CN111004169B - 一种多取代吡啶衍生物的合成方法及用途 - Google Patents

一种多取代吡啶衍生物的合成方法及用途 Download PDF

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CN111004169B
CN111004169B CN201911363454.4A CN201911363454A CN111004169B CN 111004169 B CN111004169 B CN 111004169B CN 201911363454 A CN201911363454 A CN 201911363454A CN 111004169 B CN111004169 B CN 111004169B
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李葆生
张远
罗翰
卢棋星
徐鸣川
安峤宇
唐宗元
李珊珊
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Chongqing University
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Abstract

本发明属于有机化学合成领域，涉及一种多取代吡啶衍生物的合成方法及用途，该方法以,2,3‑三嗪类化合物和酮类化合物为反应底物，能够在催化量的碱作用下仅通过一步反应合成多取代的吡啶，反应中不涉及到危险及管制药品的使用，为合成多取代吡啶提供了一种简单、安全、高效和环保的途径。本发明反应还可用于药物分子的合成，如一步合成药物分子依托考昔及其衍生物，此外，本发明所得产物经过进一步衍生化，还能够得到多种类型的含吡啶官能团活性分子，如二步合成活性分子2‑SORA。

Description

一种多取代吡啶衍生物的合成方法及用途
技术领域
本发明属于有机合成化学领域，具体涉及一种多取代吡啶衍生物的合成方法及用途。
背景技术
吡啶是最简单的含氮芳香杂环结构，这也意味着吡啶化合物是最普遍存在且重要的一类含氮芳香杂环化合物。该结构单元广泛存在于许多天然产物、药物、生物活性分子、有机催化剂和配体中，具有重要科研意义。
含吡啶结构的天然产物、药物分子和活性分子中普遍存在着C3、C5取代的吡啶衍生物，例如已经上市的药物依托考昔(Etoricoxib)和有效的orexin 2受体拮抗剂等就含有2,3-二取代或2,3,5-三取代吡啶，在这些重要的药物分子和生物活性分子中，无论是哪一种取代基被首先引入，都会因为受到不利去向效应或电子效应的影响而难以选择性地实现后续转化，相对于吡啶的C2、C4和C6位，吡啶的C3、C5直接功能化的挑战更大。
为此，Boger(Boger,D.L.Chem.Rev.1986,86,781)、Okatani(Okatani,T.；Koyama,J.；Tagahara,K.Heterocycles 1989,29,1809)、Igeta(Igeta,H.Chem.Pharm.Bull.1985,33,3050.)和Neunhoeffer(Neunhoeffer,H.；Clausen,M.；Voetter,H.；Ohl,H.；Krueger,C.；Angermund,K.Liebigs Ann.Chem.1985,1732.)等做出了开创性的贡献，他们从三嗪出发，可制备出C3、C5取代的吡啶衍生物，这一合成方法大大地提高了芳香杂环分子的合成效率，具有重要的意义，但遗憾的是，这些研究工作中，都需要使用高活性且难制备的分子，例如烯胺、炔胺等，这些活性组分需要繁琐的合成工艺，再加之对储藏和运输的高要求，使得该反应方法很难实现工艺化。
发明内容
本发明提出了一种多取代吡啶及其衍生物的一步合成方法，所述的“多取代”是指吡啶被两个及以上官能团所取代。该方法以1,2,3-三嗪和酮为反应物，能够在催化量的碱作用下仅通过一步反应合成多取代的吡啶，反应中不涉及到危险及管制药品的使用，为合成多取代吡啶提供了一种简单、安全、高效的途径，反应方程通式一为：
Figure BDA0002337796040000021
其中R1、R2可为烷基、芳基、卤素、酯基、氢等，使得反应物三嗪包括但不限于1,2,3-三嗪、4-溴-1,2,3-三嗪、5-溴-1,2,3-三嗪、4-甲基-1,2,3-三嗪、5-甲基-1,2,3-三嗪、4-溴-5-甲基-1,2,3-三嗪、5-溴-4-甲基-1,2,3-三嗪、4,5-二溴-1,2,3-三嗪、4,5-二甲基-1,2,3-三嗪、1,2,3-三嗪-5-羧酸乙酯、5-氯-1,2,3-三嗪、5-硝基-1,2,3-三嗪、5-苯基-1,2,3-三嗪中的一种。
R3为吸电子基团，选自硝基、三卤甲基、氰基、磺酰基、酰胺、酯基、膦酯、含吸电子基团的芳基、卤素、吡啶基。R4为烷基、烯基、炔基、芳基、卤素、醛、酮、酯磺酸、醇、酚、醚、硝基、氰基、巯基、膦酯、磺酰基中的一种。进一步地，R4不能为氨基。
上述反应所用的碱试剂选自N甲基哌啶、N-甲基吗啡啉、三乙烯二胺(DABCO)、三乙胺、氟化铯、氢氧化钠、叔丁醇钾、氢化钠、甲醇钠、碳酸钾、碳酸氢钾、氢氧化钾、磷酸钾、磷酸钠、碳酸钙、碳酸氢钙、碳酸氢钠、乙酸铯、二甲胺、吡啶中的一种，优选氢氧化钾。
上述反应溶剂选自乙酸乙酯、苯甲醚、乙醚、乙二醇二甲醚、二苯醚、二氯甲烷、三氯甲烷、1,2-二氯乙烷、均三甲苯、苯、氟苯、氯苯、溴苯、乙腈、丙酮、二甲亚砜、N,N-二甲基甲酰胺、四氢呋喃、1,4-二氧六环、乙醚中的一种，优选乙腈。
上述反应的合成步骤为：在干燥的真空反应容器中，加入1,2,3-三嗪类化合物a，酮类化合物b和碱试剂，氮气置换三次实现氮气保护氛围，然后加入溶剂，反应容器在恒温条件下，反应期间用TLC跟踪，终止反应后，经萃取，分离有机相，干燥后采用真空浓缩有机相，然后经过柱层析得到目标产物，并计算收率。
上述反应物1,2,3-三嗪类化合物a、酮类化合物b和碱试剂的摩尔比为1:0.5～2.0:1～2，1,2,3-三嗪类化合物的浓度为0.05～0.50M，反应温度为-20℃～100℃，优选80℃。
上述反应通式，通过选择含有不同取代基组合的反应底物，能够制备出双取代吡啶、三取代吡啶和四取代吡啶等多种不同取代基数量的多取代吡啶衍生物。
上述反应通式，通过选择R4为含单吡啶基团的取代基，能够一步制备出二联吡啶和三联吡啶衍生物。
根据本发明提供的多取代吡啶衍生物合成方法得到的产物经过偶联、水解、酰化、卤化、还原等进一步衍生化，能够得到多种类型的含吡啶衍生产物，可以用于药物的制备，例如可以用于依托考昔(Etoricoxib)及其衍生物的制备，当R1、R2为烷基、卤素、氢，R3和R4为芳基时，一步反应即可得到药物分子依托考昔及其衍生物d，其收率为85％～95％，而且依托考昔可以克级规模合成。反应通式二为：
Figure BDA0002337796040000031
上述反应试剂商业化可得。
还可以用于有治疗失眠症效果的活性分子2-SORA(Selective Orexin 2ReceptorAntagonist)的制备，当R3和R4分别为吡啶基和酯基时，经过上述通式一反应获得多取代吡啶产物c，而后对c使用胺试剂酰化后得到含酰胺类联吡啶衍生物e，化合物e(当R1为氢,R2为卤素时)与硼酸偶联后，二步反应得到有治疗失眠症效果的活性分子f(2-SORA)。反应通式三为：
Figure BDA0002337796040000032
上述反应试剂商业化可得。
本发明取得的有益效果有：
(1)本发明从酮出发，在催化量的碱作用下异构为烯醇结构，再与1,2,3-三嗪发生环加成反应，可一步合成多取代吡啶及其类似物，提供了一种简单、高效、环保的合成方法，产率高，反应原料易得，方法适用性广泛。
(2)本发明不涉及贵金属催化剂，环境友好，绿色安全。
(3)本发明反应条件容易控制，反应温和，副反应少。
(4)本发明反应可用于药物分子的合成，如一步合成药物分子依托考昔(Etoricoxib)及其衍生物。
(5)本发明所得产物经过进一步衍生化，能够得到多种类型的含吡啶衍生活性分子，如二步合成活性分子2-SORA。
附图说明
图1为实施例12中产物1d(依托考昔)的克级合成产物。
图2为实施例12中产物1d(依托考昔)的氢谱谱图。
图3为实施例12中产物1d(依托考昔)的碳谱谱图。
具体实施方式
下面结合附图和具体实施方式对本发明内容作进一步说明。
本发明的反应通式一为：
Figure BDA0002337796040000041
实施例1
Figure BDA0002337796040000042
Figure BDA0002337796040000043
Figure BDA0002337796040000051
上述反应中，除非特别说明，反应物的用量为：氮气氛围下，1a:1b:碱＝1:1.5:0.5
在反应条件筛选过程中，考察了碱对反应的影响(标号1-9)，溶剂对反应的影响(标号10-16)，温度对反应的影响(标号17-23)。最终确定了KOH为最佳碱，MeCN为最佳溶剂，80℃为最佳温度。
上述标号21的反应步骤为：在10mL的真空管中，加入5-溴-1,2,3-三嗪3a(15.9mg,0.10mmol)，乙酰乙酸甲酯1b(17.4mg,0.15mmol)和KOH(2.8mg,0.05mmol)。氮气置换三次，然后加入0.5mL MeCN，将反应管置于80℃下反应8h。用TLC跟踪反应，终止反应后，加入MeCN(3x 10mL)进行萃取，分离有机相，用Na2SO4干燥，真空浓缩有机相，然后经过柱层析得到目标产物1c，收率(19.7mg,86％)。
在其他条件固定的情况下，仅考察碱的用量对反应收率的影响，以1a和1b反应生成1c为例，反应方程式如下：
Figure BDA0002337796040000061
3a(0.10mmol)，1b(0.15mmol)KOH(0.01mmol)，1c yield：60％-70％。
3a(0.10mmol)，1b(0.15mmol)KOH(0.05mmol)，1c yield：80％-86％。
3a(0.10mmol)，1b(0.15mmol)KOH(0.10mmol)，1c yield：75％-85％。
3a(0.10mmol)，1b(0.15mmol)KOH(0.15mmol)，1c yield：70％-80％。
3a(0.10mmol)，1b(0.15mmol)KOH(0.20mmol)，1c yield：65％-75％。
实施例2-3为二取代吡啶的合成
实施例2：(R1、R2为氢，R3为甲酯基，R4为甲基)
2-甲基烟酸甲酯(化合物2c)的合成
在10mL的真空管中，加入1,2,3-三嗪2a(8.1mg,0.10mmol)，乙酰乙酸甲酯1b(17.4mg,0.15mmol)和KOH(2.8mg,0.05mmol)。氮气置换三次，然后加入0.5mL MeCN，将反应管置于80℃下反应8h。用TLC跟踪反应，终止反应后，加入CH2Cl2进行萃取，分离有机相，用Na2SO4干燥，真空浓缩有机相，然后经过柱层析得到目标产物2c，收率(13.9mg,92％)。
实施例3：(R1、R2、R3为氢，R4为苯基，R5为氰基)
2-苯基烟腈(化合物3c)的合成
在10mL的真空管中，加入1,2,3-三嗪1a(8.1mg,0.10mmol)，3-氧代-3-苯基丙腈2b(21.8mg,0.15mmol)和KOH(2.8mg,0.05mmol)。氮气置换三次，然后加入0.5mL MeCN，将反应管置于80℃下反应8h。用TLC跟踪反应，终止反应后，加入CH2Cl2进行萃取，分离有机相，用Na2SO4干燥，真空浓缩有机相，然后经过柱层析得到目标产物3c，收率(16.4mg,91％)。经NMR检测，结果为：1H NMR(500MHz,CDCl3)δ8.90–8.89(m,1H),8.10(dd,J＝8.0,1.5Hz,1H),7.94–7.92(m,2H),7.56–7.53(m,3H),7.40(dd,J＝8.0,5.0Hz,1H)；13C NMR(125MHz,CDCl3)δ163.0,152.7,141.8,133.1,130.3,128.9,128.7,121.5,117.6,110.7。
在上述实施例2-3反应条件和操作的基础上，仅改变底物，得到如下结构式的化合物：
Figure BDA0002337796040000071
实施例4-5为三取代吡啶的合成
实施例4：(R1为氢，R2为氯，R3为甲酯基，R4苯基)
5-溴-2-苯基烟酸甲酯(化合物13c)的合成
在10mL的真空管中，加入5-溴-1,2,3-三嗪1a(15.9mg,0.10mmol)，3-氧代-3-苯基丙酸甲酯3b(26.9mg,0.15mmol)和KOH(2.8mg,0.05mmol)。氮气置换三次，然后加入0.5mLMeCN，将反应管置于80℃下反应8h。用TLC跟踪反应，终止反应后，加入CH2Cl2(3x 10mL)进行萃取，分离有机相，用Na2SO4干燥，真空浓缩有机相，然后经过柱层析得到目标产物13c，收率(24.8mg,85％)。
实施例5：(R1为氢，R2为甲基，R3为氰基，R4为苯基)
5-甲基-2-苯基烟腈(化合物15c)的合成
在10mL的真空管中，加入5-甲基-1,2,3-三嗪3a(9.5mg,0.1.0mmol)，3-氧代-3-苯基丙腈2b(17.4mg,0.15mmol)和KOH(2.8mg,0.05mmol)。氮气置换三次，然后加入0.5mLMeCN，将反应管置于80℃下反应8h。用TLC跟踪反应，终止反应后，加入CH2Cl2(3x 10mL)进行萃取，分离有机相，用Na2SO4干燥，真空浓缩有机相，然后经过柱层析得到目标产物15c，收率(13.8mg,71％)。经NMR检测，结果为：1H NMR(500MHz,CDCl3)δ8.63(s,1H),7.84–7.80(m,3H),7.47–7.42(m,3H),2.37(s,3H)；13C NMR(125MHz,CDCl3)δ158.3,153.4,141.8,137.1,131.6,129.9,128.7,128.6,117.8,106.9,17.76；HRMS m/z(ESI)calcd for C13H11N2(M+H)+195.0917,found 195.0920。
在上述实施例4-5反应条件和操作的基础上，仅改变底物，得到如下结构式的化合物：
Figure BDA0002337796040000081
实施例6-7为四取代吡啶的合成
实施例6：(R1为甲基，R2为溴，R3为甲酯基，R4为甲基)
5-溴-2,6-二甲基烟酸甲酯(化合物41c)的合成
在10mL的真空管中，加入5-溴-4-甲基-1,2,3-三嗪4a(17.3mg,0.10mmol)，乙酰乙酸甲酯1b(17.4mg,0.15mmol)和KOH(2.8mg,0.05mmol)。氮气置换三次，然后加入0.5mLMeCN，将反应管置于80℃下反应8h。用TLC跟踪反应，终止反应后，加入CH2Cl2(3x 10mL)进行萃取，分离有机相，用Na2SO4干燥，真空浓缩有机相，然后经过柱层析得到目标产物43c，收率(22.4mg,92％)。
实施例7：(R1为甲基，R2为溴，R3为氰基，R4为苯基)
5-溴-6-甲基-2-苯基烟腈(化合物42c)的合成
在10mL的真空管中，加入5-溴-4-甲基-1,2,3-三嗪4a(17.3mg,0.10mmol)，3-氧代-3-苯基丙腈2b(21.8mg,0.15mmol)，(21.8mg,0.15mmol)和KOH(2.8mg,0.05mmol)。氮气置换三次，然后加入0.5mL MeCN，将反应管置于80℃下反应8h。用TLC跟踪反应，终止反应后，加入CH2Cl2(3x 10mL)进行萃取，分离有机相，用Na2SO4干燥，真空浓缩有机相，然后经过柱层析得到目标产物44c，收率(25.4mg,91％)。经NMR检测，结果为：1H NMR(500MHz,CDCl3)δ8.07(s,1H),7.84–7.82(m,2H),7.45–7.44(m,3H),2.72(s,3H)；13C NMR(126MHz,CDCl3)δ161.9,158.9,144.3,136.4,135.3,130.4,128.8,119.0,116.6,105.9,25.7；HRMS m/z(ESI)calcd for C13H10BrN2(M+H)+273.0022,found 273.0023。
在上述实施例6-7反应条件和操作的基础上，仅改变底物，得到如下结构式的化合物：
Figure BDA0002337796040000091
实施例8-9为二联吡啶的合成
Figure BDA0002337796040000092
实施例8：(R1为氢，R2为氯，R3为甲酯基，R4为吡啶基)
5-氯-[2,2'-联吡啶]-3-羧酸甲酯(化合物53c)的合成
在10mL的真空管中，加入5-氯-1,2,3-三嗪5a(11.5mg,0.1mmol)，3-氧-3-(吡啶-2-基)丙酸甲酯4b(26.9mg,0.15mmol)和KOH(2mg,0.05mmol)。氮气置换三次，然后加入0.5mL MeCN，将反应管置于80℃下反应8h。用TLC跟踪反应，终止反应后，加入CH2Cl2(3x10mL)进行萃取，分离有机相，用Na2SO4干燥，真空浓缩有机相，然后经过柱层析得到目标产物53c，收率(22.8mg,92％)。
实施例9：(R1为甲基，R2为溴，R3为甲酯基，R4吡啶基)
5-溴-6-甲基-[2,2'-联吡啶]-3-羧酸甲酯(化合物54c)的合成
在10mL的真空管中，加入5-溴-4-甲基-1,2,3-三嗪4a(17.3mg,0.1mmol)，3-氧-3-(吡啶-2-基)丙酸甲酯4b(26.9mg,0.15mmol)和KOH(2mg,0.05mmol)。氮气置换三次，然后加入0.5mL MeCN，将反应管置于80℃下反应8h。用TLC跟踪反应，终止反应后，加入CH2Cl2(3x10mL)进行萃取，分离有机相，用Na2SO4干燥，真空浓缩有机相，然后经过柱层析得到目标产物54c，收率(26.6mg,87％)。经NMR检测，结果为：1H NMR(500MHz,CDCl3)δ8.52(d,J＝3.5Hz,1H),8.02(t,J＝3.5Hz,2H),7.75(t,J＝8.0Hz,1H),7.24(t,J＝5.5Hz,1H),3.71(s,3H),2.69(s,3H)；13C NMR(125MHz,CDCl3)δ167.9,158.6,155.6,153.6,148.5,140.4,136.7,127.0,123.7,122.6,120.4,52.5,25.1；HRMS m/z(ESI)calcd for C13H12BrN2O2(M+H)+307.0082,found 307.0089。
在上述实施例8-9反应条件和操作的基础上，仅改变底物，得到如下结构式的化合物：
Figure BDA0002337796040000101
实施例10-11为三联吡啶的合成
Figure BDA0002337796040000102
实施例10：(R1为氢，R2为溴，R3为乙酯基，R4为3-氧-3-(吡啶-2-基)丙酸乙酯基)
5,5”-二溴-[2,2'：6'，2”-叔吡啶]-3,3”-二羧酸二乙酯(化合物63c)的合成
在10mL的真空管中，加入5-溴-1,2,3-三嗪3a(15.9mg,0.10mmol)，3,3'-(吡啶-2,6-二吡啶)双(3-氧代丙酸)二乙酯5b(46.1mg,0.15mmol)和KOH(2.8mg,0.05mmol)。氮气置换三次，然后加入0.5mL MeCN，将反应管置于80℃下反应8h。用TLC跟踪反应，终止反应后，加入CH2Cl2(3x 10mL)进行萃取，分离有机相，用Na2SO4干燥，真空浓缩有机相，然后经过柱层析得到目标产物63c，收率(42.6mg,80％)。经NMR检测，结果为：1H NMR(500MHz,CDCl3)δ8.79(d,J＝2.0Hz,2H),8.15(d,J＝2.5Hz,2H),8.07(d,J＝7.5Hz,2H),8.00(dd,J＝8.5,7.0Hz,1H),3.90(q,J＝7.0Hz,4H),0.90(t,J＝7.0Hz,6H)；13C NMR(125MHz,CDCl3)δ166.3,154.8,154.2,151.2,139.7,137.6,129.8,122.9,119.9,61.6,13.5；HRMS m/z(ESI)calcdfor C21H18Br2N3O4(M+H)+533.9664,found 533.9664.
实施例11：(R1为甲基，R2为溴，R3为氢，R4为3-氧-3-(吡啶-2-基)丙酸乙酯基，R5为乙酯基)
5,5”-二溴-6,6”-二甲基-[2,2'：6'，2”-叔吡啶]-3,3”-二羧酸二乙酯(化合物64c)的合成
在10mL的真空管中，加入5-溴-4-甲基-1,2,3-三嗪4a(17.3mg,0.10mmol)，3,3'-(吡啶-2,6-二吡啶)双(3-氧代丙酸)二乙酯5b(46.1mg,0.15mmol)和KOH(2.8mg,0.05mmol)。氮气置换三次，然后加入0.5mL MeCN，将反应管置于80℃下反应8h。用TLC跟踪反应，终止反应后，加入CH2Cl2(3x 10mL)进行萃取，分离有机相，用Na2SO4干燥，真空浓缩有机相，然后经过柱层析得到目标产物64c，收率(46.0mg,82％)。经NMR检测，结果为：1H NMR(500MHz,CDCl3)δ8.05(s,2H),7.97(d,J＝7.5Hz,2H),7.88(dd,J＝8.5,7.0Hz,1H),3.85(q,J＝7.0Hz,4H),2.68(s,6H),0.85(t,J＝7.0Hz,6H)；13C NMR(125MHz,CDCl3)δ166.4,158.5,155.0,154.0,140.8,137.3,127.3,122.7,120.4,61.4,25.0,13.6；HRMS m/z(ESI)calcd for C23H22Br2N3O4(M+H)+561.9977,found 561.9977。
在上述实施例10-11反应条件和操作的基础上，仅改变底物，得到如下结构式的化合物：
Figure BDA0002337796040000121
实施例12-13为依托考昔(Etoricoxib)及其衍生物的合成
Figure BDA0002337796040000122
实施例12：(R1为氢，R2为氯，R3为对苯磺酰基，R4吡啶基)
药物分子--依托考昔(化合物1d)的合成
在10mL的真空管中，加入5-氯-1,2,3-三嗪2a(11.5mg,0.10mmol)，2-(4-甲磺酰基苯基)-1-(6-甲基吡啶-3-基)-乙酮6b(43.4mg,0.15mmol)和KOH(2.8mg,0.05mmol)。氮气置换三次，然后加入0.5mL MeCN，将反应管置于80℃下反应8h。用TLC跟踪反应，终止反应后，加入CH2Cl2(3x 10mL)进行萃取，分离有机相，用Na2SO4干燥，真空浓缩有机相，然后经过柱层析得到目标产物依托考昔1d，收率(30.8mg,89％)。
放大至克级制备：在100mL的真空管中，加入5-氯-1,2,3-三嗪2a(1.15g,10.0mmol)，2-(4-甲磺酰基苯基)-1-(6-甲基吡啶-3-基)-乙酮6b(4.34g,15.0mmol)和KOH(280mg,5mmol)。氮气置换三次，然后加入50mL MeCN，将反应管置于80℃下反应8h。用TLC跟踪反应，终止反应后，加入CH2Cl2(3x 100mL)进行萃取，分离有机相，用Na2SO4干燥，真空浓缩有机相，然后经过柱层析得到目标产物依托考昔1d，收率(2.94g,82％)，见附图1,证明了本发明的方法可放大至克级规模。
经NMR检测(见附图2和3)，结果为：1H NMR(500MHz,CDCl3)δ8.71(d,J＝2.0Hz,1H),8.38(d,J＝2.5Hz,1H),7.91(d,J＝8.0Hz,2H),7.74(d,J＝2.0Hz,1H),7.57(d,J＝8.0,Hz,1H),7.41(d,J＝8.0Hz,2H),7.10(d,J＝8.0Hz,1H),3.09(s,3H),2.54(s,3H).13C NMR(125MHz,CDCl3)δ158.4,152.2,149.7,148.3,143.7,140.1,137.8,137.2,135.2,131.1,131.0,130.3,127.8,122.7,44.4,24.1.
实施例13：(R1、R2为氢，R3为对苯磺酰基，R4吡啶基)
6'-甲基-3-[4-(甲磺酰基)苯基]-2,3'-联吡啶(化合物2d)的合成
在10mL的真空管中，加入1,2,3-三嗪2a(8.1mg,0.10mmol)，2-(4-甲磺酰基苯基)-1-(6-甲基吡啶-3-基)-乙酮6b(29mg,0.1mmol)和KOH(2.8mg,0.05mmol)。氮气置换三次，然后加入0.5mL MeCN，将反应管置于80℃下反应8h。用TLC跟踪反应，终止反应后，加入CH2Cl2(3x 10mL)进行萃取，分离有机相，用Na2SO4干燥，真空浓缩有机相，然后经过柱层析得到目标产物2d，收率(26.9mg,83％)。经NMR检测，结果为：1H NMR(500MHz,CDCl3)δ8.77(dd,J＝5.0,2.0Hz,1H),8.41(d,J＝2.5Hz,1H),7.89(d,J＝8.5Hz,2H),7.75(dd,J＝7.5,1.5Hz,1H),7.61(dd,J＝7.5,2.5Hz,1H),7.43–7.41(m,2H),7.40(s,1H),7.10(d,J＝8.0Hz,1H),3.09(s,3H),2.54(s,3H).13C NMR(125MHz,CDCl3)δ158.1,154.2,149.9,149.6,145.1,139.6,138.5,137.4,134.4,132.2,130.4,127.7,122.7,122.6,44.5,24.2.IR(cm-1):v3425,3049,2923,1598,1431,1311,1152,790,765,546.HRMS m/z(ESI)calcd forC18H17N2O2S(M+H)+325.1011,found 325.1018.
在上述实施例12-13反应条件和操作的基础上，仅改变底物，得到如下结构式的化合物：
Figure BDA0002337796040000131
实施例14为活性分子2-SORA的合成实施例14：(R1为氢，R2为溴，R3为甲酯基，R4吡啶基)
Figure BDA0002337796040000141
(1)5-溴-N-(3,4-二甲氧基苄基)-[2,2'-联吡啶]-3-羧酰胺(化合物e)的合成
在10mL的真空管中，加入57c(58.4mg,0.20mmol)，3,4-二甲氧基苄胺(50.2mg,0.30mmol)，KOH(4.0mg,0.10mmol)。氮气置换三次，然后加入0.5mL MeCN，将反应管置于80℃下反应8h。用TLC跟踪反应，终止反应后，加入CH2Cl2进行萃取，分离有机相，用Na2SO4干燥，真空浓缩有机相，然后经过柱层析得到目标产物e，收率(23.9mg,56％)。经NMR检测，结果为：1H NMR(500MHz,CDCl3)δ8.64(d,J＝2.5Hz,1H),8.24(d,J＝9.0Hz,1H),8.08(d,J＝2.5Hz,1H),7.85(d,J＝8.0Hz,1H),7.70(td,J＝8.0,2.0Hz,1H),7.60(t,J＝5.5Hz,1H),7.20–7.18(m,1H),6.73(s,1H),6.69(s,1H),4.38(d,J＝5.5Hz,2H),3.80(s,3H),3.73(s,3H)；13C NMR(125MHz,CDCl3)δ166.7,155.8,152.2,150.9,149.0,148.5,147.9,140.1,137.1,133.3,130.1,124.1,123.8,120.4,120.3,111.5,111.1,55.9,55.8,44.3；IR(cm-1):v 3436,3278,2923,2851,1636,1518,1264,1139,1028,813；HRMS m/z(ESI)calcd forC20H19BrN3O3(M+H)+428.0610,found 428.0608.
(2)活性分子—2-SORA(化合物f)的合成
在10mL的真空管中，加入e(42.7mg,0.10mmol)，3,4-二甲基苯硼酸(22.5mg,0.15mmol)，Pd(Cl)2(1.8mg,0.01mmol)和KOH(2.0mg,0.05mmol)。氮气置换三次，然后加入0.5mL MeCN，将反应管置于环境下反应10h。用TLC跟踪反应，终止反应后，加入CH2Cl2进行萃取，分离有机相，用Na2SO4干燥，真空浓缩有机相，然后经过柱层析得到目标产物f，收率(39.0mg,86％)。经NMR检测，结果为：1H NMR(500MHz,CDCl3)δ8.83(d,J＝2.0Hz,1H),8.29(d,J＝4.0Hz,1H),8.17(d,J＝2.0Hz,1H),7.90(d,J＝7.5Hz,1H),7.72(td,J＝8.0,2.0Hz,1H),7.53(t,J＝5.5Hz,1H),7.18(s,3H),7.00(s,1H),6.74–6.73(m,1H),6.72(s,1H),4.43(d,J＝5.5Hz,2H),3.80(s,3H),3.73(s,3H),2.33(s,6H).13C NMR(125MHz,CDCl3)δ168.4,156.8,152.3,149.0,148.4,148.3,148.0,138.8,137.0,136.3,136.2,136.0,132.0,130.3,130.2,125.0,124.2,123.5,120.4,111.5,111.1,56.0,55.9,44.3,21.3。

Claims (9)

1.一种多取代吡啶衍生物的合成方法，其特征在于，所述合成方法以1,2,3-三嗪类化合物a和酮类化合物b为反应底物，在催化量的碱、溶剂作用下，仅通过一步反应合成多取代的吡啶，所述的“多取代”是指吡啶被两个及以上官能团所取代,其反应通式为：
Figure FDA0003839679530000011
其中R1、R2为烷基、芳基、卤素、酯基、氢中的一种；R3为硝基、三卤甲基、氰基、磺酰基、酯基、含吸电子基团的芳基、卤素、吡啶基中的一种；R4为烷基、烯基、炔基、芳基、卤素、硝基、氰基、巯基、磺酰基中的一种；碱为三乙胺、氟化铯、叔丁醇钾、氢化钠、氢氧化钾、磷酸钾、碳酸氢钠中的一种；溶剂为乙酸乙酯、1,2-二氯乙烷、乙腈、二甲亚砜、N,N-二甲基甲酰胺中的一种。
2.根据权利要求1所述的多取代吡啶衍生物的合成方法，其特征在于，所述反应通式的合成步骤为：在干燥的真空反应容器中，加入1,2,3-三嗪类化合物a、酮化合物b和碱，氮气置换三次实现氮气保护氛围，然后加入溶剂，反应容器恒温条件下反应，反应期间用TLC跟踪，终止反应后，经萃取，分离有机相，干燥后采用真空浓缩有机相，然后经过柱层析得到目标产物，并计算收率。
3.根据权利要求2所述的多取代吡啶衍生物的合成方法，其特征在于，所述1,2,3-三嗪类化合物a、酮类化合物b和碱的摩尔比为1:0.5～2.0:0.1～2，且1,2,3-三嗪类化合物的浓度为0.05～0.50M。
4.根据权利要求2所述的多取代吡啶衍生物的合成方法，其特征在于，所述的反应温度为-20℃～100℃。
5.根据权利要求1所述的多取代吡啶衍生物的合成方法，其特征在于，其中R1、R2为氢；R3为硝基、三卤甲基、氰基、磺酰基、酯基、含吸电子基团的芳基、卤素、吡啶基中的一种；R4为烷基、烯基、炔基、芳基、卤素、硝基、氰基、巯基、磺酰基中的一种；碱为三乙胺、氟化铯、叔丁醇钾、氢化钠、氢氧化钾、磷酸钾、碳酸氢钠中的一种；溶剂为乙酸乙酯、1,2-二氯乙烷、乙腈、二甲亚砜、N,N-二甲基甲酰胺中的一种，制备二取代吡啶衍生物。
6.根据权利要求1所述的多取代吡啶衍生物的合成方法，其特征在于，所述的R1为氢；R2为烷基、芳基、卤素中的一种；R3为硝基、三卤甲基、氰基、磺酰基、酯基、含吸电子基团的芳基、卤素、吡啶基中的一种；R4为烷基、烯基、炔基、芳基、卤素、硝基、氰基、巯基、磺酰基中的一种；碱为三乙胺、氟化铯、叔丁醇钾、氢化钠、氢氧化钾、磷酸钾、碳酸氢钠中的一种；溶剂为乙酸乙酯、1,2-二氯乙烷、乙腈、二甲亚砜、N,N-二甲基甲酰胺中的一种，制备三取代吡啶衍生物。
7.根据权利要求1所述的多取代吡啶衍生物的合成方法，其特征在于，所述的R1、R2为烷基、芳基、卤素中的一种；R3为硝基、三卤甲基、氰基、磺酰基、酯基、含吸电子基团的芳基、卤素、吡啶基中的一种；R4为烷基、烯基、炔基、芳基、卤素、硝基、氰基、巯基、磺酰基中的一种；碱为三乙胺、氟化铯、叔丁醇钾、氢化钠、氢氧化钾、磷酸钾、碳酸氢钠中的一种；溶剂为乙酸乙酯、1,2-二氯乙烷、乙腈、二甲亚砜、N,N-二甲基甲酰胺中的一种，制备四取代吡啶衍生物。
8.一种化合物d的合成方法，其特征在于，所述合成方法以1,2,3-三嗪类化合物a和酮类化合物6b为反应底物，在碱和溶剂的作用下得到化合物d，其反应通式为：
Figure FDA0003839679530000021
其中R1为烷基、氢；R2为卤素、烷基、氢；碱为三乙胺、氟化铯、叔丁醇钾、氢化钠、氢氧化钾、磷酸钾、碳酸氢钠中的一种；溶剂为乙酸乙酯、1,2-二氯乙烷、乙腈、二甲亚砜、N,N-二甲基甲酰胺中的一种。
9.一种化合物f的制备方法，其特征在于，所述合成方法以1,2,3-三嗪类化合物a和酮类化合物4b为反应底物，在碱和溶剂的作用下得到化合物c，化合物c使用胺试剂酰化后得到化合物e，随后化合物e与硼酸类化合物偶联得到化合物f，其反应通式为：
Figure FDA0003839679530000031
其中R1为氢，R2为卤素；碱为三乙胺、氟化铯、叔丁醇钾、氢化钠、氢氧化钾、磷酸钾、碳酸氢钠中的一种；溶剂为乙酸乙酯、1,2-二氯乙烷、乙腈、二甲亚砜、N,N-二甲基甲酰胺中的一种。
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