CN101679450B - 制备拓朴替康的方法 - Google Patents

制备拓朴替康的方法 Download PDF

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CN101679450B
CN101679450B CN2008800177733A CN200880017773A CN101679450B CN 101679450 B CN101679450 B CN 101679450B CN 2008800177733 A CN2008800177733 A CN 2008800177733A CN 200880017773 A CN200880017773 A CN 200880017773A CN 101679450 B CN101679450 B CN 101679450B
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topotecan
solvent
alkali
dimethylated methylene
alcohol
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胡聪成
韩品杰
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Scinopharm Taiwan Ltd
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Abstract

本发明关于一种制备拓朴替康或其医药上可接受的盐的方法，其包括使铵盐与10-羟基喜树碱反应。

Description

制备拓朴替康的方法
技术领域
本申请请求于2007年4月11日申请的美国临时申请案第60/922,918号的优先权。该美国临时申请案第60/922,918号的内容全部并入本案中参考。
本发明涉及通过10-羟基喜树碱(10-hydroxycamptothecin)制备拓朴替康(Topotecan)或其医药上可接受的盐。
背景技术
美国专利第5,004,758号公开拓朴替康为(S)-10-[(二甲基氨基)甲基]-4-乙基-4，9-二羟基-1H-吡喃并[3′，4′：6，7]-氮茚并[1，2-b]喹啉-3，14(4H，12H)二酮单盐酸盐(也已知为9-二甲基胺基甲基-10-羟基喜树碱等)。其结构式如下：
Figure G2008800177733D00011
注射用的拓朴替康盐酸盐在美国上市为癌症化学治疗剂，其商品名为
传统上制备拓朴替康的方法为通过10-羟基喜树碱的曼尼西反应(Mannichreaction)。例如，美国专利第5,734,056号公开了二(二甲基氨基)甲烷、二(N-吗啉基)甲烷、二(N-甲基哌嗪基)甲烷、二(4′-哌啶并哌啶基)甲烷、二(环丙基胺基)甲烷、二(N-甲基苯胺基)甲烷或二(环己基胺基)甲烷与10-羟基喜树碱反应，以生成9-取代喜树碱类，其包含拓朴替康。
然而仍需发展一种简单、商业上可实施的方法以制备较少杂质存在的拓朴替康或其医药上可接受的盐。
发明内容
我们发现拓朴替康或其医药上可接受的盐可在碱与有机溶剂存在下通过10-羟基喜树碱与铵盐反应而有效地生产，该铵盐的构造如下式(I)：
[H2C＝NR1R2]+X        (I)
其中R1和R2代表甲基或CH2R3基团，R3代表保护基，X代表阴离子。
阴离子可选自由卤素、甲磺酸根(mesylate)、甲苯磺酸根(tosylate)、对溴苯磺酸根(brosylate)、硝酸苯磺酸根(nosylate)及三氟甲磺酸根(triflate)组成的群组。
碱可为有机或无机碱或其混合。有机碱可选自胺、吡啶(pyridine)、甲基吡啶(picoline)、喹啉(quinoline)、哌啶(piperdine)、吡咯啶(pyrrolidine)、N-甲基吗啡啉(N-methylmorpholine)及上述碱的组合。无机碱可选自由碱金属氢氧化物、碱金属碳酸盐、碱金属碳酸氢盐及上述的组合所组成之群。而较好的碱为三乙胺。
保护基较好为卤素或三甲基硅烷基。
铵盐较佳为N，N-二甲基亚甲基卤化铵(N，N-dimethylmethyleneiminiumhalide)，更佳为N，N-二甲基亚甲基氯化铵或N，N-二甲基亚甲基碘化铵。
有机溶剂可选自由有机卤化物溶剂、酮、腈、醇、酯、醚、偶极非质子性溶剂及其组合所组成的群。较佳的情况下，有机溶剂是一种选自C1～C4氯化烃的有机卤化物溶剂或是一种选自C1～C6的醇类。更佳的有机溶剂系统为二氯甲烷和异丙醇的混合物。
反应步骤最好于无水情况下实施。
拓朴替康的医药上可接受的盐较佳为拓朴替康盐酸盐，且前述制法进一步包括使拓朴替康与盐酸(HCI-水或HCI-有机溶剂)反应的步骤，以制造拓朴替康盐酸盐。或者，拓朴替康盐酸盐也可通过将盐酸加入到10-羟基喜树碱与式(I)的铵盐的曼尼西反应所得的混合物中加以制备而成。
根据本发明的制法，其可于无水条件下进行，因此避免产生式(II)的″羟甲基″不纯物(MW＝394)，其明显存在于制备拓朴替康的已知方法中：
Figure G2008800177733D00031
因此，根据本发明制备的拓朴替康或拓朴替康盐可实质上无如式II的任何羟甲基不纯物。在此的术语″实质上无″，意为基于最终拓朴替康或拓朴替康盐产物的总重，式II的羟甲基不纯物的量少于0.10％。更佳地，最终拓朴替康或拓朴替康盐产物不含式II的任何羟甲基杂质。
再者，使用公开在美国专利第5,734,056号的双胺化合物与10-羟基喜树碱反应制备拓朴替康时，会由双胺化合物形成副产物(例如：若反应中使用双(二甲基胺基)甲烷将会形成二甲基胺)。再者，在现有技术中，当胺应用在曼尼西反应时，需要加有效量的强酸作为催化剂。然而，在本发明所公开的曼尼西反应不需要加任何酸来催化。
本发明的其它目标与特征将于其下的详细描述和图示而显得明确。然而，应了解图示仅单独用于说明的目的，并非为定义本发明的限制，其为随后申请专利范围的参考。应更进一步了解，图示仅试图对本文所描述的结构与步骤做概念上的说明。
具体实施方式
下列为根据本发明的两种制备拓朴替康及拓朴替康盐酸盐的实施例：
实施例1：
将10-羟基喜树碱(1.0kg)、二氯甲烷(约13kg)和异丙醇(约8kg)装入适当的反应器。将N，N-二甲基亚甲基氯化铵(0.3-0.5kg)加入反应器。在20-35℃下将三乙胺(0.04-0.2kg)加入所得的混合物，并在20-35℃的温度下搅拌至少12小时。当反应完成时，将盐酸(32％，0.06-0.3kg)和异丙醇(约5kg)的混合物加入到所得的混合物中。结束添加后，搅拌所得混合物，过滤，然后以二氯甲烷(约3kg)洗涤。将湿固体干燥后产生约1.5kg的粗制拓朴替康HCl。
上述反应的合成路径如下所示：
步骤1a：曼尼西反应
Figure G2008800177733D00041
化学式：C20H16N2O5            化学式：C23H23N3O5
分子量：364.35                分子量：421.45
10-羟基喜树碱                 拓朴替康自由碱
步骤1b：盐的形成
Figure G2008800177733D00042
化学式：C23H23N3O5            化学式：C23H23N3O5
分子量：421.45                分子量：421.45
拓朴替康自由碱                拓朴替康盐酸盐
                              注：x＝1.0-1.5
无意于受限于任何理论，下图所示阐述的是上述图解反应的可能反应机理：
Figure G2008800177733D00051
三乙胺的功能可能是捕捉位于10-羟基喜树碱C10的羟基团上的质子，其作用可能类似催化剂。此外，三乙胺可作为碱而与HCl结合。因此，三乙胺可能在此反应中有多种功能。
实施例2：
将10-羟基喜树碱(0.1g)、N，N-二甲基亚甲基氯化铵(约0.06g)、二氯甲烷(约1.3g)和异丙醇(约0.8g)置于一合适的反应器，搅拌所得混合物5-10分钟，接着加入三乙胺(0.002-0.03g)，并在室温下搅拌所得混合物。反应完成后，将盐酸(37％，0.003-0.045g)和异丙醇(约0.14g)的混合物加至所得混合物中。搅拌所得混合物超过四小时，接着过滤出固体，以二氯甲烷(约1g)冲洗并且在真空下干燥，而生成约0.11g的拓朴替康HCl。
本发明并非受上述实施方式所限制，此实施方式仅以范例提供，本发明可在申请专利范围的定义的保护范围下以不同方式修改。

Claims (12)

1.一种制备拓朴替康或其医药上可接受的盐的方法，包括在碱与有机溶剂存在下使10-羟基喜树碱和下式(I)的铵盐反应：
[H2C＝NR1R2]+X             (I)
其中R1和R2代表甲基；X代表阴离子，所述阴离子选自由卤素、甲磺酸根、甲苯磺酸根、对溴苯磺酸根、硝基苯磺酸根及三氟甲磺酸根组成的组；碱为一有机碱，且其选自由胺、吡啶、甲基吡啶、喹啉、哌啶、吡咯啶、N-甲基吗啡啉和上述碱的组合所组成的组；所述有机溶剂选自由有机卤化溶剂、醇、酯、醚、偶极非质子性溶剂和上述溶剂的组合所组成的组。
2.根据权利要求1所述的方法，其中碱为三乙胺。
3.根据权利要求1所述的方法，其中铵盐为N，N-二甲基亚甲基卤化铵。
4.根据权利要求3所述的方法，其中N，N-二甲基亚甲基卤化铵为N，N-二甲基亚甲基氯化铵。
5.根据权利要求3所述的方法，其中N，N-二甲基亚甲基卤化铵为N，N-二甲基亚甲基碘化铵。
6.根据权利要求3所述的方法，其中反应步骤为在无水条件下操作。
7.根据权利要求1所述的方法，其中偶极非质子性溶剂为酮、腈或其组合。
8.根据权利要求1所述的方法，其中有机卤化溶剂为C1～C4氯化烃。
9.根据权利要求1所述的方法，其中有机溶剂系统为二氯甲烷和异丙醇的混合物。
10.根据权利要求1所述的方法，其中拓朴替康的医药上可接受盐为拓朴替康盐酸盐，且所述方法还包含使拓朴替康或反应步骤所生成的混合物与盐酸反应以制造拓朴替康盐酸盐的步骤。
11.根据权利要求1所述的方法，其中所述有机溶剂是醇。
12.根据权利要求11所述的方法，其中所述醇是C1-C6的醇。
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