CN103819524A - 3’-氟取代嘌呤核苷类似物、其制备方法及其应用 - Google Patents
3’-氟取代嘌呤核苷类似物、其制备方法及其应用 Download PDFInfo
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- CN103819524A CN103819524A CN201410075381.XA CN201410075381A CN103819524A CN 103819524 A CN103819524 A CN 103819524A CN 201410075381 A CN201410075381 A CN 201410075381A CN 103819524 A CN103819524 A CN 103819524A
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- 230000002194 synthesizing effect Effects 0.000 claims description 56
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 44
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- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical class N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 28
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 claims description 5
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- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims description 5
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- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 claims description 4
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims description 4
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 claims description 4
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims description 4
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- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 claims description 4
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 4
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims description 4
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- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims description 4
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 claims description 4
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- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 claims description 4
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Abstract
本发明公开了核苷类似物、其制备方法及其应用,其涉及3’-氟-3’-脱氧-取代嘌呤核苷类似物、其制备方法及应用,属医药化学领域。其具有通式(Ⅰ)和(II)、结构: 通式I
Description
技术领域
本发明涉及核苷类似物、其制备方法及其应用,尤其涉及3’-氟-3’-脱氧-取代嘌呤核苷类似物、其制备方法及应用,属医药化学领域。
背景技术
核苷类药物广泛地应用于治疗肿瘤、病毒等危害人类健康的重大疾病,吉西他滨、地西他宾等核苷类药物在临床应用中起到了很重要的作用。嘌呤核苷衍生物,如氟达拉滨fludarabine, 奈拉滨nelarabine, 克拉屈滨cladribine等具有抗肿瘤、抗病毒也在临床上得到应用。近年来取代嘌呤衍生物展现出很好的生物活性越来越受到人们重视(](a) Gundersen, L.-L., Nissen-Meyer, J.; Spilsberg, B. J. Med. Chem. 2002, 45, 1383; (b) Naus, P.; Perlikova, P.; Pohl, R.; Hocek, M.Collect. Czech. Chem. Commun. 2011, 76, 957; (d) Montgomery J. A.; Hewson K. J. Med. Chem. 1968, 11, 48)。例如6位带有各种不同取代基的嘌呤核糖核苷具有抗肿瘤的活性((a) Hocek M.; Holy, A.; Votruba, I.; Dvorakova, H. J. Med. Chem. 2000, 43, 1817; (b) Hocek, M.; Holy, A.; Votruba, I.; Dvorakova, H. Collect. Czech. Chem. Commun. 2001, 66, 483; (c) Naus, P.; Pohl, R.; Votruba, I.; Dzubak, P.; Hajduch, M.; Ameral, R.; Birkus, G.; Wang, T.; Ray, A. S.; Mackman, R.; Cihlar, T.; Hocek, M. J. Med. Chem. 2010, 53, 460)。氟原子在各种药物或具有生物活性的有机分子中起着非常重要的作用。它是体积小,极性大的脂溶性原子,很强的C-F键使其具有很强的体内生物稳定性。在许多情况下,它能够改善药物分子的亲电性、脂溶性,并且提高药物的药代动力学、药理学、毒理学等方面的性能。含有氟原子的核苷衍生物也很常见,然而,3’-脱氧3‘-氟代嘌呤核苷还没有得到研究者的重视,其抗肿瘤、抗病毒以及其他生物性能还没有得到研究。本发明将3’-氟代的嘌呤核苷在其碱基上进行新的修饰,以得到创新性的氟代嘌呤衍生物,进行抗肿瘤、抗病毒研究,对开发我国自主知识产权新药具有重要意义,目前未见文献报道。
发明内容
本发明的主要目的在于提供一种抗肿瘤活性好的含3’-氟-3’-脱氧取代核苷类似物;另一目的在于提供该类化合物的合成方法;又一目的在于提供该类化合物在药物方面的应用。
为实现本发明目的,技术方案如下实现:
该本发明3’-氟-取代核苷类似物,具有通式(Ⅰ)和(II)结构:
其中 X = H, Cl, NH2, OH等 ;
Y = H, NH2, NHOH, Cl, F, 羰基, OH, OR, SH, SR, NHR, NHR2, C1-C8的烷基、C3-C15烷基取代或无取代的苯基、萘基或含氮、氧、硫单取代或双取代的不饱和五元或六元杂环基或被卤素、苯基、甲氧基、苯氧基、丙炔基、4-吗啉基、哌嗪基、4-甲基哌嗪基、4-哌啶氧基取代的含氮、氧、硫单取代或双取代的不饱和五元或不饱和六元杂环基等;
Z = H, Br, Cl,等;
U = H、p-CH3C6H5CO, C6H5CO等;
V = H、CH3CO, C6H5CO等;
上述各代表性基团中的R是C1-C8的烷基等;
Y所述含氮、氧、硫不饱和五元或六元杂环基或被卤素、苯基、甲氧基、苯氧基、丙炔基、4-吗啉基、哌嗪基、苯基、4-甲基哌嗪基、4-哌啶氧基 取代的含氮、氧、硫不饱和五元或不饱和六元杂环基可以是下属代表性基团,但并不限于这些基团:
本发明所述化合物或其前体药或其5’-磷酸酯与有机酸或无机酸反应形成盐,可以盐的形式存在。这些活性化合物可以在体内形成磷酸酯的形式起到抗肿瘤或抗病毒的作用。
当U和V不是H,而是p-CH3C6H5CO, C6H5CO, RCO, CH3CO等相关基团时,本发明所述化合物可以直接用于抗肿瘤药物,也可作为前体药在体内通过酶的作用释放出U或V形成U和V是H的药物,达到抗肿瘤或抗病毒的目的。
其可以是如下化合物之一但不仅限于这些化合物:
本发明创新点在于:将3’-氟代的嘌呤核苷在其碱基上进行新的修饰,得到了创新性的氟代嘌呤衍生物,并对其进行了抗肿瘤、抗病毒研究,发现此类化合物有很好的抗肿瘤或抗病毒的作用,可以将其应用于制备抗肿瘤和抗病毒病毒药物中,对开发我国自主知识产权新药具有重要意义。
具体实施方式
为对本发明进行更好的说明,结合反应路线,列举代表性化合物的合成方法。
实施例1
本发明所述的含3’-氟-3’-脱氧取代嘌呤核苷类似物通式(I)中的一些化合物通过下面的路线合成:
化合物24的合成:取化合物6-氯嘌呤(853 mg,5.5 mmol,1.1 eq)和3’-脱氧-3’-氟代保护核糖化合物(1.77 g,5 mmol,1 eq)溶于30 m无水乙腈中,降温至0℃,向其滴加 1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)(2.22 ml,2.2 g,15 mmol,3 eq,d = 1.018),再加入三氟甲磺酸三甲基硅酯 ( TMSOTf)(3.59 ml,4.4 g,20 mmol,4 eq),加热至60℃,搅拌反应2.5 h,TLC检测反应完成。将反应液冷却到室温,加入饱和碳酸氢钠溶液和乙酸乙酯,萃取,有机层无水硫酸钠干燥,过滤,滤液浓缩,柱层析(EA:PE=1:10---1:3)得白色固体产品2.04 g 收率91%,HPLC含量96%。R f = 0.2 (EA/PE = 1:3). 1H NMR (400MHz, CDCl3): 8.47(s, 1H,Ar-H), 8.18 (s, 1H, Ar-H), 7.94 (d, 2H, J = 8.0Hz, Ar-H), 7.26 (d, 2H, J = 6.8Hz, Ar-H), 6.28 (d, J = 7.2 Hz, 1H, 1’), 6.11-6.19 (m, 1H, ), 5.55-5.70 (m, 1H, ), 4.71-4.82 (m, 2H, ), 4.50-4.54 (m, 1H,), 2.42 (s, 3H, CH3), 2.13 (s, 2H,CH3).
; MS (ESI) m/z 338 (M + H)+, 471 (M + Na)+, 487 (M + K)+.
化合物25和1的合成:化合物24 (800 mg, 1.78 mmol) 溶解到30毫升的甲醇中,加入1毫升的四氢呋喃、1毫升的三乙胺 (7.17 mmol) 和Pd/C (0.60 g, 50 % w/w)催化剂。 在50Psi的氢气压力下搅拌5 h。滤出催化剂,减压浓缩,硅胶柱提纯(乙酸乙酯)得到白色固体产品25(500 mg,68.6%)。
所得化合物25(438 mg)溶解到饱和的氨甲醇溶液中,室温搅拌过夜,减压浓缩,硅胶柱提纯得到白色固体产品1, 250 mg,收率93%,HPLC含量99%。TLC R f = 0.20 (DCM–MeOH = 10:1). 1H NMR (400 MHz, DMSO-d 6 ) 9.22 (s, 1H, Ar-H), 8.97 (s, 1H, Ar-H), 8.86 (s, 1H, Ar-H), 6.07–6.10 (d, J = 10.4Hz,1H, 1’-H), 5.97–6.00 (d, J = 8.8Hz, 1H, 2’-OH), 5.28–5.32 (t, J = 7.6Hz, 1H, 5’-OH), 5.02–5.22 (dd, J = 5.6Hz, 1H, 3’-H), 4.94–5.02 ( m, 1H, 2’-H), 4.23–4.35 (m, 1H, 4’-H), 3.63 (m, 2H, CH2). HRMS (EI) m/z 255.0894 [M + H]+; Calcd for C10H11FN4O3:255.0815 [M + H]+.
化合物2的合成:将化合物24溶解在0℃的饱和氨甲醇溶液中,室温搅拌过夜,减压抽干,用硅胶柱层析的方法得到白色固体化合物2,HPLC含量99%。R f = 0.20 (DCM–MeOH = 8:1). 1H NMR (400 MHz, DMSO-d 6 ) 8.36 (s, 1H, Ar-H), 8.14 (s, 1H, Ar-H), 7.43 (s, 2H, NH2), 5.91–5.94 (m, 2H, 1’,2’-OH), 5.87 (s, 1H, 5’-OH), 4.98–5.18 (dd, J = 5.6Hz, 1H, 3’-H), 4.96 (m, 1H, 2’-H), 4.23–4.32 ( m, 1H, 4’-H), 3.63 (s, 2H, CH2)。HRMS (EI) m/z 270.1002 [M + H]+; Calcd for C10H13FN5O3:270.1002 [M + H]+。
化合物3的合成:取500 mg(1.11 mmol)化合物24溶解约于130 ml 质量百分比50%的羟铵水溶液中,加热到80℃反应4小时,TLC检测反应完全之后,减压蒸干,再溶于过量氨甲醇溶液中搅拌反应过夜,旋干并用硅胶柱子分离提纯得最终白色固体化合物92 mg,总收率26%,HPLC含量99%。MS (ESI) m/z 286 [M + H]+ , 308 [M + Na]+.HRMS (EI) m/z 286.0952 [M + H]+; Calcd for C10H13FN5O4:286.0952 [M + H]+。
实施例2
通式(I),当R=CH3时合成路线如下:
6-甲基嘌呤iv的合成:取化合物iii (根据WO2008153947的过程制备)15g加入100ml 甲醇溶解,再向其加约150ml 2.5M HCl,室温搅拌约1h,减压蒸除甲醇和部分稀盐酸,向剩余约100ml的反应液中加入200ml 2.5M HCl,再用(300ml+200ml+100ml)DCM萃取,水相减压浓缩得到化合物iv的盐酸盐,用酸性离子交换树脂提纯。
化合物26的合成:6-甲基嘌呤(67 mg, 0.5 mmol)和N,O-双(三甲基硅烷基)乙酰胺(BAS)(70 mg 0.37 mmol 0.75 eq)加入到1.2-二氯乙烷(3 mL)中,在60°C下加热搅拌30分钟,冷却到20°C。加入保护的氟代核糖原料(177 mg,0.5 mmol)和 三氟甲磺酸三甲基硅酯(TMSOTf)(166 mg, 0.75 mmol, 1.5 eq)。反应液在70C加热搅拌18小时,冷却,用饱和的碳酸氢纳和二氯甲烷稀释,分出有机相,干燥,浓缩,用硅胶柱提纯得到349 mg化合物26,收率99%。
化合物4的合成:化合物26溶解到饱和的氨甲醇溶液中,室温搅拌过夜,浓缩后用硅胶柱提纯得到白色固体化合物4;R f = 0.40 (DCM–MeOH = 10:1). 1H NMR (400 MHz, DMSO-d 6 ) 8.79 (s, 1H, Ar-H), 8.76 (s, 1H, Ar-H), 6.03-6.06 (d, J = 10.4Hz, 1H, 1’-H), 5.94–5.97 (d, J = 8.8Hz, 1H, 2’-OH), 5.31–5.33 (t, J = 7.6 Hz, 1H, 5’-OH), 5.01–5.18 (dd, J = 5.6Hz, 1H, 3’-H), 4.94–5.02 ( m, 1H, 2’-H), 4.13–4.19 ( m, 1H, 4’-H), 3.63 (m, 2H, CH2), 2.73 (s, 2H, CH3). HRMS (EI) m/z 255.0894 [M + H]+; Calcd for C10H11FN4O3: 255.0815 [M + H]+。HRMS (EI) m/z 269.1050 [M + H]+; Calcd for C11H14FN4O3:269.1050 [M + H]+。
实施例3
化合物27的合成:取化合物24(565 mg,1.25 mmol,1 eq)和双三苯基磷二氯化钯(44 mg,0.0625 mmol)溶于15 ml的无水N,N-二甲基甲酰胺(DMF)中,向其加入三丁基(2-呋喃基)锡(3.21 g,9 mmol,3.6 eq)在N2保护下加热到95℃,搅拌反应18 h,将反应液减压蒸干,用二氯甲烷(DCM)溶解,掺入硅胶,蒸干,柱层析(EA:PE=1:5---1:3---1:1)提纯得淡黄色固体化合物27 550 mg,收率91%,
化合物5的合成:取化合物27(520 mg,1.08 mmol)加入20 ml的饱和氨甲醇溶液,密封,室温搅拌反应过夜18 h,掺入硅胶,蒸干,柱层析(DCM:MeOH=10:0—10:1)过柱提纯后所得粗产品粘稠状黄色固体,加入乙醇加热溶解,减压旋蒸,用乙醇-乙酸乙酯重结晶得淡黄色化合物5固体产品244 mg,收率:70.4% HPLC纯度:98% ; R f = 0.40 (DCM–MeOH = 50:1). 1H NMR (400 MHz, DMSO-d 6 ): 8.92 (s, 1H, Ar-H), 8.89 (s, 1H, Ar-H), 8.09 (s, 1H, Ar-H), 7.86 (d, J = 4.8Hz, 1H, Ar-H), 6.83–6.84 (m, 1H, Ar-H), 6.10–6.12 (d, J = 10.4Hz, 1H, 1’-H), 6.00–6.02 (d, J = 8.8Hz, 1H, 2’-OH), 5.33–5.37 (t, J = 7.6 Hz, 1H, 5’-OH), 5.05–5.23 (dd, J = 5.2Hz,,1H, 3’-H), 4.92–5.04 (m, 1H, 2’-H), 4.28–4.37 ( m, 1H, 4’-H), 3.67 (s, 2H, CH2); MS (ESI) m/z 321 (M + H)+, 343 (M + Na)+, 359 (M + K)+.
化合物28和6的合成:化合物24 (700 mg, 1.56 mmol),3-噻吩硼酸 (299.4 mg, 2.34 mmol, 1.5 eq)、碳酸钾(323.28 mg, 2.34 mmol, 1.5 eq )和10 mL甲醇的反应液,在搅拌下加入催化剂Pd(PPh3)4 (92.0 mg, 0.078 mmol, 0.05 eq)。在100 °C搅拌10小时,反应液冷却到室温并用二氯甲烷稀释,用饱和氯化铵溶液洗涤。水相用二氯甲烷萃取。所得有机相经无水硫酸钠干燥,减压除去溶剂。粗产品用硅胶提纯,石油醚-乙酸乙酯(3:1 至1:1)得到430 mg白色固体 产品28,收率55.5%。取保护的产品28(400 mg, 0.81 mmol),加入10 mL的饱和氨甲醇溶液,室温搅拌过夜。浓度,硅胶柱提纯,石油醚-乙酸乙酯(2:1至1:1),得到250 mg白色固体产品6,收率92%,HPLC纯度96%。R f = 0.20 (EA:PE = 1:1). 1H NMR (400MHz, DMSO d6 ): 8.95 (s, 1H, Ar-H), 8.91 (s, 1H, Ar-H), 8.88 (d, J = 10.4 Hz, 1H, Ar-H), 8.21 (d,J = 4.0 Hz, 1H, Ar-H), 7.74 (d, J = 2.4 Hz, 1H, Ar-H), 6.07-6.09 (d, J = 5.6 Hz, 1H, 1’), 5.97-5.98 (d, J = 4.8 Hz, 1H, 2’-OH), 5.32-5.34 (t, J = 5.6 Hz,1H, 5’-OH), 5.04-5.19 (dd, J = 4.4 Hz, 1H, 3’), 4.95-5.03 (m, 1H, 2’ ), 4.24-4.32 (m, 1H, 4’), 3.63-3.65 (m, 2H, CH2). HRMS (EI): m/z 337.0763[M + H]+; calcd for C14H14FN4O3S,337.0771 [M + H]+ 。
化合物29和7的合成:用上述类似方法,用1克的化合物24与苯基硼酸反应得到白色固体中间产品29(563 mg, 51.5%,HPLC纯度97%);取530 mg化合物29,经氨甲醇脱保护基后得到白色固体产品7(300 mg, 83%,HPLC纯度95%); R f = 0.20 (PE–EA = 1 : 1). 1H NMR (400MHz, DMSO-d 6 )9.00 (s, 1H, Ar-H), 8.91 (s, 1H, Ar-H), 8.78 (d, J = 1.2Hz, 2H, Ar-H), 7.57–7.59 (m, 3H, Ar-H), 6.10–6.12 (d, J = 8.0Hz,1H, 1’-H), 5.98–5.99 (d, J = 6.4Hz, 1H, 2’-OH), 5.31–5.34 (t, J = 5.6Hz,1H, 5’-OH), 5.05–5.20 (dd, J = 4.0Hz, 1H, 3’-H), 4.95–5.03 (m, 1H, 2’-H), 4.25–4.34 ( m, 1H, 4’-H), 3.64–3.66 (m, 2H, CH2); HRMS (EI): m/z 331.1204 [M + H]+; Calcd for C16H15FN4O: 331.1128 [M + H]+.
化合物30和8的合成:用上述类似方法,用1克的化合物24与萘基-2-硼酸反应得到暴色固体中间产品30(681 mg, 56.6%;HPLC纯度97%);取651 mg化合物30,经氨甲醇脱保护基后得到白色产品8(422 mg, 84%;HPLC纯度97%); R f = 0.20 (DCM–MeOH = 10:1). 1H NMR(400MHz, DMSO-d 6 ) 9.12 (s, 1H, Ar-H), 8.86 (s, 1H, Ar-H), 8.11 (d, J = 10.8Hz, 1H, Ar-H), 8.03 (d, J = 11.6Hz, 1H, Ar-H), 7.94 (d, J = 10.0Hz, 1H, Ar-H), 7.66–7.71 (t, J = 10.0Hz, 1H, Ar-H), 7.47–7.60 (m, 2H, Ar-H), 6.15–6.17 (d, J = 11.6Hz, 1H, 1’-H), 6.02–6.04 (d, J = 7.6Hz, 1H, 2’-OH), 5.31–5.35 (t, J = 8.0Hz, 1H, 5’-OH), 5.06–5.22 (m, 2H, 3’,2’-H), 4.27–4.39 ( m, 1H, 4’-H), 3.66-3.69 (m, 2H, CH2). HRMS (EI): m/z 381.1280 [M + H]+; Calcd for C20H17FN4O3: 381.1285 [M + H]+.
化合物31和9的合成:用上述类似方法,用0.6克的化合物24与吡啶-4-硼酸反应得到白色固体中间产品31(210 mg, 32%;HPLC纯度98%);取200 mg化合物31,经氨甲醇脱保护基后得到白色产品9(120 mg, 89%;HPLC纯度98%); R f = 0.20 (DCM–MeOH = 10:1). 1H NMR (400 MHz, DMSO-d 6 ) 9.10 (s, 1H, Ar-H), 9.01 (s, 1H, Ar-H), 8.82–8.83 (d, J = 2.4Hz, 2H, Ar-H), 8.64–8.65 (d, J = 6.0Hz, 2H, Ar-H), 6.12–6.14 (d, J = 8.0 Hz, 1H, 1’-H), 5.98–6.00 (d, J = 6.4Hz, 1H, 2’-OH), 5.28–5.31 (t, J = 5..6Hz, 1H, 5’-OH), 5.06–5.20 (dd, J = 4.0Hz, 1H, 3’-H), 4.94–5.05 (m, 1H, 2’-H), 4.26–4.35 ( m, 1H, 4’-H), 3.65–3.66 (m, 2H, CH2)。HRMS (EI) m/z 332.1159 [M + H]+; Calcd for C15H14FN5O3:332.1159 [M + H]+。
化合物32和10的合成:用上述类似方法,用1.0克的化合物24与吡啶-3-硼酸反应得到白色固体中间产品32(320 mg, 29%);取300 mg化合物32,经氨甲醇脱保护基后得到白色产品10(170 mg, 77%); R f = 0.20 (DCM–MeOH = 10:1). 1H NMR (400 MHz, DMSO-d 6 ) 9.88 (s, 1H, Ar-H), 9.06 (s, 1H, Ar-H), 9.02–9.04 (m, 1H, Ar-H), 8.97 (s, 1H, Ar-H), 8.74–8.75 (d, J = 1.6Hz, 1H, Ar-H), 7.26–7.65 (m, 1H, Ar-H), 6.12–6.14 (d, J = 8.0Hz, 1H, 1’-H), 5.98–5.99 (d, J = 6.4Hz, 1H, 2’-OH), 5.29–5.32 (t, J = 5.6Hz,1H, 5’-OH), 5.05–5.20 (dd, J = 4.0Hz, 1H, 3’-H), 4.96–5.03 (m, 1H, 2’-H ), 4.26–4.35 ( m, 1H, 4’-H), 3.64–3.66 (m, 2H, CH2)。HRMS (EI) m/z 332.1159 [M + H]+; Calcd for C15H15FN5O3:332.1159 [M + H]+。
化合物33和11的合成:用上述类似方法,用0.538克的化合物24与5-丙炔基吡啶-3-硼酸反应得到中间产品33;经氨甲醇脱保护基后得到白色产品11(40 mg, 总收率4%;HPLC纯度97%); R f = 0.20 (DCM–MeOH = 50:1). 1H NMR (400 MHz, DMSO-d 6 ) 9.76 (s, 1H, Ar-H), 9.08 (s, 1H, Ar-H), 9.06 (s, 1H, Ar-H), 9.00 (s, 1H, Ar-H), 8.76 (s, 1H, Ar-H), 6.13–6.15 (d, J = 8.0Hz, 1H, 1’-H), 6.01–6.03 (d, J = 6.4Hz, 1H, 2’OH), 5.31–5.34 (t, J = 5.6Hz, 1H, 5’OH), 5.07–5.22 (dd, J = 4.0Hz, 1H, 3’-H), 4.96–5.06 (m, 1H, 2’-H), 4.27–4.36 ( m, 1H, 4’-H), 3.66 (m, 2H, CH2), 2.13 (s, 3H, CH3)。HRMS (EI) m/z 370.1315 [M + H]+; Calcd for C18H17FN5O3:370.1315 [M + H]+。
化合物34和12的合成:用上述类似方法,用1.0克的化合物24与5-苯基吡啶-3-硼酸反应得到白色固体中间产品32(HPLC含量95%);经氨甲醇脱保护基后得到白色产品10(150 mg, 总收率16.4%;HPLC纯度98%); R f = 0.30 (DCM–MeOH = 10:1). 1H NMR (400 MHz, DMSO-d 6 ) 9.87 (s, 1H, Ar-H), 9.31 (s, 1H, Ar-H), 9.02–9.11 (s, 3H, Ar-H), 7.84 (d, 2H, Ar-H), 7.48–7.59 (m, 3H, Ar-H), 6.17 (d, J = 10.0Hz, 1H, 1’-H), 6.02 (d, J = 8.4Hz, 1H, 2’-OH), 5.31–5.35 (t, J = 7.2Hz, 1H, 5’-OH), 5.06–5.25 (m, 2H, 3’,2’-H), 4.28–4.37 ( m, 1H, 4’-H), 3.66 (m, 2H, CH2). HRMS (EI) m/z 408.1469 [M + H]+; Calcd for C21H18FN5O3: 408.1394 [M + H]+。
化合物35和13的合成:用上述类似方法,用0.5克的化合物24与6-苯氧基吡啶-3-硼酸反应得到中间产品35;经氨甲醇脱保护基后得到淡黄色产品13(190 mg, 总收率40%); R f = 0.10 (DCM–MeOH = 15:1). 1H NMR (400 MHz, DMSO-d 6 )9.76 (s, 1H, Ar-H), 9.06 (s, 1H, Ar-H), 8.99 (s, 1H, Ar-H), 8.60–8.63 (d, 2H, Ar-H), 7.21–7.51 (m, 5H, Ar-H), 6.13–6.15 (d, J = 8.0Hz, 1H, 1’-H), 6.02–6.03 (d, J = 6.4Hz, 1H, 2’-OH), 5.33–5.35 (t, J = 5.6Hz, 1H, 5’-OH), 5.08–5.23 (dd, J = 4.0Hz, 1H, 3’-H), 4.96–5.03 (m, 1H, 2’-H), 4.29–4.37 ( m, 1H, 4’-H), 3.68 (m, 2H, CH2). HRMS (EI) m/z 424.1419 [M + H]+; Calcd for C21H18FN5O4: 424.1343 [M + H]+。
化合物36和14的合成:用上述类似方法,用0.5克的化合物24与4-吗啡啉吡啶-3-硼酸反应得到中间产品36(500 mg, 收率48%;HPLC含量99%);取480 mg化合物36,经氨甲醇脱保护基后得到白色产品14(312 mg, 收率90%;HPLC含量95%)。R f = 0.20 (PE–EA = 1:1). 1H NMR (400MHz, DMSO-d 6 ) 9.60 (s, 1H, Ar-H), 8.85–8.89 (m, 3H, Ar-H), 7.01–7.04 (d, J = 6.9Hz, 1H, Ar-H), 6.08–6.10 (d, J = 7.6Hz, 1H, 1’-H), 5.97–5.99 (d, J = 6.4Hz, 1H, 2’-OH), 5.35–5.38 (t, J = 5.6Hz, 1H, 5’-OH), 5.05–5.20 (dd, J = 4.0Hz,1H, 3’-H), 4.94–5.04 (m, 1H, 2’-H ), 4.26–4.34 ( m, 1H, 4’-H), 3.66–3.71 (m, 10H, CH2). HRMS (EI) m/z 417.1681 [M + H]+; Calcd for C19H22FN6O4:417.1687 [M + H]+。
化合物37和15的合成:用上述类似方法,用1.0克的化合物24与6-(4-甲基哌嗪)吡啶-3-硼酸反应得到白色固体中间产品36;经氨甲醇脱保护基后得到白色产品15(107 mg, 总收率11.2%;HPLC含量99%); R f = 0.30 (MeOH–DCM = 1:8). 1H NMR (400MHz, DMSO d6 ): 9.61 (s, 1H, Ar-H), 8.88-8.92 (m, 3H, Ar-H), 7.13 (d, J = 7.2 Hz, 1H, Ar-H), 6.09-6.11 (d, J = 8.0Hz, 1H, 1’), 6.00-6.01 (d, J = 6.4 Hz, 1H, 2’-OH), 5.38-5.39 (t, J = 4.0 Hz, 1H, 5’-OH), 5.20-5.36 (dd, J = 2.4 Hz, 1H, 3’), 4.95-5.07 (m, 1H, 2’), 4.27-4.35 (m, 1H, 4’), 3.66 (m, 2H, CH2), 2.72 (s, 3H, CH3). HRMS (EI): m/z 430.2000 [M + H]+ ; calcd for C20H25FN7O3, 430.2003[M + H]+。
实施例4
化合物38的合成:含有氟糖(1.78 g, 5 mmol)、2,6-二氯嘌呤(1.05 g, 5.5 mmol, 1.1 eq)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)(2.22 mL, 3 eq)和30mL无水乙腈的反应液冷却到0 °C,加入三氟甲磺酸三甲基硅酯(TMSTf)(3.60 mL, 4 eq),在60 °C下搅拌4小时。将反应液倒入冰水中,用二氯甲烷萃取,有机相用无水硫酸钠干燥,出去干燥剂,浓缩并用硅胶柱提纯得到2.1克白色固体产品38,收率88.9%。
化合物16的合成:化合物38在0°C溶解到饱和氨甲醇溶液中,搅拌48小时,减压浓缩,硅胶柱提纯(甲醇-二氯甲烷:1:20至1:15)得到133 mg白色固体产品16;总收率42%;HPLC含量99%。R f = 0.20 (DCM–MeOH = 10:1). 1H NMR (400 MHz, DMSO-d 6 ) 8.40 (s, 1H, Ar-H), 7.92 (s, 2H, NH2), 5.93–5.95 (d, J = 6.8Hz, 1H, 1’-H), 5.85–5.87 (d, J = 8.0Hz, 1H, 2’-OH), 5.25–5.28 (t, J = 5.6 Hz, 1H, 5’-OH), 5.00–5.15 (m, 2H, 3’-H), 4.79–4.91 ( m, 1H, 2’-H), 4.22–4.31 ( m, 1H, 4’-H), 3.63 (m, 2H, CH2)。HRMS (EI) m/z 304.0613 [M + H]+; Calcd for C10H12ClFN5O3:304.0613 [M + H]+。
化合物39和17的合成:采用上述化合物27和5的合成方法,由化合物38(700 mg, 1.45 mmol)和三丁基(2-呋喃基)锡(569. 6 mg, 1.60 mmol,1.1 eq)反应,提纯后所得中间产品39经过饱和氨甲醇溶液脱保护得到112 mg淡黄色固体产品17; 总收率20%;HPLC含量95%;R f = 0.50 (DCM–MeOH = 50:1). 1H NMR (400 MHz, DMSO-d 6 ) 8.92 (s, 1H, Ar-H), 8.15 (s, 1H, Ar-H), 7.91 (d, J = 3.2Hz, 1H, Ar-H), 6.87 (s, 1H, Ar-H), 6.01–6.04 (m, 2H, 1’, 2’-OH), 5.25–5.28 (t, J = 6.4Hz, 1H, 5’-OH), 5.07–5.22 (dd, J = 4.0Hz,,1H, 3’-H), 4.87–4.97 (m, 1H, 2’-H), 4.28–4.37 (m, 1H, 4’-H), 3.67 (s, 2H, CH2)。HRMS (EI) m/z 355.0609 [M + H]+; Calcd for C14H13ClFN4O4:355.0609 [M + H]+。
化合物40和18的合成:采用上述化合物28和6的合成方法,由化合物38 (800 mg, 1.66 mmol)和3-噻吩硼酸(319 mg, 2.49 mmol,1.5 eq)反应,提纯后所得中间产品40经过饱和氨甲醇溶液脱保护得到80 mg白色固体产品18;,总收率11%;HPLC含量95%;R f = 0.50 (DCM–MeOH = 10:1). 1H NMR (400 MHz, DMSO-d 6 ) 8.99 (s, 1H, Ar-H), 8.95 (s, 1H, Ar-H), 8.18–8.19 (d, J = 5.2Hz, 1H, Ar-H), 7.78 (d, J = 3.2Hz, 1H, Ar-H), 6.03-6.06 (m, 2H, 1’, 2’-OH), 5.28–5.31 (t, J = 4.8Hz, 1H, 5’-OH), 5.08–5.22 (dd, J = 4.4Hz, 1H, 3’-H), 4.89–4.97 (m, 1H, 2’-H ), 4.28–4.37 ( m, 1H, 4’-H), 3.67 (m, 2H, CH2)。HRMS (EI) m/z 371.0381 [M + H]+; Calcd for C14H13ClFN4O3S:371.0381 [M + H]+。
化合物41和19的合成:采用上述化合物29和7的合成方法,由化合物38 (500 mg)和苯基硼酸反应,提纯后所得白色固体中间产品41经过饱和氨甲醇溶液脱保护得到23 mg白色固体产品19;总收率6%。HRMS (EI) m/z 365.0817 [M + H]+; Calcd for C16H15ClFN4O3:365.0817 [M + H]+。
化合物42和20的合成:采用上述化合物30和8的合成方法,由化合物38 (1.0 g)和萘基-2-硼酸反应,提纯后所得中间产品42经过饱和氨甲醇溶液脱保护得到淡黄色固体产品20;总收率6%。HRMS (EI) m/z 415.0973 [M + H]+; Calcd for C20H17ClFN4O3:415.0973 [M + H]+.
实施例5
化合物43的合成:采用上述化合物24和38的合成方法,氟代糖(1.77 g, 5 mmol,1 eq)、2-氨基-6-氯嘌呤(932 mg, 5.5 mmol, 1.1 eq)、1,8-二氮杂双环[5.4.0]十一碳-7-烯 (DBU)(2.22 mL, 3 eq)、无水乙腈(30 mL)和三氟甲磺酸三甲基硅酯(TMSTf)(3.60 mL, 4 eq),反应液在60°C搅拌2小时,用水稀释后用二氯甲烷萃取,有机相干燥浓缩,硅胶柱提纯(石油醚-乙酸乙酯:5:1至3:1)得到白色固体产品43;HPLC含量98%。
化合物22的合成:化合物43(251 mg, 0.54 mmol)溶解到饱和的氨甲醇溶液中,室温搅拌过夜,浓缩并用硅胶柱提纯(DCM–MeOH:50:1 to 20:1)得到140 mg白色固体产品22;收率85%;HPLC含量98%。R f = 0.40 (DCM–MeOH = 10:1). 1H NMR (400 MHz, DMSO-d 6 ) 8.38 (s, 1H, Ar-H), 7.01 (s, 2H, NH2), 5.95–5.96 (d, J = 6.0Hz, 1H, 1’-H), 5.84–5.86 (d, J = 8.0Hz, 1H, 2’-OH), 5.23–5.26 (t, J = 5.6Hz, 1H, 5’-OH), 5.00–5.15 (dd, J = 4.0Hz, 1H, 3’-H), 4.77–4.88 (m, 1H, 2’-H ), 4.18–4.27 ( m, 1H, 4’-H), 3.60–3.63 (t, 2H, CH2)。MS (ES) m/z : 304 [M + H]+ , 326 [M + Na]+。HRMS (EI) m/z 304.0613 [M + H]+; Calcd for C10H12ClFN5O3:304.0613 [M +H]+。
化合物44和21的合成:化合物43(1.8 g, 3.9 mmol)溶解到甲醇(20 mL)、四氢呋喃(2 mL)和三乙胺(1 mL, 7.17 mmol)中,加入10%的Pd/C催化剂,在50 Psi的氢气压力下震荡3小时。硅藻土过滤除去催化剂,溶液浓缩,硅胶柱提纯(石油醚-乙酸乙酯:5:1至2:1)得到白色固体产品44。化合物44溶解到饱和氨甲醇溶液中,室温搅拌过夜,浓缩并用硅胶柱提纯得到400 mg白色固体产品21;收率38.5%;HPLC含量95%。R f = 0.30 (DCM–MeOH = 10:1). 1H NMR (400 MHz, DMSO-d 6 ) 8.62 (s, 1H, Ar-H), 8.31 (s, 2H, Ar-H), 6.59 (s, 2H, NH2), 5.93–5.94 (d, J = 6.4Hz, 1H, 1’-H), 5.87–5.89 (d, J = 8.0Hz, 1H, 2’-OH), 5.26–5.29 (t, J = 5.6Hz, 1H, 5’-OH), 5.00–5.15 (dd, J = 4.4Hz, 1H, 3’-H), 4.80–4.4.92 (m, 1H,2’-H), 4.18–4.27 (m, 1H, 4’-H), 3.60–3.63 (t, 2H, CH2)。MS (ES) m/z 270 [M + H]+, 292 [M + Na]+. HRMS (EI) m/z 270.1002 [M + H]+; Calcd for C10H13FN5O3:270.1002 [M + H]+.
实施例6
化合物b的合成:取化合物a(3 g)于60 ml无水吡啶中,加入4.5 mL二异丙基乙基胺和3.5克的Ph2NCOCl 3.5 g,室温搅拌,TLC(MeOH/DCM=1:10)跟踪,待反应完全加水淬灭并搅拌10 min,旋干,加适量乙醇、水混合溶液于90℃回流搅拌2 h后抽滤得固体,用乙醇洗涤若干次得化合物b。
化合物23的合成:采用上述化合物24、43、38的合成方法,氟代糖(1.77 g, 5 mmol,1 eq)、保护的嘌呤化合物b(2.13 g, 5.5 mmol, 1.1 eq)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)(2.22 mL, 3 eq)、无水乙腈(30 mL)和 三氟甲磺酸三甲基硅酯(TMSTf)(3.60 mL, 4 eq),反应液在60°C搅拌2小时,用水稀释后用二氯甲烷萃取,有机相干燥浓缩,硅胶柱提纯(石油醚-乙酸乙酯:5:1至3:1)得到白色固体中间产品,用饱和氨甲醇溶液脱保护3天,浓缩并用硅胶柱提纯得到白色固体产品23;HPLC含量95%。1H NMR (400MHz, DMSO d6 ): 10.54 (s, 1H, NH), 7.94 (s, 1H, Ar-H), 6.48 (s, 2H, NH2), 5.88 (d, J = 6.0 Hz, 1H, 1’), 5.73 (d, J = 8.0Hz, 1H, 2’-OH), 5.24 (s, 1H, 5’-OH), 4.95-5.09 (dd, J = 2.8Hz, 1H, 3’), 4.70 (dd, 1H,2’), 4.15 (dd, 1H, 4’), 3.59 (s, 2H, CH2); MS (ESI) m/z 285 [M]+, 286 [M + H]+, 308 [M + Na]+; HRMS (EI) m/z 308.0771 [M + Na]+; Calcd for C10H12FN5NaO4 +:308.0771 [M + Na]+.
本发明所述化合物抗肿瘤细胞活性是根据Clin. Cancer Res. 2010, 16(8), 2235-2245报道的方法测定的。部分初步结果见下表:
Claims (5)
1.3’-氟-取代核苷类似物,其特征在于,其具有通式(Ⅰ)或(II)所示结构:
X = H, Cl, NH2, OH ;
Y = H, NH2, NHOH, CH3, Cl, F, 羰基, OH, OR, SH, SR, NHR, NHR2, C1-C8的烷基、C3-C15烷基取代或无取代的苯基、萘基或含氮、氧、硫单取代或双取代的不饱和五元或六元杂环基或被卤素、苯基、甲氧基、苯氧基、丙炔基、4-吗啉基、哌嗪基、4-甲基哌嗪基、4-哌啶氧基 取代的含氮、氧、硫单取代或双取代的不饱和五元或不饱和六元杂环基;
Z = H, Br, Cl;
U = H、p-CH3C6H5CO, C6H5CO;
V = H、CH3CO, C6H5CO;
上述各代表性基团中的R是C1-C8的烷基。
4.制备如权利要求3所述的3’-氟-取代核苷类似物,其特征在于,通过如下方法合成:
A:1、2、3、24、25化合物通过以下方法合成:
化合物24的合成:取化合物6-氯嘌呤和3’-脱氧-3’-氟代保护核糖化合物溶于无水乙腈中,降温至0℃,向其滴加1,8-二氮杂双环[5.4.0]十一碳-7-烯,再加入三氟甲磺酸三甲基硅酯,加热,搅拌反应,TLC检测反应完成;将反应液冷却到室温,加入饱和碳酸氢钠溶液和乙酸乙酯,萃取,有机层干燥,过滤,滤液浓缩,柱层析,得化合物24;
化合物25和1的合成:化合物24溶解到甲醇中,加入四氢呋喃及三乙胺和Pd/C催化剂,在氢气压力下搅拌反应,滤出催化剂,减压浓缩,硅胶柱提纯得到化合物25;
将所得化合物25溶解到饱和的氨甲醇溶液中,室温搅拌过夜,减压浓缩,硅胶柱提纯得到化合物1;
化合物2的合成:将化合物24溶解在0℃的饱和氨甲醇溶液中,室温搅拌过夜,减压抽干,用硅胶柱层析的方法得到白色固体化合物2;
化合物3的合成:将化合物24溶解于羟铵水溶液中,加热到反应,TLC检测反应完全之后,减压蒸干,再溶于过量氨甲醇溶液中搅拌反应过夜,旋干并用硅胶柱子分离提纯得化合物3;
B:化合物4、26的合成方法如下:
6-甲基嘌呤iv的合成:取化合物iii 加入甲醇溶解,再向其加HCl,室温搅拌,减压蒸除甲醇和部分稀盐酸,向剩余反应液中加入HCl,经萃取,水相减压浓缩得到化合物iv的盐酸盐,用酸性离子交换树脂提纯;
化合物26的合成:6-甲基嘌呤和N,O-双(三甲基硅烷基)乙酰胺加入到1.2-二氯乙烷中,加热搅拌,冷却,加入保护的氟代核糖原料和三氟甲磺酸三甲基硅酯,加热搅拌反应,冷却,分出有机相,干燥,浓缩,用硅胶柱提纯得到化合物26;
化合物4的合成:化合物26溶解到饱和的氨甲醇溶液中,室温搅拌过夜,浓缩后用硅胶柱提纯得到白色固体化合物4;
C:化合物5-15、27-37通过以下方法合成:
化合物27的合成:取化合物24和双三苯基磷二氯化钯溶于无水N,N-二甲基甲酰胺中,向其加入三丁基(2-呋喃基)锡在N2保护下加热,搅拌反应,将反应液减压蒸干,用二氯甲烷溶解,掺入硅胶,蒸干,柱层析提纯得化合物;
化合物5的合成:取化合物27加入饱和氨甲醇溶液,密封,室温搅拌反应过夜,掺入硅胶,蒸干,柱层析过柱提纯后所得粗产品,加入乙醇加热溶解,减压旋蒸,用乙醇-乙酸乙酯重结晶得化合物5;
化合物28和6的合成:化合物24,3-噻吩硼酸、碳酸钾和甲醇的反应液中,在搅拌下加入催化剂Pd(PPh3)4 ,加热反应,反应后将反应液冷却到室温,经稀释,萃取,所得有机相经干燥,减压除去溶剂,粗产品用硅胶提纯,得到化合物28;
在化合物28中加入饱和氨甲醇溶液,室温搅拌过夜,硅胶柱提纯得到化合物6;
化合物29和7的合成:将化合物24与苯基硼酸加热反应,在搅拌下加入催化剂Pd(PPh3)4 ,反应后将反应液冷却到室温,经稀释,萃取,所得有机相经干燥,减压除去溶剂,粗产品用硅胶提纯,得到化合物29;取化合物29经氨甲醇脱保护基后得到化合物7;
化合物30和8的合成:将化合物24与萘基-2-硼酸加热反应,在搅拌下加入催化剂Pd(PPh3)4 ,反应后将反应液冷却到室温,经稀释,萃取,所得有机相经干燥,减压除去溶剂,粗产品用硅胶提纯,得到化合物30;取化合物30经氨甲醇脱保护基后得到化合物8;
化合物31和9的合成:将化合物24与吡啶-4-硼酸加热反应,在搅拌下加入催化剂Pd(PPh3)4 ,反应后将反应液冷却到室温,经稀释,萃取,所得有机相经干燥,减压除去溶剂,粗产品用硅胶提纯,得到化合物31;将化合物31经氨甲醇脱保护基后得到化合物9;
化合物32和10的合成:将化合物24与吡啶-3-硼酸加热反应,在搅拌下加入催化剂Pd(PPh3)4 ,反应后将反应液冷却到室温,经稀释,萃取,所得有机相经干燥,减压除去溶剂,粗产品用硅胶提纯,得到化合物32;将化合物32经氨甲醇脱保护基后得到化合物10;
化合物33和11的合成:将化合物24与5-丙炔基吡啶-3-硼酸加热反应,在搅拌下加入催化剂Pd(PPh3)4 ,反应后将反应液冷却到室温,经稀释,萃取,所得有机相经干燥,减压除去溶剂,粗产品用硅胶提纯,得到化合物33;化合物33经氨甲醇脱保护基后得到化合物11;
化合物34和12的合成:将化合物24与5-苯基吡啶-3-硼酸加热反应,在搅拌下加入催化剂Pd(PPh3)4 ,反应后将反应液冷却到室温,经稀释,萃取,所得有机相经干燥,减压除去溶剂,粗产品用硅胶提纯,得到化合物34;化合物34经氨甲醇脱保护基后得到化合物12;
化合物35和13的合成:将化合物24与6-苯氧基吡啶-3-硼酸加热反应,在搅拌下加入催化剂Pd(PPh3)4 ,反应后将反应液冷却到室温,经稀释,萃取,所得有机相经干燥,减压除去溶剂,粗产品用硅胶提纯,得到化合物35;化合物35经氨甲醇脱保护基后得到化合物13;
化合物36和14的合成:将化合物24与4-吗啡啉吡啶-3-硼酸加热反应,在搅拌下加入催化剂Pd(PPh3)4 ,反应后将反应液冷却到室温,经稀释,萃取,所得有机相经干燥,减压除去溶剂,粗产品用硅胶提纯,得到化合物36;取化合物36,经氨甲醇脱保护基后得到化合物14;
化合物37和15的合成:将化合物24与6-(4-甲基哌嗪)吡啶-3-硼酸加热反应,在搅拌下加入催化剂Pd(PPh3)4 ,反应后将反应液冷却到室温,经稀释,萃取,所得有机相经干燥,减压除去溶剂,粗产品用硅胶提纯,得到化合物37;化合物37经氨甲醇脱保护基后得到化合物15;
D:化合物16-20、38-42通过以下方法合成:
化合物38的合成:含有氟糖、2,6-二氯嘌呤、1,8-二氮杂双环[5.4.0]十一碳-7-烯和无水乙腈的反应液冷却到0 °C,加入三氟甲磺酸三甲基硅酯,加热搅拌反应,反应后将反应液倒入冰水中,经萃取,有机相干燥,浓缩并用硅胶柱提纯得到化合物38;
化合物16的合成:将化合物38溶解到饱和氨甲醇溶液中,搅拌反应,减压浓缩,硅胶柱提纯得到化合物16;
化合物39和17的合成:将化合物38和三丁基(2-呋喃基)锡反应,提纯后得化合物39,化合物39经过饱和氨甲醇溶液脱保护得到化合物17;
化合物40和18的合成:将化合物38和3-噻吩硼酸反应,提纯后得化合物40,化合物40经过饱和氨甲醇溶液脱保护得到化合物18;
化合物41和19的合成:将化合物38和苯基硼酸反应,提纯后所得化合物41,化合物41经过饱和氨甲醇溶液脱保护得到化合物19;
化合物42和20的合成:将化合物38和萘基-2-硼酸反应,提纯后所得化合物42,化合物42经过饱和氨甲醇溶液脱保护得到化合物20;
E:化合物21-22、43-44通过以下方法合成:
化合物43的合成:将氟代糖、2-氨基-6-氯嘌呤、1,8-二氮杂双环[5.4.0]十一碳-7-烯、无水乙腈和三氟甲磺酸三甲基硅酯,反应液加热搅拌反应,反应后经稀释,萃取,有机相干燥浓缩,硅胶柱提纯得到化合物43;
化合物22的合成:将化合物43溶解到饱和的氨甲醇溶液中,室温搅拌过夜,浓缩并用硅胶柱提纯得到化合物22;
化合物44和21的合成:将化合物43溶解到甲醇、四氢呋喃和三乙胺中,加入 Pd/C催化剂,在氢气压力下震荡反应;反应液经浓缩,硅胶柱提纯得到化合物44;将化合物44溶解到饱和氨甲醇溶液中,室温搅拌过夜,浓缩并用硅胶柱提纯得到化合物21;
F:化合物23通过以下方法合成:
化合物b的合成:取化合物a溶于无水吡啶中,加入二异丙基乙基胺和Ph2NCOCl ,室温搅拌,TLC跟踪,待反应完全加水淬灭并搅拌,旋干,经回流搅拌后抽滤得化合物b;
化合物23的合成:将氟代糖、化合物b、1,8-二氮杂双环[5.4.0]十一碳-7-烯、无水乙腈和三氟甲磺酸三甲基硅酯反应液加热搅拌反应,用水稀释后经萃取,有机相干燥浓缩,硅胶柱提纯得到中间产品,用饱和氨甲醇溶液脱保护,浓缩并用硅胶柱提纯得化合物23。
5.如权利要求1、2或3所述的3’-氟-取代核苷类似物在制备药物中的应用,其特征在于,将其或其5’-磷酸酯或它们与有机酸或无机酸反应形成盐,作为活性物应用于制备抗肿瘤或抗病毒药物中。
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