CN106243018B - 一种多氟苯基吡啶类化合物的合成方法 - Google Patents

一种多氟苯基吡啶类化合物的合成方法 Download PDF

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CN106243018B
CN106243018B CN201610595185.4A CN201610595185A CN106243018B CN 106243018 B CN106243018 B CN 106243018B CN 201610595185 A CN201610595185 A CN 201610595185A CN 106243018 B CN106243018 B CN 106243018B
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黄治炎
王俊亚
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Shaanxi Normal University
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

本发明公开了一种多氟苯基吡啶类化合物的合成方法，该方法在无水无氧条件下，以四氢呋喃为溶剂、烷基格氏试剂或烷基锂为活化剂，当量卤化锌辅助下，采用镍源与双膦配体形成的复合物为催化剂，实现多氟苯与卤代吡啶的交叉偶联，以90％左右的产率合成得到一系列多氟苯基吡啶类化合物，纯度达99％以上。本发明采用了较为廉价的多氟苯和镍复合物为原料和催化剂，避免了昂贵的多氟苯硼酸和钯催化剂的使用，具有明显的经济优势，而且本发明具有反应体系简单、条件温和、操作简便、后处理容易、污染小、易于工业化等优势，显示出较高的社会价值和工业推广前景。

Description

一种多氟苯基吡啶类化合物的合成方法
技术领域
本发明属于合成多氟联芳烃类化合物技术领域，具体涉及一种在镍催化温和条件下合成多氟苯基吡啶类化合物的方法。
背景技术
PIM 447是治疗恶性肿瘤和恶性血液病的有效药物(Burger,Matthew et al.ACSMed.Chem.Lett.2013,4,1193-1197；Burger,Matthew et al.J.Med.Chem.2015,58,8373-8386)。目前该药物已进入三期临床测试阶段，效果显著，是具有极高社会价值、市场价值的新型药物。
2-(2′,6′-二氟苯基)-3-氟-6-甲基吡啶(CAS:1210419-18-3)及其衍生物是合成PIM447类相关药物的重要中间体。因此开发出一种高效便捷合成此类中间体的技术路线便显得至关重要。
2-(2,6-二氟苯基)-3-氟-6-甲基吡啶及多氟苯基吡啶类衍生物
目前2-(2′,6′-二氟苯基)-3-氟-6-甲基吡啶及其衍生物的合成方法(以2-(2′,6′-二氟苯基)-3-氟-6-甲基吡啶为例)是采用多氟苯硼酸、溴代吡啶为原料，三(二亚苄基丙酮)二钯(Pd2(dba)3)、三叔丁基膦(Pt-Bu3)为催化剂，在氟化钾、硼氢化钠的辅助下进行合成(Burger,Matthew et al.PCT Int.Appl.,2013175388,28Nov 2013；Burger,Matthewet al PCT Int.Appl.,2014033631,06Mar 2014；Burger,Matthew etal.U.S.Pat.Appl.Publ.,20120225061,06Sep 2012；Burger,Matthew et al PCTInt.Appl.,2012004217,12Jan 2012；Burger,Matthew et al U.S.Pat.Appl.Publ.,20100056576,04Mar 2010)，相关化学反应方程式如下所示：
该合成方法中2-(2′,6′-二氟苯基)-3-氟-6-甲基吡啶虽然取得了很好的产率，但却存在以下问题：1)原料2,6-二氟苯硼酸昂贵且不易得；2)催化剂三(二亚苄基丙酮)二钯非常昂贵且会造成重金属残留；3)催化剂三(二亚苄基丙酮)二钯中的二亚苄基丙酮与产物极性非常相似，难以除去，必须用硼氢化钠还原后，再经硅胶柱层析步骤，才能将其与产物分离。由此可见，该方法所用原料、催化剂均昂贵，且偶联后产物需额外步骤提纯，这些因素使得该方法综合成本非常高，不利于工业化。
发明内容
本发明所要解决的技术问题在于提供一种以廉价易得的多氟苯为原料，在镍催化下，实现多氟苯与卤代吡啶的高效交叉偶联合成多氟苯基吡啶类化合物的方法。
解决上述技术问题所采用的技术方案是由下述步骤组成：
1、在无水无氧条件下，以四氢呋喃为溶剂，将式I所示的多氟苯与烷基格氏试剂在0～50℃下搅拌2～18小时或将式I所示的多氟苯与烷基锂在-20～0℃下搅拌2～6小时，然后加入卤化锌，常温搅拌1～2小时。
2、在无水无氧条件下，将镍源、双膦配体加入四氢呋喃中，常温搅拌30分钟；其中所述的镍源为双(1,5-环辛二烯)镍、醋酸镍、三氟醋酸镍、乙酰丙酮镍、三氟甲磺酸镍、氯化镍、溴化镍、乙二醇二甲醚氯化镍、乙二醇二甲醚溴化镍中的任意一种；所述的双膦配体的结构式如下所示：
式中Ar代表苯基、C1～C6烷基取代苯基、C1～C6烷氧基取代苯基、氟代苯基、三氟甲基苯基、萘基、呋喃基、硅氧基苯基中的任意一种。
3、在无水无氧条件下，将步骤1和2所得反应液混合，并加入式II所示的卤代吡啶，20～50℃下搅拌至反应完全后，加入甲醇淬灭反应，分离纯化产物，得到式III所示的多氟苯基联吡啶类化合物。
上述式I～III中，R1～R4各自独立的代表H、F、C1～C10烷基、C1～C6烷氧基、苯基、C1～C6烷基取代苯基、C1～C4烷氧基取代苯基中的任意一种，且R1～R4中至少有一个为F，R5代表H、F、C1～C10烷基、甲酸C1～C6烷基酯基、CN中的任意一种，R6代表C1～C10烷基、甲酸C1～C6烷基酯基、CN中的任意一种，X代表Br或I。
上述制备方法中，卤代吡啶、镍源、双膦配体、多氟苯、烷基格氏试剂或烷基锂、卤化锌的摩尔比为1:0.05～0.2:0.05～0.2:1.2～5.0:1.0～3.0:1.0～3.0。
上述的卤化锌为氯化锌、溴化锌、碘化锌中的任意一种，所述的烷基格氏试剂为甲基氯化镁、乙基氯化镁、正丙基氯化镁、异丙基氯化镁、甲基溴化镁、乙基溴化镁、正丙基溴化镁、异丙基溴化镁中的任意一种，所述的烷基锂为甲基锂、正丁基锂、仲丁基锂、叔丁基锂中的任意一种。
上述步骤2中，优选镍源为双(1,5-环辛二烯)镍，Ar优选3,5-二甲基-4-甲氧基苯基、苯基、3,4-二甲氧基苯基、萘基中的任意一种。
与现有技术相比，本发明的有益效果如下：
1、本发明采用廉价的多氟苯代替昂贵的多氟苯硼酸，大幅降低了生产成本。此外，与现有的钯催化技术相比，本发明合成方法采用便宜的镍复合物为催化剂，进一步降低了反应成本。所以，本发明具有明显的经济效益。
2、本发明反应干净，易于处理，反应完毕只需通过简单滤过短硅胶层，除去催化剂及盐，浓缩后即可得到纯的产物，若要得到高纯度产品，只需蒸馏即可，大大降低了后处理难度。所以本发明具有较大的工业生产价值。
3、本发明合成方法在整个生产过程中条件温和(-20℃～50℃)，无需苛刻高低温设备，而且整个过程无气体放出，因而也无需高压装置，工艺简单，多氟苯基联吡啶类化合物产率可达90％左右，有利于推广大规模工业化生产。
具体实施方式
下面结合实施例对本发明进一步详细说明，但本发明的保护范围不仅限于这些实施实例。
下面实施例中所用的双膦配体双(2-二(3′,5′-二甲基-4′-甲氧基苯基)膦)苯醚按照下述方法制备得到：
将1.89g(8.8mmol)3,5-二甲基-4-甲氧基溴苯与192mg(8mmol)镁粉置于40mL干燥四氢呋喃中，回流反应2小时，镁完全消失，然后在-78℃下，将其缓慢滴加到溶解有372mg(1.0mmol)双(2-二氯化膦)苯醚的20mL四氢呋喃溶液中，滴加完毕后缓慢升至室温，继续搅拌8小时；将反应液冷却至-20℃，缓慢加入甲醇淬灭反应，淬灭后缓慢升至室温，反应液用饱和氯化铵水溶液洗涤3次，并用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥后，过滤除去硫酸钠，滤液减压蒸干，经硅胶色谱柱层析分离，得到双(2-二(3′,5′-二甲基-4′-甲氧基苯基)膦)苯醚，其产率为62％，结构表征数据为：1H NMR(400MHz,CDCl3):δ7.11(td,J＝7.6,1.6Hz,4H),6.95-6.90(m,10H),6.83(ddd,J＝7.6,4.2,1.6Hz,2H),6.52(dd,J＝8.1,3.5Hz,2H),3.68(s,12H),2.19(s,24H)。
将上述的3,5-二甲基-4-甲氧基溴苯用等摩尔的2-溴萘替换，即可得到结构式如下的双膦配体双(2-二(2′-萘基)膦)苯醚：
其产率为55％，结构表征数据为：1H NMR(600MHz,CDCl3):δ7.73(d,J＝8.0Hz,4H),7.64(d,J＝8.3Hz,4H),7.61(d,J＝8.0Hz,4H),7.55(d,J＝8.3Hz,4H),7.45(td,J＝7.5,1.1Hz,4H),7.41(td,J＝7.5,1.1Hz,4H),7.23(dt,J＝7.8,1.4Hz,2H),7.15(t,J＝7.0Hz,4H),6.92(t,J＝7.2Hz,2H),6.87(dd,J＝8.0,4.1Hz,2H),6.81(ddd,J＝7.5,4.1,1.5Hz,2H)。
将上述的3,5-二甲基-4-甲氧基溴苯用等摩尔的3,4-二甲氧基溴苯替换，即可得到结构式如下的双膦配体双(2-二(3′,4′-二甲氧基苯基)膦)苯醚：
其产率为39％，结构表征数据为：1H NMR(400MHz,CDCl3):δ7.20(td,J＝7.7,1.5Hz,2H),6.96(td,J＝7.4,0.6Hz,2H),6.78-6.71(m,16H),3.86(s,12H),3.72(s,12H)。
实施例1
合成结构式如下的2-(2′,6′-二氟苯基)-3-氟-6-甲基吡啶
1、在无水无氧下，将3.42g(30mmol)1,3-二氟苯溶于10mL四氢呋喃中，然后缓慢加入6mL2.5mol/L正丁基锂的己烷溶液，-20℃搅拌反应4小时，然后缓慢加入22mL1mol/L氯化锌的四氢呋喃溶液，缓慢升至常温，继续搅拌2小时。
2、在无水无氧条件下，向10mL四氢呋喃中加入200mg(0.8mmol)双(1,5-环辛二烯)镍、770mg(1mmol)双(2-二(3′,5′-二甲基-4′-甲氧基苯基)膦)苯醚，常温搅拌30分钟。
3、在无水无氧条件下，将步骤1和步骤2所得反应液混合，并加入1.90g(10mmol)2-溴-3-氟-6-甲基吡啶，50℃搅拌10小时，TLC检测反应完全，加入甲醇淬灭反应后，反应液用0.1mol/L盐酸洗涤，并用乙酸乙酯萃取，乙酸乙酯萃取液用无水硫酸钠干燥后，减压蒸干，然后经硅胶过滤(洗脱剂为石油醚和乙酸乙酯的体积比为95:5的混合物)，蒸馏得到2-(2′,6′-二氟苯基)-3-氟-6-甲基吡啶纯品，其产率为91％，结构表征数据为：1H NMR(600MHz,CDCl3):δ7.43-7.36(m,2H),7.22(dd,J＝8.7,3.9Hz 1H),7.02-6.99(m,2H),2.61(s,3H)。
实施例2
合成结构式如下的2-(2′,4′,6′-三氟苯基)-3-氟-6-甲基吡啶
1、在无水无氧条件下，将3.17g(24mmol)1,3,5-三氟苯溶于10mL四氢呋喃中，然后加入10mL 2mol/L乙基氯化镁的四氢呋喃溶液，50℃搅拌反应18小时，然后加入22mL1mol/L氯化锌的四氢呋喃溶液，常温继续搅拌2小时。
2、在无水无氧条件下，向10mL四氢呋喃中加入220mg(0.8mmol)双(1,5-环辛二烯)镍、801mg(1mmol)双(2-二(3′,4′-二甲氧基苯基)膦)苯醚，常温搅拌30分钟。
3、在无水无氧条件下，将步骤1和步骤2所得反应液混合，并加入1.90g(10mmol)2-溴-3-氟-6-甲基吡啶，50℃搅拌10小时，TLC检测反应完全，加入甲醇淬灭反应后，反应液用0.1mol/L盐酸洗涤，并用乙酸乙酯萃取，乙酸乙酯萃取液用无水硫酸钠干燥后，减压蒸干，然后经硅胶过滤(洗脱剂为石油醚和乙酸乙酯的体积比为95:5的混合物)，蒸馏得到2-(2′,4′,6′-三氟苯基)-3-氟-6-甲基吡啶纯品，其产率为94％，结构表征数据为：1H NMR(600MHz,CDCl3):δ7.41(t,J＝8.6H,1H),7.22(dd,J＝8.5,3.7Hz,1H),6.79-6.76(m,2H),2.60(s,3H)。
实施例3
合成结构式如下的2-(2′,3′,5′,6′-四氟苯基)-3-氟-6-甲基吡啶
在实施例2的步骤1中，将1,3,5-三氟苯用其摩尔量0.8倍的1,2,4,5-四氟苯替换，将乙基氯化镁用等摩尔的异丙基氯化镁替换，反应温度变为室温。在实施例2的步骤3中，将双(2-二(3′,4′-二甲氧基苯基)膦)苯醚用等摩尔的双(2-二(3′,5′-二甲基-4′-甲氧基苯基)膦)苯醚替换，其他步骤与实施例2相同，得到2-(2′,3′,5′,6′-四氟苯基)-3-氟-6-甲基吡啶，其产率为87％，结构表征数据为：1H NMR(600MHz,CDCl3):δ7.46(t,J＝8.6H,1H),7.22(dd,J＝8.6,3.8Hz,1H),7.19-7.13(m,2H),2.61(s,3H)。
实施例4
合成结构式如下的2-(2′,6′-二氟苯基)-吡啶-6-甲酸甲酯
在实施例1的步骤3中，将2-溴-3-氟-6-甲基吡啶用等摩尔的4-溴-吡啶-2-甲酸甲酯替换，其他步骤与实施例1相同，得到2-(2′,6′-二氟苯基)-吡啶-6-甲酸甲酯，其产率为87％，结构表征数据为：1H NMR(600MHz,CDCl3):δ8.17(dd,J＝7.8,0.84Hz,1H),7.94(dd,J＝7.8,0.96Hz,1H),7.38-7.33(m,1H),7.00(t,J＝7.8,3H).2.61(s,3H)。
实施例5
合成结构式如下的2-氰基-5-(2′,6′-二氟苯基)吡啶
在实施例1的步骤1中，将1,3-二氟苯用等摩尔的1,2,4,5-四氟苯替换，在实施例1的步骤3中，将2-溴-3-氟-6-甲基吡啶用等摩尔的2-氰基-5-溴吡啶替换，其他步骤与实施例1相同，得到2-氰基-4-(2′,6′-二氟苯基)吡啶，其产率为87％，结构表征数据为：1H NMR(600MHz,CDCl3):δ8.85(s,1H),8.00(d,J＝7.9,1H),7.87(dd,J＝7.92,3.1Hz),7.25-7.22(m,3.1Hz)。
上述实施例中的双(1,5-环辛二烯)镍也可用等摩尔的氯化镍、溴化镍、醋酸镍、三氟醋酸镍、乙酰丙酮镍或三氟甲磺酸镍替换；双膦配体双(2-二(3′,5′-二甲基-4′-甲氧基苯基)膦)苯醚或双(2-二(3′,4′-二甲氧基苯基)膦)苯醚也可用等摩尔其他骨架结构相同或相似双膦配体替换，具体如：双(2-二(2′-萘基)膦)苯醚等；异丙基氯化镁或乙基氯化镁也可用等摩尔的甲基氯化镁、正丙基氯化镁、甲基溴化镁、乙基溴化镁、正丙基溴化镁或异丙基溴化镁替换；正丁基锂可用等摩尔的甲基锂、叔丁基锂、仲丁基锂替换，均可实现本发明的目的，得到与上述实施例相近的产物产率。

Claims (6)

1.一种多氟苯基吡啶类化合物的合成方法，其特征在于它由下述步骤组成：
（1）在无水无氧条件下，以四氢呋喃为溶剂，将式I所示的多氟苯与烷基格氏试剂在0～50℃下搅拌2～18小时或将式I所示的多氟苯与烷基锂在-20～0℃下搅拌2～6小时，然后加入卤化锌，常温搅拌1～2小时；
I
（2）在无水无氧条件下，将镍源、双膦配体加入四氢呋喃中，常温搅拌30分钟；其中所述的镍源为双(1,5-环辛二烯)镍；所述的双膦配体的结构式如下所示：
式中Ar代表3,5-二甲基-4-甲氧基苯基或3,4-二甲氧基苯基；
（3）在无水无氧条件下，将步骤（1）和（2）所得反应液混合，并加入式II所示的卤代吡啶，20～50 ℃下搅拌至反应完全后，加入甲醇淬灭反应，分离纯化产物，得到式III所示的多氟苯基吡啶类化合物；
II III
上述式I～III中，R1～R4各自独立的代表H、F、C1～C10烷基、C1～C6烷氧基、苯基、C1～C6烷基取代苯基、C1～C4烷氧基取代苯基中的任意一种，且R1～R4中至少有一个为F，R5代表H、F、C1～C10烷基、甲酸C1～C6烷基酯基、CN中的任意一种，R6代表C1～C10烷基、甲酸C1～C6烷基酯基、CN中的任意一种，X代表Br或I。
2.根据权利要求1所述的多氟苯基吡啶类化合物的合成方法，其特征在于：所述的R1～R5各自独立的代表H或F。
3.根据权利要求1或2所述的多氟苯基吡啶类化合物的合成方法，其特征在于：所述的卤代吡啶、镍源、双膦配体、多氟苯、烷基格氏试剂或烷基锂、卤化锌的摩尔比为1:0.05～0.2:0.05～0.2:1.2～5.0:1.0～3.0:1.0～3.0。
4.根据权利要求3所述的多氟苯基吡啶类化合物的合成方法，其特征在于：所述的卤化锌为氯化锌、溴化锌、碘化锌中的任意一种。
5.根据权利要求3所述的多氟苯基吡啶类化合物的合成方法，其特征在于：所述的烷基格氏试剂为甲基氯化镁、乙基氯化镁、正丙基氯化镁、异丙基氯化镁、甲基溴化镁、乙基溴化镁、正丙基溴化镁、异丙基溴化镁中的任意一种。
6.根据权利要求3所述的多氟苯基吡啶类化合物的合成方法，其特征在于：所述的烷基锂为甲基锂、正丁基锂、仲丁基锂、叔丁基锂中的任意一种。
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