CN103664917A - 一种2-取代噁唑啉或2-取代噁嗪的合成方法 - Google Patents
一种2-取代噁唑啉或2-取代噁嗪的合成方法 Download PDFInfo
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Abstract
本发明公开了一种合成2-取代噁唑啉或2-取代噁嗪的新方法,以腈和氨基乙醇或3-氨基-1-丙醇为原料,在无溶剂条件下,用可循环利用的硫来诱导合成2-取代噁唑啉和2-取代噁嗪。本发明方法具有成本低廉,反应流程简单,反应条件温和,反应时间短,产率较高等优点,适宜于工业化生成。
Description
技术领域
本发明涉及一种2-取代噁唑啉或噁嗪的合成方法,属于有机化学领域。
背景技术
2-取代噁唑啉和2-取代噁嗪是含氮杂环化合物中重要的代表物。作为医药、农药、染料和具有生物活性物质合成的关键中间体, 2-取代噁唑啉和2-取代噁嗪的应用越来越广泛。例如,2-取代噁唑啉存在于各种重要的药物分子中。如地夫可特是一种具有抗炎、抗过敏作用的药物;2-取代噁嗪是许多药用物质的关键结构单元。如乙酰胆碱脂酶抑制剂是具有抑制酶活性的物质,临床主要用于治疗重症肌无力和青光眼及抗老年性痴呆。强心苷类似物是重要的治疗心脏病的药物。目前2-取代噁唑啉和2-取代噁嗪的合成方法大致可分为两大类:其中一类是以羧酸、醛、酰胺、脂等为原料,以Ersorb-4、离子液体/氯化铟、NBS、KF(40%)/Al2O3等为催化剂的合成。另一类是以腈为原料,以K-10/KSF、H3PW12O40等为催化剂的合成。而目前常用的方法是以腈为原料的合成。现有合成方法不能用来合成双噁嗪,同时还存在反应时间长,温度高,产率较低,催化剂复杂,试剂腐蚀性强等不足。
发明内容
本发明的目的是提供一种工艺简单、反应条件温和、生产成本低、环境污染小、易于大规模工业化生产的合成2-取代噁唑啉或2-取代噁嗪的新方法。
本发明采用的技术方案如下:
结构式(I)所示化合物的合成方法,其特征在于包括以下步骤,
R独立地选自芳香基Ar及取代芳香基R1-Ar、杂环基,所述的杂环基为吡啶基、噻吩基、嘧啶基或吡嗪基,
R1为C1~C5的烷基、卤素基、氨基、氰基、硝基、噁唑基、噁嗪基,
n为1或2,
S表示单质硫,
以方程式(II)所示的腈与氨基乙醇或3-氨基-1-丙醇在硫诱导下无溶剂反应得到结构式(I)所示化合物。
上述反应中腈与氨基乙醇或3-氨基-1-丙醇摩尔比为1:1~1:6,腈与硫的摩尔比为1:0.05~1:0.2,反应温度为100~120oC,反应时间为3~11小时。
本发明提出了一种在硫诱导下腈和氨基乙醇或3-氨基-1-丙醇反应合成2-取代噁唑啉和2-取代噁嗪的简单方便廉价的合成法,该方法明具有以下优点:
1、工艺流程简单,反应条件温和,原料成本相对廉价,有利于工业化生产;
2、本发明所用的硫可经简单过滤回收,洗涤,干燥后可继续使用,重复使用8次后,无明显的产率下降。
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
2-取代噁唑啉的合成:以1a, 1d, 1k, 1l为例进行详细说明。
2-(3-吡啶基)噁唑啉(1a)的合成
将0.5mmol 3-氰基吡啶、1.0mmol氨基乙醇和0.05mmol硫加入到25mL的圆底烧瓶中,在搅拌条件下反应温度为100oC加热9h。反应结束后(TLC监测)冷却至室温。加入6mL 乙酸乙酯滤除硫。蒸出乙酸乙酯浓缩后用乙酸乙酯 / 石油醚 (1:1) 硅胶柱层析,得到白色固体57.6mg,产率为78%。
表征数据:Mp: 68-69oC; 1H NMR (400 MHz, CDCl3): δ 9.16 (s, 1H, ArH), 8.71 (d, J = 3.8 Hz, 1H, ArH), 8.22 (d, J = 7.9 Hz, 1H, ArH), 7.36 (dd, J = 7.9, 4.9 Hz, 1H, ArH), 4.47 (t, J = 9.5 Hz, 2H, CH2), 4.10 (t, J = 9.6 Hz, 2H, CH2); 13C NMR (100 MHz, CDCl3): δ 163.5, 152.8, 150.3, 136.3, 124.7, 124.0, 68.6, 55.8; IR (cm-1, KBr): 2908, 1653, 1591, 1358, 1262, 1079, 933, 818, 703; MS (EI): m/z = 148 [M]+。
2-苯基噁唑啉(1d)的合成
将0.5mmol苯甲腈、1.0mmol氨基乙醇和0.05mmol硫加入到25mL的圆底烧瓶中,在搅拌条件下反应温度为100oC加热9h。反应结束后(TLC监测)冷却至室温。加入6mL 乙酸乙酯滤除硫。蒸出乙酸乙酯浓缩后用乙酸乙酯 / 石油醚 (3:1) 硅胶柱层析,得到无色液体55.1 mg,产率为75%。
表征数据:1H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.3 Hz, 2H, ArH), 7.50 – 7.35 (m, 3H, ArH), 4.43 (t, J = 9.5 Hz, 2H, CH2), 4.06 (t, J = 9.5 Hz, 2H, CH2); 13C NMR (CDCl3, 100 MHz): δ 165.6, 132.2, 129.3, 129.1, 128.7, 68.5, 55.9; IR (cm-1, KBr): 2936, 1649, 1603, 1496, 1360, 1260, 1079, 944, 779, 694; MS (EI): m/z = 147 [M]+。
2-(4-氰基苯基)噁唑啉(1k)的合成
将0.5mmol对苯二腈、0.5mmol氨基乙醇和0.025mmol硫加入到25mL的圆底烧瓶中,在搅拌条件下反应温度为100oC加热4h。反应结束后(TLC监测)冷却至室温。加入6mL 乙酸乙酯滤除硫。蒸出乙酸乙酯浓缩后用乙酸乙酯 / 石油醚 (1:1) 硅胶柱层析,得到白色固体64.5 mg,产率为75%。
表征数据:Mp: 117-118oC; 1H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 8.3 Hz, 2H, ArH), 7.71 (d, J = 8.4 Hz, 2H, ArH), 4.48 (t, J = 9.6 Hz, 2H, CH2), 4.11 (t, J = 7.1 Hz, 2H, CH2); 13C NMR (100 MHz, CDCl3): δ 162.9, 132.0, 131.7, 128.6, 118.2, 114.5, 67.8, 55.0; IR (cm-1, KBr): 2932, 2225, 1650, 1608, 1503, 1363, 1262, 1069, 938, 847, 667; MS (EI): m/z = 172 [M]+。
2, 2'-(1, 4-亚苯基)双噁唑啉(1l)合成
将0.5mmol对苯二腈、3.0mmol氨基乙醇和0.1mmol硫加入到25mL的圆底烧瓶中,在搅拌条件下反应温度为120oC加热11h。反应结束后(TLC监测)冷却至室温。加入6mL 乙酸乙酯滤除硫。蒸出乙酸乙酯浓缩后用乙酸乙酯 / 石油醚 (1:1) 硅胶柱层析,得到白色固体85.3 mg,产率为79%。
表征数据:Mp: 247-248oC; 1H NMR (400 MHz, CDCl3): δ 7.99 (s, 4H, ArH), 4.45 (t, J = 9.6 Hz, 4H, 2CH2), 4.08 (t, J = 9.6 Hz, 4H, 2CH2); 13C NMR (100 MHz, CDCl3): δ 164.9, 131.1, 129.0, 68.6, 55.9; IR (cm-1, KBr): 2932, 1642, 1413, 1364, 1255, 1080, 941, 685; MS (EI): m/z = 216 [M]+。
发明人进行了相应的对比试验,在不加硫而其它条件与上述实施例相同的情况下合成1a, 1d, 1k, 1l,产率依次为5%、6%、7%、7%。
实施例2
2-取代噁嗪的合成:以2a, 2d, 2k, 2l为例进行详细说明。
2-(3-吡啶基)噁嗪(2a)的合成
将0.5mmol 3-氰基吡啶、1.0mmol 3-氨基-1-丙醇和0.05mmol硫加入到25mL的圆底烧瓶中,在搅拌条件下反应温度为100oC加热6h。反应结束后(TLC监测)冷却至室温。加入6mL 乙酸乙酯滤除硫。蒸出乙酸乙酯浓缩后用乙酸乙酯 / 石油醚 (1:1) 硅胶柱层析,得到黄色液体71.3 mg,产率为88%。
表征数据:1H NMR (400 MHz, CDCl3): δ 9.09 (s, 1H, ArH), 8.63 (dd, J = 4.8, 1.6 Hz, 1H, ArH), 8.16 (dt, J = 8.0, 1.9 Hz, 1H, ArH), 7.29 (ddd, J = 8.0, 4.8, 0.6 Hz, 1H, ArH), 4.41 – 4.34 (m, 2H, CH2), 3.61 (t, J = 5.9 Hz, 2H, CH2), 1.99 (dt, J = 11.3, 5.8 Hz, 2H, CH2); 13C NMR (100MHz, CDCl3): δ 153.7, 150.8, 148.3, 134.2, 129.6, 122.7, 65.1, 42.4, 21.6; IR (cm-1, KBr): 2939, 2859, 1656, 1690, 1474, 1416, 1351, 1287, 1136, 1107, 806, 711; MS (EI): m/z = 162 [M]+。
2-苯基噁嗪(2d)的合成
将0.5mmol苯甲腈、1.0mmol 3-氨基-1-丙醇和0.05mmol硫加入到25mL的圆底烧瓶中,在搅拌条件下反应温度为100oC加热7h。反应结束后(TLC监测)冷却至室温。加入6mL 乙酸乙酯滤除硫。蒸出乙酸乙酯浓缩后用乙酸乙酯 / 石油醚 (3:1) 硅胶柱层析,得到无色液体67.6 mg,产率为84%。
表征数据:1H NMR (400 MHz, CDCl3): δ 7.91 (dd, J = 8.2, 1.3 Hz, 2H, ArH), 7.44 – 7.35 (m, 3H, ArH), 4.39 (t, J = 5.4 Hz, 2H, CH2), 3.64 (t, J = 5.9 Hz, 2H, CH2), 2.04 – 1.97 (m, 2H, CH2); 13C NMR (100 MHz, CDCl3): δ 155.6, 134.0, 130.3, 128.0, 126.8, 65.2, 42.6, 21.9; IR (cm-1, KBr): 3061, 2927, 2856, 1725, 1653, 1580, 1494, 1472, 1449, 1380, 1272, 780, 696; MS (EI): m/z = 161 [M]+。
2-(4-氰基苯基)噁嗪(2k)的合成
将0.5mmol对苯二腈、0.5mmol 3-氨基-1-丙醇和0.025mmol硫加入到25mL的圆底烧瓶中,在搅拌条件下反应温度为100oC加热3h。反应结束后(TLC监测)冷却至室温。加入6mL 乙酸乙酯滤除硫。蒸出乙酸乙酯浓缩后用乙酸乙酯 / 石油醚 (1:1) 硅胶柱层析,得到白色固体76.2 mg,产率为82%。
表征数据:Mp: 114-115oC; 1H NMR (400 MHz, CDCl3): δ 8.02 (d, J = 8.5 Hz, 2H, ArH), 7.68 (d, J = 8.6 Hz, 2H, ArH), 4.41 (t, J = 5.5 Hz, 2H, CH2), 3.65 (t, J = 5.9 Hz, 2H, CH2), 2.08 – 1.96 (m, 2H, CH2); 13C NMR (100 MHz, CDCl3): δ 154.0, 138.1, 131.8, 127.4, 118.7, 113.6, 65.4, 42.8, 21.7; IR (cm-1, KBr): 3405, 2936, 2861, 2226, 1651, 1562, 1501, 1472, 1454, 1408, 1348, 1282, 1270, 1136, 1102, 848; MS (EI): m/z =186 [M]+。
2, 2'-(1, 4-亚苯基)双噁嗪(2l)的合成
将0.5mmol对苯二腈、3.0mmol 3-氨基-1-丙醇和0.1mmol硫加入到25mL的圆底烧瓶中,在搅拌条件下反应温度为120oC加热10h。反应结束后(TLC监测)冷却至室温。加入6mL 乙酸乙酯滤除硫。蒸出乙酸乙酯浓缩后用乙酸乙酯 / 石油醚 (1:1) 硅胶柱层析,得到白色固体98.8 mg,产率为81%。
表征数据:1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 12.0 Hz, 4H, ArH), 4.44 (dd, J = 9.1, 3.7 Hz, 4H, 2CH2), 3.71 – 3.63 (m, 4H, 2CH2), 2.10 – 1.98 (m, 4H, 2CH2); 13C NMR (100 MHz, CDCl3): δ 155.4, 135.6, 126.5, 65.2, 42.6, 21.7; IR (cm-1, KBr): 2965, 2888, 2854, 1650, 1128, 1099, 862; MS (EI): m/z = 244 [M]+; HRMS: m/z calcd for C14H16N2O2+H+: 245.13 [M+H]+; found: 245.1362。
发明人进行了相应的对比试验,在不加硫而其它条件与上述实施例相同的情况下合成2a, 2d, 2k, 2l,产率依次为7%、8%、8%、9%。
实施例3
硫的重复利用次数以2-(3-吡啶基)噁唑啉的合成为例进行详细说明。
与实施例1类似,不同之处在于:在合成2-(3-吡啶基)噁唑啉的过程中加入回收的已使用过3次的硫,其余反应条件相同。2-(3-吡啶基)噁唑啉产率为76%。
与实施例1类似,不同之处在于:在合成2-(3-吡啶基)噁唑啉的过程中加入回收的已使用过5次的硫,其余反应条件相同。2-(3-吡啶基)噁唑啉产率为73%。
与实施例1类似,不同之处在于:在合成2-(3-吡啶基)噁唑啉的过程中加入回收的已使用过8次的硫,其余反应条件相同。2-(3-吡啶基)噁唑啉产率为70%。
Claims (5)
2.根据权利要求1所述合成方法,其特征在于:所述的杂环基为吡啶基、噻吩基、嘧啶基或吡嗪基。
3.根据权利要求1所述合成方法,其特征在于:反应中腈与氨基乙醇或3-氨基-1-丙醇摩尔比为1:1~1:6。
4.根据权利要求1所述合成方法,其特征在于:腈与硫的摩尔比为1:0.05~1:0.2。
5.根据权利要求1所述合成方法,其特征在于:反应温度为100~120oC,反应时间为3~11小时。
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HAIXIA G,ET AL,: ""S-Co(II) cascade catalysis: cyclocondensation of aromatic nitriles with alkamine"", 《TETRAHEDRON》 * |
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