CN117924297A - 桥亚甲基修饰的杯[3]咔唑衍生物及其合成方法和应用 - Google Patents
桥亚甲基修饰的杯[3]咔唑衍生物及其合成方法和应用 Download PDFInfo
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Abstract
一种桥亚甲基修饰的杯[3]咔唑衍生物及其合成方法和应用,属于医药技术领域。杯[3]咔唑母核,其结构式为:通过该母核进行改性后得到的桥亚甲基修饰的杯[3]咔唑衍生物,其结构通式为以下结构通式(I)、(II)或(III)中的一种:
Description
技术领域
本发明属于医药技术领域,涉及桥亚甲基修饰的杯[3]咔唑衍生物及其合成方法和应用,应用方面具体涉及离子荧光传感、医药分子的载体和生物大分子的识别等应用。
背景技术
随着超分子化学领域的蓬勃发展,基于冠醚、环糊精、葫芦脲、杯芳烃和柱芳烃等大环的主客体识别的相关技术,在生命医学、材料学以及药学等领域中发挥着极其重要的作用。创制新型性能优异的超分子大环主体化合物一直以来都是此领域的研究热点。近年来,发现了一种咔唑基元的大环化合物,由于其具备易合成、大空腔、富电子等优点,以及其广泛潜在用途,如离子荧光传感、医药分子的载体和生物大分子的识别等,已成为众多研究工作者关注的热点。杯[3]咔唑是一种杯咔唑是以咔唑为基本单元的新型杯芳烃,与传统的杯芳烃相比,该分子有较大的空腔,但是仅仅能够包载和其空腔结构尺寸一致或较小的药物,本发明经过杯[3]咔唑进行氧化-衍生后,不但可包载分子尺寸较大的药物,其具有良好的紫外吸收及荧光发色性能,可以采用光谱手段研究其对药物的识别检测的性能。
发明内容
本发明提供了一种桥亚甲基修饰的杯[3]咔唑衍生物及其合成方法和应用,以咔唑为原料,经亲核取代、酯化、环合等反应首先合成杯[3]咔唑母核;然后采用氧化、氨解等反应对其桥亚甲基及上沿等位点进行结构衍生,合成结构新颖的桥亚甲基修饰的杯[3]咔唑衍生物,该桥亚甲基修饰的杯[3]咔唑衍生物属于超分子大环主体化合物,其分子有较大的空腔,不但可包载分子尺寸较大的药物,而且其具有良好的紫外吸收及荧光发色性能,可以采用光谱手段研究其对药物的包载性能,以杯[3]咔唑为研究对象,对其进行结构修饰,探索并扩宽其构象的种类和范围,探索了并发现了对羟喜树碱药物的识别及包载性能。
本发明的一种杯[3]咔唑母核,其结构式为:
本发明的桥亚甲基修饰的杯[3]咔唑衍生物,其结构通式为以下结构通式(I)、(II)或(III)中的一种:
结构(I)中:n=0或1或2;
R1、R2、R3各自独立表示为C1~C2的烷氧基、苄胺基、脂肪胺基、或含O原子的脂肪胺基、乙氧基中的一种;
X选自Br或H;
结构(II)中:
R4、R5、R6各自独立表示为烷氧基、苄胺基;
R7、R8表示为H、C2~C8的烷氧基、饱和或不饱和脂肪链的多元醇基、或取代或未取代的R7、R8形成的C2-C6的环氧醚一种。当为取代的R7、R8形成的C2-C6的环氧醚,取代基优选为Br。
结构(III)中:
R9、R10、R11各自独立表示为烷氧基、苄胺基;
R12表示为H、C2~C8的烷氧基、饱和或不饱和脂肪链的多元醇基一种。
所述的C2~C8的烷氧基包括C2~C8的直链烷氧基、C2~C8的环烷氧基、卤素取代的C2~C8的环烷氧基中的一种。
所述的饱和或不饱和脂肪链的多元醇基优选C2-C8的脂肪链的多元醇基,更优选为2-(1-氧)乙烷-1-醇基、5-甲氧基戊烷-1-醇基、1-羟基乙氧基、1-羟基戊氧基、1-羟基戊氧基、1-羟基己氧基、1-羟基辛氧基、1-羟基-2-烯-1-丁氧基。
本发明中桥亚甲基修饰的杯[3]咔唑衍生物,作为优选:
R1选自乙氧基、丁胺基、苄胺基、二甘醇胺基、三甘醇胺基中的一种;
R2选自乙氧基、丁胺基、苄胺基、二甘醇胺基、三甘醇胺基中的一种;
R3选自乙氧基、丁胺基、苄胺基、二甘醇胺基、三甘醇胺基中的一种;
R4为乙氧基、R5为乙氧基、R6为乙氧基;
R7、R8独立选自H、1-羟基乙氧基、1-羟基戊氧基、1-羟基戊氧基、1-羟基己氧基、1-羟基辛氧基、1-羟基-2-烯-1-丁氧基中的一种。
本发明的桥亚甲基修饰的杯[3]咔唑衍生物,更优选为以下结构中的一种;
本发明的杯[3]咔唑母核的合成方法为,由单体合成杯[3]咔唑母核;
所述的单体结构为:
由单体合成杯[3]咔唑母核采用溶剂为二氯甲烷,反应温度为室温,单体和路易斯酸混合后,反应30-40min至溶液完全为墨绿色后,再加入多聚甲醛,4h-12h后停止反应。合成杯[3]咔唑母核时,路易斯酸选自六水三氯化铁,其中,按摩尔比,单体:路易斯酸=1:0.5,按固液比,单体:溶剂=1g:1L;按质量比,路易斯酸:多聚甲醛=(530-540):(170-180)。
本发明提供了桥亚甲基修饰的杯[3]咔唑衍生物的合成方法,包括以下步骤:
对杯[3]咔唑母核进行桥亚甲基氧化、或桥亚甲基氧化-衍生中的一种方法进行改进,得到桥亚甲基修饰的杯[3]咔唑衍生物。
对杯[3]咔唑母核进行桥亚甲基氧化时,采用的氧化剂为2,3-二氯-5,6-二氰基苯醌(DDQ),按固液比,杯[3]咔唑母核:含有脂肪链的二醇=100mg:(1-5)mL;所述的含有脂肪链的二醇溶剂选自乙二醇、丙二醇、丁二醇中的一种。
其中,按质量比,杯[3]咔唑母核:DDQ=1:(0.6~3.0),反应时间为3-8h,反应温度为-2℃~5℃。
在桥亚甲基氧化过程中,根据桥亚甲基修饰的杯[3]咔唑衍生物的结构式,还加入脂肪醇类,用于改性。所述的脂肪醇类优选为甲醇、乙二醇、1,4-丁烯二醇、戊醇、已醇、辛醇中的一种,加入脂肪醇类的量根据桥亚甲基修饰的杯[3]咔唑衍生物的结构中的饱和或不饱和脂肪链的多元醇基的数量确定。
所述的衍生,具体操作为,按固液比,杯[3]咔唑母核或氧化后的杯[3]咔唑母核:胺类化合物=(30-100)mg:(1-10)mL,所述的胺类化合物选自丁胺、苄胺、二甘醇胺、三甘醇胺中的一种,并加热至60-120℃,时间6-48h。
本发明的桥亚甲基修饰的杯[3]咔唑衍生物在识别天然产物,作为荧光探针有良好的应用。
更具体是在离子荧光传感、医药分子的载体和生物大分子的识别中的应用,生物大分子的识别更优选为在识别黄酮类化合物、识别拆分樟脑醌中的应用。
本发明的有益效果为:
具体涉及含有杯[3]咔唑桥亚甲基氧化生成缩酮结构、以及进一步取代产物及其合成方法,以及其广泛潜在用途,如离子荧光传感、医药分子的载体和生物大分子的识别等应用。
以桥亚甲基改造后杯[3]咔唑作为大环主体化合物,固定其分子刚性,探索并发现了其对重金属汞离子以及合成的羟喜树碱药物分子的主客体识别作用,并初步探索了其羟喜树碱类药物分子载体以及荧光探针、识别检测方面的潜在应用价值。
附图说明
图1为羟喜树碱的紫外光图谱。
图2为羟喜树碱和化合物Ⅰ-16的紫外滴定光图谱。
图3为羟喜树碱和化合物Ⅰ-17的紫外滴定光图谱。
图4为羟喜树碱和化合物Ⅰ-18的紫外滴定光图谱。
图5为羟喜树碱和化合物Ⅰ-16的荧光滴定光图谱。
图6为羟喜树碱和化合物Ⅰ-17的荧光滴定光图谱。
图7为羟喜树碱和化合物Ⅰ-18的荧光滴定光图谱。
图8为化合物Ⅰ-17与黄芩苷动态光散射(DLS)实验分析图。
图9为化合物Ⅰ-17与黄芩苷电镜(TEM)实验分析图。
图10为化合物Ⅰ-17与樟脑醌电镜(TEM)实验分析图。
具体实施方式
下面结合实施例对本发明作进一步的详细说明。
杯[3]咔唑母核的制备方法为:
制备方法(Ⅰ):
制备方法(Ⅱ):
在制备方法(Ⅰ),化合物b的制备方法,包括如下步骤:
化合物b合成步骤:取1g化合物a放入干燥的圆底烧瓶中(1L),加1L二氯甲烷作为反应溶剂,打开搅拌器,并保持水浴温度在25℃,向烧瓶中加入534mg的FeCl3(三氯化铁),反应40min至溶液完全为墨绿色后,向反应瓶中加入178mg的(HCHO)n(多聚甲醛),继续搅拌,点板监测。4h后停止反应。后处理:向反应液中加入5mL氨水,淬灭后,将反应液移入大烧杯中,用二氯甲烷/水相分批萃取3遍,合并后进行减压蒸馏,得到纯品200mg,为橙黄色固体。TLC:二氯甲烷:石油醚=10:1,收率为20%。
化合物Ⅰ(1-3)合成步骤:
将100mg化合物b置于烧瓶中,加入THF溶剂以及2mL乙二醇(化合物I-1)、丙二醇(化合物I-2)、丁二醇(化合物I-3)中的一种,冰浴冷却烧瓶后,加入DDQ 150mg,加入完毕后反应8h,薄层色谱分析(TLC)检测反应。待反应结束后,水、二氯甲烷萃取,将反应混合溶液进行减压蒸馏,残液经200-300目硅胶柱层析(DCM:MeOH=100:1)分离,得到产品白色固体。
化合物Ⅰ-1:52mg收率46.3%.1H NMR(600MHz,DMSO-d6)δ8.84(s,6H),7.62(d,J=8.5Hz,6H),7.35(d,J=8.5Hz,6H),5.17(s,6H),4.11(s,12H),4.03(q,J=7.1Hz,6H),1.11(t,J=7.1Hz,9H).13C NMR(150MHz,DMSO-d6)δ168.9,140.4,136.0,123.0,122.3,118.4,110.2,108.7,64.7,61.2,44.4,14.4.(MALDI-TOF):Calculated for,969.3473found:969.3465
化合物Ⅰ-2:50mg收率44.6%.1H NMR(600MHz,DMSO-d6)δ8.74(s,6H),7.56(d,J=8.5Hz,5H),7.34(d,J=8.6Hz,5H),5.15(s,4H),4.23(s,4H),4.18(s,4H),4.04(q,J=7.4Hz,5H),1.82(s,3H),1.12(d,J=7.4Hz,8H).13C NMR(150MHz,DMSO-d6)δ168.97,140.08,135.96,123.38,122.82,118.70,108.84,101.39,61.36,61.20,44.39,26.73,25.80,14.40.(MALDI-TOF):Calculated for,1011.3942found:1011.3939
化合物Ⅰ-3:纯品92mg,收率为70%。1H NMR(600MHz,DMSO-d6)δ8.82(d,J=1.8Hz,6H),7.58(d,J=1.8Hz,6H),7.29(d,J=8.6Hz,6H),5.13(s,6H),4.02(q,J=7.1Hz,6H),3.89(d,J=26.9Hz,12H),1.73(s,12H),1.10(t,J=7.1Hz,9H).13C NMR(150MHz,DMSO-d6)δ194.48,168.89,168.77,143.68,,140.21,137.33,130.79,128.97,128.61,127.99,123.35,122.17,121.76,118.59,103.91,61.71,61.49,44.77,44.46,32.91,32.67,29.69,29.64,26.72,14.52,14.42.HRMS(MALDI-TOF):Calc:1054.4445;found:1054.4482.
化合物Ⅰ(4-11)合成步骤:
化合物Ⅰ-4合成步骤:取30mg的化合物Ⅰ-1于圆底烧瓶(25mL)中,加入3mL甲醇作为反应溶剂,加入1mL丁胺作为反应原料,放入油浴锅中加热搅拌6h,反应温度60℃,采用薄层色谱板监测反应。后处理:将反应液减压蒸馏除去甲醇,之后放入冻干机,真空下抽4h,得到黄色固体,分别用乙醚,二氯甲烷溶液洗涤,得到纯品12mg,为白色固体,TLC:甲醇:二氯甲烷=1:20,收率为40%。1H NMR(600MHz,DMSO-d6)δ8.84(s,5H),7.92(s,2H),7.61(t,J=9.4Hz,6H),7.33(d,J=27.5Hz,6H),5.17(s,4H),4.83(s,2H),4.11(s,12H),4.03(q,J=7.1Hz,4H),2.95(d,J=6.8Hz,2H),1.27(d,J=7.8Hz,4H),1.11(t,J=7.1Hz,6H),0.78(t,J=7.3Hz,3H)。.13C NMR(150MHz,DMSO-d6)δ168.96,167.33,140.62,140.39,123.06,122.29,118.45,110.26,110.19,109.67,108.74,64.73,64.16,61.24,46.10,44.40,40.40,38.59,31.66,31.39,39.38,29.06,22.46,19.78,14.39,14.33,13.94.HRMS(MALDI-TOF):Calc:996.3946;found:996.3931。
化合物Ⅰ-5的合成方法同化合物Ⅰ-4,不同在于:反应温度80℃,反应时间8h。纯品3.1mg,收率为10%。1H NMR(600MHz,DMSO-d6)δ8.84(s,5H),7.94(s,2H),7.62(t,J=8.8Hz,6H),7.33(d,J=27.0Hz,6H),5.17(s,2H),4.83(s,4H),4.10(s,12H),2.95(d,J=6.9Hz,4H),1.28(p,J=6.3Hz,4H),1.17(q,J=7.6Hz,4H),1.13–1.06(m,3H),0.78(t,J=7.3Hz,9H).13CNMR(150MHz,DMSO-d6)δ168.97,167.33,140.62,140.39,123.06,118.48,110.30,110.25,108.74,61.25,46.10,44.40,40.40,38.59,31.39,29.78,14.39,13.94.HRMS(MALDI-TOF):Calc:1023.4418;found:1023.4402。
化合物Ⅰ-6的合成方法同化合物Ⅰ-4,不同在于:反应温度100℃,反应时间10h。纯品3.2mg,为白色固体,收率为10%。1H NMR(600MHz,DMSO-d6)δ8.84(s,5H),7.96(s,3H),7.61(d,J=8.5Hz,7H),7.30(s,6H),4.83(s,6H),4.10(s,12H),2.94(s,6H),1.32–1.24(m,6H),1.18–1.08(m,6H),0.77(q,J=11.6,9.5Hz,9H).13C NMR(150MHz,DMSO-d6)δ167.32,140.62,135.85,130.03,123.05,122.25,118.43,110.30,108.72,64.68,64.13,46.10,40.43,38.58,31.48,29.38,29.07,22.47,19.89,19.79,14.02,13.94.HRMS(MALDI-TOF):Calc:1050.4891;found:1050.4877
化合物Ⅰ-7的合成方法同化合物Ⅰ-4,不同在于:加入1mL苄胺作为反应原料,反应温度60℃,反应时间6h:固体纯品12mg,为白色固体,收率为40%。.1H NMR(600MHz,DMSO-d6)δ8.84(s,5H),8.43(s,1H),7.69–7.60(m,6H),7.35(s,6H),7.25–7.16(m,4H),7.12(d,J=7.3Hz,2H),5.17(s,2H),4.93(s,2H),4.20–4.08(m,12H),4.03(q,J=7.1Hz,4H),1.23(s,4H),1.11(t,J=7.1Hz,6H).13C NMR(150MHz,DMSO-d6)δ168.96,167.71,140.61,140.39,139.43,130.04,128.52,127.52,127.09,123.05,122.29,118.53,118.41,110.27,110.19,108.76,64.69,64.16,61.23,46.14,44.40,42.48,35.50,31.66,26.93,22.47,14.40,14.33。HRMS(MALDI-TOF):Calc:1035.3020;found:1035.3248
化合物Ⅰ-8的合成方法同化合物Ⅰ-4,不同在于:加入1mL苄胺作为反应原料,反应温度80℃,反应时间8h:固体纯品1.6mg,为白色固体,收率为5%。1H NMR(600MHz,DMSO-d6)δ8.84(s,5H),8.46(s,2H),7.62(t,J=9.9Hz,6H),7.34(s,6H),7.24–7.16(m,6H),7.13(d,J=6.9Hz,4H),5.17(s,2H),4.93(s,4H),4.16(d,J=4.9Hz,4H),4.14-4.08(m,12H),4.02(d,J=7.2Hz,3H),1.10(t,J=7.1Hz,3H).13CNMR(150MHz,DMSO-d6)δ168.96,167.70,140.60,140.37,139.42,128.53,127.52,127.09,110.32,110.25,108.80,61.23,46.14,42.49,14.40.HRMS(MALDI-TOF):Calc:1091.4005;found:1091.3991
化合物Ⅰ-9的合成方法同化合物Ⅰ-4,不同在于:加入1mL苄胺作为反应原料,反应温度100℃,反应时间10h。白色固体61.0mg收率51.3%.1H NMR(600MHz,DMSO-d6)δ8.85(s,6H),8.49(s,3H),7.62(d,J=8.5Hz,6H),7.34(d,J=8.6Hz,6H),7.24–7.16(m,10H),7.13(d,J=7.3Hz,5H),4.93(s,6H),4.16(d,J=5.8Hz,6H),4.11(s,12H).13C NMR(150MHz,DMSO-d6)δ168.96,167.70,140.60,140.37,139.42,128.53,127.52,127.09,110.32,110.25,108.80,61.23,46.14,42.49,14.40.(MALDI-TOF):Calculated for,1152.4422found:1152.4438
化合物Ⅰ-10的合成方法同化合物Ⅰ-4,不同在于:加入1mL三甘醇胺,反应温度80℃:纯品10mg,收率为30%。1H NMR(600MHz,DMSO-d6)δ8.84(s,5H),8.04(s,1H),7.62(s,6H),7.34(d,J=18.4Hz,6H),5.17(s,4H),4.86(s,2H),4.58(t,J=5.5Hz,2H),4.11(s,16H),4.03(q,J=7.3Hz,4H),3.51–3.49(m,2H),3.47(d,J=5.2Hz,2H),3.46(d,J=5.2Hz,2H),3.42(d,J=5.4Hz,4H),3.39(t,J=5.3Hz,2H),3.12(q,J=6.1Hz,2H).13C NMR(150MHz,DMSO-d6)δ168.97,167.69,140.62,140.41,110.26,110.21,108.76,72.70,72.66,70.04,69.94,69.17,61.25,60.64,60.59,46.02,44.41,38.97,14.40HRMS(MALDI-TOF):Calc:1072.4106;found:1072.4108
化合物Ⅰ-11的合成方法同化合物Ⅰ-4,不同在于:加入1mL三甘醇胺,反应温度100℃:固体纯品2mg,收率为5%。1H NMR(600MHz,DMSO-d6)δ8.85(s,5H),8.14(s,4H),7.62(d,J=8.6Hz,6H),7.34(s,6H),4.88(s,6H),4.60(s,4H),4.12(s,12H),3.49(d,J=9.1,16H),3.44(dd,J=8.5,5.0Hz,8H),3.41(q,J=5.1Hz,9H).13CNMR(150MHz,DMSO-d6)δ167.68,140.59,123.02,118.41,110.29,108.75,72.70,72.66,70.04,69.98,69.94,69.30,69.18,60.57,55.30,45.98,38.97,37.52.HRMS(MALDI-TOF)m/z:[M+Na]+Calc:1301.5201;found:1301.5257
化合物Ⅰ(12-14)合成步骤:
化合物Ⅰ-12合成步骤:取100mg化合物Ⅰ-3于茄型瓶中(100mL),加入3mL甲醇作为反应溶剂,加入1mL丁胺作为反应原料,放入油浴锅中加热搅拌10h,反应温度100℃,采用薄层色谱板监测反应。后处理:将反应液减压蒸馏除去甲醇,之后放入冻干机,真空下抽4h,得到黄色固体,分别用乙醚,二氯甲烷溶液洗涤,得到纯品30mg,为白色固体,TLC:甲醇:二氯甲烷=1:20,收率为40%。得到纯品92mg,为淡黄色固体,TLC:化合物12:二氯甲烷,收率为70%。1H NMR(600MHz,DMSO-d6)δ8.82(d,J=1.8Hz,6H),7.58(d,J=1.8Hz,6H),7.29(d,J=8.6Hz,6H),5.13(s,6H),4.02(q,J=7.1Hz,6H),3.89(d,J=26.9Hz,12H),1.73(s,12H),1.10(t,J=7.1Hz,9H).13C NMR(150MHz,DMSO-d6)δ194.48,168.89,168.77,143.68,140.21,137.33,130.79,128.97,128.61,127.99,123.35,122.17,121.76,118.59,103.91,61.71,61.49,44.77,44.46,32.91,32.67,29.69,29.64,26.72,14.52,14.42.HRMS(MALDI-TOF):Calc:1054.4445;found:1054.4482.
化合物Ⅰ-13的合成方法同化合物Ⅰ-12,不同在于:加入1mL苄胺作为反应原料,放入油浴锅中加热搅拌10h,反应温度100℃:固体纯品24mg,收率为70%。1HNMR(600MHz,DMSO-d6)δ8.83(s,6H),8.45(t,J=6.2Hz,3H),7.61(d,J=8.6Hz,6H),7.29(d,J=8.6Hz,6H),7.22(t,J=7.3Hz,6H),7.19(d,J=6.9Hz,4H),4.90(s,6H),4.15(d,J=5.9Hz,6H),3.91(d,J=22.4Hz,14H),1.25(d,J=8.3Hz,12H).13C NMR(150MHz,DMSO-d6)δ167.75,140.39,139.43,137.24,129.14,129.01,128.50,127.49,127.07,123.30,122.87,118.98,108.53,105.45,46.11,42.46,29.42.HRMS(ESI/TOF-Q):Calc[M+H]+:1037.5452;found:1237.5425。
化合物Ⅰ-14的合成方法同化合物Ⅰ-12,不同在于:加入1mL二甘醇胺作为反应原料,放入油浴锅中加热搅拌10h,反应温度100℃:固体纯品22mg,收率为72%。1H NMR(600MHz,DMSO-d6)δ8.81(s,6H),8.18(t,J=5.8Hz,6H),7.59(d,J=8.6Hz,6H),7.28(d,J=8.6Hz,6H),5.77(s,6H),4.85(s,6H),3.91(d,J=18.3Hz,12H),3.62(t,J=5.2Hz,6H),3.50–3.45(m,12H),1.74(s,12H).13C NMR(150MHz,DMSO-d6)δ158.96,140.39,137.20,123.22,122.87,118.93,108.51,72.90,72.51,72.47,70.08,69.15,60.62,60.51,45.94,41.55,38.99,29.44..HRMS(ESI/TOF-Q):C alc[M+H]+:1231.5559;found:1231.5597
化合物Ⅰ(15-17)合成步骤:
化合物Ⅰ-15合成步骤:取100mg化合物b于茄型瓶中(100mL),加入2,3-二溴-1,4丁二醇50mg,以除水四氢呋喃作为反应溶剂,在冰浴条件下反应10min,加入300mg DQQ,继续搅拌,采用薄层色谱板监测反应,3h后停止反应。后处理:将反应液用二氯甲烷/水相萃取7遍,萃取至二氯甲烷层无色,将反应液合并后进行减压蒸馏,得到粗品用柱层析分离纯化(二氯甲烷:石油醚=4:1),得到纯品115mg,为淡黄色固体,TLC:二氯甲烷,收率为60%。1HNMR(600MHz,DMSO-d6)δ8.86(q,J=20.8,19.4Hz,6H),7.64(d,J=60.6Hz,6H),7.38(dd,J=12.3,7.2Hz,6H),5.22–5.13(m,6H),4.74(s,6H),4.38–4.20(m,6H),4.14–3.99(m,12H),1.12(t,J=7.1,1.8Hz,9H).13C NMR(150MHz,DMSO-d6)δ168.91,162.16,140.55,135.74,131.15,129.08,128.75,128.68,128.35,128.29,128.13,127.17,123.34,123.23,109.04,108.95,106.19,106.17,61.26,55.87,55.76,44.36,14.41.HRMS(MALDI-TOF);Calc:1526.8981;found:1526.8983
化合物Ⅰ-16的合成方法同化合物Ⅰ-15,不同在于:取30mg化合物化合物Ⅰ-15,加入1mL丁胺作为反应原料,放入油浴锅中加热搅拌10h,反应温度100℃:固体纯品15mg,收率为50%。1H NMR(600MHz,DMSO-d6)δ8.97–8.78(m,6H),8.02–7.89(m,3H),7.64(d,J=63.4Hz,6H),7.33(t,J=9.3Hz,6H),4.84(t,J=4.1Hz,6H),4.73(s,6H),4.40–4.23(m,6H),4.06(d,J=37.1Hz,6H),3.00–2.88(m,6H),1.29–1.25(m,6H),1.16(q,J=7.4Hz,6H),0.77(t,J=7.3Hz,9H).13C NMR(150MHz,DMSO-d6)δ167.24,140.75,135.48,123.33,123.22,108.91,106.27,55.83,46.10,40.45,38.92,38.60,31.41,29.42,19.89,19.79,19.46,13.96,13.86.HRMS(MALDI-TOF)Calc:1608.0401;found:1608.0402
化合物Ⅰ-17的合成方法同化合物Ⅰ-15,不同在于:取30mg化合物Ⅰ-15,加入1mL二甘醇胺作为反应原料,放入油浴锅中加热搅拌10h,反应温度100℃:固体纯品14mg,收率为45%。1H NMR(600MHz,DMSO-d6)δ8.86(q,J=20.6,19.3Hz,6H),8.09(d,J=5.3Hz,3H),7.63(d,J=59.6Hz,6H),7.34(dd,J=11.8,8.7Hz,6H),4.87(t,J=4.4Hz,6H),4.74(s,5H),4.53(d,J=5.4Hz,3H),4.42–4.22(m,6H),4.09(s,6H),3.45(q,J=5.3Hz,7H),3.38–3.33(m,12H),3.13(dd,J=7.4,4.0Hz,6H).13C NMR(150MHz,DMSO-d6)δ,169.06,168.95,168.73,143.79,143.53,141.08,140.58,130.16,128.62,124.08,122.26,121.86,110.44,110.01,108.22,106.24,64.65,61.69,61.55,61.25,56.52,55.29,44.77,44.47,14.53,14.49,14.45,14.43.HRMS(MALDI-TOF);m/z:[M+Na]+Calc:1727.0052;found:1727.0014。
化合物III 18-III 19,II20-II23合成步骤:
化合物III-18:将100mg化合物b置于烧瓶中,加入THF溶剂以及2mL乙二醇,冰浴冷却烧瓶后,加入DDQ 60mg,加入完毕后反应8h,薄层色谱分析(TLC)检测反应。待反应结束后,水、二氯甲烷萃取,将反应混合溶液进行减压蒸馏,残液经200-300目硅胶柱层析(DCM:MeOH=100:1)分离,得到白色固体20mg收率21.3%1H NMR(600MHz,DMSO-d6)δ8.68(s,2H),8.62(s,2H),8.53(s,2H),7.62(ddd,J=8.6,3.8,1.7Hz,4H),7.41(dd,J=8.3,1.7Hz,2H),7.38(s,1H),7.37(s,1H),7.35(s,1H),7.34(s,1H),7.33(s,1H),7.31(s,1H),5.18(s,2H),5.16(s,4H),4.20(s,2H),4.11(s,8H),4.06–4.01(m,6H),1.11(td,J=7.1,2.7Hz,9H).13CNMR(150MHz,DMSO-d6)δ169.03,168.96,140.44,140.34,139.74,135.95,135.53,134.65,126.69,123.40,122.93,122.90,122.62,122.26,120.29,118.25,118.18,110.22,109.21,108.94,108.69,64.47,63.16,61.25,61.19,44.42,42.25,25.47,14.43,14.40,14.33.(MALDI-TOF):Calculated for,911.3418found:911.3408
化合物III-19的合成方法同化合物III-18,不同在于:加入DDQ 60mg,反应结束后,水、二氯甲烷萃取,将反应混合溶液进行减压蒸馏,残液经200-300目硅胶柱层析(DCM:MeOH=70:1)分离白色固体25mg,收率25.6%1H NMR(600MHz,DMSO-d6)δ8.85(s,6H),7.62(t,J=10.0Hz,4H),7.51–7.44(m,2H),7.34(q,J=7.6Hz,6H),5.68(s,1H),5.17(s,6H),4.70(s,1H),4.16–4.07(m,8H),4.07–3.99(m,6H),3.73(q,J=5.4Hz,2H),3.56(s,1H),1.11(t,J=7.1Hz,9H).13C NMR(150MHz,DMSO-d6)δ168.99,168.96,140.39,123.12,122.34,118.43,110.23,108.79,108.63,70.64,64.78,64.11,63.16,61.23,61.21,61.18,60.95,44.40,14.40.(MALDI-TOF):Calculated for,971.3629found:971.3613
化合物Ⅱ-20的合成方法同化合物III-18,不同在于:加入THF溶剂以及1mL戊醇,得到冰浴冷却烧瓶后,加入DDQ 100mg,得到淡黄色固体72mg,收率65.0%,1H NMR(600MHz,DMSO-d6)δ8.96(s,2H),8.74(s,2H),8.40(s,2H),8.19(d,J=10.3Hz,2H),8.07(d,J=8.5Hz,2H),7.91(d,J=8.6Hz,2H),7.73(d,J=8.7Hz,2H),7.63(d,J=8.6Hz,2H),7.46(d,J=8.7Hz,2H),5.60(s,2H),5.36(s,4H),4.25(q,J=7.1Hz,2H),4.11(q,J=7.0Hz,5H),3.58(t,J=6.6Hz,2H),3.47(d,J=16.2,6.3Hz,4H),3.15(t,J=6.2Hz,2H),1.81–1.75(m,2H),1.67(p,J=7.3Hz,2H),1.57–1.50(m,J=4.8Hz,4H),1.28(q,J=7.0Hz,8H),1.18(t,J=7.1Hz,8H).13C NMR(150MHz,DMSO-d6)δ168.98 140.20,137.38,123.28,122.92,119.03,108.48,105.40,63.85,63.71,61.19,44.36 29.47,29.42,14.41.HRMS(MALDI-TOF):Calc:1028.4255;found:1028.4355。
化合物Ⅱ-21的合成方法同化合物Ⅱ-20,不同在于:加入THF溶剂以及1mL己醇,得到淡黄色固体75mg,收率72%,1H NMR(600MHz,DMSO-d6)δ8.97(d,J=1.7Hz,2H),8.73(d,J=1.8Hz,2H),8.42–8.36(m,2H),8.20(dd,J=8.6,1.7Hz,2H),8.07(dd,J=8.6,1.6Hz,2H),7.90(d,J=8.7Hz,2H),7.73(d,J=8.7Hz,2H),7.63(dd,J=8.6,1.6Hz,2H),7.47(d,J=8.7Hz,2H),5.60(s,2H),5.35(s,4H),4.37(t,J=5.1Hz,1H),4.25(q,J=7.1Hz,2H),4.12(q,J=6.9Hz,5H),3.58(t,J=6.7Hz,2H),3.49(t,J=7.0Hz,2H),3.44–3.39(m,2H),3.15(q,J=5.3Hz,2H),1.79(p,J=6.9Hz,2H),1.66(p,J=7.2Hz,2H),1.51(d,J=21.7,7.1,6.6Hz,4H),1.43–1.35(m,3H),1.27(d,J=19.9,7.4Hz,4H),1.21–1.08(m,12H).13CNMR(150MHz,DMSO-d6)δ194.46,168.83,168.77,143.67,143.56,140.22,137.34,130.80,128.98,128.59,127.99,125.36,124.01,123.34,122.16,121.74,118.51,110.99,110.65,109.82,103.89,61.50,61.06,60.71,44.75,44.47,32.99,32.96,32.65,29.87,29.83,26.31,26.12,25.88,25.70,14.51,14.42。HRMS(MALDI-TOF):Calc:1055.4546;found:1055.4562。
化合物Ⅱ-22的合成方法同化合物Ⅱ-20,不同在于:加入THF溶剂以及1mL辛醇。得到淡黄色固体73mg,收率68%,1H NMR(600MHz,DMSO-d6)δ8.97(s,2H),8.73(s,2H),8.38(s,2H),8.22–8.18(m,2H),8.06(dd,J=8.5,1.7Hz,2H),7.90(d,J=8.6Hz,2H),7.73(d,J=8.7Hz,2H),7.62(d,J=8.7Hz,2H),7.46(d,J=8.7Hz,2H),5.60(s,2H),5.36(s,4H),4.24(q,J=7.1Hz,3H),4.11(q,J=7.0Hz,4H),3.57(t,J=6.6Hz,2H),3.48(t,J=7.1Hz,2H),3.38(t,J=6.8Hz,3H),3.24(t,J=6.7Hz,2H),1.78(p,J=6.9Hz,2H),1.64(p,J=7.5Hz,2H),1.50(p,J=7.3Hz,2H),1.43(p,J=6.8Hz,2H),1.32–1.18(m,16H),1.13(q,J=7.4Hz,3H),1.01(d,J=15.4,7.2Hz,6H).13C NMR(150MHz,DMSO-d6)δ194.47,168.77,143.66,143.57,140.20,137.32,130.77,128.99,128.55,127.99,125.31,123.98,123.30,122.14,121.70,118.43,110.97,110.65,109.81,103.85,62.03,61.80,61.71,61.52,61.11,61.05,44.72,44.44,32.89,32.63,29.69,29.62,29.41,29.36,29.05,28.99,26.33,26.11,25.87,25.53,14.48,14.40.HRM S(MALDI-TOF):Calc:1111.5149;found:1111.5171
化合物Ⅱ-23的合成方法同化合物Ⅱ-20,不同在于:加入THF溶剂以及1mL 1,4-丁烯二醇:得到白色固体75mg,收率为60%。1H NMR(600MHz,DMSO-d6)δ8.95(d,J=1.7Hz,2H),8.80(d,J=1.7Hz,2H),8.52(s,2H),8.20(dd,J=8.6,1.7Hz,2H),8.08(dd,J=8.5,1.6Hz,2H),7.91(d,J=8.7Hz,2H),7.73(d,J=8.8Hz,2H),7.67(d,J=8.7Hz,2H),7.48(d,J=8.7Hz,2H),6.07–6.01(m,1H),6.00–5.94(m,1H),5.87–5.77(m,2H),5.61(s,2H),5.36(s,4H),4.82(d,J=5.5Hz,1H),4.59(d,J=6.3Hz,1H),4.25(t,J=7.1Hz,2H),4.16(d,J=5.3Hz,2H),4.13(dd,J=7.2,1.3Hz,2H),4.10(d,J=7.1Hz,4H),4.06(s,2H),3.84(s,2H),2.88(s,1H),2.73(s,1H),1.29(t,J=7.1Hz,3H),1.19(t,J=7.1Hz,6H).13C NMR(150MHz,DMSO-d6)δ194.47,168.87,168.78,143.70,143.57,140.32,136.95,133.34,133.00,130.75,129.00,128.64,128.06,126.34,126.09,125.57,124.18,123.77,123.50,122.23,121.81,118.88,110.97,110.65,109.85,104.67,62.90,61.70,61.49,61.40,61.18,44.74,44.47,29.40,26.93,22.47,14.53,14.42.HRMS(MALDI-TOF):Calc:996.3729;found:996.3714。
化合物Ⅱ-24合成步骤:取30mg的化合物Ⅰ-1圆底烧瓶(25mL)中,加入3mL的DMF作为反应溶剂,加入1mL苄胺作为反应原料,放入油浴锅中加热搅拌2d,反应温度120℃,有大量白色沉淀析出,反应结束。后处理:将反应液进行离心收集白色沉淀固体,二氯甲烷和石油醚的混合溶剂洗涤,离心得到固体纯品3mg,为白色固体,TLC:甲醇:二氯甲烷=1:10,收率为10%。1H NMR(600MHz,DMSO-d6)δ8.96(t,J=5.9Hz,1H),8.86(d,J=1.8Hz,2H),8.80(d,J=1.7Hz,2H),8.74(t,J=6.0Hz,2H),8.70(d,J=1.8Hz,2H),8.23(dd,J=8.6,1.7Hz,2H),8.05(d,J=8.6,,2H),7.90(d,J=8.7Hz,2H),7.72(d,J=8.7Hz,2H),7.66(dd,J=8.6,1.7Hz,2H),7.46(d,J=8.6Hz,2H),7.39–7.33(m,4H),7.27(t,J=6.6,Hz,5H),7.25–7.15(m,6H),5.37(s,2H),5.12(s,4H),4.41(d,J=5.9Hz,2H),4.31–4.21(m,4H),4.12(s,2H),4.02(s,2H).13C NMR(150MHz,DMSO-d6)δ194.47,167.34,167.31,144.02,143.76,140.68,139.40,139.33,137.32,130.55,128.75,128.63,128.36,127.91,127.75,127.61,127.35,127.22,125.66,123.67,123.52,122.64,122.15,121.90,118.31,110.89,110.72,110.09,109.64,46.20,46.08,42.80,42.63.HRMS(MALDI-TOF);Calc:1064.3987;found:1064.3913.
化合物Ⅱ-25合成步骤:取30mg化合物b于茄型瓶中(25mL),溶解于3mL二氯甲烷中,加入1mg的DDQ,将溶液pH调至6,通过TLC监测反应,磁力搅拌2h,得化合物29mg,TLC:甲醇:二氯甲烷=1:50,收率96%。1H NMR(600MHz,DMSO-d6)δ8.96(d,J=1.7Hz,2H),8.86(d,J=1.8Hz,2H),8.67(d,J=1.8Hz,2H),8.25(dd,J=8.6,1.8Hz,2H),8.11(d,J=8.6Hz,2H),7.95(d,J=8.5Hz,2H),7.76(d,J=8.9Hz,2H),7.70(dd,J=8.6,1.7Hz,2H),7.48(d,J=8.7Hz,2H),5.64(s,2H),5.39(s,4H),4.29(q,J=7.1Hz,2H),4.14(q,J=7.3,1.8Hz,4H),3.96(t,J=4.6Hz,2H),3.86(t,J=4.6Hz,2H),1.75–1.59(m,4H),1.33(t,J=6.8Hz,3H),1.21(t,J=7.1Hz,6H).13C NMR(150MHz,DMSO-d6)δ194.39,168.82,168.76,143.73,143.52,140.32,138.81,130.74,129.01,125.61,124.05,123.60,123.49,118.77,109.53,105.40,63.93,63.64,61.12,55.29,44.75,44.47,30.21,29.59,29.35,29.16,14.53,14.42.HRMS(MALDI-TOF);Calc:909.3230;found:909.3247.
化合物Ⅱ-26合成步骤:取30mg化合物b于茄型瓶中(25mL),溶解于3mL二氯甲烷中,加入1mg的DDQ,将溶液pH调至3-6,酸化后,磁力搅拌2h停止反应,得化合物28mg,TLC:甲醇:二氯甲烷=1:50,收率95%。1H NMR(600MHz,DMSO-d6)δ8.86(s,2H),8.68(s,2H),8.12(d,J=8.6Hz,2H),8.02(s,2H),7.84(d,J=8.6Hz,2H),7.58(d,J=8.6Hz,2H),7.52(t,J=7.9Hz,4H),7.41–7.33(m,2H),5.76(s,2H),5.46(s,4H),5.31(s,2H),4.59(s,2H),4.19(q,J=7.0Hz,6H),4.16–4.11(m,2H),1.23(t,J=7.1Hz,9H).13C NMR(150MHz,DMSO-d6)δ167.60,140.76,140.74,135.54,123.31,123.20,108.96,106.27,72.48,69.16,60.53,55.91,55.30,45.96,39.02.HRMS(MALDI-TOF);Calc:1297.3327;found:1297.3327.
杯[3]咔唑衍生物对羟喜树碱的识别作用
本发明采用紫外-可见及荧光光谱进行测试,选用水作为溶剂,激发波长设置为375nm,狭缝宽度设置为3nm(Ex),5nm(Em),固定客体分子羟喜树碱的浓度,通过改变水溶性杯[3]咔唑大环倍量,依次进行紫外滴定实验和荧光滴定实验,测试结果如(图1)所示。
从紫外光谱谱图(图3)中可以看到,随着化合物Ⅰ-17的滴加,紫外吸收光谱在380nm处出现减色现象,在445nm处出现了增色现象。且在这两个波长之间出现了一组“等消光点”。同样,通过荧光光谱谱图6,可以明显的看到HCPT的荧光逐渐被淬灭的现象,且0.9倍量时逐渐达到饱和状态,上述两种状态说明HCPT与化合物Ⅰ-17之间发生了特异性结合,从而使整个分子荧光性能受到影响,出现荧光淬灭现象,并计算其结合常数。
在相同的测试条件下,我们尝试使用化合物Ⅰ-17及化合物Ⅰ-18对HCPT进行紫外滴定和荧光滴定实验(图2,图4,图5,图7)。其荧光滴定光谱上也出现了不同程度的淬灭现象,通过计算,测得其结合常数4.05×103M-1(R2=0.99);6.32×103M-1(R2=0.98)。
杯[3]咔唑衍生物对黄芩苷的包载应用以及对樟脑醌的识别应用
本发明采动态光散射(DLS)实验,Zeta电位测试,透射电子显微镜(TEM)和紫外分光光度法考察化合物F包载黄芩苷的性能。
从从图8中可以看到,黄芩苷自身在水中溶解度并不好,而且不能组装成纳米粒。而化合物F与黄芩苷的混合样品则能够形成较好的纳米粒,PdI为0.225,说明粒径分布均匀。并且平均粒径较小,为84nm。这说明化合物Ⅰ-17能够包载黄芩苷,形成粒径较好的纳米药物。以1:1进行主客体包载能够极大增加药物的包封率。
透射电子显微镜(TEM)观察黄芩苷自身及其与化合物Ⅰ-17主客体复合物的的形貌。从图9中可以看出黄芩苷自身形貌主要是比较大块的晶体,而与化合物Ⅰ-17结合后,块状晶体有所分散。
图10(a)中化合物Ⅰ-17自身形成球状聚集体,图10(b)中与L-樟脑醌形成链状聚集体,图10c中化合物Ⅰ-17与D-樟脑醌形成有规则的片状聚集体,图10(d)中与DL-樟脑醌形成无规则聚集体。化合物Ⅰ-17对不同构型的樟脑醌有识别作用。
Claims (10)
1.一种杯[3]咔唑母核,其结构式为:
2.一种桥亚甲基修饰的杯[3]咔唑衍生物,其结构通式为以下结构通式(I)、(II)或(III)中的一种:
结构(I)中:n=0或1或2;
R1、R2、R3各自独立表示为C1~C2的烷氧基、苄胺基、脂肪胺基、或含O原子的脂肪胺基、乙氧基中的一种;
X选自Br或H;
结构(II)中:
R4、R5、R6各自独立表示为烷氧基、苄胺基;
R7、R8表示为H、C2~C8的烷氧基、饱和或不饱和脂肪链的多元醇基、或取代或未取代的R7、R8形成的C2-C6的环氧醚一种;
结构(III)中:
R9、R10、R11各自独立表示为烷氧基、苄胺基;
R12表示为H、C2~C8的烷氧基、饱和或不饱和脂肪链的多元醇基一种。
3.权利要求2所述的桥亚甲基修饰的杯[3]咔唑衍生物,其特征在于,所述的C2~C8的烷氧基包括C2~C8的直链烷氧基、C2~C8的环烷氧基、卤素取代的C2~C8的环烷氧基中的一种;
所述的饱和或不饱和脂肪链的多元醇基为C2-C8的脂肪链的多元醇基,具体为2-(1-氧)乙烷-1-醇基、5-甲氧基戊烷-1-醇基、1-羟基乙氧基、1-羟基戊氧基、1-羟基戊氧基、1-羟基己氧基、1-羟基辛氧基、1-羟基-2-烯-1-丁氧基。
4.权利要求2所述的桥亚甲基修饰的杯[3]咔唑衍生物,其特征在于,所述的桥亚甲基修饰的杯[3]咔唑衍生物,其中:
R1选自乙氧基、丁胺基、苄胺基、二甘醇胺基、三甘醇胺基中的一种;
R2选自乙氧基、丁胺基、苄胺基、二甘醇胺基、三甘醇胺基中的一种;
R3选自乙氧基、丁胺基、苄胺基、二甘醇胺基、三甘醇胺基中的一种;
R4为乙氧基、R5为乙氧基、R6为乙氧基;
R7、R8独立选自H、1-羟基乙氧基、1-羟基戊氧基、1-羟基戊氧基、1-羟基己氧基、1-羟基辛氧基、1-羟基-2-烯-1-丁氧基中的一种。
5.一种桥亚甲基修饰的杯[3]咔唑衍生物,为以下结构中的一种;
6.权利要求1所述的杯[3]咔唑母核的合成方法,其特征在于,由单体合成杯[3]咔唑母核;
所述的单体结构为:
由单体合成杯[3]咔唑母核采用溶剂为二氯甲烷,反应温度为室温,单体和路易斯酸混合后,反应30-40min至溶液完全为墨绿色后,再加入多聚甲醛,4h-12h后停止反应;
合成杯[3]咔唑母核时,路易斯酸选自六水三氯化铁,其中,按摩尔比,单体:路易斯酸=1:0.5,按固液比,单体:溶剂=1g:1L;按质量比,路易斯酸:多聚甲醛=(530-540):(170-180)。
7.权利要求2所述的桥亚甲基修饰的杯[3]咔唑衍生物的合成方法,其特征在于,对杯[3]咔唑母核进行桥亚甲基氧化、或桥亚甲基氧化-衍生中的一种方法进行改进,得到桥亚甲基修饰的杯[3]咔唑衍生物。
8.权利要求7所述的桥亚甲基修饰的杯[3]咔唑衍生物的合成方法,其特征在于,对杯[3]咔唑母核进行桥亚甲基氧化时,采用的氧化剂为2,3-二氯-5,6-二氰基苯醌(DDQ),按固液比,杯[3]咔唑母核:含有脂肪链的二醇=100mg:(1-5)mL;所述的含有脂肪链的二醇溶剂选自乙二醇、丙二醇、丁二醇中的一种;
其中,按质量比,杯[3]咔唑母核:DDQ=1:(0.6~3.0),反应时间为3-8h,反应温度为-2℃~5℃;
在桥亚甲基氧化过程中,根据桥亚甲基修饰的杯[3]咔唑衍生物的结构式,还加入脂肪醇类,用于改性;所述的脂肪醇类为甲醇、乙二醇、1,4-丁烯二醇、戊醇、已醇、辛醇中的一种;加入脂肪醇类的量根据桥亚甲基修饰的杯[3]咔唑衍生物的结构中的饱和或不饱和脂肪链的多元醇基的数量确定。
9.权利要求7所述的桥亚甲基修饰的杯[3]咔唑衍生物的合成方法,其特征在于,所述的衍生,具体操作为,按固液比,杯[3]咔唑母核或氧化后的杯[3]咔唑母核:胺类化合物=(30-100)mg:(1-10)mL,所述的胺类化合物选自丁胺、苄胺、二甘醇胺、三甘醇胺中的一种,并加热至60-120℃,时间6-48h。
10.权利要求2所述的桥亚甲基修饰的杯[3]咔唑衍生物在离子荧光传感、医药分子的载体和生物大分子的识别中的应用。
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