CN110128315B

CN110128315B - Compound, preparation method and application thereof, and glycosidase inhibitor

Info

Publication number: CN110128315B
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: 2021-08-20
Anticipated expiration: 2039-04-02
Also published as: CN110128315A

Abstract

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

Description

Compound, preparation method and application thereof, and glycosidase inhibitor

Technical Field

The invention relates to the field of glycometabolism, in particular to an N-alkylated polyhydroxy pyrrolidine compound, a preparation method and application thereof, and a glycosidase inhibitor.

Background

Iminosugars (iminosugars) are a class of sugar mimetics (sugar mimics) in which the oxygen atom of the sugar ring is replaced by a nitrogen atom, also known as iminosugars, azasugars, polyhydroxy alkaloids, etc. The research finds that the iminosugar has very strong inhibitory action on the glycosidase activity, thereby greatly exciting the research enthusiasm of people on the iminosugar [ Nash R.J., Kato A., Yu C. -Y., et al, future Med Chem,2011, 31513-. Glycosidases play important roles in organisms, involving important vital activities including intestinal digestion, lysosomal metabolism of glycoconjugates, synthesis and breakdown of glycoproteins [ (a) sugar a.c., Alonzi d.s., Killingbeck s.s., et al, plos segmented tropic diseases,2016,10, e0004524-e 0004524; (b) Sanchez-Fernandez E.M., Garcia Fernandez J.M., Ortiz Mellet C., ChemCommun,2016,52, 5497-; (c) borges De Melo E., Da Silveara Gomes A., Carvalho I, Tetrahedron,2006,62, 10277-. It is therefore believed that new drugs can be found from iminosugars for the treatment of diseases associated with glycosidase activity such as malignancies, bacterial infections, diabetes, bacterial and viral infections and lysosomal storage diseases etc. (a) Plummer e, Buck m.d., Sanchez m.et al, J Virol 2015,89, 5592-; (b) hurtley S., Service R., Szuromi P., Science,2001,291, 2337-; (c) nishimura Y., Satoh T., Kudo T., et al, Biorg Med Chem,1996, 91-96; (d) durantel D., Branza-Nichia N., Carrouee-Durantel S., et al, J Virol,2001,75, 8987-.

Iminosugars have highlighted a great role in the creation of new drugs, and up to now 4 iminosugar drugs have been marketed, for example, the fortosine (1) which was newly marketed in 17 years for the treatment of T-cell lymphoma and the Migalastat (2, DGJ. HCl) which was marketed in 16 years for the treatment of fabry disease are oral drugs for the treatment of fabry disease, and the miglutt (3, Miglustat, trade name zadesca) which was marketed in the previous years for the treatment of gaucher disease, Miglitol (4, Miglitol, trade name Diastabol) for the treatment of type ii diabetes [ y.x.li, y.m.jia, c.y.yu, Progress in Chemistry,2018,30,586 cup 600 ].

There are also a number of iminosugar drugs in clinical research. For example, 1-deoxynojirimycin hydrochloride (5, Duvoglusta @ Hydrochloride) for the treatment of Pompe disease, Isofagomine (6) for the treatment of gaucher's disease, MBI-3253(7, Celgosivir) for the treatment of hepatitis C, and Ulodesine (8) for the treatment of chronic gout, and the like.

Imino sugars play an important role in the development of new drugs, but due to the characteristics of high polarity and high water solubility, imino sugars are not easy to separate and purify. With the advance of separation technology, only two hundred imino sugars have been separated so far. The following five groups can be classified according to their nitrogen atom-containing skeletons: polyhydroxypiperidines (polyhydroxylated piperidines), polyhydroxypyrrolidines (polyhydroxylated pyrrolidines), polyhydroxyindolizidines (polyhydroxylated indolizidines), polyhydroxypyrrolizidines (polyhydroxylated pyrrolidines), and polyhydroxytropanes (polyhydroxylated tropanes).

Compared with imino sugars of other structures, the number of indolizidine imino sugars is smaller. The first iminosugar of the indolizidine class to be isolated was swainsonine (9), originally isolated by Broquist et al in 1973 from the fungal pathogen Rhizoctonialeucicola [ F.P.Guengerich, S.J.DiMari and H.P.Broquist, J.am.chem.Soc., 1973,95, 2055-. Subsequently, they were isolated from Swainsonia hance, distributed in Australian pastures [ S.M.Colegate, P.R.Dorling and C.R.Huxtable, Aust.J. chem.,1979,32, 2257-. The swainsonine is found to have better alpha-mannosidase inhibition effect through biological activity research [ (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.Passtuszak and A.D.Elbein, Biochemistry,1990,29, 2168-; (e) i.pastuzak, g.p.kaushal, k.a.wall, y.t.pan, a.sturm and a.d.elbein, Glycobiology,1990,1,71-82 ], and into the clinical secondary study of renal cell carcinoma. However, clinical studies have shown that swainsonine has serious toxic side effects, for example, adverse reactions such as fatigue, mental debilitation, anorexia nervosa, amylase elevation and diarrhea occur in patients during administration [ P.E.Shaheen, W.Stadler, P.Elson, J.Knox, E.Winquist and R.M.Bukowski, Investigational New Drugs,2005,23, 577-. Therefore, the swainsonine needs to be structurally modified to improve the biological activity and reduce the toxic and side effects.

The 1,4-Dideoxy-l,4-imino- α -mannitol (10, DIM) molecule was designed and synthesized in 1984 by the teaching of Fleet, uk [ g.w.j.fleet, p.w.smith, s.v.evans and l.e.fellows, j.chem.soc.chem. Commun, 1984,1240-1241 ]. DIM molecules exhibit an alpha-mannosidase inhibitory activity comparable to swainsonine and can therefore be considered pharmacophores of swainsonine. The DIM molecule is a polyhydroxy pyrrolidine imino sugar, and compared with swainsonine, the single-ring framework of the DIM molecule is simpler, and the DIM molecule is convenient for mass synthesis and structural modification. However, DIM molecules are poor in lipid solubility, are not beneficial to oral absorption, only have good inhibitory activity on alpha-mannosidase, and have poor inhibitory effect on other types of glycosidases.

Disclosure of Invention

The invention aims to overcome the problems that the glycosidase inhibitor in the prior art has single inhibition effect on glycosidase, the fat solubility of inhibitor molecules is poor, and oral absorption is not facilitated, and provides an N-alkylated polypolyhydroxypyrrolidine compound, a preparation method and an application thereof.

In order to achieve the above object, a first aspect of the present invention provides a compound having a structure represented by formula (I):

wherein, R is any one of hydrogen, aryl, hydroxyl, halogen atom, vinyl, ethynyl, alkoxy, carboxyl, ester group, nitro, amino and cyano, and n is 1-20; and the spatial configurations of the carbons at positions 2,3, 4 and 6 are all 2R, 3S, 4R and 6S, wherein when R is hydrogen, n is not 1 or 4; when R is hydroxy, n is not 2; when R is phenyl, n is not 1.

Further, in the compound shown in the formula I, R is any one of hydrogen, vinyl, ethynyl, aryl, hydroxyl, alkoxy and amino.

Still further, the aryl group may be phenyl, indol-3-yl, pyrrol-2-yl, furan-2-yl, thiophen-2-yl, partially or fully substituted phenyl, wherein the substituents in the partially or fully substituted phenyl group are indol-3-yl, pyrrol-2-yl, furan-2-yl, thiophen-2-yl, fluoro, chloro, bromo, iodo, hydroxy, methoxy, nitro, carboxy, cyano, amino, N-dimethylamino, phenyl, cyclohexyl, tert-butyl, C_1-4Straight chain alkyl, C_1-4Straight-chain alkylamino radical, C_1-4At least one of a linear chain alkoxycarbonyl group;

preferably phenyl, partially or fully substituted phenyl, wherein the substituent of the partially or fully substituted phenyl is fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, nitro, carboxyl, cyano, amino, phenyl, cyclohexyl, tert-butyl, C_1-4At least one linear alkyl group.

Still further, the halogen atom is: fluorine, chlorine, bromine, iodine; the alkoxy is: methoxy, ethoxy, propoxy, butoxy, tert-butoxy, benzyloxy.

In a second aspect, the present invention provides a process for the preparation of a compound of the invention, comprising the steps of:

(1) preparation of intermediate (III)

In the presence of a catalyst and a reducing agent, mixing a compound shown as a formula (II-1) and a compound shown as a formula (II-2) in a solvent and inert gas atmosphere, and then carrying out reductive amination reaction to obtain an intermediate (III);

(2) preparation of Compounds of formula (I)

In a solvent, under the action of acid, the intermediate (III) is subjected to a deprotection reaction to obtain the compound shown in the formula (I),

in a third aspect, the present invention provides a further process for the preparation of a compound of the invention, comprising the steps of:

(A) preparation of intermediate (III)

In a solvent, under the action of alkali, mixing a compound shown as a formula (II-1) and a halide shown as a formula (II-3) and then carrying out nucleophilic substitution reaction to obtain an intermediate (III);

wherein, X is chlorine, bromine or iodine;

(B) preparation of Compounds of formula (I)

In a solvent, under the action of acid, carrying out a protecting group removing reaction on the intermediate (III) to obtain a compound shown as a formula (I);

salts or hydrates of any of the compounds of formula I described above are also within the scope of the present invention. The salt is a pharmaceutically acceptable salt.

In a fourth aspect, the present invention provides a glycosidase inhibitor comprising the above compound, a salt thereof, or a hydrate thereof as an active ingredient, wherein the glycosidase is α -glucosidase, β -glucosidase, α -galactosidase, β -galactosidase, α -mannosidase, β -mannosidase, α -L-fucosidase, trehalase, amyloglucosidase, α -L-rhamnosidase, or β -glucuronidase.

In a fifth aspect, the present invention provides a use of the above-mentioned compound, a salt or hydrate thereof, or a hydrate of the salt as an active ingredient for the preparation of a medicament for the prevention and/or treatment of at least one of the following glycosidase-related diseases: 1) diabetes mellitus; 2) gaucher's disease; 3) a tumor; 4) viral infection, wherein the glycosidase is alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase, alpha-mannosidase, beta-mannosidase, alpha-L-fucosidase, amyloglucosidase, alpha-L-rhamnosidase or beta-glucuronidase.

The compound is an N-alkylated polyhydroxy pyrrolidine compound, improves DIM molecules (1, 4-dioxy-l, 4-imino-alpha-mannitol), introduces an alkyl chain with better lipophilicity on an N atom in the molecule, greatly improves the liposolubility of the DIM molecules, and is suitable for preparing oral medicaments.

The N-alkylated polyhydroxy pyrrolidine compound provided by the invention has a higher inhibition effect on different glycosidases, shows high selectivity, and can be used as an active ingredient for preparing various glycosidase-related medicines.

Detailed Description

The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.

In a first aspect, the present invention provides a compound having the structure shown in formula (I):

According to the present invention, the terminal group R in the structure of the compound may further be any one of hydrogen, vinyl, ethynyl, aryl, hydroxyl, alkoxy, and amino; preferably any of hydrogen, vinyl, aryl and hydroxyl.

According to the invention, the value of n in formula (I) can be determined by the choice of the end group R. Preferably, when R is hydrogen, n ═ 2,3, 5-20; preferably, when R is hydroxy, n is 3-20.

According to the invention, the aryl group is: phenyl, indol-3-yl, pyrrol-2-yl, furan-2-yl, thiophen-2-yl, partially or fully substituted phenyl, wherein the substituents in said partially or fully substituted phenyl are indol-3-yl, pyrrol-2-yl, furan-2-yl, thiophen-2-yl, fluoro, chloro, bromo, iodo, hydroxy, methoxy, nitro, carboxy, cyano, amino, N-dimethylamino, phenyl, cyclohexyl, tert-butyl, C_1-4Straight chain alkyl, C_1-4Straight-chain alkylamino radical, C_1-4At least one of linear alkoxycarbonyl groups; preferably phenyl, partially or fully substituted phenyl, wherein the substituent of the partially or fully substituted phenyl is fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, nitro, carboxyl, cyano, amino, phenyl, cyclohexyl, tert-butyl, C_1-4At least one linear alkyl group.

The halogen atoms are: fluorine, chlorine, bromine, iodine; the alkoxy is: methoxy, ethoxy, propoxy, butoxy, tert-butoxy, benzyloxy.

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

According to the present invention, preferably, the compound is any one of compounds represented by the following formulae (I-1) to (I-29):

the salt or hydrate of any compound shown as the formula I is also within the protection scope of the invention, and the salt is pharmaceutically acceptable salt.

(1) preparation of intermediate (III)

(2) preparation of Compounds of formula (I)

in the present invention, the ratio of the amount of the compound represented by the formula (II-2) to the compound represented by the formula (II-1) is more than 1, and preferably, the ratio of the amount of the compound represented by the formula (II-2) to the amount of the compound represented by the formula (II-1) is 3: 1. The dosage of the catalyst is 1 to 50 percent of that of the compound shown in the formula (II-1), preferably 10 to 30 percent; the ratio of the amount of the reducing agent to the amount of the compound represented by the formula (II-1) is more than 1, and preferably, the ratio of the amount of the reducing agent to the amount of the compound represented by the formula (II-1) is 5-10:1

In the present invention, the compound represented by the formula (II-1) can be prepared by the following specific method:

the preparation method comprises the following steps:

dissolving a compound II-8 (2.2g,9.1mmol) in 15mL of anhydrous ether under the condition of ice-water bath, adding tert-butyl hypochlorite (1.23mL,10.9mmol), reacting for 30 minutes, maintaining the condition of ice-water bath, dropwise adding DBU (1.77mL, 11.8mmol), gradually raising the temperature to room temperature after dropwise adding, continuing to react for 1 hour under the condition of room temperature, wherein TCL shows that the reaction is complete, filtering to remove salts generated by the reaction, evaporating the solvent under reduced pressure, and quickly separating by column chromatography to obtain an intermediate II-9 which is light yellow syrup and has the yield of 2.1 g: 97 percent. δ H (400 MHz; 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); Δ C (100 MHz; 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.

Dissolving compound II-9 (3.37g,13.9mmol) in 30mL of anhydrous methanol under ice-water bath conditions, adding sodium borohydride (1.6g,42.0mmol), gradually heating to room temperature from ice-water bath, reacting at room temperature for 1 hour, TLC shows reaction completion, adding saturated aqueous ammonium chloride solution to quench the reaction, removing the solvent under reduced pressure, adding 500mL of water, extracting three times with ethyl acetate (500 mL. times.3), collecting the concentrated organic phase, and separating by column chromatography to obtain 2,3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol formula (II-1), (dr >99:1) as colorless transparent syrup, 3.19 g, yield: 94 percent. δ H (400 MHz; 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); Δ C (100 MHz; 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, the above-mentioned compound II-8 can be prepared by a method described in (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.Beo and B.Wincher, Tetrahedron,1988,44, 2649-55; (d) H.Setoi, H.Kayari, H.Takeno and M Hashimoto, Schm rm Bucharm, 1987, 3935, 4095F, C.Layakiri, J.R.R.R.R.J.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.J.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.J.R.R.R.R.R.R.R.R.R.R.R.R.R.C.54. is described in detail, and R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.R.S.S.S.S.R.R.S.R.R.S.S.S.S.S.R.R.S.S.S.S.S.S.S.S.S.S.S.R.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.47.A.S.S.S.S.S.S.A.A. A. A.A.A.S.A.S.S.A.A.S.A.S.S.S.S.S.S.A.S.S.S.S.S.S.S.S.S.S.S.S.S.A.S.S.S.A. A. A.S.S.S.A.S.S.A.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.and.E.S.S.S.S.S.S.E.E.E.E.E.E.S.S.S.S.S.S.S.S.S.E.S.S.S.S.S.S.S.S.S.

The intermediate (II-8) can be synthesized according to the following process:

the preparation method comprises the following steps:

d-mannose (II-4) (100.0g,555.4mmol) is dissolved in 1000mL of acetone at room temperature, a catalytic amount of p-toluenesulfonic acid monohydrate (1.0g,5.3mmol) is added, 2-dimethoxypropane (150.2mL,1.2 mol) is added, the reaction is stirred for 3 hours under the condition, TLC shows that the raw materials disappear, the reaction is completed, sodium bicarbonate is added to quench the reaction, the solvent is neutralized to neutrality, inorganic salts are removed by filtration, and the solvent is evaporated to dryness to obtain a white solid which is the crude product 2,3:5, 6-O-diacetone-D-mannose (II-5) in the first step.

The crude product II-5 (calculated as 555.4 mol) was dissolved in 800mL of anhydrous methanol, followed by the sequential addition of triethylamine (116.6 mL,833.1mmol) and hydroxylamine hydrochloride (43.3g,666.5mmol), the reaction flask was placed in an oil bath, and when heating and refluxing were carried out for 6 hours, TCL showed the disappearance of the starting material, completion of the reaction, stoppage of the reaction, cooling to room temperature, evaporation of methanol and triethylamine under reduced pressure, addition of 500mL of water, extraction with ethyl acetate carried out three times (500 mL. times.3), and collection of the concentrated organic phase gave the crude product 2,3:5, 6-O-diacetone-alpha-D-mannoxime (II-6).

Dissolving the crude product II-6 (calculated by 555.4mmol) in 500mL pyridine, cooling to-20 ℃, dropwise adding methanesulfonyl chloride (107.5mL,1.4mol), reacting at-20 ℃ for 1 hour after dropwise adding, then gradually raising to room temperature, continuing to react for 10 hours, TLC shows that the reaction is complete, stopping the reaction, evaporating pyridine under reduced pressure, adding 500mL water, extracting with ethyl acetate for three times (500mL multiplied by 3), collecting a concentrated organic phase, and separating by column chromatography to obtain a white needle-like solid formula (II-7), 109.8g, yield: 59 percent.

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。

Dissolving the product II-7 (3.35g,10.0mmol) in 30mL of anhydrous methanol under the ice-water bath condition, adding cobalt dichloride hexahydrate (4.76g,20.0mmol), fully stirring for 30 minutes, then adding sodium borohydride (3.8g,100.0mmol), gradually raising the temperature to room temperature, reacting at room temperature for 10 hours, TLC (TLC) shows that the reaction is complete, adding saturated ammonium chloride solution to quench the reaction, evaporating the solvent under reduced pressure, adding 50mL of water, extracting with ethyl acetate for three times (50mL multiplied by 3), collecting the concentrated organic phase, and separating by column chromatography to obtain 1, 4-dideoxy-2, 3:5, 6-diacetone-1, 4-imino-D-talitol (II-8), 2.2g, yield: 91 percent.

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 invention, the catalyst used in the reductive amination reaction is Rany-nickel, palladium carbon with the palladium content of 0.5-30 percent and PtO₂At least one of; the reducing agent is at least one of hydrogen, sodium borohydride, sodium cyanoborohydride, lithium borohydride and sodium triacetoxyborohydride.

In the present invention, the reductive amination reaction temperature may be from-40 ℃ to 80 ℃, preferably from 0 ℃ to 30 ℃; the deprotection reaction temperature may be from-40 ℃ to 80 ℃, preferably from 10 ℃ to 30 ℃.

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

In the present invention, the solvent is a kind of solvent that is conventional in the art, specifically, the solvent is at least one of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, ethyl acetate, water, dioxane, methanol, ethanol, acetonitrile, formamide or N, N-dimethylformamide, and preferably, the solvent is methanol.

In the invention, the acid is at least one of inorganic acid, organic acid or lewis acid, preferably, the inorganic acid is at least one of hydrochloric acid, hydrofluoric acid and sulfuric acid; the organic acid is at least one of acetic acid, p-toluenesulfonic acid, methanesulfonic acid and trifluoroacetic acid; the Lewis acid is at least one of titanium tetrachloride, stannic chloride, bismuth trichloride or zinc bromide.

(A) preparation of intermediate (III)

In a solvent, under the action of alkali, mixing a compound shown as a formula (II-1) and a halide shown as a formula (II-3), and carrying out nucleophilic substitution reaction to obtain an intermediate (III);

wherein, X is chlorine, bromine or iodine;

(B) preparation of Compounds of formula (I)

in the present invention, the amount ratio of the compound represented by the formula (II-3) to the halogenated compound represented by the formula (II-1) is more than 1, and preferably the amount ratio of the compound represented by the formula (II-3) to the compound represented by the formula (II-1) is 1.2: 1.

In the present invention, the nucleophilic substitution reaction temperature is-40 ℃ to 100 ℃, preferably 30 ℃ to 80 ℃; the reaction temperature for removing the protecting group is-40 ℃ to 80 ℃, preferably 10 ℃ to 30 ℃.

In the present invention, the solvent is a kind of solvent that is conventional in the art, specifically, the solvent is at least one of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, ethyl acetate, water, dioxane, methanol, ethanol, acetonitrile, formamide, and N, N-dimethylformamide, and preferably, the solvent is methanol.

In the present invention, the base is an organic base and/or an inorganic base, preferably, the organic base is at least one of diethylamine, triethylamine, diisopropylamine, diisopropylethylamine, pyridine, and 2,4, 6-trimethylpyridine; the inorganic base is at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and sodium hydride.

In the present invention, the acid is at least one of an inorganic acid, an organic acid, and a lewis acid, and preferably, the inorganic acid is at least one of hydrochloric acid, hydrofluoric acid, and sulfuric acid; the organic acid is at least one of acetic acid, p-toluenesulfonic acid, methanesulfonic acid and trifluoroacetic 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 below by way of examples. In the following examples, the structures of the substances were determined by nuclear magnetic methods, and the specific operating conditions of the nuclear magnetic tests were:

in the following examples, unless otherwise specified, all experimental methods used were conventional methods; the materials, reagents, etc. used are commercially available.

The present invention will be further described with reference to the following examples, but the present invention is not limited to the following examples.

Example 1 preparation of N-ethyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-1).

The preparation method comprises the following steps:

dissolving compound II-1 (100mg,0.41mmol) in 15mL of methanol, adding acetaldehyde water solution (0.14mL, 1.23mmol), adding 10mg of 10% palladium carbon under argon atmosphere, replacing argon with hydrogen, stirring overnight at room temperature under hydrogen atmosphere, TLC indicating reactionAfter completion, the reaction was stopped, palladium on carbon was removed by filtration, the filtrate was concentrated and subjected to column chromatography to obtain N-ethyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (iii-1) as a pale yellow syrup, 99.5mg, yield: 89 percent. Delta_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) was dissolved in 10mL of methanol, 1mL of 6N hydrochloric acid was added, the reaction was stirred at room temperature for 1 hour, the reaction was stopped, and the solvent was evaporated under reduced pressure to give 16.7 mg of N-ethyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-1) as a white solid, in yield: 100 percent. Mp:142-143 deg.C; delta_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.

Example 2 preparation of N-propyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-2).

Referring to the synthesis procedure in example 1, starting from compound ii-1 (120mg,0.49mmol) and propionaldehyde (86mg,1.47 mmol), 131 mg of intermediate N-propyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (iii-2) was obtained in yield: 81 percent. Pale yellow syrup, delta_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) was stripped off with hydrochloric acidProtecting group to give N-propyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-2) as a pale yellow syrup, 25.3 mg, yield: 99 percent. Delta_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。

Example 3 preparation of N-pentyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-3).

Referring to the synthesis procedure in example 1, compound ii-1 (100.0mg,0.41mmol) and N-valeraldehyde (106mg, 12.3mmol) gave intermediate N-pentyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (iii-3) as a colorless syrup, 108 mg, yield: 84 percent. Delta_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) was deprotected under hydrochloric acid to give N-pentyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-3) as a pale yellow syrup, 13.6 mg, yield: 99 percent. Delta_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。

Example 4 preparation of N-hexyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-4).

Referring to the synthesis method in example 1, compound II-1 (59.0mg,0.24mmol) and N-hexanal (76.1mg, 0.72mmol) are used as raw materials, and catalytic hydrogenation is carried out on 10% palladium carbon to obtain intermediate N-hexyl-2, 3:5, 6-diacetone-1, 4-dideoxy1, 4-imino-D-mannitol (iii-4) as a colorless syrup, 74.6 mg, yield: 94 percent. Delta_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) was deprotected under hydrochloric acid to give N-hexyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-4) as a pale yellow syrup, 23.4 mg, yield: 100 percent. Delta_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。

Example 5 preparation of N-heptyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-5).

Referring to the synthesis procedure in example 1, starting from compound ii-1 (142.0mg,0.58mmol) and N-heptanal (198.6mg, 1.74mmol), catalytic hydrogenation was carried out using 10% palladium on carbon to give the intermediate N-heptyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (iii-5) as a colorless syrup in 140.1 mg yield: 71 percent. Delta_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) was deprotected under hydrochloric acid to give N-heptyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-5) as a pale yellow syrup, 30.5 mg, 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。

example 6 preparation of N-octyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-6).

Referring to the synthesis method in example 1, starting from compound ii-1 (96.0mg,0.23mmol) and N-octanal (88.5mg, 0.69mmol), catalytic hydrogenation was carried out using 10% palladium on carbon to obtain intermediate N-octyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (iii-6) as a colorless syrup in 64.6 mg yield: 79 percent. Delta_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) was deprotected under hydrochloric acid to give N-octyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-6) as a pale yellow syrup, 21.9 mg, yield: 100 percent. Delta_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。

Example 7 preparation of N-nonyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-7).

Referring to the synthesis method in example 1, starting from compound II-1 (60.0mg,0.16mmol) and n-nonanal (68.3mg, 0.68mmol), 10% is passedPalladium on carbon catalytic hydrogenation gave (ii-1) intermediate N-nonyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (iii-7) as a colourless syrup, 41.7 mg, yield: 71 percent. Delta_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) was deprotected under hydrochloric acid to give N-nonyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-7) as a pale yellow syrup, 26.4 mg, yield: 100 percent. Delta_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。

Example 8 preparation of N-allyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-8).

The preparation method comprises the following steps:

dissolving the compound II-1 (3.0g,12.3mmol) in 30mL of dry N, N-dimethylformamide, adding potassium carbonate (5.2g,37.1mmol) and 3-bromo-1-propene (3.0g,24.6mmol), heating to 65 ℃ under argon atmosphere, reacting overnight, TLC showing complete reaction, stopping reaction, adding 200mL of water, extracting three times with ethyl acetate (100 mL. times.3), collecting concentrated organic phase, and separating by column chromatography to obtain the intermediate N-allyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-8) as light yellow syrup with 3.0g and 87% yield. Delta_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) was dissolved in 10mL of methanol, 1mL of 6N hydrochloric acid was added, the reaction was stirred at room temperature for 1 hour, the reaction was stopped, and the solvent was evaporated under reduced pressure to give N-allyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-8) as a pale yellow syrup, 11.4 mg, yield: 100 percent. Delta_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。

Example 9 preparation of N-Enylbutyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-9).

Referring to the synthesis procedure in example 8, nucleophilic substitution reaction was performed using compound II-1 (60.1mg,0.25mmol) and 4-bromo-1-butene (66.2mg,0.49mmol) as starting materials under the action of potassium carbonate to give N-alkylated intermediate N-alkenylbutyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-9) as a colorless syrup in 63.1 mg at a yield of 86%. Delta_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。

Removing the protecting group of the intermediate III-9 (40.0mg,0.08mmol) under the action of hydrochloric acid to obtain N-alkenyl butyl-1, 4-dideoxy-1, 4-imino-D-mannitol(I-9) was pale yellow syrup, 34.1 mg, yield: 100 percent. Delta_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。

Example 10 preparation of N-Enopentyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-10).

Referring to the synthesis procedure in example 8, nucleophilic substitution reaction was performed using compound II-1 (1.0g,4.11mmol) and 5-bromo-1-pentene (1.2g, 8.22mmol) as starting materials under the action of potassium carbonate to give N-alkylated intermediate N-alkenylpentyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-10) as a colorless syrup, 0.91 g, 71% yield. Delta_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) was deprotected under hydrochloric acid to give N-alkenylpentyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-10) as a pale yellow syrup, 85.0 mg, yield: 99 percent. Delta_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。

Example 11 preparation of N-alkenylhexyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-11).

Reference exampleThe synthesis method 8 is characterized in that a compound II-1 (54.0mg,0.22mmol) and 6-bromo-1-hexene (71.8 mg,0.44mmol) are used as raw materials, and nucleophilic substitution reaction is carried out under the action of potassium carbonate to obtain an N-alkylated intermediate N-alkenyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-11) which is colorless syrup and has the yield of 40.0 mg. Delta_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) was deprotected under hydrochloric acid to give N-alkenylhexyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-11) as a pale yellow syrup, 25.9 mg, yield: 100 percent. Delta_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。

Example 12 preparation of N-alkenylheptyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-12).

Referring to the synthesis procedure in example 8, nucleophilic substitution reaction was carried out using compound II-1 (328.0mg,1.35mmol) and 7-bromo-1-heptene (471.8mg,2.70mmol) as starting materials under the action of potassium carbonate to give N-alkylated intermediate N-alkenylheptyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-12) as a colorless syrup in 398.0 mg at a yield of 87%. Delta_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) was deprotected under hydrochloric acid to give N-alkenylheptyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-12) as a pale yellow syrup, 20.0 mg, yield: 100 percent. Delta_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。

Example 13 preparation of N-Endoctyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-13).

Referring to the synthesis procedure in example 8, nucleophilic substitution reaction was performed using compound II-1 (145.0mg,0.60mmol) and 8-bromo-1-octene (229.3mg,1.20mmol) as starting materials under the action of potassium carbonate to give N-alkylated intermediate N-alkenyloctyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-13) as a colorless syrup, 134.8 mmol, 64% yield. Delta_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) was deprotected under the action of hydrochloric acid, and subjected to column chromatography to give N-alkenyloctyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-13) as a pale yellow syrup, 28.8 mg, yield: 66 percent. Delta_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。

Example 14 preparation of N-Enonyi-1, 4-dideoxy-1, 4-imino-D-mannitol (I-14).

Referring to the synthesis procedure in example 8, nucleophilic substitution reaction was carried out using compound II-1 (64.0mg,0.26mmol) and 9-bromo-1-nonene (108.7 mg,0.53mmol) as starting materials under the action of potassium carbonate to give N-alkylated intermediate N-enamonyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-14) as a colorless syrup, 66.7 mg, 69% yield. Delta_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) was deprotected under the action of hydrochloric acid, and subjected to column chromatography to give N-alkenylnonyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-14) as a pale yellow syrup, 16.2 mg, yield: 71 percent. Delta_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。

Example 15 preparation of N-phenethyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-15).

Referring to the synthesis method in example 8, nucleophilic substitution reaction was performed using compound II-1 (110.0mg,0.45mmol) and 2-phenylbromide ethane (166.5mg,0.90mmol) as starting materials under the action of potassium carbonate to give N-alkylated intermediate N-phenethyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-15) as a white solid in 116.1 mg, yield 74%. And Mp: 86-87 ℃; delta_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) was deprotected under hydrochloric acid to give N-phenethyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-15) as a pale yellow syrup, 17.5 mg, yield: 100 percent. Delta_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。

Example 16 preparation of N-phenylpropyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-16).

Referring to the synthesis method in example 8, nucleophilic substitution reaction was performed using compound II-1 (110.0mg,0.45mmol) and 1-bromo-3-phenylpropane (179.2mg,0.90mmol) as starting materials under the action of potassium carbonate to give N-alkylated intermediate N-phenylpropyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-16) as colorless syrup, 117.7 mg, yield 72%. Delta_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) was deprotected under the action of hydrochloric acid to give N-phenylpropyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-16) as a pale yellow syrup, 26.3 mg, yield: 100 percent. Delta_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。

Example 17 preparation of N-phenylbutyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-17).

Referring to the synthesis method in example 8, nucleophilic substitution reaction was performed using compound II-1 (190.0mg,0.78mmol) and 1-bromo-4-phenylbutane (332.5mg,1.56mmol) as starting materials under the action of potassium carbonate to give N-alkylated intermediate N-phenylbutyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-17) as a colorless syrup, 225.8 mg, 77% yield. Delta_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) was deprotected under hydrochloric acid to give N-phenylbutyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-17) as a pale yellow syrup, 44.3 mg, yield: 99 percent. Delta_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。

Example 18 preparation of N-phenylpentyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-18).

Referring to the synthesis procedure in example 8, nucleophilic substitution reaction was performed using compound II-1 (145.0mg,0.60mmol) and 1-bromo-5-phenylpentane (271.2mg,1.20mmol) as starting materials under the action of potassium carbonate to give N-alkylated intermediate N-phenylpentyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-18) as a colorless syrup in 169.5 mg at 73% yield. Delta_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) was deprotected under hydrochloric acid to give N-phenylpentyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-18) as a pale yellow syrup, 35.5 mg, yield: 100 percent. Delta_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。

Example 19 preparation of N-phenylhexyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-19).

According to the synthesis method in example 8, compound II-1 (110.0mg, 0.4)5mmol) and 1-bromo-6-phenylhexane (216.1mg,0.90mmol) as raw materials, and nucleophilic substitution reaction is carried out under the action of potassium carbonate to obtain N-alkylated intermediate N-phenylhexyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-19) as colorless syrup, 147.8 mmol, with a yield of 81%. Delta_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) was deprotected under hydrochloric acid to give N-phenylhexyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-19) as a pale yellow syrup, 44.5 mg, yield: 100 percent. Delta_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。

Example 20 preparation of N-phenylheptyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-20).

Referring to the synthesis procedure in example 8, nucleophilic substitution reaction was carried out using compound II-1 (150.0mg,0.62mmol) and 1-bromo-7-phenylheptane (315.1mg,1.24mmol) as starting materials under the action of potassium carbonate to give N-alkylated intermediate N-phenylheptyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-20) as a colorless syrup in 177.6 mmol, 69% yield. Delta_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) was deprotected under hydrochloric acid to give N-phenylheptyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-20) as a pale yellow syrup, 41.1 mg, yield: 100 percent. Delta_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。

Example 21 preparation of N-phenyloctyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-21).

Referring to the synthesis method in example 8, a nucleophilic substitution reaction was performed using compound II-1 (130.0mg,0.53mmol) and 1-bromo-8-phenyloctane (284.2mg,1.06mmol) as starting materials under the action of potassium carbonate to obtain N-alkylated intermediate N-phenyloctyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-21) as a colorless syrup, 140.7 mmol, yield 61%. Delta_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) was deprotected under hydrochloric acid to give N-phenyloctyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-21) as a pale yellow syrup, 54.7 mg, yield: 100 percent. Delta_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。

Example 22 preparation of N-Benzenonyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-22).

Referring to the synthesis procedure in example 8, nucleophilic substitution reaction was performed using compound II-1 (200.0mg,0.82mmol) and 1-bromo-9-phenyl-nonane (462.5mg,1.64mmol) as starting materials under the action of potassium carbonate to give N-alkylated intermediate N-phenylnonyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-22) as a colorless syrup, 201.5 mmol, yield 55%. Delta_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) was deprotected under hydrochloric acid to give N-phenyloctyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-22) as a pale yellow syrup, 55.9 mg, yield: 100 percent. Delta_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。

Example 23 preparation of N-hydroxypropyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-23).

Reference is made to the example 8The preparation method comprises the steps of taking a compound II-1 (200.0mg,0.82mmol) and (3-bromopropoxy) -tert-butyldimethylsilane (415.3mg,1.64mmol) as raw materials, and carrying out nucleophilic substitution reaction under the action of potassium carbonate to obtain an N-alkylated intermediate N-tert-butyldimethylsilyloxypropyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-23) which is pale yellow syrup, 204.5 mg and the yield of 57%. Delta_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) was deprotected under hydrochloric acid to give N-hydroxypropyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-23) as a pale yellow solid in 37.1 mg, yield: 99 percent. Mp is 78-80 ℃; delta_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。

Example 24 preparation of N-hydroxybutyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-24).

Referring to the synthesis method in example 8, nucleophilic substitution reaction was performed using compound II-1 (80.0mg,0.33mmol) and (4-bromobutoxy) -tert-butyldimethylsilane (176.4mg,0.66mmol) as starting materials under the action of potassium carbonate to give N-alkylated intermediate N-tert-butyldimethylsiloxybutyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-24) as a pale yellow syrup, 108.8 mg, 77% yield. Delta_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) was deprotected under hydrochloric acid to give N-hydroxybutyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-24) as a pale yellow syrup, 11.4 mg, yield: 100 percent. Delta_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。

Example 25 preparation of N-hydroxypentyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-25).

Referring to the synthesis procedure in example 8, nucleophilic substitution reaction was performed using compound II-1 (200.0mg,0.82mmol) and (5-bromopentyloxy) -tert-butyldimethylsilane (461.3mg,1.64mmol) as starting materials under the action of potassium carbonate to give N-alkylated intermediate N-tert-butyldimethylsilyloxypentyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-25) as a pale yellow syrup, 240.6 mg, 66% yield. Delta_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) was deprotected under hydrochloric acid to give N-hydroxypentyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-25) as a pale yellow syrup, 38.6 mg, yield: 100 percent. Delta_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。

Example 26 preparation of N-hydroxyhexyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-26).

Referring to the synthesis method in example 8, nucleophilic substitution reaction was performed using compound II-1 (200.0mg,0.82mmol) and (6-bromohexyloxy) -tert-butyldimethylsilane (484.4mg,1.64mmol) as starting materials under the action of potassium carbonate to obtain N-alkylated intermediate N-tert-butyldimethylsilyloxyhexyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-26) as a pale yellow syrup, 259.5 mg, 69% yield. Delta_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) was deprotected under hydrochloric acid to give N-hydroxyhexyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-26) as a pale yellow syrup, 39.2 mg, yield: 100 percent. Delta_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。

Example 27 preparation of N-hydroxyheptyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-27).

Referring to the synthesis procedure in example 8, the compound II-1 (130.0mg,0.53mmol) and (7-bromoheptyloxy) -tert-butyldimethylsilyl silicon were usedAlkane (327.9mg,1.06mmol) as a raw material was subjected to nucleophilic substitution reaction under the action of potassium carbonate to give N-alkylated intermediate N-t-butyldimethylsilyloxyheptyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-27) as a pale yellow syrup, 143.6 mg, yield 57%. Delta_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) was deprotected under hydrochloric acid to give N-hydroxyheptyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-27) as a pale yellow syrup, 46.5 mg, yield: 100 percent. Delta_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。

Example 28 preparation of N-hydroxyoctyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-28).

Referring to the synthesis method in example 8, nucleophilic substitution reaction was performed using compound II-1 (100.0mg,0.41mmol) and (8-bromooctyloxy) -tert-butyldimethylsilane (265.2mg,0.82mmol) as starting materials under the action of potassium carbonate to give N-alkylated intermediate N-tert-butyldimethylsiloxyoctyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-28) as a pale yellow syrup, 133.7 mg, 47% yield. Delta_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) was deprotected under hydrochloric acid to give N-hydroxyoctyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-28) as a pale yellow syrup, 33.7 mg, yield: 100 percent. Delta_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。

Example 29 preparation of N-hydroxynonyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-29).

The preparation method comprises the following steps:

dissolving a compound III-16 (130.0mg,0.35mmol) in 15mL of dry tetrahydrofuran, adding a tetrahydrofuran solution (0.39mL,0.39mmol) of borane in an argon atmosphere, reacting at room temperature for three hours, dropwise adding a sodium hydroxide solution until the reaction system is alkaline, adding hydrogen peroxide (0.43mL,4.24mmol), continuing to react for one hour, adding a saturated sodium thiosulfate solution to quench the reaction, adding hydrochloric acid to adjust the pH value to be neutral, removing the organic solvent under reduced pressure, adding 50mL of water, extracting for three times (50mL multiplied by 3) by using ethyl acetate, collecting a concentrated organic phase, and separating by column chromatography to obtain an intermediate N-hydroxynonyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (III-29) which is colorless syrup, 97.3 mg, yield 64%. Delta_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) was dissolved in 10mL of methanol, 1mL of 6N hydrochloric acid was added, the reaction was stirred at room temperature for 1 hour, the reaction was stopped, and the solvent was evaporated under reduced pressure to give N-hydroxynonyl-1, 4-dideoxy-1, 4-imino-D-mannitol (I-29) as a white solid in 30.7 mg, yield: 99 percent. Mp is 75-76 deg.C; delta_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 preparation of N-methyl-1, 4-dideoxy-1, 4-imino-D-mannitol (D-1).

The preparation method comprises the following steps:

referring to the procedure of example 1, compound ii-1 (100mg,0.41mmol) was dissolved in 15mL of methanol, aqueous formaldehyde (0.11mL,1.23mmol) was added and 10mg of palladium on carbon (10%) was added under an argon atmosphere, argon was replaced with hydrogen, and the mixture was stirred at room temperature overnight, TLC showed completion of the reaction, the reaction was stopped, palladium on carbon was removed by filtration, the filtrate was concentrated, and subjected to column chromatography to obtain N-methyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (DD-1) as a pale yellow syrup, 95.9mg, yield: 91 percent. Delta_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。

The intermediate DD-1(16.0mg,0.06mmol) was dissolved in 10mL of methanol, 1mL of 6N hydrochloric acid was added, the reaction was stirred at room temperature for 1 hour, and the reaction was stopped, and the solvent was evaporated under reduced pressure to give N-methyl-1, 4-dideoxy-1, 4-imino-D-mannitol as a pale yellow syrup (D-1) in 13.3 mg, yield: 100 percent; delta_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。

Comparative example 2 preparation of N-butyl-1, 4-dideoxy-1, 4-imino-D-mannitol (D-2).

Referring to the synthesis procedure in example 1, starting from compound ii-1 (50mg,0.21mmol) and butyraldehyde (45.4mg,0.63 mmol), the intermediate N-butyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (DD-2) was obtained as a colorless syrup, 51.1mg, yield: 87 percent. Delta_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) was deprotected under hydrochloric acid to give N-butyl-1, 4-dideoxy-1, 4-imino-D-mannitol (D-2) as a pale yellow syrup, 13.6 mg, yield: 99 percent; delta_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。

Comparative example 3 preparation of N-benzyl-1, 4-dideoxy-1, 4-imino-D-mannitol (D-3).

Referring to the synthesis in example 8, compound II-1 (100mg,0.41mmol) and benzyl bromide were used(60. mu.L, 0.49mmol) as a starting material, and nucleophilic substitution reaction under the action of sodium hydride (33mg,0.82mmol) to give an intermediate, N-benzyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (DD-3), as a colorless syrup, 107.9mg, yield: 79 percent. Delta_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) was deprotected under the action of hydrochloric acid to give N-benzyl-1, 4-dideoxy-1, 4-imino-D-mannitol (D-3) as a pale yellow syrup, 11.3 mg, yield: 100 percent; delta_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。

Comparative example 4 preparation of N-hydroxyethyl-1, 4-dideoxy-1, 4-imino-D-mannitol (D-4).

The compound II-1 (60.0mg,0.25mmol) and (2-bromoethoxy) -tert-butyldimethylsilane (119.1mg, 0.50mmol) were used as raw materials, and nucleophilic substitution reaction was carried out under the action of potassium carbonate (103.7mg,0.75mmol), to give an intermediate N-tert-butyldimethylsilyloxyethyl-2, 3:5, 6-diacetone-1, 4-dideoxy-1, 4-imino-D-mannitol (DD-4) as a pale yellow syrup, 52.4 mg, 55% yield. Delta_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) was deprotected under the action of hydrochloric acid to give N-hydroxyethyl-1, 4-dideoxy-1, 4-imino-D-mannitol (D-4) as a pale yellow syrup, 18.2 mg, yield: 99 percent. Delta_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 example

Evaluation of the glycosidase inhibitory Effect of the Compounds prepared in examples 1 to 29 and comparative examples 1 to 4, swainsonine and DIM

1) Test materials and sources

Sample preparation: the compounds (I-1) to (I-29) prepared in examples 1 to 29, the compounds (D-1) to (D-4) prepared in comparative examples 1 to 4, DIM and swainsonine.

Test materials: all 4-nitrophenol pyranoside substrates, disaccharides and glycosidases (including alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase, alpha-mannosidase, beta-mannosidase, alpha-L-fucosidase, trehalase, amyloglucosidase, alpha-L-rhamnosidase and beta-glucuronidase) were purchased from Sigma-Aldrich.

2) Test method

Kinetic studies were performed in 50mM sodium citrate/phosphate buffer at 37 ℃. According to different matrixes, the concentration of the prepared enzyme is 0.1-0.5 mg/mL. The activity test was carried out on 4-nitrophenol pyranoside as substrate, at the optimum pH for the activity of each enzyme. The substrate, suitably diluted enzyme solution and inhibitor (N-alkylated polyhydroxypyrrolidine) were incubated at 37 ℃ for 30 minutes, and the reaction was initiated in an ultraviolet-visible spectrophotometer and its absorbance at 400nm wavelength was measured. Finally, data analysis was performed using GraFit program [ leather barrow, r.j.grafit 4.0; erithocus Software: Staines, UK,1998 ].

3) Evaluation results

The results of the inhibitory activities of the compounds (I-1) to (I-29), the compounds (D-1) to (D-4), DIM and swainsonine of the present invention on glycosidase are shown in Table 1.

Wherein, IC₅₀(half maximum inhibition concentration) refers to the half inhibitory concentration of the antagonist being measured. It indicates that a drug or substance (inhibitor) is inhibiting half the amount of a biological process (or a substance, such as an enzyme, cellular receptor or microorganism, that is involved in the process). In terms of apoptosis, it is understood that a certain drug induces 50% of the tumor cells at a concentration referred to as the 50% inhibitory concentration, i.e. the concentration corresponding to the ratio of apoptotic cells to total cells equal to 50%, IC₅₀The value can be used to measure the ability of a drug to induce apoptosis, i.e., the stronger the inducing ability, the lower the value, and of course, the degree of tolerance of a cell to a drug can be inversely described.

TABLE 1

^aA source of an enzyme;^b-%, inhibition at a concentration of 1000. mu.M.

TABLE 1 (continuation)

^aA source of an enzyme;^b-%, inhibition at a concentration of 1000. mu.M.

Evaluation results show that the N-alkylated polyhydroxy pyrrolidine compounds provided by the invention all show a certain glycosidase inhibition effect. Wherein formula (I-1),The compounds shown in the formulas (I-2), (I-4), (I-8) and (I-25) all show high-selectivity alpha-mannosidase inhibitory activity, wherein the compounds shown in the formulas (I-2), (I-8) and (I-25) have high inhibitory activity on alpha-mannosidase; the compounds shown as the formulas (I-6), (I-13) and (I-14) show high selectivity to inhibit the activity of beta-galactosidase; IC when Compounds represented by formulas (I-21) and (I-22) inhibit beta-galactosidase₅₀The values are respectively 26.7 mu M and 26.6 mu M, which shows that the two have stronger inhibition effect on beta-galactosidase; the compound represented by the formula (I-29) shows a highly selective inhibition of the activity of beta-glucuronidase.

Meanwhile, compared with DIM, the compounds shown in the formulas (I-5) - (I-7), (I-13) - (I-14), (I-17) - (I-22) and (I-28) have higher inhibitory activity on beta-galactosidase against beta-galactosidase.

The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including the combination of the technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the protection scope of the invention.

Claims

1. A compound having the structure shown below:

2. a process for the preparation of a compound according to claim 1, comprising the steps of:

(1) preparation of intermediate (III)

(2) preparation of Compounds of formula (I)

wherein, the compound shown in the formula (I) has the structure shown in I-6, I-7, I-8, I-10, I-13, I-14, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-27, I-28 and I-29, and R corresponds to the groups of I-6, I-7, I-8, I-10, I-13, I-14, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-27, I-28 and I-29.

3. The process of claim 2 wherein the reductive amination reaction temperature is from-40 ℃ to 80 ℃; the reaction temperature for removing the protecting group is-40 ℃ to 80 ℃.

4. The process of claim 3, wherein the reductive amination reaction temperature is from 0 ℃ to 30 ℃; the reaction temperature for removing the protecting group is 10-30 ℃.

5. The process according to any one of claims 2 to 4, wherein the catalyst used in the reductive amination is Rany-nickel, palladium on carbon with a palladium content of 0.5 to 30% and PtO₂At least one of; the reducing agent is at least one of hydrogen, sodium borohydride, sodium cyanoborohydride, lithium borohydride and sodium triacetoxyborohydride.

6. A process for the preparation of a compound according to claim 1, comprising the steps of:

(A) preparation of intermediate (III)

In a solvent, under the action of alkali, mixing a compound shown as a formula (II-1) and a halide shown as a formula (II-3), and then carrying out nucleophilic substitution reaction to obtain an intermediate (III);

wherein, X is chlorine, bromine or iodine;

(B) preparation of Compounds of formula (I)

7. The production method according to claim 6, wherein the nucleophilic substitution reaction temperature is-40 ℃ to 100 ℃; the reaction temperature for removing the protecting group is-40 ℃ to 80 ℃; the base is an organic base and/or an inorganic base.

8. The production method according to claim 7, wherein the nucleophilic substitution reaction temperature is 30 ℃ to 80 ℃; the reaction temperature for removing the protecting group is 10 ℃ to 30 ℃; the organic base is at least one of diethylamine, triethylamine, diisopropylamine, diisopropylethylamine, pyridine and 2,4, 6-trimethylpyridine; the inorganic base is at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and sodium hydride.

9. The production method according to any one of claims 6 to 8, wherein the solvent is at least one of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, ethyl acetate, water, dioxane, methanol, ethanol, acetonitrile, formamide, and N, N-dimethylformamide; the acid is at least one of an inorganic acid, an organic acid and a Lewis acid.

10. The production method according to claim 9, wherein the solvent is methanol; the inorganic acid is at least one of hydrochloric acid, hydrofluoric acid and sulfuric acid; the organic acid is at least one of acetic acid, p-toluenesulfonic acid, methanesulfonic acid and trifluoroacetic acid; the Lewis acid is at least one of titanium tetrachloride, stannic chloride, bismuth trichloride and zinc bromide.

11. The highly selective glycosidase inhibitor comprising as an active ingredient a compound according to claim 1 or a salt thereof, wherein said glycosidase is α -glucosidase, β -glucosidase, α -galactosidase, β -galactosidase, α -mannosidase, β -mannosidase, α -L-glycoside fucosidase, amyloglucosidase, α -L-rhamnosidase or β -glucuronidase.

12. Use of the compound of claim 1 or a salt thereof as an active ingredient for the production of a medicament for the prophylaxis and/or treatment of at least one of the following glycosidase-related diseases: 1) diabetes mellitus; 2) gaucher's disease; 3) a tumor; 4) viral infection, wherein the glycosidase is alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase, alpha-mannosidase, beta-mannosidase, alpha-L-fucosidase, amyloglucosidase, alpha-L-rhamnosidase or beta-glucuronidase.