109431-87-0 (R)-1-Boc-3-羟基吡咯烷

运输信息：常温运输。危险描述：危险品运输编号UN 3077 9 / PGIII，WGK Germany:3，危险等级IRRITANT，海关编码29339900，存储类别11 - 可燃固体，危险性类别危害水生环境-急性危害类别1，眼部刺激类别2，经皮刺激类别2，特异性靶器官毒性-一次接触类别3。

化学合成，手性试剂；N-叔丁氧羰基-(R)-3-吡咯烷醇用作医药中间体，用于合成烟碱乙酰胆碱受体的配体。

医药

合成路线 1（1. 合成：109431-87-0）

• 产率：100%
• 合成条件：With triethylamine In 1,4-dioxane
• 实验步骤：3k，化合物16的合成是四个反应过程。首先，得到化合物16b，为（R）-3-吡咯烷醇（539mg，6.19mmol）的无色油状物（1.3g，100％）。光谱数据与提出的结构一致，并与文献中报道的相匹配。从化合物16b获得化合物16c，为无色油状物。从化合物16c两步获得化合物16e，为无色油状物。最后，从化合物16e获得化合物16，为黄色油状物。
• 参考文献：[1] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 10, p. 969 - 973 [2] Patent: WO2015/9731, 2015, A2. Location in patent: Paragraph 00106 [3] Journal of Medicinal Chemistry, 1998, vol. 41, # 25, p. 4983 - 4994 [4] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 17, p. 5812 - 5832 [5] Patent: WO2010/84767, 2010, A1. Location in patent: Page/Page column 86 [6] Patent: WO2004/37797, 2004, A2. Location in patent: Page 176 [7] ChemMedChem, 2014, vol. 9, # 7, p. 1476 - 1487 [8] Patent: CN105153133, 2018, B. Location in patent: Paragraph 0022; 0023; 0024; 0027; 0028 [9] Patent: EP1950198, 2008, A1. Location in patent: Page/Page column 14 [10] Journal of the American Chemical Society, 2002, vol. 124, # 51, p. 15267 - 15279 [11] Angewandte Chemie - International Edition, 2018, vol. 57, # 37, p. 12102 - 12105 [12] Angew. Chem., 2018, vol. 130, p. 12278 - 12281,4 [13] Patent: EP2803664, 2014, A1. Location in patent: Paragraph 0136; 0137 [14] Patent: US2015/5282, 2015, A1. Location in patent: Paragraph 0194; 0195 [15] Chemische Berichte, 1997, vol. 130, # 3, p. 385 - 397 [16] Patent: WO2006/50940, 2006, A1. Location in patent: Page/Page column 56 [17] Patent: US2001/14691, 2001, A1 [18] Patent: US2001/31771, 2001, A1 [19] Patent: WO2006/40625, 2006, A1. Location in patent: Page/Page column 47 [20] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 1, p. 170 - 174 [21] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4601 - 4608 [22] Patent: WO2011/160020, 2011, A2. Location in patent: Page/Page column 65 [23] Patent: EP1550660, 2005, A1. Location in patent: Page/Page column 9 [24] Patent: WO2008/133734, 2008, A2. Location in patent: Page/Page column 39-40

合成路线 2（2. 合成：109431-87-0）

• 产率：99%
• 合成条件：With triethylamine In dichloromethane at 0 - 20℃; for 0.12 h;
• 实验步骤：向搅拌的（R）-吡咯烷-3-醇氯化氢（3.0g，24.2mmol）的DCM（30ml）溶液中加入N（Et）3（10.2ml，72.8mmol）和（Boc）2O（在0℃下，6ml，26.7mmol）。将反应混合物在室温下搅拌约12小时。搅拌12小时后，加入饱和NH4Cl。将溶液用EtOAc（2x60mL）萃取。将合并的有机相用盐水洗涤，用Na2SO4干燥并减压浓缩，得到粗产物。通过快速色谱法纯化，用EtOAc-己烷（4：6）作为洗脱剂，得到所需产物（4.5g，收率：99％），为油状物。
• 参考文献：[1] Patent: WO2017/17630, 2017, A1. Location in patent: Page/Page column 36 [2] Patent: EP1947083, 2008, A1. Location in patent: Page/Page column 14 [3] Patent: WO2015/110886, 2015, A1. Location in patent: Page/Page column 14-15 [4] Patent: US2014/171432, 2014, A1. Location in patent: Paragraph 0551; 0552 [5] Patent: WO2005/811, 2005, A1. Location in patent: Page/Page column 60-61 [6] Patent: WO2005/20975, 2005, A2. Location in patent: Page/Page column 220 [7] Patent: WO2005/20976, 2005, A2. Location in patent: Page/Page column 223 [8] Patent: WO2005/60949, 2005, A2. Location in patent: Page/Page column 223 [9] Tetrahedron, 2012, vol. 68, # 36, p. 7295 - 7301 [10] Patent: WO2017/88755, 2017, A1. Location in patent: Paragraph 00061; 00062; 00063

合成路线 3（3. 合成：109431-87-0）

• 产率：92%
• 合成条件：With recombinant Chryseobacterium sp. CA 49 ketoreductase; nicotinamide adenine dinucleotide In aq. phosphate buffer; isopropyl alcohol at 40℃; for 10 h; Enzymatic reaction
• 实验步骤：一般步骤：将含有200mM底物，1mM NAD+，5％（v/v）2-丙醇和10mg粗酶READH的1mL磷酸钾缓冲液（100mM，pH7.0）的反应混合物在50℃温育。对于ChKRED20，替代地应用40％（v/v）2-丙醇和40℃的反应温度。通过TLC监测反应，并通过用甲基叔丁基醚（1mL）萃取终止反应。有机萃取液用无水硫酸钠干燥并浓缩。对样品进行手性HPLC以确定转化率和对映体过量。通过硅胶柱色谱法纯化产物，并通过NMR分析，旋光度测量和质谱法鉴定。
• 参考文献：[1] Process Biochemistry, 2017, vol. 56, p. 90 - 97 [2] Tetrahedron Asymmetry, 2005, vol. 16, # 15, p. 2539 - 2549 [3] Journal of the American Chemical Society, 2012, vol. 134, # 45, p. 18522 - 18525