CN105541854A - Swainsonine, preparing method for intermediate thereof, swainsonine derivative and preparing method and application of swainsonine derivative - Google Patents
Swainsonine, preparing method for intermediate thereof, swainsonine derivative and preparing method and application of swainsonine derivative Download PDFInfo
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- CN105541854A CN105541854A CN201610014143.7A CN201610014143A CN105541854A CN 105541854 A CN105541854 A CN 105541854A CN 201610014143 A CN201610014143 A CN 201610014143A CN 105541854 A CN105541854 A CN 105541854A
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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 invention relates to the field of natural product synthesis, and discloses a swainsonine derivative, a preparing method and application of the swainsonine derivative, swainsonine and a preparing method for an intermediate of swainsonine. The preparing method includes the following steps that primary alcohol shown in the formula IX is subjected to an oxidation reaction to obtain aldehyde shown in the formula X; the aldehyde shown in the formula X is subjected to a Ylide reaction to obtain unsaturated ester shown in the formula XI; the unsaturated ester shown in the formula XI is subjected to a catalytic hydrogenation reaction to obtain lactam shown in the formula XII. The provided swainsonine derivative can serve as a glycosidase inhibitor. The provided method for preparing the swainsonine derivative is concise in route and low in production cost and structurally modifies swainsonine conveniently.
Description
Technical field
The present invention relates to the synthesis field of natural product, particularly, relate to a kind of prepare trihydroxyoctahydroindolizidine intermediate method, a kind of prepare trihydroxyoctahydroindolizidine derivative method and the trihydroxyoctahydroindolizidine derivative prepared by the method, a kind ofly prepare the method for trihydroxyoctahydroindolizidine and the application of trihydroxyoctahydroindolizidine derivative.
Background technology
Glycosylase take part in many important bioprocesses relevant with glycoconjugates, as the composition and decomposition of the digestion in intestines, glycoprotein, the glycoconjugates metabolism of lysosome (lysosomal) etc., key player is play in life entity, closely related with numerous disease.
Iminosugar, also known as polyhydroxylated alkaloid, azasugar, imines sugar etc., is effective inhibitor of Glycosylase, have in antiviral, antitumor, treatment diabetes etc. important pharmacologically active (as inchester, B; Fleet, G.W.J.Glycobiology1992,2,199 etc.).In addition, many iminosugar have been had to be developed to medicine and go on the market (as NBDNJ, Miglitol, Miglustat).
In iminosugar, Indolizidine compounds has consequence, and a lot of Indolizidine class iminosugar has good biological activity and has huge application prospect.Due to the good nature that Indolizidine class iminosugar shows, finding the Indolizidine Alkaloid with novel structure becomes one of the focal point of researchist in this area.
Trihydroxyoctahydroindolizidine is from mushroom Rhizoctonialeguminicola, within 1973, be separated the Indolizidine class iminosugar obtained, and researchist is in succession separated and obtains this material with some other source from grey swainson pea subsequently.It is found that trihydroxyoctahydroindolizidine is a kind of good α-seminase and seminase II inhibitor by carrying out bioactivity research to it.Further research thinks that trihydroxyoctahydroindolizidine can be used to the Other diseases such as Therapeutic cancer, bacteriological infection and inflammation.Because trihydroxyoctahydroindolizidine has good biological activity and application prospect, trihydroxyoctahydroindolizidine itself has special chemical structure simultaneously, and in order to study its biological and chemical character further, people expand the research to the complete synthesis work of trihydroxyoctahydroindolizidine.
Develop the new emphasis that also can become this area researchist concern as the compound of glycosidase inhibitor.
Summary of the invention
The object of the invention is the defect overcoming prior art, there is provided a kind of newly can as the compound of glycosidase inhibitor and synthetic method thereof, and provide that a kind of route is succinct, production cost is low and be convenient to carry out trihydroxyoctahydroindolizidine the method preparing trihydroxyoctahydroindolizidine and intermediate and derivative of structural modification.
First aspect, the invention provides a kind of method preparing trihydroxyoctahydroindolizidine intermediate, and this trihydroxyoctahydroindolizidine intermediate has the structure shown in formula XII, and the method comprises the following steps:
1) primary alconol shown in formula IX is carried out oxidizing reaction, obtain the aldehyde shown in formula X;
2) aldehyde shown in described formula X is carried out Ylide reaction, obtain the unsaturated ester shown in formula XI;
3) unsaturated ester shown in described formula XI is carried out catalytic hydrogenation, obtain the lactan shown in formula XII;
Wherein, at formula IX in formula XI, the configuration of the carbon atom on 2,3,4 and 5 is R configuration or S configuration independently of one another; And in formula XII, 1,2,8 and 8a position on the configuration of carbon atom be R configuration or S configuration independently of one another;
At formula IX in formula XI, R
1for the hydrogen atom on carbobenzoxy-(Cbz) or phenyl ring is by least one in the benzyl of methoxyl group or halogen substiuted; R
2be selected from methoxyl methyl, methoxyl methyl that methyl is replaced by the straight or branched saturated alkyl of C1-C12, methyl be by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C12; R
3be selected from hydrogen atom on methyl, ethyl, the tertiary butyl, benzyl and phenyl ring by the benzyl of methoxyl group or halogen substiuted;
In formula XII, R is selected from methoxyl methyl and methyl that methoxyl methyl, methyl replaced by the straight or branched saturated alkyl of C1-C12 by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C12.
Second aspect, the invention provides a kind of method preparing trihydroxyoctahydroindolizidine derivative, and this trihydroxyoctahydroindolizidine derivative has the structure shown in formula I-1, and the method comprises the following steps:
1) primary alconol shown in formula IX is carried out oxidizing reaction, obtain the aldehyde shown in formula X;
2) aldehyde shown in described formula X is carried out Ylide reaction, obtain the unsaturated ester shown in formula XI;
3) unsaturated ester shown in described formula XI is carried out catalytic hydrogenation, obtain the lactan shown in formula XII;
4) in acid condition, the lactan shown in described formula XII is reacted, obtains iminosugar shown in formula I-1;
Wherein, at formula IX in formula XI, the configuration of the carbon atom on 2,3,4 and 5 is R configuration or S configuration independently of one another; And in formula XII and formula I-1,1,2,8 and 8a position on the configuration of carbon atom be R configuration or S configuration independently of one another;
At formula IX in formula XI, R
1for the hydrogen atom on carbobenzoxy-(Cbz) or phenyl ring is by least one in the benzyl of methoxyl group or halogen substiuted; R
2be selected from methoxyl methyl, methoxyl methyl that methyl is replaced by the straight or branched saturated alkyl of C1-C12, methyl be by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C12; R
3be selected from hydrogen atom on methyl, ethyl, the tertiary butyl, benzyl and phenyl ring by the benzyl of methoxyl group or halogen substiuted;
In formula XII, R is selected from methoxyl methyl and methyl that methoxyl methyl, methyl replaced by the straight or branched saturated alkyl of C1-C12 by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C12.
The third aspect, the invention provides a kind of method preparing trihydroxyoctahydroindolizidine, this trihydroxyoctahydroindolizidine has the structure shown in formula I-2, and the method comprises the following steps:
1) primary alconol shown in formula IX is carried out oxidizing reaction, obtain the aldehyde shown in formula X;
2) aldehyde shown in described formula X is carried out Ylide reaction, obtain the unsaturated ester shown in formula XI;
3) unsaturated ester shown in described formula XI is carried out catalytic hydrogenation, obtain the lactan shown in formula XII;
4) lactan shown in described formula XII is reduced, obtain the tertiary amine shown in formula XIII;
5) in acid condition, the tertiary amine shown in described formula XIII is reacted, obtains iminosugar shown in formula I-2;
Wherein, at formula IX in formula XI, the configuration of the carbon atom on 2,3,4 and 5 is R configuration or S configuration independently of one another; And in formula XII, formula XIII and formula I-2,1,2,8 and 8a position on the configuration of carbon atom be R configuration or S configuration independently of one another;
At formula IX in formula XI, R
1for the hydrogen atom on carbobenzoxy-(Cbz) or phenyl ring is by least one in the benzyl of methoxyl group or halogen substiuted; R
2be selected from methoxyl methyl, methoxyl methyl that methyl is replaced by the straight or branched saturated alkyl of C1-C12, methyl be by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C12; R
3be selected from hydrogen atom on methyl, ethyl, the tertiary butyl, benzyl and phenyl ring by the benzyl of methoxyl group or halogen substiuted;
In formula XII and formula XIII, R is selected from methoxyl methyl and methyl that methoxyl methyl, methyl replaced by the straight or branched saturated alkyl of C1-C12 by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C12.
Fourth aspect, the invention provides the trihydroxyoctahydroindolizidine derivative with the structure shown in formula I-1 prepared by preceding method,
Wherein, 1,2,8 and 8a position on the configuration of carbon atom be R configuration or S configuration independently of one another.
5th aspect, the invention provides aforementioned trihydroxyoctahydroindolizidine derivative as the application in glycosidase inhibitor.
Trihydroxyoctahydroindolizidine derivative provided by the invention can as glycosidase inhibitor.
The method route preparing trihydroxyoctahydroindolizidine and intermediate and derivative provided by the invention is succinct and production cost is low.
In addition, said synthesis route provided by the invention is convenient to carry out structural modification to trihydroxyoctahydroindolizidine, provides the foundation for finding lead compound further.
Other features and advantages of the present invention are described in detail in embodiment part subsequently.
Embodiment
Below the specific embodiment of the present invention is described in detail.Should be understood that, embodiment described herein, only for instruction and explanation of the present invention, is not limited to the present invention.
Heteroatoms in the present invention can be selected from least one in N, O, S.
First aspect:
The invention provides a kind of method preparing trihydroxyoctahydroindolizidine intermediate, this trihydroxyoctahydroindolizidine intermediate has the structure shown in formula XII, and the method comprises the following steps:
1) primary alconol shown in formula IX is carried out oxidizing reaction, obtain the aldehyde shown in formula X;
2) aldehyde shown in described formula X is carried out Ylide reaction, obtain the unsaturated ester shown in formula XI;
3) unsaturated ester shown in described formula XI is carried out catalytic hydrogenation, obtain the lactan shown in formula XII;
Wherein, at formula IX in formula XI, the configuration of the carbon atom on 2,3,4 and 5 is R configuration or S configuration independently of one another; And in formula XII, 1,2,8 and 8a position on the configuration of carbon atom be R configuration or S configuration independently of one another;
At formula IX in formula XI, R
1for the hydrogen atom on carbobenzoxy-(Cbz) or phenyl ring is by least one in the benzyl of methoxyl group or halogen substiuted; R
2be selected from methoxyl methyl, methoxyl methyl that methyl is replaced by the straight or branched saturated alkyl of C1-C12, methyl be by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C12; R
3be selected from hydrogen atom on methyl, ethyl, the tertiary butyl, benzyl and phenyl ring by the benzyl of methoxyl group or halogen substiuted;
In formula XII, R is selected from methoxyl methyl and methyl that methoxyl methyl, methyl replaced by the straight or branched saturated alkyl of C1-C12 by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C12.
Preferably, at formula IX in formula XI, R
1for the hydrogen atom on carbobenzoxy-(Cbz) or phenyl ring is by least one in the benzyl of methoxyl group or halogen substiuted; R
2be selected from methoxyl methyl, methoxyl methyl that methyl is replaced by the straight or branched saturated alkyl of C1-C8, methyl be by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C8; R
3be selected from hydrogen atom on methyl, ethyl, the tertiary butyl, benzyl and phenyl ring by the benzyl of methoxyl group or halogen substiuted; In formula XII, R is selected from methoxyl methyl and methyl that methoxyl methyl, methyl replaced by the straight or branched saturated alkyl of C1-C8 by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C8.
Preferably, at formula IX in formula XI, R
1for the hydrogen atom on carbobenzoxy-(Cbz) or phenyl ring is by least one in the benzyl of methoxyl group or halogen substiuted; R
2be selected from methoxyl methyl, methoxyl methyl that methyl is replaced by the straight or branched saturated alkyl of C1-C4, methyl be by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C4; R
3be selected from hydrogen atom on methyl, ethyl, the tertiary butyl, benzyl and phenyl ring by the benzyl of methoxyl group or halogen substiuted; In formula XII, R is selected from methoxyl methyl and methyl that methoxyl methyl, methyl replaced by the straight or branched saturated alkyl of C1-C4 by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C4.
Preferably, in step 1) in, described oxidizing reaction is carried out in the presence of an oxidizer, and described oxygenant is selected from least one in potassium permanganate, potassium bichromate, chromium trioxide, Manganse Dioxide, sodium periodate, dimethyl sulfoxide (DMSO)-oxalyl chloride, Dai Si-Martin's oxygenant and bromine water.
Preferably, in step 1) in, the condition of described oxidizing reaction comprises: temperature is subzero 100 DEG C to 50 DEG C above freezing, and the time is 0.5-12 hour.
Preferably, in step 1) in, the consumption mol ratio of the primary alconol shown in formula IX and oxygenant is 1:1-10, is preferably 1:1.5-2.
Preferably, in step 2) in, the condition of described Ylide reaction comprises: temperature is 0-200 DEG C, and the time is 0.5-12 hour; More preferably, the condition of described Ylide reaction comprises: temperature is 90-110 DEG C, and the time is 1-2 hour.
Preferably, in step 2) in, described Ylide reaction carries out under the existence of the ylide reagent derived by monobromo-acetic acid alkyl ester, and described monobromo-acetic acid alkyl ester is preferably selected from least one in methyl bromoacetate, Bromo-t-butylacetate and monobromo-acetic acid benzyl ester.
Preferably, in step 2) in, the consumption mol ratio of the aldehyde shown in described formula X and described ylide reagent is 1:1-10; Be more preferably 1:1.5-2.
Preferably, in step 3) in, the catalyzer carrying out catalytic hydrogenation is selected from least one in palladium carbon, palladium black, palladium hydroxide, Palladous chloride, platinum oxide and platinum black.
Preferably, in step 3) in, the condition of described catalytic hydrogenation comprises: temperature is subzero 80 DEG C to 100 DEG C, and the time is 0.5-100 hour.
Preferably, in step 3) in, the consumption mol ratio of the unsaturated ester shown in described formula XI and catalyzer is 1:0.1-1; Be more preferably 1:0.1-0.5.
Preferably, the primary alconol shown in described formula IX is obtained by following steps:
A) under the first reductive agent exists, the nitrone shown in formula II-a and/or formula II-b is carried out reduction reaction, obtains the azanol shown in formula III;
B) under the second reductive agent exists, the azanol shown in described formula III is carried out reduction reaction, obtains the secondary amine shown in formula IV;
C) secondary amine shown in described formula IV is carried out protective reaction, obtain the compound shown in formula V;
D) the compound machine shown in described formula V is carried out selectivity deprotection reaction, obtain the glycol shown in formula VI;
E) glycol shown in described formula VI is carried out protective reaction, obtain the compound shown in formula VII;
F) compound shown in described formula VII is carried out protective reaction in the basic conditions, obtain compound shown in formula VIII;
G) compound shown in described formula VIII is carried out deprotection reaction, obtain the primary alconol shown in described formula IX;
Wherein, at formula II-a, formula II-b, formula III in formula VIII, 2,3,4 is identical with the configuration of corresponding carbon atom in the primary alconol shown in described formula IX with the configuration of the carbon atom on 5;
At formula V in formula VIII, R
1and R
2respectively with the R in the primary alconol shown in described formula IX
1and R
2identical; R
3be selected from hydrogen atom on methyl, ethyl, the tertiary butyl, benzyl and phenyl ring by the benzyl of methoxyl group or halogen substiuted.
Preferably, step a) in, described first reductive agent is selected from least one in lithium aluminum hydride, diisobutyl aluminium hydride, sodium borohydride, sodium cyanoborohydride, borine, zinc powder, iron powder and Sulfothiorine.Preferably, the consumption mol ratio of described nitrone and described first reductive agent is 1:1-100, is more preferably 1:1-10.Preferably, step a) in, the condition of described reduction reaction comprises: temperature is subzero 80 DEG C to 100 DEG C above freezing, be preferably 0 DEG C; Time is 0.1-100 hour, preferred 0.5-1 hour.
Preferably, in step b) in, described second reductive agent is selected from least one in zinc powder-neutralized verdigris and hydrate, zinc powder-acid, reduced iron powder-neutralized verdigris and hydrate thereof.
Preferably, in step b) in, when selecting zinc powder-neutralized verdigris and hydrate thereof as the second reductive agent, the consumption mol ratio of the azanol shown in formula III, zinc powder and neutralized verdigris is 1:0.1-100:0.1-1, is preferably 1:0.1-20:0.1-0.5; Preferably, in described step, solvent is Glacial acetic acid, and temperature of reaction is 0-100 DEG C, and be preferably 35 DEG C, the time is 0.1-100 hour, is preferably 12 hours.
Preferably, in step b) in, when selecting zinc powder-acid as the second reductive agent, the consumption mol ratio of the azanol shown in formula III, zinc powder is 1:10-100, is preferably 1:10-20, acid used is ammonium chloride saturated solution, in described step, solvent is methyl alcohol, and temperature is 0-100 DEG C, is preferably 35 DEG C, time is 0.1-100 hour, is preferably 12 hours.
Preferably, in step c) in, the condition of described protective reaction comprises: temperature is 0-100 DEG C, and the time is 0.1-100 hour.
Preferably, in steps d) in, described selectivity deprotection reaction carries out in acid condition, and the condition of described selectivity deprotection reaction comprises: temperature is subzero 80 DEG C to 100 DEG C above freezing, and the time is 0.1-100 hour.
Preferably, in step e) in, described in when carrying out protective reaction the protection reagent of use include but not limited at least one in TERT-BUTYL DIMETHYL CHLORO SILANE, tert-butyl diphenyl chlorosilane, tri-phenyl chloride and triphenylmethyl chloride.In step e) in, the condition of described protective reaction comprises: temperature is subzero 80 DEG C to 100 DEG C above freezing, is preferably 0 DEG C; Time is 0.1-100 hour, is preferably 12 hours.
Preferably, in step f) in, described in when carrying out protective reaction the protection reagent of use include but not limited to that chloromethyl methyl ether or methyl are saturated by the straight or branched of C1-C12 or at least one in the chloromethyl ether that replaces containing heteroatomic alkyl.In step f) in, the condition of described protective reaction comprises: temperature is subzero 80 DEG C to 100 DEG C above freezing, is preferably 0 DEG C; Time is 0.1-100 hour, is preferably 36 hours.
Preferably, in step g) in, the deprotecting regent used in described deprotection reaction includes but not limited to tetrabutyl ammonium fluoride and hydrate, Potassium monofluoride, Neutral ammonium fluoride, hydrogen fluoride pyridine salt.In step g) in, the condition of described deprotection reaction comprises: temperature is subzero 20 DEG C to 100 DEG C above freezing, is preferably 25 DEG C; Time is 0.1-24 hour, is preferably 1-2 hour.
Alkaline condition of the present invention can by organic bases and/or mineral alkali add provide, described organic bases is diethylamine, triethylamine, diisopropylamine, diisopropyl ethyl amine, Tetramethyl Ethylene Diamine, pyridine, hexahydropyridine, 2, at least one in 4,6-trimethylpyridine and tetrabutyl ammonium fluoride; Described mineral alkali is at least one in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, sodium hydride, potassium hydride KH and TBAH.
Acidic conditions of the present invention can by organic acid and/or mineral acid add provide, described organic acid is at least one in formic acid, acetic acid, tosic acid, camphorsulfonic acid, para-methylbenzenepyridinsulfonate sulfonate and phenylformic acid; Described mineral acid is at least one in sulfuric acid, hydrochloric acid, nitric acid, perchloric acid, iron trichloride, titanium tetrachloride and boron trifluoride.
Also comprise the steps such as separation and purification well known in the art in described method of the present invention, these are all that the present invention does not repeat them here for known in those skilled in the art, and those skilled in the art should not be construed as the restriction to method of the present invention.
Second aspect:
The invention provides a kind of method preparing trihydroxyoctahydroindolizidine derivative, this trihydroxyoctahydroindolizidine derivative has the structure shown in formula I-1, and the method comprises the following steps:
1) primary alconol shown in formula IX is carried out oxidizing reaction, obtain the aldehyde shown in formula X;
2) aldehyde shown in described formula X is carried out Ylide reaction, obtain the unsaturated ester shown in formula XI;
3) unsaturated ester shown in described formula XI is carried out catalytic hydrogenation, obtain the lactan shown in formula XII;
4) in acid condition, the lactan shown in described formula XII is reacted, obtains iminosugar shown in formula I-1;
Wherein, at formula IX in formula XI, the configuration of the carbon atom on 2,3,4 and 5 is R configuration or S configuration independently of one another; And in formula XII and formula I-1,1,2,8 and 8a position on the configuration of carbon atom be R configuration or S configuration independently of one another;
At formula IX in formula XI, R
1for the hydrogen atom on carbobenzoxy-(Cbz) or phenyl ring is by least one in the benzyl of methoxyl group or halogen substiuted; R
2be selected from methoxyl methyl, methoxyl methyl that methyl is replaced by the straight or branched saturated alkyl of C1-C12, methyl be by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C12; R
3be selected from hydrogen atom on methyl, ethyl, the tertiary butyl, benzyl and phenyl ring by the benzyl of methoxyl group or halogen substiuted;
In formula XII, R is selected from methoxyl methyl and methyl that methoxyl methyl, methyl replaced by the straight or branched saturated alkyl of C1-C12 by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C12.
In the method for a second aspect of the present invention, identical with the method for a first aspect of the present invention by the aspect of the compound of the preparation of compounds of formula XII of formula IX, the present invention does not repeat them here.
Preferably, in step 4) in, the condition that the lactan shown in described formula XII carries out reacting is comprised: temperature is subzero 20 DEG C to 100 DEG C above freezing, and the time is 0.1-24 hour.
The third aspect:
The invention provides a kind of method preparing trihydroxyoctahydroindolizidine, this trihydroxyoctahydroindolizidine has the structure shown in formula I-2, and the method comprises the following steps:
1) primary alconol shown in formula IX is carried out oxidizing reaction, obtain the aldehyde shown in formula X;
2) aldehyde shown in described formula X is carried out Ylide reaction, obtain the unsaturated ester shown in formula XI;
3) unsaturated ester shown in described formula XI is carried out catalytic hydrogenation, obtain the lactan shown in formula XII;
4) lactan shown in described formula XII is reduced, obtain the tertiary amine shown in formula XIII;
5) in acid condition, the tertiary amine shown in described formula XIII is reacted, obtains iminosugar shown in formula I-2;
Wherein, at formula IX in formula XI, the configuration of the carbon atom on 2,3,4 and 5 is R configuration or S configuration independently of one another; And in formula XII, formula XIII and formula I-2,1,2,8 and 8a position on the configuration of carbon atom be R configuration or S configuration independently of one another;
At formula IX in formula XI, R
1for the hydrogen atom on carbobenzoxy-(Cbz) or phenyl ring is by least one in the benzyl of methoxyl group or halogen substiuted; R
2be selected from methoxyl methyl, methoxyl methyl that methyl is replaced by the straight or branched saturated alkyl of C1-C12, methyl be by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C12; R
3be selected from hydrogen atom on methyl, ethyl, the tertiary butyl, benzyl and phenyl ring by the benzyl of methoxyl group or halogen substiuted;
In formula XII and formula XIII, R is selected from methoxyl methyl and methyl that methoxyl methyl, methyl replaced by the straight or branched saturated alkyl of C1-C12 by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C12.
In the method for a third aspect of the present invention, identical with the method for a first aspect of the present invention by the aspect of the compound of the preparation of compounds of formula XII of formula IX, the present invention does not repeat them here.
Preferably, in step 4) in, the condition of described reduction comprises: temperature is subzero 80 DEG C to 100 DEG C above freezing, and the time is 0.1-100 hour.
Fourth aspect:
The invention provides the trihydroxyoctahydroindolizidine derivative with the structure shown in formula I-1 that preceding method prepares,
Wherein, 1,2,8 and 8a position on the configuration of carbon atom be R configuration or S configuration independently of one another.
5th aspect:
The invention provides aforementioned trihydroxyoctahydroindolizidine derivative as the application in glycosidase inhibitor.
Described trihydroxyoctahydroindolizidine derivative has the structure shown in formula I-1,
Wherein, 1,2,8 and 8a position on the configuration of carbon atom be R configuration or S configuration independently of one another.
Preferably, described Glycosylase is at least one in alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase enzymes, alpha-Mannosidase, beta-Mannosidase, alpha-L-fucosidase, trehalase, amyloglucosidase and alpha-L-Rhamnosidase.
Preferably, in above-mentioned each side of the present invention, described trihydroxyoctahydroindolizidine derivative is the structure shown in the structure shown in formula I-1-1 and/or formula I-1-2,
Described trihydroxyoctahydroindolizidine derivative of the present invention or its salt or its hydrate also can be used for preparing any one medicine following: the medicine 1) preventing and/or treating diabetes; 2) medicine of gaucher's disease is prevented and/or treated; 3) medicine of tumour is prevented and/or treated; 4) antiviral.
In described medicine of the present invention, one or more pharmaceutically acceptable carriers can also be added.Described carrier comprises the thinner of pharmaceutical field routine, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant and other optional additives.
Medicine prepared by trihydroxyoctahydroindolizidine derivative of the present invention or its pharmacy acceptable salt, hydrate can make the various ways such as injection liquid, tablet, pulvis, granule, capsule, oral liquid, paste, creme.The medicine of above-mentioned various formulation all can be prepared according to the ordinary method of pharmaceutical field.
Medicine of the present invention can utilize various route of administration administration, includes but not limited to oral, suction, rectum, transdermal, administration and subcutaneous, muscle or intravenous administration in mucous membrane intestines.
Compound of the present invention or their pharmaceutically acceptable simple derivatives, can be individually dosed, or with other treating diabetes known, antiviral, antibacterial administration together with antitumor drug.
The nitrone that the present invention derives with various aldohexose provides a method that is succinct, synthesized swainsonine derivative efficiently for raw material, this method can carry out structural modification to trihydroxyoctahydroindolizidine derivative simply, easily, provides the foundation for finding lead compound further.
Below will be described the present invention by embodiment.
Below in case of no particular description, the various raw materials used are all from being purchased.
Preparation example 1
The preparation of nitrone shown in formula II-a-1:
Under ice bath, agitation condition, 1 milliliter of vitriol oil is dropwise added in 500 milliliters of dry acetone, add D-MANNOSE sugar (0.2mol) reaction subsequently until raw material disappears (TLC monitoring), neutrality is neutralized to sodium bicarbonate, filter and remove inorganic salt, solvent evaporated gained crude product 2,3, the two propylidene D-furans seminose of 4,6-O-directly throws the next step.
Pyridine (0.37mol) is added above-mentioned crude product 2,3,4, in methylene dichloride (100mL) solution of the two propylidene D-furans seminose of 6-O-, toward wherein adding hydroxylamine hydrochloride (0.25mol), reflux is after 12 hours, by solvent evaporate to dryness, then in concentrated solution, ethyl acetate (150mL) and hydrochloric acid (1mol/L, 30mL) is added, through extracting and demixing, merge organic phase, drying, concentrated, obtain crude product 2,3, the two propylidene D-furans seminose oxime of 4,6-O-, directly throws in next step reaction.
Triethylamine (0.37mol) is added above-mentioned crude product 2,3,4, in methylene dichloride (100mL) solution of the two propylidene D-furans seminose oxime of 6-O-, add TERT-BUTYL DIMETHYL CHLORO SILANE (0.25mol), room temperature reaction is after 12 hours, by solvent evaporate to dryness, then in concentrated solution, ethyl acetate (150mL) is added, through extracting and demixing, merge organic phase, dry, concentrated, obtain crude product 2,3,4, the two propylidene D-furans seminose oxime silicon ether of 6-O-, directly throws in next step reaction.
By above-mentioned crude product 2,3,4, the two propylidene D-furans seminose oxime silicon ether of 6-O-is dissolved in methylene dichloride (100mL), add pyridine (0.37mol) and methane sulfonyl chloride (0.20mol), stirring at room temperature, after 2 hours, adds this reaction of aqueous hydrochloric acid (1mol/L, 50mL) cancellation.Through extracting and demixing, merge organic phase, dry, concentrated, obtain crude product (2S, 3S, 4R)-2,3,5-tri-benzyloxy-4-sulfonyloxy methyl oxygen-1-valeral methyloxime ether, be directly used in next step reaction.
Above-mentioned crude product is dissolved in tetrahydrofuran (THF) (100mL), add tetrabutyl ammonium fluoride (0.25mol), stirring at room temperature 12 hours post-heating reflux 12 hours, by solvent evaporate to dryness, then in concentrated solution, add ethyl acetate (100mL), through extracting and demixing, merge organic phase, drying, concentrated, obtain the 22.5g of nitrone shown in formula II-a-1.White solid, mp.90-92 DEG C.
IR (KBr film) ν 3078,2986,2940,1570,1370,1261,1204,1055cm
-1;
1HNMR(300MHz,CDCl
3)δ6.92(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)；
13CNMR(75MHz,CDCl
3)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 methyl alcohol, add sodium borohydride (80mmol), after reaction 4h, TLC display reacts completely, and adds saturated ammonium chloride solution cancellation reaction, most of methyl alcohol is removed under vacuum, water and each 25mL of ethyl acetate is added, extraction into ethyl acetate three times, dried over mgso in the sticky white solid obtained, solvent removed in vacate, gained crude product is directly used in next step reaction.
Be dissolved in 30mL methylene dichloride by gained crude product, add activated manganese dioxide (27mmol), after reaction 48h, TLC display reacts completely, solids removed by filtration, solvent removed in vacate, column chromatography obtains 3.1g (white solid, purity 95%).
[α]
D 20＝+16(c0.5,CH
2Cl
2)；
1HNMR(300MHz,CDCl
3)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)；
13CNMR(75MHz,CDCl
3)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
Preparation Compound I-1-1:
1) synthesis of formula III-1 compound:
Under condition of ice bath, substrate II-a-1 (0.7mmol) is dissolved in 15mL methyl alcohol, adds sodium borohydride (29mmol), after reaction 4h, TLC display reacts completely, add saturated ammonium chloride solution cancellation reaction, remove most of methyl alcohol under vacuum, in the sticky white solid obtained, add water and each 5mL of ethyl acetate, extraction into ethyl acetate three times, dried over mgso, solvent removed in vacate, not purified formula III-1 white solid 1.6g, productive rate 88%, purity 97%.
Structural identification: m.p.79-83 DEG C; [α]
d 20=-70 (c=1.0, CH
2cl
2);
1hNMR (300MHz, CDCl
3) 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).
13cNMR (75MHz, CDCl
3) δ 110.54,108.31,77.67,74.91,74.29,71.99,67.72,63.35,26.79,25.63,25.48,23.95.
2) synthesis of formula IV-1 compound:
Under room temperature condition, zinc powder (23.4mmol) and neutralized verdigris (23.4mmol) are joined in 15mL acetic acid, after 15min, system becomes red-brown from grey, substrate (14.4mmol) is dissolved in 15mL acetic acid, and adds in reaction system, room temperature for overnight, TLC display reacts completely, remove acetic acid under vacuum, ethyl acetate washing solid 3 times, add saturated NaOH solution washing organic phase, cross the floss filtered in suspension liquid, extraction into ethyl acetate, dried over mgso, filters, solvent removed in vacate, obtains formula IV-1 crude product.
3) synthesis of formula V-1 compound:
Be dissolved in 25mL tetrahydrofuran (THF) under gained formula IV-1 crude product room temperature, add 0.5mL water, then add sodium bicarbonate (25.9mmol), CbzCl (22mmol), after reaction 2h, TLC display reacts completely, add saturated ammonium chloride, extraction into ethyl acetate, dried over mgso, is spin-dried for after filtration, column chromatography obtains formula V-1 compound, step 2) and step 3) two step overall yields 89%, colorless oil, purity 96%.
Structural identification:
1hNMR (300MHz, CDCl
3) 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).
13cNMR (75MHz, CDCl
3) 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 formula VI-1 compound:
Be dissolved in 25mL methyl alcohol by substrate V-1 (13.5mmol) under room temperature condition, add 1 % by weight sulfuric acid of 15mL, reaction is spent the night, TLC display reacts completely, and adds saturated sodium bicarbonate adjust ph to weakly alkaline, removes most of acetone under vacuum, add water and each 5mL of ethyl acetate, extract three times, filter after dried over mgso, solvent removed in vacuo, column chromatography (PE/EtOAc=3:1) obtains formula VI-1 compound, colourless oil liquid, productive rate 52%, purity 97%.
Structural identification:
1hNMR (300MHz, CDCl
3) 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);
13cNMR (75MHz, CDCl
3) 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 formula VII-1 compound:
Under room temperature, VI-1 (14.2mmol) is dissolved in 25mL methylene dichloride, after adding 2mL triethylamine, slowly add TERT-BUTYL DIMETHYL CHLORO SILANE (26mmol), after stirring 7h, TLC display reacts completely, add saturated ammonium chloride solution, EtOAc (10mL × 3) extracts, dried over mgso, solids removed by filtration, solvent removed in vacate, obtains formula VII-1 crude compound.
6) synthesis of formula VIII-1 compound:
Under condition of ice bath, above-mentioned formula VII-1 crude compound is dissolved in 25mL dry methylene chloride, argon replaces, add DIPEA (25mmol), then chloromethyl methyl ether (20mmol) is slowly added, room temperature reaction 24h is proceeded to after 1h, add DIPEA (6mmol) and chloromethyl methyl ether (7.7mmol), after 2h, TLC display reacts completely, add saturated ammonium chloride solution cancellation reaction, ethyl acetate (10mL × 3) extracts, merge organic phase, after dried over mgso, suction filtration removing solid, solvent removed in vacate, obtain formula VIII-1 crude compound.
7) synthesis of formula IX-1 compound:
Under room temperature, be dissolved in the tetrahydrofuran (THF) of 25mL by above-mentioned formula VIII-1 compound, add excessive hydrogen fluoride pyridine salt, TLC display substrate completely dissolve after reaction 2h, adds saturated NaHCO
3cancellation is reacted, ethyl acetate (10mL × 3) extracts, merge organic phase, after dried over mgso, suction filtration removing solid, solvent removed in vacate, column chromatography (sherwood oil: ethyl acetate=5:1), obtain formula IX-1 compound, be colourless oil liquid (productive rate is 63%, purity 98%).
Structural identification:
1hNMR (300MHz, CDCl
3) 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).
13cNMR (75MHz, CDCl
3) δ 136.01,128.67,128.42,128.20,113.56,97.61,79.97,77.89,67.87,62.44,59.32,55.89,50.99,27.34,25.43.
8) synthesis of formula X-1 compound:
Under room temperature, DMP (1.56mmol) is joined in the methylene dichloride of 25mL drying, then adds NaHCO
3(2.34mmol), be dissolved in the dry methylene chloride of 5mL after 5min by formula IX-1 compound (0.78mmol), be added dropwise in above-mentioned reaction system, reaction system is muddy shape, adds the saturated Na of 3mL after reaction 2h
2s
2o
3, system becomes settled solution, and ethyl acetate (15mL × 3) extracts, and merge organic phase, saturated common salt water washing three times, solids removed by filtration after dried over mgso, solvent removed in vacate obtains pale yellow oily liquid body, obtains formula X-1 crude compound.
9) synthesis of formula XI-1 compound:
Formula X-1 crude compound is dissolved in dry toluene, after adding the derivative phosphonium ylide (0.936mmol) of ethyl bromoacetate, the completely dissolve of backflow 1.5h, TLC display substrate, remove toluene under vacuum, rapid column chromatography obtains XI-1 crude product.
10) synthesis of formula XII-1 compound:
Formula XII-1 crude compound is dissolved in the high-purity methyl alcohol of 5mL, the Pd/C of 10 % by weight of 30mg is added after argon replaces, pass into hydrogen, replace three times, after under room temperature, reaction is spent the night, the completely dissolve of TLC display substrate, cross and filter Pd/C, column chromatography (sherwood oil: ethyl acetate=1:1), obtains formula XII-1 (productive rate is 72%, purity 97%).
Structural identification:
1hNMR (300MHz, CDCl
3) 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).
13cNMR (75MHz, CDCl
3) δ 173.87,111.96,95.86,79.81,70.31,65.29,55.65,50.63,29.53,27.69,26.57,24.84.
11) synthesis of formula I-1-1 compound:
Under room temperature, the HCl solution of the 3M of 2mL is added, TLC display substrate completely dissolve after reaction 20min, solvent removed in vacate in the methanol solution of formula XII-1 compound (0.2mmol), obtain colloidal liquid formula I-1-1 compound (productive rate is 94%, purity 99%).
Structural identification:
1hNMR (500MHz, D
2o) 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).
13cNMR (126MHz, D
2o) δ 171.64,70.27,69.19,65.70,63.23,48.28,28.83,28.09.
Embodiment 2
Preparation Compound I-1-2:
1) synthesis of formula III-2 compound:
Under condition of ice bath, substrate II-b-2 (20mmol) is dissolved in 15mL methyl alcohol, add sodium borohydride (80mmol), after reaction 4h, TLC display reacts completely, add saturated ammonium chloride solution cancellation reaction, most of methyl alcohol is removed under vacuum, water and each 5mL of ethyl acetate is added in the sticky white solid obtained, extraction into ethyl acetate three times, dried over mgso, solvent removed in vacate, not purified formula III-1 compound as white solid (productive rate is 89%, purity 98%).
Structural identification:
1hNMR (300MHz, CDCl
3) δ 4.75 (dd, J=11.5Hz, 5.9Hz, 1H), 4.45-4.41 (m, 1H), 4.30 (q, J=6.Hz5,1H), 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);
13cNMR (75MHz, CDCl
3) δ 114.1,109.6,80.8,78.5,75.5,75.2,66.3,63.7,27.2,26.6,25.3,24.8.
2) synthesis of formula IV-2 compound:
Under room temperature condition, zinc powder (0.15mmol) and neutralized verdigris (23.4mmol) are joined in 15mL acetic acid, after 15min, system becomes red-brown from grey, formula III-1 compound (0.15mmol) is dissolved in 15mL acetic acid, and add reaction system, room temperature for overnight, TLC display reacts completely, acetic acid is removed under vacuum, ethyl acetate washing solid 3 times, add saturated NaOH solution washing organic phase, cross the floss filtered in suspension liquid, extraction into ethyl acetate, dried over mgso, filter, solvent removed in vacate, obtain formula IV-2 crude compound.
3) synthesis of formula V-2 compound:
To be dissolved in 25mL tetrahydrofuran (THF) under above-mentioned IV-2 crude compound room temperature, add 0.5mL water, then add sodium bicarbonate (25.9mmol), CbzCl (22mmol), after reaction 2h, TLC display reacts completely, and adds saturated ammonium chloride, extraction into ethyl acetate, dried over mgso, is spin-dried for after filtration, and column chromatography obtains formula V-2 compound, and (productive rate is 82%, purity 96%), colorless oil.
Structural identification:
1hNMR (300MHz, CDCl
3) 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),
13cNMR (75MHz, CDCl3) δ 155.98,155.27,128.46,128.13,127.93,127.53,127.13,126.94,111.58,109.14,108.98,83.43,82.82,80.16,77.72,67.32,67.15,67.00,66.03,65.91,65.57,64.59,63.58,54.43,54.32,26.87,26.38,26.02,25.84,25.54,25.47,25.37,25.05,24.84.
4) synthesis of formula VI-2 compound:
Under room temperature condition, formula V-2 compound (8.9mmol) is dissolved in 25mL methyl alcohol, add 1 % by weight sulfuric acid of 15mL, reaction is spent the night, TLC display reacts completely, add saturated sodium bicarbonate adjust ph to weakly alkaline, most of methyl alcohol is removed under vacuum, add water and each 5mL of ethyl acetate, extract three times, filter after dried over mgso, solvent removed in vacuo, column chromatography (sherwood oil: ethyl acetate=3:1), obtain formula VI-2 compound (productive rate is 69%, purity 96%), colourless oil liquid.
Structural identification:
1hNMR (300MHz, CDCl
3) 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);
13cNMR (75MHz, CDCl
3) δ 156.89,136.46,128.62,128.18,127.62,111.57,83.16,80.00,73.58,67.59,65.07,63.35,54.34,27.01,24.92.
5) synthesis of formula VII-2 compound:
Under room temperature, formula VI-2 compound (13mmol) is dissolved in 25mL methylene dichloride, after adding triethylamine (26mmol), slowly add TERT-BUTYL DIMETHYL CHLORO SILANE (20mmol), after stirring 7h, TLC display reacts completely, add saturated ammonium chloride solution, EtOAc (10mL × 3) extracts, dried over mgso, solids removed by filtration, solvent removed in vacate, obtains formula VII-2 crude compound.
6) synthesis of formula VIII-2 compound:
Under condition of ice bath, above-mentioned formula VII-2 crude compound is dissolved in 25mL dry methylene chloride, argon replaces, add DIPEA (25mmol), then chloromethyl methyl ether (20mmol) is slowly added, room temperature reaction 24h is proceeded to after 1h, add DIPEA (6mmol) and chloromethyl methyl ether (7.7mmol), after 2h, TLC display reacts completely, add saturated ammonium chloride solution cancellation reaction, ethyl acetate (10mL × 3) extracts, merge organic phase, after dried over mgso, suction filtration removing solid, solvent removed in vacate, obtain formula VIII-2 crude compound.
7) synthesis of formula IX-2 compound:
Under room temperature, be dissolved in the tetrahydrofuran (THF) of 25mL by above-mentioned formula VIII-2 compound, add tetrabutyl ammonium fluoride (15mmol), TLC display substrate completely dissolve after reaction 2h, adds saturated NaHCO
3cancellation is reacted, ethyl acetate (10mL × 3) extracts, merge organic phase, after dried over mgso, suction filtration removing solid, solvent removed in vacate, column chromatography (sherwood oil: ethyl acetate=5:1), obtain formula IX-2 compound, be colourless oil liquid (productive rate is 77%, purity 97%).
Structural identification:
1hNMR (300MHz, CDCl
3) 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);
13cNMR (75MHz, CDCl
3) δ 156.73,136.42,128.53,128.10,127.60,111.47,96.86,83.04,80.92,80.11,67.52,64.17,60.68,55.93,54.28,26.90,24.80.
8) synthesis of formula X-2 compound:
Under room temperature, DMP (2.3mmol) is joined in the methylene dichloride of 25mL drying, then adds NaHCO
3(3.5mmol), be dissolved in the dry methylene chloride of 5mL after 5min by formula IX-2 compound (1.3mmol), be added dropwise in above-mentioned precursor reactant system, reaction system is muddy shape, adds the saturated Na of 3mL after reaction 2h
2s
2o
3, system becomes settled solution, and ethyl acetate (15mL × 3) extracts, and merge organic phase, saturated common salt water washing three times, solids removed by filtration after dried over mgso, solvent removed in vacate obtains pale yellow oily liquid body, obtains formula X-2 crude compound.
9) synthesis of formula XI-2 compound:
Formula X-2 crude compound is dissolved in dry toluene, after adding the derivative phosphonium ylide (1.5mmol) of ethyl bromoacetate, the completely dissolve of backflow 1.5h, TLC display substrate, remove toluene under vacuum, rapid column chromatography obtains XI-2 crude product.
10) synthesis of formula XII-1 compound:
Formula XII-2 crude compound is dissolved in the high-purity methyl alcohol of 5mL, the Pd/C of 10 % by weight of 30mg is added after argon replaces, pass into hydrogen, replace three times, after under room temperature, reaction is spent the night, the completely dissolve of TLC display substrate, cross and filter Pd/C, column chromatography (sherwood oil: ethyl acetate=1:1), obtains formula XII-2 (productive rate is 63%, purity 99%).
Structural identification:
1hNMR (300MHz, CDCl
3) 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).
13cNMR (75MHz, CDCl
3) δ 168.47,113.20,95.36,79.35,76.52,67.90,66.52,56.08,49.37,27.84,26.38,25.64,25.12.
11) synthesis of formula I-1-2 compound:
Under room temperature, the HCl solution of the 3M of 2mL is added, TLC display substrate completely dissolve after reaction 20min, solvent removed in vacate in the methanol solution of formula XII-2 compound (0.2mmol), obtain colloidal liquid formula I-1-2 compound (productive rate is 99%, purity 99%).
Structural identification:
1hNMR (300MHz, D
2o) 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).
13cNMR (75MHz, D
2o) δ 172.34,70.55,67.90,62.59,61.00,51.46,26.57,25.45.
Embodiment 3
Preparation Compound I-2-1:
Following synthetic route is adopted to prepare Compound I-2-1, wherein, identical with the method in embodiment 1 by the method for formula II-a-1 preparation of compounds of formula XII-1 compound;
Wherein, by the step of formula XII-1 preparation of compounds of formula XIII-1 compound be:
Formula XII-1 compound (0.73mmol) is dissolved in the tetrahydrofuran (THF) of 10mL drying, adds LiAlH
4(3mmol), the completely dissolve of heating reflux reaction 4h, TLC display substrate, adds the 15 % by weight NaOH aqueous solution of 0.08mL after adding the water of 0.08mL, finally add the water of 0.24mL, there is white granular solid in system, suction filtration removing solid, washed with dichloromethane, gained settled solution is directly spin-dried for, column chromatography (sherwood oil: ethyl acetate=3:1) removes major impurity, obtains formula XIII-1 compound, weak yellow liquid.
By the step of formula XIII-1 preparation of compounds of formula I-2-1 compound be:
Under room temperature, the HCl solution of the 3M of 2mL is added in the methanol solution of above-mentioned formula XIII-1 compound, TLC display substrate completely dissolve after reaction 20min, solvent removed in vacate, obtain white solid, through acidic ion exchange resin process after ammonia neutralization, obtain formula I-2-1 compound (productive rate 74%, purity 99%).
Structural identification:
1hNMR (500MHz, D
2o) δ 4.33 – 4.25 (m, 1H), 4.20 (dd, J=5.7,3.6Hz, 1H), 3.75 (tdJ=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, D
2o) δ 72.29,69.09,68.53,65.66,59.90,51.23,31.85,22.54.
Embodiment 4
Preparation Compound I-2-2:
Following synthetic route is adopted to prepare Compound I-2-2, wherein, identical with the method in embodiment 2 by the method for formula II-b-2 preparation of compounds of formula XII-2 compound;
Wherein, by the step of formula XII-2 preparation of compounds of formula XIII-2 compound be:
Formula XII-2 compound (1.5mmol) is dissolved in the tetrahydrofuran (THF) of 10mL drying, adds LiAlH
4(6mmol), heating reflux reaction 4h, the completely dissolve of TLC display substrate, adds the 15 % by weight NaOH aqueous solution of 0.08mL, finally adds the water of 0.24mL after adding the water of 0.08mL, there is white granular solid in system, suction filtration removing solid, washed with dichloromethane, gained settled solution is directly spin-dried for, column chromatography (sherwood oil: ethyl acetate=3:1) obtains formula XIII-2 compound, weak yellow liquid.
Structural identification:
1hNMR (300MHz, CDCl
3) 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).
13cNMR (75MHz, CDCl
3) δ 113.82,96.06,79.58,71.41,70.52,60.54,55.82,52.37,28.13,27.34,25.28,19.73.
The synthesis of formula I-2-2 compound:
Under room temperature, the HCl solution of the 3M of 2mL is added in the methanol solution of above-mentioned formula XIII-2 compound (0.2mmol), TLC display substrate completely dissolve after reaction 20min, solvent removed in vacate, obtain white solid, through acidic ion exchange resin process after ammonia neutralization, obtain formula I-2-2 compound (productive rate 94%, purity 98%).
Structural identification: 1HNMR (500MHz, D
2o, 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) δ 69.17,69.15,66.47,62.75,59.90,52.58,29.36.
Test case
1) test materials and source
Test compound: formula I-1-1 compound and formula I-1-2 compound.
Test materials: 4-nitrophenol pyranoside matrix, disaccharides and Glycosylase (all purchased from Sigma-Aldrich).
2) test method
Dynamics research carries out in the Trisodium Citrate/phosphoric acid buffer of the 50mM of 37 DEG C.According to the difference of matrix, the enzyme concn of preparation is 0.1-0.5mg/mL.Active testing, is tested under the optimum activity pH of often kind of enzyme for matrix with 4-nitrophenol pyranoside.The enzyme solution of matrix, suitably dilution and inhibitor (formula I-1-1 compound and formula I-1-2 compound) are cultivated 30 minutes at 37 DEG C, then starts in ultraviolet-visible pectrophotometer and react, measure its absorption to 400nm wavelength light.GraFit program is finally used to carry out data analysis.
3) evaluation result
Formula I-1-1 compound and the inhibit activities result of formula I-1-2 compound to Glycosylase as shown in table 1.
Evaluation result shows, formula I-1-1 compound provided by the present invention has inhibit activities, IC to beta-glucosidase (beef liver) and beta-galactosidase enzymes (beef liver)
50be respectively 595 μMs and 491 μMs; Formula I-1-2 compound has inhibit activities to alpha-Mannosidase, IC
50it is 625 μMs.
Table 1
| Glycosylase | Formula I-1-1 compound, IC 50/μM | Formula I-1-2 compound, IC 50/μM |
| Beta-glucosidase | ||
| Almond | Inhibiting rate under 1000 μMs of concentration is 6.6% | Inhibiting rate under 1000 μMs of concentration is 6.2% |
| Beef liver | 595 | - |
| Beta-galactosidase enzymes | ||
| Beef liver | 491 | Inhibiting rate under 1000 μMs of concentration is 17.9% |
| Alpha-Mannosidase | ||
| Sword bean | Inhibiting rate under 1000 μMs of concentration is 3.8% | 625 |
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, within the scope of technical conceive 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.
It should be noted that in addition, each concrete technical characteristic described in above-mentioned embodiment, in reconcilable situation, can be combined by any suitable mode, in order to avoid unnecessary repetition, the present invention illustrates no longer separately to various possible array mode.
In addition, also can carry out arbitrary combination between various different embodiment of the present invention, as long as it is without prejudice to thought of the present invention, it should be considered as content disclosed in this invention equally.
Claims (10)
1. prepare a method for trihydroxyoctahydroindolizidine intermediate, this trihydroxyoctahydroindolizidine intermediate has the structure shown in formula XII, and the method comprises the following steps:
1) primary alconol shown in formula IX is carried out oxidizing reaction, obtain the aldehyde shown in formula X;
2) aldehyde shown in described formula X is carried out Ylide reaction, obtain the unsaturated ester shown in formula XI;
3) unsaturated ester shown in described formula XI is carried out catalytic hydrogenation, obtain the lactan shown in formula XII;
Wherein, at formula IX in formula XI, the configuration of the carbon atom on 2,3,4 and 5 is R configuration or S configuration independently of one another; And in formula XII, 1,2,8 and 8a position on the configuration of carbon atom be R configuration or S configuration independently of one another;
At formula IX in formula XI, R
1for the hydrogen atom on carbobenzoxy-(Cbz) or phenyl ring is by least one in the benzyl of methoxyl group or halogen substiuted; R
2be selected from methoxyl methyl, methoxyl methyl that methyl is replaced by the straight or branched saturated alkyl of C1-C12, methyl be by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C12; R
3be selected from hydrogen atom on methyl, ethyl, the tertiary butyl, benzyl and phenyl ring by the benzyl of methoxyl group or halogen substiuted;
In formula XII, R is selected from methoxyl methyl and methyl that methoxyl methyl, methyl replaced by the straight or branched saturated alkyl of C1-C12 by the methoxyl methyl replaced containing heteroatomic alkyl of the straight or branched of C1-C12.
2. method according to claim 1, wherein, in step 1) in, described oxidizing reaction is carried out in the presence of an oxidizer, and described oxygenant is selected from least one in potassium permanganate, potassium bichromate, chromium trioxide, Manganse Dioxide, sodium periodate, dimethyl sulfoxide (DMSO)-oxalyl chloride, Dai Si-Martin's oxygenant and bromine water; Preferably
The condition of described oxidizing reaction comprises: temperature is subzero 100 DEG C to 50 DEG C above freezing, and the time is 0.5-12 hour.
3. method according to claim 1 and 2, wherein, in step 1) in, the consumption mol ratio of the primary alconol shown in formula IX and oxygenant is 1:1-10, is preferably 1:1.5-2.
4. method according to claim 1, wherein, in step 2) in, the condition of described Ylide reaction comprises: temperature is 0-200 DEG C, and the time is 0.5-12 hour.
5. method according to claim 1, wherein, in step 3) in, the catalyzer carrying out catalytic hydrogenation is selected from least one in palladium carbon, palladium black, palladium hydroxide, Palladous chloride, platinum oxide and platinum black; Preferably
The condition of described catalytic hydrogenation comprises: temperature is subzero 80 DEG C to 100 DEG C, and the time is 0.5-100 hour.
6. according to the method in claim 1-5 described in any one, wherein, the primary alconol shown in described formula IX is obtained by following steps:
A) under the first reductive agent exists, the nitrone shown in formula II-a and/or formula II-b is carried out reduction reaction, obtains the azanol shown in formula III;
B) under the second reductive agent exists, the azanol shown in described formula III is carried out reduction reaction, obtains the secondary amine shown in formula IV;
C) secondary amine shown in described formula IV is carried out protective reaction, obtain the compound shown in formula V;
D) the compound machine shown in described formula V is carried out selectivity deprotection reaction, obtain the glycol shown in formula VI;
E) glycol shown in described formula VI is carried out protective reaction, obtain the compound shown in formula VII;
F) compound shown in described formula VII is carried out protective reaction in the basic conditions, obtain compound shown in formula VIII;
G) compound shown in described formula VIII is carried out deprotection reaction, obtain the primary alconol shown in described formula IX;
Wherein, at formula II-a, formula II-b, formula III in formula VIII, 2,3,4 is identical with the configuration of corresponding carbon atom in the primary alconol shown in described formula IX with the configuration of the carbon atom on 5;
At formula V in formula VIII, R
1and R
2respectively with the R in the primary alconol shown in described formula IX
1and R
2identical; R
3be selected from hydrogen atom on methyl, ethyl, the tertiary butyl, benzyl and phenyl ring by the benzyl of methoxyl group or halogen substiuted.
7. prepare a method for trihydroxyoctahydroindolizidine derivative, this trihydroxyoctahydroindolizidine derivative has the structure shown in formula I-1, and the method comprises the following steps:
1) lactan shown in method preparation formula XII in claim 1-6 described in any one is adopted;
2) in acid condition, the lactan shown in described formula XII is reacted, obtains iminosugar shown in formula I-1;
Wherein, 1 in formula I-1,2,8 with the configuration of the carbon atom on 8a position respectively with 1 in formula XII, 2,8 corresponding identical with the configuration of the carbon atom on 8a position.
8. prepare a method for trihydroxyoctahydroindolizidine, this trihydroxyoctahydroindolizidine has the structure shown in formula I-2, and the method comprises the following steps:
1) lactan shown in method preparation formula XII in claim 1-6 described in any one is adopted;
2) lactan shown in described formula XII is reduced, obtain the tertiary amine shown in formula XIII;
3) in acid condition, the tertiary amine shown in described formula XIII is reacted, obtains iminosugar shown in formula I-2;
Wherein, formula XIII and 1 in formula I-2,2,8 with the configuration of the carbon atom on 8a position respectively with 1 in formula XII, 2,8 corresponding identical with the configuration of the carbon atom on 8a position;
R in formula XIII is identical with the R in formula XII.
9. the trihydroxyoctahydroindolizidine derivative with the structure shown in formula I-1 prepared by method according to claim 7,
Wherein, 1,2,8 and 8a position on the configuration of carbon atom be R configuration or S configuration independently of one another.
10. trihydroxyoctahydroindolizidine derivative according to claim 9 is as the application in glycosidase inhibitor.
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|---|---|---|---|---|
| CN109651362A (en) * | 2018-12-20 | 2019-04-19 | 中国农业科学院兰州畜牧与兽药研究所 | A kind of spherosin derivative and its preparation method and application |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993009117A1 (en) * | 1991-11-06 | 1993-05-13 | Toronto Research Chemicals Inc. | Immunostimulating swainsonine analogs |
| WO2010015816A2 (en) * | 2008-08-06 | 2010-02-11 | Summit Corporation Plc | Treatment of lysosomal storage disorders and other proteostatic diseases |
| WO2010015815A2 (en) * | 2008-08-05 | 2010-02-11 | Summit Corporation Plc | Compounds for the treatment of flaviviral infections |
| WO2010029313A1 (en) * | 2008-09-11 | 2010-03-18 | Summit Corporation Plc. | Antiinfective compounds |
| WO2010049678A2 (en) * | 2008-10-31 | 2010-05-06 | Summit Corporation Plc | Treatment of energy utilization diseases |
-
2016
- 2016-01-11 CN CN201610014143.7A patent/CN105541854B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993009117A1 (en) * | 1991-11-06 | 1993-05-13 | Toronto Research Chemicals Inc. | Immunostimulating swainsonine analogs |
| WO2010015815A2 (en) * | 2008-08-05 | 2010-02-11 | Summit Corporation Plc | Compounds for the treatment of flaviviral infections |
| WO2010015816A2 (en) * | 2008-08-06 | 2010-02-11 | Summit Corporation Plc | Treatment of lysosomal storage disorders and other proteostatic diseases |
| WO2010029313A1 (en) * | 2008-09-11 | 2010-03-18 | Summit Corporation Plc. | Antiinfective compounds |
| WO2010049678A2 (en) * | 2008-10-31 | 2010-05-06 | Summit Corporation Plc | Treatment of energy utilization diseases |
Non-Patent Citations (4)
| Title |
|---|
| BARRY M. TROST等: "cis-5-Amino-6-hydroxycyclohexadiene as a Chiral Building Block: An Asymmetric Synthesis of (-)-Swainsonine", 《CHEM.EUR.J.》 * |
| GEOFFREY N. AUSTIN，等: "3,6-DIDEOXY-3,6-IMINO-l,2-O-ISOPROPYLIDENE-a-D-GLUCOFURANOSE AS A DIVDRGENT INTERMEDIATE FOR THE SYNTHESIS OF HYDROXYLATED PYRROLIDINES: SYNTHESIS OF 1,4-DIDEOXY-1,4-IMINO-L-GULITOL, 1,4-DIDEOXY-1,4-IMINO-D-LYXITOL, 2S,3S,4R-3,4-DIHYDROXYPROLINE", 《TETRAHEDRON》 * |
| NOBUYOSHI YASUDA等: "SYNTHESIS OF TWO STEREOISOMERS OF SWAINSONINE", 《CHEMISTRY LETTERS》 * |
| WONTAECK LIM等: "A concise synthetic method towards (-)-swainsonine and its 8-epimer by using palladium-catalyzed asymmetric hydroamination of alkoxyallene as the key strategy", 《TETRAHEDRON》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109651362A (en) * | 2018-12-20 | 2019-04-19 | 中国农业科学院兰州畜牧与兽药研究所 | A kind of spherosin derivative and its preparation method and application |
| CN109651362B (en) * | 2018-12-20 | 2021-06-01 | 中国农业科学院兰州畜牧与兽药研究所 | Swainsonine derivative and preparation method and application thereof |
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