阅读说明：本技术 3，4-二羟基肉桂酸酯类衍生物及其制备方法和应用 (3, 4-dihydroxy cinnamic acid ester derivatives, and preparation method and application thereof ) 是由 可钰 杨瑞华 王妮 刘宏民 徐霞 姬小明 于 2020-06-22 设计创作，主要内容包括：本发明属天然产物及药物化学领域,公开了含2,4-噻唑烷二酮(TZD)基团的3,4-二羟基肉桂酸(咖啡酸)酯类衍生物及其制备方法和应用。其制备方法：在2,4-TDZ的5位进行插烯,3位N上引入不同的羟基侧链,得到的醇与被保护的肉桂酸羧基部位进行酯化,得到肉桂酸酯,该肉桂酸酯在过量的三氟乙酸中脱除Ph-OH保护基得到3,4-二羟基肉桂酸衍生物。该类化合物具有良好的抗肿瘤活性、抗氧化活性和水溶性,可用于制备抗肿瘤药物,临床用于治疗胃癌、食管癌、乳腺癌、肺癌等疾病。其结构通式如下：<Image he="102" wi="227" file="DEST_PATH_IMAGE001.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>。(The invention belongs to the field of natural products and pharmaceutical chemistry, and discloses a 3, 4-dihydroxycinnamic acid (caffeic acid) ester derivative containing a 2, 4-Thiazolidinedione (TZD) group, and a preparation method and application thereof. The preparation method comprises the following steps: performing vinylogous insertion on the 5-position of 2, 4-TDZ, introducing different hydroxyl side chains on the 3-position N, esterifying the obtained alcohol and the protected cinnamic acid carboxyl position to obtain cinnamate, and removing a Ph-OH protecting group from excessive trifluoroacetic acid to obtain the 3, 4-dihydroxycinnamic acid derivative. The compound has good antitumor activity, antioxidant activity and water solubility, can be used for preparing antitumor drugs, and is clinically used for treating diseases such as gastric cancer, esophageal cancer, breast cancer, lung cancer and the like. The general structural formula is as follows: 。)

3，4-二羟基肉桂酸酯类衍生物及其制备方法和应用

技术领域

本发明涉及天然产物及药物化学领域，具体涉及新型3，4-二羟基肉桂酸衍生物类化合物及其制备方法和应用。

背景技术

咖啡酸别名3,4-二羟基肉桂酸(Caffeic acid，简称CA)，是一种天然存在的酚酸，广泛存在于植物种子、咖啡、蔬菜、葡萄及橄榄油中，也存在于当归、川茸等中药材中，目前在药物化学、化妆品、食品等领域较为广泛应用。咖啡酸具有抗氧化、抗肿瘤、抗菌等多种生物活性，其活性部位在于双键和两个酚羟基。咖啡酸在常见溶剂中溶解性和稳定性较低，这限制了它的应用，因此将咖啡酸与一些脂溶性较强的分子结合，既保留生物活性又增强了亲脂性，从而扩大其应用范围。噻唑烷二酮(TZD)作为一类重要的结构单元，其衍生物具有抗糖尿病、抗菌、抗病毒等多种药理活性，将其引入先导化合物中能普遍提高化合物的生物活性。

通过酯化反应将3，4-二羟基肉桂酸与含噻唑烷二酮结构单元的卤代醇连接，合成系列新化合物，并对合成的系列衍生物进行活性测试和筛选，对进一步开发具有自主知识产权的创新药物具有重要意义。目前尚未见相关报道。

发明内容

本发明目的在于提供一系列3，4-二羟基肉桂酸酯类衍生物，提高其抗肿瘤作用，为其在临床上的应用提供可能。

本发明的另一目的在于提供其制备方法及在制备抗肿瘤药物的应用。

为实现本发明目的，本发明将3，4-二羟基肉桂酸的羧基部位进行酯化得到系列衍生物，增强了其抗肿瘤活性。

本发明提供的3，4-二羟基肉桂酸酯类衍生物的结构通式I如下所示：

其中n为1-7；R为直链或含支链C1-C10烷基，苯基或取代的苯基，苯环上的取代基为单取代或多取代，被C1-C3烷基、卤素、甲氧基、氮甲基取代。

优选：n为1-4；R为直链或含支链的C1-C8烷基；R为苯基或被C1-C3烷基、卤素、甲氧基、氮甲基单取代或多取代的苯基。

优选：n为1-2；R为直链或含支链的C1-C8烷基；R为苯基或被氟、氯、溴、甲基、氮甲基、甲氧基单取代或双取代的苯基。

进一步优选：n＝1-2，R为以下取代基：

本发明所述的3，4-二羟基肉桂酸酯类衍生物通过如下合成路线得到：

1、2,4-噻唑烷二酮(a)在甲醇为溶剂，哌啶为催化剂，回流条件下与 R取代的醛类化合物发生插烯反应得到化合物b。

2、将中间体b溶解在DMF(N，N-二甲基甲酰胺)中，在碱性(KCO₃或KOH)及相转移催化剂(四丁基溴化铵或四丁基氟化铵)条件下与卤代醇类化合物进行取代反应，柱色谱纯化得到中间体c。

3、以3，4-二羟基肉桂酸(d)为原料，丙酮为溶剂，与2，2-二甲氧基丙烷反应，得到化合物e。

4、将中间体c溶于二氯甲烷中，以DCC(二环己基碳二亚胺)和DMAP (4-二甲氨基吡啶)作为催化剂与e发生酯化反应，柱色谱纯化得到中间产物f。

5、将中间产物f溶解于二氯甲烷中，加入过量的三氟乙酸和质量百分含量10％HCl，使其脱掉酚羟基保护基，将体系萃取干燥，旋蒸浓缩后，柱色谱纯化得到终产物g(通式I)。

本发明创新点：以3，4-二羟基肉桂酸为起始原料，在不破坏其活性中心的前提下，与含有噻唑烷二酮基团的卤代醇发生酯化反应，得到3，4-二羟基肉桂酸酯类衍生物，脱除酚羟基保护基，得到目标化合物。体外活性研究表明，该类衍生物具有良好的生物活性和较广的抗肿瘤活性，还具有抗氧化活性和良好的水溶性，可用于制备抗肿瘤药物，应用于临床治疗食道癌、胃癌、原发性肝癌、胰腺癌、乳腺癌等疾病，具有良好的开发前景。

具体实施方式

通过以下具体实例进一步说明本发明，但应注意本发明的范围并不受这些实施例的任何限制。

实施例1：n＝1，R₁为苯基

(1)2,4-噻唑烷二酮(a)在甲醇为溶剂，哌啶为催化剂，回流条件下与苯甲醛发生插烯反应得到b。

(2)将中间体b溶解在DMF(N，N-二甲基甲酰胺)中，在碱性(KCO₃或KOH) 及相转移(四丁基溴化铵或四丁基氟化铵)条件下与溴乙醇进行取代反应，柱色谱纯化得到中间体c。

(3)以3，4-二羟基肉桂酸(d)为原料，丙酮为溶剂，与2，2-二甲氧基丙烷反应，得到化合物e。

(4)将(300mg,1mmol)中间体c溶解在DCM(二氯甲烷)溶液中，再加入被保护的3，4-二羟基肉桂酸e(265.03mg,1mmol)，分别加入催化剂DCC(372.47mg, 1.5mmol)、4-DMAP(13.12mg,0.1mmol)冰浴下搅拌6h，TLC板检测反应至原料消失。用二氯甲烷和饱和食盐水萃取三次，并合并水层反萃一次，合并酯层，无水硫酸镁干燥过夜，旋蒸浓缩后柱色谱纯化得化合物f白色固体200mg，产率 90％。¹H NMR(400MHz,CDCl₃)δ7.92(s,1H),7.92(s,1H),7.58(d,J＝15.9Hz, 1H),7.54–7.43(m,5H),6.95(d,J＝9.4Hz,2H),6.70(d,J＝7.8Hz,1H),6.19(d,J ＝15.9Hz,1H),4.44(t,J＝5.3Hz,2H),4.11(t,J＝5.3Hz,2H),1.68(s,6H).¹³C NMR(101MHz,CDCl₃)δ167.95,166.85,166.35,161.54,149.69,148.14,145.64,134.00,132.31,128.18,125.88,124.31,118.90,118.20,114.80,114.67,108.34,106.44,60.76,55.50,40.77,25.88.ESI-HRMS:Calculated for C₂₁H₂₄NO₆S[M+H]+:410.1168,found 410.1106。

化合物I-1的制备

将100mg中间体f溶解于二氯甲烷(DCM)中，在冰浴条件下加入过量的三氟乙酸，并逐滴加质量百分含量10％HCl，保持冰浴反应4h，TLC板检测完全反应后，用二氯甲烷和饱和食盐水萃取三次，并合并水层反萃一次，合并酯层，无水硫酸镁干燥过夜，旋蒸浓缩后柱色谱纯化得化合物I-1白色固体50mg，产率60％。¹H NMR(400MHz,DMSO-d₆)δ9.77–9.50(m,1H),9.15(s,1H),7.96(s, 1H),7.67–7.60(m,2H),7.61–7.49(m,3H),7.45(d,J＝15.9Hz,1H),7.03(d,J＝ 2.1Hz,1H),6.98(dd,J＝8.2,2.1Hz,1H),6.75(d,J＝8.1Hz,1H),6.19(d,J＝15.9Hz,1H),4.36(t,J＝5.2Hz,2H),3.98(t,J＝5.2Hz,2H).¹³C NMR(101MHz, DMSO-d₆)δ167.26,166.30,165.56,148.52,145.63,145.56,133.06,132.88,130.67, 130.13,129.36,125.33,121.46,121.08,115.73,114.80,113.28,60.21,40.87. ESI-HRMS:Calculated for C₂₁H₁₇NO₆S[M-H]-:410.0704,found 410.0694。产率 87％。

实施例2：

用邻氯苯甲醛115mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-2。¹H NMR(400MHz,DMSO-d₆)δ9.61(s,1H),9.15(s,1H),8.06(s, 1H),7.69–7.63(m,1H),7.62–7.58(m,1H),7.54(tdd,J＝5.2,3.8,1.8Hz,2H), 7.46(d,J＝15.8Hz,1H),7.04(d,J＝2.1Hz,1H),6.98(dd,J＝8.2,2.1Hz,1H),6.76 (d,J＝8.2Hz,1H),6.20(d,J＝15.9Hz,1H),4.36(t,J＝5.3Hz,2H),3.98(t,J＝5.2 Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ167.05,166.31,165.20,148.52,145.67, 145.56,134.47,132.07,130.87,130.38,128.97,128.15,128.05,125.33,124.87, 121.47,115.71,114.79,113.26,60.20,40.98.ESI-HRMS:Calculated for C₂₁H₁₆ClNO₆S[M-H]-:444.0314,found 444.0304。产率78％。

实施例3：

用间氯苯甲醛(131mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-3。¹H NMR(400MHz,DMSO-d₆)δ9.61(s,1H),9.16(s,1H),7.95 (s,1H),7.72(d,J＝2.0Hz,1H),7.57(d,J＝1.3Hz,3H),7.45(d,J＝15.9Hz,1H), 7.03(d,J＝2.1Hz,1H),6.98(dd,J＝8.2,2.1Hz,1H),6.76(d,J＝8.1Hz,1H),6.19 (d,J＝15.9Hz,1H),4.36(t,J＝5.2Hz,2H),3.98(t,J＝5.2Hz,2H).¹³C NMR(101 MHz,DMSO-d₆)δ166.92,166.31,165.35,148.52,145.65,145.56,135.05,133.97, 131.43,131.17,130.23,130.10,127.78,125.31,122.90,121.47,115.72,114.79, 113.25,60.20,40.97.ESI-HRMS:Calculated forC₂₁H₁₆ClNO₆S[M-H]-:444.0314, found 444.0316。产率79％。

实施例4：

用对氯苯甲醛(189mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-4。¹H NMR(400MHz,DMSO-d₆)δ9.62(s,1H),9.17(s,1H),7.95 (s,1H),7.70–7.58(m,4H),7.45(d,J＝15.9Hz,1H),7.03(d,J＝2.1Hz,1H),6.98 (dd,J＝8.2,2.1Hz,1H),6.76(d,J＝8.2Hz,1H),6.19(d,J＝15.9Hz,1H),4.36(t,J ＝5.2Hz,2H),3.98(t,J＝5.2Hz,2H).¹³CNMR(101MHz,DMSO-d₆)δ167.00, 166.30,165.44,148.52,145.63,145.56,135.26,131.79,131.75,129.42,125.32, 121.84,121.46,115.73,114.80,113.26,60.20,40.93.ESI-HRMS:Calculated for C₂₁H₁₆ClNO₆S[M-H]-:444.0314,found 444.0307。产率72％。

实施例5：

用邻溴苯甲醛(125mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-5。¹H NMR(400MHz,DMSO-d₆)δ9.61(s,1H),9.15(s,1H),8.01 (s,1H),7.82(d,J＝8.1Hz,1H),7.63–7.54(m,2H),7.51–7.38(m,2H),7.03(s, 1H),6.98(d,J＝8.3Hz,1H),6.76(d,J＝8.2Hz,1H),6.19(d,J＝15.9Hz,1H),4.35 (d,J＝5.3Hz,2H),3.99(d,J＝5.2Hz,2H).¹³CNMR(101MHz,DMSO-d₆)δ 167.08,166.30,165.15,148.52,145.67,145.56,133.63,132.62,132.19,130.77, 129.10,128.66,125.34,125.26,124.89,121.47,115.72,114.80,113.27,60.19,40.97. ESI-HRMS:Calculated for C₂₁H₁₆NO₆S[M-H]-:487.9809,found489.9777。产率 70％。

实施例6：

用间溴苯甲醛(134mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-6。¹H NMR(400MHz,DMSO-d₆)δ9.61(s,1H),9.16(s,1H),7.94 (s,1H),7.86(t,J＝1.8Hz,1H),7.70(dd,J＝8.0,1.9Hz,1H),7.61(d,J＝7.8Hz, 1H),7.51(t,J＝7.9Hz,1H),7.45(d,J＝15.9Hz,1H),7.03(d,J＝2.1Hz,1H),6.98 (dd,J＝8.2,2.1Hz,1H),6.76(d,J＝8.1Hz,1H),6.19(d,J＝15.9Hz,1H),4.36(t,J ＝5.1Hz,2H),3.98(t,J＝5.2Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ166.92, 166.31,165.33,148.52,145.65,145.56,135.30,133.11,132.99,131.38,128.11, 125.31,122.86,122.47,121.48,115.72,114.78,113.25,60.20,40.97.ESI-HRMS: Calculated for C₂₁H₁₆NO₆S[M-H]-:487.9809,found 487.9797。产率68％。

实施例7：

用对溴苯甲醛(123mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-7。¹H NMR(400MHz,DMSO-d₆)δ9.60(s,1H),9.19(s,1H),7.93 (s,1H),7.75(d,J＝8.3Hz,2H),7.57(d,J＝8.2Hz,2H),7.45(d,J＝15.9Hz,1H), 7.03(d,J＝1.9Hz,1H),6.98(dd,J＝8.1,2.0Hz,1H),6.76(d,J＝8.1Hz,1H),6.19 (d,J＝15.9Hz,1H),4.36(t,J＝5.2Hz,2H),3.98(t,J＝5.2Hz,2H).¹³C NMR(101 MHz,DMSO-d₆)δ167.00,166.31,165.45,148.52,145.64,145.56,132.35,132.10, 131.89,131.82,125.32,124.20,121.92,121.46,115.72,114.79,113.26,60.20,40.93. ESI-HRMS:Calculated for C₂₁H₁₆NO₆S[M-H]-:487.9809,found 487.9797。产率 70％。

实施例8：

用邻氟苯甲醛(140mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-8。¹H NMR(400MHz,DMSO-d₆)δ9.61(s,1H),9.15(s,1H),7.93 (s,1H),7.58(q,J＝6.7,5.9Hz,2H),7.45(d,J＝16.1Hz,1H),7.40(t,J＝9.2Hz, 2H),7.04(d,J＝2.3Hz,1H),6.98(dd,J＝8.4,2.0Hz,1H),6.76(d,J＝8.1Hz,1H), 6.19(d,J＝15.9Hz,1H),4.36(t,J＝5.2Hz,2H),3.98(t,J＝5.2Hz,2H).¹³C NMR (101MHz,DMSO-d₆)δ166.99,166.31,165.29,161.74,148.53,145.65,145.57, 133.05,129.01,125.43,125.33,124.15,123.94,121.46,120.83,116.38,115.73, 114.78,113.26,60.18,40.99.ESI-HRMS:Calculatedfor C₂₁H₁₆FNO₆S[M-H]-: 428.0610,found 428.0599。产率72％。

实施例9：

用间氟苯甲醛(180mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-9。¹H NMR(400MHz,DMSO-d₆)δ9.58(s,1H),9.18(s,1H),7.93 (s,1H),7.64–7.54(m,2H),7.50–7.36(m,3H),7.03(d,J＝2.1Hz,1H),6.98(dd,J ＝8.2,2.0Hz,1H),6.75(d,J＝8.1Hz,1H),6.19(d,J＝15.8Hz,1H),4.36(t,J＝5.2 Hz,2H),3.98(t,J＝5.2Hz,2H).¹³CNMR(101MHz,DMSO-d₆)δ166.99,166.31, 165.29,148.52,145.66,145.56,133.06,129.00,125.48,125.32,123.95,121.47, 120.83,120.71,116.39,116.18,115.71,114.78,113.25,60.19,40.99,40.12,39.91. ESI-HRMS:Calculated for C₂₁H₁₆FNO₆S[M-H]-:428.0610,found 428.0598。产率 69％。

实施例10：

用对氟苯甲醛(145mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-10。¹H NMR(400MHz,DMSO-d₆)δ9.58(s,1H),9.20(s,1H),7.97 (s,1H),7.72(ddd,J＝8.7,5.6,2.7Hz,2H),7.48–7.37(m,3H),7.03(d,J＝2.1Hz, 1H),6.98(dd,J＝8.2,1.9Hz,1H),6.76(d,J＝8.1Hz,1H),6.19(d,J＝15.9Hz,1H), 4.36(t,J＝5.2Hz,2H),3.98(t,J＝5.2Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ 167.15,166.30,165.51,148.52,145.63,145.56,132.68,132.59,131.99,129.58, 125.32,121.46,120.78,116.66,116.44,115.72,114.79,113.26,60.20,40.89. ESI-HRMS:Calculated for C₂₁H₁₆FNO₆S[M-H]-:428.0610,found 428.0599。产率 65％。

实施例11：

用邻甲基苯甲醛(124mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-11。¹H NMR(400MHz,DMSO-d₆)δ9.56(s,1H),9.22(s,1H), 8.03(s,1H),7.50–7.41(m,2H),7.37(q,J＝6.5,5.8Hz,3H),7.04(s,1H),6.98(d,J ＝7.9Hz,1H),6.76(d,J＝8.2Hz,1H),6.20(d,J＝15.9Hz,1H),4.36(t,J＝5.2Hz, 2H),3.98(t,J＝5.2Hz,2H),2.38(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ167.53, 166.29,165.30,148.53,145.65,145.57,138.74,131.99,130.98,130.93,130.48, 127.18,126.65,125.34,122.78,121.44,115.73,114.80,113.28,60.21,40.78. ESI-HRMS:Calculated for C₂₂H₁₉NO₆S[M-H]-:424.0860,found 424.0807。产率 79％。

实施例12：

用间甲基苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-12。¹H NMR(400MHz,DMSO-d₆)δ9.50(s,1H),9.16(s,1H),δ 7.69(s,1H),7.62–7.57(m,1H),7.26–7.18(m,3H),7.14–7.09(m,1H),7.09– 7.05(m,1H),6.97(dd,J＝2.0,1.0Hz,1H),6.87(d,J＝7.5Hz,1H),6.42(d,J＝15.2 Hz,1H),5.43(s,1H),5.11(s,1H),4.41(t,J＝7.2Hz,2H),3.76(t,J＝7.3Hz,2H), 2.30(d,J＝1.0Hz,3H).¹³C NMR(100MHz,DMSO-d₆)δ167.55,166.41,165.97, 148.29,147.12,145.75,133.21,131.93,130.72,130.02,128.40,127.38,122.72, 117.73,116.34,115.89,115.14,62.69,42.78,22.53.ESI-HRMS:Calculated for C₂₂H₁₉NO₆S[M-H]-:424.0860,found 424.0842。产率77％。

实施例13：

用对甲基苯甲醛(126mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-13。¹H NMR(400MHz,DMSO-d₆)δ9.60(s,1H),9.16(s,1H), 7.91(s,1H),7.53(d,J＝8.0Hz,2H),7.44(d,J＝15.9Hz,1H),7.36(d,J＝8.0Hz, 2H),7.03(d,J＝2.1Hz,1H),6.97(dd,J＝8.1,2.0Hz,1H),6.75(d,J＝8.1Hz,1H), 6.19(d,J＝15.9Hz,1H),4.35(t,J＝5.2Hz,2H),3.97(t,J＝5.2Hz,2H),2.37(s, 3H).¹³C NMR(101MHz,DMSO-d₆)δ167.29,166.29,165.61,148.51,145.62, 145.56,141.02,133.14,130.20,130.13,129.99,125.33,121.45,119.81,115.73, 114.79,113.28,60.22,40.82,21.07.ESI-HRMS:Calculated for C₂₂H₁₉NO₆S[M-H]-: 424.0860,found 424.0853。产率78％。

实施例14：

用2，4-二氟苯甲醛(124mg,1mmol)代替苯甲醛，其他操作同实施例 1，得白色固体产物I-14。¹H NMR(400MHz,DMSO-d₆)δ9.61(s,1H),9.15(s,1H), 7.86(s,1H),7.64(td,J＝8.7,6.2Hz,1H),7.54–7.47(m,1H),7.45(d,J＝16.0Hz, 1H),7.30(td,J＝8.5,2.6Hz,1H),7.03(d,J＝2.1Hz,1H),6.97(dd,J＝8.2,2.1Hz, 1H),6.76(d,J＝8.1Hz,1H),6.19(d,J＝15.9Hz,1H),4.36(t,J＝5.2Hz,2H),3.98 (t,J＝5.2Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ166.88,166.30,165.24,148.52, 145.66,145.56,130.73,125.32,123.67,123.33,121.46,115.71,114.78,113.24, 113.06,112.88,105.38,105.12,104.86,60.18,41.01.ESI-HRMS:Calculated for C₂₁H₁₅F₂NO₆S[M-H]-:446.0515,found 446.0508。产率89％。

实施例15：

用2，6-二氟苯甲醛(130mg,1mmol)代替苯甲醛，其他操作同实施例 1，得白色固体产物I-15。¹H NMR(400MHz,DMSO-d₆)δ9.52(s,1H),9.24(s,1H), 7.80(s,1H),7.63(ddd,J＝15.0,8.4,6.5Hz,1H),7.45(d,J＝15.8Hz,1H),7.29(t,J ＝8.6Hz,2H),7.04(s,1H),6.98(d,J＝8.0Hz,1H),6.76(d,J＝8.2Hz,1H),6.20(d, J＝15.9Hz,1H),4.35(t,J＝5.2Hz,2H),3.96(t,J＝5.2Hz,2H).¹³C NMR(101 MHz,DMSO-d₆))δ166.79,166.31,164.89,160.68,158.18,148.52,145.66,145.56, 133.39,128.20,125.32,121.46,120.61,115.72,114.78,113.26,112.53,112.29, 110.35,60.20,41.06.ESI-HRMS:Calculated forC₂₁H₁₅F₂NO₆S[M-H]-:446.0515, found 446.0505。产率85％。

实施例16：

用邻甲氧基苯甲醛(160mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-16。¹H NMR(400MHz,DMSO-d₆)δ9.60(s,1H),9.15(s,1H), 8.09(s,1H),7.56–7.48(m,1H),7.48–7.41(m,2H),7.17(d,J＝8.4Hz,1H),7.11 (t,J＝7.6Hz,1H),7.03(d,J＝2.2Hz,1H),6.98(dd,J＝8.2,2.0Hz,1H),6.75(d,J＝ 8.1Hz,1H),6.19(d,J＝15.8Hz,1H),4.34(d,J＝5.3Hz,2H),3.96(d,J＝5.2Hz, 2H),3.89(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ167.52,166.29,165.67,158.03, 148.51,145.63,145.56,132.74,128.92,127.94,125.34,121.46,121.27,121.08, 121.02,115.72,114.79,113.29,111.95,60.21,55.76,40.78.ESI-HRMS:Calculated for C₂₂H₁₉NO₇S[M-H]-:440.0809,found 440.0799。产率69％。

实施例17：

用间甲氧基苯甲醛(140mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-17。¹H NMR(400MHz,DMSO-d₆)δ9.60(s,1H),9.23–8.93 (m,1H),7.93(s,1H),7.45(q,J＝8.0Hz,2H),7.23–7.16(m,2H),7.08(dd,J＝8.5, 2.3Hz,1H),7.03(d,J＝2.1Hz,1H),6.98(dd,J＝8.2,2.1Hz,1H),6.75(d,J＝8.2 Hz,1H),6.19(d,J＝15.9Hz,1H),4.36(t,J＝5.1Hz,2H),3.98(t,J＝5.1Hz,2H), 3.81(s,3H).¹³C NMR(101MHz,DMSO)δ167.21,166.30,165.51,159.64,148.52, 145.63,145.56,134.24,133.03,130.48,125.33,121.93,121.46,121.44,116.61, 115.73,115.44,114.79,113.28.ESI-HRMS:Calculated forC₂₂H₁₉NO₇S[M-H]-: 440.0809,found 440.0799。产率88％。

实施例18：

用对甲氧基苯甲醛(122mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-18。¹H NMR(400MHz,DMSO-d₆)δ9.60(s,1H),9.15(s,1H), 7.91(s,1H),7.66–7.56(m,2H),7.45(d,J＝15.9Hz,1H),7.15–7.08(m,2H),7.03 (d,J＝2.1Hz,1H),6.97(dd,J＝8.2,2.1Hz,1H),6.76(d,J＝8.2Hz,1H),6.19(d,J ＝15.9Hz,1H),4.35(t,J＝5.2Hz,2H),3.97(t,J＝5.2Hz,2H),3.84(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ167.33,166.29,165.66,161.18,148.51,145.61, 145.56,133.10,132.28,125.35,125.33,121.45,117.74,115.73,114.96,114.80, 113.29,60.23,55.49,40.77.ESI-HRMS:Calculated forC₂₂H₁₉NO₇S[M-H]-: 440.0809,found 440.0799。产率87％。

实施例19：

用2,3-甲氧基苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例 1，得白色固体产物I-19.¹H NMR(400MHz,DMSO-d₆)δ9.56(s,1H),9.23(s,1H), 8.04(s,1H),7.45(d,J＝15.9Hz,1H),7.27–7.20(m,2H),7.09–7.03(m,2H),6.98 (dd,J＝8.1,1.9Hz,1H),6.76(d,J＝8.1Hz,1H),6.20(d,J＝15.9Hz,1H),4.36(t,J ＝5.2Hz,2H),3.97(t,J＝5.3Hz,2H),3.86(s,3H),3.78(s,3H).¹³C NMR(101 MHz,DMSO-d₆)δ167.44,166.29,165.59,152.72,148.52,148.17,145.64,145.56, 127.62,126.51,125.33,124.80,122.29,121.46,119.82,115.72,115.62,114.79, 113.27,61.09,60.20,55.89,40.82.ESI-HRMS:Calculated for C₂₂H₁₉NO₇S[M-H]-: 470.0915,found 470.0904。产率85％。

实施例20：

用3,4-甲氧基苯甲醛(130mg,1mmol)代替苯甲醛，其他操作同实施例 1，得白色固体产物I-20。¹H NMR(400MHz,DMSO-d₆)δ9.38(s,2H),7.90(s,1H), 7.45(d,J＝15.9Hz,1H),7.21(dd,J＝6.2,2.2Hz,2H),7.13(d,J＝9.0Hz,1H),7.03 (d,J＝2.1Hz,1H),6.98(dd,J＝8.2,2.0Hz,1H),6.76(d,J＝8.2Hz,1H),6.19(d,J ＝15.8Hz,1H),4.36(t,J＝5.2Hz,2H),3.97(t,J＝5.2Hz,2H).¹³C NMR(101MHz, DMSO-d₆)δ167.33,166.29,165.62,151.01,148.94,148.51,145.61,145.56,133.47, 125.53,125.32,123.85,121.44,117.89,115.72,114.81,113.45,113.28,112.11, 60.23,55.68,55.53,40.77.ESI-HRMS:Calculated for C₂₂H₁₉NO₇S[M-H]-:470.0915, found 470.0902。产率79％。

实施例21：

用3，4，5-三甲氧基苯甲醛(98mg,1mmol)代替苯甲醛，其他操作同实施例1，得黄色固体产物I-21。¹H NMR(400MHz,DMSO-d₆)δ9.37(s,2H),7.90 (s,1H),7.44(d,J＝15.9Hz,1H),7.03(d,J＝2.0Hz,1H),6.98(dd,J＝8.3,2.0Hz, 1H),6.95(s,2H),6.75(d,J＝8.1Hz,1H),6.18(d,J＝15.9Hz,1H),4.36(t,J＝5.3 Hz,2H),3.98(t,J＝5.2Hz,2H),3.83(s,6H),3.73(s,3H).¹³C NMR(101MHz, DMSO-d₆)δ167.22,166.30,165.51,153.20,148.53,145.63,145.56,139.58,133.33, 128.36,125.31,121.45,119.96,115.73,114.80,113.26,107.64,60.19,56.00,40.84, 21.05.ESI-HRMS:Calculated for C₂₄H₂₃NO₉S[M-H]-:500.1021,found 500.1009。产率76％。

实施例22：

用2，3，4-三甲氧基苯甲醛(121mg,1mmol)代替苯甲醛，其他操作同实施例1，得黄色固体产物I-22。¹H NMR(400MHz,DMSO-d₆)δ9.37(s,2H), 7.90(s,1H),7.44(d,J＝15.9Hz,1H),7.03(d,J＝2.0Hz,1H),6.98(dd,J＝8.3,2.0 Hz,1H),6.95(s,2H),6.75(d,J＝8.1Hz,1H),6.18(d,J＝15.9Hz,1H),4.36(t,J＝ 5.3Hz,2H),3.98(t,J＝5.2Hz,2H),3.83(s,6H),3.73(s,3H).¹³C NMR(101MHz, DMSO-d₆)δ167.22,166.30,165.51,153.20,148.53,145.63,145.56,139.58,133.33, 128.36,125.31,121.45,119.96,115.73,114.80,113.26,107.64,60.19,56.00,40.84, 21.05.ESI-HRMS:Calculated for C₂₄H₂₃NO₉S[M-H]-:500.1021,found 500.1009。产率74％。

实施例23：

用对乙基苯甲醛(98mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-23。¹H NMR(400MHz,DMSO-d₆)δ9.61(s,1H),9.18(s,1H), 7.92(s,1H),7.55(d,J＝8.0Hz,2H),7.45(d,J＝15.9Hz,1H),7.39(d,J＝8.0Hz, 2H),7.03(d,J＝2.1Hz,1H),6.98(dd,J＝8.2,2.0Hz,1H),6.75(d,J＝8.1Hz,1H), 6.19(d,J＝15.9Hz,1H),4.36(t,J＝5.2Hz,2H),3.97(t,J＝5.2Hz,2H),2.66(q,J ＝7.6Hz,2H),1.19(t,J＝7.6Hz,3H).¹³C NMR(101MHz,DMSO-d₆)δ167.31, 166.31,165.62,148.51,147.12,145.63,145.56,133.14,130.38,130.32,128.82, 125.32,121.47,119.87,115.72,114.78,113.27,60.23,40.83,28.09,15.15. ESI-HRMS:Calculated for C₂₃H₂₁NO₆S[M-H]-:438.1017,found 438.1007。产率70％。

实施例24：

用对N，N二甲基苯甲醛(100mg,1mmol)代替苯甲醛，其他操作同实施例1，得亮黄色固体产物I-24。¹H NMR(400MHz,DMSO-d₆₎δ9.60(s,1H),9.16 (s,1H),7.81(s,1H),7.50–7.42(m,3H),7.03(d,J＝2.0Hz,1H),6.98(dd,J＝8.2, 2.0Hz,1H),6.86–6.80(m,2H),6.76(d,J＝8.1Hz,1H),6.18(d,J＝15.9Hz,1H), 4.34(t,J＝5.2Hz,2H),3.96(t,J＝5.2Hz,2H),3.03(s,6H).¹³C NMR(101MHz, DMSO-d₆)δ167.51,166.27,165.74,151.62,148.49,145.58,145.55,134.17,132.37, 125.34,121.44,119.66,115.73,114.80,113.32,112.92,112.05,60.28,40.59. ESI-HRMS:Calculated for C₂₃H₂₂N₂O₆S[M-H]-:453.1126,found 453.1118。产率 89％。

实施例25：

用对异丙基苯甲醛(90mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-25。¹H NMR(400MHz,DMSO-d₆)δ9.48(s,1H),7.92(s,1H), 7.56(d,J＝8.2Hz,2H),7.48–7.40(m,3H),7.03(d,J＝2.0Hz,1H),6.98(dd,J＝8.2,2.0Hz,1H),6.76(d,J＝8.2Hz,1H),4.36(t,J＝5.2Hz,2H),3.97(t,J＝5.2Hz, 2H),1.23(s,3H),1.21(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ167.31,166.30, 165.61,151.60,148.52,145.63,145.56,133.11,130.53,130.35,127.38,125.32, 121.45,119.91,115.72,114.79,113.27,60.22,40.83,33.40,23.46.ESI-HRMS: Calculated for C₂₄H₂₃NO₆S[M-H]-:452.1173,found 452.1165。产率81％。

实施例26：

用异丙醛(125mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-26。1H NMR(400MHz,DMSO-d₆)δ9.51(s,1H),9.24(s,1H),7.43(d,J ＝15.8Hz,1H),7.02(d,J＝2.2Hz,1H),7.00–6.95(m,1H),6.76(d,J＝8.1Hz,1H), 6.17(dd,J＝15.9,2.2Hz,1H),4.29(d,J＝5.3Hz,2H),3.88(t,J＝5.3Hz,2H),2.38 (s,3H),1.98(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ166.40,166.22,163.98, 150.98,148.50,145.56,125.34,121.39,117.36,115.74,114.78,113.33,60.17,26.50, 21.63.ESI-HRMS:Calculated for C₁₇H₁₇NO₆S[M-H]-:362.0704,found 362.0698。产率83％。

实施例27：

用正丙醛(123mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-27。¹H NMR(400MHz,DMSO-d₆)δ9.62(s,1H),9.17(s,1H),7.43(d,J ＝15.9Hz,1H),7.10–7.01(m,2H),6.98(dd,J＝8.2,2.1Hz,1H),6.76(d,J＝8.2 Hz,1H),6.17(d,J＝15.9Hz,1H),4.30(d,J＝5.3Hz,2H),3.90(t,J＝5.3Hz,2H), 2.22(p,J＝7.6Hz,2H),1.07(t,J＝7.4Hz,3H).¹³C NMR(101MHz,DMSO-d₆)δ 167.09,166.22,164.34,148.49,145.58,145.54,140.08,125.30,123.69,121.41, 115.72,114.79,113.25,60.15,24.71,12.04.ESI-HRMS:Calculated for C₁₇H₁₇NO_eS[M-H]-:362.0704,found 362.0696。产率86％。

实施例28：

用正戊醛(120mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-28。¹H NMR(400MHz,DMSO-d₆)δ9.61(s,1H),9.16(s,1H),7.42(d,J ＝15.9Hz,¹H),7.04(dd,J＝15.6,5.0Hz,2H),6.97(dd,J＝8.2,2.1Hz,1H),6.76(d, J＝8.1Hz,1H),6.30–6.07(m,1H),4.32(t,J＝5.2Hz,2H),3.91(t,J＝5.1Hz,2H), 2.11(t,J＝7.3Hz,2H),1.86(hept,J＝6.8Hz,1H),0.90(d,J＝6.6Hz,6H).¹³C NMR(101MHz,DMSO-d₆)δ167.14,166.24,164.19,148.51,145.60,145.56,137.61, 125.31,125.19,121.42,115.73,114.79,113.25,60.11,27.56,22.11.ESI-HRMS: Calculated for C₁₉H₂₁NO₉S[M-H]-:390.1017,found 390.1009。产率82％。

实施例29：

用正己醛(110mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-29。¹H NMR(400MHz,DMSO-d₆)δ9.58(s,1H),9.18(s,1H),7.43(d,J ＝15.9Hz,1H),7.08–7.00(m,2H),6.97(d,J＝8.1Hz,1H),6.76(d,J＝8.0Hz,1H), 6.17(d,J＝15.9Hz,1H),4.30(d,J＝5.3Hz,2H),3.90(d,J＝5.4Hz,2H),2.21(q,J ＝7.4Hz,2H),1.49(p,J＝7.1Hz,2H),1.26(dd,J＝7.4,3.7Hz,4H),0.84(d,J＝7.1 Hz,3H).¹³C NMR(101MHz,DMSO-d₆)δ167.10,166.23,164.26,148.52,145.57, 138.86,125.31,124.38,121.40,115.73,114.78,113.24,60.13,40.56,31.17,30.72, 26.87,21.76,13.75.ESI-HRMS:Calculated forC₂₀H₂₃NO₆S[M-H]-:404.1173,found 404.1164。产率79％。

实施例30：

用正庚醛(100mg,1mmol)代替苯甲醛，其他操作同实施例1，得白色固体产物I-30。¹H NMR(400MHz,DMSO-d₆)δ9.61(s,1H),9.16(s,1H),7.42(d,J ＝15.8Hz,1H),7.04(dd,J＝13.4,4.9Hz,2H),6.99–6.94(m,1H),6.76(d,J＝8.2 Hz,1H),6.22–6.10(m,1H),4.30(d,J＝5.4Hz,2H),3.90(d,J＝5.4Hz,2H),2.21 (q,J＝7.5Hz,2H),1.47(q,J＝7.2Hz,2H),1.25(d,J＝8.7Hz,6H),0.84(d,J＝7.1 Hz,3H).¹³C NMR(101MHz,DMSO-d₆)δ167.09,166.22,164.26,148.52,145.57, 138.85,125.32,124.38,121.40,115.72,114.77,113.24,60.12,31.21,30.88,28.21, 27.16,21.92,13.85.ESI-HRMS:Calculated forC₂₁H₂₅NO₆S[M-H]-:418.1330,found 418.1321。产率70％。

实施例31：n＝2，R₁为苯基

(1)2,4-噻唑烷二酮(a)在甲醇为溶剂，哌啶为催化剂，回流条件下与苯甲醛发生插烯反应得到b。

(2)将中间体b溶解在DMF(N，N-二甲基甲酰胺)中，在碱性(KCO₃或 KOH)及相转移(四丁基溴化铵或四丁基氟化铵)条件下与溴丙醇进行取代反应，柱色谱纯化得到中间体c。

(3)以3，4-二羟基肉桂酸(d)为原料，丙酮为溶剂，与2，2-二甲氧基丙烷反应，得到化合物e。

(4)将(300mg,1mmol)中间体c溶解在二氯甲烷溶液中，再加入被保护的3， 4-二羟基肉桂酸e(265.03mg，1mmol)，分别加入催化剂DCC(372.47mg,1.5 mmol)、4-DMAP(13.12mg,0.1mmol)冰浴下搅拌6h，TLC板检测反应至原料消失。用二氯甲烷和饱和食盐水萃取三次，并合并水层反萃一次，合并酯层，无水硫酸镁干燥过夜，旋蒸浓缩后柱色谱纯化得中间体f白色固体200mg，产率 90％。¹H NMR(400MHz,CDCl₃)δ7.90(s,1H),7.55(d,J＝15.9Hz,1H),7.50– 7.39(m,5H),6.92–6.85(m,2H),6.62(d,J＝7.8Hz,1H),6.19(d,J＝15.9Hz,1H),4.26(t,J＝5.9Hz,2H),3.94(t,J＝6.8Hz,2H),2.12(p,J＝6.4Hz,2H),1.68(s,6H). ESI-HRMS:Calculated for C₂₅H₂₃NO₆S[M+H]+:466.1324,found 466.1320。

(5)将100mg中间体f溶解于二氯甲烷中，在冰浴条件下加入过量的三氟乙酸，并逐滴加质量比分含量10％HCl，保持冰浴反应4h，TLC板检测完全反应后，用二氯甲烷和饱和食盐水萃取三次，并合并水层反萃一次，合并酯层，无水硫酸镁干燥过夜，旋蒸浓缩后柱色谱纯化得化合物II-1白色固体50mg，产率85％。¹H NMR(400MHz,DMSO-d₆)δ9.33(d,J＝152.3Hz,2H),7.92(s,1H),7.59(d,J＝ 7.4Hz,2H),7.51(q,J＝7.0Hz,3H),7.43(d,J＝15.9Hz,1H),7.00(s,1H),6.87(d, J＝8.2Hz,1H),6.65(d,J＝8.1Hz,1H),6.18(d,J＝15.9Hz,1H),4.15(t,J＝6.0Hz, 2H),3.81(t,J＝6.6Hz,2H),2.00(p,J＝6.6Hz,2H).¹³C NMR(101MHz,DMSO-d₆) δ167.39,166.27,165.69,148.34,145.50,145.07,132.90,132.88,130.53,130.02,129.27,125.31,121.33,121.08,115.66,114.82,113.59,61.97,26.23.ESI-HRMS:Calculated for C₂₂H₁₉NO₆S[M-H]-:424.0860,found 424.0851。

实施例32：

用邻氯苯甲醛(115mg,0.25mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物I-2。¹H NMR(400MHz,DMSO-d₆)δ9.55(s,1H),9.10(s,1H), 8.02(s,1H),7.67–7.58(m,1H),7.57–7.33(m,4H),6.99(s,1H),6.88(d,J＝8.3 Hz,1H),6.66(d,J＝8.2Hz,1H),6.18(d,J＝15.9Hz,1H),4.15(t,J＝5.9Hz,2H), 3.81(t,J＝6.6Hz,2H),2.02(q,J＝6.3Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ 167.17,166.26,165.35,148.36,145.50,145.07,134.41,131.93,130.86,130.31, 128.85,128.02,127.84,125.29,125.06,121.11,115.64,114.77,113.55,62.06,26.12. ESI-HRMS:Calculated for C₂₂H₁₈ClNO₆S[M-H]-:458.0471,found 458.0460。产率 80％。

实施例33：

用间氯苯甲醛(120mg,1)代替苯甲醛，其他操作同实施例31，得白色固体产物II-3。¹H NMR(400MHz,DMSO-d₆)δ9.70–8.96(m,2H),7.91(s,1H), 7.65(d,J＝1.7Hz,1H),7.52(td,J＝5.2,3.4Hz,3H),7.42(d,J＝15.9Hz,1H),6.98 (d,J＝2.1Hz,1H),6.87(dd,J＝8.2,2.0Hz,1H),6.65(d,J＝8.1Hz,1H),6.17(d,J ＝15.9Hz,1H),4.15(t,J＝5.9Hz,2H),3.81(t,J＝6.5Hz,2H),2.00(p,J＝7.0,6.6 Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ167.04,166.24,165.49,148.36,145.49, 145.05,135.03,133.91,131.25,131.02,130.09,129.95,127.69,125.26,123.10, 121.05,115.62,114.78,113.54,62.03,26.15.ESI-HRMS:Calculated for C₂₂H₁₈ClNO₆S[M-H]-:458.0471,found 458.0459。产率79％。

实施例34：

用对氯苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-4。¹H NMR(400MHz,DMSO-d₆)δ9.54(d,J＝15.5Hz,1H), 9.11(s,1H),7.91(s,1H),7.61–7.55(m,3H),7.41(d,J＝15.8Hz,1H),7.03–6.94 (m,1H),6.87(dd,J＝8.2,2.1Hz,1H),6.66(d,J＝8.1Hz,1H),6.17(dd,J＝15.8, 1.8Hz,1H),4.14(t,J＝5.9Hz,2H),3.81(t,J＝6.5Hz,2H),2.00(p,J＝6.3Hz,2H). ¹³C NMR(101MHz,DMSO-d₆)δ167.13,166.25,165.59,148.37,145.49,145.05, 135.13,131.80,131.62,131.54,129.32,125.28,122.09,121.11,115.62,114.78, 113.56,62.01,26.17.ESI-HRMS:Calculated for C₂₂H₁₈ClNO₆S[M-H]-:458.0471, found 458.0467。产率80％。

实施例35：

用邻溴苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-5。¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝2.1Hz,1H),9.11 (d,J＝2.4Hz,1H),7.98(s,1H),7.78(d,J＝8.0Hz,1H),7.50(d,J＝6.6Hz,2H), 7.46–7.37(m,2H),7.00(s,1H),6.89(d,J＝8.2Hz,1H),6.67(d,J＝8.2Hz,1H), 6.18(d,J＝15.9Hz,1H),4.16(t,J＝5.9Hz,2H),3.81(t,J＝6.6Hz,2H),2.02(q,J ＝6.6Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ167.19,166.26,165.30,148.36, 145.51,145.07,133.56,132.59,132.04,130.54,128.97,128.51,125.30,125.25, 125.04,121.13,115.64,114.78,113.56,62.06,26.13.ESI-HRMS:Calculated for C₂₂H₁₈BrNO₆S[M-H]-:501.9965,found 501.9932。产率82％。

实施例36：

用间溴苯甲醛(120mg,0.25mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-6。¹H NMR(400MHz,DMSO-d₆)δ9.57(s,1H),9.12(s,1H), 7.90(s,1H),7.80(s,1H),7.66(d,J＝7.8Hz,1H),7.55(d,J＝7.9Hz,1H),7.49– 7.39(m,2H),6.99(d,J＝2.2Hz,1H),6.87(d,J＝8.2Hz,1H),6.67(dd,J＝8.0,1.6 Hz,1H),6.17(d,J＝15.8Hz,1H),4.15(t,J＝5.9Hz,2H),3.81(t,J＝6.5Hz,2H), 2.00(p,J＝6.3Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ167.04,166.25,165.47, 148.37,145.51,145.07,135.30,132.97,132.86,131.25,131.19,128.02,125.25, 123.07,122.42,121.05,115.67,114.82,113.52,62.00,26.16.ESI-HRMS:Calculated for C₂₂H₁₈BrNO₆S[M-H]-:501.9965,found 501.9930。产率74％。

实施例37：

用对溴苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-7。¹H NMR(400MHz,DMSO-d₆)δ9.56(s,1H),9.12(s,1H), 7.89(s,1H),7.70(d,J＝8.1Hz,2H),7.52(d,J＝8.2Hz,2H),7.42(d,J＝15.9Hz, 1H),6.99(d,J＝2.1Hz,1H),6.88(d,J＝8.2Hz,1H),6.67(d,J＝8.1Hz,1H),6.17 (d,J＝15.9Hz,1H),4.14(t,J＝6.0Hz,2H),3.80(t,J＝6.6Hz,2H),2.00(p,J＝6.2 Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ167.13,166.26,165.59,148.38,145.50, 145.05,132.25,132.12,131.76,131.63,125.29,124.06,122.19,121.12,115.64, 114.77,113.57,61.98,26.18.ESI-HRMS:Calculated forC₂₂H₁₈BrNO₆S[M-H]-: 501.9965,found 501.9931。产率71％。

实施例38：

用邻氟苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-8。¹H NMR(400MHz,DMSO-d₆)δ9.54(s,1H),9.10(s,1H), 7.89(s,1H),7.53(dt,J＝21.4,7.5Hz,2H),7.45–7.31(m,3H),6.98(d,J＝2.3Hz, 1H),6.88(dd,J＝8.4,2.1Hz,1H),6.65(d,J＝8.2Hz,1H),6.17(d,J＝15.9Hz,1H), 4.15(t,J＝5.9Hz,2H),3.81(t,J＝6.6Hz,2H),2.01(q,J＝6.4Hz,2H).¹³C NMR (101MHz,DMSO-d₆)δ167.11,166.25,165.43,161.69,159.18,148.34,145.49, 145.06,132.88,132.79,128.85,125.34,125.30,125.29,124.10,123.92,123.85, 121.07,116.29,116.08,115.63,114.76,113.55,62.04,26.13.ESI-HRMS:Calculated for C₂₂H₁₈FNO₆S[M-H]-:442.0766,found 442.0755。产率79％。

实施例39：

用间氟苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-9。¹H NMR(400MHz,DMSO-d₆)δ9.32(s,2H),7.89(s,1H), 7.53(ddt,J＝14.2,8.5,4.3Hz,2H),7.42(d,J＝15.9Hz,1H),7.38–7.32(m,2H), 6.98(d,J＝2.1Hz,1H),6.88(dd,J＝8.2,2.1Hz,1H),6.65(d,J＝8.1Hz,1H),6.17 (d,J＝15.9Hz,1H),4.15(t,J＝5.9Hz,2H),3.81(t,J＝6.5Hz,2H),2.00(q,J＝6.4 Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ167.14,166.28,165.45,161.68,159.18, 148.33,145.47,145.06,132.80,128.83,125.26,124.06,123.86,121.11,116.27, 116.06,115.61,114.67,113.52,62.10,26.09.ESI-HRMS:Calculated for C₂₂H₁₈FNO₆S[M-H]-:442.0766,found 442.0755。产率71％。

实施例40：

用对氟苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-10。¹H NMR(400MHz,DMSO-d₆)δ9.55(s,1H),9.10(s,1H), 7.92(s,1H),7.68–7.62(m,2H),7.41(d,J＝15.9Hz,1H),7.34(t,J＝8.8Hz,2H), 6.98(d,J＝2.1Hz,1H),6.86(dd,J＝8.2,2.0Hz,1H),6.65(d,J＝8.1Hz,1H),6.16 (d,J＝15.9Hz,1H),4.15(t,J＝5.9Hz,2H),3.81(t,J＝6.5Hz,2H),2.51(p,J＝1.8 Hz,2H),2.00(p,J＝6.2Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ167.27,166.24, 165.65,148.35,145.48,145.04,132.54,132.45,131.82,129.56,125.27,121.09, 120.99,116.53,116.31,115.59,114.77,113.54,62.08,26.15.ESI-HRMS:Calculated for C₂₂H₁₈FNO₆S[M-H]-:442.0766,found 442.0755。产率76％。

实施例41：

用邻甲基苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-11。¹H NMR(400MHz,DMSO-d₆)δ9.32(s,2H),7.89(s,1H), 7.53(dt,J＝21.2,7.4Hz,2H),7.45–7.28(m,3H),6.98(d,J＝1.8Hz,1H),6.88(dd, J＝8.2,1.8Hz,1H),6.65(d,J＝8.1Hz,1H),6.17(d,J＝15.9Hz,1H),4.15(t,J＝ 5.8Hz,2H),3.81(t,J＝6.5Hz,2H),2.08–1.95(m,2H).¹³C NMR(101MHz, DMSO-d₆)δ167.66,166.27,165.44,148.40,145.53,145.09,138.63,132.03,130.91, 130.78,130.36,127.11,126.55,125.29,123.02,121.12,115.66,114.78,113.54, 62.05,26.21,19.31.ESI-HRMS:Calculated for C₂₃H₂₁NO₆S[M-H]-:438.1017,found 438.1005。产率74％。

实施例42：

用间甲基苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-12。¹H NMR(400MHz,DMSO-d₆)δ9.56(s,1H),9.11(s,1H), 7.86(s,1H),7.39(dd,J＝20.2,13.0Hz,4H),7.29(d,J＝7.0Hz,1H),6.99(d,J＝2.4 Hz,1H),6.86(d,J＝8.2Hz,1H),6.65(dd,J＝8.3,2.6Hz,1H),6.17(d,J＝15.9Hz, 1H),4.15(t,J＝5.9Hz,2H),3.80(t,J＝6.6Hz,2H),2.34(s,3H),2.00(p,J＝6.4Hz, 2H).¹³C NMR(101MHz,DMSO-d₆)δ167.43,166.25,165.69,148.34,145.49, 145.06,138.65,133.00,132.87,131.29,130.58,129.15,127.07,125.28,121.09, 121.06,115.64,114.81,113.55,62.05,26.18,20.86.ESI-HRMS:Calculated for C₂₃H₂₁NO₆S[M-H]-:438.1017,found 438.1006。产率69％。

实施例43：

用对甲基苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-13。¹H NMR(400MHz,DMSO-d₆)δ9.32(s,2H),7.89(s,1H), 7.53(dt,J＝21.2,7.4Hz,2H),7.45–7.28(m,3H),6.98(d,J＝1.8Hz,1H),6.88(dd, J＝8.2,1.8Hz,1H),6.65(d,J＝8.1Hz,1H),6.17(d,J＝15.9Hz,1H),4.15(t,J＝ 5.8Hz,2H),3.81(t,J＝6.5Hz,2H),2.08–1.95(m,2H).¹³C NMR(101MHz, DMSO-d₆)δ167.45,166.30,165.77,148.34,145.47,145.06,140.92,133.01,130.09, 129.90,125.27,121.12,120.00,115.61,114.71,113.54,62.04,26.18,21.08. ESI-HRMS:Calculated for C₂₃H₂₁NO₆S[M-H]-:438.1017,found 438.1008。产率 85％。

实施例44：

用2，4-二氟苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例 31，得白色固体产物II-14。¹H NMR(400MHz,DMSO-d₆)δ9.54(s,1H),9.07(s, 1H),7.81(s,1H),7.53(td,J＝8.7,6.2Hz,1H),7.47–7.32(m,2H),7.28–7.17(m, 1H),6.95(d,J＝2.1Hz,1H),6.86(dd,J＝8.2,2.1Hz,1H),6.65(d,J＝8.1Hz,1H), 6.15(d,J＝15.9Hz,1H),4.15(t,J＝5.8Hz,2H),3.81(t,J＝6.4Hz,2H),2.01(p,J ＝6.2Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ167.00,166.22,165.40,148.35, 145.46,145.02,130.50,125.24,123.77,123.13,121.07,115.55,114.70,113.50, 112.90,104.99,62.18,26.03.ESI-HRMS:Calculated forC₂₂H₁₇F₂NO₆S[M-H]-: 460.0672,found 460.0663。产率88％。

实施例45：

用2，6-二氟苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例 31，得白色固体产物II-15。¹H NMR(400MHz,DMSO-d₆)δ9.32(s,2H),7.77(s, 1H),7.60(tt,J＝8.6,6.6Hz,1H),7.43(d,J＝15.8Hz,1H),7.23(t,J＝8.6Hz,2H), 6.99(d,J＝2.1Hz,1H),6.91(dd,J＝8.3,2.1Hz,1H),6.69(d,J＝8.1Hz,1H),6.18 (d,J＝15.9Hz,1H),4.15(t,J＝5.9Hz,2H),3.79(t,J＝6.5Hz,2H),2.00(p,J＝6.3 Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ166.94,166.29,165.07,160.65,158.07, 148.35,145.48,145.12,133.24,128.27,125.31,121.09,120.33,115.61,114.76, 113.50,112.44,112.19,110.29,61.98,26.16.ESI-HRMS:Calculated for C₂₂H₁₇F₂NO₆S[M-H]-:460.0672,found 460.0660。产率76％。

实施例46：

用邻甲氧基苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例 31，得白色固体产物II-16。¹H NMR(400MHz,DMSO-d₆)δ9.33(d,J＝152.3Hz, 2H),7.92(s,1H),7.59(d,J＝7.4Hz,2H),7.51(q,J＝7.0Hz,3H),7.43(d,J＝15.9 Hz,1H),7.00(s,1H),6.87(d,J＝8.2Hz,1H),6.65(d,J＝8.1Hz,1H),6.18(d,J＝ 15.9Hz,1H),4.15(t,J＝6.0Hz,2H),3.81(t,J＝6.6Hz,2H),2.00(p,J＝6.6Hz, 2H).¹³C NMR(101MHz,DMSO-d₆)δ167.63,166.28,165.80,157.97,148.34, 145.49,145.08,132.58,128.78,127.77,125.32,121.31,121.26,121.07,120.91, 115.64,114.81,113.57,111.85,61.99,55.71,26.24.ESI-HRMS:Calculated for C₂₃H₂₁NO₇S[M-H]-:454.0966,found 454.0955.产率72％.

实施例47：

用间甲氧基苯甲醛(127mg，1mmol)代替苯甲醛，其他操作同实施例 31，得白色固体产物II-17。¹H NMR(400MHz,DMSO-d₆)δ9.32(d,J＝116.6Hz, 2H),7.90(s,1H),7.48–7.39(m,2H),7.18–7.12(m,2H),7.09–7.03(m,1H),6.99 (d,J＝2.1Hz,1H),6.87(dd,J＝8.1,1.9Hz,1H),6.65(d,J＝8.1Hz,1H),6.18(d,J ＝15.9Hz,1H),4.15(t,J＝5.9Hz,2H),3.80(d,J＝5.5Hz,5H),2.00(p,J＝6.2Hz, 2H).¹³C NMR(101MHz,DMSO-d₆)δ167.34,166.28,165.65,159.58,148.35, 145.49,145.09,134.25,132.85,130.37,125.29,121.87,121.64,121.06,116.47, 115.63,115.34,114.83,113.56,61.96,55.23,26.21.ESI-HRMS:Calculated for C₂₃H₂₁NO₇S[M-H]-:454.0966,found 454.0954。产率70％。

实施例48：

用对甲氧基苯甲醛(110mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-18。¹H NMR(400MHz,DMSO-d₆)δ9.33(s,2H),7.87(s,1H), 7.55(d,J＝8.8Hz,2H),7.42(d,J＝15.9Hz,1H),7.07(d,J＝8.7Hz,2H),6.99(d,J ＝2.1Hz,1H),6.86(dd,J＝8.2,2.0Hz,1H),6.65(d,J＝8.1Hz,1H),6.17(d,J＝ 15.9Hz,1H),4.14(t,J＝5.9Hz,2H),3.82(d,J＝13.2Hz,5H),1.99(p,J＝6.2Hz, 2H).¹³C NMR(101MHz,DMSO-d₆)δ167.46,166.27,165.81,161.08,148.34, 145.49,145.06,132.95,132.16,125.35,125.29,121.10,117.97,115.62,114.86, 114.79,113.56,62.02,55.46,26.23.ESI-HRMS:Calculated forC₂₃H₂₁NO₇S[M-H]-: 454.0966,found 454.0955。产率68％。

实施例49：

用2，3-二甲氧基苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-19。¹H NMR(400MHz,DMSO-d₆)δ9.53(s,1H),9.14 (s,1H),8.02(s,1H),7.46–7.40(m,1H),7.28–7.12(m,1H),7.06–6.96(m,2H), 6.87(dd,J＝8.1,2.0Hz,1H),6.77–6.61(m,1H),6.17(d,J＝15.9Hz,1H),4.15(t, J＝6.0Hz,2H),3.85(s,2H),3.76(s,2H),2.00(p,J＝6.3Hz,1H).¹³C NMR(101 MHz,DMSO-d₆)δ167.56,166.27,165.74,152.67,148.34,148.13,145.49,145.08, 127.40,126.53,125.65,125.29,124.72,122.45,121.06,119.74,115.63,114.82, 113.54,62.01,61.03,55.88,26.21.ESI-HRMS:Calculated for C₂₄H₂₃NO₈S[M-H]-: 484.1072,found 484.1060。产率77％。

实施例50：

用3，4-二甲氧基苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-20。¹H NMR(400MHz,DMSO-d₆)δ9.35(s,2H),7.87 (s,1H),7.42(d,J＝15.9Hz,1H),7.16(dd,J＝6.2,2.2Hz,2H),7.09(d,J＝9.0Hz, 1H),6.99(d,J＝2.1Hz,1H),6.87(dd,J＝8.2,2.1Hz,1H),6.66(d,J＝8.1Hz,1H), 6.17(d,J＝15.9Hz,1H),4.14(t,J＝5.9Hz,2H),3.87–3.74(m,8H),2.00(p,J＝ 6.3Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ167.45,166.27,165.76,150.93, 148.89,148.35,145.50,145.07,133.32,125.54,125.29,123.79,121.07,118.10, 115.62,114.83,113.55,113.35,112.03,62.01,55.65,55.47,26.23.ESI-HRMS: Calculated for C₂₄H₂₃NO₈S[M-H]-:484.1072,found 484.1061。产率80％。

实施例51：

用3，4，5-三甲氧基苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例31，得黄色固体产物II-21。¹H NMR(400MHz,DMSO-d₆)δ9.25(s,2H), 7.87(s,1H),7.41(d,J＝15.9Hz,1H),6.98(d,J＝2.1Hz,1H),6.92–6.84(m,3H), 6.65(d,J＝8.1Hz,1H),6.17(d,J＝15.9Hz,1H),4.15(t,J＝5.8Hz,2H),3.80(s, 8H),3.73(s,3H),2.00(p,J＝6.1Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ167.34, 166.25,165.66,153.14,148.33,145.48,145.06,139.52,133.17,128.37,125.28, 121.04,120.13,115.57,114.83,113.55,107.59,62.06,60.19,55.94,26.17. ESI-HRMS:Calculated for C₂₅H₂₅NO₉S[M-H]-:514.1177,found514.1166。产率 87％。

实施例52：

用2，3，4-三甲氧基苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例31，得黄色固体产物II-22。¹H NMR(400MHz,DMSO-d₆)δ9.32(s,2H), 7.89(s,1H),7.53(dt,J＝21.2,7.4Hz,2H),7.45–7.28(m,3H),6.98(d,J＝1.8Hz, 1H),6.88(dd,J＝8.2,1.8Hz,1H),6.65(d,J＝8.1Hz,1H),6.17(d,J＝15.9Hz,1H), 4.15(t,J＝5.8Hz,2H),3.81(t,J＝6.5Hz,2H),2.08–1.95(m,2H).¹³C NMR(101 MHz,DMSO-d₆)δ167.66,166.27,165.89,155.99,152.94,148.31,145.46,145.02, 141.69,127.45,125.25,124.12,121.13,119.20,119.15,115.56,114.67,113.50, 108.51,62.20,61.66,60.45,56.07,26.13.ESI-HRMS:Calculated for C₂₅H₂₅NO₉S[M-H]-:514.1177,found 514.1165。产率89％。

实施例53：

用对乙基苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-23。¹H NMR(400MHz,DMSO-d₆)δ9.54(s,1H),9.12(s,1H), 7.89(s,1H),7.50(d,J＝8.0Hz,2H),7.43(d,J＝15.9Hz,1H),7.35(d,J＝8.0Hz, 2H),6.99(d,J＝2.1Hz,1H),6.87(dd,J＝8.2,2.0Hz,1H),6.65(d,J＝8.1Hz,1H), 6.18(d,J＝15.9Hz,1H),4.14(t,J＝5.9Hz,2H),3.80(t,J＝6.5Hz,2H),2.66(q,J ＝7.6Hz,2H),2.00(p,J＝6.3Hz,2H),1.20(t,J＝7.6Hz,3H).¹³C NMR(101MHz, DMSO-d₆)δ167.43,166.31,165.75,148.35,146.96,145.49,145.07,132.98,130.39, 130.20,128.72,125.30,121.09,120.10,115.64,114.80,113.56,61.96,28.08,26.24, 15.10.ESI-HRMS:Calculated for C₂₄H₂₃NO₆S[M-H]-:452.1173,found 452.1163。产率68％。

实施例54：

用对N,N二甲基苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例31，得黄色固体产物II-24。¹H NMR(400MHz,DMSO-d₆)δ9.52(s,1H),9.15 (s,1H),7.78(s,1H),7.46–7.38(m,3H),7.00(d,J＝2.0Hz,1H),6.88(dd,J＝8.2, 1.9Hz,1H),6.79(d,J＝8.8Hz,2H),6.66(d,J＝8.1Hz,1H),6.18(d,J＝15.9Hz, 1H),4.13(t,J＝5.9Hz,2H),3.78(t,J＝6.6Hz,2H),3.02(s,6H),1.98(p,J＝6.4Hz, 2H).¹³C NMR(101MHz,DMSO-d₆)δ167.63,166.30,165.89,151.55,148.31, 145.49,145.07,134.04,132.26,125.33,121.11,119.70,115.66,114.82,113.60, 113.19,112.00,61.92,26.36.ESI-HRMS:Calculatedfor C₂₄H₂₆N₂O₆S[M-H]-: 453.1490,found 453.1493。产率76％。

实施例55：

用对异丙基苯甲醛(120mg,1mmol)代替苯甲醛，其他操作同实施例 31，得白色固体产物II-25。¹H NMR(400MHz,DMSO-d₆)δ9.34(s,2H),7.89(s, 1H),7.51(d,J＝8.3Hz,2H),7.45–7.39(m,2H),7.38(d,J＝1.9Hz,1H),7.00(d,J ＝2.0Hz,1H),6.87(dd,J＝8.2,2.0Hz,1H),6.65(d,J＝8.1Hz,1H),6.18(d,J＝ 15.9Hz,1H),4.14(t,J＝5.9Hz,2H),3.80(t,J＝6.5Hz,2H),1.99(p,J＝6.3Hz, 2H),1.23(s,3H),1.21(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ167.44,166.28, 165.76,151.46,148.37,145.50,145.08,132.95,130.54,130.25,127.30,125.28, 121.10,120.14,115.67,114.83,113.56,61.95,33.38,26.24,23.46.ESI-HRMS: Calculated for C₂₅H₂₅NO₉S[M-H]-:466.1330,found 466.1319。产率82％。

实施例56：

用异丙醛(113mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-26。¹H NMR(400MHz,DMSO-d₆)δ9.57(s,1H),9.18(s,1H),7.40(d,J＝ 15.9Hz,1H),7.00(s,1H),6.96(d,J＝8.3Hz,1H),6.77(d,J＝8.1Hz,1H),6.15(d, J＝15.9Hz,1H),4.11(s,2H),3.71(t,J＝6.6Hz,2H),2.33(s,3H),1.86(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ166.45,166.18,164.10,150.50,148.39,145.54,144.88, 125.37,121.23,117.58,115.71,114.64,113.58,62.23,26.38,26.12,21.55. ESI-HRMS:Calculated for C₁₈H₁₉ClNO₆S[M-H]-:376.0860,found 376.0853。产率 58％。

实施例57：

用正丙醛(123mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-27。¹H NMR(400MHz,DMSO-d₆)δ9.61(d,J＝7.6Hz,1H),9.16(s, 1H),7.42(dd,J＝15.9,4.6Hz,1H),7.01(dd,J＝4.8,2.7Hz,2H),6.98–6.94(m, 1H),6.76(d,J＝8.2Hz,1H),6.17(d,J＝15.9Hz,1H),4.11(t,J＝6.0Hz,2H),3.73 (t,J＝6.6Hz,2H),2.15(p,J＝7.5Hz,2H),1.95(p,J＝6.5Hz,2H),1.01(t,J＝7.6 Hz,3H).¹³C NMR(101MHz,DMSO-d₆)δ167.18,166.22,164.48,148.38,145.54, 145.01,139.77,125.36,123.88,121.24,115.69,114.68,113.56,62.04,26.14,24.65, 11.98.ESI-HRMS:Calculated for C₁₈H₁₉NO₆S[M-H]-:376.0860,found 376.0851。产率55％。

实施例58：

用正丁醛(123mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-28。¹H NMR(400MHz,DMSO-d₆)δ9.48(s,1H),9.15(s,1H),δ 7.50(d,J＝16.0Hz,1H),7.26(s,1H),7.11(d,J＝8.1Hz,1H),7.01(t,J＝7.6Hz, 1H),6.87(d,J＝8.0Hz,1H),6.37(d,J＝15.9Hz,1H),4.13(t,J＝5.9Hz,2H),3.74 (t,J＝6.5Hz,2H),2.11(q,J＝7.5Hz,2H),1.96(t,J＝6.2Hz,2H),1.45(q,J＝7.5 Hz,2H),0.86(t,J＝7.4Hz,3H).¹³C NMR(101MHz,DMSO-d₆)δ167.19,166.19, 164.39,149.01,147.59,144.50,138.24,127.91,124.59,118.89,115.12,108.29, 106.37,62.19,33.15,26.16,25.48,20.68,13.55.ESI-HRMS:Calculatedfor C₁₉H₂₁NO₆S[M-H]-:390.1017,found 390.1009。产率64％。

实施例59：

用正戊醛(123mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-29。¹H NMR(400MHz,DMSO-d₆)δ9.58(s,1H),9.14(s,1H),7.42(d,J ＝15.9Hz,1H),7.00(d,J＝8.0Hz,2H),6.96(d,J＝8.3Hz,1H),6.76(d,J＝8.1Hz, 1H),6.16(d,J＝15.9Hz,1H),4.12(t,J＝5.9Hz,2H),3.74(t,J＝6.6Hz,2H),2.03 (t,J＝7.3Hz,2H),1.96(p,J＝6.4Hz,2H),1.79(dt,J＝13.5,6.8Hz,1H),0.86(d,J ＝6.6Hz,6H).¹³C NMR(101MHz,DMSO-d₆)δ167.22,166.24,164.33,148.41, 145.56,145.04,137.30,125.38,125.34,121.26,115.69,114.70,113.56,62.08,27.50, 26.15,22.10.ESI-HRMS:Calculated forC₂₀H₂₃NO₆S[M-H]-:404.1173,found 404.1164。产率75％。

实施例60：

用正己醛(123mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-30。¹H NMR(400MHz,DMSO-d₆)δ9.58(s,1H),9.16(s,1H),7.41(d, J＝15.9Hz,1H),7.10–6.88(m,3H),6.76(d,J＝8.1Hz,1H),6.16(d,J＝15.9Hz, 1H),4.11(t,J＝5.9Hz,2H),3.73(t,J＝6.6Hz,2H),2.12(q,J＝7.5Hz,2H),1.95(h, J＝5.3,4.4Hz,2H),1.41(p,J＝7.0Hz,2H),1.27–1.17(m,4H),0.88–0.78(m, 3H).¹³C NMR(101MHz,DMSO-d₆)δ167.20,166.22,164.42,148.43,145.57, 145.01,138.57,125.36,124.49,121.23,115.69,114.68,113.55,62.12,31.15,30.75, 26.87,26.11,21.72,13.75.ESI-HRMS:Calculated forC₂₁H₂₅NO₆S[M-H]-:418.1330, found 418.1322。产率66％。

实施例61：

用正庚醛(123mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-31。¹H NMR(400MHz,DMSO-d₆)δ9.58(s,1H),9.15(s,1H),7.41 (d,J＝15.9Hz,1H),7.06–6.98(m,2H),6.96(d,J＝9.4Hz,1H),6.76(d,J＝8.1Hz, 1H),6.16(d,J＝15.9Hz,1H),4.11(t,J＝5.9Hz,2H),3.74(t,J＝6.7Hz,2H),2.12 (q,J＝7.5Hz,2H),1.95(p,J＝6.4Hz,2H),1.40(p,J＝7.2Hz,2H),1.22–1.17(m, 3H),0.84(t,J＝6.8Hz,3H).¹³C NMR(101MHz,DMSO-d₆)δ167.19,166.22, 164.42,148.43,145.56,145.01,138.56,125.36,124.49,121.23,115.68,114.66, 113.54,62.11,31.20,30.85,28.27,27.17,26.11,21.91,13.87.ESI-HRMS: Calculated for C₂₂H₂₇NO₆S[M-H]-:432.1486,found 432,1476。产率72％。

实施例62：

用正辛醛(123mg,1mmol)代替苯甲醛，其他操作同实施例31，得白色固体产物II-32。¹H NMR(400MHz,DMSO-d₆)δ9.59(s,1H),9.16(s,1H),7.41 (d,J＝15.9Hz,1H),7.03–6.98(m,2H),6.96(d,J＝9.0Hz,1H),6.76(d,J＝8.2Hz, 1H),6.16(d,J＝15.9Hz,1H),4.11(t,J＝5.9Hz,2H),3.74(t,J＝6.5Hz,2H),2.12 (q,J＝7.5Hz,2H),1.95(p,J＝6.3Hz,2H),1.40(t,J＝7.3Hz,2H),1.22(d,J＝10.4 Hz,8H),0.84(t,J＝6.8Hz,3H).¹³C NMR(101MHz,DMSO-d₆)δ167.18,166.21, 164.39,148.41,145.54,145.00,138.56,125.33,124.47,121.22,115.66,114.65, 113.51,62.09,31.19,31.08,28.55,28.30,27.20,26.11,22.00,13.90.ESI-HRMS: Calculated for C₂₂H₂₇NO₆S[M-H]-:432.1486,found 432.1467。产率78％。

实施例63：本发明合成的3，4-二羟基肉桂酸衍生物对人胃癌细胞 MGC-803，食管癌细胞Eca-109、TE-1，***细胞Hela的抗肿瘤活性。

实验方法

所合成的化合物对以上四种癌细胞的体外抗增殖活性：将对数生长期细胞用胰酶消化，计数板计数，3000个细胞/孔，接种于96孔板中，每孔加100μl培养液，在37℃、体积百分比5％CO₂湿度培养箱中培养24h。每个化合物设6个浓度梯度，每个浓度设三个平行孔，每孔加200ul不同化合物浓度的培养液，空白对照组、阳性对照组(5-氟)各加等量培养液，之后放置37℃、体积百分比5％CO₂湿度培养箱孵育72h。弃掉培养液，每孔加入20ul MTT(用PBS缓冲液按5mg/ml 新鲜配制)溶液，置37℃、体积百分比5％CO₂湿度培养箱温育4h，使MTT还原为蓝紫色甲瓒，再次弃掉上清液，每孔加150μl DMSO(二甲基亚枫)，用平板摇床摇10min，使用酶标仪测定光密度OD值(检测波长570nm)，按下述公式计算化合物对细胞的抑制率，并按中效方程计算半数抑制浓度IC₅₀：

抑制率(％)＝(对照组OD均值-给药组OD均值)/对照组OD均值*100％

3，4-二羟基肉桂酸酯类衍生物的体外抗肿瘤活性评价

CA为先导化合物3，4-二羟基肉桂酸；5-FU为阳性对照

上述实验结果表明本发明所述化合物具有较好的体外抗肿瘤活性，可用于制备抗肿瘤药物，应用于临床治疗胃癌、食道癌、***、胰腺癌、乳腺癌等。设计的该类化合物具有良好的溶解性，以本发明化合物作为活性成分用于制备新的抗癌药物，具有潜在的应用价值。

实施例64：本发明合成的3，4-二羟基肉桂酸衍生物具有抗氧化活性。

实验方法

对所合成的化合物进行抗氧化测定，采用的方法是DPPH自由基清除法。首先用DMSO配置0.1mmol/L的DPPH溶液，避光保存；将测试样品用DMSO 溶解，再将2mL测试样品溶液及2mLDPPH溶液加入到同一试管中，摇匀，室温下暗处静置30min后，测定其吸光度A sample，同时测定2mL DPPH溶液与 2mL溶剂混合后的吸光度A0。自由基清除能力的表示：DPPH清除百分率＝ (A0-A sample)/A0*100。A0为未加样品时的DPPH在517nm处的吸光度；A sample为加入样品的DPPH在520nm处的吸光度。DPPH清除百分率越大，则表明化合物清除率越强。

所有化合物的DPPH自由基清除能力统计表

从上表结果中可以看出：在相同浓度下，与CA相比，部分化合物的DPPH 清除效果优于或相当于CA，表明该类化合物具有抗氧化作用。

稳定性实验评价

根据《中国药典》2015版稳定性评价实验原则，对本系列咖啡酸衍生物中活性最好的化合物I-29进行稳定性试验评价。稳定性试验包括影响因素试验，加速试验，长期试验。影响因素试验用一批原料药进行；加速试验与长期试验要求用三批供试品进行。实验名称，条件，仪器及结果如下表所示。

I-29稳定性评价实验(加速实验与长期实验)

I-29稳定性评价实验(影响因素实验)