CN110438523B - 一种以重水为氘源的无催化剂电化学氘代方法 - Google Patents

一种以重水为氘源的无催化剂电化学氘代方法 Download PDF

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CN110438523B
CN110438523B CN201910837412.3A CN201910837412A CN110438523B CN 110438523 B CN110438523 B CN 110438523B CN 201910837412 A CN201910837412 A CN 201910837412A CN 110438523 B CN110438523 B CN 110438523B
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程旭
刘旭
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Nanjing Nanxin Medical Technology Research Institute Co ltd
Nanjing University
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Abstract

本发明涉及一种以重水为氘源的无催化剂电化学氘代方法，往反应器中加入电解质、含有烯键或炔键的有机物、重水和有机溶剂,以碳毡作为电极材料，在惰性气体氛围下，通入4‑8V的直流电压进行电解反应，将反应产物进行纯化，即得到氘代产物。本发明采用重水作为氘源，利用廉价易得的碳电极材料作为阴极和阳极，在有机溶剂中通过直流电解，获得氘化产物，反应过程无需任何过渡金属催化剂，反应的产率在50％‑90％，氘代率在90％以上。由于避免了过渡金属的使用，反应适合在后期对药物分子进行修饰，同时，由于反应路径与过渡金属催化的反应历程不同，可以实现与过渡金属催化的氘化反应不同的化学选择性。

Description

一种以重水为氘源的无催化剂电化学氘代方法
技术领域
本发明涉及一种以重水为氘源的氘代方法，尤其是一种以重水为氘源的无催化剂电化学氘代方法，属于有机合成技术领域。
背景技术
在分子中将碳氢键替换为碳氘键，可以显著提高对应位点的化学稳定性，对于药物的代谢与药效有独特的作用，目前第一例氘代药物Austedo已经于2017年获得FDA批准，在药物合成中是一个里程碑的事件。同时，在已经上市的药物中引入氘原子，可以最小程度的改变药物的性质，同时可以作为一种新药申请。由于这个独特的优势，氘代技术近两年来获得了广泛的关注。
以往的氘代技术需要用到特殊的氘代试剂，例如，需要利用氘代醇，氘代二甲亚砜，氘代乙腈等溶剂，成本高，难以大规模实施。作为最基本的氘的来源，重水廉价易得，无需昂贵的二次氘代试剂，安全环保。利用重水作为氘源直接对有机分子进行氘化，会获得最大的原子经济性和步骤经济性。但是，现有技术中利用重水作为氘源直接对有机分子进行氘化，主要是在过渡金属催化下以还原剂现场产生金属氘络合物，进而发生与氢化反应类似的氘化反应。而在药物合成中，在最后阶段需要尽量避免过渡金属催化剂的使用，以免在药物活性成分引入高毒性物质。因此，迫切需要一种以重水为氘源的无催化剂氘代方法。
发明内容
本发明的目的在于解决现有技术的不足，一种以重水为氘源的无催化剂电化学氘代方法，该方法可以利用阴极还原的方式实现将不饱和键转化为阴离子自由基，通过与重水直接反应，就可以生成碳氘键，整个反应无需过渡金属的参与。
技术方案
一种以重水为氘源的无催化剂电化学氘代方法:往反应器中加入电解质、含有烯键或炔键的有机物、重水和有机溶剂,以碳毡作为电极材料，在惰性气体氛围下，通入4-8V的直流电压进行电解反应，将反应产物进行纯化，即得到氘代产物。
所述含有烯键或炔键的有机物选自烯烃、炔烃、不饱和酯、不饱和酰胺或不饱和羧酸中的一种。
进一步，所述含有烯键或炔键的有机物选自3-苯基-2-丙烯酸乙酯、3-苯基-2-丙烯酸丁酯、3-苯基-丙酸-1-戊烯-4-酯、3-苯基-2-丙烯酸-环己酯、3-苯基-2-丙烯酸-环己酯四氢呋喃基-3酯，3-苯基-2-丙烯酸-磷酸二乙酯基甲酯，3-苯基-2-丙烯酸苄酯，3-苯基-2-丙烯酸苯酯、3-苯基-2-丙烯酸薄荷醇酯、3-苯基-2-丙烯酸雌酚酮酯、3-苯基-2-丙烯酸龙脑酯、3-苯基-2-丙烯酸孕酮酯、3-苯基-2-丙烯酸雌酚酮酯或3-苯基-2-丙酸胆固醇酯中的任意一种。
进一步，所述电解质为四丁基四氟硼酸铵或LiClO4中的任意一种，电解质浓度为0.02mol/L。
进一步，所述重水与含有烯键或炔键的有机物的摩尔比为5-20:1。
进一步，所述有机溶剂为DMF或乙腈中的任意一种。
进一步，所述惰性气体为氮气或氩气。
进一步，所述纯化过程为：先将反应产物用乙酸乙酯萃取，萃取后的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥，接着过滤，将滤液旋干，然后采用以300-400目硅胶作为固定相的柱层析技术，干法上样，以石油醚/乙酸乙酯混合液为洗脱剂进行洗脱，GC-MS检测洗脱液，将收集的层析液浓缩。
本发明的有益效果：本发明以含有烯键或炔键的有机物作为原料，采用重水作为氘源，利用廉价易得的碳电极材料作为阴极和阳极，在有机溶剂中通过直流电解，获得氘化产物，反应过程无需任何过渡金属催化剂，并且采用廉价通用玻璃仪器作为反应器，无需特殊仪器及隔膜。反应的产率在50％-90％，氘代率在90％以上。由于避免了过渡金属的使用，反应适合在后期对药物分子进行修饰。同时，由于反应路径与过渡金属催化的反应历程不同，可以实现与过渡金属催化的氘化反应不同的化学选择性，反应可以耐受富电子烯烃，多种杂环，对氢化敏感的保护基团如Cbz，Alloc等，反应无需任何酸碱添加剂，无任何辅助试剂，转化能耗为200-500mW/mmol。
具体实施方式
下面结合具体实施例对本发明作进一步说明。
实施例1
Figure BDA0002192623800000031
一种以重水为氘源的无催化剂电化学氘代方法:往容积为10mL的透明两口反应瓶中，加入四丁基四氟硼酸铵(32.9mg,0.1mmol)，将装有电极的橡胶塞塞住一个瓶口，用微量进样器加入3-苯基-2-丙烯酸乙酯(35.2mg,0.2mmol)和氘水(80.0mg,4mmol),再加入5mLN,N-二甲基甲酰胺，以氩气吹扫，将反应瓶放于磁力搅拌器上，接上电极，将电压设为6V，在6V电压下搅拌2-10小时，反应结束之后，将反应产物用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，将滤液旋干。采用以300-400目硅胶作为固定相的柱层析技术，干法上样，以石油醚/乙酸乙酯混合液为洗脱剂进行洗脱，GC-MS检测洗脱液，将收集的层析液浓缩，得到32.7mg氘代产物2a(3-苯基-2-丙酸乙酯),产率91％，氘代率为苄位99％，羰基邻位99％。
产物2a的核磁数据为：1H NMR(400MHz,Chloroform-d)δ7.30–7.25(m,2H),7.21–7.18(m,3H),4.12(q,J＝7.2Hz,1H),2.95–2.91(m,1.01H,99％D),2.62–2.58(m,1.01H,99％D),1.23(t,J＝7.1Hz,1H)；13C NMR(100MHz,CDCl3)δ172.9,140.5,128.5,128.3,126.2,60.4,35.6(t,J＝20.0Hz),30.6(t,J＝20.0Hz),14.2.
实施例2
Figure BDA0002192623800000032
的合成：
含有烯键或炔键的有机物为3-苯基-2-丙烯酸丁酯，其余与实施例1相同，最后得到氘代产物2b(3-苯基-丙酸正丁酯)，产率为89％，氘代率为苄位99％,羰基邻位98％。
1H NMR(400MHz,Chloroform-d)δ7.30–7.26(m,2H),7.21–7.17(m,3H),4.07(t,J＝6.7Hz,2H),2.95–2.91(m,1.03H,97％D),2.62–2.59(m,1.04H,96％D),1.61–1.54(m,2H),1.38–1.28(m,2H),0.91(t,J＝7.4Hz,3H)；13C NMR(100MHz,CDCl3)δ173.0,140.5,128.5,128.3,126.2,64.3,35.6(t,J＝20.0Hz),30.7,30.6(t,J＝20.0Hz),19.1,13.7.
实施例3
Figure BDA0002192623800000041
的合成：
含有烯键或炔键的有机物为3-苯基-2-丙烯酸-1-戊烯-4-酯，其余与实施例1相同，最后得到氘代产物2c(3-苯基-丙酸-1-戊烯-4-酯)，产率为86％，氘代率苄位为97％，羰基邻位为98％。
1H NMR(400MHz,Chloroform-d)δ7.30–7.25(m,2H),7.21–7.17(m,3H),5.75–5.65(m,1H),5.06(d,J＝8.3Hz,1H),5.03(s,1H),5.00–4.92(m,1H),2.94–2.91(m,1.03H,97％D),2.60–2.56(m,1.02H,98％D),2.27(qt,J＝14.1,6.6Hz,2H),1.18(d,J＝6.3Hz,3H)；13CNMR(100MHz,CDCl3)δ172.4,140.5,133.7,128.4,128.3,126.2,117.6,70.1,40.2,35.8(t,J＝20.0Hz),30.7(t,J＝20.0Hz),19.4.
实施例4
Figure BDA0002192623800000042
的合成：
含有烯键或炔键的有机物为3-苯基-2-丙烯酸-环己酯，其余与实施例1相同，最后得到氘代产物2d(3-苯基-2-丙酸-环己酯)，产率为80％，氘代率苄位为97％，羰基邻位为96％。
1H NMR(400MHz,Chloroform-d)δ7.30–7.25(m,2H),7.21–7.17(m,3H),4.75(dt,J＝9.0,4.7Hz,1H),2.95–2.91(m,1.03H,97％D),2.61–2.57(m,1.04H,96％D),1.81–1.75(m,2H),1.72–1.67(m,2H),1.56–1.49(m,1H),1.42–1.22(m,5H)；13C NMR(100MHz,CDCl3)δ172.4,140.6,128.4,128.3,126.2,72.6,35.9(t,J＝20.0Hz),31.6,30.7(t,J＝20.0Hz),25.4,23.7.
实施例5
Figure BDA0002192623800000043
的合成：
含有烯键或炔键的有机物为3-苯基-2-丙烯酸-环己酯四氢呋喃基3酯，其余与实施例1相同，最后得到氘代产物2e(3-苯基-丙酸-环己酯四氢呋喃基3酯)，产率为88％，氘代率苄位为98％，羰基邻位为95％。
1H NMR(400MHz,Chloroform-d)δ7.30–7.25(m,2H),7.22–7.18(m,3H),5.29–5.26(m,1H),3.88–3.80(m,3H),3.75(d,J＝10.5Hz,1H),2.94–2.91(m,1.02H,98％D),2.64–2.60(m,1.05H,95％D),2.17–2.08(m,1H),1.94–1.88(m,1H)；13C NMR(100MHz,CDCl3)δ172.7,140.2,128.5,128.3,126.3,74.8,73.1,67.0,35.5(t,J＝20.0Hz),32.7,30.5(t,J＝20.0Hz).
实施例6
Figure BDA0002192623800000051
的合成：
含有烯键或炔键的有机物为3-苯基-2-丙烯酸-磷酸二乙酯基甲酯，其余与实施例1相同，最后得到氘代产物2f(3-苯基-丙酸-磷酸二乙酯基甲酯)，产率为68％，氘代率苄位为96％，羰基邻位为91％。
1H NMR(400MHz,Chloroform-d)δ7.31–7.27(m,2H),7.21–7.19(m,3H),4.39(s,1H),4.36(s,1H),4.15(p,J＝8.0,7.5Hz,4H),2.98–2.94(m,1.04H,96％D),2.73–2.69(m,1.04H,96％D),1.33(t,J＝7.1Hz,3H)；13C NMR(100MHz,Chloroform-d)δ171.9(d,J＝7.6Hz),140.0,128.5,128.3,126.4,62.8(d,J＝6.2Hz),56.9(d,J＝169.4Hz),35.1(t,J＝20.0Hz),30.4(t,J＝20.0Hz),16.4(d,J＝5.8Hz).
实施例7
Figure BDA0002192623800000052
的合成：
含有烯键或炔键的有机物为3-苯基-2-丙烯酸苄酯，其余与实施例1相同，最后得到氘代产物2g(3-苯基-丙酸苄酯)，产率为77％，氘代率苄为96％，羰基邻位为91％。
1H NMR(400MHz,Chloroform-d)δ7.36–7.25(m,7H),7.21–7.17(m,3H),5.10(s,2H),2.97–2.93(m,1.04H,96％D),2.68–2.64(m,1.09H,91％D)；13C NMR(100MHz,CDCl3)δ172.7,140.4,136.0,128.6,128.5,128.3,128.2,126.3,66.3,35.6(t,J＝20.0Hz),30.6(t,J＝20.0Hz).
实施例8
Figure BDA0002192623800000061
的合成：
含有烯键或炔键的有机物为3-苯基-2-丙烯酸苯酯，其余与实施例1相同，最后得到氘代产物2h(3-苯基-丙酸苯酯)，产率为82％，氘代率苄为99％，羰基邻位为94％。
1H NMR(400MHz,Chloroform-d)δ7.37–7.30(m,4H),7.27–7.19(m,4H),7.00(d,J＝7.8Hz,2H),3.08–3.04(m,1.01H,99％D),2.88–2.85(m,1.06H,94％D)；13C NMR(100MHz,CDCl3)δ171.4,150.7,140.1,129.4,128.6,128.4,126.5,125.8,121.6,35.7(t,J＝20.0Hz),30.61(t,J＝20.0Hz).
实施例9
Figure BDA0002192623800000062
的合成：
含有烯键或炔键的有机物为3-苯基-2-丙烯酸薄荷醇酯，其余与实施例1相同，最后得到氘代产物2i(3-苯基-丙酸薄荷醇酯)，产率为73％，氘代率苄位为99％，羰基邻位为94％。
1H NMR(400MHz,Chloroform-d)δ7.29–7.25(m,2H),7.20–7.17(m,3H),4.67(td,J＝10.9,4.4Hz,1H),2.94–2.90(m,1.01H,99％D),2.61–2.57(m,1.06H,94％D),1.93(d,J＝12.0Hz,1H),1.76–1.64(m,3H),1.52–1.40(m,3H),1.36–1.29(m,1H),1.08–0.98(m,1H),0.96–0.83(m,8H),0.70(d,J＝6.9Hz,3H)；13C NMR(100MHz,CDCl3)δ172.5,140.5,128.4,128.3,126.2,74.2,47.0,40.9,35.8(t,J＝20.0Hz),34.3,31.4,30.7(t,J＝20.0Hz),26.2,23.4,22.0,20.8,16.3.
实施例10
Figure BDA0002192623800000063
的合成：
含有烯键或炔键的有机物为3-苯基-2-丙烯酸龙脑酯，其余与实施例1相同，最后得到氘代产物2j(3-苯基-2-丙烯酸龙脑酯)，产率为86％，氘代率苄位为93％，羰基邻位为97％。
1H NMR(400MHz,Chloroform-d)δ7.34–7.30(m,2H),7.26–7.21(m,3H),4.90(dt,J＝9.9,2.8Hz,1H),2.98–2.93(m,1.07H,93％D),2.69–2.66(m,1.03H,97％D),2.39–2.32(m,1H),1.94–1.88(m,1H),1.79–1.71(m,2H),1.69–1.67(m,1H),1.33–1.17(m,2H),0.92(s,3H),0.89(s,3H),0.81(s,3H)；13C NMR(100MHz,CDCl3)δ173.3,140.5,128.5,128.3,126.2,79.9,48.7,47.8,44.9,36.7,35.8(t,J＝20.0Hz),30.7(t,J＝20.0Hz),28.0,27.1,19.7,18.9,13.5.
实施例11
Figure BDA0002192623800000071
的合成：
含有烯键或炔键的有机物为3-苯基-2-丙烯酸(3aR,5S,6S,6aR)-5-((R)-2,2-二甲基-1,3-二氧戊环-4-基)-2,2-二甲基四氢呋喃[2,3-d][1,3]二氧杂-6-酯，其余与实施例1相同，最后得到氘代产物2k(3-苯基-丙酸(3aR,5S,6S,6aR)-5-((R)-2,2-二甲基-1,3-二氧戊环-4-基)-2,2-二甲基四氢呋喃[2,3-d][1,3]二氧杂-6-酯)，产率62％，氘代率苄为97％，羰基邻位为95％。
1H NMR(400MHz,Chloroform-d)δ7.30(t,J＝7.2Hz,2H),7.24–7.19(m,3H),5.73(d,J＝3.6Hz,1H),5.22(d,J＝2.3Hz,1H),4.25(d,J＝3.9Hz,1H),4.20–4.14(m,2H),4.06–3.98(m,2H),2.96–2.93(m,1.03H,97％D),2.69–2.64(m,1.05H,95％D),1.50(s,3H),1.40(s,3H),1.31(s,3H),1.27(s,3H)；13C NMR(100MHz,CDCl3)δ171.5,139.9,128.5,128.4,126.5,112.2,109.3,105.0,83.2,79.7,76.1,72.4,67.2,35.4(t,J＝20.0Hz),30.6(t,J＝20.0Hz),26.9,26.7,26.2,25.3.
实施例12
Figure BDA0002192623800000081
的合成：
含有烯键或炔键的有机物为3-苯基-2-丙烯酸孕酮酯，其余与实施例1相同，最后得到氘代产物2l(3-苯基-丙酸孕酮酯)，产率为52％，氘代率苄位为97％，羰基邻位为96％。
1H NMR(400MHz,Chloroform-d)δ7.34–7.30(m,2H),7.27–7.22(m,4H),6.78(dd,J＝8.5,2.4Hz,1H),6.74(s,1H),3.07–3.04(m,1.03H,97％D),2.89(dd,J＝9.5,4.8Hz,2H),2.85–2.83(m,1.04H,96％D),2.51(dd,J＝18.8,8.6Hz,1H),2.42–2.37(m,1H),2.31–2.24(m,1H),2.19–1.94(m,4H),1.65–1.41(m,6H),0.90(s,3H)；13C NMR(100MHz,CDCl3)δ171.7,148.5,140.1,138.0,137.4,128.6,128.4,126.4,126.4,121.6,118.7,50.5,48.0,44.2,38.0,36.0,35.7(t,J＝20.0Hz),31.6,30.6(t,J＝20.0Hz),29.4,26.4,25.8,21.6,13.8.
实施例13
Figure BDA0002192623800000082
的合成：
含有烯键或炔键的有机物为3-苯基-2-丙烯酸雌酚酮酯，其余与实施例1相同，最后得到氘代产物2m(3-苯基-丙酸雌酚酮酯)，产率为57％，氘代率苄位为98％，酯羰基邻位为96％。
1H NMR(400MHz,Chloroform-d)δ7.31–7.26(m,2H),7.20(dd,J＝7.3,5.5Hz,3H),5.37(d,J＝4.6Hz,1H),4.65–4.57(m,1H),2.95–2.91(m,1.02H,98％D),2.61–2.57(m,1.04H,96％D),2.54(t,J＝9.0Hz,1H),2.28(d,J＝7.4Hz,2H),2.22–2.17(m,1H),2.13(s,3H),2.06–1.97(m,2H),1.89–1.81(m,2H),1.68–1.44(m,8H),1.29–1.10(m,4H),1.01(s,3H),0.63(s,3H)；13C NMR(100MHz,CDCl3)δ209.6,172.4,140.5,139.7,128.5,128.3,126.2,122.3,73.9,63.7,56.8,49.9,44.0,38.8,38.0,37.0,36.6,35.9(t,J＝20.0Hz),31.8,31.8,31.6,30.7(t,J＝20.0Hz),27.7,24.5,22.8,21.0,19.3,13.2.
实施例14
Figure BDA0002192623800000091
的合成：
含有烯键或炔键的有机物为3-苯基-2-丙烯酸胆固醇酯，其余与实施例1相同，最后得到氘代产物2n(3-苯基-2-丙酸胆固醇酯)，产率为45％，氘代率苄位为99％，羰基邻位为94％。
1H NMR(400MHz,Chloroform-d)δ7.30–7.26(m,2H),7.21–7.18(m,3H),5.36(d,J＝5.0Hz,1H),4.65–4.57(m,1H),2.95–2.91(m,1.01H,99％D),2.60–2.56(m,1.06H,94％D),2.28(d,J＝8.1Hz,2H),2.04–1.76(m,6H),1.57–1.08(m,20H),1.01(s,3H),0.91(d,J＝6.4Hz,3H),0.87(d,J＝1.5Hz,3H),0.86(d,J＝1.5Hz,3H),0.67(s,3H)；13C NMR(100MHz,CDCl3)δ172.3,140.7,139.7,128.4,128.3,126.2,122.6,74.0,56.7,56.1,50.0,42.3,39.7,39.5,38.1,37.0,36.6,36.2,35.9(t,J＝20.0Hz),35.8,31.9,31.9,30.7(t,J＝20.0Hz),28.2,28.0,27.8,24.3,23.8,22.8,22.6,21.0,19.3,18.7,11.9。

Claims (4)

1.一种以重水为氘源的无催化剂电化学氘代方法，其特征在于，往反应器中加入电解质、含有烯键或炔键的有机物、重水和有机溶剂,以碳毡作为电极材料，在惰性气体氛围下，通入4-8V的直流电压进行电解反应，将反应产物进行纯化，即得到氘代产物；
所述含有烯键或炔键的有机物选自3-苯基-2-丙烯酸乙酯、3-苯基-2-丙烯酸丁酯、3-苯基-丙酸-1-戊烯-4-酯、3-苯基-2-丙烯酸-环己酯、3-苯基-2-丙烯酸-环己酯四氢呋喃基-3酯，3-苯基-2-丙烯酸-磷酸二乙酯基甲酯，3-苯基-2-丙烯酸苄酯，3-苯基-2-丙烯酸苯酯、3-苯基-2-丙烯酸薄荷醇酯、3-苯基-2-丙烯酸雌酚酮酯、3-苯基-2-丙烯酸龙脑酯、3-苯基-2-丙烯酸孕酮酯、3-苯基-2-丙烯酸雌酚酮酯或3-苯基-2-丙酸胆固醇酯中的任意一种；
所述有机溶剂为DMF或乙腈中的任意一种；
所述电解质为四丁基四氟硼酸铵或LiClO4中的任意一种，电解质浓度为0.02 mol/L。
2.如权利要求1所述以重水为氘源的无催化剂电化学氘代方法，其特征在于，所述重水与含有烯键或炔键的有机物的摩尔比为5-20:1。
3.如权利要求1所述以重水为氘源的无催化剂电化学氘代方法，其特征在于，所述惰性气体为氮气或氩气。
4.如权利要求1至3任一项所述以重水为氘源的无催化剂电化学氘代方法，其特征在于，所述纯化过程为：先将反应产物用乙酸乙酯萃取，萃取后的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥，接着过滤，将滤液旋干，然后采用以300-400目硅胶作为固定相的柱层析技术，干法上样，以石油醚/乙酸乙酯混合液为洗脱剂进行洗脱，GC-MS检测洗脱液，将收集的层析液浓缩。
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