CN117105930B - 一类3,13-双取代小檗碱衍生物及其制备方法和应用 - Google Patents
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Abstract
本发明公开了一类3,13‑双取代小檗碱衍生物及其制备方法和应用。其中3,13‑双取代小檗碱衍生物结构如所示。与之前报道的方法产率（13‑17%）相比，本发明所采用的方法制备双取代衍生物的总产率显着提高。其中，3‑,13‑双取代类似物4b对抗生素敏感和耐药的幽门螺杆菌菌株表现出最有希望的活性，最低抑制浓度（MIC）值范围为0.25‑0.5μg/mL，表明不同于一线抗幽门螺杆菌抗生素的新型机制。
Description
技术领域
本发明涉及医药技术领域，具体涉及一类3,13-双取代小檗碱衍生物及其制备方法和应用。
背景技术
幽门螺杆菌（H. pylori）是一种螺旋形革兰氏阴性微需氧细菌，可在人胃中存活和定殖。幽门螺杆菌感染是慢性胃炎、消化不良和消化性溃疡的主要危险因素，甚至被认为是慢性胃炎、消化不良和消化性溃疡的主要危险因素，也是导致胃癌及其癌前病变的关键始动因素。此外，它是唯一与胃肿瘤发生有关的致癌病原体，被世界卫生组织(WHO)国际癌症研究机构（IARC）于 1994 年列为I类致癌物。全世界幽门螺杆菌的感染率超过 50%，在环境卫生和个人卫生习惯可能不足的发展中国家甚至更高。
目前，幽门螺杆菌感染的一线根除方案主要包括抗生素三联疗法和四联疗法，其中包括两种抗菌药物，以及质子泵抑制剂（沃诺拉赞/奥美拉唑（OPZ）/兰索拉唑等）或/和铋进行协同治疗。然而，过去二十年来，全球幽门螺杆菌对临床推荐抗生素，包括左氧氟沙星（LEV）、甲硝唑（MTZ）、克拉霉素（CLA）和四环素（TC）的耐药性有所增加。在所有幽门螺杆菌根除方案中，观察到大约 10-30% 的治疗失败的案例。其中，在西欧MTZ的耐药率范围为11-70%，而CLA的耐药率为 20-50%。另外，CLA和MTZ的双重耐药率大于25%，使得反复感染极难治愈。耐CLA的幽门螺杆菌被世界卫生组织列为高度优先类别病原体，强调迫切需要新的抗生素来解决这一问题。当前的幽门螺杆菌根除方案也与副作用、容易复发和胃肠道菌群失衡有关，进一步强调需要新的治疗方案。因此，具有新作用机制的新型幽门螺杆菌药物具有重要的临床意义。
越来越多的临床研究表明，中药小檗碱（BBR）联合三联疗法可以提高幽门螺杆菌的根除率，具有药代动力学特性独特、不良反应发生率低、避免肠道菌群失衡、改善内环境和病理修复等优点。研究发现，BBR可以抑制幽门螺杆菌的生长、呼吸和糖代谢中间产物的氧化。此外，BBR可以通过抑制幽门螺杆菌的芳胺N-乙酰转移酶活性并靶向脲酶活性位点的巯基来抑制脲酶活性和脲酶成熟从而发挥抗幽门螺杆菌作用。然而，BBR对幽门螺杆菌仅表现出中等的抑制活性（MIC = 16-256 μg/mL)。
发明内容
针对现有技术的上述不足，本发明的目的在于提供一类3,13-双取代小檗碱衍生物及其制备方法和应用。通过对 BBR 的合理设计和修改，有可能获得具有改进活性、新机制和良好安全性的候选药物。
为了达到上述发明目的，本发明采用的技术方案为：
第一方面，提供一类3,13-双取代小檗碱衍生物，其结构如式I所示：
式I
其中，R1代表取代烷烃、取代环烷烃、取代烯基、取代炔基、取代苄基、取代苯基、取代酮羰基、取代酯基、含氮杂环、含氧杂环、含硫杂环、羧基、醛基、氨基、卤代取代基中的任意一种；
R2代表取代烷烃、取代环烷烃、取代烯基、取代炔基、取代苄基、取代苯基、取代酮羰基、取代酯基、含氮杂环、含氧杂环、含硫杂环、羧基、醛基、氨基、卤代取代基中的任意一种。
进一步地， R1、R2独立地选自如下组合中的任意一种：
第二方面，提供一种3,13-双取代小檗碱衍生物的制备方法，其包括以下步骤：
在氢化钠作为碱存在下，药根碱在DMF中与取代的卤代烃一起加热；使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到终产品。
进一步地，加热温度为 71℃，加热时间为 0.5-1h。
第三方面，提供一种药品组合物，其含有有效剂量的3,13-双取代小檗碱衍生物或生理上可接受的盐和药学上可接受的载体或赋形剂。
第四方面，提供一种3,13-双取代小檗碱衍生物或生理上可接受的盐或药品组合物在制备预防、缓解和/或治疗微生物感染产品中的应用。
进一步地，微生物是幽门螺杆菌。
第五方面，提供一种3,13-双取代小檗碱衍生物或生理上可接受的盐或药品组合物在制备预防、缓解和/或治疗抗菌药品中的应用。
本发明的有益效果为：
本发明提供了一类3,13-双取代小檗碱衍生物及其制备方法和应用。与之前报道的方法产率（13-17%）相比，本发明所采用的方法制备双取代衍生物的总产率显着提高。其中，3-,13-双取代类似物4b对抗生素敏感和耐药的幽门螺杆菌菌株表现出最有希望的活性，最低抑制浓度（MIC）值范围为0.25-2 μg/mL，表明不同于一线抗幽门螺杆菌抗生素的新型机制。
附图说明
图1为试验例1中小鼠进行化合物4b的急性口服毒性试验结果示意图；
图2为试验例1中小鼠在单次口服化合物4b后不同时间点的胃和血液检测结果示意图；
图3为试验例2中4b处理前后幽门螺杆菌的扫描电镜下形态学分析示意图；a、b为未处理的幽门螺杆菌的透射电镜（TEM）图像；c、d为经4b处理的幽门螺杆菌的TEM图像；
图4为试验例2中4b处理前后幽门螺杆菌的透射电镜下形态学分析示意图； a、b为未处理的幽门螺杆菌的扫描电镜（SEM）图像；c、d为经4b处理的幽门螺杆菌的SEM图像；
图5为试验例3中化合物4b的体内抗菌评价中每组菌落形成单位的中位数；
图6为试验例3中化合物4b的体内抗菌评价中每组小鼠的体重（n=5），数据以平均值±SD表示（n=5只生物独立小鼠）；
图7为试验例3中化合物4b的体内抗菌评价中胃（上）和肠（下）组织的H&E染色示意图。
具体实施方式
下面对本发明的具体实施方式进行描述，以便于本技术领域的技术人员理解本发明，但应该清楚，本发明不限于具体实施方式的范围，对本技术领域的普通技术人员来讲，只要各种变化在所附的权利要求限定和确定的本发明的精神和范围内，这些变化是显而易见的，一切利用本发明构思的发明创造均在保护之列。
实施例1化合物4b的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与取代的α-不饱和卤代烃（4.0当量）一起加热（71℃，0.5h），生成4b。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物4b，产率88%。
1H NMR(600 MHz, DMSO-d 6): δ 9.94 (s, 1H), 8.19 (d,J= 9.5 Hz, 1H), 8.00(d,J= 9.4 Hz, 1H), 7.51 (s, 1H), 7.17 (s, 1H), 6.13 (d,J= 14.3 Hz, 1H), 5.91(dd,J= 15.3, 6.5 Hz, 1H), 5.77–5.70 (m, 1H), 5.30 (dd,J= 15.7, 6.6 Hz, 1H),4.85 (s, 2H), 4.60 (d,J= 6.1 Hz, 2H), 4.09 (dd,J= 19.0, 6.9 Hz, 6H), 3.98 (s,2H), 3.76 (s, 3H), 3.12 (t,J= 5.7 Hz, 2H), 1.72 (dd,J= 21.2, 5.6 Hz, 6H).
13C NMR(151 MHz, MeOD): δ 151.67, 149.82, 146.17, 145.87, 138.94,135.15, 132.71, 132.47, 131.82, 130.86, 130.06, 127.41, 126.97, 122.94,122.80, 120.52, 114.14, 113.50, 101.40, 70.71, 62.64, 59.03, 57.56, 56.93,34.55, 28.52, 18.24, 17.95.
HRMS (ESI)m/zcalc for C28H32NO4 +[M+H]+: 446.23258, found: 446.23240.
LCMS (254 nm):m/zfor C28H32NO4 +[M+H]+ : 446.2, ≥99% pure.
实施例2 化合物2h的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成2h。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物4b，产率90%。
1H NMR(600 MHz, MeOD): δ 9.78 (s, 1H), 8.83 (s, 1H), 8.14 (d,J= 9.0Hz, 1H), 8.05 (d,J= 9.1 Hz, 1H), 7.68 (s, 1H), 7.06 (s, 1H), 5.54 (t,J= 6.9Hz, 1H), 4.70 (d,J= 7.0 Hz, 4H), 4.23 (s, 3H), 4.13 (s, 3H), 4.01 (s, 3H),3.29 (t, J = 6.4 Hz, 2H), 1.82 (d, J = 13.8 Hz, 5H), 1.44–1.25 (m, 4H).
13C NMR(151 MHz, MeOD): δ 152.95, 151.91, 151.17, 146.33, 145.72,139.92, 139.85, 135.29, 129.95, 128.07, 124.50, 123.28, 121.29, 120.43,120.33, 113.61, 110.08, 66.92, 62.57, 57.68, 57.40, 57.03, 27.82, 25.91,18.28.
HRMS (ESI)m/zcalc for C25H28NO4 +[M+H]+: 406.20128, found: 406.20087.
实施例3化合物2d的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成2d。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物4b，产率84%。
1H NMR(600 MHz, DMSO-d 6): δ 9.88 (s, 1H), 9.02 (s, 1H), 8.21 (d,J= 9.2Hz, 1H), 8.03 (d,J= 9.1 Hz, 1H), 7.70 (s, 1H), 7.09 (s, 1H), 4.93 (t,J= 6.4Hz, 2H), 4.10 (s, 3H), 4.07 (s, 3H), 3.94 (s, 3H), 3.88 (d,J= 6.3 Hz, 2H),3.21 (t,J= 6.4 Hz, 2H), 1.89–1.69 (m, 6H), 1.88–1.64 (m, 7H), 1.67 (d,J= 12.4Hz, 1H), 1.30–1.21 (m, 2H), 1.05 (qd,J= 12.3, 3.5 Hz, 2H).
13C NMR(151 MHz, DMSO-d 6): δ 151.11, 150.21, 148.87, 145.42, 143.61,137.75, 133.10, 128.68, 126.80, 123.38, 121.33, 119.78, 118.74, 112.12,108.99, 73.57, 61.90, 57.05, 56.29, 55.39, 36.96, 29.22, 26.02, 25.92, 25.17.
HRMS (ESI)m/zcalc for C27H32NO4 +[M+H]+: 434.23258, found: 434.23180.
实施例4化合物2n的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成2n。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物2n，产率78%。
1H NMR(600 MHz, DMSO-d 6): δ 9.90 (s, 1H), 9.04 (d,J= 2.7 Hz, 1H), 8.22(d,J= 9.1 Hz, 1H), 8.04 (d,J= 9.0 Hz, 1H), 7.75 (s, 1H), 7.03 (s, 1H), 4.94(t,J= 6.4 Hz, 2H), 4.91 (s, 2H), 4.20 (q,J= 7.1 Hz, 2H), 4.10 (s, 3H), 4.08(s, 3H), 3.97 (s, 3H), 3.19 (t,J= 6.4 Hz, 2H), 1.24 (t,J= 7.1 Hz, 3H).
13C NMR(151 MHz, MeOD): δ 170.32, 152.04, 151.85, 151.16, 146.47,145.75, 139.47, 135.15, 129.71, 128.04, 124.58, 123.36, 121.73, 121.62,114.41, 110.76, 66.89, 62.58, 62.54, 57.66, 57.35, 57.18, 27.68, 14.46.
HRMS (ESI)m/zcalc for C24H26NO6 +[M+H]+: 424.17546, found: 424.17556.
实施例5 化合物2k的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成2k。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物2k，产率92%。
1H NMR(600 MHz, DMSO-d 6): δ 9.91 (s, 1H), 9.06 (s, 1H), 8.23 (d,J= 9.1Hz, 1H), 8.15–7.84 (m, 1H), 7.76 (s, 1H), 7.16 (s, 1H), 4.96 (t,J= 6.3 Hz,2H), 4.93 (d,J= 2.4 Hz, 2H), 4.11 (s, 3H), 4.08 (s, 3H), 3.96 (s, 3H), 3.66(t,J= 2.4 Hz, 1H), 3.23 (t,J= 6.4 Hz, 2H).
13C NMR(151 MHz, DMSO-d 6): δ 150.34, 149.14, 149.01, 145.51, 143.66,137.48, 133.02, 128.20, 126.78, 123.45, 121.42, 120.15, 119.89, 112.96,109.15, 78.86, 78.75, 61.92, 57.05, 56.26, 56.17, 55.35, 25.95.
HRMS (ESI)m/zcalc for C23H22NO4 +[M+H]+: 376.15433, found: 376.15399.
实施例6 化合物2m的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成2m。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物2m，产率74%。
1H NMR(600 MHz, DMSO-d 6): δ 9.89 (s, 1H), 9.05 (s, 1H), 8.22 (d,J= 9.2Hz, 1H), 8.06 (d,J= 9.1 Hz, 1H), 7.74 (s, 1H), 6.89 (s, 1H), 5.26 (s, 2H),4.98 (s, 4H), 4.98 (s, 4H), 4.94 (s, 1H), 4.94 (s, 1H), 4.10 (s, 3H), 4.09(d,J= 15.7 Hz, 6H), 4.08 (s, 3H), 3.96 (s, 3H), 3.18 (t,J= 6.5 Hz, 2H), 1.20(s, 9H).
13C NMR(151 MHz, DMSO-d 6): δ 208.15, 150.27, 150.14, 148.77, 145.45,143.63, 137.62, 133.07, 128.26, 126.80, 123.41, 121.38, 119.92, 119.27,112.26, 109.28, 64.40, 61.91, 57.06, 56.32, 52.84, 43.97, 25.75, 25.43.
HRMS (ESI)m/zcalc for C26H30NO5 +[M+H]+: 436.21185, found: 436.21088.
实施例7 化合物2i的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成2i。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物2i，产率91%。
1H NMR(600 MHz, DMSO-d 6): δ 9.90 (s, 1H), 9.05 (s, 1H), 8.22 (d,J= 9.1Hz, 1H), 8.04 (d,J= 9.1 Hz, 1H), 7.76 (s, 1H), 7.15 (s, 1H), 6.20 (q,J= 1.5Hz, 1H), 5.87–5.72 (m, 1H), 4.97–4.85 (m, 3H), 5.02–4.82 (m, 4H), 4.10 (s,3H), 4.08 (s, 3H), 3.97 (s, 3H), 3.21 (t,J= 6.4 Hz, 2H).
13C NMR(151 MHz, DMSO-d 6): δ 150.36, 149.48, 149.42, 149.03, 145.55,143.68, 137.48, 133.00, 128.42, 127.01, 126.82, 123.45, 121.44, 120.44,120.12, 113.33, 109.45, 71.98, 61.92, 57.06, 56.40, 55.37, 25.90.
HRMS (ESI)m/zcalc for C23H23BrNO4 +[M+H]+: 456.08050, found: 456.08108.
实施例8 化合物3d的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成3d。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物3d，产率80%。
1H NMR(600 MHz, DMSO-d 6): δ 9.89 (s, 1H), 9.04 (s, 1H), 8.22 (d,J= 9.1Hz, 1H), 8.04 (d,J= 9.1 Hz, 1H), 7.74 (s, 1H), 7.49 (d,J= 7.0 Hz, 2H), 7.46–7.41 (m, 2H), 7.40–7.35 (m, 1H), 7.22 (s, 1H), 5.21 (s, 2H), 4.95 (t,J= 6.3Hz, 2H), 4.10 (s, 3H), 4.08 (s, 3H), 3.95 (s, 3H), 3.21 (t,J= 6.4 Hz, 2H).
13C NMR(151 MHz, DMSO-d 6): δ 173.89, 150.91, 150.77, 145.89, 143.79,141.70, 136.77, 132.73, 127.91, 126.71, 125.34, 123.75, 122.79, 121.72,121.43, 110.15, 61.97, 57.06, 56.71, 55.32, 42.73, 29.51, 29.01, 25.44.
HRMS (ESI)m/zcalc for C26H28NO5 +[M+H]+: 434.19620, found: 434.19555.
实施例9 化合物2g的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成2g。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物2g，产率86%。
1H NMR(600 MHz, DMSO-d 6): δ 9.88 (s, 1H), 9.04 (s, 1H), 8.21 (d,J= 9.2Hz, 1H), 8.04 (d,J= 9.1 Hz, 1H), 7.71 (s, 1H), 7.10 (s, 1H), 5.98–5.87 (m,1H), 5.75 (dddd,J= 15.4, 7.9, 4.5, 1.7 Hz, 1H), 4.94 (t,J= 6.4 Hz, 2H), 4.58(dt, J = 6.3, 1.3 Hz, 2H), 4.10 (s, 3H), 4.07 (s, 3H), 3.94 (s, 3H), 3.33 (s,2H), 3.21 (t,J= 6.5 Hz, 2H), 1.74–1.73 (m, 3H).
13C NMR(151 MHz, DMSO-d 6): δ 150.48, 150.22, 148.87, 145.42, 143.61,137.69, 133.08, 130.55, 128.49, 126.79, 125.88, 123.37, 121.34, 119.82,118.88, 112.30, 108.85, 68.85, 61.90, 57.05, 56.17, 55.38, 25.94, 17.56.
HRMS (ESI)m/zcalc for C24H26NO4 +[M+H]+: 392.18563, found: 392.18522.
实施例10 化合物2l的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成2l。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物2l，产率94%。
1H NMR(600 MHz, MeOD): δ 9.76 (s, 1H), 8.81 (s, 1H), 8.12 (d,J= 9.1Hz, 1H), 8.03 (d,J= 9.1 Hz, 1H), 7.67 (s, 1H), 7.05 (s, 1H), 4.21 (s, 2H),4.15 (t,J= 6.3 Hz, 2H), 4.12 (s, 2H), 4.01 (s, 2H), 3.28 (d,J= 6.5 Hz, 1H),2.30 (td,J= 7.1, 2.7 Hz, 2H), 2.25 (t,J= 2.6 Hz, 1H), 1.97 (dd,J= 8.5, 6.3Hz, 2H), 1.74 (p,J= 7.3 Hz, 2H), 1.29 (d,J= 6.9 Hz, 4H).
13C NMR(151 MHz, MeOD): δ 153.28, 151.92, 151.13, 146.33, 145.75,139.47, 135.32, 130.06, 128.12, 124.49, 123.30, 121.28, 120.43, 113.31,110.25, 84.75, 69.90, 69.78, 62.57, 57.70, 57.41, 57.12, 29.20, 27.80, 26.27,18.77.
HRMS (ESI)m/zcalc for C26H28NO4 +[M+H]+: 418.20128, found: 418.20039.
实施例11 化合物2j的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成2j。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物2j，产率85%。
1H NMR(600 MHz, DMSO-d 6): δ 10.11 (s, 1H), 9.90 (s, 1H), 8.40 (d,J=9.4 Hz, 1H), 8.17 (d,J= 9.5 Hz, 1H), 7.15 (s, 1H), 6.94 (s, 1H), 5.96 (s,2H), 4.79 (s, 3H), 4.60–4.46 (m, 1H), 4.09 (s, 3H), 4.06 (s, 3H), 3.83 (s,3H), 3.07 (td,J= 5.7, 2.7 Hz, 2H), 2.71 (d,J= 13.6 Hz, 2H), 2.50 (p,J= 1.9Hz, 3H), 2.36–2.27 (m, 2H), 1.99 (d,J= 17.3 Hz, 2H), 1.75–1.61 (m, 2H).
13C NMR(151 MHz, DMSO-d 6): δ 149.65, 149.34, 146.36, 144.53, 144.19,137.53, 135.55, 132.39, 132.16, 130.08, 125.17, 122.11, 121.60, 117.65,115.61, 114.76, 113.60, 62.00, 60.59, 57.13, 56.91, 55.84, 29.61, 26.61,24.18, 22.54.
HRMS (ESI)m/zcalc for C26H28NO4 +[M+H]+: 418.20128, found: 418.20042.
实施例12 化合物4a的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成4a。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物4a，产率82%。
1H NMR(600 MHz, MeOD): δ 9.86 (s, 1H), 8.12 (d,J= 9.4 Hz, 1H), 8.03(d,J= 9.4 Hz, 1H), 7.57 (s, 1H), 7.12 (s, 1H), 6.67–6.45 (m, 1H), 6.11 (ddt,J= 16.2, 10.5, 5.3 Hz, 1H), 5.58–5.44 (m, 2H), 5.31 (d,J= 10.6 Hz, 1H), 4.97(d,J= 17.7 Hz, 3H), 4.71 (d,J= 5.3 Hz, 2H), 4.22 (s, 3H), 4.14 (d,J= 3.9 Hz,2H), 4.11 (s, 3H), 3.85 (s, 3H), 3.18 (t,J= 5.9 Hz, 2H).
13C NMR(151 MHz, MeOD): δ 151.79, 151.70, 149.73, 146.13, 146.07,139.00, 137.51, 135.02, 134.16, 132.83, 131.64, 127.34, 122.89, 122.84,120.62, 119.31, 118.35, 114.19, 113.57, 70.79, 62.70, 59.03, 57.57, 57.23,35.63, 28.52.
HRMS (ESI)m/zcalc for C26H28NO4 +[M+H]+: 418.20128, found: 418.20073.
实施例13 化合物3e的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成3e。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物3e，产率80%。
1H NMR(600 MHz, DMSO-d 6): δ 9.98 (s, 1H), 9.29–9.22 (m, 1H), 8.26 (d,J= 9.2 Hz, 1H), 8.10 (d,J= 9.1 Hz, 1H), 7.93 (s, 1H), 7.26 (s, 1H), 4.99 (t,J=6.4 Hz, 2H), 4.12 (s, 3H), 4.09 (s, 3H), 3.96 (s, 3H), 3.24 (t,J= 6.4 Hz,2H), 2.61 (d,J= 7.4 Hz, 2H), 2.27 (p,J= 7.7 Hz, 1H), 1.90–1.83 (m, 2H), 1.65(tdd,J= 12.5, 11.2, 9.5, 4.7 Hz, 2H), 1.58–1.54 (m, 2H), 1.26 (dddd,J= 16.0,13.0, 6.5, 2.4 Hz, 2H).
13C NMR(151 MHz, DMSO-d 6): δ 170.44, 150.87, 150.79, 145.93, 143.82,141.59, 136.79, 132.69, 127.96, 126.76, 125.39, 123.71, 122.84, 121.74,121.36, 110.11, 61.96, 57.06, 56.58, 55.34, 39.15, 36.13, 31.80, 25.43,24.55.
HRMS (ESI)m/zcalc for C27H30NO5 +[M+H]+: 448.21185, found: 448.21125.
实施例14 化合物3g的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成3g。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物3g，产率85%。
1H NMR(600 MHz, DMSO-d 6): δ 9.96 (s, 1H), 9.16 (s, 1H), 8.26 (d,J= 9.1Hz, 1H), 8.08 (d,J= 9.0 Hz, 1H), 7.90 (s, 1H), 7.26 (s, 1H), 4.98 (t,J= 6.4Hz, 2H), 4.12 (s, 3H), 4.09 (s, 3H), 3.95 (s, 3H), 3.24 (t,J= 6.4 Hz, 2H),1.33 (s, 9H).
13C NMR(151 MHz, DMSO-d 6): δ 175.63, 150.92, 150.78, 145.95, 143.82,141.95, 136.83, 132.67, 128.01, 126.81, 125.30, 123.66, 122.81, 121.73,121.24, 110.05, 61.95, 57.06, 56.68, 55.36, 38.64, 26.82, 25.41.
HRMS (ESI)m/zcalc for C25H28NO5 +[M+H]+: 422.19620, found: 422.19565.
实施例15 化合物2f的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成2f。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物2f，产率95%。
1H NMR(600 MHz, DMSO-d 6): δ 9.89 (s, 1H), 9.03 (s, 1H), 8.22 (d,J= 9.1Hz, 1H), 8.04 (d,J= 9.1 Hz, 1H), 7.73 (s, 1H), 7.11 (s, 1H), 6.10 (ddt,J=17.3, 10.6, 5.3 Hz, 1H), 5.45 (dq,J= 17.2, 1.7 Hz, 1H), 5.31 (dd,J= 10.5, 1.6Hz, 1H), 4.95 (t,J= 6.4 Hz, 2H), 4.68 (dt,J= 5.4, 1.5 Hz, 2H), 4.11 (s, 3H),4.08 (s, 3H), 3.95 (s, 3H), 3.21 (t,J= 6.4 Hz, 2H).
13C NMR(151 MHz, DMSO-d 6): δ 150.33, 150.26, 148.91, 145.46, 143.64,137.66, 133.18, 133.07, 128.50, 126.81, 123.39, 121.36, 119.90, 119.13,118.12, 112.54, 109.01, 69.02, 61.90, 57.05, 56.21, 55.37, 25.95.
HRMS (ESI)m/zcalc for C23H24NO4 +[M+H]+: 378.16998, found: 378.16947.
实施例16 化合物3a的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成3a。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物3a，产率80%。
1H NMR(600 MHz, DMSO-d 6): δ 9.96 (s, 1H), 9.19 (s, 1H), 8.26 (d,J= 9.1Hz, 1H), 8.10 (d,J= 9.0 Hz, 1H), 7.91 (s, 1H), 7.27 (s, 1H), 4.99 (t,J= 6.3Hz, 2H), 4.12 (s, 3H), 4.09 (s, 3H), 3.96 (s, 3H), 3.24 (t, J = 6.3 Hz, 2H),2.60 (t,J= 7.2 Hz, 2H), 1.69 (q,J= 7.3 Hz, 2H), 1.00 (t,J= 7.4 Hz, 3H).
13C NMR(151 MHz, DMSO-d 6): δ 171.37, 151.35, 151.27, 146.42, 144.30,142.07, 137.26, 133.15, 128.45, 127.27, 125.86, 124.16, 123.35, 122.23,121.77, 110.54, 62.45, 57.56, 57.11, 55.86, 35.48, 25.93, 18.49, 13.78.
HRMS (ESI)m/zcalc for C24H26NO5 +[M+H]+: 408.18055, found: 408.17998.
实施例17 化合物3h的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成3h。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物3h，产率77%。
1H NMR(600 MHz, MeOD): δ 9.86 (s, 1H), 9.00 (s, 1H), 8.17 (d,J= 9.0Hz, 1H), 8.12 (d,J= 9.0 Hz, 1H), 7.89 (s, 1H), 7.40 (s, 1H), 4.99 (t,J= 6.3Hz, 2H), 4.23 (s, 3H), 4.13 (s, 3H), 4.08 (s, 3H), 3.49–3.45 (m, 2H), 2.83–2.76 (m, 1H), 1.96 (t,J= 7.7 Hz, 2H), 1.56 (p,J= 7.4 Hz, 2H), 1.02 (t,J= 7.4Hz, 3H), 0.94 (t,J= 7.4 Hz, 2H), 0.94 (t,J= 7.4 Hz, 2H).
13C NMR(151 MHz, MeOD): δ 153.33, 152.62, 147.07, 145.94, 141.71,138.28, 134.65, 129.15, 127.97, 127.90, 125.19, 124.96, 123.69, 123.15,111.64, 66.51, 62.66, 57.65, 57.30, 52.54, 27.29, 26.78, 22.37, 13.87.
HRMS (ESI)m/zcalc for C24H28NO6S+[M+H]+: 458.16318, found: 458.16310.
实施例18 化合物3i的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成3i。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物3i，产率75%。
1H NMR(600 MHz, MeOD): δ 9.85 (s, 1H), 9.00 (s, 1H), 8.16 (d,J= 8.9Hz, 1H), 8.11 (d,J= 9.0 Hz, 1H), 7.88 (s, 1H), 7.38 (s, 1H), 4.98 (t,J= 6.2Hz, 2H), 4.22 (s, 3H), 4.11 (s, 3H), 4.06 (s, 3H), 3.49–3.40 (m, 2H), 2.77(t,J= 8.0 Hz, 1H), 1.99–1.94 (m, 2H), 1.75 (td,J= 7.4, 6.5, 3.6 Hz, 1H), 1.51(p,J= 7.3 Hz, 2H), 1.36–1.30 (m, 10H), 1.36–1.28 (m, 8H), 0.92–0.89 (m, 3H).
13C NMR(151 MHz, MeOD): δ 153.31, 152.62, 147.09, 145.92, 141.70,138.26, 134.65, 129.15, 127.97, 127.89, 125.19, 124.97, 123.68, 123.17,111.64, 62.67, 57.65, 57.34, 57.31, 52.78, 32.87, 30.14, 30.11, 29.15, 27.30,24.80, 23.66, 14.41.
HRMS (ESI)m/zcalc for C28H36NO6S+[M+H]+: 514.22578, found: 514.22488.
实施例19 化合物2o的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成2o。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物2o，产率87%。
1H NMR(600 MHz, DMSO-d 6): δ 9.89 (s, 1H), 9.04 (s, 1H), 8.22 (d,J= 9.1Hz, 1H), 8.04 (d,J= 9.1 Hz, 1H), 7.74 (s, 1H), 7.49 (d,J= 7.0 Hz, 2H), 7.46–7.41 (m, 2H), 7.40–7.35 (m, 1H), 7.22 (s, 1H), 5.21 (s, 2H), 4.95 (t,J= 6.3Hz, 2H), 4.10 (s, 3H), 4.08 (s, 3H), 3.95 (s, 3H), 3.21 (t,J= 6.4 Hz, 2H).
13C NMR(151 MHz, DMSO-d 6): δ 150.54, 150.27, 149.00, 147.78, 147.65,145.48, 143.65, 136.43, 133.06, 128.52, 128.11, 127.94, 126.82, 123.40,121.37, 119.94, 119.23, 112.64, 109.04, 70.06, 61.90, 57.04, 56.22, 55.37,25.97.
HRMS (ESI)m/zcalc for C27H26NO4 +[M+H]+: 428.18563, found: 428.18469.
实施例20 化合物3f的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成3f。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物3f，产率79%。
1H NMR(600 MHz, DMSO-d 6): δ 9.96 (s, 1H), 9.18 (s, 1H), 8.26 (d,J= 9.1Hz, 1H), 8.10 (d,J= 9.0 Hz, 1H), 7.90 (s, 1H), 7.25 (s, 1H), 4.98 (s, 1H),4.12 (s, 3H), 4.09 (s, 3H), 3.95 (s, 3H), 3.24 (t,J= 6.4 Hz, 2H), 2.66 (tt,J=10.7, 3.8 Hz, 1H), 1.99 (dd,J= 13.1, 4.0 Hz, 2H), 1.79–1.73 (m, 2H), 1.66–1.62 (m, 1H), 1.58–1.51 (m, 2H), 1.38 (tt,J= 12.8, 3.4 Hz, 2H), 1.31–1.22 (m,2H).
13C NMR(151 MHz, DMSO-d 6): δ 173.04, 150.86, 150.77, 145.92, 143.80,141.72, 136.79, 132.66, 127.96, 126.78, 125.31, 123.66, 122.83, 121.72,121.25, 110.05, 61.95, 57.06, 56.67, 55.36, 41.83, 28.53, 25.42, 25.25,24.58.
HRMS (ESI)m/zcalc for C27H30NO5 +[M+H]+: 448.21185, found: 448.21122.
实施例21 化合物3b的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成3b。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物3b，产率76%。
1H NMR(600 MHz, DMSO-d 6): δ 9.98 (s, 1H), 9.24 (s, 1H), 8.26 (d,J= 9.1Hz, 1H), 8.10 (d,J= 9.1 Hz, 1H), 7.92 (s, 1H), 7.29 (s, 1H), 4.99 (t,J= 6.3Hz, 2H), 4.12 (s, 3H), 4.09 (s, 3H), 3.97 (s, 3H), 3.23 (t,J= 6.3 Hz, 2H),1.95 (tt,J= 8.2, 4.6 Hz, 1H), 1.17–1.09 (m, 2H), 1.07–0.90 (m, 2H).
13C NMR(151 MHz, DMSO-d 6): δ 172.12, 150.95, 150.79, 145.93, 143.82,141.46, 136.78, 132.69, 127.91, 126.76, 125.39, 123.71, 122.93, 121.74,121.37, 110.09, 61.96, 57.05, 56.61, 55.33, 25.44, 12.37, 9.13.
HRMS (ESI)m/zcalc for C24H24NO5 +[M+H]+: 406.16490, found: 406.16463.
实施例22 化合物4c的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成4c。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物4c，产率82%。
1H NMR(600 MHz, DMSO-d 6): δ 9.89 (s, 1H), 9.04 (s, 1H), 8.22 (d,J= 9.1Hz, 1H), 8.04 (d,J= 9.1 Hz, 1H), 7.74 (s, 1H), 7.49 (d,J= 7.0 Hz, 2H), 7.46–7.41 (m, 2H), 7.40–7.35 (m, 1H), 7.22 (s, 1H), 5.21 (s, 2H), 4.95 (t,J= 6.3Hz, 2H), 4.10 (s, 3H), 4.08 (s, 3H), 3.95 (s, 3H), 3.21 (t,J= 6.4 Hz, 2H).
13C NMR(151 MHz, DMSO-d 6): δ 150.15, 149.66, 147.40, 145.42, 144.22,138.98, 137.47, 136.36, 133.04, 131.49, 129.30, 128.98, 128.50, 128.15,128.11, 127.95, 126.74, 126.28, 121.42, 121.18, 119.05, 112.42, 112.03,70.03, 62.06, 57.08, 56.94, 54.27, 35.74, 26.68.
HRMS (ESI)m/zcalc for C34H32NO4 +[M+H]+: 518.23258, found: 518.23188.
LCMS (254 nm):m/zfor C34H32NO4 +[M+H]+ : 518.2, 96.2% pure.
实施例23 化合物3c的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成3c。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物3c，产率72%。
1H NMR(600 MHz, DMSO-d 6): δ 9.98 (s, 1H), 9.26 (s, 1H), 8.26 (d,J= 9.1Hz, 1H), 8.11 (d,J= 9.0 Hz, 1H), 7.94 (s, 1H), 7.28 (s, 1H), 5.00 (t,J= 6.3Hz, 2H), 4.12 (s, 3H), 4.09 (s, 3H), 3.97 (s, 3H), 3.53–3.47 (m, 1H), 3.24(t,J= 6.3 Hz, 2H), 2.39–2.29 (m, 4H), 2.03 (dp,J= 11.0, 8.7 Hz, 1H), 1.96–1.88 (m, 1H).
13C NMR(151 MHz, DMSO-d 6): δ 172.63, 150.90, 150.78, 145.92, 143.81,141.60, 136.79, 132.70, 127.95, 126.76, 125.37, 123.72, 122.82, 121.73,121.38, 110.11, 61.96, 57.06, 56.66, 55.33, 36.90, 25.44, 24.73, 17.86.
HRMS (ESI)m/zcalc for C25H26NO5 +[M+H]+: 420.18055, found: 420.18085.
实施例24 化合物2b的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成2b。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物2b，产率83%。
1H NMR(600 MHz, DMSO-d 6): δ 9.89 (s, 1H), 9.04 (s, 1H), 8.22 (d,J= 9.1Hz, 1H), 8.04 (d,J= 9.1 Hz, 1H), 7.74 (s, 1H), 7.49 (d,J= 7.0 Hz, 2H), 7.46–7.41 (m, 2H), 7.40–7.35 (m, 1H), 7.22 (s, 1H), 5.21 (s, 2H), 4.95 (t,J= 6.3Hz, 2H), 4.10 (s, 3H), 4.08 (s, 3H), 3.95 (s, 3H), 3.21 (t,J= 6.4 Hz, 2H).
13C NMR(151 MHz, DMSO-d 6): δ 151.07, 150.22, 148.86, 145.43, 143.61,137.71, 133.11, 128.62, 126.78, 123.40, 121.34, 119.83, 118.84, 112.28,109.03, 72.47, 61.90, 57.05, 56.26, 55.38, 33.82, 25.93, 24.43, 18.13.
HRMS (ESI)m/zcalc for C25H28NO4 +[M+H]+: 406.20128, found: 406.20050.
实施例25 化合物2a的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成2a。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物2a，产率83%。
1H NMR(600 MHz, DMSO-d 6): δ 9.88 (s, 1H), 9.03 (s, 1H), 8.21 (d,J= 9.1Hz, 1H), 8.04 (d,J= 9.1 Hz, 1H), 7.70 (s, 1H), 7.06 (s, 1H), 4.94 (t,J= 6.4Hz, 2H), 4.10 (s, 2H), 4.07 (s, 2H), 3.95 (s, 3H), 3.92 (d,J= 7.1 Hz, 2H),3.20 (t,J= 6.3 Hz, 2H), 1.35–1.25 (m, 1H), 1.34–1.22 (m, 2H), 1.23 (s, 1H),0.67 - 0.57 (m, 2H), 0.35 (dt,J= 6.1, 4.3 Hz, 2H).
13C NMR(151 MHz, DMSO-d 6): δ 150.86, 150.19, 148.78, 145.41, 143.60,137.72, 133.10, 128.53, 126.79, 123.36, 121.32, 119.77, 118.73, 112.10,108.78, 73.07, 61.89, 57.04, 56.12, 55.38, 25.92, 10.03, 3.25.
HRMS (ESI)m/zcalc for C24H26NO4 +[M+H]+: 392.18563, found: 392.18504.
实施例26 化合物2e的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成2e。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物2e，产率77%。
1H NMR(600 MHz, MeOD): δ 9.74 (s, 1H), 8.79 (s, 1H), 8.10 (d,J= 9.0Hz, 1H), 8.06–7.96 (m, 1H), 7.65 (s, 1H), 7.02 (s, 1H), 4.20 (s, 3H), 4.14(t,J= 6.6 Hz, 3H), 4.10 (s, 3H), 4.00 (s, 3H), 3.35 (s, 1H), 3.27 (t,J= 6.4Hz, 2H), 2.27 (dd,J= 14.1, 6.8 Hz, 1H), 2.10 (dq,J= 14.2, 7.2 Hz, 1H), 1.81(dd,J= 10.7, 4.6 Hz, 4H), 1.74 (dd,J= 11.7, 4.9 Hz, 4H), 1.36–1.27 (m, 6H).
13C NMR(151 MHz, MeOD): δ 153.37, 151.85, 151.07, 146.28, 145.69,139.84, 135.28, 130.04, 128.05, 124.48, 123.24, 121.22, 120.25, 113.20,110.22, 68.27, 66.51, 62.56, 57.67, 57.13, 37.57, 35.82, 34.39, 34.28, 32.09,27.63, 27.37, 21.54.
HRMS (ESI)m/zcalc for C28H34NO4 +[M+H]+: 448.24824, found: 448.24780.
LCMS (254 nm):m/zfor C28H34NO4 +[M+H]+ : 448.2, 99.0% pure.
实施例27 化合物2c的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成2c。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物2c，产率75%。
1H NMR(600 MHz, DMSO-d 6): δ 9.89 (s, 1H), 9.03 (s, 1H), 8.22 (d,J= 9.1Hz, 1H), 8.04 (d,J= 9.1 Hz, 1H), 7.71 (s, 1H), 7.11 (s, 1H), 4.94 (t,J= 6.4Hz, 2H), 4.11 (s, 3H), 4.08 (s, 2H), 3.95 (s, 3H), 3.22 (t,J= 6.4 Hz, 2H),2.36 (tt,J= 18.5, 10.1 Hz, 2H), 1.79 (dt,J= 19.5, 6.4 Hz, 4H), 1.66–1.56 (m,3H), 1.36 (d,J= 5.7 Hz, 2H), 1.24 (s, 1H).
13C NMR(151 MHz, DMSO-d 6): δ 151.14, 150.22, 148.86, 145.43, 143.62,137.74, 133.10, 128.68, 126.80, 123.38, 121.33, 119.79, 118.80, 112.27,109.09, 72.54, 66.32, 61.90, 57.04, 56.30, 38.41, 29.04, 25.93, 24.87.
HRMS (ESI)m/zcalc for C26H30NO4 +[M+H]+: 420.21693, found: 420.21682.
实施例28 化合物4d的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成4d。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物4d，产率79%。
1H NMR(600 MHz, DMSO-d 6): δ 10.04 (s, 1H), 8.13 (d,J= 9.5 Hz, 1H),7.81 (d,J= 9.4 Hz, 1H), 7.26 (s, 1H), 7.13 (s, 1H), 6.61 (d,J= 2.3 Hz, 2H),6.48 (t,J= 2.3 Hz, 1H), 6.44 (d,J= 2.3 Hz, 1H), 6.37 (s, 2H), 5.13 (s, 2H),4.89 (s, 2H), 4.68 (s, 2H), 4.13 (s, 3H), 4.05 (s, 3H), 3.74 (s, 6H), 3.70(s, 6H), 3.21 (s, 3H), 3.15 (t,J= 6.0 Hz, 2H).
13C NMR(151 MHz, DMSO-d 6): δ 161.02, 160.57, 150.12, 149.59, 147.41,145.40, 144.12, 141.34, 138.74, 137.45, 133.12, 131.54, 129.14, 126.25,121.42, 121.15, 119.15, 112.46, 112.27, 106.71, 105.71, 99.44, 97.78, 69.87,62.04, 56.91, 55.22, 54.45, 35.82, 26.69.
HRMS (ESI)m/zcalc for C38H40NO8 +[M+H]+: 638.27484, found: 638.27407.
实施例29 化合物2p的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成2p。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物2p，产率80%。
1H NMR(600 MHz, DMSO-d 6): δ 9.89 (s, 1H), 9.05 (s, 1H), 8.22 (d,J= 9.1Hz, 1H), 8.04 (d,J= 9.1 Hz, 1H), 7.75 (s, 1H), 7.18 (s, 1H), 6.64 (d,J= 2.3Hz, 2H), 6.49 (t,J= 2.3 Hz, 1H), 5.15 (s, 2H), 4.94 (t,J= 6.4 Hz, 2H), 4.10(s, 3H), 4.08 (s, 3H), 3.97 (s, 3H), 3.76 (s, 6H), 3.21 (dd,J= 8.7, 4.1 Hz,2H).
13C NMR(151 MHz, DMSO-d 6): δ 160.58, 150.28, 149.03, 147.97, 145.48,143.65, 138.81, 137.63, 133.06, 128.49, 126.81, 123.41, 121.38, 119.96,119.31, 112.73, 109.13, 105.66, 99.46, 69.89, 61.90, 57.04, 56.29, 55.22,25.95.
HRMS (ESI)m/zcalc for C29H30NO6 +[M+H]+: 488.20676, found: 488.20675.
实施例30 化合物2q的制备方法及结构鉴定数据
在氢化钠（NaH，2.0当量）作为碱存在下，药根碱在DMF中与卤代烃（4.0当量）一起加热（71℃，0.5h），生成2q。使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到化合物2q，产率83%。
1H NMR(600 MHz, DMSO-d 6): δ 10.06 (d,J= 6.9 Hz, 1H), 9.90 (s, 1H),9.07 (s, 1H), 8.34–8.29 (m, 2H), 8.24 (dd,J= 15.4, 9.1 Hz, 2H), 8.07 (dd,J=19.3, 9.3 Hz, 2H), 7.79–7.72 (m, 4H), 7.20 (s, 1H), 6.85–6.79 (m, 1H), 5.39(s, 2H), 4.13 (s, 2H), 4.10 (s, 3H), 4.08 (s, 4H), 4.03 (s, 1H), 3.99 (s,3H), 3.21 (t,J= 6.4 Hz, 2H), 3.12 (d,J= 10.1 Hz, 2H).
13C NMR(151 MHz, DMSO-d 6): δ 150.33, 149.01, 147.14, 146.35, 145.53,144.38, 143.66, 137.50, 133.01, 129.16, 128.45, 128.33, 126.81, 123.71,123.43, 121.41, 120.06, 119.70, 113.68, 112.86, 109.16, 68.82, 61.91, 57.05,56.35, 55.36, 29.01.
HRMS (ESI)m/zcalc for C27H25N2O6 +[M+H]+: 473.17071, found: 473.17060.
试验例1 抗幽门螺杆菌体外活性评估
使用易于操作的一步合成程序设计并制备了30种具有3-单取代或 3-,13-二取代的 BBR 新衍生物。所有新构建的BBR衍生物均筛选了6种不同的幽门螺杆菌菌株的活性，其中包括ATCC43504和ATCC700392的两种标准菌株，以及其他4种临床分离株，以BBR、CLA和MTZ作为阳性对照。测试菌株包括CLA抗性菌株（280、289）和MTZ抗性菌株（280、370、289和SS1）。表 1列出了 30 种化合物的化学结构及其对测试的幽门螺杆菌菌株的 MIC 值。构效关系（SAR）分析表明，与单取代衍生物相比，位置 3 和 13 上的共同取代可能提高其抗菌活性（表 1）。在这些构建的衍生物中，选择具有最佳抗菌活性的化合物2e、4b和4c作为代表性化合物进行进一步研究。
表1
体外和体内代表性化合物的初步安全性和药代动力学评估使用MTT测定在GES-1、HepG2、H460和293T细胞中进一步评估化合物2e、4b和4c对细胞活力的影响。暴露于不同浓度的这些化合物后测定细胞活力。如表2所示，与2e（17.68-24.96 μM）和4d（8.81-12.70 μM）相比，化合物4b表现出较低的细胞毒性，细胞毒性浓度（TC50）值范围为50.59至57.07 μM。因此，选择化合物4b作为下一步的潜在候选化合物。在昆明小鼠中进行化合物4b的急性口服毒性试验。对小鼠进行14天的密切监测，4b的半数致死剂量（LD50）值超过500 mg∙kg-1，这表明4b的口服体内安全性较高。然后，对上述小鼠采集的血液样本进行肝肾功能生化指标评估。如图1所示，4b并未导致谷氨酸草乙酸转氨酶（GOT）、谷氨酸丙酮酸转氨酶（GPT）、血尿素氮（BUN）或肌酸（CRE）明显升高，表明4b对肝或肾功能没有显著影响。
表2
为了探究化合物4b的药代动力学性能，C57BL/6小鼠在单次口服30 mg/kg剂量后，采集不同时间点的胃和血液并进行检测。如图2所示，24小时后4b的胃浓度维持在其MIC值以上，表明其具有理想的胃滞留性能，可以确保其抗幽门螺杆菌在体内的功效。同时，血浆中4b的最大浓度（Cmax）低于0.1 μg/mL，并且在6小时后变得不可检测（低于检测限），表明全身副作用的可能性较低。因此，4b的药代动力学特性，包括胃肠道滞留时间长和血浆浓度低，使其适合根除胃内定植的幽门螺杆菌。
试验例2幽门螺杆菌菌株4b的形态分析
由于细菌细胞形态的变化可以为抗菌作用模式提供有价值的线索，并且通常用于研究机制。 因此，本实施例对经过和未经4b处理的幽门螺杆菌菌株进行了扫描电子显微镜（SEM）和透射电子显微镜（TEM）分析。为了确定4b处理的幽门螺杆菌菌株是否存在形态变化，将 1/2 MIC (0.25 μg/mL) 的4b与细菌一起孵育3天。 SEM和TEM分析结果显示，与未处理的对照组相比，幽门螺杆菌外膜的完整性受到损害，并观察到明显的穿孔。这表明4b的作用机制可能与其对外膜完整性的影响有关（图3-4），值得进一步研究。
试验例3 代表性化合物4b的体内活性评价
在C57BL/6小鼠感染模型中评估了4b的体内抗菌活性。将小鼠随机分为五组：未感染对照组和四个感染治疗组，其中包括媒介羧甲基纤维素（CMC）对照组、两药联合治疗组（奥美拉唑加4b[OPZ + 4b]）、三药联合治疗组（OPZ + 阿莫西林 + CLA [OPZ + AC]），以及四联疗法组（OPZ + 阿莫西林 + CLA +4b[OPZ + AC +4b]）。感染小鼠口服幽门螺杆菌（一株经过长期驯化的可定植小鼠的多重耐药菌株），每隔一天一次，共四次。通过细菌计数和比较小鼠胃中的幽门螺杆菌计数来评估治疗效果。两周的接种期后，连续五天进行不同的治疗。 结果表明，OPZ +4b（28.5 mg∙kg-1）处理导致胃内细菌计数显着下降（图5）；相应的中位菌落数（CFU）从1.3×106显着下降至2.4×105CFU∙g-1，与传统三联疗法组（OPZ + AC，5.8×105CFU∙g-1）相似）。值得注意的是，四联疗法（OPZ + AC +4b）显着降低细菌载量至1.6×104CFU∙g-1，与PBS组相比，胃部定植幽门螺杆菌清除率可达98.70%，显示出高于三联疗法组更好的杀菌能力（图5）。这些结果表明，4b在体内与抗生素联用时可以发挥协同抗菌功效，从而提高多重耐药幽门螺杆菌胃定植的清除率。
此外，如图6所示，不同组之间的体重没有显着差异。固定胃切片的组织病理学检查显示，与未感染的组织相比，幽门螺杆菌感染导致胃腺结构更加多孔和肿胀，并伴有明显的炎症浸润（图7）。这种病变在二联和四联治疗组中显着减轻，表明4b治疗可以显着减轻细菌感染引起的炎症相关损害。
抗生素的使用通常会导致肠道菌群紊乱和肠道微生物群多样性下降。 为了研究4b是否影响肠道微生物群和不同细菌的丰度，收集了每组的粪便样本，并采用16S rRNA基因测序来分析肠道微生物群的变化。利用 Pieloi_e 分析，发现感染组（C）和三联治疗组（A）的微生物群多样性在属水平上较未感染组（U）显着下降。值得注意的是，通过施用 OPZ+4b（T），多样性可以恢复到与未感染组总体相似的水平。
接下来，进行属水平的分析，以丰度最高的十种细菌种属作为判断标准。未感染组的肠道菌群含有一定丰度的乳酸菌、杜氏菌等益生菌。然而，在感染组（C）中，微生物群的上述种属的益生菌水平和菌群多样性显著下降。此外，在三联疗法组（A）中，观察到一些属的过度生长，包括克雷伯氏菌属和拟杆菌属。在T组中，包括Dubosiella和Akkermansia在内的益生菌丰度部分恢复或显着增加。这些结果表明，4b可能会部分恢复肠道菌群的多样性以及益生菌的丰度，同时根除幽门螺杆菌。
本发明提供了一类3,13-双取代小檗碱衍生物及其制备方法和应用。与之前报道的方法产率（13-17%）相比，本发明所采用的方法制备双取代衍生物的总产率显着提高。其中，3-,13-双取代类似物4b对抗生素敏感和耐药的幽门螺杆菌菌株表现出最有希望的活性，最低抑制浓度（MIC）值范围为0.25-2 μg/mL，表明不同于一线抗幽门螺杆菌抗生素的新型机制。
于本领域技术人员而言，显然本发明不限于上述示范性实施例的细节，而且在不背离本发明的精神或基本特征的情况下，能够以其他的具体形式实现本发明。因此，无论从哪一点来看，均应将实施例看作是示范性的，而且是非限制性的，本发明的范围由所附权利要求而不是上述说明限定，因此旨在将落在权利要求的等同要件的含义和范围内的所有变化囊括在本发明内。
此外，应当理解，虽然本说明书按照实施方式加以描述，但并非每个实施方式仅包含一个独立的技术方案，说明书的这种叙述方式仅仅是为清楚起见，本领域技术人员应当将说明书作为一个整体，各实施例中的技术方案也可以经适当组合，形成本领域技术人员可以理解的其他实施方式。
Claims (2)
1.一类3,13-双取代小檗碱衍生物的制备方法，其特征在于，3,13-双取代小檗碱衍生物的结构如式I所示：
；
式I
R1、R2独立地选自如下组合中的任意一种：
；
其制备方法具体包括以下步骤：
在氢化钠作为碱存在下，药根碱在DMF中与取代的卤代烃一起加热；使用快速柱色谱法以CH3OH/CH2Cl2作为洗脱液分离产物，减压蒸馏得到终产品；
加热温度为71℃，加热时间为0.5-1h。
2.权利要求1所述的制备方法制得的3,13-双取代小檗碱衍生物或药学上可接受的盐在制备预防、缓解和/或治疗微生物感染产品中的应用；所述微生物是幽门螺杆菌。
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