CN113845515A - 一种含芳杂环结构的二甲基联苯二芳基嘧啶类衍生物及其制备方法和应用 - Google Patents
一种含芳杂环结构的二甲基联苯二芳基嘧啶类衍生物及其制备方法和应用 Download PDFInfo
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
本发明属于医药技术领域,具体为一种含芳杂环结构的二甲基联苯二芳基嘧啶类衍生物及其制备方法和应用。本发明的化合物结构含芳杂环结构的联苯二甲基二芳基嘧啶类衍生物,包含其药用盐,其立体化学异构体,其水合物和溶剂化物,其同样生物功能的前体和衍生物;本发明还包括其制备方法以及含有一个或多个此类化合物的组合物在治疗艾滋病等相关药物中的应用。体外细胞水平抗HIV‑1活性实验结果显示,该类小分子具有较强的抗HIV‑1生物活性,可以显著的抑制被HIV‑1病毒感染的MT‑4细胞内的病毒复制,并且具有较低的细胞毒性。并对其进行成盐改造,可有效改善原药水溶性,有望成为抗HIV的候选药物。
Description
技术领域
本发明属于医药技术领域,具体涉及一种含芳杂环结构的联苯二芳基嘧啶类衍生物及 其制备方法和应用。
背景技术
非核苷逆转录酶抑制剂(NNRTIs)作为高效抗逆转录病毒疗法(HAART)中不可或缺的 组成部分之一,被广泛的用于治疗Ⅰ型人类免疫缺陷病毒(HIV-1)。迄今为止,已有6种NNRTIs获得了FDA批准并广泛用于临床治疗之中,其结构式分别为:
Chemical structures of six FDA-approved anti-HIV drugs.
其中,奈韦拉平(NVP)、地拉韦定(DLV)和依非韦伦(EFV)是第一代NNRTIs,其具有高效的抗病毒活性。然而,这类NNRTIs由于具有相对刚性的结构,从而导致其遗传屏障 较低;在其广泛使用后不久,催生出了一系列的耐药突变株,其中就包括有单突变体K103N、Y181C、Y188L和双突变体K103N/Y181C(RES056)。而所有第一代NNRTI均已证实对该 类突变株均具有不理想的抗病毒活性,而这一结果也直接导致其在临床使用中受限。另一 方面,第二代NNRTIs包括有依曲韦林(ETR,4)、利匹韦林(RPV,5)和多拉韦林(DOR,6)。 其中,ETR和RPV具有二芳基嘧啶(DAP Y)结构骨架,并可以对结合口袋柔性结合。这种 结合的柔性可以有助于最大限度地减少由突变引起的结合稳定性的损失,并使ETR和RPV 对多种临床耐药株具有比第一代NNRTIs更好的抑制活性。然而,虽然ETR和RPV对病 毒的耐药性的产生有所延缓,但K103N和E138K的突变仍然诞生并对其临床效果进行了 干扰。因此,寻找新的具有优秀对抗突变株活性的DAPY类抑制剂依然十分重要。
因此,二甲基联苯-DAPY是基于RPV结构骨架所设计合成出的一类新型DAPYs。其中大多数抑制剂分子均对WT和突变株显示出了优良的抗病毒活性。其中,化合物7更是 对野生型HIV-1毒株(EC50=1nM)和多种临床常见突变株表现出不俗的抑制活性。然而, 伴随着二甲基联苯的强疏水性,该类抑制剂分子表现出了极差的溶解性(S<1μg/mL)和并不 理想的类药性特征。在此基础上,一系列具有二氟-联苯结构的DAPYs也随之应运而生, 如:
Representative biphenyl-DAPYs developed by our group with theiradvantages and drawbacks
其中,化合物8和9均对于野生型HIV-1毒株保持有极其优异的抑制活性(EC50=1nM), 同时对于抑制剂分子的成药性也有所改善。与化合物7相较(S<1μg/mL,pH=2.0),化合物 8具有明显更高的溶解度(S=5.6μg/mL,pH=2.0)。为了进一步提高抑制剂分子的溶解度, 本课题组采用在联苯片段中引入了杂环这一策略,得到了一系列杂芳基-联苯-DAPYs。其 中,化合物10不仅具有极高的抑制活性(EC50=1nM),而且还有极高的溶解性(S=611 μg/mL,pH=2.0)。然而,与二甲基-联苯-DAPYs相比,上述化合物均失去了对双突变株的 抑制活性,对突变株Y188L的抑制活性也显著降低。因此,寻找具有高溶解性且对WT和突变株均具有高抑制活性的新型DAPY仍然是必要的。
发明内容
本发明的目的在于提供一种生物活性强、细胞毒性较小的含芳杂环结构的二甲基联苯 二芳基嘧啶类化合物及其制备方法和用途
本发明提供的含芳杂环结构的二甲基联苯二芳基嘧啶类衍生物,具有如下(Ⅰ)式所 示的结构式:
其中,R1选自呋喃基,噻吩基,吡唑基,咪唑基,噻唑基,吡啶基,嘧啶基,对胺基 苯基,C7~10芳杂环基,任选被取代的呋喃基,噻吩基,吡唑基,咪唑基,噻唑基,吡啶基, 嘧啶基,C7~10芳杂环基;
本发明提供的含芳杂环结构的二甲基联苯二芳基嘧啶类衍生物,还包括其药用盐,其 立体化学异构体,其水合物和溶剂化物,其多晶或共晶及单一对映体的X射线衍射单晶, 其同样生物功能的前体和衍生物。
本发明涉及的含芳杂环结构的二甲基联苯二芳基嘧啶类衍生物的药用盐,包括盐酸盐、 氢溴酸盐、甲酸盐、甲磺酸盐、三氟甲磺酸盐、硫酸盐、磷酸盐、醋酸盐、对甲苯磺酸盐、 酒石酸盐、柠檬酸盐、琥珀酸盐、马来酸盐、富马酸盐或苹果酸盐,。
本发明还提出含芳杂环结构的二甲基联苯二芳基嘧啶类衍生物的制备方法,具体步骤 为:
在溶剂中,化合物II(4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈)在 Pd(dppf)Cl2、碳酸铯(Cs2CO3)的作用下经Suzuki-偶联反应,得到所述化合物I,其制备 的反应通式如下:
反应条件如下:
使用的溶剂为甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、二氯甲烷、二氯乙烷、甲苯、四氢呋喃、***、异丙醚、甲基叔丁基醚、1,4-二氧六环、乙酸乙酯中的一种或者 多种;
所述的化合物II与杂环硼酸的摩尔比为1:1-1:8;
所述的化合物II与Pd(dppf)Cl2的摩尔比为1:0.01-1:0.10;
所述的化合物II与Cs2CO3的摩尔比为1:1-1:2;
反应温度为40~180℃;
反应时间为4~24h。
本发明还涉及一种药物组合物,该组合物含有有效剂量的上述各种化合物中至少一种, 以及相关的药用载体。
所述药物组合物,还包括采用上述化合物作为活性成分制备得到的药物组合物。
本发明还涉及所述化合物或组合物在制备预防和治疗艾滋病药物中的应用。
本发明基于含芳杂环结构的联苯二芳基嘧啶类衍生物与HIV逆转录酶的构效关系(SAR)研究发现,二甲基联苯片段可以提供比二氟联苯更高的二面角,从而进一步的稳定抑制剂的结合构象。同时这一特殊结构也是影响抑制剂抗病毒活性尤其是抗突变株抑制活性的重要组成部分。此外,前期研究也充分证实了杂环骨架可以有效提高抑制剂分子的水溶性,从而对抑制剂分子的相关成药性参数给予优化。因此,将这两个片段进行融合是生成新NNRTIs模板的合理策略。在本研究中,我们首先充分研究了多种五元和六元不饱和 杂环以深度探索其抑制活性、SAR及其溶解度特性。具有二甲基联苯结构的DAPYs因具 有更高的二面角,从而期待其能有效保持对多种临床突变株的高抑制活性。体外细胞水平 抗HIV-1活性实验结果显示,该系列化合物具有显著的抗HIV-1活性,并且具有较低的细 胞毒性。同时,对该类分子进行成盐改造,经溶解度实验证实,该系列化合物的药用盐在 多种pH范围下均表现出优秀的水溶性,具有良好的临床应用前景。
具体实施方式
通过下述实施实例可以更好地理解本发明内容,但是不能限制本发明的内容。
实施例1:目标产物(Ⅰa)的制备
化合物II在Pd(dppf)Cl2、碳酸铯的作用下经Suzuki-偶联反应,得到所述化合物I。其 中溶剂为甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、二氯甲烷、二氯乙烷、甲苯、 四氢呋喃、***、异丙醚、甲基叔丁基醚、1,4-二氧六环、乙酸乙酯等中的一种或者多种; 反应温度为40~180℃,反应时间为4~14h。
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(1.0mmol),Pd(dppf)Cl2(0.01mmol)和2-呋喃硼酸(1.2mmol)加入到1,4-二氧六环(6mL) 中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1)检测,原 料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、饱和 碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无 水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰa)。
目标产物(Ia)的表征结果:白色粉状固体;收率87%;熔点:228.9-229.1℃(fromMeOH)。 1H NMR(400MHz,DMSO–d6)δ1H NMR(400MHz,DMSO)δ9.60(s,1H,NH),8.89(s,1H,NH),8.04(m,2H,ArH),7.77(m,2H,ArH),7.73(m,1H,ArH),7.55(s,2H,ArH),7.39(m,1H,ArH),6.97(d,J=4Hz,1H,ArH),6.63(m,1H,ArH),6.39(m,1H,ArH),2.23(s,6H,CH3).13CNMR(100MHz,DMSO–d6)δ:162.5,159.8,156.2,153.5,146.1,143.2,137.0,136.4,132.9,128.9,123.6,120.2,118.4,112.5,106.0,101.8,99.2,18.8.HRMS(ESI-):m/z calcd forC23H18N5O[M-H]-380.1517,found 380.1510.HPLC analysis:retention time=7.70min;peak area,99.30%%(λ=254nm).
实施例2:目标产物(Ⅰb)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和2-噻吩硼酸(1.2mmol)加入到1,4-二氧六环(5mL) 中,经N2置换三次,调整反应温度至150℃,搅拌4h。经TLC(PE/EA=1/1)检测,原 料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、饱和 碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无 水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰb)。
目标产物(Ⅰb)的表征结果:白色粉状固体;收率81%;熔点:217.0-217.4℃。1HNMR (400MHz,DMSO–d6)δ9.56(s,1H,NH),8.86(s,1H,NH),8.07-8.02(m,2H,ArH),7.89-7.88 (m,1H,ArH),7.72-7.70(m,2H,ArH),7.66-7.65(m,1H,ArH),7.61-7.60(m,1H,ArH),7.55(s, 2H,ArH),7.38-7.35(m,1H,ArH),6.36(m,1H,ArH),2.32(s,6H,CH3).13C NMR(100MHz, DMSO–d6)δ:162.5,159.8,156.1,146.1,141.7,136.8,136.0,133.7,132.9,127.5,126.7,126.1, 121.0,120.2,118.4,101.7,99.2,18.9.HRMS(ESI-):m/z calcd forC23H18N5S[M-H]-396.1288, found 396.1287.HPLC analysis:retention time=8.05min;peak area,94.87%%(λ=254nm)。
实施例3:目标产物(Ⅰc)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和3-呋喃硼酸(1.0mmol)加入到1,4-二氧六环(6mL) 中,经N2置换三次,调整反应温度至80℃,搅拌4h。经TLC(PE/EA=1/1)检测,原料 消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、饱和碳 酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无水 硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰc)。
目标产物(Ic)的表征结果:白色粉状固体;收率87%;熔点:227.9-228.2℃。1HNMR (400MHz,DMSO–d6)δ9.58(s,1H,NH),8.86(s,1H,NH),8.22(s,1H,ArH),8.03(m,2H,ArH),7.77(s,1H,ArH),7.73-7.71(m,2H,ArH),7.46(s,2H,ArH),7.39-7.37(m,1H,ArH),7.01(s,1H,ArH),6.37(m,1H,ArH),2.21(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ: 13C NMR(101MHz,DMSO)δ162.5,159.8,156.1,146.1,144.7,139.6,136.8,135.8,132.9, 130.4,126.1,125.6,120.2,118.4,109.2,101.7,99.2,18.8.HRMS(ESI-):m/z calcd forC23H18N5O[M-H]-380.1517,found 380.1519.HPLC analysis:retention time=7.34min;peak area,97.02%(λ=254nm)。
实施例4:目标产物(Ⅰd)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和5-嘧啶硼酸(8.0mmol)加入到甲苯(6mL)中,经 N2置换三次,调整反应温度至100℃,搅拌4h。经TLC(PE/EA=1/1)检测,原料消失, 反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、饱和碳酸钠溶 液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无水硫酸钠 干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰd)。
目标产物(Id)的表征结果:白色粉状固体;收率94%;熔点:254.0-254.3℃。1HNMR (400MHz,DMSO–d6)δ9.60(s,1H,NH),9.22(m,3H,ArH),8.94(s,1H,NH),8.05-8.04(m,1H,ArH),7.72(m,2H,ArH),7.67(m,2H,ArH),7.45-7.43(m,2H,ArH),6.40(m,1H,ArH),2.28(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.4,159.8,157.6,156.2,155.0,146.0,137.9,137.5,133.4,133.0,132.1,126.9,120.2,118.4,101.8,99.3,18.9.HRMS(ESI-):m/z calcd for C23H18N7[M-H]-392.1629,found 392.1625.HPLC analysis:retention time=5.08min; peak area,99.39%(λ=254nm)。
实施例5:目标产物(Ⅰe)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和4-吡啶硼酸(8.0mmol)加入到甲醇(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌24h。经TLC(PE/EA=1/1)检测,原料消失, 反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、饱和碳酸钠溶 液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无水硫酸钠 干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰe)。
目标产物(Ie)的表征结果:白色粉状固体;收率70%;熔点:>300℃。1H NMR(400MHz,DMSO–d6)δ9.59(s,1H,NH),8.94(s,1H,NH),8.67-8.66(m,2H,ArH),8.03(m,2H, ArH),7.77-7.65(m,6H,ArH),7.38(m,1H,ArH),6.38(m,1H,ArH),2.26(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.4,159.7,156.3,150.7,147.2,146.1,138.1,137.3,135.5,132.9,126.9,121.6,120.1,118.4,101.8,99.3,18.9.HRMS(ESI-):m/z calcd for C24H19N6[M-H]-391.1677,found 391.1678.HPLC analysis:retention time=6.00min;peakarea,97.47% (λ=254nm)。
实施例6:目标产物(Ⅰf)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和3-吡啶硼酸(4.0mmol)加入到1,4-二氧六环(6mL) 中,经N2置换三次,调整反应温度至110℃,搅拌14h。经TLC(PE/EA=1/1)检测,原 料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、饱和 碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无 水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰf)。
目标产物(If)的表征结果:白色粉状固体;收率94%;熔点:224.6-224.9℃。1HNMR (400MHz,DMSO–d6)δ9.60(s,1H,NH),8.99(s,1H,ArH),8.93(s,1H,NH),8.60(d,J=4Hz. 1H,ArH),8.13(d,J=8Hz.1H,ArH),8.05(m,2H,ArH),7.75-7.73(m,2H,ArH),7.58(m,2H, ArH),7.53-7.50(m,1H,ArH),7.41(m,1H,ArH),6.40(m,1H,ArH),2.27(s,6H,CH3).13CNMR(100MHz,DMSO–d6)δ:162.5,159.8,156.1,148.8,148.1,146.1,137.4,137.2,135.7,135.4,134.4,132.9,126.9,124.3,120.2,118.4,101.8,99.3,18.9.HRMS(ESI-):m/zcalcd for C24H19N6[M-H]-391.1677,found 391.1672.HPLC analysis:retention time=8.99min;peak area,99.87%(λ=254nm)。
实施例7:目标产物(Ⅰg)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.05mmol)和3-苯并呋喃硼酸(4.0mmol)加入到1,4-二氧六环 (6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1)检测, 原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、饱 和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经 无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰg)。
目标产物(Ig)的表征结果:白色粉状固体;收率70%;熔点:245.9-246.3℃。1HNMR (400MHz,DMSO–d6)δ9.63(s,1H,NH),8.95(s,1H,NH),8.42(s,1H,ArH),8.08-8.02(m,3H,ArH),7.78-7.69(m,3H,ArH),7.60(s,2H,ArH),7.46-7.39(m,3H,ArH),6.43(m,1H,ArH),2.30(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.5,159.8,156.1,155.7,146.1,143.0,137.2,136.4,132.9,129.9,127.0,126.2,125.2,123.8,121.4,120.9,120.1,118.4,112.3, 101.8,99.3,18.9.HRMS(ESI-):m/z calcd for C27H20N5O[M-H]-430.1673,found 430.1656. HPLC analysis:retention time=8.99min;peak area,99.87%(λ=254nm)。
实施例8:目标产物(Ⅰh)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.08mmol)和2-苯并噻吩硼酸(8.0mmol)加入到1,4-二氧六环 (6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1)检测, 原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、饱 和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经 无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰh)。
目标产物(Ih)的表征结果:白色粉状固体;收率92%;熔点:266.7-267.0℃。1HNMR (400MHz,DMSO–d6)δ9.61(s,1H,NH),8.94(s,1H,NH),8.05(m,1H,ArH),7.99(d,J=8Hz.1H,ArH),7.89(m,1H,ArH),7.87(d,J=8Hz.1H,ArH),7.74(m,2H,ArH),7.62(s,2H,ArH),7.43-7.35(m,4H,ArH),6.40(m,1H,ArH),2.26(s,6H,CH3).13C NMR(100MHz, DMSO–d6)δ:162.4,159.8,156.2,146.1,143.5,141.0,139.1,137.4,132.9,132.0,126.2,125.3,125.0,124.2,122.9,120.3,120.2,118.5,101.8,18.8.HRMS(ESI-):m/z calcd forC27H20N5S [M-H]-446.1445,found 446.1444.HPLC analysis:retention time=5.30min;peak area,98.57% (λ=254nm)。
实施例9:目标产物(Ⅰi)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和6-苯并呋喃硼酸(1.2mmol)加入到1,4-二氧六环 (6mL)中,经N2置换三次,调整反应温度至100℃,搅拌4h。经TLC(PE/EA=1/1)检 测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相 经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰi)。:
目标产物(Ii)的表征结果:白色粉状固体;收率92%;熔点:218.3-219.2℃。1HNMR (400MHz,DMSO–d6)δ9.58(s,1H,NH),8.89(s,1H,NH),8.12(m,1H,ArH),8.07-8.03(m,2H,ArH),7.99(m,1H,ArH),7.79-7.65(m,4H,ArH),7.52(s,2H,ArH),7.41-7.39(m,1H,ArH),7.04(d,J=4Hz,1H,ArH),6.40(m,1H,ArH),2.27(s,6H,CH3).13C NMR(100MHz, DMSO)δ162.6,159.8,156.01,154.4,147.1,146.1,139.1,136.9,136.1,135.7,132.9,128.4,127.0,123.9,120.2,119.7,118.5,112.0,107.5,101.7,99.3,18.9.HRMS(ESI-):m/zcalcd for C27H20N5O[M-H]-430.1673,found 430.1672.HPLC analysis:retention time=8.80min;peak area,100%(λ=254nm)。
实施例10:目标产物(Ⅰj)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和吲哚-4-硼酸(1.2mmol)加入到甲醇(6mL)中,经 N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1)检测,原料消失, 反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、饱和碳酸钠溶 液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无水硫酸钠 干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰj)。
目标产物(Ij)的表征结果:白色粉状固体;收率90%;熔点:279.4-280.1℃。1HNMR (400MHz,DMSO–d6)δ11.30(s,1H,NH),9.61(s,1H,NH),8.90(s,1H,NH),8.05(m,2H,ArH),7.77-7.75(m,2H,ArH),7.51(s,2H,ArH),7.48-7.45(m,2H,ArH),7.42-7.40(m,1H,ArH),7.23(t,J=8Hz.1H,ArH),7.16(t,J=8Hz.1H,ArH),6.66(s,1H,ArH),6.42(m,1H,ArH),2.29(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ162.6,159.8,156.1,146.2,139.6,136.9,136.6,135.8,133.2,132.9,128.2,126.2,126.1,121.8,120.1,118.9,118.5,111.3,101.7, 100.8,99.2,19.0.HRMS(ESI-):m/z calcd for C27H21N6[M-H]-429.1833,found 429.1808. HPLC analysis:retention time=7.23min;peak area,99.33%(λ=254nm)。
实施例11:目标产物(Ⅰk)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.08mmol)和4-喹啉硼酸(1.2mmol)加入到1,4-二氧六环(6 mL)中,经N2置换三次,调整反应温度至170℃,搅拌4h。经TLC(PE/EA=1/1)检测, 原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经 无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰk)。
目标产物(Ik)的表征结果:白色粉状固体;收率90%;熔点:191.0-191.6℃。1HNMR (400MHz,DMSO–d6)δ9.65(s,1H,ArH),8.99(d,J=4Hz.2H,ArH),8.15(d,J=8Hz.1H,ArH),8.06(d,J=8Hz.1H,ArH),7.99(d,J=8Hz.1H,ArH),7.85-7.81(m,1H,ArH),7.74(m,1H,ArH),7.63(t,J=8Hz.1H,ArH),7.50(d,J=4Hz.1H,ArH),7.43(m,1H,ArH),7.39(s,2H,ArH),6.42(m,1H,ArH),2.28(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.5, 159.8,156.4,150.6,148.7,147.8,146.1,137.5,136.9,135.9,133.0,130.1,129.9,129.4,127.3, 126.5,126.0,121.8,120.1,118.4,101.8,99.2,18.8.HRMS(ESI-):m/z calcd forC28H21N6 [M-H]-441.1833,found 441.1827.HPLC analysis:retention time=7.58min;peak area,96.81% (λ=254nm)。
实施例12:目标产物(Ⅰl)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.10mmol)和吲哚-7-硼酸(1.2mmol)加入到1,4-二氧六环(6 mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1)检测, 原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、饱 和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经 无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰl)。
目标产物(Il)的表征结果:白色粉状固体;收率77%;熔点:309.4-310.5℃。1HNMR (400MHz,DMSO)δ11.17(s,1H,NH),9.57(s,1H,NH),8.85(s,1H,NH),8.12-7.99(m,2H,ArH),7.90(s,1H,ArH),7.76(m,2H,ArH),7.54-7.46(m,4H,ArH),7.40(t,J=4Hz.2H,ArH),6.53(s,1H,ArH),6.39(s,1H,ArH),2.26(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ: 162.6,159.8,157.4,156.0,146.2,140.4,136.6,136.0,135.3,132.8,131.6,128.8,126.7,126.5, 120.8,120.2,118.5,112.3,102.0,101.7,99.3,19.0.HRMS(ESI-):m/z calcd forC27H21N6 [M-H]-429.1833,found 429.1821.HPLC analysis:retention time=7.42min;peak area,99.50% (λ=254nm)。
实施例13:目标产物(Ⅰm)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.02mmol)和吲哚-4-硼酸硼酸(1.6mmol)加入到1,4-二氧六 环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1)检 测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相 经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰm)。
目标产物(Im)的表征结果:白色粉状固体;收率95%;熔点:238.6-239.5℃。1HNMR (400MHz,DMSO)δ11.17(s,1H,ArH),9.56(s,1H,NH),8.86(s,1H,NH),8.04(m,2H,ArH),7.75-7.72(m,3H,ArH),7.65(d,J=8Hz,1H,ArH),7.50(s,2H,ArH),7.42-7.36(m,3H,ArH),6.48(s,1H,ArH),6.39(m,1H,ArH),2.26(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ: 162.6,159.8,156.0,146.2,140.2,137.0,136.7,135.6,133.6,133.3,132.9,127.6,126.6,120.9, 120.2,118.7,118.5,109.7,101.7,101.5,99.3,19.0.HRMS(ESI-):m/z calcd forC27H21N6 [M-H]-429.1833,found 429.1832.HPLC analysis:retention time=7.88min;peak area,99.89% (λ=254nm)。
实施例14:目标产物(Ⅰn)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和4-甲基-2-噻吩硼酸(10.0mmol)加入到1,4-二 氧六环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1) 检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰn)。
目标产物(In)的表征结果:白色粉状固体;收率77%;熔点:208.7-209.3℃。1HNMR (400MHz,DMSO–d6)δ9.59(s,1H,NH),8.88(s,1H,NH),8.03(m,2H,ArH),7.72(m,2H,ArH),7.45(s,2H,ArH),7.39(m,1H,ArH),7.35(s,1H,ArH),7.11(s,1H,ArH),6.38(m,1H,ArH),2.27(s,3H,CH3),2.21(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.5,159.8,156.2,146.1,143.3,138.8,137.2,136.5,132.9,132.5,126.2,125.3,121.1,120.2,118.5,101.8, 99.2,18.8,16.0.HRMS(ESI-):m/z calcd for C24H20N5S[M-H]-410.1445,found 410.1436. HPLC analysis:retention time=8.91min;peak area,99.06%(λ=254nm)。
实施例15:目标产物(Ⅰo)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和4-甲基-2-呋喃硼酸(5.0mmol)加入到1,4-二氧 六环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1) 检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰo)。
目标产物(Io)的表征结果:白色粉状固体;收率74%;熔点:238.7-239.0℃。1HNMR (400MHz,DMSO–d6)δ9.57(s,1H,NH),8.86(s,1H,NH),8.02(m,2H,ArH),7.70(m,2H,ArH),7.47(s,2H,ArH),7.38(m,1H,ArH),6.82(d,J=4Hz,1H,ArH),6.36(m,1H,ArH), 6.22(d,J=4Hz,1H,ArH),2.37(s,3H,CH3),2.21(s,6H,CH3).13C NMR(100MHz,DMSO –d6)δ:162.5,159.8,157.5,156.1,152.06,146.1,136.9,135.9,132.9,129.2,123.1,120.2,118.4, 108.7,106.9,101.7,99.1,40.4,18.8,13.9.HRMS(ESI-):m/z calcd for C24H20N5O[M-H]- 394.1673,found 394.1674.HPLC analysis:retention time=8.13min;peakarea,95.76%(λ=254 nm)。
实施例16:目标产物(Ⅰp)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.02mmol)和5-甲基-2-噻吩硼酸(6.0mmol)加入到1,4-二氧 六环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1) 检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰp)。
目标产物(Ip)的表征结果:白色粉状固体;收率77%;熔点:232.4-232.9℃。1HNMR (400MHz,DMSO–d6)δ9.57(s,1H,NH),8.86(s,1H,NH),8.02(m,2H,ArH),7.71(m,2H,ArH),7.40(m,3H,ArH),7.30(d,J=4Hz,1H,ArH),6.84-6.83(m,1H,ArH),6.36(m,1H,ArH),2.49(s,3H,CH3),2.19(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.5,159.8,156.1,146.1,141.3,139.4,137.1,136.1,132.9,132.5,127.2,125.0,123.8,120.2,118.4,101.7, 99.2,18.8,15.5.HRMS(ESI-):m/z calcd for C24H20N5S[M-H]-410.1445,found 410.1444. HPLC analysis:retention time=9.00min;peak area,96.38%(λ=254nm)。
实施例17:目标产物(Ⅰq)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.03mmol)和2-甲基-4-吡啶硼酸(7.0mmol)加入到1,4-二氧 六环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌10h。经TLC(PE/EA=1/1) 检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰq)。
目标产物(Ip)的表征结果:白色粉状固体;收率83%;熔点:193.2-193.5℃。1HNMR (400MHz,DMSO–d6)δ9.64(s,1H,NH),8.96(s,1H,NH),8.54(d,J=4Hz,1H,ArH),8.06(m,1H,ArH),7.72(m,2H,ArH),7.65(m,1H,ArH),7.63(m,2H,ArH),7.54(m,1H,ArH), 7.40(m,1H,ArH),6.41(m,1H,ArH),2.58(s,3H,CH3),2.28(s,6H,CH3).13C NMR(100 MHz,DMSO–d6)δ:162.4,159.8,159.0,156.3,149.9,147.5,146.1,138.0,137.3,135.8,132.9,126.8,120.8,120.2,118.7,118.4,101.8,99.2,24.6,18.8.HRMS(ESI-):m/z calcd forC25H21N6 [M-H]-405.1833,found 405.1831.HPLC analysis:retention time=6.70min;peak area,99.07% (λ=254nm)。
实施例18:目标产物(Ⅰr)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.10mmol)和2-氟-4-吡啶硼酸(2.5mmol)加入到1,4-二氧六 环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1)检 测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相 经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰr)。
目标产物(Ir)的表征结果:白色粉状固体;收率81%;熔点:254.5-254.9℃。1HNMR (400MHz,DMSO–d6)δ9.63(s,1H,NH),8.97(s,1H,NH),8.34(d,J=4Hz,1H,ArH), 8.07-8.05(m,2H,ArH),7.77-7.76(m,2H,ArH),7.73(s,3H,ArH),7.60(s,1H,ArH),7.46-7.43(m,1H,ArH),6.41(m,1H,ArH),2.28(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:165.8,163.5,162.3,159.8,153.3(d,JC-F=8Hz),148.5(d,JC-F=17Hz),146.0,137.4,133.0,127.1, 120.1,119.9,119.9,118.4,107.0,106.6,101.8,99.3,18.8.HRMS(ESI-):m/zcalcd for C24H18FN6[M-H]-409.1582,found 409.1582.HPLC analysis:retention time=6.61min;peak area,99.93%(λ=254nm)。HPLC:tR=6.37min,97.99%,(λ=254nm)。
实施例19:目标产物(Ⅰs)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.02mmol)和2-三氟甲基-4-吡啶硼酸(3.3mmol)加入到1,4- 二氧六环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1) 检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相 经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰs)。
目标产物(Is)的表征结果:白色粉状固体;收率76%;熔点:207.7-208.5℃。1HNMR (400MHz,DMSO–d6)δ9.66(s,1H,NH),9.00(s,1H,NH),8.87(d,J=4Hz,1H,ArH),8.27(m,1H,ArH),8.12(d,J=4Hz,1H,ArH),8.08(d,J=8Hz,1H,ArH),7.81(m,4H,ArH),7.45(m,2H,ArH),6.43(m,1H,ArH),2.32(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.3,159.8,156.4,151.2,149.4,147.9(q,JC-F=33Hz),146.0,137.6,134.1,132.9,127.2,126.4, 124.7,123.6,120.9,120.1,118.4,118.3,101.3,18.8.HRMS(ESI-):m/z calcdfor C25H18F3N6 [M-H]-459.1551,found 459.1544.HPLC analysis:retention time=7.46min;peak area,99.85% (λ=254nm)。
实施例20:目标产物(Ⅰt)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.03mmol)和2,6-二甲基-4-吡啶硼酸(1.2mmol)加入到1, 4-二氧六环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA= 1/1)检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL ×2)、饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有 机相经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰt)。
目标产物(It)的表征结果:白色粉状固体;收率80%;熔点:280.3-281.0℃。1HNMR (400MHz,DMSO–d6)δ9.60(s,1H,NH),8.93(s,1H,NH),8.04(m,2H,ArH),7.68(m,2H,ArH),7.60(s,2H,ArH),7.42(s,2H,ArH),7.37(m,1H,ArH),6.38(m,1H,ArH),2.52(s,6H,CH3),2.25(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.4,159.7,158.3,156.3,147.9,146.1,137.9,137.2,136.1,132.9,126.8,120.1,118.42,118.0,101.7,99.2,24.5,18.8.HRMS (ESI-):m/z calcd for C26H23N6[M-H]-419.1990,found 419.1977.HPLCanalysis:retention time =7.27min;peak area,99.73%(λ=254nm)。
实施例21:目标产物(Ⅰu)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和2,6-二氟-4-吡啶硼酸(5.0mmol)加入到四氢呋 喃(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1)检 测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰu)。
目标产物(Iu)的表征结果:白色粉状固体;收率88%;熔点:260.1-261.0℃。1HNMR (400MHz,DMSO–d6)δ9.61(s,1H,NH),8.95(s,1H,NH),8.04-8.02(m,2H,ArH),7.76(m,3H,ArH),7.59(m,2H,ArH),7.43-7.39(m,2H,ArH),6.38(m,1H,ArH),2.26(s,6H,CH3).13CNMR(100MHz,DMSO–d6)δ:165.7,165.5,164.5,163.3,163.1,162.0,160.3,158.6,148.2,139.6,135.2,129.6,122.4,120.6,106.4-106.0(dd,JC-F=13Hz,JC-F=13Hz),104.1,21.0.HRMS(ESI-):m/z calcd for C24H17F2N6[M-H]-427.1488,found 427.1482.HPLC analysis:retention time=7.54min;peak area,97.57%(λ=254nm)。
实施例22:目标产物(Ⅰv)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.02mmol)和3-氟-3-吡啶硼酸(2.2mmol)加入到1,4-二氧六 环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1)检 测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相 经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰv)。
目标产物(Iv)的表征结果:白色粉状固体;收率77%;熔点:242.4-242.9℃。1HNMR (400MHz,DMSO)δ9.61(s,1H,NH),8.94(s,1H,NH),8.90(s,1H,ArH),8.60(d,J=4Hz,1H,NH),8.14-8.10(m,1H,ArH),8.06-8.05(m,1H,ArH),7.77-7.74(m,2H,ArH),7.66(s,2H,ArH),7.43(m,2H,ArH),6.41(m,1H,ArH),2.28(s,6H,CH3).13C NMR(100MHz,DMSO –d6)δ:162.4,161.2,159.8,158.7,156.2,146.1,144.3,144.2,137.5(d,JC-F=26Hz),136.8,136.7(d,JC-F=23Hz),133.9,133.0,127.2,121.1(d,JC-F=19Hz),120.2,118.4,101.8,99.3, 18.8.HRMS(ESI-):m/z calcd for C24H18FN6[M-H]-409.1582,found 409.1576.HPLCanalysis: retention time=6.75min;peak area,98.76%(λ=254nm)。
实施例23:目标产物(Ⅰw)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.05mmol)和3-氟-3-吡啶硼酸(1.2mmol)加入到1,4-二氧六 环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1)检 测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相 经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰw)。
目标产物(Iw)的表征结果:白色粉状固体;收率95%;熔点:236.9-237.2℃。1HNMR (400MHz,DMSO)δ9.61(s,1H,NH),8.96(s,1H,ArH),8.93(s,1H,NH),8.64(d,J=4Hz,1H, ArH),8.30-8.29(m,1H,ArH),8.06-8.04(m,1H,ArH),7.75(m,2H,ArH),7.66(s,2H,ArH), 7.46-7.40(m,2H,ArH),6.41(m,1H,ArH),2.28(s,6H,CH3).13C NMR(100MHz,DMSO–d6) δ:162.4,159.8,156.2,147.1,146.3,146.1,137.7,137.4,137.2,133.9,133.2,133.0,132.0, 127.2,120.2,118.4,101.8,99.3,18.8.HRMS(ESI-):m/z calcd forC24H18ClN6[M-H]-425.1287, found 425.1281.HPLC analysis:retention time=7.66min;peak area,99.37%(λ=254nm)。
实施例24:目标产物(Ⅰx)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和3-甲基-5-吡啶硼酸(1.2mmol)加入到1,4-二氧六 环(5mL)中,经N2置换三次,调整反应温度至150℃,搅拌4h。经TLC(PE/EA=1/1) 检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰx)。
目标产物(Ⅰx)的表征结果:白色粉状固体;收率77%;熔点:257.8-258.2℃。1HNMR (400MHz,DMSO–d6)δ9.61(s,1H,NH),9.60(s,1H,NH),8.78(s,1H,ArH),8.45(s,1H,ArH),8.05-8.04(m,2H,ArH),7.96(s,1H,ArH),7.73(m,2H,ArH),7.57(s,2H,ArH), 7.40-7.37(m,1H,ArH),6.41(m,1H,ArH),2.41(s,3H,CH3),2.27(s,6H,CH3).13C NMR(100 MHz,DMSO–d6)δ:162.5,159.8,156.2,149.2,146.1,145.2,137.2,135.6,135.3,134.8,133.5,133.1,132.9,126.9,120.2,118.4,101.8,99.2,18.9,18.4.HRMS(ESI-):m/z calcd forC25H21N6 [M-H]-405.1833,found 405.1823.HPLC analysis:retention time=6.86min;peak area,99.62% (λ=254nm)。
实施例25:目标产物(Ⅰy)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和3-乙基-5-吡啶硼酸(1.0mmol)加入到1,4-二氧六 环(6mL)中,经N2置换三次,调整反应温度至80℃,搅拌4h。经TLC(PE/EA=1/1)检 测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相 经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰy)。
目标产物(Ⅰy)的表征结果:白色粉状固体;收率74%;熔点:204.3-204.7℃。1HNMR (400MHz,DMSO–d6)δ9.60(s,1H,NH),8.93(s,1H,NH),8.79(m,1H,ArH),8.47(s,1H,ArH),8.05-8.04(m,2H,ArH),7.98-7.97(m,1H,ArH),7.72(m,2H,ArH),7.58(s,2H,ArH),7.39(s,1H,ArH),6.40(s,1H,ArH),2.73(q,J=8Hz,2H,CH2),2.27(s,6H,CH3),1.29(t,J=8Hz,3H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.5,159.8,156.2,148.5,146.1,145.5,139.6,137.2,135.7,135.4,133.7,132.9,127.3,126.9,120.1,118.4,101.8,99.2,25.8,18.8,15.9. HRMS(ESI-):m/z calcd for C26H23N6[M-H]-419.1990,found 419.1989.HPLCanalysis: retention time=7.49min;peak area,99.81%(λ=254nm)。
实施例26:目标产物(Ⅰz)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和5-甲氧基-3-吡啶硼酸(8.0mmol)加入到甲苯(6mL) 中,经N2置换三次,调整反应温度至100℃,搅拌4h。经TLC(PE/EA=1/1)检测,原 料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、饱和 碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无 水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰz)。
目标产物(Ⅰz)的表征结果:白色粉状固体;收率77%;熔点:216.4-217.4℃。1HNMR (400MHz,DMSO–d6)δ9.62(s,1H,NH),8.93(s,1H,NH),8.26(d,J=8Hz,1H,ArH), 8.05-8.04(m,1H,ArH),7.73(m,2H,ArH),7.63(s,2H,ArH),7.42-7.36(m,3H,ArH),7.18(s, 1H,ArH),6.39(m,1H,ArH),3.94(s,3H,OCH3),2.27(s,6H,CH3).13C NMR(100MHz, DMSO–d6)δ:165.0,162.4,159.8,156.2,150.4,147.9,146.1,146.0,137.2,135.5,132.9,126.9,120.2,118.4,115.4,107.7,101.8,99.3,53.7,18.8.HRMS(ESI-):m/z calcd for C25H21N6O[M-H]-421.1782,found 421.1778.HPLC analysis:retention time=7.40min;peakarea,99.22% (λ=254nm)。
实施例27:目标产物(Ⅰaa)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和5-三氟甲基-3-吡啶硼酸(8.0mmol)加入到甲醇(6 mL)中,经N2置换三次,调整反应温度至110℃,搅拌24h。经TLC(PE/EA=1/1)检测, 原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、饱 和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经 无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰaa)。
目标产物(Ⅰaa)的表征结果:白色粉状固体;收率83%;熔点:268.7-269.2℃。1HNMR (400MHz,DMSO–d6)δ9.64(s,1H,NH),9.32(s,1H,ArH),9.00(s,1H,ArH),8.99(s,1H,NH),8.54(s,1H,ArH),8.09-8.07(m,2H,ArH),7.75(s,3H,ArH),7.44(m,2H,ArH),6.44(m,1H,ArH),2.32(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.4,159.8,156.2,151.9,146.1,145.1,137.5,136.0,133.6,131.3,128.3,127.3,126.0(q,JC-F=32Hz),122.8,120.1, 120.1,118.4,101.8,99.3,18.8.HRMS(ESI-):m/z calcd for C25H18F3N6[M-H]-459.1551,found 459.1549.HPLC analysis:retention time=7.85min;peak area,99.76%(λ=254nm)。
实施例28:目标产物(Ⅰab)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和5-氰基-3-吡啶硼酸(4.0mmol)加入到1,4-二氧六 环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌14h。经TLC(PE/EA=1/1) 检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰab)。
目标产物(Ⅰab)的表征结果:白色粉状固体;收率81%;熔点:243.1-243.5℃。1HNMR (400MHz,DMSO–d6)δ9.60(s,1H,NH),9.28(s,1H,ArH),9.03(d,J=4Hz,1H,NH),8.93(s, 1H,NH),8.73-8.72(m,1H,ArH),8.16-7.96(m,2H,ArH),7.90-7.70(m,4H,ArH),7.44(m, 1H,ArH),6.46-6.40(m,1H,ArH),2.28(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.4,159.8,156.2,151.5,151.2,146.0,137.8,137.4,135.7,133.4,133.0,127.6,127.2,120.2,118.4, 117.5,109.9,101.8,99.3,18.9.HRMS(ESI-):m/z calcd for C25H18N7[M-H]-416.1629,found 416.1623.HPLC analysis:retention time=5.96min;peak area,98.07%(λ=254nm)。
实施例29:目标产物(Ⅰac)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.05mmol)和4-氟-3-吡啶硼酸(4.0mmol)加入到1,4-二氧六环 (6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1)检测, 原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、饱 和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经 无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰac)。
目标产物(Ⅰac)的表征结果:白色粉状固体;收率76%;熔点:227.4-227.9℃。1HNMR (400MHz,DMSO–d6)δ9.61(s,1H,NH),8.93(s,1H,NH),8.64(s,1H,ArH),8.36-8.31(m,1H,ArH),8.07-8.06(m,2H,ArH),7.76(m,2H,ArH),7.57(m,2H,ArH),7.43(m,1H,ArH),7.30(dd,J=4Hz,J=4Hz,1H,ArH),6.42(m,1H,ArH),2.28(s,3H,CH3).13C NMR(100 MHz,DMSO–d6)δ:164.2,162.5,161.8,159.8,156.1,146.1,145.7(d,JC-F=25Hz),140.5(d, JC-F=18Hz),137.2,134.3,132.9,126.8,120.2,118.4,110.2,109.9,101.8,99.3,18.9.HRMS(ESI-):m/z calcd for C24H18FN6[M-H]-409.1582,found 409.1584.HPLC analysis:retention time=6.65min;peak area,99.81%(λ=254nm)。
实施例30:目标产物(Ⅰad)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.08mmol)和4-甲基-3-吡啶硼酸(8.0mmol)加入到1,4-二氧六 环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1)检 测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰad)。
目标产物(Ⅰad)的表征结果:白色粉状固体;收率80%;熔点:250.9-251.4℃。1HNMR(400MHz,DMSO–d6)δ9.61(s,1H,NH),8.92(s,1H,NH),8.84(s,1H,ArH),8.05(m, 2H,ArH),8.01(d,J=4Hz,1H,ArH),7.75-7.74(m,2H,ArH),7.54(s,2H,ArH),7.40(m,1H,ArH),7.35(d,J=8Hz,1H,ArH),6.41-6.40(m,1H,ArH),2.54(s,3H,CH3),2.26(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.5,159.8,157.2,156.1,147.2,146.1,137.1,136.8,135.5,134.6,132.9,126.8,126.5,123.6,120.2,118.4,101.8,99.3,24.1,18.9.HRMS(ESI-):m/z calcd for C25H21N6[M-H]-405.1833,found 405.1809.HPLC analysis:retention time=6.79min; peak area,99.60%(λ=254nm)。
实施例31:目标产物(Ⅰae)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和4-甲氧基-3-吡啶硼酸(1.2mmol)加入到1,4-二氧 六环(6mL)中,经N2置换三次,调整反应温度至100℃,搅拌4h。经TLC(PE/EA=1/1) 检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相 经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰae)。:
目标产物(Ⅰae)的表征结果:白色粉状固体;收率88%;熔点:218.6-218.9℃。1HNMR (400MHz,DMSO–d6)δ9.57(s,1H,NH),8.88(s,1H,NH),8.55(m,1H,ArH),8.07-8.04(m,3H, ArH),7.73(m,2H,ArH),7.49(s,2H,ArH),7.40(m,1H,ArH),6.93(d,J=8Hz,1H,ArH),6.39(m,1H,ArH),3.93(s,3H,OCH3),2.25(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ: 163.5,162.5,159.8,156.1,146.1,145.0,137.9,137.0,136.4,135.4,132.9,129.5,126.3,120.2, 118.4,111.0,101.8,99.3,53.7,18.9.HRMS(ESI-):m/z calcd for C25H21N6O[M-H]-421.1782, found 421.1778.HPLC analysis:retention time=7.62min;peak area,99.95%(λ=254nm)。
实施例32:目标产物(Ⅰaf)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和4-甲硫基-3-吡啶硼酸(1.2mmol)加入到甲醇(6 mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1)检测, 原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、饱 和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经 无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰaf)。
目标产物(Ⅰaf)的表征结果:白色粉状固体;收率92%;熔点:209.6-210.1℃。1HNMR (400MHz,DMSO–d6)δ9.59(s,1H,NH),8.91(s,1H,NH),8.85(s,1H,ArH),8.05(m,2H,ArH),8.00(d,J=8Hz,1H,ArH),7.76-7.74(m,2H,ArH),7.54(s,2H,ArH),7.40(d,J=8Hz,2H,ArH),6.41(m,1H,ArH),2.59(s,3H,SCH3),2.26(s,6H,CH3).13C NMR(100MHz, DMSO–d6)δ:162.5,159.8,158.6,156.1,147.5,146.1,137.2,136.8,135.2,134.8,132.9,131.5,126.4,121.4,120.2,118.4,101.8,99.3,18.9,13.3.HRMS(ESI-):m/z calcd for C25H21N6S[M-H]-437.1554,found 437.1548.HPLC analysis:retention time=7.88min;peakarea,96.02% (λ=254nm)。
实施例33:目标产物(Ⅰag)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.08mmol)和4-胺基-3-吡啶硼酸(1.2mmol)加入到1,4-二氧 六环(6mL)中,经N2置换三次,调整反应温度至170℃,搅拌4h。经TLC(PE/EA=1/1) 检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰag)。
目标产物(Ⅰag)的表征结果:白色粉状固体;收率92%;熔点:277.6-278.3℃。1HNMR(400MHz,DMSO–d6)δ9.57(s,1H,NH),8.85(s,1H,NH),8.34(s,1H,ArH),8.11-7.98 (m,2H,ArH),7.79-7.73(m,3H,ArH),7.41(s,3H,ArH),6.60(d,J=8Hz,1H,ArH),6.38(m, 1H,ArH),6.11(s,2H,NH),2.23(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.5, 159.8,159.6,157.5,156.0,146.1,137.2,136.8,136.6,135.8,132.8,125.3,124.2,120.2,118.4,108.5,101.7,99.2,18.9.HRMS(ESI-):m/z calcd for C24H20N7[M-H]-406.1786,found406.1786.HPLC analysis:retention time=5.32min;peak area,99.33%(λ=254nm)。
实施例34:目标产物(Ⅰah)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.10mmol)和4-N,N-二甲胺基-3-吡啶硼酸(1.2mmol)加入到1, 4-二氧六环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA= 1/1)检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL ×2)、饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有 机相经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰah)。
目标产物(Ⅰah)的表征结果:白色粉状固体;收率92%;熔点:289.2-290.1℃。1HNMR(400MHz,DMSO–d6)δ9.56(s,1H,NH),8.84(s,1H,NH),8.50(s,1H,ArH),8.10-7.97 (m,2H,ArH),7.86(d,J=8Hz,1H,ArH),7.75-7.73(m,2H,ArH),7.42-7.38(m,3H,ArH), 6.72(d,J=12Hz,1H,ArH),6.37(m,1H,ArH),3.08(s,6H,CH3),2.22(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.5,159.8,158.8,156.0,146.1,145.9,136.8,136.3,135.8,135.5, 132.9,125.4,123.5,120.2,118.4,106.2,101.7,99.3,38.2,19.0.HRMS(ESI-):m/z calcd for C26H24N7[M-H]-434.2099,found 434.2103.HPLC analysis:retention time=11.40min;peak area,99.22%(λ=254nm)。
实施例35:目标产物(Ⅰai)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.02mmol)和4-硝基苯硼酸(1.6mmol)加入到1,4-二氧六环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1)检测, 原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经 无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰai)。
目标产物(Ⅰai)的表征结果:白色粉状固体;收率92%;熔点:262.0-263.0℃。1HNMR (400MHz,DMSO–d6)δ9.60(s,1H,NH),8.94(s,1H,NH),8.33(d,J=8Hz,2H,ArH),8.02(m,3H,ArH),7.75-7.72(m,2H,ArH),7.63(s,2H,ArH),7.41-7.36((m,2H,ArH)),6.46-6.40(m,1H,ArH),2.27(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.4,159.8,156.2,147.0,146.8,146.1,137.4,136.1,132.9,128.1,127.4,127.3,124.5,120.1,118.4,101.8,99.3,18.8. HRMS(ESI-):m/z calcd for C25H19N6O2[M-H]-435.1569,found 435.1471.HPLCanalysis: retention time=8.16min;peak area,99.55%(λ=254nm)。
实施例36:目标产物(Ⅰaj)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和4-三氟甲基-3-吡啶硼酸(10.0mmol)加入到1, 4-二氧六环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA= 1/1)检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL ×2)、饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有 机相经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰaj)。
目标产物(Ⅰaj)的表征结果:白色粉状固体;收率90%;熔点:234.2-234.9℃。1HNMR (400MHz,DMSO–d6)δ9.65(s,1H,NH),9.19(s,1H,ArH),8.98(s,1H,NH),8.41(d,J=4Hz, 1H,ArH),8.08(m,2H,ArH),8.00(d,J=8Hz,1H,ArH),7.77-7.69(m,4H,ArH),7.45(m,1H, ArH),6.43(m,1H,ArH),2.30(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.4,159.8,156.2,148.6,146.1,145.5(q,JC-F=34Hz),139.0,137.5,136.2,133.9,133.0,127.3,123.7, 121.3(q,JC-F=3Hz),121.0,120.2,118.4,101.9,99.3,18.9.HRMS(ESI+):m/zcalcd for C25H18F3N6[M-H]-459.1551,found 459.1532.HPLC analysis:retention time=7.58min;peak area,99.56%(λ=254nm)。
实施例37:目标产物(Ⅰak)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.01mmol)和4-氰基-3-吡啶硼酸(5.0mmol)加入到1,4-二氧 六环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1) 检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰak)。
目标产物(Ⅰak)的表征结果:白色粉状固体;收率91%;熔点:245.9-246.6℃。1HNMR(400MHz,DMSO–d6)δ9.63(s,1H,NH),9.19(s,1H,ArH),8.97(s,1H,NH),8.41(d,J=4Hz,1H,ArH),8.15(d,J=4Hz,1H,ArH),8.07-8.06(m,1H,ArH),7.76-7.70(m,4H,ArH),7.50-7.45(m,2H,ArH),6.42(m,1H,ArH),2.29(s,6H,CH3).13C NMR(100MHz,DMSO–d6) δ:162.3,159.8,156.3,149.6,146.0,139.1,138.3,137.5,135.5,133.5,133.0,131.4,129.5, 127.4,120.2,118.4,118.2,101.8,99.3,18.89.HRMS(ESI-):m/z calcd forC25H18N7[M-H]- 416.1629,found 416.1617.HPLC analysis:retention time=6.13min;peak area,99.58%(λ=254 nm)。
实施例38:目标产物(Ⅰal)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.02mmol)和4-氟-5-甲基-3-吡啶硼酸硼酸(6.0mmol)加入到 1,4-二氧六环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA =1/1)检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20 mL×2)、饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰal)。
目标产物(Ⅰal)的表征结果:白色粉状固体;收率92%;熔点:244.5-244.8℃。1HNMR (400MHz,DMSO–d6)δ1H NMR(400MHz,DMSO)δ9.60(s,1H,NH),8.93(s,1H,NH),8.42 (s,1H,ArH),8.20(d,J=8Hz,1H,ArH),8.05(m,2H,ArH),7.74(m,2H,ArH),7.56(m,2H, ArH),7.41(m,1H,ArH),6.41(m,1H,ArH),2.36(s,3H,CH3),2.27(s,6H,CH3).13C NMR (100MHz,DMSO–d6)δ:13C NMR(101MHz,DMSO)δ162.8,162.5,160.5,159.8,156.1, 146.1,142.7(d,JC-F=15Hz),140.8(d,JC-F=6Hz),137.2,134.4,132.9,126.8,120.12,119.8, 119.5,118.4,101.8,99.3,18.9,14.5.HRMS(ESI-):m/z calcd for C25H20FN6[M-H]-423.1739,found 423.1740.HPLC analysis:retention time=7.43min;peak area,99.16%(λ=254nm)。
实施例39:目标产物(Ⅰam)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.03mmol)和2-甲基-4-嘧啶硼酸(7.0mmol)加入到1,4-二氧 六环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌10h。经TLC(PE/EA=1/1) 检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰam)。
目标产物(Ⅰam)的表征结果:白色粉状固体;收率92%;熔点:264.8-265.0℃。1HNMR(400MHz,DMSO–d6)δ9.57(s,1H,NH),9.07(m,2H,ArH),8.91(m,1H,NH),8.03(m, 2H,ArH),7.72(m,2H,ArH),7.62(m,2H,ArH),7.43(m,1H,ArH),6.38(m,1H,ArH),2.69(s, 3H,CH3),2.25(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:166.5,162.4,159.8,156.2, 155.0,146.1,137.4,133.0,132.4,130.2,126.9,126.6,120.2,118.4,101.8,99.3,25.8,18.9.HRMS(ESI-):m/z calcd for C24H20N7[M-H]-406.1786,found 406.1776.HPLC analysis:retention time=5.65min;peak area,100%(λ=254nm)。
实施例40:目标产物(Ⅰan)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.10mmol)和2-甲氧基-4-嘧啶硼酸(2.5mmol)加入到1,4- 二氧六环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1) 检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相 经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰan)。
目标产物(Ⅰan)的表征结果:白色粉状固体;收率90%;熔点:238.8-239.5℃。1HNMR(400MHz,DMSO–d6)δ9.61(s,1H,NH),9.00-8.93(m,3H,NH,ArH),8.06(m,2H,ArH), 7.77(m,2H,ArH),7.57(m,2H,ArH),7.45(m,1H,ArH),6.42(m,1H,ArH),4.01(s,3H, OCH3),2.27(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:165.0,162.4,159.8,157.6, 156.1,146.1,137.3,137.0,133,0,132.2,127.6,126.2,120.2,118.4,101.8,99.3,55.1,18.9. HRMS(ESI+):m/z calcd for C24H20N7O[M-H]-422.1735,found 422.1725.HPLC analysis:retention time=6.35min;peak area,99.91%(λ=254nm)。
实施例41:目标产物(Ⅰao)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.02mmol)和2-氰基-5-嘧啶硼酸(3.3mmol)加入到1,4-二氧 六环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1) 检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰao)。
目标产物(Ⅰao)的表征结果:白色粉状固体;收率91%;熔点:258.9-259.4℃。1HNMR(400MHz,DMSO–d6)δ9.65(s,1H,NH),9.45(m,2H,ArH),8.99(s,1H,NH),8.07(m, 1H,ArH),7.79(m,4H,ArH),7.51(m,2H,ArH),6.45(m,1H,ArH),2.30(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.3,159.8,156.3,146.0,142.7,139.0,137.7,135.6,133.0,132.1,130.5,127.4,120.2,118.4,116.8,101.9,99.5,18.9.HRMS(ESI-):m/z calcd forC24H17N8[M-H]-417.1582,found 417.1575.HPLC analysis:retention time=6.20min;peak area,95.72%(λ=254nm)。
实施例42:目标产物(Ⅰap)的制备
室温下,将4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈(1.0mmol),碳 酸铯(2.0mmol),Pd(dppf)Cl2(0.03mmol)和2-三氟甲基-5-嘧啶硼酸(1.2mmol)加入到1,4- 二氧六环(6mL)中,经N2置换三次,调整反应温度至110℃,搅拌4h。经TLC(PE/EA=1/1) 检测,原料消失,反应完全。调整反应温度至室温,依次用饱和亚硫酸钠溶液(20mL×2)、 饱和碳酸钠溶液(20mL×2)、水(20mL×2)、饱和食盐水(20mL×2)洗涤,有机相 经无水硫酸钠干燥过夜。过滤,浓缩,甲醇重结晶,得到固体—目标化合物(Ⅰap)。
目标产物(Ⅰap)的表征结果:白色粉状固体;收率92%;熔点:263.6-264.3℃。1HNMR(400MHz,DMSO–d6)δ9.63(s,1H,NH),9.48(m,2H,ArH),8.98(s,1H,NH),8.07(m, 1H,ArH),7.78(m,4H,ArH),7.48(m,2H,ArH),6.41(m,1H,ArH),2.30(s,6H,CH3).13C NMR(100MHz,DMSO–d6)δ:162.3,159.8,156.3,154.6-153,5(q,JC-F=34Hz,JC-F=36Hz,),146.0, 137.6,135.5,133.0,127.4,124.4,121.7,120.2,119.0,118.4,116.2,101.9,99.2,18.9.HRMS (ESI-):m/z calcd for C24H17F3N7[M+H]+460.1503,found 460.1502.HPLCanalysis:retention time=7.33min;peak area,99.94%(λ=254nm)。
实施43:化合物的成盐改造及水溶性测量
对化合物进行成盐改造,并通过标准曲线法对成盐产物进行多pH范围的水溶性测量。
成盐复合物的制备:在室温或加热条件下,使某一完全在溶剂中完全溶解,随后加入 待成盐的酸,于N2保护下搅拌18-48h,直至有大量固体析出。过滤即得该分子的成盐复合物。此处所选溶剂为甲醇、乙醇、正丙醇、异丙醇、正丁醇、二氯甲烷、二氯乙烷、四 氢呋喃、***、甲基叔丁基醚、乙酸乙酯,正己烷、环己烷、石油醚中的一种或者多种。 以下以4-吡啶基取代的化合物为例具体阐述盐酸盐的制备方法及水溶性测试结果。
在33℃下,将4-吡啶基取代Ⅰe(100mg)溶于15ml乙酸乙酯中,加入10滴酸,于 33℃搅拌24h。待有大量固体析出,过滤,获得目标物的成盐复合物。分别取该复合物5-10mg, 依次加入pH=2.0、7.0、7.4的缓冲液水溶液种,并于20~25℃下搅拌超过18h,滤取上清 液,经反相HPLC分析,测试该复合物在多种pH范围下的水溶性。其水溶性结果如下:
表1.化合物Ⅰe及其成盐复合物水溶性结果
实施例44:抗HIV生物活性测试
体外细胞水平的抗HIV病毒活性由比利时Katholleke大学的Rega药物研究所测定, 主要包括:对HIV感染的MT-4细胞的抑制活性及细胞毒性两方面。方法如下:使化合物在HIV感染的MT-4细胞中,于感染HIV不同时间,用MTT法测定药物对HIV诱变的细 胞病变的保护作用,计算使50%的细胞免于HIV诱导的细胞病变所需的浓度半数有效浓度 EC50,毒性测定与抗HIV活性实验平行进行,也是在MT-4细胞培养中,用MTT法测定 使50%的未感染细胞发生细胞病变的浓度(CC50),并计算选择性指数SI=CC50/EC50。
材料与方法:
各化合物的抗HIV活性由药物对HIV在细胞中引起的细胞病变的抑制作用效率来监 控。采用MT-4细胞进行细胞培养。采用的病毒株有:HIV-1病毒株ⅢB及HIV-2病毒株ROD。
具体操作如下:将化合物用DMSO或水溶解后在磷酸盐缓冲食盐水溶液稀释,将3×105 MT-4细胞用100μL各化合物不同浓度此溶液在37℃预培养1h,然后向该化合物中加入100μL适当的病毒稀释液,将细胞于37℃培养1h。洗涤三次后,将细胞再次分别悬浮于 含有或不含有化合物的培养介质中。接着将细胞在5%CO2氛围中,于37℃下再培养7天, 并于感染后第三天用含有或不含有化合物的培养介质替换补充培养液。每种培养液条件重 复操作两次。对病毒的细胞病变作用每天都用反向光学显微镜监控。典型来讲,本实验中 所用的病毒稀释液常常会在病毒感染后第五天导致细胞病变。药物抑制浓度以药物对病毒 细胞病变作用产生50%抑制作用而同时对细胞无直接毒性的浓度(CC50)表示。需要强调的是,当化合物水溶性较差,需要DMSO才能溶解时,DMSO比浓度相对于水来讲,一般 低于10%(DMSO在MT-4细胞培养介质中最终浓度小于2%)。因为DMSO能影响测试化 合物的抗病毒活性,对含有相同浓度DMSO溶液抗病毒活性对比空白实验也应该平行进行。 另外,DMSO最终浓度(1/1000)远远低于HIV-1在T细胞中复制所需的浓度。
本发明用已上市药物奈维拉平(Nevirapine,NVP)、依非韦伦(Efavirenz,EFV)和依曲韦 林(Etravirine,ETV)作对照品,部分目标化合物对HIV的抑制活性结果见表2(化合物 Ⅰa-Ⅰap在MT-4细胞中的抗HIV活性及细胞毒性)。
表2[a]
a所有数据代表至少三个独立实验的平均值;bEC50:使50%的细胞免受病毒感染的有效浓度; cCC50:使50%的细胞发生病变时的药物浓度;dSI:选择指数,CC50值与EC50值的比值,用 于判断药物效果的安全范围。
实验结果表明,化学通式(I)中所包含的化合物普遍具有较强的抗HIV-1病毒活性, 可以显著的抑制被HIV-1病毒感染的MT-4细胞内的病毒复制,并且具有较小的细胞毒性 和较高的选择性指数。
需要说明的是,尽管在本文中已经对上述各实施例进行了描述,但并非因此限制本发 明的专利保护范围,其中未尽详细描述的技术参数和原料组分在本发明列举的参数范围内 变化时,仍能够得到与上述实施例相同或相近的技术效果,仍属与本发明的保护范围。因 此,基于本发明的创新理念,对本文所述实施例进行的变更和修改,或利用本发明说明书 内容所作的等效结构或等效流程变换,直接或间接地将以上技术方案运用在其他相关的技 术领域,均包括在本发明的专利保护范围之内。
Claims (6)
2.根据权利要求1所述含芳杂环结构的二甲基联苯二芳基嘧啶类衍生物,其特征在于,还包括其药用盐,其立体化学异构体,其水合物和溶剂化物,其多晶或共晶及单一对映体的X射线衍射单晶,其同样生物功能的前体和衍生物。
3.根据权利要求2所述含芳杂环结构的二甲基联苯二芳基嘧啶类衍生物,其特征在于,所述药用盐,包括盐酸盐、氢溴酸盐、甲酸盐、甲磺酸盐、三氟甲磺酸盐、硫酸盐、磷酸盐、醋酸盐、对甲苯磺酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、马来酸盐、富马酸盐或苹果酸盐,以及药学上可接受的前体药物和衍生物。
4.如权利要求1所述的含芳杂环结构的二甲基联苯二芳基嘧啶类的制备方法,其特征在于,具体步骤为:
在溶剂中,化合物II(4-((4-((4-溴-2,6-二甲基苯基)(甲基)胺基)嘧啶-2-)胺基)苯腈)在Pd(dppf)Cl2、Cs2CO3的作用下经Suzuki-偶联反应,得到所述化合物I,其反应通式如下:
其中,所用溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、二氯甲烷、二氯乙烷、甲苯、四氢呋喃、***、异丙醚、甲基叔丁基醚、1,4-二氧六环、乙酸乙酯中的一种或者多种;
化合物II与杂环硼酸的摩尔比为1:1-1:8;
化合物II与Pd(dppf)Cl2的摩尔比为1:0.01-1:0.10;
化合物II与Cs2CO3的摩尔比为1:1-1:2;
Suzuki-偶联反应温度为40~180℃,反应时间为4~24h。
5.一种药物组合物,其用于预防和治疗艾滋病,其特征在于,所述药物组包含如权利要求1-3所述的任一含芳杂环结构的二甲基联苯二芳基嘧啶类衍生物以及相关药用载体。
6.根据权利要求5所述的药物组合物,其特征在于,采用所述含芳杂环的二芳基嘧啶类化合物作为活性成分制备得到的药物组合物。
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