CN110128315A

CN110128315A - Compound and the preparation method and application thereof, glycosidase inhibitor

Info

Publication number: CN110128315A
Application number: CN201910261497.5A
Authority: CN
Inventors: 俞初一; 杨林丰; 贾月梅; 李意羡; 加藤敦
Original assignee: Institute of Chemistry CAS
Current assignee: Institute of Chemistry CAS
Priority date: 2019-04-02
Filing date: 2019-04-02
Publication date: 2019-08-16
Anticipated expiration: 2039-04-02
Also published as: CN110128315B

Abstract

The present invention relates to enzyme inhibitor field, a kind of compound and the preparation method and application thereof, glycosidase inhibitor are disclosed.The compound has structure shown in formula (I),

Description

Compound and the preparation method and application thereof, glycosidase inhibitor

Technical field

The present invention relates to glycometabolism fields, and in particular, to a kind of N- alkylation polyhydroxy pyrrole class compound and its Preparation method and application and glycosidase inhibitor.

Background technique

Iminosugar (iminosugars) is the sugared analogies (sugar that oxygen atom is replaced by nitrogen-atoms in a kind of saccharide ring Mimic), also referred to as imines sugar, azasugar, polyhydroxylated alkaloid etc..The study found that iminosugar has glycosidase activity Very strong inhibiting effect, therefore excite significantly people to the research of iminosugar enthusiasm [Nash R.J., Kato A., Yu C.-Y.,et al.Future Med Chem,2011,3 1513-1521.].Glycosidase has important in organism It acts on, takes part in living including intestinal digestion, the lysosome metabolism of sugared yoke object, the synthesis of glycoprotein and the important life such as decomposition Dynamic [(a) Sayce A.C., Alonzi D.S., Killingbeck S.S., et al.PLoS neglected tropical diseases,2016,10, e0004524-e0004524；(b)Sanchez-Fernandez E.M.,Garcia Fernandez J.M.,Ortiz Mellet C., ChemCommun,2016,52,5497-5515；(c)Borges De Melo E.,Da Silveira Gomes A.,Carvalho I,Tetrahedron,2006,62,10277-10302.].Therefore And it is believed that can find new drug from iminosugar, for treat with the movable relevant disease of glycosidase, such as dislike Property tumour, bacterium infection, diabetes, bacterium and virus infection and lysosomal storage disease etc. [(a) Plummer E., Buck M.D.,Sanchez M.,et al,J Virol,2015,89, 5592-5601；(b)Hurtley S.,Service R., Szuromi P.,Science,2001,291,2337-2337；(c) Nishimura Y.,Satoh T.,Kudo T.,et al,Biorg Med Chem,1996,91-96；(d)Durantel D., Branza-Nichita N.,Carrouee- Durantel S.,et al.,J Virol,2001,75,8987-8998.]。

Iminosugar shows great function in new drug initiative convexity, has up to the present there is 4 imino group Carbohydrate drugs Listing, for example, the Forodosine (1) of newest listing in 17 years be used for treat T- cell lymphoma and 16 years listing Migalastat (2, DGJHCl) is the oral medicine for treating Fabry disease, and list a few years ago for treating height The magerut (3, Miglustat, trade name Zavesca) of Xue Shi disease, treat type II diabetes Miglitol (4, Miglitol, trade name Diastabol) [Y.X.Li, Y.M.Jia, C.Y.Yu, Progress in Chemistry, 2018, 30,586-600.]。

Be in clinical investigation phase imino group Carbohydrate drugs also have it is multiple.For example, the 1- for treating Pompeii disease is de- Oxygen nojirimycin hydrochloride (5, Duvoglusta tHydrochloride) treats the Isofagomine (6) of gaucher's disease, Treat the MBI-3253 (7, Celgosivir) of hepatitis C, and the Ulodesine (8) etc. for the treatment of chronic gout.

Iminosugar in the exploitation of new drug in occupation of critical role, but due to big polarity and the spy of highly-water-soluble Point, iminosugar are not readily separated purifying.With the progress of isolation technics, up to the present, only more than 200 kind iminosugar quilts It is isolated.Following five class: polyhydroxy piperidines can be divided into according to its nitrogen atom skeleton (polyhydroxylatedpiperdine), polyhydroxy pyrrole class (polyhydroxylated pyrrolidine), polyhydroxy Base Indolizidine class (polyhydroxylated indolizidine), polyhydroxy Pyrrolizidine class (polyhydroxylated pyrrolizidine) and polyhydroxy demethyl tropine alkanes (polyhydroxylatednortropane)。

In comparison with the iminosugars of other structures, Indolizidine class iminosugar negligible amounts.First is divided It is spherosin (9) from obtained Indolizidine class iminosugar, is initially Broquist et al. in 1973 from nosomycosis Isolated [F.P.Guengerich, the S.J.DiMari and of substance Rhizoctonialeguminicola H.P.Broquist,J. Am.Chem.Soc.,1973,95,2055–2056.].Subsequent people herd from being distributed in Australia again Isolated [S.M.Colegate, the P.R.Dorling and of grey swainson pea Swainsonacanescens of field C.R.Huxtable,Aust.J. Chem.,1979,32,2257-2264.].Bioactivity research discovery swainson pea is carried out to it Element has preferable alpha-Mannosidase inhibiting effect [(a) M.J.Schneider, F.S.Ungemach, H.P.Broquist and T.M.Harris, Tetrahedron,1983,39,29-32.(b)Y.-F.Liao,A.Lal and K.W.Moremen, J.Biol.Chem.,1996, 271,28348-28358.(c)A.D.Elbein,R.Solf,P.R.Dorling and K.Vosbeck,Proc.Natl.Acad. Sci.U.S.A.,1981,78,7393-7397；(d)G.P.Kaushal, T.Szumilo,I.Pastuszak and A.D.Elbein, Biochemistry,1990,29,2168-2176；(e) I.Pastuszak,G.P.Kaushal,K.A.Wall,Y.T.Pan,A. Sturm and A.D.Elbein, Glycobiology, 1990,1,71-82.], and enter the clinical second phase research of clear-cell carcinoma.But clinical research shows swainson pea There are serious toxic side effects for element, for example, patient will appear fatigue, mental fatigue, anorexia nervosa, shallow lake in duration of medication Powder enzyme increases and adverse reactions [P.E.Shaheen, W.Stadler, P.Elson, J.Knox, the E.Winquist such as diarrhea and R.M.Bukowski,Investigational New Drugs,2005,23,577-581.].Therefore it needs to bitter horse Legumin carries out structural modification, and Lai Tigao bioactivity reduces toxic side effect.

1,4-Dideoxy-l, 4-imino- α-mannitol (10, DIM) molecule is to be taught by Britain Fleet in 1984 years Design and synthesize [G.W.J.Fleet, P.W.Smith, S.V.Evans and L.E.Fellows, J.Chem.Soc.Chem. Commun.,1984,1240-1241].DIM molecule displays go out with the comparable alpha-Mannosidase inhibitory activity of spherosin, because This can regard DIM molecule as the pharmacophore of spherosin.DIM molecule is a kind of polyhydroxy pyrrole class iminosugar, with hardship Horsebean element is compared, and monocyclic backbone is more simple, convenient for a large amount of synthesis and structural modification.But DIM molecule is fat-soluble poor, no Conducive to oral absorption, and only there is preferable inhibitory activity to alpha-Mannosidase, the suppression for other kinds of glycosidase It makes of poor.

Summary of the invention

The purpose of the invention is to overcome glycosidase inhibitor of the existing technology to the inhibiting effect of glycosidase compared with The problem of to be single, and inhibitor molecules is fat-soluble poor, is unfavorable for oral absorption provides a kind of N- alkylation polyhydroxy Pyrrolidines and the preparation method and application thereof, N- alkylation polyhydroxy pyrrole class compound can be directed to a variety of Different glycosidases all has good inhibitory activity, and with excellent fat-soluble.

To achieve the goals above, first aspect present invention provides a kind of compound, which has as shown in formula (I) Structure:

Wherein, R is hydrogen, aryl, hydroxyl, halogen atom, vinyl, acetenyl, alkoxy, carboxyl, ester group, nitro, amino With any one in cyano, n=1-20；And the spatial configuration of 2,3,4,6 carbon is 2R, 3S, 4R, 6S, wherein R is hydrogen When, n is not 1 and 4；When R is hydroxyl, n is not 2；When R is phenyl, n is not 1.

Further, R is hydrogen, vinyl, acetenyl, aryl, hydroxyl, alkoxy and amino in compound shown in the Formulas I In any one.

Further, the aryl can for phenyl, indol-3-yl, pyrroles -2- base, furans -2- base, thiophene -2- base, The phenyl partly or entirely replaced, wherein the substituent group in the phenyl partly or entirely replaced is indol-3-yl, pyrroles- 2- base, furans -2- base, thiophene -2- base, fluorine, chlorine, bromine, iodine, hydroxyl, methoxyl group, nitro, carboxyl, cyano, amino, N, N- bis- Methylamino, phenyl, cyclohexyl, tert-butyl, C_1-4Straight chained alkyl, C_1-4Straight chain alkylamino, C_1-4In straight chain alkoxy carbonyl group extremely Few one kind；

Preferably phenyl, the phenyl partly or entirely replaced, wherein the substitution in the phenyl partly or entirely replaced Base is fluorine, chlorine, bromine, iodine, hydroxyl, methoxyl group, nitro, carboxyl, cyano, amino, phenyl, cyclohexyl, tert-butyl, C_1-4Straight chain alkane At least one of base.

Further, the halogen atom are as follows: fluorine, chlorine, bromine, iodine；The alkoxy are as follows: methoxyl group, ethyoxyl, propoxyl group, Butoxy, tert-butoxy, benzyloxy.

Second aspect of the present invention provides a kind of preparation method of the compound of the present invention, includes the following steps:

(1) preparation of intermediate (III)

In the presence of catalyst and reducing agent, in solvent and inert gas atmosphere, by compound shown in formula (II -1) After being mixed with compound shown in formula (II -2), carries out reductive amination process and obtain intermediate (III)；

(2) preparation of formula (I) compound

In a solvent, under acid effect, intermediate (III) carries out the reaction of deprotection base, obtains chemical combination described in formula (I) Object,

Third aspect present invention provides a kind of another preparation method of the compound of the present invention, includes the following steps:

(A) preparation of intermediate (III)

In a solvent, it under alkali effect, is carried out after compound shown in formula (II -1) is mixed with halides shown in (II -3) Nucleophilic substitution obtains intermediate (III)；

Wherein, X is chlorine, bromine, iodine；

(B) preparation of formula (I) compound

In a solvent, under acid effect, intermediate (III) carries out the reaction of deprotection base, obtains compound shown in formula (I)；

The salt or hydrate of any above-mentioned Formulas I compound represented also belong within protection scope of the present invention.It is described Salt be pharmaceutically acceptable salt.

Fourth aspect present invention provides a kind of glycosidase of above compound or its salt or its hydrate as active constituent Inhibitor, wherein the glycosidase be alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta galactosidase, Alpha-Mannosidase, beta-Mannosidase, alpha-L-fucosidase, mycoside enzyme, amyloglucosidase, α-L- sandlwood Glycosidase or beta-glucuronidase enzyme.

Fifth aspect present invention provides a kind of above compound and its salt or its hydrate as active constituent and is preparing medicine Application in object, wherein the drug is used at least one of prevent and/or treat following diseases relevant to glycosidase: 1) diabetes；2) gaucher's disease；3) tumour；4) virus infection, the glycosidase be alpha-glucosidase, beta-glucosidase, Alpha-galactosidase, beta galactosidase, alpha-Mannosidase, beta-Mannosidase, alpha-L-fucosidase, mycoside Enzyme, amyloglucosidase, alpha-L-Rhamnosidase or beta-glucuronidase enzyme.

Compound of the present invention is that N- is alkylated polyhydroxy pyrrole class compound, to DIM molecule (Isosorbide-5-Nitrae- Dideoxy-l, 4-imino- α-mannitol) it improves, lipophilic preferable alkane is introduced on N atom in the molecule thereof Base chain significantly improves the fat-soluble of DIM molecule, can be used conveniently to prepare oral drugs.

N- alkylation polyhydroxy pyrrole class compound of the present invention can play different types of glycosidase higher Inhibiting effect, and show high selectivity, all kinds of medicines relevant to glycosidase can be used to prepare as active constituent Object.

Specific embodiment

The endpoint of disclosed range and any value are not limited to the accurate range or value herein, these ranges or Value should be understood as comprising the value close to these ranges or value.For numberical range, between the endpoint value of each range, Can be combined with each other between the endpoint value of each range and individual point value, and individually between point value obtain one or Multiple new numberical ranges, these numberical ranges should be considered as specific open herein.

First aspect present invention provides a kind of compound, which has structure shown in formula (I):

According to the present invention, in the structure of the compound end group R can further be hydrogen, vinyl, acetenyl, aryl, Any one in hydroxyl, alkoxy and amino；Any one preferably in hydrogen, vinyl, aryl and hydroxyl.

According to the present invention, the value of n can be determined with the selection of end group R in the formula (I).Preferably, when R is hydrogen When, n=2,3,5-20；Preferably, when R is hydroxyl, n=3-20.

According to the present invention, the aryl are as follows: phenyl, indol-3-yl, pyrroles -2- base, furans -2- base, thiophene -2- base, The phenyl partly or entirely replaced, wherein the substituent group in the phenyl partly or entirely replaced is indol-3-yl, pyrrole Cough up -2- base, furans -2- base, thiophene -2- base, fluorine, chlorine, bromine, iodine, hydroxyl, methoxyl group, nitro, carboxyl, cyano, amino, N, N- Dimethylamino, phenyl, cyclohexyl, tert-butyl, C_1-4Straight chained alkyl, C_1-4Straight chain alkylamino, C_1-4In straight chain alkoxy carbonyl group extremely Few one kind；Preferably phenyl, the phenyl partly or entirely replaced, wherein the substitution in the phenyl partly or entirely replaced Base is fluorine, chlorine, bromine, iodine, hydroxyl, methoxyl group, nitro, carboxyl, cyano, amino, phenyl, cyclohexyl, tert-butyl, C_1-4Straight chain alkane At least one of base.

The halogen atom are as follows: fluorine, chlorine, bromine, iodine；The alkoxy are as follows: methoxyl group, ethyoxyl, propoxyl group, butoxy, uncle Butoxy, benzyloxy.

Preferably, R is any one in hydrogen, vinyl, phenyl and hydroxyl.

In accordance with the present invention it is preferred that the compound is to appoint in compound shown in following formula (I-1) to formula (I-29) It is a kind of:

The salt or hydrate of any above-mentioned Formulas I compound represented also belong within protection scope of the present invention, described Salt be pharmaceutically acceptable salt.

Second aspect of the present invention provide it is a kind of the present invention in compound preparation method, comprising the following steps:

(1) preparation of intermediate (III)

(2) preparation of formula (I) compound

In the present invention, the amount ratio of compound shown in compound shown in the formula (II -2) and formula (II -1) is greater than 1, excellent Selection of land, the amount ratio of compound shown in compound shown in the formula (II -2) and formula (II -1) are 3:1.The dosage of catalyst is The 1%-50%, preferably 10-30% of compound amount shown in formula (II -1)；The dosage and formula (II -1) shownization of reducing agent The amount ratio for closing object is greater than 1, it is preferable that the amount ratio of compound shown in the dosage of reducing agent and formula (II -1) is 5-10:1

In the present invention, compound shown in formula (II -1) can be prepared according to following specific method:

It is prepared as follows:

Under the conditions of ice-water bath, compound ii -8 (2.2g, 9.1mmol) is dissolved in 15mL anhydrous ether, time chlorine is added Sour tertiary butyl ester (1.23mL, 10.9mmol), react 30 minutes, keep ice-water bath condition, be added dropwise DBU (1.77mL, 11.8mmol), it after being added dropwise, gradually rises to room temperature, at room temperature, the reaction was continued 1 hour, and TCL display has been reacted Entirely, it is filtered to remove the salt that reaction generates, it is yellowish that decompression, which boils off solvent, chromatographs quick separating through column, obtain intermediate II -9, Sugar colour slurry, 2.1 grams, yield: 97%.δH(400MHz；CDCl3) 5.15 (1H, d, J=5.8Hz), 4.87 (1H, t, J= 6.2Hz), 4.76 (1H, t, J=5.1Hz), 4.30-4.24 (2H, m), 4.07-3.94 (2H, m), 1.43 (3H, s), 1.42 (3H,s),1.38(3H,s),1.36(3H,s)；δC(100MHz；CDCl3)174.9,112.0,110.0,85.5,77.7, 73.4,67.3,65.4,26.8,26.3,25.39,25.36。

Under the conditions of ice-water bath, compound ii -9 (3.37g, 13.9mmol) is dissolved in 30mL anhydrous methanol, boron is added Sodium hydride (1.6g, 42.0mmol) is gradually increased to room temperature by ice-water bath, reflects 1 hour at room temperature, and TLC shows fully reacting, The aqueous ammonium chloride solution quenching reaction of saturation is added, solvent is removed under reduced pressure, 500mL water is added, carries out extraction three with ethyl acetate Secondary (500mL × 3) collect concentration organic phase through column chromatography for separation and obtain 2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae- Imini-D-mannitol formula (II -1), (dr > 99:1) be colorless transparent syrup, 3.19 grams, yield: 94%. δH (400MHz；CDCl3) 4.66 (2H, ddd, J=14.3Hz, 3.8Hz, 5.5Hz), 4.26-4.21 (1H, m), 4.09 (1H, dd, J=8.4Hz, 6.2Hz), 3.99 (1H, dd, J=8.4Hz, 5.5Hz), 3.09 (1H, d, J=13.0Hz), 2.69 (1H, dd, J =8.2Hz, 3.7Hz), 2.62 (1H, dd, J=13.0Hz, 3.7Hz), 1.45 (3H, s), 1.42 (3H, s), 1.38 (3H, s), 1.32(3H,s)；δC(100MHz；CDCl3)110.7,108.9,81.6,80.7,73.9,67.7,66.4,53.3, 26.9, 25.7,25.4,23.8。

In the present invention, above compound II -8 can be reference literature ((a) J.Grant.Buchanan, K.W.Lumbard, R.J.Sturgeon,D.K.Thompson and R.H.Wightman,J Chem Soc,1990,699- 706；(b)A. Vasella,HeIvChimActa,1977,60,1273-1295；(C)G.W.J.Fleet,J.C.Son, D.S.C.Green,I. C.D.Bello and B.Winchester,Tetrahedron,1988,44,2649-55；(d) H.Setoi.,H.Kayakiri,H. Takeno and M Hashimoto,Chem Pharm Bull,1987,35,3995- 3999；(F)C.Laroche,J.B.Behr, J.Szymoniak,P.Bertus,Schutz C,Vogel and P.R.Richard, Bioorg Med Chem, 2006,14,4047-4054.) what method documented by was prepared, specifically Preparation method is as described below.

Intermediate (II -8) can be synthesized according to following procedure:

It is prepared as follows:

At room temperature, D-MANNOSE (II -4) (100.0g, 555.4mmol) is dissolved in 1000mL acetone, is added The p-methyl benzenesulfonic acid monohydrate (1.0g, 5.3mmol) of catalytic amount, then be added 2,2-dimethoxypropane (150.2mL, 1.2 Mol), it is stirred to react with this condition 3 hours, TLC shows that raw material disappears, and sodium bicarbonate quenching reaction is added in fully reacting, Solvent is neutralized to neutrality, filtering removal inorganic salts, solvent evaporated, obtaining white solid is first step crude product 2,3:5,6-O- Diacetone-D-MANNOSE (II -5).

Crude product II -5 is dissolved in 800mL anhydrous methanol (based on 555.4mol), then sequentially adds triethylamine (116.6 mL, 833.1mmol), hydroxylamine hydrochloride (43.3g, 666.5mmol), reaction flask is placed in oil bath pan, is heated to reflux 6 Hour, TCL shows that raw material disappears, and fully reacting stops reaction, is down to room temperature, and decompression boils off methanol and triethylamine, is added 500mL water is extracted (500mL × 3) three times with ethyl acetate, is collected concentration organic phase, is obtained crude product 2,3:5,6-O- Diacetone-α-D-MANNOSE oxime (II -6).

Crude product II -6 is dissolved in 500mL pyridine (based on 555.4mmol), cools down in -20 DEG C, methylsulphur is added dropwise Acyl chlorides (107.5mL, 1.4mol) after being added dropwise, reacts 1 hour under the conditions of -20 DEG C, then gradually rises in room temperature, after Continuous reaction 10 hours, TLC shows fully reacting, stops reaction, and decompression boils off pyridine, and 500mL water is added, with ethyl acetate into Row extraction three times (500mL × 3), collects concentration organic phase through column chromatography for separation and obtains white needles formula (II -7), 109.8g, yield: 59%.

Mp:80-81℃；δ_H(500MHz；CDCl₃) 4.91 (1H, d, J=4.7Hz), 4.82 (1H, t, J=9.0Hz), 4.30-4.27 (2H, m), 4.14 (1H, dd, J=9.0Hz, 6.7Hz), 4.11-4.06 (1H, m), 3.15 (3H, s), 1.62 (3H, s),1.49(3H,s),1.42(3H,s),1.36(3H,s)；δ_C(125MHz；CDCl₃)116.6,112.0,111.6, 80.8,77.8, 74.1 67.7,66.6,38.9,26.9,26.2,25.6,25.4。

Under the conditions of ice-water bath, product II -7 (3.35g, 10.0mmol) is dissolved in 30mL anhydrous methanol, dichloro is added Change cobalt hexahydrate (4.76g, 20.0mmol), be sufficiently stirred 30 minutes, sodium borohydride (3.8g, 100.0mmol) then is added, It gradually rises to room temperature, in room temperature reaction 10 hours, TLC showed fully reacting, saturated ammonium chloride solution quenching reaction is added, Decompression boils off solvent, and 50mL water is added, is extracted (50mL × 3) three times with ethyl acetate, concentration organic phase is collected, through column Chromatography, obtains white solid Isosorbide-5-Nitrae-dideoxy -2,3:5,6- diacetone-Isosorbide-5-Nitrae-imino group-D- talitol (II -8), 2.2g, yield: 91%.

Mp:58-59℃；δH(500MHz；CDCl3) 4.72 (1H, ddd, J=5.5Hz, 4.1Hz, 1.3Hz), 4.47 (1H, Dd, J=5.8Hz, 1.4Hz), 4.07 (1H, dd, J=11.7Hz, 6.3Hz), 4.02 (1H, dd, J=7.7Hz, 6.4Hz), 3.84 (1H, t, J=7.5Hz), 3.15 (1H, dd, J=5.7Hz, 1.1Hz), 3.09-3.02 (2H, m), 2.32 (1H, br s),1.47 (3H,s),1.41(3H,s),1.33(3H,s),1.31(3H,s)；δC(125MHz；CDCl3)111.5,109.4, 84.0,82.2, 76.0,66.83,66.81,53.2,26.48,26.46,25.3,24.2。

In the present invention, reductive amination process used catalyst be Rany- nickel, palladium content be 0.5%-30% palladium carbon and PtO₂At least one of；Reducing agent is hydrogen, sodium borohydride, sodium cyanoborohydride, lithium borohydride, triacetyl oxygen hydroboration At least one of sodium.

In the present invention, reductive amination process temperature can be -40 DEG C to 80 DEG C, preferably 0 DEG C to 30 DEG C；Removing is protected Protecting base reaction temperature can be -40 DEG C to 80 DEG C, preferably 10 DEG C to 30 DEG C.

In the present invention, the inert gas atmosphere is nitrogen, helium, argon gas, preferably argon gas.

In the present invention, the solvent is the Conventional solvents type in this field, specifically, the solvent is dichloromethane Alkane, chloroform, tetrahydrofuran, ether, ethyl acetate, water, dioxane, methanol, ethyl alcohol, acetonitrile, formamide or N, N- diformazan At least one of base formamide, it is preferable that solvent is methanol.

In the present invention, the acid is at least one of inorganic acid, organic acid or lewis acid, it is preferable that the nothing Machine acid is at least one of hydrochloric acid, hydrofluoric acid, sulfuric acid；The organic acid is acetic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, trifluoro second At least one of acid；The lewis acid is at least one of titanium tetrachloride, stannic chloride, bismuth trichloride or zinc bromide.

Third aspect present invention provides another preparation method of the compound of the present invention, comprising the following steps:

(A) preparation of intermediate (III)

In a solvent, it under alkali effect, after compound shown in formula (II -1) is mixed with halides shown in (II -3), carries out Nucleophilic substitution obtains intermediate (III)；

Wherein, X is chlorine, bromine, iodine；

(B) preparation of formula (I) compound

In the present invention, compound shown in formula (II -3), halides shown in formula (II -1) amount ratio be greater than 1, preferably The amount ratio of compound shown in compound shown in the formula (II -3) and formula (II -1) is 1.2:1.

In the present invention, nucleophilic substitution temperature is -40 DEG C to 100 DEG C, preferably 30 DEG C to 80 DEG C；Deprotection Base reaction temperature is -40 DEG C to 80 DEG C, preferably 10 DEG C to 30 DEG C.

In the present invention, the solvent is the Conventional solvents type in this field, specifically, the solvent is dichloromethane Alkane, chloroform, tetrahydrofuran, ether, ethyl acetate, water, dioxane, methanol, ethyl alcohol, acetonitrile, formamide and N, N- diformazan At least one of base formamide, it is preferable that solvent is methanol.

In the present invention, the alkali is organic base and/or inorganic base, it is preferable that the organic base is diethylamine, three second At least one of amine, diisopropylamine, diisopropyl ethyl amine, pyridine and 2,4,6- trimethylpyridine；The inorganic base is At least one of sodium carbonate, sodium bicarbonate, potassium carbonate, saleratus, sodium hydroxide, potassium hydroxide and sodium hydride.

In the present invention, the acid is at least one of inorganic acid, organic acid and lewis acid, it is preferable that the nothing Machine acid is at least one of hydrochloric acid, hydrofluoric acid and sulfuric acid；The organic acid is acetic acid, p-methyl benzenesulfonic acid, methanesulfonic acid and trifluoro At least one of acetic acid；The lewis acid is at least one of titanium tetrachloride, stannic chloride, bismuth trichloride and zinc bromide.

The present invention will be described in detail by way of examples below.In following embodiment, the structure of each substance passes through core Magnetism method measures, the concrete operations condition of nuclear-magnetism test are as follows:

In following embodiments unless otherwise specified, used experimental method is conventional method；Material used, examination Agent etc., commercially obtains.

The present invention is further described combined with specific embodiments below, but the present invention is not limited to following embodiments.

The preparation of embodiment 1, N- ethyl -1,4- dideoxy -1,4- imini-D-mannitol (I-1).

It is specific the preparation method is as follows:

Compound ii -1 (100mg, 0.41mmol) is dissolved in 15mL methanol, addition acetaldehyde solution (0.14mL, 10mg10% palladium carbon 1.23mmol) is added under argon atmosphere, displacement argon gas is that hydrogen stirs at room temperature in atmosphere of hydrogen Overnight, TLC shows fully reacting, stops reaction, is filtered to remove palladium carbon, and filtrate is concentrated through column chromatography for separation and obtains N- ethyl- 2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -1) are faint yellow syrup, and 99.5mg is received Rate: 89%.δ_H(500MHz；CDCl₃) 4.60-4.56 (2H, m), 4.46 (1H, td, J=7.5Hz, 2.0Hz), 4.19 (1H, T, J=7.8Hz), 3.99 (1H, t, J=7.5Hz), 3.26 (1H, d, J=11.1Hz), 3.11 (1H, dq, J=12.4Hz, 7.5Hz) 2.62 (1H, d, J=2.3Hz), 2.15-2.08 (2H, m), 1.45 (3H, s), 1.43 (3H, s), 1.33 (3H, s), 1.28 (3H, s), 1.04 (1H, t, J=7.5Hz)；δ_C(125MHz；CDCl₃)110.9,107.1,81.2,77.6, 75.2, 67.6,65.8,58.5,47.8,26.2,25.8,24.7,24.0,12.5.

Intermediate III -1 (20mg, 0.09mmol) is dissolved in 10mL methanol, 1mL 6N hydrochloric acid is added, stirs at room temperature Reaction 1 hour is mixed, reaction is stopped, decompression boils off solvent, obtains white solid N- ethyl-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imino group- 16.7 milligrams of D-mannital (I-1), yield: 100%.Mp:142-143℃；δ_H(500MHz；D₂O)4.57-4.51 (2H, M), 4.22 (1H, dd, J=11.0Hz, 5.0Hz), 3.83 (2H, m), 3.65 (1H, t, J=4.1Hz), 3.59 (3H, m) 3.16 (1H, dq, J=13.0Hz, 7.3Hz) 1.35 (1H, t, J=7.3Hz)；δ_C(125MHz；D₂O)70.8,68.5,68.1, 67.3, 62.5,54.6,49.3,9.3.

The preparation of embodiment 2, N- propyl -1,4- dideoxy -1,4- imini-D-mannitol (I-2).

Referring to the synthetic method in embodiment 1, with compound ii -1 (120mg, 0.49mmol) and propionic aldehyde (86mg, 1.47 Mmol it is) raw material, obtains intermediate N propyl -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol 131 milligrams of (III -2), yield: 81%.Faint yellow syrup, δ_H(400MHz；CDCl₃)4.60-4.54(2H,m,),4.46(1H, Td, J=7.2Hz, 1.6Hz), 4.21 (1H, t, J=8.0Hz), 3.98 (1H, t, J=7.6Hz), 3.25 (1H, d, J=10.8 ), Hz 3.05-2.98 (1H, m) 2.61 (1H, d, J=2.8Hz), 2.07-1.99 (2H, m), 1.51-1.42 (8H, m), 1.32 (3H, s), 1.27 (3H, s), 0.90 (1H, t, J=7.4Hz)；δ_C(100MHz；CDCl₃)110.0,107.1,81.1,77.7, 75.3,67.9,65.7,59.1,56.0,26.2,25.9,24.9,24.0,20.9,11.8。

Intermediate III -2 (30.0mg, 0.10mmol) sloughs protecting group under hydrochloric acid effect, and it is de- to obtain N- propyl-Isosorbide-5-Nitrae-two Oxygen-Isosorbide-5-Nitrae-imini-D-mannitol (I-2) be faint yellow syrup, 25.3 milligrams, yield: 99%.δ_H(400MHz；D₂O) 4.55-4.51(2H,m),4.23-4.22(1H,m),3.88-3.80(2H,m),3.66(1H,s),3.57-3.59(2H,m) 3.40-3.33 (1H, m), 3.10-3.03 (1H, m), 1.77-1.75 (2H, m), 0.98 (1H, t, J=7.2Hz)；δ_C (100MHz； D₂O)70.7,68.8,68.6,67.3,62.6,55.0,55.4,18.1,10.1。

The preparation of embodiment 3, N- amyl -1,4- dideoxy -1,4- imini-D-mannitol (I-3).

Referring to the synthetic method in embodiment 1, with compound ii -1 (100.0mg, 0.41mmol) and valeraldehyde (106mg, 12.3mmol) obtain intermediate N amyl -2,3:5,6- diacetone -1,4- dideoxy -1,4- imini-D-mannitol (III - It 3) is colourless syrup, 108 milligrams, yield: 84%.δ_H(400MHz；CDCl₃) 4.59-4.54 (2H, m), 4.46 (1H, td, J= 7.2Hz, 1.6Hz), 4.19 (1H, t, J=7.6Hz), 3.98 (1H, t, J=7.6Hz), 3.25 (1H, d, J=11.0Hz), 3.09-3.01 (1H, m), 2.59 (1H, d, J=2.7Hz), 2.06-1.97 (2H, m), 1.46-1.21 (18H, m), 0.88 (3H, T, J=7.2Hz)；δ_C(100MHz；CDCl₃)111.0,107.1,81.1,77.7,75.3,68.0,65.7,59.1,54.2, 29.6, 27.4,26.3,25.9,24.9,24.0,22.6,14.1。

Intermediate III -3 (16.0mg, 0.05mmol) sloughs protecting group under hydrochloric acid effect, and it is de- to obtain N- amyl-Isosorbide-5-Nitrae-two Oxygen-Isosorbide-5-Nitrae-imini-D-mannitol (I-3) be faint yellow syrup, 13.6 milligrams, yield: 99%.δ_H(400MHz；D₂O) 4.53-4.47 (2H, m), 4.18 (1H, dd, J=10.4Hz, 5.2Hz), 3.86-3.78 (2H, m), 3.53 (1H, s), 3.45- 3.44(2H,m),3.32-3.24(1H,m),3.02-2.95(1H,m),1.71-1.65(2H,m),1.36-1.31(4H,m), 0.89 (3H, t, J=7.2Hz)；δ_C(100MHz；D₂O)71.0,68.8,68.4,67.8,62.7,55.4,54.8,28.0, 24.4, 21.5,13.0。

The preparation of embodiment 4, N- hexyl -1,4- dideoxy -1,4- imini-D-mannitol (I-4).

Referring to the synthetic method in embodiment 1, with compound ii -1 (59.0mg, 0.24mmol) and n-hexyl aldehyde (76.1mg, 0.72mmol) it is raw material, obtains intermediate N hexyl -2,3:5 by 10% palladium carbon catalytic hydrogenation, 6- diacetone-Isosorbide-5-Nitrae-two is de- Oxygen-Isosorbide-5-Nitrae-imini-D-mannitol (III -4) be colourless syrup, 74.6 milligrams, yield: 94%.δ_H(400MHz；CDCl₃) 4.60-4.55 (2H, m), 4.46 (1H, td, J=7.3Hz, 1.6Hz), 4.20 (1H, t, J=7.6Hz), 3.98 (1H, t, J= 7.6 Hz), 3.26 (1H, d, J=11.0Hz), 3.09-3.02 (1H, m), 2.59 (1H, d, J=2.6Hz), 2.07-1.98 (2H, m), 1.44-1.27 (20H, m), 0.88 (3H, t, J=6.4Hz)；δ_C(100MHz；CDCl₃)111.0,107.1,81.1, 77.7, 75.3,68.0,65.8,59.1,54.2,31.8,27.7,27.0,26.3,25.9,24.9,24.0,22.6,14.0。

Intermediate III -4 (27.0mg, 0.08mmol) sloughs protecting group under hydrochloric acid effect, and it is de- to obtain N- hexyl-Isosorbide-5-Nitrae-two Oxygen-Isosorbide-5-Nitrae-imini-D-mannitol (I-4) be faint yellow syrup, 23.4 milligrams, yield: 100%.δ_H(500MHz；D₂O) 4.57-4.51 (2H, m), 4.22 (1H, dd, J=9.0Hz, 4.5Hz), 3.84 (2H, qd, J=11.9Hz, 6.2Hz), 3.66 (1H, s), 3.55 (2H, d, J=7.4Hz), 3.42-3.35 (1H, m), 3.12-3.07 (1H, m), 1.78-1.69 (2H, m), 1.39-1.32 (6H, m), 0.87 (3H, t, J=5.5Hz)；δ_C(125MHz；D₂O)70.7,68.7,68.6,67.2,62.5, 55.3,54.5,30.3,25.3,24.2,21.6,13.1。

The preparation of embodiment 5, N- heptyl -1,4- dideoxy -1,4- imini-D-mannitol (I-5).

Referring to the synthetic method in embodiment 1, with compound ii -1 (142.0mg, 0.58mmol) and n-Heptaldehyde (198.6mg, 1.74mmol) is raw material, obtains intermediate N heptyl -2,3:5,6- bis- third by 10% palladium carbon catalytic hydrogenation Ketone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -5) be colourless syrup, 140.1 milligrams, yield: 71%.δ_H (500MHz；CDCl₃) 4.58-4.54 (2H, m), 4.46 (1H, t, J=7.5Hz), 4.18 (1H, t, J=7.5Hz), 3.98 (1H, t, J=7.5Hz, H1), 3.25 (1H, d, J=11.0Hz), 3.08-3.02 (1H, m), 2.59 (1H, d, J=3.5Hz), 2.06-1.98 (2H, m), 1.43-1.27 (22H, m), 0.87 (3H, t, J=6.3Hz)；δ_C(125MHz；CDCl₃)111.0, 107.1,81.1,77.7, 75.3,68.0,65.8,59.1,54.3,31.9,29.3,27.7,27.4,26,3,25.9,24.9, 24.0,22.7,14.1。

Intermediate III -5 (35.0mg, 0.10mmol) sloughs protecting group under hydrochloric acid effect, and it is de- to obtain N- heptyl-Isosorbide-5-Nitrae-two Oxygen-Isosorbide-5-Nitrae-imini-D-mannitol (I-5) be faint yellow syrup, 30.5 milligrams, yield: 100%.δ_H(400MHz；D₂O) 4.59-4.51 (2H, m), 4.23 (1H, dd, J=10.3Hz, 5.1Hz), 3.88 (2H, qd, J=12.0Hz, 6.0Hz, 5.2Hz), 3.67 (1H, t, J=4.0Hz), 3.56 (2H, d, J=7.6Hz), 3.44-3.37 (1H, m), 3.15-3.07 (1H, M), 1.80-1.71 (2H, m), 1.37-1.30 (8H, m), 0.88 (3H, t, J=7.2Hz)；δ_C(100MHz；D₂O)70.7, 68.8, 68.6,67.3,62.6,55.4,54.6,30.7,27.8,24.3,21.8,13.3。

The preparation of embodiment 6, N- octyl -1,4- dideoxy -1,4- imini-D-mannitol (I-6).

Referring to the synthetic method in embodiment 1, with compound ii -1 (96.0mg, 0.23mmol) and n-octaldehyde (88.5mg, 0.69mmol) it is raw material, obtains intermediate N octyl -2,3:5 by 10% palladium carbon catalytic hydrogenation, 6- diacetone-Isosorbide-5-Nitrae-two is de- Oxygen-Isosorbide-5-Nitrae-imini-D-mannitol (III -6) be colourless syrup, 64.6 milligrams, yield: 79%.δ_H(500MHz；CDCl₃) 4.59-4.55 (2H, m), 4.46 (1H, td, J=7.5Hz, 1.5Hz), 4.19 (1H, t, J=7.5Hz), 3.98 (1H, t, J= 7.5Hz), 3.25 (1H, d, J=11.0Hz), 3.08-3.02 (1H, m), 2.59 (1H, d, J=3.0Hz), 2.06-1.98 (2H, M), 1.47-1.27 (24H, m), 0.87 (3H, t, J=6.5Hz)；δ_C(125MHz；CDCl₃)111.0,107.1,81.1, 77.71,75.3,68.0,65.8,59.1,54.3,31.9,29.6,29.3,27.8,27.4,26.3,25.87,24.9,24.1, 22.7, 14.1。

Intermediate III -6 (25.0mg, 0.07mmol) sloughs protecting group under hydrochloric acid effect, and it is de- to obtain N- octyl-Isosorbide-5-Nitrae-two Oxygen-Isosorbide-5-Nitrae-imini-D-mannitol (I-6) be faint yellow syrup, 21.9 milligrams, yield: 100%.δ_H(400MHz；D₂O) 4.58-4.50 (2H, m), 4.22 (1H, dd, J=10.3Hz, 5.1Hz), 3.84 (2H, qd, J=11.9Hz, 6.1Hz, 5.0Hz), 3.66 (1H, t, J=4.2Hz), 3.56 (2H, d, J=7.4Hz), 3.44-3.36 (1H, m), 3.13-3.06 (1H, M), 1.79-1.67 (2H, m), 1.36-1.28 (10H, m), 0.86 (3H, t, J=6.4Hz)；δ_C(100MHz；D₂O)70.7, 68.7, 68.6,67.3,62.5,55.3,54.6,30.9,28.1,28.1,25.7,24.3,21.9,13.4。

The preparation of embodiment 7, N- nonyl -1,4- dideoxy -1,4- imini-D-mannitol (I-7).

Referring to the synthetic method in embodiment 1, with compound ii -1 (60.0mg, 0.16mmol) and n-nonyl aldehyde (68.3mg, 0.68mmol) it is raw material, obtains (II -1) intermediate N nonyl -2,3:5 by 10% palladium carbon catalytic hydrogenation, diacetone -1 6-, 4- dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -7) be colourless syrup, 41.7 milligrams, yield: 71%.δ_H(500MHz； CDCl₃) 4.59-4.55 (2H, m), 4.46 (1H, t, J=7.0Hz), 4.19 (1H, t, J=7.5Hz), 3.98 (1H, t, J= 7.5Hz), 3.25 (1H, d, J=11.5Hz), 3.08-3.02 (1H, m), 2.59 (1H, d, J=3.0Hz), 2.06-1.98 (2H, M), 1.43-1.25 (24H, m), 0.87 (3H, t, J=6.5Hz)；δ_C(125MHz；CDCl₃)111.0,107.1,81.1,77.7, 75.3,68.0,65.7,59.1,54.3,31.9,29.6,29.3,27.7,27.4,26.3,25.9,24.9,24.1,22.7, 14.1。

Intermediate III -7 (30.1mg, 0.08mmol) sloughs protecting group under hydrochloric acid effect, and it is de- to obtain N- nonyl-Isosorbide-5-Nitrae-two Oxygen-Isosorbide-5-Nitrae-imini-D-mannitol (I-7) be faint yellow syrup, 26.4 milligrams, yield: 100%.δ_H(400MHz；D₂O) 4.53-4.50 (2H, m), 4.20 (1H, m), 3.82 (2H, s), 3.64 (1H, s), 3.53 (2H, d, J=6.7Hz), 3.38- 3.34 (1H,m),3.11-3.07(1H,m),1.73(2H,s),1.32-1.26(12H,m),0.84(3H,s)；δ_C(100MHz； D₂O) 70.7,68.7,68.5,67.2,62.5,55.3,54.5,31.0,28.3,28.2,28.1,25.6,24.2,21.9, 13.3。

The preparation of embodiment 8, N- allyl -1,4- dideoxy -1,4- imini-D-mannitol (I-8).

It is specific the preparation method is as follows:

Compound ii -1 (3.0g, 12.3mmol) is dissolved in the dry n,N-Dimethylformamide of 30mL, carbonic acid is added Potassium (5.2g, 37.1mmol) and the bromo- 1- propylene (3.0g, 24.6mmol) of 3- are heated to 65 DEG C, reacted in argon atmosphere Night, TLC show that fully reacting stops reaction, and 200mL water is added, is extracted (100 mL × 3) three times with ethyl acetate, receive Collection concentration organic phase obtains intermediate N allyl -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-through column chromatography for separation Imini-D-mannitol (III -8) be faint yellow syrup, 3.0 grams, yield 87%.δ_H(500MHz；CDCl₃) 5.92-5.84 (1H, m), 5.17 (1H, dd, J=17.5Hz, 1.5Hz), 5.08 (1H, d, J=10.5Hz) 4.58-4.54 (2H, m), 4.47 (1H, td, J=7.5Hz, 2.0Hz), 4.22 (1H, t, J=8.0Hz), 4.00 (1H, t, J=7.5Hz), 3.77 (1H, ddt, J =17.5Hz, 6.5Hz, 2.0Hz), 3.20 (1H, d, J=14.0Hz), 3.76-3.71 (2H, m), 2.13 (1H, dd, J= 14Hz,5.5Hz),1.45(3H,s),1.43(3H,s),1.33(3H,s),1.27(3H,s)；δ_C(125MHz；CDCl₃) 135.2,116.7,111.0,107.1,81.0,77.5,75.2,66.8,65.7,58.6,56.5,26.2,25.8,24.6, 23.9。

Intermediate III -8 (13.5mg, 0.05mmol) is dissolved in 10mL methanol, 1mL 6N hydrochloric acid is added, at room temperature It is stirred to react 1 hour, stops reaction, decompression boils off solvent, it is sweet to obtain N- allyl-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imino group-D- Reveal sugar alcohol (I-8) be faint yellow syrup, 11.4 milligrams, yield: 100%.δ_H(400MHz；D₂O)6.02-5.91(1H, m), 5.66-5.60 (2H, m), 4.53-4.48 (2H, m), 4.22 (1H, dd, J=10.4Hz, 5.1Hz), 4.01 (1H, dd, J= 13.2Hz, 6.4Hz), 3.87-3.68 (4H, m), 3.60-3.55 (1H, m), 3.46 (1H, d, J=12.1Hz, 6.4Hz)； δ_C (100MHz；D₂O)126.7,125.6,70.9,68.5,67.6,67.3,62.5,55.8,54.6。

The preparation of embodiment 9, N- alkene butyl -1,4- dideoxy -1,4- imini-D-mannitol (I-9).

Referring to the synthetic method in embodiment 8, with compound ii -1 (60.1mg, 0.25mmol) and the bromo- 1- butylene of 4- (66.2mg, 0.49mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- alkene Butyl -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -9) are colourless syrup, 63.1 millis Gram, yield 86%.δ_H(400MHz；CDCl₃) 5.81 (1H, ddt, J=17.0Hz, 10.3Hz, 6.5Hz), 5.06-4.95 (2H, M), 4.60-4.55 (2H, m), 4.46 (1H, td, J=6.4Hz, 1.6Hz), 4.21 (1H, t, J=8.0Hz), 3.98 (1H, t, J =7.6Hz), 3.27 (1H, d, J=10.8Hz), 3.20-3.13 (1H, m), 2.67 (1H, dd, J=4.3Hz, 1.1Hz), 2.24-2.11(4H,m),1.43(6H,s),1.32(3H,s),1.27(3H,s)；δ_C(100MHz；CDCl₃)136.7,115.3, 111.1,107.1,81.0,77.7,75.3,67.6,65.7,59.1,53.3,31.9,26.2,25.8,24.8,24.0。

Intermediate III -9 (40.0mg, 0.08mmol) sloughs protecting group under hydrochloric acid effect, obtains N- alkene butyl-Isosorbide-5-Nitrae-two Deoxidation-Isosorbide-5-Nitrae-imini-D-mannitol (I-9) be faint yellow syrup, 34.1 milligrams, yield: 100%.δ_H(400MHz； D₂O) 5.83 (1H, ddt, J=17.1Hz, 10.3Hz, 6.7Hz), 5.30-5.21 (2H, m), 4.59-4.52 (2H, m), 4.24 (1H, dd, J=10.1Hz, 4.9Hz), 3.90 (1H, dd, J=11.9Hz, 5.9Hz), 3.83 (1H, dd, 11.8Hz, 4.8 ), Hz 3.72 (1H, t, J=4.3Hz), 3.59-3.51 (3H, m), 3.25-3.18 (1H, m), 2.61-2.49 (2H, m)；δ_C (100 MHz；D₂O)132.4,118.8,70.6,69.3,68.6,67.1,62.6,67.1,62.6,55.4,53.6,28.9。

The preparation of embodiment 10, N- alkene amyl -1,4- dideoxy -1,4- imini-D-mannitol (I-10).

Referring to the synthetic method in embodiment 8, with compound ii -1 (1.0g, 4.11mmol) and the bromo- 1- amylene of 5- (1.2g, 8.22mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- alkene penta Base -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -10) be colourless syrup, 0.91 gram, Yield 71%.δ_H(400MHz；CDCl₃) 5.83 (1H, ddt, J=17.0Hz, 10.3Hz, 6.6Hz), 5.03-4.92 (2H, m), 4.60-4.55 (2H, m), 4.46 (1H, td, J=7.8Hz, 1.7Hz), 3.98 (1H, t, J=7.5Hz), 3.98 (1H, t, J= 7.6Hz), 3.26 (1H, d, J=11.0Hz), 3.20-3.13 (1H, dt, J=12.2Hz, 8.5Hz), 2.60 (1H, d, J= 2.7Hz), 2.07-2.03(4H,m),1.60-1.55(2H,m),1.43(6H,s),1.32(3H,s),1.27(3H,s)；δ_C (100MHz； CDCl₃)138.8,114.4,111.0,107.1,81.1,77.7,75.3,68.1,65.7,59.1,53.7, 31.5,27.1,26.3, 25.9,24.8,24.0。

Intermediate III -10 (100.0mg, 0.32mmol) sloughs protecting group under hydrochloric acid effect, obtains N- alkene amyl-Isosorbide-5-Nitrae - Dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-10) be faint yellow syrup, 85.0 milligrams, yield: 99%.δ_H(400MHz； D₂O)5.83(1H,m),5.14-5.06(2H,m),4.53-4.50(2H,m),4.20(1H,s),3.86-3.82(2H,m), 3.65 (1H,s),3.56-3.54(2H,m),3.43-3.36(1H,m),3.13-3.06(1H,m),2.16-2.15(2H,m), 1.86(2H, s)；δ_C(100MHz；D₂O)137.0,116.0,70.7,68.8,68.6,67.2,62.5,55.4,53.9,29.8, 23.5。

The preparation of embodiment 11, N- alkene hexyl -1,4- dideoxy -1,4- imini-D-mannitol (I-11).

Referring to the synthetic method in embodiment 8, with compound ii -1 (54.0mg, 0.22mmol) and the bromo- 1- hexene of 6- (71.8 mg, 0.44mmol) are raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- alkene Hexyl -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -11) are colourless syrup, 40.0 millis Gram, yield 56%.δ_H(400MHz；CDCl₃) 5.83 (1H, ddt, J=17.0Hz, 10.3Hz, 6.6Hz), 5.02-4.92 (2H, M), 4.59-4.55 (2H, m), 4.47 (1H, t, J=7.2Hz), 3.20 (1H, t, J=7.7Hz), 3.98 (1H, t, J= 7.6Hz), 3.25 (1H, d, J=11.0Hz), 3.20-3.13 (1H, dt, J=14.2Hz, 8.3Hz), 2.60 (1H, d, J= 2.7Hz), 2.07-2.00(4H,m),1.47-1.35(10H,m),1.33(3H,s),1.27(3H,s)；δ_C(100MHz； CDCl₃)139.0, 114.3,111.0,107.1,81.1,77.7,75.3,68.1,65.7,59.1,54.0,33.7,27.2, 26.7,26.3,25.9,24.8, 23.9。

Intermediate III -11 (30.0mg, 0.09mmol) sloughs protecting group under hydrochloric acid effect, obtains N- alkene hexyl-Isosorbide-5-Nitrae - Dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-11) be faint yellow syrup, 25.9 milligrams, yield: 100%.δ_H (400MHz； D₂O) 5.88 (1H, ddt, J=17.1Hz, 10.3Hz, 6.7Hz), 5.11-5.03 (2H, m), 4.57-4.50 (2H, m), 4.22 (1H, dd, J=10.2Hz, 5Hz), 3.88-3.79 (2H, m), 3.66 (1H, t, J=4.1Hz), 3.56- 3.54 (2H, m), 3.45-3.35 (1H, m), 3.15-3.07 (1H, m), 2.12 (2H, dd, J=17Hz, 6.8Hz), 1.78- 1.75(2H,m), 1.51-1.47(2H,m)；δ_C(100MHz；D₂O)138.6,115.0,70.6,68.7,68.5,67.2, 62.5,55.3,54.17, 3.19,24.8,23.6。

The preparation of embodiment 12, N- alkene heptyl -1,4- dideoxy -1,4- imini-D-mannitol (I-12).

Referring to the synthetic method in embodiment 8, with compound ii -1 (328.0mg, 1.35mmol) and the bromo- 1- heptene of 7- (471.8mg, 2.70mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- Alkene heptyl -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -12) be colourless syrup, 398.0 Milligram, yield 87%.δ_H(400MHz；CDCl₃) 5.79 (1H, ddt, J=17.0Hz, 10.2Hz, 6.6Hz), 5.00-4.90 (2H, m), 4.59-4.54 (2H, m), 4.46 (1H, t, J=7.3Hz), 4.18 (1H, t, J=7.8Hz), 3.98 (1H, t, J= 7.6Hz), 3.25 (1H, d, J=11.0Hz), 3.20-3.13 (1H, dt, J=12.0Hz, 8.1Hz), 2.59 (1H, d, J=2.4 Hz),2.06-1.98(4H,m),1.51-1.27(18H,m)；δ_C(100MHz；CDCl₃)139.0,114.2,111.0,107.1, 81.1,77.7,75.3,68.0,65.7,59.1,54.1,33.8,28.8,27.6,26.87,26.28,25.86,24.9, 24.0。

Intermediate III -12 (22.0mg, 0.06mmol) sloughs protecting group under hydrochloric acid effect, obtains N- alkene heptyl-Isosorbide-5-Nitrae - Dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-12) be faint yellow syrup, 20.0 milligrams, yield: 100%.δ_H (400MHz； D₂O) 5.93 (1H, ddt, J=17.1Hz, 10.3Hz, 6.7Hz), 5.11-5.01 (2H, m), 4.60-4.53 (2H, m), 4.24 (1H, dd, J=10.3Hz, 5.0Hz), 3.91-3.82 (2H, m), 3.68 (1H, t, J=4.1Hz), 3.59- 3.57 (2H, m), 3.46-3.39 (1H, m), 3.16-3.09 (1H, m), 2.11 (2H, dd, J=13.4Hz, 6.5Hz), 1.80- 1.74(2H,m), 1.53-1.39(2H,m)；δ_C(100MHz；D₂O)139.6,114.5,70.7,68.8,68.6,67.3, 62.6,55.4,54.5, 32.7,24.4,25.2,24.2。

The preparation of embodiment 13, N- alkene octyl -1,4- dideoxy -1,4- imini-D-mannitol (I-13).

Referring to the synthetic method in embodiment 8, with compound ii -1 (145.0mg, 0.60mmol) and the bromo- 1- octene of 8- (229.3mg, 1.20mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- Alkene octyl -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -13) be colourless syrup, 134.8 Milligram, yield 64%.δ_H(400MHz；CDCl₃) 5.79 (1H, ddt, J=17.0Hz, 10.2Hz, 6.6Hz), 5.00-4.90 (2H, m), 4.59-4.54 (2H, m), 4.45 (1H, td, J=7.3Hz, 1.6Hz), 4.19 (1H, t, J=7.7Hz), 3.97 (1H, t, J=7.5Hz), 3.24 (1H, d, J=11.0Hz), 3.20-3.13 (1H, dt, J=11.8Hz, 8.1Hz), 2.59 (1H, d, J=2.8Hz), 2.06-1.98 (4H, m), 1.48-1.24 (20H, m)；δ_C(100MHz；CDCl₃)139.2,114.1, 111.0, 107.1,81.1,77.7,75.3,68.0,65.7,59.1,54.2,33.8,29.1,28.9,27.7,27.2, 26.3,25.9,24.9,24.0。

Intermediate III -13 (50.0mg, 0.06mmol) sloughs protecting group under hydrochloric acid effect, by column chromatography for separation, obtains To N- alkene octyl-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-13) be faint yellow syrup, 28.8 milligrams, yield: 66%.δ_H(400MHz；D₂O) 5.93 (1H, ddt, J=17.2Hz, 10.3Hz, 6.7Hz), 5.11-5.00 (2H, m), 4.59- 4.52 (2H, m), 4.23 (1H, dd, J=10.4Hz, 5.1Hz), 3.90-3.81 (2H, m), 3.66 (1H, t, J=4.2 Hz), 3.56-3.54 (2H, m), 3.43-3.36 (1H, m), 3.14-3.06 (1H, m), 2.11 (2H, dd, J=12.4Hz, 7.8 Hz), 1.82-1.71(2H,m),1.47-1.40(6H,m)；δ_C(100MHz；D₂O)140.1,114.2,70.8,68.7,68.6, 67.4,62.6,55.4,54.6,32.9,27.7,27.6,25.5,24.3。

The preparation of embodiment 14, N- alkene nonyl -1,4- dideoxy -1,4- imini-D-mannitol (I-14).

Referring to the synthetic method in embodiment 8, with compound ii -1 (64.0mg, 0.26mmol) and the bromo- 1- nonene of 9- (108.7 mg, 0.53mmol) are raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- Alkene nonyl -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -14) be colourless syrup, 66.7 Milligram, yield 69%.δ_H(400MHz；CDCl₃) 5.79 (1H, ddt, J=17.0Hz, 10.2Hz, 6.7Hz), 5.00-4.90 (2H, m), 4.58-4.54 (2H, m), 4.45 (1H, td, J=7.3Hz, 1.6Hz), 4.18 (1H, t, J=7.8Hz), 3.97 (1H, t, J=7.5Hz), 3.24 (1H, d, J=11.0Hz), 3.05 (1H, dt, J=12.1Hz, 8.0Hz), 2.58 (1H, d, J =2.4Hz), 2.06-1.97 (4H, m), 1.43-1.26 (22H, m)；δ_C(100MHz；CDCl₃)139.2,114.1,111.0, 107.1,81.1, 77.7,75.3,68.1,65.8,59.1,54.2,33.8,29.4,29.1,28.9,27.7,27.3,26.3, 25.9,24.8,24.0。

Intermediate III -14 (26.0mg, 0.07mmol) sloughs protecting group under hydrochloric acid effect, by column chromatography for separation, obtains To N- alkene nonyl-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-14) be faint yellow syrup, 16.2 milligrams, yield: 71%.δ_H(400MHz；D₂O) 5.95 (1H, ddt, J=17.1Hz, 10.3Hz, 6.7Hz), 5.11-5.00 (2H, m), 4.61- 4.54 (2H, m), 4.25 (1H, dd, J=10.3Hz, 5.1Hz), 3.92-3.83 (2H, m), 3.69 (1H, t, J=4.2 Hz), 3.59-3.58 (2H, m), 3.46-3.39 (1H, m), 3.17-3.10 (1H, m), 2.10 (2H, dd, J=13.4Hz, 6.5 Hz), 1.83-1.73(2H,m),1.54-1.29(8H,m)；δ_C(100MHz；D₂O)140.4,114.1,70.8,68.8,68.6, 67.3,62.6,55.4,54.6,33.0,28.0,25.6,24.3。

The preparation of embodiment 15, N- phenethyl -1,4- dideoxy -1,4- imini-D-mannitol (I-15).

Referring to the synthetic method in embodiment 8, with compound ii -1 (110.0mg, 0.45mmol) and 2- phenyl bromoethane (166.5mg, 0.90mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- Phenethyl -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -15) be white solid, 116.1 Milligram, yield 74%.Mp:86-87 DEG C；δ_H(400MHz；CDCl₃)7.30-7.26(2H,m),7.23-7.17(2H,m), 4.64-4.57 (2H, m), 4.47 (2H, td, J=7.3Hz, 1.4Hz), 4.06 (1H, t, J=7.8Hz), 3.93 (1H, t, J= 7.5Hz), 3.41-3.34 (2H, m), 2.80-2.77 (2H, m), 2.73 (1H, d, J=3.8Hz), 2.40-2.34 (1H, m), 2.23 (1H, dd, J=10.9Hz, 4.6Hz), 1.42 (3H, s), 1.41 (3H, s), 1.33 (3H, s), 1.29 (3H, s)；δ_C (100MHz； CDCl₃)140.6,128.8,128.2,125.9,111.1,107.1,81.0,77.7,75.2,67.4,65.6, 59.2,55.5,34.1, 26.3,25.9,24.8,23.9。

Intermediate III -15 (22.0mg, 0.06mmol) sloughs protecting group under hydrochloric acid effect, obtains N- phenethyl-Isosorbide-5-Nitrae - Dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-15) be faint yellow syrup, 17.5 milligrams, yield: 100%.δ_H (500MHz； D₂O)7.44-7.41(2H,m),7.37-7.36(3H,m),4.59-4.55(1H,m),4.53-4.52(1H,m), 4.22-4.21 (1H, m), 3.86 (1H, dd, J=11.8Hz, 6.8Hz), 3.79 (1H, dd, J=11.8Hz, 4.6Hz), 3.72-3.58(4H, m),3.41-3.55(1H,m),3.18-3.07(2H,m)；δ_C(125MHz；D₂O)136.0,129.1, 128.8,127.4,70.5, 69.3,68.6,67.0,62.5,55.4,55.3,30.7。

The preparation of embodiment 16, N- phenylpropyl -1,4- dideoxy -1,4- imini-D-mannitol (I-16).

Referring to the synthetic method in embodiment 8, with compound ii -1 (110.0mg, 0.45mmol) and the bromo- 3- phenyl third of 1- Alkane (179.2mg, 0.90mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- phenylpropyl -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -16) are colourless syrup, 117.7 milligrams, yield 72%.δ_H(400MHz；CDCl₃)7.28-7.25(2H,m),7.19-7.14(3H,m),4.60-4.56 (2H, m), 4.45 (2H, td, J=7.3Hz, 1.9Hz), 4.16 (1H, t, J=7.8Hz), 3.95 (1H, t, J=7.5Hz), 3.29 (1H, d, J=10.9Hz), 3.11 (1H, m, dt, J=12.2Hz, 8.4Hz), 2.75-2.68 (1H, m), 2.62-2.54 (2H,m), 2.13-2.06(2H,m),1.85-1.73(2H,m),1.45(3H,s),1.36(3H,s),1.32(3H,s),1.28 (3H,s)；δ_C(100MHz；CDCl₃)142.4,128.4,128.3,125.7,111.0,107.1,81.1,77.7,75.3, 68.1,65.8,59.1, 53.8,33.6,29.5,26.2,25.9,24.9,24.0。

Intermediate III -16 (30.0mg, 0.08mmol) sloughs protecting group under hydrochloric acid effect, obtains N- phenylpropyl-Isosorbide-5-Nitrae - Dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-16) be faint yellow syrup, 26.3 milligrams, yield: 100%.δ_H (400MHz； D₂O)7.43-7.39(2H,m),7.34-7.32(3H,m),4.52-4.49(2H,m),4.17-4.14(1H,m), 3.84-3.76 (2H,m),3.61(1H,s),3.57-3.48(2H,m),3.45-3.38(1H,m),3.41-3.55(1H,m), 2.82-2.69(2H, m),2.14-2.06(2H,m)；δ_C(100MHz；D₂O)140.5,128.9,128.5,126.6,70.7, 68.8,68.6,67.2, 62.5,55.4,53.7,31.7,26.0。

The preparation of embodiment 17, N- benzene butyl -1,4- dideoxy -1,4- imini-D-mannitol (I-17).

Referring to the synthetic method in embodiment 8, with compound ii -1 (190.0mg, 0.78mmol) and the bromo- 4- phenyl fourth of 1- Alkane (332.5mg, 1.56mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- benzene butyl -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -17) are colourless syrup, 225.8 milligrams, yield 77%.δ_H(400MHz；CDCl₃)7.29-7.25(2H,m),7.19-7.15(3H,m),4.59-4.55 (2H, m), 4.48 (2H, td, J=7.2Hz, 1.3Hz), 4.22 (1H, t, J=7.7Hz), 3.99 (1H, t, J=7.6Hz), 3.25 (1H, d, J=11.0Hz), 3.12 (1H, dt, J=12.2Hz, 8.4Hz), 2.69-2.58 (1H, m), 2.08-2.02 (2H,m), 1.77-1.47(4H,m),1.45-1.44(6H,m),1.33(3H,s),1.28(3H,s)；δ_C(100MHz；CDCl₃) 142.7, 128.4,128.3,125.6,111.0,107.1,81.1,77.7,75.3,68.1,65.7,59.1,54.0,35.8, 29.1,27.4,26.3, 25.9,24.8,23.9。

Intermediate III -17 (50.0mg, 0.13mmol) sloughs protecting group under hydrochloric acid effect, obtains N- benzene butyl-Isosorbide-5-Nitrae - Dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-17) be faint yellow syrup, 44.3 milligrams, yield: 99%.δ_H(400MHz； D₂O) 7.40-7.36 (2H, m), 7.31-7.26 (3H, m), 4.44 (2H, s), 4.12-4.11 (1H, m), 3.78 (2H, d, J= 5.2 Hz),3.42(1H,s),3.38-3.27(2H,m),3.22-3.20(1H,m),2.99-2.92(1H,m),2.68(2H, s),1.68 (4H,s)；δ_C(100MHz；D₂O)142.3,128.7,128.6,126.1,71.1,68.9,68.3,68.1,62.7, 55.4,54.7, 34.4,27.7,24.4。

The preparation of embodiment 18, N- benzene amyl -1,4- dideoxy -1,4- imini-D-mannitol (I-18).

Referring to the synthetic method in embodiment 8, with compound ii -1 (145.0mg, 0.60mmol) and the bromo- 5- phenyl penta of 1- Alkane (271.2mg, 1.20mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- benzene amyl -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -18) are colourless syrup, 169.5 milligrams, yield 73%.δ_H(400MHz；CDCl₃)7.27-7.24(2H,m),7.17-7.14(3H,m),4.59-4.54 (2H, m), 4.46 (2H, td, J=7.3Hz, 1.6Hz), 4.19 (1H, t, J=7.8Hz), 3.98 (1H, t, J=7.5Hz), 3.25 (1H, d, J=11.0Hz), 3.07 (1H, m, dt, J=11.7Hz, 8.1Hz), 2.62-2.58 (3H, m), 2.06-1.99 (2H,m), 1.68-1.58(2H,m),1.54-1.27(16H,m)；δ_C(100MHz；CDCl₃)142.8,128.4,128.2, 125.6, 111.0,107.1,81.1,77.7,75.2,68.0,65.7,59.1,54.1,36.0,31.5,27.6,27.1, 26.3,25.9,24.8, 24.0。

Intermediate III -18 (40.0mg, 0.10mmol) sloughs protecting group under hydrochloric acid effect, obtains N- benzene amyl-Isosorbide-5-Nitrae - Dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-18) be faint yellow syrup, 35.5 milligrams, yield: 100%.δ_H (500MHz； D₂O) 7.39-7.36 (2H, m), 7.31-7.26 (3H, m), 4.54-4.49 (2H, m), 4.19 (1H, dd, J= 10.5Hz, 5.0 Hz), 3.83 (2H, ddd, J=42.2Hz, 11.9Hz, 6.1Hz), 3.62 (1H, t, J=4.1Hz), 3.55- 3.47 (2H, m), 3.39-3.33 (1H, m), 3.08-3.02 (1H, m), 2.67 (2H, t, J=7.5Hz), 1.81-1.72 (2H, m),1.71-1.65(2H, m),1.45-1.33(2H,m)；δ_C(125MHz；D₂O)142.9,128.6,125.9,70.7,68.7, 68.6,67.2,62.5, 55.3,54.4,34.7,30.0,25.2,24.2。

The preparation of embodiment 19, N- benzene hexyl -1,4- dideoxy -1,4- imini-D-mannitol (I-19).

Referring to the synthetic method in embodiment 8, with compound ii -1 (110.0mg, 0.45mmol) and the bromo- 6- phenyl of 1- oneself Alkane (216.1mg, 0.90mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- benzene hexyl -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -19) are colourless syrup, 147.8 milligrams, yield 81%.δ_H(500MHz；CDCl₃)7.28-7.25(2H,m),7.18-7.15(3H,m),4.59-4.55 (2H, m), 4.46 (2H, td, J=7.3Hz, 1.3Hz), 4.19 (1H, t, J=7.8Hz), 3.98 (1H, t, J=7.5Hz), 3.25 (1H, d, J=11.0Hz), 3.07 (1H, dt, J=11.9Hz, 8.2Hz), 2.61-2.58 (3H, m), 2.06-1.99 (2H,m),1.64-1.56 (2H,m),1.48-1.27(18H,m)；δ_C(125MHz；CDCl₃)142.9,128.4,128.2, 125.5,112.0,107.1, 81.1,77.7,75.3,68.0,65.7,59.1,54.2,35.94,31.5,29.3,27.7, 27.3,26.3,25.9,24.8,24.0。

Intermediate III -19 (50.0mg, 0.12mmol) sloughs protecting group under hydrochloric acid effect, obtains N- benzene hexyl-Isosorbide-5-Nitrae - Dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-19) be faint yellow syrup, 44.5 milligrams, yield: 100%.δ_H (500MHz； D₂O) 7.39-7.36 (2H, m), 7.31-7.25 (3H, m), 4.55-4.50 (2H, m), 4.20 (1H, dd, J= 10.5Hz, 5.0 Hz), 3.87-3.80 (2H, m), 3.66 (1H, t, J=4.2Hz), 3.56-3.49 (2H, m), 3.39-3.34 (1H, m), 3.08-3.03 (1H, m), 2.67 (2H, t, J=7.5Hz), 1.76-1.71 (2H, m), 1.67-1.61 (2H, m), 1.45-1.33(2H, m)；δ_C(125MHz；D₂O)143.3,128.6,128.5,125.8,70.7,68.7,68.6,67.2, 62.5,55.3,54.4,34.8, 30.3,27.6,25.5,24.2。

The preparation of embodiment 20, N- benzene heptyl -1,4- dideoxy -1,4- imini-D-mannitol (I-20).

Referring to the synthetic method in embodiment 8, with compound ii -1 (150.0mg, 0.62mmol) and 1- bromo- 7- phenyl heptan Alkane (315.1mg, 1.24mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- Benzene heptyl -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -20) be colourless syrup, 177.6 Milligram, yield 69%.δ_H(400MHz；CDCl₃)7.29-7.25(2H,m),7.18-7.15(3H,m),4.59-4.55(2H, M), 4.46 (2H, td, J=7.2Hz, 1.2Hz), 4.20 (1H, t, J=7.7Hz), 3.98 (1H, t, J=7.5Hz), 3.25 (1H, d, J=11.0Hz), 3.06 (1H, dt, J=11.9Hz, 8.0Hz), 2.61-2.57 (3H, m), 2.06-1.97 (2H, m),1.66-1.57 (2H,m),1.44-1.27(20H,m)；δ_C(100MHz；CDCl₃)142.9,128.4,128.2,125.5, 111.0,107.1, 81.1,77.7,75.3,68.0,65.7,59.1,54.2,36.0,31.5,29.5,29.3,27.7, 27.3,26.3,25.9,24.9,24.0。

Intermediate III -20 (46.0mg, 0.11mmol) sloughs protecting group under hydrochloric acid effect, obtains N- benzene heptyl-Isosorbide-5-Nitrae - Dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-20) be faint yellow syrup, 41.1 milligrams, yield: 100%.δ_H (500MHz； D₂O) 7.37-7.34 (2H, m), 7.30-7.23 (3H, m), 4.53-4.50 (2H, m), 4.20 (1H, d, J= 4.9Hz), 3.87-3.80(2H,qm),3.62-3.61(1H,m),3.54-3.46(2H,m),3.38-3.32(1H,m), 3.07-3.01 (1H, m), 2.63 (2H, t, J=7.4Hz), 1.70 (2H, s), 1.65-1.59 (2H, m), 1.35-1.33 (6H, m)；δ_C(125MHz； D₂O)143.4,128.6,128.5,125.8,70.7,68.7,68.6,67.3,62.6,55.3,54.5, 34.9,30.5,27.9,25.6, 24.3。

The preparation of embodiment 21, N- benzene octyl -1,4- dideoxy -1,4- imini-D-mannitol (I-21).

It is pungent with compound ii -1 (130.0mg, 0.53mmol) and the bromo- 8- phenyl of 1- referring to the synthetic method in embodiment 8 Alkane (284.2mg, 1.06mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- benzene octyl -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -21) are colourless syrup, 140.7 milligrams, yield 61%.δ_H(500MHz；CDCl₃)7.28-7.25(2H,m),7.18-7.15(3H,m),4.59-4.55 (2H, m), 4.46 (2H, td, J=7.3Hz, 1.6Hz), 4.19 (1H, t, J=7.8Hz), 3.98 (1H, t, J=7.5Hz), 3.25 (1H, d, J=11.0Hz), 3.05 (1H, dt, J=12.3Hz, 8.4Hz), 2.61-2.58 (3H, m), 2.06-1.98 (2H,m),1.62-1.56 (2H,m),1.45-1.27(22H,m)；δ_C(125MHz；CDCl₃)142.9,128.4,128.2, 125.5,111.0,107.1, 81.1,77.7,75.3,68.0,65.7,59.1,54.2,36.0,31.5,29.5,29.5, 29.3,27.7,27.4,26.3,25.9,24.9, 24.0。

Intermediate III -21 (61.0mg, 0.11mmol) sloughs protecting group under hydrochloric acid effect, obtains N- benzene octyl-Isosorbide-5-Nitrae - Dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-21) be faint yellow syrup, 54.7 milligrams, yield: 100%.δ_H (500MHz； D₂O) 7.22-7.18 (2H, m), 7.13-7.08 (3H, m), 4.53-4.51 (2H, m), 4.18 (1H, dd, J= 9.7Hz,4.8Hz), 3.89-3.81(2H,m),3.59(1H,s),3.52-3.49(1H,m),3.41-3.37(1H,m), 3.32-3.37 (1H, m), 2.98-2.93 (1H, m), 2.51 (2H, t, J=7.5Hz), 1.64-1.63 (2H, m), 1.52 (2H, s),1.23(8H,m)； δ_C(125MHz；D₂O)143.0,128.4,128.3,125.6,70.6,69.0,68.6,67.3,62.6, 55.3,54.4,35.4, 31.1,28.8,28.6,28.5,26.0,24.5。

The preparation of embodiment 22, N- benzene nonyl -1,4- dideoxy -1,4- imini-D-mannitol (I-22).

Referring to the synthetic method in embodiment 8, with compound ii -1 (200.0mg, 0.82mmol) and the bromo- 9- phenyl nonyl of 1- Alkane (462.5mg, 1.64mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- benzene nonyl -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -22) are colourless syrup, 201.5 milligrams, yield 55%.δ_H(500MHz；CDCl₃)7.29-7.26(2H,m),7.18-7.15(3H,m),4.59-4.55 (2H, m), 4.46 (2H, td, J=7.3Hz, 1.5Hz), 4.20 (1H, t, J=7.7Hz), 3.99 (1H, t, J=7.5Hz), 3.25 (1H, d, J=11.1Hz), 3.06 (1H, dt, J=12.2Hz, 8.3Hz), 2.61-2.58 (3H, m), 2.06-1.98 (2H,m),1.63-1.56 (2H,m),1.44-1.28(24H,m)；δ_C(125MHz；CDCl₃)143.0,128.4,128.2, 125.5,111.0,107.1, 81.1,77.7,75.3,68.0,65.8,59.1,54.3,36.0,31.5,29.6,29.6, 29.5,27.7,27.4,26.3,25.9,24.9, 24.0。

Intermediate III -22 (62.0mg, 0.14mmol) sloughs protecting group under hydrochloric acid effect, obtains N- benzene octyl-Isosorbide-5-Nitrae - Dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-22) be faint yellow syrup, 55.9 milligrams, yield: 100%.δ_H (500MHz； D₂O) 7.13-7.10 (2H, m), 7.05-7.00 (3H, m), 4.51 (2H, s), 4.18 (1H, d, J=4.6Hz), 3.88-3.81 (2H,m),3.59(1H,s),3.51-3.48(1H,m),3.34-3.26(2H,m),2.95-2.93(1H,m), 2.45 (2H, t, J=7.5Hz), 1.64-1.58 (2H, m), 1.48 (2H, m), 1.19 (10H, m)；δ_C(125MHz；D₂O) 142.7,128.3, 128.2,125.6,70.6,69.1,68.6,67.3,62.6,55.4,54.4,35.7,31.3,29.2, 29.1,28.8,26.2,24.7。

The preparation of embodiment 23, N- hydroxypropyl -1,4- dideoxy -1,4- imini-D-mannitol (I-23).

Referring to the synthetic method in embodiment 8, with compound ii -1 (200.0mg, 0.82mmol) and (3- bromine propoxyl group) - T-butyldimethyl silane (415.3mg, 1.64mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- tertiary butyl dimethyl Si base propyl -2,3:5,6- diacetone -1,4- dideoxy -1,4- imino group - D-mannital (III -23) be faint yellow syrup, 204.5 milligrams, yield 57%.δ_H(400MHz；CDCl₃)4.59-4.55 (2H, m), 4.43 (1H, td, J=7.3Hz, 1.9Hz), 4.13 (1H, t, J=7.8Hz), 3.98 (1H, t, J=7.4Hz), 3.73-3.60 (2H, m), 3.24 (1H, d, J=11.0Hz), 3.278 (1H, dt, J=12.3Hz, 8.2Hz), 2.58 (1H, d, ), J=1.5Hz 2.11-2.05 (2H, m), 1.71-1.65 (2H, m), 1.42 (6H, s), 1.32 (3H, s), 1.27 (3H, s), 0.88 (9H,s),0.04(6H,s)；δ_C(100MHz；CDCl₃)110.0,107.1,81.2,77.6,75.3,68.1,65.9, 61.6,59.3, 50.8,31.0,26.4,26.0,25.87,24.9,24.1,18.4,-5.3。

Intermediate III -23 (60.0mg, 0.14mmol) sloughs protecting group under hydrochloric acid effect, obtains N- hydroxypropyl-Isosorbide-5-Nitrae - Dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-23) be faint yellow solid, 37.1 milligrams, yield: 99%.Mp:78-80 ℃； δ_H(400MHz；D₂O) 44.63-4.55 (2H, m), 4.26 (1H, dd, J=10.4Hz, 4.8Hz), 3.93-3.84 (2H, m), 3.82-3.71(3H,m),3.63-3.54(3H,m),3.30-3.23(1H,m),2.12-1.96(2H,m)；δ_C (100MHz； D₂O)70.8,69.1,68.65,67.3,62.6,56.2,55.6,52.6,26.9。

The preparation of embodiment 24, N- hydroxyl butyl -1,4- dideoxy -1,4- imini-D-mannitol (I-24).

Referring to the synthetic method in embodiment 8, with compound ii -1 (80.0mg, 0.33mmol) and (4- bromine butoxy) - T-butyldimethyl silane (176.4mg, 0.66mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- tertiary butyl dimethyl Si base butyl -2,3:5,6- diacetone -1,4- dideoxy -1,4- imino group - D-mannital (III -24) be faint yellow syrup, 108.8 milligrams, yield 77%.δ_H(400MHz；CDCl₃)4.59-4.54 (2H, m), 4.45 (1H, td, J=7.2Hz, 1.2Hz), 4.18 (1H, t, J=7.8Hz), 3.98 (1H, t, J=7.6Hz), 3.61 (2H, t, J=5.2Hz), 3.25 (1H, d, J=11.0Hz), 3.06 (1H, dt, J=12.1Hz, 7.4Hz), 2.60 (1H, d, J=2.4 Hz), 2.08-2.02 (2H, m), 1.61-1.46 (4H, m), 1.43 (6H, s), 1.32 (3H, s), 1.27 (3H,s),0.88(9H,s), 0.04(6H,s)；δ_C(100MHz；CDCl₃)110.0,107.1,81.1,77.7,75.3,68.0, 65.7,63.2,59.1,54.1, 30.7,26.3,26.0,25.9,24.9,24.1,24.0,18.4,-5.2,-5.3。

Intermediate III -24 (18.0mg, 0.04mmol) sloughs protecting group under hydrochloric acid effect, obtains N- hydroxyl butyl-Isosorbide-5-Nitrae - Dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-24) be faint yellow syrup, 11.4 milligrams, yield: 100%.δ_H (400MHz； D₂O) 4.57-4.50 (2H, m), 4.22 (1H, dd, J=10.0Hz, 4.9Hz), 3.89-3.79 (2H, m), 3.68-3.60 (3H, m), 3.56 (2H, d, J=7.4Hz), 3.47-3.40 (1H, m), 3.17-3.10 (1H, m), 1.88- 1.74(2H,m), 1.66-1.59(2H,m)；δ_C(100MHz；D₂O)70.7,68.8,68.6,67.2,62.5,60.8,55.3, 54.2,28.4,21.4。

The preparation of embodiment 25, N- hydroxyl amyl -1,4- dideoxy -1,4- imini-D-mannitol (I-25).

Referring to the synthetic method in embodiment 8, with compound ii -1 (200.0mg, 0.82mmol) and (5- bromine amoxy) - T-butyldimethyl silane (461.3mg, 1.64mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- tertiary butyl dimethyl Si base amyl -2,3:5,6- diacetone -1,4- dideoxy -1,4- imino group - D-mannital (III -25) be faint yellow syrup, 240.6 milligrams, yield 66%.δ_H(400MHz；CDCl₃)4.59-4.54 (2H, m), 4.45 (1H, td, J=7.3Hz, 1.4Hz), 4.18 (1H, t, J=7.7Hz), 3.98 (1H, t, J=7.5Hz), 3.59 (2H, t, J=6.5Hz), 3.25 (1H, d, J=11.0Hz), 3.06 (1H, dt, J=11.8Hz, 8.1Hz), 2.59 (1H, d, J=2.7 Hz), 2.07-1.99 (2H, m), 1.56-1.27 (18H, m), 0.88 (9H, s), 0.03 (6H, s) δ_C (100MHz；CDCl₃) 111.1,107.1,81.1,77.7,75.3,68.0,65.8,63.2,54.3,32.9,27.6,26.3, 26.0,25.9,24.9,24.0, 23.8,18.3,-5.3。

Intermediate III -25 (60.0mg, 0.14mmol) sloughs protecting group under hydrochloric acid effect, obtains N- hydroxyl amyl-Isosorbide-5-Nitrae - Dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-25) be faint yellow syrup, 38.6 milligrams, yield: 100%.δ_H (500MHz； D₂O) 4.56-4.52 (1H, m), 4.50 (1H, t, J=4.0Hz), 4.23-4.20 (1H, m), 3.87-3.79 (2H, m), 3.66 (1H, t, J=4.0Hz), 3.60 (2H, t, J=6.5Hz), 3.55 (2H, d, J=7.5Hz), 3.44-3.38 (1H,m),3.13-3.08 (1H,m),1.84-1.71(2H,m),1.61-1.56(2H,m),1.48-1.35(2H,m)；δ_C (125MHz；D₂O)70.7, 68.8,68.6,67.2,62.5,61.2,55.3,54.3,30.6,24.1,22.2。

The preparation of embodiment 26, N- hydroxyl hexyl -1,4- dideoxy -1,4- imini-D-mannitol (I-26).

Referring to the synthetic method in embodiment 8, with compound ii -1 (200.0mg, 0.82mmol) and (6- bromine hexyloxy) - T-butyldimethyl silane (484.4mg, 1.64mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- tertiary butyl dimethyl Si base hexyl -2,3:5,6- diacetone -1,4- dideoxy -1,4- imino group - D-mannital (III -26) be faint yellow syrup, 259.5 milligrams, yield 69%.δ_H(500MHz；CDCl₃)；4.59-4.54 (2H, m), 4.45 (1H, td, J=7.3Hz, 1.4Hz), 4.18 (1H, t, J=7.8Hz), 3.98 (1H, t, J=7.5Hz), 3.58 (2H, t, J=6.7Hz), 3.25 (1H, d, J=11.0Hz), 3.05 (1H, dt, J=12.0Hz, 8.1Hz), 2.59 (1H, d, J=2.8Hz), 2.06-1.99 (2H, m), 1.53-1.48 (2H, m), 1.43-1.27 (18H, m), 0.89 (9H, s), 0.04(6H,s)； δ_C(125MHz；CDCl₃)111.0,107.1,81.1,77.7,75.3,68.0,65.7,63.3,59.1, 54.2,32.9,27.7, 26.3,26.3,26.0,25.9,25.8,24.8,24.0,18.4,-5.3。

Intermediate III -26 (60.0mg, 0.13mmol) sloughs protecting group under hydrochloric acid effect, obtains N- hydroxyl hexyl-Isosorbide-5-Nitrae - Dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-26) be faint yellow syrup, 39.2 milligrams, yield: 100%.δ_H (500MHz； D₂O) 4.57-4.50 (2H, m), 4.22 (1H, dd, J=10.3Hz, 5.4Hz), 3.88-3.80 (2H, m), 3.67 (1H, t, J=4.0Hz), 3.60 (2H, t, J=6.5Hz), 3.56 (2H, d, J=7.5Hz), 3.44-3.38 (1H, m), 3.14-3.08(1H,m), 1.77(2H,m),1.57-1.55(2H,m),1.40-1.40(4H,m)；δ_C(125MHz；D₂O) 70.7,68.7,68.6,67.2, 62.5,61.5,55.3,54.4,30.9,24.4,24.5,24.2。

The preparation of embodiment 27, N- hydroxyl heptyl -1,4- dideoxy -1,4- imini-D-mannitol (I-27).

Referring to the synthetic method in embodiment 8, with compound ii -1 (130.0mg, 0.53mmol) and (7- bromine oxygroup in heptan) - T-butyldimethyl silane (327.9mg, 1.06mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- tertiary butyl dimethyl Si base heptyl -2,3:5,6- diacetone -1,4- dideoxy -1,4- imino group - D-mannital (III -27) be faint yellow syrup, 143.6 milligrams, yield 57%.δ_H(400MHz；CDCl₃)4.58-4.53 (2H, m), 4.45 (1H, td, J=7.2Hz, 1.5Hz), 4.18 (1H, t, J=7.8Hz), 3.98 (1H, t, J=7.5Hz), 3.58 (1H, t, J=6.6Hz), 3.24 (1H, d, J=11.0Hz), 3.08-3.01 (1H, m), 2.58 (1H, d, J= 2.6Hz), 2.05-1.98(2H,m),1.50-1.42(10H,m),1.34-1.23(12H,m),0.88(9H,s),0.04(6H, s)；δ_C(100 MHz；CDCl₃)111.0,107.1,81.1,77.7,75.3,68.0,65.7,63.3,59.1,54.2,32.9, 29.4,27.7, 27.4,26.3,26.0,25.9,25.8,24.9,24.0,18.4,-5.3。

Intermediate III -27 (70.0mg, 0.15mmol) sloughs protecting group under hydrochloric acid effect, obtains N- hydroxyl heptyl-Isosorbide-5-Nitrae - Dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-27) be faint yellow syrup, 46.5 milligrams, yield: 100%.δ_H (400MHz； CDCl₃) 4.57-4.50 (2H, m), 4.21 (1H, dd, J=10.0Hz, 5.0Hz), 3.87-3.79 (2H, m), 3.66 (1H, t, J=3.8Hz), 3.60-3.54 (4H, m), 3.43-3.35 (1H, m), 3.13-3.06 (1H, m), 1.75 (2H, m),1.55-1.52 (2H,m),1.34(6H,m)；δ_C(100MHz；CDCl₃)70.7,68.8,68.6,67.3,62.6,61.7, 55.4,54.5,31.1. 27.9,25.6,24.7,24.3。

The preparation of embodiment 28, N- hydroxyl octyl -1,4- dideoxy -1,4- imini-D-mannitol (I-28).

Referring to the synthetic method in embodiment 8, with compound ii -1 (100.0mg, 0.41mmol) and (8- bromine octyloxy) - T-butyldimethyl silane (265.2mg, 0.82mmol) is raw material, and nucleophilic substitution occurs under potassium carbonate effect and obtains N- alkylated intermediate N- tertiary butyl dimethyl Si Ji Xinji -2,3:5,6- diacetone -1,4- dideoxy -1,4- imino group - D-mannital (III -28) be faint yellow syrup, 133.7 milligrams, yield 47%.δ_H(500MHz；CDCl₃)4.59-4.54 (2H, m), 4.45 (1H, td, J=7.3Hz, 1.5Hz), 4.18 (1H, t, J=7.8Hz), 3.98 (1H, t, J=7.5Hz), 3.58 (1H, t, J=6.7Hz), 3.24 (1H, d, J=11.1Hz), 3.05 (1H, dt, J=12.2Hz, 8.3Hz), 2.59 (1H, d, J=2.8Hz), 2.06-1.98 (2H, m), 1.51-1.43 (10H, m), 1.32-1.27 (14H, m), 0.88 (9H, s),0.04(6H, s)；δ_C(125MHz；CDCl₃)111.0,107.1,81.1,77.7,75.3,68.0,65.8,63.3,59.1, 54.3,32.9,29.6, 29.5,27.7,27.4,26.3,26.0,25.9,25.8,24.9,24.0,18.4,-5.2。

Intermediate III -28 (50.0mg, 0.10mmol) sloughs protecting group under hydrochloric acid effect, obtains N- hydroxyl octyl-Isosorbide-5-Nitrae - Dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (I-28) be faint yellow syrup, 33.7 milligrams, yield: 100%.δ_H (500MHz； CDCl₃) 4.57-4.50 (2H, m), 4.22 (1H, dd, J=10.5Hz, 5.0Hz), 3.88-3.80 (2H, m), 3.66 (1H, t, J=4.2Hz), 3.59 (2H, m), 3.55 (2H, m), 3.43-3.35 (1H, m), 3.13-3.07 (1H, m), 1.79-1.69(2H,m), 1.55-1.53(2H,m),1.36-1.33(8H,m)；δ_C(125MHz；CDCl₃)70.7,68.7, 68.6,67.3,62.5,61.8, 55.3,54.5,31.1,28.1,28.0,25.6,24.8,24.5。

The preparation of embodiment 29, N- hydroxyl nonyl -1,4- dideoxy -1,4- imini-D-mannitol (I-29).

It is prepared as follows:

Compound III -16 (130.0mg, 0.35mmol) is dissolved in the dry tetrahydrofuran of 15mL, in argon atmosphere, The tetrahydrofuran solution (0.39mL, 0.39mmol) of borine is added, reacts three hours at room temperature, it is molten that sodium hydroxide is added dropwise Liquid to reaction system is alkalinity, is added hydrogen peroxide (0.43mL, 4.24mmol), the reaction was continued a hour, and the sulphur of saturation is added Sodium thiosulfate solution quenching reaction, it is neutrality that salt acid for adjusting pH value, which is added, and organic solvent is removed under reduced pressure, and 50mL water is added, uses second Acetoacetic ester is extracted (50mL × 3) three times, is collected concentration organic phase through column chromatography for separation and is obtained intermediate N hydroxyl nonyl- 2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (III -29) are colourless syrup, 97.3 milligrams, are received Rate 64%.δ_H(400MHz；CDCl₃) 4.59-4.54 (2H, m), 4.46 (1H, td, J=7.3Hz, 1.6Hz), 4.19 (1H, t, J =7.7Hz), 3.97 (1H, t, J=7.6Hz), 3.62 (1H, t, J=6.6Hz), 3.24 (1H, d, J=11.0 Hz), 3.05 (1H, dt, J=11.9Hz, 8.1Hz), 2.58 (1H, d, J=2.7Hz), 2.06-1.97 (2H, m), 1.58-1.50 (2H, m), 1.43-1.27(24H,m)；δ_C(100MHz；CDCl₃),111.0,107.1,81.1,77.7,75.3,68.0,65.7, 63.0, 59.1,54.2,32.8,29.5,29.4,29.3,27.7,27.7,26.3,25.9,25.7,24.8,24.0。

Intermediate III -29 (35.0mg, 0.09mmol) is dissolved in 10mL methanol, 1mL 6N hydrochloric acid is added, at room temperature It is stirred to react 1 hour, stops reaction, decompression boils off solvent, it is sweet to obtain N- hydroxyl nonyl-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imino group-D- Reveal sugar alcohol (I-29) be white solid, 30.7 milligrams, yield: 99%.Mp:75-76℃；δ_H(500MHz；CDCl₃) 4.57- 4.51 (2H, m), 4.22 (1H, dd, J=10.4Hz, 5.0Hz), 3.88-3.81 (2H, m), 3.67 (1H, t, J=4.2 Hz), 3.60 (2H, t, J=6.5Hz), 3.55 (2H, d, J=7.5Hz), 3.43-3.37 (1H, m), 3.13-3.07 (1H, m), 1.79-1.69(2H,m),1.56-1.53(2H,m),1.41-1.33(10H,m)；δ_C(125MHz；CDCl₃),77.7,68.7, 68.6,67.3,62.5,61.8,55.3,54.5,31.2,28.3,28.3,28.0,25.6,24.9,24.3。

Comparative example 1, N- methyl-1, the preparation of 4- dideoxy -1,4- imini-D-mannitol (D-1).

It is specific the preparation method is as follows:

Referring to the method for embodiment 1, compound ii -1 (100mg, 0.41mmol) is dissolved in 15mL methanol, first is added 10mg palladium carbon (10%) is added in aldehyde aqueous solution (0.11mL, 1.23mmol) under argon atmosphere, and displacement argon gas is hydrogen, in hydrogen It during atmosphere is enclosed, is stirred overnight at room temperature, TLC shows fully reacting, stops reaction, is filtered to remove palladium carbon, filtrate is concentrated, through column Chromatography, obtains N- methyl -2,3:5, and 6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (DD-1) is Faint yellow syrup, 95.9mg, yield: 91%.δ_H(400MHz；CDCl₃) 4.61-4.55 (2H, m), 4.44 (1H, td, J= 7.3Hz, 2.0Hz), 4.15 (1H, t, J=7.7Hz), 4.02 (1H, t, J=7.4Hz), 3.16 (1H, d, J=11.2 Hz), 2.39 (1H, s), 2.33 (3H, s), 2.17 (1H, dd, J=11.2Hz, 4.2Hz), 1.46 (3H, s), 1.45 (3H, s), 1.34 (3H,s),1.28(3H,s)；δ_C(100MHz；CDCl₃)110.9,107.2,81.3,77.7,75.0.,70.0,65.9,62.5, 41.6,26.3,25.7,24.4,24.2。

Intermediate DD-1 (16.0mg, 0.06mmol) is dissolved in 10mL methanol, 1mL 6N hydrochloric acid is added, at room temperature It is stirred to react 1 hour, stops reaction, decompression boils off solvent, obtains N- methyl-1,4- dideoxy-Isosorbide-5-Nitrae-imino group-D- sweet dew Sugar alcohol is 13.3 milligrams of faint yellow syrup (D-1), yield: 100%；δ_H(400MHz；CDCl₃)4.62-4.55(2H, m),4.24 (1H, dd, J=10.4Hz, 4.8Hz), 3.90-3.81 (2H, m), 3.66-3.61 (2H, m), 3.50 (1H, dd, J= 12.4Hz,8.4Hz),3.00(3H,s)；δ_C(100MHz；CDCl₃)70.9,69.7,68.5,67.0,62.5,58.4,39.9。

The preparation of comparative example 2, N- butyl -1,4- dideoxy -1,4- imini-D-mannitol (D-2).

Referring to the synthetic method in embodiment 1, with compound ii -1 (50mg, 0.21mmol) and butyraldehyde (45.4mg, 0.63 Mmol it is) raw material, obtains intermediate N butyl -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol It (DD-2) is colourless syrup, 51.1mg, yield: 87%.δ_H(400MHz；CDCl₃)4.59-4.54(2H,m),4.46(1H, t,J =7.2Hz), 4.20 (1H, t, J=7.6Hz), 3.98 (1H, t, J=7.6Hz), 3.25 (1H, d, J=10.8Hz), 3.11- 3.04 (H, m), 2.59 (1H, d, J=2.0Hz), 2.06-1.98 (2H, m), 1.43-1.27 (16H, m), 0.90 (3H, t, J= 7.2Hz)；δ_C(100MHz；CDCl₃)111.0,107.1,81.1,77.7,75.3,68.1,65.7,59.1,54.0,30.0, 26.3,25.9,24.9,24.0,20.6,14.1。

Intermediate DD-2 (16.0mg, 0.05mmol) sloughs protecting group under hydrochloric acid effect, and it is de- to obtain N- butyl-Isosorbide-5-Nitrae-two Oxygen-Isosorbide-5-Nitrae-imini-D-mannitol (D-2) be faint yellow syrup, 13.6 milligrams, yield: 99%；δ_H(400MHz；CDCl₃) 4.62-4.55 (2H, m), 4.24 (1H, dd, J=10.4Hz, 4.8Hz), 3.90-3.81 (2H, m), 3.66-3.61 (2H, m), 3.50 (1H, dd, J=12.4Hz, 8.4Hz), 3.00 (3H, s)；δ_C(100MHz；CDCl₃)70.9,69.7,68.5,67.0, 62.5,58.4,39.9。

The preparation of comparative example 3, N- benzyl -1,4- dideoxy -1,4- imini-D-mannitol (D-3).

Referring to the synthetic method in embodiment 8, with compound ii -1 (100mg, 0.41mmol) and cylite (60 μ L, 0.49mmol) it is raw material, acts on lower generation nucleophilic substitution at sodium hydride (33mg, 0.82mmol), obtain intermediate N benzene Methyl -2,3:5,6- diacetone-Isosorbide-5-Nitrae-dideoxy-Isosorbide-5-Nitrae-imini-D-mannitol (DD-3) be colourless syrup, 107.9mg, Yield: 79%.δ_H(500MHz；CDCl₃) 7.35 (2H, d, J=7.2Hz), 7.32-7.29 (2H, m), 7.22 (1H, t, J= 7.2Hz), 4.62-4.53 (3H, m), 4.46-4.42 (2H, m), 4.07 (1H, t, J=7.6Hz), 3.14 (1H, d, J=13.6 ), Hz 3.04 (1H, d, J=11.3Hz), 2.83 (1H, d, J=4.65Hz), 2.05 (1H, dd, J=11.3Hz, 4.6Hz), 1.46 (3H,s),1.43(3H,s),1.36(3H,s),1.26(3H,s)；δ_C(125MHz；CDCl₃)138.7,128.7, 128.2, 126.8,111.1,107.3,81.0,77.6,75.4,67.0,65.8,59.1,58.2,26.3,24.7,23.8。

Intermediate DD-3 (13.0mg, 0.04mmol) sloughs protecting group under hydrochloric acid effect, obtains N- benzyl-Isosorbide-5-Nitrae-two Deoxidation-Isosorbide-5-Nitrae-imini-D-mannitol (D-3) be faint yellow syrup, 11.3 milligrams, yield: 100%；δ_H((400MHz； D₂O) 7.58-7.51 (5H, m), 4.61 (1H, d, J=13.0Hz), 3.96 (1H, dd, J=10.0Hz, 4.8Hz), 3.89- 3.78 (3H, m), 3.64 (1H, dd, J=12Hz, 7.2Hz), 3.38 (1H, dd, J=12Hz, 7.2Hz)；δ_C(100 MHz；D₂O) 131.0,130.4,129.4,129.0,70.9,68.5,68.4,67.7,62.6,58.3,55.21。

The preparation of comparative example 4N- ethoxy -1,4- dideoxy -1,4- imini-D-mannitol (D-4).

With compound ii -1 (60.0mg, 0.25mmol) and (2- bromine oxethyl)-t-butyldimethyl silane (119.1mg, It is 0.50mmol) raw material, nucleophilic substitution occurs under the action of potassium carbonate (103.7mg, 0.75mmol), obtains centre Body N- tertiary butyl dimethyl Si base ethyl -2,3:5,6- diacetone -1,4- dideoxy -1,4- imini-D-mannitol It (DD-4) is faint yellow syrup, 52.4 milligrams, yield 55%.δ_H(400MHz；CDCl₃)4.59-4.52(2H,m),4.46(1H, Td, J=7.2Hz, 1.1Hz), 4.22 (1H, t, J=7.8Hz), 3.97 (1H, t, J=7.5Hz), 3.75-3.66 (2H, m), 3.34 (1H, d, J=11.3Hz), 3.278 (1H, dt, J=12.8Hz, 6.2Hz), 2.71 (1H, d, J=1.7Hz), 2.25- 2.19 (2H,m),1.43(6H,s),1.32(3H,s),1.26(3H,s),0.88(9H,s),0.04(6H,s)；δ_C(100MHz； CDCl₃)111.0,107.1,80.7,78.0,75.3,67.7,65.7,62.1,60.5,56.1,26.2,25.9,25.8, 24.7,24.0, 18.2,-5.5。

Intermediate DD-4 (30.mg, 0.07mmol) sloughs protecting group under hydrochloric acid effect, obtains N- ethoxy-Isosorbide-5-Nitrae-two Deoxidation-Isosorbide-5-Nitrae-imini-D-mannitol (D-4) be faint yellow syrup, 18.2 milligrams, yield: 99%.δ_H(400MHz；D₂O) 4.59-4.55 (2H, m), 4.26 (1H, d, J=4.4Hz), 3.96-3.81 (5H, m), 3.66-3.59 (3H, m), 3.35-3.32 (1H, m)；δ_C(100MHz；D₂O)70.4,69.4,68.7,67.1,62.5,56.3,56.1,55.7。

Test case

The preparation-obtained compound of above-described embodiment 1-29 and comparative example 1-4, spherosin and DIM are subjected to sugar The evaluation of glycosides enzyme inhibitory effect

1) test material and source

Sample: the compound that compound (I-1)-(I-29), the comparative example 1-4 that embodiment 1-29 is prepared are prepared (D-1)-(D-4), DIM and spherosin.

Test material: all 4- nitrophenols pyranoside matrix, disaccharides and glycosidase (including alpha-glucosidase, β-Portugal Polyglycoside enzyme, alpha-galactosidase, beta galactosidase, alpha-Mannosidase, beta-Mannosidase, alpha-L-fucosidase, Mycoside enzyme, amyloglucosidase, alpha-L-Rhamnosidase and beta-glucuronidase enzyme) it is purchased from Sigma- Aldrich。

2) test method

Dynamics research carries out in 37 DEG C of 50mM sodium citrate/phosphate buffer.According to the difference of matrix, prepare Enzyme concentration be 0.1-0.5mg/mL.Active testing is using 4- nitrophenols pyranoside as matrix, in the optimum activity PH of every kind of enzyme Under tested.Matrix, appropriate diluted enzyme solutions and inhibitor (N- is alkylated polyhydroxy pyrrole) are cultivated at 37 DEG C 30 minutes, then starts reaction in ultraviolet-uisible spectrophotometer, measure its absorption to 400nm wavelength light.Finally use GraFit program carries out data analysis [Leatherbarrow, R.J.Grafit 4.0；Erithacus Software: Staines,UK,1998.]。

3) evaluation result

The compounds of this invention (I-1)-(I-29), compound (D-1)-(D-4), DIM and spherosin are to glycosidase The results are shown in Table 1 for inhibitory activity.

Wherein, IC₅₀(half maximal inhibitory concentration) refers to the half of measured antagonist Inhibition concentration.It can indicate a certain drug or substance (inhibitor) inhibit certain biological process (or comprising in this journey Cucumber in sequence, such as enzyme, cell receptor or microorganism) half amount.In terms of apoptosis, it can be understood as certain dense Certain drug-induced apoptosis of tumor cells 50% of degree, the concentration are known as 50% inhibition concentration, i.e. apoptotic cell and whole cells The ratio between number is equal to concentration corresponding when 50%, IC₅₀Value can be used to measure the ability of drug-induced apoptosis, i.e. inducibility Stronger, the numerical value is lower, naturally it is also possible to tolerance degree of certain cell of reverse instruction to drug.

Table 1

^aThe source of enzyme；^b-- %: the inhibiting rate under 1000 μM of concentration.

1 (Continued) of table

It is certain that evaluation result shows that N- alkylation polyhydroxy pyrrole class compound provided by the present invention is shown Glycosidase inhibiting function.Wherein formula (I-1), (I-2), (I-4), (I-8), compound shows high selection shown in (I-25) Property α-mannoside enzyme inhibition activity, wherein formula (I-2), (I-8), compound has alpha-Mannosidase shown in (I-25) Higher inhibitory activity；Compound shown in formula (I-6), (I-13) and (I-14) shows to inhibit β-gala with high selectivity The activity of glycosidase；Compound shown in formula (I-21) and (I-22) inhibits IC when beta galactosidase₅₀Value is respectively 26.7 μM With 26.6 μM, both show to there is stronger inhibiting effect to beta galactosidase；Compound shown in formula (I-29) shows height Selectively inhibit the activity of beta-glucuronidase enzyme.

At the same time, for beta galactosidase, compared with DIM, formula (I-5)-(I-7), (I-13)-(I- 14), (I-17)-(I-22), compound shown in (I-28) have higher inhibitory activity to beta galactosidase.

The preferred embodiment of the present invention has been described above in detail, and still, the present invention is not limited thereto.In skill of the invention In art conception range, can with various simple variants of the technical solution of the present invention are made, including each technical characteristic with it is any its Its suitable method is combined, and it should also be regarded as the disclosure of the present invention for these simple variants and combination, is belonged to Protection scope of the present invention.

Claims

1. a kind of compound, which has structure shown in formula (I):

Wherein, R is hydrogen, aryl, hydroxyl, halogen atom, vinyl, acetenyl, alkoxy, carboxyl, ester group, nitro, amino and cyanogen Any one in base, n=1-20；And the spatial configuration of 2,3,4,6 carbon is respectively 2R, 3S, 4R, 6S, wherein when R is hydrogen, N is not 1 and 4；When R is hydroxyl, n is not 2；When R is phenyl, n is not 1.

2. compound according to claim 1, wherein R is hydrogen, vinyl, acetenyl, aryl, hydroxyl, alkoxy and ammonia Any one in base；

Preferably, R is any one in hydrogen, vinyl, aryl and hydroxyl；

It is highly preferred that the aryl is phenyl, indol-3-yl, pyrroles -2- base, furans -2- base, thiophene -2- base, part or complete The phenyl that portion replaces, wherein the substituent group in the phenyl partly or entirely replaced is indol-3-yl, pyrroles -2- base, furan It mutters -2- base, thiophene -2- base, fluorine, chlorine, bromine, iodine, hydroxyl, methoxyl group, nitro, carboxyl, cyano, amino, N, N- dimethylamino, Phenyl, cyclohexyl, tert-butyl, C_1-4Straight chained alkyl, C_1-4Straight chain alkylamino, C_1-4At least one of straight chain alkoxy carbonyl group；

It is further preferred that the phenyl that the aryl is phenyl, partly or entirely replaces, wherein described partly or entirely to take Substituent group in the phenyl in generation be fluorine, chlorine, bromine, iodine, hydroxyl, methoxyl group, nitro, carboxyl, cyano, amino, phenyl, cyclohexyl, Tert-butyl, C_1-4At least one of straight chained alkyl.

3. compound according to claim 1 or 2, wherein the halogen atom is fluorine, chlorine, bromine, iodine；The alkoxy is Methoxyl group, ethyoxyl, propoxyl group, butoxy, tert-butoxy, benzyloxy.

4. compound described in any one of -3 according to claim 1, wherein the compound is following formula (I-1) to formula (I-29) any in compound shown in:

5. the preparation method of compound described in any one of claim 1-4, includes the following steps:

(1) preparation of intermediate (III)

In the presence of catalyst and reducing agent, in solvent and inert gas atmosphere, by compound and formula shown in formula (II -1) After the mixing of compound shown in (II -2), carries out reductive amination process and obtain intermediate (III)；

(2) preparation of formula (I) compound

In a solvent, under acid effect, intermediate (III) carries out the reaction of deprotection base, obtains compound described in formula (I),

6. preparation method according to claim 5, wherein reductive amination process temperature be -40 DEG C to 80 DEG C, preferably 0 DEG C to 30 DEG C；Deprotection base reaction temperature is -40 DEG C to 80 DEG C, preferably 10 DEG C to 30 DEG C；

Reductive amination process used catalyst is Rany- nickel, palladium content is 0.5%-30% palladium carbon and PtO₂At least one of； Reducing agent is at least one of hydrogen, sodium borohydride, sodium cyanoborohydride, lithium borohydride, triacetyl oxygen sodium borohydride.

7. the preparation method of compound described in any one of claim 1-4, includes the following steps:

(A) preparation of intermediate (III)

In a solvent, under alkali effect, after compound shown in formula (II -1) is mixed with halides shown in (II -3), nucleophilic is carried out Substitution reaction obtains intermediate (III)；

Wherein, X is chlorine, bromine, iodine；

(B) preparation of formula (I) compound

8. preparation method according to claim 7, wherein nucleophilic substitution temperature is -40 DEG C to 100 DEG C, preferably 30 DEG C to 80 DEG C；Deprotection base reaction temperature is -40 DEG C to 80 DEG C, preferably 10 DEG C to 30 DEG C；The alkali be organic base and/ Or inorganic base；Preferably, the organic base be diethylamine, triethylamine, diisopropylamine, diisopropyl ethyl amine, pyridine and 2, At least one of 4,6- trimethylpyridine；The inorganic base is sodium carbonate, sodium bicarbonate, potassium carbonate, saleratus, hydroxide At least one of sodium, potassium hydroxide and sodium hydride；

The solvent is methylene chloride, chloroform, tetrahydrofuran, ether, ethyl acetate, water, dioxane, methanol, ethyl alcohol, second At least one of nitrile, formamide and N,N-dimethylformamide；Preferably, solvent is methanol；The acid is inorganic acid, organic At least one of acid and lewis acid, it is preferable that the inorganic acid is at least one of hydrochloric acid, hydrofluoric acid and sulfuric acid；Institute Stating organic acid is at least one of acetic acid, p-methyl benzenesulfonic acid, methanesulfonic acid and trifluoroacetic acid；The lewis acid is four chlorinations At least one of titanium, stannic chloride, bismuth trichloride and zinc bromide.

9. compound or its salt described in any one of claim 1-4 or its hydrate press down as the glycosidase of active constituent Preparation, wherein the glycosidase is alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta galactosidase, α- Mannosidase, beta-Mannosidase, α-L- glycosides fucosidase, mycoside enzyme, amyloglucosidase, α-L- rhamnose Glycosides enzyme or beta-glucuronidase enzyme.

10. compound and its salt described in any one of claim 1-4 or its hydrate are preparing medicine as active constituent Application in object, wherein the drug is used at least one of prevent and/or treat following diseases relevant to glycosidase: 1) diabetes；2) gaucher's disease；3) tumour；4) virus infection, the glycosidase be alpha-glucosidase, beta-glucosidase, Alpha-galactosidase, beta galactosidase, alpha-Mannosidase, beta-Mannosidase, alpha-L-fucosidase, mycoside Enzyme, amyloglucosidase, alpha-L-Rhamnosidase or beta-glucuronidase enzyme.