CN111196819B - 一类d-a-d型苯并吡嗪类化合物及制备方法和应用 - Google Patents

一类d-a-d型苯并吡嗪类化合物及制备方法和应用 Download PDF

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CN111196819B
CN111196819B CN201811367544.6A CN201811367544A CN111196819B CN 111196819 B CN111196819 B CN 111196819B CN 201811367544 A CN201811367544 A CN 201811367544A CN 111196819 B CN111196819 B CN 111196819B
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丁春勇
徐志爱
张文
吉爱艳
王凤阳
于海军
张翱
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Abstract

本发明提供了一类可用于生物活体成像的近红外二区荧光探针的D‑A‑D型苯并吡嗪类化合物,组合物及其制备方法和应用。所述苯并吡嗪类化合物具有通式I所示结构。本发明以邻苯二胺类的电子供体‑受体‑供体(D‑A‑D)型的化合物为原料,与邻二羰基化合物反应成环,扩大荧光分子的刚性结构,其荧光发射波长位于近红外二区窗口。该分子可用于细胞、组织和生物体的荧光成像,并具有低毒性、良好的生物兼容性及光稳定性。

Description

一类D-A-D型苯并吡嗪类化合物及制备方法和应用
技术领域
本发明属于有机小分子荧光探针领域,涉及一类苯并吡嗪类化合物、组合物及其制备方法及应用。
背景技术
荧光成像技术利用荧光探针(分子)经特定波长照射下所激发的光,对生物分子、细胞及组织/器官进行实时、可视化的监测,跟踪生物体内各种生理/病理过程,了解生物分子及其结构与功能的关系,已成为当前生物医学领域的一个重要研究工具。荧光成像技术具有无创、可视化、高时空分辨率、廉价和安全等优势,被广泛用于肿瘤诊断、血管及淋巴结成像、手术导航等诸多领域(Chemical Science,2018,9,DOI:10.1039/c8sc01153b)。
然而,生物体一些组分(黑色素、血红蛋白及细胞色素等)在可见光(400–700nm)存在自荧光及光散射现象,严重干扰成像效果(Chemical Society Reviews.2018,47:4258-4278)。相较于可见光波段,近红外一区(700–1000nm)和近红外二区荧光探针(1000–1700nm)因其光子散射低、光信号衰减少、组织自荧光现象和体内干扰物质光吸收降低等优势,成为研究热点(Nanoscale Horizons,2016,1,168–184.)。由于近红外二区较近红外一区荧光探针具更强生物组织穿透力,可实现更深组织、高信噪比及高分辨率的活体成像,在疾病诊断方面极具优势。近来开发的基于电子给体-电子受体-电子给体(D-A-D)的有机小分子近红外二区荧光探针,其最大发射波长>1000nm,显著改善成像效果。考虑到近红外二区荧光探针成像优势,开发生物相容性好、代谢性质佳、发射波长更长的新型D-A-D型荧光探针十分必要。
发明内容
对有机小分子荧光分子结构的文献调研中,我们发现邻苯二胺这一结构普遍存在于荧光分子或合成荧光分子的中间体中。这主要是由于氨基具有较强的可修饰性,在合成和生物应用过程中均具有重要价值。本发明以邻苯二胺类的电子供体-受体-供体(D-A-D)型的化合物为原料,与邻二羰基化合物反应成环,并引入不同长度聚乙二醇链,增加化合物的刚性结构及溶解度,成功设计出一类结构新颖的近红外二区荧光探针。
本发明的一方面提供了作为近红外二区荧光探针的通式I所示的苯并吡嗪类化合物或其盐:
Figure BDA0001868979510000021
其中,X为S、O或Se;
R1,R2各自独立地为H、C1-C8烷基、C1-C8烷氧基、卤素,或,R1和R2与其相邻的C一起形成5-10元杂环基;
R3,R4各自独立地为H、C1-C8烷基、取代或非取代芳环或芳杂环化合物;
Figure BDA0001868979510000022
为被C1-C8烷基、羟基C1-C8烷基、氨基C1-C8烷基、巯基C1-C8烷基、卤代C1-C8烷基、式-(CH2)n1-(OCH2CH2)n2-OR的聚乙二醇基、氨基、卤素、C1-C8烷氧基、脂肪羧基、C1-C8烷基酰氧基、-NR6R7取代或未取代的C6-C14芳基,被C1-C8烷基、式-(CH2)n1-(OCH2CH2)n2-OR的聚乙二醇基、氨基、卤素取代或未取代的5-18元杂芳基,
如,
Figure BDA0001868979510000023
等;
其中,R5和R52各自独立地为H、C1-C8烷基、式-(CH2)n1-(OCH2CH2)n2-OR的聚乙二醇基;n1和n2分别为0~500的整数,R选自H、C1-C8烷基、羟基、氨基、羧基、磺酸基、卤素;所述的式-(CH2)n1-(OCH2CH2)n2-OR的聚乙二醇基可进一步被C1-C8烷基、羟基、氨基、巯基、卤素中的一种或多种所取代;
R6和R7各自独立地为H、C1-C8烷基、C1-C8烷基硅基、被C1-C8烷基取代或未取代的C6-C12芳基、被羧基、C1-C8烷基硅基C1-C8烷氧基羰基(例如,三甲基硅基乙氧基羰基)、磺酸基C1-C8烷基胺酰基(例如,-CONH(CH2)3SO3H)取代或未取代的C1-C8烷基C6-C12芳基、式-(CH2)n1-(OCH2CH2)n2-OR的聚乙二醇基,n1和n2分别为0~500的整数,R选自H、C1-C8烷基、羟基、氨基、羧基、磺酸基、卤素,所述的聚乙二醇基可一步被C1-C8烷基、羟基、氨基、巯基、卤素取代;或,R6和R7与其相邻的N一起形成5-10元杂环基;
R8和R9各自独立地为H、被羟基、氨基、巯基、卤素取代或未取代的C1-C8烷基、C1-C8烷氧基、C1-C8烷基酰氧基。
进一步优选地,X为O、S或Se;
R1,R2为H,或R1和R2与其相邻的C一起形成二氧六环基(例如,1,4-二氧六环基);
Figure BDA0001868979510000031
Figure BDA0001868979510000032
Figure BDA0001868979510000033
在一优选实施方式中,
R5和R52各自独立地为H、C1-C4烷基、-(CH2)n1-(OCH2CH2)n2-OR的聚乙二醇基,其中,n1和n2各自独立地为1~4的整数,R为C1-C4烷基;进一步优选地,R5和R52各自独立地为H、-(CH2)n1-(OCH2CH2)n2-OR的聚乙二醇基,其中,n1和n2均为2,R为甲基;
R6、R7各自独立地为苯基、C1-C4烷基硅基C1-C4烷氧基羰基苯基(例如,三甲基硅基乙氧基羰基丙基苯基)、磺酸基C1-C4烷基胺酰基C1-C4烷基苯基(例如,-C6H4(CH2)2CONH(CH2)3SO3H)、羧基C1-C4烷基苯基(例如,羧乙基苯基)、-(CH2)n1-(OCH2CH2)n2-OR的聚乙二醇基,其中,n1和n2各自独立地为1~4的整数,R为C1-C4烷基;进一步优选地,R6、R7各自独立地为苯基、4-(3-羰基-3-(2-(三甲基硅基)乙氧基)丙基)苯基、4-(2-羧乙基)苯基、-(CH2)n1-(OCH2CH2)n2-OR的聚乙二醇基,其中,n1和n2均为2,R为甲基。
在一优选实施方式中,本发明通式I所示的苯并吡嗪类化合物最优选为如下化合物:
Figure BDA0001868979510000041
Figure BDA0001868979510000051
术语“卤素”是指氟、氯、溴或碘。
术语“C1-C8烷基”是指链上具有1至8个碳原子的直链或支链饱和烃基,非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基等。
术语“C1-C8烷氧基”是指上述链上具有1至8个碳原子的直链或支链烷基的氧醚基。例如,甲氧基、乙氧基、正丙氧基、仲丁氧基、叔丁基、正己氧基等。
术语“C1-C8烷基硅基”为结构RaRbRcSi-,其中,Ra、Rb和Rc中至少有一个为C1-C8烷基,其余为氢的基团,例如,三甲基硅烷、三乙基硅烷。
术语“磺酸基”是指-SO3H。
术语“C1-C8烷基酰氧基”是指具有酰氧基-OC(O)Rd取代基的C1-C8烷基,其中,Rd包括H、“C1-C8烷基”、“C2-C8烯基”、“C2-C8炔基”、“杂环烷基”、“芳基”、“杂芳基”、“C1-C8烷基芳基”、“C1-C8烷基杂芳基”;“C1-C8烷基酰氧基”非限制地包括2-(乙酰氧基)乙基。
术语“C1-C8烷基硅基C1-C8烷氧基羰基”是指被C1-C8烷基硅基取代的具有1-8个碳原子的烷基-O-C(=O)-基团,非限制性地包括三甲基硅基乙氧基羰基。
术语“烷基芳基氨基”是指具有一个或两个烷基取代基(相互独立地选择)的-N(芳基)2或-NH(芳基)的基团,例如甲基苯基氨基,甲基二苯基氨基,乙基苯基氨基,正丙基苯基氨基、正丙基二苯基氨基、异丙基苯基氨基、叔丁基苯基氨基;
术语“C1-C8烷基硅基C1-C8烷氧基羰基C1-C8烷基氨基”是指被C1-C8烷基硅基C1-C8烷氧基羰基取代的烷基芳基氨基,非限制性地包括二(三甲基硅基乙氧基羰基丙基苯基)氨基。
术语“5-10元杂环基”是指含有一个或多个饱和和/或部分饱和环,其包括5至10个环原子,其中一个或多个环原子选自氮、氧或硫的杂原子,其余环原子为碳;例如,环氧丙烷、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基。
术语“C6-C14芳基”是指包含6-14个环原子但环原子中不含杂原子的单环或双环芳香族环基,例如,苯基、萘基。
术语“C1-C8烷基C6-C10芳基”是指被C1-C8烷基取代的C6-C10芳基,非限制性的包括,苄基、甲基萘基、丙基苯基。
术语“5-18元杂芳基”是指包含5-18个环原子且在环原子中含有1-4个杂原子作为环成员的单价芳香环基团。杂原子可以选自氮、氧或硫。杂芳基可以是具有5-7个环原子的单环杂芳基,或者具有7-12个环原子的双环杂芳基。所述双环杂芳基中只要一个环是杂芳环即可,另一个可以是芳香环或非芳香环的,含杂原子的或不含杂原子的。杂芳基的例子包括但不限于吡咯基、吡唑基、咪唑基、噁唑基、吡啶基、嘧啶基、呋喃基、噻吩基、噻唑基、噻二唑基、四唑基、三氮唑基、异噁唑基、吲哚基、甲基吡啶鎓基噻唑基、苯并[d]恶唑、苯并[d]咪唑等。优选地,所述5-12元杂芳基选自吡啶基,嘧啶基,噁唑基,噻吩基,吲哚基,1,3-二氧代异吲哚基,1-氧代异吲哚基,咪唑基,咔唑基、苯并咔唑基、吡唑基,异噁唑基,苯并咪唑基和呋喃基。
本发明的另一方面提供了制备近红外荧光探针的通式I所示的苯并吡嗪类化合物的方法,所述方法包括以下步骤:
Figure BDA0001868979510000071
其中,X、R1、R2、R3、R4
Figure BDA0001868979510000072
与上文中通式I的定义相同;
通式II所示化合物在邻二羰基化合物作为酰化剂,在溶剂存在条件下室温反应1-8h,得到通式I所示的苯并吡嗪类化合物。
优选地,所述的溶剂选自甲醇、乙醇、二氯甲烷中的一种或几种。
其中,所述通式II所示化合物可由以下步骤制备:
Figure BDA0001868979510000073
其中,X、R1、R2
Figure BDA0001868979510000074
的定义与上文中通式I的定义相同;
1)通式化合物A、化合物B经Pd催化偶联反应得到通式化合物C;
2)通式化合物C在还原剂、溶剂存在的条件下,60–120℃反应,得到通式II所示的化合物。
优选地,步骤2)中,所述的还原剂为铁单质,所述溶剂为乙酸;所述反应的反应时间为2-10h。
优选地,步骤1)中,所述偶联反应使用四(三苯基膦)钯Pd(PPh3)4作为Pd催化剂。
本发明的另一方面是提供通式I所示苯并吡嗪类化合物或其盐作为近红外二区荧光探针在丙酮醛检测中的用途。本发明所述的通式I所示化合物或其盐可直接作为丙酮醛响应性荧光探针。
本发明的另一方面提供了包含本发明通式I所示的苯并吡嗪类化合物的组合物,所述组合物包括至少一种本发明通式I所示的苯并吡嗪类化合物,和任选的药学上可接受的赋形剂。
本发明的另一方面提供了通式I所示的苯并吡嗪类化合物或其盐作为近红外二区荧光探针的用途,以及通式I所示的苯并吡嗪类化合物或其盐在制备近红外二区荧光探针中的用途。
本发明的另一方面提供了通式I所示的苯并吡嗪类化合物或其盐在生物样本活体成像中的用途。
本发明的另一方面提供了通式I所示的苯并吡嗪类化合物或其盐在制备用于生物样本活体成像试剂盒中的用途。
所述的生物样品包括但不局限于肿瘤细胞、神经细胞、活体斑马鱼及啮齿类动物等。
本发明的苯并吡嗪类化合物荧光探针的使用方法没有特别的限定,可以和以往公知的荧光探针同样使用。通常选自用上述通式I所示的化合物或其盐的物质溶解在生理盐水或缓冲液等水性介质或者乙醇、丙酮、乙二醇、二甲亚砜、二甲基甲酰胺等水混合性有机溶剂和水性介质的混合物等中,再测定荧光光谱即可。
附图说明
图1为化合物S5(20μM)的吸收(A)和发射(B)光谱,测试条件:激发波长为808nm,10mM PB(pH=7.4),50Wt.%DMAC;
图2为化合物S6(20μM)的吸收(A)和发射(B)光谱,测试条件:激发波长为808nm,10mM PB(pH=7.4),50Wt.%DMAC;
图3为化合物S7(20μM)的吸收(A)和发射(B)光谱,测试条件:激发波长为808nm,10mM PB(pH=7.4),50Wt.%DMAC;
图4为化合物S8(20μM)的吸收(A)和发射(B)光谱,测试条件:激发波长为808nm,10mM PB(pH=7.4),50Wt.%DMAC。
图5为化合物是S7(100μM),尾静脉给药后立即、10min和120min成像图;测试条件:5Wt.%DMAC,10mM PB(pH=7.4),给药剂量100μL,激发波长808nm。
具体实施方式
下面结合具体实施例对本发明做进一步阐述。这些实施例仅是出于解释说明的目的,而不限于不发明的范围和实质。
所有实施例中,1H NMR由Avance III-300型核磁共振仪记录,化学位移以δ(ppm)表示;质谱由MS质谱-LCQ-DECA离子阱质谱仪(ESI/LR)与MS质谱-Q-TOF四极杆飞行时间质谱仪(ESI-HR)记录;反应检测中使用的薄层层析硅胶板(HSGF254)来自国药集团化学试剂有限公司;化合物分离选用国药集团化学试剂有限公司的200-300目硅胶。试剂购买于国药集团化学试剂有限公司。
预备实施例1化合物A1的制备
Figure BDA0001868979510000091
化合物A1-c制备参考文献方法(Chem.Sci.,2016,7:6203-6207)合成。然后将化合物A1-c(100mg,0.06mmol)溶入3mL醋酸,加入Fe粉(100mg,1.79mmol),反应液升温至100℃,在氮气保护下,反应6h。待反应结束后,用饱和碳酸氢钠溶液调节反应液的pH值为7~8,二氯甲烷萃取三次,合并有机相。饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得黄色固体化合物A1。1H NMR(300MHz,CDCl3)δ7.50(d,J=8.49Hz,4H),7.32(m,4H),7.07(m,20H),4.19(t,J=8.43Hz,8H),2.92(m,8H),2.61(m,8H),0.99(t,J=8.46Hz,8H),0.05(s,36H).13C NMR(125MHz,CDCl3)δ174.56,152.20,149.05,147.38,147.05,140.71,136.96,135.09,131.15,130.66,129.12,128.12,126.16,124.35,123.82,108.59,64.13,37.45,31.84,31.04,18.89,0.00.ESI-MS理论值为C82H100N6O8S3Si4:1504.58,实测值为1504.45。
预备实施例2化合物A2的制备
Figure BDA0001868979510000101
化合物A2-a经两步合成:1,4-二溴-2,3-二硝基苯并噻唑(100.0mg,0.26mmol)、三丁基(2,3-二氢噻吩并[3,4-B]-[1,4]二噁英-5-基)锡烷(336.0mg,0.78mmol)和双三苯基磷二氯化钯(52.0mg,0.074mmol)加入到8.0mL重蒸甲苯中,氮气保护,回流反应12h。TLC检测反应完毕后加水及乙酸乙酯萃取,有机层依次用水、饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得橙色固体的化合物i。1H NMR(300MHz,CDCl3)δ6.77(s,2H),4.22(dd,J=11.5,5.5Hz,8H).13C NMR(125MHz,CDCl3)δ152.63,143.07,142.52,141.21,120.28,105.49,104.61,64.53.
化合物i(80.0mg,0.158mmol)、NBS(62.0mg,0.347mmol)加入到3.0mLDMF中,60℃下搅拌3.5h。TLC检测反应完毕后加水及乙酸乙酯萃取,有机层依次用水、饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得棕红色固体的化合物A2-a。
化合物A2-a(108.0mg,0.151mmol)、化合物A1-b(50.2mg,0.075mmol)和四(三苯基膦)钯(9.0mg,0.0077mmol)加入到8.0mL重蒸甲苯和2.7mL 1M碳酸钾水溶液中,氮气保护,回流反应12h。TLC检测反应完毕后加水及乙酸乙酯萃取,有机层依次用水、饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得蓝色固体的化合物A2-c。1H NMR(300MHz,CDCl3)δ7.62(d,J=8.8Hz,4H),7.06(m,20H),4.29(d,J=24.9Hz,8H),4.22–4.13(m,8H),2.91(t,J=7.8Hz,8H),2.61(t,J=7.8Hz,8H),1.04–0.92(m,8H),0.05(s,36H).13C NMR(125MHz,CDCl3)δ176.71,156.26,151.20,149.11,146.55,140.50,139.31,132.84,130.97,128.48,126.10,123.07,105.53,68.09,66.30,39.74,34.03,20.97,2.17。
化合物A2-c(50mg,0.03mmol)溶于2mL醋酸中,加入Fe粉(33.5mg,0.60mmol),反应液升温至100℃,在氮气保护下反应6h。待反应结束后,用饱和碳酸氢钠溶液调节反应液pH至7~8,二氯甲烷萃取三次,合并有机相。饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得黄色固体的化合物A2。1H NMR(300MHz,CDCl3)δ7.60(d,J=8.4Hz,4H),7.05(m,20H),4.34(d,J=8.6Hz,12H),4.24–4.03(m,8H),2.91(t,J=7.6Hz,8H),2.60(t,J=7.8Hz,8H),1.07–0.85(m,8H),0.05(s,36H).13C NMR(125MHz,CDCl3)δ176.54,154.53,150.05,149.14,143.20,140.46,138.68,132.54,130.51,128.13,122.56,109.59,17.84,68.16,66.07,39.55,33.81,20.75,1.96。
预备实施例3化合物A3的制备
Figure BDA0001868979510000111
化合物A3-b制备参考文献方法(Sensors andActuators B.2018,267:403–411.)化合物A1-a(100.0mg,0.183mmol)、化合物A3-b(161.7mg,0.366mmol)和四(三苯基膦)钯(25.41mg,0.022mmol)加入到6.0mL重蒸甲苯和3.0mL 1M碳酸钾水溶液中,氮气保护,回流反应12h。TLC检测反应完毕后加水及乙酸乙酯萃取,有机层依次用水、饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得蓝色固体的化合物A3-c,收率35%。1H NMR(300MHz,CDCl3)δ7.48(m,6H),7.33(t,J=7.6Hz,4H),7.24(d,J=4.1Hz,2H),7.19(d,J=7.7Hz,4H),7.09(t,J=7.4Hz,2H),6.93(d,J=8.5Hz,4H),3.97(t,J=6.3Hz,4H),3.71(t,J=6.0Hz,4H),3.62(m,12H),3.58–3.48(m,4H),3.37(s,6H).ESI-MS理论值为C52H52N6O10S3:1016.3,实测值为1017.0[M+H]+
将化合物A3-c(56.6mg,0.056mmol)溶于2mL醋酸中,加入Fe粉(62.2mg,1.11mmol),反应液加热至100℃,在氮气保护下反应6h;待反应结束后,用饱和碳酸氢钠溶液调节反应液pH至7~8,二氯甲烷萃取三次,合并有机相。饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得黄色固体的化合物A3。1H NMR(300MHz,CDCl3)δ7.52(d,J=8.7Hz,4H),7.33–7.29(m,8H),7.15(d,J=7.6Hz,4H),7.06–6.97(m,6H),4.52(s,4H),3.97(t,J=6.4Hz,4H),3.71(t,J=6.3Hz,4H),3.67–3.58(m,12H),3.56–3.50(m,4H),3.37(s,6H).13C NMR(125MHz,CDCl3)δ150.81,147.65,147.28,146.21,139.29,133.28,129.69,129.46,126.84,126.18,123.01,122.75,122.01,119.15,107.16,71.95,70.76,70.68,70.61,68.19,59.07,51.63.ESI-HRMS理论值为C52H57N6O6S3:957.3496,实测值为957.3505[M+H]+
预备实施例4化合物A4的制备
Figure BDA0001868979510000121
化合物A2-a(100.0mg,0.151mmol)、化合物A3-b(133.4mg,0.302mmol)和四(三苯基膦)钯(20.95mg,0.018mmol)加入到3.0mL重蒸甲苯和1.0mL 1M碳酸钾水溶液中,氮气保护,回流反应12h。TLC检测反应完毕后加水及乙酸乙酯萃取,有机层依次用水、饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得蓝色固体的化合物A4-c。1H NMR(300MHz,CDCl3)δ7.64(d,J=8.8Hz,3H),7.31(t,J=7.9Hz,4H),7.16(d,J=7.8Hz,4H),7.08–7.03(m,3H),6.97(d,J=8.8Hz,4H),4.37–4.17(m,8H),3.98(t,J=6.3Hz,4H),3.71(t,J=6.5Hz,4H),3.66–3.59(m,12H),3.57–3.50(m,4H),3.37(s,6H).ESI-MS理论值为C56H56N6O14S3:1132.30,实测值为1133.1[M+H]+
将化合物A4-c(74mg,0.065mmol)溶于2mL醋酸中,加入Fe粉(73mg,1.31mmol),升温至100℃,在氮气保护反应6h。待反应结束后,用饱和碳酸氢钠溶液调节反应液pH至7~8,二氯甲烷萃取三次,合并有机相。饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得黄色固体的化合物A4。1H NMR(300MHz,CDCl3)δ7.63(d,J=8.8Hz,4H),7.31–7.25(m,4H),7.11(d,J=8.4Hz,4H),7.01–6.96(m,6H),4.36(d,J=5.1Hz,4H),4.32(d,J=4.6Hz,4H),3.96(t,J=6.5Hz,4H),3.70(t,J=6.4Hz,4H),3.65–3.59(m,12H),3.56–3.51(m,4H),3.37(s,6H).13C-NMR(125MHz,CDCl3)δ151.17,147.50,146.64,140.13,139.48,136.84,129.34,127.30,125.26,122.16,122.11,119.76,119.35,105.83,104.43,71.96,70.75,70.67,70.60,68.21,64.92,64.60,59.05,51.57.ESI-HRMS理论值为C56H61N6O10S3:1073.3606,实测值为1073.3604[M+H]+
预备实施例5化合物A5的制备
Figure BDA0001868979510000131
化合物A5-b经两步合成。3-溴咔唑(250mg,1.016mmol)、氢氧化钾(105.0mg,1.86mmol)与适量18-冠-6溶于5mL DMSO中,室温搅拌1h后,加入对甲基三甘醇单甲醚苯磺酸酯(500mg,1.58mmol),室温搅拌过夜。向反应液中加入水,乙酸乙酯萃取。有机层依次用水、饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得无色油状物的化合物ii。1H NMR(300MHz,CDCl3)δ8.14(d,J=1.8Hz,1H),7.97(d,J=7.8Hz,1H),7.50–7.37(m,3H),7.28–7.19(m,2H),4.34(t,J=5.8Hz,2H),3.77(t,J=5.8Hz,2H),3.48–3.36(m,8H),3.34(s,3H)。
化合物ii(1.56g,3.98mmol)、频哪醇联硼酸酯(1.22g,4.79mmol)、乙酸钾(938mg,9.57mmol)与催化剂二(三苯基膦)二氯化钯(279.2mg,0.398mmol)溶于15mL DMF中,氩气保护,至80℃油浴锅过夜反应。向反应液中加入水,乙酸乙酯萃取。有机层依次用水、饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得浅黄色油状物的化合物A5-b。1H NMR(300MHz,CDCl3)δ8.59(s,1H),8.12(d,J=7.7Hz,1H),7.92(d,J=8.3Hz,1H),7.49–7.41(m,3H),7.27–7.22(m,1H),4.50(t,J=6.0Hz,2H),3.86(t,J=6.0Hz,2H),3.53–3.37(m,8H),3.33(s,3H),1.41(s,12H).ESI-MS理论值为C25H34BNO5:439.3,实测值为462.3[M+Na]+
化合物A1-a(100.0mg,0.183mmol)、化合物A5-b(160.9mg,0.366mmol)和四(三苯基膦)钯(25.41mg,0.022mmol)加入到3.0mL重蒸甲苯和1.0mL 1M碳酸钾水溶液中,氮气保护,回流反应12h。TLC检测反应完毕后加水及乙酸乙酯萃取,有机层依次用水、饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得蓝色固体的化合物A5-c。1H NMR(300MHz,CDCl3)δ8.37(s,2H),8.13(d,J=7.7Hz,2H),7.77(d,J=7.6Hz,2H),7.55–7.42(m,10H),7.30–7.26(m,2H),4.51(t,J=5.8Hz,4H),3.89(t,J=5.7Hz,4H),3.54–3.47(m,12H),3.43–3.41(m,4H),3.33(s,6H).ESI-MS理论值为C52H48N6O10S3:1012.3,实测值为1035.0[M+Na]+
将化合物A5-c(120mg,0.12mmol)溶于3mL醋酸中,加入Fe粉(132.8mg,2.37mmol),升温至100℃,于氮气保护下反应6h;待反应结束后,用饱和碳酸氢钠溶液调节反应液pH至7~8,二氯甲烷萃取三次,合并有机相。饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得黄色固体的化合物A5。1H NMR(300MHz,CDCl3)δ8.37(s,2H),8.13(d,J=7.7Hz,2H),7.78(d,J=8.7Hz,2H),7.49–7.45(dd,J=7.2,3.5Hz,8H),7.38(d,J=3.6Hz,2H),7.27–7.22(m,2H),4.57(s,4H),4.51(t,J=5.9Hz,4H),3.89(t,J=5.8Hz,4H),3.53–3.48(m,12H),3.45–3.42(m,4H),3.34(s,6H).13C-NMR(125MHz,CDCl3)δ150.88,147.36,141.09,140.41,139.37,133.48,129.72,126.07,125.61,124.26,123.40,122.91,122.29,120.51,119.38,117.82,109.40,109.15,107.20,71.87,71.02,70.64,70.55,69.37,59.00,43.35.ESI-HRMS理论值为C52H53N6O6S3:953.3183,实测值为953.3192[M+H]+
预备实施例6化合物A6的制备
Figure BDA0001868979510000141
化合物A2-a(100.0mg,0.151mmol)、化合物A5-b(132.75mg,0.302mmol)和四(三苯基膦)钯(20.95mg,0.018mmol)加入到3.0mL重蒸甲苯和1.0mL 1M碳酸钾水溶液中,氮气保护,回流反应12h。TLC检测反应完毕后加水及乙酸乙酯萃取,有机层依次用水、饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得蓝色固体的化合物A6-c。1H NMR(300MHz,CDCl3)δ8.51(s,2H),8.15(d,J=7.8Hz,2H),7.90(d,J=8.9Hz,2H),7.51–7.47(m,6H),7.27(m,2H),4.51(t,J=5.4Hz,4H),4.40(brs,4H),4.31(brs,4H),3.89(t,J=5.5Hz,4H),3.50(m,12H),3.44(m,4H),3.34(s,6H).ESI-MS理论值为C56H52N6O14S3:1128.3,实测值为1129.8[M+H]+
将化合物A6-c(44mg,0.04mmol)溶于2mL醋酸中,加入Fe粉(43.7mg,0.78mmol),升温至100℃,于氮气保护下反应6h;待反应结束后,用饱和碳酸氢钠溶液调节反应液pH至7~8,二氯甲烷萃取三次,合并有机相。饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得黄色固体的化合物A6。1H NMR(300MHz,CDCl3)δ8.48(s,2H),8.14(d,J=7.9Hz,2H),7.89(d,J=10.0Hz,2H),7.50–7.43(m,6H),7.26–7.21(m,2H),4.51(t,J=5.8Hz,4H),4.47–4.41(m,8H),4.39–4.34(m,4H),3.89(t,J=5.8Hz,4H),3.57–3.48(m,12H),3.47–3.41(m,4H),3.34(s,6H).13C-NMR(125MHz,CDCl3)δ151.27,140.99,140.19,139.75,139.58,136.69,125.86,124.78,124.08,123.20,123.04,120.58,120.43,119.20,118.46,109.07,109.04,105.83,104.49,71.87,71.03,70.64,70.57,69.34,65.02,64.68,59.01,43.28.ESI-HRMS理论值为C56H57N6O10S3:1069.3293,实测值为1069.3294[M+H]+
预备实施例7化合物A7的制备
Figure BDA0001868979510000151
化合物A7-b经三步合成。将六甘醇单甲醚(1g,3.37mmol)溶于5mL二氯甲烷中,加入三乙胺(409.5mg,4.05mmol)、对甲基苯磺酰氯(769.3mg,4.05mmol),并于60℃油浴锅反应过夜。次日反应液浓缩,粗产物柱层析分离,得无色油状物iii。1H NMR(400MHz,CDCl3)δ7.77(d,J=7.6Hz,2H),7.32(d,J=7.4Hz,2H),4.13(s,2H),3.65–3.52(m 22H),3.35(s,3H),2.42(s,3H).
3-溴咔唑(595mg,2.42mmol)、氢氧化钾(247.8mg,4.43mmol)与适量18-冠-6溶于5mL DMSO中,室温搅拌1h后,加入iii(1.2g,3.77mmol),室温搅拌过夜。向反应液中加入水,乙酸乙酯萃取。有机层依次用水、饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得无色油状物iv。1HNMR(400MHz,CDCl3)δ8.17(s,1H),8.01(d,J=7.7Hz,1H),7.53–7.22(m,5H),4.44(m,2H),3.83(m,2H),3.65–3.38(m,20H),3.38(s,3H).
化合物iv(1.56g,3.98mmol)、频哪醇联硼酸酯(1.22g,4.79mmol)、乙酸钾(938mg,9.57mmol)与催化剂二(三苯基膦)二氯化钯(279.2mg,0.398mmol)溶于15mL DMF中,氩气保护,至80℃油浴锅过夜反应。向反应液中加入水,乙酸乙酯萃取。有机层依次用水、饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得浅黄色油状物A7-b。1HNMR(400MHz,CDCl3)δ8.58(s,1H),8.16(s,1H),7.99(d,J=8.9Hz,1H),7.67(d,J=8.1Hz,1H),7.48–7.43(m,3H),7.22(m,1H),4.43(m,2H),3.83(m,2H),3.66–3.55(m,10H),3.54–3.44(m,10H),3.35(s,3H),1.21(s,12H).
化合物A1(200.0mg,0.366mmol)、化合物A7-b(418.73mg,0.732mmol)和四(三苯基膦)钯(50.8mg,0.044mmol)加入到6.0mL重蒸甲苯和2.0mL 1M碳酸钾水溶液中,氮气保护,回流反应12h。TLC检测反应完毕后加水及乙酸乙酯萃取,有机层依次用水、饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得蓝色固体A7-c。1H NMR(400MHz,CDCl3)δ8.41(s,2H),8.17(d,J=7.7Hz,2H),7.82(d,J=8.5Hz,2H),7.59–7.47(m10H),7.33–7.29(m,2H),4.55(t,J=5.9Hz,4H),3.92(t,J=5.9Hz,4H),3.66–3.50(m,40H),3.39(s,6H).
将化合物A7-c(84.1mg,0.066mmol)溶于3mL醋酸中,加入Fe粉(73.66mg,1.32mmol),升温至90℃,于氮气保护下反应6h;待反应结束后,用饱和碳酸氢钠溶液调节反应液pH至7~8,二氯甲烷萃取三次,合并有机相。饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得黄色固体化合物A7。1H NMR(400MHz,CDCl3)δ8.38(s,2H),8.18–8.08(m,2H),7.86–7.74(m,2H),7.61–7.35(m,10H),7.29-7.27(m,2H),4.65(s,4H),4.51(m,4H),3.88(m,4H),3.74–3.43(m,40H),3.39(s,6H).13C NMR(126MHz,CDCl3)δ150.87,147.30,141.07,140.43,139.44,133.55,129.73,126.07,125.63,124.25,123.39,122.91,122.29,120.50,119.37,117.79,109.45,109.14,106.96,71.92,71.04,70.59,70.53,70.48,69.38,59.01,43.37.
预备实施例8化合物A8的制备
Figure BDA0001868979510000171
化合物A8-b经三步合成。冰浴下,将对甲基苯磺酰氯(750mg,3.95mmol)与十二甘醇单甲醚(2g,3.57mmol)溶于四氢呋喃中,加入氢氧化钠(357mg,8.93mmol)的50%水溶液,加毕,转移至室温反应过夜。次日向反应液中加入水,乙酸乙酯萃取。有机层依次用水、饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得无色油状物v。1HNMR(400MHz,CDCl3)δ7.70(d,J=5.7Hz,2H),7.27(d,J=5.7Hz,2H),4.07(m,2H),3.56(m,46H),3.28(s,3H),2.36(s,3H).
3-溴咔唑(620mg,2.52mmol)与化合物v(1.8g,2.52mmol)溶于适量四氢呋喃,加入氢氧化钠(100mg,2.52mmol)的50%氢氧化钠溶液。置于油浴锅中回流反应过夜。次日向反应液中加入水,乙酸乙酯萃取。有机层依次用水、饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得无色油状物vi。1H NMR(400MHz,CDCl3)δ8.15(s,1H),8.00(d,J=7.8Hz,1H),7.54–7.40(m,3H),7.34(m,1H),7.22(m,1H),4.44(t,J=5.4Hz,2H),3.82(t,J=5.6Hz,2H),3.63–3.48(m,44H),3.36(s,3H).
化合物vi(1.7g,2.15mmol)、频哪醇联硼酸酯(656.4mg,2.58mmol)、乙酸钾(506mg,5.16mmol)与催化剂二(三苯基膦)二氯化钯(150.64mg,0.215mmol)溶于15mL DMF中,氩气保护,至80℃油浴锅过夜反应。向反应液中加入水,乙酸乙酯萃取。有机层依次用水、饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得浅黄色油状物A8-b。1H NMR(400MHz,CDCl3)δ8.58(s,1H),8.11(d,J=7.1Hz,1H),7.91(d,J=8.2Hz,1H),7.49–7.43(m,3H),7.26–7.21(m,1H),4.50(t,J=5.9Hz,2H),3.86(t,J=5.9Hz,2H),3.66–3.48(m,44H),3.37(s,3H),1.37(s,12H).
化合物A1(100.0mg,0.183mmol)、化合物A8-b(306,2mg,0.366mmol)和四(三苯基膦)钯(25.41mg,0.022mmol)加入到3.0mL重蒸甲苯和1.0mL 1M碳酸钾水溶液中,氮气保护,回流反应12h。TLC检测反应完毕后加水及乙酸乙酯萃取,有机层依次用水、饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得蓝色固体A8-c。1H NMR(400MHz,CDCl3)δ8.40(s,2H),8.17(d,J=8.7Hz,2H),7.81(d,J=8.7Hz,2H),7.61–7.42(m,10H),7.31(m,2H),4.55(t,J=5.9Hz,4H),3.92(t,J=5.9Hz,4H),3.69–3.51(m,88H),3.39(s,6H).
将化合物A8-c(100mg,0.055mmol)溶于5mL醋酸中,加入Fe粉(62.1mg,1.11mmol),升温至100℃,于氮气保护下反应6h;待反应结束后,用饱和碳酸氢钠溶液调节反应液pH至7~8,二氯甲烷萃取三次,合并有机相。饱和食盐水洗涤,无水硫酸钠干燥。抽滤,滤液减压浓缩,粗产物柱层析分离,得黄色固体化合物A8。1HNMR(400MHz,CDCl3)δ8.40(s,2H),8.15(d,J=7.7Hz,2H),7.81(d,J=7.8Hz,2H),7.56–7.40(m,10H),7.30-7.26(m,2H),4.54(t,J=5.8Hz,4H),3.91(t,J=5.8Hz,4H),3.71–3.48(m,88H),3.38(s,6H).13C NMR(126MHz,CDCl3)δ150.85,147.18,141.06,140.43,139.57,133.70,129.69,126.06,125.66,124.24,123.38,122.91,122.28,120.50,119.37,117.77,109.46,109.14,106.50,71.92,71.05,70.54,69.40,59.01,43.38.ESI-HRMS Calcd for:C88H124N6O24S3Na:1767.7721,found1767.7745[M+Na]+.
实施例1、化合物S1的合成
Figure BDA0001868979510000181
化合物A1(10.0mg,0.0064mmol)溶解在1mL混合溶剂中(甲醇:二氯甲烷=1:1,v/v)中,加入0.5mLMGO(丙酮醛)水溶液(c=30wt.%),室温搅拌4h。TLC检测反应完毕后减压浓缩,制备板分离,得绿色化合物S2-1,6.5mg,收率63.5%。1H NMR(300MHz,CDCl3)δ8.92(d,J=4.17Hz,1H),8.86(d,J=4.17Hz,1H),8.57(s,1H),7.63(d,J=8.52Hz,4H),7.36(m,2H),7.07(m,20H),4.20(t,J=8.48Hz,8H),2.94(m,8H),2.73(s,3H),2.63(m,8H),1.00(t,J=8.49Hz,8H),0.06(s,36H).13C NMR(125MHz,CDCl3)δ174.54,154.23,152.76,152.38,150.57,149.11,149.07,147.04,146.30,136.99,136.61,136.44,136.16,135.95,135.82,130.67,129.74,129.64,128.12,128.09,126.19,124.38,123.80,123.68,122.48,121.67,64.13,37.56,31.84,31.99,23.75,18.77,0.00.ESI-LRMS理论值为C85H100N6O8S3Si4:1540.58,实测值为1541.31[M+H]+
实施例2、化合物S2的合成
Figure BDA0001868979510000191
将化合物S1(10mg,0.0065mmol)溶于适量二氯甲烷中,加入三氟乙酸(二氯甲烷:三氟乙酸=10:1,v/v),室温搅拌5h。反应液减压浓缩,粗产物柱层析分离,得3mg黄色固体的化合物S2-2,收率41%。ESI-MS理论值为C65H52N6O8S3:1140.3,实测值为1139.4[M-H]-
实施例3、化合物S3的合成
Figure BDA0001868979510000192
化合物A2(10mg,0.0062mmol)溶解在0.5mL混合溶剂中(甲醇:二氯甲烷=1:1,v/v)中,加入0.3mLMGO水溶液(c=30wt.%),室温搅拌4h。TLC检测反应完毕后减压浓缩,制备板分离,得蓝绿色化合物S2-3,3.6mg,收率29%。1H NMR(300MHz,CDCl3)δ8.76(s,1H),7.71–7.63(m,4H),7.06(m,20H),4.34(d,J=35.9Hz,8H),4.22–4.14(m,8H),2.91(t,J=7.7Hz,8H),2.80(s,3H),2.60(t,J=7.8Hz,8H),1.02–0.95(m,8H),0.05(s,36H).13C NMR(125MHz,CDCl3)δ176.00,157.28,155.60,150.20,149.53,148.59,144.49,141.01,140.13,138.13,131.99,130.06,129.63127.44,125.81,124.18,110.00,67.32,65.53,39.01,33.26,26.25,20.19,1.40。
实施例4、化合物S4的合成
Figure BDA0001868979510000201
将化合物S3(10mg,0.006mmol)溶于适量二氯甲烷中,加入三氟乙酸(二氯甲烷:三氟乙酸=10:1,v/v),室温搅拌5h。反应液减压浓缩,粗产物柱层析分离,得黄色固体的化合物S2-4,5mg,收率42%。ESI-MS理论值为C69H56N6O12S3:1256.3,实测值为1255.4[M-H]-
实施例5、化合物S5的合成
Figure BDA0001868979510000202
化合物A3(15.0mg,0.0157mmol)溶解在1.0mL混合溶剂中(甲醇:二氯甲烷=1:1,v/v)中,加入0.6mLMGO水溶液(c=30wt.%),室温搅拌4h。TLC检测反应完毕后减压浓缩,制备板分离,得绿色化合物S2-5,8.3mg,收率53%。1HNMR(300MHz,CDCl3)δ8.68(s,1H),7.66(d,J=8.6Hz,4H),7.43–7.28(m,7H),7.19(d,J=7.7Hz,4H),7.01–7.09(m,7H),4.01(brs,4H),3.75(t,J=6.3Hz,4H),3.70–3.60(m,12H),3.57–3.53(m,4H),3.38(s,6H),2.81(s,3H).13CNMR(125MHz,CDCl3)δ152.93,151.58,151.20,149.87,149.57,147.79,147.75,147.29,147.28,145.08,135.47,134.81,134.71,134.40,129.49,126.86,126.73,126.59,123.19,122.87,122.06,121.96,121.30,120.48,119.06,119.03,71.97,70.79,70.70,70.62,68.23,59.06,51.68,22.42.ESI-MS理论值为C55H57N6O6S3:993.3496,实测值为993.3479[M+H]+
实施例6、化合物S6的合成
Figure BDA0001868979510000211
化合物A4(8.4mg,0.0078mmol)溶解在0.6mL混合溶剂中(甲醇:二氯甲烷=1:1,v/v)中,加入0.3mLMGO水溶液(c=30wt.%)室温搅拌4h。TLC检测反应完毕后减压浓缩,制备板分离,得蓝绿色化合物2.7mg,收率31%。1H NMR(300MHz,CDCl3)δ8.77(s,1H),7.73–7.65(m,4H),7.30(d,J=7.5Hz,4H),7.13(d,J=8.0Hz,4H),7.04–6.97(m,6H),4.41(m,4H),4.29(m,4H),3.98(t,J=6.3Hz,4H),3.72(t,J=6.3Hz,4H),3.65–3.61(m,12H),3.57–3.51(m,4H),3.38(s,6H),2.80(s,3H).13C NMR(125MHz,CDCl3)δ154.37,152.77,152.50,147.50,147.30,146.72,146.70,141.65,141.60,138.16,137.70,137.26,137.17,129.35,127.45,127.40,125.56,125.44,122.31,122.25,122.18,122.15,122.00,121.58,121.50,121.43,119.68,119.58,107.00,106.66,71.97,70.77,70.69,70.61,68.22,64.65,64.63,64.48,64.39,59.06,51.59,23.39.ESI-MS理论值为C59H61N6O10S3:1109.3606,实测值为1109.3585[M+H]+
实施例7、化合物S7的合成
Figure BDA0001868979510000212
化合物A5(20mg,0.021mmol)溶解在1.0mL混合溶剂中(甲醇:二氯甲烷=1:1,v/v)中,加入0.8mL MGO水溶液(c=30wt.%)室温搅拌4h。TLC检测反应完毕后减压浓缩,制备板分离,得蓝绿色化合物3.6mg,收率58%。1HNMR(300MHz,CDCl3)δ8.95(dd,J=10.6,4.1Hz,2H),8.64(s,1H),8.43(d,J=5.2Hz,2H),8.14(d,J=9.0Hz,2H),7.87(d,J=8.6Hz,2H),7.51–7.45(m,8H),7.24–7.21(m,2H),4.48(t,J=6.2Hz,4H),3.88(t,J=5.8Hz,4H),3.59–3.47(m,12H),3.45–3.34(m,4H),3.34(s,6H),2.79(s,3H).13C NMR(125MHz,CDCl3)δ152.75,151.45,151.05,150.89,150.58,144.89,141.03,140.44,140.40,135.36,134.91,134.75,134.67,134.58,134.40,126.24,126.09,125.98,124.25,124.15,123.40,122.95,122.93,122.26,122.19,121.17,120.58,120.51,120.35,119.31,117.76,117.68,109.30,109.14,71.88,71.02,70.64,70.56,69.36,59.00,43.30,22.47.ESI-HRMS理论值为C55H53N6O6S3:989.3183,实测值为989.3178[M+H]+
实施例8、化合物S8的合成
Figure BDA0001868979510000221
化合物A6(15mg,0.014mmol)溶解在1.0mL混合溶剂中(甲醇:二氯甲烷=1:1,v/v)中,加入0.6mL MGO水溶液(c=30wt.%)室温搅拌4h。TLC检测反应完毕后减压浓缩,制备板分离,得蓝绿色化合物4.2mg,收率27%。1HNMR(300MHz,CDCl3)δ8.81(s,1H),8.55(d,J=4.9Hz,2H),8.16(d,J=8.2Hz,2H),7.99–7.94(m,2H),7.49(m,6H),7.28–7.23(m,2H),4.55–4.46(m,8H),4.38–4.32(m,4H),3.90(t,J=5.5Hz,4H),3.55–3.51(m,12H),3.46–3.42(m,4H),3.35(s,6H),2.84(s,3H).13C NMR(125MHz,CDCl3)δ.154.44,152.88,152.59,147.40,141.80,141.74,141.00,139.82,138.25,137.80,137.15,137.07,125.85,124.94,124.91,124.42,124.35,123.23,123.21,123.10,122.61,122.53,122.08,121.52,120.59,119.19,118.59,109.05,106.97,106.62.ESI-HRMS理论值为C59H57N6O10S3:1105.3293,实测值为1105.3308[M+H]+
实施例9、化合物S9的合成
Figure BDA0001868979510000222
化合物S2制备参考文献(Nature Communication.2017,8:15269.)化合物S2-2(7mg,0.006mmol)、牛磺酸(29.77mg,0.24mmol)、N,N-二异丙基乙胺(30.78mg,0.24mmol)溶于400uL DMSO中,反应10min后,加入O-苯并三氮唑-四甲基脲六氟磷酸酯(29.85mg,0.075mmol),于氮气保护下过夜反应。次日加入等量水搅拌4h,淬灭反应。加入二氯甲烷,收集水层,于反相C18硅胶柱层析分离,得黄色固体6mg,收率62.5%。ESI-LRMS Calcd for:C73H72N10O16S71568.3,found1592.6[M–H+Na].
实施例10、化合物S10的合成
Figure BDA0001868979510000231
化合物A7(5mg,0.0041mmol)溶解在1.0mL混合溶剂中(甲醇:二氯甲烷=1:1v/v)中,加入0.6mL MGO水溶液(c=30wt.%)室温搅拌4h。TLC检测反应完毕后减压浓缩,制备板分离,得蓝绿色化合物2.4mg,收率46.8%。1H NMR(400MHz,CDCl3)δ9.08(d,J=4.1Hz,1H),9.03(d,J=5.7Hz,1H),8.89(s,1H),8.51(d,J=7.4Hz,2H),8.20(d,J=7.8Hz,2H),7.94(d,J=10.1Hz,2H),7.61–7.49(m,8H),7.32-7.30(m,2H),4.56(t,J=6.0Hz,4H),3.93(t,J=5.9Hz,4H),3.67–3.61(m,20H),3.59–3.52(m,20H),3.38(s,6H),2.98(s,3H).13C NMR(126MHz,CDCl3)δ153.14,151.79,151.39,151.10,150.79,145.36,141.10,140.55,140.51,135.76,135.08,134.85,134.82,134.52,126.21,126.06,124.38,124.27,123.46,122.99,122.97,122.44,122.40,121.59,120.75,120.58,120.53,119.38,117.85,117.81,109.40,109.18,71.92,71.03,70.61,70.57,70.54,70.51,70.49,69.36,59.01,43.36,22.64..
实施例11、化合物S11的合成
Figure BDA0001868979510000232
化合物A8(7.5mg,0.0043mmol)溶解在1.0mL混合溶剂中(甲醇:二氯甲烷=1:1v/v)中,加入0.6mL MGO水溶液(c=30wt.%)室温搅拌4h。TLC检测反应完毕后减压浓缩,制备板分离,得蓝绿色化合物2.4mg,收率32.5%。1H NMR(400MHz,CDCl3)δ9.05(d,J=4.0Hz,1H),9.00(d,J=4.0Hz,1H),8.85(s,1H),8.48(d,J=8.0Hz,2H),8.17(d,J=9.9Hz,2H),7.91(d,J=8.0Hz,2H),7.58–7.46(m,8H),7.27–7.29(m,2H),4.53(t,J=6.9Hz,4H),3.90(t,J=6.2Hz,4H),3.64–3.52(m,88H),3.37(s,6H),2.94(s,3H).13C NMR(126MHz,CDCl3)δ153.11,151.76,151.35,151.08,150.77,145.32,141.10,140.53,140.49,135.72,135.04,134.85,134.83,134.52,126.21,126.06,124.36,124.25,123.46,122.98,122.96,122.43,122.39,121.54,120.71,120.58,120.52,119.39,117.85,117.80,109.38,109.19,71.94,71.03,70.56,69.36,59.02,43.36,22.64.ESI-HRMSCalcd for:C91H124N6O24S3Na:1803.7721,found 1803.7760[M+Na]+
实施例12、新型D-A-D近红外荧光探针紫外和二区荧光光谱检测方法:
20μM产物(S5、S6、S7和S8)溶于50Wt.%二甲基乙酰胺DMAC中,在10mM磷酸缓冲液PB(pH=7.4),用1cm常量比色皿,体积2mL,分别测吸收光谱与二区荧光光谱。吸收检测波长范围:300-1000nm;荧光光谱参数:808激光器,功率:2W,激发狭缝宽度:5nm,发射狭缝宽度:10nm,收集波长:850-1500nm。仪器名称:安捷伦Cary60紫外-可见分光光度计,爱丁堡FLS980荧光光谱仪。结果如图1-4所示,产物S5、S6、S7和S8的最大吸收峰在650nM至900nM之间,最大二区荧光发射峰在1000nM至1100nM之间。
实施例13、新型D-A-D近红外二区荧光探针小鼠活体成像方法
将本发明制备的化合物S7(探针S7)溶于5wt.%二甲基乙酰胺DMAC和10Wt.%FBS中,10mM磷酸缓冲液PB(pH=7.4)的缓冲液调节探针浓度至100μM,尾静脉注射100μL,分布在注射后即时、注射后10min和注射后120min行荧光成像。荧光光谱参数:808激光器,功率:2W,激发狭缝宽度:5nm,发射狭缝宽度:10nm,收集波长:1000-1250nm。结果如图5所示,探针S7主要在肝脏中呈高二区荧光信号,同时,可在部分血管中可见二区荧光信号。

Claims (10)

1.一种通式I所示的苯并吡嗪类化合物或其盐:
Figure FDA0004055983060000011
其中,X为S、O或Se;
R1,R2各自独立地为H、C1-C8烷基、C1-C8烷氧基、卤素,或,R1和R2与其相邻的C一起形成5-10元杂环基;
R3,R4各自独立地为H、C1-C8烷基、取代或非取代芳环或芳杂环化合物;
Figure FDA0004055983060000012
Figure FDA0004055983060000013
其中,R5和R52各自独立地为H、C1-C8烷基或式-(CH2)n1-(OCH2CH2)n2-OR的聚乙二醇基;n1和n2分别为0~500的整数,R选自H、C1-C8烷基、羟基、氨基、羧基、磺酸基和卤素;所述的式-(CH2)n1-(OCH2CH2)n2-OR的聚乙二醇基为无取代或被C1-C8烷基、羟基、氨基、巯基、卤素中的一种或多种所取代;
R6和R7各自独立地为H,C1-C8烷基,C1-C8烷基硅基、被C1-C8烷基取代或未取代的C6-C12芳基,被羧基、C1-C8烷基硅基C1-C8烷氧基羰基、磺酸基C1-C8烷基胺酰基取代或未取代的C1-C8烷基C6-C12芳基,式-(CH2)n1-(OCH2CH2)n2-OR的聚乙二醇基,其中,n1和n2分别为0~500的整数,R选自H,C1-C8烷基,羟基,氨基,羧基,磺酸基和卤素,所述的聚乙二醇基为无取代或被C1-C8烷基、羟基、氨基、巯基、卤素中的一种或多种取代;或,R6和R7与其相邻的N一起形成5-10元杂环基,
R8和R9各自独立地为H、被羟基、氨基、巯基、卤素取代或未取代的C1-C8烷基、C1-C8烷氧基或C1-C8烷基酰氧基。
2.如权利要求1所述的通式I所示的苯并吡嗪类化合物或其盐,
其中,R5和R52各自独立地为H、C1-C4烷基或式-(CH2)n1-(OCH2CH2)n2-OR的聚乙二醇基,其中,n1和n2各自独立地为1~4的整数,R为C1-C4烷基;
R6、R7各自独立地为苯基、C1-C4烷基硅基C1-C4烷氧基羰基苯基、羧基C1-C4烷基苯基、-(CH2)n1-(OCH2CH2)n2-OR的聚乙二醇基,其中,n1和n2各自独立地为1~4的整数,R为C1-C4烷基。
3.如权利要求1所述的通式I所示的苯并吡嗪类化合物或其盐,
其中,R5和R52各自独立地为H或式-(CH2)n1-(OCH2CH2)n2-OR的聚乙二醇基,其中,n1和n2均为2,R为甲基;
R6、R7各自独立地为苯基、4-(3-羰基-3-(2-(三甲基硅基)乙氧基)丙基)苯基、4-(2-羧乙基)苯基、-(CH2)n1-(OCH2CH2)n2-OR的聚乙二醇基,其中,n1和n2均为2,R为甲基。
4.如权利要求1-3中任意一项所述的通式I所示的苯并吡嗪类化合物或其盐,
其中,R1,R2为H,或R1和R2与其相邻的C一起形成二氧六环基;
Figure FDA0004055983060000021
Figure FDA0004055983060000022
Figure FDA0004055983060000023
5.如权利要求1-3中任意一项所述的通式I所示的苯并吡嗪类化合物或其盐,通式I所示的苯并吡嗪类化合物为如下化合物之一:
Figure FDA0004055983060000031
Figure FDA0004055983060000041
6.一种组合物,其包含如权利要求1-5中任意一项所述的通式I所示的苯并吡嗪类化合物或其盐,和任选的药学上可接受的赋形剂。
7.一种制备权利要求1~5中任一项所述的通式I所示的苯并吡嗪类化合物的方法,所述方法包括以下步骤:
Figure FDA0004055983060000051
其中,X、R1、R2、R3、R4
Figure FDA0004055983060000052
与相应权利要求中通式I的定义相同;
通式II所示化合物在邻二羰基化合物作为酰化剂,溶剂存在条件下室温反应1-8h,得到通式I所示的苯并吡嗪类化合物。
8.权利要求1~5中任一项所述的通式I所示的苯并吡嗪类化合物或其盐作为近红外二区荧光探针的用途。
9.权利要求1~5中任一项所述的通式I所示的苯并吡嗪类化合物或其盐在制备用于生物样本活体成像试剂盒中的用途。
10.根据权利要求9所述的用途,其特征在于:所述的生物样本包括肿瘤细胞、神经细胞、活体斑马鱼及啮齿类动物。
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