化学合成；生命科学。制法：Cbz-L-羟脯氨酸是一种氨基酸衍生物，可由L-脯氨酸通过CbzCl保护得到，缚酸剂可选用氢氧化钠和碳酸氢钠。
化学合成; 生命科学
合成路线 1（1. 合成：13504-85-3）
- 步骤: 向1或7（78.7g，600mmol）和NaHCO₃（126g，1.5mol）的H₂O（900mL）溶液中加入氯甲酸苄酯（89.6mL，630mmol）的二恶烷（90mL）溶液，反应搅拌过夜。完成后（通过TLC监测），将反应在冰浴中冷却至0℃，并用12M HCl酸化至pH2（约75mL）。然后萃取水相（3×500mL EtOAc），有机相用盐水（3×200mL）洗涤，用Na₂SO₄干燥，浓缩，得到无色粘性油状物。产量是定量的，产物在未经纯化的情况下在下一步骤中使用。
- 条件: With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃
- 产率: 100%
- 参考文献: [1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, #16, p. 1845-1847 [2] Angewandte Chemie - International Edition, 2007, vol. 46, #47, p. 9073-9077 [3] Patent: EP1193270, 2002, A2. Location in patent: Page 14, 35-36, 105 [4] Tetrahedron Letters, 2016, vol. 57, #44, p. 4882-4884 [5] Chemical and Pharmaceutical Bulletin, 2018, vol. 66, #5, p. 575-580 [6] Organic Process Research and Development, 2018, vol. 22, #9, p. 1241-1256 [7] Journal of Medicinal Chemistry, 1991, vol. 34, #2, p. 717-725 [8] Tetrahedron, 2006, vol. 62, #10, p. 2321-2330 [9] Chemical communications (Cambridge, England), 2003, #20, p. 2606-2607 [10] Tetrahedron Asymmetry, 2003, vol. 14, #1, p. 139-143 [11] Tetrahedron Letters, 2011, vol. 52, #13, p. 1493-1494 [12] Tetrahedron Asymmetry, 2006, vol. 17, #17, p. 2479-2486 [13] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2008, vol. 63, #11, p. 1300-1304 [14] Synlett, 2010, #13, p. 1943-1946 [15] Journal of the American Chemical Society, 2003, vol. 125, #16, p. 4702-4703 [16] Journal of Organic Chemistry, 2017, vol. 82, #23, p. 12366-12376 [17] Tetrahedron, 2008, vol. 64, #10, p. 2480-2488 [18] Advanced Synthesis and Catalysis, 2010, vol. 352, #1, p. 108-112 [19] Chinese Chemical Letters, 2014, vol. 25, #3, p. 479-481 [20] Helvetica Chimica Acta, 1996, vol. 79, #8, p. 2235-2248 [21] Tetrahedron Letters, 2015, vol. 56, #26, p. 4036-4038 [22] Tetrahedron Letters, 1994, vol. 35, #3, p. 451-454 [23] Tetrahedron, 1998, vol. 54, #5-6, p. 981-996 [24] Patent: JP5709101, 2015, B2. Location in patent: Paragraph 0054 [25] Tetrahedron, 2009, vol. 65, #4, p. 862-876 [26] Journal of Molecular Catalysis A: Chemical, 2012, vol. 363-364, p. 404-410,7 [27] Chemical and Pharmaceutical Bulletin, 1998, vol. 46, #4, p. 697-703 [28] Patent: WO2005/40170, 2005, A2. Location in patent: Page/Page column 33 [29] Journal of Organic Chemistry, 2016, vol. 81, #3, p. 956-968 [30] Patent: WO2007/22638, 2007, A1. Location in patent: Page/Page column 100-101 [31] Journal of the American Chemical Society, 1957, vol. 79, p. 185,190 [32] Chemische Berichte, 1958, vol. 91, p. 449,453 [33] Canadian Journal of Biochemistry and Physiology, 1959, vol. 37, p. 583,584 [34] Journal of Fluorine Chemistry, 1991, vol. 54, #1-3, p. 195 [35] Journal of Organic Chemistry, 1991, vol. 56, #8, p. 2787-2800 [36] Journal of Organic Chemistry, 1994, vol. 59, #13, p. 3616-3625 [37] Bioscience, Biotechnology, and Biochemistry, 1995, vol. 59, #6, p. 1161-1162 [38] Journal of Organic Chemistry, 1997, vol. 62, #4, p. 790-791 [39] Collection of Czechoslovak Chemical Communications, 1996, vol. 61, p. S234-S237 [40] Journal of Organic Chemistry, 1997, vol. 62, #20, p. 6773-6783 [41] Carbohydrate Research, 1996, vol. 286, p. 123-138 [42] Synlett, 1999, #9, p. 1465-1467 [43] Nucleosides, Nucleotides and Nucleic Acids, 2001, vol. 20, #4-7, p. 1193-1196 [44] Journal of Medicinal Chemistry, 2004, vol. 47, #2, p. 489-492 [45] Nucleosides, Nucleotides and Nucleic Acids, 2003, vol. 22, #5-8, p. 1285-1288 [46] Journal of Organic Chemistry, 2006, vol. 71, #13, p. 5004-5007 [47] Tetrahedron Asymmetry, 2006, vol. 17, #17, p. 2479-2486 [48] Tetrahedron Letters, 2007, vol. 48, #5, p. 841-844 [49] Patent: JP2005/112761, 2005, A. Location in patent: Page/Page column 8 [50] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, #3, p. 1096-1101 [51] European Journal of Organic Chemistry, 2010, #5, p. 927-936 [52] Synlett, 2011, #4, p. 503-507 [53] Patent: WO2011/92671, 2011, A1. Location in patent: Page/Page column 33-34 [54] Macromolecules, 2010, vol. 43, #15, p. 6374-6380 [55] Chemistry - A European Journal, 2011, vol. 17, #48, p. 13433-13437 [56] Molecular BioSystems, 2011, vol. 7, #5, p. 1564-1575 [57] Patent: US2013/65935, 2013, A1. Location in patent: Paragraph 0096 [58] Tetrahedron, 2013, vol. 69, #33, p. 6866-6874 [59] European Journal of Organic Chemistry, 2014, vol. 2014, #24, p. 5351-5355 [60] Chemistry - A European Journal, 2016, vol. 22, #20, p. 6750-6754 [61] Chemical Communications, 2018, vol. 54, #66, p. 9202-9205
合成路线 2（2. 合成：13504-85-3）
- 步骤: 将氯甲酸苄基酯（12.5mL，87.7mL）的甲苯（40mL）溶液加入到反式-4的溶液中。在15分钟内，羟基-L-脯氨酸11（10g，76.3mmol）和NaHCO₃（16g，190mmol）的H₂O（165mL）溶液。在室温下搅拌12小时后，使两相分离。将水相用乙醚（4×50mL）洗涤，在冰浴中冷却，然后用浓盐酸酸化至pH 2。盐酸。用乙酸乙酯（5×50mL）萃取所得产物，干燥（MgSO₄）合并的有机萃取物，真空蒸发过量溶剂，得到无色粘性油状物（20.30g，100％）。 [α]²⁷D = -565°（c 0.1，MeOH）。 ¹H NMR（CDCl₃）：δ2.07-2.31（m，3H，H1），3.52-3.59（m，2H，H3），4.43-4.53（m，2H，H2，H11a），5.8和5.11（s，2H，H6,1：2），6.0（bs，2H，OH），7.26-7.29和7.32-7.34（m，5H，H的主要和主要旋转异构体，1：2）的次要和主要旋转异构体。 IR（薄膜）：ν= 3414（OH），2940（OH），1682（C=O），1495,1429,1359（CO₂-），1314,1269,1205,1108,1174,1127,1082,1051，993,914,866,826,769,741,697cm⁻¹。 MS（EI）：m/e（相对强度）：266（M+。，1），265（6），220（5），176（15），130（34），108（2）。 91（100），86（4），68（11）。 HRMS计算。 C₁₃H₁₁NO = 265.0950，实测值265.0976
- 条件: With sodium hydrogencarbonate In water; toluene
- 产率: 100%
- 参考文献: [1] Patent: US2003/120069, 2003, A1
