448-19-1 2-硝基-5-氟苯甲醚

常温运输。危险等级为IRRITANT（刺激性），海关编码2909309090，非危险化学品。

化学合成

化学合成

路线1：以4-氟-2-羟基硝基苯为原料

• 步骤：在5L四颈烧瓶中，加入DMF 2500g，4-氟-2-羟基硝基苯（500g，3.20mol）和碳酸钾（483g，3.50mol）并加热至60℃。滴加424g（3.36mol）硫酸二甲酯约2-3小时。滴加完成后，加热至90-100℃，保持5-6小时。取样GC分析4-氟-2-羟基硝基苯<0.5％后，将混合物冷却至50℃，产生单甲基硫酸钾盐。减压蒸馏滤液，回收DMF，得到515g 4-氟-2-甲氧基硝基苯，为黄色油状液体。
• 条件：碳酸钾；N,N-二甲基甲酰胺；60-100℃
• 收率：94.1%
• GC含量：99.5%
• 参考文献： [1] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 9, p. 2323 - 2332 [2] Patent: CN106083536, 2016, A. Location in patent: Paragraph 0035; 0036 [3] Heterocycles, 1992, vol. 34, # 12, p. 2301 - 2311 [4] Patent: WO2010/71885, 2010, A1. Location in patent: Page/Page column 443 [5] Patent: WO2010/115688, 2010, A1. Location in patent: Page/Page column 146

路线2：以4-硝基-2-羟基-1-硝基苯为原料

• 步骤：向4-硝基-2-羟基-1-硝基苯（100mg，0.637mmol）的N,N-二甲基甲酰胺（3.2mL）溶液中加入碳酸钾（132mg，0.955mmol），然后在冰冷条件下加入甲基碘（48μL，0.764mmol），室温搅拌1小时。再在冰冷条件下添加碳酸钾（132mg，0.955mmol）和甲基碘（48μL，0.764mmol），60℃搅拌1小时。反应液加水后用乙酸乙酯萃取，有机层用盐水洗涤，无水硫酸钠干燥，真空浓缩得到4-氟-2-甲氧基-1-硝基苯（118mg）。
• 条件：碳酸钾；N,N-二甲基甲酰胺；60℃；冰冷条件
• 收率：>100%
• 产物性质：黄色油状物；1H-NMR（CDCl3）δ：3.97（3H，s），6.74（1H，ddd，J=2.4,7.8,9.0Hz），6.80（1H，dd，J=2.4,10.2Hz），7.97（1H，dd，J=6.1,9.0Hz）
• 参考文献： [1] Patent: US2010/48610, 2010, A1. Location in patent: Page/Page column 73 [2] Journal of the American Chemical Society, 2009, vol. 131, # 38, p. 13860 - 13869 [3] Journal of Medicinal Chemistry, 2013, vol. 56, # 17, p. 7025 - 7048 [4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 16, p. 3436 - 3446 [5] Patent: EP3381925, 2018, A1. Location in patent: Paragraph 0159 [6] Patent: US2006/46990, 2006, A1. Location in patent: Page/Page column 6 [7] Patent: US2017/112833, 2017, A1. Location in patent: Paragraph 0539-0540 [8] Journal of Molecular Structure, 2017, vol. 1147, p. 266 - 280 [9] Patent: US2007/49618, 2007, A1. Location in patent: Page/Page column 82 [10] European Journal of Medicinal Chemistry, 2013, vol. 68, p. 233 - 243 [11] Patent: WO2015/22073, 2015, A1. Location in patent: Page/Page column 52 [12] Patent: WO2015/90580, 2015, A1. Location in patent: Page/Page column 32 [13] Patent: US2008/300242, 2008, A1. Location in patent: Page/Page column 51 [14] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 3, p. 1004 - 1008 [15] Patent: WO2010/104899, 2010, A1. Location in patent: Page/Page column 143 [16] Patent: WO2009/84970, 2009, A1. Location in patent: Page/Page column 73 [17] Patent: US2010/280268, 2010, A1. Location in patent: Page/Page column 48 [18] Patent: WO2006/71730, 2006, A1. Location in patent: Page/Page column 78 [19] Patent: US6352993, 2002, B1. Location in patent: Page column 29-30 [20] Journal of Medicinal Chemistry, 1997, vol. 40, # 17, p. 2674 - 2687 [21] Patent: US2003/93866, 2003, A1 [22] Patent: US6455528, 2002, B1 [23] Patent: US2004/97589, 2004, A1 [24] Patent: US2009/23773, 2009, A1. Location in patent: Page/Page column 59 [25] Patent: WO2005/35520, 2005, A1. Location in patent: Page/Page column 62-63 [26] Patent: WO2006/44823, 2006, A2. Location in patent: Page/Page column 166 [27] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 22, p. 6192 - 6196 [28] Patent: WO2013/186692, 2013, A1. Location in patent: Page/Page column 86; 87 [29] European Journal of Medicinal Chemistry, 2014, vol. 77, p. 75 - 83 [30] Patent: US2015/152069, 2015, A1. Location in patent: Paragraph 0180; 0181 [31] Patent: EP2883875, 2015, A1. Location in patent: Paragraph 0064 [32] Patent: WO2018/45104, 2018, A1. Location in patent: Paragraph 00125

路线3：以2,4-二氟-1-硝基苯为原料

• 步骤：将甲苯（500ml）加入圆底烧瓶，加入2,4-二氟-1-硝基苯（500g）。冷却至0℃，缓慢加入甲醇（100ml），分批加入叔丁醇钾（353克，10批）。0℃搅拌15-30分钟，升温至20℃搅拌4小时。反应液加水（1500ml）分解，搅拌后加甲苯，分离层。水层用甲苯萃取，合并有机层，用水（1000ml）、盐水（NaCl 50g+水500ml）洗涤，硫酸钠干燥。蒸馏溶剂后加石油醚（1000ml），冷却至10℃以下搅拌30分钟，过滤固体用石油醚洗涤，50-60℃干燥3-5小时得产物（470克）。
• 条件：叔丁醇钾；甲苯；0-20℃
• 收率：87.38%
• 参考文献： [1] Patent: WO2018/207120, 2018, A1. Location in patent: Page/Page column 11 [2] Organic Process Research and Development, 2014, vol. 18, # 7, p. 912 - 918