CN103936814A - 一种色氨酸羟化酶-1抑制剂熊果酸类衍生物及其制备方法和应用 - Google Patents
一种色氨酸羟化酶-1抑制剂熊果酸类衍生物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种色氨酸羟化酶-1抑制剂熊果酸类衍生物及其制备方法和应用,属于生物医药技术领域。本发明通过实验证实,部分熊果酸衍生物可以特异性的抑制Tph-1的活性,而不影响Tph-2,同时,脊椎骨骨密度数据也表明大鼠脊椎骨骨密度明显增加,可见该熊果酸衍生物可有效的防止骨质疏松,在制备用于治疗骨质疏松药物中具有广泛的用途。
Description
技术领域
本发明属于熊果酸类衍生物技术领域,具体涉及一种色氨酸羟化酶-1抑制剂熊果酸类衍生物及其制备方法和应用。
背景技术
随着人口的老龄化,骨质疏松症(osteoporosis,OP)的患病率在逐年渐增加。其特征是骨吸收的速度大于骨形成的速度,是一个世界范围内的健康难题,尤其常见于绝经期的妇女。目前仅在美国就有超过1千万人患骨质疏松症,到2020年这个数字可能达到1400万。根据统计数据2010年欧洲大约有250万患者,中国约有8400万骨质疏松症患者。如此众多的骨质疏松症患者不仅给人们的生活带来很大的压力,也造成当今社会造成了很严重的经济负担。
5-羟基色氨(5-hydroxytryptamine,5-HT)是一种古老的神经传导分子,在很多组织中发挥很大的作用,调节中枢神经和外周循环的一些功能。色氨酸羟化酶(Tryptophan hydroxylase,Tph)是合成5-羟基色氨初始酶。在2003年Walther等报道色氨酸羟化酶存在两种结构形式:Tph-1和Tph-2。Tph-1主要由肠嗜铬细胞,松果体中大量表达;而Tph-2主要由神经细胞表达。近年的研究发现肠嗜铬细胞合成的5-羟基色氨(肠源性血清素,gut-derived serotonin,GDS)可以进入外周循环系统,抑制成骨细胞的分化,影响骨质量,却不能穿透血脑屏障。
基于以上理论我们寻找靶向性的Tph-1抑制剂。熊果酸广泛分布在自然界中,具有抗氧化,抗炎,抗癌,抗溃疡等方面的活性。但是很少有报道涉及熊果酸衍生物作为抗骨质疏松药物的研究。本发明的立足点在于研发具有抗骨质疏松活性的熊果酸衍生物。
发明内容
发明目的:针对现有技术中存在的不足,本发明的目的在于提供一种色氨酸羟化酶-1抑制剂熊果酸类衍生物,满足制备药物的使用需求。本发明的另一目的是提供一种制备上述熊果酸类衍生物的方法。本发明还有一目的是提供一种上述熊果酸类衍生物的用途。
技术方案:为了实现上述发明目的,本发明采用的技术方案为:
一种色氨酸羟化酶-1抑制剂熊果酸衍生物,结构式如下:
式中,Het基团为在C2,C3位引入杂环,所述杂环选自基团: 其中,R2选自基团Cl,CH3,NO2,CF3,CN,H等;R3选自基团H,OH,Cl,Br,I,NO2,NH2等相同或不同的基团;R4选自基团H, 等;R5选自基团H,NH2,CH3等;R62选自基团H、NH2、CH3等;
R1为氨基酸或杂环等,选自基团: 等,以及其他氨基酸或氨基酸羧基用酯保护的基团等;其中,n=2-9的整数,R7选自基团H,Cl,NO2,CH3等。
一种色氨酸羟化酶-1抑制剂熊果酸衍生物的制备方法,反应式为:
步骤如下:
首先用双氧水氧化熊果酸(UA)母核的3位羟基氧化为羰基,然后在乙酸作用下与对氯或对溴苯肼盐酸盐发生缩合反应得到吲哚熊果酸衍生物4-5。3-羰基熊果酸在强碱叔丁醇钾作用下用空气氧化为2,3-二羰基熊果酸,再与4,5-二氯邻苯二胺或者邻苯二胺反应得到中喹喔啉熊果酸衍生物6-7。4-7先与草酰氯作用得到吲哚或喹喔啉酰氯熊果酸,再与相应的胺反应,三乙胺为缚酸剂,得到目标产物4a-7k。
一种色氨酸羟化酶-1抑制剂熊果酸衍生物的制备方法,反应式为:
步骤如下:
将3-羰基熊果酸先在强碱甲醇钠作用下与甲酸乙酯作用得到中间体8,然后8再与盐酸肼,盐酸苯肼或者对氟盐酸苯肼作用得到母核产物吡唑熊果酸衍生物。吡唑熊果酸衍生物9-11先与草酰氯作用得到吡唑酰氯熊果酸,再与相应的胺反应,三乙胺为缚酸剂,得到目标产物9a-11k。
一种色氨酸羟化酶-1抑制剂熊果酸衍生物的制备方法,反应式为:
步骤如下:
中间体8先与盐酸羟胺作用得到异恶唑熊果酸衍生物12。12在强碱甲醇钠作用下让异恶唑开环,再用DDQ脱氢即得到氰基熊果酸衍生物13。12-13先与草酰氯作用得到异恶唑酰氯熊果酸,再与相应的胺反应,三乙胺为缚酸剂,得到目标产物12a-13k。
一种色氨酸羟化酶-1抑制剂熊果酸衍生物的制备方法,反应式为:
步骤如下:
3-羰基熊果酸先与N,N-二甲基甲酰胺二甲基缩醛(DMFDMA)作用得到2-烯胺-3-羰基熊果酸,再与醋酸甲脒关环得到嘧啶熊果酸酯15,用无水碘化锂脱去酯基后与草酰氯作用得到嘧啶酰氯熊果酸,再与相应的胺反应,三乙胺为缚酸剂,得到目标产物16a-16k。
一种色氨酸羟化酶-1抑制剂熊果酸衍生物的制备方法,反应式为:
步骤如下:
3-羰基熊果酸先与5,5-二溴-2,2-二甲基-4,6-二酮-1,3-二氧杂环己烷在乙醚中作用得到2-溴-3-羰基熊果酸,再与硫脲关环生成噻唑熊果酸衍生物18。噻唑熊果酸衍生物先与草酰氯作用得到噻唑酰氯熊果酸,再与相应的胺反应,三乙胺为缚酸剂,得到目标产物18a-18k。
所述色氨酸羟化酶-1抑制剂熊果酸衍生物在制备用于抗骨质疏松药物中的应用。
有益效果:与现有技术相比,本发明的熊果酸衍生物,通过实验证实,部分熊果酸衍生物可以特异性的抑制Tph-1的活性,而不影响Tph-2,同时,脊椎骨骨密度数据也表明大鼠脊椎骨骨密度明显增加,可见该熊果酸衍生物可有效的防止骨质疏松,在制备用于治疗骨质疏松药物中具有广泛的用途。
附图说明
图1是化合物7a体内活性数据,表示5-HT在血清的含量;数据表示为平均值±S.D.#p<0.05vs Sham;*p<0.05;**p<0.01vs OVX;
图2是化合物7a体内活性数据,表示5-HT在脑中的含量;数据表示为平均值±S.D.#p<0.05vs Sham;*p<0.05;**p<0.01vs OVX;
图3是化合物7a体内活性数据,表示脊椎骨骨密度数据;BMD为骨密度;数据表示为平均值±S.D.#p<0.05vs Sham;*p<0.05;**p<0.01vs OVX;
图4是化合物12g体内活性数据,表示5-HT在血清的含量;数据表示为平均值±S.D.#p<0.05vs Sham;*p<0.05;**p<0.01vs OVX;
图5是化合物12g体内活性数据,表示5-HT在脑中的含量;数据表示为平均值±S.D.#p<0.05vs Sham;*p<0.05;**p<0.01vs OVX;
图6是化合物12g体内活性数据,表示脊椎骨骨密度数据;BMD为骨密度;数据表示为平均值±S.D.#p<0.05vs Sham;*p<0.05;**p<0.01vs OVX。
具体实施方式
下面结合具体实施例对本发明作进一步的说明。
实施例1
化合物2的制备,反应式为:
称取13.25g(28.8mmol)熊果酸于90℃溶于150.0mL N,N-二甲基乙酰胺或者N,N-二甲基甲酰胺中,缓慢滴加10.0mL双氧水/钨酸钠/磷酸氢二钠/磷酸二氢钠(12.5/0.5/0.2/0.2,摩尔当量)混合溶液,控制滴加时间在1小时左右。反应一小时后冷却,倾倒入冷水中,乙酸乙酯萃取,洗涤,无水硫酸钠干燥,蒸除溶剂得3.92g3-羰基熊果酸2,收率:86%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:5.30(s,1H),2.76(d,J=15.0Hz,1H),2.28–2.14(m,3H),2.09–1.97(m,2H),1.84–1.69(m,3H),1.64–1.47(m,6H),1.33(d,J=2.8Hz,3H),1.31(s,2H),1.28(d,J=2.1Hz,3H),1.23(s,3H),1.18(s,3H),0.99(s,3H),0.97(s,2H),0.95(s,4H),0.83(s,3H).13CNMR(75MHz,CDCl3)δ:178.1,142.4,138.9,134.4,126.4,124.5,120.9,117.4,111.2,106.7,61.4,53.8,52.9,47.7,46.2,42.4,41.7,39.8,39.6,38.9,37.9,36.9,36.8,34.0,32.1,30.8,29.6,27.8,24.9,23.4,23.2,21.1,19.1,17.1,16.2,15.6,14.1。
化合物3的制备,反应式为:
250mL三井瓶中加入化合物2(9.08g,20mmol),叔丁醇(100mL),叔丁醇钾(13.4g,120mmol),四氢呋喃(12mL),40℃下反应小时,浓缩,200mL乙酸乙酯溶解,1N盐酸洗涤(200mL×3),饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析(石油醚/乙酸乙酯=6/1)得化合物3:8.28g,收率:86%。产物表征,数据为:1H NMR(400MHz,CDCl3)δ:6.35(s,1H),6.05(s,1H),5.32(t,J=3.6Hz,1H),2.90–2.79(m,1H),2.11–1.85(m,4H),1.80–1.45(m,10H),1.39–1.29(m,3H),1.22(s,3H),1.22(s,3H),1.13(s,3H),1.10(s,3H),0.94(s,3H),0.91(s,3H),0.89-0.83(m,1H),0.82(s,3H)。13CNMR(100MHz,CDCl3)δ:201.0,184.3,143.9,143.8,128.2,122.1,53.8,46.60,45.6,43.9,43.0,41.9,41.1,40.0,38.5,33.8,33.1,32.4,32.4,30.7,27.6,27.2,25.9,23.5,23.4,22.8,21.8,19.7,18.7,17.5。
化合物4的制备,反应式为:
称取3-羰基熊果酸2114.12mg(0.25mmol)和对氯苯肼盐酸盐54.03mg(0.30mmol),乙酸中回流3h后冷却,减压蒸去溶剂,用饱和碳酸钠溶液中和,乙酸乙酯萃取,无水硫酸钠干燥,过滤,浓缩,柱层析分离(石油醚/乙酸乙酯=5/1)得化合物对氯吲哚熊果酸4:85.71mg,收率:61%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.42(d,J=8.6Hz,2H),7.34(d,J=4.5Hz,2H),7.30(s,1H),5.31(s,1H),2.63(d,J=15.0Hz,1H),2.06–1.84(m,2H),2.06–1.84(m,4H),1.75–1.67(m,3H),1.54–1.36(m,6H),1.25(s,6H),1.10(s,3H),1.04(s,3H),0.96(s,3H),0.88(d,J=6.1Hz,3H),0.82(s,3H)。13CNMR(75MHz,CDCl3)δ:183.6,146.4,140.6,138.4,137.8,134.9,130.3,128.6,125.7,114.4,54.4,52.6,48.0,46.2,42.0,39.3,39.0,38.7,37.9,37.0,36.6,34.5,32.3,31.8,30.6,29.6,29.3,29.2,27.9,24.0,23.3,22.6,22.3,21.1,19.0,16.9,16.8,15.3,14.0。
化合物4a的制备,反应式为:
称取对氯吲哚熊果酸4112.62mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入甘氨基酸乙酯盐酸盐33.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物4a:141.04mg。收率:82%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),6.58(s,1H),5.53(s,1H),4.22(q,J=7.1Hz,2H),4.10(dd,J=18.6,5.3Hz,1H),3.85(dd,J=18.8,3.3Hz,1H),2.74(d,J=15.0Hz,1H),2.24–2.11(m,3H),2.07–1.99(m,2H),1.93–1.72(m,4H),1.64–1.55(m,4H),1.44–1.37(m,3H),1.30(d,J=3.6Hz,3H),1.26(s,6H),1.21(s,3H),1.16(s,3H),0.98–0.94(m,5H),0.93(s,3H),0.87(d,J=6.9Hz,3H),0.81(s,3H)。13CNMR(75MHz,CDCl3)δ:178.1,170.0,142.2,138.9,134.7,130.0,126.4,123.5,120.5,111.6,106.6,61.4,53.8,52.9,47.8,46.2,42.4,41.7,39.8,39.6,38.9,37.9,36.9,36.8,33.9,32.1,30.8,29.6,29.3,27.8,24.9,23.4,23.3,22.6,21.1,19.1,17.1,16.2,15.6,14.1。
化合物4b的制备,反应式为:
称取对氯吲哚熊果酸4112.62mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入亮氨基酸甲酯盐酸盐37.45mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物4b:139.22mg。收率:78%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.86(s,1H),7.37(d,J=1.5Hz,1H),7.20(d,J=8.5Hz,1H),7.05(dd,J=8.5,1.8Hz,1H),6.42(d,J=7.0Hz,1H),5.50(t,J=3.5Hz1H),4.66–4.52(m,1H),3.70(s,3H),2.75(d,J=15.0Hz,1H),2.24–2.15(m,2H),2.06–1.97(m,2H),1.85–1.72(m,4H),1.64–1.56(m,6H),1.52–1.37(m,5H),1.30(s,3H),1.26(s,1H),1.21(s,3H),1.15(s,3H),0.98(s,3H),0.95(s,3H),0.93(s,6H),0.79(s,3H)。13CNMR(75MHz,CDCl3)δ:177.4,173.4,142.4,138.2,134.4,129.3,126.5,124.5,120.9,117.4,111.2,106.7,53.9,53.0,52.0,50.8,47.8,46.2,42.5,42.3,39.7,39.6,39.0,37.9,37.4,36.8,34.0,32.4,30.8,27.8,24.8,23.4,23.3,22.6,22.4,21.1,19.2,17.1,16.5,15.6。
化合物4c的制备,反应式为:
称取对氯吲哚熊果酸4112.62mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苯丙氨基酸甲酯盐酸盐47.40mg(0.24mmol)和1.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物4c:126.64mg。收率:70%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.97(s,1H),7.36(d,J=1.9Hz,1H),7.29(d,J=7.2Hz,2H),7.19(d,J=8.5Hz,1H),7.12(dd,J=7.6,1.6Hz,2H),7.05(dd,J=8.5,2.0Hz,1H),6.47(d,J=6.3Hz,1H),5.37(s,1H),4.82–4.71(m,1H),3.67(s,3H),3.11(qd,J=13.7,5.9Hz,2H),2.72(d,J=15.0Hz,1H),2.22–1.98(m,4H),1.92–1.69(m,5H),1.52–1.38(m,6H),1.30(s,3H),1.26(s,3H),1.20(s,3H),1.12(s,3H),0.96(s,3H),0.92–0.88(m,3H),0.90(d,J=6.5Hz,6H),0.72(s,3H)。13CNMR(75MHz,CDCl3)δ:177.5,172.0,142.5,138.1,136.1,134.4,129.3,128.4,126.9,126.6,124.4,120.8,117.4,111.2,106.6,53.7,53.5,53.0,52.1,47.8,46.2,42.4,39.7,39.6,39.0,38.2,37.8,37.2,36.8,34.0,32.2,31.8,30.8,29.6,27.8,24.8,23.3,23.2,21.1,19.1,17.1,16.3,15.6。
化合物4d的制备,反应式为:
称取对氯吲哚熊果酸4112.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入正丙胺14.46mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物4d:85.09mg。收率:70%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),5.89(s,1H),5.36(s,1H),3.35–3.22(m,1H),3.05–2.93(m,1H),2.44(d,J=15.1Hz,1H),2.07–1.86(m,6H),1.74–1.70(m,3H),1.53–1.40(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.90(s,3H),0.88(d,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.7,172.9,150.0,139.9,125.0,108.6,53.9,53.3,47.6,45.9,42.5,41.1,40.1,39.6,38.9,38.5,37.1,35.5,34.6,31.9,30.8,28.7,27.8,24.7,23.1,22.4,21.1,18.7,17.1,16.6,15.4,11.4。
化合物4e的制备,反应式为:
称取对氯吲哚熊果酸4112.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对氯苯胺32.00mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物4e:78.21mg。收率:74%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),7.69(s,1H),7.41(d,J=8.8Hz,2H),7.23(s,1H),5.54(s,1H),2.45(d,J=15.1Hz,1H),2.12–2.02(m,6H),1.78(dd,J=28.3,18.7Hz,4H),1.61–1.47(m,6H),1.30(s,3H),1.25(s,3H),1.19(s,3H),1.16(s,3H),0.99(s,3H),0.94(d,J=6.4Hz,3H),0.87(s,3H),0.73(s,3H)。13CNMR(75MHz,CDCl3)δ:176.1,172.9,150.0,140.1,136.5,128.8,125.7,120.7,108.5,54.2,53.3,48.6,45.9,42.6,39.8,39.4,39.2,38.7,36.9,35.5,34.6,31.9,30.7,29.6,28.7,27.8,24.9,23.4,23.1,21.1,18.6,17.1,16.5,15.4。
化合物4f的制备,反应式为:
称取对氯吲哚熊果酸4112.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对甲氧基苯胺29.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物4f:75.10mg。收率:78%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),7.57(s,1H),7.36(d,J=8.9Hz,2H),6.83(d,J=8.9Hz,2H),5.52(s,1H),3.77(s,3H),2.45(d,J=15.1Hz,1H),2.13–1.94(m,6H),1.87–1.70(m,4H),1.60–1.51(m,4H),1.30(s,3H),1.18(s,3H),1.16(s,3H),0.98(s,3H),0.93(d,J=6.4Hz,3H),0.87(s,3H),0.78(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物4g的制备,反应式为:
称取对氯吲哚熊果酸4112.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对硝基苯胺35.56mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物4g:70.38mg。收率:70%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.18(d,J=9.1Hz,2H),8.03(s,1H),7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),7.64(d,J=9.1Hz,2H),5.59(s,1H),2.45(d,J=15.1Hz,1H),2.15–2.02(m,5H),1.90–1.70(m,4H),1.58–1.53(m,5H),1.43–1.32(m,4H),1.29(s,3H),1.17(s,3H),1.17(s,3H),1.00(s,3H),0.95(d,J=6.4Hz,3H),0.85(s,3H),0.69(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物4h的制备,反应式为:
称取对氯吲哚熊果酸4112.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入1-苄基-4氨基哌啶46.75mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物4h:65.64mg。收率:64%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),7.31(s,1H),7.23–7.21(m,2H),5.67(d,J=7.5Hz,1H),5.31(s,1H),3.82–3.71(m,1H),3.49(s,2H),2.84–2.74(m,2H),2.45(d,J=15.1Hz,1H),2.10–2.05(m,6H),1.94–1.66(m,8H),1.52–1.41(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.89(s,6H),0.86(s,3H)。13CNMR(75MHz,CDCl3)δ:176.9,172.9,150.0,139.4,137.8,129.1,128.1,127.0,125.1,108.6,63.0,54.0,53.3,52.1,47.7,46.0,42.6,39.6,38.9,38.5,37.4,35.5,34.6,31.9,31.6,30.8,28.7,27.8,24.5,23.1,22.8,21.1,18.6,17.1,15.4。
化合物4i的制备,反应式为:
称取对氯吲哚熊果酸4112.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨乙基哌啶31.43mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物4i:60.46mg。收率:62%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),6.56(s,1H),5.36(s,1H),3.42–3.30(m,1H),3.26–3.15(m,1H),2.47–240(m,7H),2.09–2.00(m,3H),1.99–1.83(m,3H),1.75–1.71(m,3H),1.64–1.54(m,6H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.92(s,3H),0.89(d,J=6.0Hz,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.2,125.1,108.6,56.8,54.5,54.0,53.3,47.6,45.9,42.4,39.6,38.9,38.5,37.2,35.6,34.6,31.9,30.8,28.7,27.8,25.9,24.6,24.2,23.1,21.1,18.7,17.1,16.5,15.3。
化合物4j的制备,反应式为:
称取对氯吲哚熊果酸4112.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨基丙基吗啉35.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物4j:61.07mg。收率:61%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),6.41(d,J=5.1Hz,1H),5.34(s,1H),3.82–3.61(m,4H),3.47–3.41(m,1H),3.15–3.00(m,1H),2.48–2.37(m,6H),2.05–2.01(m,6H),1.74–1.70(m,6H),1.56–1.38(m,6H),1.30(s,3H),1.21(s,3H),1.11(s,3H),0.96(s,3H),0.92(s,3H),0.89(d,J=6.9Hz,6H),0.83(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.6,125.0,108.6,66.7,57.4,53.7,53.3,47.5,45.9,42.4,39.5,38.9,38.5,37.3,35.5,34.6,32.0,30.7,29.5,28.7,27.7,25.3,24.6,23.2,21.1,18.7,17.1,16.6,15.3。
化合物4k的制备,反应式为:
称取对氯吲哚熊果酸4112.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苄胺26.33mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物4k:74.23mg。收率:75%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),7.40–7.27(m,3H),7.23(s,2H),6.16(t,J=5.1Hz,1H),5.27(d,J=3.3Hz,1H),4.52(dd,J=14.5,5.8Hz,1H),4.21(dd,J=14.5,4.6Hz,1H),2.43(d,J=15.1Hz,1H),2.07–1.83(m,7H),1.80–1.68(m,3H),1.58–1.36(m,7H),1.30(s,3H),1.21(s,3H),1.10(s,3H),0.95(s,3H),0.86(d,J=6.1Hz,3H),0.85(s,3H),0.75(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.7,138.2,128.5,127.8,127.3,125.3,108.6,54.0,53.3,47.7,45.9,43.6,42.5,39.6,38.9,38.4,37.1,35.5,34.6,32.0,30.8,28.7,27.8,24.7,23.1,21.1,18.6,17.0,16.7,15.3。
化合物5的制备,反应式为:
称取3-羰基熊果酸2151.41mg(0.25mmol)和对溴苯肼盐酸盐67.05mg(0.30mmol),乙酸中回流3h后冷却,减压蒸去溶剂,用饱和碳酸钠溶液中和,乙酸乙酯萃取,无水硫酸钠干燥,过滤,浓缩,柱层析分离(石油醚/乙酸乙酯=5/1)得化合物5:85.71mg,收率:55%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.42(d,J=8.6Hz,2H),7.34(d,J=4.5Hz,2H),7.30(s,1H),5.31(s,1H),2.63(d,J=15.0Hz,1H),2.06–1.84(m,2H),2.06–1.84(m,4H),1.75–1.67(m,3H),1.54–1.36(m,6H),1.25(s,6H),1.10(s,3H),1.04(s,3H),0.96(s,3H),0.88(d,J=6.1Hz,3H),0.82(s,3H)。13CNMR(75MHz,CDCl3)δ:183.6,146.4,140.6,138.4,137.8,134.9,130.3,128.6,125.7,114.4,54.4,52.6,48.0,46.2,42.0,39.3,39.0,38.7,37.9,37.0,36.6,34.5,32.3,31.8,30.6,29.6,29.3,29.2,27.9,24.0,23.3,22.6,22.3,21.1,19.0,16.9,16.8,15.3,14.0。
化合物5a的制备,反应式为:
称取对溴吲哚熊果酸5151.41mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入甘氨基酸乙酯盐酸盐33.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物5a:140.17mg。收率:75%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),6.58(s,1H),5.53(s,1H),4.22(q,J=7.1Hz,2H),4.10(dd,J=18.6,5.3Hz,1H),3.85(dd,J=18.8,3.3Hz,1H),2.74(d,J=15.0Hz,1H),2.24–2.11(m,3H),2.07–1.99(m,2H),1.93–1.72(m,4H),1.64–1.55(m,4H),1.44–1.37(m,3H),1.30(d,J=3.6Hz,3H),1.26(s,6H),1.21(s,3H),1.16(s,3H),0.98–0.94(m,5H),0.93(s,3H),0.87(d,J=6.9Hz,3H),0.81(s,3H)。13CNMR(75MHz,CDCl3)δ:178.1,170.0,142.2,138.9,134.7,130.0,126.4,123.5,120.5,111.6,106.6,61.4,53.8,52.9,47.8,46.2,42.4,41.7,39.8,39.6,38.9,37.9,36.9,36.8,33.9,32.1,30.8,29.6,29.3,27.8,24.9,23.4,23.3,22.6,21.1,19.1,17.1,16.2,15.6,14.1。
化合物5b的制备,反应式为:
称取对溴吲哚熊果酸5151.41mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入亮氨基酸甲酯盐酸盐37.45mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物5b:119.90mg。收率:69%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.88(s,1H),7.53(s,1H),7.17(s,2H),6.42(d,J=7.1Hz,1H),5.50(s,1H),4.63–4.55(m,1H),3.70(s,3H),2.75(d,J=15.0Hz,1H),2.22–2.00(m,5H),1.83–1.72(m,3H),1.66–1.59(m,7H),1.51–1.40(m,5H),1.30(s,3H),1.26(s,6H),1.21(s,3H),1.14(s,3H),0.98(s,3H),0.95(s,3H),0.93(s,6H),0.79(s,3H)。13CNMR(75MHz,CDCl3)δ:177.4,173.4,142.2,138.2,134.7,130.0,126.6,123.5,120.5,112.0,111.7,106.6,53.9,53.0,52.0,50.8,47.8,46.2,42.5,42.3,39.7,39.6,39.0,38.98(s),37.9,37.4,36.8,34.0,32.3,31.8,30.8,29.4,27.8,24.8,23.4,23.2,22.6,22.4,21.1,19.2,17.1,16.5,15.6,14.0。
化合物5c的制备,反应式为:
称取对溴吲哚熊果酸5151.41mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苯丙氨基酸甲酯盐酸盐47.40mg(0.24mmol)和1.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物5c:136.64mg。收率:71%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.83(s,1H),7.52(s,1H),7.29(d,J=7.3Hz,2H),7.16(s,1H),7.12(d,J=7.8Hz,2H),6.45(d,J=6.4Hz,1H),5.37(s,1H),4.80–4.69(m,1H),3.67(s,3H),3.11(qd,J=13.8,6.0Hz,2H),2.72(d,J=15.0Hz,1H),2.21–2.03(m,3H),1.91–1.68(m,5H),1.41(s,2H),1.29(s,3H),1.26(s,6H),1.20(s,3H),1.12(s,3H),0.96(s,3H),0.90(s,3H),0.88(s,3H),0.86(s,2H),0.71(s,3H)。13CNMR(75MHz,CDCl3)δ:177.4,172.0,142.2,138.1,136.1,134.6,130.0,129.3,128.3,126.9,126.6,123.5,120.5,112.0,111.6,53.7,53.5,53.0,52.0,47.8,46.1,42.4,39.7,39.6,39.0,38.1,37.8,37.2,36.8,33.9,32.2,31.8,30.8,29.6,29.3,27.8,24.8,23.3,23.2,22.6,21.1,19.1,17.1,16.3,15.6,14.0。
化合物5d的制备,反应式为:
称取对溴吲哚熊果酸5120.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入正丙胺14.46mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物5d:87.09mg。收率:71%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),5.89(s,1H),5.36(s,1H),3.35–3.22(m,1H),3.05–2.93(m,1H),2.44(d,J=15.1Hz,1H),2.07–1.86(m,6H),1.74–1.70(m,3H),1.53–1.40(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.90(s,3H),0.88(d,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.7,172.9,150.0,139.9,125.0,108.6,53.9,53.3,47.6,45.9,42.5,41.1,40.1,39.6,38.9,38.5,37.1,35.5,34.6,31.9,30.8,28.7,27.8,24.7,23.1,22.4,21.1,18.7,17.1,16.6,15.4,11.4。
化合物5e的制备,反应式为:
称取对溴吲哚熊果酸5120.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对氯苯胺32.00mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物5e:76.21mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),7.69(s,1H),7.41(d,J=8.8Hz,2H),7.23(s,1H),5.54(s,1H),2.45(d,J=15.1Hz,1H),2.12–2.02(m,6H),1.78(dd,J=28.3,18.7Hz,4H),1.61–1.47(m,6H),1.30(s,3H),1.25(s,3H),1.19(s,3H),1.16(s,3H),0.99(s,3H),0.94(d,J=6.4Hz,3H),0.87(s,3H),0.73(s,3H)。13CNMR(75MHz,CDCl3)δ:176.1,172.9,150.0,140.1,136.5,128.8,125.7,120.7,108.5,54.2,53.3,48.6,45.9,42.6,39.8,39.4,39.2,38.7,36.9,35.5,34.6,31.9,30.7,29.6,28.7,27.8,24.9,23.4,23.1,21.1,18.6,17.1,16.5,15.4。
化合物5f的制备,反应式为:
称取对溴吲哚熊果酸5112.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对甲氧基苯胺29.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物5f:72.10mg。收率:73%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),7.57(s,1H),7.36(d,J=8.9Hz,2H),6.83(d,J=8.9Hz,2H),5.52(s,1H),3.77(s,3H),2.45(d,J=15.1Hz,1H),2.13–1.94(m,6H),1.87–1.70(m,4H),1.60–1.51(m,4H),1.30(s,3H),1.18(s,3H),1.16(s,3H),0.98(s,3H),0.93(d,J=6.4Hz,3H),0.87(s,3H),0.78(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物5g的制备,反应式为:
称取对溴吲哚熊果酸5112.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对硝基苯胺35.56mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物5g:72.38mg。收率:71%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.18(d,J=9.1Hz,2H),8.03(s,1H),7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),7.64(d,J=9.1Hz,2H),5.59(s,1H),2.45(d,J=15.1Hz,1H),2.15–2.02(m,5H),1.90–1.70(m,4H),1.58–1.53(m,5H),1.43–1.32(m,4H),1.29(s,3H),1.17(s,3H),1.17(s,3H),1.00(s,3H),0.95(d,J=6.4Hz,3H),0.85(s,3H),0.69(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物5h的制备,反应式为:
称取对溴吲哚熊果酸5112.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入1-苄基-4氨基哌啶46.75mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物5h:62.64mg。收率:62%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),7.31(s,1H),7.23–7.21(m,2H),5.67(d,J=7.5Hz,1H),5.31(s,1H),3.82–3.71(m,1H),3.49(s,2H),2.84–2.74(m,2H),2.45(d,J=15.1Hz,1H),2.10–2.05(m,6H),1.94–1.66(m,8H),1.52–1.41(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.89(s,6H),0.86(s,3H)。13CNMR(75MHz,CDCl3)δ:176.9,172.9,150.0,139.4,137.8,129.1,128.1,127.0,125.1,108.6,63.0,54.0,53.3,52.1,47.7,46.0,42.6,39.6,38.9,38.5,37.4,35.5,34.6,31.9,31.6,30.8,28.7,27.8,24.5,23.1,22.8,21.1,18.6,17.1,15.4。
化合物5i的制备,反应式为:
称取对溴吲哚熊果酸5112.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨乙基哌啶31.43mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物5i:61.46mg。收率:61%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),6.56(s,1H),5.36(s,1H),3.42–3.30(m,1H),3.26–3.15(m,1H),2.47–240(m,7H),2.09–2.00(m,3H),1.99–1.83(m,3H),1.75–1.71(m,3H),1.64–1.54(m,6H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.92(s,3H),0.89(d,J=6.0Hz,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.2,125.1,108.6,56.8,54.5,54.0,53.3,47.6,45.9,42.4,39.6,38.9,38.5,37.2,35.6,34.6,31.9,30.8,28.7,27.8,25.9,24.6,24.2,23.1,21.1,18.7,17.1,16.5,15.3。
化合物5j的制备,反应式为:
称取对溴吲哚熊果酸5112.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨基丙基吗啉35.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物5j:60.07mg。收率:59%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),6.41(d,J=5.1Hz,1H),5.34(s,1H),3.82–3.61(m,4H),3.47–3.41(m,1H),3.15–3.00(m,1H),2.48–2.37(m,6H),2.05–2.01(m,6H),1.74–1.70(m,6H),1.56–1.38(m,6H),1.30(s,3H),1.21(s,3H),1.11(s,3H),0.96(s,3H),0.92(s,3H),0.89(d,J=6.9Hz,6H),0.83(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.6,125.0,108.6,66.7,57.4,53.7,53.3,47.5,45.9,42.4,39.5,38.9,38.5,37.3,35.5,34.6,32.0,30.7,29.5,28.7,27.7,25.3,24.6,23.2,21.1,18.7,17.1,16.6,15.3。
化合物5k的制备,反应式为:
称取对溴吲哚熊果酸5112.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苄胺26.33mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物5k:72.23mg。收率:73%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.85(s,1H),7.53(s,1H),7.17(d,J=2.7Hz,2H),7.40–7.27(m,3H),7.23(s,2H),6.16(t,J=5.1Hz,1H),5.27(d,J=3.3Hz,1H),4.52(dd,J=14.5,5.8Hz,1H),4.21(dd,J=14.5,4.6Hz,1H),2.43(d,J=15.1Hz,1H),2.07–1.83(m,7H),1.80–1.68(m,3H),1.58–1.36(m,7H),1.30(s,3H),1.21(s,3H),1.10(s,3H),0.95(s,3H),0.86(d,J=6.1Hz,3H),0.85(s,3H),0.75(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.7,138.2,128.5,127.8,127.3,125.3,108.6,54.0,53.3,47.7,45.9,43.6,42.5,39.6,38.9,38.4,37.1,35.5,34.6,32.0,30.8,28.7,27.8,24.7,23.1,21.1,18.6,17.0,16.7,15.3。
化合物6的制备,反应式为:
称取2,3-羰基熊果酸34.82g(10.0mmol)和4,5-二氯邻苯二胺2.12g(12.0mmol),乙醇中回流3h后冷却,减压蒸去溶剂,水洗,乙酸乙酯萃取,无水硫酸钠干燥,过滤,浓缩,柱层析分离(石油醚/乙酸乙酯=6/1)得化合物6:7.37g,收率:79%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.14(s,1H),8.10(s,1H),5.45(s,1H),2.58(d,J=12.8Hz,1H),2.10–2.05(m,4H),1.85–1.80(m,4H),1.45–1.38(m,6H),1.31–1.25(m,4H),1.17(s,3H),0.98(s,3H),0.95(d,J=6.9Hz,3H),0.94(s,3H),0.90(d,J=7.5Hz,3H),0.88(s,3H)。13CNMR(75MHz,CDCl3)δ:178.1,162.4,153.5,142.1,139.9,139.1,133.5,132.2,128.7,128.2,125.6,62.2,53.4,53.1,49.0,47.8,45.5,41.4,41.1,40.3,39.3,38.9,38.6,36.3,32.2,30.1,29.5,29.0,27.5,25.0,24.1,23.0,21.1,20.3,17.7,16.5,15.4,14.9。
化合物6a的制备,反应式为:
称取二氯喹喔啉熊果酸6122.41mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入甘氨基酸乙酯盐酸盐33.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物6a:90.17mg。收率:78%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.13(s,1H),8.07(s,1H),6.58(s,1H),5.53(s,1H),4.22(q,J=7.1Hz,2H),4.10(dd,J=18.6,5.3Hz,1H),3.85(dd,J=18.8,3.3Hz,1H),2.74(d,J=15.0Hz,1H),2.24–2.11(m,3H),2.07–1.99(m,2H),1.93–1.72(m,4H),1.64–1.55(m,4H),1.44–1.37(m,3H),1.30(d,J=3.6Hz,3H),1.26(s,6H),1.21(s,3H),1.16(s,3H),0.98–0.94(m,5H),0.93(s,3H),0.87(d,J=6.9Hz,3H),0.81(s,3H)。13CNMR(75MHz,CDCl3)δ:178.1,170.0,142.2,138.9,134.7,130.0,126.4,123.5,120.5,111.6,106.6,61.4,53.8,52.9,47.8,46.2,42.4,41.7,39.8,39.6,38.9,37.9,36.9,36.8,33.9,32.1,30.8,29.6,29.3,27.8,24.9,23.4,23.3,22.6,21.1,19.1,17.1,16.2,15.6,14.1。
化合物6b的制备,反应式为:
称取二氯喹喔啉熊果酸6122.41mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入亮氨基酸甲酯盐酸盐37.45mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物6b:87.90mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.13(s,1H),8.07(s,1H),6.35(d,J=7.1Hz,1H),5.47(s,1H),4.64–4.50(m,1H),3.69(s,3H),3.24(d,J=16.7Hz,1H),2.65(d,J=16.7Hz,1H),2.18–2.07(m,2H),2.06–1.98(m,2H),1.86–1.70(m,4H),1.64–1.53(m,6H),1.40(s,3H),1.39(s,3H),1.25(s,2H),1.16(s,3H),0.97(s,3H),0.94(s,3H),0.92(s,3H),0.91(d,J=7.2Hz,3H),0.80(s,3H)。13CNMR(75MHz,CDCl3)δ:177.3,173.5,162.4,153.3,140.8,139.5,138.4,133.0,132.8,129.4,128.7,126.1,53.8,53.3,52.0,50.7,49.5,47.8,45.3,42.5,42.2,40.4,39.7,39.4,38.9,37.4,36.6,32.2,30.8,29.6,27.7,25.2,24.8,24.7,23.3,23.2,22.6,22.3,21.1,20.2,17.1,16.4,15.7。
化合物6c的制备,反应式为:
称取二氯喹喔啉熊果酸6122.41mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苯丙氨基酸甲酯盐酸盐47.40mg(0.24mmol)和1.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物6c:101.64mg。收率:80%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.14(s,1H),8.08(s,1H),7.29(s,2H),7.14–7.06(m,2H),6.39(d,J=6.3Hz,1H),5.34(s,1H),4.81–4.70(m,1H),3.66(s,3H),3.10(qd,J=13.7,5.9Hz,2H),2.14–1.81(m,4H),1.76–1.66(m,5H),1.58–1.47(m,4H),1.40(s,3H),1.39(s,3H),1.25(s,3H),1.13(s,3H),0.96(s,3H),0.88(d,J=6.7Hz,3H),0.87(s,6H),0.72(s,3H)。13CNMR(75MHz,CDCl3)δ:177.3,172.0,162.3,153.3,140.7,139.5,138.3,136.1,133.0,132.8,129.4,129.3,128.7,128.4,126.9,126.1,53.6,53.4,53.3,52.0,49.4,47.7,45.3,42.4,40.4,39.6,39.4,39.0,38.1,37.2,36.6,32.2,32.1,30.8,29.6,27.6,25.2,24.7,23.3,23.2,21.1,20.1,17.1,16.21,15.71。
化合物6d的制备,反应式为:
称取二氯喹喔啉熊果酸6122.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入正丙胺14.46mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物6d:102.09mg。收率:81%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.13(s,1H),8.07(s,1H),5.89(s,1H),5.36(s,1H),3.35–3.22(m,1H),3.05–2.93(m,1H),2.44(d,J=15.1Hz,1H),2.07–1.86(m,6H),1.74–1.70(m,3H),1.53–1.40(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.90(s,3H),0.88(d,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.7,172.9,150.0,139.9,125.0,108.6,53.9,53.3,47.6,45.9,42.5,41.1,40.1,39.6,38.9,38.5,37.1,35.5,34.6,31.9,30.8,28.7,27.8,24.7,23.1,22.4,21.1,18.7,17.1,16.6,15.4,11.4。
化合物6e的制备,反应式为:
称取二氯喹喔啉熊果酸6122.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对氯苯胺32.00mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物6e:96.21mg。收率:74%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.13(s,1H),8.07(s,1H),7.69(s,1H),7.41(d,J=8.8Hz,2H),7.23(s,1H),5.54(s,1H),2.45(d,J=15.1Hz,1H),2.12–2.02(m,6H),1.78(dd,J=28.3,18.7Hz,4H),1.61–1.47(m,6H),1.30(s,3H),1.25(s,3H),1.19(s,3H),1.16(s,3H),0.99(s,3H),0.94(d,J=6.4Hz,3H),0.87(s,3H),0.73(s,3H)。13CNMR(75MHz,CDCl3)δ:176.1,172.9,150.0,140.1,136.5,128.8,125.7,120.7,108.5,54.2,53.3,48.6,45.9,42.6,39.8,39.4,39.2,38.7,36.9,35.5,34.6,31.9,30.7,29.6,28.7,27.8,24.9,23.4,23.1,21.1,18.6,17.1,16.5,15.4。
化合物6f的制备,反应式为:
称取二氯喹喔啉熊果酸6122.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对甲氧基苯胺29.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物6f:94.20mg。收率:70%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.13(s,1H),8.07(s,1H),7.57(s,1H),7.36(d,J=8.9Hz,2H),6.83(d,J=8.9Hz,2H),5.52(s,1H),3.77(s,3H),2.45(d,J=15.1Hz,1H),2.13–1.94(m,6H),1.87–1.70(m,4H),1.60–1.51(m,4H),1.30(s,3H),1.18(s,3H),1.16(s,3H),0.98(s,3H),0.93(d,J=6.4Hz,3H),0.87(s,3H),0.78(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物6g的制备,反应式为:
称取二氯喹喔啉熊果酸6122.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对硝基苯胺35.56mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物6g:83.34mg。收率:67%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.18(d,J=9.1Hz,2H),8.03(s,1H),8.13(s,1H),8.07(s,1H),7.64(d,J=9.1Hz,2H),5.59(s,1H),2.45(d,J=15.1Hz,1H),2.15–2.02(m,5H),1.90–1.70(m,4H),1.58–1.53(m,5H),1.43–1.32(m,4H),1.29(s,3H),1.17(s,3H),1.17(s,3H),1.00(s,3H),0.95(d,J=6.4Hz,3H),0.85(s,3H),0.69(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物6h的制备,反应式为:
称取二氯喹喔啉熊果酸6122.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入1-苄基-4氨基哌啶46.75mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物6h:89.64mg。收率:71%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.18(d,J=9.1Hz,2H),8.03(s,1H),7.31(s,1H),7.23–7.21(m,2H),5.67(d,J=7.5Hz,1H),5.31(s,1H),3.82–3.71(m,1H),3.49(s,2H),2.84–2.74(m,2H),2.45(d,J=15.1Hz,1H),2.10–2.05(m,6H),1.94–1.66(m,8H),1.52–1.41(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.89(s,6H),0.86(s,3H)。13CNMR(75MHz,CDCl3)δ:176.9,172.9,150.0,139.4,137.8,129.1,128.1,127.0,125.1,108.6,63.0,54.0,53.3,52.1,47.7,46.0,42.6,39.6,38.9,38.5,37.4,35.5,34.6,31.9,31.6,30.8,28.7,27.8,24.5,23.1,22.8,21.1,18.6,17.1,15.4。
化合物6i的制备,反应式为:
称取二氯喹喔啉熊果酸6122.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨乙基哌啶31.43mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物6i:90.46mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.18(d,J=9.1Hz,2H),8.03(s,1H),6.56(s,1H),5.36(s,1H),3.42–3.30(m,1H),3.26–3.15(m,1H),2.47–240(m,7H),2.09–2.00(m,3H),1.99–1.83(m,3H),1.75–1.71(m,3H),1.64–1.54(m,6H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.92(s,3H),0.89(d,J=6.0Hz,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.2,125.1,108.6,56.8,54.5,54.0,53.3,47.6,45.9,42.4,39.6,38.9,38.5,37.2,35.6,34.6,31.9,30.8,28.7,27.8,25.9,24.6,24.2,23.1,21.1,18.7,17.1,16.5,15.3。
化合物6j的制备,反应式为:
称取二氯喹喔啉熊果酸6122.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨基丙基吗啉35.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物6j:101.07mg。收率:81%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.18(d,J=9.1Hz,2H),8.03(s,1H),6.41(d,J=5.1Hz,1H),5.34(s,1H),3.82–3.61(m,4H),3.47–3.41(m,1H),3.15–3.00(m,1H),2.48–2.37(m,6H),2.05–2.01(m,6H),1.74–1.70(m,6H),1.56–1.38(m,6H),1.30(s,3H),1.21(s,3H),1.11(s,3H),0.96(s,3H),0.92(s,3H),0.89(d,J=6.9Hz,6H),0.83(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.6,125.0,108.6,66.7,57.4,53.7,53.3,47.5,45.9,42.4,39.5,38.9,38.5,37.3,35.5,34.6,32.0,30.7,29.5,28.7,27.7,25.3,24.6,23.2,21.1,18.7,17.1,16.6,15.3。
化合物6k的制备,反应式为:
称取二氯喹喔啉熊果酸6122.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苄胺26.33mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物6k:102.23mg。收率:82%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.18(d,J=9.1Hz,2H),8.03(s,1H),7.40–7.27(m,3H),7.23(s,2H),6.16(t,J=5.1Hz,1H),5.27(d,J=3.3Hz,1H),4.52(dd,J=14.5,5.8Hz,1H),4.21(dd,J=14.5,4.6Hz,1H),2.43(d,J=15.1Hz,1H),2.07–1.83(m,7H),1.80–1.68(m,3H),1.58–1.36(m,7H),1.30(s,3H),1.21(s,3H),1.10(s,3H),0.95(s,3H),0.86(d,J=6.1Hz,3H),0.85(s,3H),0.75(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.7,138.2,128.5,127.8,127.3,125.3,108.6,54.0,53.3,47.7,45.9,43.6,42.5,39.6,38.9,38.4,37.1,35.5,34.6,32.0,30.8,28.7,27.8,24.7,23.1,21.1,18.6,17.0,16.7,15.3。
化合物7的制备,反应式为:
称取2,3-羰基熊果酸34.82g(10.0mmol)和邻苯二胺1.98g(12.0mmol),乙醇中回流3h后冷却,减压蒸去溶剂,水洗,乙酸乙酯萃取,无水硫酸钠干燥,过滤,浓缩,柱层析分离(石油醚/乙酸乙酯=6/1)得化合物喹喔啉熊果酸7:7.40g,收率:82%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.09–7.92(d,J=6.4Hz,2H),7.65(dd,J=6.2,3.3Hz,2H),5.35(t,J=3.4Hz,1H),3.28(d,J=16.6Hz,1H),2.68(d,J=16.7Hz,1H),2.27–2.25(m,1H),2.17–1.98(m,3H),1.83–1.65(m,5H),1.55–1.53(m,4H),1.42(s,3H),1.38(s,3H),1.15(s,3H),0.95(d,J=6.8Hz,3H),0.94(s,3H),0.91(d,J=7.5Hz,3H),0.89(s,3H)。13CNMR(75MHz,CDCl3)δ:183.0,161.3,142.2,137.9,129.0,127.2,125.5,53.4,52.6,48.8,48.0,45.3,42.1,40.3,39.3,39.1,38.7,36.7,32.2,30.6,29.6,27.9,25.3,23.7,23.3,21.1,20.2,16.9,15.8。
化合物7a的制备,反应式为:
称取喹喔啉熊果酸7108.56mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入甘氨基酸乙酯盐酸盐33.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物7a:88.16mg。收率:78%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.98(dd,J=6.5,3.4Hz,2H),7.65(dd,J=6.3,3.4Hz,2H),6.55(s,1H),5.50(s,1H),4.21(q,J=7.1Hz,2H),4.09(dd,J=18.6,5.2Hz,1H),3.84(dd,J=18.7,3.5Hz,1H),3.26(d,J=16.4Hz,1H),2.69(d,J=16.4Hz,1H),2.23–1.98(m,4H),1.86–1.64(m,5H),1.60–1.55(m,2H),1.44(s,3H),1.43(s,3H),1.27(t,J=7.2Hz,3H),1.26(d,J=7.3Hz,3H),1.18(s,3H),0.97(s,3H),0.93(d,J=6.9Hz,3H),0.92(s,3H),0.82(s,3H)。13CNMR(75MHz,CDCl3)δ:178.0,170.1,160.9,151.8,142.1,140.7,139.0,128.6,128.0,126.1,61.4,53.8,53.4,49.5,47.7,45.4,42.5,41.6,40.2,39.6,39.4,39.1,38.9,36.8,32.1,30.8,29.6,27.7,25.2,24.8,23.3,21.1,20.2,17.2,16.1,15.7,14.0。
化合物7b的制备,反应式为:
称取喹喔啉熊果酸7108.56mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入亮氨基酸甲酯盐酸盐37.45mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物7b:79.89mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.98(dd,J=6.6,3.5Hz,2H),7.72–7.56(m,2H),6.37(d,J=7.1Hz,1H),5.47(s,1H),4.66–4.46(m,1H),3.69(s,3H),3.27(d,J=16.4Hz,1H),2.69(d,J=16.4Hz,1H),2.19–2.14(m,1H),2.05–1.96(m,2H),1.86–1.69(m,5H),1.64–1.53(m,6H),1.44(s,3H),1.43(s,3H),1.25(s,2H),1.17(s,3H),0.97(s,3H),0.93(d,J=6.3Hz,3H),0.921(s,6H),0.81(s,3H)。13CNMR(75MHz,CDCl3)δ:177.3,173.4,160.9,151.8,142.1,140.7,138.3,128.8,128.6,128.0,126.3,53.8,53.4,52.0,50.7,49.5,47.8,45.4,42.5,42.2,40.3,39.7,39.4,39.0,37.4,36.7,32.3,30.8,29.6,27.7,25.2,24.8,23.3,22.5,21.1,20.2,17.1,16.4,15.7。
化合物7c的制备,反应式为:
称取喹喔啉熊果酸7108.56mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苯丙氨基酸甲酯盐酸盐47.40mg(0.24mmol)和1.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物7c:102.64mg。收率:80%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.98(dd,J=6.3,3.4Hz,2H),7.65(dd,J=6.3,3.4Hz,2H),7.30(d,J=6.5Hz,1H),7.11(d,J=7.1Hz,2H),6.41(d,J=6.3Hz,1H),5.35(s,1H),4.82–4.67(m,1H),3.67(s,3H),3.24(d,J=16.4Hz,1H),3.10(qd,J=13.8,6.0Hz,2H),2.66(d,J=16.6Hz,1H),2.14–1.94(m,3H),1.92–1.66(m,6H),1.58–1.44(m,4H),1.43(s,3H),1.42(s,3H),1.25(s,2H),1.14(s,3H),0.96(s,3H),0.89(s,3H),0.88(d,J=3.7Hz,3H),0.72(s,3H)。13CNMR(75MHz,CDCl3)δ:177.3,172.0,160.9,151.8,142.0,140.7,138.2,136.1,129.3,128.7,128.4,128.3,128.0,126.9,126.3,53.5,52.0,49.5,47.8,45.3,42.4,40.2,39.7,39.5,39.0,38.1,37.2,36.7,32.2,30.8,29.6,27.8,25.2,24.7,23.2,21.1,20.2,17.1,16.2,15.7。
化合物7d的制备,反应式为:
称取喹喔啉熊果酸7108.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入正丙胺14.46mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物7d:92.09mg。收率:81%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.09–7.92(d,J=6.4Hz,2H),5.89(s,1H),5.36(s,1H),3.35–3.22(m,1H),3.05–2.93(m,1H),2.44(d,J=15.1Hz,1H),2.07–1.86(m,6H),1.74–1.70(m,3H),1.53–1.40(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.90(s,3H),0.88(d,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.7,172.9,150.0,139.9,125.0,108.6,53.9,53.3,47.6,45.9,42.5,41.1,40.1,39.6,38.9,38.5,37.1,35.5,34.6,31.9,30.8,28.7,27.8,24.7,23.1,22.4,21.1,18.7,17.1,16.6,15.4,11.4。
化合物7e的制备,反应式为:
称取喹喔啉熊果酸7108.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对氯苯胺32.00mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物7e:96.21mg。收率:84%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.09–7.92(d,J=6.4Hz,2H),7.65(dd,J=6.2,3.3Hz,2H),7.69(s,1H),7.41(d,J=8.8Hz,2H),7.23(s,1H),5.54(s,1H),2.45(d,J=15.1Hz,1H),2.12–2.02(m,6H),1.78(dd,J=28.3,18.7Hz,4H),1.61–1.47(m,6H),1.30(s,3H),1.25(s,3H),1.19(s,3H),1.16(s,3H),0.99(s,3H),0.94(d,J=6.4Hz,3H),0.87(s,3H),0.73(s,3H)。13CNMR(75MHz,CDCl3)δ:176.1,172.9,150.0,140.1,136.5,128.8,125.7,120.7,108.5,54.2,53.3,48.6,45.9,42.6,39.8,39.4,39.2,38.7,36.9,35.5,34.6,31.9,30.7,29.6,28.7,27.8,24.9,23.4,23.1,21.1,18.6,17.1,16.5,15.4。
化合物7f的制备,反应式为:
称取喹喔啉熊果酸7108.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对甲氧基苯胺29.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物7f:84.20mg。收率:70%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.09–7.92(d,J=6.4Hz,2H),7.65(dd,J=6.2,3.3Hz,2H),7.57(s,1H),7.36(d,J=8.9Hz,2H),6.83(d,J=8.9Hz,2H),5.52(s,1H),3.77(s,3H),2.45(d,J=15.1Hz,1H),2.13–1.94(m,6H),1.87–1.70(m,4H),1.60–1.51(m,4H),1.30(s,3H),1.18(s,3H),1.16(s,3H),0.98(s,3H),0.93(d,J=6.4Hz,3H),0.87(s,3H),0.78(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物7g的制备,反应式为:
称取喹喔啉熊果酸7108.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对硝基苯胺35.56mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物7g:83.34mg。收率:67%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.09–7.92(d,J=6.4Hz,2H),8.13(s,1H),8.07(s,1H),7.65(dd,J=6.2,3.3Hz,2H),7.64(d,J=9.1Hz,2H),5.59(s,1H),2.45(d,J=15.1Hz,1H),2.15–2.02(m,5H),1.90–1.70(m,4H),1.58–1.53(m,5H),1.43–1.32(m,4H),1.29(s,3H),1.17(s,3H),1.17(s,3H),1.00(s,3H),0.95(d,J=6.4Hz,3H),0.85(s,3H),0.69(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物7h的制备,反应式为:
称取喹喔啉熊果酸7108.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入1-苄基-4氨基哌啶46.75mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物7h:89.64mg。收率:81%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.09–7.92(d,J=6.4Hz,2H),7.65(dd,J=6.2,3.3Hz,2H),7.75(s,1H),7.31(s,1H),7.23–7.21(m,2H),5.67(d,J=7.5Hz,1H),5.31(s,1H),3.82–3.71(m,1H),3.49(s,2H),2.84–2.74(m,2H),2.45(d,J=15.1Hz,1H),2.10–2.05(m,6H),1.94–1.66(m,8H),1.52–1.41(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.89(s,6H),0.86(s,3H)。13CNMR(75MHz,CDCl3)δ:176.9,172.9,150.0,139.4,137.8,129.1,128.1,127.0,125.1,108.6,63.0,54.0,53.3,52.1,47.7,46.0,42.6,39.6,38.9,38.5,37.4,35.5,34.6,31.9,31.6,30.8,28.7,27.8,24.5,23.1,22.8,21.1,18.6,17.1,15.4。
化合物7i的制备,反应式为:
称取喹喔啉熊果酸7108.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨乙基哌啶31.43mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物7i:60.46mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.09–7.92(d,J=6.4Hz,2H),7.65(dd,J=6.2,3.3Hz,2H),6.56(s,1H),5.36(s,1H),3.42–3.30(m,1H),3.26–3.15(m,1H),2.47–240(m,7H),2.09–2.00(m,3H),1.99–1.83(m,3H),1.75–1.71(m,3H),1.64–1.54(m,6H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.92(s,3H),0.89(d,J=6.0Hz,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.2,125.1,108.6,56.8,54.5,54.0,53.3,47.6,45.9,42.4,39.6,38.9,38.5,37.2,35.6,34.6,31.9,30.8,28.7,27.8,25.9,24.6,24.2,23.1,21.1,18.7,17.1,16.5,15.3。
化合物7j的制备,反应式为:
称取喹喔啉熊果酸7108.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨基丙基吗啉35.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物7j:96.07mg。收率:81%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.09–7.92(d,J=6.4Hz,2H),7.65(dd,J=6.2,3.3Hz,2H),6.41(d,J=5.1Hz,1H),5.34(s,1H),3.82–3.61(m,4H),3.47–3.41(m,1H),3.15–3.00(m,1H),2.48–2.37(m,6H),2.05–2.01(m,6H),1.74–1.70(m,6H),1.56–1.38(m,6H),1.30(s,3H),1.21(s,3H),1.11(s,3H),0.96(s,3H),0.92(s,3H),0.89(d,J=6.9Hz,6H),0.83(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.6,125.0,108.6,66.7,57.4,53.7,53.3,47.5,45.9,42.4,39.5,38.9,38.5,37.3,35.5,34.6,32.0,30.7,29.5,28.7,27.7,25.3,24.6,23.2,21.1,18.7,17.1,16.6,15.3。
化合物7k的制备,反应式为:
称取喹喔啉熊果酸7108.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苄胺26.33mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物7k:97.23mg。收率:82%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.09–7.92(d,J=6.4Hz,2H),7.65(dd,J=6.2,3.3Hz,2H),7.40–7.27(m,3H),7.23(s,2H),6.16(t,J=5.1Hz,1H),5.27(d,J=3.3Hz,1H),4.52(dd,J=14.5,5.8Hz,1H),4.21(dd,J=14.5,4.6Hz,1H),2.43(d,J=15.1Hz,1H),2.07–1.83(m,7H),1.80–1.68(m,3H),1.58–1.36(m,7H),1.30(s,3H),1.21(s,3H),1.10(s,3H),0.95(s,3H),0.86(d,J=6.1Hz,3H),0.85(s,3H),0.75(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.7,138.2,128.5,127.8,127.3,125.3,108.6,54.0,53.3,47.7,45.9,43.6,42.5,39.6,38.9,38.4,37.1,35.5,34.6,32.0,30.8,28.7,27.8,24.7,23.1,21.1,18.6,17.0,16.7,15.3。
化合物9的制备,反应式为:
称取2-醛基-3-羰基熊果酸84.83g(10.0mmol)和盐酸肼1.25g(12.0mmol),乙醇中回流3h后冷却,减压蒸去溶剂,水洗,乙酸乙酯萃取,无水硫酸钠干燥,过滤,浓缩,柱层析分离(石油醚/乙酸乙酯=2/1)得化合物9:3.69g,收率:77%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.19(s,1H),5.31(t,J=3.7Hz,1H),2.59(d,J=14.7Hz,1H),2.25(d,J=10.7Hz,1H),2.07–1.99(m,4H),1.72–1.69(m,4H),1.55–1.50(m,3H),1.33(s,2H),1.33–1.28(m,2H),1.27(d,J=6.0Hz,3H),1.26(s,3H),1.16(s,3H),1.11(s,3H),0.95(d,J=5.9Hz,1H),0.90–0.88(m,6H),0.81(s,3H)。13CNMR(75MHz,CDCl3)δ:182.8,150.4,138.0,131.3,125.5,113.0,53.2,52.8,47.9,46.0,42.1,39.5,39.1,38.8,38.2,36.7,36.3,33.3,31.8,31.3,30.6,30.1,29.6,29.3,28.0,24.6,21.1,19.0,16.8,15.2,14.0。
化合物9a的制备,反应式为:
称取吡唑熊果酸9119.56mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入甘氨基酸乙酯盐酸盐33.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物9a:76.00mg。收率:75%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.24(s,1H),6.60(t,J=4.2Hz,1H),5.46(s,1H),4.20(q,J=7.1Hz,2H),4.07(dd,J=18.6,6.1Hz,2H),3.83(dd,J=18.6,3.4Hz,1H),2.58(d,J=14.8Hz,1H),2.09–1.98(m,6H),1.77–1.65(m,3H),1.57–1.44(m,5H),1.32–1.28(m,5H),1.27–1.19(m,6H),1.25(d,J=7.5Hz,3H),1.11(s,3H),0.94(s,3H),0.89(d,J=6.4Hz,3H),0.85(s,3H),0.76(s,3H)。13CNMR(75MHz,CDCl3)δ:178.1,170.2,149.3,138.8,133.9,126.3,112.2,61.4,53.7,53.2,47.5,46.0,42.4,41.6,39.7,39.5,38.9,38.2,36.9,36.4,33.2,32.0,31.2,30.8,29.6,27.8,24.8,23.3,23.1,21.1,19.0,17.1,16.1,15.2,14.0。
化合物9b的制备,反应式为:
称取吡唑熊果酸9119.56mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入亮氨基酸甲酯盐酸盐37.45mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物9b:78.09mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.24(s,1H),6.38(d,J=7.1Hz,1H),5.44(s,1H),4.61–4.54(m,1H),3.70(s,3H),2.60(d,J=14.8Hz,1H),2.09–1.98(m,4H),1.63–1.41(m,9H),1.30(s,3H),1.20(s,3H),1.12(s,3H),0.96(s,3H),0.95(d,J=6.2Hz,3H),0.9–0.89(m,6H),0.87(s,3H),0.76(s,3H)。13CNMR(75MHz,CDCl3)δ:177.4,173.5,149.2,138.1,133.6,126.4,112.0,53.7,53.2,52.6,52.0,51.7,50.6,47.7,45.9,43.9,42.3,42.1,39.6,39.5,38.9,38.2,33.2,31.1,29.5,24.6,23.8,22.9,22.6,22.3,22.2,21.7,21.0,17.0,16.4,15.2。
化合物9c的制备,反应式为:
称取吡唑熊果酸9119.56mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苯丙氨基酸甲酯盐酸盐47.40mg(0.24mmol)和1.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物9c:90.98mg。收率:80%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.23(s,2H),7.10(d,J=6.1Hz,3H),6.46(d,J=5.1Hz,1H),5.31(s,1H),4.80–4.67(m,1H),3.66(s,3H),3.09(qd,J=13.6,5.8Hz,2H),2.57(d,J=14.8Hz,1H),2.06–1.94(m,5H),1.70–1.41(m,9H),1.31–1.24(m,6H),1.20(s,3H),1.08(s,3H),0.94(s,3H),0.88–0.81(m,6H),0.67(s,3H)。13CNMR(75MHz,CDCl3)δ:177.4,172.1,149.2,138.0,136.1,134.1,129.3,128.3,126.9,126.4,112.2,60.3,53.6,53.5,53.2,52.0,47.7,46.0,42.3,39.5,38.2,37.1,36.4,33.2,32.2,31.1,29.6,27.7,24.7,23.8,23.1,21.1,19.0,17.0,16.2,15.2,14.1。
化合物9d的制备,反应式为:
称取吡唑熊果酸995.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入正丙胺14.46mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物9d:77.09mg。收率:77%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.19(s,1H),5.89(s,1H),5.36(s,1H),3.35–3.22(m,1H),3.05–2.93(m,1H),2.44(d,J=15.1Hz,1H),2.07–1.86(m,6H),1.74–1.70(m,3H),1.53–1.40(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.90(s,3H),0.88(d,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.7,172.9,150.0,139.9,125.0,108.6,53.9,53.3,47.6,45.9,42.5,41.1,40.1,39.6,38.9,38.5,37.1,35.5,34.6,31.9,30.8,28.7,27.8,24.7,23.1,22.4,21.1,18.7,17.1,16.6,15.4,11.4。
化合物9e的制备,反应式为:
称取吡唑熊果酸995.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对氯苯胺32.00mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物9e:74.21mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.19(s,1H),7.69(s,1H),7.41(d,J=8.8Hz,2H),7.23(s,1H),5.54(s,1H),2.45(d,J=15.1Hz,1H),2.12–2.02(m,6H),1.78(dd,J=28.3,18.7Hz,4H),1.61–1.47(m,6H),1.30(s,3H),1.25(s,3H),1.19(s,3H),1.16(s,3H),0.99(s,3H),0.94(d,J=6.4Hz,3H),0.87(s,3H),0.73(s,3H)。13CNMR(75MHz,CDCl3)δ:176.1,172.9,150.0,140.1,136.5,128.8,125.7,120.7,108.5,54.2,53.3,48.6,45.9,42.6,39.8,39.4,39.2,38.7,36.9,35.5,34.6,31.9,30.7,29.6,28.7,27.8,24.9,23.4,23.1,21.1,18.6,17.1,16.5,15.4。
化合物9f的制备,反应式为:
称取吡唑熊果酸995.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对甲氧基苯胺29.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物9f:72.20mg。收率:70%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.19(s,1H),7.57(s,1H),7.36(d,J=8.9Hz,2H),6.83(d,J=8.9Hz,2H),5.52(s,1H),3.77(s,3H),2.45(d,J=15.1Hz,1H),2.13–1.94(m,6H),1.87–1.70(m,4H),1.60–1.51(m,4H),1.30(s,3H),1.18(s,3H),1.16(s,3H),0.98(s,3H),0.93(d,J=6.4Hz,3H),0.87(s,3H),0.78(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物9g的制备,反应式为:
称取吡唑熊果酸995.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对硝基苯胺35.56mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物9g:78.34mg。收率:73%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.18(d,J=9.1Hz,2H),8.03(s,1H),7.19(s,1H),7.64(d,J=9.1Hz,2H),5.59(s,1H),2.45(d,J=15.1Hz,1H),2.15–2.02(m,5H),1.90–1.70(m,4H),1.58–1.53(m,5H),1.43–1.32(m,4H),1.29(s,3H),1.17(s,3H),1.17(s,3H),1.00(s,3H),0.95(d,J=6.4Hz,3H),0.85(s,3H),0.69(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物9h的制备,反应式为:
称取吡唑熊果酸995.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入1-苄基-4氨基哌啶46.75mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物9h:70.64mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.19(s,1H),7.31(s,1H),7.23–7.21(m,2H),5.67(d,J=7.5Hz,1H),5.31(s,1H),3.82–3.71(m,1H),3.49(s,2H),2.84–2.74(m,2H),2.45(d,J=15.1Hz,1H),2.10–2.05(m,6H),1.94–1.66(m,8H),1.52–1.41(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.89(s,6H),0.86(s,3H)。13CNMR(75MHz,CDCl3)δ:176.9,172.9,150.0,139.4,137.8,129.1,128.1,127.0,125.1,108.6,63.0,54.0,53.3,52.1,47.7,46.0,42.6,39.6,38.9,38.5,37.4,35.5,34.6,31.9,31.6,30.8,28.7,27.8,24.5,23.1,22.8,21.1,18.6,17.1,15.4。
化合物9i的制备,反应式为:
称取吡唑熊果酸995.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨乙基哌啶31.43mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物9i:73.46mg。收率:69%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.19(s,1H),6.56(s,1H),5.36(s,1H),3.42–3.30(m,1H),3.26–3.15(m,1H),2.47–240(m,7H),2.09–2.00(m,3H),1.99–1.83(m,3H),1.75–1.71(m,3H),1.64–1.54(m,6H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.92(s,3H),0.89(d,J=6.0Hz,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.2,125.1,108.6,56.8,54.5,54.0,53.3,47.6,45.9,42.4,39.6,38.9,38.5,37.2,35.6,34.6,31.9,30.8,28.7,27.8,25.9,24.6,24.2,23.1,21.1,18.7,17.1,16.5,15.3。
化合物9j的制备,反应式为:
称取吡唑熊果酸995.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨基丙基吗啉35.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物9j:72.07mg。收率:69%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.19(s,1H),6.41(d,J=5.1Hz,1H),5.34(s,1H),3.82–3.61(m,4H),3.47–3.41(m,1H),3.15–3.00(m,1H),2.48–2.37(m,6H),2.05–2.01(m,6H),1.74–1.70(m,6H),1.56–1.38(m,6H),1.30(s,3H),1.21(s,3H),1.11(s,3H),0.96(s,3H),0.92(s,3H),0.89(d,J=6.9Hz,6H),0.83(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.6,125.0,108.6,66.7,57.4,53.7,53.3,47.5,45.9,42.4,39.5,38.9,38.5,37.3,35.5,34.6,32.0,30.7,29.5,28.7,27.7,25.3,24.6,23.2,21.1,18.7,17.1,16.6,15.3。
化合物9k的制备,反应式为:
称取吡唑熊果酸996.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苄胺26.33mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物9k:76.23mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.40–7.27(m,3H),7.23(s,2H),7.19(s,1H),6.16(t,J=5.1Hz,1H),5.27(d,J=3.3Hz,1H),4.52(dd,J=14.5,5.8Hz,1H),4.21(dd,J=14.5,4.6Hz,1H),2.43(d,J=15.1Hz,1H),2.07–1.83(m,7H),1.80–1.68(m,3H),1.58–1.36(m,7H),1.30(s,3H),1.21(s,3H),1.10(s,3H),0.95(s,3H),0.86(d,J=6.1Hz,3H),0.85(s,3H),0.75(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.7,138.2,128.5,127.8,127.3,125.3,108.6,54.0,53.3,47.7,45.9,43.6,42.5,39.6,38.9,38.4,37.1,35.5,34.6,32.0,30.8,28.7,27.8,24.7,23.1,21.1,18.6,17.0,16.7,15.3。
化合物10的制备,反应式为:
称取2-醛基-3-羰基熊果酸84.83g(10.0mmol)和盐酸肼1.73g(12.0mmol),乙醇中回流3h后冷却,减压蒸去溶剂,水洗,乙酸乙酯萃取,无水硫酸钠干燥,过滤,浓缩,柱层析分离(石油醚/乙酸乙酯=2/1)得化合物苯基吡唑熊果酸10:3.60g,收率:65%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.44(d,J=5.4Hz,3H),7.40–7.34(m,2H),7.34(s,1H),5.31(s,1H),2.63(d,J=14.9Hz,1H),2.25–2.09(m,2H),2.07–1.83(m,5H),1.73–1.64(m,4H),1.53–1.44(m,3H),1.43–1.32(m,4H),1.25(s,3H),1.10(s,3H),1.03(s,3H),0.96(s,3H),0.95(d,J=7.5Hz,3H),0.88(d,J=6.0Hz,3H),0.82(s,3H)。13CNMR(75MHz,CDCl3)δ:183.6,146.1,142.2,138.1,137.7,129.0,128.9,128.4,125.8,114.0,54.5,52.6,48.0,46.2,42.0,39.4,39.0,38.7,37.9,37.1,36.6,34.6,32.4,30.6,29.6,29.3,27.9,24.0,23.3,22.2,21.1,19.1,16.9,16.8,15.3。
化合物10a的制备,反应式为:
称取苯基吡唑熊果酸10118.50mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入甘氨基酸乙酯盐酸盐33.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物10a:74.46mg。收率:78%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.42(d,J=3.7Hz,3H),7.37(d,J=4.6Hz,2H),7.33(s,1H),6.56(s,1H),5.49(s,1H),4.21(q,J=7.1Hz,2H),4.07(dd,J=18.8,5.0Hz,1H),3.83(dd,J=18.7,3.2Hz,1H),2.63(d,J=14.8Hz,1H),2.18–1.99(m,5H),1.89–1.65(m,4H),1.47(s,5H),1.28(t,J=7.1Hz,3H),1.27(d,J=7.2Hz,3H),1.12(s,3H),1.04(s,3H),0.99(s,3H),0.95(s,3H),0.92(s,3H),0.91(d,J=7.8Hz,3H),0.77(s,3H)。13CNMR(75MHz,CDCl3)δ:178.0,170.1,146.0,142.3,138.9,138.1,129.0,128.8,128.4,126.3,113.9,61.3,54.5,53.8,47.7,46.2,42.4,41.6,39.7,39.4,38.9,37.9,37.1,36.9,34.6,32.1,30.8,29.3,27.8,24.8,23.3,23.1,22.2,21.1,19.1,17.1,16.1,15.3,14.1。
化合物10b的制备,反应式为:
称取苯基吡唑熊果酸10118.50mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入亮氨基酸甲酯盐酸盐37.45mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物10b:70.89mg。收率:69%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.42(d,J=4.0Hz,3H),7.38(d,J=5.3Hz,2H),7.33(s,1H),7.29(s,1H),7.10(d,J=6.5Hz,2H),6.42(d,J=6.2Hz,1H),5.34(s,1H),4.78–4.68(m,1H),3.68(s,3H),3.09(qd,J=13.7,5.9Hz,2H),2.62(d,J=14.9Hz,1H),2.16–1.83(m,6H),1.73–1.67(m,2H),1.51–1.22(m,10H),1.08(s,3H),1.03(s,3H),0.99(s,3H),0.95(s,3H),0.90(s,3H),0.87(d,J=6.3Hz,3H),0.68(s,3H)。13CNMR(75MHz,CDCl3)δ:177.4,172.0,146.0,142.3,138.1,136.1,129.3,129.0,128.8,128.4,128.3,126.9,126.5,114.0,54.5,53.7,53.4,52.0,47.8,46.2,42.3,39.7,39.4,39.0,38.1,37.9,37.1,34.6,32.3,30.8,29.3,27.7,24.7,23.2,23.1,22.2,21.1,19.0,17.0,16.2,15.3。
化合物10c的制备,反应式为:
称取苯基吡唑熊果酸10118.50mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苯丙氨基酸甲酯盐酸盐47.40mg(0.24mmol)和1.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物10c:89.08mg。收率:81%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.46–7.40(m,3H),7.38(d,J=5.5Hz,2H),7.33(s,1H),7.29(s,1H),7.10(d,J=6.2Hz,2H),6.43(d,J=6.3Hz,1H),5.34(s,1H),4.83–4.68(m,1H),3.68(s,3H),3.08(qd,J=13.7,6.7Hz,2H),2.62(d,J=14.9Hz,1H),2.17–1.96(m,4H),1.91–1.79(m,2H),1.77–1.60(m,3H),1.52–1.44(m,4H),1.31–1.20(m,6H),1.08(s,3H),1.04(s,3H),0.99(s,3H),0.95(s,3H),0.90(s,3H),0.87(d,J=6.4Hz,3H),0.68(s,3H)。13CNMR(75MHz,CDCl3)δ:177.4,172.0,146.1,142.2,138.1,138.0,136.1,129.3,129.0,128.9,128.4,128.3,126.9,126.5,114.0,54.5,53.7,53.4,52.1,47.8,46.2,42.3,39.7,39.4,39.0,38.1,37.9,37.2,37.1,34.6,32.3,30.8,29.6,29.3,27.7,24.7,23.2,22.2,21.1,19.0,17.0,16.2,15.3。
化合物10d的制备,反应式为:
称取苯基吡唑熊果酸10110.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入正丙胺14.46mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物10d:87.09mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.42(d,J=4.0Hz,3H),7.38(d,J=5.3Hz,2H),7.33(s,1H),7.29(s,1H),7.10(d,J=6.5Hz,2H),5.89(s,1H),5.36(s,1H),3.35–3.22(m,1H),3.05–2.93(m,1H),2.44(d,J=15.1Hz,1H),2.07–1.86(m,6H),1.74–1.70(m,3H),1.53–1.40(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.90(s,3H),0.88(d,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.7,172.9,150.0,139.9,125.0,108.6,53.9,53.3,47.6,45.9,42.5,41.1,40.1,39.6,38.9,38.5,37.1,35.5,34.6,31.9,30.8,28.7,27.8,24.7,23.1,22.4,21.1,18.7,17.1,16.6,15.4,11.4。
化合物10e的制备,反应式为:
称取苯基吡唑熊果酸10110.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对氯苯胺32.00mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物10e:74.21mg。收率:68%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.42(d,J=4.0Hz,3H),7.38(d,J=5.3Hz,2H),7.33(s,1H),7.29(s,1H),7.10(d,J=6.5Hz,2H),7.69(s,1H),7.41(d,J=8.8Hz,2H),7.23(s,1H),5.54(s,1H),2.45(d,J=15.1Hz,1H),2.12–2.02(m,6H),1.78(dd,J=28.3,18.7Hz,4H),1.61–1.47(m,6H),1.30(s,3H),1.25(s,3H),1.19(s,3H),1.16(s,3H),0.99(s,3H),0.94(d,J=6.4Hz,3H),0.87(s,3H),0.73(s,3H)。13CNMR(75MHz,CDCl3)δ:176.1,172.9,150.0,140.1,136.5,128.8,125.7,120.7,108.5,54.2,53.3,48.6,45.9,42.6,39.8,39.4,39.2,38.7,36.9,35.5,34.6,31.9,30.7,29.6,28.7,27.8,24.9,23.4,23.1,21.1,18.6,17.1,16.5,15.4。
化合物10f的制备,反应式为:
称取苯基吡唑熊果酸10110.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对甲氧基苯胺29.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物10f:72.20mg。收率:65%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.42(d,J=4.0Hz,3H),7.38(d,J=5.3Hz,2H),7.33(s,1H),7.29(s,1H),7.10(d,J=6.5Hz,2H),7.57(s,1H),7.36(d,J=8.9Hz,2H),6.83(d,J=8.9Hz,2H),5.52(s,1H),3.77(s,3H),2.45(d,J=15.1Hz,1H),2.13–1.94(m,6H),1.87–1.70(m,4H),1.60–1.51(m,4H),1.30(s,3H),1.18(s,3H),1.16(s,3H),0.98(s,3H),0.93(d,J=6.4Hz,3H),0.87(s,3H),0.78(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物10g的制备,反应式为:
称取苯基吡唑熊果酸10110.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对硝基苯胺35.56mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物10g:76.34mg。收率:70%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.18(d,J=9.1Hz,2H),8.03(s,1H),7.42(d,J=4.0Hz,3H),7.38(d,J=5.3Hz,2H),7.33(s,1H),7.29(s,1H),7.10(d,J=6.5Hz,2H),7.64(d,J=9.1Hz,2H),5.59(s,1H),2.45(d,J=15.1Hz,1H),2.15–2.02(m,5H),1.90–1.70(m,4H),1.58–1.53(m,5H),1.43–1.32(m,4H),1.29(s,3H),1.17(s,3H),1.17(s,3H),1.00(s,3H),0.95(d,J=6.4Hz,3H),0.85(s,3H),0.69(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物10h的制备,反应式为:
称取苯基吡唑熊果酸10110.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入1-苄基-4氨基哌啶46.75mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物10h:72.60mg。收率:75%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.42(d,J=4.0Hz,3H),7.38(d,J=5.3Hz,2H),7.33(s,1H),7.29(s,1H),7.10(d,J=6.5Hz,2H),7.31(s,1H),7.23–7.21(m,2H),5.67(d,J=7.5Hz,1H),5.31(s,1H),3.82–3.71(m,1H),3.49(s,2H),2.84–2.74(m,2H),2.45(d,J=15.1Hz,1H),2.10–2.05(m,6H),1.94–1.66(m,8H),1.52–1.41(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.89(s,6H),0.86(s,3H)。13CNMR(75MHz,CDCl3)δ:176.9,172.9,150.0,139.4,137.8,129.1,128.1,127.0,125.1,108.6,63.0,54.0,53.3,52.1,47.7,46.0,42.6,39.6,38.9,38.5,37.4,35.5,34.6,31.9,31.6,30.8,28.7,27.8,24.5,23.1,22.8,21.1,18.6,17.1,15.4。
化合物10i的制备,反应式为:
称取苯基吡唑熊果酸10110.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨乙基哌啶31.43mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物10i:70.89mg。收率:68%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.42(d,J=4.0Hz,3H),7.38(d,J=5.3Hz,2H),7.33(s,1H),7.29(s,1H),7.10(d,J=6.5Hz,2H),6.56(s,1H),5.36(s,1H),3.42–3.30(m,1H),3.26–3.15(m,1H),2.47–240(m,7H),2.09–2.00(m,3H),1.99–1.83(m,3H),1.75–1.71(m,3H),1.64–1.54(m,6H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.92(s,3H),0.89(d,J=6.0Hz,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.2,125.1,108.6,56.8,54.5,54.0,53.3,47.6,45.9,42.4,39.6,38.9,38.5,37.2,35.6,34.6,31.9,30.8,28.7,27.8,25.9,24.6,24.2,23.1,21.1,18.7,17.1,16.5,15.3。
化合物10j的制备,反应式为:
称取苯基吡唑熊果酸10110.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨基丙基吗啉35.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物10j:70.07mg。收率:69%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.42(d,J=4.0Hz,3H),7.38(d,J=5.3Hz,2H),7.33(s,1H),7.29(s,1H),7.10(d,J=6.5Hz,2H),6.41(d,J=5.1Hz,1H),5.34(s,1H),3.82–3.61(m,4H),3.47–3.41(m,1H),3.15–3.00(m,1H),2.48–2.37(m,6H),2.05–2.01(m,6H),1.74–1.70(m,6H),1.56–1.38(m,6H),1.30(s,3H),1.21(s,3H),1.11(s,3H),0.96(s,3H),0.92(s,3H),0.89(d,J=6.9Hz,6H),0.83(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.6,125.0,108.6,66.7,57.4,53.7,53.3,47.5,45.9,42.4,39.5,38.9,38.5,37.3,35.5,34.6,32.0,30.7,29.5,28.7,27.7,25.3,24.6,23.2,21.1,18.7,17.1,16.6,15.3。
化合物10k的制备,反应式为:
称取苯基吡唑熊果酸10110.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苄胺26.33mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物10k:69.23mg。收率:67%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.40–7.27(m,3H),7.23(s,2H),7.42(d,J=4.0Hz,3H),7.38(d,J=5.3Hz,2H),7.33(s,1H),7.29(s,1H),7.10(d,J=6.5Hz,2H),6.16(t,J=5.1Hz,1H),5.27(d,J=3.3Hz,1H),4.52(dd,J=14.5,5.8Hz,1H),4.21(dd,J=14.5,4.6Hz,1H),2.43(d,J=15.1Hz,1H),2.07–1.83(m,7H),1.80–1.68(m,3H),1.58–1.36(m,7H),1.30(s,3H),1.21(s,3H),1.10(s,3H),0.95(s,3H),0.86(d,J=6.1Hz,3H),0.85(s,3H),0.75(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.7,138.2,128.5,127.8,127.3,125.3,108.6,54.0,53.3,47.7,45.9,43.6,42.5,39.6,38.9,38.4,37.1,35.5,34.6,32.0,30.8,28.7,27.8,24.7,23.1,21.1,18.6,17.0,16.7,15.3。
化合物11的制备,反应式为:
称取2-醛基-3-羰基熊果酸84.83g(10.0mmol)和盐酸苯肼1.86g(12.0mmol),乙醇中回流3h后冷却,减压蒸去溶剂,水洗,乙酸乙酯萃取,无水硫酸钠干燥,过滤,浓缩,柱层析分离(石油醚/乙酸乙酯=2/1)得化合物氟代苯基吡唑熊果酸11:3.740g,收率:68%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.46–7.30(m,3H),7.12(t,J=8.5Hz,2H),5.32(s,1H),2.64(d,J=15.0Hz,1H),2.27–2.13(m,2H),2.09–1.82(m,6H),1.74–1.64(m,4H),1.55–1.45(m,3H),1.43–1.32(m,4H),1.31–1.22(m,4H),1.10(s,3H),1.04(s,3H),0.96(s,3H),0.92(s,3H),0.88(d,J=6.4Hz,3H),0.83(s,3H)。13CNMR(75MHz,CDCl3)δ:183.6,164.2,160.9,146.6,138.0,137.7,130.9,130.8,125.7,115.5,115.2,114.4,54.4,52.6,48.0,46.2,42.0,39.3,39.0,38.7,37.9,37.0,36.6,34.5,32.3,30.5,29.3,27.9,24.0,23.3,23.2,22.2,21.1,19.0,16.9,16.8,15.3。
化合物11a的制备,反应式为:
称取氟代苯基吡唑熊果酸11119.50mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入甘氨基酸乙酯盐酸盐33.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物11a:74.80mg。收率:78%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.39–7.30(m,3H),7.16–7.05(m,2H),6.55(t,J=4.1Hz,1H),5.49(s,1H),4.21(q,J=7.1Hz,2H),4.07(dd,J=18.7,5.2Hz,1H),3.84(dd,J=18.7,3.5Hz,1H),2.63(d,J=14.9Hz,1H),2.18–1.97(m,5H),1.78–1.64(m,3H),1.56–1.43(m,5H),1.28(t,J=7.1Hz,3H),1.27(d,J=7.3Hz,3H),1.12(s,3H),1.04(s,3H),0.99(s,3H),0.96(s,3H),0.92(s,3H),0.91(d,J=6.2Hz,3H),0.77(s,3H)。13CNMR(75MHz,CDCl3)δ:178.0,170.1,164.1,160.8,146.2,138.9,138.3,130.8,130.7,126.3,115.4,115.2,114.1,61.4,54.4,53.8,47.8,46.2,42.4,41.6,39.7,39.4,38.9,37.9,37.1,36.9,34.6,32.1,30.8,29.6,29.3,27.8,24.8,23.3,23.1,22.3,21.1,19.0,17.1,16.1,15.3,14.0。
化合物11b的制备,反应式为:
称取氟代苯基吡唑熊果酸11119.50mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入亮氨基酸甲酯盐酸盐37.45mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物11b:71.11mg。收率:69%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.38–7.31(m,3H),7.14–7.07(m,2H),6.37(d,J=7.1Hz,1H),5.45(s,1H),4.60–4.53(m,1H),3.70(s,3H),2.63(d,J=14.8Hz,1H),2.16–1.98(m,5H),1.85–1.64(m,5H),1.60–1.45(m,7H),1.30–1.21(m,5H),1.11(s,3H),1.03(s,3H),0.99(s,3H),0.96(s,3H),0.94(s,3H),0.92(s,3H),0.91(d,J=6.4Hz,3H),0.75(s,3H)。13CNMR(75MHz,CDCl3)δ:177.3,173.5,164.1,160.8,146.2,138.4,138.2,130.9,130.7,126.4,115.4,115.1,114.2,54.5,53.8,52.0,50.7,47.8,46.3,42.4,42.2,39.7,39.5,38.9,37.9,37.4,37.1,34.5,32.4,30.8,29.6,29.3,27.8,24.7,23.3,23.1,22.6,22.4,22.3,21.1,19.0,17.1,16.5,15.3。
化合物11c的制备,反应式为:
称取氟代苯基吡唑熊果酸11118.50mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苯丙氨基酸甲酯盐酸盐47.40mg(0.24mmol)和1.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物11c:90.08mg。收率:82%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.34(s,3H),7.29(s,1H),7.11(d,J=7.1Hz,3H),6.41(d,J=5.9Hz,1H),5.34(s,1H),4.83–4.66(m,1H),3.68(s,3H),3.10(qd,J=13.5,5.8Hz,2H),2.62(d,J=14.3Hz,1H),2.10–1.93(m,3H),1.87–1.60(m,6H),1.51–1.43(m,3H),1.26(s,3H),1.09(s,3H),1.04(s,3H),1.01–0.92(m,6H),0.90(s,3H),0.87(d,J=6.4Hz,3H),0.68(s,3H)。13CNMR(75MHz,CDCl3)δ:177.4,172.0,164.2,160.9,146.3,138.3,138.1,136.1,130.9,130.8,129.3,128.3,126.9,126.4,115.5,115.2,114.2,54.5,53.8,53.4,52.0,47.8,46.2,42.3,39.7,39.4,39.0,38.1,37.9,37.2,37.1,34.5,32.2,30.8,29.6,29.3,27.7,24.7,23.2,23.1,22.3,21.0,19.0,17.0,16.2,15.3。
化合物11d的制备,反应式为:
称取氟代苯基吡唑熊果酸11114.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入正丙胺14.46mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物11d:78.09mg。收率:77%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.46–7.30(m,3H),7.12(t,J=8.5Hz,2H),5.89(s,1H),5.36(s,1H),3.35–3.22(m,1H),3.05–2.93(m,1H),2.44(d,J=15.1Hz,1H),2.07–1.86(m,6H),1.74–1.70(m,3H),1.53–1.40(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.90(s,3H),0.88(d,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.7,172.9,150.0,139.9,125.0,108.6,53.9,53.3,47.6,45.9,42.5,41.1,40.1,39.6,38.9,38.5,37.1,35.5,34.6,31.9,30.8,28.7,27.8,24.7,23.1,22.4,21.1,18.7,17.1,16.6,15.4,11.4。
化合物11e的制备,反应式为:
称取氟代苯基吡唑熊果酸11114.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对氯苯胺32.00mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物11e:75.21mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.46–7.30(m,3H),7.12(t,J=8.5Hz,2H),7.69(s,1H),7.41(d,J=8.8Hz,2H),7.23(s,1H),5.54(s,1H),2.45(d,J=15.1Hz,1H),2.12–2.02(m,6H),1.78(dd,J=28.3,18.7Hz,4H),1.61–1.47(m,6H),1.30(s,3H),1.25(s,3H),1.19(s,3H),1.16(s,3H),0.99(s,3H),0.94(d,J=6.4Hz,3H),0.87(s,3H),0.73(s,3H)。13CNMR(75MHz,CDCl3)δ:176.1,172.9,150.0,140.1,136.5,128.8,125.7,120.7,108.5,54.2,53.3,48.6,45.9,42.6,39.8,39.4,39.2,38.7,36.9,35.5,34.6,31.9,30.7,29.6,28.7,27.8,24.9,23.4,23.1,21.1,18.6,17.1,16.5,15.4。
化合物11f的制备,反应式为:
称取氟代苯基吡唑熊果酸11114.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对甲氧基苯胺29.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物11f:76.20mg。收率:70%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.46–7.30(m,3H),7.12(t,J=8.5Hz,2H),7.57(s,1H),7.36(d,J=8.9Hz,2H),6.83(d,J=8.9Hz,2H),5.52(s,1H),3.77(s,3H),2.45(d,J=15.1Hz,1H),2.13–1.94(m,6H),1.87–1.70(m,4H),1.60–1.51(m,4H),1.30(s,3H),1.18(s,3H),1.16(s,3H),0.98(s,3H),0.93(d,J=6.4Hz,3H),0.87(s,3H),0.78(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物11g的制备,反应式为:
称取氟代苯基吡唑熊果酸11114.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对硝基苯胺35.56mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物11g:79.34mg。收率:73%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.18(d,J=9.1Hz,2H),8.03(s,1H),7.46–7.30(m,3H),7.12(t,J=8.5Hz,2H),7.64(d,J=9.1Hz,2H),5.59(s,1H),2.45(d,J=15.1Hz,1H),2.15–2.02(m,5H),1.90–1.70(m,4H),1.58–1.53(m,5H),1.43–1.32(m,4H),1.29(s,3H),1.17(s,3H),1.17(s,3H),1.00(s,3H),0.95(d,J=6.4Hz,3H),0.85(s,3H),0.69(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物11h的制备,反应式为:
称取氟代苯基吡唑熊果酸11114.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入1-苄基-4氨基哌啶46.75mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物11h:74.64mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.46–7.30(m,3H),7.12(t,J=8.5Hz,2H),7.31(s,1H),7.23–7.21(m,2H),5.67(d,J=7.5Hz,1H),5.31(s,1H),3.82–3.71(m,1H),3.49(s,2H),2.84–2.74(m,2H),2.45(d,J=15.1Hz,1H),2.10–2.05(m,6H),1.94–1.66(m,8H),1.52–1.41(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.89(s,6H),0.86(s,3H)。13CNMR(75MHz,CDCl3)δ:176.9,172.9,150.0,139.4,137.8,129.1,128.1,127.0,125.1,108.6,63.0,54.0,53.3,52.1,47.7,46.0,42.6,39.6,38.9,38.5,37.4,35.5,34.6,31.9,31.6,30.8,28.7,27.8,24.5,23.1,22.8,21.1,18.6,17.1,15.4。
化合物11i的制备,反应式为:
称取氟代苯基吡唑熊果酸11114.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨乙基哌啶31.43mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物11i:70.46mg。收率:69%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.46–7.30(m,3H),7.12(t,J=8.5Hz,2H),6.56(s,1H),5.36(s,1H),3.42–3.30(m,1H),3.26–3.15(m,1H),2.47–240(m,7H),2.09–2.00(m,3H),1.99–1.83(m,3H),1.75–1.71(m,3H),1.64–1.54(m,6H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.92(s,3H),0.89(d,J=6.0Hz,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.2,125.1,108.6,56.8,54.5,54.0,53.3,47.6,45.9,42.4,39.6,38.9,38.5,37.2,35.6,34.6,31.9,30.8,28.7,27.8,25.9,24.6,24.2,23.1,21.1,18.7,17.1,16.5,15.3。
化合物11j的制备,反应式为:
称取氟代苯基吡唑熊果酸11114.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨基丙基吗啉35.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物11j:70.07mg。收率:69%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.46–7.30(m,3H),7.12(t,J=8.5Hz,2H),6.41(d,J=5.1Hz,1H),5.34(s,1H),3.82–3.61(m,4H),3.47–3.41(m,1H),3.15–3.00(m,1H),2.48–2.37(m,6H),2.05–2.01(m,6H),1.74–1.70(m,6H),1.56–1.38(m,6H),1.30(s,3H),1.21(s,3H),1.11(s,3H),0.96(s,3H),0.92(s,3H),0.89(d,J=6.9Hz,6H),0.83(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.6,125.0,108.6,66.7,57.4,53.7,53.3,47.5,45.9,42.4,39.5,38.9,38.5,37.3,35.5,34.6,32.0,30.7,29.5,28.7,27.7,25.3,24.6,23.2,21.1,18.7,17.1,16.6,15.3。
化合物11k的制备,反应式为:
称取氟代苯基吡唑熊果酸11114.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苄胺26.33mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物11k:76.23mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.40–7.27(m,3H),7.23(s,2H),7.46–7.30(m,3H),7.12(t,J=8.5Hz,2H),6.16(t,J=5.1Hz,1H),5.27(d,J=3.3Hz,1H),4.52(dd,J=14.5,5.8Hz,1H),4.21(dd,J=14.5,4.6Hz,1H),2.43(d,J=15.1Hz,1H),2.07–1.83(m,7H),1.80–1.68(m,3H),1.58–1.36(m,7H),1.30(s,3H),1.21(s,3H),1.10(s,3H),0.95(s,3H),0.86(d,J=6.1Hz,3H),0.85(s,3H),0.75(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.7,138.2,128.5,127.8,127.3,125.3,108.6,54.0,53.3,47.7,45.9,43.6,42.5,39.6,38.9,38.4,37.1,35.5,34.6,32.0,30.8,28.7,27.8,24.7,23.1,21.1,18.6,17.0,16.7,15.3。
化合物12的制备,反应式为:
称取2-醛基-3-羰基熊果酸84.83g(10.0mmol)和盐酸苯肼0.84g(12.0mmol),乙醇中回流3h后冷却,减压蒸去溶剂,水洗,乙酸乙酯萃取,无水硫酸钠干燥,过滤,浓缩,柱层析分离(石油醚/乙酸乙酯=2/1)得化合物异恶唑熊果酸12:4.58g,收率:92%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.98(s,1H),5.30(s,1H),2.45(d,J=15.2Hz,1H),2.22(d,J=11.4Hz,1H),2.09–1.96(m,4H),1.75–1.64(m,4H),1.58–1.47(m,3H),1.45–1.39(m,2H),1.30(s,3H),1.17(s,3H),1.10(s,3H),0.95(d,J=6.1Hz,3H),0.90(s,3H),0.89(d,J=6.3Hz,3H),0.83(s,3H)。13CNMR(75MHz,CDCl3)δ:184.3,172.9,150.0,137.9,125.4,108.7,53.4,52.5,47.9,46.0,42.0,39.4,39.0,38.7,38.5,36.6,35.5,34.6,32.1,30.5,28.7,27.9,26.8,23.9,23.4,23.2,21.2,21.1,18.7,16.9,16.8,15.3。
化合物12a的制备,反应式为:
称取异恶唑熊果酸1296.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入甘氨基酸乙酯盐酸盐33.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物12a:91.80mg。收率:88%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.97(s,1H),6.52(s,1H),5.46(s,1H),4.21(q,J=7.1Hz,2H),4.06(dd,J=18.7,5.1Hz,1H),3.84(dd,J=18.7,3.5Hz,1H),2.44(d,J=15.1Hz,1H),2.11–1.95(m,5H),1.89–1.69(m,4H),1.57–1.40(m,8H),1.31–1.24(m,8H),1.20(s,3H),1.12(s,3H),0.95(s,3H),0.89(d,J=8.4Hz,6H),0.88(s,3H),0.77(s,3H)。13CNMR(75MHz,CDCl3)δ:177.8,172.8,170.0,150.0,138.9,125.8,108.6,61.3,53.6,53.3,47.6,45.9,42.3,41.6,39.6,39.4,38.9,38.4,36.9,35.5,34.6,31.9,30.7,29.5,28.7,27.7,26.8,24.7,23.3,23.1,22.5,21.2,21.1,18.7,17.0,16.1,15.3,14.0。
化合物12b的制备,反应式为:
称取异恶唑熊果酸1296.50mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入亮氨基酸甲酯盐酸盐37.45mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物12b:86.11mg。收率:89%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.98(s,1H),6.34(d,J=7.1Hz,1H),5.43(s,1H),4.62–4.52(m,1H),3.70(s,3H),2.45(d,J=15.1Hz,1H),2.10–1.92(m,5H),1.85–1.69(m,4H),1.62–1.47(m,7H),1.42(s,3H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.96(s,3H),0.94(s,3H),0.92–0.87(m,5H),0.90(d,J=7.6Hz,3H),0.75(s,3H)。13CNMR(75MHz,CDCl3)δ:177.3,173.5,172.9,150.0,138.3,126.0,108.7,53.7,53.4,52.0,50.6,47.7,46.0,42.4,42.2,39.6,39.5,38.9,38.5,37.3,35.5,34.6,32.1,30.8,28.7,27.8,26.8,24.7,24.6,23.3,23.1,22.6,22.3,21.2,21.0,18.7,17.0,16.4,15.4。
化合物12c的制备,反应式为:
称取异恶唑熊果酸12118.50mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苯丙氨基酸甲酯盐酸盐47.40mg(0.24mmol)和1.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物12c:80.08mg。收率:84%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.97(s,1H),7.29(s,1H),7.13–7.06(m,2H),6.39(d,J=6.3Hz,1H),5.31(s,1H),4.78–4.69(m,1H),3.67(s,3H),3.09(qd,J=13.7,5.9Hz,2H),2.42(d,J=15.1Hz,1H),2.05–1.77(m,6H),1.71–1.63(m,2H),1.57–1.39(m,6H),1.29(s,3H),1.20(s,3H),1.08(s,3H),0.94(s,3H),0.86(d,J=4.6Hz,3H),0.85(s,3H),0.66(s,3H)。13CNMR(75MHz,CDCl3)δ:177.2,172.8,172.0,150.0,138.2,136.1,129.2,128.3,126.9,126.0,108.7,53.5,53.4,53.3,52.0,47.7,45.9,42.2,39.6,39.5,38.9,38.4,38.0,37.1,35.5,34.6,32.0,30.8,29.6,28.7,27.7,24.7,23.1,21.3,21.1,18.6,17.0,16.2,15.3。
化合物12d的制备,反应式为:
称取异恶唑熊果酸1296.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入正丙胺14.46mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物12d:72.09mg。收率:73%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.97(s,1H),5.89(s,1H),5.36(s,1H),3.35–3.22(m,1H),3.05–2.93(m,1H),2.44(d,J=15.1Hz,1H),2.07–1.86(m,6H),1.74–1.70(m,3H),1.53–1.40(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.90(s,3H),0.88(d,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.7,172.9,150.0,139.9,125.0,108.6,53.9,53.3,47.6,45.9,42.5,41.1,40.1,39.6,38.9,38.5,37.1,35.5,34.6,31.9,30.8,28.7,27.8,24.7,23.1,22.4,21.1,18.7,17.1,16.6,15.4,11.4。
化合物12e的制备,反应式为:
称取异恶唑熊果酸1296.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对氯苯胺32.00mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物12e:76.21mg。收率:75%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.98(s,1H),7.69(s,1H),7.41(d,J=8.8Hz,2H),7.23(s,1H),5.54(s,1H),2.45(d,J=15.1Hz,1H),2.12–2.02(m,6H),1.78(dd,J=28.3,18.7Hz,4H),1.61–1.47(m,6H),1.30(s,3H),1.25(s,3H),1.19(s,3H),1.16(s,3H),0.99(s,3H),0.94(d,J=6.4Hz,3H),0.87(s,3H),0.73(s,3H)。13CNMR(75MHz,CDCl3)δ:176.1,172.9,150.0,140.1,136.5,128.8,125.7,120.7,108.5,54.2,53.3,48.6,45.9,42.6,39.8,39.4,39.2,38.7,36.9,35.5,34.6,31.9,30.7,29.6,28.7,27.8,24.9,23.4,23.1,21.1,18.6,17.1,16.5,15.4。
化合物12f的制备,反应式为:
称取异恶唑熊果酸1296.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对甲氧基苯胺29.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物12f:74.20mg。收率:74%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.98(s,1H),7.57(s,1H),7.36(d,J=8.9Hz,2H),6.83(d,J=8.9Hz,2H),5.52(s,1H),3.77(s,3H),2.45(d,J=15.1Hz,1H),2.13–1.94(m,6H),1.87–1.70(m,4H),1.60–1.51(m,4H),1.30(s,3H),1.18(s,3H),1.16(s,3H),0.98(s,3H),0.93(d,J=6.4Hz,3H),0.87(s,3H),0.78(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物12g的制备,反应式为:
称取异恶唑熊果酸1296.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对硝基苯胺35.56mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物12g:73.34mg。收率:71%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.18(d,J=9.1Hz,2H),8.03(s,1H),7.98(s,1H),7.64(d,J=9.1Hz,2H),5.59(s,1H),2.45(d,J=15.1Hz,1H),2.15–2.02(m,5H),1.90–1.70(m,4H),1.58–1.53(m,5H),1.43–1.32(m,4H),1.29(s,3H),1.17(s,3H),1.17(s,3H),1.00(s,3H),0.95(d,J=6.4Hz,3H),0.85(s,3H),0.69(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物12h的制备,反应式为:
称取异恶唑熊果酸1296.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入1-苄基-4氨基哌啶46.75mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物12h:79.64mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.98(s,1H),7.31(s,1H),7.23–7.21(m,2H),5.67(d,J=7.5Hz,1H),5.31(s,1H),3.82–3.71(m,1H),3.49(s,2H),2.84–2.74(m,2H),2.45(d,J=15.1Hz,1H),2.10–2.05(m,6H),1.94–1.66(m,8H),1.52–1.41(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.89(s,6H),0.86(s,3H)。13CNMR(75MHz,CDCl3)δ:176.9,172.9,150.0,139.4,137.8,129.1,128.1,127.0,125.1,108.6,63.0,54.0,53.3,52.1,47.7,46.0,42.6,39.6,38.9,38.5,37.4,35.5,34.6,31.9,31.6,30.8,28.7,27.8,24.5,23.1,22.8,21.1,18.6,17.1,15.4。
化合物12i的制备,反应式为:
称取异恶唑熊果酸1296.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨乙基哌啶31.43mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物12i:70.46mg。收率:69%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.97(s,1H),6.56(s,1H),5.36(s,1H),3.42–3.30(m,1H),3.26–3.15(m,1H),2.47–240(m,7H),2.09–2.00(m,3H),1.99–1.83(m,3H),1.75–1.71(m,3H),1.64–1.54(m,6H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.92(s,3H),0.89(d,J=6.0Hz,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.2,125.1,108.6,56.8,54.5,54.0,53.3,47.6,45.9,42.4,39.6,38.9,38.5,37.2,35.6,34.6,31.9,30.8,28.7,27.8,25.9,24.6,24.2,23.1,21.1,18.7,17.1,16.5,15.3。
化合物12j的制备,反应式为:
称取异恶唑熊果酸1296.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨基丙基吗啉35.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物12j:71.07mg。收率:71%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.97(s,1H),6.41(d,J=5.1Hz,1H),5.34(s,1H),3.82–3.61(m,4H),3.47–3.41(m,1H),3.15–3.00(m,1H),2.48–2.37(m,6H),2.05–2.01(m,6H),1.74–1.70(m,6H),1.56–1.38(m,6H),1.30(s,3H),1.21(s,3H),1.11(s,3H),0.96(s,3H),0.92(s,3H),0.89(d,J=6.9Hz,6H),0.83(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.6,125.0,108.6,66.7,57.4,53.7,53.3,47.5,45.9,42.4,39.5,38.9,38.5,37.3,35.5,34.6,32.0,30.7,29.5,28.7,27.7,25.3,24.6,23.2,21.1,18.7,17.1,16.6,15.3。
化合物12k的制备,反应式为:
称取异恶唑熊果酸1296.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苄胺26.33mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物12k:72.23mg。收率:74%。产物表征,数据为:1HNMR(300MHz,CDCl3)δ:7.96(s,1H),7.40–7.27(m,3H),7.23(s,2H),6.16(t,J=5.1Hz,1H),5.27(d,J=3.3Hz,1H),4.52(dd,J=14.5,5.8Hz,1H),4.21(dd,J=14.5,4.6Hz,1H),2.43(d,J=15.1Hz,1H),2.07–1.83(m,7H),1.80–1.68(m,3H),1.58–1.36(m,7H),1.30(s,3H),1.21(s,3H),1.10(s,3H),0.95(s,3H),0.86(d,J=6.1Hz,3H),0.85(s,3H),0.75(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.7,138.2,128.5,127.8,127.3,125.3,108.6,54.0,53.3,47.7,45.9,43.6,42.5,39.6,38.9,38.4,37.1,35.5,34.6,32.0,30.8,28.7,27.8,24.7,23.1,21.1,18.6,17.0,16.7,15.3。
化合物13的制备,反应式为:
称取异恶唑熊果酸124.83g(10.0mmol)溶于100mL甲醇和乙醚的混合溶剂中,常温反应过夜后蒸除溶剂,用1N的盐酸溶液酸化,乙酸乙酯萃取,无水硫酸钠干燥,过滤,浓缩得粗品,无需分离直接进行下一步反应。向上述粗品中加入DDQ2.56g(12.0mmol),乙醇100mL,回流反应3h后冷却,减压蒸去溶剂,水洗,乙酸乙酯萃取,无水硫酸钠干燥,过滤,浓缩,柱层析分离(石油醚/乙酸乙酯=5/1)得化合物氰基熊果酸13:4.23g,收率:91%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.76(s,1H),5.32(s,1H),2.24(d,J=11.5Hz,1H),2.15–1.98(m,4H),1.92–1.78(m,2H),1.76–1.63(m,3H),1.63–1.48(m,5H),1.28–1.24(m,3H),1.22(s,3H),1.20(s,3H),1.12(s,3H),1.11(s,3H),0.95(d,J=5.9Hz,3H),0.88(s,3H),0.87(d,J=6.0Hz,3H)。13CNMR(75MHz,CDCl3)δ:198.0,183.2,169.9,138.8,124.2,114.8,113.8,52.6,52.5,47.9,44.8,42.3,40.9,40.4,38.8,38.7,36.4,32.3,30.4,29.6,27.7,23.8,23.4,23.0,21.5,21.0,18.6,18.0,17.5,16.9。
化合物13a的制备,反应式为:
称取氰基熊果酸1395.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入甘氨基酸乙酯盐酸盐33.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物13a:90.67mg。收率:88%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.75(s,1H),6.45(t,J=4.3Hz,1H),5.46(t,J=3.3Hz,1H),4.21(q,J=7.1Hz,2H),4.03(dd,J=18.7,5.0Hz,1H),3.87(dd,J=18.7,3.8Hz,1H),2.20–1.97(m,4H),1.89–1.70(m,4H),1.60–1.47(m,6H),1.42–1.37(m,3H),1.28(t,J=7.2Hz,1H),1.26(d,J=7.3Hz,1H),1.24(s,3H),1.20(s,3H),1.19(s,3H),1.12(s,3H),1.11(s,3H),0.96(s,3H),0.89(d,J=6.4Hz,3H),0.87–0.83(m,2H),0.81(s,3H)。13CNMR(75MHz,CDCl3)δ:198.0,177.6,169.8,139.7,124.6,114.8,113.8,61.4,53.6,52.4,47.6,44.7,42.6,41.6,41.0,40.4,40.3,39.5,38.8,36.9,32.1,31.8,30.7,29.6,29.2,27.7,27.6,24.6,23.2,22.6,21.5,21.0,18.6,17.9,17.1,17.0,14.0。
化合物13b的制备,反应式为:
称取氰基熊果酸1395.50mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入亮氨基酸甲酯盐酸盐37.45mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物13b:88.11mg。收率:90%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.75(s,1H),6.27(d,J=7.2Hz,1H),5.44(s,1H),4.61–4.51(m,1H),3.69(s,3H),2.16–2.01(m,3H),1.88–1.64(m,5H),1.64–1.46(m,9H),1.20(d,J=3.5Hz,3H),1.12(s,3H),1.10(s,3H),0.96(s,3H),0.94–0.87(m,6H),0.92(d,J=5.8Hz,3H),0.79(s,3H)。13CNMR(75MHz,CDCl3)δ:198.0,177.1,173.6,169.9,139.1,124.7,114.8,113.8,53.7,52.5,52.0,50.6,47.8,44.8,42.7,42.1,41.0,40.5,40.4,39.5,38.9,37.3,32.3,30.7,27.7,27.6,24.8,24.5,23.1,22.6,22.3,21.5,21.0,18.6,17.9,17.3,17.1。
化合物13c的制备,反应式为:
称取氰基熊果酸1395.50mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苯丙氨基酸甲酯盐酸盐47.40mg(0.24mmol)和1.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物13c:82.78mg。收率:85%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.72(s,1H),7.30(d,J=6.2Hz,1H),7.10(d,J=6.4Hz,2H),6.30(d,J=6.4Hz,1H),5.30(s,1H),4.79–4.66(m,1H),3.68(s,3H),3.08(qd,J=13.7,5.9Hz,2H),2.14–1.86(m,4H),1.83–1.75(m,2H),1.57–1.43(m,6H),1.41–1.29(m,3H),1.18(d,J=4.5Hz,3H),1.12(s,3H),1.07(s,3H),0.94(s,3H),0.85(d,J=6.3Hz,3H),0.69(s,3H)。13CNMR(75MHz,CDCl3)δ:198.0,177.1,172.1,169.9,139.0,136.1,129.2,128.4,127.0,124.7,114.8,113.8,53.5,53.3,52.4,52.1,47.7,44.7,42.6,41.0,40.4,40.3,39.4,38.9,38.0,37.1,32.2,30.7,27.7,27.5,24.5,23.1,23.0,21.5,21.0,18.6,17.9,17.1,17.0。
化合物13d的制备,反应式为:
称取氰基熊果酸1396.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入正丙胺14.46mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物13d:72.09mg。收率:73%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.75(s,1H),5.89(s,1H),5.36(s,1H),3.35–3.22(m,1H),3.05–2.93(m,1H),2.44(d,J=15.1Hz,1H),2.07–1.86(m,6H),1.74–1.70(m,3H),1.53–1.40(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.90(s,3H),0.88(d,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.7,172.9,150.0,139.9,125.0,108.6,53.9,53.3,47.6,45.9,42.5,41.1,40.1,39.6,38.9,38.5,37.1,35.5,34.6,31.9,30.8,28.7,27.8,24.7,23.1,22.4,21.1,18.7,17.1,16.6,15.4,11.4。
化合物13e的制备,反应式为:
称取氰基熊果酸1396.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对氯苯胺32.00mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物13e:76.21mg。收率:75%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.75(s,1H),7.69(s,1H),7.41(d,J=8.8Hz,2H),7.23(s,1H),5.54(s,1H),2.45(d,J=15.1Hz,1H),2.12–2.02(m,6H),1.78(dd,J=28.3,18.7Hz,4H),1.61–1.47(m,6H),1.30(s,3H),1.25(s,3H),1.19(s,3H),1.16(s,3H),0.99(s,3H),0.94(d,J=6.4Hz,3H),0.87(s,3H),0.73(s,3H)。13CNMR(75MHz,CDCl3)δ:176.1,172.9,150.0,140.1,136.5,128.8,125.7,120.7,108.5,54.2,53.3,48.6,45.9,42.6,39.8,39.4,39.2,38.7,36.9,35.5,34.6,31.9,30.7,29.6,28.7,27.8,24.9,23.4,23.1,21.1,18.6,17.1,16.5,15.4。
化合物13f的制备,反应式为:
称取氰基熊果酸1396.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对甲氧基苯胺29.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物13f:74.20mg。收率:74%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.75(s,1H),7.57(s,1H),7.36(d,J=8.9Hz,2H),6.83(d,J=8.9Hz,2H),5.52(s,1H),3.77(s,3H),2.45(d,J=15.1Hz,1H),2.13–1.94(m,6H),1.87–1.70(m,4H),1.60–1.51(m,4H),1.30(s,3H),1.18(s,3H),1.16(s,3H),0.98(s,3H),0.93(d,J=6.4Hz,3H),0.87(s,3H),0.78(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物13g的制备,反应式为:
称取氰基熊果酸1396.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对硝基苯胺35.56mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物13g:73.34mg。收率:71%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.18(d,J=9.1Hz,2H),8.03(s,1H),7.75(s,1H),7.64(d,J=9.1Hz,2H),5.59(s,1H),2.45(d,J=15.1Hz,1H),2.15–2.02(m,5H),1.90–1.70(m,4H),1.58–1.53(m,5H),1.43–1.32(m,4H),1.29(s,3H),1.17(s,3H),1.17(s,3H),1.00(s,3H),0.95(d,J=6.4Hz,3H),0.85(s,3H),0.69(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物13h的制备,反应式为:
称取氰基熊果酸1396.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入1-苄基-4氨基哌啶46.75mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物13h:79.64mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.75(s,1H),7.31(s,1H),7.23–7.21(m,2H),5.67(d,J=7.5Hz,1H),5.31(s,1H),3.82–3.71(m,1H),3.49(s,2H),2.84–2.74(m,2H),2.45(d,J=15.1Hz,1H),2.10–2.05(m,6H),1.94–1.66(m,8H),1.52–1.41(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.89(s,6H),0.86(s,3H)。13CNMR(75MHz,CDCl3)δ:176.9,172.9,150.0,139.4,137.8,129.1,128.1,127.0,125.1,108.6,63.0,54.0,53.3,52.1,47.7,46.0,42.6,39.6,38.9,38.5,37.4,35.5,34.6,31.9,31.6,30.8,28.7,27.8,24.5,23.1,22.8,21.1,18.6,17.1,15.4。
化合物13i的制备,反应式为:
称取氰基熊果酸1396.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨乙基哌啶31.43mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物13i:70.46mg。收率:69%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.75(s,1H),6.56(s,1H),5.36(s,1H),3.42–3.30(m,1H),3.26–3.15(m,1H),2.47–240(m,7H),2.09–2.00(m,3H),1.99–1.83(m,3H),1.75–1.71(m,3H),1.64–1.54(m,6H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.92(s,3H),0.89(d,J=6.0Hz,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.2,125.1,108.6,56.8,54.5,54.0,53.3,47.6,45.9,42.4,39.6,38.9,38.5,37.2,35.6,34.6,31.9,30.8,28.7,27.8,25.9,24.6,24.2,23.1,21.1,18.7,17.1,16.5,15.3。
化合物13j的制备,反应式为:
称取氰基熊果酸1396.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨基丙基吗啉35.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物13j:71.07mg。收率:71%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.75(s,1H),6.41(d,J=5.1Hz,1H),5.34(s,1H),3.82–3.61(m,4H),3.47–3.41(m,1H),3.15–3.00(m,1H),2.48–2.37(m,6H),2.05–2.01(m,6H),1.74–1.70(m,6H),1.56–1.38(m,6H),1.30(s,3H),1.21(s,3H),1.11(s,3H),0.96(s,3H),0.92(s,3H),0.89(d,J=6.9Hz,6H),0.83(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.6,125.0,108.6,66.7,57.4,53.7,53.3,47.5,45.9,42.4,39.5,38.9,38.5,37.3,35.5,34.6,32.0,30.7,29.5,28.7,27.7,25.3,24.6,23.2,21.1,18.7,17.1,16.6,15.3。
化合物13k的制备,反应式为:
称取氰基熊果酸1396.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苄胺26.33mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物13k:72.23mg。收率:74%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.75(s,1H),7.40–7.27(m,3H),7.23(s,2H),6.16(t,J=5.1Hz,1H),5.27(d,J=3.3Hz,1H),4.52(dd,J=14.5,5.8Hz,1H),4.21(dd,J=14.5,4.6Hz,1H),2.43(d,J=15.1Hz,1H),2.07–1.83(m,7H),1.80–1.68(m,3H),1.58–1.36(m,7H),1.30(s,3H),1.21(s,3H),1.10(s,3H),0.95(s,3H),0.86(d,J=6.1Hz,3H),0.85(s,3H),0.75(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.7,138.2,128.5,127.8,127.3,125.3,108.6,54.0,53.3,47.7,45.9,43.6,42.5,39.6,38.9,38.4,37.1,35.5,34.6,32.0,30.8,28.7,27.8,24.7,23.1,21.1,18.6,17.0,16.7,15.3。
化合物16的制备,反应式为:
称取3-羰基熊果酸(2)4.54g(10.0mmol)和N,N-二甲基甲酰胺二甲基缩醛2.38g(20.0mmol),甲醇钠1.08g(20.0mmol)溶于150mL无水甲苯中回流,加入分水器除去蒸发出的水,反应完毕后除去溶剂,无需进一步分离直接进入下一步反应。向其中加入醋酸甲脒1.55g(15.0mmol),150mL无水乙醇和几滴三乙胺,回流5h后除去溶剂,水洗,乙酸乙酯萃取,无水硫酸钠干燥,柱层析分离得嘧啶熊果酸酯151.66g。收率:33%。嘧啶熊果酸酯15504mg(1.00mmol)和无水碘化锂1.33g(10.0mmol)于DMF中回流48h后冷却,加入冷水后用乙酸乙酯萃取,洗涤,无水硫酸钠干燥,柱层析分离得嘧啶熊果酸衍生物16274.09mg。收率:56%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:9.00(s,1H),8.28(s,1H),5.44(s,1H),2.71(d,J=15.8Hz,1H),2.34(d,J=15.7Hz,1H),2.13–1.96(m,4H),1.82–1.67(m,6H),1.58–1.50(m,5H),1.49–1.39(m,5H),1.29(s,3H),1.24(d,J=5.4Hz,3H),1.23(s,3H),1.12(s,3H),0.92(d,J=6.4Hz,3H),0.91(s,3H),0.84(s,3H),0.77(s,3H)。13CNMR(75MHz,CDCl3)δ:177.3,157.3,156.7,138.4,127.3,126.0,53.8,52.8,50.6,47.8,45.6,42.5,39.6,39.1,38.9,37.3,35.8,32.2,30.8,29.6,27.7,24.8,24.7,23.9,22.3,21.0,19.84,17.0,16.5,15.1。
化合物16a的制备,反应式为:
称取嘧啶熊果酸1698.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入甘氨基酸乙酯盐酸盐33.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物16a:45.78mg。收率:48%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:9.01(s,1H),8.29(s,1H),6.53(s,1H),5.48(s,1H),4.20(q,J=7.2Hz,2H),4.06(dd,J=18.0,4.4Hz,1H),3.85(dd,J=18.7,1.6Hz,1H),2.71(d,J=15.7Hz,1H),2.35(d,J=15.7Hz,1H),2.15–1.82(m,6H),1.78–1.66(m,3H),1.54–1.38(m,7H),1.30(s,3H),1.24(s,6H),1.14(s,3H),0.96(s,3H),0.90(d,J=6.7Hz,3H),0.88–0.82(m,6H),0.80(s,3H)。13CNMR(75MHz,CDCl3)δ:177.9,172.4,170.1157.3,156.7,139.1,127.3,125.9,61.4,53.8,52.8,47.7,45.6,42.5,42.2,41.6,39.7,39.4,39.1,38.9,36.9,35.8,32.0,31.8,29.6,29.2,27.7,24.8,23.6,22.6,21.1,19.8,17.1,16.2,15.1,14.0。
化合物16b的制备,反应式为:
称取嘧啶熊果酸1698.50mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入亮氨基酸甲酯盐酸盐37.45mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物16b:44.41mg。收率:47%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:9.02(s,1H),8.31(s,1H),6.35(d,J=7.2Hz,1H),5.46(t,J=3.4Hz,1H),4.61–4.55(m,1H),3.70(s,3H),2.73(d,J=15.8Hz,1H),2.36(d,J=15.8Hz,1H),2.14–2.02(m,4H),1.85–1.69(m,4H),1.66–1.55(m,5H),1.55–1.44(m,5H),1.32(s,3H),1.28(s,3H),1.14(s,3H),0.97(s,3H),0.95(s,3H),0.93(s,3H),0.92(d,J=7.6Hz,3H),0.86(s,3H),0.79(s,3H)。13CNMR(75MHz,CDCl3)δ:177.4,173.6,156.7,138.5,126.1,53.9,53.0,52.1,50.8,47.9,45.7,42.6,42.3,39.8,39.5,39.3,39.0,37.5,35.9,32.3,31.1,30.9,27.8,24.9,24.8,23.7,23.5,23.2,22.7,22.4,21.2,20.0,17.2,16.6,15.2。
化合物16c的制备,反应式为:
称取嘧啶熊果酸1698.50mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苯丙氨基酸甲酯盐酸盐47.40mg(0.24mmol)和1.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物16c:42.50mg。收率:45%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:9.02(s,1H),8.30(s,1H),7.29(s,1H),7.11(d,J=6.2Hz,2H),6.39(d,J=6.2Hz,1H),5.33(s,1H),4.80–4.69(m,1H),3.67(s,3H),3.10(qd,J=13.6,5.9Hz,2H),2.70(d,J=15.9Hz,1H),2.33(d,J=15.8Hz,1H),2.06–2.01(m,2H),1.94–1.78(m,2H),1.74–1.60(m,5H),1.44–1.36(m,4H),1.31(s,3H),1.26(s,6H),1.10(s,3H),0.95(s,3H),0.88(s,3H),0.87(d,J=6.5Hz,3H),0.82(s,3H),0.70(s,3H)。13CNMR(75MHz,CDCl3)δ:177.3,172.5,172.1,157.3,156.7,138.4,136.1,129.3,128.4,127.3,126.9,126.0,53.5,52.8,52.0,47.7,45.6,42.3,39.5,39.1,39.0,38.1,37.6,35.7,32.0,30.9,30.8,29.6,29.4,27.6,24.7,23.6,23.2,22.6,21.0,19.8,17.0,16.3,15.1,14.0。
化合物16d的制备,反应式为:
称取嘧啶熊果酸1698.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入正丙胺14.46mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物16d:77.09mg。收率:67%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:9.01(s,1H),8.29(s,1H),5.89(s,1H),5.36(s,1H),3.35–3.22(m,1H),3.05–2.93(m,1H),2.44(d,J=15.1Hz,1H),2.07–1.86(m,6H),1.74–1.70(m,3H),1.53–1.40(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.90(s,3H),0.88(d,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.7,172.9,150.0,139.9,125.0,108.6,53.9,53.3,47.6,45.9,42.5,41.1,40.1,39.6,38.9,38.5,37.1,35.5,34.6,31.9,30.8,28.7,27.8,24.7,23.1,22.4,21.1,18.7,17.1,16.6,15.4,11.4。
化合物16e的制备,反应式为:
称取嘧啶熊果酸1698.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对氯苯胺32.00mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物16e:84.21mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:9.01(s,1H),8.29(s,1H),7.69(s,1H),7.41(d,J=8.8Hz,2H),7.23(s,1H),5.54(s,1H),2.45(d,J=15.1Hz,1H),2.12–2.02(m,6H),1.78(dd,J=28.3,18.7Hz,4H),1.61–1.47(m,6H),1.30(s,3H),1.25(s,3H),1.19(s,3H),1.16(s,3H),0.99(s,3H),0.94(d,J=6.4Hz,3H),0.87(s,3H),0.73(s,3H)。13CNMR(75MHz,CDCl3)δ:176.1,172.9,150.0,140.1,136.5,128.8,125.7,120.7,108.5,54.2,53.3,48.6,45.9,42.6,39.8,39.4,39.2,38.7,36.9,35.5,34.6,31.9,30.7,29.6,28.7,27.8,24.9,23.4,23.1,21.1,18.6,17.1,16.5,15.4。
化合物16f的制备,反应式为:
称取嘧啶熊果酸1698.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对甲氧基苯胺29.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物16f:82.20mg。收率:70%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:9.01(s,1H),8.29(s,1H),7.57(s,1H),7.36(d,J=8.9Hz,2H),6.83(d,J=8.9Hz,2H),5.52(s,1H),3.77(s,3H),2.45(d,J=15.1Hz,1H),2.13–1.94(m,6H),1.87–1.70(m,4H),1.60–1.51(m,4H),1.30(s,3H),1.18(s,3H),1.16(s,3H),0.98(s,3H),0.93(d,J=6.4Hz,3H),0.87(s,3H),0.78(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物16g的制备,反应式为:
称取嘧啶熊果酸1698.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对硝基苯胺35.56mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物16g:82.34mg。收率:73%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.18(d,J=9.1Hz,2H),8.03(s,1H),9.01(s,1H),8.29(s,1H),7.64(d,J=9.1Hz,2H),5.59(s,1H),2.45(d,J=15.1Hz,1H),2.15–2.02(m,5H),1.90–1.70(m,4H),1.58–1.53(m,5H),1.43–1.32(m,4H),1.29(s,3H),1.17(s,3H),1.17(s,3H),1.00(s,3H),0.95(d,J=6.4Hz,3H),0.85(s,3H),0.69(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物16h的制备,反应式为:
称取嘧啶熊果酸1698.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入1-苄基-4氨基哌啶46.75mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物16h:86.64mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:9.01(s,1H),8.29(s,1H),7.31(s,1H),7.23–7.21(m,2H),5.67(d,J=7.5Hz,1H),5.31(s,1H),3.82–3.71(m,1H),3.49(s,2H),2.84–2.74(m,2H),2.45(d,J=15.1Hz,1H),2.10–2.05(m,6H),1.94–1.66(m,8H),1.52–1.41(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.89(s,6H),0.86(s,3H)。13CNMR(75MHz,CDCl3)δ:176.9,172.9,150.0,139.4,137.8,129.1,128.1,127.0,125.1,108.6,63.0,54.0,53.3,52.1,47.7,46.0,42.6,39.6,38.9,38.5,37.4,35.5,34.6,31.9,31.6,30.8,28.7,27.8,24.5,23.1,22.8,21.1,18.6,17.1,15.4。
化合物16i的制备,反应式为:
称取嘧啶熊果酸1698.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨乙基哌啶31.43mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物16i:79.46mg。收率:69%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:9.01(s,1H),8.29(s,1H),6.56(s,1H),5.36(s,1H),3.42–3.30(m,1H),3.26–3.15(m,1H),2.47–240(m,7H),2.09–2.00(m,3H),1.99–1.83(m,3H),1.75–1.71(m,3H),1.64–1.54(m,6H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.92(s,3H),0.89(d,J=6.0Hz,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.2,125.1,108.6,56.8,54.5,54.0,53.3,47.6,45.9,42.4,39.6,38.9,38.5,37.2,35.6,34.6,31.9,30.8,28.7,27.8,25.9,24.6,24.2,23.1,21.1,18.7,17.1,16.5,15.3。
化合物16j的制备,反应式为:
称取嘧啶熊果酸1698.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨基丙基吗啉35.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物16j:78.07mg。收率:69%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:9.01(s,1H),8.29(s,1H),6.41(d,J=5.1Hz,1H),5.34(s,1H),3.82–3.61(m,4H),3.47–3.41(m,1H),3.15–3.00(m,1H),2.48–2.37(m,6H),2.05–2.01(m,6H),1.74–1.70(m,6H),1.56–1.38(m,6H),1.30(s,3H),1.21(s,3H),1.11(s,3H),0.96(s,3H),0.92(s,3H),0.89(d,J=6.9Hz,6H),0.83(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.6,125.0,108.6,66.7,57.4,53.7,53.3,47.5,45.9,42.4,39.5,38.9,38.5,37.3,35.5,34.6,32.0,30.7,29.5,28.7,27.7,25.3,24.6,23.2,21.1,18.7,17.1,16.6,15.3。
化合物16k的制备,反应式为:
称取嘧啶熊果酸1698.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苄胺26.33mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物16k:76.23mg。收率:70%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.40–7.27(m,3H),7.23(s,2H),9.01(s,1H),8.29(s,1H),6.16(t,J=5.1Hz,1H),5.27(d,J=3.3Hz,1H),4.52(dd,J=14.5,5.8Hz,1H),4.21(dd,J=14.5,4.6Hz,1H),2.43(d,J=15.1Hz,1H),2.07–1.83(m,7H),1.80–1.68(m,3H),1.58–1.36(m,7H),1.30(s,3H),1.21(s,3H),1.10(s,3H),0.95(s,3H),0.86(d,J=6.1Hz,3H),0.85(s,3H),0.75(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.7,138.2,128.5,127.8,127.3,125.3,108.6,54.0,53.3,47.7,45.9,43.6,42.5,39.6,38.9,38.4,37.1,35.5,34.6,32.0,30.8,28.7,27.8,24.7,23.1,21.1,18.6,17.0,16.7,15.3。
化合物18的制备,反应式为:
称取3-羰基熊果酸(2)4.54g(10.0mmol)和5,5-二溴-2,2-二甲基-4,6-二酮-1,3-二氧杂环己烷3.64g(0.3mmol)溶于100mL无水乙醚中,室温搅拌过夜。反应完全后,水洗,乙酸乙酯萃取,干燥,浓缩得2-溴-3-羰基熊果酸17。将化合物17与硫脲1.14g(15.0mmol)于100mL乙醇中回流3h,冷却后蒸除溶剂,水洗,乙酸乙酯萃取,无水硫酸钠干燥,柱层析分离得氨基噻唑熊果酸衍生物18:2.56g。收率:55%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:5.30(s,1H),2.86(dd,J=13.7,4.0Hz,1H),2.59-2.46(m,1H),2.42-2.30(m,1H),2.02-1.82(m,4H),1.80-1.53(m,6H),1.50-1.26(m,7H),1.24-0.99(m,15H),0.91(s,3H),0.89(s,3H),0.79(s,3H)。13CNMR(100MHz,CDCl3)δ(ppm)184.6,143.6,121.7,55.3,47.4,46.9,46.6,45.8,41.7,41.0,39.3,39.1,36.8,34.1,33.8,33.9,32.3,32.2,30.6,27.0,26.3,25.8,23.6,23.4,22.3,21.5,19.6,17.5,14.1。
化合物18a的制备,反应式为:
称取氨基噻唑熊果酸18100.25mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入甘氨基酸乙酯盐酸盐33.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物18a:56.82mg。收率:55%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:2.71(d,J=15.7Hz,1H),2.35(d,J=15.7Hz,1H),2.15–1.82(m,6H),1.78–1.66(m,3H),1.54–1.38(m,7H),1.30(s,3H),1.24(s,6H),1.14(s,3H),0.96(s,3H),0.90(d,J=6.7Hz,3H),0.88–0.82(m,6H),0.80(s,3H)。13CNMR(75MHz,CDCl3)δ:177.9,172.4,170.1157.3,156.7,139.1,127.3,125.9,61.4,53.8,52.8,47.7,45.6,42.5,42.2,41.6,39.7,39.4,39.1,38.9,36.9,35.8,32.0,31.8,29.6,29.2,27.7,24.8,23.6,22.6,21.1,19.8,17.1,16.2,15.1,14.0。
化合物18b的制备,反应式为:
称取氨基噻唑熊果酸18100.25mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入亮氨基酸甲酯盐酸盐37.45mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物18b:46.49mg。收率:59%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:2.73(d,J=15.8Hz,1H),2.36(d,J=15.8Hz,1H),2.14–2.02(m,4H),1.85–1.69(m,4H),1.66–1.55(m,5H),1.55–1.44(m,5H),1.32(s,3H),1.28(s,3H),1.14(s,3H),0.97(s,3H),0.95(s,3H),0.93(s,3H),0.92(d,J=7.6Hz,3H),0.86(s,3H),0.79(s,3H)。13CNMR(75MHz,CDCl3)δ:177.4,173.6,156.7,138.5,126.1,53.9,53.0,52.1,50.8,47.9,45.7,42.6,42.3,39.8,39.5,39.3,39.0,37.5,35.9,32.3,31.1,30.9,27.8,24.9,24.8,23.7,23.5,23.2,22.7,22.4,21.2,20.0,17.2,16.6,15.2。
化合物18c的制备,反应式为:
称取氨基噻唑熊果酸18100.25mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苯丙氨基酸甲酯盐酸盐47.40mg(0.24mmol)和1.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物18c:43.50mg。收率:52%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:2.70(d,J=15.9Hz,1H),2.33(d,J=15.8Hz,1H),2.06–2.01(m,2H),1.94–1.78(m,2H),1.74–1.60(m,5H),1.44–1.36(m,4H),1.31(s,3H),1.26(s,6H),1.10(s,3H),0.95(s,3H),0.88(s,3H),0.87(d,J=6.5Hz,3H),0.82(s,3H),0.70(s,3H)。13CNMR(75MHz,CDCl3)δ:177.3,172.5,172.1,157.3,156.7,138.4,136.1,129.3,128.4,127.3,126.9,126.0,53.5,52.8,52.0,47.7,45.6,42.3,39.5,39.1,39.0,38.1,37.6,35.7,32.0,30.9,30.8,29.6,29.4,27.6,24.7,23.6,23.2,22.6,21.0,19.8,17.0,16.3,15.1,14.0。
化合物18d的制备,反应式为:
称取氨基噻唑熊果酸18102.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入正丙胺14.46mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物18d:78.09mg。收率:67%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:5.89(s,1H),5.36(s,1H),3.35–3.22(m,1H),3.05–2.93(m,1H),2.44(d,J=15.1Hz,1H),2.07–1.86(m,6H),1.74–1.70(m,3H),1.53–1.40(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.90(s,3H),0.88(d,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.7,172.9,150.0,139.9,125.0,108.6,53.9,53.3,47.6,45.9,42.5,41.1,40.1,39.6,38.9,38.5,37.1,35.5,34.6,31.9,30.8,28.7,27.8,24.7,23.1,22.4,21.1,18.7,17.1,16.6,15.4,11.4。
化合物18e的制备,反应式为:
称取氨基噻唑熊果酸18102.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对氯苯胺32.00mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物18e:85.21mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.69(s,1H),7.41(d,J=8.8Hz,2H),7.23(s,1H),5.54(s,1H),2.45(d,J=15.1Hz,1H),2.12–2.02(m,6H),1.78(dd,J=28.3,18.7Hz,4H),1.61–1.47(m,6H),1.30(s,3H),1.25(s,3H),1.19(s,3H),1.16(s,3H),0.99(s,3H),0.94(d,J=6.4Hz,3H),0.87(s,3H),0.73(s,3H)。13CNMR(75MHz,CDCl3)δ:176.1,172.9,150.0,140.1,136.5,128.8,125.7,120.7,108.5,54.2,53.3,48.6,45.9,42.6,39.8,39.4,39.2,38.7,36.9,35.5,34.6,31.9,30.7,29.6,28.7,27.8,24.9,23.4,23.1,21.1,18.6,17.1,16.5,15.4。
化合物18f的制备,反应式为:
称取氨基噻唑熊果酸18102.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对甲氧基苯胺29.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物18f:83.20mg。收率:70%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.57(s,1H),7.36(d,J=8.9Hz,2H),6.83(d,J=8.9Hz,2H),5.52(s,1H),3.77(s,3H),2.45(d,J=15.1Hz,1H),2.13–1.94(m,6H),1.87–1.70(m,4H),1.60–1.51(m,4H),1.30(s,3H),1.18(s,3H),1.16(s,3H),0.98(s,3H),0.93(d,J=6.4Hz,3H),0.87(s,3H),0.78(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物18g的制备,反应式为:
称取氨基噻唑熊果酸18102.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入对硝基苯胺35.56mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物18g:83.34mg。收率:73%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:8.18(d,J=9.1Hz,2H),8.03(s,1H),7.64(d,J=9.1Hz,2H),5.59(s,1H),2.45(d,J=15.1Hz,1H),2.15–2.02(m,5H),1.90–1.70(m,4H),1.58–1.53(m,5H),1.43–1.32(m,4H),1.29(s,3H),1.17(s,3H),1.17(s,3H),1.00(s,3H),0.95(d,J=6.4Hz,3H),0.85(s,3H),0.69(s,3H)。13CNMR(75MHz,CDCl3)δ:175.8,172.9,156.1,150.0,140.0,131.1,125.5,121.3,113.9,108.6,55.3,54.2,53.3,48.3,45.9,42.6,39.8,39.5,39.0,38.4,37.0,35.5,34.6,31.9,30.8,28.7,27.8,24.9,23.2,23.0,21.1,18.6,17.1,16.6,15.4。
化合物18h的制备,反应式为:
称取氨基噻唑熊果酸18102.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入1-苄基-4氨基哌啶46.75mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物18h:76.64mg。收率:72%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.31(s,1H),7.23–7.21(m,2H),5.67(d,J=7.5Hz,1H),5.31(s,1H),3.82–3.71(m,1H),3.49(s,2H),2.84–2.74(m,2H),2.45(d,J=15.1Hz,1H),2.10–2.05(m,6H),1.94–1.66(m,8H),1.52–1.41(m,7H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.89(s,6H),0.86(s,3H)。13CNMR(75MHz,CDCl3)δ:176.9,172.9,150.0,139.4,137.8,129.1,128.1,127.0,125.1,108.6,63.0,54.0,53.3,52.1,47.7,46.0,42.6,39.6,38.9,38.5,37.4,35.5,34.6,31.9,31.6,30.8,28.7,27.8,24.5,23.1,22.8,21.1,18.6,17.1,15.4。
化合物18i的制备,反应式为:
称取氨基噻唑熊果酸18102.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨乙基哌啶31.43mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物18i:72.46mg。收率:69%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:6.56(s,1H),5.36(s,1H),3.42–3.30(m,1H),3.26–3.15(m,1H),2.47–240(m,7H),2.09–2.00(m,3H),1.99–1.83(m,3H),1.75–1.71(m,3H),1.64–1.54(m,6H),1.30(s,3H),1.20(s,3H),1.11(s,3H),0.95(s,3H),0.92(s,3H),0.89(d,J=6.0Hz,3H),0.84(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.2,125.1,108.6,56.8,54.5,54.0,53.3,47.6,45.9,42.4,39.6,38.9,38.5,37.2,35.6,34.6,31.9,30.8,28.7,27.8,25.9,24.6,24.2,23.1,21.1,18.7,17.1,16.5,15.3。
化合物18j的制备,反应式为:
称取氨基噻唑熊果酸18102.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入氨基丙基吗啉35.36mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物18j:73.07mg。收率:69%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:6.41(d,J=5.1Hz,1H),5.34(s,1H),3.82–3.61(m,4H),3.47–3.41(m,1H),3.15–3.00(m,1H),2.48–2.37(m,6H),2.05–2.01(m,6H),1.74–1.70(m,6H),1.56–1.38(m,6H),1.30(s,3H),1.21(s,3H),1.11(s,3H),0.96(s,3H),0.92(s,3H),0.89(d,J=6.9Hz,6H),0.83(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.6,125.0,108.6,66.7,57.4,53.7,53.3,47.5,45.9,42.4,39.5,38.9,38.5,37.3,35.5,34.6,32.0,30.7,29.5,28.7,27.7,25.3,24.6,23.2,21.1,18.7,17.1,16.6,15.3。
化合物18k的制备,反应式为:
称取氨基噻唑熊果酸18102.59mg(0.20mmol)和草酰氯0.10mL溶于二氯甲烷中,氮气氛围下常温反应过夜,反应完毕后蒸除溶剂并且用正己烷或者环己烷移除残留的草酰氯,加入苄胺26.33mg(0.24mmol)和0.50mL的三乙胺常温反应过夜,原料消耗完毕后蒸除溶剂,柱层析分离得熊果酸衍生物18k:75.20mg。收率:71%。产物表征,数据为:1H NMR(300MHz,CDCl3)δ:7.40–7.27(m,3H),7.23(s,2H),6.16(t,J=5.1Hz,1H),5.27(d,J=3.3Hz,1H),4.52(dd,J=14.5,5.8Hz,1H),4.21(dd,J=14.5,4.6Hz,1H),2.43(d,J=15.1Hz,1H),2.07–1.83(m,7H),1.80–1.68(m,3H),1.58–1.36(m,7H),1.30(s,3H),1.21(s,3H),1.10(s,3H),0.95(s,3H),0.86(d,J=6.1Hz,3H),0.85(s,3H),0.75(s,3H)。13CNMR(75MHz,CDCl3)δ:177.6,172.9,150.0,139.7,138.2,128.5,127.8,127.3,125.3,108.6,54.0,53.3,47.7,45.9,43.6,42.5,39.6,38.9,38.4,37.1,35.5,34.6,32.0,30.8,28.7,27.8,24.7,23.1,21.1,18.6,17.0,16.7,15.3。
实施例2熊果酸衍生物具体实验实例:
1)体外抑制5-HT合成实验
实验所用细胞为色氨酸羟化酶-1的表达细胞RBL2H3,购自中科院细胞库。首先将购进的大鼠RBL2H3在37℃复苏,于37℃下用含有10%胎牛血清的α-MEM培养基(含有10%FBS,100U/mL盘尼西林,100μg/mL链霉素)培养于细胞培养箱(5%CO2/95%空气)。如无其他说明,所用实验都在此条件下进行。
体外活性实验分为两个组:对照组和给药组,每组设置三个复孔,对照组用0.1%DMSO作为对照。将细胞种于24孔板,细胞密度:5×104个/孔。待细胞完全贴壁后给药或者培养基,药物最终浓度保持在10μM。连续作用48小时后去除培养基,每孔用200μL强裂解液RIPA裂解,吹打4-5次,用流动相(乙腈:NaH2PO4水溶液=20:80,V/V)稀释,12000r/min离心十分钟后取上清,直接用高效液相(岛津,LC-20AT)色谱仪检测5-HT的含量,检测器采用RF-20A荧光检测器,激发波长和发射波长分别定为:280nm和330nm;分析柱采用Waters色谱柱(50mm×4.6mm,5μm,C18);流速设为0.4mL/min;采样时间10min。5-HT标准品购自上海有机所。首先用5-HT标准品确定样品中5-HT的保留时间,然后用积分所得面积比计算药物对5-HT生物合成的抑制率。抑制率数值越大,说明药物对5-HT生物合成抑制作用越强。结果如表1所示,表明部分化合物在体外对5-HT的合成具有明显的抑制作用。
表1:熊果酸衍生物对5-HT的抑制活性。
a抑制率=100%–(给药组5-HT峰面积/对照组5-HT峰面积×100%)。数据表示为平均值±SD;*p<0.05,**p<0.01。
2)体内抑制5-HT合成实验
体内实验分为两组,体内用药分别为7a和12g,每组实验流程如下:12周大的雌鼠,购进后分为6组:给药组(低、中、高三个剂量组),空白组,阳性药对照组,假手术组,每组8只。禁食24h后摘除卵巢造模,手术三天后给药。给药剂量分别为:1.0mg/kg.d,10mg/kg.d,20mg/kg.d。阳性对照组采用腹腔注射PTH(20μg/kg.d)。连续灌胃给药4周后颈动脉取全血,静置于37℃水浴30min得到血清,将血清用5%高氯酸酸化,用流动相稀释后12000r/min离心十分钟后取上清,直接用高效液相(岛津,LC-20AT)色谱仪检测5-HT的含量,检测器采用RF-20A荧光检测器,激发波长和发射波长分别定为:280nm和330nm;分析柱采用Waters色谱柱(50mm×4.6mm,5μm,C18);流速设为0.4mL/min;采样时间10min。
向大鼠的大脑加入2.0mL生理盐水,充分研磨后加入5%高氯酸酸化后12000r/min离心十分钟,取上清直接用高效液相色谱仪测试5-HT含量,方法和条件如前所述。
大鼠脊椎骨骨密度用μCT(eXploreL℃usSPscanner,GEHealthCare)测试,数据用eXploreMicro-View(version2.0)处理,结果如图1-6所示,其中,图1-3为化合物7a体内活性数据,分别为5-HT在血清(图1)和脑中(图2)的含量,脊椎骨骨密度数据(图3);图4-6为化合物12g体内活性数据,分别为5-HT在血清(图4)和脑中(图5)的含量,脊椎骨骨密度数据(图6);表明大鼠脊椎骨骨密度明显增加。说明此类化合有效的防止骨质疏松大鼠骨量的减少。
Claims (7)
1.一种色氨酸羟化酶-1抑制剂熊果酸衍生物,其特征在于,结构式如下:
式中,Het基团为在C2,C3位引入杂环,所述杂环选自基团: 等,但并不局限于这些基团;其中,R2选自基团H,Cl,CH3,NO2,CF3,CN等;R3选自基团H,OH,Cl,Br,I,NO2,NH2等相同或不同的基团,但并不局限于这些基团;R4选自基团H, 等,但并不局限于这些基团;R5选自基团H、NH2,CH3等;R6选自基团H、NH2、CH3等;R1为选自基团:以及其他氨基酸及相应氨基酸的羧基被保护的基团,等杂环,等,但并不局限于这些基团,其中,n=2-9的整数,R7选自基团H、Cl、CH3、NO2等,但并不局限于这些基团。
2.一种色氨酸羟化酶-1抑制剂熊果酸衍生物的制备方法,其特征在于:首先用双氧水或其他氧化剂氧化熊果酸母核的3位羟基氧化为羰基,然后在乙酸作用下与对氯或对溴苯肼盐酸盐发生缩合反应得到吲哚熊果酸衍生物;3-羰基熊果酸在强碱叔丁醇钾作用下用空气氧化为2,3-二羰基熊果酸,再与4,5-二氯邻苯二胺或者邻苯二胺反应得到中喹喔啉熊果酸衍生物。吲哚熊果酸衍生物、喹喔啉熊果酸衍生物分别先与草酰氯作用得到吲哚或喹喔啉酰氯熊果酸,再与相应的胺反应,三乙胺为缚酸剂,得到目标产物。
3.一种色氨酸羟化酶-1抑制剂熊果酸衍生物的制备方法,其特征在于:将3-羰基熊果酸先在强碱甲醇钠作用下与甲酸乙酯作用得到中间体,然后中间体再与盐酸肼,盐酸苯肼或者对氟盐酸苯肼作用得到母核产物吡唑熊果酸衍生物;吡唑熊果酸衍生物分别先与草酰氯作用得到吡唑酰氯熊果酸,再与相应的胺反应,三乙胺为缚酸剂,得到目标产物。
4.一种色氨酸羟化酶-1抑制剂熊果酸衍生物的制备方法,其特征在于:将3-羰基熊果酸先在强碱甲醇钠作用下与甲酸乙酯作用得到中间体,中间体先与盐酸羟胺作用得到异恶唑熊果酸衍生物;异恶唑熊果酸衍生物在强碱甲醇钠作用下让异恶唑开环,再用DDQ脱氢即得到氰基熊果酸衍生物;异恶唑熊果酸衍生物、氰基熊果酸衍生物分别先与草酰氯作用得到异恶唑酰氯熊果酸,再与相应的胺反应,三乙胺为缚酸剂,得到目标产物。
5.一种色氨酸羟化酶-1抑制剂熊果酸衍生物的制备方法,其特征在于:3-羰基熊果酸先与N,N-二甲基甲酰胺二甲基缩醛作用得到2-烯胺-3-羰基熊果酸,再与醋酸甲脒关环得到嘧啶熊果酸酯,用无水碘化锂脱去酯基后与草酰氯作用得到嘧啶酰氯熊果酸,再与相应的胺反应,三乙胺为缚酸剂,得到目标产物。
6.一种色氨酸羟化酶-1抑制剂熊果酸衍生物的制备方法,其特征在于:3-羰基熊果酸先与5,5-二溴-2,2-二甲基-4,6-二酮-1,3-二氧杂环己烷在乙醚中作用得到2-溴-3-羰基熊果酸,再与硫脲关环生成噻唑熊果酸衍生物。噻唑熊果酸衍生物先与草酰氯作用得到噻唑酰氯熊果酸,再与相应的胺反应,三乙胺为缚酸剂,得到目标产物。
7.权利要求1所述的色氨酸羟化酶-1抑制剂熊果酸衍生物在制备用于抗骨质疏松药物中的应用。
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CN104098645A (zh) * | 2014-07-14 | 2014-10-15 | 南京林业大学 | 一类熊果酸吲哚衍生物、制备方法及其用途 |
WO2015198232A1 (en) * | 2014-06-25 | 2015-12-30 | Piramal Enterprises Limited | Fused triterpene compounds and uses thereof |
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EP3160981A4 (en) * | 2014-06-25 | 2017-12-06 | Piramal Enterprises Limited | Fused triterpene compounds and uses thereof |
WO2015198232A1 (en) * | 2014-06-25 | 2015-12-30 | Piramal Enterprises Limited | Fused triterpene compounds and uses thereof |
US10105373B2 (en) | 2014-06-25 | 2018-10-23 | Piramal Enterprises Limited | Fused triterpene compounds and uses thereof |
CN104098645A (zh) * | 2014-07-14 | 2014-10-15 | 南京林业大学 | 一类熊果酸吲哚衍生物、制备方法及其用途 |
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CN105693815B (zh) * | 2016-04-14 | 2017-09-22 | 福州大学 | 一种哌嗪修饰的乌索酸衍生物及其制备方法和应用 |
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CN106946974B (zh) * | 2017-03-17 | 2020-03-31 | 中国科学院上海高等研究院 | 一类含吡唑杂环的熊果酰胺衍生物及其合成与应用 |
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CN112390709A (zh) * | 2019-08-15 | 2021-02-23 | 香港理工大学深圳研究院 | Tph-1抑制剂及其制备方法和应用 |
CN115403658A (zh) * | 2022-05-19 | 2022-11-29 | 首都医科大学 | 熊果酰-Tyr-Gly-Phe-Gly-Gly,其合成,活性和应用 |
CN115403658B (zh) * | 2022-05-19 | 2024-04-23 | 首都医科大学 | 熊果酰-Tyr-Gly-Phe-Gly-Gly,其合成,活性和应用 |
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