作为选择性H1受体拮抗剂，具有抗过敏和抗炎活性，用于治疗季节性过敏性鼻炎、慢性特发性荨麻疹等过敏性疾病；是氯雷他定的活性代谢物，可通过选择性拮抗外周H1受体缓解相关症状，体外研究显示能抑制组胺从人肥大细胞释放，动物研究提示不易通过血脑屏障。
医药
路线1：
- 步骤：将40g氯雷他定、40g氢氧化钠、500ml无水乙醇和125ml纯净水加入反应烧瓶中，在氮气氛下回流反应，浓缩至大量固体沉淀，过滤、洗涤并干燥，得到地氯雷他定32g。
- 条件：Reflux; Inert atmosphere; Alkaline conditions；氯雷他定与氢氧化钠的摩尔比为1:20；纯净水与无水乙醇的体积比为1:4。
- 收率：98.5%。
- 参考文献：[1] Patent: CN103804357, 2016, B. Location in patent: Paragraph 0041-0042 [2] Patent: CN106565671, 2017, A. Location in patent: Paragraph 0018 [3] Organic Process Research and Development, 2008, vol. 12, # 5, p. 855 - 859 [4] Patent: CN106565670, 2017, A. Location in patent: Paragraph 0015; 0019; 0020 [5] Patent: CN106565669, 2017, A. Location in patent: Paragraph 0018 [6] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2701 - 2704 [7] Patent: US2013/85127, 2013, A1. Location in patent: Paragraph 0286; 0287; 0288 [8] Patent: WO2004/29039, 2004, A1. Location in patent: Page 12 [9] Patent: WO2006/3479, 2006, A2. Location in patent: Page/Page column 21-22; 23-24; 25-26 [10] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 4, p. 1626 - 1632 [11] Patent: WO2004/29039, 2004, A1. Location in patent: Page 7-8; 12 [12] Patent: WO2004/29039, 2004, A1. Location in patent: Page 10; 12 [13] Patent: WO2004/29039, 2004, A1. Location in patent: Page 8-9; 12 [14] Patent: WO2004/29039, 2004, A1. Location in patent: Page 10; 12 [15] Patent: WO2004/29039, 2004, A1. Location in patent: Page 9; 12 [16] Patent: WO2004/29039, 2004, A1. Location in patent: Page 12 [17] Patent: WO2004/29039, 2004, A1. Location in patent: Page 10; 12 [18] Patent: WO2004/29039, 2004, A1. Location in patent: Page 10; 12 [19] Patent: WO2004/29039, 2004, A1. Location in patent: Page 12 [20] Patent: WO2004/29039, 2004, A1. Location in patent: Page 12 [21] Patent: WO2004/29039, 2004, A1. Location in patent: Page 9; 12 [22] Patent: WO2004/29039, 2004, A1. Location in patent: Page 8; 12 [23] Patent: US2007/60756, 2007, A1. Location in patent: Page/Page column 3 [24] Patent: WO2008/32136, 2008, A1. Location in patent: Page/Page column 4-5 [25] Journal of Medicinal Chemistry, 1991, vol. 34, # 1, p. 457 - 461 [26] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 24, p. 2977 - 2982 [27] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 23, p. 7258 - 7273 [28] Patent: US6075025, 2000, A [29] Patent: US5422351, 1995, A [30] Patent: US5661152, 1997, A [31] Patent: US5719148, 1998, A [32] Patent: US5700806, 1997, A [33] Patent: US5151423, 1992, A [34] Patent: US2007/135472, 2007, A1. Location in patent: Page/Page column 6 [35] Patent: US2007/244144, 2007, A1. Location in patent: Page/Page column 3 [36] Patent: US2008/287481, 2008, A1. Location in patent: Page/Page column 5 [37] Patent: US2008/287481, 2008, A1. Location in patent: Page/Page column 5 [38] Patent: US2003/229099, 2003, A1. Location in patent: Page 98 - 99 [39] Patent: US2004/122018, 2004, A1. Location in patent: Page 136 [40] Patent: US2009/197907, 2009, A1. Location in patent: Page/Page column 2 [41] Patent: WO2010/109442, 2010, A1. Location in patent: Page/Page column 5-6 [42] Patent: WO2006/103688, 2006, A1. Location in patent: Page/Page column 5 [43] Patent: US2012/101281, 2012, A1. Location in patent: Page/Page column 2 [44] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 7, p. 1436 - 1442
路线2：
- 步骤：在120ml乙醇中，将40g地氯雷他定与Vi摩尔二氧化碳的加合物煮沸1小时，蒸发溶剂；向温热残余物中加入360ml丙酮和20ml甲醇，煮沸并用碳脱色，过滤；滤液冷却至25℃搅拌1小时，-10℃搅拌4小时，过滤；产物50℃干燥2小时。
- 条件：Stage #1: for 1 h; Heating / reflux; Stage #2: Heating / reflux。
- 收率：23.5g（63.0％）。
- 熔点：257-258℃。
- 产品特性：多晶型1的纯地氯雷他定碱。
- 参考文献：[1] Patent: WO2008/50162, 2008, A1. Location in patent: Page/Page column 20-21
路线3：
- 步骤：1. 氯雷他定制备：将8-氯-6,11-二氢-11-(1-甲基-4-哌啶叉)-5H-苯并[5,6]-环庚并[1,2-b]吡啶45.g(0.141mol)和甲苯320ml搅拌溶解，80℃加入氯甲酸乙酯45.9g(40.4ml,0.423mol)，80℃搅拌反应1h；TLC跟踪，减压蒸除过量氯甲酸乙酯，加水450ml和甲苯，60℃搅拌1h；NaOH水溶液调pH10，分层，水相甲苯提取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩，溶于乙腈，活性炭脱色，热过滤，浓缩至结晶，5℃结晶析出，过滤干燥得氯雷他定42.2g。2. 地洛他定合成：乙醇305ml、KOH 150g(2.68mol)和氯雷他定39g(0.101mol)，N2保护下搅拌回流5-6h，减压浓缩回收乙醇，盐水稀释，乙酸乙酯提取3次，合并有机层，水洗，无水Na2SO4干燥，过滤，蒸除溶剂得地洛他定粗品24.5g；粗品用MIBK 245ml控温70-80℃溶解，补加MIBK，冷却加活性炭，80℃搅拌20-30min，热过滤，冷却析晶，过滤干燥得纯品22.3g。
- 收率：氯雷他定收率78.2%；地洛他定粗品收率77%，精制收率91%。
- 条件：N2保护；80℃反应；60℃搅拌；70-80℃溶解。
- 参考文献：[1] 例6; 地氯雷他定碱的多晶型1; [2] 氯雷他定[4-(8-氯-5,6-二氢-11H-苯并[5,6]环庚并[1,2-b]吡啶-11-亚基)-1-哌啶羧酸乙酯]的制备；[3] 8-氯-6,11-二氢-11-(4-亚哌啶基)-5H-苯并[5,6]环庚并[1,2-b]吡啶(地洛他定)的合成。
路线4：
- 步骤：将40g 4-(8-氯-5H-苯并[5,6]环庚[1,2-b]吡啶-11(6H)-亚基)哌啶-1-羧酸乙酯、40g氢氧化钠、500ml无水乙醇和125ml纯净水加入反应烧瓶，N2保护下搅拌至溶解，浓缩至大量固体析出，过滤、洗涤、干燥得32g目标产物。
- 条件：4-(8-氯-5H-苯并[5,6]环庚[1,2-b]吡啶-11(6H)-亚基)哌啶-1-羧酸乙酯与NaOH摩尔比1:20；纯净水与无水乙醇体积比1:4。
- 收率：98.5%。
- 参考文献：[3] Organic Process Research and Development, 2008, vol. 12, # 5, p. 855 - 859
