138647-49-1 4-(((三氟甲基)磺酰基)氧基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯

海关编码:2933399990

作为医药中间体，用于后续化学反应（如专利中提及的多种药物合成路线）。

医药中间体

合成路线 1（1. 合成：138647-49-1）

产率：96% 合成条件：Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 1.25 h; Stage #2: at -78 - 20℃; 实验步骤：将二异丙胺（22ml）溶于无水TηF（125ml）中并冷却至-78℃。 逐滴加入72-丁基锂（62.5ml，2.5M）。 将溶液搅拌15分钟，然后滴加在TηF（100ml）中的叔丁基4-氧代哌啶-1-羧酸酯（28.32g）。 将反应混合物在-78℃下搅拌1小时，然后滴加在THF（150ml）中的N-苯基三氟甲磺酰亚胺（53.8g）。 将反应混合物在-78℃下搅拌2小时，并使其温热至室温并搅拌过夜。 然后将反应混合物真空浓缩，将残余物溶于乙醚（1000ml）中。 将其用水（500ml），2M氢氧化钠溶液（3×500ml），水（500ml）和盐水（500ml）洗涤，然后经硫酸镁干燥并浓缩，得到标题化合物，为浅棕色油状物（ 45.38g，96％），无需进一步纯化即可使用; 1H NMR（CDCl3）δ1.48（9H，s），2.44（2H，m），3.63（2H，t），4.00（2H，q），5.70（1H，br）。 参考文献：

• [1] Patent: WO2007/60409, 2007, A1. Location in patent: Page/Page column 87-88 [2] Patent: WO2003/87057, 2003, A1. Location in patent: Page/Page column 77-78 [3] Patent: WO2006/4532, 2006, A1. Location in patent: Page/Page column 25 [4] Patent: WO2007/92435, 2007, A2. Location in patent: Page/Page column 143-143 [5] Patent: WO2004/35549, 2004, A1. Location in patent: Page 127 [6] Patent: US2006/172995, 2006, A1. Location in patent: Page/Page column 61 [7] Patent: WO2006/55752, 2006, A2. Location in patent: Page/Page column 48-49 [8] Patent: US2007/276002, 2007, A1. Location in patent: Page/Page column 13-14 [9] Patent: US2008/32998, 2008, A1. Location in patent: Page/Page column 22 [10] Patent: WO2008/31772, 2008, A1. Location in patent: Page/Page column 114-115 [11] Patent: WO2008/12622, 2008, A2. Location in patent: Page/Page column 61

合成路线 2（2. 合成：138647-49-1）

产率：100% 合成条件：Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.33 h; Stage #2: at -78 - 0℃; for 3 h; 实验步骤：第9部分; 在-78℃下向LiHMDS（1.0M的THF溶液，28.7mL，28.7mmol）中滴加叔丁基-4-氧代哌啶-1-羧酸酯（5.21g，26.16mmol）的无水THF（26mL）溶液。 在氮气下。 20分钟后，加入N-苯基三氟甲磺酰亚胺（10.0g，27.99mmol）的THF（26mL）溶液，使反应物逐渐升温至0℃并搅拌3小时。 用最少量的饱和NaHCO 3淬灭反应，并将所得混合物减压浓缩。 在中性Al 2 O 3上进行快速色谱，得到所需的烯醇三氟甲磺酸酯（8.67g，100％）。 参考文献：

• [1] Patent: WO2005/37826, 2005, A1. Location in patent: Page/Page column 90 [2] Patent: WO2007/60408, 2007, A2. Location in patent: Page/Page column 104 [3] Patent: WO2006/10446, 2006, A2. Location in patent: Page/Page column 31-32 [4] Patent: WO2006/20879, 2006, A1. Location in patent: Page/Page column 100 [5] Patent: WO2007/64883, 2007, A2. Location in patent: Page/Page column 361

合成路线 3（3. 合成：138647-49-1）

产率：90% 合成条件：Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1 h; Stage #2: at -78 - 20℃; 实验步骤：在-78℃下，将4-氧代哌啶-1-甲酸叔丁酯（1-1）（80g，0.402mol）的THF（800mL）溶液加入到LiHMDS（1M的THF溶液，406mL）溶液中。 C。 添加后，将反应混合物在-78℃下搅拌1小时。 然后在-78℃下向混合物中加入N-苯基双（三氟甲磺酰亚胺）（156.4g，0.438mol）的THF（400mL）溶液。 添加后，将反应在室温下搅拌过夜。 TLC（石油醚/ EtOAc，V / V = 1：1）显示反应完成。 浓缩反应混合物，并通过硅胶柱色谱法（石油醚/ EtOAc梯度从1：0至20：1）纯化残余物，得到4-（三氟甲基磺酰氧基）-5,6-二氢吡啶-1-叔丁酯（ 2H） - 羧酸酯（I-2）（120g，90％），为黄色油状物，直接用于下一步骤。 参考文献：

• [1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 36, p. 8503 - 8519 [2] Patent: WO2016/97918, 2016, A1. Location in patent: Page/Page column 50 [3] Patent: WO2010/5783, 2010, A1. Location in patent: Page/Page column 115 [4] European Journal of Medicinal Chemistry, 2014, vol. 74, p. 246 - 257 [5] Organic and Biomolecular Chemistry, 2017, vol. 15, # 46, p. 9903 - 9909 [6] Patent: WO2006/4533, 2006, A1. Location in patent: Page/Page column 24 [7] Journal of Medicinal Chemistry, 2000, vol. 43, # 14, p. 2703 - 2718 [8] Patent: WO2014/100501, 2014, A1. Location in patent: Paragraph 00725; 00726 [9] Patent: WO2015/200534, A2. Location in patent: Paragraph 00296 [9] Patent: , 2015, . Location in patent: Paragraph 00296 [11] Patent: WO2012/37132, 2012, A1. Location in patent: Page/Page column 50; 51 [12] Journal of Medicinal Chemistry, 2004, vol. 47, # 15, p. 3853 - 3864 [13] Journal of Medicinal Chemistry, 2006, vol. 49, # 25, p. 7450 - 7465 [14] Patent: US2010/204265, 2010, A1. Location in patent: Page/Page column 90 [15] Patent: US2010/204265, 2010, A1. Location in patent: Page/Page column 124; 125 [16] Patent: WO2018/68297, 2018, A1. Location in patent: Page/Page column 101 [17] Patent: US2014/249104, 2014, A1. Location in patent: Page/Page column [18] Patent: WO2016/27284, 2016, A2. Location in patent: Page/Page column 70 [19] Patent: US6346622, 2002, B1. Location in patent: Page column 10 [20] Patent: WO2008/119825, 2008, A2. Location in patent: Page/Page column 45-46 [21] Patent: WO2008/88881, 2008, A1. Location in patent: Page/Page column 59-60 [22] Journal of the American Chemical Society, 2017, vol. 139, # 23, p. 7721 - 7724 [23] Patent: WO2012/110773, 2012, A1. Location in patent: Page/Page column 82; 83 [24] Patent: WO2014/27199, 2014, A1. Location in patent: Page/Page column 84-85 [25] Patent: US2013/150407, 2013, A1. Location in patent: Paragraph 0166 [26] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 18, p. 4993 - 4996 [27] Synthesis, 1991, # 11, p. 993 - 995 [28] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 10, p. 1403 - 1408 [29] Tetrahedron, 2003, vol. 59, # 29, p. 5507 - 5514 [30] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 8, p. 2859 - 2872 [31] Patent: US2008/114007, 2008, A1. Location in patent: Page/Page column 126 [32] Patent: WO2008/73687, 2008, A2. Location in patent: Page/Page column 32-33 [33] Patent: WO2004/5257, 2004, A1. Location in patent: Page 52 [34] Patent: US2009/176775, 2009, A1. Location in patent: Page/Page column 27 [35] Patent: WO2009/80682, 2009, A1. Location in patent: Page/Page column 55 [36] Patent: WO2009/81259, 2009, A1. Location in patent: Page/Page column 34; 40-41 [37] Patent: WO2004/24718, 2004, A1. Location in patent: Page 23 [38] Patent: US6727264, 2004, B1. Location in patent: Page column 55; 56; 91 [39] Patent: WO2005/42502, 2005, A1. Location in patent: Page/Page column 133-135 [40] Patent: US2005/154020, 2005, A1. Location in patent: Page/Page column 8 [41] Patent: US2005/154022, 2005, A1. Location in patent: Page/Page column 4; 8 [42] Patent: US2005/176727, 2005, A1. Location in patent: Page/Page column 36 [43] Patent: US2005/176727, 2005, A1. Location in patent: Page/Page column 46; 51 [44] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 3, p. 1114 - 1117 [45] Patent: US2010/125092, 2010, A1. Location in patent: Page/Page column 21 [46] Journal of Medicinal Chemistry, 2010, vol. 53, # 13, p. 4989 - 5001 [47] Patent: WO2010/94126, 2010, A1. Location in patent: Page/Page column 122-123 [48] Patent: WO2010/111406, 2010, A2. Location in patent: Page/Page column 116 [49] Patent: US2006/235037, 2006, A1. Location in patent: Page/Page column 19-20 [50] Patent: EP1764360, 2007, A1. Location in patent: Page/Page column 89; 165 [51] Patent: WO2008/12623, 2008, A1. Location in patent: Page/Page column 65 [52] Patent: US2011/15199, 2011, A1. Location in patent: Page/Page column 6 [53] Patent: US2010/324049, 2010, A1. Location in patent: Page/Page column 25 [54] Journal of Medicinal Chemistry, 2011, vol. 54, # 6, p. 1724 - 1739 [55] Patent: WO2011/45344, 2011, A1. Location in patent: Page/Page column 83-84 [56] Patent: US2011/230495, 2011, A1. Location in patent: Page/Page column 17 [57] Patent: US2011/301143, 2011, A1. Location in patent: Page/Page column 71 [58] Patent: WO2013/43232, 2013, A2. Location in patent: Paragraph 00589 [59] Patent: WO2013/80222, 2013, A1. Location in patent: Page/Page column 84 [60] Patent: WO2013/127808, 2013, A1. Location in patent: Page/Page column 31 [61] Patent: WO2014/100501, 2014, A1. Location in patent: Paragraph 00405 [62] Journal of the American Chemical Society, 2014, vol. 136, # 50, p. 17591 - 17600 [63] Patent: US2015/31541, 2015, A1. Location in patent: Paragraph 0145 [64] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 7, p. 814 - 818 [65] Patent: WO2015/112441, 2015, A1. Location in patent: Page/Page column 59 [66] Patent: US2015/307471, 2015, A1. Location in patent: Paragraph 0051 [67] Patent: CN105524058, 2016, A. Location in patent: Paragraph 0084; 0088 [68] Patent: US2016/333021, 2016, A1. Location in patent: Paragraph 0358 [69] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 5, p. 1035 - 1049 [70] Journal of the American Chemical Society, 2018, vol. 140, # 7, p. 2446 - 2449 [71] Patent: WO2018/115591, 2018, A1. Location in patent: Page/Page column 84; 85 [72] Patent: WO2009/819, 2008, A1. Location in patent: Page/Page column 51-52 [73] Patent: US6339090, 2002, B1. Location in patent: Example 1 [74] Patent: US6339090, 2002, B1. Location in patent: Page column 20-22 [75] Patent: EP1726590, 2006, A1. Location in patent: Page/Page column 62 [76] Patent: WO2003/101381, 2003, A2. Location in patent: Page 73