CN110128232B - 一种在有机物中引入氘代的方法 - Google Patents
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Abstract
本发明涉及一种在有机物中引入氘代的方法,尤其涉及一种在含有巯基或者二硫键的有机化合物中引入氘代的方法。属于分子标记技术领域。本发明一种在有机物中引入氘代的方法,将有机物溶于有机溶剂和氘水的混合溶剂中,然后加入膦试剂和自由基引发剂,在光照条件下反应3~6h,即可将底物转化为相应的氘代产物;所述有机物为硫醇、二硫化物或含有半胱氨酸的多肽类有机化合物。本发明引入氘代的方法具有氘代效率高、选择性好、官能团耐受性好、高产率、反应条件温和、无需金属参与反应、底物范围广等特点,特别适合在碳链的特定位置选择性引入氘代。同时这种方法也可适用于多肽底物。
Description
技术领域
本发明涉及一种在有机物中引入氘代的方法,尤其涉及一种在含有巯基或者二硫键的有机化合物中引入氘代的方法。属于分子标记技术领域。
背景技术
氘代作为一种重要的标记手段,在药物代谢,新反应机制研究、核磁、质谱等研究中有着重要应用1-10。在药物分子的适当位置引入氘代,能够极大地改变药物的代谢以及药代动力学性质。2017年,FDA批准了第一个氘代药物,deutetrabenazine,极大地促进了氘代药物的研究和氘代方法的发展11。
1、Helfenbein, J. et al. Isotopic effect study of propofol deuterationon the metabolism, activity, and toxicity of the anesthetic. J. Med. Chem.45,5806-5808 (2002).
2、Elmore, C. S. & Bragg, R. A. Isotope chemistry; a useful tool inthe drug discovery arsenal. Bioorg. Med. Chem. Lett.25, 167-171 (2015).
3、Simmons, E. M. & Hartwig, J. F. On the interpretation of deuteriumkinetic isotope effects in C-H bond functionalizations by transition-metalcomplexes. Angew. Chem.51, 3066-3072 (2012).
4、Scheppele, S. E. Kinetic isotope effects as a valid measure ofstructure-reactivity relations. Isotope effects and nonclassical theory.Chem. Rev.72, 511-532 (1972).
5、Busenlehner, L. S. & Armstrong, R. N. Insights into enzymestructure and dynamics elucidated by amide H/D exchange mass spectrometry.Arch. Biochem. Biophys.433, 34-46 (2005).
6、Atzrodt, J., Derdau, V., Fey, T. & Zimmermann, J. The renaissanceof H/D exchange. Angew. Chem. Int. Ed.46, 7744-7765 (2007).
7、Atzrodt, J., Derdau, V., Kerr, W. J. & Reid, M. Deuterium- andTritium-Labelled Compounds: Applications in the Life Sciences. Angew. Chem. Int. Ed. Engl.57, 1758-1784 (2018).
8、Zhu, Y., Zhou, J. & Jiao, B. Deuterated clopidogrel analogues as anew generation of antiplatelet agents. ACS medicinal chemistry letters4, 349-352 (2013).
9、Katsnelson, A. Heavy drugs draw heavy interest from pharma backers.Nature Medicine19, 656 (2013).
10、Mullard, A. Deuterated drugs draw heavier backing. Nature Reviews Drug Discovery15, 219 (2016).
11、Schmidt, C. First deuterated drug approved. Nat. Biotechnol.35,493 (2017).
但是,在碳链的特定位置选择性地引入氘代,仍然很有挑战性。有鉴于此,本领域亟需一种能够在碳链的特定位置高效选择地引入氘代的方法。
发明内容
本发明要解决上述技术问题,从而提供一种在有机物中引入氘代的方法。并且本发明引入氘代的方法具有氘代效率高、选择性好、官能团耐受性好、高产率、反应条件温和、无需金属参与反应、底物范围广等特点,特别适合在碳链的特定位置选择性引入氘代。同时这种方法也可适用于多肽底物。
本发明解决上述问题的技术方案如下:
一种在有机物中引入氘代的方法,将所述有机物溶于有机溶剂和氘水的混合溶剂中,然后加入膦试剂和自由基引发剂,在光照条件下反应3~6h,即可将底物转化为相应的氘代产物;所述有机物为硫醇、二硫化物或含有半胱氨酸的多肽类有机化合物。
作为上述技术方案的优选,当所述有机物为硫醇或二硫化物时,所述膦试剂选择为(EtO)3P、Ph2POEt、PPh3、HEPT (hexaethyl-phosphoroustriamid)或(EtO)2Par中的一种,且使用量不小于1.0eq。
作为上述技术方案的优选,当所述有机物为硫醇或二硫化物时,所述引发剂选择为过氧化二叔丁基(DTBP),过氧化二异丙苯(DCP ),过氧化二苯甲酰(BPO),优选DTBP,使用当量为0.2-50当量。
作为上述技术方案的优选,所述有机溶剂选自二氯甲烷、乙腈、乙酸乙酯、氯仿、丙酮、DMF、氘代甲醇、乙醚、四氢呋喃、甲苯中的一种。
作为上述技术方案的优选,膦试剂的用量为1~50当量,反应引发剂DTBP用量为0.2~50当量。
作为上述技术方案的优选,当所述有机物为含有二价硫的多肽类有机化合物时,所述膦试剂选择为TPPTS(Triphenylphosphine-3, 3', 3''-trisulfonic acidtrisodium salt)或TCEP(tris(2-carboxyethyl)phosphine),使用量不小于2eq。
作为上述技术方案的优选,所述有机物为R-SH或R-S-S-R;其中,R为伯碳、仲碳、叔碳基团、芳香基或酰基。
作为上述技术方案的优选,所述溶剂为二氯甲烷与氘水形成的混合溶剂,且二氯甲烷和氘水的体积比为(0.5~5):1。
本发明的另一个目的是提供上述氘代方法在多肽片段的自然化学拼接(NCL)中的应用。
本发明是一种全新的引入氘代新方法,路线如下图所示:
R为伯碳、仲碳、叔碳基团、芳香基、酰基。
本发明的合成方法优选方案的步骤如下:
对于含巯基化合物
将含巯基底物底物加入到二氯甲烷和氘水的混合溶剂中,加入1.5~3eq Ph2POE和1~2 eq DTBP,在日光灯照射下于室温反应3~6h。反应结束后,经过柱层析分离即可得到相应的目标产物。
对于含二硫键化合物
将二硫化物加入到二氯甲烷和氘水的混合溶剂中,加入1.5~3eq Ph2POEt和1~2eq DTBP,在日光灯照射下于室温反应3~6h。反应结束后,经过柱层析分离即可得到相应的目标产物。
对于多肽化合物
将多肽化合物溶于氘水中,加入10~40eq TPPTS或者10~40eq TCEP,再加入20~40eq DTBP和10-40eq叔丁基硫醇(t-BuSH)。反应体系在日光灯照射下于室温反应3~6 h。
综上所述,本发明具有以下有益效果:
本发明引入氘代的方法具有氘代效率高、选择性好、官能团耐受性好、高产率、反应条件温和、无需金属参与反应、底物范围广等特点,特别适合在碳链的特定位置选择性引入氘代。同时这种方法也可适用于多肽底物。
附图说明
图1是实施例18的质谱分析图;
图2是实施例19的质谱分析图。
具体实施方式
以下结合附图对本发明进行进一步的说明。
本具体实施方式仅仅是对本发明的解释,并不是对本发明的限制。本领域技术人员在阅读了本发明的说明书之后所做的任何改变,只要在权利要求书的范围内,都将受到专利法的保护。
实验的一般操作流程:将反应底物加入到二氯甲烷和氘水的混合溶剂(V:V=2:1)中,并依次加入Ph2POEt和DTBP;用塞子将瓶口密封并开始搅拌,将反应体系置于两盏36 W日光灯的照射下室温反应6小时。反应结束后,减压蒸除溶剂,层析柱分离获得产品。
实施例1
按照一般操作流程使用0.75 mmol底物,DTBP (1.2 equiv.)、Ph2POEt (2.0equiv.),反应溶剂二氯甲烷和氘水的混合溶剂(6ml,V:V=2:1)。反应结束后,减压蒸除溶剂,粗产品经层析柱(100% 石油醚)分离得100.1 mg无色液体,即为产物,产率89%,氘代率90%。核磁和质谱数据:1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 7.9 Hz, 2H), 7.11(d, J = 7.9 Hz, 2H), 2.37 – 2.28 (m, 2H), 1.30 (s, 9H). 13C NMR (101 MHz,CDCl3) δ 148.17, 134.84, 128.79, 125.19, 34.35, 31.48, 20.62 (t, J = 19.3Hz).GC-MS (EI): m/z = 149.14.
实施例2
按照一般操作流程使用0.75 mmol底物,过氧化二异丙苯(DCP ) (1.2 equiv.)、Ph2POEt (2.0 equiv.),反应溶剂二氯甲烷和氘水的混合溶剂(6ml,V:V=2:1)。反应结束后,减压蒸除溶剂,粗产品经层析柱(石油醚/乙酸乙酯=8:1)分离得214.8 mg白色固体,即为产物,产率96%,氘代率97%。核磁和质谱数据:11H NMR (400 MHz, CDCl3) δ 7.42 – 7.22(m, 10H), 5.12 (s, 4H), 2.70 (s, 3H).13C NMR (101 MHz, CDCl3) δ 172.03,135.72, 128.55, 128.26, 128.22, 66.56, 29.10.HRMS (ESI) calcd for C18H17DO4 [M+ Na] + m/z = 322.1160, found: 322.1167.
实施例3
将谷胱甘肽((0.0738 g, 80 mM))溶于3ml氘水中,TPPTS (0.2728g, 160 mM,2.0 equiv.) 和DTBP (0.0702 g, 160 mM, 2.0 equiv.)依次加入反应体系。反应体系在36 W 日光灯照射下室温反应6 h。经过核磁粗谱和质谱分析,反应成功,产率>95%,氘代率98%。核磁和质谱数据:1H NMR (400 MHz, D2O) δ 4.15 (t, J = 7.2 Hz, 1H), 3.79 (s,2H), 3.72 (t, J = 6.3 Hz, 2H), 2.36 (t, J = 7.2, 2H), 2.02 (dt, J = 7.2, 6.3Hz, 2H), 1.17 (d, J = 7.2 Hz, 2H).ESI-MS calcd for 6a C10H16DN3O6 [M+Na]+m/z =299.1072, found:299.1023.
实施例4
按照一般操作流程使用0.75 mmol底物,DTBP (1.2 equiv.)、Ph2POEt (2.0equiv.),反应溶剂乙腈和氘水的混合溶剂(6ml,V:V=2:1)。反应结束后,减压蒸除溶剂,粗产品经层析柱(石油醚/乙酸乙酯=5:1)分离得170.6 mg无色油状物,即为产物,产率96%,氘代率96%。核磁和质谱数据:1H NMR (400 MHz, CDCl3) δ 7.37 – 7.19 (m, 5H), 5.66 (d,J = 7.3 Hz, 1H), 5.06 (s, 2H), 4.34 (m, 1H), 3.67 (s, 3H), 1.34 (d, J = 7.2Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 173.49, 155.62, 136.22, 128.50, 128.16,128.09, 66.92, 52.44, 49.57, 18.62. HRMS (ESI) calcd for C12H15NO4 [M + Na] + m/z = 260.0893, found: 260.0851.
实施例 5
按照一般操作流程使用0.75 mmol底物,DTBP (1.2 equiv.)、Ph2POEt (2.0equiv.),反应溶剂乙酸乙酯和氘水的混合溶剂(6ml,V:V=2:1)。反应结束后,减压蒸除溶剂,粗产品经层析柱(石油醚/乙酸乙酯=30:1)分离得114.5 mg无色液体,即为产物,产率92%,氘代率95%。核磁和质谱数据:1H NMR (400 MHz, CDCl3) δ 7.37 – 7.28 (m, 5H),5.10 (s, 2H), 2.36 (t, J = 7.5 Hz, 2H), 1.13 (t, J = 7.5 Hz, 2H). GC-MS (EI):m/z = 165.15.
实施例 6
按照一般操作流程使用0.75 mmol底物,DTBP (1.2 equiv.),Ph2POEt (2.0equiv.),反应溶剂氯仿和氘水的混合溶剂(6ml,V:V=2:1)。反应结束后,减压蒸除溶剂,粗产品经层析柱(石油醚/乙酸乙酯=8:1)分离得126.4 mg无色液体,即为产物,产率94%,氘代率98%。核磁和质谱数据:1H NMR (400 MHz, CDCl3) δ 7.51 – 7.26 (m, 5H), 5.09 (s,2H), 4.81 (br s, 1H), 3.22 (dt, J = 6.4 Hz, J = 6.2 Hz, 2H), 1.11 (t, J = 6.2Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 156.28, 136.67, 128.48, 128.03, 66.50,35.84, 14.94 (t, J = 19.8 Hz). HRMS (ESI) calcd for C10H12DNO2 [M + Na] + m/z =203.0901, found: 203.0892.
实施例 7
按照一般操作流程使用0.75 mmol底物,DTBP (1.2 equiv.)、Ph2POEt (2.0equiv.),反应溶剂为氘代甲醇。反应结束后,减压蒸除溶剂,粗产品经层析柱(100% 石油醚)分离得88.0 mg无色液体,即为产物,产率81%,氘代率96%。核磁和质谱数据:1H NMR(400 MHz, CDCl3) δ 7.09 (d, J = 7.9 Hz, 2H), 6.81 (d, J = 7.9 Hz, 2H), 3.79(s, 3H), 2.28 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 157.44, 129.85, 129.77,113.67, 55.24, 20.15 (t, J = 19.8 Hz). GC-MS (EI): m/z = 123.08..
实施例 8
按照一般操作流程使用0.75 mmol底物,DTBP (1.2 equiv.)、Ph2POEt (2.0equiv.),反应溶剂乙醚和氘水的混合溶剂(6ml,V:V=2:1)。反应结束后,减压蒸除溶剂,粗产品经层析柱(100% 石油醚)分离得82.6 mg无色液体,即为产物,产率91%,氘代率85%。核磁和质谱数据:1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 8.2 Hz, 2H), 7.11 (d, J =8.2 Hz, 2H), 2.33 (s, 2H).13C NMR (101 MHz, CDCl3) δ 136.23, 136.20, 131.07,130.38, 128.27, 20.58 (t, J = 19.6 Hz). GC-MS (EI): m/z = 127.03.
实施例 9
按照一般操作流程使用0.75 mmol底物,DTBP (1.2 equiv.)、Ph2POEt (2.0equiv.),反应溶剂四氢呋喃和氘水的混合溶剂(6ml,V:V=2:1)。反应结束后,减压蒸除溶剂,粗产品经层析柱(石油醚/乙酸乙酯=1:5)分离得粗产品,核磁分析产率85%,氘代率91%。核磁和质谱数据:The crude 1H NMR (400 MHz, CDCl3) δ 2.23 (t, J = 7.5 Hz, 2H),1.58 – 1.49 (m, 2H), 1.25 – 1.14 (m, 14H), 0.78 (t, J = 7.2 Hz, 2H). GC-MS(EI): m/z = 187.17.
实施例 10
按照一般操作流程使用0.75 mmol底物,DTBP (1.2 equiv.)、Ph2POEt (2.0equiv.),反应溶剂甲苯和氘水的混合溶剂(6ml,V:V=2:1)。反应结束后,减压蒸除溶剂,粗产品经层析柱(石油醚/乙酸乙酯=30:1)分离得234.0 mg无色液体,即为产物,产率95%,氘代率99%。核磁和质谱数据:1H NMR (400 MHz, CDCl3) δ 7.31 – 7.26 (m, 5H), 5.09 (s,2H), 2.33 (q, J = 7.5 Hz, 1H), 1.10 (d, J = 7.5 Hz, 3H). GC-MS (EI): m/z =165.15.
实施例 11
按照一般操作流程使用0.75 mmol底物,DTBP (1.2 equiv.)、Ph2POEt (2.0equiv.),反应溶剂丙酮和氘水的混合溶剂(6ml,V:V=2:1)。反应结束后,减压蒸除溶剂,粗产品经层析柱(石油醚/乙酸乙酯=5:1)分离得182.8mg无色油状物,即为产物,产率97%,氘代率97%。核磁和质谱数据:1H NMR (400 MHz, CDCl3) δ 7.56 – 7.17 (m, 5H), 5.41 (d,J = 7.4 Hz, 1H), 5.10 (s, 2H), 4.34 (m, 1H), 3.72 (s, 3H), 1.89 – 1.76 (m,1H), 1.73 – 1.60 (m, 1H), 0.89 (t, J = 7.1 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ172.88, 155.88, 136.28, 128.49, 128.12, 128.07, 66.91, 54.94, 52.25, 25.70,9.21 (t, J = 19.5 Hz).HRMS (ESI) calcd for C13H16DNO4 [M + Na] + m/z = 275.1113,found: 275.1140.
实施例 12
按照一般操作流程使用0.75 mmol底物,DTBP (1.2 equiv.)、Ph2POEt (2.0equiv.),反应溶剂DMF和氘水的混合溶剂(6ml,V:V=2:1)。反应结束后,减压蒸除溶剂,粗产品经层析柱(石油醚/乙酸乙酯=1:1)分离得126.0 mg无色液体,即为产物,产率97%,氘代率95%。核磁和质谱数据:1H NMR (400 MHz, CDCl3) δ 6.23 (d, J = 8.8 Hz), 4.54 (d, J= 8.8 Hz, 1H), 3.71 (s, 3H), 2.03 (s, 3H), 0.91 (s, 3H), 0.88 (s, 3H). HRMS(ESI) calcd for C8H15NO3 [M + Na] + m/z = 197.1007, found: 197.1004.
实施例13
按照一般操作流程使用0.75 mmol底物,DTBP (1.2 equiv.)、Ph2POEt (2.0equiv.),反应溶剂二氯甲烷和氘水的混合溶剂(6ml,V:V=2:1)。反应结束后,减压蒸除溶剂,粗产品经层析柱(石油醚/乙酸乙酯=20:1)分离得109.9 mg无色液体,即为产物,产率95%,氘代率97%。核磁和质谱数据:1H NMR (400 MHz, CDCl3) δ 2.31 (m, 1H), 2.11 –1.78 (m, 5H), 1.42 – 1.22 (m, 2H), 0.97 (d, J = 6.3 Hz, 3H), 0.86 (s, 3H),0.80 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 212.41, 55.72, 50.83, 35.43, 33.88,27.76, 25.40 (t, J = 19.6 Hz), 22.27, 21.08, 18.53.
实施例14
按照一般操作流程使用0.375 mmol底物,DTBP (1.2 equiv.)、Ph2POEt (2.0equiv.),反应溶剂二氯甲烷和氘水的混合溶剂(6ml,V:V=2:1)。反应结束后,减压蒸除溶剂,粗产品经层析柱(石油醚/乙酸乙酯=30:1)分离得123.2 mg无色液体,即为产物,产率89%,氘代率95%。核磁和质谱数据:1H NMR (400 MHz, CDCl3) δ 7.33 – 7.28 (m, 5H),5.03 (s, 2H), 2.27 (t, J = 7.5 Hz, 2H), 1.04 (t, J = 7.5 Hz, 2H).
实施例15
按照一般操作流程使用0.375 mmol底物,DTBP (1.2 equiv.)、Ph2POEt (2.0equiv.),反应溶剂二氯甲烷和氘水的混合溶剂(6ml,V:V=2:1)。反应结束后,减压蒸除溶剂,粗产品经层析柱(石油醚/乙酸乙酯=8:1)分离得113.5 mg无色液体,即为产物,产率84%,氘代率99%。核磁和质谱数据:1H NMR (400 MHz, CDCl3) δ 7.48 – 7.26 (m, 5H),5.09 (s, 2H), 4.71 (br s, 1H), 3.23 (dt, J = 6.4 Hz, J = 6.2 Hz, 2H), 1.12(t, J = 6.2 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 156.28, 136.67, 128.47,128.03, 66.50, 35.84, 14.9 (t, J = 19.8 Hz). HRMS (ESI) calcd for C10H12DNO2 [M+ Na] + m/z = 203.0901, found: 203.0892.
实施例16
按照一般操作流程使用0.375 mmol底物,DTBP (1.2 equiv.)、Ph2POEt (2.0equiv.),反应溶剂二氯甲烷和氘水的混合溶剂(6ml,V:V=2:1)。反应结束后,减压蒸除溶剂,粗产品经层析柱(石油醚/乙酸乙酯=5:1)分离得157mg无色油状物,即为产物,产率90%,氘代率98%。核磁和质谱数据:1H NMR (400 MHz, CDCl3) δ7.56 – 7.21 (m, 5H), 5.36(d, J = 7.4 Hz, 1H), 5.10 (s, 2H), 4.46 – 4.23 (m, 1H), 3.73 (s, 3H), 1.93 –1.82 (m, 1H), 1.74 – 1.64 (m, 1H), 0.90 (t, J = 7.1 Hz, 2H). 13C NMR (101 MHz,CDCl3) δ 172.87, 155.85, 136.26, 128.50, 128.14, 128.07, 66.93, 54.92, 52.27,25.72, 9.19 (t, J = 19.5 Hz).HRMS (ESI) calcd for C13H16DNO4 [M + Na] + m/z =275.1113, found: 275.1140.
实施例17
按照一般操作流程使用0.375 mmol底物,DTBP (1.2 equiv.)、Ph2POEt (2.0equiv.),反应溶剂二氯甲烷和氘水的混合溶剂(6ml,V:V=2:1)。反应结束后,减压蒸除溶剂,粗产品经层析柱(石油醚/乙酸乙酯=5:1)分离得141.2 mg无色油状物,即为产物,产率79%,氘代率99%。核磁和质谱数据:1H NMR (400 MHz, CDCl3) δ 7.45 – 7.19 (m, 5H),5.37 (d, J = 4.9 Hz, 1H), 5.10 (s, 2H), 4.38 (dt, J = 6.7, 4.9 Hz, 1H), 3.74(s, 3H), 1.39 (d, J = 6.7 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 173.44, 155.58,136.25, 128.50, 128.14, 128.08, 66.90, 52.41, 49.53, 18.37 (t, J = 20.8 Hz).HRMS (ESI) calcd for C12H14DNO4 [M + Na] + m/z = 261.0956, found: 261.0947.
实施例18
将2.6mg多肽(0.002mmol)溶于2ml氘水中,加入TPPTS (33.3mg, 0.06mmol,30equiv.) 和DTBP (8.8mg, 0.06mmol, 30 equiv.)依次加入反应体系。反应体系在36 W 日光灯照射下室温反应6 h。经过质谱分析,反应成功,产率>95%,氘代率99%。ESI-MS calcdfor C55H89DN14O20 [M+H] +m/z = 1268.6591, [M+2H]2+m/z = 634.8332, found:1268.6522, 634.8337.
实施例19
将3.3mg多肽(0.002mmol)溶于2ml氘水中,加入TPPTS (33.3mg, 0.06mmol,30equiv.) 和DTBP (8.8mg, 0.06mmol, 30 equiv.)依次加入反应体系。反应体系在36 W 日光灯照射下室温反应6 h。经过质谱分析,反应成功,产率>95%,氘代率97%。ESI-MS calcdfor C61H98D2N20O28S [M+2H]2+m/z = 798.3504, found: 798.3506。
Claims (6)
2.根据权利要求1所述的一种在有机物中引入氘代的方法,其特征在于:膦试剂的用量为1~50当量,反应引发剂DTBP用量为0.2~50当量。
3.根据权利要求1所述的一种在有机物中引入氘代的方法,其特征在于:所述有机物为R-SH或R-S-S-R;其中,R为伯碳、仲碳、叔碳基团、芳香基或酰基。
6.权利要求4或5所述的氘代方法在多肽片段的自然化学拼接(NCL)中的应用。
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