CN105732620A

CN105732620A - Indolizidine imino sugar, precursor compound thereof and preparation method and application of indolizidine imino sugar and precursor compound

Info

Publication number: CN105732620A
Application number: CN201610202477.7A
Authority: CN
Inventors: 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: 2016-07-06
Anticipated expiration: 2036-04-01
Also published as: CN105732620B

Abstract

The invention relates to the field of natural product synthesis and discloses indolizidine imino sugar, a precursor compound thereof and a preparation method and application of the indolizidine imino sugar and the precursor compound.The indolizidine imino sugar is a compound or salt acceptable in pharmacy, wherein the compound or salt is of a structure as shown in formula I; the precursor compound is a compound or salt acceptable in pharmacy, wherein the compound or salt is of a structure as shown in formula XIV.The indolizidine imino sugar or slat thereof acceptable in pharmacy has activity of inhibiting glycosidase and can be used for treating diabetes; besides, the precursor compound of the indolizidine imino sugar also has the effect of inhibiting activity of glycosidase.

Description

Indolizidine iminosugar and precursor compound thereof and their preparation method and application

Technical field

The present invention relates to the synthesis field of natural product, in particular it relates to the precursor compound of a kind of Indolizidine iminosugar and this Indolizidine iminosugar, and the preparation method of described Indolizidine iminosugar and precursor compound thereof and application.

Background technology

Glycosidase take part in many important bioprocesses relevant with glycoconjugates, such as synthesis and decomposition, lysosomal glycoconjugates metabolism etc. of the digestion of enteral, glycoprotein, plays key player in life entity, closely related with numerous disease.

Iminosugar, also known as polyhydroxylated alkaloid, azasugar, imines sugar etc., is effective inhibitor of glycosidase, has important pharmacologically active in antiviral, antitumor, treatment diabetes etc..

Many iminosugar have been had to be developed to medicine and list (such as NBDNJ, Miglitol, Miglustat etc.).

In iminosugar, Indolizidine compounds has consequence, a lot of Indolizidine class iminosugar have good biological activity [such as (-)-swainsonine, (-)-castanospermine etc.], have huge application prospect.Due to the good nature that Indolizidine class iminosugar shows, finding the Indolizidine Alkaloid with novel structure becomes the field that people pay close attention to.

Folium Stevlae Rebaudianae alkali is the Indolizidine class iminosugar with alkyl side chain found first in recent years, and the structure of its novelty causes the research interest of people.In recent years, in order to study chemistry and the biological activity of Folium Stevlae Rebaudianae alkali further, the research about Folium Stevlae Rebaudianae alkali appears in the newspapers repeatly.And the bioactivity research developing a kind of convenient, general synthetic method and system becomes the emphasis that this area research worker is paid close attention to.

Summary of the invention

It is an object of the invention to provide a kind of new having suppress glycosidase activity and can be used in the compound for the treatment of diabetes and precursor compound thereof and their pharmaceutically acceptable salts.

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

Wherein, R¹For hydrogen atom or methylol, R²Hydrogen atom on the straight or branched saturated alkyl of C1-C12, pi-allyl, benzyl and phenyl ring is by least one in the benzyl of methoxyl group or halogen substiuted；1,2,3,5 and the spatial configuration of 8a position carbon be each independently R or S；And work as R¹For methylol, R²During for methyl, described iminosugar does not include the compound of 1,2,3,5 and 8a position carbon 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 provides the precursor compound of aforementioned iminosugar, and this precursor compound is compound or its pharmaceutically acceptable salt of structure shown in Formula X IV:

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

R⁷For hydrogen atom, or R⁷For oxygen atom with the hydrogen atom on the straight or branched saturated alkyl of C1-C12, pi-allyl, acetyl group, benzoyl, benzyl and phenyl ring by least one methylol being connected in the benzyl of methoxyl group or halogen substiuted；

R²Hydrogen atom on the straight or branched saturated alkyl of C1-C12, pi-allyl, benzyl and phenyl ring is by least one in the benzyl of methoxyl group or halogen substiuted；

In the compound of structure shown in Formula X IV 1,2,3,5 and the spatial configuration of 8a position carbon respectively with 1 in Formulas I, 2,3,5 and the spatial configuration of 8a position carbon identical；And work as R⁷For benzyloxymethyl, R²During for methyl, described precursor compound does not include the compound of 1,2,3,5 and 8a position carbon respectively following spatial configuration: (1S, 2R, 3S, 5S, 8aS) and (1S, 2R, 3S, 5R, 8aS).

The third aspect, the preparation method that the present invention provides aforementioned Indolizidine iminosugar, the method includes: in acid condition, in the presence of a catalyst, aforesaid for present invention precursor compound is carried out hydrogenation；Or

In the presence of a lewis acid, aforesaid for present invention precursor compound is carried out deprotection reaction.

Fourth aspect, the present invention provides a kind of method preparing the aforesaid precursor compound of the present invention, and the method comprises the following steps:

(1) nitrone shown in Formula II and Grignard reagent are reacted, obtain the azanol shown in formula III；

(2) azanol shown in described formula III is carried out reduction reaction, obtain the amine shown in Formulas I V；

(3) in the basic conditions, the amine shown in described Formulas I V is carried out protection reaction, obtains the compound shown in Formula V；

(4) compound shown in described Formula V is carried out oxidation reaction, obtain the ketone shown in Formula IV；

(5) ketone shown in described Formula IV is carried out reduction reaction, obtain the alcohol shown in Formula VII；

(6) alcohol shown in described Formula VII is carried out sulfonating reaction, obtain the compound shown in Formula VIII；

(7) compound shown in Formula VIII is carried out deprotection reaction, obtain the amine shown in Formula IX；

(8) amine shown in Formula IX is carried out ring closure reaction, obtain the precursor compound shown in Formula X IV；

Wherein, R³、R⁸And R⁷Definition identical with the aforesaid definition of the present invention；

R in Formula V-Formula VIII⁴Corresponding identical, and R⁴Hydrogen atom on tertbutyloxycarbonyl, fluorenylmethoxycarbonyl, acetyl group, pi-allyl, benzyloxycarbonyl group and phenyl ring by methoxyl group or halogen substiuted and at least one in the benzyloxycarbonyl group that obtains；

R in Formula VIII and Formula IX⁵Identical, and R⁵Be selected from hydrogen atom on mesyl, trifyl, benzenesulfonyl, p-toluenesulfonyl and phenyl ring by methoxyl group or halogen substiuted and at least one in the benzenesulfonyl that obtains；

In Formula II-Formula IX 1,2 are corresponding with the spatial configuration of 1 in the compound of structure shown in Formula X IV, 2 and 3 carbon identical respectively with the spatial configuration of 3 carbon；The spatial configuration of 4 carbon in formula III-Formula IX is identical, for R or S configuration；The spatial configuration of 8 carbon in Formula VII-Formula IX is identical, for R or S configuration.

5th aspect, the present invention provides a kind of method preparing the aforesaid precursor compound of the present invention, and the method comprises the following steps:

(4) compound shown in Formula V is carried out oxidation reaction, obtain the aldehyde shown in Formula X；

(5) aldehyde shown in Formula X and Grignard reagent are reacted, obtain the alcohol shown in Formula X I；

(6) alcohol shown in Formula X I is carried out sulfonating reaction, obtain the compound shown in Formula X II；

(7) compound shown in Formula X II is carried out deprotection reaction, obtain the amine shown in Formula X III；

(8) amine shown in Formula X III is carried out ring closure reaction, obtain the precursor compound shown in Formula X IV；

R in Formula V and Formula X-Formula X II⁴Corresponding identical, and R⁴Definition identical with the aforesaid definition of the present invention；

R in Formula X II-Formula X III⁵Identical, and R⁵Definition identical with the aforesaid definition of the present invention；

R in Formula X I and Formula X III⁶Identical, and R⁶Hydrogen atom on the straight or branched saturated alkyl of C1-C12, pi-allyl, propylidene base, acetyl group, benzoyl, benzyl and phenyl ring is by least one in the benzyl of methoxyl group or halogen substiuted；

In Formula II-Formula V and Formula X-Formula X III 1,2 are corresponding with the spatial configuration of 1 in the compound of structure shown in Formula X IV, 2 and 3 carbon identical respectively with the spatial configuration of 3 carbon；The spatial configuration of 4 carbon in formula III-Formula V and Formula X-Formula X III is identical, for R or S configuration；The spatial configuration of 8 carbon in Formula X I-Formula X III is identical, for R or S configuration.

6th aspect, the present invention provides the precursor compound of aforesaid iminosugar or aforesaid iminosugar or its pharmaceutically acceptable salt to suppress the application in the medicine of glycosidase activity in preparation.

7th aspect, the present invention provides aforesaid iminosugar or its pharmaceutically acceptable salt in the application in preparation prevention and/or treatment diabetes, prevention and/or treatment gaucher's disease, prevention and/or treatment tumor and antiviral drug.

Indolizidine iminosugar provided by the invention or its pharmaceutically acceptable salt have the activity suppressing glycosidase and can be used in treatment diabetes.And, the precursor compound of Indolizidine iminosugar provided by the invention also has the active effect suppressing glycosidase.

The method preparing described Indolizidine iminosugar and precursor compound thereof provided by the invention has advantage with low cost.

Other features and advantages of the present invention will be described in detail in detailed description of the invention part subsequently.

Detailed description of the invention

Hereinafter the specific embodiment of the present invention is described in detail.It should be appreciated that detailed description of the invention described herein is merely to illustrate and explains the present invention, it is not limited to the present invention.

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

The straight or branched saturated alkyl of described C1-C12 includes at least one in methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, n-hexyl, cyclopropyl, methylcyclopropyl groups, ethyl cyclopropyl, cyclopenta, methylcyclopentyl, cyclohexyl, n-heptyl, n-octyl, n-nonyl, positive decyl, n-undecane base and dodecyl.

Described halogen includes at least one in fluorine, chlorine, bromine and iodine.

Preferably, described iminosugar at least one in following compound or its pharmaceutically acceptable salt:

Second aspect, the invention provides the precursor compound of aforementioned iminosugar, this precursor compound is compound or its pharmaceutically acceptable salt of structure shown in Formula X IV:

The third aspect, the preparation method that the invention provides aforementioned Indolizidine iminosugar, the method includes: in acid condition, in the presence of a catalyst, aforesaid for present invention precursor compound is carried out hydrogenation；Or

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

Described hydrogenation carries out under existing preferably in hydrogen source, and described hydrogen source includes but are not limited to hydrogen, ammonium formate, connection imido, cyclohexene and cyclohexadiene.

Described acid condition carries out under existing preferably in organic acid or mineral acid, and wherein, described organic acid includes at least one in formic acid, acetic acid, p-methyl benzenesulfonic acid and benzoic acid；Described mineral acid includes at least one in sulphuric acid, hydrochloric acid, phosphoric acid and perchloric acid.

Described lewis acid is preferably selected from least one in boron trifluoride, boron chloride, Boron tribromide, Iodotrimethylsilane and titanium tetrachloride.

The preparation method of described Indolizidine iminosugar preferably carries out in the presence of solvent, described solvent include methanol, ethanol, acetonitrile, oxolane, toluene, acetone, dichloromethane, chloroform, 1, at least one in 2-dichloroethanes, DMF and dimethyl sulfoxide.

The condition of described deprotection reaction includes: temperature is 0-100 DEG C；Time is 0.1-24 hour, it is preferred to 2-3 hour.

The condition of described hydrogenation can be identical or different with the condition of described deprotection reaction；Preferably, the condition of described hydrogenation includes: temperature is 0-100 DEG C；Time is 0.1-24 hour, it is preferred to 2-3 hour.

Fourth aspect, the invention provides a kind of method preparing the aforesaid precursor compound of the present invention, the method comprises the following steps:

R in Formula V-Formula VIII⁴Corresponding identical, and R⁴Hydrogen atom on tertbutyloxycarbonyl, fluorenylmethoxycarbonyl, acetyl group, pi-allyl, benzyloxycarbonyl group and phenyl ring by methoxyl group or halogen substiuted and at least one in the benzyloxycarbonyl group that obtains

R in Formula VIII and Formula IX⁵Identical, and R⁵Hydrogen atom on mesyl, trifyl, benzenesulfonyl, p-toluenesulfonyl and phenyl ring by methoxyl group or halogen substiuted and at least one in the benzenesulfonyl that obtains,

Preferably, in step (1), described Grignard reagent is prepared by the bromo-1-amylene of 5-.The consumption mol ratio of the nitrone shown in described Formula II and Grignard reagent is 1:(1-100), it is preferable that 1:(1.5-10).The condition that nitrone shown in Formula II and Grignard reagent react includes: temperature is subzero 80 DEG C to 100 DEG C above freezing, it is preferred to subzero 10 DEG C to 20 DEG C above freezing；Time is 0.1-100h, it is preferred to 3-60h.

Preferably, in step (2), described reduction reaction carries out in the presence of a reducing agent.Described reducing agent includes but not limited at least one in zinc powder-Schweinfurt green and hydrate thereof and zinc powder-acid.When described reducing agent is zinc powder-Schweinfurt green and hydrate thereof, the consumption mol ratio of the azanol shown in formula III, zinc powder and Schweinfurt green is 1:(10-100): (0.1-1), it is preferably 1:(10-20): (0.1-0.5), and the solvent of described reduction reaction is preferably glacial acetic acid, the condition of described reduction reaction includes: temperature is 0-100 DEG C, being preferably 10-55 DEG C, the time is 0.1-100h, it is preferred to 4-24h.When described reducing agent is zinc powder-acid, azanol shown in formula III, zinc powder consumption mol ratio be 1:(10-100), it is preferably 1:(10-20), acid in described reducing agent is preferably ammonium chloride saturated solution, the solvent of described reduction reaction is methanol, and the condition of described reduction reaction includes: temperature is 0-100 DEG C, it is preferred to 10-55 DEG C, time is 0.1-100h, it is preferred to 4-24h.

Preferably, in step (3), described alkali condition is formed by the existence of alkaline matter.Described alkaline matter all includes organic base and/or inorganic base.Described protection reaction carries out under protectant existence, and the amine shown in described Formulas I V, alkaline matter and protectant consumption mol ratio are 1:(1-100): (1-100), it is preferred to 1:(1-10): (1-20)；The condition of described protection reaction includes: temperature is 0-100 DEG C, it is preferred to 10-55 DEG C, and the time is 0.1-100h, it is preferred to 0.5-8h.

Preferably, in step (4), described oxidation reaction carries out under the existence of palladium salt and mantoquita.Described palladium salt is Palladous chloride. and/or palladium；Described mantoquita includes but are not limited to Cu-lyt., cuprous bromide, copper chloride, copper bromide, copper sulfate, Schweinfurt green and hydrate thereof.The consumption mol ratio of the compound shown in described Formula V, palladium salt and mantoquita is 1:(0.1-10): (0.1-10)；It is preferably 1:(0.1-0.5): (0.1-1).The condition of described oxidation reaction includes: temperature is 0-100 DEG C, it is preferred to 5-55 DEG C, and the time is 0.1-200h, it is preferred to 24-100h.

Preferably, in step (5), described reduction reaction carries out in the presence of a reducing agent, described reducing agent at least one in lithium aluminium hydride reduction, diisobutyl aluminium hydride, sodium borohydride, sodium cyanoborohydride, borine (such as borine-oxolane and/or borane-dimethyl sulfide), double; two (2-methoxyethoxy) sodium aluminate (red aluminum) of dihydro and 3-sec-butyl lithium borohydride (L-Selectride).The consumption mol ratio of the ketone shown in described Formula IV and reducing agent is 1:(1-100), it is preferred to 1:(1-10).The condition of described reduction reaction includes: temperature is subzero 80 DEG C to 100 DEG C above freezing, it is preferred to subzero 10 DEG C to 25 DEG C above freezing, the time is 0.1-100h, it is preferred to 0.5-1h.

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

Preferably; in step (7), when being tertbutyloxycarbonyl when protecting base, deprotection reaction carries out in acid condition; described acid condition is formed under acidic materials exist, and described acidic materials include hydrochloric acid, sulphuric acid, trifluoroacetic acid, boron trifluoride and boron chloride；The consumption mol ratio of the compound shown in described Formula VIII and acidic materials is 1:(1-1000), it is preferred to 1:(1-100)；The condition of described deprotection reaction includes: temperature is subzero 80 DEG C to 100 DEG C above freezing, it is preferred to subzero 10 DEG C to 25 DEG C above freezing；Time is 0.1-100h, it is preferred to 0.5-8h.When being benzyloxycarbonyl group when protecting base, deprotection reaction carries out under catalytic hydrogenation conditions, and the catalyst in described catalytic hydrogenation conditions includes but not limited to palladium carbon, palladium black, palladium dydroxide, Palladous chloride., platinum oxide and platinum black；Hydrogen source in described catalytic hydrogenation conditions includes but not limited to hydrogen, ammonium formate, connection imido, cyclohexene and cyclohexadiene；The consumption weight ratio of the compound shown in described Formula VIII and catalyst is 1:(0.1-10), it is preferred to 1:(0.1-0.5)；The condition of described deprotection reaction includes: temperature is subzero 80 DEG C to 100 DEG C above freezing, it is preferred to subzero 10 DEG C to 25 DEG C above freezing；Time is 0.1-100h, it is preferred to 2-24h.

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

Preferably, described organic base includes triethylamine, diisopropyl ethyl amine, tetramethylethylenediamine, pyridine, hexahydropyridine, 2，4，6-trimethylpyridine and tetrabutyl ammonium fluoride；Described inorganic base includes sodium hydroxide, potassium hydroxide, Lithium hydrate, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate and TBAH.

5th aspect, the invention provides a kind of method preparing the aforesaid precursor compound of the present invention, the method comprises the following steps:

In the step (1), (2) and the preparation method of (3) and a fourth aspect of the present invention that relate in the preparation method of a fifth aspect of the present invention, corresponding step (1), (2) and (3) is identical, therefore, the step (1), (2) that relate in the preparation method of the 5th aspect for the present invention are all identical with a fourth aspect of the present invention with parameter etc. with the operational approach of (3), and the present invention does not repeat them here.

Preferably, in step (4), described oxidation reaction carries out in the presence of an oxidizer, and described oxidant includes at least one in Osmic acid., potassium permanganate, potassium dichromate, chromic acid, ozone, sodium metaperiodate and lead tetra-acetate.The consumption mol ratio of the compound shown in described Formula V and described oxidant is 1:(1-100), it is preferred to 1:(1-5).The condition of described oxidation reaction includes: temperature is 0-100 DEG C, it is preferred to 5-40 DEG C, and the time is 0.1-100h, it is preferred to 2-24h.

Preferably, in step (5), described Grignard reagent is at least one in the Grignard reagent prepared by the benzyl obtained of methoxyl group or halogen substiuted of the hydrogen atom on the straight or branched saturated alkyl of halo C1-C12, pi-allyl, benzyl and phenyl ring；The consumption mol ratio of the aldehyde shown in described Formula X and described Grignard reagent is 1:(1-100), it is preferred to 1:(1-5).The condition that aldehyde shown in Formula X and Grignard reagent react includes: temperature is subzero 80 DEG C to 100 DEG C above freezing, it is preferred to subzero 10 DEG C to 25 DEG C above freezing；Time is 0.1-100h, it is preferred to 2-24h.

Preferably, in step (6), described sulfonating reaction carries out under the existence of alkaline matter and sulfonylation agent, and described alkaline matter all includes organic base and/or inorganic base.The consumption mol ratio of the alcohol shown in described Formula X I, sulfonylation agent and alkaline matter is 1:(1-10): (1-100), it is preferred to 1:(1-5): (1.5-20).The condition of described sulfonating reaction includes: temperature is subzero 80 DEG C to 100 DEG C above freezing, it is preferred to subzero 10 DEG C to 25 DEG C above freezing；Time is 0.1-100h, it is preferred to 0.5-8h.

Preferably; in step (7), when being tertbutyloxycarbonyl when protecting base, deprotection reaction carries out in acid condition; described acid condition is formed under acidic materials exist, and described acidic materials include hydrochloric acid, sulphuric acid, trifluoroacetic acid, boron trifluoride and boron chloride；The consumption mol ratio of the compound shown in described Formula X II and acidic materials is 1:(1-1000), it is preferred to 1:(1-100)；The condition of described deprotection reaction includes: temperature is subzero 80 DEG C to 100 DEG C above freezing, it is preferred to subzero 10 DEG C to 25 DEG C above freezing；Time is 0.1-100h, it is preferred to 0.5-8h.When being benzyloxycarbonyl group when protecting base, deprotection reaction carries out under catalytic hydrogenation conditions, and the catalyst in described catalytic hydrogenation conditions includes but not limited to palladium carbon, palladium black, palladium dydroxide, Palladous chloride., platinum oxide and platinum black；Hydrogen source in described catalytic hydrogenation conditions includes but not limited to hydrogen, ammonium formate, connection imido, cyclohexene and cyclohexadiene；The consumption weight ratio of the compound shown in described Formula X II and catalyst is 1:(0.1-10), it is preferred to 1:(0.1-0.5)；The condition of described deprotection reaction includes: temperature is subzero 80 DEG C to 100 DEG C above freezing, it is preferred to 0-45 DEG C；Time is 0.1-100h, it is preferred to 2-24h.

Preferably, in step (8), described ring closure reaction carries out in the presence of a basic.Described alkaline matter all includes organic base and/or inorganic base.The consumption weight ratio of the amine shown in described Formula X III and described alkaline matter is 1:(0.1-10), it is preferred to 1:(0.1-0.5).The condition of described ring closure reaction includes: temperature is subzero 80 DEG C to 100 DEG C above freezing, it is preferred to 0-45 DEG C；Time is 0.1-100h, it is preferred to 10-50h.

6th aspect, the invention provides the precursor compound of aforesaid iminosugar or aforesaid iminosugar or its pharmaceutically acceptable salt and suppress the application in the medicine of glycosidase activity in preparation.

Preferably, described glycosidase at least one in alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta galactosidase, alpha-Mannosidase, beta-Mannosidase, alpha-L-fucosidase, trehalase, amyloglucosidase and alpha-L-Rhamnosidase.

7th aspect, the invention provides aforesaid iminosugar or its pharmaceutically acceptable salt in the application in preparation prevention and/or treatment diabetes, prevention and/or treatment gaucher's disease, prevention and/or treatment tumor and antiviral drug.

In described medicine, it is also possible to add one or more pharmaceutically acceptable carriers.Described carrier includes the conventional diluent of pharmaceutical field, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier, lubricant and other additive.

Described medicine can be the various ways such as injection, tablet, powder, granule, capsule, oral liquid, unguentum, cream.The medicine of above-mentioned various dosage form all can be prepared according to the conventional method of pharmaceutical field.

Described medicine may utilize the administration of various route of administration, includes but not limited to be administered orally, sucks, rectum, transdermal, through mucous membrane enteral administration and subcutaneous, muscle or intravenous administration.

Medicine of the present invention can be individually dosed, or is administered together with known other treatment diabetes, antiviral, antibacterial and antitumor drug.

The method of the present invention also includes advantage in detail below:

With polyhydroxy nitrone for initiation material, be prepared for that there is certain bioactive Indolizidine class iminosugar through multistep reaction, it is achieved that this compounds succinct, efficiently prepare.The present invention is raw materials used can be prepared by cheap xylose, arabinose, ribose and malic acid etc., and raw material is easy to get, and preparation method is simple, and mild condition, the purification of intermediate is easy.The method of the present invention is easily achieved a large amount of synthesis, can synthesize a large amount of Indolizidine class iminosugar at short notice, has the compound of biological activity and medical value to provide solid foundation for screening.

Hereinafter will be described the present invention by embodiment.

When not contrary explanation, various raw materials used below are all from being purchased.

Preparation example: preparation Formula II-1 is to the compound (adopt with prepare the same method of Compound Phase shown in II-1 and the compound shown in II-2 to II-4 and II-6 prepared by corresponding raw material sugar) shown in II-6

Ice bath, under stirring condition, it is added dropwise over 10mL chloroacetic chloride in the dry methanol of 500mL, it is subsequently added D-xylose (0.2mol), keep zero degree reaction until raw material disappears, being neutralized to neutrality with sodium bicarbonate, filter and remove inorganic salt, solvent evaporated gained crude product D-furyl xylose first glycosides directly throws the next step.

Upper step crude product D-furyl xylose first glycosides (calculating according to 0.2mol) is dissolved in dry DMF (200mL), and dropwise it is added drop-wise in the THF (200mL) containing NaH (0.72mol) and DMF (200mL), finish, add TBAI (tetrabutylammonium iodide) (2.0g), after half an hour, it is added dropwise over BnBr (0.66mol), reaction is until raw material disappears, it is slowly added dropwise saturated aqueous ammonium chloride cancellation reaction, ethyl acetate/water extracts, washing organic facies removes DMF, solvent evaporated obtains crude product 2, 3, 5-O-tribenzyl-D-furyl xylose first glycosides, directly throw the next step.

Upper step crude product 2,3,5-O-tribenzyl-D-furyl xylose first glycosides (calculates by 0.2mol) and is dissolved in the acetic acid aqueous solution of 80 weight % (150mL) and 1, in the mixed solvent of 4-dioxane (150mL), add aqueous sulfuric acid (1mol/L, 150mL), backflow is until raw material is almost wholly absent, solvent evaporated, extract with ethyl acetate/saturated sodium carbonate solution, be evaporated organic facies, obtain crude product (hemiacetal crude product) (2,3,5-O-tribenzyl-D-furyl xyloses) directly throw in next step reaction.

Pyridine (0.37mol) is added above-mentioned crude product 2, 3, in dichloromethane (100mL) solution that 5-O-tribenzyl-D-furyl xylose (calculates according to 0.2mol), it is charged with O-methyl hydroxylamine hydrochloride (0.25mol), after 12h is stirred at room temperature, solvent is evaporated, then in concentrated solution, add ethyl acetate (150mL) and hydrochloric acid (1mol/L, 30mL), through extracting and demixing, merge organic facies, dry, concentration, obtain crude product (2S, 3S, 4R)-2, 3, 5-tri-benzyloxy-4-hydroxyl-1-valeral methyloxime ether, directly throw in next step reaction.

By above-mentioned crude product (2S, 3S, 4R)-2,3,5-tri-benzyloxy-4-hydroxyl-1-valeral methyloxime ether (calculates by 0.2mol) and is dissolved in dichloromethane (100mL), add pyridine (0.37mol) and methane sulfonyl chloride (0.20mol), after 8h is stirred at room temperature, add this reaction of aqueous hydrochloric acid solution (1mol/L) cancellation.Through extracting and demixing, merge organic facies, dry, concentration, obtain crude product (2S, 3S, 4R)-2,3,5-tri-benzyloxy-4-sulfonyloxy methyl oxygen-1-valeral methyloxime ether, be directly used in next step reaction.

Toward above-mentioned crude product (2S, 3S, 4R)-2,3, oxolane (300mL) solution that 5-tri-benzyloxy-4-sulfonyloxy methyl oxygen-1-valeral methyloxime ether (calculates by 0.2mol) adds p-methyl benzenesulfonic acid (0.2mol) and 37 weight % formalins (50mL), it is stirred at room temperature until raw material is wholly absent, in mixed liquor, then adds ethyl acetate and water, through extracting and demixing, merge organic facies, dry, concentration, gained crude product (2R, 3R, 4R)-4-mesyloxy-2,3,5-tri-benzyloxy-1-valerals.

First sodium bicarbonate (0.45mol) is added in the aqueous solution (50mL) of oxammonium hydrochloride. (0.45mol), it is added thereto to above-mentioned crude product (2R, 3R, 4R)-4-mesyloxy-2,3, the alcoholic solution (200mL) that 5-tri-benzyloxy-1-valeral (calculates by 0.2mol), is stirred at room temperature 15h, post-heating stirring 48h.Then in mixed liquor, add ethyl acetate and water, through extracting and demixing, merge organic facies, dry, concentration, obtain yellow oil.This grease is dissolved in ethyl acetate and petroleum ether, left at room temperature over night, precipitating out white solid 10.40g, mother solution continues crystallization, 9.95g white solid of getting back, mother solution is got back white solid 1.35g after purification by column chromatography, amount to 22.00g nitrone product ((3S, 4S, 5S)-3,4-benzyloxy-5-benzyloxymethyl-1-pyrrolin-N-oxide), it is the compound shown in Formula II-1.Calculating with xylose for raw material, seven step reaction gross production rates are 26%.

Its structural identification data are: m.p.:90-91 DEG C；[α] D=+45 ° of (c0.4, 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/z418.2007 [M+H]+(C₂₆H₂₈NO₄requires418.2013)。

Preparation compound shown in Formula II-5:

Under ice-water bath, being added dropwise over thionyl chloride (1.47mol) in the dehydrated alcohol (600mL) of L-TARTARIC ACID (0.67mol), room temperature reaction is overnight.Morning next day, reaction was complete, and low-temperature reduced-pressure is spin-dried for solvent, acetic acid ethyl dissolution, and saturated sodium bicarbonate aqueous solution is washed till neutrality, dries, concentrates to obtain colorless oil as product diethyl tartrate., yield 94%.

Diethyl tartrate. (36.4mmol) is dissolved into dry N, in dinethylformamide (100mL) and oxolane (50mL), gains are added dropwise to NaH (2.4 times of equivalents under-20 DEG C of conditions, 80mmol, 60%) in oxolane (50mL), add the tetrabutylammonium iodide of catalytic amount, keep 10min, it is slowly added dropwise BnBr (2.2 times of equivalents, 73.35mmol), keeping-20 DEG C of reactions, TLC (petrol ether/ethyl acetate 5:1) monitors reaction.Reacting complete, with saturated aqueous ammonium chloride careful cancellation reaction, ethyl acetate/saturated aqueous ammonium chloride extracts, and DMF is removed in washing, and dry, concentration, column chromatography obtain the diethyl tartrate. of double; two benzyl protection, yield 82%.

The diethyl tartrate. (112mmol) of double; two benzyl protections is dissolved in the 500mL ether dried; under ice-water bath; it is dividedly in some parts Lithium Aluminium Hydride (2 times of equivalents; 224mmol); after room temperature reaction 30min; ice is to 0 DEG C; with the careful cancellation reaction of ethyl acetate; it is slowly added dropwise saturated aqueous ammonium chloride to clarify to system; pouring out supernatant, ethyl acetate/water extracts pastel, merges organic facies; dry, concentration, column chromatography (petrol ether/ethyl acetate 3:2) oil product glycol, yield 93%.

The glycol (0.66mmol) that upper step is obtained by reacting is dissolved in the 5mL dichloromethane dried, add triethylamine (2.5 times of equivalents, 1.65mmol), under ice-water bath, it is added dropwise over methylsufonyl chloride (2.2 times of equivalents, 1.45mmol), room temperature reaction reacts completely for 1 hour, decompression is spin-dried for solvent, ethyl acetate/saturated aqueous ammonium chloride extracts, merge organic facies, dry, concentration, column chromatography (petrol ether/ethyl acetate 3:1) the double; two methylsulfonyl ester of rufous oil product, yield 91%.

Double; two methylsulfonyl esters (0.60mmol) are dissolved in the 10mL triethylamine dried, add oxammonium hydrochloride. (4 times of equivalents, 2.4mmol), back flow reaction 1.5 hours, reacts completely, and decompression is spin-dried for solvent, ethyl acetate/saturated aqueous ammonium chloride extracts, merge organic facies, dry, concentration, column chromatography (petrol ether/ethyl acetate 2:1) oil product cyclic hydroxylamine, yield 84%.

Cyclic hydroxylamine (0.50mmol) is dissolved in the 5mL dichloromethane dried, under ice bath, add yellow mercury oxide (2 times of equivalents, 1.0mmol), overnight, react completely room temperature reaction (TLC petrol ether/ethyl acetate 1:2), kieselguhr filters, decompression is spin-dried for solvent, and concentration, column chromatography (petrol ether/ethyl acetate 1:2) obtain oil product II-5, yield 94%.

Its structural identification data are:¹HNMR (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).¹³CNMR(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 intermediate thereof

Under argon shield; adding the bromo-1-amylene (17mmol) of 5-in heavily steaming oxolane (15mL) suspension of the magnesium chips (24mmol) of new polishing, heat to 50 DEG C of reactions, there are a large amount of bubbles in system; solution is Dark grey, continues reaction 0.5h.Nitrone II-1 (12mmol) is dissolved in dry oxolane, under condition of ice bath, above-mentioned Grignard reagent is added dropwise over by syringe, within 15 minutes, add, continue reaction 1h, TLC monitoring display raw material and disappear, add saturated ammonium chloride solution cancellation reaction, extraction into ethyl acetate, not drying, directly remove solvent under vacuo and obtain the crude product of III-1.

The crude product of III-1 is dissolved in acetic acid, joins preactivated good zinc powder (0.12mol) and Cu (OAc)₂(containing two molecular crystalline water, in glacial acetic acid mixture 1.2mmol), (zinc powder processed by dilute hydrochloric acid and Schweinfurt green are placed in glacial acetic acid and stir, until there is rufous in system), system is highly exothermic, room temperature reaction is overnight, TLC monitoring display raw material complete reaction, removing solvent under vacuum, gained solid washs through ethyl acetate, and NaOH saturated solution regulates about pH=9, extraction into ethyl acetate aqueous phase, merging organic facies, anhydrous magnesium sulfate dries, and sucking filtration removes solid, remove solvent under vacuum, obtain the crude product of IV-1.

By the crude product of IV-1 (20mL) in dichloromethane, add triethylamine (15mmol) and (Boc)₂O (13mmol), room temperature reaction 2h, TLC monitors raw material point and is wholly absent, and adds saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent under vacuum, and column chromatography (petroleum ether: ethyl acetate=30:1) obtains alkene V-1, for colorless viscous shape liquid 3.2g, productivity 48%.Structural identification:

¹HNMR(300MHz,CDCl₃null)δ7.34(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).¹³CNMR(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 mixed solvent, add palladium (0.96mmol) and Schweinfurt green (band water of crystallization, 4.8mmol), room temperature reaction 4 days under oxygen atmosphere, TLC monitoring reacts completely, add saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, remove solvent under vacuum, obtain the crude product of ketone VI-1.

Under condition of ice bath, the crude product (in 2mmol) of VI-1 is dissolved in the methanol of 15mL, is slowly added to sodium borohydride (2.5mmol), add rear system and become light gray, after 30min, TLC monitors the disappearance of raw material point, adding saturated ammonium chloride cancellation reaction, remove methanol under vacuum, the thick white oil thing of gained is redissolved in saturated ammonium chloride, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, removes solvent and obtain the crude product of VII-1 under vacuum.

The crude product of VII-1 is redissolved in 5mL dry methylene chloride, add triethylamine (3mmol), be slowly added to methylsufonyl chloride (2.4mmol) under condition of ice bath, after adding, remove ice bath, room temperature reaction 1h, TLC monitors raw material point and disappears, and adds saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent, obtain the crude product of VIII-1 under vacuum.

Being redissolved in by VIII-1 in 5mL dichloromethane, add 3mL trifluoroacetic acid, after reaction 1h, TLC shows that raw material disappears, and obtains a big product of polarity, adds saturated NaHCO₃Cancellation is reacted, extraction into ethyl acetate, and anhydrous magnesium sulfate dries, and sucking filtration removes solid, removes solvent and obtain the crude product of IX-1 under vacuum.

The crude product of IX-1 is redissolved in 10mL methanol, add 100mg Anhydrous potassium carbonate, room temperature reaction 48h, two product points that TLC monitors polarized less generate, methanol is removed under vacuum, the thick grease of gained is redissolved in saturated ammonium chloride, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removing solvent under vacuum, column chromatography (petroleum ether: ethyl acetate=15:1) obtains the less point (XIV-1a) of polarity 204mg altogether, point (XIV-1b) 225mg altogether that polarity is bigger.Structural identification:

XIV-1a:¹HNMR(400MHz,CDCl₃) δ 7.41 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)；¹³CNMR(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:¹HNMR(400MHz,CDCl₃) δ 7.38 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)；¹³CNMR(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, adds the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, overnight, TLC shows that raw material disappears to room temperature reaction, is filtered to remove palladium carbon by kieselguhr, solvent is removed under vacuum, neutralize through ammonia, processed by acidic resins post, obtain I-1a, for weak yellow liquid 72mg, productivity 85%.Structural identification:

¹HNMR(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).¹³CNMR(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, adds the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, overnight, TLC shows that raw material disappears to room temperature reaction, is filtered to remove palladium carbon by kieselguhr, solvent is removed under vacuum, neutralize through ammonia, processed by acidic resins post, obtain I-1b, for weak yellow liquid 76mg, productivity 89%.Structural identification:

¹HNMR(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).

¹³CNMR(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 intermediate thereof

Under argon shield; adding the bromo-1-amylene (17mmol) of 5-in heavily steaming oxolane (15mL) suspension of the magnesium chips (24mmol) of new polishing, heat to 50 DEG C of reactions, there are a large amount of bubbles in system; solution is Dark grey, continues to react half an hour.Nitrone II-2 (12mmol) is dissolved in dry oxolane, under condition of ice bath, above-mentioned Grignard reagent is added dropwise over by syringe, within 15 minutes, adds, continue reaction 1h, TLC monitoring display raw material disappears, add saturated ammonium chloride solution cancellation reaction, extraction into ethyl acetate, not drying, directly remove solvent under vacuo, obtain the crude product of azanol III-2.

The crude product of gained azanol III-2 is dissolved in acetic acid, joins preactivated good zinc powder (0.12mol) and Cu (OAc)₂(containing two molecular crystalline water, in glacial acetic acid mixture 1.2mmol), (zinc powder processed by dilute hydrochloric acid and Schweinfurt green are placed in glacial acetic acid and stir, until there is rufous in system), system is highly exothermic, room temperature reaction is overnight, TLC monitoring display raw material complete reaction, removing solvent under vacuum, gained solid washs through ethyl acetate, and NaOH saturated solution regulates about pH=9, extraction into ethyl acetate aqueous phase, merging organic facies, anhydrous magnesium sulfate dries, and sucking filtration removes solid, remove solvent under vacuum, obtain the crude product of IV-2.

The crude product of gained IV-2 is dissolved in dichloromethane (20mL), adds triethylamine (15mmol) and (Boc)₂O (13mmol), room temperature reaction 2h, TLC monitors raw material point and is wholly absent, adding saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removing solvent under vacuum, column chromatography (petroleum ether: ethyl acetate=30:1) obtains colorless viscous shape liquid V-2 3.2g, productivity 48% altogether.Structural identification:

¹HNMR(300MHz,CDCl₃null)δ7.56–7.14(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)；¹³CNMR(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 mixed solvent, add palladium (0.96mmol) and Schweinfurt green (band water of crystallization, 4.8mmol), room temperature reaction 4 days under oxygen atmosphere, TLC monitoring reacts completely, add saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, remove solvent under vacuum, obtain the crude product of VI-2.

Under condition of ice bath, the crude product (in 2mmol) of ketone VI-2 is dissolved in the methanol of 15mL, is slowly added to sodium borohydride (2.5mmol), add rear system and become light gray, after 30min, TLC monitors the disappearance of raw material point, adds saturated ammonium chloride cancellation reaction, removes methanol under vacuum, the thick white oil thing of gained is redissolved in saturated ammonium chloride, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, remove solvent under vacuum, obtain the crude product of VII-2.

The crude product of gained VII-2 is redissolved in 5mL dry methylene chloride, add triethylamine (3mmol), be slowly added to methylsufonyl chloride (2.4mmol) under condition of ice bath, after adding, remove ice bath, room temperature reaction 1h, TLC monitors raw material point and disappears, and adds saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent, obtain the crude product of VII-2 under vacuum.

The crude product of gained VII-2 is redissolved in 5mL dichloromethane, adds 3mL trifluoroacetic acid, and after reaction 1h, TLC shows that raw material disappears, and adds saturated NaHCO₃Cancellation is reacted, extraction into ethyl acetate, and anhydrous magnesium sulfate dries, and sucking filtration removes solid, removes solvent, obtain the crude product of IX-2 under vacuum.

The crude product of gained IX-2 is redissolved in 10mL methanol, add 100mg Anhydrous potassium carbonate, room temperature reaction 48h, removes methanol under vacuum, the thick grease of gained is redissolved in saturated ammonium chloride, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, removes solvent under vacuum, column chromatography (petroleum ether: ethyl acetate=15:1), respectively obtains the less point (XIV-2a) of polarity and the bigger point of polarity.

XIV-2a:¹HNMR(400MHz,CDCl₃) δ 7.41 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)；¹³CNMR(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:¹HNMR(400MHz,CDCl₃) δ 7.38 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)；¹³CNMR(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, add the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, room temperature reaction is overnight, TLC shows that raw material disappears, and is filtered to remove palladium carbon by kieselguhr, removes solvent under vacuum, neutralize through ammonia, processed by acidic resins post, obtain weak yellow liquid I-2a 76mg, productivity 91% altogether.Structural identification:

Substrate (200mg) is dissolved in 10mL methanol, add the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, room temperature reaction is overnight, TLC shows that raw material disappears, and is filtered to remove palladium carbon by kieselguhr, removes solvent under vacuum, neutralize through ammonia, processed by acidic resins post, obtain weak yellow liquid I-2b 74mg, productivity 86% altogether.Structural identification:

¹HNMR(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).¹³CNMR(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 intermediate thereof

Under argon shield; adding the bromo-1-amylene (17mmol) of 5-in heavily steaming oxolane (15mL) suspension of the magnesium chips (24mmol) of new polishing, heat to 50 DEG C of reactions, there are a large amount of bubbles in system; solution is Dark grey, continues to react half an hour.Nitrone II-3 (12mmol) is dissolved in dry oxolane, under condition of ice bath, above-mentioned Grignard reagent is added dropwise over by syringe, within 15 minutes, adds, continue reaction 1h, TLC monitoring display raw material disappears, add saturated ammonium chloride solution cancellation reaction, extraction into ethyl acetate, not drying, directly remove solvent under vacuo, obtain III-3 crude product.

Gained III-3 crude product is dissolved in acetic acid, joins preactivated good zinc powder (0.12mol) and Cu (OAc)₂(containing two molecular crystalline water, in glacial acetic acid mixture 1.2mmol), (zinc powder processed by dilute hydrochloric acid and Schweinfurt green are placed in glacial acetic acid and stir, until there is rufous in system), system is highly exothermic, room temperature reaction is overnight, TLC monitoring display raw material complete reaction, removing solvent under vacuum, gained solid washs through ethyl acetate, and NaOH saturated solution regulates about pH=9, extraction into ethyl acetate aqueous phase, merging organic facies, anhydrous magnesium sulfate dries, and sucking filtration removes solid, remove solvent under vacuum, obtain IV-3 crude product.

Gained IV-3 crude product is dissolved in dichloromethane (20mL), adds triethylamine (15mmol) and (Boc)₂O (13mmol), room temperature reaction 2h, TLC monitors raw material point and is wholly absent, and adds saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent under vacuum, and column chromatography (petroleum ether: ethyl acetate=30:1) obtains alkene V-3 3.9g altogether, productivity 58%, structural identification:

¹³CNMR(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 mixed solvent, add palladium (0.96mmol) and Schweinfurt green (band water of crystallization, 4.8mmol), room temperature reaction 4 days under oxygen atmosphere, TLC monitoring reacts completely, add saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, remove solvent under vacuum, obtain VI-3 crude product.

Under condition of ice bath, substrate VI-3 (in 2mmol) is dissolved in the methanol of 15mL, is slowly added to sodium borohydride (2.5mmol), add rear system and become light gray, after 30min, TLC monitors the disappearance of raw material point, adds saturated ammonium chloride cancellation reaction, removes methanol under vacuum, the thick white oil thing of gained is redissolved in saturated ammonium chloride, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, remove solvent under vacuum, obtain VII-3 crude product.

Gained VII-3 crude product is redissolved in 5mL dry methylene chloride, add triethylamine (3mmol), be slowly added to methylsufonyl chloride (2.4mmol) under condition of ice bath, after adding, remove ice bath, room temperature reaction 1h, TLC monitors raw material point and disappears, and enters saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent, obtain VIII-3 crude product under vacuum.

Gained VIII-3 crude product is redissolved in 5mL dichloromethane, adds 3mL trifluoroacetic acid, and after reaction 1h, TLC shows that raw material disappears, and adds saturated NaHCO₃Cancellation is reacted, extraction into ethyl acetate, and anhydrous magnesium sulfate dries, and sucking filtration removes solid, removes solvent, obtain IX-3 crude product under vacuum.

Gained IX-3 crude product is redissolved in 10mL methanol, add 100mg Anhydrous potassium carbonate, room temperature reaction 48h, removes methanol under vacuum, the thick grease of gained is redissolved in saturated ammonium chloride, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, removes solvent under vacuum, column chromatography (petroleum ether: ethyl acetate=15:1) obtains less point (XIV-3a) 211mg of polarity and bigger point (XIV-3b) 209mg of polarity, productivity 43%.Structural identification:

XIV-3a:¹HNMR(400MHz,CDCl₃) δ 7.41 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)；¹³CNMR(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:¹HNMR(400MHz,CDCl₃) δ 7.38 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)；¹³CNMR(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, adds the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, overnight, TLC shows that raw material disappears to room temperature reaction, is filtered to remove palladium carbon by kieselguhr, solvent is removed under vacuum, neutralize through ammonia, processed by acidic resins post, obtain I-3a, for weak yellow liquid 69mg, productivity 82%.Structural identification:

¹HNMR(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)；¹³CNMR(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, add the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, room temperature reaction is overnight, TLC shows that raw material disappears, and is filtered to remove palladium carbon by kieselguhr, removes solvent under vacuum, neutralize through ammonia, processed by acidic resins post, obtain weak yellow liquid I-3b73mg, productivity 85%.Structural identification:

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

Under argon shield; adding the bromo-1-amylene (17mmol) of 5-in heavily steaming oxolane (15mL) suspension of the magnesium chips (4mmol) of new polishing, heat to 50 DEG C of reactions, there are a large amount of bubbles in system; solution is Dark grey, continues to react half an hour.Nitrone II-4 (12mmol) is dissolved in dry oxolane, under condition of ice bath, above-mentioned Grignard reagent is added dropwise over by syringe, within 15 minutes, adds, continue reaction 1h, TLC monitoring display raw material disappears, add saturated ammonium chloride solution cancellation reaction, extraction into ethyl acetate, not drying, directly remove solvent under vacuo, obtain the crude product of III-4.

The crude product of gained III-4 is dissolved in acetic acid, joins preactivated good zinc powder (0.12mol) and Cu (OAc)₂(containing two molecular crystalline water, in glacial acetic acid mixture 1.2mmol), (zinc powder processed by dilute hydrochloric acid and Schweinfurt green are placed in glacial acetic acid and stir, until there is rufous in system), system is highly exothermic, room temperature reaction is overnight, TLC monitoring display raw material complete reaction, removing solvent under vacuum, gained solid washs through ethyl acetate, and NaOH saturated solution regulates about pH=9, extraction into ethyl acetate aqueous phase, merging organic facies, anhydrous magnesium sulfate dries, and sucking filtration removes solid, remove solvent under vacuum, obtain the crude product of IV-4.

The crude product of gained IV-4 is dissolved in dichloromethane (20mL), adds triethylamine (15mmol) and (Boc)₂O (13mmol), room temperature reaction 2h, TLC monitors raw material point and is wholly absent, and adds saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent under vacuum, and column chromatography (petroleum ether: ethyl acetate=30:1) obtains alkene V-4 4.1g altogether, for colorless viscous shape liquid, productivity 61%.Structural identification:

¹HNMR (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)；¹³CNMR(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 mixed solvent, add palladium (0.96mmol) and Schweinfurt green (band water of crystallization, 4.8mmol), room temperature reaction 4 days under oxygen atmosphere, TLC monitoring reacts completely, add saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, removing solvent under vacuum, column chromatography (petroleum ether: ethyl acetate=10:1) obtains the crude product of VI-4.

Under condition of ice bath, the crude product (in 2mmol) of substrate VI-4 is dissolved in the methanol of 15mL, is slowly added to sodium borohydride (2.5mmol), add rear system and become light gray, after 30min, TLC monitors the disappearance of raw material point, adds saturated ammonium chloride cancellation reaction, removes methanol under vacuum, the thick white oil thing of gained is redissolved in saturated ammonium chloride, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, remove solvent under vacuum, obtain the crude product of VII-4.

The crude product of gained VII-4 is redissolved in 5mL dry methylene chloride, add triethylamine (3mmol), be slowly added to methylsufonyl chloride (2.4mmol) under condition of ice bath, after adding, remove ice bath, room temperature reaction 1h, TLC monitors raw material point and disappears, and adds saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent, obtain the crude product of VIII-4 under vacuum.

The crude product of gained VIII-4 is redissolved in 5mL dichloromethane, adds 3mL trifluoroacetic acid, and after reaction 1h, TLC shows that raw material disappears, and adds saturated NaHCO₃Cancellation is reacted, extraction into ethyl acetate, and anhydrous magnesium sulfate dries, and sucking filtration removes solid, removes solvent, obtain the crude product of IX-4 under vacuum.

The crude product of IX-4 is redissolved in 10mL methanol, add 100mg Anhydrous potassium carbonate, room temperature reaction 48h, removing methanol under vacuum, the thick grease of gained is redissolved in saturated ammonium chloride, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent under vacuum, and column chromatography (petroleum ether: ethyl acetate=15:1) obtains less point (XIV-4a) 264mg of polarity and bigger point (XIV-4b) 256mg of polarity.Structural identification:

XIV-4a:1:[α]_D ²⁰=+24.0 (c1.0, CH2Cl2)；IR(cm-1):3090,3065,3030,2926,2857,1496,1455,1370,1313,1097,734,699；¹HNMR(300MHz,CDCl₃) δ 7.43 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)；¹³CNMR(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:¹HNMR(300MHz,CDCl₃) δ 7.40 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).¹³CNMR(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, adds the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, overnight, TLC shows that raw material disappears to room temperature reaction, is filtered to remove palladium carbon by kieselguhr, solvent is removed under vacuum, neutralize through ammonia, processed by acidic resins post, obtain I-4a 72mg altogether, productivity 85%, for weak yellow liquid.Structural identification:

¹HNMR(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)；¹³CNMR(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, adds the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, overnight, TLC shows that raw material disappears to room temperature reaction, is filtered to remove palladium carbon by kieselguhr, solvent is removed under vacuum, neutralize through ammonia, processed by acidic resins post, obtain I-4b 76mg altogether, productivity 89%, for weak yellow liquid.Structural identification:

¹HNMR(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)；¹³CNMR(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 intermediate thereof

Under argon shield; adding the bromo-1-amylene (17mmol) of 5-in heavily steaming oxolane (15mL) suspension of the magnesium chips (24mmol) of new polishing, heat to 50 DEG C of reactions, there are a large amount of bubbles in system; solution is Dark grey, continues to react half an hour.Nitrone II-5 (12mmol) is dissolved in dry oxolane, under condition of ice bath, above-mentioned Grignard reagent is added dropwise over by syringe, within 15 minutes, adds, continue reaction 1h, TLC monitoring display raw material disappears, add saturated ammonium chloride solution cancellation reaction, extraction into ethyl acetate, not drying, directly remove solvent under vacuo, obtain the crude product of III-5.

The crude product of III-5 is dissolved in acetic acid, joins preactivated good zinc powder (0.12mol) and Cu (OAc)₂(containing two molecular crystalline water, in glacial acetic acid mixture 1.2mmol), (zinc powder processed by dilute hydrochloric acid and Schweinfurt green are placed in glacial acetic acid and stir, until there is rufous in system), system is highly exothermic, room temperature reaction is overnight, TLC monitoring display raw material complete reaction, removing solvent under vacuum, gained solid washs through ethyl acetate, and NaOH saturated solution regulates about pH=9, extraction into ethyl acetate aqueous phase, merging organic facies, anhydrous magnesium sulfate dries, and sucking filtration removes solid, remove solvent under vacuum, obtain the crude product of IV-5.

The crude product of gained IV-5 is dissolved in dichloromethane (20mL), adds triethylamine (15mmol) and (Boc)₂O (13mmol), room temperature reaction 2h, TLC monitor raw material point and are wholly absent, and add saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, removing solvent under vacuum, column chromatography obtains colorless viscous shape liquid V-5 3.1g, productivity 65% altogether.Structural identification:

¹HNMR(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).¹³CNMR(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 mixed solvent, add palladium (0.96mmol) and Schweinfurt green (band water of crystallization, 4.8mmol), room temperature reaction 4 days under oxygen atmosphere, TLC monitoring reacts completely, add saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, removing solvent under vacuum, column chromatography (petroleum ether: ethyl acetate=10:1) obtains the crude product of VI-5.

Under condition of ice bath, the crude product (in 2mmol) of substrate VI-5 is dissolved in the methanol of 15mL, is slowly added to sodium borohydride (2.5mmol), add rear system and become light gray, after 30min, TLC monitors the disappearance of raw material point, adds saturated ammonium chloride cancellation reaction, removes methanol under vacuum, the thick white oil thing of gained is redissolved in saturated ammonium chloride, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, remove solvent under vacuum, obtain the crude product of VII-5.

The crude product of VII-5 is redissolved in 5mL dry methylene chloride, add triethylamine (3mmol), be slowly added to methylsufonyl chloride (2.4mmol) under condition of ice bath, after adding, remove ice bath, room temperature reaction 1h, TLC monitors raw material point and disappears, and adds saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent, obtain the crude product of VIII-5 under vacuum.

Being dissolved in 5mL dichloromethane by the crude product of VIII-5, add 3mL trifluoroacetic acid, after reaction 1h, TLC shows that raw material disappears, and adds saturated NaHCO₃Cancellation is reacted, extraction into ethyl acetate, and anhydrous magnesium sulfate dries, and sucking filtration removes solid, removes solvent, obtain the crude product of IX-5 under vacuum.

The crude product of IX-5 is redissolved in 10mL methanol, add 100mg Anhydrous potassium carbonate, room temperature reaction 48h, removes methanol under vacuum, the thick grease of gained is redissolved in saturated ammonium chloride, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, removes solvent under vacuum, column chromatography (petroleum ether: ethyl acetate=15:1) obtains the less point (XIV-5a) of polarity altogether 129mg and bigger point (XIV-5b) 115mg altogether of polarity, structural identification:

XIV-5a:¹HNMR(400MHz,CDCl₃) δ 7.41 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)；¹³CNMR(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:¹HNMR(400MHz,CDCl₃) δ 7.42 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)；¹³CNMR(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, adds the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, overnight, TLC shows that raw material disappears to room temperature reaction, is filtered to remove palladium carbon by kieselguhr, solvent is removed under vacuum, neutralize through ammonia, processed by acidic resins post, obtain I-5a 42mg altogether, white solid, productivity 88%.Structural identification:

¹HNMR(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)；¹³CNMR(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, add the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, room temperature reaction is overnight, TLC shows that raw material disappears, and is filtered to remove palladium carbon by kieselguhr, removes solvent under vacuum, neutralize through ammonia, processed by acidic resins post, obtain faint yellow solid 46mg, productivity 96%.Structural identification:

¹HNMR(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).¹³CNMR(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 intermediate thereof

Under argon shield; adding the bromo-1-amylene (17mmol) of 5-in heavily steaming oxolane (15mL) suspension of the magnesium chips (24mmol) of new polishing, heat to 50 DEG C of reactions, there are a large amount of bubbles in system; solution is Dark grey, continues to react half an hour.Nitrone II-4 (12mmol) is dissolved in dry oxolane, under condition of ice bath, above-mentioned Grignard reagent is added dropwise over by syringe, within 15 minutes, adds, continue reaction 1h, TLC monitoring display raw material disappears, add saturated ammonium chloride solution cancellation reaction, extraction into ethyl acetate, not drying, directly remove solvent under vacuo, obtain the crude product of III-4.

The crude product of gained IV-4 is dissolved in dichloromethane (20mL), adds triethylamine (15mmol) and (Boc)₂O (13mmol), room temperature reaction 2h, TLC monitors raw material point and is wholly absent, and adds saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent under vacuum, and column chromatography (petroleum ether: ethyl acetate=30:1) obtains V-4 4.1g altogether, for colorless viscous shape liquid, productivity 61%.Structural identification:

V-4 (1.4mmol) is dissolved in 1, in 4-dioxane (5mL), add 1mL water, be sequentially added into sodium metaperiodate (5.6mmol), 2,6-lutidines (2.8mmol) and 1 weight % Osmic acid. aqueous solution (1mL), stir 12 hours under room temperature, add saturated aqueous sodium thiosulfate cancellation reaction, filter away the solid produced, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, remove solvent under vacuum, obtain the crude product of X-1.

Under argon shield; adding 1-n-butyl bromide (2.8mmol) in heavily steaming oxolane (2mL) suspension of the magnesium chips (4.2mmol) of new polishing, heat to 50 DEG C of reactions, there are a large amount of bubbles in system; solution is Dark grey, continues to react half an hour.The crude product (in 1.4mmol) of X-1 is dissolved in dry oxolane, under condition of ice bath, above-mentioned Grignard reagent is added dropwise over by syringe, continue reflection 10h, TLC monitoring) display raw material disappearance, add saturated ammonium chloride solution cancellation reaction, extraction into ethyl acetate, not drying, directly removes solvent under vacuo, obtains the crude product of XI-1.

The crude product of gained XI-1 is redissolved in 5mL dry methylene chloride, add triethylamine (3mmol), be slowly added to methylsufonyl chloride (2.4mmol) under condition of ice bath, after adding, remove ice bath, room temperature reaction 1h, TLC monitors raw material point and disappears, and adds saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent, obtain the crude product of XII-1 under vacuum.

The crude product of gained XII-1 is redissolved in 5mL dichloromethane, adds 3mL trifluoroacetic acid, and after reaction 1h, TLC shows that raw material disappears, and adds saturated NaHCO₃Cancellation is reacted, extraction into ethyl acetate, and anhydrous magnesium sulfate dries, and sucking filtration removes solid, removes solvent, obtain the crude product of XIII-1 under vacuum.

The crude product of XIII-1 is redissolved in 10mL methanol, add 100mg Anhydrous potassium carbonate, room temperature reaction 48h, removing methanol under vacuum, the thick grease of gained is redissolved in saturated ammonium chloride, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent under vacuum, and column chromatography (petroleum ether: ethyl acetate=15:1) obtains the less point (XIV-6a) of polarity altogether 161mg and bigger point (XIV-6b) 190mg altogether of polarity.Structural identification:

XIV-6a:¹HNMR(400MHz,CDCl₃) δ 7.44 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)；¹³CNMR(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:¹HNMR(400MHz,CDCl₃) δ 7.44 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)；¹³CNMR(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, adds the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, overnight, TLC shows that raw material disappears to room temperature reaction, is filtered to remove palladium carbon by kieselguhr, solvent is removed under vacuum, neutralize through ammonia, processed by acidic resins post, obtain I-6a 44mg altogether, colorless oil, productivity 94%.Structural identification:

¹HNMR (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)；¹³CNMR(101MHz,MeOD)δ72.57,68.70,68.10,61.51,60.16,56.11,31.96,27.69,27.52,26.41,22.37,22.32,12.95。

Substrate XIV-6b (100mg) is dissolved in 10mL methanol, add the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, room temperature reaction is overnight, TLC shows that raw material disappears, and is filtered to remove palladium carbon by kieselguhr, removes solvent under vacuum, neutralize through ammonia, processed by acidic resins post, obtain faint yellow solid 45mg, productivity 97%.Structural identification:

¹HNMR (400MHz, MeOD) δ 4.50 (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)；¹³CNMR(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 intermediate thereof

The crude product of gained IV-4 is dissolved in dichloromethane (20mL), adds triethylamine (15mmol) and (Boc)₂O (13mmol), room temperature reaction 2h, TLC monitors raw material point and is wholly absent, and adds saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent under vacuum, and column chromatography (petroleum ether: ethyl acetate=30:1) obtains V-44.1g, for colorless viscous shape liquid, productivity 61%.Structural identification:

V-4 (1.4mmol) is dissolved in 1, in 4-dioxane (5mL), add 1mL water, be sequentially added into sodium metaperiodate (5.6mmol), 2,6-lutidines (2.8mmol) and 1 weight % Osmic acid. aqueous solution (1mL), 12h is stirred under room temperature, add saturated aqueous sodium thiosulfate cancellation reaction, filter away the solid produced, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, remove solvent under vacuum, obtain the crude product of X-1.

Under argon shield; adding 1-bromononane (2.8mmol) in heavily steaming oxolane (2mL) suspension of the magnesium chips (4.2mmol) of new polishing, heat to 50 DEG C of reactions, there are a large amount of bubbles in system; solution is Dark grey, continues to react half an hour.The crude product (in 1.4mmol) of X-1 is dissolved in dry oxolane, under condition of ice bath, above-mentioned Grignard reagent is added dropwise over by syringe, continue reaction 10h, TLC monitoring display raw material to disappear, add saturated ammonium chloride solution cancellation reaction, extraction into ethyl acetate, not drying, directly removes solvent under vacuo, obtains the crude product of XI-2.

The crude product of gained XI-2 is redissolved in 5mL dry methylene chloride, add triethylamine (3mmol), be slowly added to methylsufonyl chloride (2.4mmol) under condition of ice bath, after adding, remove ice bath, room temperature reaction 1h, TLC monitors raw material point and disappears, and adds saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent, obtain the crude product of XII-2 under vacuum.

The crude product of gained XII-2 is redissolved in 5mL dichloromethane, adds 3mL trifluoroacetic acid, and after reaction 1h, TLC shows that raw material disappears, and adds saturated NaHCO₃Cancellation is reacted, extraction into ethyl acetate, and anhydrous magnesium sulfate dries, and sucking filtration removes solid, removes solvent, obtain the crude product of XIII-2 under vacuum.

The crude product of XIII-2 is redissolved in 10mL methanol, add 100mg Anhydrous potassium carbonate, room temperature reaction 48h, removing methanol under vacuum, the thick grease of gained is redissolved in saturated ammonium chloride, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent under vacuum, and column chromatography (petroleum ether: ethyl acetate=15:1) obtains the less point (XIV-7a) of polarity altogether 261mg and bigger point (XIV-7b) 237mg altogether of polarity.Structural identification:

XIV-7a:¹HNMR(400MHz,CDCl₃) δ 7.39 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)；¹³CNMR(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:¹HNMR(400MHz,CDCl₃) δ 7.44 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)；¹³CNMR(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, adds the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, overnight, TLC shows that raw material disappears to room temperature reaction, is filtered to remove palladium carbon by kieselguhr, solvent is removed under vacuum, neutralize through ammonia, processed by acidic resins post, obtain I-7a 49mg altogether, colorless oil, productivity 91%.

¹HNMR (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)；¹³CNMR(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, add the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, room temperature reaction is overnight, TLC shows that raw material disappears, and is filtered to remove palladium carbon by kieselguhr, removes solvent under vacuum, neutralize through ammonia, processed by acidic resins post, obtain faint yellow solid 45mg, productivity 97%.

¹HNMR (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)；¹³CNMR(126MHz,MeOD)δ69.98,68.55,68.42,61.10,60.60,57.76,31.65,30.90,29.24,29.19,29.16,29.03,25.85,25.33,22.33,21.72,16.19,13.05。

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

Under argon shield; adding the bromo-1-amylene (17mmol) of 5-in heavily steaming oxolane (15mL) suspension of the magnesium chips (24mmol) of new polishing, heat to 50 DEG C of reactions, there are a large amount of bubbles in system; solution is Dark grey, continues to react half an hour.Nitrone II-6 (12mmol) is dissolved in dry oxolane, under condition of ice bath, above-mentioned Grignard reagent is added dropwise over by syringe, within 15 minutes, adds, continue reaction 1h, TLC monitoring display raw material disappears, add saturated ammonium chloride solution cancellation reaction, extraction into ethyl acetate, not drying, directly remove solvent under vacuo, obtain the crude product of III-6.

The crude product of gained III-6 is dissolved in acetic acid, joins preactivated good zinc powder (0.12mol) and Cu (OAc)₂(containing two molecular crystalline water, in glacial acetic acid mixture 1.2mmol), (zinc powder processed by dilute hydrochloric acid and Schweinfurt green are placed in glacial acetic acid and stir, until there is rufous in system), system is highly exothermic, room temperature reaction is overnight, TLC monitoring display raw material complete reaction, removing solvent under vacuum, gained solid washs through ethyl acetate, and NaOH saturated solution regulates about pH=9, extraction into ethyl acetate aqueous phase, merging organic facies, anhydrous magnesium sulfate dries, and sucking filtration removes solid, remove solvent under vacuum, obtain the crude product of IV-6.

The crude product of gained IV-6 is dissolved in dichloromethane (20mL), adds triethylamine (15mmol) and (Boc)₂O (13mmol), room temperature reaction 2h, TLC monitors raw material point and is wholly absent, and adds saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent under vacuum, and column chromatography (petroleum ether: ethyl acetate=30:1) obtains V-6 (4.1g, for colorless viscous shape liquid), productivity 61%.Structural identification:

V-6 (1.4mmol) is dissolved in 1, in 4-dioxane (5mL), add 1mL water, be sequentially added into sodium metaperiodate (5.6mmol), 2,6-lutidines (2.8mmol) and 1 weight % Osmic acid. aqueous solution (1mL), stir 12 hours under room temperature, add saturated aqueous sodium thiosulfate cancellation reaction, filter away the solid produced, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, remove solvent under vacuum, obtain the crude product of X-3.

Under argon shield; adding 1-n-butyl bromide (2.8mmol) in heavily steaming oxolane (2mL) suspension of the magnesium chips (4.2mmol) of new polishing, heat to 50 DEG C of reactions, there are a large amount of bubbles in system; solution is Dark grey, continues to react half an hour.The crude product (in 1.4mmol) of X-3 is dissolved in dry oxolane, under condition of ice bath, above-mentioned Grignard reagent is added dropwise over by syringe, continue reaction 10h, TLC monitoring display raw material to disappear, add saturated ammonium chloride solution cancellation reaction, extraction into ethyl acetate, not drying, directly removes solvent under vacuo, obtains the crude product of XI-3.

The crude product of gained XI-3 is redissolved in 5mL dry methylene chloride, add triethylamine (3mmol), be slowly added to methylsufonyl chloride (2.4mmol) under condition of ice bath, after adding, remove ice bath, room temperature reaction 1h, TLC monitors raw material point and disappears, and adds saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent, obtain the crude product of XII-3 under vacuum.

The crude product of gained XII-3 is redissolved in 5mL dichloromethane, adds 3mL trifluoroacetic acid, and after reaction 1h, TLC shows that raw material disappears, and adds saturated NaHCO₃Cancellation is reacted, extraction into ethyl acetate, and anhydrous magnesium sulfate dries, and sucking filtration removes solid, removes solvent, obtain the crude product of XIII-3 under vacuum.

The crude product of XIII-3 is redissolved in 10mL methanol, add 100mg Anhydrous potassium carbonate, room temperature reaction 48h, removing methanol under vacuum, the thick grease of gained is redissolved in saturated ammonium chloride, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent under vacuum, and column chromatography (petroleum ether: ethyl acetate=15:1) obtains the less point (XIV-8a) of polarity altogether 189mg and bigger point (XIV-8b) 173mg altogether of polarity.Structural identification:

XIV-8a:¹HNMR(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)；¹³CNMR(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:¹HNMR(400MHz,CDCl₃) δ 7.42 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)；¹³CNMR(101MHz,CDCl₃)δ139.02,138.96,138.86,128.55,128.28,128.25,127.74,127.70,127.59,127.49,127.42,127.34,126.97,80.66,77.65,73.31,72.87,72.04,71.88,62.90,56.84,56.19,32.72,28.93,26.50,25.71,22.99,18.82,14.26。

XIV-8a (100mg) is dissolved in 10mL methanol, adds the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, overnight, TLC shows that raw material disappears to room temperature reaction, is filtered to remove palladium carbon by kieselguhr, solvent is removed under vacuum, neutralize through ammonia, processed by acidic resins post, obtain I-8a 44mg altogether, colorless oil, productivity 94%.

¹HNMR (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)；¹³CNMR(101MHz,MeOD)δ72.57,68.70,68.09,61.51,60.16,56.11,31.96,27.69,27.51,26.41,22.38,22.32,12.95。

XIV-8b (100mg) is dissolved in 10mL methanol, add the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, room temperature reaction is overnight, TLC shows that raw material disappears, and is filtered to remove palladium carbon by kieselguhr, removes solvent under vacuum, neutralize through ammonia, processed by acidic resins post, obtain faint yellow solid 45mg, productivity 97%.

¹HNMR (400MHz, MeOD) δ 4.48 (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)；¹³CNMR(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 intermediate thereof

Under argon shield; adding the bromo-1-amylene (17mmol) of 5-in heavily steaming oxolane (15mL) suspension of the magnesium chips (24mmol) of new polishing, heat to 50 DEG C of reactions, there are a large amount of bubbles in system; solution is Dark grey, continues to react half an hour.Nitrone II-6 (12mmol) is dissolved in dry oxolane, under condition of ice bath, above-mentioned Grignard reagent is added dropwise over by syringe, within 15 minutes, adds, continue reaction 1h, TLC monitoring (petroleum ether: ethyl acetate=1:1) shows that raw material disappears, add saturated ammonium chloride solution cancellation reaction, extraction into ethyl acetate, not drying, directly remove solvent under vacuo, obtain the crude product of III-6.

¹HNMR (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).¹³CNMR(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 1, in 4-dioxane (5mL), add 1mL water, be sequentially added into sodium metaperiodate (5.6mmol), 2,6-lutidines (2.8mmol) and 1 weight % Osmic acid. aqueous solution (1mL), stir 12 hours under room temperature, add saturated aqueous sodium thiosulfate cancellation reaction, filter away the solid produced, extraction into ethyl acetate, anhydrous magnesium sulfate dries, and sucking filtration removes solid, remove solvent under vacuum, obtain the crude product of X-4.

Under argon shield; adding 1-bromononane (2.8mmol) in heavily steaming oxolane (2mL) suspension of the magnesium chips (4.2mmol) of new polishing, heat to 50 DEG C of reactions, there are a large amount of bubbles in system; solution is Dark grey, continues to react half an hour.The crude product (in 1.4mmol) of X-4 is dissolved in dry oxolane, under condition of ice bath, above-mentioned Grignard reagent is added dropwise over by syringe, continue reaction 10h, TLC monitoring display raw material to disappear, add saturated ammonium chloride solution cancellation reaction, extraction into ethyl acetate, not drying, directly removes solvent under vacuo, obtains the crude product of XI-4.

The crude product of gained XI-4 is redissolved in 5mL dry methylene chloride, add triethylamine (3mmol), be slowly added to methylsufonyl chloride (2.4mmol) under condition of ice bath, after adding, remove ice bath, room temperature reaction 1h, TLC monitors raw material point and disappears, and adds saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent, obtain the crude product of XII-4 under vacuum.

The crude product of gained XII-4 is redissolved in 5mL dichloromethane, adds 3mL trifluoroacetic acid, and after reaction 1h, TLC shows that raw material disappears, and adds saturated NaHCO₃Cancellation is reacted, extraction into ethyl acetate, and anhydrous magnesium sulfate dries, and sucking filtration removes solid, removes solvent, obtain the crude product of XIII-2 under vacuum.

The crude product of XIII-4 is redissolved in 10mL methanol, add 100mg Anhydrous potassium carbonate, room temperature reaction 48h, removing methanol under vacuum, the thick grease of gained is redissolved in saturated ammonium chloride, extraction into ethyl acetate, anhydrous magnesium sulfate dries, sucking filtration removes solid, removes solvent under vacuum, and column chromatography (petroleum ether: ethyl acetate=15:1) obtains the less point (XIV-9a) of polarity altogether 261mg and bigger point (XIV-9b) 237mg altogether of polarity.Structural identification:

XIV-9a:¹HNMR(400MHz,CDCl₃) δ 7.39 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)；¹³CNMR(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:¹HNMR(400MHz,CDCl₃) δ 7.37 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)；¹³CNMR(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, adds the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, overnight, TLC shows that raw material disappears to room temperature reaction, is filtered to remove palladium carbon by kieselguhr, solvent is removed under vacuum, neutralize through ammonia, processed by acidic resins post, obtain I-9a 49mg altogether, colorless oil, productivity 91%.Structural identification:

¹HNMR (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)；¹³CNMR(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, add the palladium carbon of the 10 weight % of 30mg, add the 3N hydrochloric acid of 0.5mL, hydrogen exchange, room temperature reaction is overnight, TLC shows that raw material disappears, and is filtered to remove palladium carbon by kieselguhr, removes solvent under vacuum, neutralize through ammonia, processed by acidic resins post, obtain faint yellow solid I-9b 45mg, productivity 97% altogether.

¹HNMR (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)；¹³CNMR(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 inhibition of Indolizidine class amino sugar compound is evaluated

1) test material and source

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

Test material: all 4-nitrophenols pyranoside substrate, disaccharide and glycosidase are all purchased from Sigma-Aldrich.

2) test method

Dynamics research carries out in the 50mM sodium citrate/phosphate buffer of 37 DEG C.Difference according to substrate, the enzyme concentration of preparation is 0.1-0.5mg/mL.Active testing, with 4-nitrophenols pyranoside for substrate, is tested under the optimum activity pH value of every kind of enzyme.Substrate, the enzymatic solution suitably diluted and inhibitor (heptatomic ring iminosugar) are cultivated 30 minutes at 37 DEG C, in ultraviolet-uisible spectrophotometer, then starts reaction, measure its absorption to 400nm wavelength light.GraFit program is finally used to carry out data analysis [Leatherbarrow, R.J.Grafit4.0；ErithacusSoftware:Staines,UK,1998.].

3) evaluation result

Embodiment 1-9 gained heptatomic ring imino sugar compounds is as shown in table 1 to the inhibitory activity result of glycosidase.

Evaluation result shows, beta galactosidase and saccharogenic amylase are had weak inhibitory activity, IC by dicyclo class amino sugar I-2a provided by the present invention₅₀Respectively 796 μMs and 241 μMs；Beta-glucosidase (Hepar Bovis seu Bubali) and beta galactosidase (Hepar Bovis seu Bubali) are had weak inhibitory activity, IC by 1-4b₅₀Respectively 469 μMs and 250 μMs.Alpha-L-Rhamnosidase is had weak to medium inhibitory activity, IC by iminosugar I-6a, I-6b, I-7a, I-7b, I-8a, I-8b, I-9a and I-9b₅₀As shown in table 2, comprehensively analyze, it is suppressed that activity seems relevant with long alkyl chains.

Table 1: the part Indolizidine class imino sugar compounds inhibitory activity IC 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 maltase	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 saccharase	173	111	(7.7%)	(6.9%)	(16.5%)	795	(24.5%)	(0.7%)
									Beta-glucosidase
Semen Armeniacae Amarum	(0%)	(0%)	(16.8%)	(0%)	(0%)	(26.7%)	(10.8%)	(0.7%)
									Hepar Bovis seu Bubali	(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
									Hepar Bovis seu Bubali	(25.2%)	(13.2%)	796	(13.2%)	(8.5%)	250	(31.1%)	(38.9%)
Alpha-Mannosidase
									Semen Canavaliae	(0%)	(0.6%)	(0%)	(0%)	(7.9%)	(28.9%)	(13.9%)	(18.5%)
Beta-Mannosidase
									Limax	(9.1%)	(1.0%)	(0%)	(4.3%)	(1.2%)	(0%)	(0%)	(1.6%)
Alpha-L-fucosidase
									Ren Bovis seu Bubali	(4.3%)	(0%)	(0%)	(9.1%)	(0%)	(4.3%)	(3.3%)	(0%)
A, a-trehalose enzyme
									Ren sus domestica	(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
									Colon bacillus	(19.9%)	43.9%)	(5.8%)	(5.9%)	(2.6%)	(42.5%)	(22.5%)	(27.9%)
Hepar Bovis seu Bubali	(4.4%)	(0%)	(4.3%)	(5.5%)	(3.8%)	(9.9%)	(10.5%)	(0.9%)

^aThe source of enzyme；^b(): the suppression ratio under 1000 μMs of concentration.

Table 2

It can be seen from the results above that the Indolizidine iminosugar of the offer of the present invention or its pharmaceutically acceptable salt have the activity suppressing glycosidase and can be used in treatment diabetes.And, the precursor compound of Indolizidine iminosugar provided by the invention also has the active effect suppressing glycosidase.

The preferred embodiment of the present invention described in detail above; but, the present invention is not limited to the detail in above-mentioned embodiment, in the technology concept of the present invention; technical scheme can being carried out multiple simple variant, these simple variant belong to protection scope of the present invention.

It is further to note that, each concrete technical characteristic described in above-mentioned detailed description of the invention, in reconcilable situation, it is possible to be combined by any suitable mode, in order to avoid unnecessary repetition, various possible compound modes are no longer illustrated by the present invention separately.

Additionally, can also carry out combination in any between the various different embodiment of the present invention, as long as it is without prejudice to the thought of the present invention, it should be considered as content disclosed in this invention equally.

Claims

1. an Indolizidine iminosugar, this iminosugar is compound or its pharmaceutically acceptable salt of the structure shown in Formulas I:

2. iminosugar according to claim 1, wherein, described iminosugar at least one in following compound or its pharmaceutically acceptable salt:

3. the precursor compound of the iminosugar described in claim 1 or 2, it is characterised in that this precursor compound is compound or its pharmaceutically acceptable salt of structure shown in Formula X IV:

4. the method preparing iminosugar described in claim 1 or 2, the method includes: in acid condition, in the presence of a catalyst, the precursor compound described in claim 3 is carried out hydrogenation；Or

In the presence of a lewis acid, the precursor compound described in claim 3 is carried out deprotection reaction.

5. method according to claim 4, wherein, described catalyst at least one in palladium carbon, palladium black, palladium dydroxide, Palladous chloride., platinum oxide, platinum black, ruthenic chloride and Wilkinson catalyst.

6. the method preparing precursor compound described in claim 3, the method comprises the following steps:

Wherein, R³、R⁸And R⁷Definition corresponding with the definition in claim 3 identical；

R in Formula VIII and Formula IX⁵Identical, and R⁵Hydrogen atom on mesyl, trifyl, benzenesulfonyl, p-toluenesulfonyl and phenyl ring by methoxyl group or halogen substiuted and at least one in the benzenesulfonyl that obtains；

7. the method preparing precursor compound described in claim 3, the method comprises the following steps:

Wherein, R³、R⁸And R⁷Definition and claim 3 in identical；

R in Formula V and Formula X-Formula X II⁴Corresponding identical, and R⁴Definition and claim 3 in identical；

R in Formula X II-Formula X III⁵Identical, and R⁵Definition and claim 3 in identical；

8. the precursor compound of the iminosugar described in claim 1 or 2 or the iminosugar described in claim 3 or its pharmaceutically acceptable salt suppress the application in the medicine of glycosidase activity in preparation.

9. application according to claim 8, wherein, described glycosidase at least one in alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta galactosidase, alpha-Mannosidase, beta-Mannosidase, alpha-L-fucosidase, trehalase, amyloglucosidase and alpha-L-Rhamnosidase.

10. iminosugar described in claim 1 or 2 or its pharmaceutically acceptable salt are in the application in preparation prevention and/or treatment diabetes, prevention and/or treatment gaucher's disease, prevention and/or treatment tumor and antiviral drug.