CN105541854B - Preparation method and spherosin derivative of spherosin and its intermediate and its preparation method and application - Google Patents
Preparation method and spherosin derivative of spherosin and its intermediate and its preparation method and application Download PDFInfo
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- CN105541854B CN105541854B CN201610014143.7A CN201610014143A CN105541854B CN 105541854 B CN105541854 B CN 105541854B CN 201610014143 A CN201610014143 A CN 201610014143A CN 105541854 B CN105541854 B CN 105541854B
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- 0 CC*N(CC1OC(C)(C)OC11)*(*)(C(*)C**C)C1(S)[I+](C)C Chemical compound CC*N(CC1OC(C)(C)OC11)*(*)(C(*)C**C)C1(S)[I+](C)C 0.000 description 8
- OTXOMSZMANJZRI-ZFXTZCCVSA-N CC1(C)OC([C@@H](CC=O)N(C2)OC(c3ccccc3)=O)[C@@H]2O1 Chemical compound CC1(C)OC([C@@H](CC=O)N(C2)OC(c3ccccc3)=O)[C@@H]2O1 OTXOMSZMANJZRI-ZFXTZCCVSA-N 0.000 description 1
- MYCOXHCWJYYCKE-JTLRNRKASA-N C[C@@H](C[C@H]1O)CN(CC(CC2)=O)[C@]1(C)[C@@H]2O Chemical compound C[C@@H](C[C@H]1O)CN(CC(CC2)=O)[C@]1(C)[C@@H]2O MYCOXHCWJYYCKE-JTLRNRKASA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
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Abstract
The present invention relates to the synthesis field of natural products, discloses a kind of spherosin derivative and its preparation method and application and the preparation method of spherosin and its intermediate, and this method comprises the following steps：1) primary alconol shown in Formula IX is subjected to oxidation reaction, obtains the aldehyde shown in Formula X；2) aldehyde shown in the Formula X is subjected to Ylide reaction, obtains the beta-unsaturated esters shown in Formula XI；3) beta-unsaturated esters shown in the Formula XI are subjected to catalytic hydrogenation, obtain the lactams shown in Formula XII.Spherosin derivative provided by the invention can be used as glycosidase inhibitor, it is provided by the invention prepare spherosin derivative method route is succinct, production cost is low, and easy to carry out structural modification to spherosin.
Description
Technical field
The present invention relates to the synthesis field of natural products, and in particular, to a kind of method for preparing spherosin intermediate,
A kind of method for preparing spherosin derivative and the spherosin derivative being prepared by this method, one kind prepare bitter horse
The method of legumin and the application of spherosin derivative.
Background technology
Glycosidase take part in many important bioprocesses related with glycoconjugates, such as the digesting of enteral, sugared egg
White synthesis and decomposition, the glycoconjugates metabolism of lysosome (lysosomal) etc., play key player in life entity,
It is closely related with many diseases.
Iminosugar, also known as polyhydroxylated alkaloid, azasugar, imines sugar etc., are effective inhibitor of glycosidase, disease-resistant
Malicious, antitumor, treatment diabetes etc. have important pharmacological activity (such as inchester, B；Fleet,
G.W.J.Glycobiology 1992,2,199 etc.).In addition, there are many iminosugars to be developed to medicine and listed
(such as NBDNJ, Miglitol, Miglustat).
In iminosugar, Indolizidine class compound has consequence, many Indolizidine class imino groups
Sugar is with good bioactivity with huge application prospect.The formedness shown due to Indolizidine class iminosugar
Matter, finding the Indolizidine Alkaloid with novel structure becomes one of focal point of researcher in the art.
Spherosin is isolated Indolizidine from mushroom Rhizoctonia leguminicola in 1973
Class iminosugar, subsequent researcher is in succession from grey swainson pea and isolated material in some other sources.By to it
Bioactivity research is carried out it is found that spherosin is a kind of good α-seminase and seminase II inhibitor.Into one
The research of step thinks that spherosin can be used for the Other diseases such as treating cancer, bacterium infection and inflammation.Due to spherosin
With good bioactivity and application prospect, while spherosin has special chemical constitution in itself, in order to further
Its biological and chemical property is studied, people expand the research to the fully synthetic work of spherosin.
The new emphasis that can also become this area researcher concern as the compound of glycosidase inhibitor of exploitation.
The content of the invention
The defects of the purpose of the present invention is overcoming the prior art, there is provided it is a kind of it is new can be as the change of glycosidase inhibitor
Compound and its synthetic method, and a kind of route of offer is succinct, production cost is low and is easy to carry out structural modification to spherosin
The method for preparing spherosin and its intermediate and derivative.
In a first aspect, the present invention provides a kind of method for preparing spherosin intermediate, which has
Structure shown in Formula XII, this method comprise the following steps：
1) primary alconol shown in Formula IX is subjected to oxidation reaction, obtains the aldehyde shown in Formula X；
2) aldehyde shown in the Formula X is subjected to Ylide reaction, obtains the beta-unsaturated esters shown in Formula XI；
3) beta-unsaturated esters shown in the Formula XI are subjected to catalytic hydrogenation, obtain the lactams shown in Formula XII；
Wherein, in Formula IX into Formula XI, the configuration of the carbon atom on 2,3,4 and 5 is each independently R configurations or S structures
Type；And in Formula XII, 1,2,8 and the configuration of the carbon atom on 8a positions be each independently R configurations or S configurations；
In Formula IX into Formula XI, R1In the benzyl substituted for the hydrogen atom on benzyloxycarbonyl group or phenyl ring by methoxyl group or halogen
At least one；R2Methoxyl methyl, the methyl substituted selected from methoxyl methyl, methyl by the straight or branched saturated alkyl of C1-C12
Heteroatomic alkyl-substituted methoxyl methyl is contained by the straight or branched of C1-C12；R3Selected from methyl, ethyl, the tert-butyl group,
The benzyl that hydrogen atom on benzyl and phenyl ring is substituted by methoxyl group or halogen；
In Formula XII, R is selected from the methoxy first that methoxyl methyl, methyl are substituted by the straight or branched saturated alkyl of C1-C12
Base and methyl contain heteroatomic alkyl-substituted methoxyl methyl by the straight or branched of C1-C12.
Second aspect, the present invention provide a kind of method for preparing spherosin derivative, which has
Structure shown in Formulas I -1, this method comprise the following steps：
1) primary alconol shown in Formula IX is subjected to oxidation reaction, obtains the aldehyde shown in Formula X；
2) aldehyde shown in the Formula X is subjected to Ylide reaction, obtains the beta-unsaturated esters shown in Formula XI；
3) beta-unsaturated esters shown in the Formula XI are subjected to catalytic hydrogenation, obtain the lactams shown in Formula XII；
4) in acid condition, the lactams shown in the Formula XII is reacted, obtains iminosugar shown in Formulas I -1；
Wherein, in Formula IX into Formula XI, the configuration of the carbon atom on 2,3,4 and 5 is each independently R configurations or S structures
Type；And in Formula XII and Formulas I -1,1,2,8 and the configuration of the carbon atom on 8a positions be each independently R configurations or S configurations；
In Formula IX into Formula XI, R1In the benzyl substituted for the hydrogen atom on benzyloxycarbonyl group or phenyl ring by methoxyl group or halogen
At least one；R2Methoxyl methyl, the methyl substituted selected from methoxyl methyl, methyl by the straight or branched saturated alkyl of C1-C12
Heteroatomic alkyl-substituted methoxyl methyl is contained by the straight or branched of C1-C12；R3Selected from methyl, ethyl, the tert-butyl group,
The benzyl that hydrogen atom on benzyl and phenyl ring is substituted by methoxyl group or halogen；
In Formula XII, R is selected from the methoxy first that methoxyl methyl, methyl are substituted by the straight or branched saturated alkyl of C1-C12
Base and methyl contain heteroatomic alkyl-substituted methoxyl methyl by the straight or branched of C1-C12.
The third aspect, the present invention provide a kind of method for preparing spherosin, which has the knot shown in Formulas I -2
Structure, this method comprise the following steps：
1) primary alconol shown in Formula IX is subjected to oxidation reaction, obtains the aldehyde shown in Formula X；
2) aldehyde shown in the Formula X is subjected to Ylide reaction, obtains the beta-unsaturated esters shown in Formula XI；
3) beta-unsaturated esters shown in the Formula XI are subjected to catalytic hydrogenation, obtain the lactams shown in Formula XII；
4) lactams shown in the Formula XII is reduced, obtains the tertiary amine shown in Formula XIII；
5) in acid condition, the tertiary amine shown in the Formula XIII is reacted, obtains imino group shown in Formulas I -2
Sugar；
Wherein, in Formula IX into Formula XI, the configuration of the carbon atom on 2,3,4 and 5 is each independently R configurations or S structures
Type；And in Formula XII, Formula XIII and Formulas I -2,1,2,8 and the configuration of the carbon atom on 8a positions be each independently R configurations or S
Configuration；
In Formula IX into Formula XI, R1In the benzyl substituted for the hydrogen atom on benzyloxycarbonyl group or phenyl ring by methoxyl group or halogen
At least one；R2Methoxyl methyl, the methyl substituted selected from methoxyl methyl, methyl by the straight or branched saturated alkyl of C1-C12
Heteroatomic alkyl-substituted methoxyl methyl is contained by the straight or branched of C1-C12；R3Selected from methyl, ethyl, the tert-butyl group,
The benzyl that hydrogen atom on benzyl and phenyl ring is substituted by methoxyl group or halogen；
In Formula XII and Formula XIII, R is selected from methoxyl methyl, methyl is substituted by the straight or branched saturated alkyl of C1-C12
Methoxyl methyl and methyl heteroatomic alkyl-substituted methoxyl methyl is contained by the straight or branched of C1-C12.
Fourth aspect, the present invention provide the spherosin with the structure shown in Formulas I -1 being prepared as preceding method
Derivative,
Wherein, 1,2,8 and the configuration of the carbon atom on 8a positions be each independently R configurations or S configurations.
5th aspect, the present invention provide application of the foregoing spherosin derivative in as glycosidase inhibitor.
Spherosin derivative provided by the invention can be used as glycosidase inhibitor.
It is provided by the invention prepare spherosin and its intermediate and derivative method route it is succinct and production cost is low.
In addition, said synthesis route provided by the invention is easy to carry out structural modification to spherosin, further to find
Lead compound provides the foundation.
Other features and advantages of the present invention will be described in detail in subsequent specific embodiment part.
Embodiment
The embodiment of the present invention is described in detail below.It is it should be appreciated that described herein specific
Embodiment is merely to illustrate and explain the present invention, and is not intended to limit the invention.
Hetero atom in the present invention can be selected from least one of N, O, S.
First aspect：
The present invention provides a kind of method for preparing spherosin intermediate, which has Formula XII institute
The structure shown, this method comprise the following steps：
1) primary alconol shown in Formula IX is subjected to oxidation reaction, obtains the aldehyde shown in Formula X；
2) aldehyde shown in the Formula X is subjected to Ylide reaction, obtains the beta-unsaturated esters shown in Formula XI；
3) beta-unsaturated esters shown in the Formula XI are subjected to catalytic hydrogenation, obtain the lactams shown in Formula XII；
Wherein, in Formula IX into Formula XI, the configuration of the carbon atom on 2,3,4 and 5 is each independently R configurations or S structures
Type；And in Formula XII, 1,2,8 and the configuration of the carbon atom on 8a positions be each independently R configurations or S configurations；
In Formula IX into Formula XI, R1In the benzyl substituted for the hydrogen atom on benzyloxycarbonyl group or phenyl ring by methoxyl group or halogen
At least one；R2Methoxyl methyl, the methyl substituted selected from methoxyl methyl, methyl by the straight or branched saturated alkyl of C1-C12
Heteroatomic alkyl-substituted methoxyl methyl is contained by the straight or branched of C1-C12；R3Selected from methyl, ethyl, the tert-butyl group,
The benzyl that hydrogen atom on benzyl and phenyl ring is substituted by methoxyl group or halogen；
In Formula XII, R is selected from the methoxy first that methoxyl methyl, methyl are substituted by the straight or branched saturated alkyl of C1-C12
Base and methyl contain heteroatomic alkyl-substituted methoxyl methyl by the straight or branched of C1-C12.
Preferably, in Formula IX into Formula XI, R1Substituted for the hydrogen atom on benzyloxycarbonyl group or phenyl ring by methoxyl group or halogen
At least one of benzyl；R2The methoxy first substituted selected from methoxyl methyl, methyl by the straight or branched saturated alkyl of C1-C8
Base, methyl contain heteroatomic alkyl-substituted methoxyl methyl by the straight or branched of C1-C8；R3Selected from methyl, ethyl, uncle
The benzyl that hydrogen atom on butyl, benzyl and phenyl ring is substituted by methoxyl group or halogen；In Formula XII, R is selected from methoxyl methyl, first
The methoxyl methyl and methyl that base is substituted by the straight or branched saturated alkyl of C1-C8 are by the straight or branched of C1-C8 containing miscellaneous
The alkyl-substituted methoxyl methyl of atom.
Preferably, in Formula IX into Formula XI, R1Substituted for the hydrogen atom on benzyloxycarbonyl group or phenyl ring by methoxyl group or halogen
At least one of benzyl；R2The methoxy first substituted selected from methoxyl methyl, methyl by the straight or branched saturated alkyl of C1-C4
Base, methyl contain heteroatomic alkyl-substituted methoxyl methyl by the straight or branched of C1-C4；R3Selected from methyl, ethyl, uncle
The benzyl that hydrogen atom on butyl, benzyl and phenyl ring is substituted by methoxyl group or halogen；In Formula XII, R is selected from methoxyl methyl, first
The methoxyl methyl and methyl that base is substituted by the straight or branched saturated alkyl of C1-C4 are by the straight or branched of C1-C4 containing miscellaneous
The alkyl-substituted methoxyl methyl of atom.
Preferably, in step 1), the oxidation reaction carries out in the presence of an oxidizer, and the oxidant is selected from permanganic acid
Potassium, potassium bichromate, chromium trioxide, manganese dioxide, sodium periodate, dimethyl sulfoxide (DMSO)-oxalyl chloride, Dai Si-Martin's oxidant and bromine
At least one of water.
Preferably, in step 1), the condition of the oxidation reaction includes：Temperature is subzero 100 DEG C to 50 DEG C above freezing, when
Between for 0.5-12 it is small when.
Preferably, in step 1), the dosage molar ratio of primary alconol and oxidant shown in Formula IX is 1：1-10, is preferably 1：
1.5-2。
Preferably, in step 2), the condition of the Ylide reaction includes：Temperature is 0-200 DEG C, time 0.5-12
Hour；It is highly preferred that the condition of the Ylide reaction includes：Temperature is 90-110 DEG C, when the time is 1-2 small.
Preferably, in step 2), the Ylide reaction is in the ylide reagent as derived from monobromo-acetic acid Arrcostab
In the presence of carry out, the monobromo-acetic acid Arrcostab is preferably selected from methyl bromoacetate, Bromo-t-butylacetate and monobromo-acetic acid benzyl
At least one of ester.
Preferably, in step 2), the dosage molar ratio of aldehyde and the ylide reagent shown in the Formula X is 1：1-
10；More preferably 1：1.5-2.
Preferably, in step 3), the catalyst for carrying out catalytic hydrogenation is selected from palladium carbon, palladium black, palladium dydroxide, chlorination
At least one of palladium, platinum oxide and platinum black.
Preferably, in step 3), the condition of the catalytic hydrogenation includes：Temperature is subzero 80 DEG C to 100 DEG C, when
Between for 0.5-100 it is small when.
Preferably, in step 3), the dosage molar ratio of beta-unsaturated esters and catalyst shown in the Formula XI is 1：0.1-
1；More preferably 1：0.1-0.5.
Preferably, the primary alconol shown in the Formula IX is made by following steps：
A) in the presence of the first reducing agent, the nitrone shown in Formula II-a and/or Formula II-b is subjected to reduction reaction, obtains formula
Azanol shown in III；
B) in the presence of the second reducing agent, the azanol shown in the formula III is subjected to reduction reaction, is obtained shown in formula IV
Secondary amine；
C) secondary amine shown in the formula IV is subjected to protection reaction, obtains the compound shown in Formula V；
D) by compound machine the making choice property deprotection reaction shown in the Formula V, the glycol shown in Formula IV is obtained；
E) glycol shown in the Formula IV is subjected to protection reaction, obtains the compound shown in Formula VII；
F) compound shown in the Formula VII is subjected to protection reaction in alkaline conditions, obtains compound shown in Formula VIII；
G) compound shown in the Formula VIII is subjected to deprotection reaction, obtains the primary alconol shown in the Formula IX；
Wherein, in Formula II-a, Formula II-b, formula III into Formula VIII, the configuration of the carbon atom on 2,3,4 and 5 with it is described
The configuration of corresponding carbon atom is identical in primary alconol shown in Formula IX；
In Formula V into Formula VIII, R1And R2Respectively with the R in the primary alconol shown in the Formula IX1And R2It is identical；R3Selected from first
The benzyl that hydrogen atom on base, ethyl, the tert-butyl group, benzyl and phenyl ring is substituted by methoxyl group or halogen.
Preferably, in step a), first reducing agent be selected from lithium aluminium hydride reduction, diisobutyl aluminium hydride, sodium borohydride,
At least one of sodium cyanoborohydride, borine, zinc powder, iron powder and sodium thiosulfate.Preferably, the nitrone and described first
The dosage molar ratio of reducing agent is 1:1-100, more preferably 1:1-10.Preferably, in step a), the bar of the reduction reaction
Part includes：Temperature is subzero 80 DEG C to 100 DEG C above freezing, is preferably 0 DEG C；When time is 0.1-100 small, when preferably 0.5-1 is small.
Preferably, in step b), second reducing agent is selected from zinc powder-copper acetate and its hydrate, zinc powder-acid, goes back
Former iron powder-at least one of copper acetate and its hydrate.
Preferably, in step b), when selecting zinc powder-copper acetate and its hydrate as the second reducing agent, formula III institute
The dosage molar ratio of the azanol, zinc powder and the copper acetate that show is 1：0.1-100：0.1-1, is preferably 1：0.1-20：0.1-0.5；It is excellent
Selection of land, solvent is glacial acetic acid in the step, and reaction temperature is 0-100 DEG C, is preferably 35 DEG C, the time for 0.1-100 it is small when, it is excellent
Elect as 12 it is small when.
Preferably, in step b), when selecting zinc powder-acid to be used as the second reducing agent, azanol, zinc powder shown in formula III
Dosage molar ratio be 1：10-100, is preferably 1：10-20, acid used are ammonium chloride saturated solution, and solvent is in the step
Methanol, temperature are 0-100 DEG C, are preferably 35 DEG C, when the time is 0.1-100 small, when being preferably 12 small.
Preferably, in step c), the condition of the protection reaction includes：Temperature is 0-100 DEG C, time 0.1-100
Hour.
Preferably, in step d), the selectivity deprotection reaction carries out in acid condition, the selectivity remove-insurance
The condition of shield reaction includes：Temperature is subzero 80 DEG C to 100 DEG C above freezing, when the time is 0.1-100 small.
Preferably, in step e), the protection reagent used during protection reaction includes but not limited to the tert-butyl group
At least one of dimethylchlorosilane, tert-butyl diphenyl chlorosilane, tri-phenyl chloride and triphenylchloromethane.In step
E) in, the condition of the protection reaction includes：Temperature is subzero 80 DEG C to 100 DEG C above freezing, is preferably 0 DEG C；Time is 0.1-100
Hour, when being preferably 12 small.
Preferably, in step f), the protection reagent used during protection reaction includes but not limited to chloromethyl
Methyl ether or methyl by the straight or branched saturation of C1-C12 or contain at least one of heteroatomic alkyl-substituted chloromethyl ether.
In step f), the condition of the protection reaction includes：Temperature is subzero 80 DEG C to 100 DEG C above freezing, is preferably 0 DEG C；Time is
When 0.1-100 is small, when being preferably 36 small.
Preferably, in step g), the deprotecting regent used in the deprotection reaction includes but not limited to the tetrabutyl
Ammonium fluoride and its hydrate, potassium fluoride, ammonium fluoride, hydrogen fluoride pyridine salt.In step g), the condition bag of the deprotection reaction
Include：Temperature is subzero 20 DEG C to 100 DEG C above freezing, is preferably 25 DEG C；When time is 0.1-24 small, when being preferably 1-2 small.
Alkaline condition of the present invention can be by the addition of organic base and/or inorganic base to provide, and the organic base is
Diethylamine, triethylamine, diisopropylamine, diisopropyl ethyl amine, tetramethylethylenediamine, pyridine, hexahydropyridine, 2,4,6- front threes
At least one of yl pyridines and tetrabutyl ammonium fluoride；The inorganic base for sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
At least one of sodium acid carbonate, sodium hydride, hydrofining and tetrabutylammonium hydroxide.
Acid condition of the present invention can be by the addition of organic acid and/or inorganic acid to provide, and the organic acid is
At least one of formic acid, acetic acid, p-methyl benzenesulfonic acid, camphorsulfonic acid, para-methylbenzenepyridinsulfonate sulfonate and benzoic acid；The inorganic acid
For at least one of sulfuric acid, hydrochloric acid, nitric acid, perchloric acid, ferric trichloride, titanium tetrachloride and boron trifluoride.
Further included in the method described in the present invention it is well known in the art isolate and purify, these are all for this area skill
Well known to art personnel, details are not described herein by the present invention, and those skilled in the art should not be construed as the limit of the method to the present invention
System.
Second aspect：
The present invention provides a kind of method for preparing spherosin derivative, which has the institute of Formulas I -1
The structure shown, this method comprise the following steps：
1) primary alconol shown in Formula IX is subjected to oxidation reaction, obtains the aldehyde shown in Formula X；
2) aldehyde shown in the Formula X is subjected to Ylide reaction, obtains the beta-unsaturated esters shown in Formula XI；
3) beta-unsaturated esters shown in the Formula XI are subjected to catalytic hydrogenation, obtain the lactams shown in Formula XII；
4) in acid condition, the lactams shown in the Formula XII is reacted, obtains iminosugar shown in Formulas I -1；
Wherein, in Formula IX into Formula XI, the configuration of the carbon atom on 2,3,4 and 5 is each independently R configurations or S structures
Type；And in Formula XII and Formulas I -1,1,2,8 and the configuration of the carbon atom on 8a positions be each independently R configurations or S configurations；
In Formula IX into Formula XI, R1In the benzyl substituted for the hydrogen atom on benzyloxycarbonyl group or phenyl ring by methoxyl group or halogen
At least one；R2Methoxyl methyl, the methyl substituted selected from methoxyl methyl, methyl by the straight or branched saturated alkyl of C1-C12
Heteroatomic alkyl-substituted methoxyl methyl is contained by the straight or branched of C1-C12；R3Selected from methyl, ethyl, the tert-butyl group,
The benzyl that hydrogen atom on benzyl and phenyl ring is substituted by methoxyl group or halogen；
In Formula XII, R is selected from the methoxy first that methoxyl methyl, methyl are substituted by the straight or branched saturated alkyl of C1-C12
Base and methyl contain heteroatomic alkyl-substituted methoxyl methyl by the straight or branched of C1-C12.
In the method for the second aspect of the present invention, by the aspect of the compound of the preparation of compounds of formula XII of Formula IX and this
The method of the first aspect of invention is identical, and details are not described herein by the present invention.
Preferably, in step 4), the condition that the lactams shown in the Formula XII is reacted is included：Temperature is zero
Lower 20 DEG C to 100 DEG C above freezing, when the time is 0.1-24 small.
The third aspect：
The present invention provides a kind of method for preparing spherosin, which has the structure shown in Formulas I -2, the party
Method comprises the following steps：
1) primary alconol shown in Formula IX is subjected to oxidation reaction, obtains the aldehyde shown in Formula X；
2) aldehyde shown in the Formula X is subjected to Ylide reaction, obtains the beta-unsaturated esters shown in Formula XI；
3) beta-unsaturated esters shown in the Formula XI are subjected to catalytic hydrogenation, obtain the lactams shown in Formula XII；
4) lactams shown in the Formula XII is reduced, obtains the tertiary amine shown in Formula XIII；
5) in acid condition, the tertiary amine shown in the Formula XIII is reacted, obtains imino group shown in Formulas I -2
Sugar；
Wherein, in Formula IX into Formula XI, the configuration of the carbon atom on 2,3,4 and 5 is each independently R configurations or S structures
Type；And in Formula XII, Formula XIII and Formulas I -2,1,2,8 and the configuration of the carbon atom on 8a positions be each independently R configurations or S
Configuration；
In Formula IX into Formula XI, R1In the benzyl substituted for the hydrogen atom on benzyloxycarbonyl group or phenyl ring by methoxyl group or halogen
At least one；R2Methoxyl methyl, the methyl substituted selected from methoxyl methyl, methyl by the straight or branched saturated alkyl of C1-C12
Heteroatomic alkyl-substituted methoxyl methyl is contained by the straight or branched of C1-C12；R3Selected from methyl, ethyl, the tert-butyl group,
The benzyl that hydrogen atom on benzyl and phenyl ring is substituted by methoxyl group or halogen；
In Formula XII and Formula XIII, R is selected from methoxyl methyl, methyl is substituted by the straight or branched saturated alkyl of C1-C12
Methoxyl methyl and methyl heteroatomic alkyl-substituted methoxyl methyl is contained by the straight or branched of C1-C12.
In the method for the third aspect of the present invention, by the aspect of the compound of the preparation of compounds of formula XII of Formula IX and this
The method of the first aspect of invention is identical, and details are not described herein by the present invention.
Preferably, in step 4), the condition of the reduction includes：Temperature is subzero 80 DEG C to 100 DEG C above freezing, and the time is
When 0.1-100 is small.
Fourth aspect：
The present invention provides preceding method be prepared have Formulas I -1 shown in structure spherosin derivative,
Wherein, 1,2,8 and the configuration of the carbon atom on 8a positions be each independently R configurations or S configurations.
5th aspect：
The present invention provides application of the foregoing spherosin derivative in as glycosidase inhibitor.
The spherosin derivative has the structure shown in Formulas I -1,
Wherein, 1,2,8 and the configuration of the carbon atom on 8a positions be each independently R configurations or S configurations.
Preferably, the glycosidase is alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta galactose glycosides
Enzyme, alpha-Mannosidase, beta-Mannosidase, alpha-L-fucosidase, trehalase, amyloglucosidase and α-L- sandlwoods
At least one of glycosidase.
Preferably, in the above-mentioned each side of the present invention, the spherosin derivative is the structure shown in Formulas I -1-1
And/or the structure shown in Formulas I -1-2,
The spherosin derivative or its salt or its hydrate of the present invention can also be used to prepare any one following medicine
Thing：1) prevent and/or treat the medicine of diabetes；2) prevent and/or treat the medicine of gaucher's disease；3) prevent and/or treat
The medicine of tumour；4) antiviral drugs.
In the medicine of the present invention, one or more pharmaceutically acceptable carriers can also be added.The carrier
Diluent, excipient, filler, adhesive, wetting agent, disintegrant, sorbefacient including pharmaceutical field routine, surface are lived
Property agent, absorption carrier, lubricant and other optional additives.
Note can be made in medicine prepared by spherosin derivative or its pharmaceutically acceptable salt, the hydrate of the present invention
Penetrate the diversified forms such as liquid, tablet, pulvis, granule, capsule, oral liquid, paste, creme.The medicine of above-mentioned various formulations
To be prepared according to the conventional method of pharmaceutical field.
The medicine of the present invention can utilize various methods of administration to be administered, including but not limited to oral, suction, rectum, transdermal, warp
Mucous membrane enteral administration and subcutaneous, muscle or intravenous injection administration.
Compound of the present invention or their pharmaceutically acceptable simple derivatives, can be administered alone, or with
Known other treating diabetes, antiviral, antibacterial and antitumor drug are administered together.
The present invention provides a succinct, efficient synthesized swainsonine as raw material using nitrone derived from various aldohexoses and spreads out
The method of biology, the method simply, easily can carry out structural modification to spherosin derivative, further to find guide
Compound provides the foundation.
The present invention will be described in detail by way of examples below.
Below in case of no particular description, used various raw materials are all from commercially available.
Preparation example 1
The preparation of nitrone shown in Formula II-a-1：
Under ice bath, stirring condition, 1 milliliter of concentrated sulfuric acid is added dropwise into 500 milliliters of dry acetones, then adds D- sweet dews
Sugared (0.2mol) reaction disappears (TLC monitorings) until raw material, is neutralized to neutrality with sodium acid carbonate, filtering removes inorganic salts, steams
The double propylidene D- furans mannoses of crude product 2,3,4,6-O- obtained by dry solvent directly throw the next step.
Pyridine (0.37mol) is added to the dichloromethane of the double propylidene D- furans mannoses of above-mentioned crude product 2,3,4,6-O-
In (100mL) solution, be charged with hydroxylamine hydrochloride (0.25mol), be heated to reflux 12 it is small when after, solvent is evaporated, then
Ethyl acetate (150mL) and hydrochloric acid (1mol/L, 30mL) are added into concentrate, by extracting and demixing, merges organic phase, does
Dry, concentration, obtains the double propylidene D- furans mannose oximes of crude product 2,3,4,6-O-, directly throws into reacting in next step.
Triethylamine (0.37mol) is added to the dichloromethane of the double propylidene D- furans mannose oximes of above-mentioned crude product 2,3,4,6-O-
In alkane (100mL) solution, add tert-butyl chloro-silicane (0.25mol), room temperature reaction 12 it is small when after, solvent is evaporated,
Then toward addition ethyl acetate (150mL) in concentrate, by extracting and demixing, organic phase is merged, dry, concentration, obtains crude product
2,3,4,6-O- double propylidene D- furans mannose oxime silicon ethers, directly throw into reacting in next step.
The double propylidene D- furans mannose oxime silicon ethers of above-mentioned crude product 2,3,4,6-O- are dissolved in dichloromethane (100mL), are added
Enter pyridine (0.37mol) and methane sulfonyl chloride (0.20mol), be stirred at room temperature 2 it is small when after, add aqueous hydrochloric acid solution (1mol/L,
The reaction 50mL) is quenched.By extracting and demixing, merging organic phase, dry, concentration obtains crude product (2S, 3S, 4R) -2, and 3,5- tri-
Benzyloxy -4- sulfonyloxy methyl oxygen -1- valeral methyloxime ethers, are directly used in and react in next step.
Above-mentioned crude product is dissolved in tetrahydrofuran (100mL), tetrabutyl ammonium fluoride (0.25mol) is added, is stirred at room temperature 12
Be heated to reflux after hour 12 it is small when, solvent is evaporated, then toward ethyl acetate (100mL) is added in concentrate, by extraction point
Layer, merges organic phase, dry, and concentration, obtains nitrone 22.5g shown in Formula II-a-1.White solid, mp.90-92 DEG C.
IR (KBr films) ν 3078,2986,2940,1570,1370,1261,1204,1055cm-1；
1H NMR(300MHz,CDCl3) δ 6.92 (s, 1H), 5.25 (dd, J=4.63,1.2Hz, 1H), 4.80 (dd, J=
5.80,2.30Hz, 1H), 4.53 (ddd, J=6.5,6.4,2.3, Hz, 1H), 4.45 (dd, J=8.7,6.9Hz, 1H), 4.20
(s, 1H), 4.07 (ddd, J=7.90,6.41,2.87Hz, 1H), 1.36,1.37,1.44,1.45, (s, 12H)；
13C NMR(75MHz,CDCl3)δ133.88,111.75,109.82,79.19,78.55,77.98,74.16,
64.88,27.33,25.96,25.23。
Preparation example 2
The preparation of nitrone shown in Formula II-b-2：
Under condition of ice bath, substrate (20mmol) is dissolved in 35mL methanol, adds sodium borohydride (80mmol), after reacting 4h
TLC shows that the reaction was complete, adds saturated ammonium chloride solution and reaction is quenched, most of methanol is removed under vacuum, sticky to what is obtained
Water and each 25mL of ethyl acetate are added in white solid, ethyl acetate extracts three times, magnesium sulfate drying, and solvent is removed under vacuum,
Gained crude product is directly used in react in next step.
Gained crude product is dissolved in 30mL dichloromethane, adds activated manganese dioxide (27mmol), TLC is shown after reacting 48h
Show that the reaction was complete, be filtered to remove solid, solvent is removed under vacuum, column chromatography obtains 3.1g (white solid, purity 95%).
[α]D 20=+16 (c 0.5, CH2Cl2)；
1H NMR(300MHz,CDCl3)δ5.37(d,6.5,1H),5.16-5.11(m,1H),4.88-4.84(m,1H),
4.45 (dd, J=9.0,7.2,1H), 4.21-4.14 (m, 2H), 4.11-4.05 (m, 1H), 1.51 (s, 3H), 1.48 (s, 3H),
1.43(s,3H),1.41(s,3H)；
13C NMR(75MHz,CDCl3)δ145.2,112.2,110.3,80.9,71.7,71.3,68.3,66.8,27.1,
26.0,25.5,24.7。
Embodiment 1
Prepare compound I-1-1：
1) synthesis of the compound of formula III -1：
Under condition of ice bath, substrate II-a-1 (0.7mmol) is dissolved in 15mL methanol, adds sodium borohydride (29mmol),
TLC shows that the reaction was complete after reaction 4h, adds saturated ammonium chloride solution and reaction is quenched, most of methanol, Xiang get are removed under vacuum
To sticky white solid in add water and each 5mL of ethyl acetate, ethyl acetate extracts three times, magnesium sulfate drying, is removed under vacuum
Solvent is removed, obtains the white solid 1.6g of formula III -1, yield 88%, purity 97% without further purification.
Structural identification：m.p.79-83℃；[α]D 20=-70 (c=1.0, CH2Cl2)；1H NMR(300MHz,CDCl3)δ
6.22 (s, 1H), 4.76-4.68 (m, 1H), 4.68-4.56 (m, 1H), 4.39 (dd, J=13.4,6.4Hz, 1H), 4.24-
4.15 (m, 1H), 4.11 (dd, J=8.5,6.1Hz, 1H), 3.52 (d, J=11.1Hz, 1H), 2.81-2.61 (m, 2H), 1.45
(s,3H),1.44(s,3H),1.41(s,3H),1.30(s,3H).13C NMR(75MHz,CDCl3)δ110.54,108.31,
77.67,74.91,74.29,71.99,67.72,63.35,26.79,25.63,25.48,23.95。
2) synthesis of the compound of formula IV -1：
Under room temperature, zinc powder (23.4mmol) and copper acetate (23.4mmol) are added in 15mL acetic acid, 15min
Afterwards, system is changed into brownish red from grey, and substrate (14.4mmol) is dissolved in 15mL acetic acid, and adds in reaction system, at room temperature
It is stirred overnight, TLC shows that the reaction was complete, acetic acid is removed under vacuum, ethyl acetate washing solid 3 times, adds saturation NaOH solution
Organic phase is washed, the floccule being filtered to remove in suspension, ethyl acetate extraction, magnesium sulfate drying, filters, removed under vacuum molten
Agent, obtains the crude product of formula IV -1.
3) synthesis of the compound of Formula V -1：
- 1 crude product of gained formula IV is dissolved in 25mL tetrahydrofurans at room temperature, is added 0.5mL water, is then added sodium acid carbonate
(25.9mmol), CbzCl (22mmol), TLC shows that the reaction was complete after reacting 2h, adds saturated ammonium chloride, and ethyl acetate extracts,
Magnesium sulfate is dried, and is spin-dried for after filtering, column chromatography obtains the compound of Formula V -1, step 2) and two step gross production rate 89% of step 3), colorless oil
Shape thing, purity 96%.
Structural identification：1H NMR(300MHz,CDCl3) δ 7.43-7.28 (m, 4H), 5.11 (d, J=3.2Hz, 2H), 4.78
(t, J=6.1Hz, 1H), 4.66 (td, J=6.4,4.0Hz, 1H), 4.56 (dd, J=14.1,6.1Hz, 1H), 4.09 (dd, J
=8.8,6.1Hz, 1H), 4.03-3.90 (m, 2H), 3.77 (dd, J=12.6,6.1Hz, 1H), 3.50 (dd, J=12.7,
3.7Hz,1H),1.48(s,3H),1.40(s,3H),1.37(s,3H),1.35(s,3H).13C NMR(75MHz,CDCl3)δ
155.14,136.30,128.51,128.14,128.02,113.07,108.97,79.97,74.45,67.82,67.26,
62.65,52.07,26.82,26.47,25.40,24.86。
4) synthesis of the compound of Formula IV -1：
Substrate V-1 (13.5mmol) is dissolved in 25mL methanol under room temperature, adds the 1 weight % sulfuric acid of 15mL, instead
It should stay overnight, TLC shows that the reaction was complete, addition saturated sodium bicarbonate adjusting pH value to alkalescent, and most of acetone is removed under vacuum,
Add water and each 5mL of ethyl acetate, extraction three times, filters after magnesium sulfate drying, solvent, column chromatography (PE/EtOAc=is removed in vacuum
3:1) compound of Formula IV -1, colourless oil liquid, yield 52%, purity 97% are obtained.
Structural identification：1H NMR(300MHz,CDCl3) δ 7.43-7.28 (m, 5H), 5.12 (d, J=1.7Hz, 2H), 4.90
(t, J=6.8Hz, 1H), 4.76 (td, J=7.0,4.7Hz, 1H), 4.19 (t, J=7.5Hz, 1H), 4.04 (d, J=
10.7Hz, 1H), 3.87 (d, J=4.1Hz, 1H), 3.77-3.64 (m, 2H), 3.59 (dt, J=12.2,3.9Hz, 1H), 3.47
(s, 1H), 3.29 (dd, J=12.5,4.6Hz, 1H), 1.54 (s, 3H), 1.35 (s, 3H)；13C NMR(75MHz,CDCl3)δ
135.89,128.63,128.40,128.15,113.88,80.01,78.20,71.06,67.85,63.34,59.89,50.59,
26.32,24.77。
5) synthesis of the compound of Formula VII -1：
At room temperature, VI-1 (14.2mmol) is dissolved in 25mL dichloromethane, after adding 2mL triethylamines, is slowly added to uncle
Butyldimethylchlorosilane (26mmol), TLC shows that the reaction was complete after stirring 7h, adds saturated ammonium chloride solution, EtOAc
(10mL × 3) extract, and magnesium sulfate drying, is filtered to remove solid, solvent is removed under vacuum, obtain the crude compound of Formula VII -1.
6) synthesis of the compound of Formula VIII -1：
Under condition of ice bath, the above-mentioned crude compound of Formula VII -1 is dissolved in 25mL dry methylene chlorides, argon gas displacement, adds
Enter DIPEA (25mmol), be then slowly added into chloromethyl methyl ether (20mmol), room temperature reaction 24h is transferred to after 1h, adds DIPEA
(6mmol) and chloromethyl methyl ether (7.7mmol), TLC shows that the reaction was complete after 2h, adds saturated ammonium chloride solution and reaction is quenched,
Ethyl acetate (10mL × 3) extracts, and merges organic phase, after magnesium sulfate drying, filters and removes solid, remove solvent under vacuum, obtain
To the crude compound of Formula VIII -1.
7) synthesis of the compound of Formula IX -1：
At room temperature, the above-mentioned compound of Formula VIII -1 is dissolved in the tetrahydrofuran of 25mL, adds excessive hydrogen fluoride pyridine
Salt, TLC display substrates are wholly absent after reacting 2h, add saturation NaHCO3Reaction is quenched, ethyl acetate (10mL × 3) extracts,
Merge organic phase, after magnesium sulfate drying, filter and remove solid, solvent, column chromatography (petroleum ether are removed under vacuum：Ethyl acetate=
5:1) compound of Formula IX -1, is obtained, is colourless oil liquid (yield 63%, purity 98%).
Structural identification：1H NMR(300MHz,CDCl3) δ 7.75-7.09 (m, 5H), 5.11 (q, J=12.3Hz, 2H),
4.85 (t, J=6.6Hz, 1H), 4.78 (d, J=6.9Hz, 1H), 4.68 (d, J=6.9Hz, 1H), 4.63 (dd, J=13.9,
7.1Hz, 1H), 4.35-4.22 (m, 1H), 4.11 (dd, J=12.0,7.5Hz, 1H), 3.97 (s, 1H), 3.83 (dd, J=
8.9,2.6Hz, 1H), 3.74 (t, J=11.7Hz, 1H), 3.59 (dt, J=12.8,3.5Hz, 1H), 3.43 (s, 3H), 3.09
(dd, J=12.0,7.0Hz, 1H), 1.50 (s, 3H), 1.32 (s, 3H)13C NMR(75MHz,CDCl3)δ136.01,
128.67,128.42,128.20,113.56,97.61,79.97,77.89,67.87,62.44,59.32,55.89,50.99,
27.34,25.43。
8) synthesis of the compound of Formula X -1：
At room temperature, DMP (1.56mmol) is added in the dichloromethane of 25mL dryings, then adds NaHCO3
The compound of Formula IX -1 (0.78mmol), is dissolved in the dry methylene chloride of 5mL after 5min by (2.34mmol), is added dropwise to above-mentioned anti-
Answer in system, reaction system is in muddy shape, and 3mL saturations Na is added after reacting 2h2S2O3, system is changed into settled solution, ethyl acetate
(15mL × 3) extract, and merge organic phase, and saturated common salt water washing three times, is filtered to remove solid after magnesium sulfate drying, is removed under vacuum
Go solvent to obtain pale yellow oily liquid, obtain the crude compound of Formula X -1.
9) synthesis of the compound of Formula XI -1：
The crude compound of Formula X -1 is dissolved in dry toluene, adds phosphonium ylide derived from bromoacetate
After (0.936mmol), flow back 1.5h, and TLC display substrates are wholly absent, and toluene are removed under vacuum, rapid column chromatography obtains XI-1
Crude product.
10) synthesis of the compound of Formula XII -1：
The crude compound of Formula XII -1 is dissolved in the high-purity methanol of 5mL, adds the 10 weight %'s of 30mg after argon gas displacement
Pd/C, is passed through hydrogen, three times, at room temperature after reaction overnight, TLC display substrates are wholly absent, and are filtered to remove Pd/C, column layer for displacement
Analyse (petroleum ether：Ethyl acetate=1:1) Formula XII -1 (yield 72%, purity 97%), is obtained.
Structural identification：1H NMR(300MHz,CDCl3) δ 4.76 (d, J=6.8Hz, 1H), 4.74-4.65 (m, 3H), 4.16
(d, J=13.5Hz, 1H), 4.12-4.01 (m, 1H), 3.38 (s, 3H), 3.33 (dd, J=7.9,2.8Hz, 1H), 3.05 (dd,
J=13.6,3.7Hz, 1H), 2.52-2.41 (m, 1H), 2.41-2.27 (m, 1H), 2.20-2.14 (m, 1H), 1.90-1.81
(m,1H),1.37(s,3H),1.29(s,3H).13C NMR(75MHz,CDCl3)δ173.87,111.96,95.86,79.81,
70.31,65.29,55.65,50.63,29.53,27.69,26.57,24.84。
11) synthesis of Formulas I -1-1 compounds：
At room temperature, the HCl solution of the 3M of 2mL, reaction are added into the methanol solution of the compound of Formula XII -1 (0.2mmol)
TLC display substrates are wholly absent after 20min, and solvent is removed under vacuum, and obtaining colloidal liquid Formulas I -1-1 compounds, (yield is
94%, purity 99%).
Structural identification：1H NMR(500MHz,D2O) δ 4.36 (td, J=8.7,3.7Hz, 1H), 4.18 (d, J=2.6Hz,
1H), 3.97-3.85 (m, 1H), 3.68-3.57 (m, 1H), 3.45 (d, J=9.1Hz, 1H), 3.16-3.06 (m, 1H), 2.41
(dd, J=18.2,6.2Hz, 1H), 2.37-2.26 (m, 1H), 2.02 (dd, J=7.5,5.0Hz, 1H), 1.79-1.70 (m,
1H).13C NMR(126MHz,D2O)δ171.64,70.27,69.19,65.70,63.23,48.28,28.83,28.09。
Embodiment 2
Prepare compound I-1-2：
1) synthesis of the compound of formula III -2：
Under condition of ice bath, substrate II-b-2 (20mmol) is dissolved in 15mL methanol, adds sodium borohydride (80mmol), instead
TLC shows that the reaction was complete after answering 4h, adds saturated ammonium chloride solution and is quenched reaction, and major part methanol is removed under vacuum, to obtaining
Sticky white solid in add water and each 5mL of ethyl acetate, ethyl acetate extracts three times, magnesium sulfate drying, is removed under vacuum
Solvent, obtains the compound as white solid of formula III -1 (yield 89%, purity 98%) without further purification.
Structural identification：1H NMR(300MHz,CDCl3) δ 4.75 (dd, J=11.5Hz, 5.9Hz, 1H), 4.45-4.41 (m,
1H), 4.30 (q, J=6.Hz 5,1H), 4.10 (dd, J=8.4Hz, 6.5Hz, 1H), 3.94 (dd, J=8.4Hz, 6.4Hz,
1H), 3.62 (dd, J=11.9Hz, 5.9Hz, 1H), 3.18-3.13 (m, 2H), 1.67 (br, 1H), 1.53 (s, 3H), 1.46
(s,3H),1.37(s,3H),1.32(s,3H)；13C NMR(75MHz,CDCl3)δ114.1,109.6,80.8,78.5,75.5,
75.2,66.3,63.7,27.2,26.6,25.3,24.8。
2) synthesis of the compound of formula IV -2：
Under room temperature, zinc powder (0.15mmol) and copper acetate (23.4mmol) are added in 15mL acetic acid, 15min
Afterwards, system is changed into brownish red from grey, the compound of formula III -1 (0.15mmol) is dissolved in 15mL acetic acid, and add reactant
System, is stirred overnight at room temperature, and TLC shows that the reaction was complete, acetic acid is removed under vacuum, ethyl acetate washing solid 3 times, adds saturation
NaOH solution washs organic phase, the floccule being filtered to remove in suspension, ethyl acetate extraction, magnesium sulfate drying, filtering, vacuum
Lower removing solvent, obtains the crude compound of formula IV -2.
3) synthesis of the compound of Formula V -2：
Above-mentioned IV-2 crude compounds are dissolved in 25mL tetrahydrofurans at room temperature, 0.5mL water is added, then adds carbonic acid
Hydrogen sodium (25.9mmol), CbzCl (22mmol), TLC shows that the reaction was complete after reacting 2h, adds saturated ammonium chloride, ethyl acetate
Extraction, magnesium sulfate drying, is spin-dried for, column chromatography obtains the compound of Formula V -2 (yield 82%, purity 96%), colorless oil after filtering
Thing.
Structural identification：1H NMR(300MHz,CDCl3) δ 7.44-7.27 (m, 5H), 5.14 (s, 2H), 4.91 (d, J=
6.0Hz, 1H), 4.79 (dd, J=17.4,6.7Hz, 1H), 4.72 (d, J=5.6Hz, 1H), 4.63 (dd, J=19.6,
6.6Hz, 1H), 4.28 (dd, J=12.0,4.5Hz, 1H), 3.94 (dd, J=23.6,12.5Hz, 2H), 3.78 (dd, J=
7.9,3.3Hz, 1H), 3.69 (dd, J=11.4,3.3Hz, 1H), 3.62-3.45 (m, 2H), 3.36 (d, J=13.0Hz, 3H),
1.39 (s, 3H), 1.30 (s, 3H), 0.87 (d, J=5.6Hz, 9H), 0.10-- 0.06 (m, 6H)；13C NMR(75MHz,
CDCl3)δ155.98,155.27,128.46,128.13,127.93,127.53,127.13,126.94,111.58,109.14,
108.98,83.43,82.82,80.16,77.72,67.32,67.15,67.00,66.03,65.91,65.57,64.59,
63.58,54.43,54.32,26.87,26.38,26.02,25.84,25.54,25.47,25.37,25.05,24.84。
4) synthesis of the compound of Formula IV -2：
The compound of Formula V -2 (8.9mmol) is dissolved in 25mL methanol under room temperature, adds the 1 weight % sulfuric acid of 15mL,
Overnight, TLC shows that the reaction was complete for reaction, addition saturated sodium bicarbonate adjusting pH value to alkalescent, and most of first is removed under vacuum
Alcohol, adds water and each 5mL of ethyl acetate, and extraction three times, filters after magnesium sulfate drying, solvent, column chromatography (petroleum ether is removed in vacuum：
Ethyl acetate=3:1) compound of Formula IV -2 (yield 69%, purity 96%), colourless oil liquid, are obtained.
Structural identification：1H NMR(300MHz,CDCl3) δ 7.43-7.27 (m, 5H), 5.18 (s, 2H), 4.77 (q, J=
5.9Hz, 2H), 4.33 (s, 1H), 4.03-3.93 (m, 1H), 3.91 (d, J=12.4Hz, 1H), 3.67 (s, 1H), 3.58 (dd,
J=12.3,4.8Hz, 2H), 3.50 (d, J=11.6Hz, 2H), 2.06 (d, J=4.5Hz, 1H), 1.41 (s, 4H), 1.31 (s,
4H)；13C NMR(75MHz,CDCl3)δ156.89,136.46,128.62,128.18,127.62,111.57,83.16,
80.00,73.58,67.59,65.07,63.35,54.34,27.01,24.92。
5) synthesis of the compound of Formula VII -2：
At room temperature, the compound of Formula IV -2 (13mmol) is dissolved in 25mL dichloromethane, after adding triethylamine (26mmol),
Tert-butyl chloro-silicane (20mmol) is slowly added to, TLC shows that the reaction was complete after stirring 7h, and it is molten to add saturated ammonium chloride
Liquid, EtOAc (10mL × 3) extractions, magnesium sulfate drying, is filtered to remove solid, solvent is removed under vacuum, obtain the compound of Formula VII -2
Crude product.
6) synthesis of the compound of Formula VIII -2：
Under condition of ice bath, the above-mentioned crude compound of Formula VII -2 is dissolved in 25mL dry methylene chlorides, argon gas displacement, adds
Enter DIPEA (25mmol), be then slowly added into chloromethyl methyl ether (20mmol), room temperature reaction 24h is transferred to after 1h, adds DIPEA
(6mmol) and chloromethyl methyl ether (7.7mmol), TLC shows that the reaction was complete after 2h, adds saturated ammonium chloride solution and reaction is quenched,
Ethyl acetate (10mL × 3) extracts, and merges organic phase, after magnesium sulfate drying, filters and removes solid, remove solvent under vacuum, obtain
To the crude compound of Formula VIII -2.
7) synthesis of the compound of Formula IX -2：
At room temperature, the above-mentioned compound of Formula VIII -2 is dissolved in the tetrahydrofuran of 25mL, adds tetrabutyl ammonium fluoride
(15mmol), TLC display substrates are wholly absent after reacting 2h, add saturation NaHCO3Reaction, ethyl acetate (10mL × 3) is quenched
Extraction, merges organic phase, after magnesium sulfate drying, filters and removes solid, solvent, column chromatography (petroleum ether are removed under vacuum：Acetic acid second
Ester=5:1) compound of Formula IX -2, is obtained, is colourless oil liquid (yield 77%, purity 97%).
Structural identification：1H NMR(300MHz,CDCl3) δ 7.42-7.27 (m, 5H), 5.19 (d, J=2.7Hz, 2H),
4.79-4.72 (m, 1H), 4.70 (d, J=6.0Hz, 1H), 4.60 (q, J=6.7Hz, 2H), 4.49 (d, J=1.9Hz, 1H),
4.17 (dd, J=9.7,5.1Hz, 1H), 3.89 (d, J=12.4Hz, 1H), 3.84 (dd, J=6.1,2.9Hz, 1H), 3.76-
3.62 (m, 1H), 3.55 (dd, J=12.3,5.0Hz, 1H), 3.46-3.36 (m, 2H), 3.35 (s, 3H), 1.40 (s, 3H),
1.31(s,3H)；13C NMR(75MHz,CDCl3)δ156.73,136.42,128.53,128.10,127.60,111.47,
96.86,83.04,80.92,80.11,67.52,64.17,60.68,55.93,54.28,26.90,24.80。
8) synthesis of the compound of Formula X -2：
At room temperature, DMP (2.3mmol) is added in the dichloromethane of 25mL dryings, then adds NaHCO3
The compound of Formula IX -2 (1.3mmol), is dissolved in the dry methylene chloride of 5mL after 5min, it is anti-to be added dropwise to above-mentioned body by (3.5mmol)
Answer in system, reaction system is in muddy shape, and 3mL saturations Na is added after reacting 2h2S2O3, system is changed into settled solution, ethyl acetate
(15mL × 3) extract, and merge organic phase, and saturated common salt water washing three times, is filtered to remove solid after magnesium sulfate drying, is removed under vacuum
Go solvent to obtain pale yellow oily liquid, obtain the crude compound of Formula X -2.
9) synthesis of the compound of Formula XI -2：
The crude compound of Formula X -2 is dissolved in dry toluene, adds phosphonium ylide (1.5mmol) derived from bromoacetate
Afterwards, flow back 1.5h, and TLC display substrates are wholly absent, and toluene are removed under vacuum, rapid column chromatography obtains XI-2 crude products.
10) synthesis of the compound of Formula XII -1：
The crude compound of Formula XII -2 is dissolved in the high-purity methanol of 5mL, adds the 10 weight %'s of 30mg after argon gas displacement
Pd/C, is passed through hydrogen, three times, at room temperature after reaction overnight, TLC display substrates are wholly absent, and are filtered to remove Pd/C, column layer for displacement
Analyse (petroleum ether：Ethyl acetate=1:1) Formula XII -2 (yield 63%, purity 99%), is obtained.
Structural identification：1H NMR(300MHz,CDCl3) δ 4.80-4.73 (m, 2H), 4.69 (ddd, J=6.9,5.1,
2.0Hz, 2H), 4.18 (dt, J=9.0,6.4Hz, 2H), 3.57 (dd, J=6.3,2.6Hz, 1H), 3.48 (d, J=13.9Hz,
1H),3.41(s,3H),2.44–2.35(m,2H),2.25(m,1H),1.87–1.73(m,1H),1.53(s,3H),1.37(s,
3H).13C NMR(75MHz,CDCl3)δ168.47,113.20,95.36,79.35,76.52,67.90,66.52,56.08,
49.37,27.84,26.38,25.64,25.12。
11) synthesis of Formulas I -1-2 compounds：
At room temperature, the HCl solution of the 3M of 2mL, reaction are added into the methanol solution of the compound of Formula XII -2 (0.2mmol)
TLC display substrates are wholly absent after 20min, and solvent is removed under vacuum, and obtaining colloidal liquid Formulas I -1-2 compounds, (yield is
99%, purity 99%).
Structural identification：1H NMR(300MHz,D2O) δ 4.22-4.18 (m, 1H), 4.16 (t, J=4.3Hz, 1H), 3.96
(dd, J=10.1,4.2Hz, 1H), 3.51 (dd, J=12.1,6.1Hz, 2H), 3.31 (d, J=14.0Hz, 1H), 2.28 (t, J
=8.3Hz, 2H), 2.04-1.91 (m, 1H), 1.91-1.76 (m, 1H)13C NMR(75MHz,D2O)δ172.34,70.55,
67.90,62.59,61.00,51.46,26.57,25.45。
Embodiment 3
Prepare compound I-2-1：
Using following synthetic route prepare compound I-2-1, wherein, by Formula II-a-1 preparation of compounds of formula XII-1 chemical combination
The method of thing is identical with the method in embodiment 1；
Wherein, it is by the step of preparation of compounds of formula XIII-1 compounds of Formula XII -1：
The compound of Formula XII -1 (0.73mmol) is dissolved in the tetrahydrofuran of 10mL dryings, adds LiAlH4(3mmol),
Heating reflux reaction 4h, TLC display substrate is wholly absent, and adds the 15 weight %NaOH water of addition 0.08mL after the water of 0.08mL
Solution, is eventually adding the water of 0.24mL, and white granular solid occurs in system, filters and removes solid, dichloromethane washing, gained
Settled solution is directly spin-dried for, column chromatography (petroleum ether：Ethyl acetate=3:1) major impurity is removed, obtains the compound of Formula XIII -1, it is light
Yellow liquid.
It is by the step of preparation of compounds of formula I-2-1 compounds of Formula XIII -1：
At room temperature, the HCl solution of the 3M of 2mL is added into the methanol solution of the above-mentioned compound of Formula XIII -1, reacts 20min
TLC display substrates are wholly absent afterwards, and solvent is removed under vacuum, obtain white solid, and ammonium hydroxide is exchanged through acid ion after neutralizing and set
Fat processing, obtains Formulas I -2-1 compounds (yield 74%, purity 99%).
Structural identification：1H NMR(500MHz,D2O) δ 4.33-4.25 (m, 1H), 4.20 (dd, J=5.7,3.6Hz, 1H),
3.75 (td J=10.7,4.6Hz, 1H), 2.90 (d, J=12.5Hz, 1H), 2.86 (dd, J=11.5,2.3Hz, 1H),
2.62-2.53 (m, 1H), 2.06-1.91 (m, 3H), 1.67 (d, J=13.8Hz, 1H), 1.53-1.38 (m, 1H), 1.18
(ddd, J=25.3,12.8,4.4Hz, 1H)；13CNMR(126MHz,D2O)δ72.29,69.09,68.53,65.66,59.90,
51.23,31.85,22.54。
Embodiment 4
Prepare compound I-2-2：
Using following synthetic route prepare compound I-2-2, wherein, by Formula II-b-2 preparation of compounds of formula XII-2 chemical combination
The method of thing is identical with the method in embodiment 2；
Wherein, it is by the step of preparation of compounds of formula XIII-2 compounds of Formula XII -2：
The compound of Formula XII -2 (1.5mmol) is dissolved in the tetrahydrofuran of 10mL dryings, adds LiAlH4(6mmol), adds
Hot back flow reaction 4h, TLC display substrates are wholly absent, add after the water of 0.08mL add 0.08mL 15 weight %NaOH it is water-soluble
Liquid, is eventually adding the water of 0.24mL, and white granular solid occurs in system, filters and removes solid, dichloromethane washing, and gained is clear
Clear solution is directly spin-dried for, column chromatography (petroleum ether：Ethyl acetate=3:1) compound of Formula XIII -2, weak yellow liquid are obtained.
Structural identification：1H NMR(300MHz,CDCl3) δ 4.73 (dd, J=22.3,6.9Hz, 2H), 4.67-4.50 (m,
2H), 3.98 (s, 1H), 3.45 (d, J=8.7Hz, 1H), 3.39 (s, 3H), 2.99 (d, J=10.4Hz, 1H), 2.28 (dd, J
=9.1,4.5Hz, 1H), 2.22-2.09 (m, 2H), 2.03 (d, J=14.1Hz, 1H), 1.80 (q, J=13.2Hz, 1H),
1.49 (s, 4H), 1.41 (d, J=18.7Hz, 2H), 1.32 (s, 4H)13C NMR(75MHz,CDCl3)δ113.82,96.06,
79.58,71.41,70.52,60.54,55.82,52.37,28.13,27.34,25.28,19.73。
The synthesis of Formulas I -2-2 compounds：
At room temperature, the HCl solution of the 3M of 2mL is added into the methanol solution of the above-mentioned compound of Formula XIII -2 (0.2mmol),
TLC display substrates are wholly absent after reaction 20min, are removed solvent under vacuum, are obtained white solid, ammonium hydroxide neutralize after through acidity from
Sub-exchange resin processing, obtains Formulas I -2-2 compounds (yield 94%, purity 98%).
Structural identification：1H NMR(500MHz,D2O, ref.MeOH) δ 4.25-4.12 (m, 2H), 3.97 (dd, J=9.4,
6.7Hz, 1H), 3.56 (dd, J=11.2,6.7Hz, 1H), 3.18-3.03 (m, 1H), 2.47 (d, J=9.2Hz, 1H), 2.42
(d, J=5.0Hz, 1H), 2.41-2.35 (m, 1H), 1.99-1.88 (m, 1H), 1.85-1.75 (m, 1H), 1.68-1.51 (m,
2H)；13CNMR(126MHz,D2O,ref.MeOH)δ69.17,69.15,66.47,62.75,59.90,52.58,29.36.
Test case
1) test material and source
Test compound：Formulas I -1-1 compounds and Formulas I -1-2 compounds.
Test material：4- nitrophenols pyranosides matrix, disaccharides and glycosidase (being purchased from Sigma-Aldrich).
2) test method
Dynamics research carries out in sodium citrate/phosphate buffer of 37 DEG C of 50mM.According to the difference of matrix, prepare
Enzyme concentration be 0.1-0.5mg/mL.Active testing is using 4- nitrophenols pyranoside as matrix, in the optimum activity pH of every kind of enzyme
Under tested.By matrix, appropriate diluted enzyme solutions and inhibitor (Formulas I -1-1 compounds and Formulas I -1-2 compounds) 37
Cultivated at DEG C 30 minutes, then start reaction in ultraviolet-uisible spectrophotometer, measure its absorption to 400nm wavelength lights.
Finally data analysis is carried out using GraFit programs.
3) evaluation result
The results are shown in Table 1 for the inhibitory activity of Formulas I -1-1 compounds and Formulas I -1-2 compounds to glycosidase.
Evaluation result shows that Formulas I -1-1 compounds provided by the present invention are to beta-glucosidase (beef liver) and β-gala
Glycosidase (beef liver) has inhibitory activity, IC50Respectively 595 μM and 491 μM；Formulas I -1-2 compounds have suppression to alpha-Mannosidase
System activity, IC50For 625 μM.
Table 1
| Glycosidase | Formulas I -1-1 compounds, IC50/μM | Formulas I -1-2 compounds, IC50/μM |
| Beta-glucosidase | ||
| Almond | Inhibiting rate under 1000 μM of concentration is 6.6% | Inhibiting rate under 1000 μM of concentration is 6.2% |
| Beef liver | 595 | - |
| Beta galactosidase | ||
| Beef liver | 491 | Inhibiting rate under 1000 μM of concentration is 17.9% |
| Alpha-Mannosidase | ||
| Sword bean | Inhibiting rate under 1000 μM of concentration is 3.8% | 625 |
The preferred embodiment of the present invention described in detail above, still, during present invention is not limited to the embodiments described above
Detail, in the range of the technology design of the present invention, a variety of simple variants can be carried out to technical scheme, this
A little simple variants belong to protection scope of the present invention.
It is further to note that each particular technique feature described in above-mentioned embodiment, in not lance
In the case of shield, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention to it is various can
The combination of energy no longer separately illustrates.
In addition, various embodiments of the present invention can be combined randomly, as long as it is without prejudice to originally
The thought of invention, it should equally be considered as content disclosed in this invention.
Claims (10)
1. a kind of method for preparing spherosin intermediate, which has the structure shown in Formula XII, this method
Comprise the following steps：
1) primary alconol shown in Formula IX is subjected to oxidation reaction, obtains the aldehyde shown in Formula X；
2) aldehyde shown in the Formula X is subjected to Ylide reaction, obtains the beta-unsaturated esters shown in Formula XI；
3) beta-unsaturated esters shown in the Formula XI are subjected to catalytic hydrogenation, obtain the lactams shown in Formula XII；
Wherein, in Formula IX into Formula XI, the configuration of the carbon atom on 2,3,4 and 5 is each independently R configurations or S configurations；And
In Formula XII, 1,2,8 and the configuration of the carbon atom on 8a positions be each independently R configurations or S configurations；
In Formula IX into Formula XII, R1In the benzyl substituted for the hydrogen atom on benzyloxycarbonyl group or phenyl ring by methoxyl group or halogen extremely
Few one kind；R2Methoxyl methyl, the methyl quilt substituted selected from methoxyl methyl, methyl by the straight or branched saturated alkyl of C1-C12
The straight or branched of C1-C12 contains heteroatomic alkyl-substituted methoxyl methyl；R3Selected from methyl, ethyl, the tert-butyl group, benzyl
The benzyl that hydrogen atom on base and phenyl ring is substituted by methoxyl group or halogen,
And the step of preparing the primary alconol shown in the Formula IX, includes：
A) in the presence of the first reducing agent, the nitrone shown in Formula II-a and/or Formula II-b is subjected to reduction reaction, obtains formula III
Shown azanol；
B) in the presence of the second reducing agent, the azanol shown in the formula III is subjected to reduction reaction, obtains the two level shown in formula IV
Amine；
C) secondary amine shown in the formula IV is subjected to protection reaction, obtains the compound shown in Formula V；
D) by compound the making choice property deprotection reaction shown in the Formula V, the glycol shown in Formula IV is obtained；
E) glycol shown in the Formula IV is subjected to protection reaction, obtains the compound shown in Formula VII；
F) compound shown in the Formula VII is subjected to protection reaction in alkaline conditions, obtains compound shown in Formula VIII；
G) compound shown in the Formula VIII is subjected to deprotection reaction, obtains the primary alconol shown in the Formula IX；
Wherein, in Formula II-a, Formula II-b, formula III into Formula VIII, configuration and the Formula IX of the carbon atom on 2,3,4 and 5
The configuration of corresponding carbon atom is identical in shown primary alconol；
In Formula V into Formula VIII, R1And R2Respectively with the R in the primary alconol shown in the Formula IX1And R2It is identical；R3For tert-butyl group diformazan
Base silane base.
2. according to the method described in claim 1, wherein, in step 1), the oxidation reaction carries out in the presence of an oxidizer,
The oxidant be selected from potassium permanganate, potassium bichromate, chromium trioxide, manganese dioxide, sodium periodate, dimethyl sulfoxide (DMSO)-oxalyl chloride,
Dai Si-at least one of Martin's oxidant and bromine water.
3. according to the method described in claim 1, wherein, the condition of the oxidation reaction includes：Temperature is subzero 100 DEG C to zero
Upper 50 DEG C, when the time is 0.5-12 small.
4. according to the method described in claim 1, wherein, in step 1), the dosage of primary alconol and oxidant shown in Formula IX is rubbed
You are than being 1：1-10.
5. according to the method described in claim 4, wherein, in step 1), the dosage of primary alconol and oxidant shown in Formula IX is rubbed
You are than being 1：1.5-2.
6. according to the method described in claim 1, wherein, in step 2), the condition of the Ylide reaction includes：Temperature is
0-200 DEG C, when the time is 0.5-12 small.
7. according to the method described in claim 1, wherein, in step 3), the catalyst for carrying out catalytic hydrogenation is selected from palladium
At least one of carbon, palladium black, palladium dydroxide, palladium bichloride, platinum oxide and platinum black.
8. according to the method described in claim 1, wherein, the condition of the catalytic hydrogenation includes：Temperature is subzero 80 DEG C
To 100 DEG C above freezing, when the time is 0.5-100 small.
9. a kind of method for preparing spherosin derivative, which has the structure shown in Formulas I -1, this method
Comprise the following steps：
1) lactams shown in the method formula XII in claim 1-8 described in any one is used；
2) in acid condition, the lactams shown in the Formula XII is reacted, obtains iminosugar shown in Formulas I -1；
Wherein, the configuration of 1,2,8 and the carbon atom on 8a positions in Formulas I -1 respectively with the carbon on 1 in Formula XII, 2,8 and 8a positions
The configuration of atom corresponds to identical.
10. a kind of method for preparing spherosin, which has the structure shown in Formulas I -2, and this method includes following step
Suddenly：
1) lactams shown in the method formula XII in claim 1-8 described in any one is used；
2) lactams shown in the Formula XII is reduced, obtains the tertiary amine shown in Formula XIII；
3) in acid condition, the tertiary amine shown in the Formula XIII is reacted, obtains iminosugar shown in Formulas I -2；
Wherein, the configuration of 1,2,8 and the carbon atom on 8a positions in Formula XIII and Formulas I -2 respectively with 1 in Formula XII, 2,8 and 8a
The configuration of carbon atom on position corresponds to identical；
R in Formula XIII2With the R in Formula XII2It is identical.
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