CN103467470A - Ocycloimino sugar compound and intermediate, medicament, preparation method and application thereof - Google Patents

Abstract

The present invention provides a kind of and cyclo-imino sugar compounds and its intermediate and drug and its preparation method and application, this and cyclo-imino sugar compounds are the compound of structure shown in Formulas I A or Formulas I B, wherein, R1 is the alkyl for the linear chain or branched chain that carbon atom number is 1-12, carbon atom number is the alkenyl of the linear chain or branched chain of 2-12, the arbitrarily substituted phenyl of hydrogen atom, furyl, pyrrole radicals on aromatic rings and any one in indyl; R5 is hydrogen or methylol; N is 0,1 or 2. Of the invention and cyclo-imino sugar compounds have excellent glycosidase activity inhibiting effect.

Description

And cyclo-imino sugar compounds and intermediate and medicine and its preparation method and application

Technical field

The present invention relates to a kind of and cyclo-imino sugar compounds, should and the midbody compound of cyclo-imino sugar compounds, should and the preparation method of cyclo-imino sugar compounds and midbody compound thereof, should and cyclo-imino sugar compounds or its pharmacy acceptable salt or medicinal composition application in glycosidase activity inhibitor class medicine, and activeconstituents be this also medicine of cyclo-imino sugar compounds or its pharmacy acceptable salt or medicinal composition.

Background technology

Polyhydroxylated alkaloid refers to that the Sauerstoffatom on the monose ring is replaced by nitrogen-atoms and the compounds that obtains, iminosugar, azasugar or imino-cyclitol are otherwise known as, a kind of analogue of monose from a structural point, transition state by analogue enztme and Binding Capacity, play the effect of glycosidase inhibitor, thereby realize the purpose for the treatment of and Glycosylase relative disease, at aspects such as antitumor, antiviral and treatment diabetes, there is potential pharmacologically active.

At present, had two kinds of imino-carbohydrate medicines to use clinically, comprised the Miglitol(miglitol for the treatment of type ii diabetes) and treat the Zavesca(Beagle spy of gaucher's disease); Also have in addition a series of iminosugar and structural modification things thereof in the clinical trial stage, as the butyryl radicals modifier of Celgosivir(castanospermine) enter clinical II research as the drug candidate for the treatment of chronic hepatitis C (HCV).

And ring skeleton imido sugar mainly contains poly-hydroxy pyrrolizidine alkaloids and poly-hydroxy Indolizidine Alkaloid; Also have in addition that many other are synthetic and encircle the skeleton iminosugar, as 1-azabicyclo [3.2.0] iieptanes compound and octahydro-1H-pyrrolo-[1,2-a] azepan compounds etc.This type of iminosugar has also ring structure and the important pharmacologically active of multiple replacement, as separated the penta hydroxy group pyrrolizidine alkaloids Casuarine obtained from Casuarina equisetifolia bark, there is multiple biological activity (be good glycosidase inhibitor, can regulate immunity system again).

Although exist some active good and encircle skeleton imido sugar, still be badly in need of more active good and encircle skeleton imido sugar.

Summary of the invention

The object of the present invention is to provide a kind of new and cyclo-imino sugar compounds, should and the midbody compound of cyclo-imino sugar compounds, and and the cyclo-imino sugar compounds and should and the preparation method and application of the midbody compound of cyclo-imino sugar compounds.

The invention provides a kind of and cyclo-imino sugar compounds, wherein, the compound that also the cyclo-imino sugar compounds is structure shown in formula IA or formula IB,

Wherein, R ¹for the alkyl of the carbonatoms straight or branched that is 1-12, the thiazolinyl of the straight or branched that carbonatoms is 2-12, any one in any substituted phenyl of the hydrogen atom on aromatic nucleus, furyl, pyrryl and indyl; R ⁵for hydrogen or methylol; N is 0,1 or 2.

The present invention also provides the compound of structure shown in a kind of formula IC,

Wherein, R ¹for the alkyl of the carbonatoms straight or branched that is 1-12, the thiazolinyl of the straight or branched that carbonatoms is 2-12, any one in any substituted phenyl of the hydrogen atom on aromatic nucleus, furyl, pyrryl and indyl; R ², R ³and R ⁴be selected from independently of one another any substituted benzyl of hydrogen atom on phenyl ring, any one in the alkoxyalkyl that the acyl group that carbonatoms is 1-10 and carbonatoms are 1-10; R ⁵for hydrogen, any one in any substituted benzyloxymethyl of the hydrogen atom on phenyl ring; N is 0,1 or 2.

The present invention also provides the compound of structure shown in a kind of formula ID,

Wherein, R ¹for the alkyl of the carbonatoms straight or branched that is 1-12, the thiazolinyl of the straight or branched that carbonatoms is 2-12, any one in any substituted phenyl of the hydrogen atom on aromatic nucleus, furyl, pyrryl and indyl; R ², R ³and R ⁴be selected from independently of one another any substituted benzyl of hydrogen atom on phenyl ring, any one in the alkoxyalkyl that the acyl group that carbonatoms is 1-10 and carbonatoms are 1-10; R ⁵for hydrogen, any one in any substituted benzyloxymethyl of the hydrogen atom on phenyl ring; N is 0,1 or 2.

The present invention also provides preparation method above-mentioned and cyclo-imino sugar compounds and midbody compound.

The present invention also provides above-mentioned and cyclo-imino sugar compounds or its pharmacy acceptable salt or the application of medicinal composition in glycosidase activity inhibitor class medicine.

And then, the present invention also provides a kind of medicine, described medicine is the medicine, the medicine that prevents and/or treats gaucher's disease that prevent and/or treat diabetes, prevent and/or treat the medicine of tumour and one or more in antiviral, wherein, its activeconstituents is of the present invention and cyclo-imino sugar compounds or its pharmacy acceptable salt or medicinal composition.

According to of the present invention and cyclo-imino sugar compounds, it has good glycosidase activity restraining effect and particularly alpha-glucosidase and beta-galactosidase enzymes is had to activity inhibition preferably.

Other features and advantages of the present invention will partly be described in detail in embodiment subsequently.

The accompanying drawing explanation

The chemical reaction flow process figure that Fig. 1 is preparation formula in embodiment 1 (I-1) and formula (I-2) compound.

The chemical reaction flow process figure that Fig. 2 is preparation formula in embodiment 2 (I-3) and formula (I-4) compound.

The chemical reaction flow process figure that Fig. 3 is preparation formula in embodiment 3 (I-5), formula (I-6) and formula (I-7) compound.

The chemical reaction flow process figure that Fig. 4 is preparation formula in embodiment 4 (I-9) compound.

The chemical reaction flow process figure that Fig. 5 is preparation formula in embodiment 5 (I-28) compound.

The chemical reaction flow process figure that Fig. 6 is preparation formula in embodiment 6 (I-30) compound.

Embodiment

Below the specific embodiment of the present invention is elaborated.Should be understood that, embodiment described herein only, for description and interpretation the present invention, is not limited to the present invention.

Provided by the invention and cyclo-imino sugar compounds is characterised in that, the compound that also the cyclo-imino sugar compounds is structure shown in formula IA or formula IB,

Wherein, R ¹for the alkyl of the carbonatoms straight or branched that is 1-12, the thiazolinyl of the straight or branched that carbonatoms is 2-12, any one in any substituted phenyl of the hydrogen atom on aromatic nucleus, furyl, pyrryl and indyl; R ⁵for hydrogen or methylol; N is 0,1 or 2.

Compound of the present invention, when relating to chiral centre, comprises R type and S type.

Preferably, R ¹alkyl for the carbonatoms straight or branched that is 3-12, the thiazolinyl of the straight or branched that carbonatoms is 3-6, phenyl, the alkyl that at least one hydrogen atom on phenyl ring is 1-3 by methoxyl group, hydroxyl, amino, halogen or carbonatoms replaces the phenyl obtained, furyl, pyrryl and indyl that on aromatic nucleus, at least one hydrogen atom is obtained by methoxyl group, hydroxyl, amino or halogen replacement, furyl, any one in pyrryl and indyl; More preferably, R ¹alkyl for the carbonatoms straight or branched that is 3-12, the thiazolinyl of the straight or branched that carbonatoms is 3-6, phenyl, the alkyl that at least one hydrogen atom on phenyl ring is 1-3 by methoxyl group, hydroxyl, amino, halogen or carbonatoms replaces the phenyl obtained, furyl, any one in pyrryl and indyl; Further preferably, R ¹for the alkyl of the carbonatoms straight or branched that is 3-6, propenyl, any one in phenyl and p-methoxyphenyl.

The alkyl of the straight or branched that described carbonatoms is 1-12 can be enumerated: methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, 2-methyl amyl, heptyl and nonyl etc.

The thiazolinyl of the straight or branched that described carbonatoms is 2-12 can be enumerated: allyl group, alkene butyl, 3-methyl alkene butyl, 4-methyl alkene amyl group and alkene nonyl etc.

Any substituted phenyl of hydrogen atom on described phenyl ring can be enumerated: 4-methoxyphenyl, 4-chloro-phenyl-, 2-methoxyphenyl, 3-aminomethyl phenyl and 4-aminomethyl phenyl etc.

Any substituted furyl of hydrogen atom on described aromatic nucleus can be enumerated: 4-methyl furan base, 3-methyl furan base, 4-ethoxycarbonyl furyl, 3-bromine furyl and 4-bromine furyl etc.

Any substituted pyrryl of hydrogen atom on described aromatic nucleus can be enumerated: 4-methylpyrrole base, 3-methylpyrrole base, 4-ethoxycarbonyl pyrryl, 3-bromine pyrryl and 4-bromine pyrryl etc.

Any substituted indyl of hydrogen atom on described aromatic nucleus can be enumerated: 5-skatole base, 3-skatole base, 5-ethoxycarbonyl indyl, 8-skatole base and 5-methoxy-Indole base etc.

Any substituted benzyl of hydrogen atom on described phenyl ring can be enumerated: to methoxybenzyl, adjacent methoxybenzyl p-chlorobenzyl, to bromobenzyl, to luorobenzyl with to methyl-benzyl etc.

The acyl group that described carbonatoms is 1-10 can be enumerated: ethanoyl, pivaloyl, chloracetyl, allyl oxygen carbonyl acyl group and benzoyl etc.

The alkoxyalkyl that described carbonatoms is 1-10 can be enumerated: methoxyl methyl, ethoxymethyl, the third oxygen methyl, fourth oxygen methyl, methoxyethyl, ethoxyethyl, the third oxygen ethyl etc.

Any substituted benzyloxymethyl of hydrogen atom on described phenyl ring can be enumerated: to methoxyl group benzyloxy methyl, to benzyl chloride oxygen methyl, to bromobenzyl oxygen methyl, to the fluorine benzyloxymethyl with to methyl benzyloxymethyl etc.

According to the present invention, the compound of structure shown in described formula IA is particularly preferably any one in following formula (I-1), formula (I-3), formula (I-5), formula (I-7), formula (I-8), formula (I-10), formula (I-12), formula (I-14), formula (I-16), formula (I-18), formula (I-21), formula (I-23), formula (I-25), formula (I-28), formula (I-29) and formula (I-30); The compound of structure shown in described formula IB is particularly preferably any one in following formula (I-2), formula (I-4), formula (I-6), formula (I-9), formula (I-11), formula (I-13), formula (I-15), formula (I-17), formula (I-19), formula (I-20), formula (I-22), formula (I-24), formula (I-26) and formula (I-27);

The present invention also provides the compound of structure shown in a kind of formula IC, the midbody compound that shown in this formula IC, the compound of structure is the compound of structure shown in described formula IA,

Wherein, R ¹for the alkyl of the carbonatoms straight or branched that is 1-12, the thiazolinyl of the straight or branched that carbonatoms is 2-12, any one in any substituted phenyl of the hydrogen atom on aromatic nucleus, furyl, pyrryl and indyl; R ², R ³and R ⁴be selected from independently of one another any substituted benzyl of hydrogen atom on phenyl ring, any one in the alkoxyalkyl that the acyl group that carbonatoms is 1-10 and carbonatoms are 1-10; R ⁵for hydrogen, any one in any substituted benzyloxymethyl of the hydrogen atom on phenyl ring; N is 0,1 or 2.

Compound of the present invention, when relating to chiral centre, comprises R type and S type.

Preferably, R ¹alkyl for the carbonatoms straight or branched that is 3-12, the thiazolinyl of the straight or branched that carbonatoms is 3-6, phenyl, the alkyl that at least one hydrogen atom on phenyl ring is 1-3 by methoxyl group, hydroxyl, amino, halogen or carbonatoms replaces the phenyl obtained, furyl, pyrryl and indyl that on aromatic nucleus, at least one hydrogen atom is obtained by methoxyl group, hydroxyl, amino or halogen replacement, furyl, any one in pyrryl and indyl; More preferably, R ¹alkyl for the carbonatoms straight or branched that is 3-12, the thiazolinyl of the straight or branched that carbonatoms is 3-6, phenyl, the alkyl that at least one hydrogen atom on phenyl ring is 1-3 by methoxyl group, hydroxyl, amino, halogen or carbonatoms replaces the phenyl obtained, furyl, any one in pyrryl and indyl; Further preferably, R ¹for the alkyl of the carbonatoms straight or branched that is 3-6, propenyl, any one in phenyl and p-methoxyphenyl.

Described R ², R ³and R ⁴by this area hydroxy-protective group commonly used.Preferably, R ², R ³and R ⁴be selected from independently of one another benzyl, the alkoxyl group that at least one hydrogen atom on phenyl ring is 1-3 by carbonatoms, the benzyl that the alkyl that halogen or carbonatoms are 1-3 replaces, ethanoyl, any one in benzoyl and methoxyl methyl; More preferably, R ², R ³and R ⁴for benzyl.

Preferably, R ⁵for hydrogen, any one in the benzyloxymethyl that the alkyl that alkoxyl group, halogen or the carbonatoms that the hydrogen atom on benzyloxymethyl and phenyl ring is 1-3 by hydroxyl, carbonatoms is 1-3 replaces; More preferably, R ⁵for hydrogen or benzyloxymethyl.

The present invention also provides the compound of structure shown in a kind of formula ID, the midbody compound that shown in this formula ID, the compound of structure is the compound of structure shown in described formula IB,

Wherein, R ¹for the alkyl of the carbonatoms straight or branched that is 1-12, the thiazolinyl of the straight or branched that carbonatoms is 2-12, any one in any substituted phenyl of the hydrogen atom on aromatic nucleus, furyl, pyrryl and indyl; R ², R ³and R ⁴be selected from independently of one another any substituted benzyl of hydrogen atom on phenyl ring, any one in the alkoxyalkyl that the acyl group that carbonatoms is 1-10 and carbonatoms are 1-10; R ⁵for hydrogen, any one in any substituted benzyloxymethyl of the hydrogen atom on phenyl ring; N is 0,1 or 2.

Compound of the present invention, when relating to chiral centre, comprises R type and S type.

Preferably, R ¹alkyl for the carbonatoms straight or branched that is 3-12, the thiazolinyl of the straight or branched that carbonatoms is 3-6, phenyl, the alkyl that at least one hydrogen atom on phenyl ring is 1-3 by methoxyl group, hydroxyl, amino, halogen or carbonatoms replaces the phenyl obtained, furyl, pyrryl and indyl that on aromatic nucleus, at least one hydrogen atom is obtained by methoxyl group, hydroxyl, amino or halogen replacement, furyl, any one in pyrryl and indyl; More preferably, R ¹alkyl for the carbonatoms straight or branched that is 3-12, the thiazolinyl of the straight or branched that carbonatoms is 3-6, phenyl, the alkyl that at least one hydrogen atom on phenyl ring is 1-3 by methoxyl group, hydroxyl, amino, halogen or carbonatoms replaces the phenyl obtained, furyl, any one in pyrryl and indyl; Further preferably, R ¹for the alkyl of the carbonatoms straight or branched that is 3-6, propenyl, any one in phenyl and p-methoxyphenyl.

Preferably, R ², R ³and R ⁴be selected from independently of one another benzyl, the alkoxyl group that at least one hydrogen atom on phenyl ring is 1-3 by carbonatoms, the benzyl that the alkyl that halogen or carbonatoms are 1-3 replaces, ethanoyl, any one in benzoyl and methoxyl methyl; More preferably, R ², R ³and R ⁴for benzyl.

Preferably, R ⁵for hydrogen, any one in the benzyloxymethyl that the alkyl that alkoxyl group, halogen or the carbonatoms that the hydrogen atom on benzyloxymethyl and phenyl ring is 1-3 by hydroxyl, carbonatoms is 1-3 replaces; More preferably, R ⁵for hydrogen or benzyloxymethyl.

The present invention also provides preparation method above-mentioned and cyclo-imino sugar compounds and above-mentioned midbody compound, below preparation method of the present invention and cyclo-imino sugar compounds and midbody compound thereof is described in detail.

1) preparation method of the compound of structure shown in formula IC

Step 1): by the nitrone of structure shown in described formula II at the carbene catalyzed lower and general formula R of azepine ¹α shown in CH=CHCHO, beta-unsaturated aldehyde reaction, obtain the intermediate of structure shown in formula III, and under the alkali effect, the original position alcoholysis obtains the γ of structure shown in formula IV-Hydroxylamine HCL methyl esters subsequently;

In above-mentioned formula II, R ², R ³and R ⁴be selected from independently of one another any substituted benzyl of hydrogen atom on phenyl ring, any one in the alkoxyalkyl that the acyl group that carbonatoms is 1-10 and carbonatoms are 1-10; R ⁵for hydrogen, any one in any substituted benzyloxymethyl of the hydrogen atom on phenyl ring; N is 0,1 or 2; Preferably, R ², R ³and R ⁴be selected from independently of one another benzyl, the benzyl that the alkyl that alkoxyl group, halogen or the carbonatoms that at least one hydrogen atom on phenyl ring is 1-3 by carbonatoms is 1-3 replaces, ethanoyl, any one in benzoyl and methoxyl methyl; More preferably, R ², R ³and R ⁴for benzyl.Preferably, R ⁵for hydrogen, any one in the benzyloxymethyl that the alkyl that alkoxyl group, halogen or the carbonatoms that the hydrogen atom on benzyloxymethyl and phenyl ring is 1-3 by hydroxyl, carbonatoms is 1-3 replaces.More preferably, R ⁵for hydrogen or benzyloxymethyl.

Above-mentioned general formula R ¹in CH=CHCHO, R ¹for the alkyl of the carbonatoms straight or branched that is 1-12, the thiazolinyl of the straight or branched that carbonatoms is 2-12, any one in any substituted phenyl of the hydrogen atom on aromatic nucleus, furyl, pyrryl and indyl; Preferably, R ¹alkyl for the carbonatoms straight or branched that is 3-12, the thiazolinyl of the straight or branched that carbonatoms is 3-6, phenyl, the alkyl that at least one hydrogen atom on phenyl ring is 1-3 by methoxyl group, hydroxyl, amino, halogen or carbonatoms replaces the phenyl obtained, furyl, pyrryl and indyl that at least one hydrogen atom on aromatic nucleus is obtained by methoxyl group, hydroxyl, amino or halogen replacement, furyl, any one in pyrryl and indyl; More preferably, R ¹alkyl for the carbonatoms straight or branched that is 3-12, the thiazolinyl of the straight or branched that carbonatoms is 3-6, phenyl, the alkyl that at least one hydrogen atom on phenyl ring is 1-3 by methoxyl group, hydroxyl, amino, halogen or carbonatoms replaces the phenyl obtained, furyl, any one in pyrryl and indyl; Further preferably, R ¹for the alkyl of the carbonatoms straight or branched that is 3-6, propenyl, any one in phenyl and p-methoxyphenyl.

According to the present invention, in step 1), the various azepine Cabbeens that described azepine Cabbeen can be commonly used for this area.But, under preferable case, described azepine Cabbeen is one or more in following triazole carbene precursor A and B and ribavirin carbene precursor C.

Above-mentioned steps 1) in, the nitrone of structure shown in described formula II and azepine Cabbeen and general formula R ¹the reaction of CH=CHCHO is preferably carried out under alkali exists, various organic basess or mineral alkali that this alkali can be commonly used for this area.But under preferable case, this alkali is salt of wormwood, cesium carbonate, triethylamine, 1, one or more in 8-diazabicylo [5.4.0] 11 carbon-7-alkene, diisopropyl ethyl amine and potassium tert.-butoxide.

The nitrone of structure shown in described formula II, azepine Cabbeen, general formula R ¹α shown in CH=CHCHO, the mol ratio of beta-unsaturated aldehyde and alkali can change in a big way, but under preferable case, the nitrone of structure, general formula R shown in described formula II ¹α shown in CH=CHCHO, the mol ratio of beta-unsaturated aldehyde, azepine Cabbeen and alkali is 1:0.4-0.6:0.1-1:0.1-1; 1:0.45-0.55:0.15-0.25:0.15-0.25 more preferably.

The nitrone of structure shown in described formula II and azepine Cabbeen and general formula R ¹the reaction conditions of CH=CHCHO comprises: temperature of reaction is-20 ℃～5 ℃, more preferably-5 ℃～5 ℃; Reaction times is 8-36 hour; 8-12 hour more preferably.

In addition, the nitrone of structure and azepine Cabbeen and general formula R shown in preferred described formula II ¹the reaction of CH=CHCHO is carried out under solvent exists.Described solvent is preferably non-protonic solvent.Can be for example one or more in methylene dichloride, trichloromethane, acetonitrile, tetrahydrofuran (THF), glycol dibromide and 1,2-ethylene dichloride.

According to the present invention, shown in the formula III obtained by aforesaid method in the intermediate of structure, R ², R ³, R ⁴, R ⁵identical with the definition in general formula I I with n, R ¹with general formula R ¹definition in CH=CHCHO is identical.

According to the present invention, in step 1), when the nitrone by structure shown in described formula II at the carbene catalyzed lower and general formula R of azepine ¹α shown in CH=CHCHO, beta-unsaturated aldehyde reaction, after obtaining the intermediate of structure shown in formula III, then the original position alcoholysis obtains the γ of structure shown in formula IV-Hydroxylamine HCL methyl esters under the alkali effect.Original position alcoholysis alcohol used is methyl alcohol; Original position alcoholysis alkali used is preferably sodium methylate or 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene.In addition, the mol ratio of the nitrone shown in the alkali that the original position alcoholysis is used and formula II is 1-2:1, more preferably 1-1.2:1.

The reaction conditions of described original position alcoholysis comprises: temperature of reaction is 0-40 ℃, more preferably 0-25 ℃; Reaction times is 0.5-24 hour, more preferably 0.5-1 hour.

In addition, above-mentioned steps 1) after reaction finishes, can for example, by the purification process (, the methods such as extraction, column chromatography or crystallization) of this area routine, to product, carry out purifying, obtain the γ of structure shown in formula IV-Hydroxylamine HCL methyl esters.

According to the present invention, in the γ of structure shown in the IV obtained by aforesaid method-Hydroxylamine HCL methyl esters, R ², R ³, R ⁴, R ⁵identical with the definition in general formula I I with n, R ¹with general formula R ¹definition in CH=CHCHO is identical.

Step 2): by the γ of structure shown in formula IV-Hydroxylamine HCL methyl esters reduction, and then under the alkali effect acidylate.

According to the present invention, in step 2) in, by the γ by structure shown in formula IV obtained above-Hydroxylamine HCL methyl esters reduction, and then acidylate obtains the compound of structure shown in formula IC under the alkali effect;

Step 2) the reductive agent hydroxylamine reduction agent commonly used by this area used in, described hydroxylamine reduction agent includes but not limited to zinc powder-neutralized verdigris, iron powder-neutralized verdigris or means of samarium iodide; Be preferably zinc powder-neutralized verdigris.The consumption that the consumption of described hydroxylamine reduction agent is this area routine.

Under preferable case, when using zinc powder-neutralized verdigris for the hydroxylamine reduction agent, the mol ratio of the γ of structure shown in formula IV-Hydroxylamine HCL methyl esters, zinc powder and neutralized verdigris is 1:2-20:0.2-2, is preferably 1:8-12:0.8-1.2.

According to the present invention, the condition of the γ of structure shown in formula IV-Hydroxylamine HCL methyl esters reduction is comprised: temperature of reaction is 35-70 ℃, more preferably 50-65 ℃; Reaction times is 3-24 hour, more preferably 4-8 hour.

Preferred steps 2) reaction is carried out under solvent exists, and all kinds of SOLVENTS that described solvent is commonly used by this area is preferably one or more in acetic acid, acetic acid-methylene dichloride and Acetic Acid-Water mixed solvent.The consumption of described solvent does not have special requirement, as long as by reactants dissolved, can be the conventional amount used of this area.

According to the present invention, step 2) in, acidylate (being ring closure reaction) alkali used is the various alkali that this area is commonly used.Be preferably salt of wormwood or cesium carbonate.The consumption of described salt of wormwood or cesium carbonate can be the consumption of those skilled in the art's routine when carrying out acylation reaction.

In addition, above-mentioned steps 2) after reaction finishes, can for example, by the purification process (, the methods such as extraction, column chromatography or crystallization) of this area routine, to product, carry out purifying, obtain the compound of structure shown in formula IC.

2) preparation method of the compound of structure shown in formula ID

According to the present invention, and then, by the lactan reduction of the compound by structure shown in formula IC, obtain the compound of structure shown in formula ID;

Wherein, the reductive agent used is generally used for the reductive agent of reducing carbonyl for this area.Can be for example lithium aluminum hydride, borine tetrahydrofuran (THF) or borine dimethyl sulphide.Be preferably lithium aluminum hydride.

The compound of structure shown in formula IC and the mol ratio of reductive agent can be 1:1-10, are preferably 1:2-5.

Preferred above-mentioned reduction reaction is carried out under solvent exists, and described solvent is that the various organic solvents that this type of reaction is commonly used are carried out in this area.Such as thinking toluene, ether or tetrahydrofuran (THF) etc.; Be preferably tetrahydrofuran (THF).

The condition of preferred above-mentioned reduction reaction comprises: temperature of reaction is 35-80 ℃, more preferably 50-65 ℃; Reaction times is 1-12 hour, more preferably 3-6 hour.

In addition, after reaction finishes, can for example, by the purification process (, the methods such as extraction, column chromatography or crystallization) of this area routine, to product, carry out purifying, obtain the compound of structure shown in formula ID.

3) structure shown in formula IA and the preparation method cyclo-imino sugar compounds

According to the present invention, can also carry out the hydroxyl deprotection by the compound by structure shown in formula IC obtained above, obtain the also cyclo-imino sugar compounds of structure shown in formula IA.

The reagent that above-mentioned deprotection is used is preferably hydroborating reagent or Lewis acid.Described hydroborating reagent is preferably Pd/C, Pd (OH) ₂, this area catalyzer and hydrogen commonly used such as palladium black or platinum catalyst; The hydro genation system that more preferably Pd/C-hydrochloric acid-hydrogen forms.Described Lewis acid is preferably boron tribromide or boron trichloride, more preferably boron trichloride.

Wherein, the compound of structure shown in formula IC and lewis acidic mol ratio are 1:2-10; Be preferably 1:4-8; Most preferably be 1:5.

The compound of structure shown in formula IC and the mass ratio of catalyzer are 1:0.1-1, are preferably 1:0.15-0.25.

The condition of above-mentioned deprotection reaction comprises: temperature of reaction is 20-80 ℃, and the reaction times is 2-24 hour; Being preferably temperature of reaction is 20-25 ℃, and the reaction times is 3-8 hour.

In addition, for the purifying after above-mentioned deprotection reaction, can adopt the whole bag of tricks known in the field to carry out (for example, the methods such as extraction, column chromatography or crystallization), thereby obtain the also cyclo-imino sugar compounds of structure shown in IA.

4) structure shown in formula IB and the preparation method cyclo-imino sugar compounds

According to the present invention, can also carry out the hydroxyl deprotection by the compound by structure shown in formula ID obtained above, obtain the also cyclo-imino sugar compounds of structure shown in formula IB.

The reagent that above-mentioned deprotection is used is preferably hydroborating reagent or Lewis acid.Described hydroborating reagent is preferably Pd/C, Pd (OH) ₂, this area catalyzer and hydrogen commonly used such as palladium black or platinum catalyst; The hydro genation system that more preferably Pd/C-hydrochloric acid-hydrogen forms.Described Lewis acid is preferably boron tribromide or boron trichloride, more preferably boron trichloride.

Wherein, the compound of structure shown in formula ID and lewis acidic mol ratio are 1:2-10; Be preferably 1:4-8; Most preferably be 1:5.

The compound of structure shown in formula ID and the mass ratio of hydroborating reagent are 1:0.1-1, are preferably 1:0.15-0.25.

The above-mentioned condition of stating deprotection reaction comprises: temperature of reaction is 20-80 ℃, and the reaction times is 2-24 hour; Being preferably temperature of reaction is 20-25 ℃, and the reaction times is 3-8 hour.

In addition, for the purifying after above-mentioned deprotection reaction, can adopt the whole bag of tricks known in the field to carry out (for example, the methods such as extraction, column chromatography or crystallization), thereby obtain the also cyclo-imino sugar compounds of structure shown in formula IB.

Above-mentioned preparation method both had been applicable to the R type, also was applicable to the S type, also was applicable to the mixture of the two, and different steric isomers can be prepared as starting raw material by the monose of selecting respective configuration.

In addition, in the present invention, the annular nitrone of structure shown in described formula II, can be prepared by sugar, sugar commonly used has wood sugar, pectinose, ribose or seminose etc., its preparation method can be with reference to following patent and document [a kind of (a) method for preparing polyhydroxy annular nitrone, application number: 200610066638.0; (b) Yu, C.-Y.; Huang, M.-H.Org.Lett., 2006,8,3021-3024; (c) Tsou, E.-L.; Yeh, Y.-T.; Liang, P.-H.; Cheng, W.-C.Tetrahedron2009,65,93-100; (d) Wang, W.-B.; Huang, M.-H.; Li, Y.-X.; Rui, P.-X.; Hu, X.-G.; Zhang, W.; Su, J.-K.; Zhang, Z.-L.; Zhu, J.-S.; Xu, W.-H.; Xie, X.-Q.; Jia, Y.-M.; Yu, C.-Y.Synlett, 2010,3,488-492.]

Particularly, the structure of the compound of structure shown in above-mentioned formula II includes but not limited to following arbitrary structure:

And; in the present invention; steric configuration to all compounds is not done clear; different steric isomers can pass through to select the nitrone of respective configuration as starting raw material; method preparation according to synthetic nitrone has single-minded stereochemical polyhydroxy annular nitrone; and as chiral synthon; the operations such as the pass cyclic amide reaction promoted by linked reaction, original position alcoholysis, hydroxylamine reduction, alkali, reduction of amide, deprotection, build the various polyhydroxylated alkaloid that has and encircle skeleton of structure fast, succinctly, efficiently.

In addition, also cyclo-imino sugar compounds pharmacy acceptable salt or the medicinal composition of structure shown in formula IA or formula IB also belong to protection scope of the present invention.

The present invention also provides of the present invention and cyclo-imino sugar compounds or its pharmacy acceptable salt or the application of medicinal composition in glycosidase activity inhibitor class medicine.

Provided by the present invention and cyclo-imino sugar compounds or its pharmacy acceptable salt or medicinal composition can be used for preparing the glycosidase activity inhibitor.

Described Glycosylase can be alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase enzymes, alpha-Mannosidase, beta-Mannosidase, α, any one in α-trehalase, alpha-L-fucosidase, alpha-L-Rhamnosidase and amyloglucosidase.

Of the present invention and cyclo-imino sugar compounds or its pharmacy acceptable salt or medicinal composition also can be used for preparing following any one medicine.Described medicine is the medicine, the medicine that prevents and/or treats gaucher's disease that prevent and/or treat diabetes, prevent and/or treat the medicine of tumour and one or more in antiviral.

Take of the present invention and cyclo-imino sugar compounds or its pharmacy acceptable salt or medicinal composition also belongs to protection scope of the present invention as following medicine prepared by effective constituent.Described medicine is the medicine, the medicine that prevents and/or treats gaucher's disease that prevent and/or treat diabetes, prevent and/or treat the medicine of tumour and one or more in antiviral.

According to the present invention, in said medicine, as the also cyclo-imino sugar compounds provided by the present invention of activeconstituents or the content of its pharmacy acceptable salt or medicinal composition, be 1-99% weight; Be preferably the 10-90 % by weight.In addition, about the using dosage of described medicine, the disease that can prevent and/or treat is as required carried out appropriate selection, and it can be the conventional amount used of this area when treating various diseases.

In addition, as required, can also add one or more pharmaceutically acceptable carriers in said medicine.Described carrier comprises thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant and other optional additives of pharmaceutical field routine.The medicine prepared with formula I compound or its pharmacy acceptable salt can be made the various ways such as injection liquid, tablet, pulvis, granule, capsule, oral liquid, paste, creme.The medicine of above-mentioned various formulations all can be according to the ordinary method preparation of pharmaceutical field.

Provided by the invention and cyclo-imino sugar compounds is tested through the Glycosylase inhibition, the compound of structure shown in proof formula I has single-minded inhibition activity to alpha-glucosidase and beta-galactosidase enzymes, particularly, I-5, I-9, I-13, I-17, I-24 are the potent inhibitor of beta-galactosidase enzymes, and I-6 and I-28 are all potent inhibitors of alpha-glucosidase.

Below by specific embodiment, the present invention will be described, but the present invention is not limited thereto.

Experimental technique described in following embodiment, if no special instructions, be ordinary method; Described reagent and material, if no special instructions, all obtain from commercial channels.

Compound shown in raw materials used in following embodiment (II-a)～(II-f) is that the method provided according to following patent documentation and non-patent literature is synthetic: a kind of (a) method for preparing polyhydroxy annular nitrone, application number: 200610066638.0; (b) Tsou, E.-L.; Yeh, Y.-T.; Liang, P.-H.; Cheng, W.-C.Tetrahedron2009,65,93-100; (c) Yu, C.-Y.; Huang, M.-H.Org.Lett., 2006,8,3021-3024; (d) Tamura, O.; Toyao, A.; Ishibashi, H.Synlett2002,1344-1346; (e) Wang, W.-B.; Huang, M.-H.; Li, Y.-X.; Rui, P.-X.; Hu, X.-G.; Zhang, W.; Su, J.-K.; Zhang, Z.-L.; Zhu, J.-S.; Xu, W.-H.; Xie, X.-Q.; Jia, Y.-M.; Yu, C.-Y.Synlett, 2010,3,488-492; (f) Zhao Wenbo, Institute of Chemistry, Academia Sinica's Ph D dissertation, 2013.

Bn in formula (II-a)～(II-f) represents benzyl.

Concrete steps prepared by each raw material are as follows:

The preparation method of nitrone is described with the preparation of II-b:

One, the preparation of II-b

Ice bath, under agitation condition, dropwise add 10 milliliters of Acetyl Chloride 98Min.s in 500 milliliters of dry methyl alcohol, add subsequently D-wood sugar (30g, 0.2mol), keep the zero degree reaction until raw material disappears, be neutralized to neutrality with sodium bicarbonate, filter and remove inorganic salt, solvent evaporated, gained crude product D-furyl xylose first glycosides is directly cast the step reaction.

Upper step crude product D-furyl xylose first glycosides (calculating according to 0.2mol) is dissolved into to dry N, in dinethylformamide (200mL), and dropwise be added drop-wise to sodium hydride (29g, 0.72mol, content 60%) tetrahydrofuran (THF) (200mL) and N, in dinethylformamide (200mL), finish, add tetrabutylammonium iodide (2.0g), after half an hour, dropwise add bromobenzyl (0.66mol, 78.3mL), reaction is until the raw material disappearance, slowly drip saturated aqueous ammonium chloride cancellation reaction, ethyl acetate/water extraction, the washing organic phase is removed N, dinethylformamide, solvent evaporated, obtain crude product 2, 3, 5-O-tribenzyl-D-furyl xylose first glycosides, directly cast the step reaction.

Upper step crude product 2,3,5-O-tribenzyl-D-furyl xylose first glycosides (calculating by 0.2mol) is dissolved into the aqueous sulfuric acid (100mL) and 1 of acetic acid (100mL), 1.5M, in the mixed solvent of 4-dioxane (100mL), 90 ℃ of reacting by heating until raw material almost completely disappear, boil off most of acetic acid and 1, the 4-dioxane, with ethyl acetate/saturated sodium carbonate solution extraction, drying, revolve desolventizing, obtains crude product (hemiacetal crude product) (2,3,5-O-tribenzyl-D-furyl xylose) directly throw in next step reaction.

By pyridine (30mL, 0.37mol) add above-mentioned crude product 2, 3, in methylene dichloride (100mL) solution of 5-O-tribenzyl-D-furyl xylose (calculating according to 0.2mol), toward wherein adding O-methyl hydroxylamine hydrochloride (20.88g, 0.25mol), after stirring at room 12 hours, by the solvent evaporate to dryness, then add ethyl acetate (100-200mL) and hydrochloric acid (1mol/L in concentrated solution, 30mL), through extracting and demixing, merge organic phase, dry, concentrated, obtain crude product (2S, 3S, 4R)-2, 3, 5-tri-benzyloxies-4-hydroxyl-1-valeral methyloxime ether, directly throw in next step reaction.

By above-mentioned crude product (2S, 3S, 4R)-2,3,5-, tri-benzyloxies-4-hydroxyl-1-valeral methyloxime ether (calculating by 0.2mol) is dissolved in methylene dichloride (100mL), adds pyridine (30mL, 0.37mol) and methane sulfonyl chloride (15.6mL, 0.20mol), stirring at room, after 8 hours, adds this reaction of aqueous hydrochloric acid (1mol/L) cancellation.Through extracting and demixing, merge organic phase, drying, concentrated, obtain crude product (2S, 3S, 4R)-2,3,5-tri-benzyloxies-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, add p-methyl benzenesulfonic acid (38.00g, 0.2mol) and 37% formalin (50mL) in tetrahydrofuran (THF) (300mL) solution of 5-tri-benzyloxies-4-sulfonyloxy methyl oxygen-1-valeral methyloxime ether (calculating by 0.2mol), stirring at room is until raw material completely dissolve (TLC monitoring), then add ethyl acetate and water in mixed solution, through extracting and demixing, merge organic phase, drying, concentrated, gained crude product (2R, 3R, 4R)-4-mesyloxy-2,3,5-, tri-benzyloxies-1-valeral.

First sodium bicarbonate (37.80g, 0.45mol) is added in water (50mL) solution of oxammonium hydrochloride (31.05g, 0.45mol), in reinforced process, can observe a large amount of Bubble formations.Toward wherein adding above-mentioned crude product (2R, 3R, 4R)-4-mesyloxy-2,3, ethanol (200mL) solution of 5-tri-benzyloxies-1-valeral (pressing 0.2mol calculates), stirring at room 15 hours, post-heating stirs 48 hours.Then add ethyl acetate and water in mixed solution, through extracting and demixing, merge organic phase, drying, concentrated, obtain yellow oil.This oily matter is dissolved in the ethyl acetate and sherwood oil of suitable proportion, room temperature is placed and is spent the night, separate out white solid 10.40g, mother liquor continues crystallization, the 9.95g white solid of getting back, the mother liquor white solid 1.35g that gets back after the column chromatography purifying, amount to 22.00g nitrone product (3S, 4S, 5S)-3,4-benzyloxy-5-benzyloxymethyl-1-pyrroline-N-oxide compound, II-b.Take wood sugar as raw material calculating, and seven steps reaction overall yields are 26%.Its structural identification data are: m.p.:90-91 ℃; [α] _d=+45 ° of (c0.4, CHCl ₃); 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, CDCl ₃) 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) and, 4.39(dd, J=3.2,2.2Hz, 1H), 4.10 – 4.04(m, 2H) and, 3.78(d, J=7.3Hz, 1H); ¹³c-NMR(75MHz, CDCl ₃) δ 66.03(CH ₂o), 71.67,71.91,73.47,80.30(CHO), and 82.74(CHO), 127.70,127.75,127.92,128.14,128.17,128.38,128.55,128.61,133.02(N=CH), 137.06(C), 137.16(C), 137.63(C); FT-ICRMS:m/z418.2007[M+H] ⁺(C ₂₆h ₂₈nO ₄requires418.2013).So far, prepare II-b.

Two, the preparation of II-a

Under ice-water bath, in the dehydrated alcohol (500mL) of L-TARTARIC ACID (100g, 0.67mol), dropwise add sulfur oxychloride (107mL, 1.47mol), stirred overnight at room temperature.The low temperature solvent evaporated, ethyl acetate-saturated sodium bicarbonate aqueous solution extraction, drying, concentrate and obtain colorless oil product 138g, is directly used in next step reaction.

By above-mentioned product (7.5g, 36.4mmol) be dissolved into tetrahydrofuran (THF) (50mL) and N, in the mixed solvent of dinethylformamide (100mL), add sodium hydride (3.46g, 60wt%) in batches under-20 ℃, add the tetrabutylammonium iodide (0.30g) of catalytic amount, stir 15min, slowly add bromobenzyl (9.2 mL, 73.4mmol), TLC monitoring reaction (about 30min).React complete, add the saturated aqueous ammonium chloride cancellation to react, the ethyl acetate extraction, DMF is removed in washing, and drying is concentrated, and the post separation obtains oily product 11.5g fast, is directly used in next step reaction.

Above-claimed cpd (21.6g, 56mmol) is dissolved in the tetrahydrofuran (THF) of 500mL drying, under frozen water is molten, add lithium aluminum hydride (4.26g in batches, 112mmol), after stirring at room 0.5h, be chilled to 0 ℃, the NaOH aqueous solution (8.6mL) and the water (12.9mL) that add successively water (4.3mL), 10 % by weight, diatomite filtration, ethyl acetate extraction, drying, concentrated, post is directly used in next step reaction after separating fast.

By above-claimed cpd (2.0g, 6.6mmol) be dissolved in dry methylene dichloride (40mL), add triethylamine (2.3mL, 16.5mmol), under ice-water bath, dropwise add methylsulfonyl chloride (1.2mL, 14.5mmol), stirring at room 1h reacts completely, methylene dichloride/water extraction, drying, concentrated, be directly used in next step reaction.

Above-claimed cpd (2.75g, 6.0mmol) is dissolved in to the Et of 50mL drying ₃in N, add oxammonium hydrochloride (1.67g, 24mmol), backflow 1.5h, react completely, concentrated, ethyl acetate/saturated aqueous ammonium chloride extraction, and drying, concentrated, post is directly used in next step reaction after separating fast.

Above-claimed cpd (3.0g, 10mmol) is dissolved in the methylene dichloride of 50mL drying, under ice-water bath, adds yellow precipitate (4.34g, 20mmol), and room temperature reaction spends the night.Diatomite filtration, concentrated, the post separation obtains the derivative nitrone II-a(2.8g of L-TARTARIC ACID), its structural confirmation data are: [α] _d ²⁰=+71 (c0.8, CHCl ₃); ¹hNMR(300MHz, CDCl ₃): δ 7.43-7.28(m, 10H), 6.89(d, J=1.7Hz, 1H) and, 4.69(s, 1H), 4.58(s, 2H) and, 4.56(s, 2H), 4.32-4.25(m, 2H) and, 3.91-3.83(m, 1H); ¹³cNMR (75MHz, CDCl ₃): δ 137.1,136.9, and 132.2,128.7,128.7,128.3,128.0,127.9,83.7,78.4,71.9,71.8,67.0.

Three, the preparation of II-c

According to the above-mentioned method for preparing II-b, change raw material D-wood sugar into D-ribose, can prepare II-c.

Four, the preparation of II-d

According to the above-mentioned method for preparing II-b, change raw material D-wood sugar into D-R, can prepare II-d.

Five, the preparation of II-e

According to the above-mentioned method for preparing II-b, change raw material D-wood sugar into D-R, and reflux obtains six-ring first glycosides when preparation first glycosides, can prepare II-e.

Six, the preparation of II-f

According to the rich Ph D dissertation (Institute of Chemistry, Academia Sinica Beijing 2013) of Zhao Wen and document [Zhao, W.-B.; Nakagawa, S.; Kato, A.; Adachi, I.; Jia, Y.-M.; Hu, X.-G.; Fleet, G.W.J.; Wilson, F.X.; Horne, G.; Yoshihara, A.; Izumori, K.; Yu, C.-Y.J.Org.Chem., 2013,78,3208] can prepare II-f.

D-MANNOSE (9.0g, 50.0mmol) is dissolved in 6N hydrochloric acid (20mL), adds 1,3-dimercaptopropane (5.55mL, 55.0mmol), under this reaction mixture room temperature, stir and spend the night.Use ethyl alcohol recrystallization after reaction solution is concentrated, filter, and use the alcohol flushing filter cake.Obtain white solid 8.6g after drying, be thioacetal, productive rate 65%.

By above-mentioned thioacetal (8.1g, 30.0mmol), pyridine (150mL) solution of triphenylmethyl chloride (8.79g, 31.5mmol) and 4-dimethylamino pyridine (37mg, 0.30mmol) stirs 48 hours under 35 ℃.Concentrate and remove pyridine, add water (200mL), be extracted with ethyl acetate (3 * 100mL).Merge the organic phase anhydrous magnesium sulfate drying, after filtration, concentrate and obtain the crude product that yellow syrup is trityl ether.

The crude product of above-mentioned trityl ether (in 30.0mmol) is dissolved in the mixed solvent of DMF (50mL) and tetrahydrofuran (THF) (200mL).Add sodium hydride (mineral oil mixture of 60 % by weight, 6.60g, 165.0mmol) in batches, add rear stirring at room and extremely emit without bubble half an hour.Add tetrabutylammonium iodide (221mg, 0.60mmol).Dropwise drip bromobenzyl (17.8mL, 150.0mmol) under room temperature, add rear stirred overnight at room temperature.The shrend on the rocks reaction of going out, add ethyl acetate (500mL), washing (5 * 200mL).The organic phase anhydrous magnesium sulfate drying, after filtration, concentrated, obtain all crude products of the thioacetals of protection of hydroxyl.

The crude product of above-mentioned thioacetal (in 30.0mmol) is dissolved in the mixed solvent of methyl alcohol (150mL) and methylene dichloride (150mL), dropwise drips the vitriol oil (6mL), drip off rear stirred overnight at room temperature.Equal 8 to adding strong aqua to be adjusted to the pH value in reaction mixture.Add water (300mL) after concentrated, be extracted with ethyl acetate (3 * 200mL).Merge organic phase and use anhydrous magnesium sulfate drying, after filtration, concentrated, crude product is through column chromatography (silica gel) separation, take ethyl acetate: be sherwood oil=1:6(V/V) leacheate, obtain primary alconol.

Above-mentioned primary alconol (6.31g, 10.0mmol) and triethylamine (2.08mL, 15.0mmol) are dissolved in to methylene dichloride (60mL), dropwise drip Acetyl Chloride 98Min. (0.85mL, 12.0mmol) under ice-water bath, add rear room temperature reaction 1 hour.Washed reaction liquid (2 * 30mL), the organic phase anhydrous magnesium sulfate drying.Obtain the crude product of acetic ester after after filtration, concentrated.

The crude product of above-mentioned acetic ester is dissolved in acetonitrile (50mL) and ethylene glycol (5mL), adds N-bromo-succinimide (5.34g, 30.0mmol) in batches, add rear stirring at room 30 minutes.Be adjusted to the pH value with saturated sodium bicarbonate solution and equal 8, ethyl acetate extraction (3 * 50mL).Merge organic phase, use anhydrous magnesium sulfate drying.Obtain the crude product of acetal after after filtration, concentrated.

Above-mentioned acetal crude product is dissolved in to methyl alcohol (50mL), adds salt of wormwood (2.76g, 20.0mmol), stir 3 hours under room temperature.Filter, concentrated filtrate, by gained crude product for column chromatography (silica gel) separated, take ethyl acetate: being sherwood oil=1:5(V/V) leacheate, obtaining primary alconol, is the 4.10g colorless oil, take primary alconol as raw material calculating, three-step reaction overall yield 70%.

Under-70 ℃, dimethyl sulfoxide (DMSO) (1.46mL, 20.5mmol) dropwise is added dropwise in dry methylene chloride (40mL) solution of oxalyl chloride (1.16mL, 13.7mmol), stirs 20 minutes at this temperature after adding.Under-70 ℃, the dry methylene chloride of above-mentioned primary alconol (4.0g, 6.84mmol) (10mL) solution dropwise is added dropwise to above-mentioned reaction system, stirs 20 minutes at this temperature after adding.Dropwise drip triethylamine (4.75mL, 34.2mmol) under 70 ℃, after adding at this temperature reaction stirring at room 1 hour after 15 minutes, produce a large amount of white solids.Washed reaction liquid (2 * 30mL), the organic phase anhydrous magnesium sulfate drying, after filtration, obtain the aldehyde crude product after concentrated.

Above-mentioned aldehyde crude product (in 6.84mmol) is dissolved in to methyl alcohol (50mL), adds successively oxammonium hydrochloride (2.36g, 34.2mmol) and sodium bicarbonate (4.60g, 54.7mmol), have gas to emit.Stirred overnight at room temperature.Concentration of reaction solution, add water (50mL), and ethyl acetate extraction (3 * 30mL) merges organic phase and uses anhydrous magnesium sulfate drying.Obtain the crude product of oxime after after filtration, concentrated.

The crude product of above-mentioned oxime (in 6.84mmol) and sodium cyanoborohydride (862mg, 13.7mmol) are dissolved in methyl alcohol (50mL), add 2 saturated methyl orange aqueous solutions to make indicator.To dropwise dripping the solution that concentrated hydrochloric acid and methyl alcohol volume ratio are 1:10 in above-mentioned system, the pH value of the hierarchy of control is 3～5, with the TLC monitoring until the oxime completely dissolve.Concentration of reaction solution, be dissolved in ethyl acetate (200mL) by residue, uses respectively the sodium hydroxide solution (1 * 50mL) of 1M and saturated aqueous common salt (2 * 50mL) to wash.Organic phase drying, filtration, concentrated, column chromatography for separation, ethyl acetate: be sherwood oil=1:1(V/V) leacheate, obtain pure azanol, quality 2.95g, be light yellow oil.Take primary alconol as raw material calculating, three-step reaction overall yield 72%.

By the tetrahydrofuran (THF) of the above-mentioned azanol of gained (600mg, 1.0mmol) (10mL) and concentrated hydrochloric acid (5mL) solution stirring at room 2 hours, add ethyl acetate (50mL), water (2 * 20mL) and saturated sodium bicarbonate solution (1 * 30mL) are washed successively.The organic phase anhydrous magnesium sulfate drying, after filtration, concentrated rear pillar separates, take methyl alcohol: methylene dichloride=1:100(V/V) obtain 443mg nitrone II-f as leacheate, productive rate 83%, be yellow oil.Its structural identification data are: ¹hNMR (300MHz, CDCl ₃): δ 7.34-7.17 (m, 20H), 7.04 (d, J=4.7Hz, 1H), 4.73-4.42 (m, 10H), 4.02-3.84 (m, 4H); ¹³cNMR (75MHz, CDCl ₃): δ 138.46,138.08, and 137.89,137.60,136.97,128.66,128.55,128.50,128.47,128.18,127.95,127.88,127.81,79.12,77.38,74.27,73.95,73.22,73.08,72.12,71.72,62.07.

Embodiment 1: (1R, 6S, the 7S shown in synthesis type (I-1), 7aS)-6,7-dihydroxyl-1 (1H)-phenyl-Pyrrolizidine-3 (2H)-one and (I-2) shown in (1S, 2S, 7R, 7aS)-7-phenyl-1-hydrogen-Pyrrolizidine-1, the 2-glycol

Add azepine Cabbeen A(0.36g in the round-bottomed flask of drying, 1.37mmol) and nitrone II-a(4.0g, 13.45mmol), add the methylene dichloride of 15mL drying, ice-water bath is cooling, then add successively (E)-3-phenylacrolein (0.85mL, 1.0mmol) and 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (0.20mL, 1.3mmol), ice-water bath stirs 0.5 hour, rises to room temperature reaction, the TLC monitoring reaction.When the olefine aldehydr raw material reaction is complete, the methanol solution (1.0M) that adds the 0.5mL sodium methylate, stirring at room half an hour, add water, dichloromethane extraction three times, the quick post of silica gel separates (ethyl acetate: sherwood oil=1:6, v/v), obtain (R)-methyl-3-[(2S, 3S, 4S)-3,4-bis-(benzyloxy)-1-hydroxyl-2-Pyrrolizidine base]-3-Phenpropionate IV-aa(2.45g), product is colorless oil, productive rate 78.1%.IV-aa structural identification data: ¹hNMR(300MHz, CDCl ₃) δ 7.31-7.11(m, 15H), 4.37(d, J=11.7Hz, 1H), 4.31-4.25(m, 2H), 4.21-4.12(m, 2H) and, 4.04(d, J=11.4Hz, 1H), 3.84-3.78(m, 1H) and, 3.68(dd, J ₁=4.2Hz, J ₂=12.3Hz, 1H), 3.41-3.31(m, 2H), 3.08(dd, J ₁=9.0Hz, J ₂=17.1Hz, 1H), 2.62(dd, J ₁=2.7Hz, J ₂=17.1Hz, 1H); ¹³cNMR(75MHz, CDCl ₃) δ 174.4,140.1,137.6,137.3,128.8,128.47,128.41,128.0,127.9,127.8,127.4,84.6,81.8,72.3,71.6,68.5,46.4,40.5,40.3.

Zinc powder (2.05g, 31.35mmol) and a water acetic acid copper (70mg, 0.35mmol) of activation are joined in 15mL acetic acid, stirring at room 5 minutes, then add above-mentioned IV-aa(1.45g, 3.13mmol) the 5mL acetum, 50 ℃ the heating 4 hours, TLC shows raw material reaction, diatomite filtration, be spin-dried for, methylene dichloride/saturated sodium bicarbonate aqueous solution extraction, drying, be directly used in next step reaction.Above-mentioned thick product is dissolved in methyl alcohol, add salt of wormwood (0.86g), 50 ℃ are heated approximately 3 hours, TLC shows that raw material reaction is complete, and diatomite filtration, be spin-dried for, silicagel column separates (ethyl acetate: sherwood oil 1:5, v/v), obtains colorless oil (1R, 6S, 7S, 7aS)-6,7-bis-(benzyloxy)-1-phenyl-Pyrrolizidine-3 (2H)-one V-aa, be total to 1.10g, productive rate 86.4%.V-aa structural identification data: ¹hNMR(300MHz, CDCl ₃) δ 7.31-7.11(m, 15H), 4.37(d, J=11.7Hz, 1H), 4.31-4.25(m, 2H), 4.21-4.12(m, 2H) and, 4.04(d, J=11.4Hz, 1H), 3.84-3.78(m, 1H) and, 3.68(dd, J ₁=4.2Hz, J ₂=12.3Hz, 1H), 3.41-3.31(m, 2H), 3.08(dd, J ₁=9.0Hz, J ₂=17.1Hz, 1H), 2.62(dd, J ₁=2.7Hz, J ₂=17.1Hz, 1H); ¹³cNMR(75MHz, CDCl ₃) δ 174.4,140.1,137.6,137.3,128.8,128.47,128.41,128.0,127.9,127.8,127.4,84.6,81.8,72.3,71.6,68.5,46.4,40.5,40.3.

By above-mentioned product V-aa(0.525g, 1.26mmol) be dissolved in anhydrous tetrahydro furan (15mL), add lithium aluminum hydride (0.25g, 6.58mmol), 50 ℃ are heated 3 hours, TLC shows that raw material reaction is complete, add successively 1.3mL water, 2.6mL10% aqueous sodium hydroxide solution and 3.9mL water also stir half an hour, diatomite filtration, the ethyl acetate extraction, dry, post separates (ethyl acetate: sherwood oil 1:3, v/v) obtain (1S, 2S, 7R, 7aS)-1, 2-benzyloxy-7-phenyl-1H-Pyrrolizidine VI-aa(0.464g, 91.9%), colorless oil.The structural confirmation data of VI-aa: ¹hNMR(CDCl ₃, 300MHz) δ 7.32-7.12(m, 13H), 6.98-6.95(m, 2H), 4.44(s, 2H) and, 4.10(d, J=11.1Hz, 1H), 4.02(q, J=5.1Hz, 1H) and, 3.72-3.65(m, 3H), 3.49(t, J=4.5Hz, 1H) and, 3.35(dd, J ₁=5.4Hz, J ₂=11.4Hz, 1H), 3.18-3.09(m, 1H), 2.96-2.83(m, 2H) and, 2.28-2.14(m, 1H), 1.96-1.88(m, 1H); ¹³cNMR(CDCl ₃, 75MHz) δ 140.1,138.28, and 138.25,128.5,128.4,128.3,127.9,127.8,127.7,127.5,126.6,85.0,84.9,73.0,72.0,71.9,58.2,54.8,47.5,27.8.

By above-mentioned product IV-aa(209mg, 0.5mmol) be dissolved in MeOH(20mL) in, add successively 10%Pd/C(20mg) and concentrated hydrochloric acid (1mL), the air of rushing in reaction flask with nitrogen, then use hydrogen exchange nitrogen three times, after stirring 12h, TLC shows completely dissolve of raw material, and has generated the product of large polarity.The hydrogen of rushing in reaction flask with nitrogen, remove by filter catalyzer 10%Pd/C, filtrate is concentrated under vacuum condition, and silicagel column separates (ethyl acetate: methyl alcohol 1:10, v/v), obtain colorless oil product (1R, 6S, 7S, 7aS)-6,7-dihydroxyl-1 (1H)-phenyl-Pyrrolizidine-3 (2H)-one I-1, be total to 110mg, yield: 94.0%.The structural confirmation data of I-1: ¹hNMR(D ₂o, 300MHz) δ 7.47-7.35(m, 3H), 7.19(d, J=6.9Hz, 2H) and, 4.33(q, J=7.2Hz, 1H), 4.25(t, J=7.8Hz, 1H) and, 3.94(t, J=7.8Hz, 1H), 3.64-3.58(m, 1H) and, 3.28(dd, J ₁=8.4Hz, J ₂=17.2Hz, 1H), 3.20-3.10(m, 2H), 2.62(d, J=17.2Hz, 1H); ¹³cNMR(D ₂o, 75MHz) δ 176.0,139.5,128.9,127.5,127.4,77.3,74.5,67.8,48.8,46.0,40.2.

By above-mentioned product VI-aa(375mg, 0.938mmol) be dissolved in MeOH(20mL) in, add successively 10%Pd/C(20mg) and concentrated hydrochloric acid (1mL), the air of rushing in reaction flask with nitrogen, then use hydrogen exchange nitrogen three times, after stirring 12h, TLC shows completely dissolve of raw material, and has generated the product of large polarity.The hydrogen of rushing in reaction flask with nitrogen, remove by filter catalyzer 10%Pd/C, and filtrate is concentrated under vacuum condition, crude product is dissolved in methyl alcohol again, and neutralizes with strong aqua, and excess of ammonia water is removed through concentrated, triplicate like this, product is crossed storng-acid cation exchange resin (ammonia soln of 1mol/L is eluent), obtains colorless oil (1S, 2S, 7R, 7aS)-7-phenyl-1-hydrogen-Pyrrolizidine-1,2-glycol I-2, be total to 0.20g, yield 97.1%.I-2 structural confirmation data: ¹hNMR(D ₂o, 300MHz) δ 7.46-7.40(m, 4H), 7.37-7.31(m, 1H), 4.05-3.97(m, 1H), 3.67-3.59(m, 1H), 3.57-3.52(m, 1H), 3.49-3.44(m, 1H), 3.38-3.32(m, 1H), 3.04-2.89(m, 2H), 2.60(t, J=9.6Hz, 1H), 2.37-2.22(m, 1H), 2.01-1.92(m, 1H); ¹³cNMR(D ₂o, 75MHz) δ 138.2,128.6,128.4,126.9,76.5,75.3,69.8,56.8,53.5,46.4,26.4.

Embodiment 2: (1R, 6S, the 7S shown in synthesis type (I-3), 7aS)-6,7-dihydroxyl-1 (1H)-p-methoxyphenyl Pyrrolizidine-3 (2H)-one and (I-4) shown in (1S, 2S, 7R, 7aS)-7-p-methoxyphenyl-1-hydrogen-Pyrrolizidine-1, the 2-glycol

Add azepine Cabbeen A(0.227g in the round-bottomed flask of oven drying, 0.86mmol) and nitrone II-a(2.58g, 8.68mmol), add the methylene dichloride of 15mL drying, ice-water bath is cooling, then add successively (E)-3-p-methoxyphenyl propenal (0.69g, 4.28mmol) and 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (0.14mL, 0.936mmol), ice-water bath stirs 0.5 hour, rises to room temperature reaction, the TLC monitoring reaction.When the olefine aldehydr raw material reaction is complete, add the methanol solution (1.0M) of 4.3mL sodium methylate, stirring at room half an hour.Add the 5mL ether, silicagel column filters, be spin-dried for the quick post of silica gel and separate (ethyl acetate: sherwood oil=1:6, v/v), obtain (R)-3-[(2S, 3S, 4S)-3,4-bis-(benzyloxy)-1-hydroxyl-2-Pyrrolizidine base]-3-p-methoxyphenyl-methyl propionate IV-ab(1.92g), product is colorless oil, productive rate 90.8%.IV-ab structural identification data: ¹hNMR(300MHz, CDCl ₃) δ 7.28-7.23(m, 5H), 7.16-7.14(m, 3H), 7.06(d, J=8.7Hz, 2H), 6.86-6.83(m, 2H), 6.73(d, J=8.7Hz, 2H), 5.47(s, 1H), 4.46(d, J=12.0Hz, 1H), 4.33(d, J=12.0Hz, 1H), 4.08(d, J=11.4Hz, 1H), 3.97(d, J=11.4Hz, 1H), 3.77(d, J=5.1Hz, 1H), 3.67-3.66(m, 4H), 3.58(d, J=5.7Hz, 1H), 3.52(s, 3H), 3.29(d, J=10.8Hz, 1H), 3.01-2.91(m, 2H), 2.89-2.81(m, 1H), 2.57(dd, J ₁=6.6Hz, J ₂=15.9Hz, 1H), ¹³cNMR(75MHz, CDCl ₃) δ 174.4,158.4,138.0,137.6,133.0,129.0,128.5,128.3,127.84,127.80,127.79,127.71,113.9,83.7,79.3,77.4,71.4,71.0,59.9,55.2,51.9,40.4,35.4.

Zinc powder (1.19g, 18.2mmol) and a water acetic acid copper (40mg, 0.20mmol) of activation are joined in 15mL acetic acid, stirring at room 5 minutes, then add above-mentioned IV-ab(0.891g, 1.81mmol) the 5mL acetum, 50 ℃ the heating 4 hours, TLC shows raw material reaction, diatomite filtration, be spin-dried for, methylene dichloride/saturated sodium bicarbonate aqueous solution extraction, drying, be directly used in next step reaction.Above-mentioned thick product is dissolved in methyl alcohol, add salt of wormwood (0.50g), 50 ℃ are heated approximately 3 hours, TLC shows that raw material reaction is complete, and diatomite filtration, be spin-dried for, silicagel column separates (ethyl acetate: sherwood oil 1:5, v/v), obtains colorless oil (1R, 6S, 7S, 7aS)-6,7-bis-(benzyloxy)-1-p-methoxyphenyl-Pyrrolizidine 3 (2H)-one V-ab, be total to 684mg, productive rate 85.2%.V-ab structural identification data: ¹hNMR(300MHz, CDCl ₃) δ 7.31-7.13(m, 10H), 7.02(d, J=8.7Hz, 2H), 6.75(d, J=8.7Hz, 2H), 4.35(t, J=11.4Hz, 2H), 4.26(d, J=11.7Hz, 1H), 4.17-4.10(m, 3H), 3.77-3.71(m, 4H), 3.67(d, J=4.2Hz, 1H), 3.40-3.32(m, 2H), 3.05(dd, J ₁=9.0Hz, J ₂=16.9Hz, 1H), 2.55(dd, J ₁=2.7Hz, J ₂=16.9Hz, 1H); ¹³cNMR(75MHz, CDCl ₃) δ 174.3,158.6,137.6,137.3,132.1,128.9,128.4,128.3,127.8,127.77,127.74,127.72,114.0,84.7,81.7,72.2,71.5,68.7,55.1,46.3,40.6,39.9.

By above-mentioned product V-ab(0.320g, 0.721mmol) be dissolved in anhydrous tetrahydro furan (15mL), add lithium aluminum hydride (0.13g, 3.42mmol), 50 ℃ are heated 3 hours, TLC shows that raw material reaction is complete, add successively 0.13mL water, 0.26mL10% aqueous sodium hydroxide solution and 0.39mL water also stir half hour, diatomite filtration, the ethyl acetate extraction, dry, post separates (ethyl acetate: sherwood oil 1:3, v/v) obtain (1S of colorless oil, 2S, 7R, 7aS)-1, 2-benzyloxy-7-p-methoxyphenyl-1H-Pyrrolizidine VI-ab, be total to 310mg, productive rate: 99.9%.The structural confirmation data of VI-ab: ¹hNMR(CDCl ₃, 300MHz) δ 7.32-7.19(m, 10H), 7.00-6.97(m, 2H), 6.84(d, J=8.7Hz, 2H), 4.45(s, 2H), 4.15(d, J=11.1Hz, 1H), 4.05-4.00(m, 1H), 3.81-3.77(s, 4H), 3.63-3.59(m, 2H), 3.50(t, J=4.5Hz, 1H), 3.35(dd, J ₁=5.4Hz, J ₂=11.4Hz, 1H), 3.15-3.08(m, 1H), 2.95-2.83(m, 2H) and, 2.23-2.09(m, 1H), 1.93-1.87(m, 1H); ¹³cNMR(CDCl ₃, 75MHz) δ 158.2,138.3, and 138.2,132.1,129.2,128.5,128.2,127.8,127.7,127.6,127.4,113.7,85.0,84.7,73.0,71.9,71.8,58.2,55.3,54.7,46.6,28.1.

By above-mentioned product V-ab(110mg, 0.266mmol) be dissolved in MeOH(10mL) in, add successively 10%Pd/C(20mg) and concentrated hydrochloric acid (1mL), the air of rushing in reaction flask with nitrogen, then use hydrogen exchange nitrogen three times, stirring is spent the night, and TLC shows completely dissolve of raw material, and has generated the product of large polarity.Diatomite filtration is removed catalyzer 10%Pd/C, filtrate is concentrated under vacuum condition, silicagel column separates (ethyl acetate: methyl alcohol 1:10, v/v), obtains colorless oil product (1R, 6S, 7S, 7aS)-6,7-dihydroxyl-1 (1H)-p-methoxyphenyl Pyrrolizidine-3 (2H)-one I-3, be total to 70mg, yield: 99.9%.The structural confirmation data of I-3: ¹hNMR(D ₂o, 300MHz) δ 7.04(d, J=8.7Hz, 2H), 6.94(d, J=8.7Hz, 2H) and, 4.26(q, J=7.2Hz, 1H), 4.14(t, J=7.8Hz, 1H) and, 3.83-3.78(m, 1H), 3.76(s, 3H) and, 3.57-3.48(m, 1H), 3.19(dd, J ₁=8.4Hz, J ₂=17.1Hz, 1H), 3.11-3.03(m, 2H), 2.49(dd, J ₁=0.9Hz, J ₂=17.1Hz, 1H); ¹³cNMR(D ₂o, 75MHz) δ 176.3,158.0,132.2,128.7,114.3,77.3,74.5,68.0,55.2,46.0,40.4,39.6.

By above-mentioned product VI-ab(226mg, 0.938mmol) be dissolved in MeOH(20mL) in, add successively 10%Pd/C(25mg) and concentrated hydrochloric acid (1mL), the air of rushing in reaction flask with nitrogen, then use hydrogen exchange nitrogen three times, after stirring 12h, TLC shows completely dissolve of raw material, and has generated the product of large polarity.Diatomite filtration is removed catalyzer 10%Pd/C, and filtrate is concentrated under vacuum condition, and crude product is dissolved in methyl alcohol again, and neutralize with strong aqua, excess of ammonia water is removed through concentrated, triplicate like this, and product is crossed storng-acid cation exchange resin (ammonia soln of 6mol/L is eluent), obtain colorless oil (1S, 2S, 7R, 7aS)-7-p-methoxyphenyl-1H-Pyrrolizidine-1,2-glycol I-4(0.127g), yield 96.9%.I-4 structural confirmation data: ¹hNMR(D ₂o, 300MHz) δ 7.22(d, J=8.4Hz, 2H), 6.90(d, J=8.4Hz, 2H), 4.00-3.93(m, 1H), 3.74(s, 3H), 3.47-3.40(m, 2H), 3.38-3.34(m, 1H), 3.32-3.22(m, 1H), 2.87-2.75(m, 2H), 2.49(t, J=9.6Hz, 1H), 2.16-2.04(m, 1H), 1.85-1.75(m, 1H); ¹³cNMR(D ₂o, 75MHz) δ 157.5,130.9,129.4,113.8,76.7,75.5,69.9,57.0,55.2,53.4,45.7,26.8.

Embodiment 3: (1S, 6S, the 7S shown in synthesis type (I-5), 7aS)-6, western pyridine-3 (2H)-alkane ketone in 7-dihydroxyl-1 (1H)-propyl pyrrole, (1S shown in (I-6), 2S, 7R, 7aS)-7-propyl group-1-hydrogen-Pyrrolizidine-1, the 2-glycol and (I-7) shown in (1R, 6S, 7S, 7aS)-6,7-dihydroxyl-1-allyl group-1H-Pyrrolizidine-3 (2H)-one

Add azepine Cabbeen A(0.240g in the round-bottomed flask of oven drying, 0.909mmol) and nitrone II-a(2.694g, 9.06mmol), add the methylene dichloride of 15mL drying, ice-water bath is cooling, then add successively (E)-3-allyl group-propenal (0.50mL, 4.53mmol) and 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (0.15mL, 1.00mmol), ice-water bath stirs 0.5 hour, rises to room temperature reaction, the TLC monitoring reaction.When the olefine aldehydr raw material reaction is complete, add the methanol solution (1.0M) of 4.55mL sodium methylate, stirring at room half an hour.Add the 5mL ether, filtered through silica gel, be spin-dried for, the quick post of silica gel separates (ethyl acetate: sherwood oil=1:6, v/v), obtain (R)-3-[(2S, 3S, 4S)-3,4-bis-(benzyloxy)-1-hydroxyl-2-Pyrrolizidine base]-3-allyl group-methyl propionate IV-ac(1.28g), product is colorless oil, productive rate 66.5%.IV-ac structural identification data: ¹hNMR(300MHz, CDCl ₃) δ 7.36-7.27(m, 10H), 5.85(s, 1H), 5.52-5.35(m, 2H), 4.56-4.38(m, 4H), 3.90(d, J=5.8Hz, 1H), 3.68(d, J=6.6Hz, 1H), 3.62(s, 3H), 3.38(d, J=10.7Hz, 1H), 3.08-3.00(m, 2H), 2.90-2.86(m, 1H), 2.59(dd, J ₁=6.9Hz, J ₂=15.3Hz, 1H), 2.31(dd, J ₁=7.2Hz, J ₂=15.6Hz, 1H), 1.63(d, J=5.7Hz, 3H); ¹³cNMR(75MHz, CDCl ₃) δ 174.4,137.9,137.7,130.6,128.5,128.4,127.9,127.9,127.8,126.8,83.4,79.4,75.5,71.6,71.0,60.4,51.7,39.4,35.7,18.1.

Zinc powder (0.874g, 13.37mmol) and a water acetic acid copper (27mg, 0.135mmol) of activation are joined in 15mL acetic acid, stirring at room 5 minutes, then add above-mentioned IV-ac(0.569g, 1.337mmol) the 5mL acetum, 50 ℃ the heating 4 hours, TLC shows raw material reaction, diatomite filtration, be spin-dried for, methylene dichloride/saturated sodium bicarbonate aqueous solution extraction, drying, be directly used in next step reaction.Above-mentioned thick product is dissolved in methyl alcohol, add salt of wormwood (0.37g), 50 ℃ are heated approximately 3 hours, TLC shows that raw material reaction is complete, and diatomite filtration, be spin-dried for, silicagel column separates (ethyl acetate: sherwood oil 1:5, v/v), obtains colorless oil (1R, 6S, 7S, 7aS)-6,7-bis-(benzyloxy)-1-allyl group Pyrrolizidine-3 (2H)-one V-ac, be total to 403mg, productive rate 79.8%.V-ac structural identification data: ¹hNMR(300MHz, CDCl ₃) δ 7.37-7.29(m, 10H), 5.53-5.30(m, 2H), 4.58-4.43(m, 4H), 4.18-4.15(m, 1H) and, 3.97-3.91(m, 2H), 3.78(dd, J ₁=3.0Hz, J ₂=12.3Hz, 1H), 3.28(dd, J ₁=6.0Hz, J ₂=12.3Hz, 1H), 3.16-3.06(m, 1H), 2.86-2.78(m, 1H) and, 2.16(dd, J ₁=1.6Hz, J ₂=16.5Hz, 1H), 1.58(d, J=6.0Hz, 3H); ¹³cNMR(75MHz, CDCl ₃) δ 174.4,137.7,137.4,129.6,128.5,128.4,127.9,127.8,127.7,127.5,84.3,81.7,72.0,71.5,68.3,46.3,40.1,39.0,17.8.

By above-mentioned product V-ac(0.195g, 0.517mmol) be dissolved in anhydrous tetrahydro furan (10mL), add lithium aluminum hydride (0.098g, 2.58mmol), 50 ℃ are heated 3 hours, TLC shows that raw material reaction is complete, add successively 0.10mL water, 0.20mL10% aqueous sodium hydroxide solution and 0.30mL water, stir half hour, diatomite filtration, the ethyl acetate extraction, dry, post separates (ethyl acetate: sherwood oil 1:3, v/v) obtain (1S of colorless oil, 2S, 7R, 7aS)-1, 2-benzyloxy-7-allyl group-1H-Pyrrolizidine VI-ac(160mg), productive rate: 85.1%.The structural confirmation data of VI-ac: ¹hNMR(CDCl ₃, 300MHz) δ 7.37-7.25(m, 10H), 5.56-5.42(m, 2H), 4.63-4.49(m, 4H), 4.19-4.13(m, 1H), 3.92-3.85(m, 1H), 3.51-3.46(m, 1H), 3.42-3.37(m, 1H), 3.09-3.03(m, 1H), 2.89-2.86(m, 1H), 2.79-2.70(m, 2H), 1.80-1.74(m, 2H), 1.65(d, J=6.3Hz, 3H); ¹³cNMR(CDCl ₃, 75MHz) δ 138.4,138.2, and 130.6,128.57,128.45,128.40,127.9,127.88,127.78,127.73,126.7,84.9,83.5,72.3,72.0,71.8,57.8,54.1,44.9,30.7,18.2.

By above-mentioned product V-ac(110mg, 0.29mmol) be dissolved in methyl alcohol (10mL), add successively 10%Pd/C(20mg) and concentrated hydrochloric acid (1mL), the air of rushing in reaction flask with nitrogen, then use hydrogen exchange nitrogen three times, stirring is spent the night, and TLC shows completely dissolve of raw material, and has generated the product of large polarity.Diatomite filtration is removed catalyzer 10%Pd/C, filtrate is concentrated under vacuum condition, silicagel column separates (ethyl acetate: methyl alcohol 1:10, v/v), obtains colorless oil product (1S, 6S, 7S, 7aS)-6, western pyridine-3 (2H)-one I-5 in 7-dihydroxyl-1 (1H)-propyl pyrrole, be total to 57mg, yield: 99.9%.The structural confirmation data of I-5: ¹hNMR(D ₂o, 300MHz) δ 4.41-4.34(m, 1H), 3.98-3.96(m, 2H) and, 3.61-3.54(m, 1H), 3.25(dd, J ₁=6.0Hz, J ₂=12.0Hz, 1H), 2.86(dd, J ₁=8.4Hz, J ₂=17.1Hz, 1H), 2.63-2.61(m, 1H), 2.22(dd, J ₁=5.7Hz, J ₂=17.1Hz, 1H), 1.56-1.26(m, 4H), 0.92(t, J=7.2Hz, 3H); ¹³cNMR(D ₂o, 75MHz) δ 177.2,77.5,74.1,67.2,46.3,38.6,33.2,31.5,19.8,13.2177.2,77.5,74.1,67.2,46.3,38.6,33.2,31.5,19.8,13.2.

By above-mentioned product VI-ac(100mg, 0.275mmol) be dissolved in MeOH(10mL) in, add successively 10%Pd/C(20mg) and concentrated hydrochloric acid (1mL), the air of rushing in reaction flask with nitrogen, then use hydrogen exchange nitrogen three times, after stirring 12h, TLC shows completely dissolve of raw material, and has generated the product of large polarity.Diatomite filtration is removed catalyzer 10%Pd/C, and filtrate is concentrated under vacuum condition, and crude product is dissolved in methyl alcohol again, and neutralize with strong aqua, excess of ammonia water is removed through concentrated, so triplicate, product is crossed storng-acid cation exchange resin (ammonia soln of 6mol/L is eluent), obtain colorless oil (1S, 2S, 7R, 7aS)-7-propyl group-1H-Pyrrolizidine-1,2-glycol I-6, be total to 55mg, yield 96.9%.I-6 structural confirmation data: ¹hNMR(D ₂o, 300MHz) δ 4.16-4.09(m, 1H), 3.98(t, J=7.5Hz, 1H), 3.64-3.53(m, 2H), 3.17-3.07(m, 1H), 3.02-2.96(m, 1H), 2.76-2.70(m, 1H), 2.37-2.26(m, 1H), 2.04-1.92(m, 1H), 1.77-1.42(m, 5H), 0.93(t, J=7.2Hz, 3H); ¹³cNMR(D ₂o, 75MHz) δ 75.0,74.6,70.1,56.7,54.6,40.6,30.4,28.3,21.3,13.4.

By above-mentioned product VI-ac(36mg, 0.095mmol) be dissolved in methylene dichloride (10mL), argon shield, ice-water bath is cooled to 0 ℃, then add boron tribromide (0.037mL), 0 ℃ is reacted half an hour, add 3mL methyl alcohol cancellation reaction, revolve desolventizing, add again 3mL methyl alcohol concentrated removing, triplicate like this, crude product is dissolved in methyl alcohol again, and neutralize with strong aqua, excess of ammonia water is removed through concentrated, triplicate like this, product is crossed storng-acid cation exchange resin (ammonia soln of 6mol/L is eluent), obtain colorless oil (1R, 6S, 7S, 7aS)-6, 7-dihydroxyl-1-allyl group-1H-Pyrrolizidine-3 (2H)-diketone I-7, be total to 18mg, yield 95.7%.I-7 structural confirmation data: ¹hNMR(D ₂o, 300MHz) δ 5.65-5.58(m, 1H), 5.50-5.42(m, 1H) and, 4.35-4.31(m, 1H), 3.99-3.88(m, 2H) and, 3.54-3.47(m, 1H), 3.26-3.20(m, 2H) and, 2.96(dd, J ₁=7.5Hz, J ₂=17.1Hz, 1H), 2.24-2.19(m, 1H), 1.67-1.65(m, 3H); ¹³cNMR(D ₂o, 75MHz) δ 176.5,128.6,128.0,127.6,77.6,74.5,68.0,46.5,39.6,37.6,17.1.

Embodiment 4: (1S, 2S, 3S, 7R, the 7aS)-3-methylol shown in synthesis type (I-9)-7-phenyl-1-hydrogen-Pyrrolizidine-1,2-glycol

Add azepine Cabbeen A(0.252g in the round-bottomed flask of oven drying, 1.0mmol) and nitrone II-b(4.00g, 9.58mmol), add the methylene dichloride of 15mL drying, ice-water bath is cooling, then add successively (E)-3-phenyl-propenal (0.60mL, 4.77mmol) and 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (0.15mL, 1.00mmol), ice-water bath stirs 0.5 hour, rises to room temperature reaction, the TLC monitoring reaction.When the olefine aldehydr raw material reaction is complete, add the methanol solution (1.0M) of 4.55mL sodium methylate, stirring at room half an hour.Add the 5mL ether, filtered through silica gel, be spin-dried for, and the quick post of silica gel separates (ethyl acetate: sherwood oil=1:6, v/v), obtain (R)-3-[(2S, 3S, 4S, 5S)-3,4-bis-(benzyloxy)-5-benzyloxymethyl 1-hydroxyl-2-Pyrrolizidine base]-3-phenylpropionic acid methyl esters IV-ba(2.18g), product is colorless oil, productive rate 78.4%.IV-ba structural identification data: ¹hNMR(300MHz, CDCl ₃) δ 7.32-7.16(m, 18H), 6.88-6.85(m, 2H), 5.57(s, 1H), 4.59(d, J=12.0Hz, 1H) and, 4.52-4.39(m, 3H), 4.07(t, J=11.1Hz, 2H) and, 3.99-3.96(m, 1H), 3.89(dd, J ₁=3.6Hz, J ₂=8.4Hz, 1H), 3.80-3.73(m, 2H), 3.63-3.52(m, 5H) and, 3.40(t, J=6.0Hz, 1H), 2.97(dd, J ₁=8.4Hz, J ₂=15.9Hz, 1H), 2.62(dd, J ₁=6.0Hz, J ₂=15.9Hz, 1H); ¹³cNMR(75MHz, CDCl ₃) δ 174.3,141.2,138.3,138.1,137.7,128.5,128.3,128.2,128.1,127.7,127.69,127.6,127.5,126.7,83.8,82.7,74.3,73.3,71.3,71.2,68.2,66.1,51.7,41.5,35.2.

Zinc powder (1.20g, 18.4mmol) and a water acetic acid copper (37mg, 0.20mmol) of activation are joined in 15mL acetic acid, stirring at room 5 minutes, then add above-mentioned IV-ba(1.06g, 1.83mmol) the 5mL acetum, 50 ℃ the heating 4 hours, TLC shows raw material reaction, diatomite filtration, be spin-dried for, methylene dichloride/saturated sodium bicarbonate aqueous solution extraction, drying, be directly used in next step reaction.Above-mentioned thick product is dissolved in methyl alcohol, add salt of wormwood (0.51g), 50 ℃ are heated approximately 3 hours, TLC shows that raw material reaction is complete, and diatomite filtration, be spin-dried for, silicagel column separates (ethyl acetate: sherwood oil 1:5, v/v), obtains colorless oil (1R, 5S, 6S, 7S, 7aS)-6, western pyridine-3 (2H)-one V-ba in 7-bis-(benzyloxy)-5-benzyloxymethyl-1-phenylpyrrole, be total to 890mg, productive rate 90.0%.V-ba structural identification data: ¹hNMR(300MHz, CDCl ₃) δ 7.32-7.24(m, 14H), 7.18-7.14(m, 4H), 7.07-7.04(m, 2H), 4.58-4.33(m, 4H), 4.29-4.18(m, 3H), 4.08(q, J=4.5Hz, 1H) and, 3.89(d, J=11.1Hz, 1H), 3.80-3.67(m, 2H), 3.56(dd, J ₁=4.2Hz, J ₂=9.6Hz, 1H), 3.38(dd, J ₁=5.4Hz, J ₂=8.1Hz, 1H), 3.07(dd, J ₁=9.0Hz, J ₂=17.1Hz, 1H), 2.60(dd, J ₁=2.7Hz, J ₂=17.1Hz, 1H); ¹³cNMR(75MHz, CDCl ₃) δ 174.0,140.1,137.9,137.7,137.6,128.8,128.4,128.36,128.32,128.0,127.9,127.8,127.7,127.4,87.7,83.0,73.3,72.3,72.2,69.0,67.4,58.9,40.26,40.24.

By above-mentioned product V-ac(0.25g, 0.47mmol) be dissolved in anhydrous tetrahydro furan (10mL), add lithium aluminum hydride (0.090g, 2.4mmol), 50 ℃ are heated 3 hours, TLC shows that raw material reaction is complete, add successively 0.10mL water, 0.20mL10% aqueous sodium hydroxide solution and 0.30mL water, stir half hour, diatomite filtration, the ethyl acetate extraction, dry, post separates (ethyl acetate: sherwood oil 1:3, v/v) obtain (1S of colorless oil, 2S, 3S, 7R, 7aS)-1, 2-benzyloxy-3-benzyloxymethyl-7-phenyl-1H-Pyrrolizidine VI-ba, be total to 230mg, productive rate: 89.8%.The structural confirmation data of VI-ba: ¹hNMR(CDCl ₃, 300MHz) δ 7.33-6.92(m, 20H), 4.60-4.48(m, 4H), 4.08-3.96(m, 2H), 3.74(t, J=7.5Hz, 1H), 3.66-3.46(m, 5H), 3.19-3.00(m, 3H), 2.22-2.03(m, 1H), 1.93-1.86(m, 1H); ¹³cNMR(CDCl ₃, 75MHz) δ 139.8,138.5, and 138.4,138.3,128.6,128.44,128.39,128.2,127.8,127.7,127.6,127.4,126.6,86.1,84.9,73.5,72.8,72.0,70.9,69.0,54.6,47.7,27.9.

By above-mentioned product VI-ba(50mg, 0.096mmol) be dissolved in methyl alcohol (10mL), add successively 10%Pd/C(20mg) and concentrated hydrochloric acid (1mL), the air of rushing in reaction flask with nitrogen, then use hydrogen exchange nitrogen three times, after stirring 12h, TLC shows completely dissolve of raw material, and has generated the product of large polarity.Diatomite filtration is removed catalyzer 10%Pd/C, and filtrate is concentrated under vacuum condition, and crude product is dissolved in methyl alcohol again, and neutralize with strong aqua, excess of ammonia water is removed through concentrated, so triplicate, product is crossed storng-acid cation exchange resin (ammonia soln of 6mol/L is eluent), obtains colorless oil (1S, 2S, 3S, 7R, 7aS)-3-methylol-7-phenyl-1H-Pyrrolizidine-1,2-glycol I-9, be total to 22mg, yield 91.7%.I-9 structural confirmation data: ¹hNMR(D ₂o, 300MHz) δ 7.44-7.43(m, 4H), 7.38-7.34(m, 1H) and, 3.86(dd, J ₁=3.3Hz, J ₂=12.0Hz, 1H), 3.78-3.57(m, 5H), 3.16-3.11(m, 2H) and, 2.93-2.87(m, 1H), 2.41-2.27(m, 1H) and, 2.09-2.01(m, 1H); ¹³cNMR(D ₂o, 75MHz) δ 137.0,128.6,128.5,127.1,75.4,74.9,68.5,68.4,61.2,53.7,45.9,26.3.

Embodiment 5: (1S, 6R, 7R, 8R, the 8aR)-6,7 shown in synthesis type (I-28), western pyridine-3 (2H)-one in 8-trihydroxy--1-Phenylindole

Add azepine Cabbeen A(0.227g in the round-bottomed flask of oven drying, 0.860mmol) and nitrone II-e(3.60g, 8.60mmol), add the methylene dichloride of 15mL drying, ice-water bath is cooling, then add successively (E)-3-phenyl-propenal (0.50mL, 3.97mmol) and 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (0.13mL, 0.869mmol), ice-water bath stirs 0.5 hour, rises to room temperature reaction, the TLC monitoring reaction.When the olefine aldehydr raw material reaction is complete, add the methanol solution (1.0M) of 4mL sodium methylate, stirring at room half an hour.Add the 5mL ether, filtered through silica gel, be spin-dried for, the quick post of silica gel separates (ethyl acetate: sherwood oil=1:6, v/v), obtain (S)-3-[(2R, 3R, 4R, 5R)-3,4,5-tri-(benzyloxy)-1-hydroxyl-2-pyridyl]-3-phenyl-methyl propionate IV-ea(1.50g), product is colorless oil, productive rate 63.8%.IV-ea structural identification data: ¹hNMR(300MHz, CDCl ₃) δ 7.35-7.19(m, 18H), 6.83-6.82(m, 2H), 5.41(s, 1H), 4.69-4.46(m, 4H) and, 3.90-3.77(m, 5H), 3.66(dd, J ₁=4.2Hz, J ₂=8.7Hz, 1H), 3.59(s, 3H), 3.53(d, J=4.5Hz, 1H) and, 3.43-3.37(m, 1H), 3.22(t, J=5.1Hz, 1H) and, 2.88(dd, J ₁=9.0Hz, J ₂=15.9Hz, 1H), 2.59(dd, J ₁=5.1Hz, J ₂=15.9Hz, 1H); ¹³cNMR(75MHz, CDCl ₃) δ 174.7,141.0,138.5,138.4,137.6,128.6,128.48,128.47,128.3,128.2,127.9,127.8,127.72,127.69,127.6,126.8,81.9,79.2,78.0,73.6,72.0,71.2,68.0,67.3,51.8,41.0,34.7.

Zinc powder (1.30g, 19.8mmol) and a water acetic acid copper (33mg, 0.165mmol) of activation are joined in 15mL acetic acid, stirring at room 5 minutes, then add above-mentioned IV-ea(1.157g, 1.9mmol) the 5mL acetum, 50 ℃ the heating 4 hours, TLC shows raw material reaction, diatomite filtration, be spin-dried for, methylene dichloride/saturated sodium bicarbonate aqueous solution extraction, drying, be directly used in next step reaction.Above-mentioned thick product is dissolved in methyl alcohol, add salt of wormwood (0.55g), 50 ℃ are heated approximately 3 hours, TLC shows that raw material reaction is complete, and diatomite filtration, be spin-dried for, silicagel column separates (ethyl acetate: sherwood oil 1:5, v/v), obtains colorless oil (1S, 6R, 7R, 8R, 8aR)-6,7, western pyridine-3 (2H)-one V-ea in 8-tri-(benzyloxy)-1-phenyl-indole, be total to 0.80g, productive rate 75.4%.V-ea structural identification data: ¹hNMR(300MHz, CDCl ₃) δ 7.37-7.11(m, 18H), 7.08-7.03(m, 2H), 4.54-4.40(m, 4H), 4.38(d, J=11.1Hz, 1H), 4.23(t, J=7.2Hz, 1H), 4.18-4.13(m, 1H), 4.10-4.02(m, 1H), 3.96-3.92(m, 1H), 3.78-3.75(m, 1H), 3.70(t, J=8.1Hz, 1H), 3.50(t, J=7.8Hz, 1H), 3.08(dd, J ₁=8.7Hz, J ₂=17.1Hz, 1H)), 2.61(d, J=17.1Hz, 1H); ¹³cNMR(75MHz, CDCl ₃) δ 172.9,140.4,138.5,138.2,137.8,128.5,128.4,128.0,127.9,127.8,127.5,127.3,86.0,79.3,73.4,73.2,72.7,66.5,64.2,55.5,42.1,40.8.

By above-mentioned product V-ea(102mg, 0.19mmol) be dissolved in methyl alcohol (10mL), add successively 10%Pd/C(20mg) and concentrated hydrochloric acid (1mL), the air of rushing in reaction flask with nitrogen, then use hydrogen exchange nitrogen three times, stirring is spent the night, and TLC shows completely dissolve of raw material, and has generated the product of large polarity.Diatomite filtration is removed catalyzer 10%Pd/C, and filtrate is concentrated under vacuum condition, and silicagel column separates (ethyl acetate: methyl alcohol 1:10, v/v), obtain colorless oil product (1S, 6R, 7R, 8R, 8aR)-6,7, western pyridine-3 (2H)-one I-28 in 8-trihydroxy--1-Phenylindole, be total to 43mg, yield: 90.0%.The structural confirmation data of I-28: ¹hNMR(D ₂o, 300MHz) δ 7.46-7.38(m, 3H), 7.27(d, J=6.9Hz, 2H) and, 4.37(t, J=8.4Hz, 1H), 4.21-4.18(m, 1H) and, 4.03(dd, J ₁=3.6Hz, J ₂=12.3Hz, 1H), 3.92-3.87(m, 2H), 3.74(dd, J ₁=3.0Hz, J ₂=12.3Hz, 1H), 3.30(dd, J ₁=7.8Hz, J ₂=17.1Hz, 1H), 3.14(t, J=8.7Hz, 1H), 2.70(d, J=17.4Hz, 1H); ¹³cNMR(D ₂o, 75MHz) δ 175.7,139.3,128.7,128.0,127.5,78.1,72.4,66.3,56.8,56.7,41.0,40.0.

Embodiment 6: (1S, 6R, 7R, 8R, 9R, the 9aS)-6,7,8 shown in synthesis type (I-30), 9-tetrahydroxy-1 (1H)-phenyl-six hydrogen-3 (2H)-pyrrolo-[1,2-a] azepan ketone

Add azepine Cabbeen A(0.150g in the round-bottomed flask of oven drying, 0.60mmol) and nitrone II-e(2.99g, 5.56mmol), add the methylene dichloride of 10mL drying, ice-water bath is cooling, then add successively (E)-3-phenyl-propenal (0.35mL, 2.78mmol) and 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (0.09mL, 0.60mmol), ice-water bath stirs 0.5 hour, rises to room temperature reaction, the TLC monitoring reaction.When the olefine aldehydr raw material reaction is complete, add the methanol solution (1.0M) of 3.1mL sodium methylate, stirring at room half an hour.Add the 5mL ether, filtered through silica gel, be spin-dried for, the quick post of silica gel separates (ethyl acetate: sherwood oil=1:6, v/v), obtain (S)-3-[(2R, 3R, 4R, 5R, 6R)-3,4,5,6-tetra-(benzyloxy)-1-hydroxyl-2-azepan base]-3-phenyl-methyl propionate IV-fa(1.50g), product is colorless oil, productive rate 81.0%.IV-fa structural identification data: ¹hNMR(300MHz, CDCl ₃) δ 7.36-7.20(m, 20H), 7.04-7.03(m, 5H), 4.76-4.58(m, 4H), 4.49-4.42(m, 1H), 4.31-4.29(m, 3H), 3.95-3.75(m, 5H), 3.68(m, 1H), 3.40(d, J=14.5Hz, 1H), 3.26(m, 1H), 3.11-3.03(m, 1H), 2.49(dd, J ₁=2.7Hz, J ₂=14.7Hz, 1H); ¹³cNMR(75MHz, CDCl ₃) δ 174.9,143.2,138.8138.42,138.40,137.4,128.8,128.5,128.38,128.36,127.95,127.92,127.90,127.8,127.74,127.70,127.6,127.1,78.2,77.4,76.0,73.7,73.4,72.5,72.3,71.5,52.4,42.3,36.0.

Zinc powder (0.558g, 8.53mmol) and a water acetic acid copper (18mg, 0.1mmol) of activation are joined in 15mL acetic acid, stirring at room 5 minutes, then add above-mentioned IV-fa(0.599g, 0.853mmol) the 5mL acetum, 50 ℃ the heating 4 hours, TLC shows raw material reaction, diatomite filtration, be spin-dried for, methylene dichloride/saturated sodium bicarbonate aqueous solution extraction, drying, be directly used in next step reaction.Above-mentioned thick product is dissolved in methyl alcohol, add salt of wormwood (0.24g), 50 ℃ are heated approximately 3 hours, and TLC shows that raw material reaction is complete, diatomite filtration, be spin-dried for, and silicagel column separates (ethyl acetate: sherwood oil 1:5, v/v), obtain colorless oil (1S, 6R, 7R, 8R, 9R, 9aR)-6,7,8,9-tetra-(benzyloxy)-1-phenyl-1H-pyrrolo-[1,2-a] azepan-3 (2H)-one V-fa, be total to 0.40g, productive rate 71.8%.V-fa structural identification data: ¹hNMR(300MHz, CDCl ₃) δ 7.50-7.19(m, 21H), 7.08-7.00(m, 4H), 4.80(d, J=12.3Hz, 1H), 4.73-4.63(m, 3H) and, 4.64-4.57(m, 2H), 4.50(d, J=12.0Hz, 1H) and, 4.37(d, J=12.0Hz, 1H), 4.24(dd, J ₁=6.9Hz, J ₂=14.1Hz, 1H), 4.04-3.96(m, 2H), 3.89-3.85(m, 2H) and, 3.67(d, J=3.3Hz, 1H), 3.04-2.91(m, 2H) and, 2.65(dd, J ₁=6.0Hz, J ₂=16.8Hz, 1H), 2.45(dd, J ₁=9.0Hz, J ₂=17.1Hz, 1H); ¹³cNMR(75MHz, CDCl ₃) δ 173.4,140.8,138.9,138.8,138.7,137.7,128.9,128.6,128.4,128.3,128.29,128.1,128.0,127.8,127.69,27.66,127.6,127.5,127.4,127.2,127.0,79.7,79.0,75.7,74.0,73.7,72.2,71.8,66.5,42.2,39.6,38.8.

By above-mentioned product V-fa(87mg, 0.133mmol) be dissolved in methyl alcohol (10mL), add successively 10%Pd/C(20mg) and concentrated hydrochloric acid (1mL), the air of rushing in reaction flask with nitrogen, then use hydrogen exchange nitrogen three times, stirring is spent the night, and TLC shows completely dissolve of raw material, and has generated the product of large polarity.Diatomite filtration is removed catalyzer 10%Pd/C, and filtrate is concentrated under vacuum condition, and silicagel column separates (ethyl acetate: methyl alcohol 1:10, v/v), obtain colorless oil product (1S, 6R, 7R, 8R, 9R, 9aS)-6,7,8,9-tetrahydroxy-1 (1H)-phenyl-six hydrogen-3 (2H)-pyrrolo-[1,2-a] azepan ketone I-30, be total to 37mg, yield: 94.9%.The structural confirmation data of I-30: ¹hNMR(D ₂o, 300MHz) δ 7.50-7.42(m, 5H), 4.20-4.17(m, 2H) and, 4.13-4.05(m, 2H), 4.03-3.98(m, 2H) and, 3.36(q, J=9.6Hz, 1H), 3.14(d, J=13.5Hz, 1H) and, 2.88(dd, J ₁=8.7Hz, J ₂=17.1Hz, 1H), 2.71(dd, J ₁=10.5Hz, J ₂=16.8Hz, 1H); ¹³cNMR(D ₂o, 75MHz) δ 176.9,139.5,129.1,128.0,127.7,72.6,70.9,69.7,68.3,42.4,42.2,38.5.

Embodiment 7: the compounds of this invention is tested the Glycosylase inhibition

1) test materials and source

Test compound: provided by the present invention and cyclo-imino sugar compounds.

Test materials: all 4-nitrophenol pyranoside matrix, disaccharides and Glycosylase (comprising alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase enzymes, alpha-Mannosidase, beta-Mannosidase, α, α-trehalase, alpha-L-fucosidase, alpha-L-Rhamnosidase or amyloglucosidase) are all purchased from Sigma-Aldrich.

2) test method

Dynamics research carries out in the 50mM Trisodium Citrate/phosphoric acid buffer of 37 ℃.According to the difference of matrix, the enzyme concn of preparation is 0.1-0.5mg/mL.It is matrix that active testing be take 4-nitrophenol pyranoside, under the optimum activity pH of every kind of enzyme, is tested.Enzyme solution and the inhibitor (poly-hydroxy Pyrrolizidine and Indolizidine alcaloid-derivatives (being above-mentioned I-1～I-7 and I-28)) of matrix, suitably dilution are cultivated 30 minutes under 37 ℃, then start reaction in ultraviolet-visible pectrophotometer, measure its absorption to the 400nm wavelength light.Finally use the GraFit program carry out data analysis [referring to Leatherbarrow, R.J.Grafit4.0; Erithacus Software:Staines, UK, 1998.].

3) evaluation result

Provided by the invention and cyclo-imino sugar compounds is as shown in table 1 to the active result of the inhibition of Glycosylase:

Table 1

Wherein ^a() is illustrated in the inhibiting rate of 1000 μ M, and non-parenthesis part means IC ₅₀.

Above bioassay result shows, provided by the invention and cyclo-imino sugar compounds all has certain biological activity to all kinds of Glycosylases, wherein, and to the IC of the beta-glucosidase that derives from beef liver ₅₀value: Compound I-2 are 806 μ M; I-4 is 549 μ M.

More than describe the preferred embodiment of the present invention in detail; but the present invention is not limited to the detail in above-mentioned embodiment, in technical conceive scope of the present invention; can carry out multiple simple variant to technical scheme of the present invention, these simple variant all belong to protection scope of the present invention.

Claims (13)

1. one kind and cyclo-imino sugar compounds, is characterized in that, the compound that also the cyclo-imino sugar compounds is structure shown in following formula IA or formula IB,

Wherein, R ¹for the alkyl of the carbonatoms straight or branched that is 1-12, the thiazolinyl of the straight or branched that carbonatoms is 2-12, any one in any substituted phenyl of the hydrogen atom on aromatic nucleus, furyl, pyrryl and indyl; R ⁵for hydrogen or methylol; N is 0,1 or 2.

2. according to claim 1 and cyclo-imino sugar compounds, wherein, R ¹alkyl for the carbonatoms straight or branched that is 3-12, the thiazolinyl of the straight or branched that carbonatoms is 3-6, phenyl, the alkyl that at least one hydrogen atom on phenyl ring is 1-3 by methoxyl group, hydroxyl, amino, halogen or carbonatoms replaces the phenyl obtained, furyl, any one in pyrryl and indyl.

3. according to claim 1 and 2 and cyclo-imino sugar compounds, wherein, R ¹for the alkyl of the carbonatoms straight or branched that is 3-6, propenyl, any one in phenyl and p-methoxyphenyl; R ⁵for hydrogen or methylol.

4. according to claim 1 and cyclo-imino sugar compounds, wherein, the compound of structure shown in described formula IA is any one in following formula (I-1), formula (I-3), formula (I-5), formula (I-7), formula (I-8), formula (I-10), formula (I-12), formula (I-14), formula (I-16), formula (I-18), formula (I-21), formula (I-23), formula (I-25), formula (I-28), formula (I-29) and formula (I-30); The compound of structure shown in described formula IB is any one in following formula (I-2), formula (I-4), formula (I-6), formula (I-9), formula (I-11), formula (I-13), formula (I-15), formula (I-17), formula (I-19), formula (I-20), formula (I-22), formula (I-24), formula (I-26) and formula (I-27);

5. the compound of structure shown in a formula IC,

Wherein, R ¹for the alkyl of the carbonatoms straight or branched that is 1-12, the thiazolinyl of the straight or branched that carbonatoms is 2-12, any one in any substituted phenyl of the hydrogen atom on aromatic nucleus, furyl, pyrryl and indyl; R ², R ³and R ⁴be selected from independently of one another any substituted benzyl of hydrogen atom on phenyl ring, any one in the alkoxyalkyl that the acyl group that carbonatoms is 1-10 and carbonatoms are 1-10; R ⁵for hydrogen, any one in any substituted benzyloxymethyl of the hydrogen atom on phenyl ring; N is 0,1 or 2;

Preferably, R ¹alkyl for the carbonatoms straight or branched that is 3-12, the thiazolinyl of the straight or branched that carbonatoms is 3-6, phenyl, the alkyl that at least one hydrogen atom on phenyl ring is 1-3 by methoxyl group, hydroxyl, amino, halogen or carbonatoms replaces the phenyl obtained, furyl, any one in pyrryl and indyl;

More preferably, R ², R ³and R ⁴be selected from independently of one another benzyl, the benzyl that the alkyl that alkoxyl group, halogen or the carbonatoms that at least one hydrogen atom on phenyl ring is 1-3 by carbonatoms is 1-3 replaces, ethanoyl, any one in benzoyl and methoxyl methyl;

Further preferably, R ⁵for hydrogen, any one in the benzyloxymethyl that the alkyl that alkoxyl group, halogen or the carbonatoms that the hydrogen atom on benzyloxymethyl and phenyl ring is 1-3 by hydroxyl, carbonatoms is 1-3 replaces.

6. the compound of structure shown in a formula ID,

Wherein, R ¹for the alkyl of the carbonatoms straight or branched that is 1-12, the thiazolinyl of the straight or branched that carbonatoms is 2-12, any one in any substituted phenyl of the hydrogen atom on aromatic nucleus, furyl, pyrryl and indyl; R ², R ³and R ⁴be selected from independently of one another any substituted benzyl of hydrogen atom on phenyl ring, any one in the alkoxyalkyl that the acyl group that carbonatoms is 1-10 and carbonatoms are 1-10; R ⁵for hydrogen, any one in any substituted benzyloxymethyl of the hydrogen atom on phenyl ring; N is 0,1 or 2;

Preferably, R ¹alkyl for the carbonatoms straight or branched that is 3-12, the thiazolinyl of the straight or branched that carbonatoms is 3-6, phenyl, the alkyl that at least one hydrogen atom on phenyl ring is 1-3 by methoxyl group, hydroxyl, amino, halogen or carbonatoms replaces the phenyl obtained, furyl, any one in pyrryl and indyl;

More preferably, R ², R ³and R ⁴be selected from independently of one another benzyl, the benzyl that the alkyl that alkoxyl group, halogen or the carbonatoms that at least one hydrogen atom on phenyl ring is 1-3 by carbonatoms is 1-3 replaces, ethanoyl, any one in benzoyl and methoxyl methyl;

Further preferably, R ⁵for hydrogen, any one in the benzyloxymethyl that the alkyl that alkoxyl group, halogen or the carbonatoms that the hydrogen atom on benzyloxymethyl and phenyl ring is 1-3 by hydroxyl, carbonatoms is 1-3 replaces.

7. the preparation method of the compound of structure shown in formula IC claimed in claim 5, is characterized in that, the method comprises:

1) by the nitrone of structure shown in formula II at the carbene catalyzed lower and general formula R of azepine ¹α shown in CH=CHCHO, beta-unsaturated aldehyde reaction, obtain the intermediate of structure shown in formula III, and under the alkali effect, the original position alcoholysis obtains the γ of structure shown in formula IV-Hydroxylamine HCL methyl esters subsequently;

2) by the γ of structure shown in formula IV-Hydroxylamine HCL methyl esters reduction, and then under the alkali effect acidylate;

Wherein, at described general formula R ¹cH=CHCHO and described formula II to formula IV, n, R ¹-R ⁵definition all identical with the definition in above-mentioned formula IC.

8. structure shown in the described formula IA of any one in claim 1-4 and the preparation method cyclo-imino sugar compounds, is characterized in that, the method comprises:

1) pass through the operation of the compound of structure shown in the described method preparation formula of the claims 7 IC;

Shown in the formula IC that 2) will prepare by the described method of the claims 7, the compound of structure carries out the operation of hydroxyl deprotection.

9. the preparation method of the compound of structure shown in formula ID claimed in claim 6, is characterized in that, the method comprises:

1) pass through the operation of the compound of structure shown in the described method preparation formula of the claims 7 IC;

The operation that shown in the formula IC that 2) will prepare by the described method of the claims 7, the lactan of the compound of structure carries out the lactan reduction.

10. structure shown in the described formula IB of any one in claim 1-4 and the preparation method cyclo-imino sugar compounds, is characterized in that, the method comprises:

1) pass through the operation of the compound of structure shown in the described method preparation formula of the claims 9 ID;

Shown in the formula ID that 2) will prepare by the described method of the claims 9, the compound of structure carries out the operation of hydroxyl deprotection.

11. described and cyclo-imino sugar compounds or its pharmacy acceptable salt or the application of medicinal composition in glycosidase activity inhibitor class medicine of any one in claim 1-4.

12. application according to claim 11, wherein, described Glycosylase is alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase enzymes, alpha-Mannosidase, beta-Mannosidase, α, at least one in α-trehalase, alpha-L-fucosidase and alpha-L-Rhamnosidase.

A 13. medicine, described medicine is the medicine, the medicine that prevents and/or treats gaucher's disease that prevent and/or treat diabetes, prevent and/or treat the medicine of tumour and one or more in antiviral, it is characterized in that, its activeconstituents is described and cyclo-imino sugar compounds or its pharmacy acceptable salt or medicinal composition of any one in claim 1-4.

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