CN113234037B - Z-2-(2-酰基亚甲基)噻唑烷-4-酮类衍生物及其制备方法和应用 - Google Patents
Z-2-(2-酰基亚甲基)噻唑烷-4-酮类衍生物及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及化学合成领域，具体为Z‑2‑(2‑酰基亚甲基)噻唑烷‑4‑酮类衍生物及其制备方法和应用。Z‑2‑(2‑酰基亚甲基)噻唑烷‑4‑酮类衍生物结构式如下式化合物Ⅰ所示
采用α‑烯醇二硫酯和α‑卤代酰胺在碳酸钠的促进下高效合成Z‑2‑(2‑酰基亚甲基)噻唑烷‑4‑酮类衍生物。该反应条件温和，操作简单，无过渡金属污染，可以一步构造包含硫和氮原子的五元环产物，且专一性地产生Z‑式环外双键，无E‑式异构体产生，方法简洁高效，反应过程耗时短(多数底物仅需0.5小时)，环境污染小，反应结束时后处理方便，所需产物产率普遍较高，反应在进行过程中对空气不敏感，无需惰性气体保护，而且反应规模可以适当扩大而产率基本不降低。
Description
技术领域
本发明涉及化学合成领域，具体为Z-2-(2-酰基亚甲基)噻唑烷-4-酮类衍生物及其制备方法和应用。
背景技术
含氮杂环化合物普遍存在于自然界中，绝大多数具有一定的生理活性，在生物的新城代谢活动中发挥着重要的作用。此外，含氮杂环化合物在医药、农药、染料以及功能材料方面有着广泛的用途，因而备受人们的关注。噻唑烷-4-酮是一类含有氮和硫原子的五元杂环化合物，含有该结构的许多化合物被发现具有一些重要的生物活性，比如抗菌、抗病毒、抗炎、抗真菌以及镇痛等。本专利主要涉及Z-2-(2-酰基亚甲基)噻唑烷-4-酮类衍生物的合成，其结构特点是在噻唑烷-4-酮的2-位包含有一个环外双键。含有2-亚甲基噻唑烷-4-酮结构的一些化合物已实现商品化并被注册成药，如抗癫痫药物雷利托林可用于治疗神经疾病，利胆剂哌普唑林可用于治疗肝脏疾病，而依托唑啉则是一种利尿剂可用来缓解血管紧张治疗心衰。这些2-亚甲基噻唑烷-4-酮衍生物的临床医学应用充分显示了该结构的重要医药价值和广阔的市场空间。因此，对这类衍生物的高效合成具有重要的意义。
目前，针对本发明涉及的2-亚甲基噻唑烷-4-酮类衍生物的合成方法比较有限。传统上，该结构主要依赖于α-巯基羧酸衍生物和含α-氢的腈类化合物，或者含α-氢的硫代酰胺与α-卤代羧酸或其衍生物缩合反应产生。虽然相关底物较为容易获得，但小分子巯基化合物和硫代酰胺多数具有恶臭气味，储存和使用不便。此外，多数合成方法不能精确控制产物中的环外双键构型，这使得传统方法在使用过程中因上述缺陷受到限制。
因此，反应条件温和、操作方便简单、能够精确控制环外双键构型的合成方法实现该类化合物的高效快速合成十分有必要。
发明内容
本发明的目的之一是提供Z-2-(2-酰基亚甲基)噻唑烷-4-酮类衍生物，结构式如Ⅰ所示，
其中：R1为苯基、取代苯基、2-噻吩基、2-萘基或者甲基取代基；R2为苯基、取代苯基、氢原子、1-萘基或烷基；R3为苄基、烯丙基或者烷基。
其中：所述R1取代苯基包括2-氯、3-氯、4-氯或4-氟；
所述R2取代苯基包括4-氯、2-氟、2-甲氧基、3-甲氧基或2，4-二甲基；
所述R2烷基为甲基或者乙基；
所述R3烷基为甲基或者乙基。
本发明的另一目的是提供Z-2-(2-酰基亚甲基)噻唑烷-4-酮类衍生物的制备方法，合成方法如下式所示：
式中，X表示卤原子，包括氯或者溴。
化合物Ⅰ制备步骤为：
S1、化合物Ⅱ和化合物Ⅲ混合于乙腈中，加入碳酸钠固体，反应混合物在室温或者加热至80℃进行反应；
S2、待化合物Ⅱ消失完全后，冷却至室温，将反应混合物过滤除去固体，滤液在减压条件下除去有机溶剂；
S3、使用硅胶柱层析洗脱得到化合物Ⅰ。
所述合成方法中使用乙腈作为反应溶剂，化合物Ⅱ和Ⅲ在碳酸钠作为碱的促进下实现反应；
所述化合物Ⅱ和化合物Ⅲ的摩尔比为Ⅱ：Ⅲ＝1.0：1.2，碳酸钠所需使用摩尔量为化合物Ⅱ的2倍，乙腈所需用量使化合物Ⅱ的浓度为0.1mol·L-1；
所述反应溶剂还包括1，2-二氯乙烷溶剂、N，N-二甲基甲酰胺溶剂、甲苯溶剂、二氧六环溶剂、乙酸乙酯溶剂、六氟异丙醇溶剂。
所述反应使用的碱还包括三乙胺、4-二甲氨基吡啶、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、碳酸钾、碳酸铯、NaOH。
所述硅胶柱层析所用的洗脱液为石油醚与乙酸乙酯的混合溶剂，且体积比V石油醚:V乙酸乙酯＝10:1～6:1。
本发明还提供了一种应用方式，一种包含Z-2-(2-酰基亚甲基)噻唑烷-4-酮类衍生物的合成物，所述合成物中包含Z-2-(2-酰基亚甲基)噻唑烷-4-酮类衍生物。
本发明的有益效果为：发明涉及的方法是采用α-烯醇二硫酯和α-卤代酰胺在碳酸钠的促进下高效合成Z-2-(2-酰基亚甲基)噻唑烷-4-酮类衍生物。该反应条件温和，操作简单，无过渡金属污染，可以一步构造包含硫和氮原子的五元环产物，且专一性地产生Z-式环外双键，无E-式异构体产生，方法简洁高效，反应过程耗时短(多数底物仅需0.5小时)，环境污染小，反应结束时后处理方便，所需产物产率普遍较高，反应在进行过程中对空气不敏感，无需惰性气体保护，而且反应规模可以适当扩大而产率基本不降低。
附图说明
图1为本发明实施例所得到的产物Ⅰ-1的核磁谱图(氢谱)；
图2为本发明实施例所得到的产物Ⅰ-1的核磁谱图(碳谱)。
具体实施方式
下面结合附图并通过具体的实施例进一步的说明本发明的技术方案：
本发明以下结合具体实施例进行解说。
以下是本发明制备化合物的最佳实施例。在以下所有实施例中，核磁谱检测通过Bruker400,JEOL400仪器在CDCl3中获得。δ值(ppm)为内标相对值(残存未氘代的CDCl3定标δ7.261H NMR和77.1613C NMR，残留未氘代的(CD3)2CO定标δ2.051H NMR和29.8413C NMR)。高分辨质谱(HRMS)通过4G quadrupole time-of-flight(QTof)质谱仪器得到。
实施例1
实施例1的化学反应式，具体使用的化合物II-1、III-1以及产物Ⅰ-1结构如下，筛选实验表明在所尝试的溶剂中乙腈是最优的反应溶剂，所述反应得到的产物最高分离收率为91％，反应物II-1、III-1的最优配比(摩尔比)为II-1：III-1＝1.0:1.2，碳酸钠的使用摩尔用量为化合物II-1的2倍，其中化合物II-1用量为当量，其它反应物和试剂均为过量，反应中化合物II-1的最优浓度为0.1mol·L-1。
具体实验步骤是：将42.0mg(0.20mmol，1.0当量)的化合物II-1和61.9mg(0.24mmol，1.2当量)化合物III-1混合溶于2mL乙腈中，加入42.4mg碳酸钠固体(0.40mmol，2.0当量)，混合体系加热至80℃反应30分钟。反应结束后，将反应混合物经减压抽滤除去固体杂质，收集滤液并将其在水泵减压下旋转蒸发除去溶剂乙腈。残留不挥发物经过硅胶柱层析(使用200-300目硅胶)，使用洗脱液(体积比V石油醚:V乙酸乙酯＝10:1～6:1)淋洗得到Ⅰ-1所示化合物61.7mg，其产物经过核磁(氢谱、碳谱)、高分辨质谱鉴定。
所述产物Ⅰ-1为白色固体，产率为91％.1H NMR(400MHz,CDCl3)δ7.91–7.82(m,2H),7.56–7.49(m,3H),7.48–7.39(m,5H),6.86(s,1H),5.25–5.11(m,2H),3.83(q,J＝7.3Hz,1H),1.63(d,J＝7.3Hz,3H)；13C NMR(100MHz,CDCl3)δ188.89,169.87,154.09,138.20,133.20,132.50,130.18,129.90,128.98,128.68,127.75,94.74,78.26,37.67,18.73；ESI-HRMS m/z calcd for C19H18NO3S[M+H]+340.1002,found 340.1001.
实施例2
本发明所涉及其它Z-2-(2-酰基亚甲基)噻唑烷-4-酮类化合物(化合物Ⅰ-2至化合物Ⅰ-20)的制备实施例所用的方法与实施例1基本相同，反应条件和操作如下：化合物II(0.20mmol，1.0当量)、化合物III(0.24mmol，1.2当量)混合溶于2mL的乙腈中，加入碳酸钠固体(0.40mmol，2.0当量)，反应混合物加热至80℃或在室温下反应。反应进程用薄层色谱监测，待反应完全后，将反应混合物经减压抽滤除去固体杂质，收集滤液并将其在水泵减压下旋转蒸发除去溶剂乙腈。残留不挥发物经过硅胶柱层析(使用200-300目硅胶)，使用洗脱液(体积比V石油醚:V乙酸乙酯＝10:1～6:1)淋洗得到Ⅰ所示化合物。
本发明用来制备化合物Ⅰ-2至Ⅰ-20所需的原料化合物化学式如下所示：
化合物II-2至II-8的制备方法为(以II-2的制备为例)：
氢化钠(2.0当量)悬浮于无水的N,N-二甲基甲酰胺和正己烷的混合溶液(VDMF:V正己烷＝1:2，15mL)中，0℃下边搅拌边缓慢滴加对氯苯乙酮(1mmol，1.0当量)，氮气氛围下缓慢加入二硫化碳(1.2当量)，反应体系在0℃下搅拌反应1小时之后逐滴滴加碘甲烷(1.0当量)，继续反应10小时。反应完全后，缓慢加入水淬灭反应，并加入稀盐酸中和，用二氯甲烷萃取，有机相用无水硫酸钠干燥，浓缩之后残留物经硅胶柱层析(使用200-300目硅胶)，使用洗脱液(体积比V石油醚:V乙酸乙酯＝50:1～40:1)淋洗得到化合物II-2。
本发明用来制备化合物Ⅰ-2至Ⅰ-20所需的原料化合物III化学式如下所示：
化合物III-2与III-14的制备方法为(以III-2的制备为例)：
将O-甲基羟胺盐酸盐(1mmol，1.1当量)悬浮于二氯甲烷(4mL)中，0℃下边搅拌边缓慢加入三乙胺(2.5当量)，之后再逐滴加入2-溴丙酰氯(1.0当量)，反应保持在0℃下进行直到反应完全。升至室温后，加水淬灭反应，用二氯甲烷萃取，有机相用无水硫酸钠干燥，浓缩之后残留物经硅胶柱层析(使用200-300目硅胶)，使用洗脱液(体积比V石油醚:V乙酸乙酯＝5:1～3:1)淋洗得到化合物III-2。
所得各产物结构和数据表征如下：
结构所示Ⅰ-2产物收率为77％(使用II-5和III-1于80℃反应)，呈白色固体结晶，熔点154-155℃。1H NMR(400MHz,CDCl3)δ7.98–7.78(m,2H),7.60–7.37(m,5H),7.19–7.04(m,2H),6.76(s,1H),5.31–5.11(m,2H),3.82(q,J＝7.3Hz,1H),1.62(d,J＝7.3Hz,3H)；13CNMR(100MHz,CDCl3)δ187.37,169.86,166.68,164.15,154.42,134.54,133.21,130.15(dd,J＝22.2Hz),129.01,115.74(d,J＝35.5Hz),94.40,78.34,37.68,18.72.19F NMR(376MHz,CDCl3)δ-106.27ESI-HRMS m/z calcd for C19H17FNO3S[M+H]+358.0908,found 358.0908.
结构所示Ⅰ-3产物收率为84％(使用II-2和III-1于80℃反应)，呈白色固体，熔点为124-125℃。1H NMR(400MHz,CDCl3)δ7.81–7.72(m,2H),7.52–7.47(m,2H),7.43–7.38(m,5H),6.76(s,1H),5.24–5.11(m,2H),3.83(q,J＝7.3Hz,1H),1.63(d,J＝7.3Hz,3H)；13C NMR(100MHz,CDCl3)δ187.53,169.85,154.77,138.79,136.52,133.19,130.17,129.96,129.14,129.01,128.95,94.37,78.38,37.71,18.71；ESI-HRMS m/z calcd forC19H17ClNO3S[M+H]+374.0612,found 374.0612.
结构所示Ⅰ-4产物收率为85％(使用II-3和III-1于80℃反应)，呈白色固体，熔点为124-125℃。1HNMR(400MHz,CDCl3)δ7.77(t,J＝1.9Hz,1H),7.70(dt,J＝7.7,1.4Hz,1H),7.53–7.46(m,3H),7.45–7.35(m,4H),6.72(s,1H),5.25–5.10(m,2H),3.84(q,J＝7.3Hz,1H),1.63(d,J＝7.3Hz,3H；13C NMR(100MHz,CDCl3)δ187.30,169.88,155.14,139.82,134.85,133.23,132.33,130.22,130.03,130.01,129.07,127.88,125.79,94.42,78.49,37.73,18.69；ESI-HRMS m/zcalcd for C19H17ClNO3S[M+H]+374.0612,found 374.0612.
结构所示Ⅰ-5产物收率为85％(使用II-4和III-1于80℃反应)，呈白色固体，熔点为109-110℃。1H NMR(400MHz,CDCl3)δ7.53–7.46(m,3H),7.44–7.36(m,5H),7.36–7.29(m,1H),6.71(s,1H),5.21–5.11(m,2H),3.84(q,J＝7.3Hz,1H),1.63(d,J＝7.3Hz,3H)；13C NMR(100MHz,CDCl3)δ190.01,169.77,153.84,139.43,132.85,131.68,131.25,130.55,130.23,129.96,129.85,128.89,127.10,98.71,78.18,37.77,18.64；ESI-HRMS m/z calcdfor C19H17ClNO3S[M+H]+374.0612,found 374.0616.
结构所示Ⅰ-6产物收率为85％(使用II-6和III-1于80℃反应)，呈白色固体，熔点为156-157℃。1HNMR(400MHz,CDCl3)δ8.36–8.32(m,1H),8.00–7.85(m,4H),7.63–7.52(m,4H),7.50–7.41(m,3H),7.00(s,1H),5.34–5.13(m,2H),3.86(q,J＝7.3Hz,1H),1.66(d,J＝7.3Hz,3H)；13C NMR(100MHz,CDCl3)δ188.76,169.91,154.02,135.54,135.39,133.30,132.71,130.24,129.97,129.56,129.04,128.88,128.56,128.28,127.90,126.81,124.01,94.97,78.44,37.73,18.78；ESI-HRMS m/z calcd for C23H20NO3S[M+H]+390.1158,found390.1161.
结构所示Ⅰ-7产物收率为92％(使用II-7和III-1于80℃反应)，呈白色固体，熔点为129-130℃。1HNMR(400MHz,CDCl3)δ7.61–7.54(m,2H),7.54–7.46(m,2H),7.41(dd,J＝5.0,2.1Hz,3H),7.11(dd,J＝4.9,3.8Hz,1H),6.67(s,1H),5.24–5.10(m,2H),3.82(q,J＝7.3Hz,1H),1.61(d,J＝7.3Hz,3H)；13C NMR(100MHz,CDCl3)δ181.46,169.74,153.37,145.44,133.10,132.83,130.20,129.93,129.51,129.00,128.21,94.92,78.27,37.77,18.7；ESI-HRMS m/z calcd for C17H16NO3S2[M+H]+346.0566,found 346.0567.
结构所示Ⅰ-8产物收率为70％(使用II-8和III-1于80℃反应)，呈白色固体，熔点为75-76℃。1HNMR(400MHz,CDCl3)δ7.50–7.44(m,2H),7.43–7.38(m,3H),6.14(s,1H),5.10(q,J＝9.8Hz,2H),3.76(q,J＝7.3Hz,1H),2.17(s,3H),1.58(d,J＝7.3Hz,3H；13C NMR(100MHz,CDCl3)δ196.20,169.74,151.48,133.01,130.01,129.75,128.81,98.00,77.89,37.40,30.27,18.67；ESI-HRMS m/zcalcd for C14H16NO3S[M+H]+278.0845,found278.0845.
结构所示Ⅰ-9产物收率为89％(使用II-1和III-2于80℃反应)，呈白色固体，熔点为108-109℃。1HNMR(400MHz,CDCl3)δ7.99–7.91(m,2H),7.58–7.50(m,1H),7.47(dd,J＝7.2,1.2Hz,2H),6.93(s,1H),4.02(s,3H),3.83(q,J＝7.3Hz,1H),1.64(d,J＝7.3Hz,3H).；13C NMR(100MHz,CDCl3)δ189.06,169.44,153.40,138.18,132.58,128.71,127.81,94.17,63.49,37.73,18.58；ESI-HRMS m/z calcd for C13H14NO3S[M+H]+264.0689,found264.0689.
结构所示Ⅰ-10产物收率为80％(使用II-1和III-3于80℃反应)，呈白色固体，熔点为74-75℃。1H NMR(400MHz,CDCl3)δ7.94(d,J＝7.7Hz,2H),7.72–7.39(m,3H),6.92(s,1H),4.27(d,J＝7.6Hz,2H),3.83(d,J＝7.3Hz,1H),1.65(d,J＝7.3Hz,3H),1.44(t,J＝7.0Hz,3H；13C NMR(100MHz,CDCl3)δ188.98,169.75,154.20,138.27,132.44,128.64,127.70,94.27,72.12,37.63,18.63,13.64；ESI-HRMS m/z calcd for C14H16NO3S[M+H]+278.0845,found 278.0848.
结构所示Ⅰ-11产物收率为83％(使用II-1和III-4于80℃反应)，呈白色固体，熔点为75-76℃。1H NMR(400MHz,CDCl3)δ8.00–7.89(m,2H),δ7.55(t,J＝7.3Hz,1H),7.48(t,J＝7.5Hz,2H),6.95(s,1H),6.23–6.01(m,1H),5.52–5.40(m,2H),4.79–4.67(m,2H),3.83(q,J＝7.3Hz,1H),1.64(d,J＝7.3Hz,3H)；13CNMR(100MHz,CDCl3)δ188.93,169.88,154.30,138.26,132.47,130.35,128.66,127.73,123.13,94.54,77.05,37.59,18.81；ESI-HRMS m/z calcd for C15H16NO3S[M+H]+290.0845,found 290.0845.
结构所示Ⅰ-12产物收率为64％(使用II-1和III-5于80℃反应)，呈白色固体，熔点为134-135℃。1H NMR(400MHz,CDCl3)δ7.92–7.79(m,2H),7.51(m,3H),7.48–7.39(m,5H),6.86(s,1H),5.17(s,2H),3.65(s,2H)；13C NMR(100MHz,CDCl3)δ188.93,166.45,155.09,138.04,133.22,132.57,130.09,129.91,129.02,128.70,127.76,95.19,78.38,29.04；ESI-HRMS m/z calcd for C18H16NO3S[M+H]+326.0845,found 326.0848.
结构所示Ⅰ-13产物收率为85％(使用II-1和III-6于80℃反应)，呈白色固体，熔点为72-73℃。1HNMR(400MHz,CDCl3)δ7.92–7.82(m,2H),7.57–7.48(m,3H),7.48–7.38(m,5H),6.86(s,1H),5.17(s,2H),3.79(dd,J＝8.2,4.4Hz,1H),2.19–2.06(m,1H),1.91(ddd,J＝14.0,8.1,7.0Hz,1H),1.08(t,J＝7.3Hz,3H)；13CNMR(100MHz,CDCl3)δ188.82,169.08,154.41,138.22,133.26,132.49,130.13,129.87,128.98,128.68,127.76,94.79,78.32,44.64,26.26,10.50；ESI-HRMS m/z calcd for C20H20NO3S[M+H]+354.1158,found354.1160.
结构所示Ⅰ-14产物收率为66％(使用II-1和III-7于室温反应)或者62％(使用II-1和III-8于室温反应)，呈白色固体，熔点为150-151℃。1H NMR(400MHz,CDCl3)δ7.89(d,J＝7.5Hz,2H),7.51(m,5H),7.40(m,8H),6.94(s,1H),5.22(d,J＝5.8Hz,2H),4.92(s,1H)；13CNMR(100MHz,CDCl3)δ188.96,167.51,153.77,138.06,134.59,133.12,132.53,130.19,129.88,129.22,128.98,128.94,128.65,128.49,127.76,95.07,78.30,47.37；ESI-HRMSm/z calcd for C24H20NO3S[M+H]+402.1158,found 402.1161.
结构所示Ⅰ-15产物收率为69％(使用II-1和III-9于室温反应)，呈白色固体，熔点为128-129℃。1H NMR(400MHz,CDCl3)δ7.88(dt,J＝7.2,1.4Hz,2H),7.59–7.52(m,3H),7.50–7.42(m,5H),7.36(tdd,J＝7.6,5.3,1.8Hz,1H),7.29(td,J＝7.6,1.8Hz,1H),7.20–7.08(m,2H),6.94(s,1H),5.26(q,J＝10Hz,2H),5.14(s,1H)；13C NMR(100MHz,CDCl3)δδ188.99,166.93,160.95(d,J＝249.2Hz),153.77,137.97,133.27,132.55,130.98(d,J＝8.6Hz),130.37(d,J＝2.8Hz),130.12,129.83,128.98,128.65,127.76,124.85(d,J＝3.6Hz),122.57(d,J＝13.1Hz),116.37,116.21,94.97,78.33,42.02(d,J＝2.2Hz)；19F NMR(376MHz,CDCl3)δ-115.26；ESI-HRMS m/z calcd for C24H19FNO3S[M+H]+420.1064,found420.1065.
结构所示Ⅰ-16产物收率为54％(使用II-1和III-10于室温反应)，呈白色固体，熔点为168-169℃。1H NMR(400MHz,CDCl3)δ7.90(d,J＝7.5Hz,2H),7.63–7.40(m,8H),7.38–7.28(m,1H),7.24–7.15(m,1H),7.02–6.77(m,3H),5.26(q,J＝9.6,2H),5.12(s,1H),3.83(s,3H)；13C NMR(100MHz,CDCl3)δ188.85,167.99,157.29,155.17,138.20,133.30,132.32,130.43,130.07,129.89,129.76,128.94,128.58,127.68,123.16,121.03,111.38,93.97,78.11,55.86,43.74；ESI-HRMS m/z calcd for C25H22NO4S[M+H]+432.1264,found432.1266.
结构所示Ⅰ-17产物收率为64％(使用II-1和III-11于室温反应)，呈白色固体，熔点为150-151℃。1H NMR(400MHz,CDCl3)δ7.94–7.85(m,2H),7.54(d,J＝7.1Hz,1H),7.52–7.46(m,3H),7.46–7.38(m,3H),7.31(t,J＝7.9Hz,1H),6.94(m,4H),5.21(q,J＝10.2,2H),4.90(s,1H),3.82(s,3H)；13C NMR(100MHz,CDCl3)δ189.02,167.45,160.26,153.82,138.13,136.01,133.21,132.61,130.35,130.26,129.96,129.03,128.73,127.84,120.80,114.58,114.30,95.16,78.39,55.52,47.43；ESI-HRMS m/z calcd for C25H22NO4S[M+H]+432.1264,found 432.1266.
结构所示Ⅰ-18产物收率为64％(使用II-1和III-12于室温反应)，呈白色固体，熔点为176-177℃。1H NMR(400MHz,CDCl3)δ7.89(d,J＝7.6Hz,2H),δ7.56(d,J＝7.3Hz,1H),7.49(d,J＝7.0Hz,4H),7.42(s,3H),7.37(d,J＝8.1Hz,2H),7.31(d,J＝8.2Hz,2H),7.26(s,1H),6.94(s,1H),5.22(q,J＝10.0,2H),4.89(s,1H)；13C NMR(100MHz,CDCl3)δ189.08,167.18,153.40,138.00,135.13,133.10(d,J＝5.5Hz),132.73,130.28,130.02,129.93,129.48,129.03,128.77,127.86,95.40,78.41,53.55,46.77；ESI-HRMS m/z calcd forC24H19ClNO3S[M+H]+436.0769,found436.0771.
结构所示Ⅰ-19产物收率为61％(使用II-1和III-13于室温反应)，呈白色固体，熔点为110-111℃。1H NMR(400MHz,CDCl3)δ7.89(dt,J＝7.1,1.4Hz,2H),7.54(m,3H),7.51–7.38(m,5H),7.12(d,J＝7.8Hz,1H),7.07–6.99(m,2H),6.94(s,1H),5.24(t,J＝10.0Hz,2H),5.17(s,1H),2.40(s,3H),2.32(s,3H)；13C NMR(100MHz,CDCl3)δ188.97,167.98,154.20,138.94,138.20,136.98,133.30,132.55,132.14,130.24,130.05,129.93,129.04,128.72,128.47,127.82,127.65,94.91,78.39,44.73,21.19,19.72；ESI-HRMS m/z calcdfor C26H24NO3S[M+H]+430.1471,found430.1472.
结构所示Ⅰ-20产物收率为44％(使用II-1和III-14于室温反应)，呈白色固体，熔点为172-173℃。1H NMR(400MHz,CDCl3)δ7.91(m,5H),7.69–7.52(m,5H),7.53–7.40(m,7H),7.00(s,1H),5.73(s,1H),5.32(q,J＝9.6,2H)；13C NMR(100MHz,CDCl3)δ188.89,167.66,153.95,138.03,134.20,133.19,132.53,131.43,130.73,130.22,129.90,129.75,129.29,128.99,128.66,127.77,127.25,126.39,125.46,122.81,95.05,78.43,44.30；ESI-HRMSm/z calcd for C28H22NO3S[M+H]+452.1315,found452.1316.
对于本领域技术人员而言，显然本发明不限于上述示范性实施例的细节，而且在不背离本发明的精神或基本特征的情况下，能够以其他的具体形式实现本发明。因此，无论从哪一点来看，均应将实施例看作是示范性的，而且是非限制性的，本发明的范围由所附权利要求而不是上述说明限定，因此旨在将落在权利要求的等同要件的含义和范围内的所有变化囊括在本发明内。
此外，应当理解，虽然本说明书按照实施方式加以描述，但并非每个实施方式仅包含一个独立的技术方案，说明书的这种叙述方式仅仅是为清楚起见，本领域技术人员应当将说明书作为一个整体，各实施例中的技术方案也可以经适当组合，形成本领域技术人员可以理解的其他实施方式。
Claims (6)
1.一种制备Z-2-(2-酰基亚甲基)噻唑烷-4-酮类衍生物的方法，其特征在于，制备方法如下式：
式中，X表示卤原子，包括氯或者溴；R1为苯基、取代苯基、2-噻吩基、2-萘基或者甲基取代基；R2为苯基、取代苯基、氢原子、1-萘基或烷基；R3为苄基、烯丙基或者烷基；
化合物Ⅰ制备步骤为：
S1、化合物Ⅱ和化合物Ⅲ混合于乙腈中，加入碳酸钠固体，进行反应；
S2、待化合物Ⅱ消失完全后，冷却过滤，再将滤液除去有机溶剂；
S3、使用硅胶柱层析将滤液洗脱得到化合物Ⅰ。
2.根据权利要求1所述的一种制备Z-2-(2-酰基亚甲基)噻唑烷-4-酮类衍生物的方法，其特征在于：所述S2中，滤液在减压条件下除去有机溶剂。
3.根据权利要求1所述的一种制备Z-2-(2-酰基亚甲基)噻唑烷-4-酮类衍生物的方法，其特征在于：所述化合物Ⅱ和化合物Ⅲ的摩尔比为Ⅱ：Ⅲ＝1.0∶1.2，碳酸钠所需使用摩尔量为化合物Ⅱ的2倍，乙腈所需用量使化合物Ⅱ的浓度为0.1mol·L-1
4.根据权利要求1或3所述的一种制备Z-2-(2-酰基亚甲基)噻唑烷-4-酮类衍生物的方法，其特征在于：所述乙腈的替代物为1，2-二氯乙烷溶剂、N，N-二甲基甲酰胺溶剂、甲苯溶剂、二氧六环溶剂、乙酸乙酯溶剂。
5.根据权利要求1或3所述的一种制备Z-2-(2-酰基亚甲基)噻唑烷-4-酮类衍生物的方法，其特征在于：所述碳酸钠的替代物三乙胺、4-二甲氨基吡啶、NaOH。
6.根据权利要求1所述的一种制备Z-2-(2-酰基亚甲基)噻唑烷-4-酮类衍生物的方法，其特征在于：所述硅胶柱层析所用的洗脱液为石油醚与乙酸乙酯的混合溶剂，且体积比V石油醚:V乙酸乙酯＝10:1～6:1。
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