CN110964024B - 一种海兰地嗪盐及其制备方法 - Google Patents
一种海兰地嗪盐及其制备方法 Download PDFInfo
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- CN110964024B CN110964024B CN201811547140.5A CN201811547140A CN110964024B CN 110964024 B CN110964024 B CN 110964024B CN 201811547140 A CN201811547140 A CN 201811547140A CN 110964024 B CN110964024 B CN 110964024B
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- Prior art keywords
- acid
- compound
- solvent
- tetrandrine
- salt
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- 150000003839 salts Chemical class 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title abstract description 19
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- WVTKBKWTSCPRNU-KYJUHHDHSA-N (+)-Tetrandrine Chemical compound C([C@H]1C=2C=C(C(=CC=2CCN1C)OC)O1)C(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2C[C@@H]2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-KYJUHHDHSA-N 0.000 claims abstract description 36
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 claims abstract description 28
- WVTKBKWTSCPRNU-UHFFFAOYSA-N rac-Tetrandrin Natural products O1C(C(=CC=2CCN3C)OC)=CC=2C3CC(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2CC2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000002253 acid Substances 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 12
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 8
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 8
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 4
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- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims abstract description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims abstract description 4
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- 239000004472 Lysine Substances 0.000 claims abstract description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims abstract description 4
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 claims abstract description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims abstract description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 4
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 claims abstract description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 235000009697 arginine Nutrition 0.000 claims abstract description 4
- 235000010323 ascorbic acid Nutrition 0.000 claims abstract description 4
- 239000011668 ascorbic acid Substances 0.000 claims abstract description 4
- 229960005070 ascorbic acid Drugs 0.000 claims abstract description 4
- 235000003704 aspartic acid Nutrition 0.000 claims abstract description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 claims abstract description 4
- 235000010233 benzoic acid Nutrition 0.000 claims abstract description 4
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims abstract description 4
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims abstract description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims abstract description 4
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims abstract description 4
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Abstract
本发明公开了一种海兰地嗪盐，是由海兰地嗪与酸制备得到，所述酸为盐酸、氢溴酸、碳酸、硫酸、磷酸、硝酸、马来酸、富马酸、丁二酸、草酸、三氟乙酸、酒石酸、抗坏血酸、N‑苯甲酰基甘氨酸、L‑焦谷氨酸、L‑脯氨酸、2‑羟基乙磺酸、乙酸、苯甲酸、甘氨酸、赖氨酸、精氨酸、天冬氨酸、没食子酸、乳酸、乳清酸、苹果酸、柠檬酸、甲基磺酸、苯磺酸、对甲基苯磺酸中的至少一种。本发明提供的海兰地嗪盐以汉防己乙素为原料，经过溴代、甲氧基化、甲基化反应制备海兰地嗪，反应收率高，中间体和产物易于纯化，可以用于海兰地嗪盐的工业制备。
Description
技术领域
本发明属于药物化学技术领域，具体地说，涉及一种海兰地嗪盐及其制备方法。
背景技术
海兰地嗪(Hernandezine)，又名金丝马尾连碱甲，鹤氏唐松草碱。分子式为C39H44N2O7，分子量为652.79，是一种双苄基异喹啉生物碱，主要存在于毛莨科唐松草属植物中。药理研究表明，海兰地嗪具有多种生物活性。徐承熊等人从金丝马尾连提取的总生物碱及其主要成分碱甲(heritandezine)对P388白血病小鼠、腹水型S180及C26结肠癌小鼠有一定的治疗作用。在体外，海兰地嗪明显地抑制小鼠白血病L1210细密及人口腔癌KB细胞的生长，对小鼠正常造血细胞(CFU-GM)的抑制作用较弱(药学学报Pharmaceutica Sinica1990；25(5)：330～335)。马丽娟等人报道了海兰地嗪具有良好的抗血小板聚集作用(马丽绢,尹钟沫,刘干中；海兰地嗪对血小板聚集的影响及机理探讨。中国药理学与毒理学杂志,1991；5(1):41)。郭景珍等人发现海兰地嗪具有和维拉帕米相似的钙离子通道阻滞作用(中药临床与药理1995(5))。Vincent Kam Wai Wong和Liang Liu等人报道了海兰地嗪作为一种有效的AMPK激动剂，可以诱导耐药的肿瘤细胞凋亡(Oncotarget,Vol.7,No.7)。Chung-PuWu等人报道了海兰地嗪能够与阿霉素、长春碱以及秋水仙碱等联用，在纳摩尔极浓度下，能够有效的逆转多药耐药，是一种有效的肿瘤多药耐药逆转剂。研究表明海兰地嗪选择性好，毒性很低，有望开发为高效低毒的肿瘤多药耐药逆转剂(J.Nat.Prod.2016,79,2135-2142)。
经过文献检索，目前尚未发现海兰地嗪及其盐的合成方法。中国专利CN201210363078公开了一种海兰地嗪的提取方法。该方法将金丝马尾连原料粉碎，加盐酸或硫酸溶液提取，通过阳离子交换树脂分离、萃取，然后采用高速逆流色谱和制备液相色谱分离，经过低温干燥得到产物，纯度98％以上。该方法并未报道海兰地嗪的回收率，提取过程产生大量废酸，纯化过程过于复杂，采用制备液相色谱分离将大大增加成本，难以实现工业化生产。
发明内容
本发明的第一个目的是提供一种海兰地嗪盐。
本发明的第二个目的是提供一种所述海兰地嗪盐的制备方法，该方法反应收率高，中间体和产物易于纯化。
为了实现上述目的，本发明采用的技术方案如下：
本发明的第一个方面提供了一种海兰地嗪盐，是由海兰地嗪与酸制备得到，
所述酸为盐酸、氢溴酸、碳酸、硫酸、磷酸、硝酸、马来酸、富马酸、丁二酸、草酸、三氟乙酸、酒石酸、抗坏血酸、N-苯甲酰基甘氨酸、L-焦谷氨酸、L-脯氨酸、2-羟基乙磺酸、乙酸、苯甲酸、甘氨酸、赖氨酸、精氨酸、天冬氨酸、没食子酸、乳酸、乳清酸、苹果酸、柠檬酸、甲基磺酸、苯磺酸、对甲基苯磺酸中的至少一种。
所述海兰地嗪盐为以下结构中的一种：
本发明的第二个方面提供了一种海兰地嗪盐的制备方法，包括以下步骤：
将海兰地嗪溶解在溶剂中，将酸溶于溶剂中，室温下将上述酸溶液滴加到海兰地嗪溶液中，室温搅拌、浓缩、过滤、减压干燥，得到所述海兰地嗪盐。
所述溶剂为甲醇、乙醇、异丙醇、四氢呋喃、丙酮、乙腈、乙酸乙酯、石油醚、正己烷、水、N,N-二甲基甲酰胺、二甲基亚砜、二氧六环中的至少一种。
所述酸与海兰地嗪的摩尔比为(1～2):1。
所述酸为盐酸、氢溴酸、碳酸、硫酸、磷酸、硝酸、马来酸、富马酸、丁二酸、草酸、三氟乙酸、酒石酸、抗坏血酸、N-苯甲酰基甘氨酸、L-焦谷氨酸、L-脯氨酸、2-羟基乙磺酸、乙酸、苯甲酸、甘氨酸、赖氨酸、精氨酸、天冬氨酸、没食子酸、乳酸、乳清酸、苹果酸、柠檬酸、甲基磺酸、苯磺酸、对甲基苯磺酸中的至少一种。
所述海兰地嗪的制备方法，包括以下步骤：
第一步，以汉防己乙素即化合物1为原料，在溶剂中，用溴代试剂在-10～30℃进行反应，制备获得5-溴汉防己乙素即化合物2；
第二步，5-溴汉防己乙素即化合物2溶于溶剂中，在催化剂作用下与碱进行取代反应，反应温度为60℃～250℃，时间为1min～20h，得到5-甲氧基汉防己乙素即化合物3；
第三步，5-甲氧基汉防己乙素即化合物3溶于溶剂中，加入甲基化试剂反应，反应温度为-20℃～80℃，时间为5min～20h，得到粗品，粗品经重结晶纯化得到海兰地嗪即化合物4。
所述第一步中溶剂为酸性溶剂，具体为三氟乙酸。
所述第一步中溴代试剂为N-溴代丁二酰亚胺、1,3-二溴-5,5-二甲基海因、溴单质。
所述第一步中溴代试剂与汉防己乙素即化合物1的摩尔比为(1～2):1。
所述第二步中溶剂为N,N-二甲基甲酰胺、甲醇。
所述第二步中碱为甲醇钠、甲醇钾。
所述第二步中催化剂为一价铜盐或者其复合物，优选为氯化亚铜、溴化亚铜、碘化亚铜、Cu2Cl2-DMF复合物、Cu2Cl2-CO2复合物等。
所述第二步中5-溴汉防己乙素即化合物2与碱的摩尔比为1:1～1:100。
所述第二步中5-溴汉防己乙素与催化剂的摩尔比为1:0.001～1:0.1。
所述第三步中溶剂为二甲基亚砜。
所述第三步中甲基化试剂为硫酸二甲酯、碘甲烷、重氮甲烷、碳酸二甲酯、溴代甲烷中的至少一种。
所述第三步中甲基化试剂与5-甲氧基汉防己乙素的摩尔比为1:1～2:1。
由于采用上述技术方案，本发明具有以下优点和有益效果：
本发明提供的海兰地嗪的制备方法以汉防己乙素为原料，经过溴代、甲氧基化、甲基化反应制备海兰地嗪，反应收率高，中间体和产物易于纯化，可以用于海兰地嗪盐的工业制备。
附图说明
图1是5-溴汉防己乙素的1H-NMR图谱。
图2是5-溴汉防己乙素的13C-NMR图谱。
图3是5-溴汉防己乙素的ESI-MS图谱。
图4是5-甲氧基汉防己乙素的1H-NMR图谱。
图5是5-甲氧基汉防己乙素的13C-NMR图谱。
图6是5-甲氧基汉防己乙素的ESI-MS图谱。
图7是海兰地嗪的1H-NMR图谱。
图8是海兰地嗪的13C-NMR图谱。
图9是海兰地嗪的ESI-MS图谱。
图10是海兰地嗪没食子酸的1H-NMR图谱。
图11是海兰地嗪没食子酸的13C-NMR图谱。
图12是海兰地嗪没食子酸的ESI-MS图谱。
具体实施方式
为了更清楚地说明本发明，下面结合优选实施例对本发明做进一步的说明。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
汉防己乙素(化合物1)购自西安昊轩生物科技有限公司，纯度98％；N-溴代丁二酰亚胺，购自阿达玛斯试剂有限公司，纯度99％；1,3-二溴-5,5-二甲基海因购自阿达玛斯试剂有限公司，纯度98％。
下列实施例中未注明具体条件的实验方法，通常按照常规条件，所用试剂均为常规试剂，均可从市场购买得到。
实施例
一种海兰地嗪盐的制备方法的反应方程式如下：
5-溴汉防己乙素(化合物2)的制备
以汉防己乙素(化合物1)为原料，在溶剂中，用溴代试剂进行反应，制备获得5-溴汉防己乙素(化合物2)。其中，溶剂为酸性溶剂，常温常压下为液态，溶剂可以单独使用，或两种以任意比例混合使用；溴代试剂为N-溴代丁二酰亚胺、1,3-二溴-5,5-二甲基海因、溴单质。
表1中实施例1至3为使用不同的溴代试剂获得的反应收率；实施例4和5为使用N-溴代丁二酰亚胺作为溴代试剂的十克及以上放大反应收率。
表1、不同溴代试剂的溴代反应
| 实施例 | 汉防己乙素用量(克) | 溴代试剂 | 收率(％) |
| 1 | 0.5 | N-溴代丁二酰亚胺 | 85 |
| 2 | 0.5 | 1,3-二溴-5,5-二甲基海因 | 82 |
| 3 | 0.5 | 溴单质 | 84 |
| 4 | 10 | N-溴代丁二酰亚胺 | 85 |
| 5 | 50 | N-溴代丁二酰亚胺 | 86 |
化合物2的制备方法包括以下步骤：按照表1中的重量，在反应瓶中加入5mL三氟乙酸，0℃下加入汉防己乙素(化合物1)，分批加入1.1倍量溴代试剂，加完后自然升温至20℃，继续搅拌20分钟，减压浓缩至20mL，将此反应液滴加至饱和碳酸氢钠中，析出大量固体，过滤，滤饼水洗，减压干燥，粗品经重结晶得5-溴汉防己乙素(化合物2)。1H NMR(400MHz,CDCl3)δ7.34(dd,J＝8.2,2.1Hz,1H),7.14(dd,J＝8.2,2.5Hz,1H),6.90–6.82(m,2H),6.80(dd,J＝8.3,2.5Hz,1H),6.55(s,1H),6.51(s,1H),6.31(dd,J＝8.3,2.1Hz,1H),6.05(s,1H),3.92(d,J＝3.8Hz,3H),3.88(dd,J＝10.9,5.6Hz,1H),3.80(d,J＝9.9Hz,1H),3.74(s,3H),3.52(ddd,J＝13.8,11.8,5.6Hz,1H),3.41–3.27(m,4H),3.22(dd,J＝12.5,5.5Hz,1H),3.04–2.88(m,2H),2.87–2.65(m,5H),2.59(s,3H),2.54–2.44(m,2H),2.28(d,J＝7.9Hz,3H).13C NMR(101MHz,CDCl3)δ153.79,149.40,148.64,147.15,143.50,142.68,142.15,139.08,135.05,134.44,132.61,130.16,128.70,128.54,128.24,123.89,122.84,121.98,120.43,116.17,112.50,111.56,77.36,77.05,76.73,63.61,61.57,60.74,56.15,50.81,45.06,43.77,42.49,42.14,41.37,37.54,25.51,22.32.ESI-MS m/z:701.33(M+H),703.34(M+H)。
重结晶产物5-溴汉防己乙素经1H-NMR、13C-NMR及ESI-MS检测结构正确，其检测结果如图1、图2、图3所示。图1是5-溴汉防己乙素1H-NMR图谱，图2是5-溴汉防己乙素13C-NMR图谱，图3是5-溴汉防己乙素ESI-MS图谱。
5-甲氧基汉防己乙素(化合物3)的制备：
5-溴汉防己乙素在N,N-二甲基甲酰胺和甲醇中，在催化剂作用下与甲醇钠或甲醇钾进行取代反应，得到5-甲氧基汉防己乙素；催化剂为一价铜盐或者其复合物，如氯化亚铜、溴化亚铜、碘化亚铜、Cu2Cl2-DMF复合物、Cu2Cl2-CO2复合物等。
表2中实施例6至8为使用不同的催化剂，以5-溴汉防己乙素制备5-甲氧基汉防己乙素获得的反应收率；实施例9和10为克级放大反应收率。
表2、不同催化剂的甲氧基化反应
| 实施例 | 5-溴汉防己乙素用量(克) | 催化剂 | 收率(％) |
| 6 | 0.5 | 溴化亚铜 | 85 |
| 7 | 0.5 | 碘化亚铜 | 82 |
| 8 | 0.5 | Cu<sub>2</sub>Cl<sub>2</sub>-DMF复合物 | 83 |
| 9 | 5 | 溴化亚铜 | 86 |
| 10 | 10 | 溴化亚铜 | 87 |
化合物3的制备方法包括以下步骤：按照表2中的重量，在反应瓶中加入5-溴汉防己乙素，5％摩尔比的催化剂，10倍量甲醇钠、甲醇和DMF，氮气置换3次，氮气保护下油浴加热，120℃搅拌反应5小时，减压浓缩，加水和乙酸乙酯分层，水相萃取两次，有机相用饱和食盐水洗两次、干燥、浓缩，粗品经重结晶得5-甲氧基汉防己乙素(化合物3)。1H NMR(400MHz,CDCl3)δ7.33(dd,J＝8.2,2.1Hz,1H),7.13(dd,J＝8.2,2.5Hz,1H),6.85(d,J＝0.7Hz,2H),6.80(dd,J＝8.3,2.5Hz,1H),6.56(s,1H),6.52(s,1H),6.32(dd,J＝8.3,2.1Hz,1H),6.03(s,1H),3.93(s,3H),3.88(dd,J＝10.9,5.5Hz,1H),3.78(d,J＝5.9Hz,6H),3.76(d,J＝4.7Hz,1H),3.52–3.41(m,1H),3.38(dd,J＝8.3,4.1Hz,1H),3.34(s,3H),3.23(dd,J＝12.5,5.5Hz,1H),3.00–2.81(m,3H),2.80–2.67(m,4H),2.61(s,3H),2.57–2.44(m,2H),2.30(s,3H).13C NMR(101MHz,CDCl3)δ153.72,149.40,148.61,147.07,144.80,143.25,138.51,138.29,138.21,135.15,134.83,132.57,130.14,128.88,128.10,125.90,122.77,121.96,121.93,120.41,117.28,116.14,113.03,111.49,63.69,61.37,60.83,60.22,56.14,56.00,45.25,43.68,42.61,42.36,41.69,37.66,25.53,16.15.ESI-MS m/z:639.39(M+H)。
重结晶产物5-甲氧基汉防己乙素经1H-NMR、13C-NMR及ESI-MS检测结构正确，其检测结果如图4、图5、图6所示。图4是5-甲氧基汉防己乙素1H-NMR图谱，图5是5-甲氧基汉防己乙素13C-NMR图谱，图6是5-甲氧基汉防己乙素ESI-MS图谱。
海兰地嗪(化合物4)的制备：
5-甲氧基汉防己乙素(化合物3)0.5g溶于20mL溶剂(二甲基亚砜)中，加入甲基化试剂(甲基化试剂碳酸二甲酯与5-甲氧基汉防己乙素的摩尔比为1.5:1)在50℃反应2h，得到海兰地嗪；粗品经重结晶纯化得到海兰地嗪(化合物4)。
1H NMR(400MHz,CDCl3)δ7.34(dd,J＝8.2,2.1Hz,1H),7.14(dd,J＝8.2,2.5Hz,1H),6.86(d,J＝0.6Hz,2H),6.80(dd,J＝8.3,2.5Hz,1H),6.56(s,1H),6.51(s,1H),6.31(dd,J＝8.3,2.1Hz,1H),6.00(s,1H),3.93(s,3H),3.89(dd,J＝10.9,5.6Hz,1H),3.81(s,3H),3.79–3.73(m,4H),3.51–3.37(m,2H),3.36(d,J＝9.6Hz,3H),3.29–3.18(m,4H),3.02–2.84(m,3H),2.83–2.68(m,4H),2.63(s,3H),2.56–2.45(m,2H),2.30(s,3H).13C NMR(101MHz,CDCl3)δ153.70,149.39,148.34,147.08,145.53,144.39,144.393,143.74,142.37,135.20,134.79,132.62,130.13,128.42,127.79,125.61,122.76,121.96,121.88,121.71,120.21,116.12,112.69,111.49,77.37,77.05,76.73,63.77,61.40,60.87,60.53,60.50,56.14,55.67,45.22,43.57,42.65,42.31,41.73,37.77,25.39,16.48.ESI-MS m/z:653.46(M+H)。
重结晶产物海兰地嗪经1H-NMR、13C-NMR及ESI-MS检测结构正确，其检测结果如图7、图8、图9所示。图7是海兰地嗪1H-NMR图谱，图8是海兰地嗪13C-NMR图谱，图9是海兰地嗪ESI-MS图谱。
海兰地嗪没食子酸盐(化合物5)的制备：
将652mg海兰地嗪(化合物4)溶解在15mL乙醇中，将374mg没食子酸溶于5mL无水乙醇中，室温下将上述没食子酸乙醇溶液滴加到海兰地嗪乙醇溶液中，室温搅拌30分钟，浓缩乙醇至10mL左右，过滤，收集滤饼减压干燥，得到海兰地嗪没食子酸盐(化合物5)，收率97％。1H NMR(400MHz,DMSO-d6)δ10.07–8.47(s,6H),7.46(dd,J＝8.2,1.9Hz,1H),7.10(dd,J＝8.2,2.5Hz,1H),6.99–6.85(m,5H),6.75(dd,J＝8.2,1.6Hz,1H),6.69(dd,J＝8.2,2.5Hz,1H),6.63(s,1H),6.44–6.29(m,2H),5.91(s,1H),3.92(dd,J＝10.3,5.7Hz,1H),3.81(s,3H),3.69(d,J＝12.1Hz,6H),3.52(d,J＝10.0Hz,1H),3.41–3.34(m,2H),3.28(s,3H),3.19(dd,J＝12.4,5.7Hz,2H),3.14(s,3H),2.87–2.63(m,6H),2.53(s,3H),2.43–2.25(m,2H),2.14(s,3H).13C NMR(101MHz,DMSO-d6)δ168.05,153.36,149.41,148.09,147.15,145.88,145.58,144.38(d,J＝7.3Hz),143.39,142.49,138.41,136.04,134.51,133.07,131.03,128.42,125.45,123.45,121.99(d,J＝11.0Hz),121.04,119.75,115.64,113.47,112.39,109.16,63.09,61.32(d,J＝54.1Hz),60.91–60.84(m),60.58,56.10,45.12,43.91–43.14(m),43.14–42.37(m),42.37–42.12(m),25.49,16.16.ESI-MS m/z:653.45(M+H)，171.11(M+H)。
海兰地嗪没食子酸盐经1H-NMR、13C-NMR及ESI-MS检测结构正确，其检测结果如图10、图11、图12所示。图10是海兰地嗪没食子酸1H-NMR图谱，图11是海兰地嗪没食子酸13C-NMR图谱，图12是海兰地嗪没食子酸ESI-MS图谱。
海兰地嗪盐酸盐(化合物6)的制备：
将652mg海兰地嗪(化合物4)溶解在15mL乙醇中，将1mL浓盐酸溶于5mL无水乙醇中，室温下将上述盐酸乙醇溶液滴加到海兰地嗪乙醇溶液中，室温搅拌30分钟，浓缩乙醇至10mL左右，过滤，收集滤饼减压干燥，得到海兰地嗪盐酸盐(化合物6)，收率97％。1H NMR(400MHz,CD3OD)δ7.63(dd,J＝8.3,1.9Hz,1H),7.15(d,J＝7.4Hz,1H),7.07(s,2H),6.93(s,1H),6.90(d,J＝7.6Hz,1H),6.56(d,J＝8.1Hz,2H),6.23(s,1H),4.48(s,1H),4.09–4.01(m,1H),3.94(s,3H),3.89(s,3H),3.81(s,3H),3.65(dt,J＝16.9,11.7Hz,2H),3.52(m,4H),3.40–3.23(m,7H),3.23–2.99(m,7H),2.94(d,J＝15.7Hz,1H),2.83(s,3H).13C NMR(101MHz,CD3OD)δ154.12,150.10,148.85,148.77,146.45,146.35,143.80,143.76,143.67,132.67,131.99,131.08,125.86,125.16,123.22,123.20,122.02,121.95,121.61,120.03,119.96,118.21,118.17,114.58,112.36,112.17,63.80,60.09,60.03,59.85,55.30,55.01,47.91,47.69,44.84,44.57,44.35,40.95,40.79,39.95.ESI-MS m/z:653.45(M+H)。
海兰地嗪盐酸盐经1H-NMR、13C-NMR及ESI-MS检测结构正确。
测定海兰地嗪盐的溶解度：
测定方法：按照中国药典2010年版二部范例中溶解度测定方法，取样品，精密称取适量，置于一定量的溶剂(水)中(25±2℃)，每隔5分钟强力振摇30秒，观察30分钟内的溶解情况。实验结果显示，海兰地嗪盐的溶解度较海兰地嗪有较大幅度增加。表3为海兰地嗪及海兰地嗪盐的溶解度：
表3
| 名称 | 溶解度 | 溶解度增加倍数 |
| 海兰地嗪 | 9.2mg/100mL | ---- |
| 海兰地嗪没食子酸盐 | 382.5mg/100mL | 41.6 |
| 海兰地嗪盐酸盐 | 526.3mg/100mL | 57.2 |
以上显示和描述了本发明的基本原理、主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等同物界定。
Claims (9)
1.一种制备海兰地嗪的方法，其包括以下步骤：
第一步，以汉防己乙素即化合物1为原料，在溶剂中，用溴代试剂在-10℃～30℃进行反应，获得5-溴汉防己乙素即化合物2；
第二步，将化合物2溶于溶剂中，在催化剂作用下与碱进行取代反应，反应温度为60℃～250℃，时间为1min～20h，得到5-甲氧基汉防己乙素即化合物3；
第三步，将化合物3溶于溶剂中，加入甲基化试剂反应，反应温度为-20℃～80℃，时间为5min～20h，得到粗品，粗品经重结晶纯化得到目标物即化合物4。
2.根据权利要求1所述的方法，其特征在于，其中，第一步中所述溶剂为酸性溶剂，第一步中所述溴代试剂为N-溴代丁二酰亚胺、1,3-二溴-5,5-二甲基海因或溴单质，第一步中所述溴代试剂与化合物1的摩尔比为(1～2):1。
3.根据权利要求1所述的方法，其特征在于，其中，第二步中所述溶剂为N,N-二甲基甲酰胺或甲醇，第二步中所述碱为甲醇钠或甲醇钾，第二步中所述催化剂为一价铜盐或其复合物。
4.根据权利要求3所述的方法，其特征在于，其中所述催化剂为氯化亚铜、溴化亚铜、碘化亚铜、Cu2Cl2-DMF复合物或Cu2Cl2-CO2复合物。
5.根据权利要求1所述的方法，其特征在于，第二步中化合物2与碱的摩尔比为1:1～1:100，第二步中化合物2与催化剂的摩尔比为1:0.001～1:0.1。
6.根据权利要求1所述的方法，其特征在于，所述第三步中所述溶剂为二甲基亚砜，第三步中甲基化试剂与化合物3的摩尔比为1:1～2:1，所述甲基化试剂为硫酸二甲酯、碘甲烷、重氮甲烷、碳酸二甲酯或溴代甲烷中的至少一种。
7.一种制备海兰地嗪盐的方法，其特征在于，所述方法包括以下步骤：
由权利要求1～6中任意一项方法制备海兰地嗪，将海兰地嗪溶解在溶剂中，得到海兰地嗪溶液；将酸溶于溶剂中，得到酸溶液；
室温条件下，将所得酸溶液滴加到所得海兰地嗪溶液中，室温搅拌、浓缩、过滤和减压干燥，得到目标物；
其中，酸与海兰地嗪的摩尔比为(1～2):1。
8.根据权利要求7所述的方法，其特征在于，其中所述酸为盐酸、氢溴酸、碳酸、硫酸、磷酸、硝酸、马来酸、富马酸、丁二酸、草酸、三氟乙酸、酒石酸、抗坏血酸、N-苯甲酰基甘氨酸、L-焦谷氨酸、L-脯氨酸、2-羟基乙磺酸、乙酸、苯甲酸、甘氨酸、赖氨酸、精氨酸、天冬氨酸、没食子酸、乳酸、乳清酸、苹果酸、柠檬酸、甲基磺酸、苯磺酸或对甲基苯磺酸中的至少一种。
9.根据权利要求7所述的方法，其特征在于，其中所述溶剂为甲醇、乙醇、异丙醇、四氢呋喃、丙酮、乙腈、乙酸乙酯、石油醚、正己烷、水、N,N-二甲基甲酰胺、二甲基亚砜、二氧六环中的至少一种。
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