CN113387823B - 邻氨基苯甲酸及其衍生物及其合成方法和应用 - Google Patents

邻氨基苯甲酸及其衍生物及其合成方法和应用 Download PDF

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CN113387823B
CN113387823B CN202010164757.XA CN202010164757A CN113387823B CN 113387823 B CN113387823 B CN 113387823B CN 202010164757 A CN202010164757 A CN 202010164757A CN 113387823 B CN113387823 B CN 113387823B
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姜雪峰
李一鸣
王玉红
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East China Normal University
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Abstract

本发明公开了一种邻氨基苯甲酸及其衍生物的合成方法，在反应溶剂中，以邻甲基(杂)芳基硝基化合物为反应原料，在水、催化剂、碱和添加剂作用下，合成所述邻氨基苯甲酸及其衍生物。本发明合成方法原料廉价易得，反应操作简单，产率较高，官能团耐受性优秀，为实现在染料、医药、农药、香料等方面具有广泛应用的邻氨基苯甲酸的合成提供了一种简单高效的方法。本发明还公开了所述邻氨基苯甲酸及其衍生物及其应用，具有广泛的应用前景。

Description

邻氨基苯甲酸及其衍生物及其合成方法和应用
技术领域
本发明属于有机化合物工艺应用技术领域，具体涉及邻氨基苯甲酸及其衍生物及其合成方法。
背景技术
邻氨基苯甲酸及其衍生物是一类非常重要的化工原料，它广泛存在于各类天然产物、医药、农药、染料中，并且每年生产20多万吨邻氨基苯甲酸用于合成数十亿种药物(如Alprazolam,Furosemide,Clonazepam等)和数千吨农药(如Bentazone)。基于邻氨基苯甲酸的重要性，从一些结构简单、商业大量可得的原料高效构建邻氨基苯甲酸及其衍生物显得尤为重要。
Figure BDA0002407033620000011
含邻氨基苯甲酸骨架的药物分子、染料及农药
传统地合成邻氨基苯甲酸的方法，一是由邻硝基甲苯经历还原、保护、氧化和脱保护等一系列过程而来，另一方法则是由靛红生成邻氨基苯甲酸，但这些方法在使用过程中大都不可避免地需要额外的氧化剂、还原剂、强酸、强碱等，在原子经济性和步骤经济性等方面均存在一定问题。因此，寻找一种合适的催化剂，设计通过邻硝基甲苯中氢原子与氧原子的直接交换，实现邻氨基苯甲酸的有效合成的策略成为本发明立题依据及所要解决的技术问题。
发明内容
本发明公开了一种邻氨基苯甲酸及其衍生物的合成方法，在反应溶剂中，以式(I)所示的邻甲基(杂)芳基硝基化合物为反应原料，在水、催化剂、碱和添加剂作用下，在加热的条件下，合成邻氨基苯甲酸及其衍生物。本发明合成方法原料廉价易得，反应操作简单，产率较高，官能团耐受性优秀，为实现在染料、医药、农药、香料等方面具有广泛应用的邻氨基苯甲酸的合成提供了一种简单高效的方法。
其中，所述反应过程如以下反应式(a)所示。
Figure BDA0002407033620000021
反应式(a)
以上反应式(a)中，其中，A环是苯基、取代苯基、芳杂环、取代芳杂环、稠环、取代稠环；R包括但不限于苯基、取代苯基、萘基、稠环、烷基、烷氧基、苄氧基、三氟甲基、氰基、卤素、醛基、羧基、酰基、胺酰基、砜基、磺胺基、烷硫基、芳硫基、氢等。
优选地，A环是苯基、取代苯基、芳杂环、取代芳杂环、稠环、取代稠环；R是苯基、取代苯基、萘基、稠环、C1-C10烷基、C1-C10烷氧基、苄氧基、三氟甲基、氰基、卤素、醛基、羧基、胺酰基、砜基、磺胺基、烷硫基、芳硫基、氢。
进一步优选地，A环是苯基、萘环、吡啶环、喹啉环、异喹啉环；R是氢、甲基、乙基、丙基、丁基、异丙基、叔丁基、甲氧基、苄氧基、三氟甲基、卤素、氰基、砜基、胺酰基、醛基、羧基、苯基、萘基、卤素取代的苯基。
本发明式(II)邻氨基苯甲酸及其衍生物中，所述反应在氮气氛围下进行；所述氮气压力为1-5个大气压；优选地，为1个大气压。
本发明式(II)邻氨基苯甲酸及其衍生物中，所述反应的温度为80-120℃；优选地，为90℃。
本发明式(II)邻氨基苯甲酸及其衍生物中，所述反应的时间为12-96h；优选地，为36h。
本发明式(II)邻氨基苯甲酸及其衍生物合成中，所述催化剂为单质硒，所述单质硒可以为硒粉。
本发明式(II)邻氨基苯甲酸及其衍生物合成中，所述催化剂的摩尔用量为如式(I)所示的邻甲基(杂)芳基硝基化合物(底物I)的5-50mol％；优选地，为30mol％。
本发明式(II)邻氨基苯甲酸及其衍生物合成中，所述碱包括但不限于选自氢氧化钠、氢氧化钾、氢氧化铯、氢氧化锂、叔丁醇锂、叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、碳酸铯等中的一种或多种；优选地，为氢氧化钠。
本发明式(II)邻氨基苯甲酸及其衍生物合成中，所述碱的摩尔用量为式(I)邻硝基(杂)芳香硝基化合物摩尔用量的1.5～4当量；优选地，所述碱的摩尔用量是2当量。
本发明式(II)邻氨基苯甲酸及其衍生物合成中，所述水的摩尔用量为式(I)邻硝基(杂)芳香硝基化合物摩尔用量的0.5-100当量。优选地，所述水的摩尔用量是2当量。
本发明式(II)邻氨基苯甲酸及其衍生物合成中，所述添加剂包括但不限于硝基苯，氯化钴中的一种或多种。
本发明式(II)邻氨基苯甲酸及其衍生物合成中，所述添加剂的摩尔用量为所述式(I)邻甲基(杂)芳基硝基化合物摩尔用量的0.1-2当量；优选地，为0.1当量，或0.2当量。
本发明式(II)邻氨基苯甲酸及其衍生物合成中，当添加剂为硝基苯时，所述添加剂硝基苯的摩尔用量为式(I)邻硝基(杂)芳香硝基化合物摩尔用量的0.1-2当量；优选地，其摩尔用量为式(I)邻硝基(杂)芳香硝基化合物摩尔用量的0.2当量。
本发明式(II)邻氨基苯甲酸及其衍生物合成中，当氯化钴为硝基苯时，所述添加剂氯化钴的摩尔用量为式(I)邻硝基(杂)芳香硝基化合物摩尔用量的0.1％-1当量；优选地，其摩尔用量为式(I)邻硝基(杂)芳香硝基化合物摩尔用量的0.1％当量。
本发明式(II)邻氨基苯甲酸及其衍生物合成中，所述反应溶剂选自甲醇、乙醇、DMSO之任意一种或任意组合；优选地，所述反应溶剂为甲醇和/或DMSO。
在一具体实施方式中，本发明利用式(I)所示的邻硝基(杂)芳香硝基化合物作为起始原料，在催化剂和碱的作用下，在N2氛围下，在反应溶剂中进行反应，简单高效地合成如式(II)所示的邻氨基苯甲酸及其衍生物。
在另一具体实施方式中，所述邻氨基苯甲酸及其衍生物的合成方法如下反应式(a’)所示：
Figure BDA0002407033620000031
反应式(a’)
在另一具体实施方式中，本发明合成反应包括以下步骤：对反应管A严格除水，之后将体系内的空气置换为氮气，加入硒粉，加入式(I)所示的原料邻甲基(杂)芳基硝基化合物，水，硒粉，硝基苯，反应溶剂1，得到混合物；另取反应管B，加入碱，并用反应溶剂2溶解；将反应管A中的混合物置于90℃下搅拌，并将B中的碱溶液通过注射泵滴加到反应管A中，得到式(II)所示的邻氨基苯甲酸衍生物。其中，反应溶剂1和反应溶剂2可以相同或不同。
本发明还提供了由上述方法制备得到的邻氨基苯甲酸及其衍生物。
本发明还提供了一种邻氨基苯甲酸及其衍生物，其结构如式(II)所示：
Figure BDA0002407033620000041
其中，A环是苯基、取代苯基、芳杂环、取代芳杂环、稠环、取代稠环；R是苯基、取代苯环、萘基、稠环、烷基、烷氧基、苄氧基、三氟甲基、氰基、卤素、醛基、羧基、酰基、胺酰基、砜基、磺胺基、烷硫基、芳硫基、氢。
优选地，所述A环是苯基、取代苯基、芳杂环、取代芳杂环、稠环、取代稠环；R是苯基、取代苯基、萘基、稠环、C1-C10烷基、C1-C10烷氧基、苄氧基、三氟甲基、氰基、卤素、醛基、羧基、胺酰基、砜基、磺胺基、烷硫基、芳硫基、氢。
进一步优选地，A环是苯基、萘环、吡啶环、喹啉环、异喹啉环；R是氢、甲基、乙基、丙基、丁基、异丙基、叔丁基、甲氧基、苄氧基、三氟甲基、卤素、氰基、砜基、胺酰基、醛基、羧基、苯基、萘基、卤素取代的苯基。
本发明还提供了所述的邻氨基苯甲酸及其衍生物在制备医药、农药、染料等产品中的应用。
本发明优点包括：本发明合成方法所使用的各原料简单易得，价格低廉，来源广泛；本发明使用无毒廉价的单质硒催化反应，绿色环保，操作简单；本发明使用的反应溶剂(如甲醇)易于处理；本发明底物普适性广，官能团耐受性强，产率较高，为实现在染料、医药、农药、香料等方面具有广泛应用的邻氨基苯甲酸的合成提供了一种简单高效的方法。本发明所述邻氨基苯甲酸及其衍生物及其合成方法，具有广泛的应用前景。
具体实施方式
结合以下具体实施例，对本发明作进一步的详细说明，实施本发明的过程、条件、试剂、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。以下实施例所给出的数据包括具体操作和反应条件及产物。产物纯度通过核磁鉴定。
本发明式(II)邻氨基苯甲酸及其衍生物的合成反应包括以下步骤：对反应管A严格除水，之后将体系内的空气置换为氮气，加入硒粉，式(I)邻甲基(杂)芳基硝基化合物，水，硝基苯，溶剂；另取反应管B，加入碱，并用溶剂溶解；将反应管A中的混合物置于90℃下搅拌，并将B中的碱溶液通过注射泵滴加到A中，TLC监测至原料邻甲基(杂)芳基硝基化合物消耗完全。将所得混合物冷却至室温，然后，通过旋转蒸发仪将溶剂蒸干。随后，将NaOH(2N水溶液)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(MTBE)洗涤，合并有机层，再次用NaOH(2N水溶液)洗涤。合并水相，用HCl(6N)酸化，然后用乙酸乙酯萃取，合并有机层，干燥，过滤，浓缩。
实施例1
化合物2的合成
Figure BDA0002407033620000051
化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料邻硝基甲苯消耗完全。反应体系冷却至室温，冰浴下用盐酸调节pH＝3～4。HPLC(外标法)测定产率为75％；1H NMR(400MHz,Methanol-d4)δ7.80(dd,J＝8.1,1.5Hz,1H),7.22(ddd,J＝8.5,7.1,1.6Hz,1H),6.76–6.68(m,1H),6.61–6.51(m,1H).13C NMR(101MHz,Methanol-d4)δ171.60,152.78,134.98,132.65,117.74,116.57,111.73.IR(film)3070,1703,1612,1517,1431,1346,1240,945,750,709,665cm-1.
实施例2
化合物3的合成
取50mL反应管严格除水，之后将体系内的空气置换为氮气，加入硒粉(28.4mg,0.36mmol)，1,2-二甲基硝基苯(161μL,1.2mmol)，水(44μL,2.4mmol)，硝基苯(25μL,0.24mmol)，甲醇(1mL)，DMSO(0.2mL)，将混合物置于90℃下搅拌；另称取叔丁醇锂(192.1mg,2.4mmol)溶于1mL甲醇，通过注射泵将叔丁醇锂的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系
Figure BDA0002407033620000061
172.48,150.56,140.97,132.63,121.03,116.02,115.78,22.90.IR(film)3383,2924,2854,1666,1604,1465,1381,1263,1049,804,777,723cm-1.HRMS(EI)Calcd for C8H9NO2151.0633,Found 151.0633.
实施例3
化合物4的合成
Figure BDA0002407033620000062
合物置于90℃下搅拌；另称取氢氧化钠(96mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料2,5-二甲基硝基苯消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝3.9，然后用乙酸乙酯萃取，合并有机层，干燥，过滤，浓缩。粗产品称重，取其1/15，以MeNO2作为内标计算核磁产率为70％；1H NMR(400MHz,DMSO-d6)δ7.56(d,J＝8.1Hz,1H),6.52(s,1H),6.32(d,J＝8.2Hz,1H),2.17(s,3H).13C NMR(101MHz,DMSO-d6)δ169.52,151.54,143.75,131.19,116.20,116.11,107.33,21.25.IR(film)3479,3371,2976,2887,1654,1593,1548,1427,1315,1240,1091,1053,883,771cm-1.
实施例4
化合物5的合成
Figure BDA0002407033620000071
将混合物置于90℃下搅拌；另称取氢氧化钠(96mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料2-甲基-4-异丙基硝基苯消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝3.5，然后用乙酸乙酯萃取，合并有机层，干燥，过滤，浓缩。粗产品称重，取其1/15，以N-甲基吡咯作为内标计算核磁产率为68％；1H NMR(400MHz,Chloroform-d)δ7.86(d,J＝8.3Hz,1H),6.72–6.28(m,2H),2.99–2.62(m,1H),1.23(d,J＝6.9Hz,6H).13C NMR(101MHz,CDCl3)δ173.72,156.94,151.45,132.33,115.67,114.44,107.71,34.40,23.50.IR(film)3496,3387,2927,2879,1676,1624,1589,1421,1309,1228,1051,881,775cm-1.HRMS(EI)Calcd for C10H13NO2179.0946,Found 179.0949.
实施例5
化合物6的合成
Figure BDA0002407033620000072
物置于90℃下搅拌；另称取氢氧化钠(96mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料2-甲基-4-甲氧基硝基苯消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝3.6，然后用乙酸乙酯萃取，合并有机层，干燥，过滤，浓缩。粗产品称重，取其1/12，以MeNO2作为内标计算核磁产率为60％；1H NMR(400MHz,DMSO-d6)δ7.61(d,J＝8.9Hz,1H),6.24(d,J＝2.4Hz,1H),6.11(dd,J＝8.9,2.4Hz,1H),3.71(s,3H).13C NMR(101MHz,DMSO-d6)δ169.22,163.62,153.51,132.97,103.27,103.21,98.65,54.90.IR(film)3495,3377,3005,2920,2848,1660,1618,1597,1556,1425,1244,1219,1149,1022,831cm-1.
实施例6
化合物7的合成
Figure BDA0002407033620000081
mmol,15μL,10mg溶于1mLMeOH),甲醇(0.5mL)，DMSO(0.1mL)，将混合物置于90℃下搅拌；另称取氢氧化钠(48mg,1.2mmol)溶于0.5mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间2.5h)，反应体系在90℃下搅拌，TLC监测至原料2-甲基-4-苄氧基硝基苯消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2Naq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝3.5，然后用乙酸乙酯萃取，合并有机层，干燥，过滤，浓缩。粗产品称重，取其1/12，以N-甲基吡咯作为内标计算核磁产率为62％；1HNMR(400MHz,DMSO-d6)δ7.63(d,J＝8.9Hz,1H),7.48–7.25(m,5H),6.34(d,J＝2.2Hz,1H),6.19(dd,J＝8.9,2.2Hz,1H),5.06(s,2H).13C NMR(101MHz,DMSO-d6)δ169.18,162.70,153.44,136.77,133.03,128.44,127.89,127.68,103.64,103.49,99.72,68.96.IR(film)3462,3427,2970,2879,2256,2129,1672,1620,1500,1234,1147,1051,1026,1004,823,763cm-1.HRMS(EI)Calcd for C14H13NO3 243.0895,Found 243.0900.
实施例7
化合物8的合成
Figure BDA0002407033620000082
溶于0.5mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间2.5h)，反应体系在90℃下搅拌，TLC监测至原料3-甲基-4-硝基联苯消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝3.8，然后用乙酸乙酯萃取，合并有机层，干燥，过滤，浓缩。粗产品称重，取其1/6，以MeNO2作为内标计算核磁产率为55％；1H NMR(400MHz,Methanol-d4)δ8.09(d,J＝2.3Hz,1H),7.58–7.46(m,3H),7.37(t,J＝7.8Hz,2H),7.23(t,J＝7.4Hz,1H),6.83(d,J＝8.6Hz,1H).13C NMR(101MHz,Methanol-d4)δ171.56,152.16,141.89,133.58,130.65,129.76,127.27,126.91,118.36,111.85.IR(film)3506,3394,1678,1627,1583,1481,1425,1327,1228,1107,898,825,761,698,677cm-1.HRMS(ESI)Calcd for C13H12NO2214.0868(M+H),Found 214.0858.
实施例8
化合物9的合成
Figure BDA0002407033620000091
物中(滴加时间2.5h)，反应体系在90℃下搅拌，TLC监测至原料3-甲基-4-硝基联苯消耗完全。反应体系冷却至室温，用HCl(6N)酸化至pH＝2.5，旋干溶剂后柱层析(PE/EA＝20/1-5/1)得浅黄色固体，产率为62％；Rf＝0.4(PE/EA＝2/1)；1H NMR(400MHz,DMSO-d6)δ7.97(dd,J＝7.7,1.7Hz,1H),7.92–7.83(m,2H),7.79(d,J＝2.2Hz,1H),7.57–7.43(m,3H),7.38(dd,J＝8.3,2.4Hz,2H),6.91(d,J＝8.4Hz,1H).13C NMR(101MHz,DMSO-d6)δ169.95,151.32,139.67,135.70,134.05,132.58,131.53,128.84,127.45,126.99,126.64,126.55,126.28,126.13,125.72,117.03,110.01.IR(film)3414,3377,2974,289,1624,1583,1577,1560,1492,1419,1394,1298,1230,1091,1051,881,777,698,669cm-1.HRMS(ESI)Calcd forC17H14NO2 264.1025(M+H),Found 264.1025.
实施例9
化合物10的合成
Figure BDA0002407033620000101
物置于90℃下搅拌；另称取氢氧化钠(48mg,1.2mmol)溶于0.5mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间2.5h)，反应体系在90℃下搅拌，TLC监测至原料2-甲基-4-三氟甲基硝基苯消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝3.5，然后用乙酸乙酯萃取，合并有机层，干燥，过滤，浓缩。粗产品称重，取其1/7，以MeNO2作为内标计算核磁产率为73％；1H NMR(400MHz,DMSO-d6)δ7.86(d,J＝8.3Hz,1H),7.10(s,1H),6.82–6.67(m,1H).13C NMR(101MHz,DMSO-d6)δ169.07,151.74,133.78(q,J＝31.3Hz),132.94,124.24(q,J＝272.6Hz),113.18,113.00,110.39(d,J＝4.0Hz).19F NMR(376MHz,DMSO-d6)δ-64.07.IR(film)3394,2976,2920,2848,1678,1597,1562,1502,1330,1242,1178,1132,1091,1051,931,883,783cm-1.HRMS(EI)Calcd for C8H6NO2F3 205.0351,Found 205.0355.
实施例10
化合物11的合成
Figure BDA0002407033620000102
0.06mmol)，六水合氯化钴(0.0006mmol,15μL,10mg溶于1mL MeOH),MeOH(1mL),and DMSO(0.2mL)，将混合物置于90℃下搅拌，TLC监测至原料4-甲基-3-硝基苯甲腈消耗完全。反应体系冷却至室温，用HCl(6N)酸化至pH＝4，经HPLC(外标法)计算产率为83％；1H NMR(400MHz,DMSO-d6)δ7.82(d,J＝8.2Hz,1H),7.13(s,1H),6.84(d,J＝8.2Hz,1H).13C NMR(126MHz,DMSO-d6)δ168.54,151.12,132.45,119.81,118.52,116.56,115.54,113.16.IR(film)3350,2974,2926,2245,1697,1400,1222,1093,1051,881,773cm-1.HRMS(EI)Calcdfor C8H6N2O2 162.0429,Found 162.0430.
实施例11
化合物12的合成
Figure BDA0002407033620000111
将混合物置于90℃下搅拌；另称取氢氧化钠(96mg,2.4mmol)溶于0.5mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料1-甲基-4-甲砜基硝基苯消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2Naq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝2.5，然后用乙酸乙酯萃取，合并有机层，干燥，过滤，浓缩。柱层析(PE/EA＝5/1-1/1)得黄色固体，产率为59％；Rf＝0.3(PE/EA＝1/1)；1H NMR(400MHz,DMSO-d6)δ7.90(d,J＝8.3Hz,1H),7.32(s,1H),6.97(d,J＝8.3Hz,1H),3.17(s,3H).13C NMR(101MHz,DMSO-d6)δ168.59,151.41,144.92,132.66,114.56,112.95,111.46,43.19.IR(film)3468,3356,2924,1691,1620,1421,1301,1234,1147,1045,968,761,688cm-1.HRMS(EI)Calcd for C8H9NO4S 215.0252,Found 215.0250.
实施例12
化合物13的合成
Figure BDA0002407033620000112
拌；另称取氢氧化钠(48mg,1.2mmol)溶于0.5mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间2.5h)，反应体系在90℃下搅拌，TLC监测至原料(4-氟苯基)(3-甲基-4-硝基苯基)硫醚消耗完全。反应体系冷却至室温，用HCl(6N)酸化至pH＝2.5，旋干溶剂后柱层析(PE/EA＝20/1-5/1)得浅黄色固体，产率为51％；Rf＝0.4(PE/EA＝2/1)；1HNMR(400MHz,DMSO-d6)δ7.83(d,J＝2.3Hz,1H),7.33(dd,J＝8.6,2.3Hz,1H),7.13(d,J＝7.1Hz,4H),6.82(d,J＝8.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ169.21,161.06(d,J＝242.9Hz),152.53,140.20,138.35,134.80(d,J＝3.0Hz),129.69(d,J＝8.1Hz),118.51,116.66(d,J＝22.0Hz),115.74,110.88.19F NMR(376MHz,DMSO-d6)δ-117.09.IR(film)3487,3365,2922,1676,1608,1575,1546,1489,1427,1242,1159,1083,908,823,623cm- 1.HRMS(ESI)Calcd for C13H11NO2FS 264.0495(M+H),Found 264.0488.
实施例13
化合物14的合成
Figure BDA0002407033620000121
氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料4-氟-2-硝基甲苯消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝2.8，然后用乙酸乙酯萃取，合并有机层，干燥，过滤，浓缩。粗产品称重，取其1/12，以MeNO2作为内标计算核磁产率为62％；1H NMR(400MHz,Methanol-d4)δ7.84(dd,J＝8.9,6.8Hz,1H),6.41(dd,J＝11.5,2.5Hz,1H),6.27(td,J＝8.6,2.5Hz,1H).19F NMR(376MHz,DMSO-d6)δ-108.52.13C NMR(101MHz,DMSO-d6)δ168.80,165.67(d,J＝247.4Hz),153.68(d,J＝13.2Hz),134.13(d,J＝11.7Hz),106.78,102.31(d,J＝22.8Hz),101.14(d,J＝24.3Hz).IR(film)3387,2976,2883,1662,1570,1496,1429,1269,1141,1051,979,883,763,613cm-1.HRMS(EI)Calcd forC7H6NO2F 155.0383,Found 155.0381.
实施例14
化合物15的合成
Figure BDA0002407033620000122
10mg溶于1mLMeOH),甲醇(1mL)，DMSO(0.2mL)，将混合物置于90℃下搅拌；另称取氢氧化钠(96mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料5-氯-2-硝基甲苯消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝3.9，然后用乙酸乙酯萃取，合并有机层，干燥，过滤，浓缩。粗产品称重，取其1/4，以N-甲基吡咯作为内标计算核磁产率为47％；1H NMR(400MHz,DMSO-d6)δ7.62(d,J＝2.6Hz,1H),7.24(dd,J＝8.9,2.6Hz,1H),6.77(d,J＝8.9Hz,1H).13C NMR(101MHz,DMSO-d6)δ168.44,150.28,133.48,129.85,118.29,117.48,110.51.IR(film)3500,3387,2924,2852,1660,1585,1481,1419,1288,1230,1155,1132,881,810,704,650cm-1.HRMS(EI)Calcd for C7H6NO2Cl 171.0087,Found 171.0089.
实施例15
化合物16的合成
Figure BDA0002407033620000131
混合物置于90℃下搅拌；另称取氢氧化钠(96mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料4-氯-2-硝基甲苯消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝2.7，然后用乙酸乙酯萃取，合并有机层，干燥，过滤，浓缩。粗产品称重，取其1/12，以MeNO2作为内标计算核磁产率为74％；1H NMR(300MHz,DMSO-d6)δ7.68(d,J＝8.6Hz,1H),6.81(d,J＝2.1Hz,1H),6.51(dd,J＝8.6,2.1Hz,1H).13C NMR(101MHz,DMSO-d6)δ168.88,152.44,138.26,133.10,115.09,114.55,108.60.IR(film)3502,3385,2974,2920,1664,1612,1585,1550,1483,1429,1315,1249,1099,920,835,761cm-1.HRMS(EI)Calcd for C7H6NO2Cl 171.0087,Found 171.0085.
实施例16
化合物17的合成
Figure BDA0002407033620000132
2.4mmol)，硝基苯(25μL,0.24mmol)，甲醇(1mL)，DMSO(0.2mL)，将混合物置于90℃下搅拌；另称取MeOLi(91mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料3,5-二氯-2-硝基甲苯消耗完全。反应体系冷却至室温，用HCl(6N)酸化至pH＝4，经HPLC(外标法)计算产率为51％；1H NMR(400MHz,DMSO-d6)δ7.69(d,J＝2.5Hz,1H),7.58(d,J＝2.5Hz,1H).13C NMR(101MHz,DMSO-d6)δ168.22,145.86,132.40,129.47,119.78,117.42,113.71.IR(film)3367,2976,2881,1672,1571,1541,1456,1421,1307,1217,1053,875,702,599cm-1.HRMS(EI)Calcd forC7H5NO2Cl2 204.9697,Found 204.9695.
实施例17
化合物18的合成
Figure BDA0002407033620000141
混合物置于90℃下搅拌；另称取氢氧化钠(96mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料4-溴-2-硝基甲苯消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝2.3，然后用乙酸乙酯萃取，合并有机层，干燥，过滤，浓缩。粗产品称重，取其1/12，以MeNO2作为内标计算核磁产率为79％；1H NMR(400MHz,DMSO-d6)δ7.59(d,J＝8.5Hz,1H),7.09–6.84(m,1H),6.69–6.50(m,1H).13C NMR(101MHz,DMSO-d6)δ169.44,152.97,133.55,127.83,118.60,117.80,109.35.IR(film)3495,3423,3379,2920,2848,1666,1604,1546,1427,1311,1244,1091,1051,896,761cm-1.HRMS(EI)Calcd for C7H6NO2Br 214.9582,Found 214.9583.
实施例18
化合物19的合成
Figure BDA0002407033620000142
mL)，将混合物置于90℃下搅拌；另称取氢氧化钠(96mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料4-溴-5-氟-2-硝基甲苯消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2Naq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝3.9，然后用乙酸乙酯萃取，合并有机层，干燥，过滤，浓缩。粗产品称重，取其1/13，以MeNO2作为内标计算核磁产率为51％；1H NMR(400MHz,DMSO-d6)δ7.28(s,1H),7.07(s,1H),3.72(s,3H).13C NMR(101MHz,DMSO-d6)δ168.78,146.72,145.15,120.58,118.56,113.52,109.09,56.48.IR(film)3381,2929,2848,1666,1581,1489,1357,1215,1099,1039,954,885,771,750cm- 1.HRMS(EI)Calcd for C8H8NO3Br 244.9688,Found 244.9686.
实施例19
化合物20的合成
Figure BDA0002407033620000151
取50mL反应管严格除水，之后将体系内的空气置换为氮气，加入硒粉(28.4mg,0.36mmol)，4-碘-2-硝基甲苯(315.6mg,1.2mmol)，水(44μL,2.4mmol)，硝基苯(25μL,0.24mmol)，甲醇(1mL)，DMSO(0.2mL)，将混合物置于90℃下搅拌；另称取氢氧化钠(96mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料4-碘-2-硝基甲苯消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝3.9，然后用乙酸乙酯萃取，合并有机层，干燥，过滤，浓缩。粗产品称重，取其1/18，以MeNO2作为内标计算核磁产率为80％；1H NMR(300MHz,DMSO-d6)δ7.40(d,J＝8.4Hz,1H),7.18(d,J＝1.7Hz,1H),6.82(dd,J＝8.4,1.7Hz,1H).13C NMR(101MHz,DMSO-d6)δ169.23,152.26,132.70,124.44,123.21,109.18,101.86.IR(film)3377,3043,1666,1604,1541,1423,1309,1232,1157,763cm-1.HRMS(EI)Calcd for C7H6NO2I 262.9443,Found262.9448.
实施例20
化合物21的合成
Figure BDA0002407033620000161
取50mL反应管严格除水，之后将体系内的空气置换为氮气，加入硒粉(28.4mg,0.36mmol)，4-甲基-3-硝基苯甲醛(198.2mg,1.2mmol)，水(44μL,2.4mmol)，硝基苯(13μL,0.12mmol)，六水合氯化钴(0.0012mmol,29μL,10mg溶于1mLMeOH),甲醇(1mL)，DMSO(0.2mL)，将混合物置于90℃下搅拌；另称取氢氧化钠(96mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料4-甲基-3-硝基苯甲醛消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝3.5，然后用乙酸乙酯萃取，合并有机层，干燥，过滤，浓缩。柱层析(PE/EA＝20/1-5/1)，Rf＝0.4(PE/EA＝2/1)，得黄色固体产率43％；1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),7.87(d,J＝8.1Hz,1H),7.41–7.14(m,1H),6.98(dd,J＝8.1,1.4Hz,1H).13C NMR(101MHz,DMSO-d6)δ193.34,168.97,151.51,139.65,132.07,117.95,113.99,113.90.IR(film)3361,2976,2931,1693,1620,1589,1446,1230,1101,1049,877,779,698cm-1.HRMS(EI)Calcd forC8H7NO3 165.0426,Found 165.0432.
实施例21
化合物22的合成
Figure BDA0002407033620000162
取50mL反应管严格除水，之后将体系内的空气置换为氮气，加入硒粉(28.4mg,0.36mmol)，3-甲基-4-硝基苯甲酸(217.4mg,1.2mmol)，水(44μL,2.4mmol)，硝基苯(25μL,0.24mmol)，甲醇(1mL)，DMSO(0.2mL)，将混合物置于90℃下搅拌；另称取氢氧化钠(96mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料3-甲基-4-硝基苯甲酸消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝2.5，将溶剂旋干。粗产品称重，取其1/12，以N-甲基吡咯作为内标计算核磁产率为54％；1H NMR(500MHz,DMSO-d6)δ8.35(d,J＝2.2Hz,1H),7.74(d,J＝2.1Hz,1H),6.77(d,J＝8.7Hz,1H).13C NMR(101MHz,DMSO-d6)δ168.99,166.83,154.67,134.21,134.07,116.40,115.97,108.76.IR(film)3381,2976,2887,1678,1625,1427,1294,1244,1165,1091,883,692cm-1.HRMS(EI)Calcd for C8H7NO4 181.0375,Found181.0374.
实施例22
化合物23的合成
Figure BDA0002407033620000171
mL)，将混合物置于90℃下搅拌；另称取氢氧化钠(96mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料4-甲基-3-硝基苯甲酸消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2Naq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝2.7，将溶剂旋干。粗产品称重，取其1/12，以N-甲基吡咯作为内标计算核磁产率为71％；1H NMR(400MHz,DMSO-d6)δ7.75(d,J＝8.3Hz,1H),7.38(s,1H),7.00(d,J＝8.1Hz,1H).13C NMR(101MHz,DMSO-d6)δ169.00,167.03,151.12,135.18,131.39,117.60,114.64,112.60.IR(film)3365,2974,2887,1691,1425,1230,1093,1053,883,754cm-1.HRMS(EI)Calcd for C8H7NO4181.0375,Found 181.0378.
实施例23
化合物24的合成
Figure BDA0002407033620000172
mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料3-甲基-4-硝基苯甲酰胺消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝2.6，将溶剂旋干。粗产品称重，取其1/12，以MeNO2作为内标计算核磁产率为44％；1H NMR(400MHz,Methanol-d4)δ8.45(d,J＝2.3Hz,1H),7.75(dd,J＝8.7,2.3Hz,1H),6.75(d,J＝8.7Hz,1H).13C NMR(101MHz,Methanol-d4)δ171.96,171.10,155.77,133.99,133.72,120.86,117.08,110.55.IR(film)3408,3400,1670,1625,1444,1294,1195,1134,844,800,725cm-1.HRMS(EI)Calcd for C8H8N2O3 180.0535,Found180.0531.
实施例24
化合物25的合成
Figure BDA0002407033620000181
mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料4-甲基-3-硝基苯磺酰胺消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝2.5，然后用乙酸乙酯萃取，合并有机层，干燥，过滤，浓缩，粗产品称重，取其1/12，以MeNO2作为内标计算核磁产率为72％；1H NMR(500MHz,DMSO-d6)δ7.83(d,J＝8.4Hz,1H),7.35(s,2H),7.23(d,J＝1.8Hz,1H),6.90(dd,J＝8.4,1.8Hz,1H).13C NMR(126MHz,DMSO-d6)δ168.87,151.39,148.30,132.28,113.45,111.55,111.03.IR(film)3481,3365,3244,1618,1552,1309,1236,1147,1101,943,894,852,702cm-1.HRMS(ESI)Calcd for C7H7N2O4S 215.0127(M-H),Found 215.0128.
实施例25
化合物26的合成
Figure BDA0002407033620000182
基苯(13μL,0.12mmol)，六水合氯化钴(0.0012mmol,29μL,10mg溶于1mL MeOH),甲醇(1mL)，DMSO(0.2mL)，将混合物置于90℃下搅拌；另称取氢氧化钠(96mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料5-氯-2-硝基甲苯消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2Naq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝4.9，旋干溶剂，粗产品称重，取其1/12，以MeNO2作为内标计算核磁产率为70％；1H NMR(400MHz,DMSO-d6)δ8.20(s,1H),7.72(d,J＝5.1Hz,1H),7.46(d,J＝5.1Hz,1H).13C NMR(101MHz,DMSO-d6)δ168.83,145.82,140.38,135.12,123.14,115.27.IR(film)3396,2976,2893,1633,1579,1411,1336,1091,1049,881,794,584cm-1.HRMS(EI)Calcd for C6H6N3O2 138.0429,Found138.0432.
实施例26
化合物27的合成
Figure BDA0002407033620000191
mmol,29μL,10mg溶于1mL MeOH),甲醇(1mL)，DMSO(0.2mL)，将混合物置于90℃下搅拌；另称取氢氧化钠(96mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料6-溴-2-甲基-3-硝基吡啶消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝2.5，旋干溶剂，粗产品称重，取其1/5，以MeNO2作为内标计算核磁产率为48％；1H NMR(400MHz,DMSO-d6)δ7.27(d,J＝8.9Hz,1H),6.88(d,J＝8.9Hz,1H),3.80(s,3H).13C NMR(101MHz,DMSO-d6)δ168.69,153.55,144.14,130.87,120.23,118.53,53.50.IR(film)3350,2976,2885,1720,1680,1585,1487,1332,1288,1093,1053,883,729cm-1.HRMS(EI)Calcd for C7H8N2O3168.0535,Found 168.0537.
实施例27
化合物28的合成
Figure BDA0002407033620000201
DMSO(0.2mL)，将混合物置于90℃下搅拌；另称取氢氧化钠(96mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料6-甲基-5-硝基异喹啉消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝4.7，旋干溶剂，粗产品称重，取其1/13，以MeNO2作为内标计算核磁产率为67％；1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.49(d,J＝5.9Hz,1H),8.19(d,J＝5.9Hz,1H),7.89(d,J＝8.7Hz,1H),7.14(d,J＝8.7Hz,1H).13C NMR(101MHz,DMSO-d6)δ170.60,152.40,148.91,142.84,130.92,129.38,126.82,116.66,112.94,106.53.IR(film)3415,3375,2976,2918,1656,1585,1408,1382,1273,1091,1049,1022,881,813cm-1.HRMS(EI)Calcd for C10H8N2O2188.0586,Found 188.0583.
实施例28
化合物29的合成
Figure BDA0002407033620000202
29μL,10mg溶于1mL MeOH),甲醇(1mL)，DMSO(0.2mL)，将混合物置于90℃下搅拌；另称取氢氧化钠(96mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料7-甲基-8-硝基喹啉消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝4.0，旋干溶剂，粗产品称重，取其1/6，以N-甲基吡咯作为内标计算核磁产率为76％；1H NMR(400MHz,DMSO-d6)δ8.80(dd,J＝4.2,1.7Hz,1H),8.22(dd,J＝8.2,1.7Hz,1H),7.79(d,J＝8.8Hz,1H),7.61(dd,J＝8.2,4.2Hz,1H),6.98(d,J＝8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ170.20,149.78,148.07,138.53,136.38,131.01,128.28,124.33,112.53,104.83.IR(film)3356,2918,2848,1666,1579,1537,1454,1396,1261,1091,1051,1016,794,754cm-1.HRMS(EI)Calcd for C10H8N2O2 188.0586,Found 188.0583.
实施例29
化合物30的合成
Figure BDA0002407033620000211
醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料7-甲基-8-硝基喹啉消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝4.7，旋干溶剂，粗产品称重，取其1/12，以MeNO2作为内标计算核磁产率为80％；1H NMR(400MHz,DMSO-d6)δ8.82(dd,J＝4.2,1.6Hz,1H),8.71(d,J＝8.5Hz,1H),8.03(d,J＝8.8Hz,1H),7.42(dd,J＝8.6,4.2Hz,1H),7.05(d,J＝8.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ170.79,151.29,150.50,149.34,131.85,131.82,119.29,118.21,114.48,106.48.IR(film)3392,2976,2900,1678,1610,1442,1201,1134,1049,881,790,725cm-1.HRMS(EI)Calcd for C10H8N2O2 188.0586,Found 188.0584.
实施例30
化合物31的合成
Figure BDA0002407033620000212
混合物置于90℃下搅拌；另称取氢氧化钠(96mg,2.4mmol)溶于1mL甲醇，通过注射泵将氢氧化钠的甲醇溶液滴加到上述混合物中(滴加时间5h)，反应体系在90℃下搅拌，TLC监测至原料2-甲基-1-硝基萘酚消耗完全。反应体系冷却至室温，旋干溶剂，将NaOH(2N aq.,20mL)加入到残余物中并搅拌5分钟。将所得混合物用叔丁基甲基醚(10mL×2)洗涤，合并有机层，再次用NaOH(2N aq.,10mL)洗涤。合并水相，用HCl(6N)酸化至pH＝4.2，然后用乙酸乙酯萃取，合并有机层，干燥，过滤，浓缩，粗产品称重，取其1/14，以MeNO2作为内标计算核磁产率为65％；1H NMR(400MHz,Methanol-d4)δ8.13(d,J＝8.4Hz,1H),7.83(d,J＝8.9Hz,1H),7.70(d,J＝8.0Hz,1H),7.51(t,J＝7.4Hz,1H),7.47–7.35(m,1H),6.99(d,J＝8.8Hz,1H).13CNMR(101MHz,Methanol-d4)δ172.49,151.36,138.08,129.32,129.12,128.35,125.92,124.80,123.63,115.97,104.67.IR(film)3361,2920,1668,1620,1552,1433,1300,1261,1236,1211,785,763cm-1.HRMS(EI)Calcd for C11H9NO2 187.0633,Found 187.0637.
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求书为保护范围。

Claims (5)

1.一种邻氨基苯甲酸及其衍生物的合成方法，其特征在于，在溶剂中，以式（I）邻甲基（杂）芳基硝基化合物为反应原料，在水、催化剂、碱和添加剂的作用下，在加热的条件下，进行反应合成所述邻氨基苯甲酸及其衍生物，其结构如式（II）所示，所述反应过程如下反应式（a）所示：
Figure 577786DEST_PATH_IMAGE001
反应式（a）
其中，A环是苯基、萘环、吡啶环、喹啉环、异喹啉环；所述R是氢、甲基、乙基、丙基、丁基、异丙基、叔丁基、甲氧基、苄氧基、三氟甲基、卤素、氰基、砜基、胺酰基、醛基、羧基、苯基、萘基、卤素取代的苯基；
所述反应在氮气氛围下进行；所述氮气压力为1-5个大气压；
所述催化剂为硒；所述催化剂的摩尔用量为所述式（I）邻甲基（杂）芳基硝基化合物摩尔用量的5-50mol%；
所述添加剂选自硝基苯、氯化钴中的一种或两种；所述添加剂的摩尔用量为所述式（I）邻甲基（杂）芳基硝基化合物摩尔用量的0.1-2当量。
2.如权利要求1所述的合成方法，其特征在于，所述溶剂选自甲醇、乙醇、DMSO之任意一种或任意组合；所述加热的温度为80-120℃；所述反应的时间为12-96 h。
3.如权利要求1所述的合成方法，其特征在于，所述碱选自氢氧化钠、氢氧化钾、氢氧化铯、氢氧化锂、叔丁醇锂、叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、碳酸铯中的一种或多种。
4.如权利要求1所述的合成方法，其特征在于，所述碱的摩尔用量为所述式（I）邻硝基（杂）芳香硝基化合物的1.5~4当量。
5.如权利要求1所述的合成方法，其特征在于，所述水的摩尔用量为所述式（I）邻硝基（杂）芳香硝基化合物的0.5-100当量。
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