CN1560059A - 抗乙肝病毒药物阿德福韦酯的合成方法 - Google Patents
抗乙肝病毒药物阿德福韦酯的合成方法 Download PDFInfo
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Abstract
本发明提供了一种抗乙肝病毒药物阿德福韦酯的合成方法，其特征在于包括下述步骤：(1)制备氯乙基氯甲醚；(2)制备氯乙基氯甲醚；(3)制备2－[双(三氟乙基)－膦酰基甲氧基]乙基氯；(4)制备9－[(双(三氟乙氧基)－膦酰基甲氧基乙基)－腺嘌呤；(5)制备PMEA；(6)制备9－[双[(异戊酰氧基)甲氧基]氧膦基]－甲氧基]乙基]腺嘌呤；本发明具有工艺易行、环保、收率较高的特点。
Description
技术领域
本发明是关于制备抗乙肝病毒药物阿德福韦酯的合成工艺。
技术背景
乙型病毒性肝炎是严重威胁我国人民健康的重大疾病。我国乙肝病毒携带者约占总人口的十分之一，有临床症状者高达3000万。目前临床有效抗乙肝病毒药物主要为干扰素和那米呋啶。但是，干扰素治疗的有效率只有30-50％，而且常伴随流感样症状及白细胞减少等毒副作用；那米呋啶具有确切的抗乙肝病毒作用，但是目前尚未实现国产化，费用昂贵，而且那米呋啶治疗易产生耐药性，连续用药2年后，耐药性的发生率高达40-50％。由此可引发肝炎的急性发作等严重后果。
阿德福韦酯[化学名9-[双[(异戊酰氧基)甲氧基]氧膦基]-甲氧基]乙基]腺嘌呤，I]是核苷酸类的抗乙肝病毒药物。它是腺核苷单磷酸的无环类似物阿德福韦[(9-(2-磷酰基甲氧基乙基)-腺嘌呤，PMEA，II]的前体药物，在体内解离为阿德福韦；阿德福韦转运进入细胞后，在细胞激酶的作用下，通过二次磷酸化转化为活性代谢物二磷酸阿德福韦。后者作为病毒DNA聚合酶和逆转录酶的抑制剂而起到抗病毒作用。二磷酸阿德福韦
能够替代天然底物脱氧腺核苷三磷酸嵌入DNA链，由于它没有3’-羟基，引起DNA合成的过早中止，造成DNA链的中断。进入体内，在细胞酶的作用下转化为活性代谢物二磷酸阿德福韦。后者作为DNA聚合酶和逆转录酶抑制剂抑制病毒复制。
临床研究结果表明，阿德福韦酯能够快速而有效地降低乙肝患者的血清HBV DNA水平，改善肝脏组织学，降低转氨酶；长期用药不产生抗药性，而且对那米呋啶耐药株有效；对转氨酶升高和肝功正常的乙肝患者具有相同的疗效；对e-抗原阴性和阳性患者同样有效；与那米呋啶合用有协同作用。因此，阿德福韦酯显示了巨大的应用前景。
由于阿德福韦酯治疗的疗程较长，同时我国是乙肝大国，为满足临床用药需要必须具备适合工业生产的阿德福韦酯的合成工艺。
文献报道的合成方法均是以腺嘌呤为原料，经不同的合成路线制得9-(二烷氧基磷酰基甲氧基乙基)-腺嘌呤，经水解得到关键中间体PMEA，再与新戊酰氯甲酯缩合，制备目标化合物：
9-(二烷氧基磷酰基甲氧基乙基)-腺嘌呤的合成路线主要有三条：
第一条合成路线(Holy A，et al.Synthesis of N-(phosphonylmethoxyethyl)derivatives of heterocyclic bases.Collect Czech Chem Commun 1989；5：2190.)以腺嘌呤为原料与二乙氧基-膦酰基甲氧基-乙基氯缩合制得9-(二乙氧基磷酰基甲氧基乙基)-腺嘌呤：
美国专利(US Patent 6451340)公开的第二条合成路线(2)为腺嘌呤与二乙基对甲苯磺酰氧基乙氧基甲基磷酸酯缩合制得9-(二乙氧基磷酰基甲氧基乙基)-腺嘌呤：
第三条合成路线(Yu RH，et al.Process optimization in the synthesis of 9-[2-(diethyl-phosphonomethoxy)ethyl]adenine：Replacement of sodium hydride withsodium tert-butoxide as the base for oxygen alkylation.Org Process Res Dev 1999；3：53.)为腺嘌呤与碳酸乙二醇内酯反应，生成碳酸乙二醇内酯9-(2’-羟基乙基)腺嘌呤，再与二乙基对甲苯磺酰氧基甲基磷酸酯缩合制得：
这些工艺存在两个缺点：
1.侧链与腺嘌呤的缩合生成9-位取代物的同时，易形成7-异构体，两者性质相似，必须通过硅胶柱层析才能分离纯化，不适合工业化生产；
2.由9-(二烷氧基磷酰基甲氧基乙基)-腺嘌呤水解制备关键中间体PMEA，需使用水解试剂三甲基溴硅烷，同时反应在乙腈中进行，二者均为有毒危险品，易带来较严重的环保问题。
发明内容
针对现有技术的不足，本发明的目的在于提供一种工艺易行、环保、收率较高的一种抗乙肝病毒药物阿德福韦酯的合成方法。
本发明的目的是这样实现的：一种抗乙肝病毒药物阿德福韦酯的合成方法，包括下述步骤：
(1)乙醇与多聚甲醛反应制得氯乙基氯甲醚；
(2)三氟乙醇与三氯化磷反应制得氯乙基氯甲醚；
(3)氯乙基氯甲醚与氯乙基氯甲醚缩合制得2-[双(三氟乙基)-膦酰基甲氧基]乙基氯；
(4)2-[双(三氟乙基)-膦酰基甲氧基]乙基氯与腺嘌呤缩合制得9-[(双(三氟乙氧基)-膦酰基甲氧基乙基)-腺嘌呤；
(5)产物9-[(双(三氟乙氧基)-膦酰基甲氧基乙基)-腺嘌呤在含盐酸、水及水溶性有机介质中加热水解制得9-(2-磷酰基甲氧基乙基)-腺嘌呤(PMEA)；
(6)PMEA与新戊酰氯甲酯缩合，制备得到目标化合物9-[双[(异戊酰氧基)甲氧基]氧膦基]-甲氧基]乙基]腺嘌呤。
本发明的方法中步骤(4)的缩合反应在二甲基甲酰胺、二甲亚砜中进行，加入催化量的冠醚。
本发明的方法中步骤(5)的盐酸、水及水溶性有机介质比例为1∶2-10∶4-20，最佳比例为1∶4-6∶8-12；水解温度为60-100℃；所说的水溶性有机介质包括甲醇、乙醇、异丙醇、丙酮、四氢呋喃、二氧六环、二甲基甲酰胺、二甲亚砜。
本发明中阿德福韦酯的具体合成路线如下：
本发明通过对关键中间体PMEA的制备方法进行了改革，先制备9-[(双(三氟乙氧基)-膦酰基甲氧基乙基)-腺嘌呤，在盐酸、水及水溶性有机溶剂溶液中经简单的酸处理即可得到PMEA，革除了水解试剂三甲基溴硅烷和溶剂乙腈，既减少了污染，又降低了成本；侧链试剂与腺嘌呤缩合时，加入催化量的冠醚，既能提高产率，又能减少7-异构体的生成，产物不经硅胶柱层析分离就能用于下步反应。
附图说明
图1是本发明的工艺流程图。
具体实施方式
下面结合附图和实施例对本发明作进一步地描述，但本发明的范围并不限于下述实施例。
本发明的工艺流程简述如下：1、制备氯乙基氯甲醚，2、制备氯乙基氯甲醚，3、制备2-[双(三氟乙基)-膦酰基甲氧基]乙基氯，4、制备9-[(双(三氟乙氧基)-膦酰基甲氧基乙基)-腺嘌呤，5、制备PMEA，6、制备9-[双[(异戊酰氧基)甲氧基]氧膦基]-甲氧基]乙基]腺嘌呤。
实施例：
(一)氯乙基氯甲醚(III)的制备
在1500ml三口瓶中，加入846g(705ml，10.5mol)2-氯乙醇及316g(10.9mol)粉碎的多聚甲醛，搅拌下通入干燥的氯化氢气体，持续24小时。停止搅拌后反应液分为两层；分出下层，以氯化钙干燥。过滤后，将滤液减压分馏，收集沸程为80-84℃/28-30mmHg的馏分，得氯乙基氯甲醚(III)743g，收率54.9％。
(二)三-(2，2，2-三氟乙基)亚磷酸酯(IV)的制备
在46克三氟乙醇中，加入21克三氯化磷，在80-90℃搅拌反应4小时。分级蒸馏，得三-(2，2，2-三氟乙基)亚磷酸酯(IV)41克，130-131℃/74-78mmHg。
(三)2-[双(2，2，2-三氟乙基)-膦酰基甲氧基]-乙基氯(V)的制备
将18克氯乙基氯甲醚(III)与40克三-(2，2，2-三氟乙基)亚磷酸酯(IV)混合，于160℃搅拌反应5小时。减压蒸去溶剂后，分馏得到二(2，2，2-三氟乙基)-膦酰基乙基氯(V)，沸点125-128℃/3mmHg。
(四)9-[双(2，2，2-三氟乙基)-膦酰基甲氧基]乙基-嘌呤(VI)的制备
在1000ml三口瓶中，将54g(0.4mol)腺嘌呤悬浮于560ml二甲基甲酰胺中，加入0.5克18-冠-6，搅拌下加入55.4g(0.4mol)无水碳酸钾，于100℃油浴中加热。搅拌下滴加113.6g(0.44mol)9-[双(2，2，2-三氟乙基)-膦酰基甲氧基]乙基-嘌呤(V)；加完后继续搅拌反应4小时，HPLC检测反应完全，7-异构体含量小于1％。待反应液冷却后，滤去固体，将滤液减压蒸干，残留物用乙腈重结晶两次，得9-[双(2，2，2-三氟乙基)-膦酰基甲氧基]乙基-嘌呤(VI)的白色固体94.6g，熔点133-135℃，产率66.46％。
(五)9-(2-磷酰基甲氧基乙基)-腺嘌呤(II)的制备
在氮气下，将9-[双(2，2，2-三氟乙基)-膦酰基甲氧基]乙基-嘌呤(VI)94.6 g(0.26mol)悬浮于1000ml 70％乙醇中，加入30ml浓盐酸，搅拌回流6小时，硅胶薄层检测原料消失(展开剂：氯仿∶甲醇＝8.5∶1.5，原料IV的Rf＝0.6，产物V的Rf＝0)。减压蒸去乙醇，于残留物中加入500ml水，立即产生白色沉淀，加入600ml丙酮，室温搅拌14小时。过滤，将滤饼以150ml丙酮洗2次，用150ml无水乙醚洗1次，得9-(2-磷酰基甲氧基乙基)-腺嘌呤(II)的类白色固体66.4g，产率91.8％，熔点285℃(分解)。
(六)阿德福韦酯(I)的制备
在氮气下，向反应器中依次加入600ml干燥的乙腈，66.4g(0.24mol)9-(2-磷酰基甲氧基乙基)-腺嘌呤(II)，138.2g(0.49mol)N’-二环己基-4-吗啉脒及182g(1.21mol)新戊酰氯甲酯，于室温搅拌24小时。硅胶薄层检测反应基本完全(展开剂：二氯甲烷∶甲醇＝95∶5，Rf＝0.32)。将反应混合物用700ml乙酸乙酯稀释，冷却至25℃，搅拌30分钟。滤去固体，用250ml乙酸乙酯洗。合并洗滤液，用水洗(100ml/次，2次)。将有机层于35℃减压浓缩至250ml，过滤，用50ml乙酸乙酯洗。于35℃减压蒸去溶剂，得油状物；以硅胶柱层析分离，用含5％乙醇的二氯甲烷洗脱，得目标化合物阿德福韦酯(I)白色固体53.6g，熔点94-97℃，产率44％。
Claims (4)
1.一种抗乙肝病毒药物阿德福韦酯的合成方法，其特征在于包括下述步骤：
(1)乙醇与多聚甲醛反应制得氯乙基氯甲醚；
(2)三氟乙醇与三氯化磷反应制得氯乙基氯甲醚；
(3)氯乙基氯甲醚与氯乙基氯甲醚缩合制得2-[双(三氟乙基)-膦酰基甲氧基]乙基氯；
(4)2-[双(三氟乙基)-膦酰基甲氧基]乙基氯与腺嘌呤缩合制得9-[(双(三氟乙氧基)-膦酰基甲氧基乙基)-腺嘌呤；
(5)产物9-[(双(三氟乙氧基)-膦酰基甲氧基乙基)-腺嘌呤在含盐酸、水及水溶性有机介质中加热水解制得PMEA；
(6)PMEA与新戊酰氯甲酯缩合，制备得到目标化合物9-[双[(异戊酰氧基)甲氧基]氧膦基]-甲氧基]乙基]腺嘌呤。
2.根据权利要求1所述的方法，其特征在于：步骤(4)的缩合反应在二甲基甲酰胺、二甲亚砜中进行，加入催化量的冠醚。
3.根据权利要求1所述的方法，其特征在于：步骤(5)中盐酸、水及水溶性有机介质比例为1∶2-10∶4-20，水解温度为60-100℃。
4.根据权利要求1或3所述的方法，其特征在于：所说的水溶性有机介质包括甲醇、乙醇、异丙醇、丙酮、四氢呋喃、二氧六环、二甲基甲酰胺、二甲亚砜。
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| CN100395248C (zh) * | 2006-05-26 | 2008-06-18 | 华东理工大学 | 一种9-(二乙氧基磷酰基甲氧基乙基)-腺嘌啉的制备方法 |
| CN101450954A (zh) * | 2007-12-05 | 2009-06-10 | 中国人民解放军第二军医大学 | 核苷酸类似物及其应用,以及含该核苷酸类似物的药物组合物 |
| CN101817847A (zh) * | 2009-02-26 | 2010-09-01 | 湖南欧亚生物有限公司 | 一种生产阿德福韦的方法 |
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| CN101450954A (zh) * | 2007-12-05 | 2009-06-10 | 中国人民解放军第二军医大学 | 核苷酸类似物及其应用,以及含该核苷酸类似物的药物组合物 |
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| CN102120748B (zh) * | 2011-01-18 | 2014-01-08 | 浙江山峪染料化工有限公司 | 高纯度9-(2-二乙氧基膦酰甲氧乙基)腺嘌呤的制备方法 |
| CN102250146A (zh) * | 2011-05-27 | 2011-11-23 | 扬州三友合成化工有限公司 | 抗乙肝药物阿德福韦的一种合成方法 |
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