CN102993095B - Seven-element-ring polyhydroxy nitrone and preparation method and application thereof - Google Patents
Seven-element-ring polyhydroxy nitrone and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses seven-element-ring polyhydroxy nitrone and a preparation method and an application thereof. The seven-element-ring polyhydroxy nitrone is shown as the formula I, wherein R<1>, R<2>, R<3> and R<4> are respectively selected from the following groups: C1-C12 linear or branched saturated alkyl groups, allyl, propylidene, acetyl, benzoyl, benzyl, or benzyl of which partial or all the positions of the benzene ring are replaced by alkoxy or halogen; and the spatial configurations of the Cs at the positions 1, 2, 3 and 4 are in R or S. According to the seven-element-ring polyhydroxy nitrone, various kinds of aldohexose are taken as raw materials, and the condensation reaction of intramolecular hydroxylamine and aldehyde is taken as a key step, so as to finish the preparation of seven-element-ring polyhydroxy nitrone, so that a method for simply and effectively synthesizing seven-element-ring polyhydroxy nitrone is provided; and seven-element-ring polyhydroxy nitrone prepared by using the method can be used for preparing imino sugar with glycosidase inhibitory activity.
Description
Technical field
The present invention relates to a kind of preparation of seven-membered ring polyhydroxy nitrone and the application in the synthesis of seven-membered ring iminosugar thereof.
Background technology
Glycosylase take part in many important bioprocesses relevant with glycoconjugates, as the composition and decomposition of the digestion in intestines, glycoprotein, the glycoconjugates metabolism of lysosome (lysosomal) etc., key player is play in life entity, closely related with numerous disease.Iminosugar, also known as polyhydroxylated alkaloid, azasugar, imines sugar etc., is effective inhibitor of Glycosylase, in antiviral, antitumor, treatment diabetes etc., have important pharmacologically active [(a) Winchester, B; Fleet, G.W.J.Glycobiology 1992,2,199. (b) St ü tz, A.E.Iminosugars asGlycosidase Inhibitors:Nojirimycin and Beyond; Wiley-VCH:Weinheim, 1999. (c) Asano, N.; Nash, R.J.; Molyneux, R.J.; Fleet, G.W.J.Tetrahedron:Asymmetry 2000,11,1645. (d) Watson, A.A.; Fleet, G.W.J.; Asana, N.; Molyneux, R.J.; Nash, R.J.Phytochemistry 2001,56,265. (e) Compain, P.; Martin O.R.Curr.Top.Med.Chem.2003,3,541. (f) Compain, P.et al.Iminosugars:From Synthesis to Therapeutic Applications; Willey, 2007].Many iminosugar have been had to be developed to medicine and go on the market (as NBDNJ, Miglitol, Miglustat).Only containing five-ring and six-ring in naturally occurring iminosugar skeleton, therefore finding new iminosugar skeleton is also the important directions that people study.
Seven-membered ring iminosugar (poly-hydroxy azepan) synthesized [Paulsen, H. by Paulsen first in 1967; Todt, K.Chem.Ber.1967,100,512.].After 30 years, Wong have studied their glycosidase inhibiting function, finds that seven-membered ring iminosugar has biological activity [Mor í s-Varas, the F. suitable with six-ring iminosugar with five-ring; Qian, X.H.; Wong, C.H.J.Am.Chem.Soc.1996,118,7647.], cause people greatly to pay attention to.The flexibility of seven-membered ring iminosugar skeleton can be combined with enzyme with the conformation be more suitable for, and this is that it is different from the key character of five-ring and six-ring iminosugar.In recent years the research of seven-membered ring iminosugar is increased gradually, particularly increase the research of molecular diversity.Such as, on poly-hydroxy azepan ring, the α position of nitrogen-atoms increases a methylol to simulate monose structure [Li, H.Q.; Bl é riot, Y.; Chantereau, C.; Mallet, J.M.; Sollogoub, M.; Zhang, Y.M.; Rodr í guez-Garc í a, E.; Vogel, P.; Jim é nez-Barbero, J.;
p.Org.Biomol.Chem.2004,2,1492.], methylol is moved to 1-azasugar [(a) Li, H.Q. that nitrogen-atoms β position obtains seven-membered ring; Zhang, Y.M.; Vogel, P.;
p.; Bl é riot, Y.Chem.Commun.2007,183. (b) Deschamp, J.; Mondon, M.; Nakagawa, S.; Kato, A.; Alonzi, D.S.; Butters, T.D.; Zhang, Y.M.; Sollogoub, M.; Bl é riot, Y.Bioorg.Med.Chem.2012,20,641.], hydroxyl [(a) Li, the H.Q. of poly-hydroxy azepan is replaced with amino or kharophen; Bl é riot, Y.; Mallet, J.M.; Rodriguez-Garcia, E.; Vogel, P.; Zhang, Y.M.;
p.Tetrahedron-Asymmetry 2005,16,313. (b) Marcelo, F.; He, Y.; Yuzwa, S.A.; Nieto, L.; Jim é nez-Barbero, J.; Sollogoub, M.; Vocadlo, D.J.; Davies, G.D.; Bl é riot, Y.J.Am.Chem.Soc.2009,131,5390.], or poly-hydroxy azepan is placed in and ring [(a) Bande, O.P.; Jadhav, V.H.; Puranik, V.G.; Dhavale, D.D.Tetrahedron-Asymmetry 2007,18,1176. (b) Markad, S.D.; Karanjule, N.S.; Sharma, T.; Sabharwal, S.G.; Puranik, V.G.; Dhavale, D.D.Org.Biomol.Chem.2006,4,2549.] and bridged ring [Chagnault, V.; Compain, P.; Lewinski, K.; Ikeda, K.; Asano, N.; Martin, O.R.J.Org.Chem.2009,74,3179.] in system.But at present the synthesis of seven-membered ring iminosugar mostly is to the strategy of based target product, only a limited number of compound can be prepared with loaded down with trivial details tediously long route, and not by simply modifying the compound obtaining structural similitude, be unfavorable for structure and the structure activity study of compound library.
Polyhydroxy annular nitrone is one of effective intermediate of preparation iminosugar.Wherein, five-ring polyhydroxy nitrone is widely used [(a) Revuelta, J. in the synthesis of polyhydroxy pyrrole, poly-hydroxy pyrrolizidine alkaloids; Cicchi, S.; Goti, A.; Brandi, A.Synthesis 2007,485. (b) Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F.M.; Goti, A.Chem.-Eur.J.2009,15,7808. (c) Delso, I.; Tejero, T.; Goti, A.; Merino, P.Tetrahedron 2010,66,1220. (d) D'Adamio, G.; Goti, A.; Parmeggiani, C.; Moreno-Clavijo, E.; Robina, I.; Cardona, F.Eur.J.Org.Chem.2011,7155. (e) Delso, I.; Tejero, T.; Goti, A.; Merino, P.J.Org.Chem.2011,76,4139. (f) Tsou, E.-L.; Chen, S.-Y.; Yang, M.-H.; Wang, S.-C.; Cheng, T.-R.R.; Cheng, W.-C.Bioorg.Med.Chem.2008,16,10198. (g) Tsou, E.-L.; Yeh, Y.-T.; Liang, P.-H.; Cheng, W.-C.Tetrahedron 2009,65,93. (h) Yu, C.-Y.; Huang, M.-H.Org.Lett.2006,8,3021. (i) Hu, X.G.; Bartholomew, B.; Nash, R.J.; Wilson, F.X.; Fleet, G.W.J.; Nakagawa, S.; Kato, A.; Jia, Y.M.; Van Well, R.; Yu, C.Y.Org.Lett.2010,12,2562. (j) Zhang, W.; Sato, K.; Kato, A.; Jia, Y.M.; Hu, X.G.; Wilson, F.X.; Van Well, R.; Horne, G.; Fleet, G.W.J.; Nash, R.J.; Yu, C.Y.Org.Lett.2011,13,4414.]; Six-membered polyhydroxy nitrone also has certain application [(a) Wang, W.-B. in the alkaloidal synthesis of polyhydroxy piperidines; Huang, M.-H.; Li, Y.-X.; Rui, P.-X.; Hu, X.-G.; Zhang, W.; Su, J.-K.; Zhang, Z.-L.; Zhu, J.-S.; Xu, W.-H.; Xie, X.-Q.; Jia, Y.-M.; Yu, C.-Y.Synlett 2010,488. (b) Chan, T.H.; Chang, Y.F.; Hsu, J.J.; Cheng, W.C.Eur.J.Org.Chem.2010,5555.].This seminar SEPARATE APPLICATION patent of synthesizing five-membered ring and six-membered polyhydroxy nitrone [(a) Yu Chuyi, yellowwood China, Hu Suqin, Hu Xiangguo, Hou Yanbo, yellow will boring, prepare a method for polyhydroxy annular nitrone, CN200610066638.0. (b) Yu Chuyi, Wang Wubao, Jia Yuemei, Li Yixian, Rui Peixin, Zhang Wei, prepare a method for six-membered polyhydroxy nitrone, CN200910235668.3.], and authorized.
The polyhydroxy nitrone of synthesis seven-membered ring, becomes possibility by the preparation and structure activity study that make the seven-membered ring iminosugar taking molecular diversity as guiding.The synthesis of five-ring and six-membered polyhydroxy nitrone adopts the alkylating method of the N-of oxime in molecule more, but this method is inapplicable in the synthesis of seven-membered ring polyhydroxy nitrone, prepared by the method that therefore we have developed the condensation of azanol and aldehyde in a kind of molecule.Though seven-membered ring nitrone has bibliographical information [(a) Dondas, H.A.; Frederickson, M.; Grigg, R.; Markandu, J.; ThorntonPett, M.Tetrahedron 1997,53,14339. (b) Smith, B.T.; Wendt, J.A.; Aub é, J.Org.Lett.2002,4,2577. (c) Gracias, V; Zeng, Y.B.; Desai, P.; Aub é, J.Org.Lett.2003,5,4999.], but with sugar be that the poly-hydroxy seven-membered ring nitrone of the multichiral center of Material synthesis there is no report.
Summary of the invention
The object of this invention is to provide a kind of seven-membered ring polyhydroxy nitrone and preparation method thereof and application.
The invention provides seven-membered ring polyhydroxy nitrone, shown in I general structure,
In described formula I, R
1, R
2, R
3and R
4all be selected from hydrogen atom on the straight or branched saturated alkyl of C1-C12, allyl group, propylidene, ethanoyl, benzoyl, benzyl and phenyl ring by methoxyl group or halogen substiuted and at least one in the benzyl obtained;
1, the steric configuration of 2,3 and 4 carbon is R or S.
Shown in the described formula I general structure of preparation provided by the invention, the method for seven-membered ring polyhydroxy nitrone, comprises the steps:
Compound shown in formula XIII is carried out intermolecular condensation in acid condition, obtains the seven-membered ring polyhydroxy nitrone shown in formula I;
In described formula XIII, R
1, R
2, R
3, R
4definition identical with formula I; R is hydrogen, trimethyl silicon based, triethyl is silica-based, t-Butyldimethylsilyl, the tertiary butyl, to methoxy-benzyl, methoxyl methyl, 2-methoxyl group ethoxymethyl, THP trtrahydropyranyl, tetrahydrofuran base, ethanoyl, benzoyl; 1, the steric configuration of 2,3,4 carbon is R or S.
In aforesaid method, described acid is organic acid or mineral acid; Wherein, described organic acid is specially formic acid, acetic acid, tosic acid, camphorsulfonic acid, para-methylbenzenepyridinsulfonate sulfonate or phenylformic acid; Described mineral acid is specially sulfuric acid, hydrochloric acid, nitric acid, perchloric acid, iron trichloride, titanium tetrachloride or boron trifluoride;
Described reaction is carried out in following at least one solvent: methyl alcohol, ethanol, acetonitrile, tetrahydrofuran (THF), toluene, acetone, methylene dichloride, chloroform, 1,2-ethylene dichloride, DMF and dimethyl sulfoxide (DMSO);
In reaction, the consumption of acid depends on the kind of acid, and when acid is concentrated hydrochloric acid, the azanol shown in formula XIII feeds intake mole dosage than being 1:(1-500 with concentrated hydrochloric acid), preferred 1:(10-100).
In described reactions steps, temperature is 0-100 DEG C, preferably 25 DEG C, and the time is 0-24 hour, preferred 2-3 hour.
The intermediate of compound shown in preparation formula I provided by the invention is azanol shown in formula XIII.
In described formula XIII, R
1, R
2, R
3and R
4all be selected from least one in the benzyl that the straight or branched saturated alkyl of C1-C12, allyl group, propylidene, ethanoyl, benzoyl, benzyl and phenyl ring are replaced by the alkoxy or halogen of C1-C4; R is hydrogen, trimethyl silicon based, triethyl is silica-based, t-Butyldimethylsilyl, the tertiary butyl, to methoxy-benzyl, methoxyl methyl, 2-methoxyl group ethoxymethyl, THP trtrahydropyranyl, tetrahydrofuran base, ethanoyl, benzoyl.
1, the steric configuration of 2,3 and 4 carbon is R or S.
The method of azanol shown in preparation formula XIII provided by the invention is following method a or b:
Described method a comprises:
1) thioacetal shown in formula II, alkali and triphenylmethyl chloride are reacted, obtain the trityl ether shown in formula III;
2) by the trityl ether shown in formula III, alkali and halohydrocarbons reaction, the thioacetal of the hydroxyl full guard shown in formula IV is obtained;
3) thioacetal shown in formula IV and acid are carried out the reaction of sloughing trityl, obtain the primary alconol shown in formula V;
4) by the primary alconol shown in formula V, alkali and excess acetyl chloride, the acetic ester shown in formula VI is obtained;
5) by the acetic ester shown in formula VI and N-bromo-succinimide and glycol reaction, the acetal shown in formula VII is obtained;
6) acetal shown in formula VII and alkali are carried out the reaction of deacetylate, obtain the primary alconol shown in formula VIII;
7) by the primary alconol shown in formula VIII with oxidizing be the aldehyde shown in formula IX-a;
11) by the azanol reaction that the aldehyde shown in formula IX-a and oxygen are protected, the oxime shown in formula XII is obtained;
12) the oxime reductive agent shown in formula XII is reduced, obtain the azanol shown in formula XIII;
Described method b comprises:
1) thioacetal shown in formula II, alkali and triphenylmethyl chloride are reacted, obtain the trityl ether shown in formula III;
2) by the trityl ether shown in formula III, alkali and halohydrocarbons reaction, the thioacetal of the hydroxyl full guard shown in formula IV is obtained;
3) thioacetal shown in formula IV and acid are carried out the reaction of sloughing trityl, obtain the primary alconol shown in formula V;
8) by the primary alconol shown in formula V with oxidizing be the aldehyde shown in formula X;
9) by the aldehyde shown in formula X, acid and glycol reaction, the acetal shown in formula XI is obtained;
10) acetal shown in formula XI and N-bromo-succinimide are reacted, obtain the aldehyde shown in formula IX-b;
11) by the azanol reaction that the aldehyde shown in formula IX-b and oxygen are protected, the oxime shown in formula XII is obtained;
12) the oxime reductive agent shown in formula XII is reduced, obtain the azanol shown in formula XIII;
Described formula II in formula XII, R
1, R
2, R
3, R
4definition all identical with claim 1;
R be trimethyl silicon based, triethyl is silica-based, t-Butyldimethylsilyl, the tertiary butyl, to methoxy-benzyl, methoxyl methyl, 2-methoxyl group ethoxymethyl, THP trtrahydropyranyl, tetrahydrofuran base, ethanoyl, benzoyl;
Tr represents trityl group, and Ac represents ethanoyl;
N is 0 or 1;
1, the steric configuration of 2,3 and 4 carbon is R or S.
Step 1), the step 2 of above-mentioned two methods), in step 4) and step 6), described alkali is organic bases or mineral alkali;
Described step 2) in, described halohydrocarbon be methyl iodide, monobromethane, bromination of n-butane, bromobenzyl, benzyl chloride, to methoxyl group benzyl chloride or allyl bromide 98;
Described step 3) and step 9), described acid is organic acid or mineral acid;
In described step 7) and step 8), described oxygenant is potassium permanganate, potassium bichromate, chromium trioxide, Manganse Dioxide, sodium periodate, dimethyl sulfoxide (DMSO), Dess-Martin reagent or bromine water;
In described step 11), the azanol of described oxygen protection is oxammonium hydrochloride;
In described step 12), described reductive agent is selected from least one in lithium aluminum hydride, diisobutyl aluminium hydride, sodium borohydride, sodium cyanoborohydride, borine, zinc powder, iron powder and Sulfothiorine.
Described step 1), step 2), in step 4) and step 6), described organic bases is diethylamine, triethylamine, diisopropylamine, diisopropyl ethyl amine, Tetramethyl Ethylene Diamine, pyridine, hexahydropyridine, 2，4，6-trimethylpyridine or tetrabutyl ammonium fluoride; Described mineral alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, sodium hydride, potassium hydride KH or TBAH;
In described step 3) and step 9), described organic acid is formic acid, acetic acid, tosic acid, camphorsulfonic acid, para-methylbenzenepyridinsulfonate sulfonate or phenylformic acid; Described mineral acid is sulfuric acid, hydrochloric acid, nitric acid, perchloric acid, iron trichloride, titanium tetrachloride or boron trifluoride;
In described step 1), the thioacetal shown in formula II, triphenylmethyl chloride feed intake mole dosage than being 1:(1-2 with alkali): (1-500), preferred 1:1.05:(50-100); In described reactions steps, temperature is 0-100 DEG C, preferably 35 DEG C, and the time is 0-100 hour, preferably 48 hours; Thioacetal shown in formula II can be prepared by aldohexose, sugar used can be glucose, seminose, semi-lactosi and allose etc. (concrete preparation method can reference [
o.; Redlich, H.; Frank, H.Synthesis 1995,1383] carry out).
Described step 2) in, the trityl ether shown in formula III, halohydrocarbon feed intake mole dosage than being 1:(4-10 with alkali): (4-20), preferred 1:5:5.5; In described reactions steps, temperature is 0-80 DEG C, preferably 25 DEG C, and the time is 0-24 hour, preferred 5-12 hour;
In described step 3), the thioacetal shown in formula IV feeds intake mole dosage than being 1:(1-50 with acid), preferred 1:(3-10); In described reactions steps, temperature is-20-100 DEG C, preferably 25 DEG C, and the time is 0-24 hour, preferred 5-12 hour;
In described step 4), the primary alconol shown in formula V, Acetyl Chloride 98Min. feed intake mole dosage than being 1:(1-3 with alkali): (1-10), preferred 1:1.2:1.5; In described reactions steps, temperature is-20-50 DEG C, preferred 0-25 DEG C, and the time is 0-12 hour, preferably 1 hour;
In described step 5), the acetic ester shown in formula VI is 1:(1-5 with the mole dosage ratio that feeds intake of N-bromo-succinimide and ethylene glycol): (1-50), preferred 1:3:(2-10); In described reactions steps, temperature is-20-50 DEG C, preferably 25 DEG C, and the time is 0-24 hour, preferred 0.5-1 hour;
In described step 6), the acetal shown in formula VII feeds intake mole dosage than being 1:(1-10 with alkali), preferred 1:2; In described reactions steps, temperature is 0-50 DEG C, preferably 25 DEG C, and the time is 0-24 hour, preferred 2-3 hour;
In described step 7), the primary alconol shown in formula VIII feeds intake mole dosage than being 1:(1-10 with oxygenant), preferred 1:(1.5-2); In described reactions steps, temperature is-100-50 DEG C, and preferably-70 DEG C, the time is 0-12 hour, preferred 0.5-2 hour;
In described step 8), the primary alconol shown in formula V feeds intake mole dosage than being 1:(1-10 with oxygenant), preferred 1:2; In described reactions steps, temperature is 0-50 DEG C, preferably 25 DEG C, and the time is 0-24 hour, preferred 2-3 hour;
In described step 9), the aldehyde shown in formula X, acid feed intake mole dosage than being 1:(0.01-0.1 with ethylene glycol): (1-50), preferred 1:0.05:(2-10); In described reactions steps, temperature is 0-200 DEG C, preferably 110 DEG C, and the time is 0-12 hour, preferably 1 hour;
In described step 10), the acetal shown in formula XI feeds intake mole dosage than being 1:(1-10 with N-bromo-succinimide), preferred 1:2; In described reactions steps, temperature is-20-50 DEG C, preferably 25 DEG C, and the time is 0-12 hour, preferably 0.5 hour;
In described step 11), the mole dosage ratio that feeds intake of the azanol that the aldehyde shown in formula IX is protected with oxygen is 1:(1-10), be preferably 1:5; In described reactions steps, temperature is 0-100 DEG C, preferably 25 DEG C, and the time is 0-24 hour, preferred 6-12 hour;
In described step 12), the oxime shown in formula XII feeds intake mole dosage than being 1:(1-10 with reductive agent), preferred 1:2; In described reactions steps, temperature is 0-100 DEG C, preferably 25 DEG C, and the time is 0-24 hour, preferred 0.5-3 hour.
Compound or its salt shown in the formula I that the invention described above provides or formula XIII suppresses the application in glycosidase activity medicine in preparation, also belongs to protection scope of the present invention.Wherein, described Glycosylase is alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase enzymes, alpha-Mannosidase, beta-Mannosidase, alpha-L-fucosidase, trehalase, amyloglucosidase or alpha-L-Rhamnosidase etc.
The present invention for raw material, has prepared the seven-membered ring polyhydroxy nitrone with height reactive behavior through the reaction of a few step with various aldohexose, achieve this compounds succinct, efficiently prepare.The present invention is raw materials used is the various aldohexoses such as cheap glucose, seminose and semi-lactosi, and raw material is easy to get, and preparation method is simple, and mild condition, the purifying of intermediate is easy.Present method is easy to realize a large amount of synthesis, can synthesize a large amount of seven-membered ring iminosugar compounds at short notice, for screening has the compound of biological activity and pharmaceutical use to provide solid basis.
The present invention for raw material, with the condensation reaction of azanol in molecule and aldehyde for committed step, completes the preparation of seven-membered ring polyhydroxy nitrone with various aldohexose.Thus invented a method that is succinct, synthesis seven-membered ring polyhydroxy nitrone efficiently.This type of seven-membered ring nitrone can be used for preparing the iminosugar with glucoside inhibiting activity.
Accompanying drawing explanation
Fig. 1 is the schema synthesizing seven-membered ring polyhydroxy nitrone I-1 in embodiment 1;
Fig. 2 is the schema synthesizing seven-membered ring polyhydroxy nitrone I-2 in embodiment 2;
Fig. 3 is the schema synthesizing seven-membered ring polyhydroxy nitrone I-3 in embodiment 3;
Fig. 4 is the schema synthesizing seven-membered ring iminosugar XIV-2 and XIV-5 in embodiment 4;
Fig. 5 is the schema synthesizing seven-membered ring iminosugar XV-1 and XV-2 in embodiment 5;
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated, but the present invention is not limited to following examples.Described method is ordinary method if no special instructions.Described starting material all can obtain from open commercial sources if no special instructions.
First various aldohexose open loop is made thioacetal II by the present invention, and the primary hydroxyl of this thioacetal II is optionally used trityl as protecting group (III), then protects 4 secondary hydroxyls to obtain the thioacetal IV of full guard, sloughs trityl and discharge primary hydroxyl (V).After this route is divided into two.Route A: with the primary hydroxyl (VI) of ethanoyl protection primary alconol V, then change thioacetal into acetal and obtain VII, deacetylate obtains primary alconol VIII, is aldehyde IX-a by this oxidation of primary alcohols; Route B: primary alconol V is oxidized to aldehyde X, spent glycol protects newly-generated aldehyde radical (XI), and the protection of sloughing thioacetal discharges another aldehyde radical (IX-b).Meaning representated by shown in formula IX-a with IX-b two aldehyde is identical, and reaction is afterwards also identical, for convenience of statement, all replaces with aldehyde IX.Aldehyde IX is made oxime XII, and reduction oxime XII obtains azanol XIII, and namely azanol XIII acid treatment is obtained nitrone I.For glucose and semi-lactosi, two lines finally respectively obtain a kind of nitrone I-1 and I-2, and for seminose, two lines finally obtain same nitrone I-3, specifically see embodiment.The purifying of intermediate is many through extraction, drying and can be concentrated, and crude product directly drops into next step reaction, and the four-step reaction only comprising final step needs to be separated through column chromatography (silica gel).
Reaction formula is as follows:
Below with specific embodiment, the method being prepared by the present invention to seven-membered ring polyhydroxy nitrone is illustrated, but the present invention is not limited thereto.
Experimental technique described in following embodiment, if no special instructions, is ordinary method; Described reagent and material, if no special instructions, all can obtain from commercial channels.
Nitrone shown in above-mentioned formula I can be used for the seven-membered ring imino sugar compounds of synthesizing, shown in XIV and formula XV:
Wherein, R
1, R
2, R
3, R
4be hydrogen or benzyl; R
5for hydrogen, C1-C12 straight or branched saturated alkane; R
6, R
7hydrogen or hydroxyl; R be the saturated or unsaturated alkane of hydrogen, C1-C12 straight or branched, trifluoromethyl, methylol, hydroxyethyl, by hydroxyl or methoxyl group one to the full phenyl replaced; The steric configuration of 1,2,3,4,5 carbon of compound shown in formula XIV and formula XV is R or S; The steric configuration of 6,7 carbon of compound shown in formula XV is R or S.
Above-mentioned seven-membered ring imino sugar compounds specifically to can be in following formula XIV-1 to formula XIV-6 and formula XV-1, XV-2 any one but is not limited only to this:
R in embodiment 1, seven-membered ring polyhydroxy nitrone I-1(formula I
1, R
2, R
3and R
4be the compound of benzyl) and the synthesis (reaction process as shown in Figure 1) of intermediate formula XIII-1
According to document [
o.; Redlich, H.; Frank, H.Synthesis 1995,1383] method prepares thioacetal II-1 by D-Glucose.D-Glucose (10.0g, 55.6mmol) is dissolved in concentrated hydrochloric acid (10mL), adds 1,3-dimercaptopropane (5.6mL, 55.6mmol), this reaction mixture room temperature for overnight.In reaction solution, add ethanol (200mL), separate out a large amount of white solid.Filter, and use alcohol flushing filter cake.Obtain white solid 13.4g after drying, be thioacetal II-1, productive rate 89%.
By thioacetal II-1(11.3g, 42.0mmol), pyridine (150mL) solution of triphenylmethyl chloride (12.3g, 44.0mmol) and 4-dimethylamino pyridine (51mg, 0.42mmol) stirs 48 hours at 35 DEG C.Concentrated removing pyridine, adds water (200mL), is extracted with ethyl acetate (3 × 100mL).Merge organic phase anhydrous magnesium sulfate drying, after filtration, concentratedly obtain the crude product that yellow syrup is trityl ether III-1.
The crude product (in 42.0mmol) of above-mentioned trityl ether III-1 is dissolved in N, in the mixed solvent of N-METHYLFORMAMIDE (50mL) and tetrahydrofuran (THF) (200mL).Add sodium hydride (mineral oil mixture of 60%, 9.24g, 231.0mmol) in batches, add rear stirring at room temperature and release to bubble-free half an hour.Add tetrabutylammonium iodide (310mg, 0.84mmol).Dropwise at room temperature drips bromobenzyl (24.9mL, 210mmol), adds rear stirred overnight at room temperature.Shrend on the rocks is gone out reaction, adds ethyl acetate (500mL), washing (5 × 200mL).Organic phase anhydrous magnesium sulfate drying, after filtration, concentrates, obtains the crude product of the thioacetal IV-1 of hydroxyl full guard.
The crude product (in 42.0mmol) of above-mentioned thioacetal IV-1 is dissolved in the mixed solvent of methyl alcohol (150mL) and methylene dichloride (150mL), dropwise drips the vitriol oil (10mL), drip off rear stirred overnight at room temperature.In reaction mixture, add strong aqua be adjusted to pH value and equal 8.Add water (300mL) after concentrated, be extracted with ethyl acetate (3 × 200mL).Merge organic phase and with anhydrous magnesium sulfate drying, filter, concentrated after, crude product is separated through column chromatography (silica gel), with ethyl acetate: sherwood oil=1:6 is leacheate, obtains primary alconol V-1.Quality is 18.3g, yellow oil.With thioacetal II-1 for raw material calculates, three-step reaction overall yield 69%.Structural identification:
1h NMR (300MHz, CDCl
3) δ 7.40-7.23 (m, 20H), 4.92-4.40 (m, 8H), 4.02 (dd; J=4.8,6.0Hz, 1H), 3.97-3.80 (m; 4H), 3.67 (dd, J=4.4,8.9Hz; 1H), 2.88-2.75 (m, 2H), 2.71-2.61 (m; 2H), 2.20 (t, J=6.1Hz, 1H); 2.03-1.98 (m, 1H), 1.91-1.82 (m, 1H);
13c NMR (75MHz, CDCl
3) δ 138.42,138.26,138.17,138.12,128.48,128.37,128.35,128.32,128.10,127.86,127.81,127.77,127.67,127.63,81.80,80.39,79.78,78.64,75.31,74.43,74.13,71.76,61.14,49.54,30.40,29.83,26.10.
By primary alconol V-1(6.31g, 10.0mmol) and triethylamine (2.08mL, 15.0mmol) be dissolved in methylene dichloride (60mL), dropwise drip Acetyl Chloride 98Min. (0.85mL, 12.0mmol) at ice-water bath 0 DEG C, add rear room temperature reaction 1 hour.Washed reaction liquid (2 × 30mL), organic phase anhydrous magnesium sulfate drying.After filtration, the crude product of acetic ester VI-1 is obtained after concentrating.
The crude product of acetic ester VI-1 is dissolved in acetonitrile (50mL) and ethylene glycol (5mL), adds N-bromo-succinimide (5.34g, 30.0mmol) in batches, add rear stirring at room temperature 1 hour.Be adjusted to pH value with saturated sodium bicarbonate solution and equal 8, with extraction into ethyl acetate (3 × 50mL), merge organic phase and use anhydrous magnesium sulfate drying.After filtration, the crude product of acetal VII-I is obtained after concentrating.
The crude product of acetal VII-1 is dissolved in methyl alcohol (50mL), adds salt of wormwood (2.76g, 20.0mmol), in stirred at ambient temperature 3 hours.Filter, concentrated filtrate, is separated gained crude product column chromatography (silica gel), with ethyl acetate: sherwood oil=1:5 is leacheate, obtains primary alconol VIII-1, is 4.27g colorless oil, with primary alconol V-1 for raw material calculates, and three-step reaction overall yield 73%.Structural identification: [α]
d 20=+20.0 (c 0.5, CHCl
3);
1h NMR (300MHz, CDCl
3) δ 7.33 – 7.24 (m, 20H), 5.13 (d; J=3.9Hz, 1H), 4.87 – 4.60 (m; 8H), 4.48 – 4.39 (m, 8H); 4.04 – 3.79 (m; 8H), 3.65 – 3.61 (m, 2H); 2.30 (brs, 1H);
13c NMR (75MHz, CDCl
3) δ 138.83,138.71,138.57,138.48,128.48,128.43,128.36,128.29,128.19,127.69,127.59,104.08,80.15,79.71,79.68,79.61,75.30,74.82,74.19,71.54,65.40,64.92,61.28.
Dimethyl sulfoxide (DMSO) (468mg, 6.0mmol) is dropwise added dropwise in dry methylene chloride (30mL) solution of oxalyl chloride (508mg, 4.0mmol) at-70 DEG C, has in process and obviously heat up and have gas to release, stir 20 minutes at this temperature after adding.By primary alconol VIII-1(1.17g, 2.0mmol at-70 DEG C) dry methylene chloride (2mL) dropwise be added dropwise to above-mentioned reaction system, stir 20 minutes at this temperature after adding.Dropwise drip triethylamine (1.38ml, 10.0mmol) at 70 DEG C, after adding, reaction stirring at room temperature 1 hour after 15 minutes at this temperature, produces a large amount of white solid.Washed reaction liquid (2 × 10mL), organic phase anhydrous magnesium sulfate drying, after filtration, concentrated after obtain the crude product of aldehyde IX-1.
The crude product (in 2.0mmol) of aldehyde IX-1 is dissolved in methyl alcohol (50mL), adds oxammonium hydrochloride (690mg, 10.0mmol) and sodium bicarbonate (1.344g, 16.0mmol) successively, have gas to release.Stirred overnight at room temperature.Concentration of reaction solution, add water (30mL), extraction into ethyl acetate (3 × 20mL), merges organic phase and use anhydrous magnesium sulfate drying.After filtration, the crude product of oxime XII-1 is obtained after concentrating.
The crude product (in 2.0mmol) of oxime XII-1 and sodium cyanoborohydride (252mg, 4.0mmol) are dissolved in methyl alcohol (20mL), add 2 saturated methyl orange aqueous solutions and make indicator.In above-mentioned system, dropwise drip concentrated hydrochloric acid and methyl alcohol volume ratio is the solution of 1 to 10, the pH value of the hierarchy of control is 3 ~ 5, with TLC monitoring until oxime XII-1 completely dissolve.Concentration of reaction solution, is dissolved in ethyl acetate (50mL) by residue, use the sodium hydroxide solution of 1M (1 × 20mL) and saturated aqueous common salt (2 × 20mL) to wash respectively.Organic phase drying, filtration, concentrated, column chromatography for separation, ethyl acetate: sherwood oil=1:1 is leacheate, obtains pure azanol XIII-1, quality 607mg, is colorless oil.With primary alconol VIII-1 for raw material calculates, three-step reaction overall yield 67%.Structural identification: [α]
d 20=+32.0 (c 1.0, CHCl
3);
1h NMR (300MHz, CDCl
3) δ 7.36-7.23 (m, 20H), 5.15 (dd; J=2.1,4.5Hz, 1H); 4.95-4.31 (m, 8H), 4.18-4.15 (m; 1H), 4.97-3.73 (m, 6H); (3.58 d, J=2.7Hz, 1H); (3.17 d, J=5.1Hz, 2H);
13c NMR (75MHz, CDCl
3) δ 138.78,138.76,138.45,128.36,128.30,128.26,128.21,128.15,128.05,127.62,127.54,127.49,127.44,103.96,80.10,79.83,79.38,76.73,75.31,74.84,73.84,71.68,65.32,64.73,53.84.
As from the foregoing, this product structure is correct, is intermediate shown in formula XIII (XIII-1).
By gained intermediate azanol XIII-1(600mg, tetrahydrofuran (THF) (10mL) 1.0mmol) and concentrated hydrochloric acid (5mL) solution stirring at room temperature 3 hours, add ethyl acetate (50mL), use water (2 × 20mL) and saturated sodium bicarbonate solution (1 × 30mL) to wash successively.Organic phase anhydrous magnesium sulfate drying, after filtration, concentrates rear pillar separation, with methyl alcohol: methylene dichloride=1:100 is that leacheate obtains 424mg nitrone I-1, productive rate 79%, is white solid.Structural identification:
1h NMR (300MHz, CDCl
3) δ 7.36 – 7.20 (m, 20H), 7.14 (d, J=4.8Hz, 1H), 4.87 – 4.58 (m; 9H), 4.09 (dd, J=4.8,8.1Hz, 1H), 3.95 – 3.88 (m; 3H), 3.62 (dd, J=2.4,6.9Hz, 1H);
13c NMR (75MHz, CDCl
3) δ 138.16,137.94,137.48,137.08,136.29,128.55,128.48,128.43,128.39,128.04,127.91,127.89,127.86,127.74,81.98,77.94,75.64,74.98,73.74,73.14,71.88,71.71,62.77.
As from the foregoing, this product structure is correct, is the polyhydroxy nitrone I-1 of seven-membered ring shown in formula I.
R in embodiment 2, seven-membered ring polyhydroxy nitrone I-2(formula I
1, R
2, R
3and R
4be the compound of benzyl) and formula XIII-2 shown in the synthesis (reaction process as shown in Figure 2) of intermediate
Raw materials used primary alconol V-1 obtains by the step preparation of embodiment 1.
By dimethyl sulfoxide (DMSO) (2.13mL at-70 DEG C, 30.0mmol) be dropwise added dropwise to oxalyl chloride (1.69mL, in dry methylene chloride (50mL) solution 20.0mmol), have in process and obviously heat up and have a large amount of gas to release, stir 30 minutes at this temperature after adding.By primary alconol V-1(6.31g, 10.0mmol at-70 DEG C) dry methylene chloride (20mL) dropwise be added dropwise to above-mentioned reaction system, stir 30 minutes at this temperature after adding.Dropwise drip triethylamine (6.95mL, 50.0mmol) at-70 DEG C, after adding, reaction stirring at room temperature 1 hour after 20 minutes at this temperature, produces a large amount of white solid.Washed reaction liquid (2 × 30mL), organic phase anhydrous magnesium sulfate drying, after filtration, concentrated after obtain the crude product of aldehyde X-2.
The crude product (in 10.0mmol) of aldehyde X-2 is dissolved in toluene (50mL), adds ethylene glycol (5mL) and tosic acid (86mg, 0.5mmol), oil bath refluxes 1 hour.Add ethyl acetate (50mL) dilution, washing (2 × 30mL), organic phase anhydrous magnesium sulfate drying.After filtration, the crude product of acetal XI-2 is obtained after concentrating.
The crude product (in 10.0mmol) of acetal XI-2 is dissolved in the mixed solvent (50mL, volume ratio 4:1) of acetonitrile and water, adds N-bromo-succinimide (3.56g, 20.0mmol) in batches, add rear stirring at room temperature 30 minutes.Add saturated sodium bicarbonate solution to be adjusted to pH value and to equal 8, be extracted with ethyl acetate (3 × 50mL), merge organic phase and also use anhydrous magnesium sulfate drying.After filtration, concentrate, residue post is separated, and with ethyl acetate: sherwood oil=1:10 is leacheate, obtaining aldehyde IX-2, is 3.74g colorless oil.With primary alconol VI-1 for raw material calculates, three-step reaction overall yield 64%.Structural identification: [α]
d 20=+6.0 (c 1.0, CHCl
3);
1h NMR (300MHz, CDCl
3) δ 9.76 (s, 1H), 7.31 – 7.16 (m; 20H), 5.26 (d, J=1.8Hz; 1H), 4.88 – 4.77 (m, 4H); 4.63 – 4.44 (m, 6H), 4.16 (dd; J=3.3,5.1Hz, 1H); 4.06 – 3.85 (m, 7H);
13c NMR (75MHz, CDCl
3) δ 200.77,138.71,137.98,137.78,137.35,128.50,128.44,128.35,128.26,128.19,128.12,128.03,127.91,127.55,127.50,127.47,104.01,80.55,80.03,77.91,77.86,74.33,73.82,73.46,73.00,65.55,65.25.
By aldehyde IX-2(1.5g, 2.6mmol) be dissolved in methyl alcohol (10mL), add oxammonium hydrochloride (897mg, 13.0mmol) and sodium bicarbonate (1.75g, 20.8mmol) successively, have gas to release.Stirred overnight at room temperature.Concentration of reaction solution, add water (30mL), extraction into ethyl acetate (3 × 30mL), merges organic phase and use anhydrous magnesium sulfate drying.After filtration, the crude product of oxime XII-2 is obtained after concentrating.
The crude product (in 2.6mmol) of oxime XII-2 and sodium cyanoborohydride (325mg, 5.1mmol) are dissolved in methyl alcohol (20mL), add 2 saturated methyl orange aqueous solutions and make indicator.In above-mentioned system, dropwise drip concentrated hydrochloric acid and methyl alcohol volume ratio is the solution of 1 to 10, the pH value of the hierarchy of control is 3 ~ 5, with TLC monitoring until oxime XII-2 completely dissolve.Concentration of reaction solution, is dissolved in ethyl acetate (50mL) by residue, use the sodium hydroxide solution of 1M (1 × 20mL) and saturated aqueous common salt (2 × 20mL) to wash respectively.Organic phase drying, filtration, concentrated, column chromatography for separation, ethyl acetate: sherwood oil=1:1 is leacheate, obtains azanol XIII-2, is light yellow oil 1.23g, two-step reaction overall yield 78%.Structural identification:
1h NMR (300MHz, CDCl
3) δ 7.31-7.23 (m, 20H), 5.27 (d, J=3.0Hz, 1H), 4.82 – 4.43 (m; 8H), 4.02-3.81 (m, 8H), 3.16 (dd, J=3.9,13.5Hz; 1H), 2.93 (dd, J=7.5,13.5Hz, 1H);
13c NMR (75MHz, CDCl
3) δ 138.79,138.71,138.63,138.53,128.45,128.37,128.34,128.14,128.12,128.00,127.70,127.60,127.58,127.53,104.18,79.32,78.76,78.72,75.71,74.19,74.07,74.02,73.02,65.34,65.21,54.39.
As from the foregoing, this product structure is correct, is intermediate shown in formula XIII (XIII-2).
By gained intermediate azanol XIII-2(600mg, tetrahydrofuran (THF) (10mL) 1.0mmol) and concentrated hydrochloric acid (5mL) solution stirring at room temperature 3 hours, add ethyl acetate (50mL), use water (2 × 20mL) and saturated sodium bicarbonate solution (1 × 30mL) to wash successively.Organic phase anhydrous magnesium sulfate drying, after filtration, concentrates rear pillar separation, with methyl alcohol: methylene dichloride=1:100 is that leacheate obtains 415mg nitrone I-2, productive rate 77%, is yellow oil.Structural identification: [α]
d 20=-18.0 (c 1.0, CHCl
3);
1h NMR (300MHz, CDCl
3) δ 7.33-7.20 (m, 20H), 7.04 (d, J=5.4Hz; 1H), 4.80-4.51 (m, 9H), 4.26 (d; J=4.8Hz, 1H), 4.09 (d, J=13.5Hz; 1H), 3.99 (t, J=7.2Hz, 1H); 3.70 (t, J=7.5Hz, 1H); 3.62 (d, J=6.6Hz, 1H);
13c NMR (75MHz, CDCl
3) δ 138.16,137.89,137.46,136.92,134.57,128.68,128.53,128.47,128.25,128.01,127.97,127.94,127.92,127.86,127.80,81.07,79.77,76.61,75.11,73.60,72.71,72.21,63.27.
As from the foregoing, this product structure is correct, is the polyhydroxy nitrone I-2 of seven-membered ring shown in formula I.
R in embodiment 3, seven-membered ring polyhydroxy nitrone I-3(formula I
1, R
2, R
3and R
4be the compound of benzyl) and formula XIII-3 shown in the synthesis (reaction process as shown in Figure 3) of intermediate
According to document [
o.; Redlich, H.; Frank, H.Synthesis 1995,1383] similar method prepares thioacetal II-3 by D-MANNOSE.D-MANNOSE (9.0g, 50.0mmol) is dissolved in 6N hydrochloric acid (20mL), adds 1,3-dimercaptopropane (5.55mL, 55.0mmol), this reaction mixture room temperature for overnight.Reaction solution concentrates rear ethyl alcohol recrystallization, filters, and uses alcohol flushing filter cake.Obtain white solid 8.6g after drying, be thioacetal II-3, productive rate 65%.
By thioacetal II-3(8.1g, 30.0mmol), pyridine (150mL) solution of triphenylmethyl chloride (8.79g, 31.5mmol) and 4-dimethylamino pyridine (37mg, 0.30mmol) stirs 48 hours at 35 DEG C.Concentrated removing pyridine, adds water (200mL), is extracted with ethyl acetate (3 × 100mL).Merge organic phase anhydrous magnesium sulfate drying, after filtration, concentratedly obtain the crude product that yellow syrup is trityl ether III-3.
The crude product (in 30.0mmol) of above-mentioned trityl ether III-3 is dissolved in DMF (50mL) and tetrahydrofuran (THF) (200mL).Add sodium hydride (mineral oil mixture of 60%, 6.60g, 165.0mmol) in batches, add rear stirring at room temperature and release to bubble-free half an hour.Add tetrabutylammonium iodide (221mg, 0.60mmol).Dropwise at room temperature drips bromobenzyl (17.8mL, 150.0mmol), adds rear stirred overnight at room temperature.Shrend on the rocks is gone out reaction, adds ethyl acetate (500mL), washing (5 × 200mL).Organic phase anhydrous magnesium sulfate drying, after filtration, concentrates, obtains the crude product of the thioacetal IV-3 of hydroxyl full guard.
The crude product (in 30.0mmol) of above-mentioned thioacetal IV-3 is dissolved in the mixed solvent of methyl alcohol (150mL) and methylene dichloride (150mL), dropwise drips the vitriol oil (6mL), drip off rear stirred overnight at room temperature.In reaction mixture, add strong aqua be adjusted to pH value and equal 8.Add water (300mL) after concentrated, be extracted with ethyl acetate (3 × 200mL).Merge organic phase and with anhydrous magnesium sulfate drying, after filtration, concentrate, crude product, through column chromatography (silica gel) separation, with ethyl acetate: sherwood oil=1:6 is leacheate, obtains primary alconol V-3.
Quality is 13.4g, yellow oil.With thioacetal II-3 for raw material calculates, three-step reaction overall yield 71%.Structural identification: [α]
d 20=+6.0 (c 1.0, CHCl
3);
1h NMR (300MHz, CDCl
3) δ 7.37 – 7.26 (m, 20H), 5.11 (d; J=12.9Hz, 1H), 4.73 – 4.39 (m; 8H), 3.82 – 3.76 (m, 1H); 3.75 – 3.69 (m, 1H), 2.84 – 2.59 (m; 4H), 2.08 – 2.02 (m, 2H); 1.93 – 1.74 (m, 1H);
13c NMR (75MHz, CDCl
3) δ 138.62,138.54,138.20,137.91,128.51,128.46,128.38,128.37,128.04,127.93,127.79,127.74,127.69,127.59,82.01,79.85,78.68,78.38,74.25,74.10,73.82,71.47,60.57,51.33,32.41,30.48,26.48.
By primary alconol V-3(6.31g, 10.0mmol) and triethylamine (2.08mL, 15.0mmol) be dissolved in methylene dichloride (60mL), dropwise drip Acetyl Chloride 98Min. (0.85mL, 12.0mmol) at ice-water bath 0 DEG C, add rear room temperature reaction 1 hour.Washed reaction liquid (2 × 30mL), organic phase anhydrous magnesium sulfate drying.After filtration, the crude product of acetic ester VI-3 is obtained after concentrating.
The crude product of acetic ester VI-3 is dissolved in acetonitrile (50mL) and ethylene glycol (5mL), adds N-bromo-succinimide (5.34g, 30.0mmol) in batches, add rear stirring at room temperature 30 minutes.Be adjusted to pH value with saturated sodium bicarbonate solution and equal 8, extraction into ethyl acetate (3 × 50mL).Merge organic phase, use anhydrous magnesium sulfate drying.After filtration, the crude product of acetal VII-3 is obtained after concentrating.
The crude product of acetal VII-3 is dissolved in methyl alcohol (50mL), adds salt of wormwood (2.76g, 20.0mmol), in stirred at ambient temperature 3 hours.Filter, concentrated filtrate, is separated gained crude product column chromatography (silica gel), with ethyl acetate: sherwood oil=1:5 is leacheate, obtains primary alconol VIII-3, is 4.10g colorless oil, with primary alconol V-3 for raw material calculates, and three-step reaction overall yield 70%.Structural identification: [α]
d 20=+2.0 (c 1.0, CHCl
3);
1hNMR (300MHz, CDCl
3) δ 7.33-7.17 (m, 20H), 5.27 (d, J=3.0Hz; 1H), 4.88-4.43 (m, 8H), 4.11 (t; J=4.5Hz, 1H), 4.00-3.96 (m; 1H), 3.95-3.78 (m, 7H); 3.68 (dd, J=4.2,8.7Hz; 1H), 2.26 (brs, 1H);
13c NMR (75MHz, CDCl
3) δ 138.69,138.56,138.53,138.32,128.52,128.42,128.38,128.06,127.91,127.81,127.78,127.75,127.66,127.60,104.14,79.96 (2C), 79.08,78.71,74.43,74.28,74.18,71.38,65.42,65.20,60.95.
By dimethyl sulfoxide (DMSO) (1.46mL at-70 DEG C, 20.5mmol) be dropwise added dropwise to oxalyl chloride (1.16mL, in dry methylene chloride (40mL) solution 13.7mmol), have in process and obviously heat up and have a large amount of gas to release, stir 20 minutes at this temperature after adding.By primary alconol VIII-3(4.0g, 6.84mmol at-70 DEG C) dry methylene chloride (10mL) dropwise be added dropwise to above-mentioned reaction system, stir 20 minutes at this temperature after adding.Dropwise drip triethylamine (4.75mL, 34.2mmol) at 70 DEG C, after adding, reaction stirring at room temperature 1 hour after 15 minutes at this temperature, produces a large amount of white solid.Washed reaction liquid (2 × 30mL), organic phase anhydrous magnesium sulfate drying, after filtration, concentrated after obtain the crude product of aldehyde IX-3.
The crude product (in 6.84mmol) of aldehyde IX-3 is dissolved in methyl alcohol (50mL), adds oxammonium hydrochloride (2.36g, 34.2mmol) and sodium bicarbonate (4.60g, 54.7mmol) successively, have gas to release.Stirred overnight at room temperature.Concentration of reaction solution, add water (50mL), extraction into ethyl acetate (3 × 30mL), merges organic phase and use anhydrous magnesium sulfate drying.After filtration, the crude product of oxime XII-3 is obtained after concentrating.
The crude product (in 6.84mmol) of oxime XII-3 and sodium cyanoborohydride (862mg, 13.7mmol) are dissolved in methyl alcohol (50mL), add 2 saturated methyl orange aqueous solutions and make indicator.In above-mentioned system, dropwise drip concentrated hydrochloric acid and methyl alcohol volume ratio is the solution of 1 to 10, the pH value of the hierarchy of control is 3 ~ 5, with TLC monitoring until oxime XII-3 completely dissolve.Concentration of reaction solution, is dissolved in ethyl acetate (200mL) by residue, use the sodium hydroxide solution of 1M (1 × 50mL) and saturated aqueous common salt (2 × 50mL) to wash respectively.Organic phase drying, filtration, concentrated, column chromatography for separation, ethyl acetate: sherwood oil=1:1 is leacheate, obtains pure azanol XIII-3, quality 2.95g, is light yellow oil.With primary alconol V-3 for raw material calculates, three-step reaction overall yield 72%.Structural identification: [α]
d 20=-6.0 (c 1.0, CHCl
3);
1h NMR (300MHz, CDCl
3) δ 7.33 – 7.21 (m, 20H), 5.28 (d, J=3.9Hz; 1H), 4.84 – 4.44 (m, 8H), 4.21 (dd; J=2.1,5.4Hz, 1H), 4.04 – 3.97 (m; 2H), 3.95 – 3.78 (m, 4H); 3.72 (t, J=4.5Hz, 1H); 3.13 (d, J=5.7Hz, 2H);
13c NMR (75MHz, CDCl
3) δ 138.86,138.57,138.55,138.44,128.43,128.35,128.27,128.26,128.04,127.87,127.84,127.73,127.66,127.60,127.53,127.45,103.91,81.20,79.30,79.02,76.99,74.67,74.45,73.90,71.76,65.22,65.14,53.87.
As from the foregoing, this product structure is correct, is intermediate shown in formula XIII (XIII-3).
By gained intermediate azanol XIII-3(600mg, tetrahydrofuran (THF) (10mL) 1.0mmol) and concentrated hydrochloric acid (5mL) solution stirring at room temperature 2 hours, add ethyl acetate (50mL), use water (2 × 20mL) and saturated sodium bicarbonate solution (1 × 30mL) to wash successively.Organic phase anhydrous magnesium sulfate drying, after filtration, concentrates rear pillar separation, with methyl alcohol: methylene dichloride=1:100 is that leacheate obtains 443mg nitrone I-3, productive rate 83%, is yellow oil.Structural identification:
1h NMR (300MHz, CDCl
3) δ 7.347.17 (m, 20H), 7.04 (d, J=4.7Hz, 1H), 4.73 – 4.42 (m, 10H), 4.02-3.84 (m, 4H);
13c NMR (75MHz, CDCl
3) δ 138.46,138.08,137.89,137.60,136.97,128.66,128.55,128.50,128.47,128.18,127.95,127.88,127.81,79.12,77.38,74.27,73.95,73.22,73.08,72.12,71.72,62.07.
As from the foregoing, this product structure is correct, is the polyhydroxy nitrone I-3 of seven-membered ring shown in formula I.
The preparation (reaction process as shown in Figure 4) of embodiment 4, seven-membered ring iminosugar XIV-2, XIV-5
For seven-membered ring iminosugar XIV-2, XIV-10, the step of being synthesized seven-membered ring iminosugar by embodiment 3 gained seven-membered ring polyhydroxy nitrone I-3 is described.
Under nitrogen protection, joined by 1-butyl iodide (0.37mL, 3.25mmol) in anhydrous diethyl ether (3mL) suspension liquid of magnesium chips (125mg, 5.20mmol), stirring at room temperature prepares the tetrahydrofuran solution of normal-butyl magnesium iodide for 1 hour.At ice-water bath 0 DEG C, above-mentioned grignard reagent is dropwise added dropwise to nitrone I-3(350mg, 0.65mmol) tetrahydrofuran (THF) (5mL) solution in, stir 1 hour at this temperature after adding.Add saturated ammonium chloride solution cancellation reaction, be extracted with ethyl acetate (3 × 20mL), merge organic phase, use anhydrous sodium sulfate drying.After filtration, concentrated after, thick product post is separated, obtains light yellow oil (334mg, 86%), be azanol XIV-2-1.Structural identification: [α]
d 20=-16.0 (c 1.0, CHCl
3);
1h NMR (300MHz, CDCl
3) δ 7.33 – 7.16 (m, 20H), 6.57 (brs, 1H); 4.81 – 4.40 (m, 8H), 4.15 (d, J=7.5Hz; 1H), 3.88 (s, 2H), 3.74 (d; J=7.5Hz, 1H), 3.37 – 3.23 (m, 2H); 3.17 – 3.13 (m, 1H), 1.48 – 1.26 (m, 6H); 0.87 (t, J=7.2Hz, 3H);
13cNMR (75MHz, CDCl
3) δ 138.67,138.15,137.63,128.49,128.40,128.38,127.96,127.75,127.72,127.70,127.61,126.98,80.83,77.15,76.50,74.08,73.47,72.70,72.52,71.84,68.17,52.84,32.43,28.87,22.86,14.11.
To azanol XIV-2-1(112mg, 0.188mmol) methyl alcohol (5mL) solution in add 10% palladium carbon (20mg) and 6N hydrochloric acid (1mL), stirring at room temperature 24 hours in a hydrogen atmosphere.Elimination catalyzer, concentrated filtrate, with strong aqua neutralization, concentrates again.By resistates acidic ion exchange resin post removing inorganic salt, obtain iminosugar XIV-2(38mg, 92%).Structural identification: [α]
d 20=-26.0 (c 1.0, MeOH);
1h NMR (300MHz, D
2o) δ 4.05-3.99 (m, 2H), 3.95-3.87 (m, 2H); 3.08 (dd, J=4.8,14.4Hz, 1H); 2.89 (dd, J=1.8,14.4Hz, 1H); 2.70 (dd, J=5.4,12.6Hz; 1H), 1.67-1.30 (m, 6H); 0.89 (t, J=6.6Hz, 3H);
13c NMR (75MHz, D
2o) δ 74.33,70.44,69.13,69.08,61.52,48.35,32.82,27.35,21.94,13.16.
Under nitrogen protection, joined by bromobenzene (0.34mL, 3.25mmol) in anhydrous tetrahydro furan (3mL) suspension liquid of magnesium chips (125mg, 5.20mmol), reflux prepares the tetrahydrofuran solution of phenyl-magnesium-bromide for 1 hour.At ice-water bath 0 DEG C, above-mentioned grignard reagent dropwise is added dropwise to nitrone I-3(350mg, 0.65mmol) tetrahydrofuran (THF) (5mL) solution in, stir 1 hour at this temperature after adding.Add saturated ammonium chloride solution cancellation reaction, be extracted with ethyl acetate (3 × 20mL), merge organic phase, use anhydrous sodium sulfate drying.After filtration, concentrated after, thick product post is separated, obtains light yellow oil (352mg, 88%), be azanol XIV-5-1.Structural identification: [α]
d 20=-2.0 (c 1.0, CHCl
3);
1h NMR (300MHz, CDCl
3) δ 7.43 – 7.18 (m, 25H), 6.90 – 6.88 (m, 1H); 5.41 (brs, 1H), 4.75 – 4.53 (m, 6H); 4.41 (d, J=7.2Hz, 1H), 4.19 (d; J=11.7Hz, 1H), 4.11 (d, J=9.3Hz; 1H), 3.97 (d, J=6.0Hz; 1H), 3.92 (dd, J=2.1; 6.0Hz, 1H), 3.87 (d; J=7.2Hz, 1H), 3.75 (dd; J=8.4,15.3Hz, 1H); 3.37 (d, J=15.3Hz, 1H);
13c NMR (75MHz, CDCl
3) δ 142.38,138.84,138.52,138.01,128.58,128.35,128.31,128.21,128.11,127.89,127.80,127.77,127.73,127.60,127.54,127.53,127.44,127.01,79.30,77.91,77.53,73.49,73.22,72.96,72.65,71.43,71.35,55.52.
To azanol XIV-5-1(125mg, 0.203mmol) methyl alcohol (5mL) solution in add 10% palladium carbon (20mg) and 6N hydrochloric acid (1mL), stirring at room temperature 24 hours in a hydrogen atmosphere.Elimination catalyzer, concentrated filtrate, with strong aqua neutralization, concentrates again.By resistates acidic ion exchange resin post removing inorganic salt, obtain seven-membered ring iminosugar XIV-5(45mg, 93%).Structural identification: [α]
d 20=-24.0 (c 1.0, MeOH);
1h NMR (300MHz, D
2o) δ 7.46 – 7.34 (m, 5H), 4.27 (dd, J=3.3,8.1Hz; 1H), 4.21 (dd, J=3.3,8.1Hz, 1H); 4.11-4.08 (m, 1H), 4.05 (dd, J=2.4,8.1Hz; 1H), 3.68 (d, J=8.1Hz, 1H); 3.09 (dd, J=5.4,14.4Hz, 1H); 2.94 (dd, J=2.7,8.4Hz, 1H);
13c NMR (75MHz, D
2o) δ 142.45,128.93,127.83,127.21,74.20,71.30,70.39,69.96,64.92,49.88.
The preparation (reaction process as shown in Figure 5) of embodiment 5, seven-membered ring iminosugar XV-1 and XV-2
By embodiment 3 gained seven-membered ring polyhydroxy nitrone I-3 (538mg, 1.0mmol) and methyl acrylate (135 μ L, methylene dichloride (10mL) solution 1.5mmol) was in stirring at room temperature 2 hours, solvent evaporated, post is separated the mixture (536mg obtaining XV-1-1 and XV-2-1,86%), the two cannot separate, and this mixture is directly used in next step.
Joined by neutralized verdigris (32mg, 0.16mmol) in acetic acid (5mL) suspension liquid of zinc powder (1.04g, 16.0mmol), stirring at room temperature 15 minutes is brown to becoming.By the mixture (1.0g of XV-1-1 and XV-2-1, methylene dichloride (5mL) dropwise 1.6mmol) joins in above-mentioned system, 40 ° of C react evaporate to dryness after 2 hours, pH=8 is adjusted to saturated sodium bicarbonate solution, extraction into ethyl acetate (3 × 20mL), merges organic phase and uses anhydrous magnesium sulfate drying.Post is separated the mixture (904mg, 95%) obtaining lactan XV-1-2 and XV-2-2, and the two cannot be separated, and be brown oil, this mixture is directly used in next step.
Joined by Lithium Aluminium Hydride (130mg, 3.43mmol) in the mixture (680mg, 1.14mmol) of lactan XV-1-2 and XV-2-2, reflux the cancellation reaction that to add water after 1 hour.Add diatomite filtration, filtrate is extracted with ethyl acetate (3 × 20mL), merges organic phase and uses anhydrous magnesium sulfate drying.Post is separated and obtains amine XV-1-3 (331mg, 50%) and XV-2-3 (179mg, 27%), is colorless oil.XV-1-3：
1H NMR(300MHz,CDCl
3)δ7.29–7.20(m,20H),4.77-4.49(m,8H),4.08-4.03(m,3H),3.97(dd,J=1.3,6.0Hz,1H),3.75(dd,J=2.4,6.9Hz,1H),3.16(dd,J=8.1,11.7Hz,1H),2.95(d,J=10.2Hz,1H),2.79–2.75(m,1H),2.55–2.49(m,1H),2.35–2.25(m,1H),1.72(dd,J=6.0,8.1Hz,1H);
13C NMR(75MHz,CDCl
3)δ139.05,138.86,138.73,138.61,128.38,128.36,128.34,128.06,127.95,127.89,127.75,127.64,127.55,82.77,79.48,78.03,76.36,73.81,73.44,72.87,71.68,70.19,65.11,62.22,54.43,41.43.XV-2-3：
1H NMR(300MHz,CDCl
3)δ7.28–7.20(m,20H),4.78–4.40(m,8H),4.23(brs,1H),4.07(dd,J=3.0,5.4Hz,1H),3.94(s,2H),3.64(d,J=7.2Hz,1H),3.36(dd,J=7.5,15.3Hz,1H),3.20–3.13(m,2H),2.70(dd,J=3.3,11.7Hz,1H),2.60(dd,J=2.1,10.2Hz,1H),2.04–1.97(m,1H),1.85–1.75(m,1H);
13C NMR(75MHz,CDCl
3)δ139.02,138.78,138.72,138.45,128.39,128.36,128.00,127.83,127.76,127.67,127.59,127.56,80.57,78.85,76.37,73.73,73.27,72.46,71.67,69.93,65.12,60.25,53.60,41.36.
10% palladium carbon (10mg) and 6N hydrochloric acid (1mL) is added, in a hydrogen atmosphere stirring at room temperature 24 hours by methyl alcohol (5mL) solution of amine XV-1-3 (61mg, 0.105mmol).Elimination catalyzer, concentrated filtrate, with strong aqua neutralization, concentrates again.By resistates acidic ion exchange resin post removing inorganic salt, obtain seven-membered ring iminosugar XV-1 (21mg, 91%), yellow oil.Structural identification:
1h NMR (300MHz, D
2o) δ 4.24-4.22 (m, 1H), 4.03-3.96 (m; 2H), 3.79-3.75 (m, 2H); 2.95 – 2.85 (m, 2H), 2.59 – 2.50 (m; 3H), 2.44 – 2.34 (m, 1H); 1.66 (dd; J=5.7,14.1Hz, 1H);
13c NMR (75MHz, D
2o) δ 73.87,72.22,69.57,69.47,69.25,64.70,63.85,57.61,39.68.
Same operation is done to amine XV-2-3 (47mg, 0.081mmol), obtains seven-membered ring iminosugar XV-2 (17mg, 96%), yellow oil.Structural identification:
1h NMR (300MHz, D
2o) δ 4.25-4.19 (m, 1H), 3.97-3.93 (m, 2H); 3.76 (d, J=8.4Hz, 1H), 3.69 (dd; J=4.2,8.4Hz, 1H), 3.18 (dd; J=5.4,10.8Hz, 1H), 2.95 (dd; J=4.8,13.5Hz, 1H), 2.75 (dd; J=8.1,16.5Hz, 1H); 2.60 (dd, J=2.7,13.5Hz; 1H), 2.39 (dd, J=4.8; 10.8Hz, 1H), 2.03-1.94 (m; 1H), 1.91-1.82 (m, 1H);
13c NMR (75MHz, D
2o) δ 73.24,71.88,69.65,69.63,68.63,64.39,63.85,58.74,40.06.
The Glycosylase inhibition of embodiment 6, seven-membered ring imino sugar compounds is evaluated
1) test materials and source
Test compound: embodiment 4 and 5 gained seven-membered ring imino sugar compounds.
Test materials: all 4-nitrophenol pyranoside matrix, disaccharides and Glycosylase are all purchased from Sigma-Aldrich.
2) test method
Dynamics research carries out in the 50mM Trisodium Citrate/phosphoric acid buffer of 37 DEG C.According to the difference of matrix, the enzyme concn of preparation is 0.1-0.5mg/mL.Active testing, is tested under the optimum activity PH of often kind of enzyme for matrix with 4-nitrophenol pyranoside.The enzyme solution of matrix, suitably dilution and inhibitor (seven-membered ring iminosugar) are cultivated 30 minutes at 37 DEG C, then starts in ultraviolet-visible pectrophotometer and react, measure its absorption to 400nm wavelength light.GraFit program is finally used to carry out data analysis [Leatherbarrow, R.J.Grafit4.0; ErithacusSoftware:Staines, UK, 1998.].
3) evaluation result
The inhibit activities result of embodiment 4 and 5 gained seven-membered ring imino sugar compounds to Glycosylase is as shown in table 1.
Evaluation result shows, seven-membered ring iminosugar XIV-2 provided by the present invention has weak inhibit activities to beta-galactosidase enzymes, IC
50it is 505 μMs; XIV-3 has medium inhibit activities to beta-glucosidase (beef liver) and beta-galactosidase enzymes (beef liver), and is optionally beta-galactosidase enzymes inhibitor, IC
50be respectively 12 μMs and 4.5 μMs.In conjunction with XIV-1, XIV-2 and XIV-3, inhibit activities seems relevant with long alkyl chains.Other compounds are more weak glycosidase inhibitor.
Table 1 part seven-membered ring imino sugar compounds is to the inhibit activities IC of Glycosylase
50(μM)
athe source of enzyme;
b(): the inhibiting rate under 1000 μMs of concentration.
Claims (10)
1. the seven-membered ring polyhydroxy nitrone shown in formula I general structure:
In described formula I, R
1, R
2, R
3and R
4all be selected from hydrogen atom on benzyl and phenyl ring by methoxyl group or halogen substiuted and at least one in the benzyl obtained;
1, the steric configuration of 2,3 and 4 carbon is R or S.
2. prepare a method for seven-membered ring polyhydroxy nitrone shown in formula I general structure described in claim 1, comprise the steps: compound shown in formula XIII to carry out intermolecular condensation in acid condition, obtain the seven-membered ring polyhydroxy nitrone shown in formula I;
In described formula XIII, R
1, R
2, R
3, R
4definition identical with claim 1; R is hydrogen, trimethyl silicon based, triethyl is silica-based, t-Butyldimethylsilyl, the tertiary butyl, to methoxy-benzyl, methoxyl methyl, 2-methoxyl group ethoxymethyl, THP trtrahydropyranyl, tetrahydrofuran base, acetyl or benzoyl base;
1, the steric configuration of 2,3 and 4 carbon is R or S.
3. method according to claim 2, is characterized in that: described acid is organic acid or mineral acid;
Described reaction is carried out in following at least one solvent: methyl alcohol, ethanol, acetonitrile, tetrahydrofuran (THF), toluene, acetone, methylene dichloride, chloroform, 1,2-ethylene dichloride, DMF and dimethyl sulfoxide (DMSO);
When described acid is concentrated hydrochloric acid, the azanol shown in formula XIII feeds intake mole dosage than being 1:(1-500 with concentrated hydrochloric acid);
In described reactions steps, temperature is 0-100 DEG C, and the time is 0-24 hour.
4. method according to claim 3, is characterized in that: described organic acid is formic acid, acetic acid, tosic acid, camphorsulfonic acid, para-methylbenzenepyridinsulfonate sulfonate or phenylformic acid; Described mineral acid is sulfuric acid, hydrochloric acid, nitric acid, perchloric acid, iron trichloride, titanium tetrachloride or boron trifluoride;
When described acid is concentrated hydrochloric acid, the azanol shown in formula XIII feeds intake mole dosage than being 1:(10-100 with concentrated hydrochloric acid);
In described reactions steps, temperature is 25 DEG C, and the time is 2-3 hour.
5. compound shown in formula XIII,
In described formula XIII, R
1, R
2, R
3, R
4definition identical with claim 1; R is hydrogen, trimethyl silicon based, triethyl is silica-based, t-Butyldimethylsilyl, the tertiary butyl, to methoxy-benzyl, methoxyl methyl, 2-methoxyl group ethoxymethyl, THP trtrahydropyranyl, tetrahydrofuran base, acetyl or benzoyl base;
1, the steric configuration of 2,3 and 4 carbon is R or S.
6. preparing a method for compound shown in formula XIII described in claim 5, is following method a or b:
Described method a comprises:
1) thioacetal shown in formula II, alkali and triphenylmethyl chloride are reacted, obtain the trityl ether shown in formula III;
2) by the trityl ether shown in formula III, alkali and halohydrocarbons reaction, the thioacetal of the hydroxyl full guard shown in formula IV is obtained;
3) thioacetal shown in formula IV and acid are carried out the reaction of sloughing trityl, obtain the primary alconol shown in formula V;
4) by the primary alconol shown in formula V, alkali and excess acetyl chloride, the acetic ester shown in formula VI is obtained;
5) by the acetic ester shown in formula VI and N-bromo-succinimide and glycol reaction, the acetal shown in formula VII is obtained;
6) acetal shown in formula VII and alkali are carried out the reaction of deacetylate, obtain the primary alconol shown in formula VIII;
7) by the primary alconol shown in formula VIII with oxidizing be the aldehyde shown in formula IX-a;
11) by the azanol reaction that the aldehyde shown in formula IX-a and oxygen are protected, the oxime shown in formula XII is obtained;
12) the oxime reductive agent shown in formula XII is reduced, obtain the azanol shown in formula XIII;
Described method b comprises:
1) thioacetal shown in formula II, alkali and triphenylmethyl chloride are reacted, obtain the trityl ether shown in formula III;
2) by the trityl ether shown in formula III, alkali and halohydrocarbons reaction, the thioacetal of the hydroxyl full guard shown in formula IV is obtained;
3) thioacetal shown in formula IV and acid are carried out the reaction of sloughing trityl, obtain the primary alconol shown in formula V;
8) by the primary alconol shown in formula V with oxidizing be the aldehyde shown in formula X;
9) by the aldehyde shown in formula X, acid and glycol reaction, the acetal shown in formula XI is obtained;
10) acetal shown in formula XI and N-bromo-succinimide are reacted, obtain the aldehyde shown in formula IX-b;
11) by the azanol reaction that the aldehyde shown in formula IX-b and oxygen are protected, the oxime shown in formula XII is obtained;
12) the oxime reductive agent shown in formula XII is reduced, obtain the azanol shown in formula XIII;
Described formula II in formula XII, R
1, R
2, R
3, R
4definition all identical with claim 1;
R be trimethyl silicon based, triethyl is silica-based, t-Butyldimethylsilyl, the tertiary butyl, to methoxy-benzyl, methoxyl methyl, 2-methoxyl group ethoxymethyl, THP trtrahydropyranyl, tetrahydrofuran base, ethanoyl, benzoyl;
Tr represents trityl group, and Ac represents ethanoyl;
N is 0 or 1;
1, the steric configuration of 2,3 and 4 carbon is R or S;
Described step 1), step 2), step 4) and step 6) in, described alkali is organic bases or mineral alkali; Described organic bases is diethylamine, triethylamine, diisopropylamine, diisopropyl ethyl amine, Tetramethyl Ethylene Diamine, pyridine, hexahydropyridine, 2，4，6-trimethylpyridine or tetrabutyl ammonium fluoride; Described mineral alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, sodium hydride, potassium hydride KH or TBAH;
Described step 2) in, described halohydrocarbon is bromobenzyl, benzyl chloride or to methoxyl group benzyl chloride;
Described step 3) and step 9), described acid is organic acid or mineral acid; Described organic acid is formic acid, acetic acid, tosic acid, camphorsulfonic acid, para-methylbenzenepyridinsulfonate sulfonate or phenylformic acid; Described mineral acid is sulfuric acid, hydrochloric acid, nitric acid, perchloric acid, iron trichloride, titanium tetrachloride or boron trifluoride;
Described step 7) and step 8) in, described oxygenant is potassium permanganate, potassium bichromate, chromium trioxide, Manganse Dioxide, sodium periodate, dimethyl sulfoxide (DMSO), Dess-Martin reagent or bromine water;
Described step 11) in, the azanol of described oxygen protection is oxammonium hydrochloride;
Described step 12) in, described reductive agent is selected from least one in lithium aluminum hydride, diisobutyl aluminium hydride, sodium borohydride, sodium cyanoborohydride, borine, zinc powder, iron powder and Sulfothiorine.
7. method according to claim 6, is characterized in that: described step 1) in, the thioacetal shown in formula II, triphenylmethyl chloride feed intake mole dosage than being 1:(1-2 with alkali): (1-500); In described reactions steps, temperature is 0-100 DEG C, the time is 0-100 hour;
Described step 2) in, the trityl ether shown in formula III, halohydrocarbon feed intake mole dosage than being 1:(4-10 with alkali): (4-20); In described reactions steps, temperature is 0-80 DEG C, and the time is 0-24 hour;
Described step 3) in, the thioacetal shown in formula IV feeds intake mole dosage than being 1:(1-50 with acid); In described reactions steps, temperature is-20-100 DEG C, and the time is 0-24 hour;
Described step 4) in, the primary alconol shown in formula V, Acetyl Chloride 98Min. feed intake mole dosage than being 1:(1-3 with alkali): (1-10); In described reactions steps, temperature is-20-50 DEG C, and the time is 0-12 hour;
Described step 5) in, the acetic ester shown in formula VI is 1:(1-5 with the mole dosage ratio that feeds intake of N-bromo-succinimide and ethylene glycol): (1-50); In described reactions steps, temperature is-20-50 DEG C, and the time is 0-24 hour;
Described step 6) in, the acetal shown in formula VII feeds intake mole dosage than being 1:(1-10 with alkali); In described reactions steps, temperature is 0-50 DEG C, and the time is 0-24 hour;
Described step 7) in, the primary alconol shown in formula VIII feeds intake mole dosage than being 1:(1-10 with oxygenant); In described reactions steps, temperature is-100-50 DEG C, and the time is 0-12 hour;
Described step 8) in, the primary alconol shown in formula V feeds intake mole dosage than being 1:(1-10 with oxygenant); In described reactions steps, temperature is 0-50 DEG C, and the time is 0-24 hour;
Described step 9) in, the aldehyde shown in formula X, acid feed intake mole dosage than being 1:(0.01-0.1 with ethylene glycol): (1-50); In described reactions steps, temperature is 0-200 DEG C, and the time is 0-12 hour;
Described step 10) in, the acetal shown in formula XI feeds intake mole dosage than being 1:(1-10 with N-bromo-succinimide); In described reactions steps, temperature is-20-50 DEG C, and the time is 0-12 hour;
Described step 11) in, the mole dosage ratio that feeds intake of the azanol that the aldehyde shown in formula IX is protected with oxygen is 1:(1-10); In described reactions steps, temperature is 0-100 DEG C, and the time is 0-24 hour;
Described step 12) in, the oxime shown in formula XII feeds intake mole dosage than being 1:(1-10 with reductive agent); In described reactions steps, temperature is 0-100 DEG C, and the time is 0-24 hour.
8. method according to claim 7, is characterized in that:
Described step 1) in, the thioacetal shown in formula II, triphenylmethyl chloride feed intake mole dosage than being 1:1.05:(50-100 with alkali); In described reactions steps, temperature is 35 DEG C, and the time is 48 hours;
Described step 2) in, the trityl ether shown in formula III, halohydrocarbon feed intake mole dosage than being 1:5:5.5 with alkali; In described reactions steps, temperature is 25 DEG C, and the time is 5-12 hour;
Described step 3) in, the thioacetal shown in formula IV feeds intake mole dosage than being 1:(3-10 with acid); In described reactions steps, temperature is 25 DEG C, and the time is 5-12 hour;
Described step 4) in, the primary alconol shown in formula V, Acetyl Chloride 98Min. feed intake mole dosage than being 1:1.2:1.5 with alkali; In described reactions steps, temperature is 0-25 DEG C, and the time is 1 hour;
Described step 5) in, the acetic ester shown in formula VI is 1:3:(2-10 with the mole dosage ratio that feeds intake of N-bromo-succinimide and ethylene glycol); In described reactions steps, temperature is 25 DEG C, and the time is 0.5-1 hour;
Described step 6) in, the acetal shown in formula VII feeds intake mole dosage than being 1:2 with alkali; In described reactions steps, temperature is 25 DEG C, and the time is 2-3 hour;
Described step 7) in, the primary alconol shown in formula VIII feeds intake mole dosage than being 1:(1.5-2 with oxygenant); In described reactions steps, temperature is-70 DEG C, and the time is 0.5-2 hour;
Described step 8) in, the primary alconol shown in formula V feeds intake mole dosage than being 1:2 with oxygenant; In described reactions steps, temperature is 25 DEG C, and the time is 2-3 hour;
Described step 9) in, the aldehyde shown in formula X, acid feed intake mole dosage than being 1:0.05:(2-10 with ethylene glycol); In described reactions steps, temperature is 110 DEG C, and the time is 1 hour;
Described step 10) in, the acetal shown in formula XI feeds intake mole dosage than being 1:2 with N-bromo-succinimide; In described reactions steps, temperature is 25 DEG C, and the time is 0.5 hour;
Described step 11) in, the mole dosage ratio that feeds intake of the azanol that the aldehyde shown in formula IX is protected with oxygen is 1:5; In described reactions steps, temperature is 25 DEG C, and the time is 6-12 hour;
Described step 12) in, the oxime shown in formula XII feeds intake mole dosage than being 1:2 with reductive agent; In described reactions steps, temperature is 25 DEG C, and the time is 0.5-3 hour.
9. compound or its salt described in claim 1 or claim 5 suppresses the application in glycosidase activity medicine in preparation.
10. application according to claim 9, is characterized in that: described Glycosylase is alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase enzymes, alpha-Mannosidase, beta-Mannosidase, alpha-L-fucosidase, trehalase, amyloglucosidase or alpha-L-Rhamnosidase.
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