CN113912632B - 一种氟硼荧光染料及其制备方法和用途 - Google Patents
一种氟硼荧光染料及其制备方法和用途 Download PDFInfo
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- 239000007850 fluorescent dye Substances 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims description 8
- BVBRZOLXXOIMQG-UHFFFAOYSA-N fluoroborane Chemical compound FB BVBRZOLXXOIMQG-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 106
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 67
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 229960000583 acetic acid Drugs 0.000 claims description 9
- 239000012362 glacial acetic acid Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 4
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 4
- 238000012984 biological imaging Methods 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 229940126062 Compound A Drugs 0.000 claims description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000012216 imaging agent Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 35
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- 239000000975 dye Substances 0.000 abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 16
- 230000004048 modification Effects 0.000 abstract description 14
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- 230000003287 optical effect Effects 0.000 abstract description 14
- 238000010521 absorption reaction Methods 0.000 abstract description 12
- 230000008033 biological extinction Effects 0.000 abstract description 10
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- 150000001413 amino acids Chemical class 0.000 abstract description 2
- 150000001720 carbohydrates Chemical class 0.000 abstract description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 44
- 238000010898 silica gel chromatography Methods 0.000 description 23
- 239000011734 sodium Substances 0.000 description 23
- 239000007787 solid Substances 0.000 description 23
- 229910052786 argon Inorganic materials 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 150000002632 lipids Chemical class 0.000 description 12
- 238000005192 partition Methods 0.000 description 8
- 238000006862 quantum yield reaction Methods 0.000 description 8
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 7
- 239000012346 acetyl chloride Substances 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 6
- 150000002772 monosaccharides Chemical group 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
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- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 230000006181 N-acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001215 fluorescent labelling Methods 0.000 description 2
- YMAWOPBAYDPSLA-UHFFFAOYSA-N glycylglycine Chemical compound [NH3+]CC(=O)NCC([O-])=O YMAWOPBAYDPSLA-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- GVHLQHHQXWSDDM-UHFFFAOYSA-N 2-(2-prop-2-ynoxyethoxy)ethanamine Chemical compound NCCOCCOCC#C GVHLQHHQXWSDDM-UHFFFAOYSA-N 0.000 description 1
- FPVCVHVTMPCZTH-UHFFFAOYSA-N 2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethanamine Chemical compound NCCOCCOCCOCCN=[N+]=[N-] FPVCVHVTMPCZTH-UHFFFAOYSA-N 0.000 description 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 108010008488 Glycylglycine Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- LIQLLTGUOSHGKY-UHFFFAOYSA-N [B].[F] Chemical compound [B].[F] LIQLLTGUOSHGKY-UHFFFAOYSA-N 0.000 description 1
- 150000001345 alkine derivatives Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229940043257 glycylglycine Drugs 0.000 description 1
- 230000005283 ground state Effects 0.000 description 1
- 150000002402 hexoses Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 230000001443 photoexcitation Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000001429 visible spectrum Methods 0.000 description 1
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Abstract
本发明提供了一种式I所示的化合物或其盐、水合物,是一种新型BODIPY染料,吸收光谱覆盖可见光到近红外范围,与现有的BODIPY荧光染料相比,吸收和发射波长红移,摩尔消光系数提高,斯托克斯位移增加,综合光学性能优异,应用前景佳;并且,本发明提供的对BODIPY荧光染料的修饰方法可以在兼容不同的生物正交基团的同时不影响BODIPY的荧光性能,还可进一步兼容氨基酸、糖类修饰以改善BODIPY的水溶性,为设计合成性质优异的新型荧光染料提供了途径。
Description
技术领域
本发明属于化学合成领域,具体涉及一种新型氟硼荧光染料及其制备方法和用途。
背景技术
氟硼荧光染料(BODIPY)是荧光染料领域的研究热点。自首次合成以来已经被广泛用于荧光标记、生物成像以及光动力治疗等领域。BODIPY具有诸多优异的性质:良好的光稳定性和化学稳定性、高的摩尔消光系数(通常ε>80000M-1·cm-1)和量子产率(通常ΦF>0.50)等。通过在BODIPY骨架的适宜位置上引入修饰基团,可以有效的调控它们的性能。因此,吸引了科学家们对BODIPY结构进行修饰,探索合成能够更有效地用于活细胞以及整个生物体成像的荧光染料。
目前已有多种BODIPY的结构修饰方法,其中,有报道表明BODIPY的光学性能也受C-8位取代基类型的调控。例如Xu和Liu等人通过理论计算化学研究了BODIPY荧光染料的C-8位取代基的构效关系,发现当C-8位为N,N-二甲基时,在基态作为电子供体的取代基能在光激发后转变为电子受体,并迅速发生自身90°的扭转,由电子受体再次转变为电子供体,经分子内扭转电荷穿梭过程(Twisted Intramolecular Charge Shuttle,TICS)来调控染料荧光(Chi W,Qiao Q,Lee R,et al.A Photoexcitation-Induced TwistedIntramolecular Charge Shuttle[J].Angewandte Chemie International Edition,2019,58(21):7073-7.)。
近年来已有若干通过对不同染料的C-8位进行胺基修饰从而调控其光学性能的报道。而通过C-8位引入胺基基团来调控BODIPY性能的修饰策略却鲜有报道。文献报道的C-8位胺基BODIPY染料的最大吸收波长均位于可见光区域,难以构建新型近红外BODIPY染料,且无法改善BODIPY染料本身水溶性差及斯托克斯位移小等不足((1)J,/>V,/>C F A,et al.New 8-Amino-BODIPY Derivatives:Surpassing LaserDyes at Blue-Edge Wavelengths[J].Chemistry-A European Journal,2011,17(26):7261-70;(2)Esnal I,/>A,/>C F A,et al.Reaction ofAmines with 8-MethylthioBODIPY:Dramatic Optical and Laser Response to AmineSubstitution[J].Chemistry-An Asian Journal,2013,8(11):2691-700;(3)Epelde-Elezcano N,/>V,/>E,et al.Modulation of SingletOxygen Generation in Halogenated BODIPY Dyes by Substitution at Their MesoPosition:towards A Solvent-independent Standard in the Vis Region[J].RSCAdvances,2016,6(48):41991-8.)。
因此,进一步研究对BODIPY新的修饰方式,进而进一步改善BODIPY荧光染料的光学性能和物理化学性能,具有重要意义。
发明内容
本发明的目的在于提供一种通过对BODIPY荧光染料的C-8位进行酰基化修饰进而改善性能的新型BODIPY荧光染料。
本发明提供了式I所示的化合物或其盐、水合物:
其中R1为卤素取代或未取代的C1~C3的烷基;
R2为C1~C3的烷基、苄基、
T为多肽基团,Rb为炔基、叠氮基或单糖基团,m为1~3的整数;
R3为C1~C3的烷基或Rd、Re分别独立选自/>R’为C1~C3的烷基或/>p为1~4的整数。
进一步地,上述R1为F取代或未取代的甲基;
R2为甲基、苄基、
T为二肽基团,Rb为炔基、叠氮基或己糖基团,m为2或3;
R3为甲基或Rd选自/>Re选自H或/>R’为甲基或/>
更进一步地,上述T为Rb为炔基、叠氮基或
更进一步地,上述R1为甲基或三氟甲基;
R2为甲基、苄基、
R3为甲基、
进一步地,上述的化合物具有式II所示结构:
更进一步地,上述化合物具有如下结构:
进一步地,上述化合物具有式III所示结构:
更进一步地,上述化合物具有如下结构:
本发明还提供了上述的化合物的制备方法,包括如下步骤:
(1)以化合物A为原料,与化合物B在室温下反应制得化合物C;
(2)化合物C与化合物D在有机碱作用下室温反应得到化合物E即为所述化合物;
或化合物E与化合物F在催化剂作用下于100~120℃反应制得化合物G即为所述化合物;
反应式如下:
其中,X为卤素;
优选地,步骤(2)所述有机碱为三乙胺;步骤(3)所述催化剂为哌啶和冰醋酸。
本发明还提供了上述的化合物或其盐、水合物在荧光标记和/或生物成像试剂中的用途。
本发明的有益效果:利用BODIPY的C-8位在调控荧光染料的光学性能上的优势,以及C-8位结构修饰在合成操作上的典型性和易操作性,实现了对BODIPY母核C-8位氨基的N-酰基化修饰,为BODIPY染料的修饰改性提供了新策略。进而通过修饰改性改善BODIPY荧光染料的斯托克斯位移小、水溶性差、最大吸收波长难以达到近红外区等不足,制备了光学性能优异的一系列新型BODIPY荧光染料,具有广泛应用前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为多肽及单糖修饰BODIPY荧光染料的脂水分配系数测量:待测物(从左至右依次为荧光染料F12、F13、D1、D2)溶于pH 7.4的混合溶液中(上层为正辛醇溶液,下层为磷酸钠缓冲液),涡旋(2000rpm,5min),静置30min后(a)于日光灯下拍图;(b)于365nm灯光下拍图。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品或根据现有文献或本说明书记载的合成方法制备所得。
本发明实施例的实验得到国家自然科学基金(21801178)和中央高校基本科研业务费专项资金(2019SCU12025,四川大学专职博士后基金)的支持。
实施例1、本发明化合物的制备
1、化合物F1:
化合物B1根据参考文献(Goud T V,Tutar A,Biellmann J-F.Synthesis of8-heteroatom-substituted 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene dyes(BODIPY)[J].Tetrahedron,2006,62(21):5084-5091.)公开的方法合成:
1H NMR(400MHz,CDCl3)δ7.29(d,J=4.0Hz,2H),6.26(d,J=4.1Hz,2H),2.70(s,3H),2.60(s,6H).
化合物B2的合成:
将B1(200mg,0.75mmol)加入到25mL反应瓶内,氩气保护下,加入4mL的DCM;再将甲胺的乙醇溶液(188μL,1.50mmol)溶于2mL的DCM中,滴加到反应液中;然后在室温(25℃)下搅拌1h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得黄色固体化合物B2(141mg),收率:64%。
1H NMR(400MHz,MeOD)δ7.14(d,J=72.1Hz,2H),6.17(d,J=79.3Hz,2H),3.28(s,3H),2.47(d,J=28.6Hz,6H).
13C NMR(101MHz,DMSO-d6)δ147.28,147.17,146.28,142.46,124.66,124.19,122.48,116.07,115.51,113.47,34.25,34.11,14.30,14.03.
HRMS[M+Na]+m/z calcd.for[C12H14BF2N3Na]+272.1141,found272.1143.
化合物F1的合成:
将B2(400mg,1.61mmol)加入到100mL反应瓶内,氩气保护下,加入40mL的DCM。在冰浴下滴加DIPEA(797μL,4.83mmol),乙酰氯(229μL,3.21mmol)。然后在室温(25℃)下搅拌8h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得橙红色固体化合物F1(440mg),收率:94%。
1H NMR(400MHz,CDCl3)δ6.93(d,J=4.1Hz,2H),6.33(d,J=4.2Hz,2H),3.35(s,3H),2.64(s,6H),2.02(s,3H).
13C NMR(101MHz,CDCl3)δ170.18,159.79,140.57,133.12,126.85,120.54,38.92,22.07,15.01.
HRMS[M+Na]+m/z calcd.for[C14H16BF2N3NaO]+314.1247,found314.1245.
2、化合物F2:
化合物F2的合成:
将B2(74.7mg,0.3mmol)加入到25mL反应瓶内,氩气保护下,加入8mL的DCM。在冰浴下滴加DIPEA(149μL,0.9mmol),三氟乙酸酐(50μL,0.36mmol)。然后在室温(25℃)下搅拌15h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得橙红色固体化合物F2(53mg),收率:51%。
1H NMR(400MHz,CDCl3)δ6.90(d,J=4.2Hz,2H),6.34(d,J=4.2Hz,2H),3.47(s,3H),2.64(s,6H).
13C NMR(101MHz,CDCl3)δ160.90,136.23,132.73,126.77,120.93,117.37,41.33,15.14.
HRMS[M+Na]+m/z calcd.for[C14H13BF5N3NaO]+368.0964,found368.0965.
3、化合物F3:
化合物B3的合成:
将B1(500mg,1.88mmol)加入到25mL反应瓶内,氩气保护下,加入15mL的DCM;再将苯甲胺(411μL,3.80mmol)滴加到反应液中;加入TEA(314μL,2.30mmol)然后在室温(25℃)下搅拌2h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得黄色固体化合物B3(574mg),收率:94%。
1H NMR(400MHz,CDCl3)δ7.46–7.37(m,3H),7.37–7.29(m,2H),6.89(s,2H),6.16(d,J=3.8Hz,3H),4.75(d,J=5.2Hz,2H),2.57(s,6H).
13C NMR(101MHz,CDCl3)δ145.54,135.44,129.50,128.91,127.92,115.21,51.48,14.19.
HRMS[M+Na]+m/z calcd.for[C18H18BF2N3Na]+348.1454,found348.1458.
化合物F3的合成:
将B3(162.5mg,0.5mmol)加入到25mL反应瓶内,氩气保护下,加入10mL的DCM。在冰浴下滴加DIPEA(247μL,1.5mmol),乙酰氯(71μL,1mmol)。然后在室温(25℃)下搅拌13h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得橙红色固体化合物F3(169mg),收率:92%。
1H NMR(400MHz,CDCl3)δ7.29(dd,J=7.0,3.0Hz,2H),7.25(dd,J=4.5,2.3Hz,2H),6.50(d,J=4.1Hz,2H),6.18(d,J=4.2Hz,2H),4.91(s,2H),2.60(s,6H),2.01(s,3H).
13C NMR(101MHz,CDCl3)δ169.86,159.75,138.85,136.78,133.74,129.88,128.47,128.14,127.59,120.27,54.46,22.41,15.05.
HRMS[M+Na]+m/z calcd.for[C20H20BF2N3NaO]+390.1560,found390.1562.
4、化合物F4:
化合物B4的合成:
将B1(500mg,1.88mmol)加入到25mL反应瓶内,氩气保护下,加入15mL的DCM;再将炔丙胺(244μL,3.80mmol)滴加到反应液中;加入TEA(314μL,2.30mmol)然后在室温(25℃)下搅拌2h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得黄色固体化合物B4(500mg),收率:98%。
1H NMR(400MHz,CDCl3)δ6.92(d,J=3.9Hz,2H),6.18(d,J=4.0Hz,3H),4.28(dd,J=5.6,2.5Hz,2H),2.57(s,6H),2.47(s,1H).
13C NMR(101MHz,CDCl3)δ148.42,144.78,122.92,119.77,115.54,74.78,36.55,14.21.
HRMS[M+Na]+m/z calcd.for[C14H14BF2N3Na]+296.1141,found296.1147.
化合物F4的合成:
将B4(136.5mg,0.5mmol)加入到25mL反应瓶内,氩气保护下,加入10mL的DCM。在冰浴下滴加DIPEA(247μL,1.5mmol),乙酰氯(71μL,1mmol)。然后在室温(25℃)下搅拌0.5h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得橙红色固体化合物F4(146mg),收率:93%。
1H NMR(400MHz,CDCl3)δ7.01(d,J=4.1Hz,2H),6.33(d,J=4.2Hz,2H),4.50(d,J=2.4Hz,2H),2.64(s,6H),2.32(s,1H),2.04(s,3H).
13C NMR(101MHz,CDCl3)δ169.62,160.34,138.01,133.69,127.73,120.57,78.14,73.89,39.91,22.06,15.11.
HRMS[M+Na]+m/z calcd.for[C16H16BF2N3NaO]+338.1247,found338.1247.
5、化合物F5:
化合物F5的合成:
将F1(25mg,0.086mmol)加入到10mL反应管内,氩气保护下,加入1mL的甲苯。随后加入对甲氧基苯甲醛(38μL,0.32mmol),在冰浴下滴加哌啶(40μL,0.43mmol),冰醋酸(25μL,0.43mmol)。然后在110℃下搅拌1h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得绿色固体化合物F5(25mg),收率:56%。
1H NMR(400MHz,CDCl3)δ7.68–7.54(m,6H),7.34(d,J=16.2Hz,2H),6.95(t,J=4.3Hz,8H),3.86(s,6H),3.36(s,3H),2.04(s,3H).
13C NMR(101MHz,CDCl3)δ170.62,161.01,156.37,137.85,136.18,134.71,129.43,129.11,125.56,117.09,116.88,114.47,55.43,38.61,22.04.
HRMS[M+Na]+m/z calcd.for[C30H28BF2N3NaO3]+550.2084,found550.2083.
6、化合物F6:
化合物F6的合成:
将F3(55mg,0.15mmol)加入到10mL反应管内,氩气保护下,加入1mL的甲苯。随后加入对甲氧基苯甲醛(55μL,0.45mmol),在冰浴下滴加哌啶(69μL,0.75mmol),冰醋酸(44μL,0.75mmol)。然后在110℃下搅拌1h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得绿色固体化合物F6(87mg),收率:96%。
1H NMR(400MHz,CDCl3)δ7.67–7.50(m,6H),7.30(d,J=7.0Hz,3H),7.25(d,J=2.9Hz,3H),6.91(d,J=8.6Hz,4H),6.80(d,J=4.5Hz,2H),6.52(d,J=4.4Hz,2H),4.91(s,2H),3.82(s,6H),2.01(s,3H).
13C NMR(101MHz,CDCl3)δ170.26,160.98,156.26,137.82,136.96,135.37,134.55,129.98,129.43,129.12,128.51,128.11,126.29,116.86,114.48,55.44,55.42,54.26,22.37.
HRMS[M+Na]+m/z calcd.for[C36H32BF2N3NaO3]+626.2397,found626.2402.
7、化合物F7:
化合物F7的合成:
将化合物F2(15mg,0.04mmol)加入到10mL反应管内,氩气保护下,加入0.5mL的甲苯。随后加入对甲氧基苯甲醛(16μL,0.13mmol),在冰浴下滴加哌啶(20μL,0.215mmol),冰醋酸(12.5μL,0.215mmol)。然后在110℃下搅拌0.5h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得绿色固体化合物F7(6.5mg),收率:26%。
1H NMR(400MHz,CDCl3)δ7.64–7.59(m,5H),7.57(s,1H),7.36(d,J=16.2Hz,2H),6.98–6.94(m,6H),6.92(d,J=4.6Hz,2H),3.87(s,6H),3.49(s,3H).
13C NMR(101MHz,CDCl3)δ161.12,156.94,138.44,134.46,131.58,129.56,129.05,125.34,117.43,116.84,114.49,55.46,55.44,41.04.
HRMS[M+Na]+m/z calcd.for[C30H25BF5N3NaO3]+604.1801,found604.1810.
8、化合物F8:
化合物F8的合成:
将F1(29mg,0.1mmol)和C9(129mg,0.3mmol)加入到10mL反应管内,氩气保护下,加入1mL的甲苯。在冰浴下滴加哌啶(46μL,0.5mmol),冰醋酸(29μL,0.5mmol)。然后在110℃下搅拌1.5h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得绿色固体化合物F8(96mg),收率:87%。
1H NMR(400MHz,CDCl3)δ7.55(d,J=16.2Hz,2H),7.36–7.27(m,4H),7.17(d,J=1.7Hz,2H),6.96(d,J=6.4Hz,6H),4.41–4.14(m,8H),3.97–3.85(m,8H),3.81–3.72(m,8H),3.71–3.62(m,16H),3.55(ddd,J=9.2,5.7,3.6Hz,8H),3.37(d,J=9.8Hz,15H),2.05(s,3H).
13C NMR(101MHz,CDCl3)δ170.54,156.25,150.73,148.92,138.16,136.13,134.75,129.76,125.56,121.96,117.25,117.10,114.44,114.14,71.91,71.89,70.85,70.67,70.53,70.51,69.77,69.60,69.24,68.68,59.01,58.97,38.58,22.03.
HRMS[M+Na]+m/z calcd.for[C56H80BF2N3NaO17]+1138.5441,found1138.5443.
9、化合物F9:
化合物F9的合成:
将F1(29mg,0.1mmol)和对二甲氨基苯甲醛(45mg,0.3mmol)加入到10mL反应管内,氩气保护下,加入1mL的甲苯。在冰浴下滴加哌啶(46μL,0.5mmol),冰醋酸(29μL,0.5mmol)。然后在110℃下搅拌0.5h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得绿色固体化合物F9(56mg),收率:95%。
1H NMR(400MHz,CDCl3)δ7.60–7.48(m,6H),7.30(d,J=16.1Hz,2H),6.90(dd,J=17.2,4.5Hz,4H),6.70(d,J=8.8Hz,4H),3.34(s,3H),3.03(s,12H),2.03(s,3H).
13C NMR(101MHz,CDCl3)δ170.96,156.27,151.29,138.41,134.53,133.97,129.56,124.69,124.57,116.74,114.44,112.09,40.21,38.44,21.96.
HRMS[M+Na]+m/z calcd.for[C32H34BF2N5NaO]+576.2717,found576.2721.
10、化合物F10:
化合物B5的合成:
将B1(26.6mg,0.1mmol)和1-氨基-11-叠氮-3,6,9-三氧杂十一烷(43.6mg,0.2mmol)加入到10mL反应管内,氩气保护下,加入1mL的DCM;再将三乙胺(16.7μL,0.12mmol)滴加到反应液中;然后在室温(25℃)下搅拌3.5h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得黄色固体化合物B5(39mg),收率:83%。
1H NMR(400MHz,CDCl3)δ6.97(d,J=3.8Hz,3H),6.18(d,J=3.6Hz,2H),3.91–3.79(m,4H),3.74(s,4H),3.70(dd,J=5.9,2.9Hz,2H),3.65(dd,J=6.0,3.0Hz,2H),3.63–3.56(m,2H),3.35–3.29(m,2H),2.57(s,6H).
13C NMR(101MHz,CDCl3)δ151.33,146.02,135.77,123.33,121.07,70.75,70.65,70.56,70.08,70.07,67.82,50.66,46.40,14.12.
HRMS[M+Na]+m/z calcd.for[C19H27BF2N6NaO3]+459.2098,found459.2101.
化合物B6的合成:
将B5(35mg,0.075mmol)加入到10mL反应瓶内,氩气保护下,加入1mL的DCM。在冰浴下滴加DIPEA(37μL,0.23mmol),乙酰氯(11μL,0.15mmol)。然后在室温(25℃)下搅拌14h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得橙红色固体化合物B6(12mg),收率:32%。
1H NMR(400MHz,CDCl3)δ7.02(d,J=4.0Hz,2H),6.31(d,J=4.1Hz,2H),3.99(t,J=5.5Hz,2H),3.71–3.56(m,8H),3.53(d,J=4.0Hz,4H),3.37(t,J=5.0Hz,2H),2.63(s,6H),2.01(s,3H).
13C NMR(101MHz,CDCl3)δ170.28,159.63,139.56,133.78,127.56,120.38,70.64,70.52,70.14,70.01,68.36,50.68,50.04,22.49,15.04,14.21.
HRMS[M+Na]+m/z calcd.for[C21H29BF2N6NaO4]+501.2204,found501.2204.
化合物F10的合成:
将B6(12mg,0.026mmol)和C9(33mg,0.077mmol)加入到10mL反应管内,氩气保护下,加入0.5mL的甲苯。在冰浴下滴加哌啶(12μL,0.13mmol),冰醋酸(7.4μL,0.13mmol)。然后在110℃下搅拌1h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得绿色油状化合物F10(16mg),收率:48%。
1H NMR(400MHz,CDCl3)δ7.55(d,J=16.4Hz,2H),7.34–7.30(m,2H),7.29(s,2H),7.15(d,J=1.6Hz,2H),7.06(d,J=4.4Hz,2H),7.00–6.87(m,4H),4.32–4.16(m,8H),4.02(t,J=5.2Hz,2H),3.91(t,J=6.2Hz,8H),3.77(td,J=6.0,3.7Hz,8H),3.74–3.58(m,24H),3.59–3.46(m,12H),3.37(dd,J=10.8,6.1Hz,13H),2.05(s,3H).
13C NMR(101MHz,CDCl3)δ170.71,156.17,150.71,148.95,138.02,135.46,135.21,129.88,126.28,121.89,117.25,114.51,114.22,71.95,70.89,70.71,70.64,70.57,70.17,69.98,69.80,69.65,69.25,68.71,68.41,59.05,59.02,50.68,22.46.
HRMS[M+Na]+m/z calcd.for[C63H93BF2N6NaO20]+1325.6398,found1325.6396.
11、化合物F11:
化合物B7的合成:
将B1(26.6mg,0.1mmol)和2-[2-(炔丙基氧)乙氧基]乙胺(28.6mg,0.2mmol)加入到10mL反应管内,氩气保护下,加入1mL的DCM;再将三乙胺(16.7μL,0.12mmol)滴加到反应液中;然后在室温(25℃)下搅拌3.5h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得黄色固体化合物B7(35mg),收率:97%。
1H NMR(400MHz,CDCl3)δ6.96(d,J=3.8Hz,2H),6.81(s,1H),6.19(d,J=3.7Hz,2H),4.23(d,J=2.4Hz,2H),3.93–3.79(m,4H),3.77(s,4H),2.57(s,6H),2.46(t,J=2.4Hz,1H).
13C NMR(101MHz,CDCl3)δ176.80,145.93,130.22,129.76,114.87,79.23,75.08,75.03,70.09,68.97,67.65,58.51,46.11,14.12.
HRMS[M+Na]+m/z calcd.for[C18H22BF2N3NaO2]+384.1665,found384.1672.
化合物B8的合成:
将B7(35mg,0.097mmol)加入到10mL反应瓶内,氩气保护下,加入1mL的DCM。在冰浴下滴加DIPEA(48μL,0.29mmol),乙酰氯(14μL,0.19mmol)。然后在室温(25℃)下搅拌14h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得橙红色固体化合物B8(29mg),收率:74%。
1H NMR(400MHz,CDCl3)δ7.03(d,J=3.9Hz,2H),6.31(d,J=4.1Hz,2H),4.10(d,J=7.1Hz,2H),4.00(t,J=5.5Hz,2H),3.64(t,J=5.5Hz,2H),3.56(dd,J=13.5,5.2Hz,4H),2.63(s,6H),2.41(t,J=2.0Hz,1H),2.02(s,3H).
13C NMR(101MHz,CDCl3)δ171.16,170.32,159.64,139.52,133.76,127.59,120.37,99.99,79.62,74.50,74.45,69.88,69.01,68.37,58.39,50.00,22.48,15.04.
HRMS[M+Na]+m/z calcd.for[C20H24BF2N3NaO3]+426.1771,found426.1776.
化合物F11的合成:
将B8(15mg,0.04mmol)和化合物7(48mg,0.11mmol)加入到10mL反应管内,氩气保护下,加入0.5mL的甲苯。在冰浴下滴加哌啶(17μL,0.19mmol),冰醋酸(11μL,0.19mmol)。然后在110℃下搅拌1h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得绿色油状化合物F11(38mg),收率:83%。
1H NMR(400MHz,CDCl3)δ7.55(d,J=16.2Hz,2H),7.35–7.29(m,2H),7.28(s,2H),7.16(s,2H),7.07(d,J=4.4Hz,2H),6.95(t,J=7.1Hz,4H),4.30–4.18(m,8H),4.15(d,J=2.3Hz,2H),4.02(t,J=5.3Hz,2H),3.91(t,J=6.1Hz,8H),3.80–3.74(m,8H),3.72–3.63(m,18H),3.60(dd,J=5.8,2.5Hz,3H),3.58–3.49(m,10H),3.37(d,J=9.4Hz,11H),2.42(t,J=2.3Hz,1H),2.05(s,3H).
13C NMR(101MHz,CDCl3)δ170.75,156.18,150.69,148.94,138.00,135.46,135.15,129.88,126.31,121.90,117.26,117.11,114.48,114.20,79.67,74.55,74.52,71.93,70.88,70.70,70.55,69.88,69.79,69.64,69.24,69.02,68.70,68.35,59.04,59.01,58.41,49.68,22.44.
HRMS[M+Na]+m/z calcd.for[C62H88BF2N3NaO19]+1250.5965,found1250.5973.
12、化合物F12:
化合物B21的合成:
化合物B21根据参考文献[75]合成,具体操作如下:将甘氨酰-甘氨酰-甘氨酸(1g,5.3mmol)加入到50mL反应瓶内,加入15mL的甲醇,在冰浴下滴加二氯亚砜(576μL,8mmol),然后在室温(25℃)下搅拌3h,经TLC确认反应完全后,浓缩,用乙醚洗(10mL×3),得白色固体化合物B21(1g),收率:93%。
1H NMR(400MHz,DMSO-d6)δ8.83(s,1H),8.57(s,1H),8.29(s,2H),3.90–3.78(m,4H),3.63(s,3H),3.60(d,J=5.3Hz,2H).
化合物B22的合成:
将B1(53.2mg,0.2mmol)、B21(121.8mg,0.6mmol)和甲醇钠(32.4mg,0.6mmol)加入到10mL反应管内,氩气保护下,加入2mL的甲醇;然后在室温(25℃)下搅拌10h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得黄色固体化合物B22(77mg),收率:92%。
1H NMR(400MHz,DMSO-d6)δ9.17(t,J=6.0Hz,1H),8.64(t,J=5.4Hz,1H),8.39(t,J=5.5Hz,1H),7.17(d,J=88.6Hz,2H),6.23(d,J=51.3Hz,2H),4.37(d,J=6.0Hz,2H),3.85(dd,J=15.5,5.5Hz,4H),3.63(s,3H),2.42(s,6H).
13C NMR(101MHz,DMSO-d6)δ170.66,169.45,167.67,146.87,143.57,123.43,122.02,115.89,52.20,48.85,42.27,40.98,14.19.
HRMS[M–H]–m/z.for[C18H21BF2N5O4]–420.1660,found 420.1671.
化合物B23的合成:
将B22(50mg,0.12mmol)加入到10mL反应瓶内,氩气保护下,加入2mL的DCM。在冰浴下滴加TEA(67μL,0.48mmol),乙酰氯(17μL,0.24mmol)。然后在室温(25℃)下搅拌24h,经TLC确认后,浓缩,采用硅胶柱层析纯化后,得橙红色固体化合物B23(12mg),收率:22%。
1H NMR(400MHz,CDCl3)δ7.25(d,J=4.3Hz,2H),7.03(s,1H),6.88(d,J=5.0Hz,1H),6.33(d,J=3.9Hz,2H),4.23(s,2H),4.06(dd,J=11.1,5.6Hz,4H),3.76(s,3H),2.63(s,6H),2.08(s,3H).
13C NMR(101MHz,CDCl3)δ171.58,170.26,168.94,167.91,160.55,138.48,133.17,128.00,120.79,54.78,52.43,43.02,41.13,21.95,15.10,14.13.
HRMS[M–H]–m/z.for[C20H23BF2N5O5]–462.1766,found 462.1776.
化合物F12的合成:
将B23(2.4mg,0.005mmol)和氯化钙(8.6mg,0.075mmol)加入到5mL反应管内,加入200μL的异丙醇和50μL的四氢呋喃。再将氢氧化锂(0.9mg,0.021mmol)溶于110μL的纯水中,滴入反应液中。然后在室温(25℃)下搅拌12h,经TLC确认反应完全后,于0℃下缓慢加入盐酸(1M)至溶液pH为3,用乙酸乙酯萃取水相(30mL×6),有机相经无水Na2SO4干燥,过滤浓缩,经HPLC制备柱制备后,得橙红色固体化合物F12(1.5mg),收率:68%。
1H NMR(400MHz,D2O)δ7.19(d,J=4.1Hz,2H),6.39(d,J=4.3Hz,2H),4.39(s,2H),3.87(d,J=20.1Hz,2H),3.64(s,2H),2.47(s,6H),1.68(s,3H).
13C NMR(201MHz,D2O)δ171.19,171.01,170.81,170.15,161.01,160.96,129.99,128.88,128.77,121.15,54.07,53.31,42.45,42.28,21.10,14.26.
HRMS[M-H]-m/z.for[C19H21BF2N5O5]-448.1609,found 448.1611.
13、化合物F13:
化合物B24的合成:
化合物B24根据参考文献[76]合成,具体步骤如下:将1,2,3,4,6-O-五乙基-Α-甘露糖(1240mg,3.2mmol)和叠氮-三聚乙二醇(800mg,4.5mmol)加入到50mL反应瓶内,氩气保护下,加入12mL的DCM。再将三氟化硼乙醚(1.22mL,10mmol)溶于8mL的DCM中,在冰浴下滴加进反应液中。然后在室温(25℃)下搅拌15h,经TLC确认反应完全后,加入饱和碳酸氢钠溶液淬灭反应,DCM萃取(20mL×3),饱和食盐水洗(30mL×1),有机相经无水Na2SO4干燥,过滤浓缩,采用硅胶柱层析纯化后,得无色透明液体B24(756mg),收率:47%。
1H NMR(400MHz,CDCl3)δ5.37(dd,J=10.1,3.3Hz,1H),5.29(dd,J=12.7,6.5Hz,2H),4.88(s,1H),4.30(dd,J=12.0,4.8Hz,1H),4.13(dd,J=8.5,4.9Hz,1H),4.07(dd,J=9.6,4.8Hz,1H),3.82(dd,J=9.6,3.9Hz,1H),3.69(dd,J=9.0,4.9Hz,9H),3.40(t,J=4.9Hz,2H),2.16(s,3H),2.11(s,3H),2.04(s,3H),1.99(s,3H).
化合物B25的合成:
化合物B25根据参考文献[76]合成,具体步骤如下:将B24(210mg,0.42mmol)和10%钯碳(23.7mg)加入到50mL反应瓶内,氢气保护下,加入14mL的甲醇。然后在室温(25℃)下搅拌0.5h,经TLC确认反应完全后,过滤除去钯碳,浓缩反应液,得无色透明液体B25(133mg),收率:67%。
1H NMR(400MHz,CDCl3)δ5.44–5.24(m,3H),4.90(d,J=17.2Hz,1H),4.30(dd,J=12.4,5.1Hz,1H),4.10(d,J=10.7Hz,1H),4.06–3.99(m,1H),3.82(d,J=4.0Hz,1H),3.69–3.63(m,9H),2.87(d,J=5.1Hz,2H),2.16(s,3H),2.11(s,3H),2.05(s,3H),1.99(s,3H).
化合物B26的合成:
将B1(61.5mg,0.23mmol)和B25(133mg,0.28mmol)加入到10mL反应管内,氩气保护下,加入2mL的乙腈;再将三乙胺(96μL,0.69mmol)滴加到反应液中;然后在室温(25℃)下搅拌2.5h,经TLC确认反应完全后,浓缩,采用硅胶柱层析纯化后,得黄色固体化合物B26(38mg),收率:24%。
1H NMR(400MHz,CDCl3)δ7.00(d,J=2.7Hz,2H),6.18(d,J=3.3Hz,2H),5.31–5.19(m,3H),4.86(s,1H),4.22(dd,J=12.2,5.1Hz,1H),4.08(dd,J=12.4,1.9Hz,1H),4.03–3.95(m,1H),3.91(d,J=4.3Hz,2H),3.90–3.83(m,3H),3.76–3.67(m,6H),2.57(s,6H),2.14(s,3H),2.09(s,3H),1.97(d,J=4.3Hz,6H).
HRMS[M–H]–m/z.for[C31H41BF2N3O12]–696.2757,found 696.2752.
化合物B27的合成:
将B26(38mg,0.055mmol)加入到10mL反应瓶内,氩气保护下,加入2mL的DCM。在冰浴下滴加TEA(24.7μL,0.165mmol),乙酰氯(7.8μL,0.11mmol)。然后在40℃油浴锅下搅拌24h,经TLC确认后,浓缩,采用硅胶柱层析纯化后,得橙红色固体化合物B27(5mg),收率:12%。
1H NMR(400MHz,CDCl3)δ7.02(d,J=0.9Hz,2H),6.32(d,J=3.8Hz,2H),5.27(d,J=10.2Hz,3H),4.85(s,1H),4.34–4.21(m,1H),4.09(dd,J=12.3,1.6Hz,1H),4.01(dd,J=6.0,4.0Hz,1H),3.80–3.73(m,1H),3.66–3.57(m,6H),3.55–3.45(m,5H),2.63(s,6H),2.15(s,3H),2.10(s,3H),2.03(s,3H),2.02(s,3H),1.99(s,3H).
13C NMR(151MHz,CDCl3)δ170.62,170.21,169.97,169.83,169.69,129.98,129.88,129.84,129.69,127.50,127.49,127.45,120.34,120.32,97.68,70.51,70.09,70.00,69.52,69.04,68.38,67.34,66.12,62.38,49.95,25.51,25.49,20.85,20.71,20.66,20.65,14.98,14.08.
HRMS[M–H]–m/z.for[C33H43BF2N3O13]–738.2862,found 738.2862.
化合物F13的合成:
将B27(4mg,0.005mmol)加入到10mL反应瓶内,加入2mL的甲醇钠的甲醇溶液(0.05M)。然后在室温(25℃)下搅拌0.5h,经TLC确认反应完全后,加入安伯莱特离子交换树脂IR120(H+型),继续搅拌直到反应液变为中性;过滤去除安伯莱特离子交换树脂IR120(H+型),甲醇洗涤(5mL×3),有机相浓缩后,经HPLC制备柱制备后,得橙红色固体化合物F13(2mg),收率:70%。
1H NMR(400MHz,D2O)δ7.12(d,J=3.9Hz,2H),6.40(d,J=4.1Hz,2H),4.03–3.88(m,2H),3.82–3.70(m,2H),3.70–3.60(m,3H),3.62–3.53(m,3H),3.48(d,J=17.5Hz,5H),3.34(s,4H),2.48(s,6H),1.94(s,3H).
13C NMR(201MHz,D2O)δ173.70,160.41,138.32,137.61,128.60,121.01,99.87,72.65,70.47,69.92,69.59,69.56,69.19,68.47,66.64,66.31,60.82,49.96,21.59,14.21.
HRMS[M+H]+m/z calcd.for[C25H37BF2N3O9]+572.2585,found 572.2582.
以下通过实验例证明本发明的有益效果。
实验例1、本发明化合物荧光染料的光学性能
对本发明化合物,以及文献报道的其它BODIPY荧光染料的光学性能(包括发射波长λex、吸收波长λem、摩尔消光系数ε、斯托克斯位移Δλ、荧光量子产率Φ),结果如表1所示。
作为对比的文献报道的BOIDIPY荧光染料D1~D4的结构如下所示:
表1、C-8位N-酰基BODIPY染料的光学性能结果
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*发射波长超出仪器量程,未检测出结果(ND)。
从上表可以看出:I.对于C-8位N-酰基修饰的荧光染料F1-F4而言:(1)最大吸收和发射波长分别位于520-525nm和529-538nm,为可见光谱范围的染料;(2)具有较高的量子产率(ΦF=0.50-0.99)和较高的摩尔消光系数(ε=5×104-9×104M-1cm-1),斯托克斯位移为9-10nm;(3)与C-8位为苯基或甲基的BODIPY荧光染料(D1、D2)相比:最大吸收和发射波长分别红移约10-20nm,量子产率相比D1增加约3倍,摩尔消光系数和斯托克斯位移与D1、D2相当;
II.对于C-8位N-酰基修饰的荧光染料F5-F9而言:(1)最大吸收和发射波长分别位于673-773nm和693-902nm,为近红外光谱范围的染料;(2)所有新型染料均有较高的量子产率(ΦF=0.22-0.50)和较高的摩尔消光系数(ε=7×104-16×104M-1cm-1),斯托克斯位移为20-129nm;(3)与3,5位苯环上取代基为对甲氧基的荧光染料D3相比:3,5位相同取代基的荧光染料F5-F7的最大吸收与发射波长均红移约50nm,量子产率相当;摩尔消光系数由8×104变为16×104M-1cm-1,最高可增加2倍;斯托克斯位移由15nm变为最大29nm,增加约2倍;(3)与3,5位苯环上取代基为N,N-二甲基的荧光染料D4相比:3,5位相同取代基的荧光染料F9的最大吸收与发射波长分别红移约70nm与150nm,斯托克斯位移由29nm变为最大129nm,增加约4倍;
III.对于C-8位取代基为叠氮和炔基的荧光染料F10-F11而言:最大吸收和发射波长分别位于689-691nm和721-722nm,量子产率和摩尔消光系数分别为0.30和8×104M-1cm-1左右,斯托克斯位移为95-133nm,光学性能与染料F5-F9类似。
上述结果说明,本发明对BODIPY的C-8进行N-酰基化修饰,能够有效调控染料的光学性能,本发明制备的C-8位N-酰基化修饰的化合物,吸收光谱从可见光覆盖到近红外区域,具有优异的光学性能,斯托克斯位移大,荧光量子产率、摩尔消光系数高;本发明的修饰方法可以兼容不同的生物正交基团(叠氮和炔基),且不降低BODIPY的荧光性能。
实验例2、本发明化合物荧光染料的脂水分配系数
脂水分配系数(lipid-water partition coefficient)为化合物在脂相(通常选用正辛醇)和水相间达到热力学平衡时的浓度比值。脂水分配系数越大,表明化合物越易溶于脂相,反之则越易溶于水相。经典的C-8位苯基及甲基修饰的BODIPY荧光染料D1和D2(见实验例1给出的结构式)的水溶性较差,模拟的脂水分配系数(CLogP)分别为5.049和4.010(表2)。而我们利用多肽、单糖对BODIPY的C-8位进行N-酰基化修饰,设计合成的BODIPY荧光染料(F12和F13),F12和F13的CLogP分别为1.747和1.341(表2),远远小于荧光染料D1和D2的CLogP值,有效提高了BODIPY染料的水溶性,使其能够达到理想的脂水分配比例,有望拓展其在生物医学领域的应用。
表2-4BODIPY荧光染料的脂水分配系数
注:[a]CLogP值为通过chembiodraw模拟的荧光染料的脂水分配系数。
进一步通过实验测试了BODIPY荧光染料F12和F13在水相的pH为7.4时测定的脂水分配系数(LogD7.4),当Log D7.4<1时说明化合物极性较大,具有很高的水溶性。
实验结果表明,多肽及单糖修饰的N-酰基BODIPY荧光染料(F12和F13)和C-8位苯基及甲基修饰的BODIPY荧光染料(D1和D2)的脂水分配系数测量结果如图1所示:F12的LogD7.4为0.079,F13的LogD7.4为-0.930。
可见,本发明在C-8位引入多肽及单糖得到的BODIPY荧光染料(F12和F13)水溶性较好,与C-8位为苯基或甲基的BODIPY荧光染料(D1、D2)相比,水溶性得到明显提升,为设计合成合理脂水分配系数的靶向荧光染料提供了新途径。
综上,本发明提供了一种C-8位酰基化修饰的新型BODIPY染料,吸收光谱从可见光到近红外光谱范围,与现有技术报道的C-8位为苯基修饰的BODIPY荧光染料相比,吸收和发射波长红移,摩尔消光系数提高,斯托克斯位移增加,综合光学性能优异,具有很好的应用前景;并且,本发明的修饰方法可以在兼容不同的生物正交基团的同时不影响BODIPY的荧光性能,还可进一步兼容氨基酸、糖类修饰以改善BODIPY的水溶性,为设计合成性质优异的新型荧光染料提供了途径。
Claims (6)
1.式I所示的化合物或其盐:
其中R1为甲基或三氟甲基;
R2为甲基、苄基、
R3为甲基、
2.如权利要求1所述的化合物或其盐,其特征在于,所述化合物具有式II所示结构:
3.一种化合物,其特征在于,所述化合物具有如下结构:
4.权利要求1所述的化合物的制备方法,其特征在于,包括如下步骤:
(1)以化合物A为原料,与化合物B在室温下反应制得化合物C;
(2)化合物C与化合物D在有机碱作用下室温反应得到化合物E即为所述化合物;
或化合物E与化合物F在催化剂作用下于100~120℃反应制得化合物G即为所述化合物;
反应式如下:
其中,X为卤素;
Rd、Re为R’为/>
5.如权利要求4所述的制备方法,其特征在于,步骤(2)所述有机碱为三乙胺;步骤(3)所述催化剂为哌啶和冰醋酸。
6.权利要求1~3任一项所述的化合物或其盐在制备荧光标记或生物成像试剂中的用途。
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