CN111635426A - 一种烷氧基羰基取代硅基罗丹明衍生物及其制备方法与应用 - Google Patents
一种烷氧基羰基取代硅基罗丹明衍生物及其制备方法与应用 Download PDFInfo
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- 239000010703 silicon Substances 0.000 title claims abstract description 38
- 125000004453 alkoxycarbonyl group Chemical group 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
- C07F7/0816—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring comprising Si as a ring atom
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Abstract
本发明公开了一种烷氧基羰基取代硅基罗丹明衍生物及其制备方法与应用。所述烷氧基羰基取代硅基罗丹明衍生物是通过硅基中间体与烃氧基羰基取代邻醛基苯甲酸在无溶剂条件下,在催化剂存在时,加热封管反应制备得到。本发明提供的硅基罗丹明衍生物合成方法反应条件简单,操作方便,总收率高,可用于大量制备;本发明硅基罗丹明衍生物在碱性条件下反应,可高效制备羧基取代硅基罗丹明衍生物,用于多种荧光染料及探针的制备。
Description
技术领域
本发明涉及一种硅基罗丹明衍生物及制备方法与应用,具体涉及一种烷氧基羰基取代硅基罗丹明衍生物及其制备方法与应用,属于化合物及其制备领域。
背景技术
硅基罗丹明类荧光染料分子由于其优良的光谱学和化学性质,被广泛应用于荧光探针的设计合成中。通过将罗丹明分子中的氧原子用硅原子进行取代,使其广谱范围红移,可以满足近红外荧光检测需求,同时保留了罗丹明染料诸多优良的性质,如荧光量子产率高、性质稳定等。
硅基罗丹明类荧光染料近年来受到越来越多的关注,其应用范围也越来越广泛。羧基取代硅基罗丹明由于可方便地进行化学修饰,非常适合用于荧光探针分子的设计开发。相关文献(Lukinavicius,G.,et al.(2013)."A near-infrared fluorophore forlive-cell super-resolution microscopy of cellular proteins."Nat.Chem.5(2):132-139.)及专利申请(WO2013029650A1)中报道了羧基取代硅基罗丹明目前其常用的合成方法,即先对溴代苯二甲酸中双羧基进行保护,再在叔丁基锂条件下与硅酮中间体进行反应,脱去羧基保护基,得到羧基取代硅基罗丹明。文献(Wang,B.,et al.(2014)."A generalapproach to spirolactonized Si-rhodamines."Chem.Commun.50(92):14374-14377.)及专利申请(ZL201410428067.5)中报道了羧基取代硅基罗丹明的另一种合成方法,即用双羧基取代苯甲醛与硅基中间体在对甲苯磺酸一水合物存在下,高温封管反应制得。对于第一种合成方法,需要使用危险性极高的叔丁基锂试剂,且总产率较低,限制了其应用;对于第二种合成方法,双羧基取代苯甲醛与硅基中间体反应效率过低,只有10%左右,不适于羧基取代硅基罗丹明的制备。因此需要提供一种简便合成羧基取代硅基罗丹明衍生物的方法。
发明内容
本发明的目的是提供一种烷氧基羰基取代硅基罗丹明衍生物及其制备方法,通过在碱性条件下水解该烷氧基羰基取代硅基罗丹明衍生物,可方便高效地制备得到羧基取代硅基罗丹明衍生物,从而可进一步合成荧光染料或探针分子的制备。
本发明所提供的烷氧基羰基取代硅基罗丹明衍生物的结构式如式Ⅰ所示,
式Ⅰ中,R1为C1~C6的烷基,或同一N原子上的R1连接成环形成环丁胺基、环戊胺基或环己胺基;
R2和R3的取代情况如下述1)或2):
1)R2为C1~C6的直链或支链饱和或不饱和的烷氧基羰基,R3为H;
2)R3为C1~C6的直链或支链饱和或不饱和的烷氧基羰基,R2为H。
具体地,R1为C1~C3的烷基,优选甲基或乙基。
具体地,R2和R3的取代情况如下述1)或2):
1)R2为C1~C3的直链饱和的烷氧基羰基,优选甲氧基羰基,R3为H;
2)R3为C1~C3的直链饱和的烷氧基羰基,优选甲氧基羰基,R2为H。
本发明还提供了所述烷氧基羰基取代硅基罗丹明衍生物的制备方法,包括如下步骤:
(1)式Ⅱ所示烷氧羰基取代苯酞经NBS溴代,然后在加热条件下进行水解得到式Ⅲ所示烷氧羰基取邻醛基苯甲酸;
式Ⅱ和式Ⅲ中,R2和R3的定义同式Ⅰ;
(2)在加热和催化剂存在的条件下,式Ⅲ所示烷氧羰基取邻醛基苯甲酸与式Ⅳ所示硅基中间体进行反应即得权利要求1-3中任一项所述烷氧基羰基取代硅基罗丹明衍生物;
式Ⅳ中,R1的定义同式Ⅰ。
上述的制备方法中,步骤(1)中,所述水解的温度为30~100℃,时间为2~24h。
上述的制备方法中,步骤(2)中,式Ⅲ所示烷氧羰基取邻醛基苯甲酸与式Ⅳ所示硅基中间体的摩尔比为3~5:1。
上述的制备方法中,步骤(2)中,所述催化剂可为CuBr2;
所述催化剂的加入量为式Ⅳ所示硅基中间体摩尔量的0.1~1.0倍;
所述反应在开放体系或封管条件下进行,优选在封管条件下进行;
所述反应的温度为120~160℃,时间为2.0~12.0h;
所述反应结束后,所述方法还包括柱层析分离提纯的步骤,所述柱层析采用的洗脱剂为体积比为1~40:1的石油醚和乙酸乙酯的混合液。
本发明提供得的所述烷氧基羰基取代硅基罗丹明衍生物可用于制备羧基取代硅基罗丹明衍生物,如式Ⅴ-1或式Ⅴ-2所示,
式Ⅴ-1和式Ⅴ-2中,R1的定义同式Ⅰ。
具体地,可按照下述方法制备所述羧基取代硅基罗丹明衍生物:
所述烷氧基羰基取代硅基罗丹明衍生物在碱性条件下进行水解反应,然后经酸化即得所述羧基取代硅基罗丹明衍生物;
所述水解反应在甲醇或THF与甲醇的混合溶剂中进行,优选THF与甲醇体积比为1:2的混合溶剂;
采用NaOH、KOH或LiOH调控碱性,优选NaOH;
采用盐酸调酸,如1.0M盐酸,调控体系的pH至3~4。
本发明所提供的羧基取代硅基罗丹明衍生物经过化学修饰,如通过酯键或酰胺键与其他功能性分子连接,可制备功能化荧光染料或探针,可用于细胞染料、生物染色剂、生物分子或生物粒子荧光标记中(如文献Nat.Chem.,5(2):132报道羧基取代硅基罗丹明衍生物通过酰胺键与功能分子相连,制备得到SiR-SNAP、SiR-Halo、SiR-CLIP、SiR-tetrazine分子,用于细胞内蛋白质的超高分辨纤维成像;文献Nat.Methods.,11(7):731报道羧基取代硅基罗丹明衍生物通过酰胺键与多烯紫杉醇连接,用于细胞骨架成像;文献Chem.Commun.,2014,50:4504报道羧基取代硅基罗丹明衍生物通过酰胺键与药物分子相连,用于药物分子在细胞内定位研究)。
附图说明
图1为本发明式I-1所示化合物的核磁共振H谱图。
图2为本发明式I-1所示化合物的核磁共振C谱图。
图3为本发明式I-1所示化合物的高分辨质谱图。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明,均为常规方法。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1、中间体2-醛基-4-甲氧基羰基苯甲酸的制备
将5-羧基苯酞19.217g(100.0mmol,1.0equiv)NBS 19.579g(110.0mol,1.1equiv),AIBN 1.642g(10.0mol,0.1equiv)加入反应瓶中,加入1,2-二氯乙烷200mL,磁力搅拌,加热回流条件下反应4h,自然冷却至室温,继续0℃下磁力搅拌2h,过滤除去沉淀,减压蒸干溶剂,加入水1.5L,40℃下磁力搅拌反应12h,4℃条件下静置过夜,过滤得白色固体2-醛基-4-甲氧基羰基苯甲酸。滤液继续用乙酸乙酯萃取3次(100mL/次),合并酯层,无水Na2SO4干燥,过滤,减压蒸干溶剂,得白色固体,共得产物2-醛基-4-甲氧基羰基苯甲酸17.070g,产率82%。
其结构表征数据如下:
1H NMR(400MHz,DMSO-d6)δ3.93(s,3H),6.75(s,1H),7.97(d,J=8.0Hz,1H),8.15(s,1H),8.19(d,J=8.0Hz,1H),10.47(s,1H);13C NMR(101MHz,DMSO-d6)δ192.57,168.01,165.70,148.19,135.40,131.77,130.90,125.58,124.82,53.27;HRMS(ESI)calcd.forC10H9O5 +[M+1]+:209.0444,found:209.0446。
由上述结果可知,本实施例制备得到了2-醛基-4-甲氧基羰基苯甲酸。
实施例2、甲氧基羰基取代硅基罗丹明衍生物的制备
在15mL厚壁耐压反应管中加入原料NMe4Si中间体(式Ⅳ-1)0.118g(0.4mmol,1.0equiv),2-醛基-4-甲氧基羰基苯甲酸0.416g(2.0mmol,5.0equiv),CuBr2 0.009g(0.04mmol,0.1equiv),封管条件下140℃油浴中磁力搅拌(置于防护罩中),反应5h,冷却至室温,柱层析分离,洗脱剂以体积计为石油醚:乙酸乙酯=4:1,得到甲氧基羰基取代硅基罗丹明衍生物(式Ⅰ-1)70mg,产率36%。
本实施例制备的式I-1所示化合物的核磁共振H谱图、核磁共振C谱图和高分辨质谱图分别如图1、图2和图3所示,表征数据如下:
1H NMR(400MHz,CDCl3)δ0.60(3H,s),0.68(s,3H),2.97(s,12H),3.88(s,3H),6.56(dd,J=3.2,7.2Hz,2H),6.78(d,J=8.8Hz,2H),6.97(d,J=3.2Hz),7.94(s,1H),8.01(dd,J=0.8,8.0Hz,1H),8.18(dd,J=1.2,8.0Hz,1H);13C NMR(100MHz,CDCl3)δ169.89,165.90,155.07,149.38,136.69,135.07,131.26,130.15,129.88,127.97,125.65,116.64,113.47,91.99,52.55,40.23,0.33,-1.27;HRMS(ESI)calcd.for C28H31N2O4Si+[M+1]+:487.2048,found:487.2043。
由上述结果可知,本实施例制备得到了式Ⅰ-1所示甲氧基羰基取代硅基罗丹明衍生物。
实施例3、甲氧基羰基取代硅基罗丹明衍生物的制备
方法同实施例2,区别在于原料式Ⅳ-1所示的NMe4Si中间体替换为式Ⅳ-2所示的NEt4Si中间体142mg(4.0mmol,1.0equiv),得目标化合物式Ⅰ-2所示甲氧基羰基取代硅基罗丹明衍生物72mg,产率33%。
其结构表征数据如下:
1H NMR(400MHz,CDCl3)δ0.60(3H,s),0.66(s,3H),1.17(t,J=7.2Hz,12H),3.37(q,J=7.2Hz,12H),3.89(s,3H),6.51(dd,J=3.0,9.0Hz,2H),6.71(d,J=9.0Hz,2H),6.94(d,J=2.4Hz),7.99-8.01(m,2H),8.22(d,J=1.8Hz,1H);13C NMR(150MHz,CDCl3)δ172.12,155.22,147.11,137.87,136.27,130.63,130.37,130.06,128.49,126.83,126.01,116.35,112.60,85.42,52.51,44.38,12.53,0.28,-1.71;HRMS(ESI)calcd.forC32H39N2O4Si[M+H]+:543.2674,found:543.2672。
由上述结果可知,本实施例制备得到了式Ⅰ-2所示甲氧基羰基取代硅基罗丹明衍生物。
实施例4、羧基取代硅基罗丹明衍生物的制备
将式Ⅰ-1所示的SiR-COOCH3 49mg(0.1mmol,1.0equiv)溶于6mL THF与甲醇体积比为1:2混合溶剂中,室温下磁力搅拌,加入1M NaOH溶液0.5mL(5.0equiv),室温下反应12h,加入1M盐酸调pH 3~4,二氯甲烷萃取3次,合并二氯甲烷层,无水Na2SO4干燥,过滤,减压蒸除溶剂,柱层析分离,洗脱剂以体积计为石油醚:乙酸乙酯=1:1,得产物式Ⅴ-1-A所示SiR-COOH 42mg,产率89%。
其结构表征数据如下:
1H NMR(400MHz,CDCl3)δ0.60(3H,s),0.67(s,3H),2.97(s,12H),6.57(dd,J=2.4,8.8Hz,2H),6.79(d,J=7.2Hz,2H),6.98(d,J=2.0Hz),7.98(s,1H),8.03(d,J=8.0Hz,1H),8.22(dd,J=1.2,8.0Hz,1H);13C NMR(100MHz,CDCl3)δ169.77,168.86,155.13,149.37,136.69,134.09,130.73,130.38,127.91,126.21,125.80,116.82,113.64,101.33,40.31,0.30,-1.21;HRMS(ESI)calcd.for C27H29N2O4Si+[M+1]+:473.1891,found:473.1888。
由上述结果可知,本实施例制备得到了式Ⅴ-1-A所示羧基取代硅基罗丹明衍生物。
本实施例制备的式Ⅴ-1-A所示羧基取代硅基罗丹明衍生物,进一步经化学修饰通过酯键或酰胺键与其他功能性分子连接,进而得到了一种功能化荧光染料(探针),可用于细胞染料、生物染色剂、生物分子或生物粒子荧光标记中,如通过酰胺键与功能分子相连,制备得到SiR-SNAP、SiR-Halo、SiR-CLIP、SiR-tetrazine分子,用于细胞内蛋白质的超高分辨纤维成像(Nat.Chem.,5(2):132),或通过酰胺键与多烯紫杉醇连接,用于细胞骨架成像(Nat.Methods.,11(7):731),或通过酰胺键与药物分子相连,用于药物分子在细胞内定位研究(Chem.Commun.,2014,50:4504)。
实施例5、羧基取代硅基罗丹明衍生物的制备
方法同实施例4,区别在于将式Ⅰ-1所示SiR-COOCH3替换为式Ⅰ-2所示SiRB-COOCH354mg(0.1mmol,1.0equiv),得产物式Ⅴ-1-B所示SiR-COOH 45mg,产率85%。
其结构表征数据如下:
1H NMR(600MHz,CDCl3)δ0.59(3H,s),0.65(s,3H),1.16(t,J=7.2Hz,12H),3.36(q,J=7.2Hz,12H),6.50(dd,J=3.0,9.0Hz,2H),6.69(d,J=9.0Hz,2H),6.93(d,J=2.4Hz),8.00-8.02(m,2H),8.23(d,J=1.8Hz,1H);13C NMR(150MHz,CDCl3)δ170.66,154.55,146.86,137.40,136.04,130.59,130.35,130.08,128.53,126.43,125.58,116.24,112.80,89.42,44.42,12.55,0.32,-1.66;HRMS(ESI)calcd.for C31H36N2O4Si[M+H]+:529.2517,found:529.2519。
由上述结果可知,本实施例制备得到了式Ⅴ-1-B所示羧基取代硅基罗丹明衍生物。
本实施例制备的式Ⅴ-1-B所示羧基取代硅基罗丹明衍生物,进一步经化学修饰通过酯键或酰胺键与其他功能性分子连接,进而得到了一种功能化荧光染料(探针),可用于细胞染料、生物染色剂、生物分子或生物粒子荧光标记中。
Claims (10)
2.根据权利要求1所述的烷氧基羰基取代硅基罗丹明衍生物,其特征在于:R1为C1~C3的烷基。
3.根据权利要求1或2所述的烷氧基羰基取代硅基罗丹明衍生物,其特征在于:R2和R3的取代情况如下述1)或2):
1)R2为C1~C3的直链饱和的烷氧基羰基,R3为H;
2)R3为C1~C3的直链饱和的烷氧基羰基,R2为H。
5.根据权利要求4所述的制备方法,其特征在于:步骤(1)中,所述水解的温度为30~100℃,时间为2~24h。
6.根据权利要求4或5所述的制备方法,其特征在于:步骤(2)中,式Ⅲ所示烷氧羰基取邻醛基苯甲酸与式Ⅳ所示硅基中间体的摩尔比为3~5:1。
7.根据权利要求4-6中任一项所述的制备方法,其特征在于:步骤(2)中,所述催化剂为CuBr2;
所述催化剂的加入量为式Ⅳ所示硅基中间体摩尔量的0.1~1.0倍;
所述反应在开放体系或封管条件下进行;
所述反应的温度为120~160℃,时间为2.0~12.0h;
所述反应结束后,所述方法还包括柱层析分离提纯的步骤,所述柱层析采用的洗脱剂为体积比为1~40:1的石油醚和乙酸乙酯的混合液。
10.根据权利要求9所述的制备方法,其特征在于:所述水解反应在甲醇或THF与甲醇的混合溶剂中进行;
采用NaOH、KOH或LiOH调控碱性;
采用盐酸调酸。
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