CN111808121A - 一类含杂原子的新型高b环小檗碱类似物及其c-h活化合成方法 - Google Patents
一类含杂原子的新型高b环小檗碱类似物及其c-h活化合成方法 Download PDFInfo
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- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 claims abstract description 32
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
- C07D513/14—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明提供了一类含杂原子的新型高B环小檗碱类似物及其C‑H活化合成方法。这类具有潜在p300组蛋白乙酰化转移酶抑制活性的新型高B环小檗碱类似物包括：5‑氧杂高B环小檗碱、5‑氮杂高B环小檗碱和5‑硫杂高B环小檗碱；该方法借助钴催化的N‑吡啶酰胺与芳乙炔硅烷的脱硅、C‑H活化/环化完成它们的全合成。与已有报道相比，本发明打破了对小檗碱基本骨架改造的局限性，提供了新颖的结构类型，同时也发明了一种更加经济、高效的小檗碱类似物的合成方法，具有广阔的应用前景。
Description
技术领域
本发明属于化合物药物领域，具体涉及一类含杂原子的新型高B环小檗碱类似物及其C-H活化合成方法。
背景技术
小檗碱（Berberine）是从中药黄连中分离的一种异喹啉生物碱，具有抗病原微生物、抗炎、抗肿瘤、心脏保护、降血糖、调节脂质代谢、免疫抑制等多种药理作用，临床上主要用于心律失常、高血压、充血性心力衰竭、短暂性脑出血、腹泻型肠易激综合征、细菌性痢疾、消化性溃疡、高脂血症、2型糖尿病及其并发症、肿瘤、术后黏连和炎症、沙眼衣原体感染等疾病的治疗[1-2]。由于小檗碱在长期的临床使用中疗效确切，且质量稳定，不需要专业医护人员的指导就能安全使用，于1999年被国家列入第一批非处方药品中。
小檗碱的药理活性广泛，且具有天然毒副作用小的特点，从上世纪中期开始便有许多课题组以其为先导化合物进行结构修饰和改造[3-4]。但目前为止，研究仍存在较大的局限性，包括：已报道的结构改造主要集中在小檗碱的外围位置上，很少有针对小檗碱的基本骨架及原子种类的化学改造；已有的改造策略多是改造成烷氧基、烃基等，官能团种类偏少；每一次改造需要从头全合成，路线繁琐，成本较高。以上诸多限制，极大地降低了小檗碱类似物结构的多样性，使性质优越的候选化合物不易被发现。
最近几十年，过渡金属催化的C-H键活化/转化得到迅猛发展，因其具有优良的原子经济性和步骤简捷性，在有机方法学、药物化学及天然产物全合成领域得到了广泛应用[5]。国内外已有多篇利用C-H活化方法合成天然产物的报道[6-8]。从结构上分析，小檗碱是由两个异喹啉环稠合而成的含氮杂环，这启发我们可以借助C-H活化的方法来完成小檗碱及其类似物的全合成。
p300组蛋白乙酰化转移酶是组蛋白乙酰化转移酶家族的重要成员，它参与了多种生物过程和细胞信号通路的调控，在细胞生长、损伤修复等过程中发挥着重要作用[9]。越来越多的研究表明p300是一个潜在的抗肿瘤新靶标[10]。2016年本课题组首次发现小檗碱对p300具有抑制作用，并且设计的衍生物CX-55对p300抑制活性卓越[11-12]。在此基础上我们又设计了5-氧杂高B环小檗碱、5-氮杂高B环小檗碱、5-硫杂高B环小檗碱等新型类似物，希望能获得临床抗肿瘤候选药物，并尝试利用C-H活化反应开发全新高效的合成方法。
发明内容
本发明的目的在于提供一类具有潜在p300组蛋白乙酰化转移酶抑制活性的全新结构类型的小檗碱类似物及合成方法，如式
所示的化合物。
本发明还提供了一种所述的类似物的全新合成方法,它包括如下工艺流程：
(i) 5-氧杂高B环小檗碱的制备方法：
(ii) 5-氮杂高B环小檗碱的制备方法：
(iii) 5-硫杂高B环小檗碱的制备方法：
综上,利用本发明实施例的方法,可以有效地合成含杂原子的新型高B环小檗碱类似物，为靶向p300驱动的抗肿瘤药物研究提供候选化合物。根据发明实施例的方法,该合成路线所用的原料简单易得,实施步骤便捷，合成效率远远高于传统方法。同时，本发明打破了对小檗碱结构改造的局限性，为新的作用靶点和药理活性的发现提供了有力的支撑。
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的前提下,还可以做出其它多种形式的修改、替换或变更。
具体实施方式
下面详细描述本发明的实施例，需要说明的是下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。另外，如果没有明确说明，在下面实施例中所采用的所有试剂均为市场上可以购得的，或者可以按照本文或已知的方法合成的，对于没有列出的反应条件也均为本领域技术人员容易获得的。
实施实例1：5-氧杂高B环小檗碱（Ber-1）的合成
以2,3-二甲氧基苄胺和3,4-亚甲二氧基溴苯为初始原料，经过酰化、碘代、Sonogashira偶联、C-H活化/环化、亲核取代、环合等步骤得到目标化合物5-氧杂高B环小檗碱（Ber-1）。
（1）化合物3的合成：
向干燥的50 mL双颈瓶中加入2,3-二甲氧基苄胺1（4 mmol）和2-吡啶羧酸2（4 mmol，1.0 equiv.），氩气置换3次，注入DCM（20 mL）溶解，将反应液至于-10 °C预冷5分钟。加入Et3N（8 mmol，2.0 equiv.），搅拌均匀后，缓慢滴加POCl3（8 mmol，2.0 equiv.）。滴毕，于-10°C反应5小时后移至室温过夜。TLC监测反应完毕后，移入分液漏斗，依次用饱和Na2CO3溶液、H2O、饱和NaCl溶液反洗，经无水Na2SO4干燥、减压浓缩得粗品。粗品经柱层析纯化（洗脱剂为石油醚/乙酸乙酯 = 5/1）得化合物3，收率为84 %。
化合物3为白色固体，1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.4 Hz, 1H),8.44 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 7.83 (td, J = 7.8, 1.6 Hz, 1H), 7.41– 7.38 (m, 1H), 7.04 – 6.96 (m, 2H), 6.86 (dd, J = 8.0, 1.6 Hz, 1H), 4.69 (d,J = 6.0 Hz, 2H), 3.91 (s, 3H), 3.87 (s, 3H)。
（2）化合物5的合成：
向500 mL圆底瓶中加入3,4-亚甲二氧基溴苯4（6.0 g，3.0 mol）、AgTFA（7.24 g，3.3mol），注入70 mL DCM溶解。降温至-20 °C，向反应体系缓慢滴加I2的DCM/Et2O（150 mL / 70mL）溶液，滴毕室温过夜。反应液经减压浓缩、柱层析（洗脱液为石油醚）得目标化合物5，收率为85 %。
化合物5为白色固体，1H NMR (400 MHz, CDCl3) 7.26 (s, 1H), 7.10 (s, 1H),5.99 (s, 2H)。
（3）化合物6的合成：
向100 mL双颈瓶中加入化合物5（13.2 mmol）、Pd(PPh3)2Cl2（0.66 mmol，0.07equiv.）、CuI（1.3 mmol，0.1 equiv.），Ar换气3次。注入干燥的Et3N （40 mL），室温搅拌均匀后，加入三甲基硅乙炔（14.5 mmol，1.1 equiv.）。室温过夜反应。TLC监测反应完成后，直接减压浓缩除去溶剂。然后向残留物中加入水和乙酸乙酯进行萃取，合并乙酸乙酯层，并用饱和NaCl溶液反洗、无水Na2SO4干燥，减压浓缩后得到深棕色油状物。最后通过硅胶柱层析（洗脱液为石油醚）分离纯化得到目标化合物6，收率为58%。
化合物6为白色固体， 1H NMR (400 MHz, CDCl3) δ 7.01 (s, 1H), 6.92 (s,1H), 5.98 (s, 2H), 0.26 (s, 9H)。
（4）化合物7的合成：
于15 mL封管中依次加入化合物3（0.2 mmol）、化合物6（0.3 mmol）、Co(OAc)2·4H2O（0.31 mmol）、KPF6（0.1 mmol）和2.5 mL PEG-400。反应液氧气置换3次后置于140 °C油浴反应24小时。TLC监测反应完成后，加入乙醚萃取。合并乙醚层，无水硫酸钠干燥，经减压蒸馏除去溶剂，残留物采用硅胶柱层析（洗脱剂为石油醚/乙酸乙酯 = 20/1）分离纯化得目标产品7，收率为51%。
化合物7为黄色固体，1H NMR (400 MHz, CDCl3) δ 9.59 (s, 1H), 7.83 – 7.82(m, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.14 (s, 1H),7.12 (s, 1H), 6.03 (s, 2H), 4.10 (s, 3H), 4.03 (s, 3H)。
（5）化合物8的合成：
将化合物7（0.26 mmol）、CuCl2（0.013 mmol，0.05 equiv.）、K2CO3（0.78 mmol，3.0equiv.）、乙二醇4.0 mL依次加入到10 mL圆底瓶中。反应液置于130 °C反应20小时。TLC监测反应完成后，直接柱层析（洗脱剂为石油醚/乙酸乙酯 = 2/1）分离纯化得化合物8，收率为60%。
化合物8为黄色固体，1H NMR (400 MHz, DMSO-d 6) δ 9.40 (s, 1H), 8.49 (s,1H), 7.74 – 7.68 (m, 2H), 7.56 (s, 1H), 6.95 (s, 1H), 6.04 (s, 2H), 5.12 (s,1H), 4.08 (t, J = 4.8 Hz, 2H), 3.99 – 3.97 (m, 6H), 3.76 (t, J = 4.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d 6) δ 152.1, 148.5, 147.8, 146.1, 145.5, 142.64,141.5, 131.6, 123.4, 121.8, 121.1, 120.7, 119.9, 109.2, 101.3, 97.3, 71.6,61.3, 59.8, 56.9。
（6）化合物Ber-1的合成：
向圆底瓶中加入化合物8（0.283 mmol）、SOCl2（3 mL），室温搅拌3小时。搅拌下将反应液缓慢倾倒入冰水中，室温搅拌5分钟。然后加入乙酸乙酯萃取，乙酸乙酯层用饱和NaCl溶液反洗，无水Na2SO4干燥。减压浓缩后通过硅胶柱层析（洗脱剂为二氯甲烷/甲醇 = 10/1）分离纯化得目标产品Ber-1，收率为63%。
化合物Ber-1为黄色固体，1H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 8.28 (s,1H), 7.61 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), 6.63(s, 1H), 5.99 (s, 2H), 4.20 (t, J = 5.4 Hz, 2H), 4.10 (s, 3H), 4.02 (s, 3H),3.77 (t, J = 5.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 151.3, 149.0, 148.7,145.9, 144.2, 143.0, 132.7, 123.3, 122.6, 121.5, 121.4, 110.5, 101.8, 97.3,70.3, 61.9, 57.3, 42.6.HRMS (ESI): 计算值C20H18ClNO4OH+: 388.0946, 实测值:388.0948。
实施实例2：5-氮杂高B环小檗碱（Ber-2）的合成
如上合成路线所示，以关键中间体7为原料，经亲核取代、环合等步骤得到目标化合物5-氮杂高B环小檗碱（Ber-2）。
（1）化合物9的合成：
将化合物7（0.26 mmol）、CuCl（0.026 mmol，0.1 equiv.）、KOH（0.52 mmol，2.0equiv.）和4.0 mL氨基乙醇依次加入到10 mL圆底瓶中。反应液置于90 °C反应8小时。TLC监测反应完成后，直接柱层析（洗脱剂为石油醚/乙酸乙酯 = 2/1）分离纯化得化合物9，收率为45%。
化合物9为黄色固体，1H NMR (400 MHz, DMSO-d 6) δ 9.36 (s, 1H), 8.06 –8.03 (m, 2H), 7.74 (s, 2H), 7.22 (s, 1H), 6.45 (s, 1H), 5.94 (s, 2H), 4.78(t, J = 5.2 Hz, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 3.60 (q, J = 5.4 Hz, 2H),3.15 (q, J = 5.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d 6) δ 151.0, 148.6, 148.1,144.5, 144.2, 142.6, 138.1, 132.4, 123.2, 121.3, 121.1, 117.0, 113.9, 109.0,100.4, 93.5, 61.3, 59.7, 56.9, 46.1. HRMS (ESI): 计算值C20H20N2O5H+: 369.1445,实测值: 369.1448。
（2）化合物Ber-2的合成：
向圆底瓶中加入化合物9（0.283 mmol）、SOCl2（3 mL），室温搅拌3小时。搅拌下将反应液缓慢倾倒入冰水中，室温搅拌5分钟。然后加入乙酸乙酯萃取，乙酸乙酯层用饱和NaCl溶液反洗，无水Na2SO4干燥。减压浓缩后通过硅胶柱层析（洗脱剂为二氯甲烷/甲醇 = 10/1）分离纯化得目标产品Ber-2，收率为50%。
化合物Ber-2为黄色固体，1H NMR (400 MHz, DMSO-d 6) δ 9.36 (s, 1H), 8.37(t, J = 6.0 Hz, 1H), 8.07 (s, 1H), 7.75 (s, 2H), 7.27 (s, 1H), 6.53 (s, 1H),5.96 (s, 2H), 3.99 (s, 3H), 3.97 (s, 3H), 3.80 (t, J = 6.0 Hz, 2H), 3.49 (q,J = 5.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d 6) δ 150.7, 148.7, 148.2, 144.4,143.2, 142.6, 138.7, 132.4, 123.2, 121.3, 121.2, 117.1, 114.2, 108.9, 100.6,93.9, 61.3, 56.9, 45.2, 44.2. HRMS (ESI): 计算值 C20H19ClN2O4H+: 387.1106, 实测值: 387.1099。
实施实例3：5-硫杂高B环小檗碱（Ber-3）的合成
如上合成路线所示，以关键中间体7为原料，经亲核取代、环合等步骤得到目标化合物5-硫杂高B环小檗碱（Ber-3）。
（1）化合物10的合成：
将化合物7（0.13 mmol）、CuO（0.26 mmol，2.0 equiv.）、巯基乙醇（1.3 mmol，10.0equiv.）和二氧六环2.0 mL依次加入到15 mL封管中。反应液于130°C反应24小时。TLC监测反应完成后，加入水和乙酸乙酯萃取，有机层浓缩后柱层析（洗脱剂为石油醚/乙酸乙酯 =2/1）得化合物10，收率为85%。
化合物10为黄色固体，1H NMR (400 MHz, DMSO-d 6) δ 9.40 (s, 1H), 7.87 –7.77 (m, 3H), 7.19 (s, 1H), 7.08 (s, 1H), 6.10 (s, 2H), 4.95 (s, 1H), 4.00 –3.99 (m, 6H), 3.44 – 3.42 (m, 2H), 2.90 – 2.87 (m, 2H); 13C NMR (100 MHz,DMSO-d 6) δ 149.6, 148.7, 147.5, 145.9, 145.4, 142.7, 135.6, 131.1, 127.4,123.1, 122.0, 120.8, 112.0, 110.3, 109.9, 101.5, 61.3, 59.7, 56.9, 37.0. HRMS(ESI): 计算值C20H19NO5SH+: 386.1057, 实测值: 386.1051。
（2）化合物Ber-3的合成：
向圆底瓶中加入化合物10（0.283 mmol）、SOCl2（3 mL），室温搅拌3小时。搅拌下将反应液缓慢倾倒入冰水中，室温搅拌5分钟。然后加入乙酸乙酯萃取，乙酸乙酯层用饱和NaCl溶液反洗，无水Na2SO4干燥。减压浓缩后通过硅胶柱层析（洗脱剂为二氯甲烷/甲醇 = 10/1）分离纯化得目标产品Ber-3，收率为85%。
化合物Ber-3为黄色固体，1H NMR (400 MHz, DMSO-d 6) δ 9.40 (s, 1H), 7.87 –7.77 (m, 3H), 7.19 (s, 1H), 7.08 (s, 1H), 6.10 (s, 2H), 4.95 (s, 1H), 4.00 –3.99 (m, 6H), 3.44 – 3.42 (m, 2H), 2.90 – 2.87 (m, 2H); 13C NMR (100 MHz,DMSO-d 6) δ 149.6, 148.7, 147.5, 145.9, 145.4, 142.7, 135.6, 131.1, 127.4,123.1, 122.0, 120.8, 112.0, 110.3, 109.9, 101.5, 61.3, 59.7, 56.9, 37.0. HRMS(ESI): 计算值 C20H19NO5SH+: 386.1057, 实测值: 386.1051。
参考文献
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Claims (2)
1.一类含杂原子的新型高B环小檗碱类似物，其特征在于，结构式如式所示：
小檗碱的B环为高B环，5位为氧、氮、硫等杂原子。
2.一种制备权利要求1所述的含杂原子的新型高B环小檗碱类似物的方法，它包括如下工艺流程：
(i) 5-氧杂高B环小檗碱的制备方法：
(ii) 5-氮杂高B环小檗碱的制备方法：
(iii) 5-硫杂高B环小檗碱的制备方法：
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| ZHONGZHEN YANG，等: "Total Synthesis and Evaluation of B‐Homo Palmatine and Berberine Derivatives as p300 Histone Acetyltransferase Inhibitors", 《EUR. J. ORG. CHEM.》 * |
| 方慧华，等: "小檗碱及其衍生物抗肿瘤作用研究进展", 《小檗碱及其衍生物抗肿瘤作用研究进展》 * |
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