CN111675673B - 3，4-二羟基肉桂酸酯类衍生物及其制备方法和应用 - Google Patents

3，4-二羟基肉桂酸酯类衍生物及其制备方法和应用 Download PDF

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CN111675673B
CN111675673B CN202010572578.XA CN202010572578A CN111675673B CN 111675673 B CN111675673 B CN 111675673B CN 202010572578 A CN202010572578 A CN 202010572578A CN 111675673 B CN111675673 B CN 111675673B
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可钰
杨瑞华
王妮
刘宏民
徐霞
姬小明
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Abstract

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：

Description

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：
Figure BDA0002549948940000011
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：
Figure BDA0002549948940000021
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：
Figure BDA0002549948940000022
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)。
Figure BDA0002549948940000023
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
Figure BDA0002549948940000031
(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＝15.9 Hz,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：
Figure BDA0002549948940000041
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：
Figure BDA0002549948940000042
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：
Figure BDA0002549948940000043
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：
Figure BDA0002549948940000051
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：
Figure BDA0002549948940000052
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：
Figure BDA0002549948940000053
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：
Figure BDA0002549948940000061
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：
Figure BDA0002549948940000062
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：
Figure BDA0002549948940000071
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：
Figure BDA0002549948940000072
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：
Figure BDA0002549948940000073
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：
Figure BDA0002549948940000081
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：
Figure BDA0002549948940000082
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：
Figure BDA0002549948940000083
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：
Figure BDA0002549948940000091
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：
Figure BDA0002549948940000092
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：
Figure BDA0002549948940000101
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：
Figure BDA0002549948940000102
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：
Figure BDA0002549948940000103
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：
Figure BDA0002549948940000111
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：
Figure BDA0002549948940000112
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：
Figure BDA0002549948940000121
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：
Figure BDA0002549948940000122
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：
Figure BDA0002549948940000123
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：
Figure BDA0002549948940000131
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：
Figure BDA0002549948940000132
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 C17H17NOeS[M-H]-:362.0704,found 362.0696。产率86％。
实施例28：
Figure BDA0002549948940000133
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：
Figure BDA0002549948940000141
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：
Figure BDA0002549948940000142
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
Figure BDA0002549948940000143
Figure BDA0002549948940000151
(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).13CNMR(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：
Figure BDA0002549948940000152
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：
Figure BDA0002549948940000161
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：
Figure BDA0002549948940000162
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：
Figure BDA0002549948940000163
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：
Figure BDA0002549948940000171
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：
Figure BDA0002549948940000172
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：
Figure BDA0002549948940000173
Figure BDA0002549948940000181
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：
Figure BDA0002549948940000182
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：
Figure BDA0002549948940000183
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：
Figure BDA0002549948940000191
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：
Figure BDA0002549948940000192
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：
Figure BDA0002549948940000193
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：
Figure BDA0002549948940000201
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：
Figure BDA0002549948940000202
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：
Figure BDA0002549948940000203
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：
Figure BDA0002549948940000211
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：
Figure BDA0002549948940000212
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：
Figure BDA0002549948940000221
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：
Figure BDA0002549948940000222
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：
Figure BDA0002549948940000223
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：
Figure BDA0002549948940000231
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：
Figure BDA0002549948940000232
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：
Figure BDA0002549948940000233
Figure BDA0002549948940000241
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：
Figure BDA0002549948940000242
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：
Figure BDA0002549948940000243
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：
Figure BDA0002549948940000251
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：
Figure BDA0002549948940000252
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：
Figure BDA0002549948940000253
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：
Figure BDA0002549948940000261
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：
Figure BDA0002549948940000262
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：
Figure BDA0002549948940000263
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，宫颈癌细胞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
Figure BDA0002549948940000271
Figure BDA0002549948940000281
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、宫颈癌、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2mL DPPH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Asample，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；Asample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
Figure BDA0002549948940000291
Figure BDA0002549948940000301
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)
Figure BDA0002549948940000302
I-29稳定性评价实验(影响因素实验)
Figure BDA0002549948940000303

Claims (5)

1.3，4-二羟基肉桂酸酯类衍生物，其特征在于，具有通式Ⅰ所示结构：
Figure FDA0003644244960000011
n为1-2；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、甲氧基单取代或多取代的苯基或被N,N-二甲基氨基单取代的苯基。
2.如权利要求1所述的3，4-二羟基肉桂酸酯类衍生物，其特征在于，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、甲氧基单取代或双取代的苯基或被N,N-二甲基氨基单取代的苯基。
3.如权利要求2所述的3，4-二羟基肉桂酸酯类衍生物，其特征在于，n为1-2；R为如下基团之一：
Figure FDA0003644244960000012
4.如权利要求1所述的3，4-二羟基肉桂酸酯类衍生物，其特征在于，选如下化合物：
Figure FDA0003644244960000013
Figure FDA0003644244960000021
Figure FDA0003644244960000031
Figure FDA0003644244960000041
Figure FDA0003644244960000051
5.如权利要求1-4其中之一所述的3，4-二羟基肉桂酸酯类衍生物在制备药物中的应用，其特征在于，以其为活性成份，制备治疗胃癌或食管癌药物。
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