CN1331878C - Chemical synthesis method of franosterol saponin and its derivative - Google Patents

Abstract

The present invention relates to a new chemical method taking C27 spirostane type saponins and different saccharides as raw materials to synthesize furostanol saponins and derivatives thereof. The method comprises the following steps: (1) the synthesis of full protection type C27 spirostane saponins: the C27 spirostane saponins react with acyls, alkyls and glycosyl donors protected by silicone bases, under the conditions that dehydrating agents exist, and Lewis acid or protonic acid is taken as the accelerant, and full protection type oligosaccharide chains R1 are introduced into 3-bit OH; (2) oxidation: oxidation products are obtained by the reaction of the full protection type spirostane saponins with oxidants; (3) the generation replacement of saponin derivatives by 26-bit halogen: 26-bit halogenated products are obtained by the reaction of the oxidized spirostane saponins with oxytropic reagents; (4) the introduction of XR3 substituents: XR3 substituents are introduced by the nucleophilic substitution reaction of nucleophilic reagents and the halogenated products under alkaline conditions; (5) 16-bit carbonyls in saponins are selectively reduced by reducing agents; (6) furostanol saponins or analogs thereof are obtained after all protective groups are disengaged under the conditions of alkalinity or hydrogenization, etc.

Description

The chemical synthesis process of furostanol saponin and derivative thereof

Technical field

The present invention relates to spirostane type sapogenin and various carbohydrate is the chemical process of synthetic furostanol saponin of raw material and derivative thereof.

Technical background

22-OH/OMe furans gonane type saponin(e is a class formation saponin(e as shown below.Its constructional feature is: (1)

Aglycon is C ₂₇Furans gonane type aglycon; (2) 5 can with 6 form two key (Δs ⁵), also can be the saturated carbon of α/β-H; (3) 12 bit substituent Y=O or H, H or OH, H; (4) 22 OH/OMe/OEt can transform mutually: reflux in MeOH/EtOH, OH can be converted into OMe/OEt; Reflux in acetone, OMe/OEt can be converted into OH[Hu, K.; Dong, A.; Yao, X.; Kobayashi, H.; Iwasaki, S.Planta Med.1997,63,161-165]; (5) R ₁Can be H, but D-glucose (D-Glc), D one semi-lactosi (D-Gal), L-rhamnosyl (L-Rha), D (L)-pectinose (D monose such as (L)-Ara) and be the oligosaccharyl of 2～8 chains or ramiform by the polymerization degree that they are formed normally; (6) in present this saponins of finding, R ₃Be generally β-D-Glcp, only a few is α-L-Rhap, [Sarmbi Reddy, K.; Shekhani, M.S.; Berry, D.E.; Lynn, D.G.; Hecht, S.M.J. Chem.Soc.Perkin Trans.I 1984,987-992].

Owing to 22-OH/OMe furans gonane type saponin(e can (furostanol glycoside26-O-β-glucosidase) enzymolysis specifically loses 26 glucosyl group and is converted into spirostane type saponin(e [(a) Wang, L. by the intravital F26G enzyme of plant; You, S.; Jiang, Y. H.; Yao, X.S.Chin.J. Med.Chem.2001,11,326-328; (b) Jin, J.-M.; Liu, X.-K.; Teng, R.-W.Yang, C.-R.Acta Botanica Sinica, 2002,44,1243-1249; (c) Inoue, K.; Shimomura, K.; Kobayashi, S.; Sankawa, U.; Ebizuka, Y.Phytochemistry, 1996,41,725-727; (d) Li, X.C.; Wang, D.Z.; Yang, C.R.hytochemistry, 1990,33,3559-3563; (e) Kawasaki, T.; Komori, T.; Miyahara, K.; Nohara, T.; Hosokawa, I.; Mihashi, K.Chem.Pharm.Bull.1974,22 (9), 2164-2175], this saponins is also degraded under extraction conditions such as acid, high temperature easily simultaneously, does not therefore find them in the research work in early days.Up to nineteen forty-seven, people such as Marker think that just furostanol saponin is parent compound [Marker, the R.E. of spirostanol saponin when Trillium erectum is carried out extraction separation; Wagner, R.B.; Ulshafer, P. R.; Wittbecker, E.L.; Goldsmith, D.P. J.J. Am.Chem.Soc.1947,68,2167-].Yet the discovery of-individual furans gonane type saponin(e jurubine but is thing [Schreiber, K. in 1966; Ripperger, H.Tetrahedron Lett.1966,5997].After this, along with to the intensification of furostanol saponin character and the progress of separate analytical technique, a large amount of furostanol saponins are found.From the various plants of sections such as Asparagaceae, garlic section, Liliaceae, Dioscoreaceae and Solanaceae, separated so far and obtained more than 200 furostanol saponin.

Along with the development of glycobiology, the biological activity of furans gonane type saponin(e is familiar with gradually and is used.For example: the cardiac vascular activity of (1) furostanol saponin: DIAOXINXUE KANG JIAONANG is widely used in treating cardiovascular disordeies such as coronary heart disease, stenocardia clinically.In fact, DIAOXINXUE KANG JIAONANG is to be made by the total steroid saponin that extracts from the Dioscorea panthaica Prain et Burkill root, wherein contains furostanol saponin protogracillin 1, protodioscin 2 and uncle deltoside Li 3[are firm, Zhou Zhengzhi new drug and clinical, 1994,13,75-76] (reaction formula 1).

Reaction formula 1: the structure of furostanol saponin in the Diaoxinxuekang

Recently, studies show that again of fresh Dioscorea panthaica Prain et Burkill contained a large amount of furostanol saponins in the Dioscorea panthaica Prain et Burkill, and saponin(es such as spiral shell steroid may be enzymolysis product or the artifact in the extraction separation process [Geng, Y. after medicinal material is put for a long time; Tan, N.-H.; Zhou, J.; Kong, L.-Y. Chin.J. Nat.Med. 2004,2,25-27].(2) cytotoxicity of furostanol saponin: recently, Yao new life etc. has tested the activity of protodioscin 2 (Scheme 1) to 60 human cancer cell strains, and the result shows the GI of this compound to leukemia cell MOLT-4, colon cancer cell HCT-116 and SW-620, CNS cancer cells SNB-75 and kidney cancer cell 786-0 etc. ₅₀≤ 2.0 μ M[Hu, K.; Yao, X.S.Planta Med.2002,68,297-301]; Protodioscin is to the GI of lung carcinoma cell PC-6, breast cancer cell MCF-7, stomach cancer cell NUGC-3, mouse leukemia cell P388 in addition ₅₀＜1.9 μ M[Nakamura, T.; Komori, C.; Lee, Y.-y.; Hashimoto, F.; Yahara, S.; Nohara, T.; Ejima, A.Biol.Pharm.Bull.1996,19,564-566]; Yet, when the two keys in the protodioscin 2 are the GI of furostanol saponin 4 pair cell PC-6 and NCT-116 by the saponin(e after saturated ₅₀Value is all greater than 5 μ M[Ikeda, T.; Tsumagari, H.; Okawa, M.; Nohara, T.Chem.Pharm.Bull.2004,52,142-145].

Reaction formula 2: the structure of furostanol saponin 4

In addition, furostanol saponin also has antifertility isoreactivity [Yoshi, J.; Dev, S.Indian J.Chem.1988,27B, 12-16].Zhang Jianbo etc. summarize the research work of relevant furans gonane type saponin(e in the recent period, this to understand this compounds in plant distribution and study its chemical structure helpful [Zhang Jianbo, Yu Biao, Hui Yongzheng organic chemistry, 2000,20,663].

It not merely is energy and structural material that the continuous development of glycobiology has disclosed sugar, but also [the Varki that in processes such as the unusual increment of the keeping of the permanent attitude of neural system, immunity system, inflammation, autoimmune disease, aging, cancer cells and transfer, pathogenic infection, plays an important role, A.Glycobioiogy, 1993,3,97].Yet for 2-OH/OMe furans gonane type saponin(e, since it usually with the association of other saponin(e with and the unstable of structure make their separation and purification and part degraded difficult, thereby limit the research of this compounds structure activity relationship, also restricted its further development and utilization.Utilize chemosynthesis not only can obtain having the furans saponin(e of different sugar chains, but also may suppress F26G enzyme enzymolysis at the heteroatoms beyond 26 introducing oxygen, these all provide basic substance for the structure activity study of furostanol saponin, thereby help the development and utilization of this compounds.So far, two pieces of reports about the furostanol saponin chemosynthesis [(a) Yu, B. are only arranged; Liao, J.C.; Zhang, J.B.; Hui, Y. Z.Tetrahedron Lett, 2001,42,77-79; (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.2003,68,3658-60].

Summary of the invention

It is a kind of with C that this patent provides ₂₇Spirostane type sapogenin and various carbohydrate are the new chemical method of raw material synthetic furostanol saponin and derivative thereof, and synthetic furostanol saponin structure is as follows:

This method comprises the steps: (1) C ₂₇Synthesizing of spirostanol saponin: in the presence of dewatering agent, be promotor with Lewis acid or protonic acid, C ₂₇The glycosyl donor reaction of spiral shell sterioside unit and acyl group, alkyl and silica-based protection is at the oligonucleotide chain R of its 3 OH introducing full guard ₁, obtain the spirostanol saponin of full guard: the oxidation of the spirostanol saponin of (2) full guard: full guard spirostanol saponin and oxidant reaction obtain oxidation products; (3) 26 halogens replace the generation of saponin derivative: in the presence of dewatering agent, the spirostanol saponin of oxidation and oxyphie reagent react obtain 26 halogenated product; (4) XR ₃Substituent introducing: under alkaline condition, with nucleophilic reagent and halogenated product generation nucleophilic substitution reaction and introduce required XR ₃Substituting group; (5) reductive agent optionally reduces 16 carbonyls in the kryptogenin saponin(e; (6) preparation of furostanol saponin or its analogue: under conditions such as alkalescence or hydrogenation, slough all protecting groups and get furostanol saponin or its analogue.

Concrete each step is as follows:

(1), C ₂₇Synthesizing of spirostanol saponin:

In organic solvent, in the presence of dewatering agent and promotor, C27 spirostanol saponin unit obtained the monose spirostanol saponin with glycosyl donor in 3～10 hours in-40～40 ℃ of reactions; When R1 is that the polymerization degree is 2～8 oligonucleotide chain, structural formula is as follows:

The time, be intermediate then, through C with corresponding monose spirostanol saponin ₁～C ₈Fatty acyl group, C ₇～C ₁₀Aromaticacyl radical, C ₇～C ₁₀Aromatic series halohydrocarbon (as benzyl, to methoxy-benzyl), C ₁～C ₆The operation of trialkyl silyl protecting group, adopting progressively, the strategy of glucosidesization obtains; The mol ratio of described glycosyl acceptor, promotor and glycosyl donor is 1: 0.05～0.5: 1.0～5.0; Described C ₂₇The weight ratio of spiral shell sterioside unit and dewatering agent is 1.0: 3.0～10.0;

Described organic solvent is C ₁～C ₆Halohydrocarbon, 1,4-dioxane, ether (Et ₂O), acetonitrile (CH ₃CN), 2,2,2-trimethylacetonitrile (t-BuCN), tetrahydrofuran (THF) (THF), N, dinethylformamide (DMF), N,N-dimethylacetamide (DMA), hexamethylphosphoramide (HMPA), toluene (PhCH ₃) or benzene (PhH) or their mixture:

Described dewatering agent is 3 , 4 , 5  molecular sieves (AW-3 , AW-4 , AW-5 ), the Na of 3 , 4 , 5  molecular sieves, pickling ₂SO ₄, CaSO ₄, CuSO ₄Or MgSO ₄

Described promotor is C ₁～C ₆Trialkyl silyl triflate, boron trifluoride diethyl etherate (BF ₃Ey ₂O), silver trifluoromethanesulfonate (AgOTf), trifluoromethanesulfonic acid lithium (LiOTf), copper trifluoromethanesulfcomposite [Cu (OTf) ₂], trifluoromethanesulfonic acid zinc [Zn (OTf) ₂], trifluoromethanesulfonic acid scandium [Sc (OTf) ₃], trifluoromethanesulfonic acid lanthanum [La (OTf) ₃], Ytterbiumtriflate [Yb (OTf) ₃], trifluoromethanesulfonic acid indium [In (OTf) ₃], trityl group perchlorate (Ph ₃CClO ₄), trityl group a tetrafluoro borate (Ph ₃CBF ₄), trifluoromethanesulfonic acid (TfOH), perchloric acid (HClO ₄), Tetrafluoroboric acid (HBF ₄), four (phenyl-pentafluoride base) boric acid [HB (C ₆F ₅) ₄] or two (fluoroform sulphonyl) imines (HNTf ₂);

Described C ₂₇Spirostanol saponin unit is that [△ 5, Y=H, H for diosgenin (diosgenin), 25 (R)], [△ 5, Y=H, H for refined nurse sapogenin (yamogenin), 25 (S)], for accusing sapogenin (tigogenin) [5 α-H, Y=H, H, 25 (R)], NSC 232021 (neotigogenin) [5 α-H, Y=H, H, 25 (S)], hecogenin (hecogenin) [5 α-H, Y=O, 25 (R)], Chinaroot Greenbier Rhizome sapogenin (smilagenin) [5 β H, Y=H, H, 25 (R)], timosaponin unit (sarsasapogenin) [5 β H, Y=H, H, 25 (S)], [△ 5 for botogenin (botogenin), Y=O, 25 (R)], [△ 5, Y=O for Neobotogenin (neobotogenin), 25 (S)] or different chiapagenin (isochiapagenin) [△ 5, Y=β-OH, α-H, 25 (S)]

Described glycosyl donor is C ₁～C ₈Fatty acyl group, C ₇～C ₁₀Aromaticacyl radical, C ₇～C ₁₀Aromatic series halohydrocarbon (as Benzyl Chloride, to the methoxyl group benzyl chloride), C ₁～C ₆D-glucose (D-Glc), D-semi-lactosi (D-Gal), D-seminose (D-Man), D-wood sugar (D-Xyl), 2-glucosamine, L-rhamnosyl (L-Rha), D (L)-pectinose (sulphur glycosides, tribromo-acetyl imines ester or trifluoroacetyl imines ester or the fluorine glycosides of the monose of D (L)-Ara), D-glucuronic acid (D-GlcA), D-galacturonic, (D-GalA) of trialkyl silyl protection.

(2) oxidation of the spirostanol saponin of full guard:

With organic solvent, water or their mixture as medium, full guard spirostanol saponin and oxone (oxone), peroxy propanone, 1,1,1-trifluoromethyl peroxy propanone, metachloroperbenzoic acid, Peracetic Acid, CrO ₃, KMnO ₄, NaIO ₄, (Bu) ₄N ⁺IO ₄ ^-Or the mol ratio of their mixture is to obtain oxidation products in 10～60 hours in-20～40 ℃ of reactions at 1: 3.0～25.0 o'clock.

(3) 26 halogens replace the generation of saponin derivative:

In the presence of organic solvent neutralization-40-30 ℃ and dewatering agent, above-mentioned oxidation products and oxyphie reagent react obtained 26 halogens in 0.1～2 hour and replace saponin derivatives; The mol ratio of the spirostanol saponin of oxidation and oxyphie reagent is 1: 3.0～25.0; The spirostanol saponin of oxidation and the weight ratio of dewatering agent are 1.0: 3.0～10.0; Described oxyphie reagent is MgCl ₂, MgBr ₂, MgI ₂, AlCl ₃, AlBr ₃, AlI ₃, NaI, LiI, LiCl, LiBr, ZrCl ₄, (Cp) ₂ZrCl ₂, C ₁～C ₆Trialkyl silyl halogenide or their mixture.

(4) XR ₃Substituent introducing:

Under-78～60 ℃ of the organic solvent neutralizations, alkali or reductive agent in the presence of, with nucleophilic reagent and halogenated product reaction 3～10 hours, generation nucleophilic substitution reaction and introduce required XR ₃Substituting group; The mol ratio of described halogenated product, alkali or reductive agent and nucleophilic reagent is 1: 1.5～4.0: 1.5～4.0;

Described alkali can be mineral alkali, as NaOH, KOH, LiOH, CsOH, Na ₂CO ₃, K ₂CO ₃, Cs ₂CO ₃, NaH, KH or LiH; Also can be organic bases, as two-sec.-propyl Lithamide (LDA), potassium tert.-butoxide (t-BuOK), n-Butyl Lithium (n-BuLi), isobutyl-lithium (s-BuLi), tert-butyl lithium (t-BuLi), NaOMe, NaOEt, Mg (OMe) ₂, 1,8-two-azabicyclic [5.4.0] undecane-7-alkene (DBU), 1,5-two-azabicyclic [4.3.0] nine alkane-7-alkene (DBN), 1,4-two-azabicyclic [2.2.2] heptane (DABCO), Et ₂NH, Et ₃N, pyridine (pyridine), imidazoles (imidazole) or 4-N, N-lutidine (DMAP);

Described reductive agent is sodium borohydride (NaBH ₄), lithium borohydride (LiBH ₄) or POTASSIUM BOROHYDRIDE (KBH ₄);

Described nucleophilic reagent is C ₁～C ₇Alkyl magnesium, lithium, copper, zinc, boron, tin metal reagent, C ₆～C ₁₂Aryl magnesium, lithium, copper, zinc, boron, tin metal reagent, C ₁～C ₇Alkyl sulfhydryl, selenol or above-mentioned mercaptan or the corresponding acetylate of selenol, C ₆～C ₁₂Aryl mercaptan, selenol or above-mentioned mercaptan or the corresponding acetylate of selenol, different head position be OH, SH, SeH, NH2, SAc, SeAc ,-S-S-,-Se-Se-, C ₁～C ₇Alkylsulfonamido, C ₆～C ₁₂Aryl-sulfonyl amino by C ₁～C ₈Fatty acyl group, C ₇～C ₁₀Aromaticacyl radical, C ₇～C ₁₀Aromatic series halohydrocarbon (as the halogenation benzyl, to methoxyl group halogenation benzyl), C ₁～C ₆β-D-the glucose of trialkyl silyl protection (β-D-Glc); alpha-D-glucose (α-D-Glc); β-D-semi-lactosi (β-D-Gal); α-D-semi-lactosi (α-D-Gal); β-D-seminose (β-D-Man); α-D-seminose (α-D-Man); β-D-wood sugar (β-D-Xyl); alpha-D-xylose (α-D-Xyl); β-D-2-glucosamine; α-D-2-glucosamine; α-L-rhamnosyl (α-L-Rha); β-L-rhamnosyl (β-L-Rha); α-D-pectinose (α-D-Ara); β-D-pectinose (β-D-Ara); α-L-arabinose (α-L-Ara); β-L-arabinose (β-L-Ara); α-L-Fucose (α-L-Fuc); β-L-Fucose (β-L-Fuc); alpha-D-glucose aldehydic acid (α-D-GlcA); β-D-glucuronic acid (β-D-GlcA); α-D-galacturonic acid (α-D-GalA); β-D-galacturonic acid (β-D-GalA) or be the oligosaccharide compound of 2～8 chains or ramiform by the polymerization degree that these monose are formed; tetrabutyl fluoride amine (TBAF); trimethyl azide base silane (TMSN ₃), trimethylammonium cyano group silane (TMSCN), sodiumazide (NaN ₃), potassium cyanide (KCN) or sodium cyanoborohydride (NaCNBH ₃).

(5) reductive agent optionally reduces 16 carbonyls:

In organic solvent, under 1.0～10.0 normal atmosphere and-40～40 ℃, the product of (4) and reductive agent reaction obtained the hemiacetal product in 15～50 hours; (4) the product and the mol ratio of reductive agent are 1: 0.2～20.0.

Described reductive agent is NaBH ₄, LiBH ₄, KBH ₄, tetrahydrochysene lithium aluminium (LiAlH ₄), three (triphenylphosphine) POTASSIUM BOROHYDRIDE [K (Ph ₃P) ₃BH], three (isopropoxy) POTASSIUM BOROHYDRIDE [K (i-PrO) ₃BH], three (tert.-butoxy) Li-Al hydrogen [Li (t-BuO) ₃AlH] or Raney nickel;

When reductive agent is NaBH ₄, LiBH ₄, KBH ₄, LiAlH ₄, K (Ph ₃P) ₃BH, K (i-PrO) ₃BH or Li (t-BuO) ₃During AlH the mol ratio of the product of (4) and reductive agent be recommended as 1: 5.0～20.0;

When reductive agent is Raney nickel, the product of (4) and the mol ratio of reductive agent be recommended as 1: 0.2～and 1.0.

(6) preparation of furostanol saponin or its analogue:

In organic solvent, water or their mixture; in the presence of inorganic or organic bases or hydrogenation catalyst; above-mentioned hemiacetal reacted 20～60 hours under-20-60 ℃ and 1.0～10.0 normal atmosphere, and all protecting groups of sloughing hemiacetal obtain furostanol saponin or its analogue.Above-mentioned hemiacetal, mol ratio inorganic or organic bases are 1: 1.0～10.0; The mol ratio of above-mentioned hemiacetal and hydrogenation catalyst is 1: 0.2～1.0

Described alkali can be mineral alkali, as NaOH, KOH, LiOH, CsOH, Na ₂CO ₃, K ₂CO ₃, Cs ₂CO ₃, NaH, KH or LiH; Also can be organic bases, as LDA, t-BuOK, BuLi, s-BuLi, t-BuLi, NaOMe, Mg (OMe) ₂, DBU, DBN, DABCO, Et ₂NH, Et ₃N, pyridine, imidazoles or 4-N, the N-lutidine.

Described hydrogenation catalyst is 10% palladium charcoal, palladium hydroxide [Pd (OH) ₂] or lithium+liquefied ammonia;

Method of the present invention is recommended under the rare gas element carries out, as protections such as argon gas, nitrogen down.

Method of the present invention is a kind of easy, effective chemical process of synthetic Furost saponine and its analogue.This method not only can obtain having the furans saponin(e of different sugar chains, but also may suppress F26G enzyme enzymolysis at the heteroatoms beyond 26 introducing oxygen, these all provide basic substance for the structure activity study of furostanol saponin, thereby help the development and utilization of this compounds.

Embodiment

Following embodiment will help to understand the present invention, but be not limited to content of the present invention.

Synthetic embodiment

26 sulfo-furostanol saponin VIII's is synthetic:

Reaction formula 1:26 position sulfo-furostanol saponin VIII's is synthetic

Reagent and condition: a) 4  MS, trimethylsilyl trifluoromethanesulfonate (TMSOTf), CH ₂Cl ₂, rt; B) oxone, acetone, H ₂O, C ₁-C ₆Halohydrocarbon, rt; C) AlI ₃, CH ₃CN ,-40-80 ℃; D) MeONa, MeOH, CH ₂Cl ₂,-78-40 ℃; E) NaBH ₄, i-PrOH, CH ₂Cl ₂, rt; F) NaOH, CH ₃OH, H ₂O, 60 ℃

(1) under the glucosides condition, diosgenin and 2,2, the glucose three chlorimide esters of 2-pivaloyl (Piv) protection obtain full guard spiral steroidal saponin II for body I reaction; (2) II obtains the product III of two keys and 16 oxidations with the oxone oxidation; (3) III and AlI ₃Reaction obtains epoxy and removes the product IV of 26 iodos simultaneously; 4) under alkaline condition, V and IV reaction generate the disaccharide chain saponin(e VI of 26 sulfo-s; (5) NaBH ₄16 carbonyls that optionally reduce get the hemiacetal product VII; (6) under the alkaline condition, remove the furostanol saponin VIII (Scheme 1) that Piv, Bz protecting group obtain 26 sulfo-s.

Experimentation and data:

Compound I I's is synthetic:

Under the argon shield, (1.50g 3.40mmol) gives body I[Zimmermann, P. with the glucose of Piv protection with diosgenin; Bommer, R.; Bar, T.; Schmidt, R.R.J.Carbohydr.Chem.1988,7,435-452] (3.45g, 5.22mmol 1.54equiv.) are dissolved in the anhydrous CH of 30ml ₂Cl ₂In, to wherein adding exsiccant 4  molecular sieves (10.0g), stirring at room is after half an hour, add the silica-based triflate of trifluoromethyl base (TMSOTf) (0.06ml, 0.34mmol, 0.1equiv.), continue to stir 2 hours, the TLC demonstration reacts completely, triethylamine cancellation reaction is filtered, and concentrated, rapid column chromatography gets white solid (2.80g, 3.07mmol, 90%).

[α] _D ²⁵＝-50.84(c?0.90，CHCl ₃)；

¹H?NMR(300MHz，CDCl ₃)δ5.34-5.28(m，2H)，5.06(t，1H，J＝9.6Hz)，4.98(dd，1H，J＝7.5，9.9Hz)，4.61(d，1H，J＝7.8Hz)，4.40(m，1H)，4.20(d，1H，J＝12.0Hz)，4.01(dd，1H，J＝6.6，12.0Hz)，3.75-3.69(m，1H)，3.54-3.36(m，3H)，2.22(m，2H)，1.20，1.16，1.14，1.10(s，each?9H)； ¹³C?NMR(75MHz，CDCl ₃)δ177.99，177.17，176.50，176.33，140.39，121.73，109.24，99.63，80.78，79.55，72.40，72.16，71.37，68.41，66.83，62.31，62.71，56.49，50.12，41.62，40.27，39.76，38.88，38.82，38.74，38.66，37.16，36.86，32.06，31.85，31.44，31.41，30.29，29.59，28.81，27.16，27.13，27.08，27.04，20.83，19.30，17.10，16.23，14.47；MS(ESI)m/z?91?3.7[M+H ⁺]，936.0[M+Na ⁺]；

Ultimate analysis: calculated value: C ₅₃H ₈₄O ₁₂1/2 H ₂O, C69.02%, H9.29%, measured value: C69.13%, H, 8.94%

Synthesizing of compound III:

Under the room temperature condition, (1.70g 1.86mmol) is dissolved in by CH with compound III ₂Cl ₂: acetone: the mixed solvent (21ml) that water=1: 0.2: 3 is formed under the argon shield, adds NaHCO ₃(2.34g, 27.90mmol, 15.0equiv.) and oxone (12equiv.), TLC detection reaction raw material disappears after 48 hours, separates organic phase, water CH for 13.72g, 22.32mmol ₂Cl ₂Extraction merges all organic phases, and through Na ₂SO ₄After the drying, filter, concentrate, rapid column chromatography gets full guard and gets Compound I I (1.32g, 1.40mmol, 75%).

α epoxide isomer (α eposide isomers)

1H?NMR(300MHz，CDCl ₃)δ?5.30(t，1H，J＝9.3Hz)，5.07(t，1H，J＝9.9Hz)，4.98(dd，1H，J＝7.g，9.3Hz)，4.60(d，1H，J＝g.4Hz)，4.21(t，1H，J＝9.9Hz)，4.02(dd，1H，J＝6.3，12.0Hz)，3.80-3.55(m，4H)，3.00(d，1H，J＝2.1Hz)；

β epoxide isomer (β eposide isomers)

1H?NMR(300MHz，CDCl3)δ?5.28(t，1H，J＝9.6Hz)，5.07(t，1H，J＝9.3Hz)，4.98(dd，1H，J＝7.8，9.3Hz)，4.60(d，1H，J＝8.4Hz)，4.21(t，1H，J＝9.9Hz)，4.02(dd，1H，J＝6.3，12.0Hz)，3.80-3.55(m，4H)，2.86(d，1H，J＝4.2Hz)；

HRMS (MALDI) calculated value: C ₅₃H ₈₄O ₁₄Na967.5759, measured value: C ₅₃H ₈₆O ₁₂Na ⁺967.5753 compound IV is synthetic:

Under the argon shield; the glucose bromine glycosides (3.48g of benzoyl (Bz) protection; 5.28mmol), (950mg 8.32mmol) is dissolved among the anhydrous DMSO of 30ml KSAc; 30 ℃ of stirring reactions 10 hours; the TLC demonstration reacts completely, and decompression is spin-dried for, and rapid column chromatography obtains white solid (2.12g; 3.23mmol, 61%).

[α] _D ²⁴＝86.50(c?0.93，CHCl ₃)；

¹H?NMR(300MHz，CDCl ₃)δ?8.06～7.79(m，8H)，7.58～7.24(m，12H)，6.02～5.96(m，1H)，5.73(t，1H，J＝9.89Hz)，5.67～5.61(m，2H)，4.60(dd，1H，J＝3.02，12.36Hz)，4.46(dd，1H，J＝4.65，12.36Hz)，4.34～4.28(m，1H)，2.31(s，3H)；

¹³C?NMR(75MHz，CDCl ₃)δ?192.13，166.10，165.65，165.13，133.52，133.26，133.08，129.92，129.82，129.71，128.69，128.42，128.23，80.63，76.82，74.16，69.84，69.11，62.89，30.82；

Ultimate analysis: calculated value: C ₃₆H ₃₀O ₁₀S C66.05%, H4.62%; Measured value: C66.09%, H4.44%.

Compound V's is synthetic:

Under the argon shield, to compound III (640mg, 0.6gmol) and AlI ₃(832mg, 2.04mmol add CH in mixture 3.0eqiuv.) ₃CN: CH ₂Cl ₂=2: 3 mixed solvent 5ml stirred under-20～0 ℃ of condition after 2 hours, and the TLC demonstration reacts completely.The Na that the reaction solution impouring is saturated ₂S ₂O ₃In the aqueous solution, CH ₂Cl ₂Extraction, organic phase is through Na ₂SO ₄After the drying, filter, concentrate, rapid column chromatography gets compound V (595mg, 0.57mmol, 85%).

[α] _D ²⁵＝-82.16(c?1.19，CHCl ₃)；

¹H?NMR(300MHz，CDCl ₃)δ5.35-5.28(m，2H)，5.08(t，1H，J＝9.6Hz)，4.99(dd，1H，J＝8.1，9.3Hz)，4.62(d，1H，J＝8.1Hz)，4.21(d，1H，J＝11.7Hz)，4.02(dd，1H，J＝6.3，12.3Hz)，3.75-3.70(m，1H)，3.48-3.45(m，1H)，3.27(d，2H，J＝4.8Hz)，2.73-2.57(m，4H)，2.24-2.18(m，3H)，1.21，1.15，1.12，1.10(s，each?9H)，0.79(s，3H)；

¹³C?NMR(75MHz，CDCl ₃)δ217.87，212.95，177.97，177.17，176.50，176.33，140.56，121.50，99.74，79.50，72.36，72.17，71.35，68.36，66.22，62.28，51.24，49.76，43.22，41.65，39.45?38.84，38.72，38.66，38.60，37.15，36.84，36.77，33.64，31.71，30.94，29.89，29.51，27.14，27.11，27.08，27.02，20.63，20.50，19.27，17.60，15.37，12.94；

HRMS (MALDI) calculated value: C ₅₃H ₈₃IO ₁₂Na1061.4827, measured value: C ₅₃H ₈₃IO ₁₂Na ⁺1061.4821.

Synthesizing of compound VI:

Under the argon shield, with compound IV (618mg, 0.94mmol, 1.68equiv.) and V (586mg 0.56mmol) is dissolved in 10ml MeOH: CH ₂Cl ₂In=1: 4 mixed solvents of forming, add then freshly prepd MeONa (52.42mg, 1.01mmol, 1.80equiv.),-78 ℃ were stirred 2 hours, then be warming up to 40 ℃ and stir after 1 hour, the TLC demonstration reacts completely, AcOH cancellation reaction, concentrate, column chromatography obtains thio-compounds VI (825mg, 0.54mmol, 96%).

[α] _D ²⁴＝-53.45(c?0.94，CHCl ₃)；

¹H?NMR(300MHz，CDCl ₃)δ8.02-7.81(m，8H)，7.52-7.27(m，12H)，5.93(t，1H，J＝9.6Hz)，5.64(t，1H，J＝9.9Hz)，5.55(t，1H，J＝9.6Hz)，5.36-5.30(m，2H)，5.08(t，1H，J＝9.6Hz)，5.02(d，1H，J＝9.9Hz)，5.01(t，1H，J＝9.9Hz)，4.68-4.63(m，2H)，4.47(dd，1H，J＝4.8，12.0Hz)，4.31-4.20(m，2H)，4.03(dd，1H，J＝6.6，12.0Hz)，3.78-3.72(m，1H)，3.50-3.47(m，2H)，2.91(dd，1H，J＝3.9，12.9Hz)，2.66-2.63(m，2H)，2.53-2.39(m，3H)，2.32-2.26(m，3H)，1.22，1.18，1.16，1.12(s，each?9H)，1.00(s，3H)，0.99(d，3H，J＝7.5Hz)，0.89(d，3H，J＝6.3Hz)，0.77(s，3H)；

¹³C?NMR(75MHz，CDCl ₃)δ218.16，213.00，177.99，177.17，176.50，176.33，166.00，165.75，165.19，140.55，133.32，133.11，129.85，129.68，129.21，128.89，128.31，121.15，99.71，83.84，79.47，75.92，74.13，72.31，72.16，71.31，70.79，70.02，68.33，66.24，63.52，62.26，51.21，49.73，43.22，41.62，39.27，38.82，38.66，37.13，37.01，36.77，32.70，31.68，30.91，29.50，29.36，27.08，27.02，20.48，19.28，15.40，12.91；

HRMS (MALDI) calculated value: C ₈₇H ₁₁₀O ₂₁SNa1545.7158, measured value; C ₈₇H ₁₁₀O ₂₁SNa ⁺1545.7153;

Ultimate analysis; Calculated value: C ₈₇H ₁₁₀O ₂₁H ₂O, C67.77%, H7.32%, measured value: C67.50%, H, 6.96%.

Compound VI I's is synthetic:

With compound V (600mg, 0.39mol) molten sub-10ml i-PrOH: CH ₂Cl ₂In=1: 5 mixed solvents, argon shield adds NaBH down ₄(147.54mg, 3.90mmol 10.0equiv.), stir under-20-40 ℃ of the condition after 40 hours, in the reaction solution impouring aqueous solution, and CH ₂Cl ₂Extraction, organic phase is through Na ₂SO ₄After the drying, filter, concentrate, rapid column chromatography gets full guard and gets compound V (300mg, 0.20mmol, 50%).

[α] _D ²⁵＝-8.89(c?0.82，EtOAc?containing?1％Et ₃N)；

¹H?NMR(300MHz，pyridine-d ₅)δ?8.25-7.99(m，8H)，7.52-7.11(m，12H)，6.73(brs，1H)，6.55(t，1H，J＝9.3Hz)，6.24(t，1H，J＝9.6Hz)，6.16(t，1H，J＝9.6Hz)，5.74(t，1H，J＝9.6Hz)，5.52-5.46(m，4H)，4.72-4.66(m，1H)，4.55(brd，1H，J＝11.1Hz)，4.41(dd，1H，J＝5.7，12.3Hz)，4.10-4.06(m，1H)，3.83-3.76(m，1H)，3.10(dd，1H，J＝5.7，12.6Hz)，2.87(dd，1H，J＝7.5，12.6Hz)，2.61-2.57(m，1H)，2.47-2.43(m，1H)，1.00(s，3H)，0.96(d，3H，J＝6.6Hz)，0.90(s，3H)；

¹³C NMR (75MHz, pyridine-d ₅) δ 177.84,177.24,176.68,166.22,165,75,140.57,133.72,133.47,130.37,130.08,129.90,129.52,128.88,128.78,122.25,110.55,99.68,84.52,81.14,79.54,76.52,75.25,73.15,72.49,72.02,71.77,70.50,68.78,63.82,62.54,56.66,50.42,40.84,40.68,39.98,39.39,38.88,37.67,37.44,37.11,34.13,32.49,31.69,30.89,29.99,27.32,27.27,27.12,21.19,19.40,16.54,16.42;

MS(MALDI)m/z?1529.7[M-H ₂O+Na ⁺]，1547.7[M+Na ⁺]，1562.8[M+K ⁺]；

HRMS (MALDI) calculated value: C ₅₇H ₁₁₂O ₂₁SNa1547.7315, measured value:

C ₅₇H ₁₁₂O ₂₁SNa ⁺1547.7309。

Synthesizing of compound VIII:

(267mg 0.17mol) is dissolved in by MeOH: CH with compound VI I ₂Cl ₂: water==1: the mixed solvent of forming at 4: 0.5 (10ml); under the argon shield; add NaOH (34.00mg; 0.85mmol; 5.0equiv.), in 30 ℃ of reactions 48 hours, acidic resins neutralization then, concentrate, rapid column chromatography gets full guard and gets Smilax saponin B (106mg; 0.13mmol, 79%).

[α] _D ²⁶＝-67.58(c0.62，MeOH∶CH ₂Cl ₂＝1∶1?containing?1％EtN ₃)；

¹H NMR (400MHz, pyridine-d ₅) δ 5.40 (d, 1H, J=3.68Hz), 5.12 (d, 1H, J=7.67Hz), 5.08 (d, 1H, J=9.46Hz), 4.65-4.60 (m, 2H), and 4.54-4.46 (m, 2H), 4.43 (dd, 1H, J=5.44,11.91Hz), 4.39-4.31 (m, 4H), 4.14-4.11 (m, 2H), and 4.08-4.02 (m, 3H), 3.11 (dd, 1H, J=5.62,12.81Hz), 2.87 (dd, 1H, J=7.68,12.82Hz), 2.56-2.51 (m, 1H), 2,32-2.30 (m, 1H), 2.22 (m, 1H), 1.26 (d, 3H, J=6.80Hz), 1.15 (d, 3H, J=6.58Hz), 1.00 (s, 3H), 0.91 (s, 3H);

¹³C NMR (100MHz, pyridine-d ₅) δ 141.10,121.82,112.76,102.76,87.63,82.76,81.48,80.35,78.75,78.59,78.28,75.48,74.92,71.89,71.73,64.24,63.03,56.73,50.43,43.45,40.95,40.59,39.90,39.50,37.68,37.59,37.19,34.44,32.40,32.29,3 1.75,30.97,30.88,30.39,21.19,19.64,19.54,16.45,16.38;

MS(MALDI)m/z?777.4[M-H ₂O+Na ⁺]，795.4[M-CH ₂+Na ⁺]，809.4[M+Na ⁺]；

HRMS (MALDI) calculated value: C ₄₀H ₆₆₆O ₁₃SNa 809.4122, measured value; C ₄₀H ₆₆₆O ₁₃SNa ⁺809.4116.

Claims (12)

1. the chemical process of a synthetic furostanol saponin or derivatives thereof, the general structure of described furostanol saponin or derivatives thereof is as follows:

, wherein,

R ₁It is β-D-glucosyl group, the alpha-D-glucose base, β-D-galactosyl, α-D-galactosyl, β-D-mannose group, α-D-mannose group, β-D-xylosyl, the alpha-D-xylose base, β-D-2-glucosamine base, α-D-2-glucosamine base, α-L-rhamanopyranosyl, β-L-rhamanopyranosyl, the Arabic glycosyl of α-D-, the Arabic glycosyl of β-D-, α-L-arabinose base, β-L-arabinose base, α-L-fucosido, β-L-fucosido, alpha-D-glucose aldehydic acid base, β-D-glucal acidic group, α-D-galacturonic acidic group, β-D-galacturonic acidic group or be the oligosaccharyl of 2～8 chains or ramiform by the polymerization degree that these monose are formed;

R ₂=H or Me or Et;

XR ₃Be F, N ₃, guanidine radicals, CN or H; Perhaps XR ₃In, X=C, O, S, N or Se; R ₃It is β-D-glucosyl group, the alpha-D-glucose base, β-D-galactosyl, α-D-galactosyl, β-D-mannose group, α-D-mannose group, β-D-xylosyl, the alpha-D-xylose base, β-D-2-glucosamine base, α-D-2-glucosamine base, α-L-rhamanopyranosyl, β-L-rhamanopyranosyl, the Arabic glycosyl of α-D-, the Arabic glycosyl of β-D-, α-L-arabinose base, β-L-arabinose base, α-L-fucosido, β-L-fucosido, alpha-D-glucose aldehydic acid base, β-D-glucal acidic group, α-D-galacturonic acidic group, β-D-galacturonic acidic group or be the oligosaccharyl of 2～8 chains or ramiform by the polymerization degree that these monose are formed;

It is characterized in that this method comprises the steps:

(1) C ₂₇Synthesizing of spirostanol saponin:

In organic solvent and dewatering agent in the presence of, at-40～40 ℃, be promotor with Lewis acid or protonic acid, C ₂₇The glycosyl donor reaction of spiral shell sterioside unit and acyl group, alkyl and silica-based protection 3-10 hour is at the oligonucleotide chain R of its 3 OH introducing full guard ₁, obtain the spirostanol saponin of full guard; Wherein, C ₂₇Spiral shell sterioside unit is 1: 1.0～5.0: 0.05～0.5 with the mol ratio of glycosyl acceptor and promotor; C ₂₇Spiral shell sterioside unit is 1.0: 3.0～10.0 with the weight ratio of dewatering agent;

(2) oxidation of the spirostanol saponin of full guard:

In organic solvent or water or their mixture, full guard spirostanol saponin and oxidant reaction obtained oxidation products in 10～60 hours; The mol ratio of full guard spirostanol saponin and oxygenant is 1: 3.0～25.0, and described oxygenant is oxone, peroxy propanone, 1,1,1-trifluoromethyl peroxy propanone, metachloroperbenzoic acid, Peracetic Acid, CrO ₃, KMnO ₄, NaIO ₄Or (Bu) ₄N ⁺IO ₄ ^-Or their mixture;

The introducing of (3) 26 halogenic substituents:

In the presence of organic solvent neutralization-40-30 ℃ and dewatering agent, the spirostanol saponin of above-mentioned oxidation and oxyphie reagent react obtained 26 halogenated product in 0.1～2 hour, and the mol ratio of the spirostanol saponin of oxidation and oxyphie reagent is 1: 3.0～25.0; Described oxyphie reagent is MgCl ₂, MgBr ₂, MgI ₂, AlCl ₃, AlBr ₃, AlI ₃, NaI, LiI, LiCl, LiBr, ZrCl ₄, (Cp) ₂ZrCl ₂, C ₁～C ₆Trialkyl silyl halogenide or their mixture, wherein Cp is a cyclopentadienyl;

(4) XR ₃Substituent introducing:

In organic solvent, under the existence of alkali or reductive agent, with nucleophilic reagent and halogenated product reaction 3～10 hours, generation nucleophilic substitution reaction and introduce required XR ₃Substituting group; The mol ratio of described halogenated product, alkali or reductive agent and nucleophilic reagent is 1: 1.5～4.0: 1.5～4.0;

(5) reductive agent optionally reduces 16 carbonyls of saponin(e;

In organic solvent, under 1.0～10.0 normal atmosphere and-40～40 ℃, the product of (4) and reductive agent reaction obtained the hemiacetal product in 15～50 hours; (4) the product and the mol ratio of reductive agent are 1: 0.2～20.0;

Described reductive agent is NaBH ₄, LiBH ₄, KBH ₄, LiAlH ₄, K (Ph ₃P) ₃BH, K (i-PrO) ₃BH, Li (t-BuO) ₃AlH or Raney nickel;

(6) preparation of furostanol saponin or its analogue:

In organic solvent or water or their mixture ,-20～60 ℃ and 1.0～10.0 normal atmosphere, the hemiacetal product reacts and sloughed all protecting groups in 20～60 hours and get furostanol saponin or its analogue in the presence of alkali or hydrogenation catalyst; Described alkali is inorganic or organic bases; The mol ratio of described hemiacetal product and alkali or hydrogenation catalyst is 1: 0.2～20;

Described hydrogenation catalyst is 10% palladium charcoal, palladium hydroxide or lithium+liquefied ammonia;

Described dewatering agent is 3 , 4 , 5  molecular sieves, the Na of 3 , 4 , 5  molecular sieves, pickling ₂SO ₄, CaSO ₄, CuSO ₄Or MgSO ₄

2. synthetic method as claimed in claim 1 is characterized in that described by β-D-glucose, alpha-D-glucose, β-D-semi-lactosi, α-D-semi-lactosi, β-D-seminose, α-D-seminose, β-D-wood sugar, alpha-D-xylose, β-D-2-glucosamine, α-D-2-glucosamine, α-L-rhamnosyl, β-L-rhamnosyl, α-D-pectinose, β-D-pectinose, α-L-arabinose, β-L-arabinose, α-L-Fucose, β-L-Fucose, alpha-D-glucose aldehydic acid, β-D-glucuronic acid, the polymerization degree that α-D-galacturonic acid or β-D-galacturonic acid is formed is that the oligosaccharyl structural formula of 2～8 chains or ramiform is as follows:

3. synthetic method as claimed in claim 1, the steric configuration that it is characterized in that 22 asymmetric carbons of described furostanol saponin or derivatives thereof are S or R configuration.

4. synthetic method as claimed in claim 1 is characterized in that described C ₂₇Spiral shell sterioside unit is a diosgenin; Refined nurse sapogenin; For accusing sapogenin; NSC 232021; Hecogenin; The Chinaroot Greenbier Rhizome sapogenin; Timosaponin unit; Botogenin; Neobotogenin or different chiapagenin.

5. synthetic method as claimed in claim 1 is characterized in that described lewis acid is C ₁～C ₆Trialkyl silyl triflate, boron trifluoride diethyl etherate, silver trifluoromethanesulfonate, trifluoromethanesulfonic acid lithium, copper trifluoromethanesulfcomposite, trifluoromethanesulfonic acid zinc, trifluoromethanesulfonic acid scandium, trifluoromethanesulfonic acid lanthanum, Ytterbiumtriflate, trifluoromethanesulfonic acid indium, trityl group perchlorate or trityl group a tetrafluoro borate; Protonic acid is trifluoromethanesulfonic acid, perchloric acid, Tetrafluoroboric acid, four (phenyl-pentafluoride base) boric acid or two (fluoroform sulphonyl) imines.

6. synthetic method as claimed in claim 1 is characterized in that described nucleophilic reagent is C ₁～C ₇Alkyl magnesium, lithium, copper, zinc, boron, tin metal reagent, C ₆～C ₁₂Aryl magnesium, lithium, copper, zinc, boron, tin metal reagent, C ₁～C ₇Corresponding acetylate, the C of alkyl sulfhydryl, selenol or above-mentioned mercaptan or selenol ₆～C ₁₂The corresponding acetylate of aryl mercaptan, selenol or above-mentioned mercaptan or selenol, different head position are OH, SH, SeH, NH ₂SAc; SeAc;-S-S-;-Se-Se-by acyl group; the following sugar of alkyl and silica-based full guard: β-D-glucose; alpha-D-glucose; β-D-semi-lactosi; α-D-semi-lactosi; β-D-seminose; α-D-seminose; β-D-wood sugar; alpha-D-xylose; β-D-2-glucosamine; α-D-2-glucosamine; α-L-rhamnosyl; β-L-rhamnosyl; α-D-pectinose; β-D-pectinose; α-L-arabinose; β-L-arabinose; α-L-Fucose; β-L-Fucose; alpha-D-glucose aldehydic acid; β-D-glucuronic acid; α-D-galacturonic acid; β-D-galacturonic acid or be the oligosaccharide compound of 2～8 chains or ramiform by the polymerization degree that these monose are formed; tetrabutyl fluoride amine; the trimethyl azide base silane; trimethylammonium cyano group silane; sodiumazide; potassium cyanide or sodium cyanoborohydride.

7. synthetic method as claimed in claim 1 is characterized in that described mineral alkali refers to oxyhydroxide, hydride or the carbonate of monovalence metal; Organic bases is two-sec.-propyl Lithamide, potassium tert.-butoxide, n-Butyl Lithium, isobutyl-lithium, tert-butyl lithium, NaOMe, NaOEt, Mg (OMe) ₂, 1,8-two-azabicyclic [5.4.0] undecane-7-alkene, 1,5-two-azabicyclic [4.3.0] nine alkane-7-alkene, 1,4-two-azabicyclic [2.2.2] heptane, Et ₂NH, Et ₃N, pyridine, imidazoles, 4-N, the N-lutidine.

8. as claim 1 or 6 described synthetic methods, it is characterized in that described acyl group is C ₁～C ₈Fatty acyl group or C ₇～C ₁₀Aromaticacyl radical, silica-based be C ₁～C ₆Trialkyl silyl.

9. synthetic method as claimed in claim 1 is characterized in that described acyl group; the glycosyl donor of alkyl and silica-based protection is β-D-glucose; alpha-D-glucose; β-D-semi-lactosi; α-D-semi-lactosi; β-D-seminose; α-D-seminose; β-D-wood sugar; alpha-D-xylose; β-D-2-glucosamine; α-D-2-glucosamine; α-L-rhamnosyl; β-L-rhamnosyl; α-D-pectinose; β-D-Arab; α-L-arabinose; β-L-arabinose; α-L-Fucose; β-L-Fucose; alpha-D-glucose aldehydic acid; β-D-glucuronic acid; α-D-galacturonic acid; the sulphur glycosides of β-D-galacturonic acid monosaccharide groups; tribromo-acetyl imines ester; trifluoroacetyl imines ester or fluorine glycosides.

10. synthetic method as claimed in claim 1 is characterized in that the reductive agent described in the described step (5) is NaBH ₄, LiBH ₄, KBH ₄, LiAlH ₄, K (Ph ₃P) ₃BH, K (i-PrO) ₃BH or Li (t-BuO) ₃During AlH, the product of (4) and the mol ratio of reductive agent are 1: 5.0～20.0; Or described reductive agent is when being Raney nickel, and the product of (4) and the mol ratio of reductive agent are 1: 0.2～1.0.

11. synthetic method as claimed in claim 1, the mol ratio that it is characterized in that hemiacetal product described in the described step (6) and alkali is 1: 1.0～20; The mol ratio of described hemiacetal product and hydrogenation catalyst is 1: 0.2～1.0.

12. synthetic method as claimed in claim 1 is characterized in that described method is to carry out under protection of inert gas.