CN110835341B - 含四氢咔啉骨架氧化偶联重排产物及其制备方法和应用 - Google Patents
含四氢咔啉骨架氧化偶联重排产物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种含四氢咔啉骨架结构的氧化偶联重排产物及其制备方法和应用,利用过氧叔丁醇对复杂结构四氢咔啉类化合物进行氧化,然后将其与吲哚类化合物进行偶联,之后使其进行过氧化物重排反应,通过一种温和的过氧化物的重排条件,对四氢咔啉类衍生物进行末期官能团化。该制备方法简单,反应条件温和,收率高,实用性强,且所合成的化合物,其相对分子质量在500左右,该类骨架结构首次合成,具有显著的抗肿瘤活性,可用于开发成治疗乳腺癌、肺癌和宫颈癌的药物。
Description
技术领域
本发明属于药物化学领域,具体涉及一类含四氢咔啉骨架氧化偶联重排产物及其制备方法。
背景技术
四氢咔啉类衍生物具有广泛的生物学活性。它们能够抑制拓扑异构酶、细胞周期蛋白依赖性激酶和DNA的合成,能够嵌入到DNA中,这些作用使它们具有很强的抗肿瘤活性。四氢-β-咔啉类(THβCs)和四氢-γ-咔啉类(THγCs)生物碱作为优势骨架进行结构修饰获得的先导化合物,体外试验表明其具有很强的杀伤肿瘤细胞的作用。四氢咔啉类衍生物特有的骨架结构决定了它的化学反应性不易控制,我们前期对这些骨架结构进行了大量的末期官能团化研究工作,通过简洁的合成路线,合成处一系列THβCs或THγCs的衍生物,并显现出更强效、更有选择性的肿瘤细胞杀伤作用(Angew. Chem. Int. Ed. 2017, 56,14968–14972;Org. Lett. 2018, 20, 5457-5460;Org. Lett.2019, 21, 6160-6163;Org. Lett. 2019, 21, 7475-7477;Org. Lett. 2019, 21, 8884-8887;Adv. Synth. Catal.2019, 361,432-435)。
本发明通过氧化偶联重排反应得到一类含四氢咔啉骨架氧化偶联重排产物,利用过氧叔丁醇对复杂结构四氢咔啉类化合物进行氧化,然后将其与吲哚类化合物进行偶联,之后使其进行过氧化物重排反应,通过一种温和的过氧化物的重排条件,对四氢咔啉类衍生物进行末期官能团化。该制备方法简单,反应条件温和,收率高,实用性强,且所合成的化合物,其相对分子质量在500左右,该类骨架结构首次合成,具有显著的抗肿瘤活性,有望开发成治疗乳腺癌、肺癌和宫颈癌的药物。
发明内容
本发明的目的在于提供一类含四氢咔啉骨架氧化偶联重排产物及其制备方法和应用,制备方法简单,实验条件温和,不要求高温高压、强酸强碱等苛刻条件,且反应收率高。
为实现上述目的,本发明采用如下技术方案:
一类含四氢咔啉骨架氧化偶联重排产物及其制备方法,具有如下结构:
、或;在通式(一)和通式(二)中,当X = N,Y为C,R1 为H, R2为、、或 ,R3为H或Me,R4为H、Me、F、Cl、Br、OMe或t-Bu,R5为H、Me、F、Cl、Br、OMe或t-Bu;
四氢咔啉骨架氧化偶联重排产物的制备方法如下:
将原料溶解于溶剂中,加入抗坏血酸、硼氢化钠、甲磺酸得到四氢咔啉骨架氧化偶联吲哚的重排产物,反应收率一般在60%以上,个别产率可到达99%。
应用:所述的含四氢咔啉骨架氧化偶联重排产物在制备治疗乳腺癌、肺癌和宫颈癌的药物中的应用。
本发明的显著优点在于:
(1)本发明的合成方法简单,反应条件温和,能耗低,收率高,实用性强,不要求高温高压、强酸强碱等苛刻条件;反应时间短且收率一般可达到60%以上,部分化合物的收率可达到99%。
(2)所设计合成的四氢咔啉骨架结构的氧化偶联重排产物的分子量较小,一般在500左右,本发明得到的化合物有望用于制备相关的癌症治疗药物,同时也为其他同类化合物的合成提供新的解决思路和方案。
具体实施例
为了使本发明所述的内容更加便于理解,下面结合具体实施方式对本发明所述的技术方案做进一步的说明,但是本发明不仅限于此。
原料的合成:
通用步骤:
将原料A(合成路线详见Angew. Chem. Int. Ed. 2017, 56, 14968–14972;Org. Lett. 2018, 20, 5457-5460;Org. Lett.2019, 21, 6160-6163;Org. Lett. 2019, 21,7475-7477;Org. Lett. 2019, 21, 8884-8887;Adv. Synth. Catal. 2019, 361,432-435)溶于乙腈(CH3CN)中,缓慢加入0.025 当量的酞菁铁(FePc)和1.5当量的醋酸(AcOH),在5 ℃下反应3-5 min后,加入2.0 当量的60%叔丁基过氧化氢的水溶液(aq. t-BuOOH),监测反应完全后,用乙酸乙酯/水(EtOAc/H2O = 1:1)萃取3次,收集有机相,将得到的有机相干燥、旋干,过硅胶柱层析分离得到中间体Int。将中间体Int溶解在乙腈(CH3CN)中,加入各种取代的吲哚(1.2 当量)和0.1 当量的1 mol/L盐酸乙腈溶液中(1N HCl/ CH3CN),在室温下搅拌反应5-10 min,监测反应完全后,将反应液抽滤得到原料B。
实施例1;化合物1的制备
(1)根据通用步骤得到原料B1物理状态:白色固体;熔点: 223.4 – 224.1 oC.
TLC: Rf = 0.46 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 10.76 (s, 1H), 7.72 (s, 1H), 7.65 (d, J =7.6 Hz, 2H), 7.44 (d, J = 7.7 Hz, 2H), 7.29 (d, J = 7.3 Hz, 1H), 7.17 (s,1H), 7.16 – 7.15 (m, 1H), 7.14 (s, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.70 (d, J = 7.3 Hz, 1H), 4.06 (d, J = 11.8 Hz, 1H), 2.84 (t,J = 10.6 Hz, 1H), 2.75 (d, J = 11.9 Hz, 1H), 2.61 (d, J = 14.2 Hz, 1H), 2.40(s, 3H), 2.30 (s, 3H), 2.07 (d, J = 1.5 Hz, 1H), 1.78 – 1.70 (m, 1H), 0.78(s, 9H).
13C NMR (101 MHz, DMSO-d 6 ) δ 151.04, 144.08, 135.01, 133.26, 130.42(2C), 130.02, 128.13, 127.80 (2C), 126.60, 126.21, 124.32, 123.33, 122.86,117.15, 113.15, 111.01, 110.63, 88.17, 79.79, 67.43, 46.50, 44.56, 37.68,31.77, 26.12 (3C), 21.73, 21.50.
HRMS (ESI): calcd for C31H35N3O4S [M + H]+ m/z 546.2421, found546.2437.
(2)化合物1的制备:
将73 mg B1溶于甲醇中,加入111 mg Vc。该反应体系在此条件下搅拌24 h后,将反应物抽滤、干燥后得到44 mg白色固体(化合物1),反应收率为66%。
物理状态:白色固体;熔点:223.4–224.1 oC.
TLC: Rf = 0.46 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 8.68 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H),7.94 (d, J = 6.3 Hz, 3H), 7.83 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.55 (t, J= 7.4 Hz, 1H), 7.42 (s, 3H), 7.08 (s, 1H), 5.08 (s, 4H), 2.54 (s, 3H), 2.34(s, 3H).
13C NMR (101 MHz, DMSO-d 6) δ 151.18, 147.47, 144.20, 142.68, 135.52,133.69, 130.48, 130.06, 129.47, 129.04, 128.65, 128.02, 126.90, 126.77,126.09, 124.56, 124.46, 123.04, 121.03, 114.05, 111.82, 55.41, 53.30, 22.09,21.39.
HRMS (ESI): calcd for C27H23N3O2S [M + H]+ m/z 454.1584, found 454.1616.
实施例2;化合物2的制备
(1)根据通用步骤得到原料B2物理状态:白色固体;熔点: 220.1 – 220.8 oC.
TLC: Rf = 0.58 (PE/EtOAc = 2:1).
1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 7.8Hz, 2H), 7.48 (d, J = 7.3 Hz, 1H), 7.29 (d, J = 7.9 Hz, 2H), 7.25 (s, 1H),7.23 (s, 1H), 7.21 – 7.19 (m, 1H), 7.17 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 7.4Hz, 1H), 7.01 (s, 1H), 6.84 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 7.7 Hz, 1H),4.36 (d, J = 12.3 Hz, 1H), 3.69 (s, 3H), 3.50 – 3.44 (m, 1H), 3.18 (d, J =12.2 Hz, 1H), 2.87 (t, J = 10.3 Hz, 1H), 2.64 (d, J = 13.9 Hz, 1H), 2.43 (s,3H), 2.05 – 1.99 (m, 1H), 0.81 (s, 9H).
13C NMR (101 MHz, DMSO-d 6) δ 144.08, 137.02, 133.89, 130.48 (2C),130.32, 129.97, 129.05, 127.91, 127.69 (2C), 126.70, 123.25, 121.56, 121.41,120.73, 119.31, 118.57, 110.05, 109.73, 87.97, 79.94, 67.94, 46.24, 43.84,37.39, 32.88, 26.20 (3C), 21.50.
HRMS (ESI): calcd for C31H35N3O4S[M + H]+ m/z 546.2421, found 546.2437.
(2)化合物2的制备:
将65 mg B2溶于甲醇中,加入105 mg Vc。该反应体系在此条件下搅拌24 h后,将反应物抽滤、干燥后得到40 mg白色固体(化合物2),反应收率为74%。
物理状态:白色固体;熔点:220.1–220.8 oC.
TLC: Rf = 0.58 (PE/EtOAc = 2:1).
1H NMR (400 MHz, CHCl3) δ 8.84 (s, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.83(d, J = 6.4 Hz, 2H), 7.68 (s, 1H), 7.49 (d, J = 19.8 Hz, 2H), 7.39 – 7.22 (m,6H), 4.98 (s, 4H), 3.87 (s, 3H), 2.36 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 150.32, 147.75, 143.99, 142.05, 137.42,134.02, 130.05, 129.69, 129.59, 129.46, 127.42, 127.08, 126.60, 125.96,123.31, 123.12, 123.02, 121.31, 121.17, 114.51, 109.26, 55.18, 52.97, 33.31,21.48.
HRMS (ESI): calcd for C27H23N3O2S[M + H]+ m/z 454.1584, found 454.1612.
实施例3;化合物3的制备
(1)根据通用步骤得到原料B3物理状态:浅黄色固体;熔点:134.9 – 135.6 oC.
TLC: Rf = 0.29 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.15 (s, 1H), 7.93 (s, 1H), 7.65 (d, J =7.8 Hz, 2H), 7.44 (d, J = 7.8 Hz, 2H), 7.32 (s, 1H), 7.30 (s, 1H), 7.28 (d, J= 2.0 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.03 – 6.98 (m, 1H), 6.76 (d, J =7.6 Hz, 1H), 6.72 (d, J = 7.3 Hz, 1H), 4.19 (d, J = 11.9 Hz, 1H), 3.48 – 3.42(m, 1H), 2.82 (t, J = 11.5 Hz, 1H), 2.61 (d, J = 11.8 Hz, 1H), 2.56 (s, 1H),2.40 (s, 3H), 2.07 (d, J = 1.9 Hz, 1H), 1.78 – 1.69 (m, 1H), 0.75 (s, 9H).
13C NMR (101 MHz, DMSO-d 6) δ 150.86, 144.10, 135.00, 133.40, 130.44(2C), 130.21, 129.18, 127.89, 127.76 (2C), 126.65, 125.96, 123.01, 122.97,121.19, 117.43, 113.49, 112.81, 110.81, 88.02, 79.82, 67.17, 46.14, 44.56,37.95, 31.77, 26.11, 21.51.
HRMS (ESI): calcd for C30H32ClN3O4S[M + H]+ m/z 566.1875, found566.1896.
(2)化合物3的制备:
将68 mg B3溶于甲醇中,加入105 mg Vc。该反应体系在此条件下搅拌20 h后,将反应物抽滤、干燥后得到40 mg白色固体(化合物3),反应收率为71%。
物理状态:白色固体;熔点: 247.6 - 248.3 oC.
TLC: Rf = 0.38 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.92 (s, 1H), 8.87 (s, 1H), 8.03 (d, J =8.7 Hz, 2H), 7.90 (s, 2H), 7.80 (s, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.53 (d, J= 8.7 Hz, 2H), 7.36 (s, 2H), 7.24 (s, 1H), 5.04 (s, 4H), 2.29 (s, 3H).
13C NMR (101 MHz, DMSO-d 6) δ 150.49, 147.26, 144.23, 143.04, 135.65,133.57, 130.49, 130.27, 128.95, 128.06, 127.67, 126.73, 126.38, 125.59,124.68, 124.65, 122.94, 122.43, 121.13, 114.10, 113.79, 55.29, 53.28, 21.40.
HRMS (ESI): calcd for C26H20ClN3O2S[M + H]+ m/z 474.1038, found474.1070.
实施例4;化合物4的制备
(1)根据通用步骤得到原料B4物理状态:浅黄色固体;熔点: 146.5 - 147.6 oC.
TLC: Rf = 0.28 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.11 (s, 1H), 8.07 (s, 1H), 7.64 (d, J =7.4 Hz, 2H), 7.45 (d, J = 7.5 Hz, 2H), 7.28 (s, 1H), 7.23 (s, 1H), 7.17 (t, J= 7.5 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 6.73 (d, J = 5.9 Hz, 1H), 6.73 –6.67 (m, 1H), 6.25 (s, 1H), 4.18 (d, J = 11.9 Hz, 1H), 2.82 (t, J = 11.0 Hz,1H), 2.57 (s, 1H), 2.54 (s, 1H), 2.41 (s, 3H), 2.07 (s, 1H), 1.72 (t, J =12.0 Hz, 1H), 0.74 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 143.71, 134.99, 134.83, 133.53, 130.04,129.78 (2C), 129.01, 128.74, 127.50 (2C), 126.86, 125.24, 124.61, 124.46,119.87, 112.75, 112.46, 112.39, 112.11, 88.09, 80.34, 67.44, 46.03, 43.61,37.17, 25.77 (3C), 21.42.
HRMS (ESI): calcd for C30H32BrN3O4S [M+ H]+m/z 610.1370, found610.1380.
(2)化合物4的制备:
将79 mg B4溶于甲醇中,加入114 mg Vc。该反应体系在此条件下搅拌20 h后,将反应物抽滤、干燥后得到54 mg白色固体(化合物4),反应收率为80%。
物理状态:白色固体;熔点: 246.5–247.4 oC.
TLC: Rf = 0.35 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.91 (s, 1H), 9.03 (s, 1H), 8.02 (d, J =9.0 Hz, 2H), 7.91 (d, J = 7.6 Hz, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.73 (t, J =7.5 Hz, 1H), 7.51 (m, J = 13.8, 7.7 Hz, 2H), 7.37 (d, J = 6.7 Hz, 3H), 5.04(s, 4H), 2.29 (s, 3H).
13C NMR (101 MHz, DMSO-d 6) δ 150.47, 147.27, 144.21, 143.05, 135.90,133.66, 130.47, 130.28, 130.04, 128.93, 128.34, 128.04, 126.77, 126.39,126.34, 125.47, 124.64, 121.16, 114.24, 113.93, 113.70, 55.28, 53.28, 21.40.
HRMS (ESI): calcd for C31H30N4O2[M + H]+ m/z 518.0532, found 518.0562.
实施例5;化合物5的制备
(1)根据通用步骤得到原料B5物理状态:黄色固体;熔点: 146.1 - 147.1 oC.
TLC: Rf = 0.38 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.00 (s, 1H), 7.89 – 7.84 (m, 1H), 7.64(d, J = 7.8 Hz, 2H), 7.44 (d, J = 7.7 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.22(s, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.04 (d, J = 9.9 Hz, 1H), 6.76 (s, 1H),6.74 (s, 1H), 6.71 (d, J = 8.5 Hz, 1H), 4.16 (d, J = 11.9 Hz, 1H), 3.44 –3.37 (m, 1H), 2.82 (t, J = 10.7 Hz, 1H), 2.71 (d, J = 12.0 Hz, 1H), 2.57 (d,J = 14.2 Hz, 1H), 2.41 (s, 3H), 2.07 (t, J = 1.6 Hz, 1H), 1.78 – 1.69 (m,1H), 0.72 (s, 9H).
13C NMR (101 MHz, DMSO-d 6) δ 158.94 (d, J = 234.1 Hz), 144.06, 136.39(d, J = 12.5 Hz), 133.51, 130.43 (2C), 130.17, 127.98, 127.76 (2C), 126.63,124.81, 124.75 (d, J = 2.9 Hz), 124.48 (d, J = 9.9 Hz), 117.42, 113.94,110.75, 106.66 (d, J = 23.3 Hz), 97.11 (d, J = 24.9 Hz), 87.94, 79.73, 67.25,46.24, 44.27, 37.74, 31.78, 26.23 (3C), 21.51.
HRMS (ESI): calcd for C30H32FN3O4S[M + H]+ m/z 550.2170, found 550.2203.
(2)化合物5的制备:
将77 mg B5溶于甲醇中,加入123 mg Vc。该反应体系在此条件下搅拌22 h后,将反应物抽滤、干燥后得到50 mg白色固体(化合物5),反应收率为78%。
物理状态:白色固体;熔点: 247.6–248.5 oC.
TLC: Rf = 0.47 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.76 (s, 1H), 8.93 – 8.79 (m, 1H), 8.05(d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.91 (d, J = 7.5 Hz, 2H), 7.78 (d, J = 8.1Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.37 (d, J = 7.7Hz, 2H), 7.28 (d, J = 9.7 Hz, 1H), 7.05 (t, J = 9.2 Hz, 1H), 5.03 (s, 4H),2.29 (s, 3H).
13C NMR (101 MHz, DMSO-d 6) δ 150.60, 147.35, 144.23, 142.93, 137.11,133.66, 130.49, 130.17, 129.26, 129.04, 128.04, 126.78, 126.32, 124.62,123.41, 121.16, 114.51, 109.39, 109.15, 98.30, 98.04, 55.33, 53.29, 21.41.
HRMS (ESI): calcd for C26H20FN3O2S[M + H]+ m/z 458.1333, found 458.1363.
实施例6;化合物6的制备
(1)根据通用步骤得到原料B6物理状态:黄色固体;熔点: 218.9 – 219.5 oC.
TLC: Rf = 0.53 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.00 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H),7.65 (d, J = 7.6 Hz, 2H), 7.44 (s, 1H), 7.42 (s, 1H), 7.31 (d, J = 7.6 Hz,2H), 7.27 (s, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.91 (t, J = 7.2 Hz, 1H), 6.83(d, J = 6.9 Hz, 1H), 6.41 (s, 1H), 4.35 (d, J = 11.8 Hz, 1H), 2.72 (d, J =12.2 Hz, 1H), 2.67 (d, J = 10.5 Hz, 1H), 2.58 (s, 1H), 2.40 (s, 3H), 2.07 (s,1H), 1.78 – 1.70 (m, 1H), 1.31 (s, 9H), 0.72 (s, 9H).
13C NMR (101 MHz, DMSO-d 6) δ 154.06, 154.01, 144.17, 138.12, 136.55,133.82, 130.49 (2C), 128.14, 127.66 (2C), 127.35, 126.70, 125.58, 123.92,122.11, 121.79, 118.99, 111.95, 88.22, 80.35, 67.43, 46.01, 43.65, 34.71,31.85 (3C), 31.75, 31.23, 26.00 (3C), 21.49.
HRMS (ESI): calcd for C34H41N3O4S[M + H]+ m/z 588.2891, found 588.2894.
(2)化合物6的制备:
将294 mg B6溶于甲醇中,加入440 mg Vc。该反应体系在此条件下搅拌36 h后,将反应物抽滤、干燥后得到186 mg白色固体(化合物6),反应收率为75%。
物理状态:白色固体;熔点: 218.9 – 219.5 oC.
TLC: Rf = 0.53 (PE/EtOAc = 2:1).
1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.70 (d, J = 6.9 Hz, 1H), 8.17(d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.80 (s, 1H), 7.47 (s, 1H),7.42 (d, J = 6.3 Hz, 1H), 7.36 (s, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.28 (d, J= 2.7 Hz, 1H), 5.06 (s, 2H), 4.95 (s, 2H), 2.37 (s, 3H), 1.44 (s, 9H).
13C NMR (101 MHz, DMSO-d 6) δ 150.36, 148.73, 145.97, 144.15, 142.66,137.13, 133.73, 130.47 (2C), 128.77, 128.73, 128.24, 128.20, 128.06 (2C),126.66, 123.33, 122.83, 120.80, 120.73, 119.41, 114.53, 112.11, 55.33, 53.33,35.27, 31.48 (3C), 21.42.
HRMS (ESI): calcd for C30H29N3O2S[M + H]+ m/z 496.2053, found 496.2054.
实施例7;化合物7的制备(1)根据通用步骤得到原料B7物理状态:黄色固体;熔点:144.2 – 145.1 oC. TLC:
Rf = 0.44 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 10.96 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H),7.65 (d, J = 7.7 Hz, 2H), 7.43 (d, J = 7.6 Hz, 2H), 7.28 (s, 1H), 7.13 (s,1H), 7.02 (s, 1H), 6.98 (s, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.0Hz, 1H), 4.27 (d, J = 13.7 Hz, 1H), 3.84 (s, 1H), 3.76 (s, 3H), 2.94 (d, J =12.3 Hz, 1H), 2.65 (d, J = 14.5 Hz, 1H), 2.40 (s, 3H), 2.36 (s, 3H), 2.07 (s,1H), 1.79 – 1.71 (m, 1H), 1.11 (s, 1H), 0.81 (s, 9H).
13C NMR (101 MHz, DMSO-d 6) δ 144.41, 144.27, 137.62, 137.03, 133.55,133.45, 130.96, 130.55, 130.51 (2C), 128.05, 127.67 (2C), 127.23, 121.38,120.95, 116.16, 112.76, 111.80, 88.07, 80.54, 67.44, 56.71, 56.22, 46.30,43.39, 31.75, 26.66, 26.17, 21.70, 21.50, 21.42.
HRMS (ESI): calcd for C32H37N3O5S[M + H]+ m/z 576.2527, found 576.2530.
(2)化合物7的制备:
将288 mg B7溶于甲醇中,加入440 mg Vc。该反应体系在此条件下搅拌24 h后,将反应物抽滤、干燥后得到193 mg白色固体(化合物7),反应收率为80%。
物理状态:白色固体;熔点: 217.8 – 218.5 oC.
TLC: Rf = 0.44 (PE/EtOAc = 2:1).
1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 8.1 Hz, 1H), 8.48 (s, 1H), 8.10(d, J = 9.0 Hz, 1H), 7.83 (d, J = 7.4 Hz, 2H), 7.37 (d, J = 2.4 Hz, 1H), 7.35(d, J = 6.2 Hz, 1H), 7.31 (d, J = 7.6 Hz, 2H), 7.22 (s, 1H), 7.09 (s, 1H),6.78 (d, J = 2.5 Hz, 1H), 5.00 (d, J = 3.1 Hz, 2H), 4.96 (d, J = 3.1 Hz, 2H),3.93 (s, 3H), 2.49 (s, 3H), 2.38 (s, 3H).
13C NMR (101 MHz, DMSO-d 6) δ 157.33, 148.53, 144.23, 143.18, 141.70,137.52, 133.72, 131.88, 130.51 (2C), 128.01 (2C), 127.21, 126.91, 124.49,123.00, 122.47, 122.27, 121.92, 114.36, 111.85, 103.06, 99.98, 56.15, 55.38,53.44, 21.87, 21.41.
HRMS (ESI): calcd for C28H25N3O3S[M + H]+ m/z 484.1689, found 484.1694.
实施例8;化合物8的制备
(1)根据通用步骤得到原料B8
物理状态:白色固体;熔点: 140.9 – 141.5 oC
TLC: Rf = 0.48 (PE/EtOAc = 4:1)
1H NMR (400 MHz, DMSO-d 6) δ 10.92 (s, 1H), 7.83 (s, 1H), 7.78 (d, J =2.5 Hz, 1H), 7.56 (d, J = 7.5 Hz, 2H), 7.38 (d, J = 7.6 Hz, 2H), 7.22 (d, J =8.1 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.87 (d, J =8.2 Hz, 1H), 6.65 (d, J = 7.7 Hz, 1H), 6.61 (t, J = 7.2 Hz, 1H), 6.25 (s,1H), 4.13 (d, J = 11.6 Hz, 1H), 3.82 (d, J = 10.1 Hz, 1H), 2.75 (d, J = 13.0Hz, 1H), 2.34 (s, 3H), 2.29 (s, 3H), 2.10 (t, J = 12.1 Hz, 1H), 1.94 (d, J =13.2 Hz, 1H), 1.89 (s, 1H), 0.65 (s, 9H).
13C NMR (101 MHz, DMSO-d 6) δ 151.23, 144.42, 134.52, 132.44, 130.54(2C), 130.32, 128.80, 127.78 (2C), 127.24, 126.42, 125.98, 124.35, 123.67,122.75, 117.03, 112.71, 110.87, 110.58, 88.24, 79.26, 67.38, 56.92, 44.58,27.36, 25.99 (3C), 21.76, 21.48.
HRMS (ESI):calcd for C31H35N3O4S [M + H]+ m/z 546.2421, found 546.2415.
(2)化合物8的制备:
将55 mg B8溶于甲醇中,加入70 mg Vc。该反应体系在此条件下搅拌60 h后,将反应物抽滤、干燥、过柱得到44 mg白色固体(化合物8),反应收率为97%。
物理状态:白色固体;熔点: 149.8-150.7 oC.
TLC: Rf = 0.20 (PE/EtOAc = 2:1).
1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.62 (s, 1H), 8.29 (s, 1H),8.22 (d, J = 8.4 Hz, 1H), 7.68 – 7.63 (m, 1H), 7.38 (d, J = 5.6 Hz, 2H), 7.28(s, 1H), 7.27 (s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H),6.98 (d, J = 7.6 Hz, 2H), 4.19 (t, J = 6.8 Hz, 2H), 2.55 (s, 3H), 2.47 (t, J= 6.8 Hz, 2H), 2.28 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 150.50, 147.14, 144.43, 143.66, 134.60,134.53, 133.28, 130.01, 129.38 (2C), 129.33, 129.21, 128.98, 128.00 (2C),126.56, 125.58, 123.88, 123.51, 123.23, 122.34, 114.50, 111.04, 52.53, 27.72,21.96, 21.52.
HRMS (ESI): calcd for C27H23N3O2S [M + H]+ m/z 454.1584, found 454.1582.
实施例9;化合物9的制备(1)根据通用步骤得到原料B9物理状态:白色固体;熔点:150.6 - 151.1 oC.
TLC: Rf = 0.54 (PE/EtOAc = 4:1).
1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.60– 7.57 (m, 2H), 7.30 (d, J = 8.2 Hz, 1H), 7.28 – 7.25 (m, 2H), 7.25 – 7.24(m, 1H), 7.23 (s, 1H), 7.21 – 7.19 (m, 1H), 7.18 – 7.15 (m, 1H), 7.03 (t, J =7.5 Hz, 1H), 6.76 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 7.8 Hz, 1H), 4.16 (d, J =9.6 Hz, 1H), 3.92 (d, J = 11.1 Hz, 1H), 3.81 (s, 3H), 2.85 – 2.79 (m, 1H),2.39 (s, 3H), 2.36 – 2.30 (m, 1H), 2.27 – 2.23 (m, 1H), 2.23 – 2.21 (m, 1H),0.71 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 149.75, 143.80, 136.53, 133.02, 129.94,129.91 (2C), 128.98, 128.54, 127.66, 127.57 (2C), 126.36, 123.52, 121.23,118.42, 117.94, 111.43, 110.77, 108.83, 87.93, 79.51, 67.32, 56.79, 44.08,33.01, 27.45, 25.91 (3C), 21.57.
HRMS (ESI): calcd for C31H35N3O4S[M + H]+ m/z 546.2421, found 546.2430.
(2)化合物9的制备:
将82 mg B9溶于甲醇中,加入106 mg Vc。该反应体系在此条件下搅拌9 h后,将反应物抽滤、干燥、过柱得到56 mg黄色固体(化合物9),反应收率为83%。物理状态:黄色固体;熔点: 196.8–197.6 oC.
TLC: Rf = 0.22 (PE/EtOAc = 4:1).
1H NMR (400 MHz, CDCl3) δ 8.91 – 8.84 (m, 1H), 8.28 (s, 1H), 8.19 (d,J = 8.4 Hz, 1H), 7.69 – 7.62 (m, 1H), 7.37 (d, J = 3.8 Hz, 2H), 7.34 (d, J =3.3 Hz, 1H), 7.31 (s, 1H), 7.30 (s, 1H), 7.27 (d, J = 6.8 Hz, 2H), 7.01 (s,1H), 6.99 (s, 1H), 4.23 (t, J = 7.2 Hz, 2H), 3.88 (s, 3H), 2.50 (t, J = 7.1Hz, 2H), 2.30 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 150.13, 147.22, 144.38, 143.51, 137.19,134.36, 133.44, 133.03, 129.40, 129.33 (2C), 129.16, 128.07 (2C), 127.18,125.47, 123.40, 123.25, 123.13, 122.08, 120.79, 113.76, 109.24, 52.62, 33.31,27.74, 21.55.
HRMS (ESI): calcd for C27H23N3O2S [M + H]+ m/z 454.1584, found 454.1582.
实施例10;化合物10的制备
(1)根据通用步骤得到原料B10
物理状态:白色固体;熔点: 144.5 – 145.2 o
TLC: Rf = 0.76 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.06 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H),7.79 (s, 1H), 7.55 (d, J = 7.7 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 7.33 (d, J= 8.1 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), 7.02 (d, J= 7.7 Hz, 1H), 6.87 (t, J = 7.4 Hz, 1H), 6.64 (d, J = 8.1 Hz, 1H), 6.60 (t, J= 7.3 Hz, 1H), 6.24 (s, 1H), 4.09 (d, J = 11.6 Hz, 1H), 3.81 (d, J = 10.1 Hz,1H), 2.75 (d, J = 13.3 Hz, 1H), 2.32 (s, 3H), 2.07 (t, J = 12.1 Hz, 1H), 1.98– 1.91 (m, 1H), 1.89 (d, J = 11.4 Hz, 1H), 0.60 (s, 9H).
13C NMR (101 MHz, DMSO-d 6) δ 151.19, 144.52, 136.05, 132.30, 130.53(2C), 130.39, 128.44, 127.78 (2C), 127.14, 126.42, 123.98, 123.70, 121.28,118.11, 117.20, 113.32, 111.31, 110.63, 88.03, 79.29, 67.38, 56.93, 44.53,27.32, 26.08 (3C), 21.42.
HRMS (ESI): calcd for C30H33N3O4S[M + H]+ m/z 532.2265, found 532.2273.
(2)化合物10的制备:
将74 mg B10溶于甲醇中,加入99 mg Vc。该反应体系在此条件下搅拌11 h后,将反应物抽滤、干燥、过柱得到43 mg黄色固体(化合物10),反应收率为71%。物理状态:黄色固体;熔点: 213.9–214.8 oC。
Rf = 0.39 (PE/EtOAc = 2:1).
1H NMR (400 MHz, CDCl3) δ 8.86 (d, J = 7.8 Hz, 1H), 8.58 (s, 1H), 8.39(d, J = 2.6 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.69 – 7.64 (m, 1H), 7.40 (s,1H), 7.39 (d, J = 2.3 Hz, 1H), 7.37 (d, J = 6.9 Hz, 1H), 7.30 (s, 1H), 7.29(s, 2H), 7.23 (s, 1H), 7.01 (d, J = 7.6 Hz, 2H), 4.23 (t, J = 7.0 Hz, 2H),2.49 (t, J = 7.1 Hz, 2H), 2.30 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 150.23, 147.18, 144.44, 143.55, 136.18,134.54, 133.30, 129.51, 129.41 (2C), 129.20, 128.61, 128.06 (2C), 126.42,125.67, 123.42, 123.25, 122.91, 122.40, 120.95, 115.24, 111.20, 52.63, 27.69,21.55.
HRMS (ESI): calcd for C26H21N3O2S [M + H]+ m/z 440.1427, found 440.1427.
实施例11;化合物11的制备
(1)根据通用步骤得到原料B11
物理状态:白色固体;熔点: 147.9 – 148.6 oC.
TLC: Rf = 0.51 (PE/EtOAc = 4:1).
1H NMR (400 MHz, DMSO-d 6) δ 10.89 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H),7.72 (s, 1H), 7.55 (d, J = 7.7 Hz, 2H), 7.37 (d, J = 7.7 Hz, 2H), 7.15 (s,1H), 7.13 (s, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.64(d, J = 8.7 Hz, 1H), 6.59 (d, J = 7.3 Hz, 1H), 6.25 (s, 1H), 4.09 (d, J =11.6 Hz, 1H), 3.82 (d, J = 10.2 Hz, 1H), 2.76 (d, J = 13.2 Hz, 1H), 2.36 (s,3H), 2.33 (s, 3H), 2.09 (t, J = 12.1 Hz, 1H), 1.97 (d, J = 10.2 Hz, 1H), 1.90(d, J = 11.8 Hz, 1H), 0.63 (s, 9H).
13C NMR (101 MHz, DMSO-d 6) δ 151.28, 144.40, 136.50, 132.49, 130.53(2C), 130.30, 129.93, 127.76 (2C), 127.23, 126.50, 126.40, 123.39 (2C),119.84, 117.04, 113.17, 111.06, 110.55, 88.00, 79.19, 67.45, 56.97, 44.55,27.35, 26.17 (3C), 21.85, 21.47.
HRMS (ESI):calcd for C31H35N3O4S [M + H]+ m/z 546.2421, found 546.2415.
(2)化合物11的制备:
将109 mg B11溶于甲醇中,加入141mg Vc。该反应体系在此条件下搅拌31h后,将反应物抽滤、干燥、过柱得到73 mg黄色固体(化合物11),反应收率为80%。
物理状态:黄色固体;熔点: 157.7-158.3 oC.
TLC: Rf = 0.20 (PE/EtOAc = 2:1).
1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 8.1 Hz, 1H), 8.54 (s, 1H), 8.28(s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.68 – 7.63 (m, 1H), 7.38 (s, 1H), 7.37(d, J = 1.9 Hz, 1H), 7.28 (d, J = 7.8 Hz, 2H), 7.11 (s, 1H), 7.08 (s, 1H),6.99 (d, J = 7.7 Hz, 2H), 4.20 (t, J = 7.0 Hz, 2H), 2.47 (d, J = 7.8 Hz, 2H),2.45 (s, 3H), 2.29 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 150.38, 147.20, 144.38, 143.48, 136.63,134.51, 133.34, 132.01, 129.46, 129.38 (2C), 129.15, 128.13, 128.04 (2C),125.55, 124.22, 123.43, 123.23, 122.66, 122.47, 115.09, 111.20, 52.60, 27.68,21.72, 21.54.
HRMS (ESI): calcd for C27H23N3O2S [M + H]+ m/z 454.1584, found 454.1582.
实施例12;化合物12的制备
(1)根据通用步骤得到原料B12
物理状态:白色固体;熔点: 166.8 – 167.7 oC.
TLC: Rf = 0.58 (PE/EtOAc = 4:1).
1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.97 (d, J = 4.9 Hz, 1H), 7.95(s, 1H), 7.58 (d, J = 7.5 Hz, 2H), 7.26 (s, 2H), 7.24 (s, 1H), 7.21 (d, J =7.4 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 1.8 Hz, 1H), 6.94 (d, J =2.2 Hz, 1H), 6.74 (t, J = 7.4 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 4.15 (s,1H), 4.13 (s, 1H), 3.89 (d, J = 10.4 Hz, 1H), 2.79 (d, J = 13.3 Hz, 1H), 2.51(s, 3H), 2.39 (s, 3H), 2.31 (s, 1H), 2.22 (d, J = 4.4 Hz, 1H), 0.68 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 149.94, 143.82, 135.22, 132.91, 129.90(2C), 129.86, 127.59 (2C), 127.55 (2C), 126.28, 124.10, 122.01, 121.23,119.75, 118.91, 117.81, 113.53, 110.73, 87.87, 79.42, 67.21, 56.63, 44.05,27.39, 25.88 (3C), 21.54, 16.70.
HRMS (ESI): calcd for C31H35N3O4S [M + H]+ m/z 546.2421, found 546.2421.
(2)化合物12的制备:
将82 mg B12溶于甲醇中,加入106mg Vc。该反应体系在此条件下搅拌7h后,将反应物抽滤、干燥、过柱得到50 mg黄色固体(化合物12),反应收率为73%。
物理状态:黄色固体;熔点: 220.0–220.8 oC.
TLC: Rf = 0.74 (PE/EtOAc = 3:2).
1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.57 (s, 1H), 8.47 (d, J = 2.8Hz, 1H), 8.31 (d, J = 7.3 Hz, 1H), 7.70 – 7.66 (m, 1H), 7.42 (d, J = 4.0 Hz,2H), 7.28 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.7 Hz, 1H), 7.02 (s, 1H), 7.00(s, 1H), 4.26 (t, J = 7.2 Hz, 2H), 2.57 (t, J = 7.5 Hz, 2H), 2.42 (s, 3H),2.31 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 144.44, 135.71, 134.69, 133.34, 129.56,129.40 (2C), 128.64, 127.99 (4C), 125.90, 125.77, 123.46 (2C), 123.18, 123.07(2C), 121.19 (2C), 120.45, 120.35, 52.62, 27.87, 21.58, 16.57.
HRMS (ESI): calcd for C27H23N3O2S [M + H]+ m/z 454.1584, found 454.1582.
实施例13;化合物13的制备
(1)根据通用步骤得到原料B13
物理状态:白色固体;熔点: 156.0 - 156.8 oC.
TLC: Rf = 0.49 (PE/EtOAc = 4:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.21 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H),7.82 (s, 1H), 7.56 (s, 1H), 7.54 (s, 2H), 7.38 (d, J = 7.6 Hz, 2H), 7.15 (d,J = 7.2 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.65 (d,J = 8.3 Hz, 1H), 6.61 (d, J = 7.2 Hz, 1H), 6.30 (s, 1H), 4.09 (d, J = 11.6Hz, 1H), 3.83 (d, J = 10.0 Hz, 1H), 2.76 (d, J = 13.0 Hz, 1H), 2.34 (s, 3H),2.08 (t, J = 12.1 Hz, 1H), 2.01 – 1.92 (m, 1H), 1.89 (d, J = 11.9 Hz, 1H),0.61 (s, 9H).
13C NMR (101 MHz, DMSO-d 6) δ 151.16, 144.48, 136.97, 132.40, 130.55(2C), 130.40, 127.77 (2C), 127.62, 127.07, 126.40, 125.34, 124.93, 120.97,117.33, 114.01, 113.91, 113.80, 110.70, 87.93, 79.21, 67.23, 56.81, 44.56,27.31, 26.16 (3C), 21.48.
HRMS (ESI):calcd for C30H32BrN3O4S [M + H]+ m/z 610.1370, found610.1364.
(2)化合物13的制备:
将92 mg B13溶于甲醇中,加入106mg Vc。该反应体系在此条件下搅拌40 h后,将反应物抽滤、干燥、过柱得到39 mg黄色固体(化合物13),反应收率为50%。物理状态:白色固体;熔点: 156.5 – 157.3 oC.
TLC: Rf = 0.40 (PE/EtOAc = 2:1).
1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.64 (s, 1H), 8.21 (d, J = 2.6Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.69 – 7.65 (m, 1H), 7.41 (s, 1H), 7.39(s, 1H), 7.35 (s, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 6.8 Hz, 2H),7.01 (d, J = 7.6 Hz, 2H), 4.21 (t, J = 7.0 Hz, 2H), 2.49 (t, J = 7.0 Hz, 2H),2.30 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 149.64, 146.98, 144.62, 143.91, 136.96,134.49, 133.12, 129.49 (2C), 129.46, 129.36, 129.03, 127.97 (2C), 125.98,125.14, 124.05, 124.00, 123.53, 123.34, 115.83, 115.17, 114.24, 52.61, 27.72,21.59.
HRMS (ESI): calcd for C26H20BrN3O2S [M + H]+ m/z 518.0532, found518.0526.
实施例14;化合物14的制备
(1)根据通用步骤得到原料B14
物理状态:白色固体;熔点: 161.7 - 162.3 oC.
TLC: Rf = 0.26 (PE/EtOAc = 4:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.28 (s, 1H), 8.17 (s, 1H), 7.85 (s, 1H),7.56 (d, J = 7.4 Hz, 2H), 7.39 (d, J = 7.7 Hz, 2H), 7.33 (d, J = 8.6 Hz, 1H),7.21 – 7.15 (m, 1H), 7.14 (d, J = 6.1 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.68(d, J = 7.8 Hz, 1H), 6.63 (t, J = 7.3 Hz, 1H), 6.30 (s, 1H), 4.11 (d, J =11.8 Hz, 1H), 3.82 (d, J = 10.2 Hz, 1H), 2.76 (d, J = 13.2 Hz, 1H), 2.34 (s,3H), 2.08 (t, J = 12.1 Hz, 1H), 2.01 – 1.89 (m, 1H), 1.86 (s, 1H), 0.64 (s,9H).
13C NMR (101 MHz, DMSO-d 6) δ 151.10, 144.52, 134.75, 132.34, 130.58(2C), 130.47, 130.34, 127.78 (2C), 127.07, 126.43, 126.06, 125.61, 123.60,117.38, 113.27, 113.20, 111.10, 110.76, 88.16, 79.33, 67.14, 56.69, 44.59,27.28, 26.04 (3C), 21.48.
HRMS (ESI): calcd for C30H32BrN3O4S [M + H]+ m/z 610.1370, found610.1367.
(2)化合物14的制备:
将79 mg B14溶于甲醇中,加入92mg Vc。该反应体系在此条件下搅拌39 h后,将反应物抽滤、干燥、过柱得到34 mg黄色固体(化合物14),反应收率为50%。
物理状态:黄色固体;熔点: 168.5 – 169.4 oC.
TLC: Rf = 0.62 (PE/EtOAc = 3:2).
1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.67 (s, 1H), 8.43 (t, J = 1.9Hz, 1H), 8.27 (d, J = 8.5 Hz, 1H), 7.70 (t, J = 7.3 Hz, 1H), 7.45 (d, J = 7.9Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 7.7 Hz, 2H), 7.28 (s, 1H),7.23 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.9 Hz, 2H), 4.25 (t, J = 7.2 Hz, 2H),2.52 (t, J = 7.2 Hz, 2H), 2.33 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 149.56, 147.07, 144.65, 143.77, 134.77,134.39, 133.05, 129.56, 129.54, 129.51 (2C), 129.40, 128.01 (2C), 127.95,125.97, 125.39, 125.23, 123.42, 123.27, 114.76, 114.47, 112.66, 52.62, 27.66,21.59.
HRMS (ESI): calcd for C26H20BrN3O2S [M + H]+ m/z 518.0532, found518.0526.
实施例15;化合物15的制备
(1)根据通用步骤得到原料B1
B1核磁见实施例1
(2)化合物15的制备:
将109 mg B1溶于甲醇中,加入38 mg NaBH4。该反应体系在此条件下搅拌9 h后,将反应物抽滤、干燥、过柱得到88 mg黄色固体(化合物15),反应收率为93%。物理状态:黄色固体;熔点: 164.5–165.2 oC.
TLC: Rf = 0.41 (PE/EtOAc = 1:1).
1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.61(d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.18– 7.14 (m, 1H), 7.12 (d, J = 7.6 Hz, 2H), 7.03 (d, J = 8.2 Hz, 1H), 6.95 (s,1H), 6.76 – 6.69 (m, 1H), 6.57 (d, J = 8.3 Hz, 1H), 4.68 (s, 1H), 4.66 (s,1H), 3.66 (q, J = 7.6, 7.1 Hz, 1H), 3.53 (q, J = 8.1 Hz, 1H), 2.44 (d, J =2.2 Hz, 1H), 2.44 – 2.41 (m, 1H), 2.39 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 190.97, 148.36, 143.11, 136.08, 135.60,134.20, 129.24 (2C), 129.05, 128.17, 127.33 (2C), 124.66, 123.95, 122.99,118.78, 117.68, 115.35, 115.24, 113.32, 111.82, 67.25, 63.63, 45.80, 35.05,21.61, 21.53.
HRMS (ESI): calcd for C27H25N3O3S[M + H]+ m/z 472.1689, found 472.1718.
实施例16;化合物16的制备
(1)根据通用步骤得到原料B2
B2核磁见实施例2
(2)化合物16的制备:
将109 mg B2溶于甲醇中,加入38 mg NaBH4。该反应体系在此条件下搅拌24 h后,将反应物抽滤、干燥、过柱得到87 mg黄色固体(化合物16),反应收率为92%。物理状态:黄色固体;熔点: 229.4–229.9 oC.
TLC: Rf = 0.39 (PE/EtOAc = 1:1).
1H NMR (400 MHz, DMSO-d 6) δ 7.55 (d, J = 5.8 Hz, 2H), 7.54 (s, 1H),7.43 (s, 1H), 7.41 (s, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 7.9 Hz,2H), 7.21 (t, J = 7.8 Hz, 1H), 7.11 – 7.07 (m, 1H), 7.03 (d, J = 8.0 Hz, 1H),6.99 – 6.94 (m, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.66 (t, J = 7.7 Hz, 1H), 4.17(s, 1H), 3.70 (d, J = 7.8 Hz, 2H), 3.64 (s, 3H), 2.55 (s, 3H), 2.34 (d, J =7.2 Hz, 2H).
13C NMR (101 MHz, DMSO-d 6) δ 190.15, 149.79, 143.76, 138.01, 136.09,133.70, 129.94 (2C), 128.04, 127.78 (2C), 127.52, 124.91, 121.90, 119.47,119.40, 116.42, 115.63, 114.42, 112.43, 110.72, 67.75, 64.19, 47.64, 36.09,32.73, 21.59.
HRMS (ESI): calcd for C27H25N3O3S[M + H]+ m/z 472.1689, found 472.1724.
实施例17;化合物17的制备
(1)根据通用步骤得到原料B3
B3核磁见实施例3
(2)化合物17的制备:
将68 mg B3溶于甲醇中,加入23 mg NaBH4。该反应体系在此条件下搅拌25 h后,将反应物抽滤、干燥、过柱得到54 mg黄色固体(化合物17),反应收率为91%。物理状态:黄色固体;熔点: 248.5–249.2 oC.
TLC: Rf = 0.28 (PE/EtOAc = 1:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.16 (s, 1H), 7.65 (d, J = 6.9 Hz, 2H),7.50 (d, J = 7.7 Hz, 1H), 7.46 (s, 1H), 7.38 (d, J = 6.9 Hz, 2H), 7.34 (d, J= 8.1 Hz, 1H), 7.13 (s, 1H), 7.09 (d, J = 8.7 Hz, 1H), 7.06 (s, 1H), 6.84 (d,J = 8.4 Hz, 1H), 6.65 – 6.58 (m, 1H), 3.97 (s, 1H), 3.72 (d, J = 8.9 Hz, 1H),3.68 (d, J = 8.4 Hz, 1H), 2.43 (s, 3H), 2.36 – 2.29 (m, 1H), 2.22 (d, J =10.8 Hz, 1H).
13C NMR (101 MHz, DMSO-d 6) δ 190.22, 149.77, 144.11, 136.15, 136.10,133.30, 130.20 (2C), 127.86 (2C), 127.54, 125.83, 125.57, 124.11, 121.84,118.41, 116.57, 115.59, 114.62, 114.11, 112.93, 67.74, 64.62, 48.21, 36.27,21.68.
HRMS (ESI): calcd for C26H22ClN3O3S[M + H]+ m/z 492.1143, found492.1177.
实施例18;化合物18的制备
(1)根据通用步骤得到原料B18
物理状态:黄色固体;熔点: 146.5 - 147.6 oC.
TLC: Rf = 0.28 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.11 (s, 1H), 8.07 (s, 1H), 7.64 (d, J =7.4 Hz, 2H), 7.45 (d, J = 7.5 Hz, 2H), 7.28 (s, 1H), 7.23 (s, 1H), 7.17 (t, J= 7.5 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 6.73 (d, J = 5.9 Hz, 1H), 6.73 –6.67 (m, 1H), 6.25 (s, 1H), 4.18 (d, J = 11.9 Hz, 1H), 2.82 (t, J = 11.0 Hz,1H), 2.57 (s, 1H), 2.54 (s, 1H), 2.41 (s, 3H), 2.07 (s, 1H), 1.72 (t, J =12.0 Hz, 1H), 0.74 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 143.71, 134.99, 134.83, 133.53, 130.04,129.78 (2C), 129.01, 128.74, 127.50 (2C), 126.86, 125.24, 124.61, 124.46,119.87, 112.75, 112.46, 112.39, 112.11, 88.09, 80.34, 67.44, 46.03, 43.61,37.17, 25.77 (3C), 21.42.
HRMS (ESI): calcd for C30H32BrN3O4S[M + H]+ m/z 610.1370, found610.1380.
(2)化合物18的制备:
将79 mg B18溶于甲醇中,加入25mg NaBH4。该反应体系在此条件下搅拌24 h后,将反应物抽滤、干燥、过柱得到59 mg黄色固体(化合物18),反应收率为85%。
物理状态:黄色固体;熔点: 245.4–246.5 oC
TLC: Rf = 0.28 (PE/EtOAc = 1:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.21 (s, 1H), 7.64 (d, J = 7.5 Hz, 2H),7.49 (d, J = 8.1 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J = 7.9 Hz, 2H), 7.35 (s,1H), 7.32 (d, J = 9.1 Hz, 1H), 7.23 (s, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.11(s, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.61 (t, J = 7.2 Hz, 1H), 3.95 (s, 1H),3.71 (d, J = 8.7 Hz, 1H), 3.64 (q, J = 9.2, 7.8 Hz, 1H), 2.44 (s, 3H), 2.32(q, J = 7.3, 4.7 Hz, 1H), 2.26 – 2.17 (m, 1H).
13C NMR (101 MHz, DMSO-d 6) δ 190.23, 149.74, 144.10, 136.36, 136.10,133.23, 130.22 (2C), 127.83 (2C), 127.53, 126.28, 125.67, 124.39, 121.40,116.57, 115.58, 114.60, 114.56, 112.80, 112.11, 67.75, 64.61, 48.15, 36.25,21.77.
HRMS (ESI): calcd for C26H22BrN3O3S[M + H]+ m/z 536.0638, found536.0676.
实施例19;化合物19的制备
(1)根据通用步骤得到原料B19
物理状态:黄色固体;熔点: 146.1 - 147.1 oC
TLC: Rf = 0.38 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.00 (s, 1H), 7.89 – 7.84 (m, 1H), 7.64(d, J = 7.8 Hz, 2H), 7.44 (d, J = 7.7 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.22(s, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.04 (d, J = 9.9 Hz, 1H), 6.76 (s, 1H),6.74 (s, 1H), 6.71 (d, J = 8.5 Hz, 1H), 4.16 (d, J = 11.9 Hz, 1H), 3.44 –3.37 (m, 1H), 2.82 (t, J = 10.7 Hz, 1H), 2.71 (d, J = 12.0 Hz, 1H), 2.57 (d,J = 14.2 Hz, 1H), 2.41 (s, 3H), 2.07 (t, J = 1.6 Hz, 1H), 1.78 – 1.69 (m,1H), 0.72 (s, 9H).
13C NMR (101 MHz, DMSO-d 6) δ 158.94 (d, J = 234.1 Hz), 144.06, 136.39(d, J = 12.5 Hz), 133.51, 130.43 (2C), 130.17, 127.98, 127.76 (2C), 126.63,124.81, 124.75 (d, J = 2.9 Hz), 124.48 (d, J = 9.9 Hz), 117.42, 113.94,110.75, 106.66 (d, J = 23.3 Hz), 97.11 (d, J = 24.9 Hz), 87.94, 79.73, 67.25,46.24, 44.27, 37.74, 31.78, 26.23 (3C), 21.51.
HRMS (ESI): calcd for C30H32FN3O4S[M + H]+ m/z 550.2170, found 550.2203.
(2)化合物19的制备:
将77 mg B19溶于甲醇中,加入26mg NaBH4。该反应体系在此条件下搅拌7 h后,将反应物抽滤、干燥、过柱得到59 mg黄色固体(化合物19),反应收率为89%。物理状态:黄色固体;熔点: 147.6–148.3 oC.
TLC: Rf = 0.33 (PE/EtOAc = 1:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.00 (s, 1H), 7.55 (d, J = 7.6 Hz, 2H),7.49 (d, J = 7.8 Hz, 1H), 7.41 (s, 1H), 7.34 (s, 2H), 7.32 (s, 1H), 7.12 (d,J = 9.9 Hz, 1H), 7.05 (s, 1H), 7.02 – 6.97 (m, 1H), 6.80 (d, J = 8.4 Hz, 1H),6.74 (t, J = 9.0 Hz, 1H), 6.60 (t, J = 7.4 Hz, 1H), 4.03 (s, 1H), 3.65 (t, J= 7.1 Hz, 2H), 2.44 (s, 3H), 2.35 – 2.28 (m, 1H), 2.28 – 2.22 (m, 1H).
13C NMR (101 MHz, DMSO-d6) δ 190.16, 160.34, 158.01, 149.80, 143.93, δ137.59 (d, J = 12.6 Hz), 136.09, 133.67, 130.04 (2C), 127.77 (2C), 127.52,124.68, 124.65, 121.46, 120.26 (d, J = 10.1 Hz), 116.04 (d, J = 87.9 Hz),114.00 (d, J = 103.3 Hz), 107.75 (d, J = 24.2 Hz), 98.43 (d, J = 25.4 Hz),67.82, 64.34, 47.84, 36.12, 21.57.
19F NMR (376 MHz, DMSO-d 6) δ -121.65 (q, J = 9.4 Hz, 1F).
HRMS (ESI): calcd for C26H22FN3O3S[M + H]+ m/z 476.1439, found 476.1425.
实施例20;化合物20的制备
(1)根据通用步骤得到原料B20
该原料室温下为黄色固体,该化合物不稳定,直接往下反应。
(2)化合物20的制备:
将165 mg B20溶于甲醇中,加入57mg NaBH4。该反应体系在此条件下搅拌48 h后,将反应物抽滤、干燥、过柱得到108 mg黄色固体(化合物20),反应收率为76%。
物理状态:黄色油状物
TLC: Rf = 0.24 (PE/EtOAc = 2:1).
1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.55(d, J = 7.6 Hz, 2H), 7.34 (d, J = 3.0 Hz, 1H), 7.32 (d, J = 3.8 Hz, 1H), 7.19(d, J = 7.5 Hz, 1H), 7.15 (d, J = 10.9 Hz, 1H), 7.07 (d, J = 8.0 Hz, 2H),7.03 (d, J = 7.5 Hz, 1H), 6.97 (s, 1H), 6.64 (q, J = 7.3 Hz, 1H), 4.88 (s,1H), 4.66 (s, 1H), 3.71 (q, J = 7.1 Hz, 1H), 3.56 (q, J = 8.2 Hz, 1H), 2.45(d, J = 7.2 Hz, 1H), 2.42 (d, J = 5.4 Hz, 1H), 2.37 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 190.05 (d, J = 3.2 Hz), 151.69, 149.29,143.26, 137.30, 137.20, 134.29, 129.34 (2C), 127.47 (2C), 124.36, 123.45 (d,J = 3.4 Hz), 122.57 (d, J = 2.4 Hz), 120.15 (d, J = 7.2 Hz), 120.01, 119.12,117.45 (d, J = 2.4 Hz), 116.53 (d, J = 6.4 Hz), 113.80, 112.09, 67.33, 63.94,45.92, 35.69, 21.57.
19F NMR (376 MHz, CDCl3) δ -136.79 (d, J = 10.3 Hz,1F).
HRMS (ESI): calcd for C26H22FN3O3S[M + H]+ m/z 476.1439, found 476.1434.
实施例21;化合物21的制备
(1)根据通用步骤得到原料B21
物理状态:黄色固体;熔点: 127.2 – 123.9 oC
TLC: Rf = 0.35 (PE/EtOAc = 1:2).
1H NMR (400 MHz, DMSO-d 6) δ 10.93 (s, 0.5H), 10.87 (s, 0.5H), 7.80 (d,J = 8.0 Hz, 0.5H), 7.61 (d, J = 8.1 Hz, 0.5H), 7.41 (d, J = 2.2 Hz, 0.5H),7.31 (d, J = 2.5 Hz, 1H), 7.30 – 7.27 (m, 1H), 7.16 (d, J = 7.3 Hz, 0.5H),7.10 (d, J = 7.3 Hz, 1H), 7.02 – 6.97 (m, 1H), 6.85 (q, J = 6.9 Hz, 1H), 6.66– 6.62 (m, 1H), 6.60 – 6.52 (m, 1H), 6.27 (s, 0.5H), 6.24 (s, 0.5H), 5.06 (d,J = 13.3 Hz, 0.5H), 4.04 (s, 0.5H), 3.85 (d, J = 13.5 Hz, 0.5H), 3.46 (s,1H), 3.44 – 3.38 (m, 1H), 3.07 (d, J = 13.2 Hz, 0.5H), 2.79 – 2.71 (m, 1H),2.01 (s, 1H), 1.81 (s, 2H), 1.77 (d, J = 12.6 Hz, 1H), 0.68 (s, 4.5H), 0.65(s, 4.5H).
13C NMR (101 MHz, DMSO-d 6) δ 173.73, 173.67, 156.71, 156.70, 141.74,141.56, 135.03, 134.99, 132.85, 132.49, 132.05, 132.03, 131.55, 131.29,128.62, 128.54, 127.84, 127.44, 125.77, 125.69, 122.93, 122.85, 121.25,120.94, 120.34, 119.30, 116.18, 116.09, 113.70, 113.65, 93.67, 93.47, 84.25,83.93, 72.07, 71.99, 52.10, 47.08, 45.72, 43.50, 41.88, 39.08, 36.53, 31.05(2C), 30.99 (3C), 26.56, 26.47.
HRMS (ESI): calcd for C25H29N3O3[M + H]+ m/z 420.2282, found 420.2283.
(2)化合物21的制备:
将126 mg B21溶于甲醇中,加入57mg NaBH4。该反应体系在此条件下搅拌24 h后,将反应物抽滤、干燥、过柱得到91 mg黄色固体(化合物21),反应收率为88%。物理状态:黄色固体;熔点: 159.6 – 160.4 oC.
TLC: Rf = 0.75 (CH2Cl2/MeOH = 10:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.14 (s, 0.7H), 11.09 (s, 0.3H), 7.78 (d,J = 8.1 Hz, 0.6H), 7.63 (t, J = 8.5 Hz, 1H), 7.55 (s, 0.6H), 7.54 – 7.43 (m,1H), 7.41 (d, J = 9.1 Hz, 1.4H), 7.31 (d, J = 8.2 Hz, 1.4H), 7.12 (q, J = 7.1Hz, 1H), 7.04 – 6.97 (m, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.64 – 6.55 (m, 1H),5.75 (s, 1H), 5.08 (s, 1H), 3.67 (d, J = 9.0 Hz, 0.3H), 3.51 (d, J = 8.1 Hz,0.7H), 2.67 (s, 0.3H), 2.58 (d, J = 5.1 Hz, 0.7H), 2.28 (s, 0.3H), 2.19 (d, J= 11.5 Hz, 0.7H), 1.86 (s, 0.9H), 1.75 (s, 2.1H).(Note: rotamers seen)
13C NMR (101 MHz, DMSO-d6) δ 190.16, 160.34, 158.01, 149.80, 143.93, δ137.59 (d, J = 12.6 Hz), 136.09, 133.67, 130.04 (2C), 127.77 (2C), 127.52,124.68, 124.65, 121.46, 120.26 (d, J = 10.1 Hz), 116.04 (d, J = 87.9 Hz),114.00 (d, J = 103.3 Hz), 107.75 (d, J = 24.2 Hz), 98.43 (d, J = 25.4 Hz),67.82, 64.34, 47.84, 36.12, 21.57.
HRMS (ESI): calcd for C21H19N3O2[M + H]+ m/z 346.1550, found 346.1544.
实施例22;化合物22的制备
(1)根据通用步骤得到原料B8
B8核磁见实施例8
(2)化合物22的制备:
将55 mg B8溶于甲醇中,加入15 mg NaBH4。该反应体系在此条件下搅拌90 h后,将反应物抽滤、干燥、过柱得到43 mg白色固体(化合物22),反应收率为91%。物理状态:白色固体;熔点: 206.0–206.9 oC.
TLC: Rf = 0.70 (PE/EtOAc = 3:2).
1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.71 (d, J = 7.6 Hz, 2H), 7.66(d, J = 7.8 Hz, 1H), 7.30 (s, 2H), 7.28 (s, 1H), 7.23 (s, 1H), 7.21 (s, 1H),7.01 (d, J = 7.7 Hz, 1H), 6.99 (d, J = 3.2 Hz, 1H), 6.68 (t, J = 7.3 Hz, 1H),6.52 (d, J = 8.1 Hz, 1H), 4.72 (s, 1H), 3.89 (d, J = 10.5 Hz, 1H), 3.85 –3.79 (m, 1H), 3.73 (d, J = 10.6 Hz, 1H), 3.65 (t, J = 8.8 Hz, 1H), 3.36 (t, J= 6.9 Hz, 1H), 2.44 (s, 3H), 2.40 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 191.14, 148.36, 143.76, 136.10, 135.37,133.90, 129.84 (2C), 129.50, 127.73, 127.51 (2C), 124.58, 124.33, 122.82,119.00, 118.15, 115.75, 115.71, 114.08, 111.62, 63.82, 57.09, 53.00, 49.11,21.56.
HRMS (ESI): calcd for C27H25N3O3S [M + H]+ m/z 472.1689, found 472.1689.
实施例23;化合物23的制备
(1)根据通用步骤得到原料B9
B9核磁见实施例9
(2)化合物23的制备:
将82 mg B9溶于甲醇中,加入23 mg NaBH4。该反应体系在此条件下搅拌9 h后,将反应物抽滤、干燥、过柱得到63 mg白色固体(化合物23),反应收率为83%。物理状态:白色固体;熔点: 257.3–258.2 oC.
TLC: Rf = 0.43 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 7.77 (d, J = 7.9 Hz, 2H), 7.46 (d, J = 3.0Hz, 2H), 7.44 (d, J = 2.7 Hz, 1H), 7.39 (s, 1H), 7.37 (d, J = 8.3 Hz, 1H),7.30 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H),6.95 (t, J = 7.5 Hz, 1H), 6.88 (s, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.57 (t, J= 7.4 Hz, 1H), 3.84 (d, J = 10.6 Hz, 1H), 3.74 (t, J = 9.2 Hz, 1H), 3.65 (s,1H), 3.62 (s, 3H), 3.48 (t, J = 9.6 Hz, 1H), 3.28 (s, 1H), 2.46 (s, 3H).
13C NMR (101 MHz, DMSO-d 6) δ 190.88, 149.89, 144.15, 137.87, 136.38,133.64, 130.44 (2C), 128.02, 127.98 (2C), 127.01, 124.76, 122.04, 119.74,119.55, 117.05, 116.32, 114.50, 112.40, 110.77, 64.31, 58.68, 53.13, 49.79,32.86, 21.57.
HRMS (ESI): calcd for C27H25N3O3S [M + H]+ m/z 472.1689, found 472.1700.
实施例24;化合物24的制备
(1)根据通用步骤得到原料B10
B10核磁见实施例10
(2)化合物24的制备:
将74 mg B10溶于甲醇中,加入21 mg NaBH4。该反应体系在此条件下搅拌11h后,将反应物抽滤、干燥、过柱得到47 mg黄色固体(化合物24),反应收率为73%。物理状态:黄色固体;熔点: 324.5–324.9 oC.
TLC: Rf = 0.30 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.01 (s, 1H), 7.78 (d, J = 7.7 Hz, 2H),7.46 (s, 2H), 7.44 (s, 1H), 7.36 (s, 1H), 7.33 (s, 1H), 7.30 (d, J = 7.6 Hz,1H), 7.15 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.94 (s, 1H), 6.90(t, J = 7.5 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.57 (t, J = 7.3 Hz, 1H), 3.83(d, J = 10.9 Hz, 1H), 3.77 (d, J = 9.1 Hz, 1H), 3.68 (d, J = 10.6 Hz, 1H),3.48 (t, J = 9.8 Hz, 1H), 3.30 (s, 1H), 2.46 (s, 3H).
13C NMR (101 MHz, DMSO-d 6) δ 190.96, 150.09, 144.15, 137.53, 136.37,133.74, 130.44 (2C), 127.96 (2C), 127.00, 124.42, 124.09, 121.91, 119.41(2C), 117.07, 116.26, 114.59, 113.02, 112.56, 64.70, 58.78, 53.25, 49.81,21.58.
HRMS (ESI): calcd for C26H23N3O3S [M + H]+ m/z 458.1533, found 458.1524.
实施例25;化合物25的制备
(1)根据通用步骤得到原料B25
物理状态:白色固体;熔点: 156.0 - 156.8 oC.
TLC: Rf = 0.49 (PE/EtOAc = 4:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.21 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H),7.82 (s, 1H), 7.56 (s, 1H), 7.54 (s, 2H), 7.38 (d, J = 7.6 Hz, 2H), 7.15 (d,J = 7.2 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.65 (d,J = 8.3 Hz, 1H), 6.61 (d, J = 7.2 Hz, 1H), 6.30 (s, 1H), 4.09 (d, J = 11.6Hz, 1H), 3.83 (d, J = 10.0 Hz, 1H), 2.76 (d, J = 13.0 Hz, 1H), 2.34 (s, 3H),2.08 (t, J = 12.1 Hz, 1H), 2.01 – 1.92 (m, 1H), 1.89 (d, J = 11.9 Hz, 1H),0.61 (s, 9H).
13C NMR (101 MHz, DMSO-d 6) δ 151.16, 144.48, 136.97, 132.40, 130.55(2C), 130.40, 127.77 (2C), 127.62, 127.07, 126.40, 125.34, 124.93, 120.97,117.33, 114.01, 113.91, 113.80, 110.70, 87.93, 79.21, 67.23, 56.81, 44.56,27.31, 26.16 (3C), 21.48.
HRMS (ESI):calcd for C30H32BrN3O4S [M + H]+ m/z 610.1370, found610.1364.
(2)化合物25的制备:
将92 mg B25溶于甲醇中,加入23mg NaBH4。该反应体系在此条件下搅拌40h后,将反应物抽滤、干燥、过柱得到80 mg绿色固体(化合物25),反应收率为99%。物理状态:绿色固体;熔点: 236.8-237.7 oC。
Rf = 0.32 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.15 (s, 1H), 7.75 (d, J = 7.8 Hz, 2H),7.54 (s, 1H), 7.45 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.32 (s, 1H), 7.30 (s,1H), 7.27 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.99 (s, 1H), 6.70(d, J = 8.3 Hz, 1H), 6.57 (t, J = 7.3 Hz, 1H), 3.82 (d, J = 10.7 Hz, 1H),3.72 (t, J = 9.0 Hz, 1H), 3.65 (d, J = 10.6 Hz, 1H), 3.46 (t, J = 9.5 Hz,1H), 3.30 (s, 1H), 2.44 (s, 3H).
13C NMR (101 MHz, DMSO-d 6) δ 190.86, 149.85, 144.07, 138.37, 136.36,133.74, 130.35 (2C), 127.90 (2C), 126.99, 125.14, 123.57, 122.22, 121.36,117.14, 116.27, 115.06, 114.71, 114.58, 113.63, 64.20, 58.58, 53.16, 49.63,21.55.
HRMS (ESI): calcd for C26H22BrN3O3S [M + H]+ m/z 536.0638, found536.0633.
实施例26;化合物26的制备
(1)根据通用步骤得到原料B26
该原料室温下为黄色固体,该化合物不稳定,直接往下反应。
(2)化合物26的制备:
将70 mg B26溶于甲醇中,加入19mg NaBH4。该反应体系在此条件下搅拌58h后,将反应物抽滤、干燥、过柱得到58 mg黄色固体(化合物26),反应收率为99%。物理状态:黄色固体;熔点: 151.8-152.7 oC.
TLC: Rf = 0.26 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.05 (s, 1H), 7.76 (d, J = 7.5 Hz, 2H),7.57 (s, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.35 (s, 1H), 7.35 (s, 1H), 7.33 (d,J = 3.0 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.95 (d,J = 2.4 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 3.80 (d,J = 11.2 Hz, 1H), 3.74 (d, J = 9.4 Hz, 1H), 3.70 (d, J = 10.7 Hz, 1H), 3.48(s, 1H), 3.34 (s, 1H), 2.45 (s, 3H).
13C NMR (101 MHz, DMSO-d 6) δ 190.17, 148.67, 144.21, 137.54, 136.05,133.57, 130.43 (2C), 127.96 (2C), 125.66, 124.32, 124.09, 121.99, 120.98,119.49, 119.40, 118.58, 115.13, 112.58 (2C), 64.66, 58.51, 52.88, 49.64,21.57.
HRMS (ESI): calcd for C26H22ClN3O3S [M + H]+ m/z 492.1143, found492.1143.
实施例27;化合物27的制备
(1)根据通用步骤得到原料B11
B11核磁见实施例11
(2)化合物27的制备:
将109 mg B11溶于甲醇中,加入30mg NaBH4。该反应体系在此条件下搅拌56 h后,将反应物抽滤、干燥、过柱得到91 mg绿色固体(化合物27),反应收率为97%。物理状态:白色固体;熔点: 213.5 – 214.2 oC.
TLC: Rf = 0.69 (PE/EtOAc = 3:2).
1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.72 (d, J = 7.2 Hz, 2H), 7.67(d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 7.7 Hz, 2H), 7.28(s, 1H), 7.15 (s, 1H), 7.02 (t, J = 2.2 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H),6.69 (t, J = 7.5 Hz, 1H), 6.46 (d, J = 8.2 Hz, 1H), 4.52 (s, 1H), 3.89 (d, J= 10.7 Hz, 1H), 3.86 – 3.82 (m, 1H), 3.75 – 3.71 (m, 1H), 3.70 – 3.65 (m,1H), 3.35 (t, J = 7.1 Hz, 1H), 2.46 (s, 3H), 2.44 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 191.03, 148.23, 143.75, 137.47, 136.07,133.94, 132.71, 129.82 (2C), 127.73, 127.51 (2C), 122.20, 122.04, 121.92,119.04, 118.16, 115.73, 115.68, 114.66, 111.82, 63.74, 57.10, 53.01, 49.05,21.57 (2C).
HRMS (ESI): calcd for C27H25N3O3S [M + H]+ m/z 472.1689, found 472.1687.
实施例28;化合物28的制备
(1)根据通用步骤得到原料B12
B12核磁见实施例12
(2)化合物28的制备:
将82 mg B12溶于甲醇中,加入23mg NaBH4。该反应体系在此条件下搅拌7 h后,将反应物抽滤、干燥、过柱得到68 mg黄色固体(化合物28),反应收率为96%。物理状态:白色固体;熔点: 168.4 - 169.3 oC.
TLC: Rf= 0.66 (PE/EtOAc = 3:2).
1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.72 (d, J = 7.5 Hz, 2H), 7.66(d, J = 7.8 Hz, 1H), 7.32 (s, 2H), 7.30 (s, 1H), 7.27 (s, 1H), 7.09 (s, 1H),7.02 (s, 1H), 7.00 (s, 1H), 6.68 (t, J = 7.3 Hz, 1H), 6.47 (d, J = 8.2 Hz,1H), 4.60 (s, 1H), 3.89 (d, J = 10.7 Hz, 1H), 3.86 – 3.82 (m, 1H), 3.75 (d, J= 10.7 Hz, 1H), 3.68 (t, J = 9.0 Hz, 1H), 3.36 (t, J = 7.1 Hz, 1H), 2.46 (s,3H), 2.44 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 191.01, 148.18, 143.76, 136.58, 136.08,133.99, 129.83 (2C), 127.75, 127.52 (2C), 123.95, 123.25, 122.34, 121.25,120.44, 118.21, 117.09, 115.76, 115.70, 115.33, 63.77, 57.19, 52.99, 49.04,21.59, 16.55.
HRMS (ESI): calcd for C27H25N3O3S [M + H]+ m/z 472.1689, found 472.1687.
实施例29;化合物29的制备
(1)根据通用步骤得到原料B29
物理状态:白色固体;熔点: 150.7 - 151.6 oC.
TLC: Rf = 0.66 (PE/EtOAc = 2:1).
1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.86(d, J = 2.4 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.24 (s, 2H), 7.21 (d, J = 7.3Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 6.75 (d, J = 7.4Hz, 1H), 6.71 (d, J = 3.1 Hz, 1H), 6.70 – 6.68 (m, 1H), 4.16 (d, J = 11.5 Hz,1H), 4.10 (s, 1H), 3.88 (d, J = 10.8 Hz, 1H), 3.84 (s, 3H), 2.79 (d, J = 13.1Hz, 1H), 2.38 (s, 3H), 2.30 (s, 1H), 2.24 (d, J = 11.3 Hz, 1H), 2.20 (d, J =5.2 Hz, 1H), 0.69 (s, 9H).
13C NMR (101 MHz, DMSO-d 6) δ 155.53, 151.27, 144.43, 136.64, 132.41,130.55 (2C), 127.76 (2C), 127.20, 126.41, 124.25, 122.91, 122.69, 117.06,113.32, 110.54, 108.52, 93.82, 87.97, 79.23, 67.37, 56.91, 55.41, 44.56,31.77, 27.28, 26.15 (3C), 21.48.
HRMS (ESI): calcd for C31H35N3O5S [M + H]+ m/z 562.2370, found 562.2362.
(2)化合物29的制备:
将169 mg B29溶于乙腈中,加入58mg MsOH。该反应体系在此条件下搅拌1h后,将反应物抽滤、干燥、过柱得到120 mg黄色固体(化合物29),反应收率为85%。物理状态:黄色固体;熔点: 203.1-203.9 oC.
TLC: Rf = 0.28 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.71 (s, 1H), 8.48 (d, J = 8.6 Hz, 1H),7.82 (s, 1H), 7.81 (s, 2H), 7.54 (s, 1H), 7.52 (s, 2H), 7.29 (t, J = 7.3 Hz,1H), 7.02 (s, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.52(d, J = 7.1 Hz, 1H), 3.87 (d, J = 8.8 Hz, 1H), 3.82 (s, 3H), 3.77 (d, J =10.6 Hz, 1H), 3.47 (d, J = 8.6 Hz, 1H), 3.24 (d, J = 10.5 Hz, 1H), 2.65 (d, J= 10.6 Hz, 1H), 2.52 (s, 3H), 1.93 – 1.88 (m, 1H).
13C NMR (101 MHz, DMSO-d 6) δ 176.00, 157.01, 155.09, 144.80, 144.56,137.89, 132.45, 130.51 (2C), 128.59, 128.45, 128.26 (2C), 124.76, 124.06,120.92, 120.52, 119.84, 111.58, 108.39, 95.30, 61.23, 57.23, 55.69, 48.64,37.87, 21.59.
HRMS (ESI): calcd for C27H25N3O3S [M + H]+ m/z 472.1689, found 472.1692.
实施例30;化合物30的制备
(1)根据通用步骤得到原料B30
物理状态:白色固体;熔点: 157.8 - 158.6 oC.
TLC: Rf = 0.25 (PE/EtOAc = 4:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.28 (s, 1H), 8.02 (s, 1H), 7.87 (s, 1H),7.56 (d, J = 7.7 Hz, 2H), 7.39 (d, J = 7.9 Hz, 2H), 7.37 – 7.34 (m, 1H), 7.16(d, J = 7.3 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.68(d, J = 7.8 Hz, 1H), 6.63 (t, J = 7.3 Hz, 1H), 6.31 (s, 1H), 4.11 (d, J =11.7 Hz, 1H), 3.82 (d, J = 10.2 Hz, 1H), 2.76 (d, J = 13.4 Hz, 1H), 2.34 (s,3H), 2.08 (t, J = 12.1 Hz, 1H), 1.96 – 1.89 (m, 1H), 1.88 (d, J = 11.5 Hz,1H), 0.64 (s, 9H).
13C NMR (101 MHz, DMSO-d 6) δ 151.11, 144.53, 134.52, 132.32, 130.58(2C), 130.48, 129.64, 127.78 (2C), 127.08, 126.43, 125.76, 123.01, 122.91,121.09, 117.37, 113.26, 112.79, 110.74, 88.17, 79.31, 67.14, 56.71, 44.59,27.27, 26.03 (3C), 21.49.
HRMS (ESI): calcd for C30H32ClN3O4S [M + H]+ m/z 566.1875, found566.1869.
(2)化合物30的制备:
将170 mg B30溶于乙腈中,加入58mg MsOH。该反应体系在此条件下搅拌2h后,将反应物抽滤、干燥、过柱得到141 mg黄色固体(化合物30),反应收率为99%。物理状态:黄色固体;熔点: 217.6-218.5 oC.
TLC: Rf = 0.48 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 12.02 (s, 1H), 8.62 (d, J = 8.5 Hz, 1H),8.01 (s, 1H), 7.81 (d, J = 7.6 Hz, 2H), 7.59 (s, 1H), 7.56 (s, 1H), 7.53 (d,J = 7.6 Hz, 2H), 7.31 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.93 (t,J = 7.3 Hz, 1H), 6.49 (d, J = 7.2 Hz, 1H), 3.89 (t, J = 8.8 Hz, 1H), 3.79 (d,J = 10.7 Hz, 1H), 3.47 (d, J = 8.9 Hz, 1H), 3.24 (d, J = 10.6 Hz, 1H), 2.72 –2.64 (m, 1H), 2.52 (s, 3H), 1.95 – 1.87 (m, 1H).
13C NMR (101 MHz, DMSO-d 6) δ 175.65, 154.84, 144.69, 144.57, 137.47,132.50, 130.51 (3C), 128.64, 128.24 (2C), 128.01, 125.32, 125.02, 124.73,121.95, 120.96, 120.01, 112.07, 108.39, 61.33, 56.90, 48.57, 37.49, 21.59.
HRMS (ESI): calcd for C26H22ClN3O2S [M + H]+ m/z 476.1194, found476.1198.
实施例31;化合物31的制备
(1)根据通用步骤得到原料B31
该原料常温下不稳定,直接往下反应。
(2)化合物31的制备:
将112 mg B31溶于乙腈中,加入58mg MsOH。该反应体系在此条件下搅拌1 h后,将反应物抽滤、干燥、过柱得到89 mg黄色固体(化合物31),反应收率为95%。物理状态:黄色固体;熔点: 171.8 – 172.5 oC.
TLC: Rf = 0.38 (PE/EtOAc = 2:1).
1H NMR (400 MHz, CDCl3) δ 9.23 (s, 1H), 9.16 (s, 1H), 8.15 (d, J = 2.8Hz, 1H), 7.79 (d, J = 7.5 Hz, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H),7.51 (s, 1H), 7.45 (d, J = 7.7 Hz, 2H), 7.33 (d, J = 7.2 Hz, 1H), 7.00 (t, J= 7.4 Hz, 1H), 6.55 (d, J = 7.2 Hz, 1H), 4.02 (d, J = 9.4 Hz, 1H), 3.96 (d, J= 10.8 Hz, 1H), 3.31 – 3.25 (m, 1H), 3.21 (d, J = 11.9 Hz, 1H), 2.68 – 2.61(m, 1H), 2.53 (s, 3H), 2.02 – 1.97 (m, 1H).
13C NMR (101 MHz, DMSO-d 6) δ 175.37, 154.62, 144.57, 144.54, 138.88,132.58, 131.81, 130.51 (2C), 128.70, 128.53, 128.21 (2C), 126.36, 126.20,125.33, 121.00, 120.92, 120.33, 113.91, 108.79, 103.79, 61.39, 56.65, 48.51,37.16, 21.58.
HRMS (ESI): calcd for C27H22N4O2S [M + H]+ m/z 467.1536, found 467.1533.
实施例32;化合物32的制备
(1)根据通用步骤得到原料B32
物理状态:白色固体;熔点: 154.6 - 155.5 oC.
TLC: Rf = 0.29 (PE/EtOAc = 4:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.14 (s, 1H), 8.03 – 7.98 (m, 1H), 7.80(t, J = 2.0 Hz, 1H), 7.55 (d, J = 7.6 Hz, 2H), 7.38 (d, J = 7.8 Hz, 2H), 7.15(d, J = 7.4 Hz, 1H), 7.13 – 7.10 (m, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.76 (t,J = 9.3 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 7.3 Hz, 1H), 6.31 (s,1H), 4.09 (d, J = 11.6 Hz, 1H), 3.82 (d, J = 10.0 Hz, 1H), 2.76 (d, J = 13.2Hz, 1H), 2.34 (s, 3H), 2.08 (t, J = 12.1 Hz, 1H), 2.00 – 1.91 (m, 1H), 1.88(d, J = 11.8 Hz, 1H), 0.61 (s, 9H).
13C NMR (101 MHz, DMSO-d 6)δ 158.96 (d, J = 234.0 Hz), 151.20, 144.47,135.82 (d, J = 12.6 Hz), 132.39, 130.56 (2C), 130.40, 127.77 (2C), 127.10,126.41, 125.41, 124.65 (d, J = 10.1 Hz), 124.55 (d, J = 2.8 Hz), 117.25,113.65, 110.63, 106.56 (d, J = 23.8 Hz), 97.07 (d, J = 25.3 Hz), 87.97,79.22, 67.25, 56.84, 44.56, 27.26, 26.13 (3C), 21.48.
HRMS (ESI): calcd for C30H32BrN3O4S [M + H]+ m/z 550.2170, found550.2166.
(2)化合物32的制备:
将165 mg B32溶于乙腈中,加入58mg MsOH。该反应体系在此条件下搅拌1 h后,将反应物抽滤、干燥、过柱得到74 mg黄色固体(化合物32),反应收率为54%。物理状态:黄色固体;熔点: 227.4 - 228.4 oC.
TLC: Rf = 0.55 (PE/EtOAc = 2:1).
1H NMR (400 MHz, DMSO-d 6) δ 11.96 (s, 1H), 8.64 – 8.59 (m, 1H), 7.96(s, 1H), 7.81 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 4.0 Hz, 2H), 7.52 (s, 1H),7.32 (d, J = 7.0 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.09 (t, J = 9.2 Hz, 1H),6.93 (t, J = 7.4 Hz, 1H), 6.50 (d, J = 7.3 Hz, 1H), 3.89 (t, J = 8.8 Hz, 1H),3.78 (d, J = 10.6 Hz, 1H), 3.47 (d, J = 8.1 Hz, 1H), 3.24 (d, J = 10.7 Hz,1H), 2.66 (d, J = 11.3 Hz, 1H), 2.51 (d, J = 2.1 Hz, 3H), 1.94 – 1.88 (m,1H).
13C NMR (101 MHz, DMSO-d 6) δ 175.74, 159.94 (d, J = 236.7 Hz), 154.89,144.66 (d, J = 16.4 Hz), 137.05 (d, J = 12.7 Hz), 132.47, 130.52 (2C), 130.19(d, J = 2.0 Hz), 128.63, 128.25 (2C), 124.98, 124.60 (d, J = 9.7 Hz), 123.22,120.96, 119.98, 109.98 (d, J = 23.6 Hz), 108.36, 98.54 (d, J = 25.6 Hz),61.31, 57.02, 48.59, 37.61, 21.59.
19F NMR (376 MHz, CDCl3) δ -118.58 (tt, J = 9.2, 3.8 Hz, 1F).
HRMS (ESI): calcd for C26H22FN3O2S [M + H]+ m/z 460.1490, found460.1481.
生物活性测试具体实施例:
以人乳腺癌细胞系MCF-7细胞、人肺癌细胞系A549细胞和宫颈癌细胞株Hela为测试细胞系(细胞购自中国科学院上海生命科学研究所细胞资源中心)。
应用实施例1:对人乳腺癌细胞系MCF-7细胞增殖和存活的抑制作用
材料:人乳腺癌细胞系MCF-7;
受试药物:1 μΜ;
细胞培养方法:取出液氮中冻存的MCF-7细胞,在37℃的温水中解冻,将细胞悬液移入15 mL离心管中,加5 mL DMEM完全培养液,轻轻吹打均匀,置于离心机中,3000 rpm离心5 min,弃去上清液,加入2 mL DMEM完全培养液,轻轻吹打均匀,将细胞悬液加入培养皿中,补加6 mL DMEM完全培养液,将培养皿置于5% CO2、37℃培养箱中培养。
2. 细胞毒性实验:将MCF-7以2×104个细胞/孔的密度接种到96孔培养板中,培养24 h后,更换培养液为新鲜血清培养液,分别加入1μM的化合物,孵育72h后,吸弃孔中溶液,用PBS洗涤3遍,加入新鲜培养液180 μL,同时每孔加入20 μL MTT 溶液(5 mg/mL),继续在37℃、5% CO2(相对湿度90%)培养箱中培养4 h后,终止培养,小心吸弃上清液,每孔加入150μLDMSO,避光振荡10 min使结晶物充分溶解。以酶标仪检测570 nm处的吸收度(A),按照以下公式计算:细胞存活率%=(试验组平均A值/空白对照组平均A值)×100%。
应用实施例2:对Α549肿瘤细胞增殖和存活的抑制作用
材料:肺癌细胞株Α549;
受试药物:1 μΜ;
细胞培养方法:取出液氮中冻存的A549 细胞,在37℃的温水中解冻,将细胞悬液移入5 mL 离心管中,置于离心机中,2000 rpm 离心10 min,弃去上清液,加入1 mL RPMI1640 完全培养液,轻轻吹打均匀,将细胞悬液加入培养皿中,补加3 mL RPMI 1640 完全培养液,将培养皿置于5% CO2、37℃培养箱中培养。
细胞毒性实验:将A549 细胞以8×103 个细胞/ 孔的密度接种到96 孔培养板中,培养48 h 后,吸弃旧培养基,并于每孔中加入浓度为1μΜ的化合物,另设溶剂对照组和空白对照组,在培养箱中孵育48h后,小心吸弃培养基,用PBS缓冲溶液洗涤3 遍,每孔中加入90 µL无血清、无酚红的1640培养基和10 µL MTT溶液(5 mg/mL),继续孵育4 h后,终止培养,小心吸弃96孔板中的培养液,并于每孔中加入150 µL DMSO溶液,避光振荡10 min 使紫色结晶物充分溶解;用多功能酶标仪于570 nm波长处测定各孔的吸收度(A),并按下式计算细胞的存活率:细胞存活率 =(试验组A 值/ 空白对照组A 值)×100%。
应用实施例3:对Hela肿瘤细胞增殖和存活的抑制作用
材料:宫颈癌细胞株Hela
受试药物:1 μΜ;
细胞培养方法:取出液氮中冻存的Hela 细胞,在37℃的温水中解冻,将细胞悬液移入1.5 mL 离心管中,置于离心机中,2000 rpm 离心10 min,弃去上清液,加入1 mL DMEM完全培养液,轻轻吹打均匀,将细胞悬液加入培养皿中,补加3 mL DMEM完全培养液,将培养皿置于5% CO2、37℃培养箱中培养。
细胞毒性实验:将Hela细胞以8×103 个细胞/ 孔的密度接种到96 孔培养板中,培养24 h 后,吸弃旧的培养基,并于每孔中加入1μΜ的化合物,另设溶剂对照组和空白对照组,在培养箱中孵育72h后,小心吸弃培养基,用PBS 洗涤3 遍,每孔中加入90 µL无血清、无酚红的1640培养基和10 µL MTT溶液(5 mg/mL),继续孵育4 h后,终止培养,小心吸弃96孔板中的培养液,并于每孔中加入150 µL DMSO溶液,避光振荡10 min 使紫色结晶物充分溶解;用多功能酶标仪于570 nm波长处测定各孔的吸收度(A),并按下式计算细胞的存活率:细胞存活率 =(试验组A 值/ 空白对照组A 值)×100%。
上述应用实施例所测的部分含四氢咔啉骨架氧化偶联吲哚的重排产物的活性参数如表1所示:表中M.W.为对应化合物的相对分子质量,存活率为浓度为1 μM化合物。
表1. 部分化合物的活性参数
以上所述仅为本发明的较佳实施例,凡依本发明申请专利范围所做的均等变化与修饰,皆应属本发明的涵盖范围。
Claims (4)
3.根据权利要求2所述的制备方法,其特征在于:原料B的制备方法包括如下步骤:将原料A溶于乙腈中,缓慢加入0.025 当量的酞菁铁和1.5当量的醋酸,在5 ℃下反应3-5 min后,加入2.0 当量的60wt%叔丁基过氧化氢的水溶液,监测反应完全后,用体积比乙酸乙酯/水= 1:1的溶剂萃取3次,收集有机相,将得到的有机相干燥、旋干,过硅胶柱层析分离得到中间体Int,将中间体Int溶解在乙腈中,加入1.2 当量吲哚衍生物和0.1 当量的1 mol/L盐酸乙腈溶液中,在室温下搅拌反应5-10 min,监测反应完全后,将反应液抽滤得到原料B;
4.一种如权利要求1所述的含四氢咔啉骨架氧化偶联重排产物的应用,其特征在于:所述的含四氢咔啉骨架氧化偶联重排产物在制备治疗乳腺癌、肺癌和宫颈癌的药物中的应用。
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