74844-91-0 N-Boc-反式-4-羟基-L-脯氨酸甲酯

中文名称: N-Boc-反式-4-羟基-L-脯氨酸甲酯
英文名称: N-Boc-trans-4-Hydroxy-L-proline methyl ester
CAS号
分子式: C₁₁H₁₉NO₅
分子量: 245.27
更新日期: 2026-06-23

名称和标识

中文名: N-Boc-反式-4-羟基-L-脯氨酸甲酯
英文名: N-Boc-trans-4-Hydroxy-L-proline methyl ester
CAS号: 74844-91-0
分子式: C11H19NO5
分子量: 245.27
中文别名: N-叔丁氧羰基-反式-4-羟基-L-脯氨酸甲酯; BOC-L-羟脯氨酸甲酯; N-BOC-反式-L-羟脯氨酸甲酯; BOC-反-4-羟基-L-脯氨酸甲酯; N-(叔丁氧羰基)-反-4-羟基-L-脯氨酸甲酯; (2S,4R)-N-Boc-4-羟基-2-吡咯啉甲酸甲酯; BOC-L-羟基脯氨酸; Boc-Hyp-OMe; (2S,4R)-1-叔丁基 2-甲基 4-羟基吡咯烷-1,2-二羧酸二乙酯
英文别名: N-T-BOC-TRANS-4-HYDROXY-L-PROLINE METHYL ESTER; N-(TERT-BUTOXYCARBONYL)-TRANS-HYDROXYL-L-PROLINE METHYL ESTER; N-ALPHA-T-BUTOXYCARBONYL-L-HYDROXYPROLINE METHYL ESTER; N-BOC-TRANS-4-HYDROXYL-L-PROLINE METHYL ESTER; N-BOC-4-HYDROXY-L-PROLINE METHYL ESTER; N-BOC-L-TRANS-4-HYDROXY-PROLINE METHYL ESTER; 1-(tert-Butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate; N-BOC-transydro-L-prolinemethylester; N-Boc-trans-hydro-L-prolinemethylester; N-Boc-trans-4-Hydroxy-L-prolinemethylester; BOC-HYDROXYPROLINE-OME; BOC-L-4-HYDROXYPROLINE METHYL ESTER; Boc-Hyp-Ome; BOC-L-HYDROXYPROLINE METHYL ESTER; BOC-L-T-4-HYDROXYPROLINE METHYL ESTER; Boc-trans-4-hydroxy-L-proline methyl ester; N-BOC-L-Hydroxyproline methyl ester

物化属性

LogP: 0.62
LogS (Ali): -1.75
LogS (ESOL): -1.4
LogS (SILICOS-IT): -0.27
MLOGP: 0.22
PSA: 76.07 Å²
SILICOS-IT LogP: -0.11
WLOGP: 0.15
XLogP3: 0.58
iLOGP: 2.57
储存条件: 存放在密封容器内，并放在阴凉，干燥处
外观: 白色或类白色结晶性固体、粉末或晶状体粉末
密度: 1.2±0.1 g/cm³
折射率: 1.501
旋光度: [α]20/D -65°, c = 1% in chloroform
水溶解性: 可溶于：甲醇
沸点: 335.2±42.0 °C (760 mmHg)
溶解性: 易溶于氯仿、二氯甲烷和乙酸乙酯
熔点: 92-96 °C(lit.)
稳定性: 常温常压下稳定，远离氧化剂
蒸汽压: 0.0±1.6 mmHg (25 °C)
闪点: 156.6±27.9 °C

安全信息

安全说明

运输方式：冰袋运输。危险描述：非危险化学品，WGK Germany:3，危险等级为IRRITANT，海关编码29339900，存储类别11 - 可燃固体。

生产及用途

用途与制备

N-Boc-反式-4-羟基-L-脯氨酸甲酯是一种氨基酸类衍生物，可用作医药中间体；可用于合成基于Met的For-Met-Leu-Phe-OMe（fMLF-OMe）类似物，残基被4-氨基脯氨酸支架置换。

医药

合成路线 1（1. 合成：74844-91-0）

步骤：向冷却至0℃的反式-4-羟基-L-脯氨酸甲酯盐酸盐（14.5g，0.1mol）在CH₂Cl₂（400mL）中的搅拌悬浮液中加入Et₃N（28mL，0.2mol）、DMAP（0.61g，5mmol）和Boc酐（27.5mL，0.12mol）；将反应混合物逐渐温热至室温并搅拌2小时；减压蒸发溶剂，加入乙醚，过滤收集固体并用乙醚洗涤；合并滤液，减压浓缩，残余物用CH₂Cl₂溶解，依次用饱和NaHCO₃水溶液和饱和NaCl水溶液洗涤，无水Na₂SO₄干燥，减压蒸发溶剂，高真空处理固化，己烷研磨，高真空干燥得产物。
条件：With triethylamine In dichloromethane at 0 - 20℃; for 2 h
收率：100%
产物：1-叔丁基-2-甲基（2S，4R）-4-羟基吡咯烷-1,2-二甲酸酯（白色固体，24.5g）
参考文献：[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, #22, p.5699-5702；[2] Patent: WO2007/113634, 2007, A1. Location in patent: Page/Page column 60-61；[3] Tetrahedron Asymmetry, 2009, vol.20, #12, p.1433-1436；[4] Journal of Chemical Research, 2009, #11, p.668-670；[5] Tetrahedron Letters, 2012, vol.53, #30, p.3847-3849；[6] Patent: TW2017/8221, 2017, A. Location in patent: Page/Page column 44; 45；[7] Patent: US2005/192302, 2005, A1. Location in patent: Page/Page column 41；[8] Patent: WO2012/114223, 2012, A1. Location in patent: Page/Page column 72-73；[9] Bioorganic and Medicinal Chemistry Letters, 2011, vol.21, #12, p.3767-3770；[10] Tetrahedron Letters, 2013, vol.54, #39, p.5345-5347；[11] Tetrahedron, 2003, vol.59, #18, p.3307-3314；[12] Patent: WO2006/27694, 2006, A1. Location in patent: Page/Page column 69-70；[13] Tetrahedron Letters, 1998, vol.39, #10, p.1169-1172；[14] Tetrahedron Letters, 2003, vol.44, #42, p.7809-7812；[15] Journal of Medicinal Chemistry, 1983, vol.26, #4, p.549-554；[16] Heterocycles, 2003, vol.60, #5, p.1203-1209；[17] Bioorganic and Medicinal Chemistry, 2008, vol.16, #1, p.578-585；[18] Tetrahedron Asymmetry, 1998, vol.9, #1, p.47-53；[19] Patent: US2009/163472, 2009, A1. Location in patent: Page/Page column 21；[20] European Journal of Medicinal Chemistry, 2014, vol.86, p.242-256；[21] Patent: WO2018/26792, 2018, A1. Location in patent: Page/Page column 138-139；[22] Bioorganic and Medicinal Chemistry Letters, 2011, vol.21, #12, p.3730-3733；[23] Patent: WO2011/50146, 2011, A1. Location in patent: Page/Page column 45；[24] ACS Medicinal Chemistry Letters, 2013, vol.4, #10, p.969-973；[25] Chemical Communications, 2014, vol.50, #68, p.9657-9660；[26] Helvetica Chimica Acta, 1996, vol.79, #7, p.1825-1842；[27] Journal of Organic Chemistry, 2001, vol.66, #10, p.3593-3596；[28] Patent: US2013/115194, 2013, A1. Location in patent: Paragraph 0410；[29] Bioorganic and Medicinal Chemistry, 2015, vol.23, #24, p.7685-7693；[30] Patent: WO2015/28850, 2015, A1. Location in patent: Page/Page column 85；[31] Patent: WO2016/59622, 2016, A2. Location in patent: Page/Page column 124；[32] Organic Letters, 2018, vol.20, #1, p.162-165；[33] Patent: US5317016, 1994, A；[34] Journal of the Chemical Society - Perkin Transactions 1, 1998, #22, p.3777-3793；[35] Journal of the Chemical Society. Perkin Transactions 1, 2001, #20, p.2623-2631；[36] Dalton Transactions, 2016, vol.45, #34, p.13483-13490；[37] Patent: WO2009/158571, 2009, A1. Location in patent: Page/Page column 400; 401；[38] Journal of Fluorine Chemistry, 2015, vol.173, p.77-83；[39] Bioorganic and Medicinal Chemistry, 2002, vol.10, #5, p.1399-1415；[40] Tetrahedron Letters, 2005, vol.46, #30, p.4985-4987；[41] Bioorganic and Medicinal Chemistry, 2006, vol.14, #7, p.2253-2265；[42] Journal of Organic Chemistry, 2000, vol.65, #5, p.1590-1596；[43] Organic Letters, 2007, vol.9, #15, p.2939-2941；[44] Patent: WO2005/42533, 2005, A2. Location in patent: Page/Page column 54-55；[45] Chemical Communications, 2009, #4, p.463-465；[46] Patent: WO2004/99185, 2004, A1. Location in patent: Page 22-23；[47] Patent: WO2007/65883, 2007, A1. Location in patent: Page/Page column 6; 13-14；[48] Journal of Organic Chemistry, 2012, vol.77, #11, p.4917-4923；[49] Bioorganic and Medicinal Chemistry, 2013, vol.21, #23, p.7418-7429；[50] European Journal of Medicinal Chemistry, 2014, vol.75, p.111-122；[51] Patent: US2014/179668, 2014, A1. Location in patent: Paragraph 0860；[52] Patent: US2014/179680, 2014, A1. Location in patent: Paragraph 0778；[53] Patent: WO2015/6740, 2015, A2. Location in patent: Page/Page column 97; 98；[54] Bioorganic and Medicinal Chemistry, 2016, vol.24, #18, p.4016-4022

合成路线 2（2. 合成：74844-91-0）

步骤：由反式-4-羟基-L-脯氨酸合成化合物（2S，4R）-4-（叔丁基二甲基甲硅烷基氧基）-2-（羟甲基）-吡咯烷-1-羧酸叔丁酯（8），具体程序参考Rosen等，J.Med.Chem.1988,31,1598。
条件：With sodium carbonate In 1,4-dioxane; water
收率：100%
产物：1H NMR (400MHz, CDCl3) δ 0.08 (s, 6H), 0.87 (s, 9H), 1.47 (s, 9H), 1.96 (m, 1H), 1.98 (s, 1H), 3.34 (dd, J=4.0,14.6 Hz, 1H), 3.42 (d, J=12.0 Hz, 1H), 3.55 (m, 1H), 3.71 (m, 1H), 4.11 (m, 1H), 4.27 (m, 1H), 4.91 (dd, J=0.8Hz,12.0Hz,1H)
参考文献：[1] Tetrahedron Letters, 2001, vol.42, #32, p.5335-5338；[2] Bioorganic and Medicinal Chemistry, 2009, vol.17, #4, p.1557-1572；[3] Patent: US2007/117986, 2007, A1. Location in patent: Page/Page column 21; 22；[4] Journal of Organic Chemistry, 2005, vol.70, #2, p.499-504；[5] Tetrahedron Asymmetry, 2010, vol.21, #2, p.222-225；[6] Bioorganic and Medicinal Chemistry Letters, 2011, vol.21, #12, p.3771-3773；[7] Bioorganic and Medicinal Chemistry Letters, 2009, vol.19, #15, p.4130-4133；[8] Patent: WO2013/149121, 2013, A1. Location in patent: Page/Page column 132; 133；[9] Angewandte Chemie - International Edition, 2002, vol.41, #9, p.1600-1602；[10] Patent: WO2018/26792, 2018, A1. Location in patent: Page/Page column 63-64；[11] Patent: WO2018/152134, 2018, A1. Location in patent: Paragraph 000213；[12] ACS Medicinal Chemistry Letters, 2014, vol.5, #1, p.56-60；[13] Patent: WO2018/86139, 2018, A1. Location in patent: Page/Page column 181；[14] Journal of Organic Chemistry, 2006, vol.71, #14, p.5186-5190；[15] Patent: WO2017/177326, 2017, A1. Location in patent: Page/Page column 96; 97；[16] Patent: WO2018/191278, 2018, A2. Location in patent: Page/Page column 123；[17] ChemMedChem, 2018, vol.13, #3, p.220-226；[18] European Journal of Medicinal Chemistry, 2018, vol.152, p.358-369；[19] Journal of Antibiotics, 1996, vol.49, #5, p.478-484；[20] Tetrahedron Letters, 2005, vol.46, #45, p.7813-7816；[21] Patent: WO2016/73623, 2016, A2. Location in patent: Paragraph 0126；[22] Patent: WO2013/102242, 2013, A1. Location in patent: Page/Page column 71；[23] Tetrahedron Letters, 1992, vol.33, #52, p.8103-8104；[24] Bioorganic and Medicinal Chemistry Letters, 2001, vol.11, #4, p.587-590；[25] Synlett, 2001, #10, p.1575-1577；[26] Bioorganic and Medicinal Chemistry Letters, 2003, vol.13, #3, p.489-493；[27] Synthesis, 2004, #3, p.334-340；[28] Journal of Organic Chemistry, 2005, vol.70, #10, p.3826-3837；[29] Tetrahedron Letters, 2006, vol.47, #37, p.6553-6556；[30] Tetrahedron Letters, 2006, vol.47, #50, p.8929-8932；[31] Patent: US5756528, 1998, A；[32] Patent: EP1813614, 2007, A1. Location in patent: Page/Page column 41；[33] Tetrahedron Letters, 2009, vol.50, #20, p.2363-2366；[34] Patent: WO2010/62821, 2010, A1. Location in patent: Page/Page column 57；[35] Advanced Synthesis and Catalysis, 2012, vol.354, #6, p.1035-1042；[36] Journal of the Chinese Chemical Society, 2012, vol.59, #3, p.436-442；[37] Journal of Organic Chemistry, 2012, vol.77, #12, p.5286-5296；[38] European Journal of Organic Chemistry, 2012, #31, p.6280-6284,5；[39] European Journal of Organic Chemistry, 2012, #31, p.6280-6284；[40] Chemical Communications, 2013, vol.49, #40, p.4561-4563；[41] Bioorganic and Medicinal Chemistry, 2013, vol.21, #14, p.4092-4101；[42] Patent: US2013/287731, 2013, A1. Location in patent: Paragraph 0240；[43] RSC Advances, 2013, vol.3, #42, p.19533-19544；[44] Organic Process Research and Development, 2008, vol.12, #4, p.626-631；[45] Tetrahedron Asymmetry, 2014, vol.25, #3, p.212-218；[46] Patent: US2014/179680, 2014, A1. Location in patent: Paragraph 0766；[47] Organic and Biomolecular Chemistry, 2015, vol.13, #11, p.3171-3181；[48] Bioorganic and Medicinal Chemistry, 2017, vol.25, #1, p.138-152；[49] Patent: US9994614, 2018, B2. Location in patent: Page/Page column 60; 62

合成路线 3（3. 合成：74844-91-0）

步骤：向（4R）-1-Boc-4-羟基-L-脯氨酸（8g，34.63mmol）在DMF中的溶液中加入K₂CO₃（14g，101mmol）和碘甲烷（2.6ml，20.6mmol），反应混合物在室温下搅拌5小时。
条件：With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 5 h
收率：95%
产物：甲基（2S，4R）-1-Boc-4-羟基吡咯烷-2-羧酸甲酯（8.0g，95%），MS [M+H]=246（M+1）
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