CN114605378B - 一种噻吩稠环类化合物及合成方法与应用 - Google Patents
一种噻吩稠环类化合物及合成方法与应用 Download PDFInfo
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- CN114605378B CN114605378B CN202210300282.1A CN202210300282A CN114605378B CN 114605378 B CN114605378 B CN 114605378B CN 202210300282 A CN202210300282 A CN 202210300282A CN 114605378 B CN114605378 B CN 114605378B
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Abstract
本发明涉及一种噻吩稠环类化合物及合成方法与应用,属有机化学技术领域。本发明合成的噻吩稠环类化合物,具有式(P)所示的结构。该方法简单高效、绿色环保、底物易得、未使用金属试剂还具有良好的官能团兼容性等优点,有效解决了已有方法需要多步反应、底物昂贵、需使用金属试剂或强酸强碱等问题。该发明合成的苯并[b]萘[1,2‑d]噻吩(BNT)衍生物具有高的光致发光荧光效应,可作为荧光染料用于生物成像及作为荧光探针用于质子酸的识别。
Description
技术领域
本发明属有机化学技术领域,更具体地,涉及一种噻吩稠环类化合物及合成方法与应用,尤其涉及一种新的噻吩稠环类化合物的合成方法及在生物成像和质子酸识别技术领域中的应用。
背景技术
噻吩稠环化合物通常具有较高的光致发光量子效率和优异的载流子迁移率,这使得它们在有机场效应晶体管(OFET)、有机发光二极管(OLED)和有机光伏(OPV)等材料科学中具有广泛的应用(Chem.Sci.2021,DOI:10.1039/D1SC05070B;J.Org.Chem.2019,84,698-709;J.Org.Chem.2019,84,698-709;Acc.Chem.Res.2014,47,1493-1502)。例如,S,S-二氧-二苯并噻吩已被广泛用作荧光聚合物材料的主链,通过对称的二卤代和交叉偶联反应与侧链连接(Adv.Mater.2021,33,2100986-2100991;Front.Chem.2020,8,332-340;J.Mater.Chem.A 2020,8,7125-7129;J.Am.Chem.Soc.2020,142,14574-14587;Dyes.Pigm.2020,180,108526-108532;J.Photochem.2019,382,111946-11954;Nat.Commun.2017,8,14987-14997)。相比之下,具有不同偶联位置的不对称噻吩稠环化合物很少被探索,尤其是亚砜衍生物。苯并[b]萘并[1,2-d]噻吩(BNT)相比于二苯并噻吩多了一个额外的苯环,是研究发光齐聚物的理想非对称骨架单元(Org.Electron.2018,61,366-375;Mater.Chem.Phys.2018,212,155-160;J.Org.Chem.2007,72,9141-9151)。然而,这种骨架的合成往往需要多步反应、底物昂贵、需使用金属试剂或强酸强碱等剧烈苛刻的反应条件,这些已报道的方法并没有系统的研究BNT化合物的底物适用性,且并不适用于多取代BNT的合成,(Beilstein J.Org.Chem.2021,17,396-403;Asian J.Org.Chem.2017,6,1390-1393;Eur.J.Org.Chem.2017,2017,5892-5895;J.Am.Chem.Soc.2017,139,2960-2963;Angew.Chem.Int.Ed.2017,56,7166-7170;Chem.Commun.2015,51,10295-10298;Eur.J.Org.Chem.2011,2011,53-57;J.Org.Chem.1993,58,2593-2598)。有趣的是,有文献报道在苯并噻吩的细菌代谢物中发现了少量的BNT衍生物。并认为在氧化酶存在下生成的苯并噻吩亚砜是关键中间体,其发生二聚化,从而生成了BNT类化合物(Org.Biomol.Chem.2012,10,782-790;Microbiology 2008,154,3804-3812;Appl.Environ.1994,60,3624-3631)。受该过程的启发,我们将苯并噻吩选择性氧化为亚砜,然后通过Diels-Alder二聚化反应来生成BNT亚砜类化合物,该方法为BNT分子的合成提供了一种简洁有效的方法。且该类化合物还可以通过交叉偶联、氧化、还原、脱烷基化等方法进一步衍生化,构建丰富的BNT类化合物库。
噻吩稠环化合物通常具有很强的光致发光荧光效应,我们合成的BNT类化合物同样也具有该性质,尤其是BNT亚砜类化合物的荧光特性从未被研究过,具有很大应用潜力。
因此,本发明旨在报道一种新的噻吩稠环衍生物的合成方法及应用的新技术。
发明内容
本发明的目的是提供一种新的噻吩稠环BNT衍生物合成方法。该方法具有简单高效、绿色环保、底物易得、不需金属试剂还具有良好的官能团兼容性等优点的,用以解决现有方法需要多步制备、底物昂贵、使用金属试剂或强酸强碱等反应条件,官能团兼容性受限,难实现多类型取代的缺陷和不足。
根据本发明第一方面,提供了一种噻吩稠环类化合物,具有式(P)所示的结构:
其中:X为S、SO、SO2、氨基、芳基胺、烷基胺或磺胺;
R1选自氢、氘、卤素、硝基、烷基、磺酸基、磺胺基、酯基、羧基、氰基、羟基、巯基、烷氧基、羰基、酰胺基、叠氮、氨基、硒基、硼酸基、磺酰氧基、硅基、烯基、炔基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基、五元杂环、六元杂环、取代杂环、芴基、芳胺基、芳氧基和芳硫基中的任意一种;
R2和R3各自独立地选自氢、氘、卤素、硝基、烷基、磺酸基、磺胺基、酯基、羧基、氰基、羟基、巯基、烷氧基、羰基、酰胺基、叠氮、氨基、硒基、硼酸基、磺酰氧基、硅基、烯基、炔基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基、五元杂环、六元杂环、取代杂环、芴基、芳胺基、芳氧基和芳硫基中的任意一种或几种。
根据本发明另一方面,提供了一种噻吩稠环类化合物的合成方法,所述合成方法为自身二聚化反应或者交叉二聚化反应:
所述自身二聚化反应的路线图为:
所述交叉二聚化反应的路线图为:
其中R1和R4各自独立地选自氢、氘、卤素、氰基、磺酸基、酯基、烷基、芳香基、烯基、炔基、烷氧基、巯基、硒基、羟基、氨基、硅基、硼酸基、磺酰氧基和磺胺基中任意一种;
R2和R3为不同的基团,且均选自氢、氘、卤素、烷基、磺酸基、酯基、磺胺基、羧基、氰基、羟基、巯基、硒基、烷氧基、羰基、酯基、硼酸基、磺酰氧基、硅基、酰胺基、叠氮、氨基、烯基、炔基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基、五元杂环、六元杂环、取代杂环、芴基、芳胺基、芳氧基和芳硫基中的任意一种或几种;
所述合成方法包括以下步骤:
a、式1的化合物在氧化剂的作用下经氧化得到式2的化合物;
b、式2的化合物在溶剂中,通过[4+2]环加成二聚化反应得到式3的化合物。
根据本发明另一方面,提供了一种噻吩稠环类化合物的合成方法,所述合成方法为自身二聚化反应或者交叉二聚化反应:
所述自身二聚化反应的路线图为:
所述交叉二聚化反应的路线图为:
其中R1和R4各自独立地选自氢、氘、卤素、氰基、磺酸基、酯基、烷基、芳香基、烯基、炔基、烷氧基、巯基、硒基、羟基、氨基、硅基、硼酸基、磺酰氧基和磺胺基中任意一种;
R2和R3为不同的基团,且均选自氢、氘、卤素、烷基、氰基、羟基、巯基、硒基、烷氧基、羰基、酯基、硼酸基、磺酰氧基、硅基、酰胺基、叠氮、氨基、烯基、炔基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基、五元杂环、六元杂环、取代杂环、芴基、芳胺基、芳氧基和芳硫基中的任意一种或几种;
所述合成方法包括以下步骤:
a、式1的化合物在氧化剂的作用下经氧化得到式2的化合物;
b、式2的化合物在溶剂中,通过[4+2]环加成二聚化反应得到式4的化合物。
根据本发明另一方面,提供了一种噻吩稠环类化合物的合成方法,反应式如下:
其中,X1、X2和X3各自独立地选自F、Cl、Br、I、硼酸基、磺酰氧基和硅基;
R1选自氢、氘、烷基、烷氧基、氨基、硝基、氰基、叠氮、酯基、烯基、炔基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基、芴基和芳胺基中的任意一种;
R2和R3各自独立地选自氢、氘、卤素、烷基、烷氧基、氨基、硝基、氰基、叠氮、酯基、烯基、炔基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基、芴基、芳胺基中的任意一种或几种;
所述合成方法为:式3a的化合物在金属试剂的作用下经偶联反应得到式3的化合物。
根据本发明另一方面,提供了一种噻吩稠环类化合物的合成方法,反应式如下:
其中R1选自氢、氘、卤素、硝基、烷基、磺酸基、磺胺基、酯基、羧基、氰基、羟基、巯基、烷氧基、羰基、酰胺基、叠氮、氨基、硒基、硼酸基、磺酰氧基、硅基、烯基、炔基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基、五元杂环、六元杂环、取代杂环、芴基、芳胺基、芳氧基和芳硫基中的任意一种;
R2和R3各自独立地选自氢、氘、卤素、硝基、烷基、磺酸基、磺胺基、酯基、羧基、氰基、羟基、巯基、烷氧基、羰基、酰胺基、叠氮、氨基、硒基、硼酸基、磺酰氧基、硅基、烯基、炔基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基、五元杂环、六元杂环、取代杂环、芴基、芳胺基、芳氧基和芳硫基中的任意一种或几种;
所述合成方法为:式3的化合物在还原剂的作用下还原为式5的化合物。
根据本发明另一方面,提供了一种噻吩稠环类化合物的合成方法,反应式如下:
其中R1选自氢、氘、卤素、硝基、烷基、磺酸基、磺胺基、酯基、羧基、氰基、羟基、巯基、烷氧基、羰基、酰胺基、叠氮、氨基、硒基、硼酸基、磺酰氧基、硅基、烯基、炔基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基、五元杂环、六元杂环、取代杂环、芴基、芳胺基、芳氧基和芳硫基中的任意一种;
R2和R3各自独立地选自氢、氘、卤素、硝基、烷基、磺酸基、磺胺基、酯基、羧基、氰基、羟基、巯基、烷氧基、羰基、酰胺基、叠氮、氨基、硒基、硼酸基、磺酰氧基、硅基、烯基、炔基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基、五元杂环、六元杂环、取代杂环、芴基、芳胺基、芳氧基和芳硫基中的任意一种或几种;
所述合成方法为:式3的化合物在氧化剂的作用下氧化为式6的化合物。
根据本发明另一方面,提供了一种噻吩稠环类化合物的合成方法,反应式如下:
其中R1选自氢、氘、卤素、硝基、烷基、磺酸基、磺胺基、酯基、羧基、氰基、羟基、巯基、烷氧基、羰基、酰胺基、叠氮、氨基、硒基、硼酸基、磺酰氧基、硅基、烯基、炔基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基、五元杂环、六元杂环、取代杂环、芴基、芳胺基、芳氧基和芳硫基中的任意一种;
R2和R3各自独立地选自氢、氘、卤素、硝基、烷基、磺酸基、磺胺基、酯基、羧基、氰基、羟基、巯基、烷氧基、羰基、酰胺基、叠氮、氨基、硒基、硼酸基、磺酰氧基、硅基、烯基、炔基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基、五元杂环、六元杂环、取代杂环、芴基、芳胺基、芳氧基和芳硫基中的任意一种或几种;
R4选自氢、氘、烷基、磺酰基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基中的任意一种;
所述合成方法包括以下步骤:
a、式3的化合物在氧化剂的作用下氧化为式6的化合物;
b、式6的化合物在碱作用下被亲核试剂两次进攻后得到式7的化合物。
根据本发明另一方面,提供了一种噻吩稠环类化合物的合成方法,反应式如下:
其中R1为氢或烷氧基中的一种;R2和R3各自独立地选自氢、烷氧基中的一种或两种;
所述合成方法为:式3的化合物在脱烷基试剂的作用下脱甲基并导致亚砜被还原,再氧化为式8的化合物。
根据本发明另一方面,提供了式(P)所述的噻吩稠环类化合物用于制备成像试剂的应用;
优选地,所述成像试剂为活细胞成像试剂。
根据本发明另一方面,提供了所述的噻吩稠环类化合物用于识别质子酸的应用;
优选地,所述质子酸为有机酸或无机酸;
优选地,所述有机酸为甲酸和乙酸;所述无机酸为HCl、H2SO4、HNO3和H3PO4。
总体而言,通过本发明所构思的以上技术方案与现有技术相比,主要具备以下的技术优点:
(1)本申请提供了一种新的噻吩稠环BNT类化合物的合成方法。通过苯并噻吩亚砜的Diels-Alder二聚化反应合成了BNT亚砜和二氢BNT亚砜化合物,所得产物可以进一步衍生化,有利于该类骨架分子的多样性化合物库构建,促进该类化合物的应用研究。该合成方法具有简单高效、绿色环保、底物易得、未使用金属试剂、具有良好的官能团兼容性等优点,有效解决了已有方法需要多步反应、底物昂贵、需使用金属试剂或强酸强碱,官能团兼容性受限,难实现多类型取代的缺陷和不足。
(2)本发明合成的BNT衍生物具有高的光致发光荧光效应,可作为荧光染料用于生物成像并表现出低毒性,具有应用于生物成像与医疗诊断领域的巨大潜力;还可作为荧光探针用于常用质子酸的快速识别,该方法具有简单高效,安全,低成本等优点。
附图说明
图1为化合物P34在不同溶剂中的荧光颜色示意图。
图2为荧光强度随激发光照射时间而减弱及停止照射后荧光强度恢复示意图。
图3为P40对BV2(A,B,C)的细胞成像示意图。
图4为化合物P33在加入HCl,H2SO4,HNO3和H3PO4 10min和1h时的颜色变化(A,C),与在加入甲酸和乙酸10min和1h时的颜色变化(B,D)示意图。
图5为H2SO4对P33溶液荧光颜色的改变随时间变化的示意图。
图6为化合物P31在加入HCl,H2SO4,HNO3和H3PO4 10min和1h时的颜色变化(A,C),与在加入甲酸和乙酸10min和1h时的颜色变化(B,D)示意图。
图7为化合物P32在加入HCl,H2SO4,HNO3和H3PO4 10min和1h时的颜色变化(A,C),与在加入甲酸和乙酸10min和1h时的颜色变化(B,D)示意图。
图8为化合物P34在加入HCl,H2SO4,HNO3和H3PO4 10min和1h时的颜色变化(A,C),与在加入甲酸和乙酸10min和1h时的颜色变化(B,D)示意图。
图9为化合物P42在加入HCl,H2SO4,HNO3和H3PO4 10min和1h时的颜色变化(A,C),与在加入甲酸和乙酸10min和1h时的颜色变化(B,D)示意图。
图10为化合物P43在加入HCl,H2SO4,HNO3和H3PO4 10min和1h时的颜色变化(A,C),与在加入甲酸和乙酸10min和1h时的颜色变化(B,D)示意图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。此外,下面所描述的本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
本发明的一个目的在于提供一种通过苯并噻吩的氧化-Diels-Alder二聚化反应合成噻吩稠环BNT衍生物的新方法。
本发明的另一个目的在于对通过上述方法合成的BNT化合物的进一步衍生化。
本发明的再一个目的在于提供上述具有高荧光性质的BNT衍生物的应用。
为实现上述发明目的,本发明所采用的技术方案是:采用取代或未取代苯并噻吩1为底物,通过文献的方法在间氯过氧苯甲酸和三氟化硼乙醚的体系下将其选择性氧化为苯并噻吩亚砜2。将苯并噻吩亚砜2于有机溶剂中反应。对于主产物为BNT亚砜3,因少量二氢产物影响其分离纯化的反应,可进一步加碱以除去少量二氢产物,易于产物3的分离纯化。对于主产物为二氢产物4的反应不需后续的过程,直接分离纯化即可,所述反应方程式如下:
其中R1为氢、氘、卤素、氰基、磺酸基、酯基、烷基、芳香基、烯基、炔基、烷氧基、巯基、硒基、羟基、氨基、硅基、硼酸基、磺酰氧基和磺胺基中任意一种;R2和R3为氢、氘、卤素、烷基、磺酸基、酯基、磺胺基、羧基、氰基、羟基、巯基、硒基、烷氧基、羰基、酯基、硼酸基、磺酰氧基、硅基、酰胺基、叠氮、氨基、烯基、炔基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基、五元杂环、六元杂环、取代杂环、芴基、芳胺基、芳氧基和芳硫基中的任意一种或几种。其中R2可以等于R3,R2也可以不等于R3。
优选地,所述有机溶剂为DMSO,DMF,甲苯,二氧六环,乙醇,水,乙腈中的任意一种。
更优地,所述有机溶剂为DMSO。
优选地,所述反应状态为敞口反应或封口反应。
更优地,所述反应状态为敞口反应。
优选地,所述反应温度为25~140℃。
更优地,所述反应温度为80℃。
优选地,所述反应时间为1-36h。
更优地,所述反应时间为12h。
优选地,所述碱为碳酸钾,碳酸钠、碳酸氢钾、碳酸氢钠、碳酸铯,磷酸钾,氢氧化钠,氢氧化钾,氢氧化铯、三乙胺、吡啶中的任意一种。
更优地,所述碱为碳酸钾。
优选地,所述碱的摩尔量为苯并噻吩亚砜的0.2~5倍。
更优地,所述碱的摩尔量为苯并噻吩亚砜的2倍。
优选地,所述加碱反应的温度为25~120℃。
更优地,所述加碱反应的温度为60℃。
优选地,所述加碱反应的时间为1~24h。
更优地,所述加碱反应的时间为3h。
优选地,所述化合物3选自以下结构式:
优选地,所述化合物4选自以下结构式:
本发明还公开了通过上述方法合成的产物进一步衍生化所用方法,包括如下步骤:
(a)卤素取代的BNT亚砜3a通过交叉偶联反应生成取代BNT亚砜3b;
(b)BNT亚砜可通过还原反应将其还原成BNT,以3b为例但不仅限于3b,通过还原反应生成化合物5;
(c)BNT亚砜可通过氧化反应将其氧化成BNT砜,以3b为例但不仅限于3b,通过氧化反应生成化合物6;
(d)BNT砜可通过芳胺的两次的亲核进攻进行将硫原子转化为氮原子生成化合物7;
(e)BNT砜上的取代R1为氢,R2为烷氧基时,可脱烷基生成羟基取代产物8。
所述合成步骤如式所示:
其中,X为卤素、硼酸基、磺酰氧基、硅基;R1选自氢、氘、卤素、硝基、烷基、磺酸基、磺胺基、酯基、羧基、氰基、羟基、巯基、烷氧基、羰基、酰胺基、叠氮、氨基、硒基、硼酸基、磺酰氧基、硅基、烯基、炔基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基、五元杂环、六元杂环、取代杂环、芴基、芳胺基、芳氧基和芳硫基中的任意一种;R2和R3各自独立地选自氢、氘、卤素、硝基、烷基、磺酸基、磺胺基、酯基、羧基、氰基、羟基、巯基、烷氧基、羰基、酰胺基、叠氮、氨基、硒基、硼酸基、磺酰氧基、硅基、烯基、炔基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基、五元杂环、六元杂环、取代杂环、芴基、芳胺基、芳氧基和芳硫基中的任意一种或几种;R4选自氢、氘、烷基、磺酰基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基中的任意一种;
优选地,进一步衍生化合物选自以下结构式:
本发明提供了任一所述方法合成得到的噻吩稠环类化合物,具有式(P)所示的结构:
其中:X为S或SO或SO2或氨基或芳基胺或烷基胺或磺胺;R1选自氢、氘、卤素、硝基、烷基、磺酸基、磺胺基、酯基、羧基、氰基、羟基、巯基、烷氧基、羰基、酰胺基、叠氮、氨基、硒基、硼酸基、磺酰氧基、硅基、烯基、炔基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基、五元杂环、六元杂环、取代杂环、芴基、芳胺基、芳氧基和芳硫基中的任意一种;R2和R3各自独立地选自氢、氘、卤素、硝基、烷基、磺酸基、磺胺基、酯基、羧基、氰基、羟基、巯基、烷氧基、羰基、酰胺基、叠氮、氨基、硒基、硼酸基、磺酰氧基、硅基、烯基、炔基、取代或非取代的芳基、取代或非取代的稠环芳基、取代或非取代的稠杂环芳基、五元杂环、六元杂环、取代杂环、芴基、芳胺基、芳氧基和芳硫基中的任意一种或几种;
本发明中的噻吩稠环类化合物,无论是在溶液中还是固态通常具有很强的荧光效应,且其固体荧光强度随激发光照射时间变化,并具有可恢复性。
本发明中的噻吩稠环类化合物用于生物成像的应用,所述噻吩稠环类化合物作为荧光染料用于活细胞成像。
本发明中的噻吩稠环类化合物用于识别质子酸的应用,所述噻吩稠环类化合物可以通过荧光颜色的变化来识别HCl,H2SO4,HNO3和H3PO4,以及区分甲酸和乙酸。
所述的噻吩稠环BNT衍生物无论是在溶液中还是固态通常表现出很强的荧光性质。在溶液中具有高达87%的荧光量子产率,大的斯托克斯位移;固体荧光量子产率高达42%。部分化合物的光物理性质见下表:
[a]乙腈为溶剂;[b]荧光量子产率(ΦF)是通过溶解在0.1N H2SO4溶液中的硫酸喹啉作为标准品计算所得,激发光波长为360nm;[c]绝对量子产率。
尤其是,当噻吩稠环BNT亚砜上连接的是三苯胺基团时,如化合物P31-P34,以及P42-P43具有很强的溶剂化荧光效应,其荧光量子产率,斯托克斯位移,最大吸收峰与最大发射峰均受溶剂种类影响。以化合物P34为例,其在不同溶剂中的光物理性质见下表:
[a]荧光量子产率(ΦF)是通过利用溶解在0.1N H2SO4溶液中的硫酸喹啉作为标准品计算所得,激发光波长为360nm。
图1为化合物P34在不同溶剂中的荧光颜色示意图,由图1可知,化合物P34随着溶剂极性的变化,其荧光颜色发生明显改变,在正己烷、乙酸乙酯、四氢呋喃、二氯甲烷、丙酮、乙腈、二甲亚砜和乙醇中的荧光颜色从蓝色逐渐变为橙色。
所述噻吩稠环BNT衍生物还具有一个有趣的现象,随着激发光照射时间的延长,化合物固体荧光强度出现明显的减弱,而当停止照射一段时间后,荧光强度会绝大部分恢复。在溶液中和在晶体情况下并无该现象,只在固体粉末情况下会出现这种光照荧光强度衰减再恢复的现象。以化合物P33为例,但不限于P33,其荧光变化如图2所示,由图2可知,在398nm波长的连续照射下,P33化合物的最大荧光发射波长持续衰减,最开始衰减的速率最大,后逐渐变缓,在停止照射45min后,其荧光发射波谱的最大荧光发射波长明显恢复,较为接近最初的荧光强度。以上现象表明该类化合物具有特殊的可逆的荧光衰减与复原性质,可作为光开关具有潜在的应用价值。
所述的强荧光的噻吩稠环BNT衍生物作为荧光染料用于活细胞成像,表现出了良好的成像效果,并且具有低毒性。
优选地,所述作为荧光染料用于活细胞成像的化合物,如P40。
化合物P40成功对鼠源小胶质细胞BV2进行了染色和标记,成像结果如图3所示,由图3可知,在405nm波长的照射下,BV2细胞呈明显的深蓝色,与明场下的细胞叠加图可以清晰的看到蓝色所在位置为细胞内,表明该化合物成功透过细胞膜进入了细胞内。
P40对BV2的细胞毒性结果表明在20μM浓度下,细胞存活率分别为88%,表现出了低毒性,如下表所示:
所述的强荧光的噻吩稠环BNT衍生物作为荧光探针用于常用质子酸的识别,例如通过荧光颜色的变化来识别HCl,H2SO4,HNO3和H3PO4,以及区分甲酸和乙酸,但也不仅限于以上几种酸的识别。该方法识别速度快,操作简单,使用到的荧光物质的量极低。
优选地,所述作为荧光探针识别质子酸的化合物,包括P31-P34,以及P42-P43。
以化合物P33为例,但不限于该化合物,识别结果如图4所示,由图4可知,在加入各种酸10min到1h间,溶液的荧光颜色发生了明显的变化,其中盐酸(HCl)使溶液的颜色从原来的黄色变为蓝色;硫酸(H2SO4)则使溶液颜色从黄色变为灰白色再变为蓝色,其溶液颜色随着时间的推移而变化,如图5所示,依次顺序为:黄(0min)-白(10min)-蓝(30min至3h)-褪色(12h);硝酸(HNO3)则会立即使荧光猝灭;而磷酸(H3PO4)对溶液颜色没有任何影响和改变。此外,甲酸可以使溶液由黄色变为蓝色,而乙酸在相同的条件下并无明显变化,以此可区分甲酸和乙酸。
化合物P31、P32、P34、P42和P43均具有上述类似现象,分别见图6,图7,图8,图9和图10。
另一方面,本发明中底物的制备,取代苯并噻吩底物的合成。
如上图所示,苯并噻吩底物1a-1c、1j、1n、1q、1w、1x是从商业采购所得,1d-1i、1k-1m、1o、1p、1r-1v是按照已有文献方法制备所得。
底物1d的合成:(J.Med.Chem.2016,59,264-281;Org.Process Res.Dev.2012,16,1449-1454)
将5-氟-2-羧酸苯并噻吩(196mg,1mmol)和DBU(373μL,2.5mmol)加入DMA(N,N-二甲基乙酰胺,1.7mL,0.6M)中,于封管中在微波反应器中逐渐升温到150℃,总共反应2.5min。冷却至室温后,将反应混合物倒入水中,乙酸乙酯(3×15ml)萃取,饱和食盐水洗涤,无水Na2SO4干燥。随后过滤和浓缩,通过柱层析(石油醚作为洗脱液)纯化,得到无色油状5-氟苯并噻吩1d(100mg,66%)。反应式如下:
底物1e的合成:(J.Med.Chem.2016,59,264-281)
将5-溴苯并噻吩(1b,1.06g,5mmol,1当量)和CuCN(890mg,10mmol,2当量)溶于NMP(N-甲基吡咯烷酮,5mL)中,190℃下反应12h。将反应物冷却至0℃,加入33%乙二胺溶液,乙醚萃取。饱和食盐水洗涤,无水Na2SO4干燥,过滤,减压除去溶剂。粗产物通过柱层析纯化,得到白色固体5-氰基-苯并噻吩1e(643.5mg,81%)。反应式如下:
底物1k和1f的合成:(Org.Lett.2021,23,896-901;Angew.Chem.Int.Ed.2006,45,3484-3488)
将5-溴苯并噻吩(1.278g,6mmol)、甲基硼酸(720mg,12mmol)、K3PO4(2.544g,12mmol)、Pd(OAc)2(40.4mg,0.18mmol,3mol%)和SPhos配体(148mg,0.36mmol,6mol%)加入50mL反应瓶中,然后加入溶剂1,4-二氧六环(12mL)。用氮气鼓气1分钟,然后密封,于100℃下加热3小时。将反应物冷却至室温,加入少量无水Na2SO4,并用硅藻土为垫料过滤,滤液浓缩,粗产物通过柱层析纯化(石油醚作为洗脱液),生成白色固体5-甲基苯并噻吩1k(801mg,90%)。反应式如下:
按照相同的程序制备6-甲苯并噻吩1f(778mg,产率:88%)。
底物1r,1g,1l和1o的合成:(Org.Lett.2021,23,896-901;Tetrahedron 1989,45,5565-5578)
将5-溴苯并噻吩(1.065g,5mmol)、甲醇钠(0.81g,15mmol)和CuBr(287mg,2mmol,40mol%)加入20mL反应瓶中。在惰性气体保护下注入DMF(1.85mL)和MeOH(0.75mL)的混合溶液,并在110℃下搅拌反应7小时。然后将反应物冷却至室温,硅藻土为垫料过滤,滤液用二氯甲烷萃取,饱和NaCl溶液洗涤,将合并的有机层用无水Na2SO4干燥,过滤,减压移除溶剂,所得粗产物通过硅胶柱层析纯化,即得4-甲氧基苯并噻吩1r(676g,83%)。反应式如下:
按照相同的方法制备5-甲氧基苯并噻吩1g、6-甲氧基苯并噻吩1l、7-甲氧基苯并噻吩1o。
底物1m的合成:(J.Med.Chem.2016,59,264-281;Org.Process Res.Dev.2012,16,1449-1454;Science 2020,369(6506):eaba6098)
向溶有2-氟-4,5-二甲氧基苯甲醛(920mg,5mmol)的DMF(30mL)溶液中,加入2-巯基乙酸甲酯(491μL,5.5mmol)和碳酸钾(2.07g,15mmol)。然后将反应液于60℃下反应15小时。反应结束后冷却至室温,减压浓缩除去大部分DMF。加水稀释,大量白色沉淀析出,过滤,干燥即得5,6-二甲氧基苯并[b]噻吩-2-羧酸甲酯(844mg,67%)。
然后将5,6-二甲氧基苯并[b]噻吩-2-羧酸甲酯(844mg,3.35mmol)加入甲醇(7.5mL)溶液中,再加入氢氧化钾(1.876g,33.5mmol),THF(7.5mL)和水(7.5mL)。将所得悬浮液加热至60℃,反应30min后冷却至室温,减压浓缩除去有机溶剂,然后向其中加入水(20mL),再加入稀盐酸调节pH值至6,有大量白色固体析出,过滤,干燥,即得5,6-二甲氧基苯并[b]噻吩-2-羧酸(772g,96%)。
将5,6-二甲氧基苯并[b]噻吩-2-羧酸(238mg,1mmol)和DBU(373μL,2.5mmol)溶于DMA(N,N-二甲基乙酰胺,1.7mL,0.6M)中,于封管中在微波反应器中逐渐升温到150℃,共反应5min。然后冷却至室温。将反应混合物倒入水中,大量固体析出,过滤得到灰色滤饼,将其溶于乙酸乙酯中,用硅藻土和硅胶为垫料过滤。减压移除溶剂即得5,6-二甲氧基苯并[b]噻吩1m(397.4mg,77%)的白色固体。反应式如下:
底物1h、1i、1p、1s、1t、1u和1v的合成:(J.Org.Chem.2019,84,698-709;Tetrahedron2013,69,6305-6312)
向溶有溴苯并噻吩(1当量)和芳基硼酸(1.1-1.2当量)的DMF(0.1M)溶液中加入碳酸钾溶液(2当量,2M)。在大部分固体溶解后,加入Pd(PPh3)4(5mol%),用氩气对反应混合物进行脱气。然后将反应物在氩气保护下于90℃反应12h,冷却至室温并倒入水中。有机层用乙酸乙酯萃取,然后用饱和食盐水洗涤,无水Na2SO4干燥,过滤,减压浓缩,粗产物通过硅胶柱色谱(石油醚作为洗脱液)纯化,即得目标产物。反应式如下:
通过该方法制备了底物1h、1i、1p、1s、1t、1u和1v。
本发明中底物的制备,苯并噻吩亚砜底物的合成,参考文献方法并对其后处理过程进行了部分改进(J.Org.Chem.1997,62,7926-7936),步骤如下:
将苯并噻吩(1当量)和BF3·Et2O(8当量)溶于CH2Cl2(0.1M)中。N2保护下于-20℃,分三批逐滴加入溶于少量CH2Cl2中的m-CPBA(1.02当量),每次间隔半个小时加一次。TLC检测,待底物消耗完后,于-20℃下向混合物中加入少量饱和K2CO3并随后加入K2CO3固体。然后用无水Na2SO4和K2CO3为垫料过滤,CH2Cl2洗涤,以获得苯并噻吩亚砜溶液。反应式如下:
一些苯并噻吩亚砜在C2和C3位均无取代时,在后处理浓缩过程中不稳定,可原位制备作为溶液存在,用于下一步的反应。
对于在C2或C3位取代的苯并噻吩亚砜,滤液减压浓缩除去大部分CH2Cl2。然后向溶液中加入少量石油醚,固体析出,过滤,石油醚洗涤,即可得到纯的目标产物。通过该方法获得了苯并噻吩亚砜底物2c、2b、2j、2n、和2x。2u是在CH2Cl2滤液中重结晶得到。如下所示:
下述各实施例中的化合物均以上述底物为基础制得。
实施例1
本实施例制备化合物P1,具体合成步骤如下:
向制备好的苯并噻吩亚砜(0.2mmol)的二氯甲烷溶液中加入DMSO(2mL,0.1M),在减压条件下进行溶剂交换,然后80℃敞口反应12h。反应结束后向反应混合物中加入K2CO3(0.2mmol,1当量),并于60℃下继续反应3小时。冷却至室温,加水稀释,乙酸乙酯萃取,饱和食盐水洗涤,无水Na2SO4干燥,过滤,减压移除溶剂。粗产物纯化即得目标产物P1。反应式如下:
苯并[b]萘[1,2-d]噻吩7-氧化物(P1)。白色固体,产率:62%。1H NMR(400MHz,CDCl3)δ8.69(d,J=8.4Hz,1H),8.40(d,J=8.0Hz,1H),8.05-7.93(m,4H),7.76-7.57(m,3H),7.50(t,J=7.5Hz,1H).13C NMR(100MHz,CDCl3)δ145.98,144.07,138.08,136.10,132.60(overlapped),130.79,129.80,129.58,128.70,128.29,127.85,127.82,125.45,124.49,122.46.
实施例2
本实施例制备化合物P2,具体合成步骤同于实施例1,只是将其底物换为5-溴苯并噻吩亚砜,且后处理过程为将反应液倒入水中,大量黄色固体析出,过滤干燥得到化合物P2。
(51.4%),432.8514(48.6%),found:428.8586,430.8560,432.8565.
实施例3
本实施例制备化合物P3,具体合成步骤同于实施例1,只是将其底物换为5-氯苯并噻吩亚砜,纯化即得化合物P3。
[M+Na]+340.9565,found:340.9584.
实施例4
本实施例制备化合物P4,具体合成步骤同于实施例1,只是将其底物换为5-氟苯并噻吩亚砜,纯化即得化合物P4。
25.1Hz),115.95(d,J=23.2Hz),113.38(d,J=13.2Hz),113.23(d,J=18.7Hz).19F NMR(564MHz,CDCl3)δ-105.41(td,J=8.8,5.1Hz),-110.46–-110.51(m).HRMS-ESI:calcd forC16H8F2ONaS[M+Na]+309.0156,found:309.0159.
实施例5
本实施例制备化合物P5,具体合成步骤同于实施例1,只是将其底物换为5-氰基苯并噻吩亚砜,纯化即得化合物P5。
323.0265.
实施例6
本实施例制备化合物P6,具体合成步骤同于实施例1,只是将其底物换为5-甲基苯并噻吩亚砜,纯化即得化合物P6。
calcd for C18H14ONaS[M+Na]+301.0658,found:301.0660.
实施例7
本实施例制备化合物P7,具体合成步骤同于实施例1,只是将其底物换为5-甲氧基苯并噻吩亚砜,纯化即得化合物P7。
found:333.0555.
实施例8
本实施例制备化合物P8,具体合成步骤同于实施例1,只是将其底物换为5-苯基苯并噻吩亚砜,纯化即得化合物P8。
[M+H]+403.1151,found:403.1141.
实施例9
本实施例制备化合物P9,具体合成步骤同于实施例1,只是将其底物换为5-(2-甲氧基吡啶-3-基)苯并噻吩亚砜,纯化即得化合物P9。
CDCl3)δ161.14,161.02,147.12,146.77,144.93,144.74,141.68,138.99,138.90,138.30,136.61,136.36,132.57,131.16,129.84(overlapped),129.76,128.82,127.68,126.53,124.29,123.68,123.54,123.00,117.49,117.47,53.93,53.84.HRMS-ESI:calcd forC28H20N2O3NaS[M+Na]+487.1092,found:487.1085.
实施例10
本实施例制备化合物P10,具体合成步骤同于实施例1,只是将其底物换为6-溴苯并噻吩亚砜,且后处理过程为将反应液倒入水中,大量黄色固体析出,过滤干燥得到化合物P10。
123.17,123.02.HRMS-ESI:calcd for C16H9Br2OS[M+H]+408.8715(100.0%),406.8735(51.4%),410.8694(48.6%),found:408.8706;406.8725;410.8687.
实施例11
本实施例制备化合物P11,具体合成步骤同于实施例1,只是将其底物换为6-甲基苯并噻吩亚砜,纯化即得化合物P11。
22.46,21.35.HRMS-ESI:calcd for C18H14ONaS[M+Na]+301.0663,found:301.0670.
实施例12
本实施例制备化合物P12,具体合成步骤同于实施例1,只是将其底物换为6-甲氧基苯并噻吩亚砜,纯化即得化合物P12。
found:333.0560.
实施例13
本实施例制备化合物P13,具体合成步骤如下:
将3-溴苯并噻吩亚砜(2x,46mg,0.2mmol)溶于DMSO(2mL,0.1M)中,于120℃下敞口反应48h。冷却至室温,加水稀释,乙酸乙酯萃取,饱和食盐水洗涤,无水Na2SO4干燥,过滤,减压浓缩。所得粗品经制备薄层色谱(PE:EA=4:1)纯化,既得黄色固体P13(15.5mg,47%)。反应式如下:
5-溴苯并[b]萘[1,2-d]噻吩7-氧化物(P13)。黄色固体,产率:47%,mp:218-210℃。1H NMR(400MHz,CDCl3)δ8.77–8.74(m,1H),8.45–8.41(m,2H),8.34–8.33(m,1H),8.07(dt,J=7.6,1.5Hz,1H),7.77–7.74(m,2H),7.69(td,J=7.7,1.3Hz,1H),7.56(td,J=7.5,1.1Hz,1H).13C NMR(100MHz,CDCl3)δ145.98,144.33,137.57,134.27,132.90,132.54,130.57,129.30,129.22,129.19,129.08,128.07,126.72,125.61,125.34,125.03.HRMS-ESI:calcd for C16H9BrONaS[M+Na]+350.9455(100.0%),352.9435(97.3%),found:350.9476,352.9435.
实施例14
本实施例制备化合物P14,具体合成步骤如下:
将3-氰基苯并噻吩(31.8mg,0.2mmol,1当量)和BF3·Et2O(197.6μL,1.6mmol,8当量)溶于CH2Cl2(2mL,0.1M)中。于-10℃氮气保护下,逐滴加入溶于少量CH2Cl2的m-CPBA(44.5mg,1.1当量),分三批,每个半个小时加入一次,共1.5h内加完。后继续于-10℃下反应一晚,TLC监测,待底物消耗完后,加入少量饱和K2CO3溶液和大量K2CO3固体至反应中的酸完全被中和。然后用无水Na2SO4和K2CO3为垫料过滤,CH2Cl2洗涤。向滤液中加入DMSO(10mL,0.1M),在减压条件下进行溶剂交换,然后混合物在80℃下敞口反应12h。将反应冷却至室温并倒入水中析出大量黄色固体,过滤,干燥即得目标产物P14(17.6mg,64%)。反应式如下:
5-氰基苯并[b]萘[1,2-d]噻吩7-氧化物(P14)。白色固体,产率:64%,mp:248-251℃。1H NMR(400MHz,CDCl3)δ8.88–8.85(m,1H),8.53(d,J=8.0Hz,1H),8.44–8.40(m,2H),8.13(dd,J=7.7,1.3Hz,1H),7.90–7.84(m,2H),7.76(td,J=7.8,1.3Hz,1H),7.65(td,J=7.5,1.0Hz,1H).13C NMR(100MHz,CDCl3)δ147.07,143.36,137.44,136.75,135.01,133.15,130.51,130.46,129.83,129.33,129.07,128.33,127.20,126.53,125.40,116.87,112.09.HRMS-ESI:calcd for C17H9NONaS[M+Na]+298.0303,found:298.0297.
实施例15
本实施例制备化合物P15,具体合成步骤同于实施例1,只是将其底物换为5,6-二甲氧基苯并噻吩亚砜,且将第一步反应温度由80℃降至60℃,纯化即得化合物P15。
393.0776.
实施例16
本实施例制备化合物P16,具体合成步骤同于实施例1,只是将其底物换为7-溴苯并噻吩亚砜,纯化即得化合物P16。
(100.0%),428.8555(51.4%),432.8514(48.6%)found:428.8544,430.8540,432.8564.
实施例17
本实施例制备化合物P17,具体合成步骤同于实施例1,只是将其底物换为7-甲氧基苯并噻吩亚砜,纯化即得化合物P17。
333.0556,found:333.0550.
实施例18
本实施例制备化合物P18,具体合成步骤如下:
将5-甲氧基苯并噻吩亚砜(0.1mmol,1当量)和5-氟苯并噻吩亚砜(0.1mmol,1当量)的二氯甲烷溶液加入DMSO(2mL,0.05M)中,减压条件下置换溶剂,于80℃下敞口反应12h。然后向反应液中加入K2CO3(0.2mmol,2当量),于60℃下反应3h。冷却至室温,加水稀释,乙酸乙酯萃取,无水Na2SO4干燥,过滤,减压浓缩。所得粗品经制备薄层色谱纯化,即得交叉二聚化产物P18和P19,且其中还生成了自身二聚化产物P4和P6。反应式如下:
CDCl3)δ165.63(d,J=251.3Hz,C10),159.07(C3),143.09(C6a),141.83(d,J=3.0Hz,C11a),140.90(d,J=9.3Hz,C7a),138.20(C4a),131.84(d,J=2.9Hz,C11b),130.27(C5),129.59(d,J=9.8Hz,C9),125.58(C2),124.78(C11c),123.31(C6),121.51(C1),115.63(d,J=23.2Hz,C8),113.26(d,J=25.9Hz,C11),107.92(C4),55.67(C12).19F NMR(376MHz,CDCl3)δ-105.82(ddd,J=10.1,8.2,5.4Hz).HRMS-ESI:calcd for C17H11FNaO2S[M+Na]+321.0356,found:321.0361.
实施例19
本实施例制备化合物P19,具体合成步骤同于实施例18。
CDCl3)δ163.26(C10),161.28(d,J=250.9Hz,C3),144.68(C6a),139.78(C7a),137.54(C11a),137.49(d,J=9.5Hz,C4a),132.65(C11b),130.06(d,J=5.3Hz,C5),129.25(C9),126.85(d,J=8.9Hz,C1),126.46(C11c),123.75(C6),118.51(d,J=25.2Hz,C2),113.03(d,J=20.5Hz,C4),113.01(C11),112.46(C8),56.00(C12).19F NMR(376MHz,CDCl3)δ-111.13(td,J=8.5,5.1Hz).HRMS-ESI:calcd for C17H11FNaO2S[M+Na]+321.0356,found:321.0360.
实施例20
本实施例制备化合物P20,具体合成步骤如下:
向7-对氟苯基苯并噻吩亚砜(2,0.2mmol)的二氯甲烷溶液中加入DMSO(2mL,0.1M),减压条件下置换溶剂,然后于80℃下敞口反应12h。冷却至室温,加水稀释,乙酸乙酯萃取,无水Na2SO4干燥,过滤,减压浓缩。所得粗品纯化,只分离纯化得到目标产物P20的trans构型产物,产率:30%(trans),dr=4:1(trans/cis)。反应式如下:
(6aR,7R,11bR)-1,8-二(4-氟苯基)-6a,11b-二氢苯并[b]萘[1,2-d]噻吩7-氧化物(P20(trans))。白色固体,mp:230-231℃。1H NMR(400MHz,CDCl3)δ7.67–7.57(m,2H),7.49–7.43(m,2H),7.43–7.30(m,4H),7.23–7.16(m,2H),7.16–7.08(m,3H),6.77(dt,J=7.7,1.2Hz,1H),6.46(dd,J=9.8,2.6Hz,1H),5.70(dt,J=9.7,1.7Hz,1H),5.63(d,J=5.8Hz,1H),4.61(dt,J=5.5,2.4Hz,1H).13C NMR(100MHz,CDCl3)δ164.10(d,J=65.0Hz),161.64(d,J=63.9Hz),146.89,142.40,141.86,140.97,135.94(d,J=3.4Hz),134.85(d,J=3.4Hz),132.93,132.62,131.90,131.42,131.34,131.01,130.99,130.93,130.59,129.34,128.15,127.86,125.23,119.50,116.06,115.85,68.24,43.25.19F NMR(376MHz,CDCl3)δ-113.37(td,J=8.5,5.0Hz),-114.56(td,J=8.7,4.8Hz).HRMS-ESI:calcd forC28H18F2ONaS[M+Na]+463.0944,found:463.0940.
实施例21
本实施例制备化合物P21,具体合成步骤同于实施例20,只是将其底物换为4-溴苯并噻吩亚砜,纯化即得化合物P21,分离得到P21的两种构型产物(trans和cis),产率:90%(trans+cis),dr=1.8:1(trans/cis)。
130.54,129.51,127.48,126.03,123.50,122.85,120.04,62.90,48.99.HRMS-ESI:calcdfor C16H11Br2OS[M+H]+410.8871(100.0%),408.8892(51.4%),412.8851(48.6%),found:408.8882,410.8860,412.8894.
134.90,133.13,132.65,131.50,131.32,130.97,129.54,126.48,125.39,123.62,122.50,122.45,75.25,45.83.HRMS-ESI:calcd for C16H11Br2OS[M+H]+410.8871(100.0%),408.8892(51.4%),412.8851(48.6%),found:408.8879,410.8864,412.8841.
实施例22
本实施例制备化合物P22,具体合成步骤同于实施例20,只是将其底物换为4-甲氧基苯并噻吩亚砜,纯化即得化合物P22,只分离得到P22的trans构型产物,产率:34%(trans),dr=2.9:1(trans/cis)。
129.77,129.20,120.97,120.06,119.42,116.62,114.43,109.57,63.84,55.97,55.72,44.33.HRMS-ESI:calcd for C18H16O3NaS[M+Na]+335.0712,found:335.0715.
实施例23
本实施例制备化合物P23,具体合成步骤同于实施例20,只是将其底物换为4-苯基苯并噻吩亚砜,纯化即得化合物P23,分离得到P23的两种构型产物(trans和cis),产率:79%(trans+cis),dr=2:1(trans/cis)。
Hz,1H),5.47(d,J=7.5Hz,1H),4.00(ddd,J=7.2,5.7,0.9Hz,1H).13C NMR(100MHz,CDCl3)δ145.62,144.73,142.41,140.72,140.59,140.07,134.40,133.99,133.79,130.10,129.33,129.14,128.95,128.90,128.86,128.29,128.16,128.04,127.74,127.32,127.15,126.23,117.93,62.36,45.73.HRMS-ESI:calcd for C28H20ONaS[M+Na]+427.1127,found:427.1141.
(100MHz,CDCl3)δ147.22,141.74,140.30,140.26,140.16,139.77,133.06,130.41,129.85(overlapped),129.78,129.35,129.21,129.01,128.95,128.36,128.03,127.87,127.48,126.76,125.47,120.57,74.79,43.51.HRMS-ESI:calcd for C28H20ONaS[M+Na]+427.1127,found:427.1139.
实施例24
本实施例制备化合物P24,具体合成同于实施例14,只是在第一步氧化成亚砜,后处理浓缩的过程中就发生了Diels-Alder二聚化反应,生成了大量的二氢产物,并直接分离纯化得到化合物P24,只分离得到P24的trans构型产物,产率:24%。
HRMS-ESI:calcd for C18H10N2ONaS[M+Na]+325.0406,found:325.0392./>
实施例25
本实施例制备化合物P25,具体合成步骤同于实施例20,只是将其底物换为4-间硝基苯基苯并噻吩亚砜,纯化即得化合物P25,分离得到P25的两种构型产物(trans和cis),产率:64%(trans+cis),dr=1.3:1(trans/cis)。
J=10.0,4.9Hz,1H),5.15(d,J=7.0Hz,1H),4.25(t,J=5.5Hz,1H).13C NMR(100MHz,CDCl3)δ148.44,148.30,145.92,141.98,141.82,139.65,137.79,136.37,134.82,134.18,133.32,131.75,130.01,129.77(overlapped),129.40(overlapped),129.30,129.04,127.78,127.46,124.47,123.71,122.96,122.44,119.50,62.55,45.21.HRMS-ESI:calcdfor C28H18N2O5NaS[M+Na]+517.0829,found:517.0832.
Hz,1H),6.53(d,J=7.7Hz,1H),6.18(dd,J=9.9,4.5Hz,1H),5.24(d,J=6.5Hz,1H),4.47(ddd,J=6.2,4.5,1.3Hz,1H).13C NMR(100MHz,CDCl3)δ148.32,148.28,147.01,141.44,141.28,140.20,139.49,138.01,135.88,134.75,133.98,132.90,129.82,129.74,129.51,129.47,129.36,129.02,128.45,127.86,127.06,124.55,123.67,122.86,122.65,121.67,71.78,44.88.HRMS-ESI:calcd for C28H18N2O5NaS[M+Na]+517.0829,found:517.0831.
实施例26
本实施例制备化合物P26,具体合成步骤同于实施例20,只是将其底物换为4-对甲氧基苯基苯并噻吩亚砜,纯化即得化合物P26,分离得到P26的两种构型产物(trans和cis),产率:78%(trans+cis),dr=2:1(trans/cis)。
(100MHz,CDCl3)δ159.44,158.88,145.55,145.02,142.07,139.73,134.37,134.19,133.95,133.09,133.00,131.20,130.06,129.42,128.92,128.85,127.73,127.01,125.93,117.78,114.58,113.59,62.27,55.45,55.43,45.83.HRMS-ESI:calcd for C30H25O3S[M+H]+465.1519,found:465.1510./>
NMR(100MHz,CDCl3)δ159.46,159.13,147.18,141.37,140.31,139.98,133.21,132.96,132.51,132.10,130.97,130.53,130.07,129.92,129.43,129.18,127.85,126.43,125.08,120.45,114.47,113.81,74.96,55.48,55.46,43.49.HRMS-ESI:calcd for C30H25O3S[M+H]+465.1519,found:465.1513.
实施例27
本实施例制备化合物P27,具体合成步骤同于实施例20,只是将其底物换为4-对氟苯基苯并噻吩亚砜,纯化即得化合物P27,分离得到P27的两种构型产物(trans和cis),产率:74%(trans+cis),dr=2:1(trans/cis)。
139.09,136.63(d,J=3.4Hz),136.40(d,J=3.3Hz),134.41,133.73,133.65,131.64(overlapped),130.62,130.57,129.49,129.03,128.98,127.76,127.47,126.26,118.21,116.23,116.09,115.19,115.05,62.29,45.67.19F NMR(376MHz,CDCl3)δ-113.92(tt,J=8.6,5.2Hz),-114.93(ddd,J=13.8,8.8,5.4Hz).HRMS-ESI:calcd for C28H18F2ONaS[M+Na]+463.0944,found:463.0932.
5.7Hz,1H).13C NMR(100MHz,CDCl3)δ163.75(d,J=18.8Hz),161.29(d,J=17.7Hz),147.22,140.72,140.24,139.31,136.00(d,J=3.5Hz),135.71(d,J=3.4Hz),133.20,132.99,131.44,131.36,130.61,130.53,130.11,129.89,129.47,129.29,127.88,126.90,125.73,120.82,116.11,115.89,115.47,115.25,74.33,43.67.19F NMR(376MHz,CDCl3)δ-113.92(tt,J=8.6,5.2Hz),-114.93(tt,J=8.8,5.4Hz).HRMS-ESI:calcd forC28H18F2ONaS[M+Na]+463.0944,found:463.0938.
实施例28
本实施例制备化合物P28,参考文献方法(J.Org.Chem.2010,75,6771-6781),通过Buchwald-Hartwig反应将二卤代苯并[b]萘[1,2-d]噻吩7-氧化物与胺交叉偶联,具体实施步骤如下:
将3,10-二溴苯并[b]萘[1,2-d]噻吩7-氧化物(P2,40.8mg,0.1mmol,1当量)和咔唑(40mg,0.24mmol,2.4当量)溶于甲苯(20mL)中。然后加入Pd2(dba)3(2.3mg,2.5mol%)、Xphos(4.1mg,10mol%)、t-BuONa(6.7mg,0.07mmol,0.7当量)和t-BuOH(2mL)。反应液在氩气流下脱气15min后,氩气保护下于110℃下反应18小时,然后冷却至室温,二氯甲烷萃取,饱和食盐水洗涤,无水Na2SO4干燥,过滤,减压移除溶剂,粗品纯化即得棕色固体P28(50.9mg,88%)。反应式如下:
3,10-二(咔唑-9-基)苯并[b]萘[1,2-d]噻吩7-氧化物(P28)。棕色固体,产率:88%,mp:284-285℃。1H NMR(400MHz,CDCl3)δ8.80(d,J=9.1Hz,1H),8.72(d,J=1.7Hz,1H),8.37(d,J=8.1Hz,1H),8.23–8.19(m,4H),8.17–8.11(m,3H),7.88(dd,J=9.1,2.3Hz,1H),7.82(dd,J=8.1,1.7Hz,1H),7.55(d,d,J=8.2Hz,2H),7.52–7.47(m,4H),7.42(ddd,J=8.3,7.1,1.3Hz,2H),7.37(ddd,J=8.0,7.1,1.1Hz,2H),7.32(td,J=7.5,1.1Hz,2H).13CNMR(100MHz,CDCl3)δ145.58,144.59,142.23,140.66,140.55,140.10,137.50,137.25,132.26,131.20,129.52,128.20,127.85,127.48,126.64,126.50,126.37,126.23,124.18,124.00,123.93,123.77,120.95,120.81,120.78,120.66,109.71,109.66.HRMS-ESI:calcdfor C40H25N2OS[M+H]+581.1682,found:581.1669.
实施例29
本实施例制备化合物P29,参考文献方法(Tetrahedron 2012,68,5481-5491;Mater.Chem.Phys.2018,212,155-160),通过Suzuki偶联反应将二卤代苯并[b]萘[1,2-d]噻吩7-氧化物与芳基硼酸偶联,具体实施步骤如下:
将3,10-二溴苯并[b]萘[1,2-d]噻吩7-氧化物(P2,40.8mg,0.1mmol,1当量)与9,9-二甲基芴-2-硼酸(57mg,0.24mmol,2.4当量)溶于THF(1mL,0.1M)和K2CO3溶液(86mg,6.25当量,2M)的混合溶液中。反应混合物在氩气流下进行脱气,并在氩气氛围下加入Pd(PPh3)4(3.5mg,3mol%),然后于70℃下反应24小时,分离有机相,饱和食盐水洗涤,无水Na2SO4干燥,过滤,减压移除溶剂,所得粗品纯化即得目标产物P29。反应式如下:
3,10-二(9,9-二甲基芴-2-基)苯并[b]萘[1,2-d]噻吩7-氧化物(P29)。白色固体,产率:77%,mp:202-204℃。1H NMR(400MHz,CDCl3)δ8.93(d,J=8.9Hz,1H),8.72(d,J=1.6Hz,1H),8.26(d,J=1.9Hz,1H),8.17(d,J=7.9Hz,1H),8.10–8.09(m,3H),7.90(d,J=7.9Hz,1H),7.86(d,J=7.9Hz,1H),7.84–7.78(m,4H),7.75(td,J=4.0,1.7Hz,2H),7.71(dd,J=7.8,1.7Hz,1H),7.52–7.48(m,2H),7.43–7.35(m,4H),1.62(s,6H),1.62(s,6H).13CNMR(100MHz,CDCl3)δ154.76,154.71,154.09,154.07,146.69,144.41,144.38,140.86,139.87,139.51,139.43,138.95,138.89,138.69,138.57,136.73,132.64,131.19,128.65,128.19,128.16,128.00,127.90,127.75,127.34(overlapped),127.29,126.84,126.62,125.08,124.54,123.12,122.88,122.84,121.91,121.70,120.77,120.73,120.48,120.41,47.26,47.20,27.41,27.40.HRMS-ESI:calcd for C46H34ONaS[M+Na]+657.2223,found:657.2225.
实施例30
本实施例制备化合物P30,具体合成步骤同于实施例29,只是将芳基硼酸底物换为3,4-二甲氧基苯硼酸,纯化即得化合物P30。
143.95,140.10,138.82,136.60,133.12,132.57,132.49,130.97,128.33,128.02,127.79,127.44,126.63,124.92,124.08,122.98,120.17,119.92,111.70,111.69,110.81,110.41,56.31,56.16(overlapped),56.12.HRMS-ESI:calcd for C32H26O5NaS[M+Na]+545.1393,found:545.1392.
实施例31
本实施例制备化合物P31,具体合成步骤同于实施例29,只是将芳基硼酸底物换为4-硼酸三苯胺,纯化即得化合物P31。
130.97,129.56,129.52,129.45,128.28,128.06,128.02,127.49,127.11,126.38,124.97(overlapped),124.88,123.74,123.60,123.55,123.46,123.40,122.95.HRMS-ESI:calcd for C52H37N2OS[M+H]+737.2621,found:737.2638.
实施例32
本实施例制备化合物P32,具体合成步骤同于实施例29,只是将二卤代苯并[b]萘[1,2-d]噻吩7-氧化物换为2,9-二溴苯并[b]萘[1,2-d]噻吩7-氧化物(P10),且芳基硼酸底物换为4-硼酸三苯胺,纯化即得化合物P32。
130.01,129.54(overlapped),128.36,127.71,127.33,125.72,125.59,125.01,124.92,123.70,123.57,123.51,123.37,122.28,121.70.HRMS-ESI:calcd for C52H37N2OS[M+H]+737.2621,found:737.2649.
实施例33
本实施例制备化合物P33,具体合成步骤同于实施例29,只是将二卤代苯并[b]萘[1,2-d]噻吩7-氧化物换为1,8-二溴苯并[b]萘[1,2-d]噻吩7-氧化物(P16),且芳基硼酸底物换为4-硼酸三苯胺,纯化即得化合物P33。
129.54(overlapped),129.34,128.50,128.34,127.63,127.42,127.30,125.24(overlapped),124.34,123.54,123.08,122.64,122.23.HRMS-ESI:calcd for C52H36N2ONaS[M+Na]+759.2441,found:759.2424.
实施例34
本实施例制备化合物P34,具体合成步骤同于实施例29,只是将二卤代苯并[b]萘[1,2-d]噻吩7-氧化物换为5-溴苯并[b]萘[1,2-d]噻吩7-氧化物(P13),且芳基硼酸底物换为1.2当量的4-硼酸三苯胺,纯化即得化合物P34。
Hz,1H),7.41–7.37(m,2H),7.35–7.30(m,4H),7.23–7.19(m,6H),7.08(tt,J=7.1,1.2Hz,2H).13C NMR(100MHz,CDCl3)δ148.00,147.68,146.09,143.87,143.01,138.30,134.51,133.04,132.72,131.50,130.97,130.27,129.55,128.63,128.29,128.09,127.99,127.82,125.43,124.95,124.82,123.46,123.44,123.03.HRMS-ESI:calcd for C34H23NONaS[M+Na]+516.1393,found:516.1397.
实施例35
本实施例制备化合物P35,通过双氧水氧化亚砜成砜,具体实施步骤如下:
将33%H2O2(97μL,1mmol)和HCO2H(194μL)于室温下加入溶有3,10-二(9,9-二甲基-9H-芴-2-基)苯并[b]萘[1,2-d]噻吩7-氧化物(P29,31.7mg,0.05mmol)的DCM(2mL)溶液中。反应液于室温下反应过夜,然后加入饱和NaHCO3溶液,DCM萃取,无水Na2SO4干燥,过滤,减压移除部分溶剂,加入EA和乙醚,大量沉淀析出,过滤,干燥即得目标产物P35(白色固体,27.6mg,85%)。反应式如下:
3,10-二(9,9-二甲基-2-基)苯并[b]萘[1,2-d]噻吩7,7-二氧化物(P35)。白色固体,产率:85%,mp:221-223℃。1H NMR(400MHz,CDCl3)δ8.92(d,J=9.0Hz,1H),8.71(d,J=1.4Hz,1H),8.27(d,J=2.0Hz,1H),8.16–8.12(m,2H),8.03(d,J=7.9Hz,1H),7.94(d,J=8.4Hz,1H),7.91(d,J=7.8Hz,1H),7.88(d,J=7.9Hz,1H),7.85–7.78(m,4H),7.76(dd,J=7.9,1.7Hz,1H),7.73–7.69(m,2H),7.52–7.48(m,2H),7.43–7.35(m,4H),1.61(s,3H),1.59(s,3H),1.57(s,6H).13C NMR(150MHz,CDCl3)δ154.87,154.79,154.14,154.11,148.16,141.50,140.21,139.74,139.03,138.65,138.61,138.47,137.49,136.81,136.38,133.70,132.48,128.94,128.91,128.17,128.06,128.04,127.85,127.58,127.39,127.33,126.84,126.67,125.45,124.53,122.92,122.89,122.87,121.93,121.74,120.85,120.79,120.56,120.46,117.73,47.30,47.23,27.40(overlapped).HRMS-ESI:calcd for C46H34O2NaS[M+Na]+673.2172,found:673.2163.
实施例36
本实施例制备化合物P36,具体合成步骤同于实施例35,只是底物换为3,10-二甲氧基苯并[b]萘[1,2-d]噻吩7-氧化物,纯化即得目标产物P36。
120.07,115.03,107.52,104.12,56.14,55.72.HRMS-ESI:calcd for C18H14O4NaS[M+Na]+349.0505,found:349.0504.
实施例37
本实施例制备化合物P37,通过芳胺的两次SNAr进攻将BNT骨架上的硫原子转化为氮原子,具体实施步骤如下:
将3,10-二(9,9-二甲基芴-2-基)苯并[b]萘[1,2-d]噻吩7,7-二氧基(P35,19.5mg,0.03mmol)和对甲苯胺(6.4mg,0.06mmol)溶于二氧六环(200μL)中,然后于室温和氩气氛围下逐滴加入溶于THF的KHMDS(1M,90μL,0.09mmol)。将反应液温度升至80℃下反应22h。用饱和NH4Cl溶液(1mL)淬灭反应,乙酸乙酯萃取,无水Na2SO4干燥,过滤,减压浓缩。制备薄层色谱(PE:DCM=2/1)纯化得到化合物P37(白色固体,16mg,77%)。反应式如下:
3,10-二(9,9-二甲基-芴-1-基)-7-(对甲苯基)-7H苯并[c]咔唑(P37)。白色固体,产率:77%,mp:158-160℃。1H NMR(400MHz,CDCl3)δ9.02(d,J=8.7Hz,1H),8.91(d,J=1.8Hz,1H),8.31(d,J=2.0Hz,1H),8.13(dd,J=8.7,2.0Hz,1H),7.95(d,J=9.0Hz,1H),7.90–7.85(m,4H),7.82–7.74(m,5H),7.61(d,J=8.9Hz,1H),7.58(d,J=8.5Hz,1H),7.54–7.47(m,6H),7.42–7.33(m,4H),2.55(s,3H),1.64(s,6H),1.61(s,6H).13CNMR(100MHz,CDCl3)δ154.55,154.52,154.06,154.05,141.92,140.56,139.99,139.54,139.21,139.11,138.41,138.18,138.02,136.30,134.91,134.73,130.75(overlapped),130.03,129.15,127.95,127.67,127.34,127.28,127.26,127.18(overlapped),126.92,126.77,126.45,124.54,124.49,124.03,122.77,122.07,121.62,120.84,120.56,120.50,120.21,120.17,115.63,112.42,110.82,47.18,47.16,27.52,27.46,21.46.HRMS-ESI:calcd forC53H41NNa[M+Na]+714.3131,found:714.3134.
实施例38
本实施例制备化合物P38,在3-巯基丙酸与催化量的碘的条件下将亚砜还原为硫,具体实施步骤如下:
将3,10-二(9,9-二甲基-芴-2-基)苯并[b]萘[1,2-d]噻吩7-氧化物(P29,31.7mg,0.05mmol)和3-巯基丙酸(8.7μL,0.1mmol)溶于DCM(0.5mL)中,然后加入催化量的I2(1.3mg,10mol%),于室温下反应4h。待底物消耗完,硫代硫酸钠溶液淬灭反应,加水稀释,乙酸乙酯萃取,无水Na2SO4干燥,过滤,减压浓缩,纯化即得目标产物P38(白色固体,25.8mg,84%)。反应式如下:
3,10-二(9,9-二甲基-芴-2-基)苯并[b]萘[1,2-d]噻吩(P38)。白色固体,产率:84%,mp:121-124℃。1H NMR(400MHz,CDCl3)δ9.17(d,J=8.8Hz,1H),9.12(d,J=1.7Hz,1H),8.32(d,J=2.0Hz,1H),8.12–8.09(m,2H),8.02–7.96(m,2H),7.91(d,J=7.8Hz,1H),7.87–7.85(m,2H),7.83(q,J=1.4Hz,2H),7.82–7.78(m,4H),7.50(td,J=6.6,1.9Hz,2H),7.43–7.34(m,4H),1.63(s,6H),1.61(s,6H).13C NMR(100MHz,CDCl3)δ154.63,154.61,154.06,141.12,139.85,139.30,139.12,138.98,138.97,138.90,138.83,138.72,138.02,137.45,132.59,129.85,129.20,128.40,127.50(overlapped),127.34,127.25,127.22,126.96,126.90,126.53,125.29,123.83,123.60,123.51,122.82,122.80,122.11,121.73,121.65,120.65,120.62,120.29(overlapped),47.21,47.17,27.48,27.44.HRMS-APCI:calcd for C46H35S[M+H]+619.2459,found:619.24627.
实施例39
本实施例制备化合物P39,在微波反应的条件下,通过吡啶盐酸对甲氧基进行脱甲基化反应,得到羟基取代产物,具体实施步骤如下:
将2,9-二甲氧基苯并[b]萘[1,2-d]噻吩7-氧化物(P12,31mg,0.1mmol)和Py·HCl(774.5mg,6.7mmol)的混合物置于封管中,在微波反应器中,逐渐升温至150℃,反应2min后将反应混合物冷却至室温,加入NH4Cl溶液中,乙酸乙酯萃取,饱和食盐水洗涤(20mL)洗涤,无水Na2SO4干燥,过滤,减压浓缩。制备薄层色谱(PE:EA=1:1)分离得到苯并[b]萘-[1,2-d]噻吩-2,9-二醇中间体(灰色固体,17mg,64%)。
然后将苯并[b]萘并[1,2-d]噻吩-2,9-二醇中间体(17mg,0.064mmol)溶于DCM(400μL)和CF3COOH(400μL)中的混合溶液中,加入33%H2O2(2~3当量),TLC监测直到底物转化完全。室温下搅拌过夜,于0℃下加入饱和NaHCO3水溶液,乙酸乙酯萃取,无水Na2SO4干燥,过滤,减压浓缩,制备薄层色谱(PE:EA=1:1)纯化得到黄色固体目标产品P39(15mg,81%)。反应式如下:
2,9-二羟基苯并[b]萘[1,2-d]噻吩7-氧化物(P39)。黄色固体,产率:81%。1H NMR(400MHz,CD3OD)δ8.29(d,J=8.7Hz,1H),8.01(d,J=2.3Hz,1H),7.89(dd,J=8.7,3.6Hz,2H),7.73(d,J=8.4Hz,1H),7.45(d,J=2.5Hz,1H),7.26(dd,J=8.9,2.3Hz,1H),7.15(dd,J=8.7,2.5Hz,1H).13C NMR(150MHz,CD3OD)δ159.82,158.98,147.58,142.80,132.72,132.58,132.38,131.68,130.61,130.46,127.44,121.55,120.71,120.10,115.85,107.33.HRMS-ESI:calcd for C16H10O3NaS[M+Na]+305.0243,found:305.0247.
实施例40
本实施例制备化合物P40,具体合成步骤同于实施例39,只是第一步脱甲基化反应完成后未纯化,直接进行第二步的氧化过程,且所使用氧化剂过氧化氢的量大大增加,具体实施步骤如下:
将2,9-二甲氧基苯并[b]萘[1,2-d]噻吩7-氧化物(P12,31mg,0.1mmol)和Py·HCl(774.5mg,6.7mmol)的混合物置于封管中,在微波反应器中,逐渐升温至150℃,反应2min后将反应混合物冷却至室温,加入NH4Cl溶液中,乙酸乙酯萃取,饱和食盐水洗涤(20mL)洗涤,无水Na2SO4干燥,过滤,减压浓缩。将中间体粗产物溶解在甲醇(400μL)和CF3COOH(400μL)的混合溶液中,于室温下,加入加33%的H2O2(40当量)。反应液室温下搅拌过夜,于0℃下加入饱和NaHCO3水溶液,乙酸乙酯萃取,无水Na2SO4干燥,减压浓缩,制备薄层色谱(PE:EA:MeOH=1:1:1)纯化即得目标产物P40(黄色固体,5.5mg,37%)。反应式如下:
2,9-二羟基苯并[b]萘[1,2-d]噻吩7,7-二氧化物(P40)。黄色固体,产率:37%,mp:275℃(分解)。1H NMR(600MHz,CD3OD)δ8.28(d,J=8.6Hz,1H),7.98(d,J=2.3Hz,1H),7.89(dd,J=10.3,8.6Hz,2H),7.54(d,J=8.3Hz,1H),7.28–7.23(m,2H),7.16(dd,J=8.6,2.5Hz,1H).13C NMR(150MHz,CD3OD)δ160.45,159.40,141.10,136.67,133.04,132.63,131.47,131.20,127.77,127.50,124.79,121.85,121.54,114.45,109.98,107.70.HRMS-ESI:calcd for C16H10O4NaS[M+Na]+321.0192,found:321.0192.
实施例41
本实施例制备化合物P41,具体合成步骤同于实施例38,只是将底物换为1,8-二(4-(二苯胺基)苯基)苯并[b]萘[1,2-d]噻吩7-氧化物P33,纯化即得目标产物。
743.2491,found:743.2489.
实施例42
本实施例制备化合物P42,具体合成步骤同于实施例29,只是将二卤代苯并[b]萘[1,2-d]噻吩7-氧化物换为1,8-二溴苯并[b]萘[1,2-d]噻吩7-氧化物(P16),且芳基硼酸底物换为1当量的4-硼酸三苯胺,反应时间改为16h即可,纯化即得目标产物。
596.0477(97.3%),found:594.0470;596.0445.
实施例43
本实施例制备化合物P43,具体合成步骤同于实施例29,只是将二卤代苯并[b]萘[1,2-d]噻吩7-氧化物换为1-溴-8-(4-(二苯氨基)苯基)苯并[b]萘[1,2-d]噻吩7-氧化物(P42),且芳基硼酸底物换为1当量的3,4-二甲氧基苯硼酸,反应时间改为16h即可,纯化即得目标产物。
131.04,131.00,130.47,129.81,129.32,128.48,128.24,127.67,127.44,127.17,124.56,124.36,124.33,123.08,122.23,122.04,113.75,111.34,56.21,56.08.HRMS-ESI:calcdfor C42H31NNaO3S[M+Na]+652.1917,found:652.1910.
下面是本发明各化合物的应用实施例:
实施例44
本实施例列举的是本发明中的化合物作为荧光染料用于生物成像的例子。具体操作流程如下:
将小鼠小角质细胞BV2接种在24孔板中,加入含10%胎牛血清(FBS)、100U/mL青霉素/链霉素的DMEM高糖型培养基,在5% CO2培养箱中于37℃培养过夜。然后加入所测化合物P40(20μM),在5% CO2培养箱中于37℃下孵育40min。然后用PBS清洗细胞两次。用转盘共聚焦显微镜观察荧光成像并拍摄图片。上述过程不限于这种细胞。
实施例45
本实施例列举的是本发明中的化合物细胞毒性测试的例子。用CCK-8法测定,具体操作流程如下:
CCK-8法检测细胞活力:
取对数生长期的小鼠小胶质细胞(BV2),接种于96孔培养板上(密度为6000个细胞/孔),加入含10%胎牛血清(FBS)和100U/mL青霉素/链霉素的DMEM高糖型培养基,培养24小时后,分别加入不同浓度(0.02,0.2,2,20,200μM)的化合物P40,在5%CO2培养箱中于37℃下培养24小时后,向每个孔中加入10μL CCK-8溶液,在37℃下培养3小时。测量450nm波长处的吸光度,计算细胞活力,制作生长曲线。
实施例46
本实施例列举的是本发明中的化合物作为荧光探针用于质子酸识别的例子。具体操作流程如下:
将上述合成的BNT亚砜化合物溶解在二氯甲烷溶液(c=3*10-6M,3mL)中,然后加入不同的酸(8.7μL HCl、5.4μL H2SO4、3.8μL HNO3和5.2μL H3PO4,c=0.03M;11.4μL HCOOH和17.1μL CH3COOH,c=0.1M)后,但不限于这几种酸,且不限于溶剂种类和浓度大小,在365nm光的照射下,记录其荧光颜色的变化。
本领域的技术人员容易理解,以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (11)
1.一种噻吩稠环类化合物,其特征在于,具有式(P)所示的结构:
所述式(P)选自以下结构的化合物:
2.如权利要求1所述的噻吩稠环类化合物的合成方法,其特征在于,所述合成方法为自身二聚化反应或者交叉二聚化反应:
所述自身二聚化反应的路线图为:
所述交叉二聚化反应的路线图为:
所述合成方法包括以下步骤:
a、式1或式1,的化合物在氧化剂的作用下经氧化得到式2或式2,的化合物;
b、式2或式2,的化合物在溶剂中,通过[4+2]环加成二聚化反应得到式3或式3,的化合物,所述式3或式3,的结构式如下所示:
3.如权利要求1所述的噻吩稠环类化合物的合成方法,其特征在于,所述合成方法为自身二聚化反应或者交叉二聚化反应:
所述自身二聚化反应的路线图为:
所述交叉二聚化反应的路线图为:
所述合成方法包括以下步骤:
a、式1或式1,的化合物在氧化剂的作用下经氧化得到式2或式2,的化合物;
b、式2或式2,的化合物在溶剂中,通过[4+2]环加成二聚化反应得到式4,,或式4,的化合物,所述式4,,或式4,的结构式如下所示:
4.如权利要求2所述的噻吩稠环类化合物的合成方法,其特征在于,反应式如下:
所述合成方法为:式3的化合物在还原剂的作用下还原为式5的化合物,所述式5的结构式如下所示:
5.如权利要求2所述的噻吩稠环类化合物的合成方法,其特征在于,反应式如下:
所述合成方法为:式3的化合物在氧化剂的作用下氧化为式6的化合物,所述式6的结构式如下所示:
6.如权利要求2所述的噻吩稠环类化合物的合成方法,其特征在于,反应式如下:
所述合成方法包括以下步骤:
a、式3的化合物在氧化剂的作用下氧化为式6的化合物;
b、式6的化合物在碱作用下被亲核试剂两次进攻后得到式7的化合物,所述式7的结构式如下所示:
7.如权利要求2所述的噻吩稠环类化合物的合成方法,其特征在于,反应式如下:
其中R1为氢;R2和R3各自独立地为甲氧基;
所述合成方法为:式3的化合物在脱烷基试剂的作用下脱甲基并导致亚砜被还原,再氧化为式8的化合物,所述式8的结构式如下所示:
8.如权利要求1所述的噻吩稠环类化合物用于制备成像试剂的应用,其特征在于,所述成像试剂为活细胞成像试剂。
9.如权利要求1所述的噻吩稠环类化合物用于识别质子酸的应用。
10.如权利要求9所述的应用,其特征在于,所述质子酸为有机酸或无机酸。
11.如权利要求10所述的应用,其特征在于,所述有机酸为甲酸和乙酸;所述无机酸为HCl、H2SO4、HNO3和H3PO4。
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