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CN116354857B - 一种β-氨基砜及其衍生物的制备方法 - Google Patents

一种β-氨基砜及其衍生物的制备方法 Download PDF

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CN116354857B
CN116354857B CN202310180159.5A CN202310180159A CN116354857B CN 116354857 B CN116354857 B CN 116354857B CN 202310180159 A CN202310180159 A CN 202310180159A CN 116354857 B CN116354857 B CN 116354857B
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ethyl acetate
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CN116354857A (zh
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张卫东
王金鑫
张宇
桑冀威
杜佩豫
夏丁丁
吕帅澎
祖先鹏
田赛赛
胡志敏
程照溪
陈鸿
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Second Military Medical University SMMU
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Abstract

本发明公开了一种β‑氨基砜及其衍生物的制备方法，属于有机合成技术领域。以化合物1和化合物2为原料，在有机溶剂中光催化剂存在下光照反应，得到β‑氨基砜及其衍生物3；接着在醋酸存在下，与化合物5反应，得到阿普斯特及其类似物4。本发明采用常压下利用光催化偶联反应，合成阿普斯特中间体及其类似物，具有合成工艺简便，易于操作，可显著提高合成产率，环境污染小，绿色环保等优点，同时产品具有广阔的应用前景和市场需求。

Description

一种β-氨基砜及其衍生物的制备方法
技术领域
本发明涉及到一种β-氨基砜及其衍生物的制备方法，属于有机合成技术领域。
背景技术
β-氨基砜类化合物具有重要的价值，广泛存在于各种药物、农用化学品和天然产品中。如阿普斯特，一种用于治疗活动性银屑病关节炎的磷酸二酯酶4(PDE4)抑制剂，在2021全年销售额达到22.49亿美元。
目前，合成β-氨基砜的经典方法有：对烯基砜的氮杂迈克尔加成和环加成，砜类化合物在碱性条件下立体选择性加成亚胺或其等价物，β-氨基乙烯砜不对称氢化反应。然而，这些方法通常步骤繁琐，且官能团耐受性有限，不适用于制备多样性的β-氨基砜类化合物。烯烃双官能团化反应是合成邻二官能团的简单而普遍方法。由于磺酰自由基前体的丰富性和易得性，磺酰自由基参与的双功能化反应已被广泛研究，用于β-官能团取代砜类化合物的合成。然而对于β-氨基砜的合成报道却很有限，这源于在自由基极性交叉串联策略中较少的含氮亲核试剂能够与氧化条件兼容。而采用双自由基参与的反应，仅有苯乙烯与磺酸钠和芳胺的1,2-氨基磺酰化这一特殊底物反应，不能够实现对β-氨基砜类化合物广谱的合成。反应方程式表示如下：
上述反应使用危险试剂、额外的氧化或还原剂且底物范围狭窄。而β-氨基砜类化合物分子中的不同的官能团对其生物学性质影响显著，结构的多样性是扩展生物相关化学空间的基础。因此开发能够高效绿色合成结构丰富的β-氨基砜类化合物仍然是个挑战。
发明内容
为了克服上述技术缺陷，本发明提供了一种安全、绿色、高效β-氨基砜及其衍生物的制备方法。以化合物1和化合物2为原料，在有机溶剂中光催化剂存在下光照反应，得到β-氨基砜及其衍生物3；接着在醋酸存在下，与化合物5反应，得到阿普斯特及其类似物4。本发明采用常温常压下利用光催化双自由基偶联反应，合成阿普斯特中间体及其类似物，具有合成工艺简便，易于操作，可显著提高合成产率，环境污染小，绿色环保等优点。
本发明所述一种β-氨基砜及其衍生物的制备方法，包括以下步骤：以化合物1和化合物2为原料，在有机溶剂中光催化剂存在下光照反应，得到β-氨基砜及其衍生物3；反应方程式表示如下：
其中：R1选自C1～C20直链烷基、C1～C20支链烷基、苯基、C1～C20支链烷氧基、芳香性杂环、带有吸电子或给电子基芳基；R2选自C1～C20直链烷基、C1～C20支链烷基、C1～C20直链烷氧基、C1～C20支链烷氧基、氢、卤素、硝基、氨基；R3选自C1～C20直链烷基、C1～C20支链烷基、C1～C20直链烷氧基、C1～C20支链烷氧基、氢、卤素、硝基、氨基；R4选自C1～C20直链烷基、C1～C20支链烷基、C1～C20直链烷氧基、C1～C20支链烷氧基、苯基、芳香性杂环、带有吸电子或给电子基团的芳基、三氟甲基、氢、酯基、腈基、酰基；R5选自C1～C20直链烷基、C1～C20支链烷基、C1～C20直链烷氧基、C1～C20支链烷氧基、苯基、芳香性杂环、带有吸电子或给电子基团的芳基、三氟甲基、氢、酯基、腈基、酰基；R6选自氢、C1-C6烷基。
进一步地，在上述技术方案中，所述R1选自4-叔丁基苯基、4-三氟甲氧基苯基、4-腈基苯基、四甲基吡啶、环丙烷等；卤素选自溴；R4选自4-叔丁基苯基、4-甲氧基苯基、吡啶、4-乙酯苯基、联芳基等；R5选自4-叔丁基苯基、4-甲氧基苯基、吡啶、4-乙酯苯基、联芳基等。
进一步地，在上述技术方案中，所述光催化剂选自(4,4'-二叔丁基-2,2'-联吡啶)双[(2-吡啶基)苯基]铱(III)六氟磷酸盐、9-噻吨酮、二[2-(2,4-二氟苯基)-5-三氟甲基吡啶][2-2'-联(4-叔丁基吡啶)]铱二(六氟磷酸)盐、2,4,5,6-四(9-咔唑基)-间苯二腈、9,10-蒽醌、3,4,5,6-四(3,6-二叔丁基-9-咔唑基)-对苯二腈或fac-Ir(2-苯基吡啶基)3。
进一步地，在上述技术方案中，所述化合物1、化合物2与光催化剂摩尔比为1.2-1.6：1：0.01-0.05。
进一步地，在上述技术方案中，所述有机溶剂选自丙酮、乙腈、二氯甲烷、四氢呋喃、甲醇、甲苯、乙酸乙酯或N,N-二甲基甲酰胺，优选为乙酸乙酯。
进一步地，在上述技术方案中，光照反应波长范围为390-456nm。
进一步地，在上述技术方案中，反应温度为30-60℃，优选为40℃。
本发明还提供了一种阿普斯特及其类似物4的合成方法，包括如下步骤：采用上述方法得到β-氨基砜及其衍生物3A，接着将所得产物3A在醋酸存在下，与化合物5反应，得到阿普斯特及其类似物4；反应方程式表示如下：
其中：R7-R9各自独立选自H、C1～C20直链烷基、C1～C20支链烷基、苯基、带芳香性杂环、甲氧基、乙氧基。
发明有益效果：
本发明采用常压下利用光催化偶联反应，合成阿普斯特中间体及其类似物，具有合成工艺简便，易于操作，可显著提高合成产率，环境污染小，绿色环保等有点。同时产品具有广阔的应用前景和市场需求。
具体实施方式
为了更清楚地说明本发明，下面结合优选实施例对本发明做进一步的说明。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
条件优化实验
1、光催化剂筛选：
在干燥反应瓶中加入磁力搅拌子，充入氩气保护，依次加入光催化剂、N-二苯基亚甲基-4-甲基苯磺酰胺(0.15mol，50.3mg)和苯乙烯(0.1mol，10.4mg)，接着加入1mL乙酸乙酯溶解，充入氩气保护。密封后在光催化剂激发波长光源下光照，光源距离反应瓶约6cm，风扇降温，控制温度为40℃，3小时后加入5mL乙酸乙酯稀释，减压浓缩，直接通过柱层析分离纯化(正己烷：乙酸乙酯＝10:1)，得到β-氨基砜化合物。筛选结果如下：
采用各种光催化剂催化上述反应，分别使用(4,4'-二叔丁基-2,2'-联吡啶)双[(2-吡啶基)苯基]铱(III)六氟磷酸盐、9-噻吨酮、二[2-(2,4-二氟苯基)-5-三氟甲基吡啶][2-2'-联(4-叔丁基吡啶)]铱二(六氟磷酸)盐、2,4,5,6-四(9-咔唑基)-间苯二腈、9,10-蒽醌、3,4,5,6-四(3,6-二叔丁基-9-咔唑基)-对苯二腈、fac-Ir(2-苯基吡啶基)3在室温下进行催化反应，其中(4,4'-二叔丁基-2,2'-联吡啶)双[(2-吡啶基)苯基]铱(III)六氟磷酸盐、9-噻吨酮收率较好，产率分别达到74％和71％。随后升温到40℃产率分别达到85％和81％。
2、溶剂筛选：
在干燥反应瓶中加入磁力搅拌子，充入氩气保护，依次加入9-噻吨酮(0.05mol，1.1mg)、N-二苯基亚甲基-4-甲基苯磺酰胺(0.15mol，50.3mg)和苯乙烯(0.1mol，10.4mg)，加入1mL溶剂溶解，充入氩气保护。密封后在390nm光源下光照，光源距离反应瓶约6cm，风扇降温，控制温度为40℃，3小时后加入5mL乙酸乙酯稀释，减压浓缩，直接通过柱层析分离纯化(正己烷：乙酸乙酯＝10:1)，得到β-氨基砜。筛选结果如下：
分别使用各种溶剂，在相同浓度下(0.1M)下催化上述反应，使用乙酸乙酯产率最佳(85％)，也可使用乙腈、二氯乙烷、四氢呋喃、甲苯、丙酮、N,N–二甲基甲酰胺等，但甲醇产率不佳，不适合使用。
实施例1
在干燥反应瓶中加入磁力搅拌子，充入氩气保护，依次加入9-噻吨酮(0.05mol，1.1mg)，N-(二苯基亚甲基)甲烷磺酰胺(0.15mol，38.9mg)、2-乙氧基-1-甲氧基-4-乙烯基苯(0.1mol，17.8mg)，加入1mL乙酸乙酯溶解，充入氩气保护。密封后在390nm光源下光照，光源距离反应瓶约6cm，风扇降温，控制温度为40℃，3小时后加入5mL乙酸乙酯稀释，减压浓缩，直接通过柱层析分离纯化(正己烷：乙酸乙酯＝10:1)，得到产物27.5mg。1H NMR(500MHz,CDCl3):δ＝7.69–7.68(m,2H),7.42–7.33(m,6H),7.01–6.99(m,2H),6.76(d,J＝8.3Hz,1H),6.70(dd,J＝8.3,2.0Hz,1H),6.59(d,J＝2.0Hz,1H),4.95(dd,J＝9.3,3.1Hz,1H),4.02–3.97(m,2H),3.91–3.84(m,1H),3.84(s,3H),3.30–3.26(m,1H),2.88(s,3H),1.43(t,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3):δ＝170.3,148.8,148.4,139.0,136.1,134.2,130.8,128.8,128.6,128.5,128.4,127.6,119.2,111.7,111.5,64.4,63.4,61.4,56.0,43.3,14.9.HRMS(m/z):[M+H]+calcd for C25H28NO4S+438.1734,found 438.1749.
实施例2
在干燥反应瓶中加入磁力搅拌子，充入氩气保护，依次加入9-噻吨酮(0.05mol，1.1mg)，N-二苯基亚甲基-4-甲基苯磺酰胺(0.15mol，50.3mg)、4-氟苯乙烯(0.1mol，12.2mg)，加入1mL乙酸乙酯溶解，充入氩气保护。密封后在390nm光源下光照，光源距离反应瓶约6cm，风扇降温，控制温度为40℃，3小时后加入5mL乙酸乙酯稀释，减压浓缩，直接通过柱层析分离纯化(正己烷：乙酸乙酯＝10:1)，得到产物36.7mg。1H NMR(500MHz,CDCl3):δ＝7.64(d,J＝8.2Hz,2H),7.44–7.34(m,6H),7.27–7.23(m,2H),7.16(d,J＝8.0Hz,2H),7.07–7.04(m,2H),6.99(d,J＝6.9Hz,2H),6.92–6.89(m,2H),5.00(dd,J＝9.1,3.1Hz,1H),4.00(dd,J＝14.4,9.1Hz,1H),3.44(dd,J＝14.4,3.1Hz,1H),2.34(s,3H).13C NMR(125MHz,CDCl3):δ＝169.3,162.1(d,JC-F＝246.0Hz),144.3,139.2,138.1(d,JC-F＝3.4Hz),137.6,136.2,130.5,129.8,128.9,128.6(d,JC-F＝8.0Hz),128.5,128.1,127.9,127.8,115.7(d,JC-F＝21.4Hz),64.6,60.8,21.7.19F NMR(282MHz,CDCl3):δ＝-114.54.HRMS(m/z):[M+H]+calcd for C28H25FN O2S 458.1585,found 458.1593.
实施例3
在干燥反应瓶中加入磁力搅拌子，充入氩气保护，依次加入9-噻吨酮(0.05mol，1.1mg)，N-(二苯基亚甲基)-5-甲基吡啶-2-磺酰胺(0.15mol，50.4mg)，二苯乙烯(0.10mol，18.1mg)，加入1.0mL乙酸乙酯溶解，充入氩气保护。密封后在390nm光源下光照，光源距离反应瓶约6cm，风扇降温，控制温度为40℃，3小时后加入5.0mL乙酸乙酯稀释，减压浓缩，直接通过柱层析分离纯化(正己烷：乙酸乙酯＝10:1)，得到产物46.5mg。1H NMR(500MHz,CDCl3):δ＝8.16(d,J＝2.0Hz,1H),7.53–7.51(m,3H),7.38–7.27(m,4H),7.19–7.02(m,13H),6.72(d,J＝7.4Hz,2H),4.61(s,2H),2.13(s,3H).13C NMR(125MHz,CDCl3):δ＝168.8,155.2,150.1,147.2,141.5,138.2,137.7,137.0,130.3,128.7,127.9,127.8,127.7,127.4,127.4,126.3,122.4,66.4,61.6,18.5.HRMS(m/z):[M+H]+calcd for C33H29N2O2S517.1944,found 517.1947.
实施例4
在干燥反应瓶中加入磁力搅拌子，充入氩气保护，依次加入9-噻吨酮(0.05mol，1.1mg)，N-(二苯基亚甲基)-4-(三氟甲氧基)苯磺酰胺(0.15mol，60.8mg)、二苯乙烯(0.1mol，18.1mg)，加入1mL乙酸乙酯溶解，充入氩气保护。密封后在390nm光源下光照，光源距离反应瓶约6cm，风扇降温，控制温度为40℃，3小时后加入5mL乙酸乙酯稀释，减压浓缩，直接通过柱层析分离纯化(正己烷：乙酸乙酯＝10:1)，得到产物56.2mg。1H NMR(500MHz,CDCl3):δ＝7.71–7.69(m,2H),7.49–7.37(m,5H),7.21–7.18(m,1H),7.10–6.97(m,14H),6.67(d,J＝7.1Hz,2H),4.40(s,2H).13C NMR(125MHz,CDCl3):δ＝170.0,152.3(q,JC-F＝1.9Hz),147.2,141.6,138.8,138.4,130.8,130.5,128.8,128.2,128.2,127.7,127.5,127.4,127.1,126.5,120.3,120.3(q,JC-F＝259.4Hz),65.8,65.7.19F NMR(282MHz,CDCl3):δ＝-57.48.HRMS(m/z):[M+H]+ calcd for C34H27F3NO3S 586.1658,found 586.1662.
实施例5
在干燥反应瓶中加入磁力搅拌子，充入氩气保护，依次加入9-噻吨酮(0.05mol，1.1mg)，(二苯基亚甲基)甲烷磺酰胺(0.15mol，38.9mg)、二苯乙烯(0.1mol，18.1mg)，加入1mL乙酸乙酯溶解，充入氩气保护。密封后在390nm光源下光照，光源距离反应瓶约6cm，风扇降温，控制温度为40℃，3小时后加入5mL乙酸乙酯稀释，减压浓缩，直接通过柱层析分离纯化(正己烷：乙酸乙酯＝10:1)，得到产物37.3mg。1H NMR(500MHz,CDCl3):δ＝7.72–7.70(m,2H),7.40–7.33(m,7H),7.25–7.19(m,7H),7.10(t,J＝7.7Hz,2H),6.62(d,J＝7.0Hz,2H),4.06(s,2H),2.20(s,3H).13C NMR(125MHz,CDCl3):δ＝169.8,147.5,141.7,138.2,130.4,128.7,128.5,128.2,127.8,127.7,127.6,127.5,127.1,64.6,43.1.HRMS(m/z):[M+H]+calcd for C28H26NO2S 440.1679,found 440.1693.
实施例6
在干燥反应瓶中加入磁力搅拌子，充入氩气保护，依次加入9-噻吨酮(0.05mol，1.1mg)，N-二苯基亚甲基-4-甲基苯磺酰胺(0.15mol，50.3mg)、4-乙烯基联苯(0.1mol，18.0mg)，加入1mL乙酸乙酯溶解，充入氩气保护。密封后在390nm光源下光照，光源距离反应瓶约6cm，风扇降温，控制温度为40℃，3小时后加入5mL乙酸乙酯稀释，减压浓缩，直接通过柱层析分离纯化(正己烷：乙酸乙酯＝10:1)，得到产物38.1mg。1H NMR(500MHz,CDCl3):δ＝7.65(d,J＝8.3Hz,2H),7.54–7.52(m,2H),7.46–7.40(m,9H),7.38–7.32(m,2H),7.28–7.24(m,2H),7.17–7.15(m,4H),7.05(d,J＝7.1Hz,2H),5.06(dd,J＝9.2,3.0Hz,1H),4.06(dd,J＝14.5,9.2Hz,1H),3.52(dd,J＝14.5,3.0Hz,1H),2.33(s,3H).13C NMR(125MHz,CDCl3):δ＝169.2,144.2,141.3,140.7,140.5,137.7,136.3,130.4,129.8,128.9,128.8,128.5,128.1,127.9,127.9,127.5,127.5,127.1,64.6,61.3,21.7.HRMS(m/z):[M+H]+calcd forC34H30NO2S 516.1992,found 516.2001.
实施例7
按照实施例1-6操作，仅仅改变原料1和原料2，得到系列β-氨基砜及其衍生物3，反应结果如下：
对比例1
在干燥的反应瓶中加入二甲基亚砜(0.8g,10.7mmol)和四氢呋喃(70mL)后置于-70℃干冰丙酮浴中，滴加.n-BuLi(2.5M in hexanes,4.6mL,11.5mmol)并在该温度下继续搅拌0.5小时，得到二甲基亚砜/丁基锂溶液。.在另一反应瓶中加入苯甲醛(1.9g,10.0mmol)并用THF(20mL)溶解置于0℃环境下，加入LiHMDS(1M in THF,12mL)搅拌15分钟后加入三氟化硼-乙醚溶液(2.8mL,22mmol)继续搅拌5分钟。将上述溶液在-70℃条件下加入到二甲基亚砜/丁基锂反应瓶中，体系升至室温搅拌过夜反应。再将体系置于冰水浴中，分别加入碳酸钾(8g)和水(50mL)。水层用乙酸乙酯萃取2次(2*20mL)合并有机层并用硫酸钠干燥。浓缩后分别加入MTBE(30mL)和4N盐酸(30mL)室温反应2小时。反应结束有机层4N盐酸萃取，合并水相，并用氢氧化钠溶液调节pH>12。加入乙酸乙酯萃取3次(3*50mL)。合并有机相，干燥、旋干得到黄色固体产物(106.5mg,3.9mmol)，产率为39％。
对比例2
在充满氮气干燥密封管中，将CuCl(2.0mg,0.02mmol,10mol％)和三氟甲基磺酸钠(0.3mmol,1.5eq)溶于CH3CN(1.0mL)和H2O(0.3mL)混合溶剂，然后加入烯烃底物(0.2mmol,1.0eq)和TMSN3(54μL,0.4mmol,2eq)。接着混合物60℃搅拌16小时。加入乙酸乙酯(5mL)，NaHCO3溶液(5mL)和盐水(10mL)洗涤，无水硫酸钠干燥，真空浓缩有机层。粗产品硅胶柱层析纯化，石油醚/乙酸乙酯梯度洗脱得到产物。在充满氮气干燥密封管中，将原料(1.0g,3.34mmol,1eq)溶解在四氢呋喃(20.0mL)和H2O(5mL)混合溶剂中，然后加入PPh3(2.19g,8.35mmol,2.5eq)。将反应混合物在60℃下搅拌6小时。经旋转蒸发浓缩后用EA和水萃取，将有机相用无水硫酸钠干燥，真空浓缩有机层。反应粗产物硅胶柱层析纯化，PE/EA＝5/1梯度洗脱得到产物(794.2mg,2.91mmol)。
上述实施例收率情况对比如下：
步骤(共计) 收率％
实施例1 1 65
实施例2 1 75
实施例3 1 90
实施例4 1 96
实施例5 1 85
实施例6 1 74
对比例1 2 39
对比例2 2 67
本发明同对比例相比，只需要加光催化剂与原料，合成工艺简便，步骤少，易于操作，且反应几乎无副产物，原子经济性高，对环境污染小，绿色环保。本发明能够保证整个产品的质量得到进一步的提升，具有广阔的应用前景和市场需求。
实施例8
在配有搅拌250mL耐压管中，加入1-(3-乙氧基-4-甲氧基苯基)-2-甲基磺酰乙基-1,1-二苯基甲胺(1.84g,4.2mmol)和AcOH溶液(50mL)，搅拌均匀后，接着加入3-对乙酰氨基邻苯二甲酸酐(947.3mg,4.2mmol,1.1eq)，密封反应管。油浴120℃加热搅拌18h。反应结束后，旋转蒸发除去溶剂，然后用乙酸乙酯提取，用Na2SO4干燥，过滤，真空浓缩。然后立即用硅胶(Pet/EtOAc,2/1,v/v)闪色谱纯化粗混合物，得到产物阿普斯特(1.84g，收率95％)，并循环使用二苯甲酮(741.8mg，收率97％)。
以上所述仅是本发明的较佳实施例而已，并非对本发明作任何形式上的限制，虽然本发明已以较佳实施例揭露如上，然而并非用以限定本发明，任何熟悉本专利的技术人员在不脱离本发明技术方案范围内，当可利用上述提示的技术内容作出些许更动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属于本发明方案的范围内。

Claims (3)

1.一种β-氨基砜3的制备方法，其特征在于，包括以下步骤：以化合物1和化合物2为原料，在有机溶剂中光催化剂存在下光照反应，得到β-氨基砜3；反应方程式表示如下：
其中：R1为甲基，R2-R4和R6 为氢，R5为3-乙氧基-4-甲氧基苯基；所述有机溶剂为乙酸乙酯；反应温度为40℃；所述光催化剂为(4,4'-二叔丁基-2,2'-联吡啶)双[(2-吡啶基)苯基]铱(III)六氟磷酸盐或9-噻吨酮；光照反应的波长为390nm。
2.根据权利要求1所述β-氨基砜及其衍生物的制备方法，其特征在于：所述化合物1、化合物2与光催化剂摩尔比为1.2 -1.6：1：0.01-0.05。
3.一种阿普斯特4的合成方法，其特征在于，包括如下步骤：采用权利要求1或2所述方法得到β-氨基砜3，接着将所得产物3在醋酸存在下，与化合物5反应，得到阿普斯特4；反应方程式表示如下：
其中：R7为甲氧基，R8为氢，R9为乙氧基。
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