CN102702291A - 3'-thionucleoside synthesis method - Google Patents
3'-thionucleoside synthesis method Download PDFInfo
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Abstract
The invention relates to a 3'-thionucleoside synthesis method. According to the method, oxonucleotide which is easy to obtain is used as initial raw materials, firstly, primary hydroxyl groups of furan ring is subjected to selective protection, then, twice turning is carried out, and -SH is successfully introduced at the No.3 bit of the furan ring. The synthesis method has the advantages that the synthesis path of 3'-thionucleoside is optimized, and target products can be obtained from the initial raw materials through five-step reaction, so the yield (the yield is 4 to 5 times that in the prior art) and the purity of the target products are improved.
Description
Technical field
The present invention relates to a kind of compound method of 3 '-sulfo-nucleosides
Background technology
Nucleosides is the glucosides of ribose or ribodesose and a base (like VITAMIN B4, thymus pyrimidine, guanine, oxygen Aminometradine or uridylic) generation, is DNA and RNA important component part.In addition, some nucleosides or derivatives thereof has pharmaceutical use and (can treat acute and chronic hepatitis and rheumatic heart disease like inosine (inosine), and effect such as the white cell of increasing is arranged; 5 '-NSC-27640 can be antitumor (toxicity than 5 '-Fluracil is low), and liver cancer, cancer of the stomach, the rectum cancer, ovarian cancer, bladder cancer are had certain curative effect; Cytarabin has unusual effect to palliating leukemia; 5 '-deoxidation-5 '-the iodouracil nucleosides is the specifics of treatment viral keratitis) therefore, the study on the synthesis of nucleosides has caused people's very big interest.
3 '-sulfo-nucleosides be for fields such as antisense strand medicine and gene silencing be want in very monomer, all have extraordinary application prospect in a lot of research fields of nucleic acid, it also is a kind of extraordinary midbody simultaneously.As: with 2-cyanoethyl-N, N-di-isopropyl chloro phosphoramidite and this compounds at room temperature react just can obtain 3 '-sulfo-nucleosides phosphorous acid amide monomer (J, Lu., et al.; Bioorg.Med.Chem., 2008.16.5754-57602), the monomer of this compounds can be used as solid-phase nucleic acid synthetic raw material monomer again; Its solid phase synthesis (referring to G, Sabbagh., et al.; Nucleic Acids Research., 2004.32 (2): oligosaccharides Nucleotide product 495-501) also has the performance that is cut except that the biology performance with traditional oligosaccharides Nucleotide; Can apply to detection and the dna sequence analysis of nucleic acid, protein and other and as probe to detect metals ion (L, B, Weinstein.; Et al., J.Am.Chem.Soc., 1996.118 (43): 10341-10350; J, F, Curley., et al., J.Am.Chem.Soc., 1997.119 (51): 12691-12692).
So far, existing a lot of bibliographical informations compound method (Matulic-Adamic, the J. of 3 '-sulfo-nucleosides; Et al., Helv.Chim.Acta., 1999,82 (12), 2141-2150; Lu, J.; Et al.; Biorg.Med.Chem., 2008,16 (10); 5754-5760.), but the method for existing synthetic 3 '-sulfo-nucleosides exists the yield low (total recovery is merely about 10%) and the not high defective of purity of synthetic route tediously long (generally needing the reaction of seven steps), title product.
Given this, optimize 3 '-sulfo-nucleosides synthetic route, and the productive rate and the purity that improve 3 '-sulfo-nucleosides become the technical issues that need to address of the present invention.
Summary of the invention
The objective of the invention is to, the compound method of the higher 3 '-sulfo-nucleosides of productive rate and the purity of the succinct and title product of a kind of synthetic route is provided,
The present invention wants synthetic 3 '-sulfo-nucleosides, and it is a compound shown in the formula I.
And the method for compound shown in provided by the present invention, the synthesis type I comprises the steps:
(1) reacts through the selectivity hydroxyl protection by compound shown in the formula II, obtain the step of compound shown in the formula III;
(2) react through the hydroxyl upset by compound shown in the formula III, obtain the step of compound shown in the formula IV;
(3) react through hydroxyl protection by compound shown in the formula IV, obtain the step of compound shown in the formula V;
(4) react through sulfo-and upset by compound shown in the formula V, obtain the step of compound shown in the formula VI;
(5) by compound shown in the formula VI through reduction reaction, obtain the step of target compound (compound shown in the formula I);
Wherein, R
1Be H, halogen (F, Cl, Br or I), C
1～C
3Alkoxyl group or azido-(N
3);
R
2Be hydroxy-protective group (as: 4; 4 '-dimethoxytrityl methyl (4,4 '-dimethoxytrityl, abbreviation DMT), t-butyldiphenylsilyl (t-butyldiphenylsilyl; Abbreviation TBDPS), t-butyldimethylsilyl (t-butyldimethylsilyl; Abbreviation TBDMS), benzoyl-(benzoyl, abbreviation Bz) or ethanoyl (acetyl, abbreviation Ac) etc.);
R
3Be hydroxy-protective group (as: methyl sulphonyl
Or trifluoromethyl sulfonyl
); R
4Be Ac or Bz;
A is a base, for example, and suc as formula group shown in VII or the formula VIII etc.:
Wherein, R
5Be H,
R
6Be amino (NH
2),
R
7For-NH
2,
R
8Be H, halogen (F, Cl, Br or I), or C
1～C
3Alkyl, the curve mark is for replacing the position.
Can be known that by technique scheme the present invention is a starting raw material with the oxo nucleosides (compound shown in the formula II) that is easy to get, earlier the primary hydroxyl to furan nucleus carries out selective protection, then through twice upset, successfully at No. 3 position introducing-SH of furan nucleus.The present invention has optimized the synthetic route of 3 '-sulfo-nucleosides, and promptly reaction just can obtain the target compound product through five steps by starting raw material, thereby has improved the yield (yield is 4～5 times of prior art) and the purity of target compound product.
Embodiment
In optimized technical scheme of the present invention, R
1Be H, F, Br, methoxyl group or azido-(N
3);
In another optimized technical scheme of the present invention, R
5Be H, R
6For
In another optimized technical scheme of the present invention, R
5For
R
6Be amino (NH
2),
In another optimized technical scheme of the present invention, R
5For
R
6For
In another optimized technical scheme of the present invention, R
7For-NH
2, R
8Be H;
In another optimized technical scheme of the present invention, R
7For
R
8Be halogen (F, Cl, Br or I);
In another optimized technical scheme of the present invention, R
7For
R
8Be H or methyl.
The method of compound specifically comprises the steps: shown in the synthesis type I provided by the present invention
(1) (said organic alkali lye comprises: pyridine, DBU (1,8-diazabicyclo [5,4,0] undec-7-ene) or triethylamine etc. compound shown in the formula II to be dissolved in organic or inorganic alkali lye; Said inorganic alkali lye comprises: by salt of wormwood or yellow soda ash and tetrahydrofuran aqueous solution (THF: H
2O=1: 1, the mixture of V/V) forming etc.) in, under agitation condition; Add hydroxyl protection reagent (like DMTCl, TBDMSCl, TMSCI, TBDPSCl, BzCl or AcCl etc.), continue to stir 1-10 hour, drip protic solvent (comprising methyl alcohol, ethanol or water etc.) cancellation reaction to reaction solution; Add silica gel again; Revolve driedly, silicagel column separates, and obtains compound shown in the formula III;
(2) oxygenant (is comprised Jones reagent, Sha Ruite reagent, V
2O
5Catalytic oxidant, Pd catalytic oxidant, hypochlorite or wear this Martin's oxygenant etc. (specifically referring to Eisenhuth, R.; Richert, C., J.Org.Chem.; 2008,74 (1), (said organic solvent comprises halohydrocarbon (like methylene dichloride, chloroform or tetracol phenixin etc.), ether, THF, DMF, 1 26-37.) to be dissolved in organic solvent; Organic solvents such as 4-dioxane, acetonitrile), under agitation condition, contain in the organic solvent of oxygenant to this; Add compound shown in the formula III, room temperature condition kept 1 hour at least, cooling; The temperature of reaction solution is controlled at and is not higher than-5 ℃, adds reductive agent (said reductive agent comprises lithium aluminum hydride, Peng Qinghuana, palladium carbon, Raney Ni, reduced iron powder etc.) again and continues to stir 1-19 hour, and reaction solution dilutes with tetracol phenixin; Aqueous phase extracted merges organic phase, and organic phase is water, saturated NaHCO respectively
3, saturated NaCl washing, use anhydrous magnesium sulfate drying, the filtering siccative revolves except that organic solvent, the silicagel column separation obtains compound shown in the formula IV;
(3) (said organic alkali lye comprises: pyridine, DBU or triethylamine etc. compound shown in the formula IV to be dissolved in organic or inorganic alkali lye; Said inorganic alkali lye comprises: by salt of wormwood or yellow soda ash and tetrahydrofuran aqueous solution (THF: H
2O=I: 1, the mixture of V/V) forming etc.) in, under ice bath and agitation condition; To add hydroxyl protection reagent (as: Methanesulfonyl chloride, trifluoromethyl sulfonic acid anhydride or trifluoromethyl SULPHURYL CHLORIDE etc.) and join in the mixture of forming by compound shown in the formula IV and said alkali lye, reinforced finishing, reaction solution is under room temperature state; Kept 6-12 hour, this reaction solution is poured in the frozen water, stir; Use dichloromethane extraction, organic phase is water, saturated NaHCO respectively
3, saturated NaCl washing, use the anhydrous sodium sulfate drying organic phase again, the filtering siccative revolves except that organic solvent, silicagel column separates, obtain compound shown in the formula V;
(4) compound shown in the formula V and aprotic organic solvent (like N, dinethylformamide, 1,4-dioxane, acetonitrile or tetracol phenixin etc.) are mixed, get mixture; Having under rare gas element (like argon gas etc.) existence condition, and dithionate in the gained mixture (like thioacetic acid potassium, thioacetic acid sodium; Thiobenzoic acid sodium or thiobenzoic acid potassium etc.); Be heated to 50 ℃～60 ℃, and continue reaction 4 hours～24 hours, extraction; Merge organic phase, organic phase is water, saturated NaHCO respectively
3With saturated NaCl washing, use anhydrous sodium sulfate drying again, the filtering siccative revolves except that organic solvent, and silicagel column separates, and obtains compound shown in the formula VI.
(5) at ice bath and have under rare gas element (like argon gas etc.) existence condition, the mixture that will form by compound shown in the formula VI and anhydrous organic solvent (like anhydrous diethyl ether or anhydrous tetrahydro furan etc.) with mainly contain the mixture that reductive agent (like lithium aluminum hydride, Peng Qinghuana, palladium carbon, Raney Ni or reduced iron powder etc.) and anhydrous organic solvent (like anhydrous diethyl ether or anhydrous tetrahydro furan etc.) form and mix, and kept at ambient temperature 0.5 hour～12 hours; With saturated metabisulfite solution cancellation reaction, use the aqueous sodium hydroxide solution dissolution precipitation, reaction solution dilutes with methylene dichloride; Tell organic phase; Aqueous phase extracted merges organic phase, and organic phase is used anhydrous sodium sulfate drying; The filtering siccative; Revolve and remove organic solvent, silicagel column separates, and obtains target compound (compound shown in the formula I).
Below in conjunction with embodiment the present invention is further elaborated, its purpose only is better to understand content of the present invention.Therefore the embodiment that is lifted does not limit protection scope of the present invention.
Embodiment 1
The preparation of compound shown in the formula I a:
With 2 '-(0.2520g 1.0mmol) is dissolved in the anhydrous DBU that 10mL handled to Hypoxanthine deoxyriboside, starts stirring, and (0.4060g, 1.2mmol), reaction solution continues stirring reaction 19h at ambient temperature in two mouthfuls of flasks, to add DMTCl at leisure.Cross silicagel column, earlier with eluent (DCM: EtOH=20: 1, V/V) cross except that pyridine, after add the high polarity product, product be white solid 0.5483g (5 '-DMT-2 '-Hypoxanthine deoxyriboside, compound III a), productive rate is 98.97%.
(0.6400g 1.5mmol) is dissolved in the anhydrous methylene chloride that 8mL handled, and starts stirring with Sha Ruite reagent; Then ice bath cooling 10min, slowly add compound 5 '-DMT-2 '-Hypoxanthine deoxyriboside (0.5440g, 1.0mmol); Ice bath reaction 1h removes ice bath then, slowly rises to room temperature and continues reaction 4h; In reaction solution, drip the 8mL anhydrous isopropyl alcohol, and disposable adding NaBH4 (76.00mg, 2.0mmol); Continue reaction 13h, in reaction solution, add 8mL acetone, continue stirring and slowly rise to room temperature.Reaction solution dilutes with methylene dichloride, and organic phase is water respectively, and saturated NaHCO3 is after saturated NaCl washes; Aqueous phase extracted merges organic phase, anhydrous magnesium sulfate drying 30min, filtering siccative; Revolve and remove organic solvent, and the mistake silicagel column (DCM: EtOH=15: 1, V/V); Product be white foam shape solid 0.5182g (anti--3 '-OH-5 '-DMT-2 '-Hypoxanthine deoxyriboside, compound IV a), productive rate is 95.25%.
Will be anti--3 '-(0.2770g 0.50mmol) is dissolved in the anhydrous pyridine that 4mL handled OH-5 '-DMT-2 '-Hypoxanthine deoxyriboside, starts stirring, and (0.077mL, 1.0mmol), reaction solution continues continuation at ambient temperature and reacts 12h to add trifluoromethanesulfonyl chloride.Reaction solution is poured in the frozen water, stirring at room 10min, water is used dichloromethane extraction, and organic phase is water, saturated NaHCO3 respectively; After saturated NaCl washed, aqueous phase extracted merged organic phase, anhydrous sodium sulfate drying; The filtering siccative revolves except that organic solvent, crosses silicagel column; Earlier with eluent (DCM: EtOH=20: 1, V/V) cross except that pyridine, after add the high polarity product; Product be white foam shape solid 0.2313g (anti--3 '-OMs-5 '-DMT-2 '-Hypoxanthine deoxyriboside, compound Va), productive rate is 73.08%.
Will be anti--3 '-(0.1300g 0.22mmol) is dissolved in the anhydrous N of 8mL to OMs-5 '-DMT-2 '-Hypoxanthine deoxyriboside, in the dinethylformamide; This moment the reaction solution clear solution that is white in color, (70.30mg is 0.62mmol) to reaction flask slowly to add thioacetic acid potassium; Vacuumize with oil pump, displacement argon gas three times is opened water of condensation; Be heated to 50 ℃～60 ℃, keep 24h at this state, this moment, reaction solution was red tan solution.With reaction solution difference water, saturated NaHCO
3, after saturated NaCl washes, aqueous phase extracted; Merge organic phase, anhydrous sodium sulfate drying, filtering siccative; Revolve and remove organic solvent, and the mistake silicagel column (DCM: EtOH=15: 1, V/V); Product be white foam shape solid 0.1085g (3 '-SAc-5 '-DMT-2 '-Hypoxanthine deoxyriboside, compound VI a), productive rate is 86.41%.
Under argon shield, the about 0.5g of Raney Ni is added in the there-necked flask, get the constant pressure funnel of the anhydrous tetrahydro furan adding 50mL that 5mL handled; Start stirring, vacuumize, displacement argon gas three times with oil pump; Then under condition of ice bath, slowly drop in the there-necked flask, this moment the reaction solution suspension-s that is white in color, after dropwising; Then with 3 '-(612.0mg 0.10mmol) is dissolved in anhydrous tetrahydro furan that 5mL handled in the exsiccant constant pressure funnel to SAc-5 '-DMT-2 '-Hypoxanthine deoxyriboside, under condition of ice bath, slowly drops in the reaction solution; Dropwise continued reaction 10min; Remove ice bath, reaction solution continues to continue at ambient temperature reaction 4min, and this moment, reaction solution was colourless transparent solution.With saturated metabisulfite solution cancellation reaction, reaction solution dilutes with methylene dichloride, tells organic phase, aqueous phase extracted; Merge organic phase, anhydrous sodium sulfate drying, filtering siccative; Revolve and remove organic solvent, and the mistake silicagel column (DCM: EtOH=12: 1, V/V); Product is that (title compound, compound I a), productive rate is 92.35% to white foam shape solid 0.2101g.
The purity of title compound is 98%, and overall yield is about 55%.
1H?NMR(400MHz，CDCl
3)：δ12.62(s，1H)，8.10(s，1H)，8.04(s，1H)，7.43-6.80(m，9H)，6.32(dd，1H，J1＝4.0Hz，J2＝8Hz)，4.00(m，1H)，3.78(s，6H)，3.53(dd，1H，J1＝4.0Hz，J2＝8Hz)，3.42(dd，1H，J1＝4.0Hz，J2＝8Hz)，2.93(m，1H)，2.49(s，1H)，1.65(d，1H，J＝8Hz).
MS(ESI)：m/z?calcd?for?C31H30N4O5S：[M+H+]：571.2；found：571.3.
Embodiment 2
The preparation of compound shown in the formula I b:
Except that 2-ethanamide-2 '-Desoxyadenosine alternative embodiment 1 in 2 '-Hypoxanthine deoxyriboside, other conditions are identical with embodiment 1, obtain title compound.The purity of title compound is 98%, and its total recovery is about 45%.
1H?NMR(400MHz，CDCl
3)：δ10.32(s，1H)，8.30(s，1H)，6.97(s，2H)，7.43-6.84(m，13H)，5.94(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，4.38(m，1H)，3.83(s，6H)，3.63(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，3.38(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，2.90(m，1H)，2.68(m，1H)，2.43(m，1H)，2.04(s，3H)，1.58(d，1H，J＝8Hz).
MS(ESI)：m/z?calcd?for?C
33H
34N
6O
5S：[M+H
+]：627.2；found：627.3.
Embodiment 3
The preparation of compound shown in the formula I c:
According to present embodiment 1 described method, wherein only with raw material 2 '-Hypoxanthine deoxyriboside change into 2-ethanamide-6-BM-2 '-Desoxyadenosine, and DMTCl changes TBSCl into and just can obtain title compound smoothly.The purity of title compound is 98%, and its total recovery is about 49%.
1H?NMR(400MHz，CDCl
3)：δ11.34(s，1H)，10.32(s，1H)，8.36(s，1H)，8.05-6.84(m，5H)，5.94(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，4.38(m，1H)，4.20(m，1H)，3.73(s，1H)，2.93(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，2.68(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，2.40(m，1H)，2.08(s，3H)，1.60(d，1H，J＝8Hz)，0.21(s，9H).
MS(ESI)：m/z?calcd?for?C
22H
28N
6O
4SSi：[M+H
+]：501.2；found：502.3.
Embodiment 4
The preparation of compound shown in the formula I d:
According to present embodiment 1 described method, wherein only with raw material 2 '-Hypoxanthine deoxyriboside change into 2-ethanamide-6-BM-2 '-the fluorine Desoxyadenosine just can obtain title compound smoothly.The purity of title compound is 98%, and its total recovery is about 38%.
1H?NMR(400MHz，CDCl
3)：δ11.34(s，1H)，10.31(s，1H)，8.40(s，1H)，8.05-6.84(m，18H)，6.22(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，4.38(m，1H)，4.0(m，1H)，3.83(s，6H)，3.66(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，3.42(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，3.17(m，1H)，2.05(s，3H)，1.62(d，1H，J＝8Hz).
MS(ESI)：m/z?calcd?for?C
40H
37FN
6O
6S：[M+H
+]：749.3；found：749.4.
Embodiment 5
The preparation of compound shown in the formula I e:
According to present embodiment 1 described method, wherein only with raw material 2 '-Hypoxanthine deoxyriboside change into 2-ethanamide-6-BM-2 '-the methoxyl group Desoxyadenosine, and DMTCl is changed to TBDPSCl and just can obtains title compound smoothly.The purity of title compound is 98%, and its total recovery is 48%.
1H?NMR(400MHz，CDCl
3)：δ11.38(s，1H)，10.33(s，1H)，8.42(s，1H)，8.07-6.83(m，15H)，6.22(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，4.38(m，1H)，3.66(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，3.49(m，1H)，3.42(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，3.30(s，3H)，3.17(m，1H)，2.05(s，3H)，1.62(d，1H，J＝8Hz)，0.98(s，9H).
MS(ESI)：m/z?calcd?for?C
36H
40N
6O
5SSi：[M+H
+]：697.3；found：697.4。
Embodiment 6
The preparation of compound shown in the formula I f:
According to present embodiment 1 described method, wherein only DMTCl is changed to BzCl and just can obtains title compound smoothly.The purity of title compound is 98%, and its total recovery is 55%.
1H?NMR(400MHz，CDCl
3)：δ12.62(s，1H)，8.10(s，1H)，8.04(s，1H)，8.43-6.80(m，5H)，6.32(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，4.30(m，1H)，4.00(m，1H)，3.53(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，3.42(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，2.93(m，1H)，2.49(s，1H)，1.65(d，1H，J＝8Hz).
MS(ESI)：m/z?calcd?for?C
17H
16N
4O
4S：[M+H
+]：373.1；found：373.2。
Embodiment 7
The preparation of compound shown in the formula I g:
According to present embodiment 1 described method, wherein with raw material 2 '-Hypoxanthine deoxyriboside changes 2 into '-the bromine pancreatic desoxyribonuclease can obtain title compound smoothly.The purity of title compound is 98%, and its total recovery is about 53%.
1H?NMR(400MHz，CDCl
3)：δ12.62(s，1H)，8.04(s，1H)，7.45-6.80(m，13H)，6.36(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，4.38(m，1H)，4.12(m，1H)，3.83(s，6H)，3.63(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，3.42(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，3.33(m，1H)，1.63(d，1H，J＝8Hz).
MS(ESI)：m/z?calcd?for?C
31H
30BrN
5O
5S：[M+H
+]：664.2；found：665.3。
Embodiment 8
The preparation of compound shown in the formula I h:
According to present embodiment 1 described method, wherein only with raw material 2 '-Hypoxanthine deoxyriboside changes 2 into '-Deoxyribose cytidine, and DMTCl is changed to TMSCl and just can obtains title compound smoothly.The purity of title compound is 98%, and its total recovery is about 51%.
1H?NMR(400MHz，CDCl
3)：δ8.10(s，1H)，7.31(d，1H，J＝4Hz)，6.13(m，1H)，5.43(m，1H)，5.38(m，1H)，5.18(m，1H)，3.63(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，3.38(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，2.90(m，1H)，2.48(m，1H)，2.23(m，1H)，2.01(s，2H)，1.50(d，1H，J＝8Hz)，0.30(s，9H).
MS(ESI)：m/z?calcd?for?C
12H
23N
3O
3SSi：[M+H
+]：318.1；found：318.2。
Embodiment 9
The preparation of compound shown in the formula I i:
According to present embodiment 1 described method, wherein only with raw material 2 '-Hypoxanthine deoxyriboside change into 4-ethanamide-5-iodo-2 '-the methoxyl group Deoxyribose cytidine, obtain title compound, the purity of title compound is 98%, its total recovery is about 51%.
1H?NMR(400MHz，CDCl
3)：δ8.10(s，1H)，8.06(s，1H)，7.98(s，1H)，7.47-6.85(m，13H)，6.19(d，1H，J
1＝4.0Hz)，4.38(m，1H)，3.83(s，6H)，3.63(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，3.38(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，3.30(s，3H)，3.22(m，1H)，1.84(s，3H)，1.53(d，1H，J＝8Hz).
MS(ESI)：m/z?calcd?for?C
30H
36IN
3O
7S：[M+H
+]：746.2；found：746.2。
Embodiment 10
The preparation of compound shown in the formula I j:
According to present embodiment 1 described method, wherein only with raw material 2 '-Hypoxanthine deoxyriboside changes 2 into '-the azido-deoxyuridine, and DMTCl is changed to AcCl, obtain title compound.The purity of title compound is 98%, and its total recovery is about 48%.
1H?NMR(400MHz，CDCl
3)：δ11.23(s，1H)，9.06(s，1H)，6.38(s，1H)，6.19(d，1H，J
1＝4.0Hz)，4.38(m，1H)，4.22(m，1H)，3.65(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，3.41(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，3.22(m，1H)，2.21(s，3H)，1.53(d，1H，J＝8Hz).
MS(ESI)：m/z?calcd?for?C
11H
13N
5O
5S：[M+H
+]：328.1；found：328.2。
Embodiment 11
The preparation of compound shown in the formula I k:
According to present embodiment 1 described method, wherein only with raw material 2 '-Hypoxanthine deoxyriboside changes 2 into '-deoxyuridine, to title compound.The purity of title compound is 98%, and its total recovery is about 42%.
1H?NMR(400MHz，CDCl
3)：δ11.23(s，1H)，9.06(s，1H)，7.47-6.80(m，13H)，6.38(s，1H)，6.19(d，1H，J
1＝4.0Hz)，4.38(m，1H)，4.22(m，1H)，3.83(s，6H)，3.65(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，3.41(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，2.42(m，1H)，2.22(m，1H)，1.55(d，1H，J＝8Hz).
MS(ESI)：m/z?calcd?for?C
30H
30N
2O
6S：[M+H
+]：547.2；found：547.3。
Embodiment 12
The preparation of compound shown in the formula I 1:
According to present embodiment 1 described method, wherein only with raw material 2 '-Hypoxanthine deoxyriboside changes 2 into '-the methoxyl group deoxythymidine, and DMTCl is changed to TBDPSCl, obtains title compound.The purity of title compound is 98%, and its total recovery is about 42%.
1H?NMR(400MHz，CDCl
3)：δ11.23(s，1H)，9.06(s，1H)，7.47-6.80(m，10H)，6.38(s，1H)，6.19(d，1H，J
1＝4.0Hz)，4.38(m，1H)，4.22(m，1H)，3.65(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，3.41(dd，1H，J
1＝4.0Hz，J
2＝8Hz)，3.32(s，3H)，2.42(s，3H)，1.55(d，1H，J＝8Hz)，0.98(s，9H).
MS(ESI)：m/z?calcd?for?C
27H
34N
2O
5SSi：[M+H
+]：527.2；found：527.3。
Claims (12)
1. the method for compound shown in the synthesis type I comprises the steps:
(1) reacts through the selectivity hydroxyl protection by compound shown in the formula II, obtain the step of compound shown in the formula III;
(2) react through the hydroxyl upset by compound shown in the formula III, obtain the step of compound shown in the formula IV;
(3) react through hydroxyl protection by compound shown in the formula IV, obtain the step of compound shown in the formula V;
(4) react through sulfo-and upset by compound shown in the formula V, obtain the step of compound shown in the formula VI;
(5) by compound shown in the formula VI through reduction reaction, obtain the step of target compound;
Wherein, R
1Be H, halogen, C
1～C
3Alkoxyl group or azido-; R
2And R
3Independently be selected from respectively: a kind of in the hydroxy-protective group; R
4Be the acetyl or benzoyl base; A is a base.
2. the method for claim 1 is characterized in that, wherein R
2Be 4,4 '-dimethoxytrityl methyl, t-butyldiphenylsilyl, t-butyldimethylsilyl, benzoyl-or ethanoyl.
3. the method for claim 1 is characterized in that, wherein R
3Be methyl sulphonyl or trifluoromethyl sulfonyl.
4. like claim 1,2 or 3 described methods, it is characterized in that wherein A is a group shown in formula VII or the formula VIII:
Wherein, R
5Be H,
R
6Be amino,
R
7Be amino,
R
8Be H, halogen or C
1～C
3Alkyl.
5. like claim 1 or 4 described methods, it is characterized in that, wherein R
1Be H, F, Br, methoxyl group or azido-.
6. method as claimed in claim 5 is characterized in that, wherein R
5Be H, R
6For
R
5For
R
6Be amino,
Or R
5For
R
6For
7. method as claimed in claim 5 is characterized in that, wherein R
7For-NH
2, R
8Be H; R
7For
R
8Be halogen; Or R
7For
R
8Be H or methyl.
8. like claim 1,6 or 7 described methods, it is characterized in that said method comprises the following steps:
(1) compound shown in the formula II is dissolved in the organic or inorganic alkali lye, under agitation condition, adds hydroxyl protection reagent; Continue to stir 1-10 hour, drip protic solvent cancellation reaction, add silica gel again to reaction solution; Revolve driedly, silicagel column separates, and obtains compound shown in the formula III;
(2) oxygenant is dissolved in organic solvent, under agitation condition, contains in the organic solvent of oxygenant to this; Add compound shown in the formula III, room temperature condition kept 1 hour at least, cooling; The temperature of reaction solution is controlled at and is not higher than-5 ℃, adds reductive agent again and continues to stir 1-19 hour, and reaction solution dilutes with tetracol phenixin; Aqueous phase extracted merges organic phase, and organic phase is water, saturated NaHCO respectively
3, saturated NaCl washing, use anhydrous magnesium sulfate drying, the filtering siccative revolves except that organic solvent, the silicagel column separation obtains compound shown in the formula IV;
(3) compound shown in the formula IV is dissolved in the organic or inorganic alkali lye, under ice bath and agitation condition, joins in the mixture of forming by compound shown in the formula IV and said organic or inorganic alkali lye adding hydroxyl protection reagent; Reinforced finishing, reaction solution kept 6-12 hour under room temperature state; This reaction solution is poured in the frozen water; Stir, use dichloromethane extraction, organic phase is water, saturated NaHCO respectively
3, saturated NaCl washing, use the anhydrous sodium sulfate drying organic phase again, the filtering siccative revolves except that organic solvent, silicagel column separates, obtain compound shown in the formula V;
(4) compound shown in the formula V is mixed with aprotic organic solvent, get mixture; Having under the rare gas element existence condition, dithionate in the gained mixture is heated to 50 ℃～60 ℃, and keeps 4 hours～24 hours at this state, and extraction merges organic phase, and organic phase is water, saturated NaHCO respectively
3With saturated NaCl washing, use anhydrous sodium sulfate drying again, the filtering siccative revolves except that organic solvent, and silicagel column separates, and obtains compound shown in the formula VI;
(5) at ice bath and have under the rare gas element existence condition, the mixture that will form by compound shown in the formula VI and anhydrous organic solvent with mainly contain the mixture that reductive agent and anhydrous organic solvent form and mix, and kept at ambient temperature 0.5 hour～12 hours; With saturated metabisulfite solution cancellation reaction, use the aqueous sodium hydroxide solution dissolution precipitation, reaction solution dilutes with methylene dichloride; Tell organic phase, aqueous phase extracted merges organic phase; Organic phase is used anhydrous sodium sulfate drying, and the filtering siccative revolves except that organic solvent; Silicagel column separates, and obtains target compound.
9. method as claimed in claim 8 is characterized in that, wherein the oxygenant described in the step (2) is Jones reagent, Sha Ruite reagent, V
2O
5Catalytic oxidant, Pd catalytic oxidant, hypochlorite or wear this Martin's oxygenant.
10. method as claimed in claim 8 is characterized in that, wherein the reductive agent described in step (2) and (5) is lithium aluminum hydride, Peng Qinghuana, palladium carbon, Raney Ni or reduced iron powder.
11. method as claimed in claim 8 is characterized in that, wherein the dithionate described in the step (4) is a thioacetic acid potassium, thioacetic acid sodium, thiobenzoic acid sodium or thiobenzoic acid potassium.
12. method as claimed in claim 8 is characterized in that, wherein the organic or inorganic alkali lye described in step (1) and (3) comprises: pyridine, DBU, triethylamine or the mixture of being made up of salt of wormwood or yellow soda ash and tetrahydrofuran aqueous solution.
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