CN1821244A - 一类17-酰基青藤碱衍生物及其制备方法 - Google Patents
一类17-酰基青藤碱衍生物及其制备方法 Download PDFInfo
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Abstract
本发明公开了一类17-酰基青藤碱衍生物,它具有潜在的药物应用前景,其结构式如右式结构式I中R可以是C1-C15的链烃酰基、环烃酰基、取代烃酰基,如:乙酰基、丙酰基、丁酰基、苯乙酰基、环丙甲酰基;或者是芳酰基、芳杂环酰基,如:苯甲酰基、3,5-二甲苯甲酰基、水杨酰基、烟酰基、呋喃甲酰基。在17-酰基青藤碱衍生物的合成过程中,采用苄氧苄基代替了苄基作为保护基的方法,具有脱保护条件温和,反应速度快,副反应少、收率高的优点。
Description
一、技术领域
本发明涉及一种化学生物碱,具体地说是涉及一类17-酰基青藤碱衍生物及其制备方法。
二、背景技术
青藤碱(sinomenine)是从防风己科植物青风藤及毛青藤的根茎中提取的吗啡(morphine)类生物碱。据记载,具有抗炎、镇痛、降压、抗心律失常等药理活性,临床主要用于治疗类风湿性关节炎、脑缺血、神经功能失调等症状(王耐勤,等.药学学报,1992,23(2):81;周金黄,等主编.中药药理与临床研究进展.第二册.北京:中国科学技术出版社,1993,66;孙旭光,黄宇明,仇萍.CN 98120549;仇萍,邱赛红.CN 1142946;陈冲,许海芹,周佳.CN 114945.)。
Qin Guo-Wei等利用C环的羰基及烯醇醚的反应活性合成了系列青藤碱衍生物并首次报道青藤碱及衍生物具有益智、保护神经等功效(采用小鼠Morris water mazetest,Social recognition test,NaNO2 induced anoxia test)(Qin Guo-Wei,etal.WO 2004/048340)。庞志功等在专利CN.1153171中,报道了青络锗-金属锗的青藤碱配合物作为广谱抗癌药物,具有毒副作用小、不降低人体免疫功能、有效抑瘤的特点。
到目前为止,对青藤碱衍生物的制备及其药理活性的报道并不多见,我们设想以不同类型的官能团代替青藤碱17位甲基将会引起其生理活性的及作用方式的改变。
三、发明内容
本发明的目的在于提供一类17-酰基青藤碱衍生物及其制备方法,采用苄氧苄基代替苄基保护酚羟基的方法,脱保护时用稀三氟乙酸/二氯甲烷溶液室温进行,条件温和,反应速度快,收率较高。
本发明的目的是通过以下的技术方案来实现的:
一类17-酰基青藤碱衍生物,其结构式如下:
其中R为C1-C15的链烃酰基、环烃酰基、取代烃酰基,如:乙酰基、丙酰基、丁酰基、、苯乙酰基、环丙甲酰基;或者是芳酰基、芳杂环酰基,如:苯甲酰基、3,5-二甲苯甲酰基、水杨酰基、烟酰基、呋喃甲酰基。
本发明涉及的17-酰基青藤碱衍生物的制备方法的反应过程如下:
一类17-酰基青藤碱衍生物的制备方法,其制备步骤如下:
(1)4-苄氧苄基青藤碱(III)的制备:取青藤碱(II)、三苯基膦、4-苄氧苄醇以足够量的溶剂溶解,0-20℃下滴加偶氮二甲酸二乙酯,0.5-2hr内加完,继续搅拌至反应结束得到4-苄氧苄基青藤碱,收率80.0-99.0%;其中三苯基膦、4-苄氧苄醇、偶氮二甲酸二乙酯的用量同为青腾碱(II)用量的1.5-5.0倍(mol),所述溶剂是四氢呋喃、甲苯或两者的混合物,其总用量为青藤碱(II)质量的5-100倍。
(2)17-去甲基-4-苄氧苄基青藤碱(IV)的制备:将4-苄氧苄基青藤碱(III)用溶剂溶解,然后在缚酸剂存在下与氯甲酸-1-氯乙酯反应,得到N-(1-氯乙氧甲酰基)-4-苄氧苄基青藤碱;将反应的剩余物直接加入到足够量的绝对甲醇中,氮气保护下加热回流得到17-去甲基-4-苄氧苄基青藤碱及其盐酸盐混合物,此混合物以氯仿分散,碳酸氢钠溶液中和得到17-去甲基-4-苄氧苄基青藤碱(IV),其中所用溶剂是1,2-二氯乙烷、氯仿、二氯甲烷、丙酮、甲苯等非质子溶剂,其用量是4-苄氧苄基青藤碱的3-15倍(质量);所述缚酸剂为碱金属碳酸盐,如碳酸氢钠、碳酸钠、碳酸钾,其用量为4-苄氧苄基青藤碱的1.0-6.0倍(质量);氯甲酸-1-氯乙酯用量为4-苄氧苄基青藤碱的0.1-3.0倍(质量);
(3)、17-酰基-4-苄氧苄基青藤碱(V)的制备:取上述17-去甲基-4-苄氧苄基青藤碱(IV),用溶剂溶解后,在缚酸剂存在下与酰氯或酸酐发生酰基化反应,或在DCC(二环己基炭化二亚胺)存在下与羧酸直接缩合得到17-酰基-4-苄氧苄基青藤碱(V),所述的缚酸剂是有机碱、如三乙胺、吡啶,或是无机碱、如碳酸钠、碳酸钾、碳酸氢钠,其用量均为17-去甲基-4-苄氧苄基青藤碱的1-10倍(mol)。
(4)、17-酰基-4-苄氧苄基青藤碱(I)的制备:取17-酰基-4-苄氧苄基青藤碱在室温下以2-20%三氟乙酸/二氯甲烷溶液处理,以NaHCO3中和、干燥、脱溶得到17-酰基青藤碱(I)。
17-酰基青藤碱衍生物如结构式I所包含的部分化合物名称编号及其物化常数见下表:
四、具体实施方式
下面提供本发明所涉及化合物的制备实施例:
制备例一17-乙酰基青藤碱(化合物1)的制备:
(1)4-苄氧苄基青藤碱(III)的制备:
在100ml三口烧瓶中依次加入1.65g青藤碱(II),4gPPh3、3.17g4-苄氧苄醇和40ml绝对四氢呋喃,开动搅拌,冰浴冷却至0℃下滴加2.65gDEAD,30min内加完,取去冰浴,继续搅拌以TLC检测反应进度,约10hr后反应结束,减压旋去溶剂,以硅胶色谱柱装柱,依次用乙酸乙酯、及6∶1的氯仿/甲醇淋洗,得到浅黄产品,乙醚重结晶得到2.2g白色固体4-苄氧苄基青藤碱;
(2)N-去甲基-4-苄氧苄基青藤碱(IV)的制备:
1.0g4-苄氧苄基青藤碱III以二氯乙烷溶解,加入碳酸氢钠4.0g,搅拌下冷却到0℃,滴加1.0ml氯甲酸-1-氯乙酯,保温1-2hr,撤去冰水浴,升温至微回流0.5-1hr,TLC(乙酸乙酯展开)检测反应至完全,冷却到室温,过滤,旋去溶剂;
所得中间产物不经精制,直接加入到20ml绝对甲醇中,氮气保护下加热回流15min,TLC检测反应完全,减压旋去溶剂,所得产品为N-去甲基-4-苄氧苄基青藤碱(IV)及其盐酸盐混合物;此混合物以20ml氯仿分散,加入2g碳酸氢钠的10ml水深液,搅拌5分钟,分出有机层,无水硫酸镁干燥,减压脱去溶剂,得到N-去甲基-4-苄氧苄基青藤碱(IV);
(3)17-乙酰基-4-苄氧苄基青藤碱(V,R=Ac)的制备:
100mgN-去甲基-4-苄氧苄基青藤碱(III),二氯甲烷15ml,0.1ml三乙胺,冰水浴下滴加50mg乙酰氯,TLC跟踪反应至完全,水洗,以无水硫酸镁干燥,减压旋去溶剂以硅胶柱色谱精制,得98mg白色固体17-乙酰基-4-苄氧苄基青藤碱,收率88.8%;
(4)17-乙酰基青藤碱(化合物1)的制备:
50mg 17-乙酰基-4-苄氧苄基青藤碱用5%TFA/CH2Cl2 5ml室温搅拌处理30分钟,以5ml饱和碳酸氢钠水溶液中和,分去水层,以无水硫酸镁干燥,脱去溶剂,制备硅胶板层色谱分离得36mg化合物4,收率89.0%。
制备例二17-苯甲酰基青藤碱的制备(化合物8)
(1)4-苄氧苄基青藤碱(III)的制备[同制备例一中步骤(1)];
(2)N-去甲基-4-苄氧苄基青藤碱(IV)的制备[同制备例一中步骤(2)];
(3)17-苯甲酰-4-苄氧苄基青藤碱的制备:
向100mg苄氧苄基青藤碱的二氯甲烷(10ml)溶液中加入苯甲酸(70mg)和DCC(100mg),TLC跟踪反应至完全,过滤,所得滤液不经纯化直接用于下步反应;
(4)17-苯甲酰基青藤碱的制备:
向步骤(1)所得的溶液中加入5ml 5%三氟乙酸/二氯甲烷溶液室温处理5min,水洗、干燥,减压蒸去溶剂,产品以硅胶层析分离得到化合物8,收率:80%。
制备例三17-环丙甲酰基青藤碱(化合物4)的制备
(1)4-苄氧苄基青藤碱(III)的制备[同制备例一中步骤(1)];
(2)N-去甲基-4-苄氧苄基青藤碱(IV)的制备[同制备例一中步骤(2)];
(3)17-环丙甲酰基-4-苄氧苄基青藤碱的制备:
向100mg 17-去甲基-4-苄氧苄基青藤碱的三氯甲烷(10ml)溶液中,加入环丙甲酸(30mg)和DCC(100mg),TLC跟踪反应至完全,过滤,所得滤液不经纯化直接用于下步反应。
(4)向步骤(3)所得的溶液中加入5ml 5%三氟乙酸/二氯甲烷溶液室温处理5min,水洗、干燥,减压蒸去溶剂,产品以硅胶层析分离得到化合物4,收率:80%。
制备例四17-水杨酰基青藤碱的制备(化合物16)
(1)4-苄氧苄基青藤碱(III)的制备[同制备例一中步骤(1)];
(2)N-去甲基-4-苄氧苄基青藤碱(IV)的制备[同制备例一中步骤(2)];
(3)17-水杨酰基-4-苄氧苄基青藤碱的制备:
向100mg 17-去甲基-4-苄氧苄基青藤碱的三氯甲烷(10ml)溶液中,加入乙酰水杨酸(50mg)和DCC(100mg),TLC跟踪反应至完全,过滤,所得滤液不经纯化直接用于下步反应。
(4)17-水杨酰基青藤碱的制备:
向步骤(1)所得的溶液中加入5ml 5%三氟乙酸/二氯甲烷溶液室温处理5min,水洗、干燥,减压蒸去溶剂,产品以硅胶层析分离得到化合物16,收率:60%。
Claims (6)
1、一类17-酰基青藤碱衍生物,其结构式如下:
其中R为C1-C15的链烃酰基、环烃酰基、取代烃酰基,如:乙酰基、丙酰基、丁酰基、、苯乙酰基、环丙甲酰基;或者是芳酰基、芳杂环酰基,如:苯甲酰基、3,5-二甲苯甲酰基、水杨酰基、烟酰基、呋喃甲酰基。
2、一种制备权利要求1所述的一类17-酰基青藤碱衍生物的方法,其典型制备步骤如下:
(1)4-苄氧苄基青藤碱(III)的制备:取青藤碱(II)、三苯基膦、4-苄氧苄醇用溶剂溶解,0-20℃下滴加偶氮二甲酸二乙酯,0.5-2hr内加完,继续搅拌至反应结束得到4-苄氧苄基青藤碱(III),收率80.0-99.0%;
(2)17-去甲基-4-苄氧苄基青藤碱(IV)的制备:将4-苄氧苄基青藤碱用溶剂溶解,然后在缚酸剂存在下与氯甲酸-1-氯乙酯反应,得到N-(1-氯乙氧甲酰基)-4-苄氧苄基青藤碱;将反应的剩余物直接加入到甲醇中,氮气保护下加热回流得到17-去甲基-4-苄氧苄基青藤碱(IV)及其盐酸盐混合物,此混合物以氯仿分散,碳酸氢钠溶液中和得到17-去甲基-4-苄氧苄基青藤碱(IV);上述溶剂是二氯甲烷、三氯甲烷、TFA的浓度在1-20%之间,其用量为4-苄氧苄基青藤碱质量的5-100倍;
(3)17-酰基-4-苄氧苄基青藤碱(V)的制备:取上述17-去甲基-4-苄氧苄基青藤碱(IV),用溶剂溶解后,在缚酸剂存在下与酰氯或者酸酐发生酰基化反应,或在DDC(二环己基炭化二亚胺)存在下与羧酸直接缩合,得到17-酰基-4-苄氧苄基青藤碱(V);
(4)17-酰基青藤碱(I)的制备:取17-酰基-4-苄氧苄基青藤碱(V),以2-20%的三氟乙酸溶液室温处理,以NaHCO3中和、干燥、脱溶得到17-酰基青藤碱(I)。
3、根据权利要求2所述的一类17-酰基青藤碱衍生物的制备方法,其特征是在步骤(1)中三苯基膦、4-苄氧苄醇、偶氮二甲酸二乙酯的用量同为青藤碱(II)用量的1.5-5.0倍(mol),所述的溶剂是四氢呋喃、苯或两者的混合物,其总用量为青藤碱(II)质量的5-100倍。
4、根据权利要求2所述的一类17-酰基青藤碱衍生物的制备方法,其特征是在步骤(2)中所述的溶剂是1,2-二氯乙烷、氯仿、二氯甲烷、丙酮、甲苯这些非质子溶剂,其用量是4-苄氧苄基青藤碱的3-15倍(质量);所述缚酸剂是碱金属碳酸盐,如碳酸氢钠、碳酸钠、碳酸钾,其用量为4-苄氧苄基青藤碱的1.0-6.0倍(质量);氯甲酸-1-氯乙酯用量为4-苄氧苄基青藤碱的0.1-3.0倍(质量)。
5、根据权利要求2所述的一类17-酰基青藤碱衍生物的制备方法,其特征是在步骤(3)中所述的酰基化试剂是酰氯、酸酐或羧酸/DCC(二环己基炭化二亚胺),其用量均为17-去甲基-4-苄氧苄基青藤碱的1-10倍(mol),所述的缚酸剂是有机碱,如三乙胺、呲啶,或是无机碱,如碳酸氢钠、碳酸钠、碳酸钾,其用量均为17-去甲基-4-苄氧苄基青藤碱的1-10倍(mol)。
6、根据权利要求2所述的17-酰基青藤碱衍生物的制备方法,其特征是在步骤(2)中所述的溶液剂是二氯甲烷、三氯甲烷,TFA的浓度在1-20%之间,用量为4-苄氧苄基青藤碱质量的5-100倍。
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WO2011098035A1 (zh) | 2010-02-10 | 2011-08-18 | 中国科学院上海有机化学研究所 | 一种青藤碱衍生物、合成方法及其用途 |
CN101578101B (zh) * | 2005-12-15 | 2012-05-23 | 自然医学公司 | 青藤碱衍生物的制备和应用 |
CN103387539A (zh) * | 2012-05-08 | 2013-11-13 | 长沙理工大学 | 4-苄氧基-17-乙酰基吗啡喃-6-酮的合成 |
CN103387579A (zh) * | 2012-05-08 | 2013-11-13 | 长沙理工大学 | 4-苄氧基-17-苯磺酰吗啡喃-6-酮的合成 |
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CN1328280C (zh) * | 2002-11-28 | 2007-07-25 | 中国科学院上海药物研究所 | 汉防己碱和汉防己碱化合物,合成和应用 |
CN1298718C (zh) * | 2005-03-18 | 2007-02-07 | 中国科学院上海有机化学研究所 | C环连接有吡嗪环的青藤碱衍生物、合成方法及其用途 |
CN1298720C (zh) * | 2005-03-18 | 2007-02-07 | 中国科学院上海有机化学研究所 | C环连接有五元杂环的青藤碱衍生物和合成方法 |
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CN101578101B (zh) * | 2005-12-15 | 2012-05-23 | 自然医学公司 | 青藤碱衍生物的制备和应用 |
CN103232467B (zh) * | 2006-06-19 | 2015-11-18 | 湖南正清制药集团股份有限公司 | 一种青藤碱结构改造化合物及其制备方法 |
WO2011098035A1 (zh) | 2010-02-10 | 2011-08-18 | 中国科学院上海有机化学研究所 | 一种青藤碱衍生物、合成方法及其用途 |
CN103387539A (zh) * | 2012-05-08 | 2013-11-13 | 长沙理工大学 | 4-苄氧基-17-乙酰基吗啡喃-6-酮的合成 |
CN103387579A (zh) * | 2012-05-08 | 2013-11-13 | 长沙理工大学 | 4-苄氧基-17-苯磺酰吗啡喃-6-酮的合成 |
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