CN116143840A - 一种膦酰基去氮嘌呤衍生物及其制备方法与应用 - Google Patents
一种膦酰基去氮嘌呤衍生物及其制备方法与应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
本发明提供一种膦酰基去氮嘌呤衍生物及其制备方法与其在制备抗肿瘤药物中的应用。本发明的膦酰基去氮嘌呤衍生物具有良好的抗肿瘤活性。且本发明建立了一种温和的可见光诱导条件下、有机染料催化C‑H直接活化、高区域选择性引入膦酰化官能团的合成新方法，能快速、简便、高效地实现去氮嘌呤衍生物的官能团化修饰，具有反应操作简单、底物普适性强、反应选择性好等特点，进一步拓展了去氮嘌呤化合物的应用范围。
Description
技术领域
本发明涉及一种膦酰基去氮嘌呤衍生物及其制备方法与其在制备抗肿瘤药物中的应用。
背景技术
吡咯并[2,3-d]嘧啶(7-去氮嘌呤)是一种具有广泛生物活性的嘌呤碱基类似物。由于7-去氮嘌呤的骨架与嘌呤的骨架极为相似，因此它们经常用作DNA和RNA规范成分的替代品，并被用于核酸测序(L.M.De Coen,Chem.Rev.,2016,116,80-139；P.Perlikova,Med.Res.Rev.,2017,37,1429-1460；F.Musumeci,M.Sanna,Expert Opin.Ther.Pat.,2017,27,1305-1318.)。此外，吡咯并[2,3-d]嘧啶骨架存在于许多不同蛋白激酶的ATP竞争性小分子抑制剂的结构中，例如JAK，BTK，TAM，IGF-1R，c-Kit，Ret，CHk1和许多其他丝氨酸-苏氨酸激酶(F.Musumeci,Curr Med Chem,2017,24,2059-2085；F.Musumeci,Curr Med Chem,2019,26,1806-1832；F.Jiang,Bioorg Med Chem,2019,27,4089-4100；T.Gao,Eur J MedChem,2019,178,329-340；G.Tang,Eur J Med Chem,2019,173,167-183.)等。最近，一些含有吡咯[2,3-d]嘧啶母核结构的小分子化合物已被证实可作为抗菌剂、受体拮抗剂、抗癌剂、酶抑制剂和抗病毒核苷类药物(J.Zhao,J Med Chem,2018,61,10242-10254；Y.M.Liu,Future Med Chem,2019,11,959-974.)。
有机磷化合物在生物化学、有机合成、材料化学、药物化学及农药化学等领域中具有重要的应用价值。磷(膦)酰基团是药物、农药和材料聚合物中重要的结构单元。而传统的C-P键构建的方法因选择性差、原子经济性低、容易产生“三废”污染等弊端，其应用日益受到限制。近年来，基于直接C-H官能团化反应的膦酰化反应已成为构筑C-P键的有效方法之一，包括过渡金属催化和电化学促进的C-H膦酰化方法(J.Q.Yu,J Am Chem Soc.,2013,135,9322-9325；M.Murakami,Angew Chem Int Ed.,2013,52,9801-9804；M.Hocek,J OrgChem.,2016,81,9507-9514；J.S.Song,Angew Chem Int Ed.,2019,58,16770 -16774；K.Zhao,Org.Chem.Front.,2022,9,6540-6546)，以及可见光诱导、有机染料催化的C-H膦酰化方法(Y.Song,J Am Chem Soc.,2021,143,964-972；B.Yu,J Org Chem.,2020,85,14744-14752；X.G.Hu,Green Chem.,2022,24,8280-8291；Y.Li,Green Chem.,2021,23,3600-3606)。尤其是后者，具有条件温和、官能团普适性好、环保节能等显著优势。然而，迄今为止还未见报道可见光诱导的吡咯并[2,3-d]嘧啶衍生物的直接膦酰化反应。
综上所述，基于可见光诱导-有机染料催化策略，开发出具有条件温和、高区域选择性的直接膦酰化合成去氮嘌呤衍生物的方法显得尤为必要。
发明内容
本发明的目的是提供一种可见光诱导、有机染料催化的7-去氮嘌呤衍生物的高区域选择性C-H膦酰化方法，该方法是在伊红Y催化、LPO氧化条件下，在去氮嘌呤衍生物的C6-位进行选择性直接膦酰化，解决已有合成方法所具有的路线步骤繁琐、反应条件苛刻、底物范围有限且收率较低等问题。
为了实现上述目的，本发明的技术方案如下：
第一方面，本发明提供一种式(II)所示的膦酰基去氮嘌呤衍生物，
其中，R1为苯基、被C1-C6烷基、C1-C6烷氧基、卤素或三氟甲基取代的苯基、苯环上的H被C1-C6烷氧基取代的苯硫基、苯环上的H被C1-C6烷氧基取代的苯胺基或含N或S的C4-C5杂芳基(如吡啶基、噻吩基)；
R2为氢、C1-C6直链或支链烷基、C1-C6环烷基、苄基(Bn)或三甲基硅基乙氧甲基(SEM)；
R3、R4分别独立为C1-C6直链或支链烷基、C3-C6环烷基、C1-C6烷氧基、苯基或被卤素或C1-C6烷基取代的苯基。
进一步，R1为苯基、被甲基、氟或三氟甲基取代的苯基、苯环上的H被甲氧基取代的苯硫基、苯环上的H被乙氧基取代的苯胺基、吡啶基或噻吩基；
R2为氢、甲基、环戊基、苄基或三甲基硅基乙氧甲基；
R3、R4分别独立为甲基、环丙基、乙氧基、丁氧基、苯基或被氟或甲基取代的苯基。
优选地，所述式(Ⅱ)所示的膦酰基去氮嘌呤衍生物为下列之一：
第二方面，本发明提供一种上述式(II)所示的膦酰基去氮嘌呤衍生物的制备方法，所述方法为：
将式(Ⅰ)所示化合物、式(ⅠII)所示膦酰化试剂、氧化剂和光催化剂溶解在有机溶剂中，在蓝光照射下室温搅拌反应6-24小时(在本发明的一个实施例中为10小时)，所得反应混合物经后处理，得式(Ⅱ)所示的膦酰基去氮嘌呤衍生物；
式(Ⅰ)、(Ⅱ)中，各个取代基的定义同上述；
所述的氧化剂为过氧化月桂酰(LPO)、过氧化苯甲酰(BPO)、过氧化叔丁醇(TBHP)、过氧化二异丙苯(DCP)、过氧化苯甲酸叔丁酯(TBPB)、偶氮二异丁腈(AIBN)、过氧化氢中的一种或两种的混合物，优选为过氧化月桂酰(LPO)或过氧化苯甲酰(BPO)，最优选为LPO；
所述的光催化剂为伊红Y、伊红B、罗丹明B、罗丹明6G、孟加拉玫瑰红、亚甲基蓝、双(三联吡啶)二氯化钌中的一种或两种的混合物；优选为伊红Y或罗丹明B，最优选为伊红Y；
所述式(Ⅰ)所示化合物、膦酰基试剂、氧化剂和光催化剂的物质的量之比为1.0:1.0-3.0:1.0-3.0:0.01-0.1(优选1.0:2.0:2.0:0.05)。
进一步，所述的有机溶剂为甲醇、乙醇、异丙醇、乙腈、乙酸乙酯、二氯甲烷中的一种或两种的混合溶剂；优选为甲醇。
更进一步，所述有机溶剂的体积以式(Ⅰ)所示化合物的质量计为15mL/g。
进一步，所述后处理为：向所述反应混合物中加水(体积以化合物(I)的质量计为15mL/g)淬灭反应，用乙酸乙酯萃取，所得上层有机相经饱和氯化钠水溶液洗涤、无水硫酸钠干燥，过滤，所得滤液浓缩，以体积比为1：1的石油醚(沸程：60～90℃)与乙酸乙酯的混合溶剂为洗脱剂进行快速柱层析，收集含目标化合物的洗脱液，蒸除溶剂并干燥，得到式(II)所示的膦酰基去氮嘌呤衍生物。
本发明还提供上述式(II)所示的膦酰基去氮嘌呤衍生物在制备抗肿瘤药物中的应用。
在本发明的实施例中，所述肿瘤为Jeko-1细胞(人套细胞淋巴瘤细胞)或Mino细胞(人B细胞淋巴瘤细胞)。
尤其优选所述式(II)所示的膦酰基去氮嘌呤衍生物为式2l或2m所示化合物之一。
与现有技术相比，本发明具有以下有益效果：建立一种温和的可见光诱导条件下、有机染料催化C-H直接活化、高区域选择性引入膦酰化官能团的合成新方法，能快速、简便、高效地实现去氮嘌呤衍生物的官能团化修饰，具有反应操作简单、底物普适性强、反应选择性好等特点，进一步拓展了去氮嘌呤化合物的应用范围。且本发明的C6-位膦酰化去氮嘌呤衍生物具有良好的抗肿瘤活性。
具体实施方式
下面通过具体实施例对本发明作进一步说明，但本发明的保护范围并不仅限于此。
实施例1(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)二苯基氧化膦(2a)的制备
将7-苯基-N-甲基-7H-吡咯[2,3-d]嘧啶(210mg,1.0mmol)，LPO(800mg,2.0mmol)，二苯基氧化膦(400mg,2.0mmol)，伊红Y(34mg,0.05mmol)，溶解在甲醇(3.0mL)中，于蓝光照射下室温搅拌反应10小时，加水(3.0mL)淬灭，用乙酸乙酯(25mL)萃取所述反应混合物，有机相用饱和氯化钠溶液洗涤、无水硫酸钠干燥，过滤，滤液浓缩后，以体积比为1：1的的石油醚(沸程：60-90℃)/乙酸乙酯的混合溶剂为洗脱剂进行快速柱层析，收集含目标化合物的洗脱液，浓缩并干燥得产物为357mg(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)二苯基氧化膦，收率为87％，HPLC纯度为97.4％，产物为浅黄色固体，1H NMR(400MHz,CDCl3):δ9.06(s,1H),7.98-7.96(m,2H),7.79-7.73(m,4H),7.64(m,2H),7.55(m,4H),7.52-7.48(m,3H),6.67(d,JH-P＝3.8Hz,1H),3.96(s,3H)；13CNMR(101MHz,CDCl3)δ159.62,154.50(d,JC-P＝9.1Hz),153.51,137.47,134.03,132.82(d,JC-P＝3.0Hz),131.89(d,JC-P＝10.1Hz),131.30,130.55,130.20,129.01,128.91(d,JC-P＝5.1Hz),114.25(d,JC-P＝12.1Hz),112.43(d,JC-P＝15.1Hz),31.01；HRMS(ESI)m/z:calculated for C25H22N3OP[M+H]+410.1417,found:410.1407.
实施例2二苯基(4-苯基-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)氧化膦(2b)的制备
按照实施例1所述的方法，不同的是所用底物为：4-苯基-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(325mg,1.0mmol),得产物为430mg二苯基(4-苯基-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)氧化膦，收率为82％，HPLC纯度为96.0％，产物为白色固体，1H NMR(500MHz,CDCl3)δ9.07(s,1H),8.00-7.96(m,2H),7.80-7.74(m,4H),7.63-7.59(m,2H),7.55-7.48(m,7H),6.74(d,JH-P＝5.0Hz,1H),6.02(s,2H),3.25(t,J＝8.5Hz,2H),0.49-0.40(t,J＝8.5Hz,2H),-0.12(s,9H)；13C NMR(101MHz,CDCl3)δ159.69,155.14(d,JC-P＝9.1Hz),153.96,137.48,133.46,132.50(t,JC-P＝3.0Hz),132.33,132.02,131.93(d,JC-P＝2.0Hz),130.84,130.57,128.92(d,JC-P＝4.0Hz),128.66(d,JC-P＝13.1Hz),114.25(d,JC-P＝11.1Hz),113.83(d,JC-P＝14.1Hz),71.99,65.89,17.28,-1.50；ESI-MS(m/z)Calculated for C30H33N3O2PSi[M+H]+526.2080,found526.2070.
实施例3二苯基(4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)氧化膦(2c)的制备
按照实施例1所述的方法，不同的是所用底物为：4-苯基-7H-吡咯[2,3-d]嘧啶(195mg,1.0mmol),得产物为240mg二苯基(4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)氧化膦，收率为61％，HPLC纯度为98.5％，产物为浅黄色固体，1H NMR(500MHz,CDCl3)δ13.23(s,1H),9.09(s,1H),8.13-8.05(m,2H),7.82-7.75(m,4H),7.63-7.57(m,2H),7.56-7.46(m,7H),7.09(d,J＝4.4Hz,1H)；13C NMR(101MHz,CDCl3)δ159.88,154.68(d,JC-P＝11.1Hz),153.50,137.69,132.72(d,JC-P＝3.0Hz),131.92(d,JC-P＝11.1Hz),131.44,130.80,130.53,130.34,128.95(d,JC-P＝9.1Hz),128.83(d,JC-P＝12.1Hz),115.36(d,JC-P＝11.1Hz),111.54(d,JC-P＝14.1Hz)；HRMS(ESI)m/z:Calculated for C24H19N3OP[M+H]+396.1266,found:396.1270.
实施例4(7-环戊基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)二苯基氧化膦(2d)的制备
按照实施例1所述的方法，不同的是所用底物为：4-苯基-N-环戊基-7H-吡咯[2,3-d]嘧啶(263mg,1.0mmol),得产物为352mg(7-环戊基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)二苯基氧化膦，收率为76％，HPLC纯度为97.8％，产物为黄色固体。1H NMR(400MHz,CDCl3)δ9.02(s,1H),7.94-7.91(m,2H),7.79-7.73(m,4H),7.67-7.61(m,2H),7.55(td,J＝7.6,3.0Hz,4H),7.51-7.47(m,3H),6.57(d,JC-P＝5.1Hz,1H),5.23-5.12(m,1H),2.53-2.40(m,2H),2.07-1.99(m,2H),1.78-1.68(m,2H),1.56-1.50(m,2H)；13C NMR(101MHz,CDCl3)δ159.71,153.77(d,JC-P＝9.1Hz),152.55,137.54,134.70,133.53,132.73(d,JC-P＝3.0Hz),132.00(d,JC-P＝11.1Hz),131.45,130.37(d,JC-P＝3.0Hz),128.88,128.76,115.46(d,JC-P＝13.1Hz),112.31(d,JC-P＝16.2Hz),60.32(d,JC-P＝2.0Hz),30.62,25.05；ESI-MS(m/z)Calculated for C29H27N3OP[M+H]+464.1892,found 464.1891.
实施例5(7-苄基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)二苯基氧化膦(2e)的制备
按照实施例1所述的方法，不同的是所用底物为：4-苯基-N-苯甲基-7H-吡咯[2,3-d]嘧啶(285mg,1.0mmol),得产物为354mg(7-苄基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)二苯基氧化膦，收率为73％，HPLC纯度为97.8％，产物为黄色固体，1H NMR(400MHz,CDCl3)δ9.10(s,1H),8.01-7.97(m,2H),7.66-7.58(m,4H),7.54-7.48(m,5H),7.38(td,J＝7.7,3.0Hz,2H),7.28,7.12-7.09(m,2H),7.03-6.97(m,3H),6.69(d,JH-P＝5.0Hz,1H),5.91(s,2H)；13C NMR(101MHz,CDCl3)δ159.67,154.80(d,JC-P＝9.1Hz),153.88,137.62,136.62,133.45,132.46(d,JC-P＝3.0Hz),132.31,131.85(d,JC-P＝10.1Hz),131.58,130.48(d,JC-P＝2.0Hz),128.92(d,JC-P＝1.0Hz),128.59(d,JC-P＝12.1Hz),128.05,127.72,127.22,114.24(d,JC-P＝11.1Hz),112.97(d,JC-P＝15.1Hz),47.65；ESI-HRMS(m/z)Calculated forC31H25N3OP[M+H]+486.1735,found 486.1730.
实施例6(7-三甲基硅基乙氧甲基-4-(对甲苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)二苯基氧化膦(2f)的制备
按照实施例1所述的方法，不同的是所用底物为：7-三甲基硅基乙氧甲基-4-(对甲苯基)-7H-吡咯并[2,3-d]嘧啶(340mg,1.0mmol),得产物为383mg(7-三甲基硅基乙氧甲基-4-(对甲苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)二苯基氧化膦，收率为71％，HPLC纯度为98.3％，产物为白色固体。1H NMR(400MHz,CDCl3)δ9.06(s,1H),7.90(d,J＝8.1Hz,2H),7.81-7.74(m,4H),7.62(td,J＝7.4,1.0Hz,2H),7.53(td,J＝7.5,3.0Hz,4H),7.32(d,J＝8.0Hz,2H),6.74(d,J＝5.0Hz,1H),6.01(s,2H),3.28-3.21(m,2H),2.44(s,3H),0.48-0.42(m,2H),-0.11(s,9H)；13CNMR(101MHz,CDCl3)δ159.71,155.11(d,JC-P＝9.1Hz),153.97,140.99,134.72,133.11,132.46(d,JC-P＝3.0Hz),131.97(t,JC-P＝5.1Hz),130.86,129.66,128.83,128.63(d,JC-P＝12.1Hz),114.10(d,JC-P＝4.0Hz),113.97(d,JC-P＝6.1Hz),71.96,65.87,21.48,17.28,-1.52；ESI-HRMS(m/z)Calculated for C31H34N3O2PSi[M+H]+539.2158,found 540.2222.
实施例7(4-(4-氟苯基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)二苯基氧化膦(2g)的制备
按照实施例1所述的方法，不同的是所用底物为：4-(4-氟苯基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(343mg,1.0mmol),得产物为402mg(4-(4-氟苯基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)二苯基氧化膦，收率为74％，HPLC纯度为97.6％，产物为白色固体。1H NMR(400MHz,CDCl3)δ9.06(s,1H),8.03-7.98(m,2H),7.81-7.74(m,4H),7.63(td,J＝7.3,1.2Hz,2H),7.53(td,J＝7.7,3.0Hz,4H),7.20(t,J＝8.6Hz,2H),6.69(d,J＝5.0Hz,1H),6.01(s,2H),3.25(t,J＝8.5Hz,2H),0.45(t,J＝8.6Hz,2H),-0.11(s,9H)；13C NMR(101MHz,CDCl3)δ165.58,163.08,158.38,155.12(d,JC-P＝9.1Hz),153.77,132.56(d,JC-P＝2.0Hz),131.97(d,JC-P＝10.1Hz),131.87,130.93(d,JC-P＝8.1Hz),130.76,128.69(d,JC-P＝13.1Hz),116.10(d,JC-P＝21.2Hz),113.97(d,JC-P＝11.1Hz),113.50(d,JC-P＝15.2Hz),72.02,65.94,17.28,-1.51；ESI-HRMS(m/z)Calculated for C30H32FN3O2PSi[M+H]+544.1985,found 544.1971.
实施例8二苯基(4-(3-(三氟甲基)苯基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)氧化膦(2h)的制备
按照实施例1所述的方法，不同的是所用底物为：4-(3-(三氟甲基)苯基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(393mg,1.0mmol),得产物为428mg二苯基(4-(3-(三氟甲基)苯基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)氧化膦，收率为72％，HPLC纯度为97.6％，产物为白色固体。1H NMR(400MHz,CDCl3)δ9.09(s,1H),8.24-8.18(m,2H),7.81-7.73(m,5H),7.67-7.60(m,3H),7.53(td,J＝7.6,3.1Hz,4H),6.64(d,J＝5.1Hz,1H),6.02(s,2H),3.30-3.23(m,2H),0.50-0.43(m,2H),-0.11(s,9H)；13C NMR(101MHz,CDCl3)δ157.78,155.26(d,JC-P＝8.7Hz),153.98,138.19,134.46,133.33,132.59(d,JC-P＝2.8Hz),132.09-131.43(m),131.20,130.60,129.52,128.67(d,JC-P＝12.8Hz),127.03(dd,JC-P＝7.2,3.6Hz),125.80(q,JC-P＝3.7Hz),125.16,122.45,114.18(d,JC-P＝11.6Hz),113.35(d,JC-P＝14.4Hz),72.09,66.02,17.29,-1.53；ESI-HRMS(m/z)Calculated for C31H32F3N3O2PSi[M+H]+,594.1953,found594.1950.
实施例9(4-(3,5-二氟苯基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)二苯基氧化膦(2i)的制备
按照实施例1所述的方法，不同的是所用底物为：4-(3,5-二氟苯基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(360mg,1.0mmol),得产物为348mg(4-(3,5-二氟苯基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)二苯基氧化膦，收率为62％，HPLC纯度为97.6％，产物为白色固体。1H NMR(400MHz,CDCl3)δ9.07(s,1H),7.77(dd,J＝12.7,7.3Hz,4H),7.64(t,J＝7.4Hz,2H),7.57-7.50(m,6H),6.95(t,J＝8.6Hz,1H),6.67(d,J＝5.0Hz,1H),6.02(s,2H),3.28-3.19(t,J＝8.5Hz,2H),0.48-0.41(d,J＝8.7Hz,2H),-0.12(s,9H)；13C NMR(101MHz,CDCl3)δ164.44(d,JC-P＝12.1Hz),161.96(d,JC-P＝12.1Hz),156.83,155.30(d,JC-P＝8.1Hz),153.79,140.65(t,JC-P＝9.1Hz),134.56,133.44,132.66(d,JC-P＝3.0Hz),131.95(d,JC-P＝5.5Hz),131.65,130.54,128.72(d,JC-P＝13.1Hz),114.08(d,JC-P＝11.1Hz),112.83(d,JC-P＝14.1Hz),111.80(dd,JC-P＝19.2,7.1Hz),105.82(t,JC-P＝25.2Hz),72.06,66.00,17.28,-1.52；ESI-HRMS(m/z)Calculated for C30H31F2N3O2PSi[M+H]+,562.1891,found 562.1882.
实施例10二苯基(4-(吡啶-4-基)-7-((2-(三甲基甲硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)氧化膦(2j)的制备
按照实施例1所述的方法，不同的是所用底物为：4-(吡啶-4-基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(326mg,1.0mmol),得产物为274mg二苯基(4-(吡啶-4-基)-7-((2-(三甲基甲硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)氧化膦，收率为62％，HPLC纯度为97.6％，产物为白色固体。1H NMR(400MHz,CDCl3)δ9.11(s,1H),8.78(dd,J＝4.5,1.6Hz,2H),7.85(dd,J＝4.5,1.6Hz,2H),7.81-7.74(m,5H),7.67-7.61(m,2H),7.56-7.52(m,5H),6.70(d,J＝5.0Hz,1H),6.02(s,2H),3.26(t,J＝8.3Hz,2H),0.46(t,J＝8.4Hz,2H),-0.11(s,9H)；13CNMR(101MHz,CDCl3)δ156.83,155.32(d,JC-P＝9.1Hz),153.93,150.54,144.73,134.87,133.75,132.63(d,JC-P＝3.0Hz),131.94(d,JC-P＝11.1Hz),131.72,130.61,128.71(d,JC-P＝13.1Hz),122.77,114.50(d,JC-P＝12.1Hz),112.60(d,JC-P＝14.1Hz),72.08,66.06,29.68,17.31,-1.55；ESI-HRMS(m/z)Calculatedfor C29H31N4O2PSiK[M+K]+565.1591,found 565.1596.
实施例11二苯基(4-(噻吩-3-基)-7-((2-(三甲基甲硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)氧化膦(2k)的制备
按照实施例1所述的方法，不同的是所用底物为：4-(噻吩-3-基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(332mg,1.0mmol),得产物为270mg二苯基(4-(噻吩-3-基)-7-((2-(三甲基甲硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)氧化膦，收率为51％，纯度为98.1％，产物为黄色油状物。1H NMR(400MHz,CDCl3)δ8.43(s,1H),7.82-7.75(m,5H),7.71-7.67(dd,J＝2.8,2.2Hz 1H),7.39(td,J＝7.3,1.2Hz,2H),7.34-7.28(m,5H),6.69(d,J＝3.7Hz,1H),5.58(s,2H),3.50(t,J＝8.1Hz,2H),0.95-0.88(t,J＝2.1Hz,2H),-0.03(s,9H)；13C NMR(101MHz,CDCl3)δ151.95(d,JC-P＝11.1Hz),150.68,146.12(d,JC-P＝6.1Hz),135.35,133.86,133.16(d,JC-P＝6.1Hz),132.73,131.69(d,JC-P＝10.1Hz),131.53(d,JC-P＝3.0Hz),130.50(d,JC-P＝11.1Hz),128.72,127.91(d,JC-P＝13.1Hz),116.29,101.40,72.75,66.55,17.73,-1.38；ESI-HRMS(m/z)Calculated forC28H31N3O2PSSi[M+H]+,532.1644,found 532.1636.
实施例12(4-((4-乙氧基苯基)氨基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6基)二苯基氧化膦(2l)的制备
按照实施例1所述的方法，不同的是所用底物为：N-(4-乙氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(268mg,1.0mmol),得产物为332mg(4-((4-乙氧基苯基)氨基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6基)二苯基氧化膦，收率为71％，纯度为98.1％，产物为黄色固体。1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.65-7.45(m,7H),7.40(td,J＝7.5,3.0Hz,4H),7.18(d,J＝8.8Hz,2H),6.68(d,JC-P＝8.9Hz,2H),5.71(d,J＝50.8Hz,1H),3.94(q,J＝7.0Hz,2H),3.72(s,3H),1.44(t,J＝7.0Hz,3H)；13C NMR(101MHz,CDCl3)δ157.28,156.78,154.09(d,JC-P＝9.1Hz),153.92,132.32(d,JC-P＝3.0Hz),131.76(d,JC-P＝10.1Hz),131.66,130.50(d,JC-P＝11.1Hz),128.60(d,JC-P＝12.1Hz),127.31,126.85,144.66,112.73(d,JC-P＝15.1Hz),102.12(d,JC-P＝12.1Hz),63.51,30.88,14.91；ESI-HRMS(m/z)Calculated for C27H26N4O2P[M+H]+469.1793,found 469.1797.
实施例13(4-((4-甲氧基苯基)硫代)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6基)二苯基氧化膦(2m)的制备
按照实施例1所述的方法，不同的是所用底物为：4-((4-甲氧基苯基)硫代)-7-甲基-7H-吡咯并[2,3-d]嘧啶(271mg,1.0mmol),得产物为344mg(4-((4-甲氧基苯基)硫代)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6基)二苯基氧化膦，收率为73％，纯度为97.5％，产物为黄色油状物。1H NMR(400MHz,CDCl3)δ8.65(s,1H),7.69-7.59(m,6H),7.55-7.46(m,6H),6.86-6.81(m,2H),5.81(d,J＝4.8Hz,1H),3.85(s,3H),3.82(s,3H)；13C NMR(101MHz,CDCl3)δ165.63,160.84,152.85-152.20,137.07,132.66(d,JC-P＝2.5Hz),131.79(t,JC-P＝13.1Hz),131.20,130.77,130.09,128.79,118.09,114.94,114.20(d,JC-P＝12.2Hz),111.33(d,JC-P＝15.3Hz),55.25,30.90；HRMS(ESI)m/z:Calculated for C26H22N3O2PSNa[M+Na]+494.1068,found:494.1053.
实施例14二甲基(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)氧化膦(2n)的制备
按照实施例1所述的方法，不同的是所用底物为：7-苯基-N-甲基-7H-吡咯[2,3-d]嘧啶(210mg,1.0mmol),得产物为113.8mg二甲基(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)氧化膦，收率为53％，纯度为98.2％，产物为白色固体。1HNMR(400MHz,CDCl3)δ8.53(s,1H),7.91(s,1H),7.27-7.17(m,4H),6.26(s,1H),3.81(d,6H)；13C NMR(101MHz,CDCl3)δ153.27,153.24,152.27,151.11,140.61,140.59,139.27,139.25,131.56,130.23,129.07,128.76,128.53,126.65,124.36,124.34,122.58,120.00,119.98,104.15,97.51,30.15；HRMS(ESI)m/z:Calculated for C15H17N3OP[M+H]+286.1109,found:286.1106.
实施例15(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)膦酸二乙酯(2o)的制备
按照实施例1所述的方法，不同的是所用底物为：7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶(210mg,1.0mmol),得产物为252mg(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)膦酸二乙酯，收率为73％，纯度为98.3％，产物为黄色油状物。1H NMR(400MHz,CDCl3)δ9.09-9.03(m,1H),8.13(m,2H),7.59-7.51(m,4H),4.31-4.17(m,4H),4.05(s,3H),1.39(t,J＝7.1Hz,6H)；13C NMR(101MHz,CDCl3)δ159.83,153.97(d,JC-P＝14.2Hz),153.66,137.43,130.61,129.81,128.95(d,JC-P＝10.1Hz),127.64,114.30(d,JC-P＝14.8Hz),112.72(d,JC-P＝16.7Hz),63.05(d,JC-P＝5.4Hz),30.42,16.33(d,JC-P＝6.3Hz)；HRMS(ESI)m/z:Calculated for C25H21N3O3P[M+H]+438.1730,found:438.1733.
实施例16(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)膦酸二丁酯(2p)的制备
按照实施例1所述的方法，不同的是所用底物为：7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶(210mg,1.0mmol),得产物为273mg(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)膦酸二丁酯，收率为68％，纯度为98.3％，产物为黄色油状物。1H NMR(400MHz,CDCl3)δ9.07(s,1H),8.14(d,J＝5.9Hz,2H),7.55(dd,J＝11.2,5.3Hz,4H),4.21(dq,J＝13.8,6.9Hz,2H),4.11(dd,J＝16.5,7.3Hz,2H),4.05(s,3H),1.76-1.66(m,4H),1.43(dd,J＝14.8,7.4Hz,5H),0.94(t,J＝7.3Hz,7H)；13C NMR(101MHz,CDCl3)δ159.80(d,JC-P＝1.0Hz),153.97(d,JC-P＝14.1Hz),153.66,137.45,130.63,129.79,128.97(d,JC-P＝11.1Hz),127.63,114.32(d,JC-P＝14.1Hz),112.76(d,JC-P＝16.2Hz),66.72(d,JC-P＝6.1Hz),32.38(d,JC-P＝7.1Hz),30.45,18.75,13.55；HRMS(ESI)m/z:Calculated for C21H29N3O3P[M+H]+402.1947,found:402.1935.
实施例17(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)二对甲苯基氧化膦(2q)的制备
按照实施例1所述的方法，不同的是所用底物为：7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶(210mg,1.0mmol),得产物为340mg(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)二对甲苯基氧化膦，收率为78％，纯度为98.3％，产物为浅黄色固体。1H NMR(400MHz,CDCl3)δ9.04(s,1H),8.01-7.97(m,2H),7.63(dd,J＝12.5,8.1Hz,4H),7.52-7.48(m,3H),7.33(dd,J＝8.0,2.7Hz,4H),6.69(d,J＝4.8Hz,1H),3.96(s,3H),2.45(s,6H)；13C NMR(101MHz,CDCl3)δ159.57,154.46(d,JC-P＝9.0Hz),153.44,143.35(d,JC-P＝2.7Hz),137.67,134.46,133.31,131.84(d,JC-P＝10.7Hz),130.38,129.63(d,JC-P＝13.1Hz),128.89(d,JC-P＝3.6Hz),128.22,127.09,114.29(d,JC-P＝11.6Hz),112.07(d,JC-P＝14.7Hz),30.95,21.70；HRMS(ESI)m/z:Calculated for C25H21N3O3P[M+H]+438.1730,found:438.1733.
实施例18二环丙基(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)氧化膦(2r)的制备
按照实施例1所述的方法，不同的是所用底物为：7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶(210mg,1.0mmol),得产物为226mg二环丙基(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)氧化膦，收率为67％，纯度为98.3％，产物为无色油状物。1H NMR(400MHz,CDCl3)δ9.06(s,1H),8.11(dd,J＝7.8,1.7Hz,2H),7.62-7.55(m,3H),7.31(d,J＝4.3Hz,1H),4.21(s,3H),1.19-1.08(m,6H),1.03(m,4H)；13C NMR(101MHz,CDCl3)δ159.38,154.10(d,JC-P＝9.1Hz),153.25,137.84,135.47,134.36,130.45,128.96,114.66(d,JC-P＝11.1Hz),108.79(d,JC-P＝14.1Hz),31.24,8.08,6.97,2.96(dd,JC-P＝10.1,4.0Hz)；HRMS(ESI)m/z:Calculated for C19H21N3OP[M+H]+338.1422,found:338.1415.
实施例19(4-氟苯基)(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)(苯基)氧化膦(2s)的制备
按照实施例1所述的方法，不同的是所用底物为：7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶(210mg,1.0mmol),得产物为226mg(4-氟苯基)(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)(苯基)氧化膦，收率为67％，纯度为98.3％，产物为浅黄色固体。1H NMR(400MHz,CDCl3)δ9.07(s,1H),7.97(s,2H),7.76(dt,J＝20.4,10.4Hz,4H),7.66(t,J＝7.0Hz,1H),7.59-7.49(m,5H),7.29-7.21(m,2H),6.66(d,J＝4.5Hz,1H),3.97(s,3H)；13CNMR(101MHz,CDCl3)δ166.80(d,JC-P＝3.3Hz),164.27(d,JC-P＝3.5Hz),159.85,154.52(d,JC-P＝9.3Hz),153.71,137.50,134.49(dd,J＝11.8,9.0Hz),133.54,132.99(d,J＝2.7Hz),131.71(dd,JC-F＝110,131Hz),130.56,129.96,128.98(dd,JC-P＝14.2,10.0Hz),127.26(d,JC-P＝3.3Hz),126.13(d,JC-P＝3.4Hz),116.44(dd,JC-P＝21.6,13.9Hz),114.23(d,JC-P＝11.9Hz),112.47(d,JC-P＝14.9Hz),30.99；HRMS(ESI)m/z:calculated for C25H20FN3OP[M+H]+428.1328,found:428.1314.
实施例20(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)(苯基)亚磷酸酯乙酯(2t)的制备
按照实施例1所述的方法，不同的是所用底物为：7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶(210mg,1.0mmol),得产物为226mg(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)(苯基)亚磷酸酯乙酯，收率为58％，纯度为98.3％，产物为浅黄色油状物。1H NMR(400MHz,CDCl3)δ9.05(s,1H),8.13(d,J＝5.8Hz,2H),7.87(dd,J＝12.6,8.1Hz,2H),7.64-7.56(m,4H),7.53(s,2H),7.43(s,1H),4.34-4.23(m,2H),3.96(s,3H),1.47(t,J＝6.8Hz,3H)；13CNMR(101MHz,CDCl3)δ159.79,153.50,137.56,133.04(d,JC-P＝2.8Hz),132.70,131.72(d,JC-P＝10.9Hz),131.07(d,JC-P＝13.3Hz),130.59,129.55,128.99,128.98(d,JC-P＝7.0Hz),128.86,114.45(d,JC-P＝12.0Hz),111.79(d,JC-P＝13.7Hz),62.08(d,JC-P＝5.7Hz),30.52,16.58(d,JC-P＝6.5Hz)；HRMS(ESI)m/z:Calculated for C21H21N3O2P[M+H]+378.1371,found:378.1371.
实施例21：(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)二苯基氧化膦(2a)的制备
将7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶(210mg,1.0mmol)，LPO(800mg,2.0mmol)，二苯基氧化膦(400mg,2.0mmol)，罗丹明B(24mg,0.05mmol)，溶解在甲醇(3mL)，于蓝光照射下室温反应10小时，加水(30mL)淬灭用乙酸乙酯萃取所述反应混合物，萃取液经饱和氯化钠溶.液洗涤、无水硫酸钠干燥，过滤，滤液浓缩后，以体积比为1：1的的石油醚(沸程：60～90℃)/乙酸乙酯的混合溶剂为洗脱剂进行快速柱层析，收集含目标化合物的洗脱液，浓缩并干燥得产物为172mg(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)二苯基氧化膦，收率为42％，HPLC纯度为97.5％，产物为浅黄色固体。
实施例22：(7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)二苯基氧化膦(2a)的制备
7-甲基-4-苯基-7H-吡咯并[2,3-d]嘧啶(210mg,1.0mmol)，BPO(485mg,2.0mmol)，二苯基氧化膦(400mg,2.0mmol)，伊红Y(34mg,0.05mmol)，溶解在甲醇(1.5mL)中，于蓝光照射下室温反应10小时，加水(15mL)淬灭用乙酸乙酯萃取所述反应混合物，萃取液经饱和氯化钠溶.液洗涤、无水硫酸钠干燥，过滤，滤液浓缩后，以体积比为1：1的石油醚(沸程：60～90℃)/乙酸乙酯的混合溶剂为洗脱剂进行快速柱层析，收集含目标化合物的洗脱液，浓缩并干燥得产物为266mg吡咯[2,3-d]嘧啶，收率为65％，HPLC纯度为98.2％，产物为浅黄色固体。
实施例23：体外抗肿瘤实验
选取上述实施例合成的取代膦酰基吡咯并[2,3-d]嘧啶衍生物进行体外抗肿瘤活性实验，分别对2种细胞系进行了筛选，Jeko-1(人套细胞淋巴瘤)和mino(人B细胞淋巴瘤)的细胞株，采用MTT还原法测定吡咯并[2,3-d]嘧啶膦酰化衍生物对上述细胞株的抑制活性。
选用上述对数生长期细胞，用胰酶进行消化后，L-15培养基配成6×104/mL的细胞悬液，然后将细胞悬液加入到96孔板中，每孔细胞数为15000个，37℃下，无CO2培养24小时，将事先配置好的浓度为30μM的化合物加入到96孔板中，每个化合物设置4个副孔，37℃下，无CO2培养72小时，每孔加入10μLMTT，37℃下，无CO2培养3小时，弃去上清液，加入150μLDMSO，振荡均价后，酶标仪在490nm处测定光密度(OD值)。
抑制率计算：
生长抑制率＝(OD对照组-OD实验组)/(OD对照组-OD空白组)
表1
由表1可知，本发明所提供化合物均具有一定的抗肿瘤作用，特别是化合物2l和2m表现出了较好的生物活性，该类化合物在抗肿瘤药物化学领域拥有较好的发展前景。
需要指出的是，上述实验实例仅为说明本发明的构思及特点，其目的是让熟悉本发明的人了解本实验并据以实施，并不能限制本发明的保护范围。凡根据本发明精神实质做出的等效变化或修饰，都应涵盖在本发明的保护范围内。
Claims (10)
1.一种式(II)所示的膦酰基去氮嘌呤衍生物，
其中，R1为苯基、被C1-C6烷基、C1-C6烷氧基、卤素或三氟甲基取代的苯基、苯环上的H被C1-C6烷氧基取代的苯硫基、苯环上的H被C1-C6烷氧基取代的苯胺基或含N或S的C4-C5杂芳基，
R2为氢、C1-C6直链或支链烷基、C1-C6环烷基、苄基或三甲基硅基乙氧甲基；
R3、R4分别独立为C1-C6直链或支链烷基、C3-C6环烷基、C1-C6烷氧基、苯基或被卤素或C1-C6烷基取代的苯基。
2.如权利要求1所述的式(II)所示的膦酰基去氮嘌呤衍生物，其特征在于：R1为苯基、被甲基、氟或三氟甲基取代的苯基、苯环上的H被甲氧基取代的苯硫基、苯环上的H被乙氧基取代的苯胺基、吡啶基或噻吩基；
R2为氢、甲基、环戊基、苄基或三甲基硅基乙氧甲基；
R3、R4分别独立为甲基、环丙基、乙氧基、丁氧基、苯基或被氟或甲基取代的苯基。
3.如权利要求2所述的式(II)所示的膦酰基去氮嘌呤衍生物，其特征在于：所述式(Ⅱ)所示的膦酰基去氮嘌呤衍生物为下列之一：
4.如权利要求1所述的式(II)所示的膦酰基去氮嘌呤衍生物的制备方法，其特征在于所述方法为：
将式(Ⅰ)所示化合物、式(ⅠII)所示膦酰化试剂、氧化剂和光催化剂溶解在有机溶剂中，在蓝光照射下室温搅拌反应6-24小时，所得反应混合物经后处理，得式(Ⅱ)所示的膦酰基去氮嘌呤衍生物；
所述的氧化剂为过氧化月桂酰、过氧化苯甲酰、过氧化叔丁醇、过氧化二异丙苯、过氧化苯甲酸叔丁酯、偶氮二异丁腈、过氧化氢中的一种或两种的混合物；
所述的光催化剂为伊红Y、伊红B、罗丹明B、罗丹明6G、孟加拉玫瑰红、亚甲基蓝、双(三联吡啶)二氯化钌中的一种或两种的混合物；
所述式(Ⅰ)所示化合物、膦酰基试剂、氧化剂和光催化剂的物质的量之比为1.0:1.0-3.0:1.0-3.0:0.01-0.1。
5.如权利要求4所述的式(II)所示的膦酰基去氮嘌呤衍生物的制备方法，其特征在于：所述的有机溶剂为甲醇、乙醇、异丙醇、乙腈、乙酸乙酯、二氯甲烷中的一种或两种的混合溶剂。
6.如权利要求4所述的式(II)所示的膦酰基去氮嘌呤衍生物的制备方法，其特征在于：所述有机溶剂的体积以式(Ⅰ)所示化合物的质量计为15mL/g。
7.如权利要求4所述的式(II)所示的膦酰基去氮嘌呤衍生物的制备方法，其特征在于所述后处理为：向所述反应混合物中加水淬灭反应，用乙酸乙酯萃取，所得上层有机相经饱和氯化钠水溶液洗涤、无水硫酸钠干燥，过滤，所得滤液浓缩，以体积比为1：1的石油醚与乙酸乙酯的混合溶剂为洗脱剂进行快速柱层析，收集含目标化合物的洗脱液，蒸除溶剂并干燥，得到式(II)所示的膦酰基去氮嘌呤衍生物。
8.如权利要求1-3任一项所述的式(II)所示的膦酰基去氮嘌呤衍生物在制备抗肿瘤药物中的应用。
9.如权利要求8所述的应用，其特征在于：所述肿瘤为Jeko-1细胞或Mino细胞。
10.如权利要求8所述的应用，其特征在于：所述式(II)所示的膦酰基去氮嘌呤衍生物为式2l或2m所示化合物之一。
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