CN116102568A - 桥亚甲基修饰的杯[3]咔唑衍生物及其合成方法和药物分子识别的应用 - Google Patents
桥亚甲基修饰的杯[3]咔唑衍生物及其合成方法和药物分子识别的应用 Download PDFInfo
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- carbazole
- diglycolamine
- benzylamine
- butylamine
- methylene
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- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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Abstract
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药物分子识别的应用,应用方面具体涉及药物载体和药物识别等应用。
背景技术
由于超分子大环主体化合物(冠醚、环糊精、葫芦脲、杯芳烃或柱芳烃)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、医药分子的载体和药物辅料等),因此,一直以来都是生命医学、材料学以及药学等领域的研究热点。
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和丰富的π电子体系,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识别检测和相互作用的性能。
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及其和药物分子识别的应用,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、环氧化和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,以该形式修饰的杯[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和丰富的π电子体系,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,探索了并发现了对阿糖胞苷等药物的识别及包载性能。
本发明中桥亚甲基修饰的杯[3]咔唑衍生物,其结构通式为以下结构(I)、(II)、(Ⅲ)、(Ⅳ)或(V)中的一种:
结构(I)中:R1、R2、R3各自独立表示为烷氧基、苄胺基、脂肪胺基、或含O原子的脂肪胺基中的一种;
结构(II)中:R4、R5、R6各自独立表示为烷氧基、苄胺基、脂肪胺基、或含O原子的脂肪胺基中的一种;
结构(III)中:R7、R8、R9各自独立表示为烷氧基、苄胺基、脂肪胺基、或含O原子的脂肪胺基中的一种;
结构(Ⅳ)中:R10、R11、R12各自独立表示为烷氧基、苄胺基、脂肪胺基、或含O原子的脂肪胺基中的一种;
结构(V)中:R13、R14、R15各自独立表示为烷氧基、苄胺基、脂肪胺基、或含O原子的脂肪胺基中的一种;
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、二甘醇胺基中的一种;
R2选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R3选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R4选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R5选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R6选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R7选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R8选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R9选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R10选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R11选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R12选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R13选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R14选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R15选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
本发明中桥亚甲基修饰的杯[3]咔唑衍生物,更优选为以下结构中的一种;
以上结构的化合物,特别优选为化合物I-4。
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]咔唑母核进行氧化、或氧化后衍生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。
所述的氧化为桥亚甲基氧化、桥亚甲基氧化-桥亚甲基烯烃再氧化、桥亚甲基氧化-降解氧化、桥亚甲基氧化-降解氧化-桥亚甲基烯烃再氧化中的一种;
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),杯[3]咔唑母核:顺式-1,4-丁烯二醇100mg:(1-5)mL;其中,按摩尔比,杯[3]咔唑母核:DDQ=1:1.5,反应时间为5~10h。
桥亚甲基烯烃再氧化时,采用氧化剂间氯过氧苯甲酸(mCPBA),催化剂磷酸氢二钠;其中,按摩尔比,化合物Ⅰ-1:mCPBA:磷酸氢二钠=1:1.5:1.5;
所述的降解氧化时,采用氧化剂DDQ,盐酸水溶液;其中,按摩尔比,化合物Ⅰ-1:DDQ:盐酸水溶液=1:1.5:10,按体积比,盐酸:水=10:1,降解氧化时间为10~12h;
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=100mg:(5-10)mL,所述的胺类化合物选自丁胺、苄胺、二甘醇胺中的一种,并加热90-120℃,时间6~24h。
所述的的杯[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:;
其中,由单体合成杯[3]咔唑母核的合成工艺参数为:
采用溶剂为二氯甲烷,按固液比,六水三氯化铁:二氯甲烷=(10~11)mg:20mL;向单体中加入三水氯化铁进行反应,常温反应40-60min至溶液完全为墨绿色后,加入多聚甲醛,继续反应8h~12h后,停止反应,加入氨水淬灭,二氯甲烷/水萃取,得到杯[3]咔唑母核。
合成杯[3]咔唑母核时,其中,按摩尔比,单体:路易斯酸:多聚甲醛=1:0.5:0.5。
本发明的桥亚甲基修饰的杯[3]咔唑衍生物具有识别药物、包载药物的作用,从而能够作为前药载体和药物递送材料有良好的应用。
更优选为,桥亚甲基修饰的杯[3]咔唑衍生物为化合物I-4。
所述的识别药物更优选为在识别阿糖胞苷化合物或识别阿糖腺苷化合物,作为前药载体。
本发明的桥亚甲基修饰的杯[3]咔唑衍生物及其合成方法和药物分子识别的应用,其有益效果为:
具体涉及含有杯[3]咔唑桥亚甲基氧化生成缩酮结构、和环氧结构以及进一步取代产物及其合成方法,形成强荧光和刚性固定的大环化合物,其广泛潜在用途,如药物诊断试剂、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,探索并发现了其对阿糖胞苷药物分子的主客体识别作用,并初步探索了其作为阿糖胞苷和阿糖腺苷类药物分子载体以及前药开发的潜在应用价值。
附图说明
图1为阿糖胞苷和化合物Ⅰ-4的紫外滴定图谱。
图2为阿糖胞苷的SEM图。
图3为化合物Ⅰ-4与阿糖胞苷包载的SEM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]咔唑母核的制备路线为:
单体杯[3]咔唑母核
制备方法(Ⅰ):杯[3]咔唑母核进行桥亚甲基氧化,得到化合物I-1或化合物II-1;
制备方法(Ⅱ):对于化合物I-1进行降解氧化得到化合物IV-1;
制备方法(Ⅲ):对化合物I-1进行桥亚甲基烯烃再氧化得到化合物III-1;对化合物IV-1进行桥亚甲基烯烃再氧化得到化合物V-1;
制备方法(Ⅳ):对化合物I-1、化合物II-1、化合物III-1、化合物IV-1、化合物V-1进行衍生,得到对应的衍生化合物,其中,R为R1~R15中的一种;
杯[3]咔唑母核的制备方法,包括如下步骤:
杯[3]咔唑母核合成步骤:取1g单体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的多聚甲醛,继续搅拌,点板监测。10h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(1-4)合成步骤:
化合物Ⅰ-1的合成步骤:将100mg杯[3]咔唑母核置于烧瓶中,加入THF溶剂以及2mL顺丁烯二醇,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=500:1)分离,得到产品白色固体化合物Ⅰ-1。
化合物Ⅰ-2的合成步骤:将100mg化合物Ⅰ-1置于烧瓶中,加入丁胺5ml,磁力加热搅拌10小时,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,得白色固体化合物。
化合物Ⅰ-3的合成步骤:将100mg化合物Ⅰ-1置于烧瓶中,加入苄胺5ml,磁力加热搅拌10小时,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,得黄色固体化合物。
化合物Ⅰ-4的合成步骤:将100mg化合物Ⅰ-1置于烧瓶中,加入二甘醇胺5ml,磁力加热搅拌10小时,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,得黄色固体化合物Ⅰ-4。
化合物Ⅰ-1:52mg收率46.3%.1H NMR(600MHz,DMSO-d6)δ8.82(d,J=1.8Hz,6H),7.62(dd,J=8.5,1.7Hz,6H),7.33(d,J=8.6Hz,6H),5.80(s,6H),5.15(s,6H),4.42(d,J=12.6Hz,12H),4.02(q,J=7.1Hz,6H),1.10(t,J=7.1Hz,9H).Calculated for,1048.4020found:1048.4018
化合物Ⅰ-2:90mg收率70%.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,1029.5361found:1129.5348
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:1230.4891;found:1230.4845.
化合物Ⅰ-4:纯品98mg,收率82%。H NMR(600MHz,DMSO-d6)δ8.86–8.78(m,6H),8.11(t,J=5.7Hz,3H),7.65–7.58(m,6H),7.30(d,J=8.6Hz,6H),5.80(s,6H),4.84(s,6H),4.57(s,2H),4.42(d,J=13.3Hz,12H),3.44(t,J=5.2Hz,6H),3.33(dd,J=12.6,5.8Hz,12H),3.12(q,J=5.9Hz,6H).(MALDI-TOF):Calculated for,1224.5056;found:1224.5078
化合物II(1-4)合成步骤:
化合物II-1合成步骤:将100mg杯[3]咔唑母核置于烧瓶中,加入THF溶剂以及1mL顺丁烯二醇,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=500:1)分离,得白色固体。
化合物II-2的合成步骤:将100mg化合物II-1置于烧瓶中,加入丁胺5ml,磁力加热搅拌10小时,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,得白色固体化合物。
化合物II-3的合成步骤:将100mg化合物II-1置于烧瓶中,加入苄胺5ml,磁力加热搅拌10小时,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,得黄色固体化合物。
化合物II-4的合成步骤:将100mg化合物II-1置于烧瓶中,加入二甘醇胺胺5ml,磁力加热搅拌10小时,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,得白色固体化合物。
化合物II-1纯品8mg,收率为10%。1H NMR(600MHz,DMSO-d6)δ8.81(s,2H),8.76(s,2H),8.67(s,2H),7.68(d,J=8.6Hz,2H),7.64(d,J=8.6Hz,2H),7.43(d,J=8.4Hz,3H),7.36(dd,J=14.7,8.6Hz,4H),7.31(d,J=8.3Hz,2H),5.83(s,4H),5.17(d,J=9.3Hz,6H),4.45(d,J=13.5Hz,10H),4.05(q,J=7.1Hz,6H),1.13(t,J=7.1Hz,9H).Calculated for,986.3629;found:986.3637。
化合物II-2: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:1176.5208;found:1176.5249
化合物II-3: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II-4:固体纯品28mg,为白色固体,收率为70%。H NMR(600MHz,DMSO-d6)δ8.76(s,2H),8.71(s,2H),8.62(s,2H),7.94(t,J=5.7Hz,3H),7.64(dd,J=8.5,1.7Hz,2H),7.60(dd,J=8.5,1.7Hz,2H),7.43–7.37(m,3H),7.29(t,J=7.9Hz,4H),7.23(d,J=8.3Hz,2H),5.80(s,4H),4.80(d,J=7.4Hz,6H),4.40(td,J=16.2,15.8,7.7Hz,10H),2.98–2.90(m,6H).HRMS(MALDI-TOF):Calc:1278.4739;found:1278.4713.
化合物III(1-4)合成步骤:
化合物III-1合成步骤:取100mg化合物Ⅰ-1于茄型瓶中(100mL),采用二氯甲烷作为反应溶剂,加入间氯过氧苯甲酸50mg和磷酸氢二钠100mg,在氮气保护下反应12个小时,采用薄层色谱板监测反应。反应后处理:将反应液用二氯甲烷/饱和碳酸钠水溶液萃取5遍,萃取过程中应加入氯化钠除去乳化层,将反应液合并后进行减压蒸馏,得到粗品用硅胶柱层析(二氯甲烷:甲醇=100:1),得到纯品92mg,为淡黄色固体,TLC:化合物12:二氯甲烷,收率为70%。
化合物III-2的合成步骤:取100mg化合物III-1放置于烧瓶中,加入丁胺5ml,磁力加热搅拌10小时,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,得白色固体化合物。
化合物III-3的合成步骤:取100mg化合物III-1放置于烧瓶中,加入苄胺5ml,磁力加热搅拌10小时,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,得黄色固体化合物。
化合物III-4的合成步骤:取100mg化合物III-1放置于烧瓶中,加入二甘醇胺5ml,磁力加热搅拌10小时,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,得白色固体化合物。
化合物III-1:固体纯品55mg,收率55%。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III-2:固体纯品96mg,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III-3:固体纯品92mg,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):Calc[M+H]+:1231.5559;found:1231.5597
化合物III-4:固体纯品92mg,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):Calc[M+H]+:1231.5559;found:1231.5597.
化合物IV(1-4)合成步骤:
化合物IV-1合成步骤:取100mg化合物Ⅰ-1于茄型瓶中(100mL),以四氢呋喃作为溶剂,加入盐酸5滴和水10ml,在室温条件下反应1h,1h后加入200mgDDQ,继续搅拌,采用薄层色谱板监测反应,10h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:甲醇=400:1),得到纯品115mg,为淡黄色固体,TLC:二氯甲烷,收率为60%。
化合物IV-2的合成步骤:将100mg化合物IV-1放置于烧瓶中,加入丁胺5ml,磁力加热搅拌10小时,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,得白色固体化合物。
化合物化合物IV-3的合成步骤:将100mg化合物IV-1放置于烧瓶中,加入苄胺5ml,磁力加热搅拌10小时,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,得白色固体化合物。
化合物化合物IV-4的合成步骤:将100mg化合物IV-1放置于烧瓶中,加入二甘胺5ml,磁力加热搅拌10小时,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,得白色固体化合物。
化合物IV-1:固体纯品75mg,收率70%。1H NMR(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).13CNMR(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IV-2:固体纯品92mg,收率为70%。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IV-3:固体纯品89mg,收率为69%。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).13CNMR(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IV-4:固体纯品92mg,收率为70%。1H NMR(600MHz,DMSO-d6)δ8.97–8.78(m,6H),8.02–7.89(m,4H),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:1084.4218;found:1084.4211。
化合物V(1-4)合成步骤:
化合物V-1的合成步骤:取100mg化合物IV-1于茄型瓶中(100mL),采用二氯甲烷作为反应溶剂,加入间氯过氧苯甲酸50mg和磷酸氢二钠100mg,在氮气保护下反应12个小时,采用薄层色谱板监测反应。反应后处理:将反应液用二氯甲烷/饱和碳酸钠水溶液萃取5遍,萃取过程中应加入氯化钠除去乳化层,将反应液合并后进行减压蒸馏,得到粗品用硅胶柱层析(二氯甲烷:甲醇=100:1),得到纯品68mg,为淡黄色固体,TLC:化合物12:二氯甲烷,收率为70%。
化合物化合物V-2的合成步骤:将100mg化合物V-1置于烧瓶中,加入丁胺5ml,磁力加热搅拌10小时,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,得白色固体化合物。
化合物化合物V-3的合成步骤:将100mg化合物V-1置于烧瓶中,加入苄胺胺5ml,磁力加热搅拌10小时,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,得黄色固体化合物。
化合物化合物V-4的合成步骤:将100mg化合物V-1置于烧瓶中,加入二甘醇胺5ml,磁力加热搅拌10小时,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,得白色固体化合物。
化合物V-1:固体纯品14mg,收率为45%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V-2: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V-3: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)δ168.98140.20,137.38,123.28,122.92,119.03,108.48,105.40,63.85,63.71,61.19,44.3629.47,29.42,14.41.HRMS(MALDI-TOF):Calc:1028.4255;found:1028.4355。
化合物V-4,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。
杯[3]咔唑衍生物对阿糖胞苷的识别作用
本发明采用紫外-可见及荧光光谱进行测试,选用纯水作为溶剂,激发波长设置为375nm,狭缝宽度设置为3nm(Ex),5nm(Em),固定客体分子阿糖胞苷的浓度,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,测试结果如(图1)所示。
从紫外光谱谱图(图1)中可以看到,随着化合物Ⅰ-4的滴加,紫外吸收光谱在300nm处出现减色现象,在270nm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”。上述这种状态说明阿糖胞苷与化合物Ⅰ-4之间发生了特异性结合,并计算其结合常数为2.26×104M-1(0.97)。
同时,也进行了化合物Ⅰ-4与阿糖胞苷的场扫描电镜实验,从SEM图示可以看出,阿糖胞苷在扫描电镜下是棱柱状(图2),而与杯[3]咔唑大环衍生物结合后(图3),呈球状,说明良好的结合作用。
Claims (10)
1.具有以下结构(I)、(II)、(Ⅲ)、(Ⅳ)或(V)中的一种的桥亚甲基修饰的杯[3]咔唑衍生物:
结构(I)中:R1、R2、R3各自独立表示为烷氧基、苄胺基、脂肪胺基、或含O原子的脂肪胺基中的一种;
结构(II)中:R4、R5、R6各自独立表示为烷氧基、苄胺基、脂肪胺基、或含O原子的脂肪胺基中的一种;
结构(III)中:R7、R8、R9各自独立表示为烷氧基、苄胺基、脂肪胺基、或含O原子的脂肪胺基中的一种;
结构(Ⅳ)中:R10、R11、R12各自独立表示为烷氧基、苄胺基、脂肪胺基、或含O原子的脂肪胺基中的一种;
结构(V)中:R13、R14、R15各自独立表示为烷氧基、苄胺基、脂肪胺基、或含O原子的脂肪胺基中的一种。
2.根据权利要求1所述的桥亚甲基修饰的杯[3]咔唑衍生物,其特征在于:
R1选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R2选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R3选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R4选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R5选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R6选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R7选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R8选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R9选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R10选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R11选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R12选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R13选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R14选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种;
R15选自乙氧基、丁胺基、苄胺基、二甘醇胺基中的一种。
4.权利要求1-3任意一项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,包括以下步骤:
对杯[3]咔唑母核进行氧化、或氧化后衍生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。
5.根据权利要求4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,所述的氧化为桥亚甲基氧化、桥亚甲基氧化-桥亚甲基烯烃再氧化、桥亚甲基氧化-降解氧化、桥亚甲基氧化-降解氧化-桥亚甲基烯烃再氧化中的一种。
6.根据权利要求5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,杯[3]咔唑母核:顺式-1,4-丁烯二醇100mg:(1-5)mL;其中,按摩尔比,杯[3]咔唑母核:2,3-二氯-5,6-二氰基苯醌=1:1.5,反应时间为5~10h;
桥亚甲基烯烃再氧化时,采用氧化剂间氯过氧苯甲酸,催化剂磷酸氢二钠;其中,按摩尔比,化合物Ⅰ-1:间氯过氧苯甲酸:磷酸氢二钠=1:1.5:1.5;
所述的降解氧化时,采用氧化剂为2,3-二氯-5,6-二氰基苯醌,盐酸水溶液;其中,按摩尔比,化合物Ⅰ-1:2,3-二氯-5,6-二氰基苯醌:盐酸水溶液=1:1.5:10,按体积比,盐酸:水=10:1,降解氧化时间为10~12h。
7.根据权利要求4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=100mg:(5-10)mL,所述的胺类化合物选自丁胺、苄胺、二甘醇胺中的一种,并加热至90~120℃,时间6~24h。
9.权利要求1-3任意一项所述的桥亚甲基修饰的杯[3]咔唑衍生物作为药物识别和药物载体的应用。
10.根据权利要求9所述的应用,所述的药物为阿糖胞苷化合物或阿糖腺苷化合物。
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