CN109912672A - A method of it is glycosylation using the base of adjacent ynylphenol ether as leaving group - Google Patents
A method of it is glycosylation using the base of adjacent ynylphenol ether as leaving group Download PDFInfo
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Abstract
The present invention discloses a kind of easy to operate, mild condition, the method for the C-N glycosidic bond of the high building nucleosides of the stereoselectivity and regioselectivity of reaction.One kind is using adjacent ynylphenol ether as leaving group; in inert gas environment; in the presence of desiccant; under promotor effect; glycosylation donor and the glycosylation receptor as shown in formula S shown in formula I are subjected to glycosylation reaction as follows, product glycosylation as shown in formula P is made, wherein; RNH is base class compound, and Gly is the glycosyl that one or more hydroxyls in saccharide ring are protected by protecting group.Glycosylation reaction mild condition of the present invention can take the glycosylation product of C-N with preferable yield, enrich the glycosidation of building nucleosides key.The glycosylation donor of neighbour's alkynyl phenolic ether class disclosed by the invention is stablized, and is easy to save, is widely used in various glycosylation reactions.The leaving group of donor is ethers protecting group, it is possible to distinguish carries out protecting group operation in benzyl oxide class protecting group.
Description
Technical field
The invention belongs to pharmaceutical technology fields, in particular to a kind of alkali using adjacent ynylphenol ether as leaving group
The glycosylation method of base.
Background technique
Glycosylation reaction is exactly that glycosyl donor (containing the group for being easy to leave away in sugared different head position) and receptor (have nucleophilicity
The substrate ROH, RNH of matter2Deng) connected by acetal bonds, form the reaction of glycosidic bond.The key points and difficulties of glycosylation reaction
It is exactly control and the yield of spatial configuration.When carrying out glycosylation reaction, due to receptor nucleopilic reagent can from both direction into
It attacks donor and is formed by oxygen urn ion, and then two kinds of configurations of α, β can be generated.We to obtain the single-minded product of spatial configuration,
Corresponding measure can generally be taken.Such as: neighboring group participation remotely participates in, the conformation of saccharide ring, different head position effect, additive, solvent etc.
It is controlled.Must be stringent anhydrous when carrying out glycosylation, it otherwise will cause the hydrolysis of donor, reduce glycosylation yield.It gives
The activity of body and receptor, promotor and solvent can all influence glycosylation yield.
The glucosides that nucleosides is nitrogenous base and saccharic composition is condensed into, nucleosides in nucleic acid by purine or pyrimidine base and ribose or
Deoxyribose is condensed.Nucleotide participates in giving birth to other than the premise as DNA, RNA as compound important in organism
Gene information retains, outside the molecular mechanism of transcription and replication in object, and the instrumentality that can also be used as physiological and biochemical procedure participates in
Substance in vivo metabolism.Nucleosides and its derivative drugs play the role of extremely important in terms for the treatment of many great diseases.
The new drug for developing nucleosides (base including nucleosides) and nucleotide has become the hot spot of research.
The method of synthetic nucleosides mainly has enzymatic clarification and two kinds of chemical synthesis in vitro at present, needed for enzymatic clarification
Glycosyl transferase and glycosidase type is few, price, universality are poor, therefore its application is significantly limited.Chemical synthesis can
Accurate structural is obtained, therefore is the main flow direction studied at present.The chemical synthesis of nucleoside compound mainly passes through glycosyl
Donor and base receptor are through chemical method formation C-N glycosidic bond.There are many factor for influencing base glycosylation reaction, wherein donor
(donor), receptor (acceptor) and promotor (promoter) are three principal elements, other reaction conditions such as solvent,
Temperature and concentration etc. all have an impact to it.
The building of sugar and the C-N glycosidic bond of base is always the key points and difficulties of carbohydrate chemistry research.Nucleoside medicine at present
It is clinically for treating the important drug of disease of viral infection, tumour, one kind of AIDS.Such drug is past several
The life that countless bacteriums, fungal infections have been saved in 10 years plays vital during extending human longevity
Effect.In the chemical synthesis of such drug molecule, the building of nucleosides key is committed step.But such glycosidic bond is not spy
It Rong Yi not construct, main cause is as follows:
1) very poor in this glycosylation middle base dissolubility as receptor, even if all cannot be completely molten by it in DMSO
Solution, this makes such glycosylation reaction be difficult to carry out；2) oxygen atom and nitrogen-atoms are all affinity in pyrimidine base analog, so
Two kinds of glycosylation products of C-O, C-N may be taken when carrying out glycosylation reaction.And for purine type bio-logical bases, there are N7 and N9
Regioselectivity problem.These problems bring huge challenge to the accurate building of base glycosidic bond.
Two scientists of Fisher and Helferich are put forward for the first time to solve the problems, such as the insoluble of base and utilize base
Metal salt synthetic nucleosides.[1]They make solvent in dimethylbenzene using the silver salt of halogeno-sugar and base, take under conditions of heating
Nucleoside product.But regrettably some too low compounds of yield just do not react substantially, change the silver salt of base into alkali later
Base mercury salt yield is promoted, but mercury is that the toxic substance of heavy metal is very big to the destructiveness of environment, and which also limits such
The use of method.
Nineteen thirty, Hilbert and Johnson full acetylated glucose chlorine glycosides and 2, the reaction of 4- diethoxy pyrimidine,
It is acidified successfully to synthesize miazines glucoside.[2]This method under heating conditions, being acidified by a step
It is easy to operate to obtain glycosylation product, do not need the participation of heavy metal, but this method unfortunately glycosylation yield
Not high, by-product is more, such as: N-alkylation product and O-glycosides product etc., another deficiency is exactly that product removes alkyl
Being melted into nucleosides, there is also some difficulties.
Nineteen sixty, the N of ribose and equimolar amounts that Sato group protects full acetyl group6Acetyl group adenine is in Lewis
Acid obtains the adenosine of corresponding acetyl group protection under conditions of being condensed as promotor, high-temperature fusion,[3]This method is not pervasive
Property (substrate for being only limited to low melting point), the stereoselectivity and regioselectivity of simultaneous reactions are poor, institute in this way not by
It is widely applied in the synthesis of nucleosides.
1963, Birkofer, Nishimura, wittenburg et al. in order to improve base in organic solvent molten
Solution property has carried out some improvement on the basis of classical Hilbert-Johnson reaction, by the leading silanization of base.Solves alkali
The low problem of the dissolubility difference activity of base in organic solvent, to improve the efficiency that C-N is bonded to.[4] and base
Silanization is compared with it is alkylated, and not only nucleophilicity substantially increases but also the deprotection of silicon substrate is also relatively easy very much.It is insufficient
Place is exactly the mercury salt for needing to use equivalent or silver perchlorate as promotor, since mercury salt environmental pollution is very serious,
And silver perchlorate at high temperature be very easy to occur explosion it is dangerous, institute in this way also not synthetic kernel glycosidic bond best way.
1970, Vorbruggen was on the basis of Silyl-Hibert-Johnson method, for the first time by acyl group sugar and silane
The base of change is in SnCl4The lower synthesis for carrying out nucleosides of effect, achieves extraordinary effect.[5]With Silyl-Hilbert-
Johnson reaction compares, and using full acetylated sugar as donor, the donor of the method is more stable and is easy to for Vorbruggen reaction
Preparation, and Vorbruggen reaction is with SnCl4、TiCl4、FeCl3、BF3.Et2The Lewis acid such as O and TMSOTf makees promotor, subtracts
The small pollution to environment.This method is the most widely used mode for preparing nucleosides now, but its shortcoming be condition compared with
For harshness, the activator even more using equivalent is needed, substrate reflection effect in part is simultaneously bad, and yield is undesirable.Work as receptor
The regioselectivity of glycosylation product is not very good when being purine type bio-logical bases, generally the mixture of N7/N9.
1991, Knapp seminar was anti-using the glycosyl donor of benzenethiol and the purine and pyrimidine that are activated with trimethyl silicane
It answers,[6]1992, Jean.Marie Beau seminar was using sulfoxide glucosides with the base-pair of the TMSOTf of equivalent and silicon substrate activation
Nucleosides is synthesized,[7]The C-N key of nucleosides key and other sugar is constructed with good yield, is provided with for the synthesis of nucleosides
A kind of effective method.However the method also has unsatisfactory place, and the nucleosides synthesis of thio glycoside needs to work as
NIS is measured, TsOH is synthesized as activator, the nucleosides of sulfoxide glucosides using the TMSOTf of equivalent as activator, the reactant of the two
System is acid too strong, if the substrate for those acid labile is not applicable.
1993, Lawrence J.Marnett seminar was with NIS, TsOH or neutral iodine perchlorate (IDCP) conduct
Activator is reacted using the glycosyl donor of pentenyl with purine, and ucleosides product can be obtained with moderate yield still selectively not
It is fine[8]。
Importance of the building based on nucleosides C-N key in nucleosides and nucleotide new drug research develops easy to operate, condition
Mild hot spot is easy to operate, mild condition, the C-N glucosides of the high building nucleosides of the stereoselectivity and regioselectivity of reaction
The method of key is very necessary.
Bibliography:
[1]Fischer,E.；Helferich,B.Chem.Ber.1974,47,210.
[2]Hilbert,G.E.；Johnson,T.B.J.Am.Chem.Soc.1930,52,4489.
[3]Diekmann,E.；Friedrich,Jr.；Fritz,H-G.J.Prakt.Chem.1993,335,415.
[4]Birkofer,L.；Ritter,A.；Kiihlthau,H.P.Angew.Chem.1963,4,209.
[5]Niedball,U.；Vorbrugg,H.Angew.Chem.Int.Ed.1970,9,461.
[6]Knapp,S.；Shieh,W.-C.Tetrahedron Lett.1991,32,3627-3630.
[7]Chanteloup,L.；Beau,J.-M.Tetrahedron Lett.1992,33,5347-5350.
[8]Chapeau,M.-C.；Marnett,L.J.Org.Chem.1993,58,7258.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of easy to operate, mild condition, the stereoselectivity of reaction and
The method of the C-N glycosidic bond of the high building nucleosides of regioselectivity.
In order to solve the above technical problems, the technical solution adopted by the present invention is that: it is a kind of using adjacent ynylphenol ether as leaving away
The glycosylation method of the base of base.
In inert gas environment, in the presence of desiccant, under promotor effect, by glycosylation donor shown in formula I
Glycosylation reaction as follows is carried out with the glycosylation receptor as shown in formula S, product glycosylation as shown in formula P is made,
Wherein, RNH is base class compound, and Gly is the glycosyl that one or more hydroxyls in saccharide ring are protected by protecting group,
The temperature of the glycosylation reaction is -50~-20 DEG C；Preferably -40~-35 DEG C；
The base be pyrimidine or purine,
When the base is pyrimidine, the promotor is BSTFA, NIS and TMSOTf；
When the base is purine, the promotor is NIS and TMSOTf.
The base class compound R NH is selected from any compound shown in following formula S1~S3,
Wherein R ' is acyl group class protecting group.
The acyl group class protecting group is selected from Bz, Cbz or Boc, preferably Boc.
The glycosylation donor is selected from any compound as shown below,
When the base is purine, the molar ratio of the RNH and TMSOTf, NIS are 1:0.1:1~1:1:2, preferably
1:0.6:1.5~1:1:2；The glycosylation donor and the molar ratio of RNH are 1:1~5:1, preferably 1.2:1~2:1；It is described
The mass volume ratio of glycosylation donor and methylene chloride is 20~100mg/mL, and the time of the glycosylation reaction is 3~15 small
When.
When the base is pyrimidine, the molar ratio of the RNH and TMSOTf, NIS, BSTFA are 1:0.1:1:1~1:1:2:
The molar ratio of 4, preferably 1:0.6:1:1~1:1:2:4, the glycosylation donor and RNH are 1:1~5:1, preferably 1:0.6:
1.5~1:1:2；The mass volume ratio of the glycosylation donor and methylene chloride is 20~100mg/mL, the glycosylation reaction
Time be 3~15 hours.
Preferably, the inert gas is selected from argon gas or nitrogen；Preferably, the desiccant is selected from the molecule of pickling
Sieve.In the present invention, product Compound P includes following molecule:
In the present invention, in the glycosylation reaction of adjacent alkynyl phenolic ether donor and amino saccharide acceptor, can respectively with 60%~
100% yield takes the glycosylation product of C-N, and the reflection effect of pyrimidine base analog obviously compares purine in these glycosylation reactions
It is good, mainly since the compatibility of purine type bio-logical bases is weaker, always have during reaction it is some reaction it is endless, in turn result in
Yield is lower.
The utility model has the advantages that glycosylation reaction mild condition of the present invention, can take the glycosylation product of C-N with preferable yield, it is rich
The glycosidation of richness building nucleosides key.The glycosylation donor of neighbour's alkynyl phenolic ether class disclosed by the invention is stablized, and is easy to save, extensively
It is used in various glycosylation reactions.The leaving group of donor is ethers protecting group, it is possible to distinguish is protected in benzyl oxide class protecting group
Base operation.
Specific embodiment
According to following embodiments, the present invention may be better understood.However, as it will be easily appreciated by one skilled in the art that real
It applies content described in example and is merely to illustrate the present invention, without sheet described in detail in claims should will not be limited
Invention.
In the present invention, abbreviation represents following meaning:
Bis- (trimethylsilyl) trifluoroacetamides of BSTFA:N, O-
NIS:N- N-iodosuccinimide
TMSOTf: Trimethylsilyl trifluoromethanesulfonate
Boc: tertbutyloxycarbonyl
Bz: benzoyl
Cbz: benzyloxycarbonyl group
The preparation of compound shown in Formulas I:
1, compound I1[9]Preparation:
By solid chemical compound 1 (5.0g, 9.1mmol), Ph3P (471.7mg, 3.6mmol), Pd (PPh3)2Cl2
(637.7mg, 1.0mmol), CuI (692.1mg, 3.6mmol) Methoxy-phenylacetylene (1.8g 13.6mmol) are placed in nitrogen protection
Round-bottomed flask in, taken a breath after cooling to -78 DEG C with vacuum diaphragm pump.Then DMF (10mL) ventilation is added and adds iPr2NH
(20mL) ventilation, moves back in triplicate to room temperature 15min, moves into 70 DEG C of oil baths and react 4 hours.Point board monitoring waits having reacted
It is complete that NH is added4Cl extracts reaction of going out, and with diatomite and silica gel filtering is padded after the dilution of a large amount of ethyl acetate, filtrate is first with the NH being saturated4Cl
It washes three times, then is washed with the NaCl of saturation and merge organic phase twice.With anhydrous Na2SO4It is dry.Diatomite and silica gel filtering on pad,
Filtrate fills column after being spin-dried for.Column, which is crossed, with (PE/EA=4:1) obtains faint yellow solid I1 (4.4g, 87.1%).
Bibliography: [9] Hu, Y.；Yu,K.；Shi,L.；Liu,L.；Sui,J.；Sun,
J.J.Am.Chem.Soc.2017,139,12736-12744.
2, compound I2[9]Preparation:
Compound I1 (3.0g, 5.4mmol) is dissolved in CH3OH (10.0mL), saturation CH is added at room temperature3Na solution
(0.5ml) reacts and detects fully reacting with TLC after 2 hours, be neutralized to PH=7 with acidic resins, filter, be spin-dried for, then will
It is dissolved in Py (10.0ml), and chlorobenzoyl chloride (3.3ml, 27.0mmol) is added dropwise under ice-water bath, and it is small to react 3 at room temperature
When, CH is added in point board monitoring fully reacting3OH extracts reaction of going out, washed twice after being diluted with a large amount of ethyl acetate with saturation NaCl,
The NaCl that 1NHCl washes twice, is saturated is washed merges organic phase twice, with anhydrous Na2SO4It is dry, it filters, filtrate is spin-dried for, ties again
Crystalline substance obtains white solid I2 (3.9g, 90.5%).
Bibliography: [9] Hu, Y.；Yu,K.；Shi,L.；Liu,L.；Sui,J.；Sun,
J.J.Am.Chem.Soc.2017,139,12736-12744.
3, the preparation of compound I3
The experimental implementation of synthesis can refer to the synthesis step of I1, to Methoxy-phenylacetylene (876.5mg, 6.6mmol) and 2
Faint yellow compound I3 (4.4mg, 87.1%) is obtained after (3.0g, 4.4mmol) fully reacting.[α]28 D=-74.4 ° of (c=
1.0,CHCl3)；1H NMR(400MHz,Acetone-d6)δ8.01–7.94(m,2H),7.85–7.77(m,2H),7.61–7.54
(m,1H),7.51–7.40(m,8H),7.40–7.26(m,7H),7.08–7.01(m,1H),7.00–6.92(m,2H),6.02–
5.84 (m, 3H), 5.77 (s, 1H), 4.50 (dd, J=10.3,4.9Hz, 1H), 4.31 (t, J=9.5Hz, 1H), 4.21 (td, J
=9.7,4.9Hz, 1H), 4.00 (t, J=10.1Hz, 1H), 3.85 (s, 3H)；13C NMR(100MHz,Acetone-d6)δ
206.2,166.0,165.7,160.7,157.8,138.5,134.2,134.1,133.9,133.8,130.4,130.3,
130.2,130.2,129.7,129.4,129.2,128.8,127.1,123.4,116.2,115.5,114.7,114.5,99.6,
94.6,84.1,79.1,73.2,73.1,69.0,67.4,55.7,30.4,30.2,30.0,29.8,29.6,29.4,29.2；
HRMS(ESI)calcd for C42H34O9Na[M+Na]+705.2095,found 705.2080.
The preparation of compound I4
The experimental implementation of synthesis I4 can refer to the synthesis step of I1: will be to Methoxy-phenylacetylene (1.8g, 13.6mmol) and 3
Faint yellow compound I4 (4.5g, 89.6%) is obtained after (5.0g, 9.1mmol) fully reacting.[α]D 25=-66.3 (c 1.0,
CHCl3)；1H NMR(400MHz,CDCl3) δ 7.59-7.53 (m, 2H), 7.48 (dd, J=7.7,1.7Hz, 1H), 7.28-7.22
(m, 1H), 7.13-6.99 (m, 2H), 6.92-6.83 (m, 2H), 5.66 (dd, J=10.5,8.0Hz, 1H), 5.47 (dd, J=
3.4,1.0Hz, 1H), 5.17-5.07 (m, 2H), 4.25 (dd, J=11.2,6.9Hz, 1H), 4.16 (dd, J=11.2,
6.2Hz,1H),4.12–4.07(m,1H),3.81(s,3H),2.18(s,3H),2.06(s,3H),2.00(s,3H),1.90(s,
3H)；13C NMR(100MHz,CDCl3)δ170.5,170.4,170.3,169.6,159.7,157.1,133.5,133.4,
129.2,123.1,115.6,115.5,114.5,113.9,100.1,94.2,83.4,77.5,77.1,76.8,71.1,70.9,
68.3,67.0,61.5,55.3,20.8,20.7,20.7；HRMS(ESI)calcd for C29H30O11Na[M+Na]+
577.1680,found 577.1656.
5, the preparation of compound I5
The experimental implementation of synthesis I5 can refer to the synthesis step of I1, by I4 (3.0g, 5.4mmol) first take off acetyl group again with
BzCl (3.1ml, 27.1mmol) reaction obtains white solid I5 (4.0g, 93.0%).[α]D 25=+137.7 (c1.0,
CHCl3)；1H NMR(400MHz,CDCl3) δ 8.20-8.13 (m, 2H), 8.08 (dd, J=8.2,1.4Hz, 2H), 7.87-7.81
(m, 2H), 7.73 (dd, J=8.1,1.4Hz, 2H), 7.67-7.58 (m, 2H), 7.55-7.41 (m, 6H), 7.40-7.31 (m,
3H), 7.25 (qd, J=8.7,7.8,1.4Hz, 3H), 7.17 (t, J=7.7Hz, 2H), 7.10 (td, J=7.9,1.8Hz,
1H), 7.01 (td, J=7.5,1.1Hz, 1H), 6.86-6.78 (m, 2H), 6.25 (dd, J=10.4,8.0Hz, 1H), 6.10
(d, J=3.5Hz, 1H), 5.71 (dd, J=10.4,3.5Hz, 1H), 5.50 (d, J=8.0Hz, 1H), 4.70 (dt, J=
10.4,5.2Hz,1H),4.63–4.51(m,2H),3.83(s,3H)；13C NMR(100MHz,CDCl3)δ166.12,165.7,
165.7,165.3,159.5,157.2,133.8,133.5,133.5,133.5,133.3,133.0,130.2,129.9,
129.9,129.8,129.5,129.2,129.1,128.9,128.8,128.8,128.6,128.4,128.1,123.0,
115.6,115.5,114.6,113.7,100.3,94.2,83.2,77.5,77.1,76.8,72.0,71.9,69.2,68.1,
62.4,55.4；HRMS(ESI)calcd for C49H38O11Na[M+Na]+825.2306,found 825.2270.
6, the preparation of compound I6
The experimental implementation of synthesis compound I6 can please refer to the synthesis step of I1, to Methoxy-phenylacetylene (985.1mg,
6.7mmol) and 5 (3.0g, 4.5mmol) reaction obtains faint yellow compound I6 (2.7mg, 90.0%).[α]28 D=+29.6
(c1.0,CHCl3)；1H NMR(400MHz,CDCl3) δ 8.02 (d, J=7.3Hz, 2H), 7.95 (d, J=7.6Hz, 2H), 7.90
(d, J=7.7Hz, 2H), 7.60-7.49 (m, 4H), 7.42 (q, J=8.2,7.8Hz, 4H), 7.35-7.26 (m, 4H), 7.20
(dd, J=16.3,7.4Hz, 2H), 6.99 (td, J=7.4,1.3Hz, 1H), 6.89-6.78 (m, 2H), 6.15 (dd, J=
7.2,4.7Hz, 1H), 6.08 (d, J=4.7Hz, 1H), 6.02 (s, 1H), 4.86 (dt, J=7.2,4.6Hz, 1H), 4.75
(dd, J=11.9,4.3Hz, 1H), 4.59 (dd, J=12.0,4.8Hz, 1H), 3.77 (s, 3H)；13C NMR(100MHz,
CDCl3)δ166.3,165.4,165.2,159.6,156.3,133.7,133.5,133.2,133.1,133.0,129.9,
129.8,129.8,129.5,129.2,129.1,128.9,128.6,128.4,128.3,122.8,115.9,115.5,
114.8,114.1,104.1,94.4,84.0,79.6,75.8,72.2,65.9,64.3,55.3,15.4；HRMS(ESI)calcd
for C41H32O9Na[M+Na]+691.1939,found 691.1912.
7, the preparation of compound I7
The experimental implementation of synthesis compound I7 can refer to the synthesis step of I1, to Methoxy-phenylacetylene (1.0g, 7.8mmol)
Faint yellow compound I7 (2.9g, 83.7%) is obtained with 6 (3.5mg, 5.2mmol) reaction.[α]28 D=-72.4 (c 1.0,
CHCl3)；1H NMR(400MHz,CDCl3) δ 8.08 (ddd, J=8.4,3.2,1.4Hz, 4H), 7.95-7.87 (m, 2H), 7.59
(tt, J=7.2,1.3Hz, 1H), 7.53-7.38 (m, 5H), 7.38-7.27 (m, 8H), 7.08 (td, J=7.4,1.4Hz,
1H), 6.84-6.77 (m, 2H), 5.89 (t, J=6.1Hz, 1H), 5.77 (dd, J=6.2,4.4Hz, 1H), 5.71 (d, J=
4.4Hz, 1H), 5.42 (td, J=5.7,3.6Hz, 1H), 4.78 (dd, J=12.5,3.7Hz, 1H), 3.98 (dd, J=12.5,
5.6Hz,1H),3.83(s,3H)；13C NMR(100MHz,CDCl3)δ160.4,160.2,160.0,154.3,151.9,
128.3,128.3,128.2,128.0,127.8,124.8,124.8,124.7,124.1,124.1,123.9,123.7,
123.3,123.2,123.0,117.9,111.3,110.2,109.8,108.6,93.7,88.9,78.6,72.2,72.1,
71.9,71.6,64.4,64.1,63.4,55.9,50.1；HRMS(ESI)calcd for C41H32O9Na[M+Na]+
691.1939,found691.1908.
8, the preparation of compound I8
The experimental implementation of synthesis compound I8 please refers to the synthesis step of I1, will to Methoxy-phenylacetylene (436.1mg,
3.3mmol) and faint yellow compound I8 (1.2g, 83.2%) is obtained after 7 (1.5g, 2.2mmol) fully reactings.[α]28 D=
111.7(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ8.08–7.97(m,4H),7.94–7.85(m,2H),7.61–
7.54 (m, 1H), 7.50-7.39 (m, 5H), 7.33-7.26 (m, 8H), 7.24 (dd, J=8.4,1.3Hz, 1H), 7.06 (td, J
=7.4,1.3Hz, 1H), 6.78-6.69 (m, 2H), 6.06 (dd, J=7.5,5.4Hz, 1H), 5.82-5.74 (m, 2H), 5.54
(d, J=5.5Hz, 1H), 4.62 (dd, J=12.5,5.1Hz, 1H), 4.07 (dd, J=12.4,2.6Hz, 1H), 3.78 (s,
3H)；13C NMR(100MHz,CDCl3)δ165.6,165.2,159.4,157.2,133.5,133.4,133.3,133.2,
133.0,123.0,129.9,129.8,129.3,129.3,129.0,128.9,128.5,128.3,128.2,123.1,
116.6,115.4,115.0,113.7,99.6,93.9,83.8,77.3,77.2,77.0,76.7,69.9,69.6,67.7,
61.9,55.2；HRMS(ESI)calcd for C41H32O9Na[M+Na]+691.1939,found 691.1940.
The preparation of compound shown in formula S:
1, the preparation of compound S1[10]
Under nitrogen protection, cytimidine Sa1 (500mg, 2.7mmol), DMAP (33.0g, 0.27mmol) are dissolved in drying
THF in, be slowly added to Boc under ice-water bath2O (3.9g, 10.8mmol), overnight, system becomes orange for reaction at room temperature
Clear solution is quenched after TLC detection fully reacting with methanol.Then it is diluted with a large amount of EA, uses saturated sodium bicarbonate water respectively
Solution and saturation NaCl washing, anhydrous sodium sulfate is dry, concentration.Then upper prop puts two hours, with (PE/EA=on pillar
It is 1:1) quick to cross column, obtain white solid product S1 (1.1g, 82.0%).
2, the preparation of compound S2[10]
Under nitrogen protection, adenine Sa2 (300mg, 2.0mmol), DMAP (48.5g, 0.04mmol) are dissolved in drying
THF in, be slowly added to Boc under ice-water bath2O (2.6g, 11.9mmol), reaction is stayed overnight at room temperature, the orange become to system
Color clear solution, TLC detection fully reacting are quenched with methanol.Then it is diluted with a large amount of EA, respectively with saturation NaHCO3It is water-soluble
Liquid and saturation NaCl washing, anhydrous Na2SO4It is dry, concentration.Upper prop crosses column with (PE/EA=5:1) is quick, obtains white solid
Product Sb2 (786.1mg, 91.0%).
Sb2 (500mg, 1.1mmol) is dissolved in methanol (13ml), the saturation NaHCO of (6.5ml) is then added3Solution, so
Be placed in 50 DEG C of oil bath and react 0.5h, TLC detection fully reacting after washed 2 times with a large amount of EA thinned water, then with satisfy
It is washed 2 times with NaCl, anhydrous Na2SO4Dry, concentration, upper prop crosses column with (PE/EA=1:1) is quick, obtains white solid product
S2 (306.1mg, 79.5%).
3, the preparation of compound S3[10]
The experimental implementation of synthesis S3 can refer to the synthesis step of S2: by compound Sa3 (300mg, 1.8mmol), with DMAP
(24.4mg, 0.2mmol), Boc2O (2.6g, 11.9mmol) reaction, obtains compound S3 (510.9mg, 78.1%).
[10]Andrea,P.；Giampaolo,G.；Ivana,P.；Mariolino,C.；Giammario,
N.Eur.J.Org.Chem.2008,34,5786–5797.
Embodiment 1:
Under nitrogen protection, compound S1 (20mg, 0.064mmol) is dissolved in dry DCM (1mL), at room temperature
BSTFA (68.3 μ L, 0.26mmol) reaction 0.5h is slowly added dropwise, then by NIS (29mg, 0.13mmol) and I1 (53.2mg,
It 0.096mmol) is rapidly added in the low-temp reaction device for being wherein subsequently placed in -35 DEG C, is slowly added to TMSOTf after reacting 10min
(7.0 μ L, 0.038mmol) uses Et after reacting the fully reacting of TCL plate detection overnight at this temperature3N is quenched, and is spin-dried for column
(PE/EA=3:1) compound P1 (40.0mg, 96.8%) is obtained.[α]D 25=+18.0 (c0.5, CHCl3)；1H NMR
(400MHz,CDCl3) δ 7.62 (d, J=7.7Hz, 1H), 7.15 (d, J=7.7Hz, 1H), 6.09 (d, J=9.5Hz, 1H),
5.39 (t, J=9.4Hz, 1H), 5.14 (dt, J=19.5,9.6Hz, 2H), 4.22 (dd, J=12.5,5.1Hz, 1H), 4.07
(dd, J=12.4,1.8Hz, 1H), 3.97-3.88 (m, 1H), 2.05 (s, 3H), 2.03 (s, 3H), 1.98 (s, 3H), 1.94
(s,3H),1.52(s,18H)；13C NMR(100MHz,CDCl3)δ170.6,169.8,169.6,162.7,154.1,149.3,
143.2,97.3,85.3,81.1,77.5,77.1,76.8,75.1,72.8,70.0,68.0,61.8,27.7,20.8,20.6,
20.6,20.4；HRMS(ESI)calcd for C28H39N3O14K[M+K]+680.20636,found 680.2032.
Embodiment: 2:
The experimental implementation of synthesis P2 can refer to the synthesis step of P1: under nitrogen protection, by S1 (20mg, 0.064mmol)
2.5h is reacted with BSTFA (68.3 μ L, 0.26mmol), is then added I2 (77.1mg, 0.096mmol), NIS (29mg,
0.13mmol) and TMSOTf (7.0 μ L, 0.038mmol) reaction obtains compound P2 (57.3mg, 100%) overnight.[α]D 25=+
17.8(c 0.5,CHCl3)；1H NMR(400MHz,Acetone-d6) δ 8.49 (d, J=7.6Hz, 1H), 8.10-8.04 (m,
2H),7.98–7.93(m,2H),7.89–7.83(m,2H),7.84–7.78(m,2H),7.65–7.33(m,13H),7.04(d,J
=7.7Hz, 1H), 6.65 (d, J=9.3Hz, 1H), 6.29 (t, J=9.5Hz, 1H), 6.01 (dt, J=16.4,9.6Hz,
2H), 4.88 (ddd, J=10.0,4.7,2.8Hz, 1H), 4.72 (dd, J=12.5,2.8Hz, 1H), 4.64 (dd, J=12.5,
4.7Hz,1H),1.48(s,18H)；13C NMR(100MHz,Acetone-d6)δ166.4,166.1,165.9,165.8,
163.4,154.2,150.2,146.2,134.6,134.5,134.4,134.1,130.8,130.5,130.5,130.2,
130.0,130.0,129.6,129.5,129.4,129.4,97.4,85.4,82.1,75.6,74.4,72.6,69.8,63.6,
27.8；HRMS(ESI)calcd for C48H47N3O14Na[M+Na]+912.2950,found 912.2947.
Embodiment 3:
The experimental implementation of synthesis P3 can refer to the synthesis step of P1, obtain compound P3 (43.1mg, 87.1%).[α]D 25
=+21.7 (c1.0, CHCl3)；1H NMR(400MHz,Acetone-d6) δ 8.38 (d, J=7.7Hz, 1H), 7.96-7.91 (m,
2H),7.88–7.82(m,2H),7.59–7.53(m,2H),7.46–7.38(m,6H),7.35–7.30(m,3H),7.07(d,J
=7.7Hz, 1H), 6.55 (d, J=9.3Hz, 1H), 6.12 (t, J=9.4Hz, 1H), 5.88 (t, J=9.3Hz, 1H), 5.74
(s, 1H), 4.46 (dd, J=10.3,4.9Hz, 1H), 4.36 (t, J=9.5Hz, 1H), 4.27 (td, J=9.6,4.8Hz,
1H), 3.97 (t, J=10.1Hz, 1H), 1.48 (s, 18H)；13C NMR(100MHz,Acetone-d6)δ165.1,165.0,
162.5,153.2,149.2,145.3,137.5,133.6,133.4,129.6,129.5,129.4,128.8,128.7,
128.5,128.5,128.0,126.2,101.4,96.4,84.5,81.9,78.1,72.5,72.2,69.2,67.9,29.6,
29.5,29.4,29.2,29.0,28.8,28.6,28.4,26.9；HRMS(ESI)calcd for C41H43N3O12Na[M+Na]+
792.2739,found 792.2697.
Embodiment 4:
The experimental implementation of synthesis P4 can refer to the synthesis step of P1, obtain compound P4 (41.2mg, 100%).[α]D 25=
+29.4(c 1.0,CHCl3)；1H NMR (400MHz, Chloroform-d) δ 7.65 (d, J=7.7Hz, 1H), 7.14 (d, J=
7.7Hz, 1H), 6.04 (d, J=9.0Hz, 1H), 5.46 (d, J=3.1Hz, 1H), 5.31-5.24 (m, 1H), 5.21 (dd, J=
10.2,3.2Hz, 1H), 4.16-4.00 (m, 3H), 2.15 (s, 3H), 2.00 (s, 3H), 1.94 (d, J=4.3Hz, 6H), 1.51
(s,18H)；13C NMR(100MHz,CDCl3)δ170.4,170.0,169.9,169.7,162.6,154.1,149.2,143.6,
97.2,85.2,81.4,77.5,77.2,76.8,73.9,70.9,67.8,67.2,67.1,61.4,27.7,20.7,20.7,
20.5；HRMS(ESI)calcd for C28H39N3O14K[M+K]+680.20636,found 680.2032.
Embodiment 5:
The experimental implementation of synthesis P5 can refer to the synthesis step of P1, obtain compound P5 (53.3mg, 93.2%).[α]D 25
=+70.6 (c 1.0, CHCl3)；1H NMR(400MHz,Acetone-d6) δ 8.43 (d, J=7.7Hz, 1H), 8.25-8.20
(m,2H),8.03–7.98(m,2H),7.90–7.86(m,2H),7.81–7.76(m,2H),7.76–7.69(m,1H),7.65–
7.54 (m, 4H), 7.53-7.45 (m, 3H), 7.39 (t, J=7.8Hz, 2H), 7.35-7.29 (m, 2H), 7.14 (d, J=
7.6Hz, 1H), 6.69 (d, J=9.2Hz, 1H), 6.26 (dd, J=3.3,1.2Hz, 1H), 6.19 (dd, J=10.0,3.4Hz,
1H), 6.08 (t, J=9.5Hz, 1H), 5.14 (td, J=6.3,1.2Hz, 1H), 4.70 (dd, J=11.4,6.6Hz, 1H),
4.61 (dd, J=11.5,6.0Hz, 1H), 1.48 (s, 18H)；13C NMR(100MHz,Acetone-d6)δ166.2,166.2,
165.9,165.6,163.4,154.2,150.1,145.9,134.6,134.5,134.3,134.1,130.7,130.5,
130.4,130.3,130.2,130.1,129.9,129.7,129.5,129.4,129.3,97.6,85.3,82.4,74.9,
72.8,70.5,69.6,63.0,30.4,30.2,30.0,29.8,29.6,29.4,29.2,27.7；HRMS(ESI)calcd
for C48H47N3O14K[M+K]+928.26896,found 928.2697.
Embodiment 6:
The experimental implementation of synthesis P6 can refer to the synthesis step of P1, obtain compound P6 (48.5mg, 90.1%).[α]D 25
=-12.8 (c 1.0, CHCl3)；1H NMR(400MHz,CDCl3) δ 8.11-8.06 (m, 2H), 7.93 (ddd, J=11.1,
8.3,1.4Hz, 4H), 7.81 (d, J=7.6Hz, 1H), 7.61-7.49 (m, 3H), 7.46 (t, J=7.8Hz, 2H), 7.35
(td, J=7.7,5.1Hz, 4H), 7.03 (d, J=7.6Hz, 1H), 6.26 (d, J=3.9Hz, 1H), 5.92 (t, J=5.9Hz,
1H), 5.85 (dd, J=5.8,3.9Hz, 1H), 4.83 (dd, J=12.0,2.9Hz, 1H), 4.76 (dt, J=6.4,3.5Hz,
1H), 4.70 (dd, J=12.0,4.3Hz, 1H), 1.55 (s, 18H)；13C NMR(100MHz,CDCl3)δ166.2,165.3,
165.3,162.9,153.9,149.4,143.8,133.7,133.7,133.6,130.0,129.9,129.7,129.4,
128.7,128.5,96.8,90.9,85.2,80.5,77.5,77.2,76.8,74.9,71.0,63.8,27.8；HRMS(ESI)
calcd for C40H41N3O12K[M+K]+794.23218,found 794.2314.
Embodiment 7:
The experimental implementation of synthesis P7 can refer to the synthesis step of P1, obtain compound P7 (48.5mg, 100.0%).[α]D 25
=+27.0 (c 0.25, CHCl3)；1H NMR(400MHz,CDCl3)δ7.99–7.93(m,2H),7.89–7.84(m,4H),
7.81 (d, J=7.7Hz, 1H), 7.58-7.52 (m, 1H), 7.50-7.43 (m, 2H), 7.41 (t, J=7.7Hz, 2H), 7.32
(q, J=7.8Hz, 4H), 7.18 (d, J=7.6Hz, 1H), 6.36 (d, J=9.5Hz, 1H), 6.07 (t, J=9.6Hz, 1H),
5.64 (t, J=9.5Hz, 1H), 5.48 (td, J=10.1,5.6Hz, 1H), 4.51 (dd, J=11.5,5.7Hz, 1H), 3.80
(t, J=11.0Hz, 1H), 1.49 (s, 18H)；13C NMR(100MHz,CDCl3)δ165.7,165.5,165.5,162.7,
154.2,149.3,143.3,133.8,133.5,130.2,130.0,129.9,128.8,128.7,128.7,128.6,
128.5,128.1,97.4,85.2,82.1,77.5,77.2,76.8,72.8,70.7,69.8,66.1,27.7；HRMS(ESI)
calcd for C40H41N3O12K[M+K]+794.23218,found 794.2306.
Embodiment 8:
The experimental implementation of synthesis P8 can refer to the synthesis step of P1, obtain compound P8 (46.6mg, 96.0%).[α]D 25
=+132.7 (c 1.0, CHCl3)；1H NMR(400MHz,CDCl3)δ8.14–8.07(m,2H),7.93–7.81(m,5H),
7.68-7.60 (m, 1H), 7.53 (t, J=7.6Hz, 2H), 7.50-7.41 (m, 2H), 7.30 (dt, J=20.3,7.7Hz,
4H), 7.19 (d, J=7.6Hz, 1H), 6.38 (d, J=9.4Hz, 1H), 5.98 (t, J=9.7Hz, 1H), 5.82 (d, J=
3.5Hz, 1H), 5.77 (dd, J=9.9,3.4Hz, 1H), 4.41 (dd, J=13.5,1.9Hz, 1H), 4.16 (d, J=
13.4Hz,1H),1.49(s,18H)；13C NMR(100MHz,CDCl3)δ165.7,165.5,165.3,162.6,154.1,
149.2,143.3,133.7,133.7,133.5,130.07,129.8,129.8,129.4,128.8,128.7,128.5,
128.4,128.3,97.4,85.1,82.1,77.5,77.1,76.8,71.9,69.3,68.8,67.6,27.7；HRMS(ESI)
calcd for C40H41N3O12K[M+K]+794.2322,found 794.2305.
Embodiment 9:
Under nitrogen protection, compound S2 (20mg, 0.060mmol) and I3 (48.8mg, 0.072mmol) are dissolved in drying
DCM in, stir 0.5h at room temperature, NIS (20.1mg, 0.09mmol) be rapidly added to the low-temp reaction for being wherein placed in -350C
In device, it is slow added into TMSOTf (6.5 μ L, 0.036mmol) after reacting 10min, reacts TCL plate detection overnight at this temperature
Et is used after fully reacting3N is quenched, and was spin-dried for column (PE/EA=4:1) and obtains compound P10 (37.9mg, 80.0%).[α]D 25=
+23.5(c 1.0,CHCl3)；1H NMR(400MHz,Acetone-d6)δ8.90(s,1H),8.82(s,1H),7.98–7.93
(m,2H),7.72–7.67(m,2H),7.60–7.54(m,1H),7.52–7.41(m,5H),7.36–7.28(m,5H),6.65
(d, J=9.2Hz, 1H), 6.41 (t, J=9.2Hz, 1H), 6.21 (t, J=9.4Hz, 1H), 5.82 (s, 1H), 4.50-4.43
(m, 2H), 4.38 (td, J=9.6,4.8Hz, 1H), 4.02 (t, J=10.0Hz, 1H), 1.30 (s, 18H)；13C NMR
(100MHz,Acetone-d6)δ166.0,165.4,154.0,153.0,151.3,150.7,145.0,138.4,134.6,
134.4,130.3,130.3,129.8,129.5,129.3,129.1,129.1,128.9,127.1,102.3,83.8,82.3,
79.0,73.4,72.9,70.2,68.8,30.5,30.3,30.1,29.9,29.7,29.5,29.3,27.8；HRMS(ESI)
calcd for C42H43N5O11K[M+K]+832.2591,found 832.2530.
Embodiment 10:
The experimental implementation of synthesis P12 can refer to the synthesis step of P10, obtain compound P12 (32.1mg, 69.1%).
[α]D 25=-54.8 (c 1.0, CHCl3)；1H NMR(400MHz,Acetone-d6)δ8.74(s,1H),8.71(s,1H),
8.14–8.09(m,2H),8.08–8.04(m,2H),7.97–7.92(m,2H),7.69–7.59(m,3H),7.55–7.46(m,
4H), 7.46-7.40 (m, 2H), 6.79 (d, J=5.0Hz, 1H), 6.68 (dd, J=6.0,4.9Hz, 1H), 6.43 (t, J=
5.6Hz, 1H), 5.04-4.99 (m, 1H), 4.95 (dd, J=12.2,3.6Hz, 1H), 4.81 (dd, J=12.2,4.5Hz,
1H),1.41(s,18H)；13C NMR(100MHz,Acetone-d6)δ166.5,165.8,165.7,153.8,152.8,
151.4,151.1,146.1,134.6,134.6,134.2,130.8,130.56,130.5,130.5,130.1,130.1,
129.8,129.5,129.5,88.3,84.0,81.2,74.5,72.2,64.2,30.5,30.3,30.1,29.9,29.7,
29.5,29.3,27.9；HRMS(ESI)calcd for C41H41N5O11K[M+K]+818.2434,found 818.2376.
Embodiment 11:
The experimental implementation of synthesis P13 can refer to the synthesis step of P10, obtain compound P13 (35.0mg, 75.3%).
[α]D 25=-12.8 (c 1.0, CHCl3)；1H NMR(400MHz,Acetone-d6)δ8.97(s,1H),8.82(s,1H),
8.04–7.96(m,2H),7.93–7.86(m,2H),7.75–7.68(m,2H),7.67–7.59(m,1H),7.58–7.46(m,
4H), 7.39 (t, J=7.8Hz, 2H), 7.36-7.29 (m, 2H), 6.58 (d, J=9.1Hz, 1H), 6.45 (t, J=9.3Hz,
1H), 6.34 (t, J=9.5Hz, 1H), 5.79 (ddd, J=10.5,9.5,5.6Hz, 1H), 4.61 (dd, J=11.5,5.6Hz,
1H),4.38–4.25(m,1H),1.30(s,18H)；13C NMR(100MHz,Acetone-d6)δ166.2,166.0,165.4,
154.1,151.3,150.7,134.6,134.6,134.4,130.4,130.3,130.1,130.0,129.6,129.5,
129.4,129.1,129.1,83.8,82.3,74.0,72.3,70.4,66.23,30.5,30.3,30.1,29.9,29.7,
29.5,29.3,27.8；HRMS(ESI)calcd for C41H41N5O11K[M+K]+818.2434,found 818.2442.
Embodiment 12:
The experimental implementation of synthesis P14 can refer to the synthesis step of P10, obtain compound P14 (42.2mg, 90.7%).
[α]D 25=+80.3 (c 1.0, CHCl3)；1H NMR(400MHz,Acetone-d6)δ8.92(s,1H),8.86(s,1H),
8.41-8.32 (m, 2H), 7.87-7.80 (m, 2H), 7.78-7.71 (m, 3H), 7.66 (ddd, J=8.3,6.6,1.4Hz,
2H), 7.56-7.46 (m, 2H), 7.34 (q, J=7.9Hz, 4H), 6.77 (t, J=9.6Hz, 1H), 6.53 (d, J=9.2Hz,
1H), 6.10 (dd, J=10.0,3.4Hz, 1H), 6.02 (dt, J=3.4,1.4Hz, 1H), 4.63 (dd, J=13.5,1.2Hz,
1H), 4.52 (dd, J=13.4,2.1Hz, 1H), 1.29 (s, 18H)；13C NMR(100MHz,Acetone-d6)δ166.2,
165.8,165.5,154.1,153.0,151.4,150.7,145.2,134.6,134.4,131.0,130.7,130.3,
130.3,130.1,129.7,129.5,129.4,129.4,129.3,83.8,73.1,70.1,70.1,68.1,27.8；HRMS
(ESI)calcd for C41H41N5O11K[M+K]+818.2434,found 818.2439.
Embodiment 13:
Under nitrogen protection, compound S3 (20mg, 0.054mmol) and I2 (52.1mg, 0.11mmol) addition is filled
ActivationIn the round-bottomed flask of molecular sieve, be dissolved in dry DCM, stir 0.5h at room temperature, then by NIS (18.2mg,
It 0.08mmol) is rapidly added in the low-temp reaction device for being wherein subsequently placed in -35 DEG C, is slow added into TMSOTf after reacting 10min
(6.5 μ L, 0.036mmol) uses Et after reacting the fully reacting of TCL plate detection overnight at this temperature3N is quenched, and is spin-dried for column
(PE/EA=3:1) compound P15 (32.1mg, 62.6%) is obtained.[α]D 25=+72.6 (c 1.0, CHCl3)；1H NMR
(400MHz,Acetone-d6)δ9.22(s,1H),8.09–8.04(m,2H),8.00–7.94(m,2H),7.85–7.79(m,
2H), 7.77-7.72 (m, 2H), 7.65-7.55 (m, 2H), 7.53-7.41 (m, 6H), 7.35 (td, J=7.8,2.7Hz, 4H),
6.75 (d, J=9.1Hz, 1H), 6.55 (t, J=9.3Hz, 1H), 6.46 (t, J=9.5Hz, 1H), 6.15 (t, J=9.7Hz,
1H), 5.04 (ddd, J=10.1,4.2,2.8Hz, 1H), 4.75-4.63 (m, 2H), 1.37 (s, 18H)；13C NMR(100MHz,
Acetone-d6)δ206.2,166.3,166.0,165.8,165.5,153.9,153.1,151.3,151.1,146.7,
134.6,134.5,134.4,134.0,130.6,130.5,130.4,130.3,130.1,129.8,129.7,129.4,
129.3,129.3,128.9,83.8,81.4,75.5,74.2,72.3,69.6,63.3,30.4,30.2,30.0,29.8,
29.6,29.4,29.2,27.9；HRMS(ESI)calcd for C49H47ClN5O13[M+H]+948.28534,found
948.2882.
Embodiment 14:
The experimental implementation of synthesis P16 can refer to the synthesis step of P15, obtain compound P16 (30.8mg, 68.7%).
[α]D 25=+18.4 (c 1.0, CHCl3)；1H NMR(400MHz,Acetone-d6)δ9.05(s,1H),7.98–7.90(m,
2H),7.76–7.69(m,2H),7.59–7.49(m,2H),7.47–7.40(m,4H),7.38–7.29(m,5H),6.61(d,J
=9.3Hz, 1H), 6.42 (t, J=9.2Hz, 1H), 6.24 (t, J=9.2Hz, 1H), 5.80 (s, 1H), 4.49-4.33 (m,
3H), 3.98 (t, J=9.7Hz, 1H), 1.39 (s, 18H)；13C NMR(100MHz,Acetone-d6)δ206.2,166.1,
165.7,154.0,153.2,151.4,151.2,146.9,138.4,134.7,134.4,130.8,130.5,130.3,
130.3,129.8,129.5,129.5,129.1,128.9,127.2,102.4,84.0,82.3,80.0,73.4,72.7,
70.1,68.8,30.5,30.3,30.1,30.0,29.9,29.7,29.5,29.3,28.0；HRMS(ESI)calcd for
C42H43ClN5O11[M+H]+828.26421,found 828.2623.
Embodiment 15:
The experimental implementation of synthesis P17 can refer to the synthesis step of P15, obtain compound P17 (36.0mg, 70.2%).
[α]D 25=+56.1 (c 1.0, CHCl3)；1H NMR(400MHz,Acetone-d6) δ 9.04 (s, 1H), 8.31 (dt, J=7.1,
1.4Hz, 2H), 8.02-7.94 (m, 2H), 7.76 (ddd, J=8.4,3.9,1.4Hz, 5H), 7.69 (dd, J=8.2,6.7Hz,
2H),7.66–7.59(m,1H),7.55–7.45(m,4H),7.38–7.27(m,4H),6.72–6.62(m,2H),6.31(dd,J
=3.5,1.2Hz, 1H), 6.24 (dd, J=9.2,3.5Hz, 1H), 5.19 (td, J=6.4,1.2Hz, 1H), 4.68 (dd, J=
11.4,6.7Hz, 1H), 4.58 (dd, J=11.5,6.1Hz, 1H), 1.37 (s, 18H)；13C NMR(100MHz,Acetone-
d6)δ166.4,166.3,165.7,165.6,154.1,153.2,151.5,151.1,147.2,134.7,134.7,134.5,
134.3,131.2,130.9,130.5,130.4,130.4,130.3,130.0,129.9,129.6,129.5,129.4,
129.2,83.9,82.9,75.0,72.9,69.9,69.4,63.0,28.0；HRMS(ESI)calcd for C42H42ClN5O11K
[M+K]+866.2201,found 866.2170.
Embodiment 16:
The experimental implementation of synthesis P18 can refer to the synthesis step of P15, obtain compound P18 (31.5mg, 71.5%).
[α]D 25=-37.0 (c 1.0, CHCl3)；1H NMR(400MHz,Acetone-d6) δ 8.85 (s, 1H), 8.04 (ddt, J=
11.4,6.9,1.4Hz, 4H), 7.99-7.94 (m, 2H), 7.68-7.60 (m, 3H), 7.51-7.42 (m, 6H), 6.78 (d, J=
4.7Hz, 1H), 6.50 (dd, J=6.0,4.7Hz, 1H), 6.32 (t, J=5.7Hz, 1H), 5.03 (td, J=5.5,4.2Hz,
1H), 4.91 (dd, J=12.0,4.3Hz, 1H), 4.83 (dd, J=12.0,5.6Hz, 1H), 1.43 (s, 18H)；13C NMR
(100MHz,Acetone-d6)δ166.5,165.7,165.7,153.5,152.9,151.4,151.3,147.0,134.7,
134.6,134.2,131.4,130.7,130.6,130.5,130.4,130.1,129.8,129.5,88.3,84.0,81.5,
75.1,72.6,65.0,30.5,30.3,30.2,30.1,29.9,29.7,29.5,29.3,28.0；HRMS(ESI)calcd
for C41H40ClN5O11K[M+K]+852.2044,found 852.2041.
Embodiment 17:
The experimental implementation of synthesis P19 can refer to the synthesis step of P15, obtain compound P19 (36.0mg, 81.7%).
[α]D 25=+32.4 (c 1.0, CHCl3)；1H NMR(400MHz,Acetone-d6)δ9.10(s,1H),8.00–7.94(m,
2H), 7.91-7.85 (m, 2H), 7.75 (dd, J=8.3,1.4Hz, 2H), 7.62 (t, J=7.4Hz, 1H), 7.55-7.46 (m,
4H), 7.37 (dt, J=11.5,7.8Hz, 4H), 6.54 (d, J=9.2Hz, 1H), 6.46 (t, J=9.2Hz, 1H), 6.36 (t,
J=9.4Hz, 1H), 5.81-5.72 (m, 1H), 4.59 (dd, J=11.4,5.6Hz, 1H), 4.31 (t, J=11.0Hz, 1H),
1.39(s,18H)；13C NMR(100MHz,Acetone-d6)δ166.2,166.0,165.6,154.0,153.2,151.3,
151.3,146.9,134.7,134.6,134.5,130.7,130.5,130.3,130.1,130.0,129.7,129.6,
129.6,129.5,129.2,84.0,82.3,73.9,72.0,70.3,66.1,28.0；HRMS(ESI)calcd for
C41H40ClN5O11K[M+K]+852.2044,found 852.2029.
Embodiment 18:
The experimental implementation of synthesis P20 can refer to the synthesis step of P15, obtain compound P20 (36.0mg, 81.7%).
[α]D 25=+152.3 (c 1.0, CHCl3)；1H NMR(400MHz,Acetone-d6)δ9.01(s,1H),8.31–8.25(m,
2H), 7.82-7.72 (m, 5H), 7.66 (dd, J=8.3,6.7Hz, 2H), 7.55-7.48 (m, 2H), 7.38-7.30 (m, 4H),
(6.61 t, J=9.6Hz, 1H), 6.51 (d, J=9.3Hz, 1H), 6.15 (dd, J=9.8,3.6Hz, 1H), 6.02 (dt, J=
3.5,1.5Hz, 1H), 4.64 (dd, J=13.6,1.3Hz, 1H), 4.52 (dd, J=13.5,2.0Hz, 1H), 1.39 (s,
18H)；13C NMR(100MHz,Acetone-d6)δ166.3,165.7,165.7,154.1,153.2,151.4,151.2,
147.0,134.7,134.5,134.4,131.1,130.8,130.5,130.4,130.3,130.0,129.9,129.5,
129.4,129.3,84.0,83.1,72.8,70.1,70.0,68.3,30.5,30.3,30.1,29.9,29.7,29.5,29.3,
28.0；HRMS(ESI)calcd for C41H40ClN5O11K[M+K]+852.2044,found 852.2027.
Comparative example: the mode of operation of reference implementation example 1, to the reality of glycosyl donor and acceptor base under the conditions of differential responses
It is as follows to test result.
(1) with reference to the step and parameter in the glycosylation embodiment 1 of miazines: except that receptor is activated without BSTFA
It directly carries out glycosylation reaction to obtain being the glycosylation product of C-O, does not generate C-N product, yield 80%~90%.With reference to fast
Step and parameter in the glycosylation embodiment 9 of purine class: except that the molar ratio of the RNH and TMSOTf, NIS are 1:1:2,
Yield 20%~30%.
Comparative example 1:
Under nitrogen protection, compound S1 (20mg, 0.064mmol) and I1 (53.2mg, 0.096mmol) addition is filled
ActivationIn the round-bottomed flask of molecular sieve, dry DCM (1.0mL) is added, stirs 0.5h at room temperature, then by NIS (29mg,
It 0.13mmol) is rapidly added in the low-temp reaction device for being wherein subsequently placed in -35 DEG C, is being slowly added to TMSOTf after reacting 10min
(7.0uL, 0.038mmol) reacts obtain compound A (40.0mg, 82.5%) overnight at this temperature.[α]D 25=-5.5 (c
1.0,CHCl3)；1H NMR(400MHz,Acetone-d6) δ 8.56 (d, J=5.6Hz, 1H), 7.49 (d, J=5.6Hz, 1H),
6.24 (d, J=8.2Hz, 1H), 5.41 (t, J=9.5Hz, 1H), 5.26-5.11 (m, 2H), 4.32-4.23 (m, 1H), 4.14-
4.06(m,2H),2.02(s,3H),1.98(s,3H),1.97(s,3H),1.96(s,3H),1.56(s,18H)；13C NMR
(100MHz,Acetone-d6)δ170.7,170.3,170.0,169.6,163.7,161.2,150.7,108.4,95.4,
85.2,73.5,73.2,71.6,69.1,62.5,28.0,27.9,20.7,20.6,20.6；HRMS(ESI)calcd for
C28H39N3O14Na[M+Na]+664.2432,found 664.2443.
Comparative example 2:
The experimental implementation of synthesis B can refer to the synthesis step of A, obtain compound B (50.4mg, 88.2%).[α]D 25=+
34.3(c 1.0,CHCl3)；1H NMR(400MHz,Acetone-d6) δ 8.51 (d, J=5.6Hz, 1H), 8.06-8.00 (m,
2H), 7.95 (ddd, J=10.0,8.4,1.4Hz, 4H), 7.89-7.83 (m, 2H), 7.66-7.52 (m, 4H), 7.51-7.36
(m, 9H), 6.68 (d, J=8.1Hz, 1H), 6.20 (t, J=9.4Hz, 1H), 5.93-5.83 (m, 2H), 4.72-4.56 (m,
3H),1.50(s,18H)；13C NMR(100MHz,Acetone-d6)δ166.4,166.2,165.9,165.5,163.7,
161.2,161.1,150.5,134.5,134.5,134.4,134.1,130.8,130.5,130.5,130.5,130.4,
130.1,130.0,129.5,129.4,129.4,108.3,95.8,85.1,74.2,73.5,72.3,70.4,63.6,27.9；
HRMS(ESI)calcd for C48H47N3O14K[M+K]+928.2690,found 928.2695.
Comparative example 3:
The experimental implementation of synthesis C can refer to the synthesis step of A, obtain compound C (41.8mg, 84.5%).[α]D 25=+
44.3(c 1.0,CHCl3)；1H NMR(400MHz,Acetone-d6) δ 8.51 (d, J=5.6Hz, 1H), 8.00-7.93 (m,
2H),7.93–7.86(m,2H),7.58–7.48(m,2H),7.47–7.34(m,7H),7.33–7.26(m,3H),6.59(d,J
=8.0Hz, 1H), 5.96 (t, J=9.4Hz, 1H), 5.81-5.68 (m, 2H), 4.39 (dd, J=9.7,4.3Hz, 1H), 4.27
(t, J=9.3Hz, 1H), 4.08-3.90 (m, 2H), 1.52 (s, 16H)；13C NMR(100MHz,Acetone-d6)δ166.0,
165.5,163.6,161.2,161.1,150.5,138.4,134.4,134.3,130.4,130.0,129.7,129.4,
128.9,127.2,108.2,102.2,96.1,85.1,79.1,73.2,73.0,68.9,67.9,27.9；HRMS(ESI)
calcd for C48H47N3O14Na[M+Na]+808.2478,found 808.2477.
Comparative example 4:
The experimental implementation of synthesis D can refer to the synthesis step of A, obtain compound D (53.7mg, 93.9%).[α]D 25=+
85.9(c 1.0,CHCl3)；1H NMR(400MHz,Acetone-d6) δ 8.53 (d, J=5.6Hz, 1H), 8.17-8.10 (m,
2H),8.03–7.97(m,2H),7.96–7.91(m,2H),7.83–7.78(m,2H),7.75–7.70(m,1H),7.64–7.57
(m, 3H), 7.56-7.46 (m, 5H), 7.40 (t, J=7.8Hz, 2H), 7.36-7.30 (m, 2H), 6.68 (d, J=8.2Hz,
1H), 6.17 (dd, J=3.5,1.2Hz, 1H), 6.12 (dd, J=10.3,8.1Hz, 1H), 6.02 (dd, J=10.3,3.4Hz,
1H), 4.96-4.88 (m, 1H), 4.66 (dd, J=11.3,6.9Hz, 1H), 4.55 (dd, J=11.3,6.1Hz, 1H), 1.50
(s,18H)；13C NMR(100MHz,Acetone-d6)δ166.3,166.3,165.7,165.7,163.8,161.2,161.2,
150.6,134.7,134.4,134.41,134.7,130.7,130.6,130.4,130.4,130.3,130.2,130.0,
129.8,129.8,129.5,129.4,129.4,108.3,96.0,85.1,72.8,72.8,70.3,69.5,62.8,27.9；
HRMS(ESI)calcd for C48H47N3O14Na[M+Na]+902.3058,found 902.3065.
Comparative example 5:
Under nitrogen protection, compound S2 (20mg, 0.060mmol) and I3 (48.8mg, 0.072mmol) are dissolved in drying
DCM in, stir 0.5h at room temperature, NIS (26.8mg, 0.12mmol) be rapidly added and is wherein placed in -35 DEG C of low-temp reaction
In device, it is slow added into TMSOTf (10.8 μ L, 0.060mmol) after reacting 10min, reacts TCL plate inspection overnight at this temperature
Et is used after surveying fully reacting3N is quenched, and was spin-dried for column (PE/EA=4:1) and obtains compound P10 (9.8mg, 21.0%).
Comparative example 6:
The experimental implementation of synthesis P12 can refer to the synthesis step of P10 in comparative example 5, obtain compound P12 (11.9mg,
25.6%).
Comparative example 7:
The experimental implementation of synthesis P15 can refer to the synthesis step of P10 in comparative example 5, obtain compound P15 (14.4mg,
28.1%).
Comparative example 7:
The experimental implementation of synthesis P18 can refer to the synthesis step of P10 in comparative example 5, obtain compound P18 (9.5mg,
21.5%).
Claims (7)
1. a kind of glycosylation method of base using adjacent ynylphenol ether as leaving group, which is characterized in that in inert gas ring
In border, in the presence of desiccant, under promotor effect, by glycosylation donor and the glycosylation receptor as shown in formula S shown in formula I
Glycosylation reaction as follows is carried out, product glycosylation as shown in formula P is made,
Wherein, RNH is base class compound, and Gly is the glycosyl that one or more hydroxyls in saccharide ring are protected by protecting group, described
The temperature of glycosylation reaction is -50~-20 DEG C；
The base be pyrimidine or purine,
When the base is pyrimidine, the promotor is BSTFA, NIS and TMSOTf；
When the base is purine, the promotor is NIS and TMSOTf.
2. the glycosylation method of base according to claim 1, which is characterized in that the base class compound R NH is selected from
Any compound shown in following formula S1~S3,
Wherein R ' is acyl group class protecting group.
3. the glycosylation method of base according to claim 2, which is characterized in that the acyl group class protecting group is selected from Bz,
Cbz or Boc.
4. the glycosylation method of base according to claim 2, which is characterized in that the glycosylation donor is selected from following institute
Any compound shown,
5. the glycosylation method of base according to claim 4, which is characterized in that the base be purine, the RNH and
The molar ratio of TMSOTf, NIS are 1:0.1:1~1:1:2, and the molar ratio of the glycosylation donor and RNH are 1:1~5:1, described
The mass volume ratio of glycosylation donor and methylene chloride is 20~100mg/mL, and the time of the glycosylation reaction is 3~15 small
When.
6. according to the glycosylation method of claim 4 base, which is characterized in that the base be pyrimidine, the RNH and
The molar ratio of TMSOTf, NIS, BSTFA are 1:0.1:1:1~1:1:2:4, and the molar ratio of the glycosylation donor and RNH are 1:1
The mass volume ratio of~5:1, the glycosylation donor and methylene chloride is 20~100mg/mL, the time of the glycosylation reaction
It is 3~15 hours.
7. the glycosylation method of base according to claim 1~6, which is characterized in that the inert gas is selected from argon gas or nitrogen；
The desiccant is selected from the molecular sieve of pickling.
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| CN114891049A (en) * | 2022-06-28 | 2022-08-12 | 陕西师范大学 | Efficient glycosylation method based on o-alkynyl benzyl ether glycosyl donor |
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