CN109422740B - 一类莨菪烷型生物碱及其合成方法 - Google Patents
一类莨菪烷型生物碱及其合成方法 Download PDFInfo
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- CN109422740B CN109422740B CN201710746566.2A CN201710746566A CN109422740B CN 109422740 B CN109422740 B CN 109422740B CN 201710746566 A CN201710746566 A CN 201710746566A CN 109422740 B CN109422740 B CN 109422740B
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- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims abstract description 4
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- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 claims description 3
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- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 3
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- CYHOMWAPJJPNMW-JIGDXULJSA-N tropine Chemical compound C1[C@@H](O)C[C@H]2CC[C@@H]1N2C CYHOMWAPJJPNMW-JIGDXULJSA-N 0.000 description 1
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- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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Abstract
本发明涉及化学合成技术领域，具体公开了一类莨菪烷型生物碱及其合成方法，其目标产物莨菪烷型生物碱的结构式如式(I)：
式(I)化合物是一类含有五元氮杂桥环骨架的化合物，氮原子被2‑吡啶甲酸保护；R1是氢或甲氧羰基；R2是氢或取代苯基，所述的莨菪烷型生物碱为消旋体。式(I)化合物对KCl预收缩的大鼠胸主动脉有显著的舒张作用，表明其对血管内皮细胞或者平滑肌细胞具有调节作用，可能对高血压的发生发展有抑制作用。
Description
技术领域
本发明属于化学合成领域，具体地，涉及式(I)所示的一类含有五元氮杂桥环骨架的莨菪烷型生物碱及其合成方法。
背景技术
莨菪烷型生物碱，其结构中含有的莨菪烷(Tropane)即五元氮杂桥环，这类化合物具有显著的生物活性，比如阿托品(Atropine)，东莨菪碱(Scopolamine)，山莨菪碱(Anisodamine)等，均是M胆碱受体拮抗剂。具有抑制腺体分泌，扩散瞳孔，加速心率，松弛支气管和胃肠道平滑肌等作用。临床上用于治疗消化性胃溃疡，平滑肌痉挛导致的内脏绞痛，癫痫，晕船等。
莨菪烷型生物碱是由莨菪醇(Tropine)与不同有机酸所成的酯，莨菪醇可由莨菪酮还原得到。目前用于合成莨菪酮的方法主要是以丁二醛，甲胺与戊酮二酸为原料进行Mannich反应，进而脱羧，两步可以得到莨菪酮(Tropinone)。以阿托品(Atropine)的合成为例，其合成路线如下
内皮功能受损，血管平滑肌的病变参与高血压的发生发展。所以对内皮细胞和平滑肌细胞的调节是高血压治疗的一个重要手段。目前，大鼠离体胸主动脉是研究血管内皮、平滑肌细胞与血管舒张的一个主要手段，样品对KCl预收缩的大鼠胸主动脉有显著的舒张作用，表明样品对血管内皮细胞或者平滑肌细胞具有调节作用，很可能对高血压的发生发展有抑制作用。
发明内容
本发明的目的在于提供一类莨菪烷型生物碱及其合成方法，其目标产物莨菪烷型生物碱的结构式如式(I)所示：
式(I)化合物是一类含有五元氮杂桥环骨架的化合物，氮原子被2-吡啶甲酸保护；R1是氢或甲氧羰基；R2是氢或取代苯基，所述的莨菪烷型生物碱为消旋体。
式(I)化合物的合成方法为：以2-吡啶甲酸保护的环庚胺衍生物1为原料，以PdCl2为催化剂，Ag2CO3为氧化剂，添加取代碘苯(取代碘苯包括含有硝基、三氟甲基、卤素、氰基等吸电子取代基的碘苯，可以是单取代或者多取代；优选的，取代碘苯为4-硝基碘苯、邻碘苯腈或C6F5I)、2，6-二甲氧基苯甲酸和磷酸钠，在溶剂TCE中微波140℃反应2小时，通过钯催化选择性地对酰胺底物1 的氮δ位的sp3(C-H)键进行活化，同时发生分子内氨化环化反应，成功构建五元氮杂桥环骨架，生成莨菪烷型生物碱2(即式(I)化合物)。
反应条件：PdCl2(10mol％),Ag2CO3(2.0equiv),Iodobenzene(2.0equiv),2,6-Dimethoxybenzoic acid(2.0equiv),Na3PO4(2.5equiv),inTCE,microwave,140℃,2h.TCE＝ 1,1,2,2-tetrachloroethane.
上述合成方法中，R1是氢或甲氧羰基；R2是氢或取代苯基。
与现有技术相比，本发明的优点和有益效果在于：
本发明提供了一类新的莨菪烷型生物碱及其合成方法，采用Pd(II)为催化剂，银盐为氧化剂，苯甲酸衍生物可以交换到金属中心钯上，从而作为氢拔除剂，碱作为酸碱平衡剂，最终在取代碘苯的作用下还原消除生成五元氮杂桥环化合物。基于所述合成方法，本发明合成了三个结构新颖的莨菪烷型生物碱。
该方法以条件控制，选择性地活化氮δ位的sp3(C-H)键，高效地构建大张力的氮杂桥环，在此之前可以先引入取代基，为莨菪烷型生物碱的合成以及其逆合成分析提供了新的方法与思路。
具体实施方式
以下具体实施例仅用于详细说明本发明的具体实施方式，并不限制本发明的权利要求书请求保护的范围。
以下具体实施方式中TCE指1,1,2,2-Tetrachloroethane(1,1,2,2-四氯乙烷)；
EDCI指1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride(1-(3- 二甲氨基丙基)-3-乙基碳二亚胺盐酸盐)；
DMAP指4-dimethylaminopyridine(4-二甲氨基吡啶)。
原料的合成
(1)化合物3的制备:
操作参照文献：Gong Chen；Gang He.Angew.Chem.Int.Ed.,2011,50,5192– 5196。
(2)化合物5的制备:
操作如下：将1-氨基环庚酸(560mg，3.56mmol)和4mL甲醇加入到15mL 圆底烧瓶中，并置于冰浴中搅拌。向其中滴加氯化亚砜(0.8mL，11mmol)，渐渐恢复至室温，反应过夜。反应结束后，减压蒸干，加入少量石油醚并过滤，固体用石油醚少量多次洗涤，得到白色固体即1-氨基环庚酯盐酸盐。将所得1-氨基环庚酯盐酸盐、吡啶甲酸(529mg，4.3mmol)、EDCI(1.04mg，5.4mmol)、 DMAP(50mg，0.4mmol)以及二氯甲烷(5mL)加入到10mL圆底烧瓶中，室温下搅拌反应过夜。反应结束后直接通过硅胶色谱柱(石油醚：乙酸乙酯＝10：1) 分离得到742mg目标产物5，两步反应总产率75％，1H NMR(400MHz,CDCl3)δ 8.55(d,J＝4.2Hz,1H),8.29(s,1H),8.14(d,J＝7.8Hz,1H),7.82(t,J＝7.4Hz, 1H),7.49–7.35(m,1H),3.72(s,3H),2.32–2.13(m,4H),1.61(s,8H)；13C NMR (100MHz,CDCl3)δ174.9,163.4,149.7,148.0,137.3,126.2,122.1,62.2,52.4,36.3, 29.3,22.7；HRMS(EI)Calcd for C15H20N2O3[M+]:276.1474,found 276.1460；IR (KBr)ν(cm-1):3380,2930,1730,1670,1512,1042,750,586。
(3)化合物7的制备:
操作如下：将化合物3(262mg，1.2mmol)、醋酸钯(23.5mg，0.096)、碳酸银(496mg，1.8mmol)以及对甲氧基碘苯(2g，8.6mmol)加入到微波反应管中，功率20W，120℃反应2小时。反应结束后自然冷却至室温，硅藻土过滤，旋干。通过硅胶色谱柱(石油醚：乙酸乙酯＝15：1)分离得到154mg目标产物7，产率40％，1H NMR(400MHz,CDCl3)δ8.60–8.44(m,1H),8.13(d,J＝7.9Hz, 1H),7.88–7.70(m,1H),7.33(dd,J＝6.8and 5.3Hz,1H),7.16(d,J＝8.5Hz,1H), 7.06(d,J＝8.5Hz,1H),6.80(dd,J＝9.9and 9.0Hz,2H),5.35–5.23(m,0.45H),5.23–5.08(m,0.55H),4.83–4.65(m,1H),3.85–3.65(m,3H),3.19–3.02(m,1H), 2.87–2.72(m,1H),2.65–2.50(m,1H),2.41–2.28(m,0.5H),2.19–2.09(m, 0.5H),2.06–1.76(m,4H),1.76–1.62(m,1H)；13C NMR(100MHz,CDCl3)δ 164.1,164.0,157.74,157.71,152.3,152.2,148.2,148.0,139.7,139.6,136.7,136.6, 127.7,127.6,125.1,125.0,123.7,123.6,113.70,113.69,65.4,65.1,60.1,60.0,55.1, 41.4,41.0,40.4,37.0,32.1,31.9,31.5,29.8,28.24,28.18；HRMS(EI)Calcd for C20H22N2O2[M+]:322.1681,found 322.1689；IR(KBr)ν(cm-1):2930,1625,1512, 1449,1416,1249,1037,815,749,694。
实施例1化合物4的制备:
操作如下：在室温下，将2-吡啶甲酸保护的环庚胺3(即化合物3)(21.8mg，0.1mmol)、PdCl2(1.8mg,0.01mmol)、Ag2CO3(55.2mg,0.2mmol)、 4-Iodonitrobenzene(49.8mg,0.2mmol)、2,6-Dimethoxybenzoic acid(36.4mg, 0.2mmol)、Na3PO4(41.0mg,0.25mmol)以及TCE(1mL)加入到10mL微波反应管中，功率20W，140℃反应2小时。反应结束后自然冷却至室温，硅藻土过滤，旋干。以石油醚：乙酸乙酯＝2：1为展开剂，通过制备板分离得到19.1mg目标化合物4，产率88％。1H NMR(400MHz,CDCl3)δ8.57(d,J＝4.6Hz,1H),7.85–7.66(m,2H),7.37–7.27(m,1H),4.84(s,1H),4.57(s,1H),2.06–1.72(m,7H), 1.66–1.52(m,2H),1.51–1.41(m,1H)；13C NMR(100MHz,CDCl3)δ164.1,154.6, 148.2,136.7,124.4,123.7,56.3,52.8,32.8,31.0,28.4,26.7,16.8；HRMS(EI)Calcd for C13H16N2O[M+]:216.1263,found 216.1256；IR(KBr)ν(cm-1):3427,2942,1622, 1449,751。
实施例2化合物6的制备:
操作如下：在室温下，将2-吡啶甲酸保护的环庚胺衍生物5(即化合物5) (27.6mg，0.1mmol)、PdCl2(1.8mg,0.01mmol)、Ag2CO3(55.2mg,0.2mmol)、 2-Iodobenzonitrile(45.8mg,0.2mmol)、2,6-Dimethoxybenzoic acid(36.4mg, 0.2mmol)、Na3PO4(41.0mg,0.25mmol)以及TCE(1mL)加入到10mL微波反应管中，功率20W，140℃反应2小时。反应结束后自然冷却至室温，硅藻土过滤，旋干。以石油醚：乙酸乙酯＝2：1为展开剂，通过制备板分离得到12.0mg目标化合物6，产率44％。1H NMR(400MHz,CDCl3)δ8.57(d,J＝4.1Hz,1H),7.92–7.68(m,2H),7.35(t,J＝5.1Hz,1H),5.20–5.05(m,1H),3.73(s,3H),2.43–2.22 (m,3H),2.05–1.92(m,2H),1.85–1.68(m,3H),1.53–1.34(m,2H)；13C NMR (100MHz,CDCl3)δ172.5,166.7,153.2,148.2,136.9,125.2,124.2,65.7,58.6,52.1, 33.2,32.8,30.1,27.9,17.2HRMS(EI)Calcd for C15H18N2O3[M+]:274.1317,found 274.1315；IR(KBr)ν(cm-1):1731,1630,1405,1280,1180。
实施例3化合物8的制备:
操作如下：在室温下，将2-吡啶甲酸保护的环庚胺衍生物7(即化合物7) (32.4mg，0.1mmol)、PdCl2(1.8mg,0.01mmol)、Ag2CO3(55.2mg,0.2mmol)， C6F5I(58.8mg,0.2mmol)、2,6-Dimethoxybenzoic acid(36.4mg,0.2mmol)、Na3PO4 (41.0mg,0.25mmol)以及TCE(1mL)加入到10mL微波反应管中，功率20W，140℃反应4小时。反应结束后自然冷却至室温，硅藻土过滤，旋干。以石油醚：乙酸乙酯＝2：1为展开剂，通过制备板分离得到13.9mg目标化合物8，产率43％。1H NMR(400MHz,CDCl3)δ8.61(d,J＝4.6Hz,0.5H),8.50(d,J＝4.6Hz,0.5H),7.90 –7.65(m,2H),7.38–7.30(m,0.5H),7.29–7.21(m,0.5H),7.16(d,J＝8.6Hz,1H), 7.08(d,J＝8.6Hz,1H),6.82(d,J＝8.6Hz,1H),6.75(d,J＝8.6Hz,1H),5.10(d,J ＝7.2Hz,0.5H),4.95(d,J＝7.0Hz,0.5H),4.85(s,0.5H),4.43(s,0.5H),3.75(d,J＝ 9.4Hz,3H),3.35–3.17(m,1H),2.39–2.25(m,1H),2.13–1.90(m,4H),1.78– 1.63(m,3H)；13C NMR(100MHz,CDCl3)δ164.3,163.7,158.0,154.5,154.4,148.2, 139.4,139.3,136.8,136.6,127.6,127.5,124.6,124.5,124.0,123.6,114.1,113.8, 64.4,60.7,57.3,55.3,55.2,54.0,47.1,45.3,39.8,37.7,32.6,32.4,31.0,30.7,17.2； HRMS(EI)Calcd for C20H22N2O2[M+]:322.1681,found 322.1682；IR(KBr)ν(cm-1): 2932,1624,1513,1249,1038。
实施例1-3制备的化合物对氯化钾预收缩的大鼠胸主动脉的作用实验
(1)材料
样品：化合物4、6、8、硝苯地平
仪器：四腔器官浴槽系统，成都仪器厂(中国)；恒温浴槽，成都仪器厂(中国)；旋涡混匀器，TAITEC(日本)；ABS80-4电子天平，KERN(德国)；PHS-3C PH计，上海雷磁仪器厂(中国)；移液枪，eppendorf research plus(美国)。
试剂：DMSO、硝苯地平均购于Sigma-Aldrich；氯化乙酰胆碱、去氧肾上腺素，大连美仑生物技术有限公司；NaCl、KCl、NaHCO3、KH2PO4等均为国产分析纯。
实验动物：雄性SD大鼠，体重250-300g。动物饲养条件：每笼4只，自由摄食饮水，保持饲养温度20℃-25℃和相对湿度40％-70％。本实验经中国科学院昆明植物研究所动物实验伦理委员会同意，严格按照动物实验的相关规定执行。 (2)实验方法
样品溶液配制：检测样品均用DMSO溶解，初浓度为0.1mol/L，样品终浓度为100μmol/L。
样品对KCl预收缩的大鼠胸主动脉的作用：大鼠胸主动脉血管环的制备参考文献[1,2]方法。以RM-6240系统记录血管环的张力，用去氧肾上腺素10-5mol/L (终浓度)预收缩血管环达峰值，加入乙酰胆碱10-5mol/L(终浓度)验证内皮完整性，若加入乙酰胆碱后去氧肾上腺素预收缩的血管环舒张达80％以上，可认为内皮完整。取内皮完整性的血管环，基础张力值为T0，加入KCl使其终浓度为10-6mol/L，达收缩平台后，记最大收缩张力值为Tmax，分别加入样品。记录加药后30min以内的血管最大舒张值(T1)，同时设置溶剂DMSO对照以及硝苯地平阳性对照。结果以最大舒张率(Relaxation ratio)表示。
最大舒张率(％)＝(Tmax-T1)/(Tmax-T0)×100％
文献[1]Hui-Di Jiang；Jun Cai；Juan-Hua Xu et al.Journal ofEthnopharmacology,2005,101(1),221-226.
文献[2]Gwo-Jyh Chang；Tsung-Ping Lin；Yu-ShienKo et al.LifeSciences,2010, 86(23),869-879.
(3)实验结果
如下表所示，与DMSO空白组比较，化合物4、6、8及硝苯地平(Nifedipine) 对KCl预收缩的大鼠胸主动脉均有显著的舒张作用。
结果以means±SD表示。n＝3,*P<0.05,**P<0.01vs DMSO组。
Claims (6)
1.一种化合物2的合成方法，所述化合物2的结构式为
所述化合物2中R1是氢或甲氧羰基，R2是氢或取代苯基，所述化合物2为消旋体，其特征在于，所述化合物2的合成步骤如下：以化合物1为原料，以Pd(II)为催化剂，银盐为氧化剂，添加取代碘苯、苯甲酸衍生物、碱以及溶剂，在微波中反应得到；
所述合成方法的反应路线如下：
所述催化剂Pd(II)为醋酸钯Pd(OAc)2、二氯化钯PdCl2和/或二碘化钯PdI2，所述氧化剂银盐包括醋酸银、碳酸银和/或三氟醋酸银，
所述取代碘苯为4-硝基碘苯、邻碘苯腈和/或C6F5I，
所述苯甲酸衍生物为2，6-二甲氧基苯甲酸，
所述碱是1或2价金属的碳酸盐、碳酸氢盐、醋酸盐和/或磷酸盐，
所述溶剂是1,2-二氯乙烷或1,1,2,2-四氯乙烷，微波120～170℃下反应1～4小时。
2.根据权利要求1所述的合成方法，其特征在于：所述化合物2为
3.根据权利要求1或2所述的合成方法，其特征在于：所述催化剂用量为0.01～0.2当量。
4.根据权利要求1或2所述的合成方法，其特征在于：所述氧化剂用量为1～3当量。
5.根据权利要求2所述的合成方法，其特征在于：所述取代碘苯用量为1～10当量。
6.根据权利要求1所述的合成方法，其特征在于：所述碱为碳酸钠、碳酸钾、碳酸氢钾、醋酸钠和/或磷酸钠，碱用量为1～3当量。
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| CN1426411A (zh) * | 2000-03-03 | 2003-06-25 | 奥索-麦克尼尔药品公司 | 3－(二芳基亚甲基)－8－氮杂双环[3.2.1]辛烷衍生物 |
| CN101479265A (zh) * | 2006-06-27 | 2009-07-08 | 赛诺菲-安万特 | 拓烷尿素衍生物，它们的制备与治疗应用 |
| WO2010023161A1 (en) * | 2008-08-25 | 2010-03-04 | Boehringer Ingelheim International Gmbh | Aryl- and heteroarylcarbonyl derivatives of substituted nortropanes, medicaments containing such compounds and their use |
| CN106459030A (zh) * | 2014-05-28 | 2017-02-22 | 东亚荣养株式会社 | 取代托品烷衍生物 |
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| CN1426411A (zh) * | 2000-03-03 | 2003-06-25 | 奥索-麦克尼尔药品公司 | 3－(二芳基亚甲基)－8－氮杂双环[3.2.1]辛烷衍生物 |
| CN101479265A (zh) * | 2006-06-27 | 2009-07-08 | 赛诺菲-安万特 | 拓烷尿素衍生物，它们的制备与治疗应用 |
| WO2010023161A1 (en) * | 2008-08-25 | 2010-03-04 | Boehringer Ingelheim International Gmbh | Aryl- and heteroarylcarbonyl derivatives of substituted nortropanes, medicaments containing such compounds and their use |
| CN106459030A (zh) * | 2014-05-28 | 2017-02-22 | 东亚荣养株式会社 | 取代托品烷衍生物 |
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