化学合成
化学合成
路线1：以1H-咪唑-4-甲醛为原料的N-三苯甲基化反应
- 步骤：将1H-咪唑-4-甲醛（30.0g，0.30mol）溶于DMF（200mL），冰浴下加入三乙胺（70mL，0.375mol），分批加入三苯基氯甲烷（105g，0.375mol），室温搅拌过夜；真空蒸发混合物，残余物用无水乙醚（4×50mL）洗涤，干燥沉淀得产物。
- 条件：三乙胺作碱，N,N-二甲基甲酰胺为溶剂，反应温度0-20℃。
- 收率：100%（100g黄色固体）。
- 参考文献：[1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 23, p. 7993 - 8002；[2] Patent: WO2008/4096, 2008, A1. Location in patent: Page/Page column 79；[3] Journal of Medicinal Chemistry, 2002, vol. 45, # 1, p. 177 - 188；[4] European Journal of Organic Chemistry, 2015, vol. 2015, # 18, p. 3957 - 3962；[5] Patent: US2004/122018, 2004, A1. Location in patent: Page 317；[6] Organic and Biomolecular Chemistry, 2011, vol. 9, # 7, p. 2274 - 2278；[7] Journal of Medicinal Chemistry, 2011, vol. 54, # 6, p. 1693 - 1703；[8] Angewandte Chemie - International Edition, 2005, vol. 44, # 31, p. 4903 - 4906；[9] Journal of Medicinal Chemistry, 2006, vol. 49, # 19, p. 5710 - 5727；[10] Patent: WO2006/102159, 2006, A2. Location in patent: Page/Page column 21; 22；[11] Chemistry - A European Journal, 2006, vol. 12, # 16, p. 4321 - 4332；[12] Synlett, 2016, vol. 27, # 19, p. 2734 - 2736；[13] Chemical Communications, 2011, vol. 47, # 48, p. 12855 - 12857；[14] Patent: US6143766, 2000, A；[15] Journal of Medicinal Chemistry, 2010, vol. 53, # 4, p. 1712 - 1725；[16] Patent: WO2008/94992, 2008, A2. Location in patent: Page/Page column 188；[17] Tetrahedron Letters, 2006, vol. 47, # 8, p. 1253 - 1255；[18] Patent: WO2012/173280, 2012, A1. Location in patent: Page/Page column 35-36；[19] Patent: US2003/199522, 2003, A1；[20] Patent: US2002/82272, 2002, A1；[21] Patent: WO2010/52256, 2010, A1. Location in patent: Page/Page column 37；[22] Patent: WO2010/52255, 2010, A1. Location in patent: Page/Page column 68；[23] Patent: WO2006/23720, 2006, A2. Location in patent: Page/Page column 48；[24] Patent: US2007/49616, 2007, A1. Location in patent: Page/Page column 29；[25] Patent: EP2848618, 2015, A1. Location in patent: Paragraph 0816；[26] ChemMedChem, 2018, vol. 13, # 8, p. 842 - 851
路线2：以4（5）-咪唑甲醛为原料的N-三苯甲基化反应
- 步骤：向搅拌的4（5）-咪唑甲醛（20.0g，0.208mmol）的二氯甲烷（200mL）溶液中加入三乙胺（29.0mL，0.208mmol）；0℃下加入三苯基甲基氯（52.8g，0.18mmol），室温搅拌过夜；反应液用盐水、水洗涤后浓缩至干得白色固体。
- 条件：反应温度0-20℃。
- 收率：98%（63.0g，MH⁺=339.1）。
- 参考文献：[1] Patent: US2003/229099, 2003, A1. Location in patent: Page 269；[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 10, p. 3887 - 3898；[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 23, p. 6492 - 6499；[4] Organic Process Research and Development, 2000, vol. 4, # 6, p. 613 - 614；[5] Journal of Medicinal Chemistry, 2007, vol. 50, # 19, p. 4585 - 4605；[6] Journal of Medicinal Chemistry, 2009, vol. 52, # 12, p. 3703 - 3715
路线3：以1-三苯基甲基-咪唑-4-甲醇为原料的氧化反应
- 步骤：将步骤8.a的产物（2.04g，6.00mmol）悬浮于DMSO（10.0ml）中，室温下加入三乙胺（3.34ml，24.0mmol）和三氧化硫-吡啶络合物（2.39g，15.0mmol）；加热至约110℃反应1小时，冷却后倒入150ml水中，滤出产物；残余物用饱和NaHCO₃溶液（50ml）处理，二氯甲烷（2×100ml）萃取；合并的二氯甲烷层用5%柠檬酸溶液（100ml）洗涤，Na₂SO₄干燥，过滤并减压浓缩；残余物用MeOH和H₂O结晶得产物。
- 条件：三氧化硫-吡啶络合物为氧化剂，三乙胺为碱，二甲基亚砜为溶剂，反应温度20-110℃，反应时间1小时。
- 收率：53%（1.08g）。
- 参考文献：[1] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 10, p. 1989 - 1998；[2] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 8, p. 1941 - 1944；[3] J. Med. Chem., 1996, vol. 39, # 2, p. 353 - 358；[4] Patent: EP1382607, 2004, A2. Location in patent: Page 28；[5] Synthetic Communications, 1987, vol. 17, # 2, p. 223 - 228；[6] Tetrahedron, 2000, vol. 56, # 13, p. 1837 - 1850；[7] Collection of Czechoslovak Chemical Communications, 2002, vol. 67, # 9, p. 1335 - 1344；[8] Journal of Organic Chemistry, 2002, vol. 67, # 3, p. 620 - 624；[9] Patent: US2002/193596, 2002, A1；[10] Patent: US5034539, 1991, A
