122555-91-3 1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸三叔丁酯

危险性质：否

化学合成

化学合成

路线1：122555-91-3

• 产率：83.5%
• 合成条件：With sodium hydrogencarbonate In acetonitrile at 0 - 20℃; for 49 h; Inert atmosphere
• 实验步骤：在氮气下，在0℃下将1,4,7,10-四氮杂环十二烷（1g，5.81mmol）溶于无水乙腈（20ml）中。搅拌下加入NaHCO3（1.464g，17.44mmol）。在1小时内从滴液漏斗中缓慢加入溴乙酸叔丁酯（3.4g，17.44mmol）的10ml乙腈溶液。将反应在0℃下搅拌另外3小时并在室温下搅拌45小时。通过TLC监测反应进程，使用二氯甲烷（DCM）：甲醇（9：1）（Rf 0.67）。反应完成后，过滤反应混合物，蒸发滤液至干。通过硅胶柱色谱法纯化粗化合物，使用2％甲醇的DCM溶液作为洗脱剂，得到化合物2，为白色粉末。
• 参考文献：[1] Tetrahedron Letters, 2013, vol. 54, # 8, p. 918 - 920 [2] Tetrahedron Letters, 2009, vol. 50, # 31, p. 4459 - 4462 [3] European Journal of Medicinal Chemistry, 2013, vol. 65, p. 12 - 20 [4] Patent: WO2014/200872, 2014, A1. Location in patent: Page/Page column 73; 77 [5] Organic and Biomolecular Chemistry, 2011, vol. 9, # 5, p. 1591 - 1599 [6] Journal of Drug Targeting, 2011, vol. 19, # 9, p. 761 - 769 [7] Dalton Transactions, 2013, vol. 42, # 14, p. 4994 - 5003 [8] Molecular Pharmaceutics, 2014, vol. 11, # 2, p. 445 - 456 [9] Journal of Medicinal Chemistry, 2010, vol. 53, # 18, p. 6747 - 6757 [10] Angewandte Chemie - International Edition, 2015, vol. 54, # 3, p. 1007 - 1010 [11] Angew. Chem., 2015, vol. 127, # 3, p. 1021 - 1024,4 [12] Patent: TW2017/13632, 2017, A. Location in patent: Paragraph 0012; 0015 [13] Patent: WO2005/3105, 2005, A1. Location in patent: Page 8 [14] Chemistry - A European Journal, 2016, vol. 22, # 13, p. 4521 - 4527 [15] Journal of Materials Chemistry B, 2017, vol. 5, # 39, p. 8004 - 8012 [16] Journal of Labelled Compounds and Radiopharmaceuticals, 2012, vol. 55, # 4, p. 140 - 148 [17] Dalton Transactions, 2011, vol. 40, # 13, p. 3346 - 3351 [18] RSC Advances, 2016, vol. 6, # 9, p. 7288 - 7301 [19] Journal of the Chemical Society, Dalton Transactions, 2002, vol. 2, # 1, p. 48 - 54 [20] Patent: EP2740491, 2014, A1. Location in patent: Paragraph 0123; 0124; 0125 [21] Patent: WO2014/86942, 2014, A1. Location in patent: Page/Page column 31; 32 [22] Patent: WO2016/26841, 2016, A1. Location in patent: Page/Page column 21 [23] Patent: EP1637524, 2006, A1. Location in patent: Page/Page column 6 [24] Dalton Transactions, 2015, vol. 44, # 40, p. 17800 - 17809 [25] New Journal of Chemistry, 2016, vol. 40, # 5, p. 4606 - 4616 [26] New Journal of Chemistry, 2016, vol. 40, # 7, p. 5846 - 5854 [27] Dalton Transactions, 2007, # 45, p. 5260 - 5267 [28] Patent: US9981953, 2018, B1. Location in patent: Page/Page column 8 [29] Patent: TW2018/13964, 2018, A. Location in patent: Paragraph 0034; 0045; 0046; 0047 [30] Chemical Communications, 2007, # 12, p. 1269 - 1271 [31] Dalton Transactions, 2013, vol. 42, # 19, p. 6724 - 6727 [32] Chemistry - An Asian Journal, 2011, vol. 6, # 8, p. 1987 - 1991 [33] Inorganica Chimica Acta, 2017, vol. 462, p. 236 - 240 [34] Patent: US9115094, 2015, B2. Location in patent: Page/Page column 51; 52 [35] Dalton Transactions, 2011, vol. 40, # 24, p. 6451 - 6457 [36] Journal of Pharmacy and Pharmacology, 2002, vol. 54, # 8, p. 1073 - 1081 [37] Chemical Communications, 2011, vol. 47, # 31, p. 8835 - 8837 [38] Inorganic Chemistry, 2017, vol. 56, # 14, p. 7960 - 7974 [39] Synthetic Communications, 2015, vol. 45, # 5, p. 661 - 672 [40] Patent: WO2009/10580, 2009, A1. Location in patent: Page/Page column 28-29 [41] Patent: WO2010/84090, 2010, A1. Location in patent: Page/Page column 40; 41 [42] Chemical Communications, 2003, # 13, p. 1550 - 1551 [43] Chemical Communications, 2005, # 2, p. 259 - 261 [44] Chemical Communications, 2006, # 8, p. 909 - 911 [45] Patent: US5679810, 1997, A [46] Patent: WO2006/112723, 2006, A1. Location in patent: Page/Page column 14 [47] Patent: WO2006/60797, 2006, A2. Location in patent: Page/Page column 14-15 [48] Inorganic Chemistry, 2012, vol. 51, # 4, p. 2325 - 2331 [49] Journal of the American Chemical Society, 2012, vol. 134, # 8, p. 3647 - 3650 [50] Tetrahedron Letters, 2014, vol. 55, # 38, p. 5294 - 5297 [51] Pharmaceutical Research, 2015, vol. 32, # 3, p. 955 - 967 [52] Patent: WO2015/89639, 2015, A1. Location in patent: Paragraph 00221-00223

路线2：122555-91-3

• 产率：36%
• 合成条件：With sodium hydrogencarbonate In acetonitrile at 20℃; for 40 h;
• 实验步骤：向1,4,7,10-四氮杂环十二烷（cyclen）（2.00g，11mmol）和NaHCO3（3.22g，38.4mmol）在CH3CN（80mL）中的混合物中加入氯乙酸叔丁酯（5.42g，36mmol），将所得混合物在室温下搅拌40小时。过滤后，将滤液真空浓缩，并将CHCl3加入到残余物中。通过硅藻土垫除去不溶物质，蒸发溶剂。将粗产物从甲苯中重结晶，得到DO3A（tBu）3。产量：2.0克（36％）。1H NMR（CDCl3,270MHz）：d 1.46（s，9H），1.47（s，18H），2.89-2.92（br，12H），3.09-3.11（br，4H），3.30（s，2H），6.26（s，1H），3.38（s，4H）。
• 参考文献：[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 24, p. 7410 - 7413

路线3：122555-91-3

• 产率：100%
• 合成条件：With potassium carbonate In acetonitrile at 50℃; for 24 h; Inert atmosphere
• 实验步骤：将化合物4（5.95g，10mmol）溶于50mL含有无水K2CO3（20mmol）的无水乙腈中。将所得混合物在50℃下搅拌24小时。除去固体后，将滤液减压浓缩。将残余物重新溶解在CHCl3中并用水彻底洗涤（3×100mL）。蒸发CHCl3，以定量收率得到5。
• 参考文献：[1] Research on Chemical Intermediates, 2015, vol. 41, # 8, p. 5109 - 5119 [2] Patent: WO2007/106546, 2007, A2. Location in patent: Page/Page column 13-23