:
1H NMR (600MHz, CDCl3) δ 7.77 (d, 2H, J=7.7Hz), 7.66 (m, 4H), 7.40-7.32 (m, 8H), 5.09 (d, 1H, J=4.4Hz), 4.92 (m, 1H), 3.82 (m, 2H), 3.51 (m, 1H), 2.44 (s, 3H), 1.92 (s, 3H), 1.08 (d, 3H, J=6.6Hz), 1.05 (s, 9H), 0.98 (s, 3H), 0.87 (d, 3H, J=6.6Hz), 0.83 (s, 3H)；
13C NMR (150MHz, CDCl3) δ 212.3,169.6,144.7,141.1,135.6,134.62,134.58, 132.8,129.8,129.4,129.3,127.8,127.4,127.3,120.6,75.5,74.6,73.0,54.9,53.9, 49.7,43.4,42.3,41.7,39.5,38.0,37.0,36.3,34.7,32.3,31.7,31.4,31.1,26.9,26.2, 21.5,21.0,20.6,19.3,19.0,16.6,16.2,13.1；
HRMS-ESI TOF:m/z [M+Na]+calcd for C52H70O7NaSSi:889.4504；Found:889.4526.
The preparation of compound 4 and data
Under argon shield, by compound 3 (5.69g, 6.57mmol), NaN3(1.71g, 26.28mmol) DMF (50mL) Being sequentially added into equipped with in the single port bottle of stirrer, after being placed in 60 DEG C of oil baths reaction 2h, reactant liquor is poured in frozen water, then with two Chloromethanes extracts, and collects and merge organic facies, and organic facies is washed through saturated common salt, anhydrous sodium sulfate is dried, concentrates, silica gel column layer Analysis (petroleum ether: ethyl acetate=15: 1) purification obtains 4, productivity 95%.Its data are as follows:
1H NMR (600MHz, CDCl3) δ 7.67 (m, 4H), 7.43-7.33 (m, 6H), 5.10 (d, 1H, J=5.5Hz), 4.95 (m, 1H), 3.52 (m, 1H), 3.20 (q, 1H), 3.13 (q, 1H), 1.95 (s, 3H), 1.12 (d, 3H, J=7.7Hz), 1.05 (s, 9H), 1.23 (s, 9H), 0.98 (s, 3H), 0.94 (d, 3H, J=6.6Hz), 0.84 (s, 3H)；
13C NMR (150MHz, CDCl3) δ 212.5,169.6,141.1,135.6,134.64,134.58,129.4, 129.3,127.3,120.7,75.6,73.0,57.6,54.9,53.8,49.7,43.4,42.3,41.7,39.5,38.2, 37.0,36.3,34.7,33.0,31.7,31.4,31.1,27.5,26.9,21.0,20.6,19.3,19.0,17.3,16.6, 13.1；
HRMS-ESI TOF:m/z [M+Na]+calcd for C45H63O4N3NaSi:760.4480；Found: 760.4485。
The preparation of compound 5 and data
Under argon shield, in single port bottle, it is sequentially added into compound 4 (200mg, 0.27mmol), K2CO3(112.45mg, 0.81mmol), THF (2.5mL), CH3OH (2.5mL), is placed in 65 DEG C of oil baths after back flow reaction 10h, reactant liquor dichloromethane Alkane dilutes, and filters off solid, and concentrating filter liquor and silica gel column chromatography (petroleum ether: ethyl acetate=7: 1) are pure Change 5, productivity 95%.Its data are as follows:
1H NMR (600MHz, CDCl3) δ 7.67 (m, 4H), 7.43-7.33 (m, 6H), 5.12 (d, 1H, J=4.4Hz), 4.57 (m, 1H), 3.52 (m, 1H), 3.22 (q, 1H), 3.13 (q, 1H), 1.05 (s, 9H), 1.01 (d, 3H, J=6.6Hz), 1.00 (s, 3H), 0.96 (d, 3H, J=6.8Hz), 0.76 (s, 3H)；
13C NMR (150MHz, CDCl3) δ 141.2,135.7,134.70,134.66,129.3,127.4,120.7, 110.2,81.4,73.1,62.5,57.5,56.3,49.8,42.4,40.5,39.8,39.5,37.1,36.5,36.2,33.7, 31.9,31.7,31.3,27.9,26.9,20.6,19.3,19.0,17.6,16.2,15.4；
HRMS-ESI TOF:m/z [M-H2O+H]+calcd for C43H60O2N3Si:678.4449；Found: 678.4445。
The preparation of compound 6 and data
To equipped with the single port bottle of magnetic agitation is sequentially added into compound 5 (130mg, 0.18mmol), THF (2.5mL), EtOH (2.5mL), Lindlar catalyst (52mg), in atmospheric conditions, in 30 DEG C with H2After hydrogenation 4h, kieselguhr mistake Filter, concentrating filter liquor and silica gel column chromatography (CH2Cl2∶MeOH∶Et3N=140: 1: 0.141) compound 6, productivity are separated to obtain 91%.Its data are as follows:
1H NMR (600MHz, CDCl3) δ 7.67 (m, 4H), 7.43-7.33 (m, 6H), 5.12 (d, 1H, J=4.4Hz), 4.28 (m, 1H), 3.52 (m, 1H), 2.62 (m, 2H), 1.06 (s, 9H), 1.01 (d, 3H, J=6.6Hz), 1.00 (s, 3H), 0.94 (d, 3H, J=7.7Hz), 0.84 (d, 3H, J=5.5Hz), 0.79 (s, 3H)；
13C NMR (150MHz, CDCl3) δ 141.2,135.6,134.6,129.3,127.34,127.31,120.7, 98.1,78.6,73.1,62.6,56.4,49.9,47.5,42.3,41.1,40.4,39.8,37.0,36.5,33.9,32.0, 31.9,31.7,31.2,30.1,26.9,20.7,19.3,19.2,19.0,16.3,15.2；
HRMS-ESI TOF:m/z [M+H]+calcd for C43H62O2NSi:652.4544；Found:652.4537.
The preparation of compound 7 and data
Under argon shield, to equipped with the single port bottle of magnetic agitation adds compound 6 (50mg, 0.077mmol), add four Hydrogen furan (2.0mL), 1M TBAF tetrahydrofuran solution (0.46mL, 0.46mmol), after 70 DEG C of back flow reaction, reactant liquor Concentrated and column chromatography (CH2Cl2∶MeOH∶Et3N=60: 1: 0.06) compound 7 (28mg, 0.068mmol, 88%) is obtained.Its number According to as follows:
1H NMR (600MHz, CDCl3) 65.33 (d, 1H, J=4.4Hz), 4.30 (m, 1H), 3.50 (m, 1H), 2.64 (m, 2H), 1.01 (s, 3H), 0.96 (d, 3H, J=6.6Hz), 0.84 (d, 3H, J=6.6Hz), 0.80 (s, 3H)；
13C NMR (150MHz, CDCl3) δ 140.8,121.3,98.2,78.7,71.6,62.7,56.5,50.0,47.6, 42.2,41.2,40.5,39.9,37.2,36.6,34.0,32.1,32.0,31.6,31.4,31.3,30.2,20.9,19.4, 19.3,16.4,15.3；
HRMS-ESI TOF:m/z [M+H]+calcd for C27H44O2N:414.3367；Found:414.3364.
The preparation of compound 9 and data
Under argon shield, Weigh Compound 7 (30mg, 0.073mmol) is in equipped with new activationMolecular sieve and magnetic agitation Tube sealing in, be sequentially added into benzotrifluoride (1.5mL), tert-butyl group acetonitrile (0.3mL), dichloromethane (0.5mL) ,-20 DEG C of stirrings After 20min, it is sequentially added into HB (C6F5)4With 8 dichloromethane solution (153mg, 0.12mmol, 1.5mL) and H2SO4-SiO2 (5mg), after continuing reaction 30min, reacting with triethylamine cancellation and filter, filtrate is through concentrated by rotary evaporation, column chromatography (CH2Cl2∶MeOH =120: 1) 9 (93mg, 82%) are obtained.Its data are as follows:
1H NMR (600MHz, CDCl3) δ 8.01 (dd, 4H, J=15.5,7.6Hz), 7.93 (d, 2H, J=7.3Hz), 7.78 (d, 2H, J=7.3Hz), 7.74 (d, 2H, J=7.4Hz), 7.53 (m, 4H), 7.39 (m, 10H), 7.26 (m, 1H), 6.02 (t, 1H, J=9.7Hz), 5.57 (t, 1H, J=9.1Hz), 5.38 (m, 1H), 5.29 (d, 1H, J=5.7Hz), 5.25 (m, 2H), 5.18 (d, 1H, J=7.7Hz), 5.15 (m, 1H), 5.06 (t, 1H, J=9.9Hz), 5.00 (s, 1H), 4.90 (m, 1H), 4.62 (m, 1H), 4.38 (m, 1H), 4.29 (m, 1H), 4.23 (m, 3H), 4.06 (d, 1H, J=7.7Hz), 3.81 (m, 1H), 3.69 (t, 1H, J=8.4Hz), 3.42 (m, 1H), 3.29 (m, 2H), 3.12 (m, 1H), 2.16 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H), 2.03 (s, 3H), 1.09 (d, 3H, J=6.0Hz), 0.95 (s, 3H), 0.82 (s, 3H)；
13C NMR (150MHz, CDCl3) δ 172.8,170.63,170.57,170.1,167.3,166.4,166.0, 165.9,165.7,149.1,147.5,140.2,139.1,137.1,135.5,134.11,134.06,133.7,133.6, 130.0,129.8,129.7,129.7,129.6,129.4,129.2,129.1,128.9,128.7,128.6,128.5, 128.3,121.6,100.9,100.1,99.5,97.3,84.3,80.0,76.3,75.0,73.1,72.8,72.4,70.84, 70.76,70.3,70.2,69.0,66.9,63.2,62.6,61.6,56.3,53.6,49.8,47.6,47.2,41.8,41.3, 39.1,38.4,36.9,36.8,32.4,32.2,31.8,31.4,29.8,29.7,29.0,28.3,27.7,21.2,21.0, 20.9,20.8,20.7,19.3,18.3,17.2,16.0,14.7；
HRMS-ESI TOF:m/z [M+H]+calcd for C88H102O25N:1572.6735；Found:1572.6740.
The preparation of compound 10 and data
Weigh 9 (83mg, 0.053mmol) in equipped with in the single port bottle of magnetic agitation, add methanol (4mL), dichloromethane (1mL), then regulating pH to 12 with 1M sodium hydrate aqueous solution, be placed in 70 DEG C of oil baths after back flow reaction 10h, reactant liquor is through dense Contracting, then column chromatography purification (CH2Cl2: MeOH is containing 8% water=5: 1) obtain solasodine 10 (21mg, 45%).Its data are as follows:
1H NMR (600MHz, pyridine-d5) δ 6.30 (s, 1H), 5.33 (s, 1H), 5.20 (d, 1H, J=7.7Hz), 4.96-4.89 (m, 5H), 4.82 (s, 1H), 4.70 (m, 1H), 4.61 (dd, 1H, J=9.1,2.9Hz), 4.47 (d, 1H, J= 10.3Hz), 4.45-4.35 (m, 2H), 4.35-4.15 (m, 6H), 4.05-3.90 (m, 3H), 2.85-2.71 (m, 4H), 1.70 (d, 3H, J=5.9Hz), 1.08 (d, J=7.0Hz, 3H), 1.06 (s, 3H), 0.87 (s, 3H), 0.82 (d, J=4.4Hz, 3H)；
13C NMR (150MHz, pyridine-d5) δ 140.9,121.8,105.9,102.3,100.4,98.4,84.8, 78.8,78.5,78.4,77.5,76.5,75.1,74.9,74.2,72.9,72.6,71.6,70.5,69.5,63.5,62.6, 62.6,56.7,50.3,49.7,48.1,41.6,40.6,40.1,38.8,37.5,37.2,34.7,32.6,32.4,32.1, 31.7,31.6,31.1,30.1,30.0,29.6,26.0,22.9,21.1,19.8,19.4,18.6,16.5,15.7,14.3；
HRMS-ESI TOF:m/z [M+H]+calcd for C45H74O16N:884.5002；Found:884.5025.
The preparation of compound 12 and data
Similar with preparing of compound 9, compound 7 (10mg, 0.024mmol) and trisaccharide three chlorimide ester 11 (32mg, 0.030mmol) react to obtain compound 12 (23mg, 0.017mmol, 72%).Its data are as follows:
1H NMR (600MHz, CDCl3): δ 8.03 (t, 4H, J=7.3Hz), 7.58-7.52 (m, 2H), 7.42 (m, 4H), 5.60 (t, 1H, J=9.0Hz), 5.33 (d, 1H, J=4.3Hz), 5.14 (m, 2H), 5.10 (m, 1H), 4.96 (m, 1H), (4.92-4.83 m, 3H), 4.76 (m, 2H), 4.66 (d, 1H, J=7.7Hz), 4.49 (dd, 1H, J=12.1,5.4Hz), 4.34 (m, 2H), 3.95 (t, 1H, J=9.1Hz), 3.85 (m, 1H), 3.77 (t, 1H, J=9.0Hz), 3.70 (m, 1H), 3.56 (m, 1H), 2.69 (m, 1H), 2.62 (t, 1H, J=11.0Hz), 2.38 (m, 2H), 2.22 (t, 1H, J=11.5Hz), 1.97 (s, 6H), 1.93 (s, 3H), 1.90 (s, 3H), 1.87 (s, 3H), 1.73 (s, 3H), 1.24 (s, 3H), 1.13 (d, 3H, J= 6.2Hz), 0.94 (s, 3H), 0.84 (d, 3H, J=6.2Hz), 0.79 (s, 3H), 0.66 (d, 3H, J=6.1Hz)；
13C NMR (150MHz, CDCl3): δ 170.02,169.96,169.88,169.7,168.89,165.8,165.0, 140.0,133.3,133.0,132.3,130.9,130.0,129.9,129.8,129.1,128.39,128.35,122.0, 99.5,99.0,98.3,98.0,79.5,78.7,77.4,76.3,75.9,73.0,71.8,71.0,70.4,70.0,69.1, 68.7,68.5,67.5,66.4,62.8,62.7,56.4,49.9,47.6,41.2,40.5,39.9,38.4,36.9,36.7, 34.0,32.11,32.06,3132,31.29,30.2,29.6,27.7,20.8,20.69,20.66,20.58,20.3,19.3, 19.2,19.1,17.1,16.8,16.4,15.3.
The preparation of compound 13 and data
Similar with preparing of compound 10, compound 12 (50mg, 0.038mmol) deprotection obtains solamargine 13 (23mg, 0.026mmol, 70%).Its data are as follows:
1H NMR (600MHz, pyridine-d5) δ 6.37 (s, 1H), 5.83 (s, 1H), 5.28 (d, 1H, J=4.9Hz), 4.94-4.90 (m, 3H), 4.81 (s, 1H), 4.66 (s, 1H), 4.61 (dd, 1H, J=9.4,3.5Hz), 4.52 (dd, 1H, J= 9.1,3.4Hz), 4.41-4.31 (m, 4H), 4.22-4.17 (m, 3H), 4.07 (d, 1H, J=12.2Hz), 3.88-3.83 (m, 1H), 3.61 (m, 1H), 2.80-2.67 (m, 4H), 2.06-2.01 (m, 2H), 1.93 (t, 1H, J=7.0Hz), 1.85-1.81 (m, 2H), 1.74 (d, 3H, J=6.4Hz), 1.60 (d, 3H, J=6.2Hz), 1.05 (d, 3H, J=7.1Hz), 1.02 (s, 3H), 0.84 (s, 3H), 0.78 (d, 3H, J=5.0Hz)；
13C NMR (150MHz, pyridine-d5) δ 140.5,121.6,102.7,101.8,100.0,98.2,78.6, 78.4,77.8,77.7,77.6,76.7,73.9,73.7,72.6,72.5,72.32,72.29,70.2,69.3,63.3,61.0, 56.4,50.1,47.8,41.4,40.4,39.8,38.7,37.3,36.9,34.4,32.3,32.1,31.46,31.36,30.8, 29.9,20.9,19.5,19.2,18.4,18.3,16.3,15.5；
HRESIMS:cacld for C45H74NO15, [M+H+], 868.5058.Found:868.5053.
The above, the only detailed description of the invention of the present invention, but protection scope of the present invention is not limited thereto, and any The change expected without creative work or replacement, all should contain within protection scope of the present invention.Therefore, the present invention Protection domain should be as the criterion with the protection domain that claims are limited.

Claims (12)

1. the synthetic method of spiranostan glycoalkaloid, it is characterised in that described spiranostan glycoalkaloid (I) General structure as follows:
Wherein,
Dotted line represents 5, is singly-bound or double bond between 6, and when it is singly-bound, 5 hydrogen atoms are α or beta comfiguration；
Logical formula (I) curve represents that 27 methyl are in equatorial bond or axial bond；
Work as X1=NH, X2=CH2, the absolute configuration of 25 carbon is R, or
Work as X1=CH2, X2=NH, the absolute configuration of 25 carbon is S；
R1Be by β-D-Glucopyranose. (β-D-Glcp), β-D-galactopyranose (β-D-Galp), β-D-mannopyranose (β- D-Manp), α-D-mannopyranose (α-D-Manp), β-L-mannopyranose (β-L-Manp), α-L-mannopyranose (α-L- Manp), β-D-xylopyranose (β-D-Xylp), β-D-pyrans glucosamine (β-D-GlcNACp), α-L-rhamnopyranose (α-L-Rhap), α-D-rhamnopyranose (α-D-Rhap), β-D-pyrans/arabinofuranose (β-D-Araf/p), α-D-pyrrole Mutter/arabinofuranose (α-D-Araf/p), α-L-pyrans/arabinofuranose (α-L-Araf/p), β-L-pyrans/furan Ah Draw uncle sugar (β-L-Araf/p), α-L-pyrans fucose (α-L-Fucp), beta d glucopyranosiduronic acid (β-D-GlcAp) and/ β-D-galactopyranosyluronic (β-D-GalAp) monosaccharide composition the chain that the degree of polymerization is 2-8 or the oligosaccharyl of ramiform；
It is characterized in that the method comprises the steps:
Wherein,
R2It it is silica-based or acyl group；
R3It it is sulfonyl；
R4It is the oligosaccharyl R of acyl group protection1；
Curve in reaction equation represents that substituted methyl is in equatorial bond or axial bond；
The preparation of (a) compound (III)
In a solvent, spirostanol saponin unit (II) under lewis acid or Bronsted acid promote with acetic anhydride under the conditions of-78-50 DEG C anti- Answer 0.1-2 hour, obtain corresponding 16-acetoxyl group-22-carbonyl-26-hydroxyl cholestane (III)；Wherein, R2Be silica-based or Acyl group；Spirostanol saponin unit (II) is 1:(1.0-10.0 with the mol ratio of Louis acid and acetic anhydride): (3.0-10.0)；
The preparation of (b) compound (IV)
In a solvent, compound (III) in the presence of a base with sulfonylation agent in-78-150 DEG C of reaction, obtain compound (IV), its In, compound (III) is 1.0:(1.0-3.0 with the mol ratio of sulfonylation agent)；R3For sulfonyl；
The preparation of (c) compound (V)
Compound (IV) in a solvent with Azide reagent-78-150 DEG C of reaction, obtain compound (V)；Compound (IV) is with folded The mol ratio of sodium nitride is 1.0:(1.0-3.0)；
Prepared by (d) compound (VI)
In the presence of a base, under the conditions of-78-150 DEG C, R in compound (V) is removed in a solvent2And Acetyl Protecting Groups, then use Under the conditions of reducing agent or catalytic hydrogen reduction, in 0-100 DEG C, nitrine is reduced under 1-100 air pressure, form oxygen-nitrogen spiral shell decane Structure, obtains compound (VI)；Alkali is (0.1-5.0) with the mol ratio of compound (V): 1.0；Reducing agent and compound (V) Mol ratio is (0.1-10.0): 1.0；Catalyst needed for catalytic hydrogenation is (0.1-100.0) with the weight ratio of compound (V): 1.0；
The preparation of (e) compound (VII)
In a solvent with dehydrant in the presence of, in-78-150 DEG C, with lewis acid or Bronsted acid as accelerator, compound (VI) with the oligosaccharide three chlorimide ester of acyl group protection to precursor reactant 1-48 hour, compound (VII) is obtained；Wherein, compound (VI) It is 1.0:(1.0-5.0 with the mol ratio of oligosaccharide three chlorimide ester donor and accelerator): (0.05-3.0)；Compound (VI) with Weight ratio 1.0:(3.0-10.0 of dehydrant)；R4It is the oligosaccharyl R of acyl group protection1；
The synthesis of (f) compound (I)
In a solvent, remove the acyl protecting groups in compound (VII) in-78-150 DEG C with alkali, obtain spiranostan glucosides raw Alkaloids；Wherein alkali is (0.1 100.0) with the mol ratio of compound (VII): 1.0；
Above-mentioned solvent is C1-C6Monohaloalkyl or polyhalo alkane, 1,4 dioxane, ether, acetonitrile, 2,2,2 trimethyls Acetonitrile, oxolane, N, N dimethylformamide, N, N dimethyl acetylamide, hexamethyl phosphoramide, N-methylpyrrolidin-2- A kind of in ketone, toluene, benzotrifluoride, pyridine, methanol, ethanol, isopropanol, water or their mixture；
Above-mentioned sulfonylation agent is selected from mesyl chloride, methanesulfonic acid acid anhydride, paratoluensulfonyl chloride, p-toluenesulfonic anhydride, fluoroform sulphur One or more in anhydride, imidazoles sulfonic acid chloride；
Above-mentioned Azide reagent is selected from Hydrazoic acid,sodium salt (NaN3), Lithium Azide (LiN3), trimethyl silica-based nitrine (TMSN3), three Butyl tinbase nitrine (Bu3SnN3One or more in)；
The oligosaccharide three chlorimide ester of above-mentioned acyl group protection is the R of acyl group protection1Oligosaccharide three chlorimide ester.
2. the synthetic method of spiranostan glycoalkaloid as claimed in claim 1, it is characterised in that R1It is
α-L-Rhap-(1→4)-[α-L-Rhap-(1→2)]-β-D-Glcp；
β-D-Glcp-(1→3)-[α-L-Rhap-(1→2)]-β-D-Galp；
α-L-Araf-(1→4)-[α-L-Rhap-(1→2)]-β-D-Glcp；
α-L-Arap-(1→4)-[α-L-Rhap-(1→2)]-β-D-Glcp；
β-D-Xylp-(1→4)-[α-L-Rhap-(1→2)]-β-D-Glcp；
α-D-Manp-(1→4)-[α-D-Manp-(1→2)]-β-D-Glcp；
α-D-Rhap-(1→4)-[α-D-Rhap-(1→2)]-β-D-Glcp；
α-L-Manp-(1→4)-[α-L-Manp-(1→2)]-β-D-Glcp；
{α-L-[α-L-Rhap-(1→4)]-Rhap-(1→4)}-[α-L-Rhap-(1→2)]-β-D-Glcp；
{α-L-[β-D-Xylp-(1→4)]-Rhap-(1→4)}-[α-L-Rhap-(1→2)]-β-D-Glcp；
{β-D-Xylp-(1→3)-[α-L-Rhap-(1→2)]-β-D-Glcp-(1→4)}-β-D-Galp；
α-L-Rhap-(1→2)-β-D-Glcp；α-D-Manp-(1→2)-β-D-Glcp；
α-D-Rhap-(1→2)-β-D-Glcp；α-L-Manp-(1→2)-β-D-Glcp.
3. the synthetic method of spiranostan glycoalkaloid as claimed in claim 1 or 2, it is characterised in that acyl group is C2-C6 Straight or branched aliphatic acyl radical or C6-C10Aromaticacyl radical.
4. the synthetic method of spiranostan glycoalkaloid as claimed in claim 1 or 2, it is characterised in that acyl group is acetyl
Base, chloracetyl, pivaloyl group, 4-carbonyl valeryl, 2-chloro-2-methyl-propiono, benzoyl, adjacent azido-methyl Benzoyl, 2-(2-nitrobenzophenone)-acetyl group, tribromo-acetyl base, trifluoroacetyl group.
5. the synthetic method of spiranostan glycoalkaloid as claimed in claim 1 or 2, it is characterised in that silica-based for first Three replacements that base, ethyl, isopropyl, the tert-butyl group, phenyl are constituted are silica-based.
6. the synthetic method of spiranostan glycoalkaloid as claimed in claim 1 or 2, it is characterised in that silica-based for tertiary fourth Base dimethyl is silica-based, tert-butyl diphenyl is silica-based.
7. synthetic method as claimed in claim 1, it is characterised in that described spirostanol saponin unit is diosgenin [△5, Y= H, H, 25 (R)], refined nurse sapogenin [△5, Y=H, H, 25 (S)], Tigogenin [5 α-H, Y=H, H, 25 (R)], new for accusing Sapogenin [5 α-H, Y=H, H, 25 (S)], hecogenin [5 α-H, Y=O, 25 (R)], new hecogenin [5 α-H, Y=O, 25 (S)], Chinaroot Greenbier Rhizome sapogenin [5 β-H, Y=H, H, 25 (R)], one in Sarsasapogenin [5 β-H, Y=H, H, 25 (S)].
8. synthetic method as claimed in claim 1, it is characterised in that described reducing agent is methyl, ethyl, isopropyl, tertiary fourth The trivalent phosphine compound that base, phenyl are constituted.
9. synthetic method as claimed in claim 1, it is characterised in that described catalytic hydrogen reduction condition is by 5-10%Pd/ C or 20%Pd (OH)2/ C or Lindlar catalyst or Raney-Ni and H2Or ammonium formate composition.
10. synthetic method as claimed in claim 1, it is characterised in that described lewis acid or Bronsted acid are that trimethyl is silica-based The silica-based triflate of triflate, triethyl group, t-Butyldimethylsilyl triflate, boron trifluoride second Ether, silver trifluoromethanesulfonate, copper trifluoromethanesulfcomposite, trifluoromethanesulfonic acid zinc, trifluoromethanesulfonic acid scandium, trifluoromethanesulfonic acid lanthanum, fluoroform sulphur Acid ytterbium, trifluoromethanesulfonic acid indium, trifluoromethanesulfonic acid or perchloric acid, Tetrafluoroboric acid, four (phenyl-pentafluoride base) boric acid, two (fluoroform sulphurs Acyl) imines, SiO2-H2SO4、SiO2-HClO4、SiO2A kind of in-HOTf or their mixture.
11. synthetic methods as claimed in claim 1, described dehydrant isMolecular sieve or AW-300 divide A kind of or their mixture in son sieve or anhydrous sodium sulfate, dead plaster, anhydrous cupric sulfate, anhydrous magnesium sulfate.
12. synthetic methods as claimed in claim 1, described alkali refer to hydroxide, hydride or carbonate or potassium tert-butoxide, Sodium tert-butoxide, tert-butyl lithium, Feldalat NM, Sodium ethylate, magnesium methoxide, pyridine, 4-N, N-lutidines, 2,6-dimethyl pyrazole Pyridine, 2,4,6-trimethylpyridine, tetrabutyl ammonium fluoride.
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