CN103788160B - (2R, 5R)-5-phosphatidyl methoxy-2-(2-substituted adenines-9-base)-2,5-dihydrofuran nucleoside analog and its production and use - Google Patents

(2R, 5R)-5-phosphatidyl methoxy-2-(2-substituted adenines-9-base)-2,5-dihydrofuran nucleoside analog and its production and use Download PDF

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CN103788160B
CN103788160B CN201410024277.8A CN201410024277A CN103788160B CN 103788160 B CN103788160 B CN 103788160B CN 201410024277 A CN201410024277 A CN 201410024277A CN 103788160 B CN103788160 B CN 103788160B
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dihydrofuran
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CN103788160A (en
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刘丰五
徐锐钢
刘飞
刘应举
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Zhengzhou University
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Abstract

The invention discloses novel β-furanphosphonic Acid ester purine nucleoside analogs, it is specifically related to (2R, 5R)-5-phosphatidyl methoxy-2-(2-substituted adenines-9-base)-2,5-dihydrofuran nucleoside analog and its production and use, belongs to nucleoside chemistry and medicinal chemistry art.It has structure shown in formula 1:Wherein, R1Represent Cl, NH2、OCH3、SCH3、NHCH3Or NHNH2, R2Represent NH2、OCH3、NHCH3。Wherein, R represents H, Na or K.By 3, the chloro sugar that 5-bis--O-is higher to forming activity after toluyl-DRI first glycosides chloro, then react with base, form novel β-D-dihydrofuran phosphonate ester ribosidoadenine analog then through selective oxidation, decarboxylation, addition, elimination, functional group's conversion, de-ethyl.It has antiviral activity and good DEVELOPMENT PROSPECT.

Description

(2R, 5R)-5-phosphatidyl methoxy-2-(2-substituted adenines-9-base)-2,5-dihydrofuran nucleoside analog and its production and use
Technical field
The invention belongs to nucleotide chemistry and medicinal chemistry art, be specifically related to novel furan phosphonate ester nucleoside analog and preparation method thereof.
Background technology
Non-natural nucleoside class medicine is the primary treatment medicine of viral diseases, is also the critically important antitumor drug of a class.Great majority have under the kinase whose effect of nucleoside in cell of bioactive nucleoside analog and occur phosphorylated to change into mononucleotide and be activated; mononucleotide is converted into ribonucleoside 5'-triphosphates then through two step phosphorus acylation reactions could play antivirus action as the substrate specificity of RNA or archaeal dna polymerase, and namely nucleoside analog is the prodrug of antiviral drugs.First step phosphorylated is at a slow speed or rate-limiting reaction as a rule, directly restricts its antiviral activity.By being directly synthesized the monophosphate esterification derivative of nucleoside, effectively cross first step rate-limiting step, be the effective ways improving nucleoside antiviral activity, development of new medicine.While Nucleoside becomes nucleotide, nucleotide can be biodegradable into low-molecular-weight nucleotide under the catalysis of nucleolytic enzyme, and the phosphorus oxygen ester bond of mononucleotide easy fracture under enzyme effect makes it be degraded into nucleoside further, thus causing antiviral activity to reduce or losing.The bioisostere of phosphonate ester nucleoside mononucleotide can solve this deficiency preferably, improves the stability of mononucleotide.
Secondly, adenosine compounds has stronger cytostatic activity, but due to the rapid damage of adenosin deaminase so that it is in cell growth inhibiting and cell, the bioavailability during synthesis of DNA is substantially reduced.Adenosine can be effectively improved after 2-replaces and resist adenosin deaminase ability, its bioavailability is greatly improved, and cytotoxicity is also greatly reduced.Therefore, synthesis integrates the excellent anti-nucleolytic enzyme degradability of 5-phosphatidyl methoxy ribofuranoside and the 2-substituted adenines furanphosphonic Acid ester nucleoside analog of the good anti-adenosin deaminase capacity of decomposition of 2-substituted adenines nucleoside, will have potential excellent antiviral or anti-tumor activity.
Compound 2,5-dihydrofuran adenosine phosphonate ester (Kimetal.J.Org.Chem.1991,2642-2647 similar at present;And 3-fluoro-2 Z.Hongetal.US2004023921), 5-dihydrofuran adenosine phosphonate ester (R.L.Mackmanetal.Bioorg.Med.Chem.Lett.2008,18,1116-1119) successfully synthesized respectively through furan alkene intermediate, and all be there is good antiviral activity.But owing to nucleoside building-up process is complicated, a little change of base or sugar ring all can cause the great changes of synthetic reaction, therefore, does not see the report of object of the present invention up to now.
Summary of the invention
Present invention aim at the 2-substituted adenines dihydrofuran phosphonate ester nucleoside analog providing a class to have potential antiviral or anti-tumor activity；Another object is in that to provide its preparation method and application.
For realizing the object of the invention, by by marketable material 3, the chloro sugar that 5-bis--O-is higher to forming activity after toluyl-DRI first glycosides chloro, then react with base, form novel β-D-dihydrofuran phosphonate ester ribosidoadenine analog then through selective oxidation, decarboxylation, addition and elimination.
Described novel dihydrofuran phosphonate ester purine nucleoside analogs represents with formula 1:
Wherein, R1Represent Cl, NH2、OCH3、SCH3、NHCH3Or NHNH2, R2Represent NH2、OCH3、NHCH3；Wherein, R' represents H, Na or K.
Preferred R1For Cl, OCH3、SCH3、NH2Or NHCH3；R2For NH2、OCH3、NHCH3；R' is Na.
Select following compound:
Compound a: R1For Cl, R2For NH2, R' is Na;
Compound b:R1For SCH3,R2For NH2, R' is Na;
Compound c:R1For OCH3,R2For NH2, R' is Na;
Compound d:R1For NH2,R2For NH2, R' is Na;
Verbindung: R1For NHCH3,R2For NH2, R' is Na;
Compound f:R1For NHCH3,R2For NHCH3, R' is Na;
Compound g:R1For Cl, R2For OCH3, R' is Na.
Containing two chiral carbon atoies in described compound, it is respectively as follows: 2R, 5R.
Prepare the preparation process of compound shown in above-mentioned formula 1 as follows:
Details are as follows for preparation method:
Step (1):
By 3, toluyl-DRI first glycosides (I) is dissolved in glacial acetic acid by 5-bis--O-, passing into HCl gas at a certain temperature, reaction terminates rear filtration under diminished pressure and obtains chloro-3, the 5-bis--O-of 1-to toluyl-DRI (II).Described reaction temperature preferably 0 DEG C-80 DEG C.
Step (2):
Being dissolved in organic solvent by Compound II per and 2,6-dihalo-purine, under inert gas shielding, alkali effect coupling generates 2,6-dichloro-s purine deoxyriboside analog (III).
Wherein: described alkali is organic base or inorganic base.Organic base is the one in potassium tert-butoxide, sodium tert-butoxide, Sodium ethylate, Feldalat NM；Inorganic base is the one in sodium carbonate, potassium carbonate, sodium hydride, calcium hydride, sodium hydroxide, potassium hydroxide.
Step (3):
Compound shown in general formula III is dissolved in the methanol solution containing Feldalat NM, Deprotection 6 chlorine of substituted purin under uniform temperature, generate 2-chloro-6-methoxypurine deoxynucleoside analog (IV).Described reaction temperature preferably 0 DEG C-80 DEG C.
Step (4):
Compound shown in formula IV aoxidizes methylol with selective oxidant and generates 5'-carboxyl-2-halogen-6-methoxypurine oxolane nucleoside analog (V).Wherein described selective oxidant is: KMnO4/ KOH, diacetyl iodobenzene (PhI (OAc)2)/2,2,6,6-tetramethyl piperidine oxide (TEMPO), TEMPO/NaCl2O、O2One in/10%Pt/C, Jones reagent or PDC/DMF.
Step (5):
Compound shown in formula V is dissolved in organic solvent, and under the effect of decarboxylation reagent, decarboxylation generates furan alkene nucleoside (VI).Wherein decarboxylation reagent is: N, pungent amyl group acetal (the DMF-DNA)/N of dinethylformamide two, dinethylformamide (DMF), N,N-dimethylformamide two formal (DMF-DMA)/DMF, DMF-DNA/ methanesulfonic acid (MsOH), DMF-DMA/MsOH, triphenyl phosphorus (PPh3)/diisopropyl azo-2-carboxylic acid (DIAD) or PPh3One in/diethylazodicarboxylate (DEAD).
Step (6):
Compound shown in formula VI is dissolved in organic solvent, introduces methylol diethyl phosphate by halogen etherification reaction at a certain temperature and generates compound VII.Halogen etherifying reagent wherein used is: the one in methylol diethyl phosphate/N-N-iodosuccinimide (NIS) and methylol diethyl phosphate/IBr.Reaction temperature preferably-80 DEG C～40 DEG C.
Step (7):
Compound shown in formula VII heats dehydroiodination under the catalysis of alkali and obtains dihydrofuran nucleoside analog VIII.Alkali described in this reaction is organic base: triethylamine, DBU(1,8-diazabicylo-dicyclo (5,4,0)-7-hendecene), pyridine, tripropyl amine (TPA), triethanolamine, one in Sodium ethylate or Feldalat NM, or inorganic base: the one in sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.Preferred 40-120 DEG C of heating-up temperature, more preferably 50-90 DEG C.
The organic solvent used in above-mentioned steps 2-7 reaction is the one in dichloromethane, chloroform, oxolane, dioxane, ether, diisopropyl ether, pyridine, acetonitrile, acetone, N,N-dimethylformamide or two kinds.
Step (8):
Being dissolved in ammonia solution by compound shown in formula VIII, proceed to sealed reactor, 80-160 DEG C of reaction, reaction terminates rear concentrating under reduced pressure solvent, and column chromatography for separation obtains compound shown in formula IX.Wherein described ammonia solution is the one in saturated ammonia methanol, saturated ammonia oxolane, saturated ammonia dioxane or ammonia.
Step (9):
Nucleoside phosphonate ethyl ester (IX or VIII or 1f') is dissolved in organic solvent, adds containing silica reagent under nitrogen protection, 0-80 DEG C of reaction.Reaction is poured into NaHCO after terminating3In aqueous solution, concentration is evaporated, and column chromatography for separation obtains corresponding target compound 1a or 1f or 1g.
What use in above-mentioned reaction containing silica reagent is: bromotrimethylsilane (TMSBr), Iodotrimethylsilane (TMSI), TMSI/2,6-lutidine, TMSBr/2,6-lutidine, TMSI/2,4,6-can power pyridine, TMSBr/2,4,6-can one in power pyridine.
Step (10):
Being dissolved in organic solvent by compound 1a, add nucleopilic reagent, react at 50-180 DEG C in sealed reactor, reaction terminates column chromatography for separation and obtains corresponding compound 1b-1e.In formula, R represents methyl mercapto, methoxyl group, amido or diazanyl.
Nucleopilic reagent used in above-mentioned reaction is respectively as follows: sodium methyl mercaptide, methylamine, ammonia or hydrazine hydrate according to object difference.
The organic solvent used in described reaction is the one in oxolane, dioxane, ether, diisopropyl ether, methanol, ethanol, isopropanol, acetonitrile, acetone, N,N-dimethylformamide or two kinds.
Step (11):
Being dissolved in organic solvent by compound VIII, add methylamine water solution, react at a certain temperature in sealed reactor, reaction terminates column chromatography for separation and obtains compound 1f'.
The organic solvent used in described reaction is the one in oxolane, dioxane, acetonitrile, acetone, methanol and N,N-dimethylformamide.Preferred 30-120 DEG C of described reaction temperature.
Compound shown in formula 1 has potential antiviral activity, can be used as the main active of antiviral drugs or is used as the intermediate of synthesis antiviral drugs.
It is an advantage of the current invention that:
1, target compound provided by the invention integrates the excellent stability of 5-phosphatidyl methoxy ribofuranoside and the good anti-adenosin deaminase performance of anti-nucleolytic enzyme capacity of decomposition and 2-substituted adenines nucleoside, has potential antiviral activity and good DEVELOPMENT PROSPECT.
2, the adopted raw material of the present invention is cheap and easy to get, synthetic method is simple to operate, and the synthesis for phosphonate ester nucleoside provides a kind of new method.
Detailed description of the invention
Embodiment 1: prepare Compound II per
By 3,5-bis--O-to toluyl-DRI first glycosides (I, 7.7g, 20mmol) it is dissolved in 15ml glacial acetic acid, dry HCl gas is passed at 0 DEG C, sucking filtration after no longer precipitating out solid, filter cake washing with acetone obtains compound as white solid II7.0g(90%).
Experimental data:
White solid,1HNMR(400MHz,CDCl3)δ8.02(d,J=8.2Hz,1H,Ar-H),7.92(d,J=8.2Hz,1H,Ar-H),7.28(dd,J=11.7,7.0Hz,4H,Ar-H),6.50(d,J=5.0Hz,1H,H-1'),5.59(dd,J=7.0,2.6Hz,1H,H-3'),4.88(dd,J=6.8,3.2Hz,1H,H-4'),4.71(dd,J=12.1,3.1Hz,1H,H-5'a),4.62(dd,J=12.1,4.2Hz,1H,H-5'b),2.89(ddd,J=15.1,7.4,5.2Hz,1H,H-2'a),2.77(d,J=15.1Hz,1H,H-2'b),2.45(s,1H,-CH3),2.44(s,1H,-CH3).13CNMR(101MHz,CDCl3)δ166.4(C=O),166.1(C=O),144.3,144.1,129.9,129.7,129.3,129.2,126.8,126.7(Ar-C),95.4(C-1'),84.7(C-4'),73.6(C-3'),63.5(C-5'),44.5(C-2'),21.75(-CH3),21.71(-CH3).HRMS:calcd.forC21H21ClO5:388.1078,found:m/z389.1155[M+H]+。
Embodiment 2: preparation compound III
2,6-dichloropurine 1.15g (6mmol) are dissolved in anhydrous tetrahydro furan 12ml, until completely dissolved, are added under nitrogen protection in the 10ml acetonitrile solution containing 240mg sodium hydride.After no longer producing gas, in 25 DEG C, Compound II per 1.95g (5mmol) is dividedly in some parts.Thin layer chromatography monitoring reaction process, reaction terminates rear sucking filtration, and filter cake ethyl acetate is washed, filtrate reduced in volume, and silica gel column chromatography separates and obtains compound III 2.1g (yield 78%).
Experimental data:
Off-white color solid,1HNMR(400MHz,CDCl3):δ8.32(s,1H,H-8),7.99(d,J=8.1Hz,2H,Ar-H),7.84(d,J=8.1Hz,2H,Ar-H),7.31(d,J=8.1Hz,2H,Ar-H),7.22(d,J=8.1Hz,2H),6.57(t,J=6.9Hz,1H,H-1'),5.81(m,1H,H-3'),4.81(m,1H,H-5'a),4.69(m,2H,H-5'b,H-4'),2.99(dd,J=8.1,5.0Hz,2H,H-2'),2.47(s,3H,-CH3),2.42(s,3H,-CH3).13CNMR(101MHz,CDCl3):δ166.0(C=O),165.9(C=O),153.1(C-2),152.3(C-4),144.7(C-6),144.4(C-8),143.7,131.3,129.8,129.5,129.3,126.3(Ar-C),126.2(C-5),85.4(C-1'),83.7(C-4'),75.0(C-3'),63.8(C-5'),38.6(C-2'),21.8(-CH3),21.7(-CH3).HRMS:calcd.forC26H22Cl2N4O5:540.0967,found:m/z563.0865[M+Na]+。
Embodiment 3: prepare compounds Ⅳ
Compound III 1.2g (2.2mmol) is suspended in 50ml absolute methanol, adds Feldalat NM 375mg(7mmol), stirring reaction at 25 DEG C.Thin layer chromatography monitoring reaction process, reaction adds glacial acetic acid and adjusts pH=7, concentration of reaction solution after terminating, silica gel column chromatography separates, and obtains compounds Ⅳ 500mg(yield 75%).
Experimental data:
Dope.1HNMR(400MHz,CDCl3)δ8.14(s,1H,H-8),6.38(dd,J=8.3,5.9Hz,1H,H-1'),4.80(d,J=5.1Hz,1H,H-3'),4.20(s,4H,H-4',-OCH3),3.99(dd,J=12.7,1.5Hz,1H,H-5'a),3.84(dd,J=12.6,1.8Hz,1H,H-5'b),2.91(ddd,J=13.7,8.4,5.6Hz,1H,H-2'a),2.43(m,1H,H-2'b).13CNMR(101MHz,CDCl3)δ161.6(C-2),153.0(C-4),151.8(C-6),142.2(C-8),121.6(C-5),89.0(C-4'),86.9(C-1'),72.4(C-3'),62.9(C-5'),55.3(-OCH3),40.9(C-2').HRMS:calcd.forC11H13ClN4O4:300.0625,found:m/z323.0519[M+Na]+。
Embodiment 4: prepare compound V
Compounds Ⅳ 5.4g (18.0mmol) is dissolved in 150ml acetonitrile, is sequentially added into iodobenzene diacetate (13g, 40mmol) and 2,2,6,6 ,-tetramethyl piperidine oxide (10mmol).Stirring reaction at 25 DEG C.Thin layer chromatography monitoring reaction process, reaction terminates rear concentration of reaction solution, and silica gel column chromatography separates (ethyl acetate: methanol=3:1), obtains compound V4.35g (78%).
Experimental data:
White solid,1HNMR(400MHz,DMSO-d6):δ9.45(s,1H,H-8),6.46(dd,J=8.4,5.8Hz,1H,H-1'),4.47(d,J=3.8Hz,1H,H-3'),4.22(s,1H,H-4'),4.11(d,J=2.8Hz,3H,-OCH3),2.36(dd,J=12.8,5.8Hz,1H,H-2'a),2.27(ddd,J=12.9,8.6,4.3Hz,1H,H-2'b).13CNMR(101MHz,DMSO-d6):δ174.3(C=O),161.1(C-2),153.2(C-4),151.7(C-6),144.6(C-8),120.2(C-5),89.4(C-4'),85.3(C-1'),75.3(C-3'),55.4(-OCH3),41.4(C-2').HRMS:calcd.forC11H11ClN4O5:314.0418,found:m/z313.0344[M-H]-。
Embodiment 5: prepare compound VI
Compound V (3.2g, 10.2mmol) is dissolved in anhydrous tetrahydro furan, under nitrogen protection and ice bath, is sequentially added into triphenylphosphine 8g(30.5mmol); DIAD7.14g(35.3mmol); add recession deicing bath, room temperature reaction, thin layer chromatography monitoring reaction process.Reaction terminates rear concentrating under reduced pressure reactant liquor, and silica gel column chromatography separates (ethyl acetate: petroleum ether=1:6) and obtains product VI 1.7g (yield 66%).
Experimental data:
White solid.1HNMR(400MHz,CDCl3):δ8.04(s,1H,H-8),6.83(dd,J=9.4,3.3Hz,1H,H-1'),6.52(dd,J=4.6,2.3Hz,1H,H-4'),5.28(dd,J=4.8,2.3Hz,1H,H-3'),4.21(s,3H,-OCH3),3.37(ddt,J=16.8,9.3,2.3Hz,1H,H-2'a),2.92(dd,J=17.1,2.0Hz,1H,H-2'b).13CNMR(101MHz,CDCl3):δ161.4(C-2),156.4(C-4),153.4(C-6)144.8(C-4'),139.8(C-8),120.3(C-5),99.6(C-3'),83.5(C-1'),55.1(-OCH3),36.3(C-2').HRMS:calcd.forC10H9ClN4O2:252.0414,found:m/z275.0315[M+Na]+。
Embodiment 6: prepare compound VII
Being dissolved in 30ml anhydrous methylene chloride by compound VI 1.01g (4.0mmol) ,-40 DEG C are sequentially added into methylol diethyl phosphate 2.69g(16mmol) and IBr 1.65g(8mmol), stirring reaction at 0 DEG C.Thin layer chromatography monitoring reaction process, reaction is taken off to brownish red with saturated sodium bicarbonate solution and hypo solution washing reaction liquid after terminating successively, adds anhydrous sodium sulfate 3g and is dried overnight.Sucking filtration, concentrated filtrate, silica gel column chromatography separates (ethyl acetate: petroleum ether=2:1), obtains product VII 885mg(yield 41%).
Experimental data:
Dope,1HNMR(400MHz,CDCl3):δ8.27(s,1H,H-8),6.86(t,J=7.0Hz,1H,H-1'),5.54(s,1H,H-4'),4.53(d,J=5.7Hz,1H,H-3'),4.23(s,3H,OCH3),4.22(m,4H,CH3CH2O),3.97(dd,J=13.6,9.9Hz,1H,CH2P),3.79(dd,J=13.6,9.3Hz,1H,CH2P),3.16(m,1H,H-2'),2.94(dd,J=14.8,6.5Hz,1H.H-2'),1.40(m,6H,CH3CH2O).13CNMR(101MHz,CDCl3)δ161.4(C-2),153.6(C-4),153.0(C-6),141.0(C-8),120.3(C-5)112.1(d,J=12Hz,C-4'),84.2(C-1),62.8(d,J=6Hz,CH3CH2O),61.4(d,J=170Hz,OCH2P),55.2(-OCH3),42.02(C-2'),19.95(C-3'),16.57(CH3CH2O),16.52(CH3CH2O).HRMS:calcd.forC15H21ClIN4O6P:545.9932,found:m/z568.9830[M+Na]+。
Embodiment 7: prepare compound VIII
By compound VII (285mg, 0.52mmol) it is dissolved in the N of 2mL, in dinethylformamide (DMF), add DBU(152 μ L, 1.04mmol), 60 DEG C are reacted 6 hours, concentrating under reduced pressure reactant liquor, and silica gel column chromatography separates (ethyl acetate 100%) and obtains product VIII 200mg (yield 91.7%).
Experimental data:
Dope.1HNMR(400MHz,CDCl3):δ8.05(s,1H,H-8),7.01(s,1H,H-1'),6.43(d,J=5.8Hz,1H,H-3'),6.31(d,J=5.8Hz,1H,H-2'),5.92(s,1H,H-4'),4.21(s,3H,-OCH3),4.14(m,4H,-CH2CH3),4.02(dd,J=13.7,9.9Hz,1H,OCH2P),3.89(dd,J=13.8,8.7Hz,1H,OCH2P),1.34(m,6H,CH2CH3).13CNMR(101MHz,CDCl3)δ161.4(C-2),153.4(C-4),152.6(C-6),141.2(C-8),132.1(C-3'),130.0(C-2'),120.4(C-5),108.9(d,J=10Hz,C-4'),86.1(C-1'),62.8(d,J=7Hz,-CH2CH3),62.5(d,J=7Hz,-CH2CH3),62.4(d,J=168Hz,-CH2P),55.1(-OCH3),16.5(d,J=6Hz,-CH2CH3),16.4(d,J=6Hz,-CH2CH3).HRMS:calcd.forC15H20ClN4O6P:418.0809,found:m/z441.0703[M+Na]+。
Embodiment 8: prepare compound Ⅸ
Being dissolved in 10ml strong aqua ammonia by compound VIII 200mg (0.48mmol), heated sealed is to 100 DEG C of stirring reactions.Thin layer chromatography monitoring reaction process, reaction terminates rear concentration of reaction solution, ODS column chromatography for separation (water 100%), obtains product Ⅸ (76mg, 42%).
Experimental data:
Faint yellow solid.1HNMR(400MHz,DMSO-d6):δ7.99(s,1H,H-8),7.88(s,2H,NH2),6.74(s,1H,H-1'),6.47(d,J=5.2Hz,1H,H-3'),6.43(s,1H,H-2'),5.91(s,1H,H-4'),3.71(d,J=6.6Hz,2H,OCH2CH3),3.55(dd,J=18.9,8.5Hz,2H,CH2P),1.02(t,J=6.9Hz,3H,-CH3).13CNMR(101MHz,DMSO-d6):δ157.2(C-2),153.9(C-4),150.4(C-6),140.0(C-8),132.8(C-2'),130.1(C-3'),118.0(C-5),108.8(C-4'),85.9(C-1'),64.9(d,J=154Hz,CH2P),59.8(OCH2CH3),17.1(OCH2CH3).HRMS:calcd.forC12H15ClN5O5P:375.0499,found:m/z398.0395[M+Na]+。
Embodiment 9: prepare compound 1a
By compound Ⅸ (45mg; 0.12mmol) it is suspended in 6mL anhydrous acetonitrile; it is sequentially added into 2 under ice bath and nitrogen protection; 4; 6-can power pyridine (100 μ L; 0.76mmol), Iodotrimethylsilane (TMSI) (300 μ L; 2.2mmol); room temperature reaction is overnight; thin layer chromatography monitoring reaction process, reactant liquor is poured in the cold aqueous solution containing 200mg sodium bicarbonate (5mL) after terminating by reaction, concentrating under reduced pressure; ODS column chromatography for separation (water 100%) obtains product 1a (35mg, 81.2%).
White solid.1HNMR(400MHz,D2O)δ8.04(s,1H,H-8),6.62(s,1H,H-1'),6.46(d,J=6.0Hz,1H,H-3'),6.40(d,J=6.0Hz,1H,H-2'),5.99(s,1H,H-4'),3.51(dd,J=12.5,8.7Hz,1H,PCH2a),3.35(dd,J=12.5,8.9Hz,1H,PCH2b).13CNMR(101MHz,D2O)δ155.9(C-2),153.6(C-6),149.4(C-4),140.5(C-8),133.2(C-3'),128.5(C-2'),117.2(C-5),109.8(d,J=10.6Hz,C-4'),85.7(C-1'),66.5(d,J=150Hz,PCH2).HRMS:calcd.forC10H9ClN5Na2O5P:390.9825,found:m/z391.9902[M+H]+. list of references (J.Org.Chem.1991,56,2642-2647), the absolute configuration of this compound is (2R, 5R) as shown in FIG..
It is methyl mercapto that embodiment 10 prepares R in compound 1b(formula)
By compound 1a (94mg, 0.24mmol) it is dissolved in sodium methyl mercaptide aqueous solution (130mg, in 2.4mmol), closed reactor heats 90 DEG C, react 2 hours, reaction terminates rear concentrating under reduced pressure, and upper prop (ODS) separates to obtain compound 1b (65mg, 70%).
Off-white color solid.1HNMR(400MHz,D2O) δ 7.98 (s, 1H, H-8), 6.78 (s, 1H, H-1'), 6.46 (d, J=5.9Hz, 1H, H-3'), 6.41 (d, J=6.0Hz, 1H, H-2'), 6.00 (s, 1H, H-4'), 3.53 (dd, J=12.5,8.7Hz, 1H ,-PCH2-), 3.37 (dd, J=12.5,8.9Hz, 1H ,-PCH2-), 2.46 (s, 3H ,-SCH3).13CNMR(101MHz,D2O):δ166.4(C-2),155.9(C-6),150.0(C-4),139.8(C-8),134.0(C-3'),128.0(C-2'),116.0(C-5),109.0(d,J=10.6Hz,C-4'),84.7(C-1'),66.0(d,J=150Hz,-PCH2-),13.4(-SCH3).HRMS:calcd.forC11H12N5Na2O5PS:403.0092,found:m/z404.0165[M+H]+。
Embodiment 11: preparing R in compound 1d(formula is amino)
By the method for embodiment 8, with compound 1a for raw material, controlling reaction temperature and be 100-160 DEG C, after reaction terminates, ODS column chromatography for separation (water 100%) can obtain compound 1d.
White solid .1HNMR (400MHz, D2O) δ 8.09 (s, 1H, H-8), 6.68 (s, 1H, H-1'), 6.49 (d, J=6.0Hz, 1H, H-3'), 6.42 (d, J=6.0Hz, 1H, H-2'), 6.02 (s, 1H, H-4'), 3.54 (dd, J=12.5,8.7Hz, 1H ,-PCH2-),3.38(dd,J=12.5,8.9Hz,1H,-PCH2-).13CNMR(101MHz,D2O):δ156.6(C-2),154.0(C-6),149.9(C-4),140.5(C-8),133.5(C-3'),128.2(C-2'),118.0(C-5),110.4(d,J=10.6Hz,C-4'),85.0(C-1'),65.6(d,J=150Hz,-PCH2-).HRMS:calcd.forC10H11N6Na2O5P:372.0324,found:m/z373.0399[M+H]+。
Embodiment 12: preparing R in compound 1c(formula is methoxyl group)
By compound 1a (94mg, 0.24mmol) it is dissolved in methanol 7mL, add Feldalat NM (130mg, 2.4mmol), heating 100 DEG C in closed reactor, react 2 hours, reaction terminates rear concentrating under reduced pressure, upper prop (ODS) separates to obtain compound 1c (65mg, 70%).
White solid.1HNMR(400MHz,D2O):δ7.86(s,1H,H-8),6.68(s,1H,H-1'),6.36(d,J=6.0Hz,1H,H-3'),6.29(d,J=6.0Hz,1H,H-2'),5.91(s,1H,H-4'),3.78(s,3H,-OCH3),3.44(dd,J=12.4,9.0Hz,1H,-PCH2-),3.28(dd,J=12.4,9.0Hz,1H,-PCH2-).13CNMR(101MHz,D2O):δ162.4(C-2),156.4(C-6),150.7(C-4),139.1(C-8),132.8(C-3'),128.7(C-2'),114.6(C-5),109.5(d,J=10.6Hz,C-4'),85.3(C-1'),65.9(d,J=150Hz,-PCH2-),54.7(-OCH3).HRMS:calcd.forC11H12N5Na2O6P:387.0321,found:m/z388.0396[M+H]+。
It is methylamino that embodiment 13 prepares R in compound 1e(formula)
Replace Feldalat NM with methylamine, process by the method for embodiment 12 and obtain object 1e.
Light yellow solid.1HNMR(400MHz,D2O)δ7.77(s,1H,H-8),6.68(s,1H,H-1'),6.43(d,J=5.8Hz,1H,H-3'),6.36(d,J=5.9Hz,1H,H-2'),5.99(s,1H,H-4'),3.60–3.46(m,1H,-PCH2-),3.44–3.30(m,1H,-PCH2-),2.80(s,3H,-NHCH3).13CNMR(101MHz,D2O):δ170.5(C-2),160.0(C-6),151.3(C-4),137.7(C-8),133.1(C-3'),129.0(C-2'),112.5(C-5),108.9(d,J=10Hz,C-4'),84.8(C-1'),65.5(d,J=150Hz,-PCH2-),27.2(-NHCH3).HRMS:calcd.forC11H13N6Na2O5P:386.0480,found:m/z387.0560[M+H]+。
Embodiment 14 prepares R shown in compound 1f(formula1、R2Represent NHCH3) and 1g(R1、R2Represent chlorine and methoxyl group respectively)
Being dissolved in methylamine solution by compound VIII, heat 80-180 DEG C of reaction in closed reactor, reaction terminates rear concentrating under reduced pressure, and method described in example 9 of pressing after drying processes, and obtains corresponding compound 1f.
Compound VIII is directly processed by method described in embodiment 9, obtains corresponding compound 1g.
1f: off-white color solid1HNMR(400MHz,D2O)δ7.73(s,1H,H-8),6.70(s,1H,H-1'),6.49(d,J=5.9Hz,1H,H-3'),6.43(d,J=6.0Hz,1H,H-2'),6.04(s,1H,H-4'),3.57(dd,J=12.4,8.8Hz,1H,-PCH2-),3.41(dd,J=12.4,9.0Hz,1H,-PCH2-),2.96(s,3H,-NHCH3),2.87(s,3H,-NHCH3).13CNMR(101MHz,D2O):δ165.3(C-2),161.1(C-6),154.9(C-4),136.1(C-8),132.7(C-3'),128.8(C-2'),113.1(C-5),108.9(d,J=10Hz,C-4'),83.7(C-1'),65.8(d,J=150Hz,-PCH2-),28.1(-NHCH3).HRMS:calcd.forC12H15N6Na2O5P:400.0637,found:m/z401.0715[M+H]+.
1g: off-white color solid1HNMR(400MHz,D2O)δ8.28(s,1H,H-8),6.80(s,1H,H-1'),6.54–6.48(m,1H,H-3'),6.42(d,J=5.9Hz,1H,H-2'),6.04(s,1H,H-4'),4.09(s,3H,-OCH3),3.54(dd,J=12.5,8.7Hz,1H,-PCH2-),3.39(dd,J=12.5,8.9Hz,1H,-PCH2-).13CNMR(101MHz,D2O):δ161.0(C-2),152.7(C-6),151.7(C-4),142.6(C-8),133.3(C-3'),127.8(C-2'),118.7(C-5),110.4(d,J=10Hz,C-4'),85.8(C-1'),66.3(d,J=150Hz,-PCH2-),55.5(-OCH3).HRMS:calcd.forC11H10ClN4Na2O6P:405.9822,found:m/z406.9896[M+H]+。
Embodiment 16: anti-hepatitis B activity and cytotoxicity
With the compounds of this invention 1a-g as test medicine, detect subject cell with HepG2.2.15 cell as Anti-viral activity in vitro, adopt the toxic action of MTT colorimetric determination variable concentrations compound on intracellular, calculate half toxic concentration (TC50)；Adopt ELISA detection method detection the compounds of this invention 6 days to the inhibitory action of HBsAg and HBeAg in cell conditioned medium liquid.Preliminary detection result shows that this compounds has Anti-HBV effect and relatively low cytotoxicity.Result is as follows:

Claims (4)

1. (2R, 5R)-5-phosphatidyl methoxy-2-(2-substituted adenines-9-base)-DHF nucleoside analog or its salt, it is characterised in that this analog has structure shown in formula 1:
Wherein, R1Represent Cl, NH2、OCH3、SCH3Or NHCH3, R2Represent NH2、OCH3Or NHCH3；Wherein, R' represents H, Na or K.
2. (2R, 5R)-5-phosphatidyl methoxy-2-(2-substituted adenines-9-base)-DHF nucleoside analog as claimed in claim 1, it is characterised in that preferably R1For Cl, OCH3、SCH3、NH2Or NHCH3；R2For NH2、OCH3Or NHCH3；R' is Na.
3. (2R, 5R)-5-phosphatidyl methoxy-2-(2-substituted adenines-9-base)-DHF nucleoside analog as claimed in claim 2, it is characterised in that select following compound:
Compound a: R1For Cl, R2For NH2, R' is Na;
Compound b:R1For SCH3,R2For NH2, R' is Na;
Compound c:R1For OCH3,R2For NH2, R' is Na;
Compound d:R1For NH2,R2For NH2, R' is Na;
Verbindung: R1For NHCH3,R2For NH2, R' is Na;
Compound f:R1For NHCH3,R2For NHCH3, R' is Na;
Compound g:R1For Cl, R2For OCH3, R' is Na.
4. such as the claim 1-3 (2R as described in one of them, 5R)-5-phosphatidyl methoxy-2-(2-substituted adenines-9-base)-2, the application in preparing medicine of the 5-dihydrofuran nucleoside analog, it is characterized in that, with it for active component, it is prepared into resisting HBV virus medicine.
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