CN105732620B

CN105732620B - Indolizidine iminosugar and its precursor compound and their preparation method and application

Info

Publication number: CN105732620B
Application number: CN201610202477.7A
Authority: CN
Inventors: 俞初; 俞初一; 钱宝琛; 胡祥国
Original assignee: Institute of Chemistry CAS
Current assignee: Institute of Chemistry CAS
Priority date: 2016-04-01
Filing date: 2016-04-01
Publication date: 2018-12-11
Anticipated expiration: 2036-04-01
Also published as: CN105732620A

Abstract

The present invention relates to the synthesis fields of natural products, Indolizidine iminosugar and its precursor compound and their preparation method and application are disclosed, iminosugar of the invention is the compound or its pharmaceutically acceptable salt of structure shown in Formulas I: precursor compound is the compound or its pharmaceutically acceptable salt of structure shown in Formula XIV.Indolizidine iminosugar provided by the invention or its pharmaceutically acceptable salt have the activity for inhibiting glycosidase and can be used in treating diabetes.Moreover, the precursor compound of Indolizidine iminosugar provided by the invention also has the active effect for inhibiting glycosidase.

Description

Indolizidine iminosugar and its precursor compound and their preparation method with Using

Technical field

The present invention relates to the synthesis fields of natural products, and in particular, to a kind of Indolizidine iminosugar and should The preparation of the precursor compound of Indolizidine iminosugar and the Indolizidine iminosugar and its precursor compound Method and application.

Background technique

Glycosidase takes part in many important bioprocesses related with glycoconjugates, digestion, sugared egg such as enteral The glycoconjugates metabolism etc. of white synthesis and decomposition, lysosome, plays key player in life entity, close with many diseases Cut phase is closed.

Iminosugar, also known as polyhydroxylated alkaloid, azasugar, imines sugar etc. are effective inhibitor of glycosidase, disease-resistant Malicious, antitumor, treatment diabetes etc. have important pharmacological activity.

It is developed to drug there are many iminosugar and lists (such as NBDNJ, Miglitol, Miglustat etc.).

In iminosugar, Indolizidine class compound has consequence, many Indolizidine class imino groups Sugar has good bioactivity [such as (-)-swainsonine, (-)-castanospermine etc.], there is huge answer Use prospect.Due to the good nature that Indolizidine class iminosugar is shown, the Indolizidine with novel structure is found Alkaloid becomes field concerned by people.

STEVIA REBAUDIANA alkali is the Indolizidine class iminosugar with alkyl side chain found for the first time in recent years, novel Structure causes the research interest of people.In recent years, in order to further study the chemistry and bioactivity of STEVIA REBAUDIANA alkali, about sweet tea The research of leaf chrysanthemum alkali appears in the newspapers repeatly.And the bioactivity research for developing a kind of convenient, general synthetic method and system becomes The emphasis of this field researcher concern.

Summary of the invention

Inhibit glycosidase activity the object of the present invention is to provide a kind of new having and can be used in treating the change of diabetes Close object and its precursor compound and their pharmaceutically acceptable salts.

To achieve the goals above, in a first aspect, the present invention provides a kind of Indolizidine iminosugar, the iminosugar For the compound or its pharmaceutically acceptable salt of structure shown in Formulas I:

Wherein, R¹For hydrogen atom or methylol, R²Linear chain or branched chain saturated alkyl, allyl, benzyl selected from C1-C12 and At least one of the benzyl that hydrogen atom on phenyl ring is replaced by methoxyl group or halogen；1, the spatial configuration of 2,3,5 and 8a carbon It is each independently R or S；And work as R¹For methylol, R²When for methyl, the iminosugar does not include 1,2,3,5 and 8a carbon The compound of respectively following spatial configuration: (1R, 2R, 3R, 5R, 8aR), (1R, 2S, 3R, 5R, 8aR), (1R, 2S, 3R, 5S, 8aR), (1S, 2R, 3S, 5S, 8aS) and (1S, 2R, 3S, 5R, 8aS).

Second aspect, the present invention provide the precursor compound of aforementioned iminosugar, which is knot shown in Formula XIV The compound of structure or its pharmaceutically acceptable salt:

Wherein, R³And R⁸It is each independently selected from the linear chain or branched chain saturated alkyl, allyl, propylidene base, acetyl of C1-C12 The benzyl that hydrogen atom on base, benzoyl, benzyl and phenyl ring is replaced by methoxyl group or halogen；

R⁷For hydrogen atom or R⁷For linear chain or branched chain saturated alkyl, allyl, acetyl group, the benzene of oxygen atom and C1-C12 The methylol that at least one of the benzyl that hydrogen atom on formoxyl, benzyl and phenyl ring is replaced by methoxyl group or halogen is connected；

R²Hydrogen atom on linear chain or branched chain saturated alkyl, allyl, benzyl and phenyl ring selected from C1-C12 is by methoxyl group Or at least one of the benzyl that halogen replaces；

The spatial configuration of 1,2,3,5 and 8a carbon in the compound of structure shown in Formula XIV respectively in Formulas I 1,2,3, 5 is identical with the spatial configuration of 8a carbon；And work as R⁷For benzyloxymethyl, R²When for methyl, the precursor compound do not include 1,2, 3,5 and 8a carbon is respectively the compound of following spatial configuration: (1S, 2R, 3S, 5S, 8aS) and (1S, 2R, 3S, 5R, 8aS).

The third aspect, the present invention provides the preparation method of aforementioned Indolizidine iminosugar, this method comprises: in acidity Under the conditions of, in the presence of a catalyst, present invention precursor compound above-mentioned is subjected to hydrogenation；Or

In the presence of a lewis acid, present invention precursor compound above-mentioned is subjected to deprotection reaction.

Fourth aspect, the present invention provide a kind of method for preparing present invention precursor compound above-mentioned, this method include with Lower step:

(1) nitrone shown in Formula II is reacted with Grignard Reagent, obtains azanol shown in formula III；

(2) azanol shown in the formula III is subjected to reduction reaction, obtains amine shown in formula IV；

(3) under alkaline condition, amine shown in the formula IV is subjected to protection reaction, obtains Formula V compound represented；

(4) the Formula V compound represented is subjected to oxidation reaction, obtains ketone shown in Formula IV；

(5) ketone shown in the Formula IV is subjected to reduction reaction, obtains alcohol shown in Formula VII；

(6) alcohol shown in the Formula VII is subjected to sulfonating reaction, obtains Formula VIII compound represented；

(7) Formula VIII compound represented is subjected to deprotection reaction, obtains amine shown in Formula IX；

(8) amine shown in Formula IX is subjected to ring closure reaction, obtains precursor compound shown in Formula XIV；

Wherein, R³、R⁸And R⁷Definition it is identical as present invention definition above-mentioned；

R in Formula V-Formula VIII⁴Correspondence is identical, and R⁴Selected from tertbutyloxycarbonyl, fluorenylmethoxycarbonyl, acetyl group, allyl, benzyl At least one of benzyloxycarbonyl group obtained by hydrogen atom in oxygen carbonyl and phenyl ring is replaced by methoxyl group or halogen；

R in Formula VIII and Formula IX⁵It is identical, and R⁵Selected from selected from mesyl, trifyl, benzenesulfonyl, to first At least one of benzenesulfonyl obtained by hydrogen atom on benzenesulfonyl and phenyl ring is replaced by methoxyl group or halogen；

The spatial configuration of 1,2 and 3 carbon in Formula II-Formula IX respectively in the compound of structure shown in Formula XIV 1,2 and The spatial configuration of 3 carbon corresponds to identical；The spatial configuration of 4 carbon in formula III-Formula IX is identical, is R or S configuration；Formula VII-formula The spatial configuration of 8 carbon in IX is identical, is R or S configuration.

5th aspect, the present invention provide a kind of method for preparing present invention precursor compound above-mentioned, this method include with Lower step:

(4) Formula V compound represented is subjected to oxidation reaction, obtains aldehyde shown in Formula X；

(5) aldehyde shown in Formula X is reacted with Grignard Reagent, obtains alcohol shown in Formula XI；

(6) alcohol shown in Formula XI is subjected to sulfonating reaction, obtains Formula XII compound represented；

(7) Formula XII compound represented is subjected to deprotection reaction, obtains amine shown in Formula XIII；

(8) amine shown in Formula XIII is subjected to ring closure reaction, obtains precursor compound shown in Formula XIV；

R in Formula V and Formula X-Formula XII⁴Correspondence is identical, and R⁴Definition it is identical as present invention definition above-mentioned；

R in Formula XII-Formula XIII⁵It is identical, and R⁵Definition it is identical as present invention definition above-mentioned；

R in Formula XI and Formula XIII⁶It is identical, and R⁶Linear chain or branched chain saturated alkyl, allyl, propylidene selected from C1-C12 At least one of the benzyl that hydrogen atom on base, acetyl group, benzoyl, benzyl and phenyl ring is replaced by methoxyl group or halogen；

The spatial configuration change with structure shown in Formula XIV respectively of 1,2 and 3 carbon in Formula II-Formula V and Formula X-Formula XIII The spatial configuration of 1,2 and 3 carbon in conjunction object corresponds to identical；The three-dimensional structure of 4 carbon in formula III-Formula V and Formula X-Formula XIII Type is identical, is R or S configuration；The spatial configuration of 8 carbon in Formula XI-Formula XIII is identical, is R or S configuration.

6th aspect, the present invention provide the precursor compound or its medicine of iminosugar above-mentioned or iminosugar above-mentioned Application of the acceptable salt in the drug that preparation inhibits glycosidase activity on.

7th aspect, the present invention provide iminosugar above-mentioned or its pharmaceutically acceptable salt preparation prevention and/ Or the application in treatment diabetes, prevention and/or treatment gaucher's disease, prevention and/or treatment tumour and antiviral drug.

Indolizidine iminosugar provided by the invention or its pharmaceutically acceptable salt have the work for inhibiting glycosidase Property and can be used in treat diabetes.Moreover, the precursor compound of Indolizidine iminosugar provided by the invention also has Inhibit the active effect of glycosidase.

The method provided by the invention for preparing the Indolizidine iminosugar and its precursor compound is at low cost Honest and clean advantage.

Other features and advantages of the present invention will the following detailed description will be given in the detailed implementation section.

Specific embodiment

Detailed description of the preferred embodiments below.It should be understood that described herein specific Embodiment is merely to illustrate and explain the present invention, and is not intended to restrict the invention.

First aspect, the present invention provides a kind of Indolizidine iminosugar, which is structure shown in Formulas I Compound or its pharmaceutically acceptable salt:

The linear chain or branched chain saturated alkyl of the C1-C12 includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl Base, tert-butyl, n-pentyl, isopentyl, n-hexyl, cyclopropyl, methylcyclopropyl groups, ethyl cyclopropyl, cyclopenta, methyl ring penta At least one of base, cyclohexyl, n-heptyl, n-octyl, n-nonyl, positive decyl, n-undecane base and dodecyl.

The halogen includes at least one of fluorine, chlorine, bromine and iodine.

Preferably, the iminosugar is selected from least one of following compound or its pharmaceutically acceptable salt:

Second aspect, the present invention provides the precursor compound of aforementioned iminosugar, which is shown in Formula XIV The compound of structure or its pharmaceutically acceptable salt:

The third aspect, the present invention provides the preparation methods of aforementioned Indolizidine iminosugar, this method comprises: in acid Property under the conditions of, in the presence of a catalyst, present invention precursor compound above-mentioned is subjected to hydrogenation；Or

In the preparation method of the Indolizidine iminosugar, the catalyst includes but are not limited to palladium carbon, palladium Black, palladium dydroxide, palladium chloride, platinum oxide, platinum black, ruthenic chloride and Wilkinson catalyst.

The hydrogenation preferably carries out in the presence of hydrogen source, and the hydrogen source includes but are not limited to hydrogen, ammonium formate, connection Imido, cyclohexene and cyclohexadiene.

The acid condition preferably carries out in the presence of organic acid or inorganic acid, wherein the organic acid includes formic acid, second At least one of acid, p-methyl benzenesulfonic acid and benzoic acid；The inorganic acid include in sulfuric acid, hydrochloric acid, phosphoric acid and perchloric acid extremely Few one kind.

The lewis acid is preferably selected from boron trifluoride, boron chloride, Boron tribromide, Iodotrimethylsilane and titanium tetrachloride At least one of.

The preparation method of the Indolizidine iminosugar preferably carries out in the presence of solvent, and the solvent includes first Alcohol, ethyl alcohol, acetonitrile, tetrahydrofuran, toluene, acetone, methylene chloride, chloroform, 1,2- dichloroethanes, N,N-dimethylformamide and At least one of dimethyl sulfoxide.

The condition of the deprotection reaction includes: that temperature is 0-100 DEG C；Time is 0.1-24 hours, and preferably 2-3 is small When.

The condition of the hydrogenation can be identical or different with the condition of the deprotection reaction；Preferably, the hydrogen It is 0-100 DEG C that the condition for changing reaction, which includes: temperature,；Time is 0.1-24 hours, preferably 2-3 hours.

Fourth aspect, the present invention provides a kind of method for preparing present invention precursor compound above-mentioned, this method includes Following steps:

R in Formula V-Formula VIII⁴Correspondence is identical, and R⁴Selected from tertbutyloxycarbonyl, fluorenylmethoxycarbonyl, acetyl group, allyl, benzyl At least one of benzyloxycarbonyl group obtained by hydrogen atom in oxygen carbonyl and phenyl ring is replaced by methoxyl group or halogen

R in Formula VIII and Formula IX⁵It is identical, and R⁵Selected from mesyl, trifyl, benzenesulfonyl, to toluene sulphur At least one of benzenesulfonyl obtained by hydrogen atom on acyl group and phenyl ring is replaced by methoxyl group or halogen,

Preferably, in step (1), the Grignard Reagent is prepared by the bromo- 1- amylene of 5-.Nitre shown in the Formula II The dosage molar ratio of ketone and Grignard Reagent is 1:(1-100), preferably 1:(1.5-10).Nitrone and Grignard Reagent shown in Formula II into The condition of row reaction includes: that temperature is subzero 80 DEG C to 100 DEG C above freezing, preferably subzero 10 DEG C to 20 DEG C above freezing；Time is 0.1-100h, preferably 3-60h.

Preferably, in step (2), the reduction reaction carries out in the presence of a reducing agent.The reducing agent includes but not It is limited at least one of zinc powder-copper acetate and its hydrate and zinc powder-acid.When the reducing agent be zinc powder-copper acetate and its When hydrate, the dosage molar ratio of azanol, zinc powder shown in formula III and copper acetate is 1:(10-100): (0.1-1), preferably 1:(10-20): (0.1-0.5), and the solvent of the reduction reaction is preferably glacial acetic acid, the condition of the reduction reaction includes: Temperature be 0-100 DEG C, preferably 10-55 DEG C, time 0.1-100h, preferably 4-24h.When the reducing agent is zinc powder-acid When, the dosage molar ratio of azanol, zinc powder shown in formula III is 1:(10-100), preferably 1:(10-20), in the reducing agent Acid be preferably ammonium chloride saturated solution, the solvent of the reduction reaction is methanol, and the condition of the reduction reaction includes: temperature Degree be 0-100 DEG C, preferably 10-55 DEG C, time 0.1-100h, preferably 4-24h.

Preferably, in step (3), the alkaline condition is formed by the presence of alkaline matter.The alkaline matter It include organic base and/or inorganic base.The protection reaction carries out in the presence of protectant, amine shown in the formula IV, alkali Property substance and protectant dosage molar ratio be 1:(1-100): (1-100), preferably 1:(1-10): (1-20)；The protection The condition of reaction include: temperature be 0-100 DEG C, preferably 10-55 DEG C, time 0.1-100h, preferably 0.5-8h.

Preferably, in step (4), the oxidation reaction carries out in the presence of palladium salt and mantoquita.The palladium salt is chlorine Change palladium and/or palladium acetate；The mantoquita include but are not limited to stannous chloride, cuprous bromide, copper chloride, copper bromide, copper sulphate, Copper acetate and its hydrate.The dosage molar ratio of the Formula V compound represented, palladium salt and mantoquita is 1:(0.1-10): (0.1- 10)；Preferably 1:(0.1-0.5): (0.1-1).The condition of the oxidation reaction includes: that temperature is 0-100 DEG C, preferably 5-55 DEG C, time 0.1-200h, preferably 24-100h.

Preferably, in step (5), the reduction reaction carries out in the presence of a reducing agent, and the reducing agent is selected from hydrogenation Aluminium lithium, diisobutyl aluminium hydride, sodium borohydride, sodium cyanoborohydride, borine (such as borine-tetrahydrofuran and/or borine-two Methyl sulfide), in bis- (2- methoxyethoxy) sodium aluminates (red aluminum) of dihydro and 3-sec-butyl lithium borohydride (L-Selectride) It is at least one.The dosage molar ratio of ketone shown in the Formula IV and reducing agent is 1:(1-100), preferably 1:(1-10).It is described The condition of reduction reaction includes: that temperature is subzero 80 DEG C to 100 DEG C above freezing, and preferably subzero 10 DEG C to 25 DEG C above freezing, the time is 0.1-100h, preferably 0.5-1h.

Preferably, in step (6), the sulfonating reaction carries out in the presence of alkaline matter and sulfonylation agent.It is described Alkaline matter includes organic base and/or inorganic base.The dosage of alcohol shown in the Formula VII, sulfonylation agent and alkaline matter Molar ratio is 1:(1-10): (1-100)；Preferably 1:(1-5): (1.5-20).The condition of the sulfonating reaction includes: that temperature is Subzero 80 DEG C to 100 DEG C above freezing, preferably subzero 10 DEG C to 25 DEG C above freezing；Time is 0.1-100h, preferably 0.5-8h.

Preferably, in step (7), when protecting group is tertbutyloxycarbonyl, deprotection reaction carries out in acid condition, The acid condition is formed in the presence of acidic materials, and the acidic materials include hydrochloric acid, sulfuric acid, trifluoroacetic acid, boron trifluoride And boron chloride；The Formula VIII compound represented and the dosage molar ratio of acidic materials are 1:(1-1000), preferably 1: (1-100)；The condition of the deprotection reaction includes: that temperature is subzero 80 DEG C to 100 DEG C above freezing, 10 DEG C to zero preferably subzero Upper 25 DEG C；Time is 0.1-100h, preferably 0.5-8h.When protecting group is benzyloxycarbonyl group, deprotection reaction is in catalytic hydrogenation Under the conditions of carry out, the catalyst in the catalytic hydrogenation conditions includes but is not limited to palladium carbon, palladium black, palladium dydroxide, palladium chloride, oxygen Change platinum and platinum black；Hydrogen source in the catalytic hydrogenation conditions includes but is not limited to hydrogen, ammonium formate, connection imido, cyclohexene and ring Hexadiene；The Formula VIII compound represented and the dosage weight ratio of catalyst are 1:(0.1-10), preferably 1:(0.1- 0.5)；The condition of the deprotection reaction includes: that temperature is subzero 80 DEG C to 100 DEG C above freezing, and preferably subzero 10 DEG C extremely above freezing 25℃；Time is 0.1-100h, preferably 2-24h.

Preferably, in step (8), the ring closure reaction carries out in the presence of a basic.The alkaline matter wraps Include organic base and/or inorganic base.The dosage weight ratio of amine shown in the Formula IX and the alkaline matter is 1:(0.1-10)；It is excellent It is selected as 1:(0.1-0.5).The condition of the ring closure reaction includes: that temperature is subzero 80 DEG C to 100 DEG C above freezing, preferably 10-45 ℃；Time is 0.1-100h, preferably 10-40h.

Preferably, the organic base includes triethylamine, diisopropyl ethyl amine, tetramethylethylenediamine, pyridine, hexahydro pyrrole Pyridine, 2,4,6- trimethylpyridine and tetrabutyl ammonium fluoride；The inorganic base includes sodium hydroxide, potassium hydroxide, lithium hydroxide, carbon Sour sodium, potassium carbonate, sodium bicarbonate, cesium carbonate and tetrabutylammonium hydroxide.

5th aspect, the present invention provides a kind of method for preparing present invention precursor compound above-mentioned, this method includes Following steps:

The step of involved in the preparation method of the fifth aspect of the present invention (1), (2) and (3) and the fourth aspect of the present invention Preparation method in corresponding step (1), (2) and (3) it is identical, therefore, it is for the present invention 5th aspect preparation method in The operating method and parameter of the step of being related to (1), (2) and (3) etc. are identical as the fourth aspect of the present invention, and the present invention is herein not It repeats again.

Preferably, in step (4), the oxidation reaction carries out in the presence of an oxidizer, and the oxidant includes four oxygen Change at least one of osmium, potassium permanganate, potassium bichromate, chromium trioxide, ozone, sodium metaperiodate and lead tetra-acetate.The Formula V institute The dosage molar ratio of the compound and the oxidant that show is 1:(1-100), preferably 1:(1-5).The item of the oxidation reaction Part include: temperature be 0-100 DEG C, preferably 5-40 DEG C, time 0.1-100h, preferably 2-24h.

Preferably, in step (5), the Grignard Reagent is linear chain or branched chain saturated alkyl, the allyl of halogenated C1-C12 In Grignard Reagent prepared by benzyl obtained by hydrogen atom on base, benzyl and phenyl ring is replaced by methoxyl group or halogen at least It is a kind of；The dosage molar ratio of aldehyde shown in the Formula X and the Grignard Reagent is 1:(1-100), preferably 1:(1-5).Formula X institute The condition that the aldehyde shown is reacted with Grignard Reagent includes: that temperature is subzero 80 DEG C to 100 DEG C above freezing, and preferably subzero 10 DEG C extremely 25 DEG C above freezing；Time is 0.1-100h, preferably 2-24h.

Preferably, in step (6), the sulfonating reaction carries out in the presence of alkaline matter and sulfonylation agent, institute Stating alkaline matter includes organic base and/or inorganic base.The dosage of alcohol shown in the Formula XI, sulfonylation agent and alkaline matter Molar ratio is 1:(1-10): (1-100), preferably 1:(1-5): (1.5-20).The condition of the sulfonating reaction includes: that temperature is Subzero 80 DEG C to 100 DEG C above freezing, preferably subzero 10 DEG C to 25 DEG C above freezing；Time is 0.1-100h, preferably 0.5-8h.

Preferably, in step (7), when protecting group is tertbutyloxycarbonyl, deprotection reaction carries out in acid condition, The acid condition is formed in the presence of acidic materials, and the acidic materials include hydrochloric acid, sulfuric acid, trifluoroacetic acid, boron trifluoride And boron chloride；The Formula XII compound represented and the dosage molar ratio of acidic materials are 1:(1-1000), preferably 1: (1-100)；The condition of the deprotection reaction includes: that temperature is subzero 80 DEG C to 100 DEG C above freezing, 10 DEG C to zero preferably subzero Upper 25 DEG C；Time is 0.1-100h, preferably 0.5-8h.When protecting group is benzyloxycarbonyl group, deprotection reaction is in catalytic hydrogenation Under the conditions of carry out, the catalyst in the catalytic hydrogenation conditions includes but is not limited to palladium carbon, palladium black, palladium dydroxide, palladium chloride, oxygen Change platinum and platinum black；Hydrogen source in the catalytic hydrogenation conditions includes but is not limited to hydrogen, ammonium formate, connection imido, cyclohexene and ring Hexadiene；The Formula XII compound represented and the dosage weight ratio of catalyst are 1:(0.1-10), preferably 1:(0.1- 0.5)；The condition of the deprotection reaction includes: that temperature is subzero 80 DEG C to 100 DEG C above freezing, preferably 0-45 DEG C；Time is 0.1-100h, preferably 2-24h.

Preferably, in step (8), the ring closure reaction carries out in the presence of a basic.The alkaline matter wraps Include organic base and/or inorganic base.The dosage weight ratio of amine shown in the Formula XIII and the alkaline matter is 1:(0.1-10), Preferably 1:(0.1-0.5).The condition of the ring closure reaction includes: that temperature is subzero 80 DEG C to 100 DEG C above freezing, preferably 0-45 ℃；Time is 0.1-100h, preferably 10-50h.

6th aspect, the present invention provides the precursor compound of iminosugar above-mentioned or iminosugar above-mentioned or its Application of the pharmaceutically acceptable salt in the drug that preparation inhibits glycosidase activity.

Preferably, the glycosidase is selected from alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta galactose Glycosides enzyme, alpha-Mannosidase, beta-Mannosidase, alpha-L-fucosidase, trehalase, amyloglucosidase and α-L- mouse At least one of Lee's glycosidase.

7th aspect, the present invention provides iminosugars above-mentioned or its pharmaceutically acceptable salt to prevent in preparation And/or treat answering in diabetes, prevention and/or treatment gaucher's disease, prevention and/or treatment tumour and antiviral drug With.

In the drug, one or more pharmaceutically acceptable carriers can also be added.The carrier includes pharmacy Diluent, excipient, filler, adhesive, wetting agent, disintegrating agent, sorbefacient, the surfactant, suction of field routine Appendix body, lubricant and other additives.

The drug can be a variety of shapes such as injection, tablet, pulvis, granule, capsule, oral solution, paste, creme Formula.The drug of above-mentioned various dosage forms can be prepared according to the conventional method of pharmaceutical field.

The drug can be administered using various administration routes, including but not limited to oral, sucking, rectum, transdermal, transmucosal Enteral administration and subcutaneous, muscle or intravenous injection administration.

Drug of the present invention can be administered alone, or with known other treatment diabetes, antiviral, antibacterial and anti-swollen Tumor medicine is administered together.

The advantages of method of the invention further includes in detail below:

Using polyhydroxy nitrone as starting material, the Indolizidine with certain bioactivity is prepared for by multistep reaction Class iminosugar realizes succinct, the efficient preparation of such compound.The raw materials used in the present invention can by cheap xylose, The preparation such as arabinose, ribose and malic acid, raw material are easy to get, and preparation method is simple, mild condition, and the purifying of intermediate is held Easily.Method of the invention is easily achieved a large amount of synthesis, can synthesize a large amount of Indolizidine class iminosugars in a short time, for sieve Choosing has the compound of bioactivity and medical value to provide solid foundation.

The present invention will be described in detail by way of examples below.

In the case where no explanation on the contrary, various raw materials used below are all from commercially available.

Preparation example: preparation formula II-1 to II-6 compound represented is (using side identical with compound shown in preparation II-1 Method and corresponding raw material sugar prepare II-2 to II-4 and II-6 compound represented)

Ice bath under stirring condition, is added dropwise 10mL chloroacetic chloride into the dry methanol of 500mL, D- xylose is then added (0.2mol), keeps zero degree reaction until raw material disappearance, is neutralized to neutrality with sodium bicarbonate, filtering removal inorganic salts are evaporated molten Crude product D- furyl xylose first glycosides obtained by agent directly throws the next step.

Upper step crude product D- furyl xylose first glycosides (calculating according to 0.2mol) is dissolved into dry DMF (200mL), and It is added drop-wise in the THF containing NaH (0.72mol) (200mL) and DMF (200mL), finishes dropwise, TBAI (tetrabutyl iodate is added Ammonium) (2.0g), it after half an hour, is added dropwise BnBr (0.66mol), reaction disappears until raw material, and saturated ammonium chloride is slowly added dropwise Aqueous solution quenching reaction, ethyl acetate/water extraction, washing organic phase remove DMF, and solvent evaporated obtains 2,3,5-O- tri- benzyl of crude product Base-D- furyl xylose first glycosides, directly throwing the next step.

Upper step crude product 2,3,5-O- tribenzyl-D- furyl xylose first glycosides (calculating by 0.2mol) is dissolved into 80 weight % Acetic acid aqueous solution in (150mL) and Isosorbide-5-Nitrae-dioxane (150mL) in the mixed solvent, add aqueous sulfuric acid (1mol/ L, 150mL), reflux almost disappears until raw material, solvent evaporated, with ethyl acetate/saturated sodium carbonate solution extraction, is evaporated Organic phase obtains crude product (hemiacetal crude product) (2,3,5-O- tribenzyl-D- furyl xylose) and directly throws into reaction in next step.

Above-mentioned crude product 2,3,5-O- tribenzyl-D- furyl xylose is added in pyridine (0.37mol) (to count according to 0.2mol Calculate) methylene chloride (100mL) solution in, be charged with O- methyl hydroxylamine hydrochloride (0.25mol), after 12h is stirred at room temperature, Solvent is evaporated, ethyl acetate (150mL) and hydrochloric acid (1mol/L, 30mL) are then added into concentrate, by extracting and demixing, Merge organic phase, dry, concentration obtains crude product (2S, 3S, 4R) -2,3,5- tri- benzyloxy -4- hydroxyl -1- valeral methyloxime ethers, It directly throws into reaction in next step.

Three benzyloxy -4- hydroxyl -1- valeral methyloxime ether of above-mentioned crude product (2S, 3S, 4R) -2,3,5- (is pressed into 0.2mol Calculate) it is dissolved in methylene chloride (100mL), pyridine (0.37mol) and methane sulfonyl chloride (0.20mol) is added, after 8h is stirred at room temperature, Aqueous hydrochloric acid solution (1mol/L) is added, the reaction is quenched.By extracting and demixing, merge organic phase, dry, concentration obtains crude product (2S, 3S, 4R) -2,3,5- tri- benzyloxy -4- sulfonyloxy methyl oxygen -1- valeral methyloxime ethers are directly used in and react in next step.

It (is pressed toward three benzyloxy -4- sulfonyloxy methyl oxygen -1- valeral methyloxime ether of above-mentioned crude product (2S, 3S, 4R) -2,3,5- 0.2mol calculate) tetrahydrofuran (300mL) solution in be added p-methyl benzenesulfonic acid (0.2mol) and 37 weight % formaldehyde it is water-soluble Liquid (50mL) is stirred at room temperature until raw material completely disappears, and then addition ethyl acetate and water into mixed liquor, divide by extraction Layer merges organic phase, dry, concentration, gained crude product (2R, 3R, 4R) -4- mesyloxy -2,3, tri- benzyloxy -1- penta of 5- Aldehyde.

First sodium bicarbonate (0.45mol) is added in the aqueous solution (50mL) of hydroxylamine hydrochloride (0.45mol), is added thereto The ethyl alcohol of above-mentioned three benzyloxy -1- valeral of crude product (2R, 3R, 4R) -4- mesyloxy -2,3,5- (calculating by 0.2mol) is molten 15h, rear heating stirring 48h is stirred at room temperature in liquid (200mL).Then ethyl acetate and water are added into mixed liquor, by extraction point Layer merges organic phase, dry, and concentration obtains yellow oil.The grease is dissolved in ethyl acetate and petroleum ether, room temperature is put It sets overnight, white solid 10.40g is precipitated, mother liquor continues to crystallize, 9.95g white solid of getting back, and mother liquor is purified by column chromatography After get back white solid 1.35g, amount to 22.00g nitrone product ((3S, 4S, 5S) -3,4- benzyloxy -5- benzyloxymethyl - 1- pyrrolin-N- oxide), as -1 compound represented of Formula II.It is calculated by raw material of xylose, seven steps reaction gross production rate is 26%.

Its structural identification data is: m.p.:90-91 DEG C；[α] D=+45 ° of (c 0.4, CHCl₃)；IR(cm^-1): 3049 (w), 2945,2923,2901,2884,2868,2851 (w), 1593 (s), 1551 (s), 1496 (s), 1452 (s), 1361 (s), 1247 (vs), 1131 (vs), 1247 (vs), 1028 (vs)；¹H-NMR (300MHz, CDCl₃): δ 7.38-7.26 (m, 15H), 6.91 (d, J=1.9Hz, 1H), 4.69-4.67 (m, 1H), 4.64-4.46 (m, 6H), 4.39 (dd, J=3.2,2.2Hz, 1H), 4.10-4.04 (m, 2H), 3.78 (d, J=7.3Hz, 1H)；¹³C-NMR (75MHz, CDCl₃): δ 66.03,71.67,71.91, 73.47,80.30,82.74,127.70,127.75,127.92,128.14,128.17,128.38,128.55,128.61, 133.02,137.06,137.16,137.63；FT-ICRMS:m/z 418.2007 [M+H]+(C₂₆H₂₈NO₄requires 418.2013)。

Preparation formula II-5 compound represented:

Under ice-water bath, thionyl chloride is added dropwise into the dehydrated alcohol (600mL) of L-TARTARIC ACID (0.67mol) (1.47mol), room temperature reaction is overnight.Morning next day end of reaction, low-temperature reduced-pressure are spin-dried for solvent, ethyl acetate dissolution, unsaturated carbonate Hydrogen sodium water solution is washed till neutrality, and drying is concentrated to give colorless oil as product ethyl tartrate, yield 94%.

Ethyl tartrate (36.4mmol) is dissolved into dry N,N-dimethylformamide (100mL) and tetrahydrofuran In (50mL), gains are added dropwise to the tetrahydrofuran of NaH (2.4 times of equivalents, 80mmol, 60%) under the conditions of -20 DEG C In (50mL), be added the tetrabutylammonium iodide of catalytic amount, keep 10min, be slowly added dropwise BnBr (2.2 times of equivalents, 73.35mmol), -20 DEG C of reactions, TLC (petrol ether/ethyl acetate 5:1) monitoring reaction are kept.End of reaction, to be saturated chlorination The careful quenching reaction of aqueous ammonium, ethyl acetate/saturated aqueous ammonium chloride extraction, washing removal n,N-Dimethylformamide, Dry, concentration, column chromatograph double benzyl protections ethyl tartrate, yield 82%.

The ethyl tartrate (112mmol) of double benzyl protections is dissolved into the dry ether of 500mL, under ice-water bath, It is added portionwise Lithium Aluminium Hydride (2 times of equivalents, 224mmol), after reacting at room temperature 30min, ice is carefully quenched to 0 DEG C with ethyl acetate Reaction is slowly added dropwise saturated aqueous ammonium chloride to system and clarifies, pours out supernatant, and ethyl acetate/water extracts paste, merges Organic phase, dry, concentration, column chromatography (petrol ether/ethyl acetate 3:2) obtain oil product glycol, yield 93%.

The glycol (0.66mmol) that upper step is reacted is dissolved into the dry methylene chloride of 5mL, and triethylamine (2.5 is added Times equivalent, 1.65mmol), under ice-water bath, it is added dropwise methylsufonyl chloride (2.2 times of equivalents, 1.45mmol), room temperature reaction 1 is small When fully reacting, decompression is spin-dried for solvent, and ethyl acetate/saturated aqueous ammonium chloride extraction merges organic phase, dry, concentration, column It chromatographs (petrol ether/ethyl acetate 3:1) and obtains the double methylsulfonyl esters of rufous oil product, yield 91%.

Double methylsulfonyl esters (0.60mmol) are dissolved into the dry triethylamine of 10mL, addition hydroxylamine hydrochloride (4 times of equivalents, 2.4mmol), back flow reaction 1.5 hours, fully reacting, decompression are spin-dried for solvent, and ethyl acetate/saturated aqueous ammonium chloride extracts, Merge organic phase, dry, concentration, column chromatography (petrol ether/ethyl acetate 2:1) obtain oil product cyclic hydroxylamine, yield 84%.

Cyclic hydroxylamine (0.50mmol) is dissolved into the dry methylene chloride of 5mL, under ice bath, yellow mercury oxide (2 is added Times equivalent, 1.0mmol), room temperature reaction overnight, fully reacting (TLC petrol ether/ethyl acetate 1:2), diatomite filtering, decompression It is spin-dried for solvent, concentration, column chromatography (petrol ether/ethyl acetate 1:2) obtain oil product II-5, yield 94%.

Its structural identification data is:¹H NMR (300MHz, CDCl3) δ 7.43-7.28 (m, 10H), 6.89 (d, J= 1.7Hz,1H),4.69(s,1H),4.58(s,2H),4.56(s,2H),4.32–4.25(m,2H),3.91-3.83(m,1H).¹³C NMR(75MHz,CDCl3)δ136.8,136.7,132.2,128.6,128.5,128.3,128.2,128.0,127.9,83.7, 78.4,72.0,71.9,66.9.

Embodiment 1: prepare Indolizidine class iminosugar I-1a, I-1b and its intermediate

It is bromo- that 5- is added under argon gas protection, in the tetrahydrofuran of steaming again (15mL) suspension for the magnesium chips (24mmol) newly polished 1- amylene (17mmol) is heated to 50 DEG C of reactions, and a large amount of bubbles occurs in system, and solution is in Dark grey, the reaction was continued 0.5h.By nitre Ketone II-1 (12mmol) is dissolved in dry tetrahydrofuran, and under condition of ice bath, above-mentioned Grignard Reagent is added dropwise by syringe Enter, adds within 15 minutes, the reaction was continued 1h, TLC monitoring display raw material disappearance, addition saturated ammonium chloride solution quenching reaction, acetic acid Ethyl ester extraction directly removes solvent under vacuum and obtains the crude product of III-1 without drying.

The crude product of III-1 is dissolved in acetic acid, preactivated good zinc powder (0.12mol) and Cu (OAc) are added to₂(contain Two molecular crystalline water, 1.2mmol) glacial acetic acid mixture in (the processed zinc powder of dilute hydrochloric acid and copper acetate are placed in glacial acetic acid Middle stirring, until rufous occurs in system), system is highly exothermic, and overnight, TLC monitoring display raw material reacts completely for room temperature reaction, Solvent is removed under vacuum, obtained solid is washed through ethyl acetate, and NaOH saturated solution adjusts pH=9 or so, ethyl acetate extraction Water phase merges organic phase, and anhydrous magnesium sulfate is dry, filters and removes solid, removes solvent under vacuum, obtain the crude product of IV-1.

By the crude product of IV-1 in methylene chloride (20mL), it is added triethylamine (15mmol) and (Boc)₂O (13mmol), room Temperature reaction 2h, TLC monitoring raw material point completely disappears, and saturated ammonium chloride quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is added It is dry, it filters and removes solid, solvent is removed under vacuum, column chromatography (petroleum ether: ethyl acetate=30:1) obtains alkene V-1, is Colorless viscous shape liquid 3.2g, yield 48%.Structural identification:

¹H NMR(300MHz,CDCl₃) δ 7.34 (dt, J=19.1,7.7Hz, 15H), 5.87 (dq, J=11.1,7.0Hz, 1H), 5.05 (t, J=14.8Hz, 2H), 4.79-4.41 (m, 6H), 4.33 (dd, J=10.4,3.8Hz, 0.5H), 4.27 (d, J =7.9Hz, 1H), 4.21-4.08 (m, 1H), 4.01-3.83 (m, 2H), 3.78 (d, J=9.1Hz, 0.5H), 3.58 (dd, J= 19.0,9.3Hz,1H),2.28–1.99(m,3H),1.97–1.64(m,2H),1.60–1.24(m,12H).¹³C NMR(75MHz, CDCl₃)δ154.16,153.79,138.76,138.56,138.45,138.13,137.87,137.82,129.76,128.53, 128.46,128.44,128.38,127.76,127.74,127.64,127.54,114.87,114.60,84.72,83.43, 83.38,81.92,79.66,79.60,77.73,77.31,76.88,73.09,73.06,71.30,71.05,70.93, 68.86,68.10,64.73,64.50,62.74,62.57,33.72,33.60,31.20,30.07,28.62,28.58, 26.18,26.11。

Substrate V-1 (2.4mmol) is dissolved in 10mL in the mixed solvent, palladium acetate (0.96mmol) and copper acetate (band is added The crystallization water, 4.8mmol), it is reacted at room temperature 4 days under oxygen atmosphere, TLC monitors fully reacting, and saturated ammonium chloride is added and is quenched instead It answers, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, removes solvent under vacuum, obtain the crude product of ketone VI-1.

Under condition of ice bath, the crude product (in terms of 2mmol) of VI-1 is dissolved in the methanol of 15mL, sodium borohydride is slowly added to (2.5mmol) adds rear system into light gray, and TLC monitoring raw material point disappears after 30min, and saturated ammonium chloride quenching reaction is added, Methanol is removed under vacuum, the thick white oil object of gained is redissolved in saturated ammonium chloride, ethyl acetate extraction, anhydrous slufuric acid Magnesium is dry, filters and removes solid, removes solvent under vacuum and obtains the crude product of VII-1.

The crude product of VII-1 is redissolved in 5mL dry methylene chloride, is added triethylamine (3mmol), is delayed under condition of ice bath It is slow that methylsufonyl chloride (2.4mmol) is added, it adds and moves back except ice bath, react at room temperature 1h, TLC monitors raw material point and disappears, and is added full With ammonium chloride quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, removes solvent under vacuum, obtain The crude product of VIII-1.

VIII-1 is redissolved in 5mL methylene chloride, 3mL trifluoroacetic acid is added, after reacting 1h, TLC shows that raw material disappears It loses, obtains the big product of a polarity, saturation NaHCO is added₃Quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes Solid removes solvent under vacuum and obtains the crude product of IX-1.

The crude product of IX-1 is redissolved in 10mL methanol, 100mg Anhydrous potassium carbonate is added, reacts at room temperature 48h, TLC prison It surveys lesser two product points of polarized to generate, removes methanol under vacuum, the thick grease of gained is redissolved in saturation chlorination In ammonium, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, and solvent is removed under vacuum, and column chromatographs (petroleum ether: second Acetoacetic ester=15:1) obtain the polarity total 204mg of lesser point (XIV-1a), the total 225mg of the biggish point (XIV-1b) of polarity.Structure Confirmation:

XIV-1a:¹H NMR(400MHz,CDCl₃)δ7.41–7.28(m,15H),4.74–4.46(m,6H),3.96(d,J =2.6Hz, 1H), 3.77 (dd, J=8.8,3.9Hz, 1H), 3.72 (dd, J=7.7,2.6Hz, 1H), 3.62 (dd, J=9.2, 3.7Hz, 1H), 3.51 (t, J=9.0Hz, 1H), 2.65-2.59 (m, 2H), 2.00 (d, J=8.8Hz, 2H), 1.87-1.68 (m, 1H), 1.60 (d, J=9.1Hz, 1H), 1.31-1.20 (m, 4H), 1.17 (d, J=6.1Hz, 3H)；¹³C NMR(101MHz, CDCl₃)δ138.67,138.56,138.44,128.47-127.57,90.43,85.50,73.61,71.95,71.32, 65.41,64.28,62.89,52.13,34.40,30.79,24.19,20.30。

XIV-1b:¹H NMR(400MHz,CDCl₃)δ7.38–7.28(m,16H),4.65–4.50(m,6H),3.96(t,J =3.2Hz, 1H), 3.93 (dd, J=6.5,3.2Hz, 1H), 3.62 (dd, J=9.3,5.5Hz, 1H), 3.50 (t, J= 8.7Hz,1H),3.38-3.31(m,2H),3.01–2.94(m,1H),1.79–1.69(m,2H),1.66-1.54(m,3H), 1.30-1.20 (m, 3H), 1.14 (d, J=6.4Hz, 3H)；¹³C NMR(101MHz,CDCl₃)δ138.65,138.55,128.4- 127.64,88.02,85.65,73.42,72.25,71.85,71.70,66.15,59.46,51.34,29.80,24.61, 20.99,19.00。

Substrate XIV-1a (200mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, 0.5mL is added 3N hydrochloric acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, palladium carbon is filtered to remove by diatomite, under vacuum Solvent is removed, is neutralized by ammonium hydroxide, is handled by acidic resins column, obtain I-1a, is weak yellow liquid 72mg, yield 85%. Structural identification:

¹H NMR(300MHz,D₂O) δ 3.98 (dd, J=4.3,1.9Hz, 1H), 3.87 (dd, J=11.7,3.9Hz, 1H), 3.67 (dd, J=11.7,7.9Hz, 1H), 3.61 (dd, J=8.7,4.3Hz, 1H), 3.12-3.08 (m, 1H), 2.70-2.57 (m, 2H), 1.87 (d, J=11.8Hz, 1H), 1.73-1.62 (m, 2H), 1.28-1.11 (m, 3H), 1.05 (d, J=6.1Hz, 3H).¹³C NMR(75MHz,D₂O)δ82.60,79.09,66.08,65.12,57.69,51.96,32.93,28.30,22.88, 18.56。

Substrate XIV-1b (200mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, 0.5mL is added 3N hydrochloric acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, palladium carbon is filtered to remove by diatomite, under vacuum Solvent is removed, is neutralized by ammonium hydroxide, is handled by acidic resins column, obtain I-1b, is weak yellow liquid 76mg, yield 89%. Structural identification:

¹H NMR(400MHz,D₂O) δ 4.08 (dd, J=10.5,6.2Hz, 1H), 3.81 (dd, J=5.9,5.1Hz, 1H), 3.62 (dd, J=11.6,6.6Hz, 1H), 3.52 (dd, J=11.6,6.9Hz, 1H), 2.98-2.94 (m, 2H), 2.79-2.69 (m, 1H), 1.75-1.65 (m, 2H), 1.62-1.38 (m, 3H), 1.17-1.11 (m, 1H), 1.00 (d, J=6.1Hz, 3H)

¹³C NMR(101MHz,D₂O)δ79.87,75.57,69.34,62.28,60.22,54.94,31.76,22.37, 19.63,17.73。

Embodiment 2: prepare Indolizidine class iminosugar I-2a, I-2b and its intermediate

It is bromo- that 5- is added under argon gas protection, in the tetrahydrofuran of steaming again (15mL) suspension for the magnesium chips (24mmol) newly polished 1- amylene (17mmol) is heated to 50 DEG C of reactions, and a large amount of bubbles occurs in system, and solution is in Dark grey, and the reaction was continued half an hour.It will Nitrone II-2 (12mmol) is dissolved in dry tetrahydrofuran, under condition of ice bath, dropwise by syringe by above-mentioned Grignard Reagent It is added, adds within 15 minutes, the reaction was continued 1h, TLC monitoring display raw material disappearance, addition saturated ammonium chloride solution quenching reaction, second Acetoacetic ester extraction, without drying, directly removes solvent under vacuum, obtains the crude product of azanol III-2.

The crude product of gained azanol III-2 is dissolved in acetic acid, is added to preactivated good zinc powder (0.12mol) and Cu (OAc)₂(the processed zinc powder of dilute hydrochloric acid is set with copper acetate in the glacial acetic acid mixture of (containing two molecular crystalline water, 1.2mmol) Stirred in glacial acetic acid, until rufous occurs in system), system is highly exothermic, and overnight, TLC monitoring shows raw material for room temperature reaction It reacts completely, removes solvent under vacuum, obtained solid is washed through ethyl acetate, and NaOH saturated solution adjusts pH=9 or so, acetic acid Ethyl ester aqueous phase extracted merges organic phase, and anhydrous magnesium sulfate is dry, filters and removes solid, removes solvent under vacuum, obtain IV-2's Crude product.

The crude product of gained IV-2 is dissolved in methylene chloride (20mL), is added triethylamine (15mmol) and (Boc)₂O (13mmol) reacts at room temperature 2h, and TLC monitoring raw material point completely disappears, and saturated ammonium chloride quenching reaction, ethyl acetate extraction is added It takes, anhydrous magnesium sulfate is dry, filters and removes solid, and solvent is removed under vacuum, and column chromatographs (petroleum ether: ethyl acetate=30:1) and obtains The colorless viscous shape liquid total 3.2g of V-2, yield 48%.Structural identification:

¹H NMR(300MHz,CDCl₃) δ 7.56-7.14 (m, 16H), 6.00-5.77 (m, 1H), 5.08 (t, J= 14.8Hz, 2H), 4.83-4.68 (m, 2H), 4.53 (ddd, J=18.1,15.1,8.1Hz, 5H), 4.36 (dd, J=10.4, 3.4Hz, 0.5H), 4.30 (d, J=8.2Hz, 1H), 4.25-4.11 (m, 1H), 4.03-3.87 (m, 2H), 3.82 (d, J= 10.3Hz, 0.5H), 3.61 (dd, J=19.0,9.5Hz, 1H), 2.17 (tt, J=14.6,7.2Hz, 3H), 2.02-1.66 (m, 2H),1.66–1.29(m,12H)；¹³C NMR(75MHz,CDCl₃)δ154.17,153.80,138.77,138.57,138.45, 138.13,137.87,137.82,128.54,128.47,128.45,128.39,127.78,127.75,127.65,127.55, 114.88,114.61,84.72,83.43,83.38,81.92,79.66,79.61,77.75,77.33,76.90,73.10, 73.06,71.30,71.06,70.93,68.87,68.10,64.73,64.52,62.75,62.58,33.72,33.61, 31.20,30.08,28.63,28.59,26.18,26.11。

Substrate V-2 (2.4mmol) is dissolved in 10mL in the mixed solvent, palladium acetate (0.96mmol) and copper acetate (band is added The crystallization water, 4.8mmol), it is reacted at room temperature 4 days under oxygen atmosphere, TLC monitors fully reacting, and saturated ammonium chloride is added and is quenched instead It answers, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, removes solvent under vacuum, obtain the crude product of VI-2.

Under condition of ice bath, the crude product (in terms of 2mmol) of ketone VI-2 is dissolved in the methanol of 15mL, sodium borohydride is slowly added to (2.5mmol) adds rear system into light gray, and TLC monitoring raw material point disappears after 30min, and saturated ammonium chloride quenching reaction is added, Methanol is removed under vacuum, the thick white oil object of gained is redissolved in saturated ammonium chloride, ethyl acetate extraction, anhydrous slufuric acid Magnesium is dry, filters and removes solid, removes solvent under vacuum, obtain the crude product of VII-2.

The crude product of gained VII-2 is redissolved in 5mL dry methylene chloride, is added triethylamine (3mmol), under condition of ice bath It is slowly added to methylsufonyl chloride (2.4mmol), adds and moves back except ice bath, reacts at room temperature 1h, TLC monitors raw material point and disappears, is added Saturated ammonium chloride quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, removes solvent under vacuum, obtain To the crude product of VII-2.

The crude product of gained VII-2 is redissolved in 5mL methylene chloride, and 3mL trifluoroacetic acid is added, and after reacting 1h, TLC is shown Raw material disappears, and saturation NaHCO is added₃Quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, vacuum Lower removing solvent, obtains the crude product of IX-2.

The crude product of gained IX-2 is redissolved in 10mL methanol, and 100mg Anhydrous potassium carbonate is added, and reacts at room temperature 48h, vacuum Lower removing methanol, the thick grease of gained are redissolved in saturated ammonium chloride, and ethyl acetate extraction, anhydrous magnesium sulfate is dry, It filters and removes solid, solvent is removed under vacuum, column chromatographs (petroleum ether: ethyl acetate=15:1), it is lesser to respectively obtain polarity Point (XIV-2a) and the biggish point of polarity.

XIV-2a:¹H NMR(400MHz,CDCl₃)δ7.41–7.28(m,15H),4.74–4.46(m,6H),3.96(d,J =2.6Hz, 1H), 3.77 (dd, J=8.8,3.9Hz, 1H), 3.72 (dd, J=7.7,2.6Hz, 1H), 3.62 (dd, J=9.2, 3.7Hz, 1H), 3.51 (t, J=9.0Hz, 1H), 2.65-2.59 (m, 2H), 2.00 (d, J=8.8Hz, 2H), 1.87-1.68 (m, 1H), 1.60 (d, J=9.1Hz, 1H), 1.31-1.20 (m, 4H), 1.17 (d, J=6.1Hz, 3H)；¹³C NMR(101MHz, CDCl₃)δ138.67,138.56,138.44,128.47-127.57,90.43,85.50,73.61,71.95,71.32, 65.41,64.28,62.89,52.13,34.40,30.79,24.19,20.30。

XIV-2b:¹H NMR(400MHz,CDCl₃)δ7.38–7.28(m,16H),4.65–4.50(m,6H),3.96(t,J =3.2Hz, 1H), 3.93 (dd, J=6.5,3.2Hz, 1H), 3.62 (dd, J=9.3,5.5Hz, 1H), 3.50 (t, J= 8.7Hz,1H),3.38-3.31(m,2H),3.01–2.94(m,1H),1.79–1.69(m,2H),1.66-1.54(m,3H), 1.30-1.20 (m, 3H), 1.14 (d, J=6.4Hz, 3H)；¹³C NMR(101MHz,CDCl₃)δ138.65,138.55,128.4- 127.64,88.02,85.65,73.42,72.25,71.85,71.70,66.15,59.46,51.34,29.80,24.61, 20.99,19.00。

Substrate XIV-2a (200mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, 0.5mL is added 3N hydrochloric acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, palladium carbon is filtered to remove by diatomite, under vacuum Solvent is removed, neutralizes by ammonium hydroxide, is handled by acidic resins column, obtain the total 76mg of weak yellow liquid I-2a, yield 91%.Knot Structure confirmation:

¹H NMR(300MHz,D₂O) δ 3.98 (dd, J=4.3,1.9Hz, 1H), 3.87 (dd, J=11.7,3.9Hz, 1H), 3.67 (dd, J=11.7,7.9Hz, 1H), 3.61 (dd, J=8.7,4.3Hz, 1H), 3.12-3.08 (m, 1H), 2.70-2.57 (m, 2H), 1.87 (d, J=11.8Hz, 1H), 1.73-1.62 (m, 2H), 1.28-1.11 (m, 3H), 1.05 (d, J=6.1Hz, 3H)。¹³C NMR(75MHz,D₂O)δ82.60,79.09,66.08,65.12,57.69,51.96,32.93,28.30,22.88, 18.56。

Substrate (200mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, the 3N salt of 0.5mL is added Acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, is filtered to remove palladium carbon by diatomite, removes under vacuum molten Agent is neutralized by ammonium hydroxide, is handled by acidic resins column, and the total 74mg of weak yellow liquid I-2b, yield 86% are obtained.Structure is true Card:

¹H NMR(400MHz,D₂O) δ 4.08 (dd, J=10.5,6.2Hz, 1H), 3.81 (dd, J=5.9,5.1Hz, 1H), 3.62 (dd, J=11.6,6.6Hz, 1H), 3.52 (dd, J=11.6,6.9Hz, 1H), 2.98-2.94 (m, 2H), 2.79-2.69 (m, 1H), 1.75-1.65 (m, 2H), 1.62-1.38 (m, 3H), 1.17-1.11 (m, 1H), 1.00 (d, J=6.1Hz, 3H).¹³C NMR(101MHz,D₂O)δ79.87,75.57,69.34,62.28,60.22,54.94,31.76,22.37,19.63,17.73。

Embodiment 3: Indolizidine class iminosugar I-3a, I-3b and its intermediate

It is bromo- that 5- is added under argon gas protection, in the tetrahydrofuran of steaming again (15mL) suspension for the magnesium chips (24mmol) newly polished 1- amylene (17mmol) is heated to 50 DEG C of reactions, and a large amount of bubbles occurs in system, and solution is in Dark grey, and the reaction was continued half an hour.It will Nitrone II-3 (12mmol) is dissolved in dry tetrahydrofuran, under condition of ice bath, dropwise by syringe by above-mentioned Grignard Reagent It is added, adds within 15 minutes, the reaction was continued 1h, TLC monitoring display raw material disappearance, addition saturated ammonium chloride solution quenching reaction, second Acetoacetic ester extraction, without drying, directly removes solvent under vacuum, obtains III-3 crude product.

Gained III-3 crude product is dissolved in acetic acid, is added to preactivated good zinc powder (0.12mol) and Cu (OAc)₂(contain Two molecular crystalline water, 1.2mmol) glacial acetic acid mixture in (the processed zinc powder of dilute hydrochloric acid and copper acetate are placed in glacial acetic acid Middle stirring, until rufous occurs in system), system is highly exothermic, and overnight, TLC monitoring display raw material reacts completely for room temperature reaction, Solvent is removed under vacuum, obtained solid is washed through ethyl acetate, and NaOH saturated solution adjusts pH=9 or so, ethyl acetate extraction Water phase merges organic phase, and anhydrous magnesium sulfate is dry, filters and removes solid, removes solvent under vacuum, obtain IV-3 crude product.

Gained IV-3 crude product is dissolved in methylene chloride (20mL), is added triethylamine (15mmol) and (Boc)₂O (13mmol), 2h is reacted at room temperature, TLC monitoring raw material point completely disappears, and saturated ammonium chloride quenching reaction, ethyl acetate extraction, anhydrous slufuric acid is added Magnesium is dry, filters and removes solid, solvent is removed under vacuum, it is total that column chromatography (petroleum ether: ethyl acetate=30:1) obtains alkene V-3 3.9g, yield 58%, structural identification:

¹³C NMR(75MHz,CDCl₃)δ155.13,138.85,138.65,138.30,138.17,128.49,128.46, 128.34,128.00,127.84,127.81,127.75,127.70,127.48,114.56,85.29,82.86,79.71, 77.71,77.29,76.86,73.36,72.96,71.72,68.39,67.14,61.81,58.52,33.76,33.07, 28.56,25.33。

Substrate V-3 (2.4mmol) is dissolved in 10mL in the mixed solvent, palladium acetate (0.96mmol) and copper acetate (band is added The crystallization water, 4.8mmol), it is reacted at room temperature 4 days under oxygen atmosphere, TLC monitors fully reacting, and saturated ammonium chloride is added and is quenched instead It answers, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, removes solvent under vacuum, obtain VI-3 crude product.

Under condition of ice bath, substrate VI-3 (in terms of 2mmol) is dissolved in the methanol of 15mL, sodium borohydride is slowly added to (2.5mmol) adds rear system into light gray, and TLC monitoring raw material point disappears after 30min, and saturated ammonium chloride quenching reaction is added, Methanol is removed under vacuum, the thick white oil object of gained is redissolved in saturated ammonium chloride, ethyl acetate extraction, anhydrous slufuric acid Magnesium is dry, filters and removes solid, removes solvent under vacuum, obtain VII-3 crude product.

Gained VII-3 crude product is redissolved in 5mL dry methylene chloride, is added triethylamine (3mmol), is delayed under condition of ice bath It is slow that methylsufonyl chloride (2.4mmol) is added, it adds and moves back except ice bath, react at room temperature 1h, TLC monitors raw material point and disappears, and enters saturation Ammonium chloride quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, removes solvent under vacuum, obtain VIII-3 crude product.

Gained VIII-3 crude product is redissolved in 5mL methylene chloride, and 3mL trifluoroacetic acid is added, and after reacting 1h, TLC is shown Raw material disappears, and saturation NaHCO is added₃Quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, vacuum Lower removing solvent, obtains IX-3 crude product.

Gained IX-3 crude product is redissolved in 10mL methanol, addition 100mg Anhydrous potassium carbonate, room temperature reaction 48h, under vacuum Methanol is removed, the thick grease of gained is redissolved in saturated ammonium chloride, and ethyl acetate extraction, anhydrous magnesium sulfate is dry, takes out Solid is filtered out, solvent is removed under vacuum, column chromatography (petroleum ether: ethyl acetate=15:1) obtains the lesser point (XIV- of polarity 3a) 211mg and biggish point (XIV-3b) 209mg of polarity, yield 43%.Structural identification:

XIV-3a:¹H NMR(400MHz,CDCl₃)δ7.41–7.28(m,15H),4.74–4.46(m,6H),3.96(d,J =2.6Hz, 1H), 3.77 (dd, J=8.8,3.9Hz, 1H), 3.72 (dd, J=7.7,2.6Hz, 1H), 3.62 (dd, J=9.2, 3.7Hz, 1H), 3.51 (t, J=9.0Hz, 1H), 2.65-2.59 (m, 2H), 2.00 (d, J=8.8Hz, 2H), 1.87-1.68 (m, 1H), 1.60 (d, J=9.1Hz, 1H), 1.31-1.20 (m, 4H), 1.17 (d, J=6.1Hz, 3H)；¹³C NMR(101MHz, CDCl₃)δ138.67,138.56,138.44,128.47-127.57,90.43,85.50,73.61,71.95,71.32, 65.41,64.28,62.89,52.13,34.40,30.79,24.19,20.30。

XIV-3b:¹H NMR(400MHz,CDCl₃)δ7.38–7.28(m,16H),4.65–4.50(m,6H),3.96(t,J =3.2Hz, 1H), 3.93 (dd, J=6.5,3.2Hz, 1H), 3.62 (dd, J=9.3,5.5Hz, 1H), 3.50 (t, J= 8.7Hz,1H),3.38-3.31(m,2H),3.01–2.94(m,1H),1.79–1.69(m,2H),1.66-1.54(m,3H), 1.30-1.20 (m, 3H), 1.14 (d, J=6.4Hz, 3H)；¹³C NMR(101MHz,CDCl₃)δ138.65,138.55,128.4- 127.64,88.02,85.65,73.42,72.25,71.85,71.70,66.15,59.46,51.34,29.80,24.61, 20.99,19.00。

Substrate XIV-3a (200mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, 0.5mL is added 3N hydrochloric acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, palladium carbon is filtered to remove by diatomite, under vacuum Solvent is removed, is neutralized by ammonium hydroxide, is handled by acidic resins column, obtain I-3a, is weak yellow liquid 69mg, yield 82%. Structural identification:

¹H NMR(300MHz,D₂O) δ 3.98 (dd, J=4.3,1.9Hz, 1H), 3.87 (dd, J=11.7,3.9Hz, 1H), 3.67 (dd, J=11.7,7.9Hz, 1H), 3.61 (dd, J=8.7,4.3Hz, 1H), 3.12-3.08 (m, 1H), 2.70-2.57 (m, 2H), 1.87 (d, J=11.8Hz, 1H), 1.73-1.62 (m, 2H), 1.28-1.11 (m, 3H), 1.05 (d, J=6.1Hz, 3H)；¹³C NMR(75MHz,D₂O)δ82.60,79.09,66.08,65.12,57.69,51.96,32.93,28.30,22.88, 18.56。

Substrate XIV-3b (200mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, 0.5mL is added 3N hydrochloric acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, palladium carbon is filtered to remove by diatomite, under vacuum Solvent is removed, neutralizes by ammonium hydroxide, is handled by acidic resins column, obtain weak yellow liquid I-3b 73mg, yield 85%.Knot Structure confirmation:

¹H NMR(400MHz,D₂O) δ 4.08 (dd, J=10.5,6.2Hz, 1H), 3.81 (dd, J=5.9,5.1Hz, 1H), 3.62 (dd, J=11.6,6.6Hz, 1H), 3.52 (dd, J=11.6,6.9Hz, 1H), 2.98-2.94 (m, 2H), 2.79-2.69 (m, 1H), 1.75-1.65 (m, 2H), 1.62-1.38 (m, 3H), 1.17-1.11 (m, 1H), 1.00 (d, J=6.1Hz, 3H)¹³C NMR(101MHz,D₂O)δ79.87,75.57,69.34,62.28,60.22,54.94,31.76,22.37,19.63,17.73。

Embodiment 4: prepare Indolizidine class iminosugar I-4a, I-4b and its intermediate

Under argon gas protection, the bromo- 1- of 5- is added in the tetrahydrofuran of steaming again (15mL) suspension for the magnesium chips (4mmol) newly polished Amylene (17mmol) is heated to 50 DEG C of reactions, and a large amount of bubbles occurs in system, and solution is in Dark grey, and the reaction was continued half an hour.By nitre Ketone II-4 (12mmol) is dissolved in dry tetrahydrofuran, and under condition of ice bath, above-mentioned Grignard Reagent is added dropwise by syringe Enter, adds within 15 minutes, the reaction was continued 1h, TLC monitoring display raw material disappearance, addition saturated ammonium chloride solution quenching reaction, acetic acid Ethyl ester extraction, without drying, directly removes solvent under vacuum, obtains the crude product of III-4.

The crude product of gained III-4 is dissolved in acetic acid, is added to preactivated good zinc powder (0.12mol) and Cu (OAc)₂ (the processed zinc powder of dilute hydrochloric acid and copper acetate are placed in ice vinegar in the glacial acetic acid mixture of (containing two molecular crystalline water, 1.2mmol) Stirred in acid, until rufous occurs in system), system is highly exothermic, and overnight, TLC monitoring display raw material is completely anti-for room temperature reaction It answers, solvent is removed under vacuum, obtained solid is washed through ethyl acetate, and NaOH saturated solution adjusts pH=9 or so, ethyl acetate extraction Water intaking phase merges organic phase, and anhydrous magnesium sulfate is dry, filters and removes solid, removes solvent under vacuum, obtain the crude product of IV-4.

The crude product of gained IV-4 is dissolved in methylene chloride (20mL), is added triethylamine (15mmol) and (Boc)₂O (13mmol) reacts at room temperature 2h, and TLC monitoring raw material point completely disappears, and saturated ammonium chloride quenching reaction, ethyl acetate extraction is added It takes, anhydrous magnesium sulfate is dry, filters and removes solid, and solvent is removed under vacuum, and column chromatographs (petroleum ether: ethyl acetate=30:1) and obtains The total 4.1g of alkene V-4 is colorless viscous shape liquid, yield 61%.Structural identification:

¹H NMR (300MHz, DMSO, 353K) δ 7.32-7.26 (m, 15H), 5.74-5.69 (m, 1H), 5.04-4.51 (m, 6H), 4.51 (s, 2H), 4.26 (d, J=4.0Hz, 1H), 4.17 (d, J=6.2Hz, 2H), 3.92 (d, J=3.1Hz, 1H), 3.64 (d, J=6.7Hz, 2H), 2.14-1.95 (m, 2H), 1.78 (s, 1H), 1.45 (s, 9H), 1.39-1.16 (m, 3H)；¹³C NMR(75MHz,DMSO,353K)δ152.01,137.72,137.40,137.36,137.04,126.76-125.69, 113.29,79.51,77.53,76.42,71.04,70.67,70.38,68.54,60.72,56.38,31.61,30.38, 26.91,23.96。

Alkene V-4 (2.4mmol) is dissolved in 10mL in the mixed solvent, palladium acetate (0.96mmol) and copper acetate (band is added The crystallization water, 4.8mmol), it is reacted at room temperature 4 days under oxygen atmosphere, TLC monitors fully reacting, and saturated ammonium chloride is added and is quenched instead It answers, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, and solvent is removed under vacuum, and column chromatographs (petroleum ether: acetic acid Ethyl ester=10:1) VI-4 crude product.

Under condition of ice bath, the crude product (in terms of 2mmol) of substrate VI-4 is dissolved in the methanol of 15mL, hydroboration is slowly added to Sodium (2.5mmol) adds rear system into light gray, and TLC monitoring raw material point disappears after 30min, and saturated ammonium chloride is added and is quenched instead It answers, methanol is removed under vacuum, the thick white oil object of gained is redissolved in saturated ammonium chloride, ethyl acetate extraction, anhydrous Magnesium sulfate is dry, filters and removes solid, removes solvent under vacuum, obtain the crude product of VII-4.

The crude product of gained VII-4 is redissolved in 5mL dry methylene chloride, is added triethylamine (3mmol), condition of ice bath Under be slowly added to methylsufonyl chloride (2.4mmol), add and move back except ice bath, react at room temperature 1h, TLC monitors raw material point and disappears, adds Entering saturated ammonium chloride quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, and it filters and removes solid, remove solvent under vacuum, Obtain the crude product of VIII-4.

The crude product of gained VIII-4 is redissolved in 5mL methylene chloride, and 3mL trifluoroacetic acid is added, and after reacting 1h, TLC is aobvious Show that raw material disappears, saturation NaHCO is added₃Quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, very Sky is lower to remove solvent, obtains the crude product of IX-4.

The crude product of IX-4 is redissolved in 10mL methanol, addition 100mg Anhydrous potassium carbonate, room temperature reaction 48h, under vacuum Methanol is removed, the thick grease of gained is redissolved in saturated ammonium chloride, and ethyl acetate extraction, anhydrous magnesium sulfate is dry, takes out Solid is filtered out, solvent is removed under vacuum, column chromatography (petroleum ether: ethyl acetate=15:1) obtains the lesser point (XIV- of polarity 4a) 264mg and biggish point (XIV-4b) 256mg of polarity.Structural identification:

XIV-4a:1:[α]_D ²⁰=+24.0 (c 1.0, CH2Cl2)；IR(cm-1):3090,3065,3030,2926, 2857,1496,1455,1370,1313,1097,734,699；¹H NMR(300MHz,CDCl₃)δ7.43–7.16(m,15H), 4.82-4.42 (m, 6H), 4.03-3.95 (m, 1H), 3.93-3.78 (m, 2H), 3.73 (dd, J=9.3,2.3Hz, 1H), 3.57 (dd, J=7.2,4.9Hz, 1H), 2.77-2.64 (m, 1H), 2.61-2.47 (m, 1H), 1.85 (d, J=10.4Hz, 1H), 1.69 (d, J=12.7Hz, 1H), 1.57 (d, J=9.0Hz, 2H), 1.41-1.21 (m, 2H), 1.17 (d, J=6.0Hz, 3H), 1.15–0.95(m,2H)；¹³C NMR(75MHz,CDCl₃)δ138.93,138.90,138.59,128.36-127.36,80.47, 77.71,77.58,77.16,76.74,73.46,72.60,72.28,66.35,64.81,59.72,53.02,34.80, 30.97,24.59,20.77。

XIV-4b:¹H NMR(300MHz,CDCl₃)δ7.40–7.13(m,15H),4.74–4.41(m,6H),4.18(dd,J =6.5,5.1Hz, 1H), 3.94-3.84 (m, 1H), 3.65 (dd, J=6.9,5.0Hz, 1H), 3.54 (dd, J=9.1, 5.4Hz, 1H), 3.42-3.24 (m, 2H), 2.66 (dd, J=7.9,5.1Hz, 1H), 1.68-1.36 (m, 4H), 1.34-1.13 (m, 2H), 1.07 (d, J=6.4Hz, 3H)¹³C NMR(75MHz,CDCl₃)δ139.05,138.75,138.70,128.35- 127.35,79.68,77.07,73.36,73.34,72.22,71.09,64.65,57.50,53.46,30.83,25.59, 20.94,18.98。

Substrate XIV-4a (200mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, 0.5mL is added 3N hydrochloric acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, palladium carbon is filtered to remove by diatomite, under vacuum Solvent is removed, neutralizes by ammonium hydroxide, is handled by acidic resins column, obtains the total 72mg of I-4a, yield 85% is light yellow liquid Body.Structural identification:

¹H NMR(300MHz,D₂O) δ 4.21 (t, J=7.5Hz, 1H), 3.86-3.75 (m, 2H), 3.68 (t, J= 7.0Hz, 1H), 3.41 (dd, J=11.4,4.7Hz, 1H), 2.72 (d, J=7.0Hz, 1H), 2.59-2.54 (m, 1H), 1.87 (d, J=12.7Hz, 1H), 1.71-1.59 (m, 2H), 1.33-1.17 (m, 1H), 1.11-0.94 (m, 2H), 2.72 (d, J= 6.2Hz,3H)；¹³C NMR(75MHz,D₂O)δ73.45,68.72,66.41,60.93,56.17,52.45,32.94,28.86, 23.32,18.88。

Substrate XIV-4b (200mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, 0.5mL is added 3N hydrochloric acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, palladium carbon is filtered to remove by diatomite, under vacuum Solvent is removed, neutralizes by ammonium hydroxide, is handled by acidic resins column, obtains the total 76mg of I-4b, yield 89% is light yellow liquid Body.Structural identification:

¹H NMR(300MHz,D₂O) δ 4.32 (s, 1H), 4.02 (dd, J=20.9,7.3Hz, 1H), 3.94-3.64 (m, 2H), 3.57 (d, J=5.9Hz, 1H), 3.32 (s, 1H), 3.05 (s, 1H), 2.59 (s, 1H), 1.79-1.50 (m, 4H), 1.55-1.19 (m, 3H), 1.19-1.06 (m, 1H), 1.01 (d, J=5.6Hz, 3H)；¹³C NMR(75MHz,D₂O)δ70.32, 69.57,66.65,59.98,58.85,55.57,31.56,22.47,19.87,17.69。

Embodiment 5: prepare Indolizidine class iminosugar I-5a, I-5b and its intermediate

It is bromo- that 5- is added under argon gas protection, in the tetrahydrofuran of steaming again (15mL) suspension for the magnesium chips (24mmol) newly polished 1- amylene (17mmol) is heated to 50 DEG C of reactions, and a large amount of bubbles occurs in system, and solution is in Dark grey, and the reaction was continued half an hour.It will Nitrone II-5 (12mmol) is dissolved in dry tetrahydrofuran, under condition of ice bath, dropwise by syringe by above-mentioned Grignard Reagent It is added, adds within 15 minutes, the reaction was continued 1h, TLC monitoring display raw material disappearance, addition saturated ammonium chloride solution quenching reaction, second Acetoacetic ester extraction, without drying, directly removes solvent under vacuum, obtains the crude product of III-5.

The crude product of III-5 is dissolved in acetic acid, preactivated good zinc powder (0.12mol) and Cu (OAc) are added to₂(contain Two molecular crystalline water, 1.2mmol) glacial acetic acid mixture in (the processed zinc powder of dilute hydrochloric acid and copper acetate are placed in glacial acetic acid Middle stirring, until rufous occurs in system), system is highly exothermic, and overnight, TLC monitoring display raw material reacts completely for room temperature reaction, Solvent is removed under vacuum, obtained solid is washed through ethyl acetate, and NaOH saturated solution adjusts pH=9 or so, ethyl acetate extraction Water phase merges organic phase, and anhydrous magnesium sulfate is dry, filters and removes solid, removes solvent under vacuum, obtain the crude product of IV-5.

The crude product of gained IV-5 is dissolved in methylene chloride (20mL), is added triethylamine (15mmol) and (Boc)₂O (13mmol) reacts at room temperature 2h, and TLC monitoring raw material point completely disappears, and saturated ammonium chloride quenching reaction, ethyl acetate extraction is added Take, anhydrous magnesium sulfate is dry, filters and removes solid, remove solvent under vacuum, column chromatograph colorless viscous shape liquid V-5 is total 3.1g, yield 65%.Structural identification:

¹H NMR(400MHz,CDCl₃) δ 7.45-7.13 (m, 10H), 5.86-5.75 (m, 1H), 5.00 (t, J= 13.7Hz, 2H), 4.66-4.43 (m, 4H), 4.05 (s, 1H), 3.87 (d, J=10.7Hz, 2H), 3.75 (s, 1H), 3.45 (d, J=11.9Hz, 1H), 2.08-2.01m, 2H), 1.96-1.52 (m, 3H), 1.52-1.20 (m, 11H)¹³C NMR(75MHz, CDCl₃)δ154.63,138.57,137.88,137.80,128.51,127.88,127.85,127.72,127.65,114.69, 85.15,83.32,81.88,80.81,79.45,71.60,71.32,62.53,50.94,50.01,33.60,31.76, 31.18,28.55,25.89,25.53。

Substrate V-5 (2.4mmol) is dissolved in 10mL in the mixed solvent, palladium acetate (0.96mmol) and copper acetate (band is added The crystallization water, 4.8mmol), it is reacted at room temperature 4 days under oxygen atmosphere, TLC monitors fully reacting, and saturated ammonium chloride is added and is quenched instead It answers, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, and solvent is removed under vacuum, and column chromatographs (petroleum ether: acetic acid Ethyl ester=10:1) VI-5 crude product.

Under condition of ice bath, the crude product (in terms of 2mmol) of substrate VI-5 is dissolved in the methanol of 15mL, hydroboration is slowly added to Sodium (2.5mmol) adds rear system into light gray, and TLC monitoring raw material point disappears after 30min, and saturated ammonium chloride is added and is quenched instead It answers, methanol is removed under vacuum, the thick white oil object of gained is redissolved in saturated ammonium chloride, ethyl acetate extraction, anhydrous Magnesium sulfate is dry, filters and removes solid, removes solvent under vacuum, obtain the crude product of VII-5.

The crude product of VII-5 is redissolved in 5mL dry methylene chloride, is added triethylamine (3mmol), is delayed under condition of ice bath It is slow that methylsufonyl chloride (2.4mmol) is added, it adds and moves back except ice bath, react at room temperature 1h, TLC monitors raw material point and disappears, and is added full With ammonium chloride quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, removes solvent under vacuum, obtain The crude product of VIII-5.

The crude product of VIII-5 is dissolved in 5mL methylene chloride, 3mL trifluoroacetic acid is added, after reacting 1h, TLC shows raw material It disappears, saturation NaHCO is added₃Quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, removes under vacuum Solvent is removed, the crude product of IX-5 is obtained.

The crude product of IX-5 is redissolved in 10mL methanol, addition 100mg Anhydrous potassium carbonate, room temperature reaction 48h, under vacuum Methanol is removed, the thick grease of gained is redissolved in saturated ammonium chloride, and ethyl acetate extraction, anhydrous magnesium sulfate is dry, takes out Solid is filtered out, solvent is removed under vacuum, column chromatography (petroleum ether: ethyl acetate=15:1) obtains the lesser point (XIV- of polarity 5a) the total 129mg and polarity total 115mg of biggish point (XIV-5b), structural identification:

XIV-5a:¹H NMR(400MHz,CDCl₃)δ7.41–7.27(m,10H),4.65–4.46(m,4H),3.98–3.92 (m, 1H), 3.79 (dd, J=8.2,2.8Hz, 1H), 3.33 (d, J=10.4Hz, 1H), 2.37 (dd, J=10.4,6.6Hz, 1H), 2.03 (dd, J=13.5,5.5Hz, 3H), 1.80-1.78 (m, 1H), 1.58-1.56 (m, 1H), 1.41-1.24 (m, 3H), 1.12 (d, J=6.2Hz, 3H)；¹³C NMR(101MHz,CDCl₃)δ138.37,138.32,128.3-127.63, 89.70,81.85,72.21,71.34,68.50,58.93,56.42,33.67,29.29,24.29,20.49.

XIV-5a:¹H NMR(400MHz,CDCl₃)δ7.42–7.31(m,10H),4.67–4.48(m,4H),3.95–3.93 (m, 1H), 3.71 (dd, J=7.2,2.5Hz, 1H), 3.26-3.23 (m, 1H), 2.95-2.87 (m, 2H), 2.58-2.52 (m, 1H), 2.01-1.97 (m, 1H), 1.88-1.81 (m, 1H), 1.68-1.32 (m, 5H), 1.00 (d, J=6.6Hz, 3H)；¹³C NMR(101MHz,CDCl₃)δ138.39,138.32,128.38-127.64,90.57,82.34,72.15,71.40,59.54, 53.81,50.13,30.87,29.95,18.82,9.33。

Substrate XIV-5a (100mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, 0.5mL is added 3N hydrochloric acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, palladium carbon is filtered to remove by diatomite, under vacuum Solvent is removed, neutralizes by ammonium hydroxide, is handled by acidic resins column, obtain the total 42mg of I-5a, white solid, yield 88%.Knot Structure confirmation:

¹H NMR(400MHz,D₂O) δ 3.97 (ddd, J=7.7,4.2,1.8Hz, 1H), 3.55 (dd, J=9.1,4.3Hz, 1H), 2.90 (dd, J=11.3,1.4Hz, 1H), 2.54 (dd, J=11.2,8.0Hz, 1H), 2.13-2.05 (m, 1H), 1.98- 1.93 (m, 1H), 1.81 (d, J=13.8Hz, 1H), 1.73-1.68 (m, 1.60-1.49 (m, 1H), 1.29-1.01 (m, 3H), 0.94 (d, J=6.3Hz, 3H)；¹³C NMR(101MHz,D₂O)δ82.36,75.08,68.60,58.85,57.77,32.46, 27.13,23.23,18.73。

Substrate XIV-5b (100mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, 0.5mL is added 3N hydrochloric acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, palladium carbon is filtered to remove by diatomite, under vacuum Solvent is removed, neutralizes by ammonium hydroxide, is handled by acidic resins column, obtain faint yellow solid 46mg, yield 96%.Structure is true Card:

¹H NMR(400MHz,D₂O) δ 3.96 (s, 1H), 3.63 (dd, J=8.1,3.9Hz, 1H), 3.06-2.97 (m, 2H), 2.60 (d, J=11.7Hz, 1H), 2.56-2.52 (m, 1H), 1.75-1.72 (m, 1H), 1.59-1.54 (m, 1H), 1.47-1.39 (m, 2H), 1.34-1.25 (m, 2H), 0.91 (d, J=6.3Hz, 3H)¹³C NMR(101MHz,D₂O)δ81.53, 75.54,60.62,54.86,51.25,29.88,26.47,17.46,10.95。

Embodiment 6: prepare Indolizidine class iminosugar I-6a, I-6b and its intermediate

It is bromo- that 5- is added under argon gas protection, in the tetrahydrofuran of steaming again (15mL) suspension for the magnesium chips (24mmol) newly polished 1- amylene (17mmol) is heated to 50 DEG C of reactions, and a large amount of bubbles occurs in system, and solution is in Dark grey, and the reaction was continued half an hour.It will Nitrone II-4 (12mmol) is dissolved in dry tetrahydrofuran, under condition of ice bath, dropwise by syringe by above-mentioned Grignard Reagent It is added, adds within 15 minutes, the reaction was continued 1h, TLC monitoring display raw material disappearance, addition saturated ammonium chloride solution quenching reaction, second Acetoacetic ester extraction, without drying, directly removes solvent under vacuum, obtains the crude product of III-4.

The crude product of gained IV-4 is dissolved in methylene chloride (20mL), is added triethylamine (15mmol) and (Boc)₂O (13mmol) reacts at room temperature 2h, and TLC monitoring raw material point completely disappears, and saturated ammonium chloride quenching reaction, ethyl acetate extraction is added It takes, anhydrous magnesium sulfate is dry, filters and removes solid, and solvent is removed under vacuum, and column chromatographs (petroleum ether: ethyl acetate=30:1) and obtains The total 4.1g of V-4 is colorless viscous shape liquid, yield 61%.Structural identification:

V-4 (1.4mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (5mL), 1mL water is added, sequentially adds sodium metaperiodate It is small to stir 12 at room temperature for (5.6mmol), 2,6- lutidines (2.8mmol) and 1 weight % osmium tetroxide aqueous solution (1mL) When, saturated aqueous sodium thiosulfate quenching reaction is added, filters away the solid generated, ethyl acetate extraction, anhydrous slufuric acid Magnesium is dry, filters and removes solid, removes solvent under vacuum, obtain the crude product of X-1.

Under argon gas protection, 1- bromine fourth is added in the tetrahydrofuran of steaming again (2mL) suspension for the magnesium chips (4.2mmol) newly polished Alkane (2.8mmol) is heated to 50 DEG C of reactions, and a large amount of bubbles occurs in system, and solution is in Dark grey, and the reaction was continued half an hour.By X-1 Crude product (in terms of 1.4mmol) be dissolved in dry tetrahydrofuran, under condition of ice bath, by above-mentioned Grignard Reagent by syringe by It is added dropwise to, continues to reflect 10h, TLC monitoring) display raw material disappearance, saturated ammonium chloride solution quenching reaction, ethyl acetate extraction is added It takes, without drying, directly removes solvent under vacuum, obtain the crude product of XI-1.

The crude product of gained XI-1 is redissolved in 5mL dry methylene chloride, is added triethylamine (3mmol), condition of ice bath Under be slowly added to methylsufonyl chloride (2.4mmol), add and move back except ice bath, react at room temperature 1h, TLC monitors raw material point and disappears, adds Entering saturated ammonium chloride quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, and it filters and removes solid, remove solvent under vacuum, Obtain the crude product of XII-1.

The crude product of gained XII-1 is redissolved in 5mL methylene chloride, and 3mL trifluoroacetic acid is added, and after reacting 1h, TLC is shown Raw material disappears, and saturation NaHCO is added₃Quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, vacuum Lower removing solvent, obtains the crude product of XIII-1.

The crude product of XIII-1 is redissolved in 10mL methanol, 100mg Anhydrous potassium carbonate is added, reacts at room temperature 48h, vacuum Lower removing methanol, the thick grease of gained are redissolved in saturated ammonium chloride, and ethyl acetate extraction, anhydrous magnesium sulfate is dry, It filters and removes solid, solvent is removed under vacuum, column chromatography (petroleum ether: ethyl acetate=15:1) obtains the lesser point of polarity (XIV-6a) the total 161mg and total 190mg of the biggish point (XIV-6b) of polarity.Structural identification:

XIV-6a:¹H NMR(400MHz,CDCl₃)δ7.44–7.16(m,16H),4.81–4.40(m,6H),4.01–3.92 (m, 1H), 3.90-3.79 (m, 2H), 3.74 (t, J=6.3Hz, 1H), 3.57 (dd, J=7.2,4.9Hz, 1H), 2.59-2.48 (m, 2H), 1.94 (d, J=13.0Hz, 1H), 1.84 (d, J=11.6Hz, 1H), 1.71 (d, J=11.3Hz, 2H), 1.42- 0.87 (m, 11H), 0.85 (t, J=7.0Hz, 3H)；¹³C NMR(101MHz,CDCl₃)δ139.03,138.91,138.71, 128.41,128.35,128.31,127.90,127.69,127.67,127.58,127.53,127.44,80.63,77.84, 73.58,72.69,72.37,66.62,64.80,59.26,57.77,33.36,31.22,31.12,27.88,24.57, 23.28,14.30。

XIV-6b:¹H NMR(400MHz,CDCl₃)δ7.44–7.23(m,16H),4.74–4.45(m,6H),4.27(dd,J =7.6,5.0Hz, 1H), 3.95 (dd, J=9.1,7.0Hz, 1H), 3.69 (t, J=4.5Hz, 1H), 3.56 (dd, J=9.2, 5.2Hz,1H),3.46–3.29(m,2H),2.70(s,1H),1.70–1.49(m,3H),1.49–1.13(m,11H),0.92(t, J=6.8Hz, 3H)；¹³C NMR(101MHz,CDCl₃)δ139.09,139.03,138.93,128.36,128.33,127.82, 127.78,127.57,127.49,127.42,77.71,73.39,72.94,62.95,56.90,56.25,32.80,29.00, 26.57,25.77,23.07,18.88,14.34。

Substrate XIV-6a (100mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, 0.5mL is added 3N hydrochloric acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, palladium carbon is filtered to remove by diatomite, under vacuum Solvent is removed, neutralizes by ammonium hydroxide, is handled by acidic resins column, obtain the total 44mg of I-6a, colorless oil, yield 94%. Structural identification:

¹H NMR (400MHz, MeOD) δ 4.52 (t, J=7.2Hz, 1H), 4.01 (d, J=9.8Hz, 1H), 3.92 (dd, J =12.2,4.3Hz, 3H), 3.36-3.31 (m, 1H), 3.20 (t, J=10.3Hz, 1H), 2.03 (d, J=13.0Hz, 2H), 1.99-1.83 (m, 2H), 1.61-1.25 (m, 9H), 0.96 (t, J=6.8Hz, 3H)；¹³C NMR(101MHz,MeOD)δ 72.57,68.70,68.10,61.51,60.16,56.11,31.96,27.69,27.52,26.41,22.37,22.32, 12.95。

Substrate XIV-6b (100mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, 0.5mL is added 3N hydrochloric acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, palladium carbon is filtered to remove by diatomite, under vacuum Solvent is removed, neutralizes by ammonium hydroxide, is handled by acidic resins column, obtain faint yellow solid 45mg, yield 97%.Structure is true Card:

¹H NMR(400MHz,MeOD)δ4.50(s,1H),4.18(s,1H),3.90-3.87(m,2H),3.83(s,1H), (3.58 d, J=5.1Hz, 1H), 3.33 (s, 1H), 2.08-1.93 (m, 2H), 1.91-1.25 (m, 11H), 0.97 (t, J= 6.7Hz,3H)；¹³C NMR(101MHz,MeOD)δ70.44,68.86,67.75,60.89,59.86,57.93,30.81, 27.65,25.70,22.23,22.16,16.48,12.89。

Embodiment 7: prepare Indolizidine class iminosugar I-7a, I-7b and its intermediate

The crude product of gained IV-4 is dissolved in methylene chloride (20mL), is added triethylamine (15mmol) and (Boc)₂O (13mmol) reacts at room temperature 2h, and TLC monitoring raw material point completely disappears, and saturated ammonium chloride quenching reaction, ethyl acetate extraction is added It takes, anhydrous magnesium sulfate is dry, filters and removes solid, and solvent is removed under vacuum, and column chromatographs (petroleum ether: ethyl acetate=30:1) and obtains V-44.1g is colorless viscous shape liquid, yield 61%.Structural identification:

V-4 (1.4mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (5mL), 1mL water is added, sequentially adds sodium metaperiodate (5.6mmol), 2,6- lutidines (2.8mmol) and 1 weight % osmium tetroxide aqueous solution (1mL), stir 12h at room temperature, Saturated aqueous sodium thiosulfate quenching reaction is added, filters away the solid generated, ethyl acetate extraction, anhydrous magnesium sulfate is done It is dry, it filters and removes solid, remove solvent under vacuum, obtain the crude product of X-1.

Under argon gas protection, 1- bromine nonyl is added in the tetrahydrofuran of steaming again (2mL) suspension for the magnesium chips (4.2mmol) newly polished Alkane (2.8mmol) is heated to 50 DEG C of reactions, and a large amount of bubbles occurs in system, and solution is in Dark grey, and the reaction was continued half an hour.By X-1 Crude product (in terms of 1.4mmol) be dissolved in dry tetrahydrofuran, under condition of ice bath, by above-mentioned Grignard Reagent by syringe by It is added dropwise to, the reaction was continued 10h, TLC monitoring display raw material disappearance, addition saturated ammonium chloride solution quenching reaction, ethyl acetate extraction It takes, without drying, directly removes solvent under vacuum, obtain the crude product of XI-2.

The crude product of gained XI-2 is redissolved in 5mL dry methylene chloride, is added triethylamine (3mmol), condition of ice bath Under be slowly added to methylsufonyl chloride (2.4mmol), add and move back except ice bath, react at room temperature 1h, TLC monitors raw material point and disappears, adds Entering saturated ammonium chloride quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, and it filters and removes solid, remove solvent under vacuum, Obtain the crude product of XII-2.

The crude product of gained XII-2 is redissolved in 5mL methylene chloride, and 3mL trifluoroacetic acid is added, and after reacting 1h, TLC is shown Raw material disappears, and saturation NaHCO is added₃Quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, vacuum Lower removing solvent, obtains the crude product of XIII-2.

The crude product of XIII-2 is redissolved in 10mL methanol, 100mg Anhydrous potassium carbonate is added, reacts at room temperature 48h, vacuum Lower removing methanol, the thick grease of gained are redissolved in saturated ammonium chloride, and ethyl acetate extraction, anhydrous magnesium sulfate is dry, It filters and removes solid, solvent is removed under vacuum, column chromatography (petroleum ether: ethyl acetate=15:1) obtains the lesser point of polarity (XIV-7a) the total 261mg and total 237mg of the biggish point (XIV-7b) of polarity.Structural identification:

XIV-7a:¹H NMR(400MHz,CDCl₃)δ7.39–7.16(m,16H),4.82–4.41(m,6H),4.02–3.92 (m, 1H), 3.91-3.81 (m, 2H), 3.73 (q, J=6.3Hz, 1H), 3.56 (dd, J=7.2,4.9Hz, 1H), 2.60-2.48 (m, 2H), 1.95 (dd, J=16.1,6.5Hz, 1H), 1.84 (d, J=11.5Hz, 1H), 1.71 (d, J=11.0Hz, 2H), 1.39-0.91 (m, 21H), 0.88 (t, J=6.8Hz, 3H)；¹³C NMR(101MHz,CDCl₃)δ128.31,128.25, 128.21,127.80,127.56,127.48,127.44,127.34,80.50,77.71,73.47,72.58,72.25, 70.22,66.52,64.70,59.15,57.70,37.36,33.56,31.98,31.85,31.11,31.01,30.20, 29.80,29.70,29.42,29.21,29.16,29.06,25.60,25.45,24.47,22.74,22.68,14.18, 14.14。

XIV-7b:¹H NMR(400MHz,CDCl₃)δ7.44–7.17(m,16H),4.72–4.42(m,6H),4.26–4.20 (m, 1H), 3.91 (dd, J=9.1,7.1Hz, 1H), 3.65 (t, J=4.5Hz, 1H), 3.51 (dd, J=9.1,5.2Hz, 1H), 3.39-3.29 (m, 2H), 2.65 (s, 1H), 1.69-1.12 (m, 27H), 0.88 (t, J=6.8Hz, 3H)；¹³C NMR (101MHz,CDCl₃)δ138.99,138.92,138.82,128.27,128.25,127.72,127.69,127.47, 127.41,127.34,127.31,80.53,77.57,73.30,72.85,72.01,71.83,62.90,56.80,56.24, 33.05,31.97,29.98,29.82,29.71,29.44,26.69,26.44,25.73,22.75,18.79,14.19。

XIV-7a (100mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, the 3N of 0.5mL is added Hydrochloric acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, is filtered to remove palladium carbon by diatomite, removes under vacuum Solvent is neutralized by ammonium hydroxide, is handled by acidic resins column, and the total 49mg of I-7a, colorless oil, yield 91% are obtained.

¹H NMR (400MHz, MeOD) δ 4.35 (t, J=7.2Hz, 1H), 3.88 (d, J=3.3Hz, 2H), 3.76 (t, J =6.1Hz, 1H), 3.67-3.59 (m, 1H), 2.93 (d, J=10.1Hz, 1H), 2.87 (t, J=9.9Hz, 1H), 1.96 (d, J =12.1Hz, 1H), 1.86 (dd, J=21.4,12.0Hz, 3H), 1.53-1.08 (m, 20H), 0.90 (t, J=6.6Hz, 3H) ；¹³C NMR(101MHz,MeOD)δ73.46,69.08,67.57,61.23,58.41,56.64,32.76,31.67,29.53, 29.34,29.30,29.18,29.06,28.30,25.41,23.22,22.35,13.09。

Substrate XIV-7b (100mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, 0.5mL is added 3N hydrochloric acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, palladium carbon is filtered to remove by diatomite, under vacuum Solvent is removed, neutralizes by ammonium hydroxide, is handled by acidic resins column, obtain faint yellow solid 45mg, yield 97%.

¹H NMR (500MHz, MeOD) δ 4.50 (s, 1H), 4.22 (dd, J=7.6,4.9Hz, 1H), 3.95-3.85 (m, 3H), 3.64 (dd, J=12.7,5.5Hz, 1H), 3.25-3.15 (m, 1H), 2.10-1.96 (m, 2H), 1.94-1.79 (m, 2H), 1.79-1.49 (m, 5H), 1.48-1.23 (m, 16H), 0.92 (t, J=6.9Hz, 3H)；¹³C NMR(126MHz,MeOD)δ 69.98,68.55,68.42,61.10,60.60,57.76,31.65,30.90,29.24,29.19,29.16,29.03, 25.85,25.33,22.33,21.72,16.19,13.05。

Embodiment 8: prepare Indolizidine class iminosugar I-8a, I-8b and its intermediate

It is bromo- that 5- is added under argon gas protection, in the tetrahydrofuran of steaming again (15mL) suspension for the magnesium chips (24mmol) newly polished 1- amylene (17mmol) is heated to 50 DEG C of reactions, and a large amount of bubbles occurs in system, and solution is in Dark grey, and the reaction was continued half an hour.It will Nitrone II-6 (12mmol) is dissolved in dry tetrahydrofuran, under condition of ice bath, dropwise by syringe by above-mentioned Grignard Reagent It is added, adds within 15 minutes, the reaction was continued 1h, TLC monitoring display raw material disappearance, addition saturated ammonium chloride solution quenching reaction, second Acetoacetic ester extraction, without drying, directly removes solvent under vacuum, obtains the crude product of III-6.

The crude product of gained III-6 is dissolved in acetic acid, is added to preactivated good zinc powder (0.12mol) and Cu (OAc)₂ (the processed zinc powder of dilute hydrochloric acid and copper acetate are placed in ice vinegar in the glacial acetic acid mixture of (containing two molecular crystalline water, 1.2mmol) Stirred in acid, until rufous occurs in system), system is highly exothermic, and overnight, TLC monitoring display raw material is completely anti-for room temperature reaction It answers, solvent is removed under vacuum, obtained solid is washed through ethyl acetate, and NaOH saturated solution adjusts pH=9 or so, ethyl acetate extraction Water intaking phase merges organic phase, and anhydrous magnesium sulfate is dry, filters and removes solid, removes solvent under vacuum, obtain the crude product of IV-6.

The crude product of gained IV-6 is dissolved in methylene chloride (20mL), is added triethylamine (15mmol) and (Boc)₂O (13mmol) reacts at room temperature 2h, and TLC monitoring raw material point completely disappears, and saturated ammonium chloride quenching reaction, ethyl acetate extraction is added It takes, anhydrous magnesium sulfate is dry, filters and removes solid, and solvent is removed under vacuum, and column chromatographs (petroleum ether: ethyl acetate=30:1) and obtains V-6 (4.1g is colorless viscous shape liquid), yield 61%.Structural identification:

V-6 (1.4mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (5mL), 1mL water is added, sequentially adds sodium metaperiodate It is small to stir 12 at room temperature for (5.6mmol), 2,6- lutidines (2.8mmol) and 1 weight % osmium tetroxide aqueous solution (1mL) When, saturated aqueous sodium thiosulfate quenching reaction is added, filters away the solid generated, ethyl acetate extraction, anhydrous slufuric acid Magnesium is dry, filters and removes solid, removes solvent under vacuum, obtain the crude product of X-3.

Under argon gas protection, 1- bromine fourth is added in the tetrahydrofuran of steaming again (2mL) suspension for the magnesium chips (4.2mmol) newly polished Alkane (2.8mmol) is heated to 50 DEG C of reactions, and a large amount of bubbles occurs in system, and solution is in Dark grey, and the reaction was continued half an hour.By X-3 Crude product (in terms of 1.4mmol) be dissolved in dry tetrahydrofuran, under condition of ice bath, by above-mentioned Grignard Reagent by syringe by It is added dropwise to, the reaction was continued 10h, TLC monitoring display raw material disappearance, addition saturated ammonium chloride solution quenching reaction, ethyl acetate extraction It takes, without drying, directly removes solvent under vacuum, obtain the crude product of XI-3.

The crude product of gained XI-3 is redissolved in 5mL dry methylene chloride, is added triethylamine (3mmol), condition of ice bath Under be slowly added to methylsufonyl chloride (2.4mmol), add and move back except ice bath, react at room temperature 1h, TLC monitors raw material point and disappears, adds Entering saturated ammonium chloride quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, and it filters and removes solid, remove solvent under vacuum, Obtain the crude product of XII-3.

The crude product of gained XII-3 is redissolved in 5mL methylene chloride, and 3mL trifluoroacetic acid is added, and after reacting 1h, TLC is shown Raw material disappears, and saturation NaHCO is added₃Quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, vacuum Lower removing solvent, obtains the crude product of XIII-3.

The crude product of XIII-3 is redissolved in 10mL methanol, 100mg Anhydrous potassium carbonate is added, reacts at room temperature 48h, vacuum Lower removing methanol, the thick grease of gained are redissolved in saturated ammonium chloride, and ethyl acetate extraction, anhydrous magnesium sulfate is dry, It filters and removes solid, solvent is removed under vacuum, column chromatography (petroleum ether: ethyl acetate=15:1) obtains the lesser point of polarity (XIV-8a) the total 189mg and total 173mg of the biggish point (XIV-8b) of polarity.Structural identification:

XIV-8a:¹H NMR(400MHz,CDCl₃) δ 7.29 (dd, J=22.8,8.7Hz, 15H), 4.82-4.42 (m, 6H), 3.96 (d, J=6.3Hz, 1H), 3.86 (d, J=5.9Hz, 2H), 3.74 (t, J=6.0Hz, 1H), 3.60-3.51 (m, 1H), 2.54 (s, 2H), 1.95 (s, 1H), 1.84 (d, J=11.6Hz, 1H), 1.71 (d, J=11.2Hz, 2H), 1.35-0.88 (m, 9H), 0.85 (t, J=6.2Hz, 3H)；¹³C NMR(101MHz,CDCl₃)δ138.97,138.85,138.65,128.34, 128.28,128.23,127.82,127.62,127.59,127.50,127.45,127.36,80.58,77.79,73.51, 72.62,72.30,66.55,64.74,59.20,57.70,33.29,31.15,31.05,27.80,24.51,23.21, 14.24.

XIV-8b:¹H NMR(400MHz,CDCl₃)δ7.42–7.19(m,16H),4.74–4.43(m,6H),4.26–4.18 (m, 1H), 3.91 (t, J=7.9Hz, 1H), 3.65 (s, 1H), 3.51 (dd, J=8.8,5.2Hz, 1H), 3.41-3.28 (m, 2H), 2.66 (s, 1H), 1.70-1.06 (m, 13H), 0.87 (d, J=6.5Hz, 3H)；¹³C NMR(101MHz,CDCl₃)δ 139.02,138.96,138.86,128.55,128.28,128.25,127.74,127.70,127.59,127.49,127.42, 127.34,126.97,80.66,77.65,73.31,72.87,72.04,71.88,62.90,56.84,56.19,32.72, 28.93,26.50,25.71,22.99,18.82,14.26。

XIV-8a (100mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, the 3N of 0.5mL is added Hydrochloric acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, is filtered to remove palladium carbon by diatomite, removes under vacuum Solvent is neutralized by ammonium hydroxide, is handled by acidic resins column, and the total 44mg of I-8a, colorless oil, yield 94% are obtained.

¹H NMR (400MHz, MeOD) δ 4.52 (t, J=7.1Hz, 1H), 4.01 (d, J=9.9Hz, 1H), 3.92 (dd, J =12.1,4.2Hz, 3H), 3.33 (d, J=1.4Hz, 1H), 3.20 (t, J=10.3Hz, 1H), 2.03 (d, J=13.0Hz, 2H), 1.98-1.83 (m, 2H), 1.64-1.23 (m, 9H), 0.96 (t, J=6.7Hz, 3H)；¹³C NMR(101MHz,MeOD)δ 72.57,68.70,68.09,61.51,60.16,56.11,31.96,27.69,27.51,26.41,22.38,22.32, 12.95。

XIV-8b (100mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, the 3N of 0.5mL is added Hydrochloric acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, is filtered to remove palladium carbon by diatomite, removes under vacuum Solvent is neutralized by ammonium hydroxide, is handled by acidic resins column, and faint yellow solid 45mg, yield 97% are obtained.

¹H NMR(400MHz,MeOD)δ4.48(s,1H),4.16(s,1H),3.84(s,2H),3.81(s,1H),3.56 (d, J=5.2Hz, 1H), 3.18-3.03 (m, 1H), 2.08-1.91 (m, 2H), 1.87-1.59 (m, 5H), 1.59-1.21 (m, 8H), 0.94 (t, J=6.7Hz, 3H)；¹³C NMR(101MHz,MeOD)δ70.43,68.85,67.76,60.89,59.87, 57.93,30.81,27.65,25.71,22.23,22.15,16.48,12.89。

Embodiment 9: prepare Indolizidine class iminosugar I-9a, I-9b and its intermediate

It is bromo- that 5- is added under argon gas protection, in the tetrahydrofuran of steaming again (15mL) suspension for the magnesium chips (24mmol) newly polished 1- amylene (17mmol) is heated to 50 DEG C of reactions, and a large amount of bubbles occurs in system, and solution is in Dark grey, and the reaction was continued half an hour.It will Nitrone II-6 (12mmol) is dissolved in dry tetrahydrofuran, under condition of ice bath, dropwise by syringe by above-mentioned Grignard Reagent It is added, adds within 15 minutes, the reaction was continued 1h, TLC monitoring (petroleum ether: ethyl acetate=1:1) display raw material disappearance, addition saturation Ammonium chloride solution quenching reaction, ethyl acetate extraction, without drying, directly removes solvent under vacuum, obtains the thick of III-6 Product.

¹H NMR (300MHz, DMSO, 353K) δ 7.51-7.08 (m, 15H), 5.89-5.71 (m, 1H), 5.00 (t, J= 13.4Hz, 2H), 4.75 (t, J=10.6Hz, 1H), 4.71-4.56 (m, 3H), 4.51 (s, 2H), 4.27 (s, 1H), 4.18 (d, J=6.2Hz, 2H), 3.92 (d, J=3.1Hz, 1H), 3.64 (d, J=6.7Hz, 2H), 1.45 (s, 9H), 1.40-1.14 (m, 4H).¹³C NMR(75MHz,DMSO,353K)δ151.99,137.70,137.39,137.35,137.03,126.77,126.63, 126.03,125.95,125.70,113.31,79.46,77.52,76.40,71.04,70.66,70.36,68.54,60.71, 56.35,31.62,30.37,26.91,23.97。

V-6 (1.4mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (5mL), 1mL water is added, sequentially adds sodium metaperiodate It is small to stir 12 at room temperature for (5.6mmol), 2,6- lutidines (2.8mmol) and 1 weight % osmium tetroxide aqueous solution (1mL) When, saturated aqueous sodium thiosulfate quenching reaction is added, filters away the solid generated, ethyl acetate extraction, anhydrous slufuric acid Magnesium is dry, filters and removes solid, removes solvent under vacuum, obtain the crude product of X-4.

Under argon gas protection, 1- bromine nonyl is added in the tetrahydrofuran of steaming again (2mL) suspension for the magnesium chips (4.2mmol) newly polished Alkane (2.8mmol) is heated to 50 DEG C of reactions, and a large amount of bubbles occurs in system, and solution is in Dark grey, and the reaction was continued half an hour.By X-4 Crude product (in terms of 1.4mmol) be dissolved in dry tetrahydrofuran, under condition of ice bath, by above-mentioned Grignard Reagent by syringe by It is added dropwise to, the reaction was continued 10h, TLC monitoring display raw material disappearance, addition saturated ammonium chloride solution quenching reaction, ethyl acetate extraction It takes, without drying, directly removes solvent under vacuum, obtain the crude product of XI-4.

The crude product of gained XI-4 is redissolved in 5mL dry methylene chloride, is added triethylamine (3mmol), condition of ice bath Under be slowly added to methylsufonyl chloride (2.4mmol), add and move back except ice bath, react at room temperature 1h, TLC monitors raw material point and disappears, adds Entering saturated ammonium chloride quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, and it filters and removes solid, remove solvent under vacuum, Obtain the crude product of XII-4.

The crude product of gained XII-4 is redissolved in 5mL methylene chloride, and 3mL trifluoroacetic acid is added, and after reacting 1h, TLC is shown Raw material disappears, and saturation NaHCO is added₃Quenching reaction, ethyl acetate extraction, anhydrous magnesium sulfate is dry, filters and removes solid, vacuum Lower removing solvent, obtains the crude product of XIII-2.

The crude product of XIII-4 is redissolved in 10mL methanol, 100mg Anhydrous potassium carbonate is added, reacts at room temperature 48h, vacuum Lower removing methanol, the thick grease of gained are redissolved in saturated ammonium chloride, and ethyl acetate extraction, anhydrous magnesium sulfate is dry, It filters and removes solid, solvent is removed under vacuum, column chromatography (petroleum ether: ethyl acetate=15:1) obtains the lesser point of polarity (XIV-9a) the total 261mg and total 237mg of the biggish point (XIV-9b) of polarity.Structural identification:

XIV-9a:¹H NMR(400MHz,CDCl₃)δ7.39–7.20(m,16H),4.83–4.37(m,6H),4.01–3.93 (m, 1H), 3.89-3.81 (m, 2H), 3.73 (q, J=6.2Hz, 1H), 3.56 (dd, J=7.2,4.9Hz, 1H), 2.57-2.47 (m, 2H), 1.95 (dd, J=16.2,6.5Hz, 1H), 1.84 (d, J=11.5Hz, 1H), 1.71 (d, J=11.0Hz, 2H), 1.37-0.92 (m, 21H), 0.88 (t, J=6.8Hz, 3H)；¹³C NMR(101MHz,CDCl₃)δ139.12,139.01, 138.80,128.50,128.44,128.40,127.98,127.75,127.67,127.62,127.53,80.71,77.92, 73.66,72.77,72.45,66.71,64.90,59.34,57.88,33.75,32.17,31.31,31.21,30.39, 29.99,29.89,29.61,25.79,24.67,22.93,14.36。

XIV-9b:¹H NMR(400MHz,CDCl₃)δ7.37–7.20(m,15H),4.70–4.42(m,6H),4.22(dd,J =7.5,5.0Hz, 1H), 3.91 (dd, J=9.0,7.1Hz, 1H), 3.64 (t, J=4.5Hz, 1H), 3.52 (dd, J=9.1, 5.2Hz, 1H), 3.40-3.28 (m, 2H), 2.66 (s, 1H), 1.68-1.06 (m, 24H), 0.88 (t, J=6.7Hz, 3H)；¹³C NMR(101MHz,CDCl₃)δ139.02,138.96,138.87,128.29,128.26,127.73,127.71,127.49, 127.42,127.34,80.62,77.64,73.32,72.86,72.06,71.86,62.90,56.82,56.22,33.05, 32.00,30.00,29.84,29.73,29.46,26.72,26.51,25.74,22.77,18.83,14.21。

Substrate XIV-9a (100mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, 0.5mL is added 3N hydrochloric acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, palladium carbon is filtered to remove by diatomite, under vacuum Solvent is removed, neutralizes by ammonium hydroxide, is handled by acidic resins column, obtain the total 49mg of I-9a, colorless oil, yield 91%. Structural identification:

¹H NMR (400MHz, MeOD) δ 4.36 (t, J=7.2Hz, 1H), 3.88 (d, J=3.4Hz, 2H), 3.76 (t, J =6.1Hz, 1H), 3.66 (d, J=3.2Hz, 1H), 2.96 (d, J=10.7Hz, 1H), 2.89 (t, J=9.4Hz, 1H), 1.97 (d, J=11.9Hz, 1H), 1.87 (dd, J=24.0,12.1Hz, 3H), 1.52-1.13 (m, 22H), 0.90 (t, J=6.5Hz, 3H)；¹³C NMR(101MHz,MeOD)δ73.38,69.06,67.60,61.23,58.57,56.59,32.70,31.66, 29.49,29.31,29.28,29.04,28.09,25.41,23.12,22.33,13.06。

Substrate XIV-9b (100mg) is dissolved in 10mL methanol, the palladium carbon of the 10 weight % of 30mg is added, 0.5mL is added 3N hydrochloric acid, hydrogen displacement, overnight, TLC shows that raw material disappears for room temperature reaction, palladium carbon is filtered to remove by diatomite, under vacuum Solvent is removed, neutralizes by ammonium hydroxide, is handled by acidic resins column, obtain the total 45mg of faint yellow solid I-9b, yield 97%.

¹H NMR (400MHz, MeOD) δ 4.48 (s, 1H), 4.27-4.14 (m, 1H), 3.88 (s, 3H), 3.62 (d, J= 6.6Hz, 1H), 3.23-3.14 (m, 1H), 2.07-1.93 (m, 2H), 1.86 (dd, J=9.9,5.0Hz, 2H), 1.76-1.46 (m, 5H), 1.31 (s, 16H), 0.90 (t, J=6.6Hz, 3H)；¹³C NMR(101MHz,MeOD)δ70.04,68.58,68.35, 61.12,60.53,57.75,31.64,30.92,29.23,29.19,29.16,29.02,25.82,25.35,22.33, 21.77,16.22,13.05。

Test case: the glycosidase inhibitory effect evaluation of Indolizidine class amino sugar compounds

1) test material and source

Test compound: 5 gained heptatomic ring imino sugar compounds of embodiment 4 and embodiment.

Test material: all 4- nitrophenols pyranoside matrix, disaccharides and glycosidase are 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, preparation Enzyme concentration is 0.1-0.5mg/mL.Active testing is using 4- nitrophenols pyranoside as matrix, in the optimum activity pH value of every kind of enzyme Under tested.Matrix, appropriate diluted enzyme solutions and inhibitor (heptatomic ring iminosugar) are cultivated 30 minutes at 37 DEG C, Then start reaction in ultraviolet-uisible spectrophotometer, measure its absorption to 400nm wavelength light.Finally use GraFit journey Sequence carries out data analysis [Leatherbarrow, R.J.Grafit 4.0；Erithacus Software:Staines,UK, 1998.]。

3) evaluation result

The results are shown in Table 1 for inhibitory activity of the heptatomic ring imino sugar compounds obtained by embodiment 1-9 to glycosidase.

Evaluation result shows bicyclic class amino sugar I-2a provided by the present invention to beta galactosidase and saccharogenic amylase There are weak inhibitory activity, IC₅₀Respectively 796 μM and 241 μM；1-4b is to beta-glucosidase (beef liver) and beta galactosidase (ox Liver) there are weak inhibitory activity, IC₅₀Respectively 469 μM and 250 μM.Iminosugar I-6a, I-6b, I-7a, I-7b, I-8a, I-8b, I-9a and I-9b has alpha-L-Rhamnosidase weak to medium inhibitory activity, IC₅₀As shown in table 2, comprehensive analysis inhibits to live Property seems related with long alkyl chains.

Table 1: inhibitory activity IC of the part Indolizidine class imino sugar compounds to glycosidase₅₀(μM)

Glycosidase	I-1a	I-1b	I-2a	I-3a	I-3b	I-4b	I-5a	I-5b
									Alpha-glucosidase
Yeast^a	^b(8.1%)	(28.1%)	(0.7%)	(5.0%)	(4.4%)	(5.0%)	(6.7%)	(0.6%)
									Rice	(44.5%)	(33.8%)	(5.7%)	(2.6%)	(0%)	933	(42.7%)	(5.0%)
Rat small intestine maltose	351	562	(7.2%)	(20.9%)	(0.5%)	(39.2%)	(41.7%)	(10.3%)
									Rat small intestine isomaltase	(37.2%)	870	(11.6%)	(11.6%)	(4.9%)	(4.5%)	(17.1%)	(14.8%)
Rat small intestine invertase	173	111	(7.7%)	(6.9%)	(16.5%)	795	(24.5%)	(0.7%)
									Beta-glucosidase
Almond	(0%)	(0%)	(16.8%)	(0%)	(0%)	(26.7%)	(10.8%)	(0.7%)
									Beef liver	(25.1%)	(14.2%)	(35.7%)	(17.6%)	(6.6%)	469	(2.0%)	(14.5%)
Alpha-galactosidase
									Coffee bean	(12.1%)	(4.7%)	(5.3%)	(2.6%)	(5.8%)	(36.4%)	(0%)	(0%)
Beta galactosidase
									Beef liver	(25.2%)	(13.2%)	796	(13.2%)	(8.5%)	250	(31.1%)	(38.9%)
Alpha-Mannosidase
									Sword bean	(0%)	(0.6%)	(0%)	(0%)	(7.9%)	(28.9%)	(13.9%)	(18.5%)
Beta-Mannosidase
									Snail	(9.1%)	(1.0%)	(0%)	(4.3%)	(1.2%)	(0%)	(0%)	(1.6%)
Alpha-L-fucosidase
									Ox kidney	(4.3%)	(0%)	(0%)	(9.1%)	(0%)	(4.3%)	(3.3%)	(0%)
A, a-trehalose enzyme
									Pig kidney	(0%)	(0%)	(0.3%)	(0%)	(3.3%)	(3.5%)	(6.6%)	(2.1%)
Saccharogenic amylase
									Aspergillus niger	(3.3%)	(0%)	241	(0%)	(0%)	(2.1%)	(21.1%)	(7.2%)
Alpha-L-Rhamnosidase
									Penicillium decumbens	(42.6%)	415	(0%)	(15.9%)	(3.4%)	722	(22.2%)	(0%)
GRD beta-glucuronidase
									Escherichia coli	(19.9%)	43.9%)	(5.8%)	(5.9%)	(2.6%)	(42.5%)	(22.5%)	(27.9%)
Beef liver	(4.4%)	(0%)	(4.3%)	(5.5%)	(3.8%)	(9.9%)	(10.5%)	(0.9%)

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

Table 2

It can be seen from the results above that the Indolizidine iminosugar of offer of the invention or its is pharmaceutically acceptable Salt has the activity for inhibiting glycosidase and can be used in treating diabetes.Moreover, Indolizidine imino group provided by the invention The precursor compound of sugar also has the active effect for inhibiting glycosidase.

The preferred embodiment of the present invention has been described above in detail, still, during present invention is not limited to the embodiments described above Detail within the scope of the technical concept of the present invention can be with various simple variants of the technical solution of the present invention are made, this A little simple variants all belong to the scope of protection of the present invention.

It is further to note that specific technical features described in the above specific embodiments, in not lance In the case where shield, can be combined in any appropriate way, in order to avoid unnecessary repetition, the present invention to it is various can No further explanation will be given for the combination of energy.

In addition, various embodiments of the present invention can be combined randomly, as long as it is without prejudice to originally The thought of invention, it should also be regarded as the disclosure of the present invention.

Claims

1. a kind of Indolizidine iminosugar, the iminosugar is in following compound or its pharmaceutically acceptable salt At least one:

2. a kind of method for preparing iminosugar described in claim 1, this method comprises: in acid condition, being deposited in catalyst Under, the precursor compound of the iminosugar is subjected to hydrogenation；Or

In the presence of a lewis acid, the precursor compound of the iminosugar is subjected to deprotection reaction；

The precursor compound is the compound or its pharmaceutically acceptable salt of structure shown in XIV:

3. according to the method described in claim 2, wherein, the catalyst is selected from palladium carbon, palladium black, palladium dydroxide, palladium chloride, oxygen Change at least one of platinum, platinum black, ruthenic chloride and Wilkinson catalyst.

4. according to the method described in claim 2, wherein, the precursor compound is structure shown in Formula XIV -6a and XIV-6b The preparation method of compound or its pharmaceutically acceptable salt, comprising the following steps:

Alternatively, the precursor compound is the compound or its pharmaceutically acceptable salt of structure shown in Formula XIV -7a and XIV-7b Preparation method, comprising the following steps:

Alternatively, the precursor compound is the compound or its pharmaceutically acceptable salt of structure shown in Formula XIV -8a and XIV-8b Preparation method, comprising the following steps:

Alternatively, the precursor compound is the compound or its pharmaceutically acceptable salt of structure shown in Formula XIV -9a and XIV-9b Preparation method, comprising the following steps:

In formula, a is to be reacted with Grignard Reagent, and b is reduction reaction, and c is that protection reaction is carried out under alkaline condition, and d is oxidation Reaction, e are to be reacted with Grignard Reagent, and f is sulfonating reaction, and g is deprotection reaction, and h is ring closure reaction.

5. iminosugar described in claim 1 or its pharmaceutically acceptable salt are in the drug that preparation inhibits glycosidase activity Application.

6. application according to claim 5, wherein the glycosidase is selected from alpha-glucosidase, beta-glucosidase, α- Galactosidase, beta galactosidase, alpha-Mannosidase, beta-Mannosidase, alpha-L-fucosidase, trehalase, shallow lake At least one of powder glucuroide and alpha-L-Rhamnosidase.

7. iminosugar described in claim 1 or its pharmaceutically acceptable salt preparation prevention and/or treatment diabetes, Application in prevention and/or treatment gaucher's disease, prevention and/or treatment tumour and antiviral drug.