CN109134354B - 2-吡啶甲基硫醚的合成方法及相关药物的合成工艺 - Google Patents

2-吡啶甲基硫醚的合成方法及相关药物的合成工艺 Download PDF

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CN109134354B
CN109134354B CN201811091737.3A CN201811091737A CN109134354B CN 109134354 B CN109134354 B CN 109134354B CN 201811091737 A CN201811091737 A CN 201811091737A CN 109134354 B CN109134354 B CN 109134354B
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王栋
郁彭
刘振林
王振涛
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Abstract

本发明涉及一种2‑吡啶甲基硫醚及相关药物的简洁合成方法，具体是以2‑甲基吡啶氮氧化物为原料，乙酸乙酯或者二氯甲烷为溶剂，与三氟乙酸酐反应得到三氟乙酸酯中间体，不需纯化，在溴化锂或四丁基溴化铵的催化下，以甲苯或乙酸乙酯为溶剂接着与硫酚反应生成2‑吡啶甲基硫醚。本方法具有操作简便，试剂便宜易得，反应条件温和，底物适用性广，位置选择性好，产率高等显著优点。此外，把该方法成功运用到了奥美拉唑硫醚及雷贝拉唑硫醚的合成中，且该合成工艺无需任何催化剂。

Description

2-吡啶甲基硫醚的合成方法及相关药物的合成工艺
技术领域
本发明属于新化合物合成和药物应用领域，涉及一种2-吡啶甲基硫醚的合成方法及相关药物的合成新工艺。
技术背景
硫醚在自然界中广泛存在，并且是许多药物或者功能材料的重要合成前体。 2-吡啶甲基硫醚是一类非常重要的硫醚，因为它是许多具有生物活性化合物的母体。此外，它也是几个上市药物的重要中间体，包括奥美拉唑，泮托拉唑，兰索拉唑，雷贝拉唑。
硫醚的传统合成方法以有机卤代物和硫醇为反应原料，在碱的作用下反应制备，与Williamson醚合成反应类似。然而，这一合成方法由于要使用高度官能团化的卤代物为原料而存在很大的局限性。此外，反应中生成的卤代物存在环境污染问题。例如，已报道的雷贝拉唑硫醚的合成路线如下所示。以III-2为原料，经过醋酸酐重排，水解，氯化，最后与2-苯并咪唑硫醇偶联得到。需要4 步反应，而且反应中用到腐蚀性很强的氢氧化钠和氯化亚砜，此外生成大量的诸如二氧化硫和氯化氢等废弃物，所以开发2-吡啶甲基硫醚简便、高效、绿色的通用合成方法意义重大。
Figure BDA0001804518940000011
发明内容
本发明的目的是提供一种2-吡啶甲基硫醚类化合物及相关药物的简洁合成方法。本发明以2-甲基吡啶氮氧化物为原料，乙酸乙酯或者二氯甲烷为溶剂，与三氟乙酸酐反应得到三氟乙酸酯中间体。不需纯化，在溴化锂或四丁基溴化铵的催化下，以甲苯或乙酸乙酯为溶剂接着与硫酚反应生成2-吡啶甲基硫醚。该方法具有操作简便，试剂便宜易得，反应条件温和，底物适用性广，位置选择性好，产率高等显著优点。
本发明的目的是通过以下技术方案实现的：
一种2-吡啶甲基硫醚的合成方法，其合成路线如下：
⑴以吡啶氮氧化物III为原料，乙酸乙酯或者二氯甲烷为溶剂，与三氟乙酸酐反应得到II，
⑵再加入溴化锂或四丁基溴化铵催化剂，在溴化锂或四丁基溴化铵的催化下，以甲苯或乙酸乙酯为溶剂接着与R1SH反应生成2-吡啶甲基硫醚I；
Figure BDA0001804518940000021
其中，R为在吡啶环3,4,5,6位一位或多位取代的氢，羟基，卤素，硝基， C3-8芳基，三氟甲基，酰胺基，酯基，C1-6烷基或C1-6烷氧基；R1为C5-10芳基。
其特征在于：所述合成方法的第一步反应溶剂为乙酸乙酯或者二氯甲烷，所述合成方法的第二步反应溶剂为乙酸乙酯或者甲苯；所用催化剂为溴化锂或四丁基溴化铵。
将上述所发明的合成方法应用于奥美拉唑硫醚，其合成路线如下：
Figure BDA0001804518940000022
以吡啶氮氧化物III-1为原料，乙酸乙酯或二氯甲烷为溶剂，与三氟乙酸酐反应得到II-1。不需纯化，以甲苯或乙酸乙酯为溶剂接着与2-巯基-5-甲氧基苯并咪唑反应生成奥美拉唑硫醚；
将上述所发明的合成方法应用于雷贝拉唑硫醚，其合成路线如下：
Figure BDA0001804518940000023
以吡啶氮氧化物III-2为原料，乙酸乙酯或二氯甲烷为溶剂，与三氟乙酸酐反应得到II-2，不需纯化，以甲苯或乙酸乙酯为溶剂接着与2-苯并咪唑硫醇反应生成雷贝拉唑硫醚；
已合成的2-吡啶甲基硫醚类化合物的结构如下所示：
Figure BDA0001804518940000031
本发明的优点和积极效果：
1、本发明采用价廉易得的2-甲基吡啶氮氧化物为原料，所发明的反应方法具有位置选择性高，底物适用性广，产率高等显著优点。
2、本发明的关键反应不需无水无氧操作，操作简便，适合大规模生产和开发。
3、本发明方法能得到不同位置取代的2-吡啶甲基硫醚类化合物，且适用于各类取代基。可以按照本发明的原理进行推广使用，适用性很好。
附图说明
图1为化合物3c在氘代三氯甲烷中的核磁氢谱图；
图2为化合物3c在氘代三氯甲烷中的核磁碳谱图；
图3为化合物3n在氘代三氯甲烷中的核磁氢谱图；
图4为化合物3n在氘代三氯甲烷中的核磁碳谱图；
图5为奥美拉唑硫醚在氘代三氯甲烷中的核磁氢谱图；
图6为雷贝拉唑硫醚在氘代三氯甲烷中的核磁氢谱图。
具体的实施方式
为了理解本发明，下面结合实施例对本发明作进一步说明：下述实施例是说明性的，不是限定性的，不能以下述实施例来限定本发明的保护范围。
一种2-吡啶甲基硫醚的简洁合成方法，步骤如下：
室温将吡啶氮氧化物III(1.0eq)溶于乙酸乙酯(0.4M)，然后加入三氟乙酸酐(2.5eq)。回流反应一小时到四个小时。TLC监测反应结束，将反应液浓缩得到三氟乙酸酯中间体II，直接投下一步。将反应中间体溶于甲苯(0.8M)，然后加入R-SH(1.0eq),四丁基溴化铵(0.2eq),回流加热反应一小时到五个小时，TLC监测反应结束，将反应液加饱和碳酸钠水溶液调pH为7～8，然后分液，水相加乙酸乙酯萃取三次，饱和食盐水洗涤有机相，无水硫酸钠干燥，浓缩，用PE～PE/EA(50:1～1:3)作为流动相，硅胶柱层析得到目标产物I。
下面通过实施例具体说明。
实施例1
Figure BDA0001804518940000041
室温将2-甲基吡啶氮氧化物(507mg,4.65mmol)溶于乙酸乙酯(12ml)，然后加入三氟乙酸酐(2.44g,11.6mmol)。回流反应两个小时。TLC监测反应结束，将反应液浓缩得到三氟乙酸酯中间体，直接投下一步。将反应中间体溶于甲苯(6ml)，然后加入4-甲基苯硫酚(577mg,4.65mmol),四丁基溴化铵(300mg, 0.93mmol)，回流加热反应五个小时，TLC监测反应结束，将反应液加饱和碳酸钠水溶液调pH为7～8，然后分液，水相加乙酸乙酯萃取三次，饱和食盐水洗涤有机相，无水硫酸钠干燥，浓缩，用PE～PE/EA(50:1～1:3)作为流动相，硅胶柱层析得到目标产物3a(770mg,77％yield)。结构参数:1H NMR(400MHz, CDCl3)δ8.53(d,J＝4.8Hz,1H),7.58(t,J＝7.6Hz,1H),7.29-7.22(m,3H), 7.15-7.13(m,1H),7.05(d,J＝8.0Hz,2H),4.21(s,2H),2.29(s,3H).
实施例2
Figure BDA0001804518940000042
实施例2的合成方法同上述合成通法。
反应收率：71％；结构参数:1H NMR(400MHz,CDCl3)δ8.54(d,J＝4.4Hz, 1H),7.62-7.58(m,1H),7.32(d,J＝7.6Hz,1H),7.16-7.7.13(m,4H),6.98(t,J＝4.0 Hz,1H),4.26(s,2H),2.28(s,3H).13C NMR(100MHz,CDCl3)δ157.4,148.9, 138.2,136.3,135.3,129.8,128.4,126.9,126.1,122.7,121.7,40.1,21.0.HRMS (+ESI-TOF)m/z:[M+H]+Calcd forC13H14NS 216.0841；Found 216.0840.
实施例3
Figure BDA0001804518940000051
实施例3的合成方法同上述合成通法。
反应收率：70％；结构参数:1H NMR(400MHz,CDCl3)δ8.51(d,J＝4.8Hz, 1H),7.59-7.55(m,1H),7.26(d,J＝8.8Hz,2H),7.18(d,J＝8.0Hz,1H),7.13(dd,J ＝5.2,6.8Hz,1H),6.77(d,J＝8.8Hz,2H),4.13(s,2H),3.75(s,3H).13C NMR(100 MHz,CDCl3)δ159.3,158.1,149.3,136.6,134.0,125.6,123.3,122.0,114.6,55.3, 42.7.HRMS(+ESI-TOF)m/z:[M+H]+Calcd for C13H14NOS 232.0791；Found 232.0777.
实施例4
Figure BDA0001804518940000052
实施例4的合成方法同上述合成通法。
反应收率：65％；结构参数:1H NMR(400MHz,CDCl3)δ8.52(d,J＝4.4Hz, 1H),7.62-7.57(m,1H),7.29(d,J＝8.0Hz,1H),7.24(dd,J＝2.0,6.8Hz,2H),7.20 (dd,J＝2.0,6.8Hz,2H),7.14(dd,J＝5.2,6.8Hz,1H),4.22(s,2H).13C NMR(100 MHz,CDCl3)δ157.4,149.4,136.8,134.3,132.5,131.1,129.0,123.1,122.3,40.7. HRMS(+ESI-TOF)m/z:[M+H]+Calcd for C12H11NSCl 236.0295；Found 236.0297.
实施例5
Figure BDA0001804518940000053
实施例5的合成方法同上述合成通法。
反应收率：67％；结构参数:1H NMR(400MHz,CDCl3)δ8.46(d,J＝4.4Hz, 1H),7.52(t,J＝7.6Hz,1H),7.32-7.29(m,2H),7.16-7.08(m,3H),4.20(s,2H).13C NMR(100MHz,CDCl3)δ157.2,149.4,141.9,136.4,132.0,130.2,128.5,123.2, 122.1,41.2.HRMS(+ESI-TOF)m/z:[M+Na]+Calcd for C12H9NSCl2Na 291.9725； Found 291.9709.
实施例6
Figure BDA0001804518940000054
实施例6的合成方法同上述合成通法。
反应收率：62％；结构参数:1H NMR(400MHz,CDCl3)δ8.54(d,J＝4.8Hz, 1H),7.60(t,J＝7.6Hz,1H),7.46(s,1H),7.31(d,J＝7.6Hz,1H),7.27-7.22(m,2H), 7.16-7.13(m,1H),7.08(t,J＝8.0Hz,1H),4.26(s,2H).13C NMR(100MHz,CDCl3) δ157.1,149.5,138.4,136.8,131.8,130.2,129.3,127.7,123.0,122.7,122.3,40.2. HRMS(+ESI-TOF)m/z:[M+H]+Calcd for C12H11NSBr 279.9790；Found 279.9781.
实施例7
Figure BDA0001804518940000061
实施例7的合成方法同上述合成通法。
反应收率：75％；结构参数:1H NMR(400MHz,CDCl3)δ7.63(d,J＝1.2Hz, 1H),7.61-7.54(m,1H),7.52(d,J＝0.8Hz,1H),7.40(d,J＝8.0Hz,1H),7.31-7.26 (m,1H)，7.21-7.03(m,2H)，7.01-6.99(m,1H),4.31(s,2H).13C NMR(100MHz, CDCl3)δ156.6,149.0,137.2,136.7,132.7,128.5,127.6,126.7,123.2,122.9,122.1, 39.2.HRMS(+ESI-TOF)m/z:[M+Na]+Calcd for C12H10NSBrNa 301.9610；Found 301.9603.
实施例8
Figure BDA0001804518940000062
实施例8的合成方法同上述合成通法。
反应收率：12％；结构参数:1H NMR(400MHz,CDCl3)δ8.56(d,J＝4.8Hz, 1H),8.09(dd,J＝2.0,6.8Hz,2H),7.67(dt,J＝1.6,9.2Hz,1H),7.45-7.40(m,3H), 7.21(dd,J＝6.0,7.2Hz,1H),4.39(s,2H).13C NMR(100MHz,CDCl3)δ156.3, 149.5,137.2,126.7,126.5,124.5,124.0,123.0,122.7,38.5.HRMS(+ESI-TOF)m/z: [M+H]+Calcd for C12H11N2O2S247.0536；Found 247.0532.
实施例9
Figure BDA0001804518940000063
实施例9的合成方法同上述合成通法。
反应收率：63％；结构参数:1H NMR(400MHz,CDCl3)δ8.55(d,J＝4.8Hz, 1H),8.45(d,J＝1.2Hz,1H),7.61-7.57(m,1H),7.48-7.44(m,2H),7.21(d,J＝8.0 Hz,1H),7.15-7.10(m,1H),7.00-6.96(m,1H),4.59(s,2H).13C NMR(100MHz, CDCl3)δ158.4,149.5,149.4,136.7,136.1,123.3,122.2,122.1,119.8,119.7,36.1. HRMS(+ESI-TOF)m/z:[M+Na]+Calcd for C11H10N2SNa 225.0457；Found 225.0448.
实施例10
Figure BDA0001804518940000071
实施例10的合成方法同上述合成通法。
反应收率：55％；结构参数:1H NMR(400MHz,CDCl3)δ8.52(d,J＝4.0Hz, 1H),7.56(dt,J＝9.6,1.6Hz,1H),7.22(d,J＝2.0Hz,1H),7.16-7.14(m,1H), 7.13-7.05(m,1H),6.21(d,J＝1.6Hz,1H),3.90(s,2H),2.02(s,3H).13C NMR(100 MHz,CDCl3)δ158.3,156.1,149.6,140.7,136.4,123.3,122.0,115.2,109.3,42.5, 11.5.HRMS(+ESI-TOF)m/z:[M+H]+Calcd for C11H11NOSNa 228.0454；Found 228.0443.
实施例11
Figure BDA0001804518940000072
实施例11的合成方法同上述合成通法。
反应收率：71％；结构参数:1H NMR(400MHz,CDCl3)δ8.54(d,J＝4.4Hz, 1H),7.63-7.59(m,1H),7.55-7.53(m,2H),7.33-7.19(m,1H),7.17(t,J＝3.2Hz,3H), 4.43(s,2H).13CNMR(100MHz,CDCl3)δ157.7,150.9,148.9,139.6,137.8,123.6, 122.9,122.0,114.3,38.0.HRMS(+ESI-TOF)m/z:[M+H]+Calcd for C13H12N3S 242.0746；Found 242.0743.
实施例12
Figure BDA0001804518940000073
实施例12的合成方法同上述合成通法。
反应收率：74％；结构参数:1H NMR(400MHz,CDCl3)δ8.60(d,J＝4.0Hz, 1H),7.67(t,J＝7.6Hz,1H),7.60(d,J＝7.6Hz,1H),7.55(d,J＝7.6Hz,1H),7.42(d, J＝7.2Hz,1H),7.29-7.18(m,3H),4.74(s,2H).13C NMR(100MHz,CDCl3)δ 164.5,156.0,152.0,149.4,141.8,137.2,124.4,124.0,123.5,122.8,118.5,110.0, 38.0.HRMS(+ESI-TOF)m/z:[M+H]+Calcd for C13H11N2OS 243.0587；Found 243.0580.
实施例13
Figure BDA0001804518940000081
实施例13的合成方法同上述合成通法。
反应收率：62％；结构参数:1H NMR(400MHz,CDCl3)δ8.64(d,J＝4.8Hz, 1H),7.75-7.71(m,1H),7.44(d,J＝8.8Hz,1H),7.37(d,J＝7.6Hz,1H),7.29(dd,J ＝5.6,7.2Hz,1H),7.05(d,J＝2.4Hz,1H),6.85(dd,J＝8.8,2.4Hz,1H),4.37(s, 2H),3.84(s,3H).13C NMR(100MHz,CDCl3)δ157.7,156.1,149.8,148.9,139.7, 137.8,134.4,123.6,122.9,115.1,111.4,97.4,55.8,38.2.HRMS(+ESI-TOF)m/z: [M+H]+Calcd for C14H14N3OS 272.0852；Found 272.0850.
实施例14
Figure BDA0001804518940000082
实施例14的合成方法同上述合成通法。
反应收率：50％；结构参数:1H NMR(400MHz,CDCl3)δ8.42(dd,J＝4.8,1.2 Hz,1H),7.80(dd,J＝8.0,1.2Hz,1H),7.31(d,J＝8.0Hz,2H),7.06(d,J＝7.6Hz, 1H),7.01(dd,J＝8.0,4.4Hz,2H),4.37(s,2H),2.29(s,3H).13C NMR(100MHz, CDCl3)δ156.3,147.8,140.6,137.0,131.8,131.5,129.7,123.4,121.4,41.6,21.1. HRMS(+ESI-TOF)m/z:[M+H]+Calcdfor C13H13NSBr 293.9947；Found 293.9937.
实施例15
Figure BDA0001804518940000083
实施例15的合成方法同上述合成通法。
反应收率：22％；结构参数:1H NMR(400MHz,CDCl3)δ8.59(dd,J＝4.8,1.6 Hz,1H),8.19(dd,J＝8.0,2.0Hz,1H),7.26-7.22(m,3H),7.04(d,J＝7.6Hz,2H), 4.65(s,2H),3.89(s,3H),2.29(s,3H).13C NMR(100MHz,CDCl3)δ166.6,159.7, 151.7,138.9,136.8,132.0,131.5,129.6,125.4,122.0,52.5,40.8,21.1.HRMS (+ESI-TOF)m/z:[M+H]+Calcd forC15H16NO2S274.0896；Found 274.0884.
实施例16
Figure BDA0001804518940000091
实施例16的合成方法同上述合成通法。
反应收率：29％；结构参数:1H NMR(400MHz,CDCl3)δ9.11(d,J＝1.6Hz, 1H),8.17(dd,J＝8.0,2.0Hz,1H),7.33(d,J＝8.0Hz,1H),7.20(d,J＝8.0Hz,2H), 7.05(d,J＝8.4Hz,2H),4.23(s,2H),3.93(s,3H),2.29(s,3H).13C NMR(100MHz, CDCl3)δ165.8,162.7,150.7,137.8,137.2,131.2,131.1,129.9,124.5,122.7,52.5, 41.5,21.2.HRMS(+ESI-TOF)m/z:[M+H]+Calcd for C15H16NO2S 274.0896；Found 274.0890.
实施例17
Figure BDA0001804518940000092
实施例17的合成方法同上述合成通法。
反应收率：70％；结构参数:1H NMR(400MHz,CDCl3)δ8.18(s,1H),7.30(d, J＝8.4Hz,2H),7.24(s,1H),7.07(d,J＝8.0Hz,2H),4.21(s,2H),2.31(s,3H),2.30 (s,3H),2.27(s,3H).13C NMR(100MHz,CDCl3)δ152.5,147.0,138.7,136.5,132.5, 131.7,131.2,130.9,129.5,39.6,21.0,18.4,17.8.HRMS(+ESI-TOF)m/z:[M+H]+ Calcd for C15H18NS244.1154；Found 244.1142.
实施例18
Figure BDA0001804518940000093
实施例18的合成方法同上述合成通法。
反应收率：40％；结构参数:1H NMR(400MHz,CDCl3)δ8.38(d,J＝5.2Hz, 1H),7.26-7.22(m,2H),7.11(s,1H),7.06(d,J＝8.0Hz,2H),6.96(d,J＝4.8Hz,1H), 4.18(s,2H),2.293(s,3H),2.287(s,3H),.13C NMR(100MHz,CDCl3)δ157.7, 149.1,147.9,136.6,132.3,130.4,129.7,124.0,123.2,41.2,21.12,21.11.HRMS (+ESI-TOF)m/z:[M+Na]+Calcd forC14H15NSNa 252.0817；Found 252.0803.
实施例19
Figure BDA0001804518940000094
实施例19的合成方法同上述合成通法。
反应收率:53％；结构参数:1HNMR(400MHz,CDCl3)δ7.43(dd,J＝7.6,6.8 Hz,1H),7.23-7.21(m,2H),7.06-7.02(m,3H),6.95(d,J＝7.6Hz,1H),4.17(s,2H), 2.51(s,3H),2.26(s,3H).13C NMR(100MHz,CDCl3)δ157.9,157.0,136.7,136.3, 132.2,130.2,129.5,121.5,119.8,41.1,24.3,20.9.HRMS(+ESI-TOF)m/z:[M+Na]+ Calcd for C14H15NSNa252.0817；Found 252.0812.
实施例20
Figure BDA0001804518940000101
实施例20的合成方法同上述合成通法。
反应收率：30％；结构参数:1H NMR(400MHz,CDCl3)δ8.33(s,1H),7.03(d, J＝8.0Hz,2H),6.89(d,J＝8.4Hz,2H),4.67(s,2H),2.35(s,3H),2.28(s,3H),2.27 (s,3H).13CNMR(100MHz,CDCl3)δ154.6,146.2,143.2,136.0,136.0,133.5, 131.9,130.0,127.7,62.0,20.9,18.7,14.6.HRMS(+ESI-TOF)m/z:[M+Na]+Calcd for C15H16N2O2SNa 311.0825；Found 311.0825.
实施例21
Figure BDA0001804518940000102
实施例21的合成方法同上述合成通法。
反应收率：12％；结构参数:1H NMR(400MHz,CDCl3)δ8.08(d,J＝5.6Hz, 1H),7.41(d,J＝8.0Hz,2H),7.27(d,J＝7.2Hz,2H),6.53(d,J＝5.6Hz,1H),4.70 (s,2H),2.42(s,3H),2.22(s,3H).13C NMR(100MHz,CDCl3)δ155.2,150.8,144.7, 140.2,135.6,130.9,126.1,125.6,119.0,61.7,21.4,12.9.HRMS(+ESI-TOF)m/z: [M+Na]+Calcd forC14H14N2O2SNa 297.0668；Found 297.0655.
实施例22
Figure BDA0001804518940000103
室温将4-甲氧基-3,5-二甲基吡啶氮氧化物(445mg,2.66mmol)溶于乙酸乙酯(6ml)，然后加入三氟乙酸酐(1.4g,6.65mmol)。回流反应三个小时。TLC 监测反应结束，将反应液浓缩得到三氟乙酸酯中间体，直接投下一步。将反应中间体溶于甲苯(3ml)，然后加入2-巯基-5-甲氧基苯并咪唑(480mg,2.66mmol), 回流加热反应四个小时，TLC监测反应结束，将反应液加饱和碳酸钠水溶液调 pH为7～8，然后分液，水相加乙酸乙酯萃取三次，饱和食盐水洗涤有机相，无水硫酸钠干燥，浓缩，用PE～PE/EA(10:1～1:3)作为流动相，硅胶柱层析得到目标产物奥美拉唑硫醚(519mg,60％yield)。结构参数:1H NMR(400MHz,CDCl3) δ8.27(s,1H),7.41(d,J＝6.4Hz,1H),7.03(s,1H),6.82(dd,J＝8.8,2.4Hz,1H), 4.35(s,2H),3.84(s,3H),3.78(s,3H),2.32(s,3H),2.28(s,3H).符合标准样品的结构特征。
实施例23
Figure BDA0001804518940000111
室温将4-(3-甲氧丙氧基)-2,3-二甲基吡啶氮氧化物(12g,56.8mmol)溶于乙酸乙酯(142ml)，然后加入三氟乙酸酐(29.8g,142mmol)。回流反应三个小时。TLC监测反应结束，将反应液浓缩得到三氟乙酸酯中间体，直接投下一步。将反应中间体溶于甲苯(71ml)，然后加入2-苯并咪唑硫醇(8.53g,56.8 mmol),回流加热反应四个小时，TLC监测反应结束，将反应液加饱和碳酸钠水溶液调pH为7～8，然后分液，水相加乙酸乙酯萃取三次，饱和食盐水洗涤有机相，无水硫酸钠干燥，浓缩，用PE～PE/EA(10:1～1:3)作为流动相，硅胶柱层析得到目标产物雷贝拉唑硫醚(17.17g,88％yield)。结构参数:1H NMR(400MHz, CDCl3)δ8.35(d,J＝6.0Hz,1H),7.54(s,2H),7.18(dd,J＝6.0,3.2Hz,2H),6.77(d, J＝6.0Hz,1H),4.38(s,2H),4.13(t,J＝6.4Hz,2H),3.57(t,J＝6.0Hz,2H),3.36(s, 3H),2.26(s,3H),2.10(t,J＝6.0Hz,2H).符合标准样品的结构特征。
实施例24
Figure BDA0001804518940000112
室温将2-甲基吡啶氮氧化物(507mg,4.65mmol)溶于乙酸乙酯(12ml)，然后加入三氟乙酸酐(2.44g,11.6mmol)。回流反应两个小时。TLC监测反应结束，将反应液浓缩得到三氟乙酸酯中间体，直接投下一步。将反应中间体溶于乙酸乙酯(6ml)，然后加入4-甲基苯硫酚(577mg,4.65mmol),四丁基溴化铵(300 mg,0.93mmol)，然后将反应瓶密封，油浴温度加热到120℃反应五个小时，TLC 监测反应结束，将反应液加饱和碳酸钠水溶液调pH为7～8，然后分液，水相加乙酸乙酯萃取三次，饱和食盐水洗涤有机相，无水硫酸钠干燥，浓缩，用PE～PE/EA(50:1～1:3)作为流动相，硅胶柱层析得到目标产物3a(710mg,71％ yield)。
实施例25
Figure BDA0001804518940000121
室温将2-甲基吡啶氮氧化物(507mg,4.65mmol)溶于乙酸乙酯(12ml)，然后加入三氟乙酸酐(2.44g,11.6mmol)。回流反应两个小时。TLC监测反应结束，将反应液浓缩得到三氟乙酸酯中间体，直接投下一步。将反应中间体溶于甲苯(6ml)，然后加入4-甲基苯硫酚(577mg,4.65mmol),溴化锂(81mg,0.93 mmol)，回流加热反应五个小时，TLC监测反应结束，将反应液加饱和碳酸钠水溶液调pH为7～8，然后分液，水相加乙酸乙酯萃取三次，饱和食盐水洗涤有机相，无水硫酸钠干燥，浓缩，用PE～PE/EA(50:1～1:3)作为流动相，硅胶柱层析得到目标产物3a(730mg,73％yield)。
实施例26
Figure BDA0001804518940000122
室温将2-甲基吡啶氮氧化物(507mg,4.65mmol)溶于二氯甲烷(12ml)，然后加入三氟乙酸酐(2.44g,11.6mmol)。回流反应两个小时。TLC监测反应结束，将反应液浓缩得到三氟乙酸酯中间体，直接投下一步。将反应中间体溶于甲苯(6ml)，然后加入4-甲基苯硫酚(577mg,4.65mmol),四丁基溴化铵(300mg, 0.93mmol)，回流加热反应五个小时，TLC监测反应结束，将反应液加饱和碳酸钠水溶液调pH为7～8，然后分液，水相加乙酸乙酯萃取三次，饱和食盐水洗涤有机相，无水硫酸钠干燥，浓缩，用PE～PE/EA(50:1～1:3)作为流动相，硅胶柱层析得到目标产物3a(750mg,75％yield)。

Claims (3)

1.一种2-吡啶甲基硫醚的合成方法，其特征在于：其合成路线如下：
⑴以吡啶氮氧化物III为原料，乙酸乙酯或者二氯甲烷为溶剂，与三氟乙酸酐反应得到II，
⑵再加入溴化锂或四丁基溴化铵催化剂，在溴化锂或四丁基溴化铵的催化下，以甲苯或乙酸乙酯为溶剂接着与R1SH反应生成2-吡啶甲基硫醚I；
Figure FDA0003401182950000011
其中，R为在吡啶环3,4,5,6位一位或多位取代的氢，卤素，C1-6烷基；R1为C5-10芳基。
2.一种奥美拉唑硫醚的合成方法，其特征在于：其合成路线如下：
Figure FDA0003401182950000012
以吡啶氮氧化物III-1为原料，乙酸乙酯或二氯甲烷为溶剂，与三氟乙酸酐反应得到II-1，不需纯化，以甲苯或乙酸乙酯为溶剂接着与2-巯基-5-甲氧基苯并咪唑反应生成奥美拉唑硫醚。
3.一种雷贝拉唑硫醚的合成方法，其特征在于：其合成路线如下：
Figure FDA0003401182950000013
以吡啶氮氧化物III-2为原料，乙酸乙酯或二氯甲烷为溶剂，与三氟乙酸酐反应得到II-2，不需纯化，以甲苯或乙酸乙酯为溶剂接着与2-苯并咪唑硫醇反应生成雷贝拉唑硫醚。
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4871736A (en) * 1986-11-25 1989-10-03 The Ohio State University Stereoisomeric tricyclic bis(dioxopiperazines) and pharmaceutical compositions
WO2004078924A2 (en) * 2003-02-28 2004-09-16 Rheogene, Inc. Bioavailable diacylhydrazine ligands for modulating the expression of exogenous genes via an ecdysone receptor complex
CN100528846C (zh) * 2002-09-11 2009-08-19 株式会社吴羽 胺化合物及其用途
WO2012087182A2 (ru) * 2010-12-21 2012-06-28 Алла Хем, Ллс Замещенные метил-амины, антагонисты серотониновых 5-нт6 рецепторов, способы получения и применения
CN105237451A (zh) * 2015-09-25 2016-01-13 海南师范大学 硫醚类辣根素化合物及其制备方法和应用
CN105658648A (zh) * 2013-08-13 2016-06-08 加利福尼亚大学董事会 脱氧胞苷激酶抑制剂
CN106674198A (zh) * 2016-12-25 2017-05-17 寿光富康制药有限公司 一种雷贝拉唑关键中间体硫醚物的制备方法
CN107400118A (zh) * 2017-08-29 2017-11-28 信泰制药（苏州）有限公司 埃索美拉唑中间体的制备方法

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4871736A (en) * 1986-11-25 1989-10-03 The Ohio State University Stereoisomeric tricyclic bis(dioxopiperazines) and pharmaceutical compositions
CN100528846C (zh) * 2002-09-11 2009-08-19 株式会社吴羽 胺化合物及其用途
WO2004078924A2 (en) * 2003-02-28 2004-09-16 Rheogene, Inc. Bioavailable diacylhydrazine ligands for modulating the expression of exogenous genes via an ecdysone receptor complex
WO2012087182A2 (ru) * 2010-12-21 2012-06-28 Алла Хем, Ллс Замещенные метил-амины, антагонисты серотониновых 5-нт6 рецепторов, способы получения и применения
CN105658648A (zh) * 2013-08-13 2016-06-08 加利福尼亚大学董事会 脱氧胞苷激酶抑制剂
CN105237451A (zh) * 2015-09-25 2016-01-13 海南师范大学 硫醚类辣根素化合物及其制备方法和应用
CN106674198A (zh) * 2016-12-25 2017-05-17 寿光富康制药有限公司 一种雷贝拉唑关键中间体硫醚物的制备方法
CN107400118A (zh) * 2017-08-29 2017-11-28 信泰制药（苏州）有限公司 埃索美拉唑中间体的制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
无过渡金属催化的C(sp2) —H键官能化反应构建C(sp2)—S键研究进展;刘云云 等;《有机化学》;20170401;第37卷(第7期);第1667-1680页 *

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