CN105418696B - A kind of synthetic method of glycosyl mercaptan and Anranofin - Google Patents

A kind of synthetic method of glycosyl mercaptan and Anranofin Download PDF

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CN105418696B
CN105418696B CN201410459125.0A CN201410459125A CN105418696B CN 105418696 B CN105418696 B CN 105418696B CN 201410459125 A CN201410459125 A CN 201410459125A CN 105418696 B CN105418696 B CN 105418696B
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mercaptan
acetyl group
anranofin
glycosyl
sugar
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CN105418696A (en
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万谦
舒朋华
曾静
赵岳琦
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Huazhong University of Science and Technology
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Huazhong University of Science and Technology
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Abstract

The invention discloses the synthetic methods of a kind of glycosyl mercaptan and Anranofin.The synthetic method of the glycosyl mercaptan, includes the following steps：(1) sugar, mercaptan and weak base that sulphur acetyl group is protected are dissolved in organic solvent, obtain raw material mixed liquor；(2) raw material mixed liquor is reacted 1 hour to 24 hours at room temperature, reaction product abstraction purification is obtained into glycosyl mercaptan.The synthetic method of the Anranofin, includes the following steps：A, 2,3,4,6 four O acetyl group β D glucopyranosyls mercaptan and triethyl phosphine chlorauride are dissolved in organic solvent, the aqueous solution of alkali metal weak is added in ice bath, continues stirring to obtain reaction solution；B, nucleophilic substitution occurs at room temperature for reaction solution, obtains reacting coarse product, Anranofin sterling is obtained after abstraction purification.Method provided by the invention, reaction condition is mild, and yield is high, and adaptability is good, and production cost is low.

Description

A kind of synthetic method of glycosyl mercaptan and Anranofin
Technical field
The invention belongs to the field of chemical synthesis, more particularly, to the synthetic method of a kind of glycosyl mercaptan and Anranofin.
Background technology
Glycosyl mercaptan is usually used in building sulphur glycosides and other carbohydrate complexes.The connection of sulphur atom makes hydrolysis of the substrate to enzyme Show good tolerance.Therefore, the carbohydrate complexes of sulfur-bearing are up-and-coming molecules in drug design process.With sugar Hemiacetal form is compared, and the end group configuration of glycosyl mercaptan is more stable, and is remained unchanged in majority chemically reacts, and is usually used in preparing Glycosyl sulfenamide/sulfamide derivative, glycosyl disulphide, glycolipid, glycopeptide and glycoprotein etc..The thiosugar of acetyl group protection can To regard the precursor of glycosyl mercaptan as, in the presence of alkali, acetyl group is removed, you can obtain glycosyl mercaptan.As same on fructosyl The other protecting groups of Shi Hanyou, such as oxygen acetyl group, when benzoyl, it is necessary to a kind of suitable reagent be selected to carry out selective remove-insurance Shield.Currently, the reagent of selectively removing sulphur acetyl group is mostly alkaline reagent, such as sodium methyl mercaptide, sodium methoxide, they all have one A little disadvantages：Reagent is unstable, moisture-sensitive, taste are unpleasant, reaction acutely, process not easy to control, alkalinity is too strong, easily generates by-product Other protecting groups etc. are also removed such as disulphide or poor selectivity, while removing sulphur acetyl group.In addition, these reagents The usage range for being deprotected substrate is relatively narrow, complicated for operation or severe reaction conditions.
Anranofin (Auranofin), trade name Ruide (Ridaura) are a kind of to treat the oral of rheumatoid arthritis Gold preparation is researched and developed by U.S. SmithKline company in early 1970s and is released, and 1985 through U.S. FDA approval for clinical (west The southern part of the country anti-medical 1996,6 (1), 10-12.), have nearly million trouble in more than 60 countries such as the U.S., Italy, China so far Person obtains effective treatment of the medicine.Anranofin structure can be regarded as to be conjugated by the glycosyl mercaptan of a molecule and the gold salt of a molecule It forms.How the Anranofin containing glycosyl mercaptan segment is efficiently synthesized by raw material simple and easy to get and has become chemists and medicine The hot spot that object scholars study.
Invention content
For the disadvantages described above or Improvement requirement of the prior art, the present invention provides the conjunctions of a kind of glycosyl mercaptan and Anranofin At method, its object is to use one-step method, glycosyl mercaptan and Anranofin are synthesized under mild reaction conditions, are thus solved existing The synthetic method of some glycosyl mercaptan and Anranofin is complicated, and reaction is violent, it is difficult to the technical issues of controlling.
To achieve the above object, according to one aspect of the present invention, a kind of synthetic method of glycosyl mercaptan is provided, including Following steps：
(1) sugar, mercaptan and weak base that sulphur acetyl group is protected are dissolved in organic solvent so that the sulphur acetyl group protection Sugar concentration in 0.1mM between 1mM, the sugar of the sulphur acetyl group protection is with the molar ratio of mercaptan 1:1 to 1:1.5 it Between, the sugar of the sulphur acetyl group protection is with the molar ratio of weak base 1:0.1 to 1:Between 1.0, raw material mixed liquor is obtained；
(2) raw material mixed liquor obtained will be obtained in step (1), reacts 1 hour to 24 hours at room temperature, reaction product is extracted Purifying is taken to obtain glycosyl mercaptan.
Preferably, the synthetic method, the sugar of the sulphur acetyl group protection, the structure with formula (I)
Wherein, R is oxygen benzyl, oxygen benzoyl, oxygen acetyl group or glycyl.
Preferably, the synthetic method, the mercaptan have the structure of formula (II)
Wherein, R1For O or NH；R2For H, C1~C10Alkyl, aryl, halogen, COOH or carboxylic acid C1~C10Arrcostab.
Preferably, the synthetic method, the mercaptan are In it is one or more.
Preferably, the synthetic method, the weak base are organic weak base or inorganic weak bases；The preferred Na of weak base2CO3、 NaHCO3、K2CO3、KHCO3, triethylamine, n,N-diisopropylethylamine, pyridine, ammonium acetate or ammonium hydroxide；More preferable NaHCO3。
Preferably, the synthetic method, the organic solvent are CH3OH、CHCl3、CH2Cl2、CH3CN, dimethyl formyl Any one in amine, dimethylacetylamide and toluene；It is preferred that dimethylacetylamide.
It is another aspect of this invention to provide that providing a kind of synthetic method of Anranofin, include the following steps：
A, tetra--O- acetyl group-β-D- glucopyranosyls mercaptan of 2,3,4,6- and triethyl phosphine chlorauride have been dissolved in In solvent, ice bath makes temperature control at 0 DEG C to 5 DEG C, the aqueous solution of alkali metal weak is added, it is anti-to continue stirring to obtain Liquid is answered, wherein the molar ratio of 2,3,4,6- tetra--O- acetyl group-β-D- glucopyranosyls mercaptan and triethyl phosphine chlorauride is 1: 1 to 1:Between 1.5, the molar ratio of 2,3,4,6- tetra--O- acetyl group-β-D- glucopyranosyls mercaptan and alkali metal weak exists 1:1 to 1:Between 1.5；
B, the reaction solution obtained in step A, occurs nucleophilic substitution at room temperature, obtains reacting coarse product, and extraction is pure Anranofin sterling is obtained after change.
Preferably, the synthetic method of the Anranofin, the organic solvent are C1~C4Low molecule halogenated alkane or C2 ~C10Low molecule ether, preferred dichloromethane.
Preferably, the synthetic method of the Anranofin, the alkali metal weak are Na2CO3、NaHCO3、K2CO3With KHCO3In any one.
Preferably, the synthetic method of the Anranofin, described 2,3,4,6- tetra--O- acetyl group-β-D- glucopyranoses Base mercaptan is synthesized according to the synthetic method of glycosyl mercaptan provided by the invention.
In general, through the invention it is contemplated above technical scheme is compared with the prior art, can obtain down and show Beneficial effect：
1, glycosyl mercaptan synthetic method provided by the invention, reaction carry out at room temperature, mild condition.Its reaction raw materials sulphur Acetyl group sugar is easily obtained, and can largely be prepared, and stability is good at room temperature, facilitates storage.Meanwhile good reaction selectivity. Other protecting groups on glycosyl, such as oxygen acetyl group, benzoyl are not influenced when removing sulphur acetyl group.In addition, reaction is suitable The substrate answered is extensive, has good applicability to the glycosyl substrate of different type, different protecting groups.
2, the synthetic method of Anranofin provided by the invention, reaction reagent is extremely common, derives from a wealth of sources.Especially, it uses It when DL-1,4- dithiothreitol (DTT) are as reaction reagent, can effectively prevent the generation of disulfide bond, reduce by-product, product purification letter Just, silica gel column chromatography or recrystallization need not be passed through.After reaction, high-purity can be taken by the extraction of simple toluene Product.Further, using DL-1, when 4- dithiothreitol (DTT)s are as reaction reagent, DL-1,4- dithiothreitol (DTT)s can recycle, And recovery processing is efficiently easy, up to 92%, recovery article can be recycled the rate of recovery, substantially reduce production cost, be suitble to industry Metaplasia is produced.
Specific implementation mode
In order to make the purpose , technical scheme and advantage of the present invention be clearer, with reference to embodiments, to the present invention It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to Limit the present invention.As long as in addition, technical characteristic involved in the various embodiments of the present invention described below each other it Between do not constitute conflict and can be combined with each other.
The synthetic method of glycosyl mercaptan provided by the invention, includes the following steps：
(1) sugar, mercaptan and weak base that sulphur acetyl group is protected are dissolved in organic solvent so that the sulphur acetyl group protection Sugar concentration in 0.1mM between 1mM, the sugar of the sulphur acetyl group protection is with the molar ratio of mercaptan 1:1 to 1:1.5 it Between, the sugar of the sulphur acetyl group protection is with the molar ratio of weak base 1:0.1 to 1:Between 1.0, raw material mixed liquor is obtained.
The sugar of the sulphur acetyl group protection, the structure with formula (I)
Wherein, R is oxygen benzyl, oxygen benzoyl, oxygen acetyl group or glycyl.
The mercaptan has the structure of formula (II)
Wherein, R1For O or NH；R2For H, C1~C10Alkyl, aryl, halogen, COOH or carboxylic acid C1~C10Arrcostab.
The mercaptan is It is one or more.
The weak base is organic weak base or inorganic weak bases；The preferred Na of weak base2CO3、NaHCO3、K2CO3、KHCO3, three second Amine, n,N-diisopropylethylamine, pyridine, ammonium acetate or ammonium hydroxide；More preferable NaHCO3。
(2) raw material mixed liquor obtained will be obtained in step (1), reacts 1 hour to 24 hours at room temperature, reaction product is extracted Purifying is taken to obtain glycosyl mercaptan.Reaction equation is as follows：
The synthetic method of Anranofin provided by the invention, includes the following steps：
A, tetra--O- acetyl group-β-D- glucopyranosyls mercaptan of 2,3,4,6- and triethyl phosphine chlorauride have been dissolved in In solvent, the aqueous solution of alkali metal weak is added at 0 DEG C, continues stirring to obtain reaction solution, wherein 2,3,4,6- tetra--O- second The molar ratio of acyl-beta-D- glucopyranosyls mercaptan and triethyl phosphine chlorauride is 1:1 to 1:Between 1.5,2,3,4,6- tetra-- The molar ratio of O- acetyl group-β-D- glucopyranosyls mercaptan and alkali metal weak is 1:1 to 1:Between 1.5；
B, the reaction solution obtained in step A, occurs nucleophilic substitution at room temperature, obtains reacting coarse product, and extraction is pure Anranofin sterling is obtained after change.
Reaction equation is as follows：
The organic solvent is C1~C4Low molecule halogenated alkane or C2~C10Low molecule ether, preferred dichloromethane.
The alkali metal weak is Na2CO3、NaHCO3、K2CO3And KHCO3In any one.
Tetra--O- acetyl group-β-D- glucopyranosyls mercaptan of the 2,3,4,6- is according to glycosyl mercaptan provided by the invention Synthetic method synthesis.
It is embodiment below：
Embodiment 1
A kind of synthetic method of glycosyl mercaptan, includes the following steps：
(1) sugar, mercaptan and weak base that sulphur acetyl group is protected are dissolved in organic solvent so that the sulphur acetyl group protection Sugar a concentration of 0.2mM, the sugar of sulphur acetyl group protection is 1 with the molar ratio of mercaptan:1.5, the sulphur acetyl group protection Sugar and the molar ratio of weak base be 1:Between 0.1, raw material mixed liquor is obtained.
The sugar of the sulphur acetyl group protection, is 2,3,4,6- tetra--O- acetyl group -1-S- acetyl group-β-D- glucopyranoses (600mg, 1.48mmol)；The mercaptan is DL-1,4- dithiothreitol (DTT)s (342mg, 2.22mmol)；The weak base is NaHCO3(13mg, 0.15mmol)；The reaction dissolvent is dimethylacetylamide (7.4ml).
(2) raw material mixed liquor obtained will be obtained in step (1), is reacted 1 hour at room temperature, is by reaction product abstraction purification Obtain tetra--O- acetyl group-β-D- glucopyranosyl mercaptan of 2,3,4,6-.1HNMR(400MHz,CDCl3)5.17(1H,dd,J2,3 =J3,4=9.6Hz, H-3), 5.08 (1H, dd, J3,4=J4,5=9.6Hz, H-4), 4.95 (1H, dd, J1,2=J2,3=9.6Hz, H-2),4.53(1H,dd,J1,2=J1,SH=9.6Hz, H-1), 4.23 (1H, dd, J6a,6b=12.5Hz, J5,6a=4.8Hz, H- 6a),4.11(1H,dd,J6a,6b=12.5Hz, J5,6b=2.4Hz, H-6b), 3.70 (1H, ddd, J4,5=9.6Hz, J5,6a= 4.8Hz,J5,6b=2.4Hz, H-5), 2.29 (1H, d, J1,SH=9.6Hz, SH), 2.08,2.06,2.00,1.99 (12H, 4 × s, COCH3)。
The concrete operations of purifying are：The dilution of 50ml water is added, toluene extracts (3 × 100ml), merges organic phase, saturation food Salt water washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure, obtains glycosyl mercaptan 525mg, yield 98%.White solid, Rf=0.48 (petroleum ether-ethyl acetate 1:1).
(3) into step (2), the water phase of extraction gained adds NaCl to being saturated, and ethyl acetate extracts (3 × 100ml), concentration, Add 1 ‰ (w/w) K2CO3- MeOH solution dissolves, and stirs 30min, suction filtered through kieselguhr at room temperature, and methanol washing concentrates, obtains DL-1, 4- dithiothreitol (DTT)s, 315mg, the rate of recovery 92%.1H NMR(400MHz,CDCl3)3.66-3.64(2H,m,CH),2.79-2.66 (4H,m,CH2), 2.64-2.62 (2H, m, OH), 1.48 (2H, t, J=8.4Hz, SH).
When mercaptan used is DL-1, when 4- dithiothreitol (DTT)s (DTT), after reaction, head product purity is up to 95%, It also can be used directly without purification step.
Embodiment 2
A kind of synthetic method of glycosyl mercaptan, includes the following steps：
(1) sugar, mercaptan and weak base that sulphur acetyl group is protected are dissolved in organic solvent so that the sulphur acetyl group protection Sugar a concentration of 0.1mM, the sugar of sulphur acetyl group protection is 1 with the molar ratio of mercaptan:1, the sulphur acetyl group protection The molar ratio of sugar and weak base is 1:Between 1, raw material mixed liquor is obtained.
The sugar of the sulphur acetyl group protection, is 2,3,4,6- tetra--O- acetyl group -1-S- acetyl group-β-D- galactopyranoses (600mg, 1.48mmol)；The mercaptan is L-cysteine methyl ester hydrochloride (254mg, 1.48mmol)；The weak base is three Ethamine (0.2ml, 1.48mmol)；The reaction dissolvent is dimethylformamide (14.8ml).
(2) raw material mixed liquor obtained will be obtained in step (1), is reacted 1.5 hours at room temperature, by reaction product abstraction purification Obtain tetra--O- acetyl group-β-D- galactopyranosyl glycosyl mercaptan of 2,3,4,6-.1HNMR(400MHz,CDCl3)δ5.38(1H,dd, J3,4=3.6Hz, J4,5=0.8Hz, H-4), 5.13 (1H, dd, J1,2=J2,3=10.0Hz, H-2), 4.96 (1H, dd, J2,3= 10.0,J3,4=3.6Hz, H-3), 4.48 (1H, dd, J1,2=J1,SH=10.0Hz, H-1), 4.08-4.06 (2H, m, H-6a, H- 6b),3.90(1H,ddd,J5,6a=J5,6b=6.8Hz, J4,5=0.8Hz, H-5), 2.32 (1H, d, J1,SH=10.0Hz, SH), 2.11,2.04,2.00,1.93(12H,4×s,COCH3)。
The concrete operations of purifying are：The dilution of 50ml water is added, toluene extracts (3 × 100ml), merges organic phase, saturation food Salt water washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure, obtains glycosyl mercaptan 517mg, yield 96%.Colorless oil, Rf=0.50 (petroleum ether-ethyl acetate 1:1).
Embodiment 3
A kind of synthetic method of glycosyl mercaptan, includes the following steps：
(1) sugar, mercaptan and weak base that sulphur acetyl group is protected are dissolved in organic solvent so that the sulphur acetyl group protection Sugar a concentration of 1mM, the sugar of sulphur acetyl group protection is 1 with the molar ratio of mercaptan:1.3, the sulphur acetyl group protection The molar ratio of sugar and weak base is 1:Between 0.2, raw material mixed liquor is obtained.
The sugar of the sulphur acetyl group protection, is 2,3,4,6- tetra--O- acetyl group -1-S- acetyl group-β-D- mannopyranoses (500mg, 1.23mmol)；The mercaptan is DL-1,4- dithiothreitol (DTT)s (247mg, 1.60mmol)；The weak base is KHCO3 (25mg, 0.25mmol)；The reaction dissolvent is chloroform (1.23ml).
(2) raw material mixed liquor obtained will be obtained in step (1), is reacted 24 hours at room temperature, by reaction product abstraction purification Obtain tetra--O- acetyl group-β-D- mannopyranose base mercaptan of 2,3,4,6-.1HNMR(400MHz,CDCl3)δ5.42(1H,dd, J2,3=3.2Hz, J1,2=0.8Hz, H-2), 5.21 (1H, dd, J3,4=J4,5=10.0Hz, H-4), 5.06 (1H, dd, J3,4= 10.0Hz,J2,3=3.2Hz, H-3), 4.87 (1H, dd, J1,SH=9.6Hz, J1,2=0.8Hz, H-1), 4.22 (1H, dd, J6a,6b =12.4Hz, J5,6a=5.6Hz, H-6a), 4.11 (1H, dd, J6a,6b=12.4Hz, J5,6b=2.4Hz, H-6b), 3.69 (1H, ddd,J4,5=10.0Hz, J5,6a=5.6Hz, J5,6b=2.4Hz, H-5), 2.52 (1H, d, J1,SH=9.6Hz, SH), 2.22, 2.08,2.02,1.96(12H,4×s,COCH3)。
The concrete operations of purifying are：The dilution of 50ml water is added, toluene extracts (3 × 100ml), merges organic phase, saturation food Salt water washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure, obtains glycosyl mercaptan 394mg, yield 88%.White solid, Rf=0.48 (petroleum ether-ethyl acetate 1:1).
The raw material and reaction product structural formula of 1 embodiment 1 to 3 of table
Embodiment 4
A kind of synthetic method of Anranofin, includes the following steps：
A, by 2,3,4,6- tetra--O- acetyl group-β-D- glucopyranosyls mercaptan (400mg, 1.1mmol) and triethyl phosphine Chlorauride (385mg, 1.1mmol) is dissolved in organic solvent, and the aqueous solution of alkali metal weak is added at 0 DEG C, lasting to stir Reaction solution is obtained, wherein mole of 2,3,4,6- tetra--O- acetyl group-β-D- glucopyranosyls mercaptan and triethyl phosphine chlorauride Than being 1:The molar ratio of 1,2,3,4,6- tetra--O- acetyl group-β-D- glucopyranosyls mercaptan and alkali metal weak is 1: 1.2；
B, the reaction solution obtained in step A, occurs nucleophilic substitution at room temperature, obtains reacting coarse product, and extraction is pure Anranofin sterling 655mg, yield 88%, white powder are obtained after change.Rf=0.45 (petroleum ether-ethyl acetate 1:1)；[α]D 20 =-52 ° of (c=1, CH3OH)；1H NMR(400MHz,CDCl3)δ5.12-5.03(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,COCH3), 1.80 (6H, dq, J=9.6,7.6Hz, CH2CH3), 1.16 (9H, dt, J=18.4,7.6Hz, CH2CH3)。
The organic solvent is dichloromethane (2ml).
The alkali metal weak is K2CO3(182mg,1.32mmol)。
Tetra--O- acetyl group-β-D- glucopyranosyls mercaptan of the 2,3,4,6- is closed according to the synthetic method in embodiment 1 At.
The concrete operations of abstraction purification are as follows：
Add water into reacting coarse product, reaction is quenched, adds dichloromethane extraction, after merging organic phase, washing, Na2SO4Dry, filtering is concentrated to give Anranofin.Product can be through methanol-water (2:5) it recrystallizes, obtains Anranofin sterling.
Embodiment 5
A kind of synthetic method of Anranofin, includes the following steps：
A, by 2,3,4,6- tetra--O- acetyl group-β-D- glucopyranosyls mercaptan (460mg, 1.26mmol) and triethyl group Phosphorus chlorauride (530mg, 1.51mmol) is dissolved in organic solvent, and the aqueous solution of alkali metal weak is added at 0 DEG C, persistently stirs Acquisition reaction solution is mixed, wherein 2,3,4,6- tetra--O- acetyl group-β-D- glucopyranosyls mercaptan and triethyl phosphine chlorauride rub You are than being 1:The molar ratio of 1.2,2,3,4,6- tetra--O- acetyl group-β-D- glucopyranosyls mercaptan and alkali metal weak is 1:1；
B, the reaction solution obtained in step A, occurs nucleophilic substitution at room temperature, obtains reacting coarse product, and extraction is pure Anranofin sterling 735mg, yield 86% are obtained after change.
The organic solvent is chloroform (2.3ml).
The alkali metal weak is Na2CO3(134mg,1.26mmol)。
Tetra--O- acetyl group-β-D- glucopyranosyls mercaptan of the 2,3,4,6- is closed according to the synthetic method in embodiment 1 At.
The concrete operations of abstraction purification are as follows：
Add water into reacting coarse product, reaction is quenched, adds chloroform extraction, after merging organic phase, washing, Na2SO4Dry, filtering is concentrated to give Anranofin.Product can be through methanol-water (2:5) it recrystallizes, obtains Anranofin sterling.
Embodiment 6
A kind of synthetic method of Anranofin, includes the following steps：
A, by 2,3,4,6- tetra--O- acetyl group-β-D- glucopyranosyls mercaptan (342mg, 0.94mmol) and triethyl group Phosphorus chlorauride (494mg, 1.41mmol) is dissolved in organic solvent, and the aqueous solution of alkali metal weak is added at 0 DEG C, persistently stirs Acquisition reaction solution is mixed, wherein 2,3,4,6- tetra--O- acetyl group-β-D- glucopyranosyls mercaptan and triethyl phosphine chlorauride rub You are than being 1:The molar ratio of 1.5,2,3,4,6- tetra--O- acetyl group-β-D- glucopyranosyls mercaptan and alkali metal weak is 1:1.5；
B, the reaction solution obtained in step A, occurs nucleophilic substitution at room temperature, obtains reacting coarse product, and extraction is pure Anranofin sterling 574mg, yield 90% are obtained after change.
The organic solvent is ether (1.7ml).
The alkali metal weak is KHCO3(141mg,1.41mmol)。
Tetra--O- acetyl group-β-D- glucopyranosyls mercaptan of the 2,3,4,6- is closed according to the synthetic method in embodiment 1 At.
The concrete operations of abstraction purification are as follows：
Add water into reacting coarse product, reaction is quenched, adds ether extraction, after merging organic phase, washing, Na2SO4It is dry Dry, filtering is concentrated to give Anranofin.Product can obtain Anranofin sterling through recrystallization.Product can be through methanol-water (2:5) it recrystallizes, Obtain Anranofin sterling.
Embodiment 7~22
The synthesis of other glycosyl sulfur alcohol compounds
The synthesis step of other glycosyl sulfur alcohol compounds is according to tetra--O- acetyl group-β-D- pyrroles of 2,3,4,6- in embodiment 1 The synthesis step of glucopyranoside base mercaptan carries out.
Reaction formula is as follows：
Reaction substrate, target product, reaction time and yield in each embodiment is as follows：
The structure of compound 2a~2p is as follows：
The character of products therefrom 2a~2p in embodiment 7~22：
2a：White solid, Rf=0.3 (petroleum ether-ethyl acetate 1:1).1H NMR(400MHz,CDCl3)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, J6a,6b= 12.0Hz,J5,6a=4.8Hz, H-6a), 4.10 (1H, dd, J6a,6b=12.0Hz, J5,6b=2.0Hz, H-6b), 2.25 (1H, d, J=6.9Hz, SH), 2.15 (3H, s, COCH3),2.09(3H,s,COCH3),2.04(3H,s,COCH3),1.99(3H,s, COCH3).
2b：White solid, Rf=0.5 (petroleum ether-ethyl acetate 1.5:1).1H NMR(400MHz,CDCl3)δ5.40 (1H,dd,J2,3=2.8Hz, J1,2=1.2Hz, H-2), 5.03-5.00 (2H, m, H-3, H-4), 4.83 (1H, dd, J1,SH= 9.6Hz,J1,2=1.2Hz, H-1), 3.58-3.52 (1H, m, H-5), 2.47 (1H, d, J1,SH=9.6Hz, SH), 2.21, 2.03,1.96(9H,3×s,COCH3),1.25(3H,d,J5,6=6.4Hz, CH3).
2c：White powder, Rf=0.3 (petroleum ether-ethyl acetate 2:1).1H NMR(400MHz,CDCl3)δ5.53(1H, dd,J2,3=J3,4=2.8Hz, H-3), 5.06 (1H, ddd, J4,5a=8.8Hz, J4,5e=4.4Hz, J3,4=2.8Hz, H-4), 4.96(1H,dd,J1,SH=J1,2=8.0Hz, H-1), 4.90 (1H, dd, J1,2=8.0Hz, J2,3=2.8Hz, H-2), 4.04 (1H,dd,J5a,5e=11.6Hz, J4,5e=4.4Hz, H-5e), 3.75 (1H, dd, J5a,5e=11.6Hz, J4,5a=8.8Hz, H- 5a),2.13(1H,d,J1,SH=8.8Hz, SH), 2.11,2.07,2.02 (9H, 3 × s, COCH3).13C NMR(100MHz, CDCl3)δ170.0,169.8,169.7(3×COCH3),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×COCH3).
2d：White powder, Rf=0.3 (petroleum ether-ethyl acetate 2:1).1H NMR(400MHz,CDCl3)δ5.14(1H, dd,J2,3=J3,4=8.8Hz, H-3), 4.96 (1H, ddd, J4,5a=9.6Hz, J3,4=8.8Hz, J4,5e=5.2Hz, H-4), 4.89(1H,dd,J1,2=J2,3=8.8Hz, H-2), 4.54 (1H, dd, J1,SH=10.0Hz, J1,2=8.8Hz, H-1) 4.18 (1H,dd,J5a,5e=11.6Hz, J4,5e=5.2Hz, H-5e), 3.36 (1H, dd, J5a,5e=11.6Hz, J4,5a=9.6Hz, H- 5a),2.26(1H,d,J1,SH=10.0Hz, SH), 2.06,2.02,2.02 (9H, 3 × s, COCH3).13C NMR(100MHz, CDCl3)δ170.2,170.0,169.9(3×COCH3),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×COCH3).
2e：White solid, Rf=0.3 (petroleum ether-ethyl acetate 2:1).1H NMR(400MHz,CDCl3)δ5.28(1H, ddd,J3,4=3.6Hz, J4,5a=2.8Hz, J4,5e=1.6Hz, H-4), 5.17 (1H, dd, J1,2=J2,3=9.2Hz, H-2), 5.02(1H,dd,J2,3=9.2Hz, J3,4=3.6Hz, H-3), 4.53 (1H, dd, J1,SH=9.6Hz, J1,2=9.2Hz, H-1), 4.06(1H,dd,J5a,5e=13.2Hz, J4,5a=2.8Hz, H-5a), 3.67 (1H, dd, J5a,5e=13.2Hz, J4,5e= 1.6Hz,H-5e),2.35(1H,d,J1,SH=9.6Hz, SH), 2.13,2.08,2.01 (9H, 3 × s, COCH3).13C NMR (100MHz,CDCl3)δ170.5,170.1,170.0(3×COCH3),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×COCH3).
2f：White solid, Rf=0.6 (methylene chloride-methanol 20:1).1H NMR(400MHz,CDCl3)δ5.59(1H,d, J2,NH=9.6Hz, NHAc), 5.11 (1H, dd, J2,3=J3,4=9.6Hz, H-4), 5.05 (1H, dd, J3,4=J4,5=9.6Hz, H-3),4.55(1H,dd,J1,2=9.6Hz, J1,SH=9.2Hz, H-1), 4.22 (1H, dd, J6a,6b=12.4Hz, J5,6a= 4.8Hz,H-6a),4.10(1H,dd,J6a,6b=12.4Hz, J5,6b=2.4Hz, H-6b), 4.07 (1H, ddd, J1,2=J2,3= J2,NH=9.6Hz, H-2), 3.66 (1H, ddd, J4,5=9.6Hz, J5,6a=4.8Hz, J5,6b=2.4Hz, H-5), 2.55 (1H, d,J1,SH=9.2Hz, SH), 2.08,2.02,2.01,1.96 (12H, 4 × s, COCH3).
2g：White powder, Rf=0.42 (petroleum ether-ethyl acetate 1:1).α/β=1.4:1).α:1H NMR(400MHz, CDCl3)δ5.75(1H,ddd,J1,SH=6.0Hz, J1,2ax=5.6Hz, J1,2eq=1.0Hz, H-1), 5.24 (1H, ddd, J2ax,3 =11.2Hz, J3,4=9.2Hz, J2eq,3=4.8Hz, H-3), 4.98 (1H, dd, J4,5=10.0Hz, J3,4=9.2Hz, H-4), 4.38(1H,ddd,J4,5=10.0Hz, J5,6a=4.4Hz, J5,6b=2.0Hz, H-5), 4.32 (1H, dd, J6a,6b=12.4Hz, J5,6a=4.4Hz, H-6a), 4.06 (1H, dd, J6a,6b=12.4Hz, J5,6b=2.0Hz, H-6b), 2.26 (1H, ddd, J2eq,2ax =13.6Hz, J2eq,3=4.8Hz, J1,2eq=1.0Hz, H-2eq), 2.17 (1H, ddd, J2eq,2ax=13.6Hz, J2ax,3= 11.2Hz,J1,2ax=5.6Hz, H-2ax), 2.16 (1H, d, J1,SH=6.0Hz, SH), 2.06,2.03,1.99 (9H, 3 × s, COCH3).β:1H NMR(400MHz,CDCl3)4.98(1H,ddd,J2ax,3=12.0Hz, J3,4=9.6Hz, J2eq,3=4.0Hz, H-3),4.96(1H,dd,J4,5=9.6Hz, J3,4=9.6Hz, H-4), 4.71 (1H, ddd, J1,2ax=11.2Hz, J1,SH= 8.8Hz,J1,2eq=2.0Hz, H-1), 4.22 (1H, dd, J6a,6b=12.4Hz, J5,6a=5.2Hz, H-6a), 4.03 (1H, dd, J6a,6b=12.4Hz, J5,6b=2.0Hz, H-6b), 3.62 (1H, ddd, J4,5=9.6Hz, J5,6a=5.2Hz, J5,6b=2.0Hz, H-5),2.50(1H,ddd,J2eq,2ax=12.8Hz, J2eq,3=4.0Hz, J1,2eq=2.0Hz, H-2eq), 2.47 (1H, d, J1,SH =8.8Hz, SH), 1.84 (1H, ddd, J2eq,2ax=12.8Hz, J2ax,3=12.0Hz, J1,2ax=11.2Hz, H-2ax), 2.06, 2.01,2.00(9H,3×s,COCH3).
2h：Colorless oil, Rf=0.48 (petroleum ether-ethyl acetate 2:1).1H NMR(400MHz,CDCl3)δ8.04- 7.25(20H,m,Ar-H),5.88(1H,dd,J2,3=J3,4=9.6Hz, H-3), 5.71 (1H, dd, J3,4=J4,5=9.6Hz, H-4),5.50(1H,dd,J1,2=J2,3=9.6Hz, H-2), 4.90 (1H, dd, J1,2=J1,SH=9.6Hz, H-1), 4.43 (1H,dd,J6a,6b=12.4Hz, J5,6a=2.8Hz, H-6a), 4.22 (1H, dd, J6a,6b=12.4Hz, J5,6b=4.8Hz, H- 6b),4.17(1H,ddd,J4,5=10.0Hz, J5,6b=4.8Hz, J5,6a=2.8Hz, H-5), 2.47 (1H, d, J1,SH= 9.6Hz,SH).
2i：White solid, Rf=0.45 (petroleum ether-ethyl acetate 2:1).1H NMR(400MHz,CDCl3)δ8.06- 7.22(20H,m,Ar-H),6.02(1H,dd,J3,4=2.7Hz, J4,5=0.8Hz, H-4), 5.75 (1H, dd, J1,2=J2,3= 9.6Hz,H-2),5.61(1H,dd,J2,3=9.6Hz, J3,4=2.7Hz, H-3), 4.90 (1H, dd, J1,2=J1,SH=9.6Hz, H-1),4.64(1H,dd,J6a,6b=10.4Hz, J5,6b=5.6Hz, H-6a), 4.42-4.34 (2H, m, H-6b, H-5), 2.56 (1H,d,J1,SH=9.6Hz, SH)
2j：White powder, Rf=0.32 (petroleum ether-ethyl acetate 1:1).1H NMR(400MHz,CDCl3)δ8.10- 7.22(20H,m,Ar-H),6.01(1H,dd,J3,4=J4,5=10.0Hz, H-4), 5.93 (1H, dd, J2,3=3.2Hz, J1,2= 0.8Hz,H-2),5.63(1H,dd,J3,4=10.0Hz, J2,3=3.2Hz, H-3), 5.17 (1H, dd, J1,SH=10.0Hz, J1,2 =0.8Hz, H-1), 4.70 (1H, dd, J6a,6b=12.4Hz, J5,6a=2.8Hz, H-6a), 4.47 (1H, dd, J6a,6b= 12.4Hz,J5,6b=4.4Hz, H-6b), 4.17 (1H, ddd, J4,5=10.0Hz, J5,6b=4.4Hz, J5,6a=2.8Hz, H-5), 2.63(1H,d,J1,SH=10.0Hz, SH)13C NMR(100MHz,CDCl3)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, Rf=0.5 (petroleum ether-ethyl acetate 3:1).1H NMR(400MHz,CDCl3)δ7.32–7.10 (15H,m,Ar-H),4.94(1H,dd,J1,2=J1,SH=10.0Hz, H-1), 4.81-4.50 (6H, m, 3 × CH2Ph),4.39 (1H,dd,J1,2=J2,3=10.0Hz, H-2), 3.75-3.66 (4H, m, H-3, H-4, H-6a, H-6b), 3.48 (1H, ddd, J4,5=10.0Hz, J5,6a=4.4Hz, J5,6b=2.4Hz, H-5), 2.25 (1H, d, J1,SH=10.0Hz, SH), 1.97 (3H, s, COCH3)；13C NMR(100MHz,CDCl3)δ170.1(COCH3),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, Rf=0.58 (petroleum ether-ethyl acetate 3:1).α/β=6:1.α:1H NMR(400MHz, CDCl3)δ7.37–7.11(20H,m,Ar-H),5.74(1H,dd,J1,2=5.2Hz, J1,SH=4.8Hz, H-1), 4.94-4.45 (8H,m,4×CH2Ph),4.19(1H,ddd,J4,5=10.0Hz, J5,6a=3.2Hz, J5,6b=2.0Hz, H-5), 3.87-3.60 (5H,m,H-2,H-3,H-4,H-6a,H-6b),1.88(d,J1,SH=4.8Hz, SH) β:1H NMR(400MHz,CDCl3)δ 7.37–7.11(20H,m,Ar-H),4.94–4.45(9H,m,4×CH2Ph,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,J1,SH=8.08Hz, SH)
2m：White solid, Rf=0.5 (petroleum ether-ethyl acetate 1:2).1H NMR(400MHz,CDCl3)δ5.32(1H, dd,J3',4'=3.0Hz, J4',5'=0.8Hz, H-4'), 5.15 (1H, dd, J2,3=J3,4=9.6Hz, H-3), 5.07 (1H, dd, J2,3=9.6Hz, J1,2=8.0Hz, H-2), 4.92 (1H, dd, J2',3'=9.6Hz, J3',4'=3.0Hz, H-3'), 4.85 (1H, dd,J2',3'=9.6Hz, J1',2'=8.0Hz, H-2'), 4.50 (1H, dd, J1,SH=9.6Hz, J1,2=8.0Hz, H-1), 4.45 (1H,d,J1',2'=8.0Hz, H-1'), 4.43 (1H, dd, J6a',6'b=12.0Hz, J5',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,J4,5=10.0Hz, J3,4=9.6Hz, H-4),3.60(1H,ddd,J4,5=10.0Hz, J5,6a=5.2Hz, J5,6b=2.0Hz, H-5), 2.21 (1H, d, J1,SH= 9.6Hz,SH),2.12,2.10,2.05,2.04,2.02,2.01,1.93(21H,7×s,COCH3).
2n：White solid, Rf=0.40 (petroleum ether-ethyl acetate 1:2).1H NMR(400MHz,CDCl3)δ5.44(1H, dd,J3',4'=3.6Hz, J4',5'=0.8Hz, H-4'), 5.34 (1H, dd, J2',3'=10.8Hz, J3',4'=3.6Hz, H-3'), 5.20(1H,d,J1',2'=3.6Hz, H-1'), 5.17 (1H, dd, J2,3=J3,4=9.6Hz, H-3), 5.07 (1H, dd, J4,5= J3,4=9.6Hz, H-4), 5.07 (1H, dd, J2',3'=10.8Hz, J1',2'=3.6Hz, H-2'), 4.89 (1H, dd, J1,2= J2,3=9.6Hz, H-2), 4.49 (1H, dd, J1,SH=J1,2=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,J1,SH=10.0Hz, SH), 2.13,2.12,2.06,2.02,2.02,1.99,1.98(21H,7×s,COCH3).
2o：White solid, Rf=0.35 (petroleum ether-ethyl acetate 1:1).1H NMR(400MHz,CDCl3)δ5.15(1H, dd,J2,3=J3,4=9.6Hz, H-3), 5.12 (1H, dd, J2',3'=J3',4'=9.6Hz, H-3'), 5.04 (1H, dd, J3',4'= J4',5'=9.6Hz, H-4'), 4.89 (1H, dd, J2',3'=9.6Hz, J1',2'=8.0Hz, H-2'), 4.85 (1H, dd, J1,2= J2,3=9.6Hz, H-2), 4.50 (1H, dd, J1,SH=J1,2=9.6Hz, H-1), 4.47 (1H, d, J1',2'=8.0Hz, H-1'), 4.45(1H,dd,J6a,6b=12.0Hz, J5,6a=0.8Hz, H-6a), 4.35 (1H, dd, J6'a,6'b=12.4Hz, J5',6'a= 4.4Hz,H-6a'),4.06(1H,dd,J6a,6b=12.0Hz, J5,6b=5.0Hz, H-6b), 4.02 (1H, dd, J6'a,6'b= 12.4Hz,J5,6'b=1.6Hz, H-6'b), 3.76 (1H, dd, J4,5=J3,4=9.6Hz, H-4), 3.63 (1H, ddd, J4',5'= 9.6Hz,J5',6a'=4.4Hz, J5',6b'=1.6Hz, H-5'), 3.60 (1H, ddd, J4,5=9.6Hz, J5,6b=5.0Hz, J5,6a =0.8Hz, H-5), 2.23 (1H, d, J1,SH=9.6Hz, SH), 2.11,2.07,2.05,2.00,2.00,1.99,1.96 (21H,7×s,COCH3).
2p：White solid, Rf=0.35 (petroleum ether-ethyl acetate 1:1).1H NMR(400MHz,CDCl3)δ5.38(1H, d,J1',2'=4.0Hz, H-1'), 5.33 (1H, dd, J2,3=9.6Hz, J3,4=9.2Hz, H-3), 5.23 (1H, dd, J1,2=J2,3 =9.6Hz, H-2), 5.03 (1H, dd, J2',3'=10.4Hz, J3',4'=9.6Hz, H-3'), 4.84 (1H, dd, J2',3'= 10.4Hz,J1',2'=4.0Hz, H-2'), 4.79 (1H, dd, J3',4'=J4',5'=9.6Hz, H-4'), 4.56 (1H, dd, J1,SH =J1,2=9.6Hz, H-1), 4.43 (1H, dd, J6a,6b=12.4Hz, J5,6a=2.4Hz, H-6a), 4.22 (1H, dd, J6a,6b= 12.4Hz,J5,6b=4.0Hz, H-6b), 4.19 (1H, dd, J6'a,6'b=12.0Hz, J5',6'a=4.4Hz, H-6a'), 4.02 (1H,dd,J6'a,6'b=12.0Hz, J5,6'b=2.0Hz, H-6'b), 3.97 (1H, dd, J4,5=J3,4=9.2Hz, H-4), 3.92 (1H,ddd,J4,5=9.2Hz, J5,6b=4.0Hz, J5,6a=2.4Hz, H-5), 3.68 (1H, ddd, J4',5'=9.6Hz, J5',6a' =4.4Hz, J5',6b'=2.0Hz, H-5'), 2.23 (1H, d, J1,SH=9.6Hz, SH), 2.13,2.08,2.03,2.02, 2.00,1.99,1.98(21H,7×s,COCH3).
As it will be easily appreciated by one skilled in the art that the foregoing is merely illustrative of the preferred embodiments of the present invention, not to The limitation present invention, all within the spirits and principles of the present invention made by all any modification, equivalent and improvement etc., should all include Within protection scope of the present invention.

Claims (2)

1. a kind of synthetic method of glycosyl mercaptan, which is characterized in that include the following steps：
(1) sugar, mercaptan and weak base that sulphur acetyl group is protected are dissolved in organic solvent so that the sugar of the sulphur acetyl group protection Concentration in 0.1mM between 1mM, the sugar of the sulphur acetyl group protection is with the molar ratio of mercaptan 1:1 to 1:Between 1.5, institute The sugar of sulphur acetyl group protection and the molar ratio of weak base are stated 1:0.1 to 1:Between 1.0, raw material mixed liquor is obtained；
The sugar of sulphur acetyl group protection is
The mercaptan is In it is one or more；
The weak base is Na2CO3、NaHCO3、K2CO3、KHCO3, triethylamine, n,N-diisopropylethylamine, pyridine, ammonium acetate or ammonia Water；
The organic solvent is dimethylformamide or dimethylacetylamide；
(2) raw material mixed liquor obtained will be obtained in step (1), is reacted 1 hour to 24 hours, reaction product is extracted pure at room temperature Change and obtains glycosyl mercaptan.
2. synthetic method as described in claim 1, which is characterized in that the weak base is NaHCO3。
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