CN110981838B - 5-亚胺-四氢呋喃基甲胺衍生物及其制备方法和应用 - Google Patents

5-亚胺-四氢呋喃基甲胺衍生物及其制备方法和应用 Download PDF

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CN110981838B
CN110981838B CN201911246366.6A CN201911246366A CN110981838B CN 110981838 B CN110981838 B CN 110981838B CN 201911246366 A CN201911246366 A CN 201911246366A CN 110981838 B CN110981838 B CN 110981838B
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何炜
邓晓军
刘慧霞
张露文
兰婷
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Abstract

本发明公开了结构通式（I）所示的5‑亚胺‑四氢呋喃基甲胺衍生物，其中：R1、R2独立地选自芳基、C1~C6的烷基，或R1和R2整体为环烷基、氧杂环烷基或氮杂环烷基；R3为甲基或氢，R4为甲基或氢，Z为苯基、甲氧基或苄基。本发明以取代的烯胺为底物，采用碘催化实现了一步构建3,3‑取代的甲胺基呋喃亚胺骨架，反应条件温和，操作简单，底物适用范围广，原料廉价易得。

Description

5-亚胺-四氢呋喃基甲胺衍生物及其制备方法和应用
技术领域
本发明涉及一种5-亚胺-四氢呋喃基甲胺衍生物及其制备方法和应用，属于医药技术领域。
背景技术
5-亚胺-四氢呋喃基甲胺衍生物是一类具有重要的生物活性的化合物，广泛存在于天然产物中，是天然产物分子中最常见的基本骨架。该类化合物性质多样，被广泛用于药物研发，精细化学品开发等诸多领域。美国的John S. Baran教授课题组首次报道了一类以1,2氧胺结构为基本骨架的药物活性分子3-烷基-3-苯基取代-5二氢甲胺基呋喃酮或亚胺类似物的合成方法， 其以2位烷基取代的苯乙酸或苯乙腈为原料，经过酯化、烯丙基偶联、环氧化、环胺化和氨基烷基化等反应步骤得到相应的目标化合物。药理活性实验证明，该类化合物具有很好的抗心律失衡作用，且与喹啉定、达舒平等一些传统的抗心律失衡药物相比具有更小的毒副作用，并可以通过口服给药。
2011年，Daniel J. Canney教授报道了一类新型毒蕈碱受体，基本骨架也是3,3二乙基取代-5价胺基呋喃酮结构，该类化合物通过3,3而取代的烯丙基戊酸经环碘化反应，进一步通过二级胺的亲电取代反应得到目标化合物。但该路线的不足之处是构建的氨基基团必须是二级胺。
Georges B. Foscolos课题组在甲胺基呋喃酮的3位引入芴基，得到了一类三环抗抑郁药物活性分子，该路线同样必需使用二级胺为氮源，限制了分子的多样性。
发明内容
本发明目的是提供一类具有重要生物活性的5-亚胺-四氢呋喃基甲胺衍生物；
本发明另一目的是提供一种工艺简单、反应条件温和、环境污染小，且易于大规模生产5-亚胺-四氢呋喃基甲胺衍生物的新方法。
本发明实现过程如下：
结构通式（I）所示的5-亚胺-四氢呋喃基甲胺衍生物：
Figure 796826DEST_PATH_IMAGE001
其中：R1、R2独立地选自芳基、C1~C6的烷基，或R1和R2整体为环烷基、氧杂环烷基或氮杂环烷基；R3 为甲基或氢，R4为甲基或氢，Z为苯基、甲氧基或苄基。
上述芳基优选为苯基。
上述5-亚胺-四氢呋喃基甲胺衍生物的制备方法，
Figure 445457DEST_PATH_IMAGE002
以烯丙基酰胺（II）为原料，在室温下，间氯过氧苯甲酸（mCPBA）为氧化剂，对甲苯磺酰苯磺酰胺（HNTs 2）为氮源，六氟异丙醇（HFIP）为溶剂，2,6-二甲氧基碘苯催化下发生氧胺化反应，得到5-亚胺-四氢呋喃基甲胺衍生物（I）。
本发明化合物很容易进一步进行分子改造得到生物活性化合物，例如：（1）5-亚胺-四氢呋喃基甲胺衍生物（I）使用H4LiAl还原开环，脱保护基合成得到化合物（III），
Figure 225194DEST_PATH_IMAGE003
。
（2）5-亚胺-四氢呋喃基甲胺衍生物（I）经过水解，脱保护基，还原胺化反应得到化 合物（
Figure 86315DEST_PATH_IMAGE004
），
Figure 900688DEST_PATH_IMAGE005
化合物（
Figure 516958DEST_PATH_IMAGE004
）中，R5为任意基团。
（3）5-亚胺-四氢呋喃基甲胺衍生物（I）经过水解，脱保护基，还原胺化反应得到化 合物（
Figure 783991DEST_PATH_IMAGE006
），
Figure 472241DEST_PATH_IMAGE007
化合物（
Figure 675208DEST_PATH_IMAGE006
）中，R5为任意基团。
本发明以取代的烯胺为底物，采用碘催化，实现了一步构建3,3-取代的甲胺基呋喃亚胺骨架。本发明反应条件温和，可以在空气条件下进行；非金属催化反应，避免了有毒过渡金属的使用；操作简单，底物适用范围广；原料廉价易得。
具体实施方式
下面通过实施例对本发明进行详述，但本发明并不限于这些实施例。
实施例1
向装有磁子的反应瓶中加入2,6-二甲氧基碘苯（15 mol%），对甲苯磺酰苯磺酰胺（HNTs 2，1.5 equiv.），间氯过氧苯甲酸（mCPBA，1.5 equiv.）和2.0 mL六氟异丙醇（HFIP）。反应混合物需要在室温条件下预先搅拌10分钟，然后加入底物相应的烯胺底物（0.20mmol, 1.0 equiv.）, 反应试管用塞子密封，反应混合物室温条件下继续搅拌7小时。 反应完成后（通过TLC监测），用旋转蒸发仪除去溶剂，得到的残渣加入10ml 氢氧化钠溶液（NaOH，1.0M，aq.），并搅拌10分钟。完成上述步骤后，再用二氯甲烷（15 mL×3）萃取、饱和氯化钠溶液水洗、无水硫酸钠干燥、过滤并在真空下浓缩。得到的粗产物用快速柱色谱纯化,得到5-亚胺-四氢呋喃基甲胺衍生物1a-1k。
Figure 472435DEST_PATH_IMAGE009
所得产物经简单转化可以方便的得到具有潜在药物活性的1,2氧胺化合物、3,3-二取代-5-甲胺基呋喃酮以及3,3-二取代的四氢呋喃甲胺化合物。以1b为例进行产物的进一步转化。
Figure 706058DEST_PATH_IMAGE010
产物结构表征：
(Z)-N-((4,4-dimethyl-5-(phenylimino)tetrahydrofuran-2-yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (1a). m.p.: 90.0 – 91.3 oC; Major isomershown: 1H NMR (600 MHz, CDCl3), δ 7.79 (d, J = 8.4 Hz, 4H), 7.29 – 7.24 (m,2H), 7.19 (d, J = 8.4 Hz, 4H), 7.06 (d, J = 7.8 Hz, 2H), 7.02 (t, J = 7.2 Hz,1H), 4.71 (ddt, J = 13.8, 7.1, 4.2 Hz, 1H), 4.13 (dd, J = 15.6, 7.2 Hz, 1H),3.57 (dd, J = 15.6, 3.6 Hz, 1H), 2.41 (s, 6H), 2.07 (dd, J = 12.6, 6.0 Hz,1H), 1.75 (dd, J = 12.6, 10.2 Hz, 1H), 1.37 (s, 3H), 1.30 (s, 3H); 13C NMR(150 MHz, CDCl3): δ 167.0, 147.2, 145.0, 136.1, 129.5, 128.6, 128.5, 123.3,122.4, 77.7, 51.6, 41.8, 40.8, 26.3, 26.3, 21.6; IR (neat): 2968, 1701, 1595,1492, 1373, 1352, 1167, 1164, 1045, 912, 815, 729, 663, 552 cm-1; HRMS (ESI):Calcd for (C27H30N2O5S2) ([M+H]+): 527.1669; found: 527.1672。
(Z)-N-((4,4-diethyl-5-(phenylimino)tetrahydrofuran-2-yl)methyl)-4-methyl-N-tosylbenzenesulfonamide (1b). mp: 97.2 – 98.4 oC;1H NMR (600 MHz,CDCl3): δ 7.79 (d, J = 8.4 Hz, 4H), 7.28 – 7.24 (m, 2H), 7.19 (d, J = 8.4 Hz,4H), 7.01 (dd, J = 15.5, 7.8 Hz, 3H), 4.66 (qt, J = 7.1, 4.2 Hz, 1H), 4.09(dd, J = 15.5, 7.3 Hz, 1H), 3.54 (dd, J = 15.6, 4.2 Hz, 1H), 2.41 (s, 6H),1.99 (dd, J = 13.2, 6.6 Hz, 1H), 1.82 (dd, J = 13.2, 9.6 Hz, 1H), 1.73 – 1.64(m, 4H), 0.97 (td, J = 7.2, 3.0 Hz, 6H);13C NMR (150 MHz, CDCl3): δ 165.5,147.6, 145.0, 136.3, 129.6, 128.6, 128.6, 123.2, 122.3, 77.9, 52.1, 48.6,36.0, 31.0, 29.7, 21.7, 8.8; IR (neat): 2959, 1701, 1596, 1495, 1373, 1354,1184, 1167, 1086, 852, 732, 663, 552 cm-1; HRMS (ESI): Calcd for (C29H34N2O5S2)([M+H]+): 555.1982; found: 555.1985。
(Z)-N-((4,4-dimethyl-5-methoxyimino-tetrahydrofuran-2-yl)methyl)-N-tosyl-(4-methylbenzenesulfon)amide (1c).mp: 42.5 – 43.8 oC; 1H NMR (400 MHz,CDCl3): δ 8.00 (d, J = 8.0 Hz, 4H), 7.34 (d, J = 8.0 Hz, 4H), 4.76 (dp, J =12.4, 6.8, 6.0 Hz, 1H), 4.17 (dd, J = 15.6, 6.8 Hz, 1H), 3.85 (s, 3H), 3.74(dd, J = 15.6, 5.2 Hz, 1H), 2.45 (s, 6H), 1.94 (dd, J = 12.4, 5.6 Hz, 1H),1.79 – 1.69 (m, 1H), 1.24 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 162.7, 145.2,136.3, 129.6, 128.9, 79.1, 62.1, 51.2, 42.7, 40.3, 26.9, 26.0, 21.7; HRMS(ESI): Calcd for (C21H26N2O5S2) ([M+H]+): 481.1462; found: 481.1461。
(Z)-N-((4,4-dimethyl-5-benzyliminotetrahydrofuran-2-yl)methyl)-N-tosyl-(4-methylbenzenesulfon)amide (1d). mp: 103.7 – 105.0 oC; Major isomershown; 1H NMR (600 MHz, CDCl3): δ 7.97 – 7.91 (m, 4H), 7.78 – 7.73 (m, 1H),7.28 (s, 1H), 7.24 (s, 6H), 7.21 (t, J = 7.2 Hz, 1H), 4.72 (dtd, J = 9.6,6.6, 6.0, 3.6Hz, 1H), 4.48 – 4.36 (m, 2H), 4.09 (dd, J = 15.7, 7.4 Hz, 1H),3.66 (dd, J = 15.6, 3.6 Hz, 1H), 2.40 (s, 6H), 2.04 (dd, J = 12.6, 5.4 Hz,1H), 1.67 (dd, J = 12.6, 10.2 Hz, 1H), 1.23 (s, 3H);13C NMR (150 MHz, CDCl3):δ 168.1, 145.2, 143.4, 140.8, 139.3, 136.6, 129.7, 129.7, 128.4, 128.2,127.4, 126.4, 126.3, 76.9, 52.2, 50.8, 42.4, 40.4, 26.4, 26.3, 21.7, 21.5; IR(neat): 2962, 1717, 1589, 1497, 1375, 1333, 1300, 1167, 1109, 1041, 933, 862,820, 729, 663, 552 cm-1; HRMS (ESI): Calcd for (C28H32N2O5S2) ([M+H]+):541.1825; found: 541.1842。
(Z)-N-((4,4-dimethyl-5-phenylimino-tetrahydrofuran-2-yl)methyl)-N-tosyl-(4-methylbenzenesulfon)amide (1e). mp: 133.4 – 134.4 oC;Major isomershown, 1H NMR (600 MHz, CDCl3): δ 7.75 (d, J = 8.4 Hz, 4H), 7.41 (d, J = 7.8Hz, 2H), 7.36 (t, J = 7.8 Hz, 4H), 7.34 – 7.26 (m, 5H), 7.26 – 7.21 (m, 2H),7.20 – 7.13 (m, 6H), 7.05 (t, J = 7.8 Hz, 1H), 4.57 (dq, J = 10.8, 5.4 Hz,1H), 4.14 (dd, J = 15.6, 6.6 Hz, 1H), 3.69 (dd, J = 15.6, 5.4 Hz, 1H), 2.92(dd, J = 13.2, 5.4 Hz, 1H), 2.69 (dd, J = 13.2, 10.2 Hz, 1H), 2.40 (s, 6H);13CNMR (100 MHz, CDCl3): δ 162.7, 146.8, 145.1, 143.1, 141.7, 136.3, 129.7,128.6 (both), 128.4 (both), 128.1, 127.8, 127.4, 127.0, 123.8, 122.6, 77.1,57.9, 51.2, 42.6, 21.7;IR (neat): 2924, 2550, 1693, 1596, 1575, 1490, 1417,1375, 1303, 1275, 1163, 1083, 810, 750, 663, 552 cm-1; HRMS (ESI): Calcd for(C37H34N2O5S2) ([M+H]+): 651.1982; found: 651.1982。
(2R,3R,Z)-N-((3-methyl-4,4-diphenyl-5-phenyliminotetrahydrofuran-2-yl)methyl)-N-tosyl-(4-methylbenzenesulfon)amide (1f). mp: 156.5 – 157.2 oC; 1HNMR (600 MHz, CDCl3): δ 7.78 (d, J = 8.4 Hz, 4H), 7.52 (d, J = 7.8 Hz, 2H),7.34 (t, J = 7.8 Hz, 2H), 7.31 – 7.24 (m, 6H), 7.17 (d, J = 8.4 Hz, 4H), 7.10(d, J = 7.8 Hz, 2H), 7.02 (t, J = 7.2 Hz, 1H), 6.86 (dd, J = 6.6, 3.0 Hz,2H), 4.26 (dd, J = 15.6, 7.8 Hz, 1H), 4.15 (td, J = 9.0, 7.8, 1.8 Hz, 1H),3.74 (dd, J = 15.6, 1.8 Hz, 1H), 3.12 – 3.00 (m, 1H), 2.41 (s, 6H), 0.88 (d,J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 163.1, 147.1, 145.0, 141.2,141.1, 136.4, 129.6, 129.2, 129.1, 128.7, 128.6, 128.0, 127.8, 127.3, 127.1,123.6, 122.4, 82.3, 60.6, 50.8, 42.3, 21.8, 12.3; IR (neat): 3043,1693, 1593,1493, 1446, 1379, 1373, 1348, 1167, 1086, 1056, 843, 719, 698, 662, 550 cm-1;HRMS (ESI): Calcd for (C38H36N2O5S2) ([M+H]+): 665.2138; found: 665.2140。
(Z)-N-((2-methyl-4,4-diphenyl-5-phenyliminotetrahydrofuran-2-yl)methyl)-N-tosyl-(4-methylbenzenesulfon)amide (1g). mp: 92.7 – 94.3 oC; 1H NMR(600 MHz, CDCl3): δ 7.67 (d, J = 8.4 Hz, 4H), 7.58 (d, J = 7.8 Hz, 2H), 7.39(d, J = 7.8 Hz, 2H), 7.36 – 7.30 (m, 4H), 7.28 (d, J = 7.2 Hz, 2H), 7.23 (d,J = 7.8 Hz, 3H), 7.11 (d, J = 8.4 Hz, 4H), 7.06 (t, J = 7.2 Hz, 1H), 4.00 (d,J = 16.2 Hz, 1H), 3.86 (d, J = 16.2 Hz, 1H), 3.05 (s, 2H), 2.35 (s, 6H), 1.08(s, 3H); 13C NMR (150 MHz, CDCl3): δ 163.0, 147.3, 144.8, 144.5, 143.6, 136.4,129.4, 128.6, 128.6, 128.4, 128.2, 128.0, 127.9 (both), 126.9, 126.7, 123.5,122.5, 85.0, 58.0, 56.6, 48.4, 24.4, 21.6.IR (neat): 3059, 1693, 1595, 1491,1446, 1373, 1356, 1226, 1167, 1084, 910, 814, 766, 732, 662,552 cm-1; HRMS(ESI): Calcd for (C38H36N2O5S2) ([M+H]+): 665.2138; found: 665.2139。
(Z)-N-((1-phenylimino-2-oxaspiro[4.5]decan-3-yl)Methyl)-N-tosyl-(4-methylbenzenesulfon)amide (1h). mp: 81.7 – 82.3 oC; 1H NMR (600 MHz, CDCl3): δ7.80 (d, J = 8.4 Hz, 4H), 7.27 – 7.24 (m, 2H), 7.20 (d, J = 8.4 Hz, 4H), 7.08– 6.99 (m, 3H), 4.67 (dtd, J = 10.2, 6.6, 4.2 Hz, 1H), 4.12 (dd, J = 15.6,7.2 Hz, 1H), 3.58 (dd, J = 15.6, 4.2 Hz, 1H), 2.42 (s, 6H), 2.28 (dd, J =12.6, 6.0 Hz, 1H), 1.95 (td, J = 13.2, 3.6 Hz, 1H), 1.81 – 1.55 (m, 7H), 1.41– 1.16 (m, 3H); 13C NMR (150 MHz, CDCl3): δ 167.6, 147.2, 145.0, 136.2, 129.6,128.6, 128.5, 123.4, 122.4, 78.2, 51.8, 45.4, 37.2, 35.6, 33.4, 25.3, 22.8,22.6, 21.7; IR (neat): 2932, 1697, 1595, 1502, 1493, 1373, 1352, 1167, 1083,912, 815, 732, 662, 552 cm-1; HRMS (ESI): Calcd for (C30H29ClN2O6S3) ([M+H]+):581.2138; found: 581.2135。
(Z)-N-((1-phenylimino-2,8-oxaspiro[4.5]decan-3-yl)methyl)-N-tosyl-(4-methylbenzenesulfon)amide (1i). mp: 90.4 – 92.1 oC; 1H NMR (600 MHz, CDCl3): δ7.80 (d, J = 8.4 Hz, 4H), 7.29 – 7.25 (m, 2H), 7.21 (d, J = 8.4 Hz, 4H), 7.08(d, J = 7.2 Hz, 2H), 7.03 (t, J = 7.2 Hz, 1H), 4.72 (dtd, J = 9.0, 6.4, 6.0,3.6 Hz, 1H), 4.14 (dd, J = 15.6, 7.2 Hz, 1H), 4.05 (ddt, J = 51.0, 12.0, 4.0Hz, 2H), 3.61 (dd, J = 15.6, 4.2 Hz, 1H), 3.56 – 3.50 (m, 1H), 3.47 (td, J =11.4, 2.4 Hz, 1H), 2.42 (s, 6H), 2.33 (dd, J = 12.6, 6.0 Hz, 1H), 2.26 (ddd,J = 14.4, 10.8, 4.2 Hz, 1H), 1.99 (ddd, J = 14.4, 10.8, 4.2 Hz, 1H), 1.73(dd, J = 12.6, 10.2 Hz, 1H), 1.53 (dd, J = 25.2, 13.8 Hz, 2H); 13C NMR (150MHz, CDCl3): δ 165.0, 146.9, 145.2, 136.2, 129.7, 128.7, 128.6, 123.6, 122.6,77.8, 64.6, 64.1, 51.6, 42.7, 37.8, 35.2, 33.9, 21.7; IR (neat): 2953, 2852,1699, 1595, 1207,1188, 1373, 1352, 1167, 1107, 1083, 912, 816, 735, 663,552cm-1; HRMS (ESI): Calcd for (C29H32N2O6S2) ([M+H]+): 569.1775; found:569.1778。
(Z)-N-((4-ethyl-4-phenyl-5-phenyliminotetrahydrofuran-2-yl)methyl)-N-tosyl-(4-methylbenzenesulfon)amide (1j). mp: 83.2 – 84.6 oC; 1-H-NMR (400 MHz,CDCl3, signals for the minor diastereoisomer are reported in italics): δ 7.81(d, J = 8.4 Hz, 4H), 7.77 – 7.68 (m, 4H), 7.52 (d, J = 9.0 Hz, 4H), 7.48 –7.29 (m, 5H), 7.24 (d, J = 8.2 Hz, 4H), 7.20 (d, J = 7.3 Hz, 4H), 7.10 (q, J= 7.1 Hz, 1H both), 4.94-4.84 (m, 1H), 4.55 – 4.41 (m, 1H), 4.18 (dd, J =15.5, 6.4 Hz, 1H), 3.85 – 3.75 (m, 1H), 3.74 – 3.68 (m, 1H), 3.40 – 3.33 (m,1H), 2.71 – 2.56 (m, 1H), 2.48 (s, 6H), 2.43 (s, 6H), 2.20 – 2.00 (m, 2H),1.01 (t, J = 7.3 Hz, 3H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3,signals for the minor diastereoisomer are reported in italics): δ 163.5,163.4, 147.3, 147.0, 145.1, 144.8, 143.2, 140.8, 136.4, 136.3, 129.7, 129.6,128.7, 128.6, 128.5, 128.5, 128.4, 127.2, 127.0, 126.9, 126.5, 123.7, 123.4,122.6, 122.5, 77.5, 77.1, 53.5, 5.19, 51.7, 51.4, 38.4, 37.8, 34.0, 33.2,21.7, 21.7, 9.4. IR (neat): 2926, 1697, 1595, 1493, 1373, 1353, 1166, 1085,816, 764, 731, 700, 663, 552 cm-1. HRMS (ESI): Calcd for (C33H34N2O5S2) ([M+H]+):603.1982; found: 603.1993。
(Z)-N-((2'-(phenylimino)-4',5'-dihydro-2'H-spiro[fluorene-9,3'-furan]-5'-yl)methyl)-N-tosyl-(4-methylbenzenesulfon)amide (1k). mp: 67.4 –68.8 oC; 1H NMR (400 MHz, CDCl3): δ 7.92 – 7.82 (m, 4H), 7.82 – 7.74 (m, 2H),7.55 – 7.35 (m, 7H), 7.29 – 7.22 (m, 6H), 7.06 – 6.93 (m, 3H), 5.28 (dtd, J =10.7, 6.6, 4.7 Hz, 1H), 4.51 – 4.35 (m, 1H), 3.82 (dd, J = 15.6, 4.4 Hz, 1H),2.66 (m, 1H), 2.52 – 2.47 (m, 1H), 2.44 (s, 6H). 13C NMR (100 MHz, CDCl3): δ162.4, 148.2, 147.0, 146.6, 145.2, 141.0, 140.1, 136.2, 129.7, 128.6, 128.5,128.4, 128.3, 127.9, 124.0, 123.6, 122.7, 122.2, 120.7, 120.3, 78.9, 59.4,51.8, 41.1, 21.7; IR (neat): 3065, 1697, 1595, 1493, 1448, 1373, 1354, 1167,1084, 910, 815, 733, 663,552 cm-1; HRMS (ESI): Calcd for (C37H32N2O5S2) ([M+H]+):649.1825; found: 649.1824。
实施例2 1,2胺醇衍生物2b的合成
在氩气保护条件下向烘干的反应瓶中加入1b（325 mg，0.50 mmol，1.0 equiv.）和5 mL二氯甲烷，将反应液置于冰水浴中搅拌15分钟，随后缓慢滴加1.0 mL氢化铝锂（H4LiAl，2.5 M in THF）。然后将混合物在室温条件下搅拌5小时。反应完成后，缓慢加入NaOH溶液（1.0 M，aq.）淬灭，将混合物用乙酸乙酯萃取（20 mL×3）、饱和氯化钠溶液水洗、无水硫酸钠干燥、过滤并在真空下浓缩。得到的粗产物用快速柱色谱纯化（10：1石油醚/ 乙酸乙酯）, 得到白色固体2a （309.4 mg，产率95％），mp: 138.3 – 139.1 oC.1H NMR (400MHz,CDCl3): δ 7.85 – 7.74 (m, 4H), 7.47 – 7.40 (m, J = 8.1, 6.6 Hz, 2H), 7.39– 7.29 (m, 6H), 7.29 – 7.24 (m, 6H 7.23 – 7.15 (m, 2H), 6.77 (tt, J = 7.5,1.1 Hz, 1H), 6.67 – 6.59 (m, 2H), 4.05 (d, J = 11.5 Hz, 1H), 4.01 – 3.86 (m,2H), 3.78 (dd, J = 15.3, 9.2 Hz, 1H), 3.58 (dd, J = 15.3, 2.9 Hz, 1H), 2.58(dd, J = 14.3, 7.7 Hz, 2H), 2.46 (s, 6H), 2.39 (dd, J = 14.3, 2.5 Hz, 1H). 13CNMR (100 MHz, CDCl3): δ 148.3, 146.7, 145.1, 144.9, 136.5, 129.6, 129.2,128.6, 128.5 (both), 128.2, 127.8, 126.7 (both), 118.1, 113.9, 67.5, 54.9,51.4, 42.8, 21.7. IR (neat): 3053, 2359, 1601, 1504, 1495, 1371, 1165, 1084,814, 700, 663, 552 cm-1; HRMS (ESI): Calcd for (C37H38N2O5S2) ([M+H]+):655.2295; found: 655.2288。
在氩气保护下向烘干的反应试管中加入奈 (5.5 equiv, 1.0 mmol, 130.8 mg)和4.5 mL新蒸四氢呋喃，再取金属钠 (5.2 equiv, 1.0 mmol, 22.1 mg) 加入反应试管，室温搅拌5h。待金属钠完全消耗，反应液呈墨绿色。将2a (95.0 mg, 0.19 mmol, 1.00equiv) 在氩气保护下溶于2 mL 新蒸四氢呋喃，用注射器将其转移至奈-钠反应液中，室温条件下继续搅拌5h。反应完成后，加20 mL 水淬灭反应，反应混合物用二氯甲烷萃取（20 mL×3），饱和氯化钠溶液水洗、无水硫酸钠干燥、过滤并在真空下浓缩。得到的粗产物用快速柱色谱纯化（20:1:0.01 二氯甲烷/甲醇/三乙胺）, 得到无色油状液体2b (62.2 mg, 产率95%). 1H-NMR (400 MHz, CDCl3): δ 7.41 – 7.18 (m, 10H), 7.04 (t, J = 7.6 Hz,2H), 6.63 (t, J = 7.3 Hz, 1H), 6.52 (d, J = 7.8 Hz, 2H), 4.07 (d, J = 11.3Hz, 1H), 3.69 (d, J = 10.9 Hz, 1H), 3.61 (s, 1H), 2.63 (dd, J = 14.0, 7.6 Hz,1H), 2.51 (t, J = 10.7 Hz, 1H), 2.25 (d, J = 12.6 Hz, 1H), 1.98 (d, J = 14.2Hz, 1H).13C NMR (100 MHz, CDCl3): δ 148.3, 146.9, 145.6, 129.2, 128.5, 128.5,128.1, 127.8, 126.6, 126.6, 118.1, 113.8, 68.87, 51.61, 49.8, 48.4, 42.9. IR(neat):3053, 2951, 1603, 1499, 908, 752, 733, 700 cm-1. HRMS (ESI): Calcd for(C23H27N2O) ([M+H]+): 347.2118; found: 347.2113。
实施例3 甲胺内酯衍生物2e和甲胺四氢呋喃基衍生物2f的合成
将1b (325.4 mg, 0.50 mmol) 溶解于5 mL四氢呋喃，加入2滴浓盐酸，室温搅拌2小时。反应完成后，用乙酸乙酯（10 mL×3）萃取、饱和氯化钠溶液水洗、无水硫酸钠干燥、过滤并在真空下浓缩。得到的粗产物用快速柱色谱纯化（8/1，石油醚/乙酸乙酯）, 得到白色固体2c (284.3 mg, 产率98%)。
将2c（150 mg）转移至厚壁反应管中，加入氢溴酸/醋酸溶液（HBr，35%wt.）2 mL。用聚四氟乙烯塞子将反应试管密封，并转移至80oC的油浴锅搅拌10小时。反应完成后，旋去溶剂，加水稀释，所得混合物用乙醚洗涤（30 mL×3），用无水碳酸钠调节水相PH>7, 接着用二氯甲烷萃取15 mL×3），所得有机相再用饱和碳酸氢钠溶液洗涤（20 mL×3），再用无水硫酸钠干燥、过滤并在真空下浓缩。得到的粗产物用快速柱色谱纯化（20/1/0.01 二氯甲烷/甲醇/三乙胺）, 得到无色油状液体2d (71.1 mg, 产率74%)。
在烘干的反应试管中将2d（80.6 mg, 0.30 mmol, 1.0 equiv）溶解于2 mL甲醇，加入46 µL苯甲醛(0.45 mmol, 1.5 equiv)，室温搅拌4小时。然后加入氰基硼氢化钠(38mg, 0.6 mmol, 2.0 equiv)，继续搅拌5小时。反应完成后，加入饱和碳酸氢钠溶液淬灭，反应混合物用二氯甲烷（20 mL×3）萃取，饱和氯化钠溶液水洗、无水硫酸钠干燥、过滤并在真空下浓缩。得到的粗产物用快速柱色谱纯化（15/1，石油醚/ 乙酸乙酯）, 得到无色油状液体2e (87.8 mg, 产率82%)。1H NMR (400 MHz, CDCl3): δ 7.53 – 7.20 (m, 16H), 4.56(ddd, J = 11.5, 7.5, 3.8 Hz, 1H), 3.88 (d, J = 2.9 Hz, 2H), 3.12 – 2.95 (m,2H), 2.90 (ddt, J = 15.7, 13.1, 6.4 Hz, 2H).13C NMR (100 MHz, CDCl3): δ 177.1,142.0, 139.8, 129.0 128.5, 128.4, 128.2, 127.8, 127.4, 127.3, 127.2, 77.0,58.1, 53.9, 52.2, 40.8. IR (neat): 3026, 2932, 1765, 1495, 1447, 1176, 966,750, 698 cm-1; HRMS (ESI): Calcd. for (C24H23NO2) ([M+H]+) 358.1802, found:358.1794.
在烘干的反应试管中将2d（112.2 mg, 0.42 mmol, 1.0 equiv）溶解于2 mL甲醇，加入31µL环丙基甲醛 (1.2 equiv)，室温搅拌4小时。然后加入硼氢化钠 (31.7 mg, 2.0equiv)，继续搅拌5小时。反应完成后，加入饱和碳酸氢钠溶液淬灭，反应混合物用二氯甲烷萃取（20 mL×3），饱和氯化钠溶液水洗、无水硫酸钠干燥、过滤并在真空下浓缩。得到的粗产物用快速柱色谱纯化（2/1/0.01 石油醚 /乙酸乙酯/三乙胺, 得到无色油状液体2f(110.6 mg, 产率86%)。1H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 7.8 Hz, 2H), 7.37– 7.25 (m, 6H), 7.21 (dd, J = 9.4, 5.1 Hz, 2H), 3.79 (tt, J = 10.6, 4.6 Hz,1H), 3.12 – 2.86 (m, 1H), 2.71 (dd, J = 12.2, 3.6 Hz, 1H), 2.49 (dd, J =12.7, 6.5 Hz, 1H), 2.38 (dd, J = 12.7, 6.8 Hz, 1H), 2.2.31 – 2.12 (m, 3H),1.14 – 0.94 (m, 1H), 0.64 (q, J = 9.8, 8.6 Hz, 2H), 0.33 – 0.13 (m, 2H). 13CNMR (100 MHz, CDCl3): δ 147.9, 146.9, 128.3, 128.1, 127.9, 127.0, 126.1,125.8, 65.8, 63.3, 62.3, 61.0, 46.1, 43.7, 8.4, 4.5, 3.9. IR (neat): 3334,2942, 2772, 1496, 1447, 1208, 1067, 1050, 911, 755, 730, 699 cm-1. HRMS (ESI):Calcd for (C21H26NO) ([M+H]+) 308.2009, found: 308.2005。

Claims (1)

1.式I所示5-亚胺-四氢呋喃基甲胺衍生物的制备方法，其特征在于：
Figure 749615DEST_PATH_IMAGE001
其中：R1、R2独立地选自苯基、C1~C3的烷基，或R1和R2整体为环烷基或氧杂环烷基；R3 为甲基或氢，R4为甲基或氢，Z为苯基、甲氧基或苄基；
以式II所示的烯丙基酰胺为原料，间氯过氧苯甲酸为氧化剂，二对甲苯磺酰胺为氮源，六氟异丙醇为溶剂，在室温下2,6-二甲氧基碘苯催化下发生氧胺化反应，得到式I所示的5-亚胺-四氢呋喃基甲胺衍生物。
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JP2009051749A (ja) * 2007-08-24 2009-03-12 Toray Ind Inc ６，１４−エポキシモルヒナン誘導体およびその医薬用途
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