CN105418696A - Synthesis methods of glycosyl mercaptan and auranofin - Google Patents
Synthesis methods of glycosyl mercaptan and auranofin Download PDFInfo
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- CN105418696A CN105418696A CN201410459125.0A CN201410459125A CN105418696A CN 105418696 A CN105418696 A CN 105418696A CN 201410459125 A CN201410459125 A CN 201410459125A CN 105418696 A CN105418696 A CN 105418696A
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- ethanoyl
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Abstract
The present invention discloses synthesis methods of glycosyl mercaptan and auranofin. The glycosyl mercaptan synthesis method comprises: (1) dissolving sulfur acetyl protecting saccharide, mercaptan and a weak alkali in an organic solvent to obtain a raw material mixing liquid; and (2) carrying out a reaction on the raw material mixing liquid for 1-24 h at a room temperature, and carrying out extraction purification on the reaction product to obtain the glycosyl mercaptan. The auranofin synthesis method comprises: A, dissolving 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl mercaptan and triethyl phosphorus gold trichloride in an organic solvent, carrying out an ice bath, adding an aqueous solution of an alkali metal weak acid salt, and continuously stirring to obtain a reaction liquid; and B, carrying out a nucleophilic substitution reaction on the reaction liquid at a room temperature to obtain a crude reaction product, and carrying out extraction purification to obtain the pure auranofin. The method of the present invention has characteristics of mild reaction condition, high yield, good adaptability, and low production cost.
Description
Technical field
The invention belongs to the field of chemical synthesis, more specifically, relate to the synthetic method of a kind of glycosyl mercaptan and auranofin.
Background technology
Glycosyl mercaptan is usually used in building sulphur glycosides and other carbohydrate complexes.The connection of sulphur atom, makes the hydrolysis of substrate to enzyme show good tolerance.Therefore, the carbohydrate complexes of sulfur-bearing is up-and-coming molecule in drug design process.Compared with the hemiacetal form of sugar, the end group configuration of glycosyl mercaptan is more stable, and remains unchanged in most chemical reaction, is usually used in preparing glycosyl sulfinyl amine/sulfone amide derivative, glycosyl disulphide, glycolipid, glycopeptide and glycoprotein etc.The thiosugar that ethanoyl is protected can regard the precursor of glycosyl mercaptan as, under the effect of alkali, removes ethanoyl, can obtain glycosyl mercaptan.As fructosyl contains other protecting group simultaneously, as oxygen ethanoyl, during benzoyl, a kind of suitable reagent is selected to carry out selectivity deprotection with regard to needing.At present; the reagent of selectively removing sulphur ethanoyl mostly is alkaline reagents; as sodium methyl mercaptide, sodium methylate etc.; all there are some shortcomings in them: reagent instability, moisture-sensitive, taste are unpleasant; react violent, wayward process; alkalescence excessivelys strong, easy generation by product as disulphide, or poor selectivity, also removes other protecting groups etc. while removing sulphur ethanoyl.In addition, the usage range of these reagent deprotection substrates is narrower, complicated operation or severe reaction conditions.
Auranofin (Auranofin), trade(brand)name Ruide (Ridaura), it is a kind of New Oral Gold preparation for the treatment of rheumatoid arthritis, release is researched and developed by SmithKline company of the U.S. in early 1970s, within 1985, be used for clinical (southwestern national defence medicine 1996 through U.S. FDA approval, 6 (1), 10-12.) effective treatment of this medicine, is obtained so far the existing nearly 1,000,000 routine patients of more than 60 countries such as the U.S., Italy, China.Auranofin structure can be regarded as to be puted together by the glycosyl mercaptan of a part and the golden salt of a part and form.How become by the raw material simple and easy to get auranofin efficiently synthesized containing glycosyl mercaptan fragment the focus that chemists and medicine scholars study.
Summary of the invention
For above defect or the Improvement requirement of prior art, the invention provides the synthetic method of a kind of glycosyl mercaptan and auranofin, its object is to adopt single stage method, glycosyl mercaptan and auranofin is synthesized under the reaction conditions of gentleness, the synthetic method solving existing glycosyl mercaptan and auranofin is thus complicated, reaction is violent, unmanageable technical problem.
For achieving the above object, according to one aspect of the present invention, provide a kind of synthetic method of glycosyl mercaptan, comprise the following steps:
(1) sugar, mercaptan and weak base that sulphur ethanoyl is protected are dissolved in organic solvent, the concentration of the sugar that described sulphur ethanoyl is protected is between 0.1mM to 1mM, the sugar of described sulphur ethanoyl protection and the mol ratio of mercaptan are between 1:1 to 1:1.5, the sugar of described sulphur ethanoyl protection and the mol ratio of weak base, between 1:0.1 to 1:1.0, obtain raw material mixed solution;
(2) obtain obtained raw material mixed solution by step (1), under room temperature, reaction 1 is little of 24 hours, and namely reaction product abstraction purification is obtained glycosyl mercaptan.
Preferably, described synthetic method, the sugar of sulphur ethanoyl protection described in it, has the structure of formula (I)
Wherein, R is oxygen benzyl, oxygen benzoyl, oxygen ethanoyl or glycyl.
Preferably, described synthetic method, mercaptan described in it has the structure of formula (II)
Wherein, R
1for O or NH; R
2for H, C
1~ C
10alkyl, aryl, halogen, COOH or carboxylic acid C
1~ C
10alkyl ester.
Preferably, described synthetic method, mercaptan described in it is
in one or more.
Preferably, described synthetic method, weak base described in it is organic weak base or inorganic weak bases; The preferred Na of described weak base
2cO
3, NaHCO
3, K
2cO
3, KHCO
3, triethylamine, DIPEA, pyridine, ammonium acetate or ammoniacal liquor; More preferably NaHCO
3.
Preferably, described synthetic method, organic solvent described in it is CH
3oH, CHCl
3, CH
2cl
2, CH
3in CN, dimethyl formamide, N,N-DIMETHYLACETAMIDE and toluene any one; Preferred N,N-DIMETHYLACETAMIDE.
According to another aspect of the present invention, provide a kind of synthetic method of auranofin, comprise the following steps:
A, by 2,3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan and triethyl phosphine gold trichloride are dissolved in organic solvent, ice bath, temperature is controlled at 0 DEG C at 5 DEG C, and add the aqueous solution of alkali metal weak, Keep agitation obtains reaction solution, wherein 2, the mol ratio of 3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan and triethyl phosphine gold trichloride is between 1:1 to 1:1.5,2, the mol ratio of 3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan and alkali metal weak is between 1:1 to 1:1.5;
, at room temperature there is nucleophilic substitution reaction in the reaction solution obtained in B, steps A, obtains reacting coarse product, obtains auranofin sterling after abstraction purification.
Preferably, the synthetic method of described auranofin, organic solvent described in it is C
1~ C
4low molecule halogenated alkane or C
2~ C
10low molecule ether, preferred methylene dichloride.
Preferably, the synthetic method of described auranofin, alkali metal weak described in it is Na
2cO
3, NaHCO
3, K
2cO
3and KHCO
3in any one.
Preferably, the synthetic method of described auranofin, described in it, 2,3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan synthesize according to the synthetic method of glycosyl mercaptan provided by the invention.
In general, the above technical scheme conceived by the present invention compared with prior art, can obtain following beneficial effect:
1, glycosyl mercaptan synthetic method provided by the invention, reaction is at room temperature carried out, mild condition.Its reaction raw materials sulphur ethanoyl sugar is easy to obtain, and can prepare in a large number, and at room temperature good stability, conveniently storage.Meanwhile, good reaction selectivity.Other protecting group on glycosyl is not affected, as oxygen ethanoyl, benzoyl etc. when removing sulphur ethanoyl.In addition, the substrate of reactive adaptation is extensive, has good suitability to the glycosyl substrate of dissimilar, different protecting group.
2, the synthetic method of auranofin provided by the invention, reaction reagent is very common, wide material sources.Especially, when adopting DL-1,4-dithiothreitol (DTT) as reaction reagent, effectively can prevent the generation of disulfide linkage, reduce by product, product purification is easy, does not need by silica gel column chromatography or recrystallization.After reaction terminates, highly purified product can be taken by simple toluene extraction.Further, when adopting DL-1,4-dithiothreitol (DTT) as reaction reagent, DL-1,4-dithiothreitol (DTT) can reclaim, and recycling is efficiently easy, and the rate of recovery reaches 92%, and recovery article can be recycled, and greatly reduces production cost, is applicable to suitability for industrialized production.
Embodiment
In order to make object of the present invention, technical scheme and advantage clearly understand, below in conjunction with embodiment, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.In addition, if below in described each embodiment of the present invention involved technical characteristic do not form conflict each other and just can mutually combine.
The synthetic method of glycosyl mercaptan provided by the invention, comprises the following steps:
(1) sugar, mercaptan and weak base that sulphur ethanoyl is protected are dissolved in organic solvent; the concentration of the sugar that described sulphur ethanoyl is protected is between 0.1mM to 1mM; the sugar of described sulphur ethanoyl protection and the mol ratio of mercaptan are between 1:1 to 1:1.5; the sugar of described sulphur ethanoyl protection and the mol ratio of weak base, between 1:0.1 to 1:1.0, obtain raw material mixed solution.
The sugar of described sulphur ethanoyl protection, has the structure of formula (I)
Wherein, R is oxygen benzyl, oxygen benzoyl, oxygen ethanoyl or glycyl.
Described mercaptan has the structure of formula (II)
Wherein, R
1for O or NH; R
2for H, C
1~ C
10alkyl, aryl, halogen, COOH or carboxylic acid C
1~ C
10alkyl ester.
Described mercaptan is
one or more.
Described weak base is organic weak base or inorganic weak bases; The preferred Na of described weak base
2cO
3, NaHCO
3, K
2cO
3, KHCO
3, triethylamine, DIPEA, pyridine, ammonium acetate or ammoniacal liquor; More preferably NaHCO
3.
(2) obtain obtained raw material mixed solution by step (1), under room temperature, reaction 1 is little of 24 hours, and namely reaction product abstraction purification is obtained glycosyl mercaptan.Reaction formula is as follows:
The synthetic method of auranofin provided by the invention, comprises the following steps:
A, by 2,3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan and triethyl phosphine gold trichloride are dissolved in organic solvent, add the aqueous solution of alkali metal weak at 0 DEG C, and Keep agitation obtains reaction solution, wherein 2, the mol ratio of 3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan and triethyl phosphine gold trichloride is between 1:1 to 1:1.5,2, the mol ratio of 3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan and alkali metal weak is between 1:1 to 1:1.5;
, at room temperature there is nucleophilic substitution reaction in the reaction solution obtained in B, steps A, obtains reacting coarse product, obtains auranofin sterling after abstraction purification.
Reaction formula is as follows:
Described organic solvent is C
1~ C
4low molecule halogenated alkane or C
2~ C
10low molecule ether, preferred methylene dichloride.
Described alkali metal weak is Na
2cO
3, NaHCO
3, K
2cO
3and KHCO
3in any one.
Described 2,3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan synthesize according to the synthetic method of glycosyl mercaptan provided by the invention.
Be below embodiment:
Embodiment 1
A synthetic method for glycosyl mercaptan, comprises the following steps:
(1) sugar, mercaptan and weak base that sulphur ethanoyl is protected are dissolved in organic solvent; the concentration of the sugar that described sulphur ethanoyl is protected is 0.2mM; the described sugar of sulphur ethanoyl protection and the mol ratio of mercaptan are 1:1.5; the described sugar of sulphur ethanoyl protection and the mol ratio of weak base are between 1:0.1, obtain raw material mixed solution.
The sugar of described sulphur ethanoyl protection is 2,3,4,6-tetra--O-ethanoyl-1-S-ethanoyl-β-D-Glucopyranose (600mg, 1.48mmol); Described mercaptan is DL-1,4-dithiothreitol (DTT) (342mg, 2.22mmol); Described weak base is NaHCO
3(13mg, 0.15mmol); Described reaction solvent is N,N-DIMETHYLACETAMIDE (7.4ml).
(2) obtain obtained raw material mixed solution by step (1), react 1 hour under room temperature, namely reaction product abstraction purification is obtained 2,3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan.
1HNMR(400MHz,CDCl
3)5.17(1H,dd,J
2,3＝J
3,4＝9.6Hz,H-3),5.08(1H,dd,J
3,4＝J
4,5＝9.6Hz,H-4),4.95(1H,dd,J
1,2＝J
2,3＝9.6Hz,H-2),4.53(1H,dd,J
1,2＝J
1,SH＝9.6Hz,H-1),4.23(1H,dd,J
6a,6b＝12.5Hz,J
5,6a＝4.8Hz,H-6a),4.11(1H,dd,J
6a,6b＝12.5Hz,J
5,6b＝2.4Hz,H-6b),3.70(1H,ddd,J
4,5＝9.6Hz,J
5,6a＝4.8Hz,J
5,6b＝2.4Hz,H-5),2.29(1H,d,J
1,SH＝9.6Hz,SH),2.08,2.06,2.00,1.99(12H,4×s,COCH
3)。
The concrete operations of purifying are: add the dilution of 50ml water, toluene extraction (3 × 100ml), merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains glycosyl mercaptan 525mg, productive rate 98%.White solid, R
f=0.48 (petroleum ether-ethyl acetate 1:1).
(3) in step (2), the aqueous phase of extraction gained adds NaCl to saturated, and extraction into ethyl acetate (3 × 100ml) is concentrated, adds 1 ‰ (w/w) K
2cO
3-MeOH solubilize, stirred at ambient temperature 30min, suction filtered through kieselguhr, methanol wash, concentrated, obtain DL-1,4-dithiothreitol (DTT), 315mg, the rate of recovery 92%.
1HNMR(400MHz,CDCl
3)3.66-3.64(2H,m,CH),2.79-2.66(4H,m,CH
2),2.64-2.62(2H,m,OH),1.48(2H,t,J＝8.4Hz,SH)。
When mercaptan used is DL-1,4-dithiothreitol (DTT) (DTT), after reaction terminates, head product high purity 95%, also can directly use without the need to purification step.
Embodiment 2
A synthetic method for glycosyl mercaptan, comprises the following steps:
(1) sugar, mercaptan and weak base that sulphur ethanoyl is protected are dissolved in organic solvent; the concentration of the sugar that described sulphur ethanoyl is protected is 0.1mM; the described sugar of sulphur ethanoyl protection and the mol ratio of mercaptan are 1:1; the described sugar of sulphur ethanoyl protection and the mol ratio of weak base are between 1:1, obtain raw material mixed solution.
The sugar of described sulphur ethanoyl protection is 2,3,4,6-tetra--O-ethanoyl-1-S-ethanoyl-β-D-galactopyranose (600mg, 1.48mmol); Described mercaptan is Cys methyl ester hydrochloride (254mg, 1.48mmol); Described weak base is triethylamine (0.2ml, 1.48mmol); Described reaction solvent is dimethyl formamide (14.8ml).
(2) obtain obtained raw material mixed solution by step (1), react 1.5 hours under room temperature, namely reaction product abstraction purification is obtained 2,3,4,6-tetra--O-ethanoyl-β-D-galactopyranosyl glycosyl mercaptan.
1HNMR(400MHz,CDCl
3)δ5.38(1H,dd,J
3,4＝3.6Hz,J
4,5＝0.8Hz,H-4),5.13(1H,dd,J
1,2＝J
2,3＝10.0Hz,H-2),4.96(1H,dd,J
2,3＝10.0,J
3,4＝3.6Hz,H-3),4.48(1H,dd,J
1,2＝J
1,SH＝10.0Hz,H-1),4.08–4.06(2H,m,H-6a,H-6b),3.90(1H,ddd,J
5,6a＝J
5,6b＝6.8Hz,J
4,5＝0.8Hz,H-5),2.32(1H,d,J
1,SH＝10.0Hz,SH),2.11,2.04,2.00,1.93(12H,4×s,COCH
3)。
The concrete operations of purifying are: add the dilution of 50ml water, toluene extraction (3 × 100ml), merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains glycosyl mercaptan 517mg, productive rate 96%.Colorless oil, R
f=0.50 (petroleum ether-ethyl acetate 1:1).
Embodiment 3
A synthetic method for glycosyl mercaptan, comprises the following steps:
(1) sugar, mercaptan and weak base that sulphur ethanoyl is protected are dissolved in organic solvent; the concentration of the sugar that described sulphur ethanoyl is protected is 1mM; the described sugar of sulphur ethanoyl protection and the mol ratio of mercaptan are 1:1.3; the described sugar of sulphur ethanoyl protection and the mol ratio of weak base are between 1:0.2, obtain raw material mixed solution.
The sugar of described sulphur ethanoyl protection is 2,3,4,6-tetra--O-ethanoyl-1-S-ethanoyl-β-D-mannopyranose (500mg, 1.23mmol); Described mercaptan is DL-1,4-dithiothreitol (DTT) (247mg, 1.60mmol); Described weak base is KHCO
3(25mg, 0.25mmol); Described reaction solvent is trichloromethane (1.23ml).
(2) obtain obtained raw material mixed solution by step (1), react 24 hours under room temperature, namely reaction product abstraction purification is obtained 2,3,4,6-tetra--O-ethanoyl-β-D-mannopyranose base mercaptan.
1HNMR(400MHz,CDCl
3)δ5.42(1H,dd,J
2,3＝3.2Hz,J
1,2＝0.8Hz,H-2),5.21(1H,dd,J
3,4＝J
4,5＝10.0Hz,H-4),5.06(1H,dd,J
3,4＝10.0Hz,J
2,3＝3.2Hz,H-3),4.87(1H,dd,J
1,SH＝9.6Hz,J
1,2＝0.8Hz,H-1),4.22(1H,dd,J
6a,6b＝12.4Hz,J
5,6a＝5.6Hz,H-6a),4.11(1H,dd,J
6a,6b＝12.4Hz,J
5,6b＝2.4Hz,H-6b),3.69(1H,ddd,J
4,5＝10.0Hz,J
5,6a＝5.6Hz,J
5,6b＝2.4Hz,H-5),2.52(1H,d,J
1,SH＝9.6Hz,SH),2.22,2.08,2.02,1.96(12H,4×s,COCH
3)。
The concrete operations of purifying are: add the dilution of 50ml water, toluene extraction (3 × 100ml), merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains glycosyl mercaptan 394mg, productive rate 88%.White solid, R
f=0.48 (petroleum ether-ethyl acetate 1:1).
The raw material of table 1 embodiment 1 to 3 and reaction product structural formula
Embodiment 4
A synthetic method for auranofin, comprises the following steps:
A, by 2,3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan (400mg, 1.1mmol) with triethyl phosphine gold trichloride (385mg, 1.1mmol) be dissolved in organic solvent, add the aqueous solution of alkali metal weak at 0 DEG C, Keep agitation obtains reaction solution, wherein 2, the mol ratio of 3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan and triethyl phosphine gold trichloride is 1:1,2, the mol ratio of 3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan and alkali metal weak is 1:1.2;
, at room temperature there is nucleophilic substitution reaction in the reaction solution obtained in B, steps A, obtains reacting coarse product, obtains auranofin sterling 655mg after abstraction purification, yield 88%, white powder.R
f=0.45 (petroleum ether-ethyl acetate 1:1); [α]
d 20=-52 ° of (c=1, CH
3oH);
1hNMR (400MHz, CDCl
3) δ 5.12-5.03 (3H, m, H-1, H-3, H-4), 4.93 (1H, m, H-2), 4.18 (1H, dd, J=12.0,4.8Hz, H-6a), 4.04 (1H, dd, J=12.0,2.4Hz, H-6b), 3.67 (1H, m, H-6), 2.03,2.01,1.96.1.94 (12H, 4 × s, COCH
3), 1.80 (6H, dq, J=9.6,7.6Hz, CH
2cH
3), 1.16 (9H, dt, J=18.4,7.6Hz, CH
2cH
3).
Described organic solvent is methylene dichloride (2ml).
Described alkali metal weak is K
2cO
3(182mg, 1.32mmol).
Described 2,3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan are according to the synthetic method synthesis in embodiment 1.
The concrete operations of abstraction purification are as follows:
Add water in reacting coarse product, cancellation is reacted, then adds dichloromethane extraction, after merging organic phase, and washing, Na
2sO
4drying, filters, and concentrates to obtain auranofin.Product through methanol-water (2:5) recrystallization, can obtain auranofin sterling.
Embodiment 5
A synthetic method for auranofin, comprises the following steps:
A, by 2,3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan (460mg, 1.26mmol) with triethyl phosphine gold trichloride (530mg, 1.51mmol) be dissolved in organic solvent, add the aqueous solution of alkali metal weak at 0 DEG C, Keep agitation obtains reaction solution, wherein 2, the mol ratio of 3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan and triethyl phosphine gold trichloride is 1:1.2,2, the mol ratio of 3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan and alkali metal weak is 1:1;
, at room temperature there is nucleophilic substitution reaction in the reaction solution obtained in B, steps A, obtains reacting coarse product, obtains auranofin sterling 735mg after abstraction purification, yield 86%.
Described organic solvent is trichloromethane (2.3ml).
Described alkali metal weak is Na
2cO
3(134mg, 1.26mmol).
Described 2,3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan are according to the synthetic method synthesis in embodiment 1.
The concrete operations of abstraction purification are as follows:
Add water in reacting coarse product, cancellation is reacted, then adds chloroform extraction, after merging organic phase, and washing, Na
2sO
4drying, filters, and concentrates to obtain auranofin.Product through methanol-water (2:5) recrystallization, can obtain auranofin sterling.
Embodiment 6
A synthetic method for auranofin, comprises the following steps:
A, by 2,3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan (342mg, 0.94mmol) with triethyl phosphine gold trichloride (494mg, 1.41mmol) be dissolved in organic solvent, add the aqueous solution of alkali metal weak at 0 DEG C, Keep agitation obtains reaction solution, wherein 2, the mol ratio of 3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan and triethyl phosphine gold trichloride is 1:1.5,2, the mol ratio of 3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan and alkali metal weak is 1:1.5;
, at room temperature there is nucleophilic substitution reaction in the reaction solution obtained in B, steps A, obtains reacting coarse product, obtains auranofin sterling 574mg after abstraction purification, yield 90%.
Described organic solvent is ether (1.7ml).
Described alkali metal weak is KHCO
3(141mg, 1.41mmol).
Described 2,3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan are according to the synthetic method synthesis in embodiment 1.
The concrete operations of abstraction purification are as follows:
Add water in reacting coarse product, cancellation is reacted, then adds extracted with diethyl ether, after merging organic phase, and washing, Na
2sO
4drying, filters, and concentrates to obtain auranofin.Product through recrystallization, can obtain auranofin sterling.Product through methanol-water (2:5) recrystallization, can obtain auranofin sterling.
Embodiment 7 ~ 22
The synthesis of other glycosyl sulfur alcohol compounds
The synthesis step of other glycosyl sulfur alcohol compounds carries out according to the synthesis step of 2,3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan in embodiment 1.
Reaction expression is as follows:
Reaction substrate in each embodiment, target product, reaction times and productive rate are as follows:
The structure of compound 2a ~ 2p is as follows:
The proterties of products therefrom 2a ~ 2p in embodiment 7 ~ 22:
2a: white solid, R
f=0.3 (petroleum ether-ethyl acetate 1:1).
1HNMR(400MHz,CDCl
3)δ5.54(1H,d,J＝6.4Hz,H-1),5.36–5.23(3H,m,H-2,H-3,H-4),4.34(1H,m,H-5),4.29(1H,dd,J
6a,6b＝12.0Hz,J
5,6a＝4.8Hz,H-6a),4.10(1H,dd,J
6a,6b＝12.0Hz,J
5,6b＝2.0Hz,H-6b),2.25(1H,d,J＝6.9Hz,SH),2.15(3H,s,COCH
3),2.09(3H,s,COCH
3),2.04(3H,s,COCH
3),1.99(3H,s,COCH
3).
2b: white solid, R
f=0.5 (petroleum ether-ethyl acetate 1.5:1).
1HNMR(400MHz,CDCl
3)δ5.40(1H,dd,J
2,3＝2.8Hz,J
1,2＝1.2Hz,H-2),5.03–5.00(2H,m,H-3,H-4),4.83(1H,dd,J
1,SH＝9.6Hz,J
1,2＝1.2Hz,H-1),3.58–3.52(1H,m,H-5),2.47(1H,d,J
1,SH＝9.6Hz,SH),2.21,2.03,1.96(9H,3×s,COCH
3),1.25(3H,d,J
5,6＝6.4Hz,CH
3).
2c: white powder, R
f=0.3 (petroleum ether-ethyl acetate 2:1).
1HNMR(400MHz,CDCl
3)δ5.53(1H,dd,J
2,3＝J
3,4＝2.8Hz,H-3),5.06(1H,ddd,J
4,5a＝8.8Hz,J
4,5e＝4.4Hz,J
3,4＝2.8Hz,H-4),4.96(1H,dd,J
1,SH＝J
1,2＝8.0Hz,H-1),4.90(1H,dd,J
1,2＝8.0Hz,J
2,3＝2.8Hz,H-2),4.04(1H,dd,J
5a,5e＝11.6Hz,J
4,5e＝4.4Hz,H-5e),3.75(1H,dd,J
5a,5e＝11.6Hz,J
4,5a＝8.8Hz,H-5a),2.13(1H,d,J
1,SH＝8.8Hz,SH),2.11,2.07,2.02(9H,3×s,COCH
3).
13CNMR(100MHz,CDCl
3)δ170.0,169.8,169.7(3×COCH
3),76.5(C-1),71.5(C-3),67.6(C-2),66.6(C-4),64.2(C-5),21.0,20.9,20.9(3×COCH
3).
2d: white powder, R
f=0.3 (petroleum ether-ethyl acetate 2:1).
1HNMR(400MHz,CDCl
3)δ5.14(1H,dd,J
2,3＝J
3,4＝8.8Hz,H-3),4.96(1H,ddd,J
4,5a＝9.6Hz,J
3,4＝8.8Hz,J
4,5e＝5.2Hz,H-4),4.89(1H,dd,J
1,2＝J
2,3＝8.8Hz,H-2),4.54(1H,dd,J
1,SH＝10.0Hz,J
1,2＝8.8Hz,H-1)4.18(1H,dd,J
5a,5e＝11.6Hz,J
4,5e＝5.2Hz,H-5e),3.36(1H,dd,J
5a,5e＝11.6Hz,J
4,5a＝9.6Hz,H-5a),2.26(1H,d,J
1,SH＝10.0Hz,SH),2.06,2.02,2.02(9H,3×s,COCH
3).
13CNMR(100MHz,CDCl
3)δ170.2,170.0,169.9(3×COCH
3),79.2(C-1),73.5(C-3),72.6(C-2),68.8(C-4),66.5(C-5),21.0,20.9,20.9(3×COCH
3).
2e: white solid, R
f=0.3 (petroleum ether-ethyl acetate 2:1).
1HNMR(400MHz,CDCl
3)δ5.28(1H,ddd,J
3,4＝3.6Hz,J
4,5a＝2.8Hz,J
4,5e＝1.6Hz,H-4),5.17(1H,dd,J
1,2＝J
2,3＝9.2Hz,H-2),5.02(1H,dd,J
2,3＝9.2Hz,J
3,4＝3.6Hz,H-3),4.53(1H,dd,J
1,SH＝9.6Hz,J
1,2＝9.2Hz,H-1),4.06(1H,dd,J
5a,5e＝13.2Hz,J
4,5a＝2.8Hz,H-5a),3.67(1H,dd,J
5a,5e＝13.2Hz,J
4,5e＝1.6Hz,H-5e),2.35(1H,d,J
1,SH＝9.6Hz,SH),2.13,2.08,2.01(9H,3×s,COCH
3).
13CNMR(100MHz,CDCl
3)δ170.5,170.1,170.0(3×COCH
3),79.3(C-1),71.5(C-3),71.0(C-2),68.1(C-4),67.3(C-5),21.1,21.1,20.9(3×COCH
3).
2f: white solid, R
f=0.6 (methylene chloride-methanol 20:1).
1HNMR(400MHz,CDCl
3)δ5.59(1H,d,J
2,NH＝9.6Hz,NHAc),5.11(1H,dd,J
2,3＝J
3,4＝9.6Hz,H-4),5.05(1H,dd,J
3,4＝J
4,5＝9.6Hz,H-3),4.55(1H,dd,J
1,2＝9.6Hz,J
1,SH＝9.2Hz,H-1),4.22(1H,dd,J
6a,6b＝12.4Hz,J
5,6a＝4.8Hz,H-6a),4.10(1H,dd,J
6a,6b＝12.4Hz,J
5,6b＝2.4Hz,H-6b),4.07(1H,ddd,J
1,2＝J
2,3＝J
2,NH＝9.6Hz,H-2),3.66(1H,ddd,J
4,5＝9.6Hz,J
5,6a＝4.8Hz,J
5,6b＝2.4Hz,H-5),2.55(1H,d,J
1,SH＝9.2Hz,SH),2.08,2.02,2.01,1.96(12H,4×s,COCH
3).
2g: white powder, R
f=0.42 (petroleum ether-ethyl acetate 1:1).α/β＝1.4:1).α:
1HNMR(400MHz,CDCl
3)δ5.75(1H,ddd,J
1,SH＝6.0Hz,J
1,2ax＝5.6Hz,J
1,2eq＝1.0Hz,H-1),5.24(1H,ddd,J
2ax,3＝11.2Hz,J
3,4＝9.2Hz,J
2eq,3＝4.8Hz,H-3),4.98(1H,dd,J
4,5＝10.0Hz,J
3,4＝9.2Hz,H-4),4.38(1H,ddd,J
4,5＝10.0Hz,J
5,6a＝4.4Hz,J
5,6b＝2.0Hz,H-5),4.32(1H,dd,J
6a,6b＝12.4Hz,J
5,6a＝4.4Hz,H-6a),4.06(1H,dd,J
6a,6b＝12.4Hz,J
5,6b＝2.0Hz,H-6b),2.26(1H,ddd,J
2eq,2ax＝13.6Hz,J
2eq,3＝4.8Hz,J
1,2eq＝1.0Hz,H-2eq),2.17(1H,ddd,J
2eq,2ax＝13.6Hz,J
2ax,3＝11.2Hz,J
1,2ax＝5.6Hz,H-2ax),2.16(1H,d,J
1,SH＝6.0Hz,SH),2.06,2.03,1.99(9H,3×s,COCH
3).β:
1HNMR(400MHz,CDCl
3)4.98(1H,ddd,J
2ax,3＝12.0Hz,J
3,4＝9.6Hz,J
2eq,3＝4.0Hz,H-3),4.96(1H,dd,J
4,5＝9.6Hz,J
3,4＝9.6Hz,H-4),4.71(1H,ddd,J
1,2ax＝11.2Hz,J
1,SH＝8.8Hz,J
1,2eq＝2.0Hz,H-1),4.22(1H,dd,J
6a,6b＝12.4Hz,J
5,6a＝5.2Hz,H-6a),4.03(1H,dd,J
6a,6b＝12.4Hz,J
5,6b＝2.0Hz,H-6b),3.62(1H,ddd,J
4,5＝9.6Hz,J
5,6a＝5.2Hz,J
5,6b＝2.0Hz,H-5),2.50(1H,ddd,J
2eq,2ax＝12.8Hz,J
2eq,3＝4.0Hz,J
1,2eq＝2.0Hz,H-2eq),2.47(1H,d,J
1,SH＝8.8Hz,SH),1.84(1H,ddd,J
2eq,2ax＝12.8Hz,J
2ax,3＝12.0Hz,J
1,2ax＝11.2Hz,H-2ax),2.06,2.01,2.00(9H,3×s,COCH
3).
2h: colorless oil, R
f=0.48 (petroleum ether-ethyl acetate 2:1).
1HNMR(400MHz,CDCl
3)δ8.04-7.25(20H,m,Ar-H),5.88(1H,dd,J
2,3＝J
3,4＝9.6Hz,H-3),5.71(1H,dd,J
3,4＝J
4,5＝9.6Hz,H-4),5.50(1H,dd,J
1,2＝J
2,3＝9.6Hz,H-2),4.90(1H,dd,J
1,2＝J
1,SH＝9.6Hz,H-1),4.43(1H,dd,J
6a,6b＝12.4Hz,J
5,6a＝2.8Hz,H-6a),4.22(1H,dd,J
6a,6b＝12.4Hz,J
5,6b＝4.8Hz,H-6b),4.17(1H,ddd,J
4,5＝10.0Hz,J
5,6b＝4.8Hz,J
5,6a＝2.8Hz,H-5),2.47(1H,d,J
1,SH＝9.6Hz,SH).
2i: white solid, R
f=0.45 (petroleum ether-ethyl acetate 2:1).
1HNMR(400MHz,CDCl
3)δ8.06-7.22(20H,m,Ar-H),6.02(1H,dd,J
3,4＝2.7Hz,J
4,5＝0.8Hz,H-4),5.75(1H,dd,J
1,2＝J
2,3＝9.6Hz,H-2),5.61(1H,dd,J
2,3＝9.6Hz,J
3,4＝2.7Hz,H-3),4.90(1H,dd,J
1,2＝J
1,SH＝9.6Hz,H-1),4.64(1H,dd,J
6a,6b＝10.4Hz,J
5,6b＝5.6Hz,H-6a),4.42-4.34(2H,m,H-6b,H-5),2.56(1H,d,J
1,SH＝9.6Hz,SH).
2j: white powder, R
f=0.32 (petroleum ether-ethyl acetate 1:1).
1HNMR(400MHz,CDCl
3)δ8.10-7.22(20H,m,Ar-H),6.01(1H,dd,J
3,4＝J
4,5＝10.0Hz,H-4),5.93(1H,dd,J
2,3＝3.2Hz,J
1,2＝0.8Hz,H-2),5.63(1H,dd,J
3,4＝10.0Hz,J
2,3＝3.2Hz,H-3),5.17(1H,dd,J
1,SH＝10.0Hz,J
1,2＝0.8Hz,H-1),4.70(1H,dd,J
6a,6b＝12.4Hz,J
5,6a＝2.8Hz,H-6a),4.47(1H,dd,J
6a,6b＝12.4Hz,J
5,6b＝4.4Hz,H-6b),4.17(1H,ddd,J
4,5＝10.0Hz,J
5,6b＝4.4Hz,J
5,6a＝2.8Hz,H-5),2.63(1H,d,J
1,SH＝10.0Hz,SH).
13CNMR(100MHz,CDCl
3)δ166.3,165.8,165.5,165.5(4×OCOPh),133.9,133.7,133.5,133.3,130.2,130.2,130.0,130.0,130.0,130.0,130.0,130.0,130.0,130.0,129.1,129.0,128.9,128.9,128.7,128.7,128.6,128.6,128.5,128.5(24×C-Ar),77.1(C-1),77.1(C-5),73.2(C-3),72.7(C-2),66.3(C-4),63.2(C-6).
2k: colorless oil, R
f=0.5 (petroleum ether-ethyl acetate 3:1).
1HNMR(400MHz,CDCl
3)δ7.32–7.10(15H,m,Ar-H),4.94(1H,dd,J
1,2＝J
1,SH＝10.0Hz,H-1),4.81–4.50(6H,m,3×CH
2Ph),4.39(1H,dd,J
1,2＝J
2,3＝10.0Hz,H-2),3.75–3.66(4H,m,H-3,H-4,H-6a,H-6b),3.48(1H,ddd,J
4,5＝10.0Hz,J
5,6a＝4.4Hz,J
5,6b＝2.4Hz,H-5),2.25(1H,d,J
1,SH＝10.0Hz,SH),1.97(3H,s,COCH
3)；
13CNMR(100MHz,CDCl
3)δ170.1(COCH
3),138.3,138.1,138.0,128.7,128.7,128.7,128.7,128.6,128.6,128.2,128.2,128.1,128.1,128.1,128.0,128.0,128.0,127.9(18×C-Ar),84.3(C-1),80.0(C-2),79.1(C-5),77.9(C-3),75.8(C-4),75.5,75.3,73.8(3×PhCH),68.8(C-6).
2l: colorless oil, R
f=0.58 (petroleum ether-ethyl acetate 3:1).α/β＝6:1。α:
1HNMR(400MHz,CDCl
3)δ7.37–7.11(20H,m,Ar-H),5.74(1H,dd,J
1,2＝5.2Hz,J
1,SH＝4.8Hz,H-1),4.94–4.45(8H,m,4×CH
2Ph),4.19(1H,ddd,J
4,5＝10.0Hz,J
5,6a＝3.2Hz,J
5,6b＝2.0Hz,H-5),3.87–3.60(5H,m,H-2,H-3,H-4,H-6a,H-6b),1.88(d,J
1,SH＝4.8Hz,SH).β:
1HNMR(400MHz,CDCl
3)δ7.37–7.11(20H,m,Ar-H),4.94–4.45(9H,m,4×CH
2Ph,H-1),3.87–3.60(4H,m,H-3,H-4,H-6a,H-6b),3.49–3.50(1H,m,H-5),3.38–3.34(1H,m,H-2),2.30(d,J
1,SH＝8.08Hz,SH).
2m: white solid, R
f=0.5 (petroleum ether-ethyl acetate 1:2).
1HNMR(400MHz,CDCl
3)δ5.32(1H,dd,J
3',4'＝3.0Hz,J
4',5'＝0.8Hz,H-4'),5.15(1H,dd,J
2,3＝J
3,4＝9.6Hz,H-3),5.07(1H,dd,J
2,3＝9.6Hz,J
1,2＝8.0Hz,H-2),4.92(1H,dd,J
2',3'＝9.6Hz,J
3',4'＝3.0Hz,H-3'),4.85(1H,dd,J
2',3'＝9.6Hz,J
1',2'＝8.0Hz,H-2'),4.50(1H,dd,J
1,SH＝9.6Hz,J
1,2＝8.0Hz,H-1),4.45(1H,d,J
1',2'＝8.0Hz,H-1'),4.43(1H,dd,J
6a',6'b＝12.0Hz,J
5',6'a＝2.0Hz,H-6'a),4.12–4.03(3H,m,H-6a,H-6b,H-6'b),3.84(1H,m,H-5'),3.78(1H,dd,J
4,5＝10.0Hz,J
3,4＝9.6Hz,H-4),3.60(1H,ddd,J
4,5＝10.0Hz,J
5,6a＝5.2Hz,J
5,6b＝2.0Hz,H-5),2.21(1H,d,J
1,SH＝9.6Hz,SH),2.12,2.10,2.05,2.04,2.02,2.01,1.93(21H,7×s,COCH
3).
2n: white solid, R
f=0.40 (petroleum ether-ethyl acetate 1:2).
1HNMR(400MHz,CDCl
3)δ5.44(1H,dd,J
3',4'＝3.6Hz,J
4',5'＝0.8Hz,H-4'),5.34(1H,dd,J
2',3'＝10.8Hz,J
3',4'＝3.6Hz,H-3'),5.20(1H,d,J
1',2'＝3.6Hz,H-1'),5.17(1H,dd,J
2,3＝J
3,4＝9.6Hz,H-3),5.07(1H,dd,J
4,5＝J
3,4＝9.6Hz,H-4),5.07(1H,dd,J
2',3'＝10.8Hz,J
1',2'＝3.6Hz,H-2'),4.89(1H,dd,J
1,2＝J
2,3＝9.6Hz,H-2),4.49(1H,dd,J
1,SH＝J
1,2＝9.6Hz,H-1),4.25(1H,m,H-5'),4.15–3.99(2H,m,H-6'a,H-6'b),3.71–3.60(3H,m,H-5,H-6a,H-6b),2.26(1H,d,J
1,SH＝10.0Hz,SH),2.13,2.12,2.06,2.02,2.02,1.99,1.98(21H,7×s,COCH
3).
2o: white solid, R
f=0.35 (petroleum ether-ethyl acetate 1:1).
1HNMR(400MHz,CDCl
3)δ5.15(1H,dd,J
2,3＝J
3,4＝9.6Hz,H-3),5.12(1H,dd,J
2',3'＝J
3',4'＝9.6Hz,H-3'),5.04(1H,dd,J
3',4'＝J
4',5'＝9.6Hz,H-4'),4.89(1H,dd,J
2',3'＝9.6Hz,J
1',2'＝8.0Hz,H-2'),4.85(1H,dd,J
1,2＝J
2,3＝9.6Hz,H-2),4.50(1H,dd,J
1,SH＝J
1,2＝9.6Hz,H-1),4.47(1H,d,J
1',2'＝8.0Hz,H-1'),4.45(1H,dd,J
6a,6b＝12.0Hz,J
5,6a＝0.8Hz,H-6a),4.35(1H,dd,J
6'a,6'b＝12.4Hz,J
5',6'a＝4.4Hz,H-6a'),4.06(1H,dd,J
6a,6b＝12.0Hz,J
5,6b＝5.0Hz,H-6b),4.02(1H,dd,J
6'a,6'b＝12.4Hz,J
5,6'b＝1.6Hz,H-6'b),3.76(1H,dd,J
4,5＝J
3,4＝9.6Hz,H-4),3.63(1H,ddd,J
4',5'＝9.6Hz,J
5',6a'＝4.4Hz,J
5',6b'＝1.6Hz,H-5'),3.60(1H,ddd,J
4,5＝9.6Hz,J
5,6b＝5.0Hz,J
5,6a＝0.8Hz,H-5),2.23(1H,d,J
1,SH＝9.6Hz,SH),2.11,2.07,2.05,2.00,2.00,1.99,1.96(21H,7×s,COCH
3).
2p: white solid, R
f=0.35 (petroleum ether-ethyl acetate 1:1).
1HNMR(400MHz,CDCl
3)δ5.38(1H,d,J
1',2'＝4.0Hz,H-1'),5.33(1H,dd,J
2,3＝9.6Hz,J
3,4＝9.2Hz,H-3),5.23(1H,dd,J
1,2＝J
2,3＝9.6Hz,H-2),5.03(1H,dd,J
2',3'＝10.4Hz,J
3',4'＝9.6Hz,H-3'),4.84(1H,dd,J
2',3'＝10.4Hz,J
1',2'＝4.0Hz,H-2'),4.79(1H,dd,J
3',4'＝J
4',5'＝9.6Hz,H-4'),4.56(1H,dd,J
1,SH＝J
1,2＝9.6Hz,H-1),4.43(1H,dd,J
6a,6b＝12.4Hz,J
5,6a＝2.4Hz,H-6a),4.22(1H,dd,J
6a,6b＝12.4Hz,J
5,6b＝4.0Hz,H-6b),4.19(1H,dd,J
6'a,6'b＝12.0Hz,J
5',6'a＝4.4Hz,H-6a'),4.02(1H,dd,J
6'a,6'b＝12.0Hz,J
5,6'b＝2.0Hz,H-6'b),3.97(1H,dd,J
4,5＝J
3,4＝9.2Hz,H-4),3.92(1H,ddd,J
4,5＝9.2Hz,J
5,6b＝4.0Hz,J
5,6a＝2.4Hz,H-5),3.68(1H,ddd,J
4',5'＝9.6Hz,J
5',6a'＝4.4Hz,J
5',6b'＝2.0Hz,H-5'),2.23(1H,d,J
1,SH＝9.6Hz,SH),2.13,2.08,2.03,2.02,2.00,1.99,1.98(21H,7×s,COCH
3).
Those skilled in the art will readily understand; the foregoing is only preferred embodiment of the present invention; not in order to limit the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1. a synthetic method for glycosyl mercaptan, is characterized in that, comprises the following steps:
(1) sugar, mercaptan and weak base that sulphur ethanoyl is protected are dissolved in organic solvent, the concentration of the sugar that described sulphur ethanoyl is protected is between 0.1mM to 1mM, the sugar of described sulphur ethanoyl protection and the mol ratio of mercaptan are between 1:1 to 1:1.5, the sugar of described sulphur ethanoyl protection and the mol ratio of weak base, between 1:0.1 to 1:1.0, obtain raw material mixed solution;
(2) obtain obtained raw material mixed solution by step (1), under room temperature, reaction 1 is little of 24 hours, and namely reaction product abstraction purification is obtained glycosyl mercaptan.
2. synthetic method as claimed in claim 1, is characterized in that, the sugar of described sulphur ethanoyl protection, has the structure of formula (I)
Wherein, R is oxygen benzyl, oxygen benzoyl, oxygen ethanoyl or glycyl.
3. synthetic method as claimed in claim 1, it is characterized in that, described mercaptan has the structure of formula (II)
Wherein, R
1for O or NH; R
2for H, C
1~ C
10alkyl, aryl, halogen, COOH or carboxylic acid C
1~ C
10alkyl ester.
4. synthetic method as claimed in claim 3, it is characterized in that, described mercaptan is
in one or more.
5. synthetic method as claimed in claim 1, it is characterized in that, described weak base is organic weak base or inorganic weak bases; The preferred Na of described weak base
2cO
3, NaHCO
3, K
2cO
3, KHCO
3, triethylamine, DIPEA, pyridine, ammonium acetate or ammoniacal liquor; More preferably NaHCO
3.
6. synthetic method as claimed in claim 1, it is characterized in that, described organic solvent is CH
3oH, CHCl
3, CH
2cl
2, CH
3in CN, dimethyl formamide, N,N-DIMETHYLACETAMIDE and toluene any one; Preferred N,N-DIMETHYLACETAMIDE.
7. a synthetic method for auranofin, is characterized in that, comprises the following steps:
A, by 2,3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan and triethyl phosphine gold trichloride are dissolved in organic solvent, add the aqueous solution of alkali metal weak under ice bath, and Keep agitation obtains reaction solution, wherein 2, the mol ratio of 3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan and triethyl phosphine gold trichloride is between 1:1 to 1:1.5,2, the mol ratio of 3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan and alkali metal weak is between 1:1 to 1:1.5;
, at room temperature there is nucleophilic substitution reaction in the reaction solution obtained in B, steps A, obtains reacting coarse product, obtains auranofin sterling after abstraction purification.
8. synthetic method as claimed in claim 7, it is characterized in that, described organic solvent is C
1~ C
4low molecule halogenated alkane or C
2~ C
10low molecule ether, preferred methylene dichloride.
9. synthetic method as claimed in claim 7, it is characterized in that, described alkali metal weak is Na
2cO
3, NaHCO
3, K
2cO
3and KHCO
3in any one.
10. synthetic method as claimed in claim 7, it is characterized in that, described 2,3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl mercaptan synthesize according to the synthetic method of the glycosyl mercaptan as described in claim 1 to 6 any one.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112538099A (en) * | 2020-12-08 | 2021-03-23 | 华中科技大学 | Preparation method and application of 1-thioglucose and glucose 1-thiol protected by total acyl |
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| US4125711A (en) * | 1977-06-30 | 1978-11-14 | Smithkline Corporation | Process for preparing auranofin |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112538099A (en) * | 2020-12-08 | 2021-03-23 | 华中科技大学 | Preparation method and application of 1-thioglucose and glucose 1-thiol protected by total acyl |
| CN112538099B (en) * | 2020-12-08 | 2022-03-11 | 华中科技大学 | Preparation method and application of 1-thioglucose and glucose 1-thiol protected by total acyl |
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| CN105418696B (en) | 2018-09-21 |
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