CN104370905A - Bcl-2抑制剂ABT-199的合成 - Google Patents
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- C07D471/04—Ortho-condensed systems
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Abstract
本发明公开了一种Bc1-2抑制剂ABT-199的合成方法。该方法以2-氟-4-硝基苯甲酸甲酯和5-羟基-7-氮杂吲哚为原料经取代，还原，环合，取代，水解，缩合等方法合成ABT-199，该方法具有反应条件温和，操作工艺简便，成本低，产率高的特点。
Description
(一)技术领域
本发明属于药物合成技术领域，具体地，本发明涉及Bcl-2抑制剂ABT-199的合成方法。
(二)技术背景
B淋巴细胞瘤-2基因简称bcl-2(B-cell lymphoma-2)，是细胞凋亡研究中最受重视的癌基因之一。Bcl-2基因(即B细胞淋巴瘤/白血病-2基因)是一种原癌基因，它具有抑制凋亡的作用，并且近年来的一些研究已开始揭示这一作用的机制。目前已经发现的Bcl-2蛋白家族按功能可分为两类，一类是像Bcl-2一样具有抑制凋亡作用，如哺乳动物的Bcl-XL、Bcl-W、Mcl-1、A1、线虫Ced-9、牛痘病毒E1B119kD等，而另一类具有促进凋亡作用，如Bax、Bcl-Xs、Bax、Bak、Bik/Nbk、Bid和Harakiri。在动物王国中，大部分细胞死亡都是通过细胞凋亡实现的。在脊椎动物中，凋亡途径主要有两条，死亡受体途径和线粒体途径。在线粒体途径中，Bcl-2家族的蛋白相互作用，从而调节和影响着线粒体外膜通透性(Mitochondrial outer membrane permeabilization，MOMP)。由于膜的通透性，线粒体内膜间隙中的蛋白质得以进入到细胞质，激活半胱天冬酶，从而使细胞产生明显的凋亡特征。MOMP是线粒体凋亡途径的关键决定因素，不同类别的Bcl-2蛋白对MOMP的控制也是这一过程的核心。
Bcl-2家族包括三种类型的蛋白：一是具有促凋亡效应的蛋白，包括BAX和BAK，它们能够影响MOMP；二是具有抗凋亡效应的蛋白，包括Bcl-2，Bcl-XL，Bcl-W，Mcl-1和A1，它们能够阻碍MOMP；三是只含BH3结构的蛋白(例如：BID，BIM，BMF，PUMA，BAD和NOXA)，又名BH3-only蛋白。它们调节着其它两个类别的蛋白。最近研究表明，BH3-only蛋白主要以启动线粒体途径为主，当细胞受到一些信号刺激时，BH3-only蛋白活化，并通过一定的方式活化Bax或Bak，使Bax和Bak在线粒体膜上形成寡聚物，从而使膜通透性增加，最终释放促凋亡蛋白如细胞色素C，驱使caspase活化并介导细胞凋亡。越来越多的研究表明，BH3-only蛋白参与了关键的生物学过程，其缺乏可引起自身免疫病和肿瘤。
ABT-199是AbbVie研发的Bcl-2抑制剂，I期试验(NCT01328626)入组了84例复发型/难治型CLL/SLL患者和44例复发型/难治型非霍奇金淋巴瘤患者。ABT-199治疗CLL/SLL的应答率为79％(完全应答率为22％)，中位持续应答时间为20.5个月；ABT-199治疗非霍奇金淋巴瘤的应答率为48％(完全应答率为7.5％)。ABT-199的疗效能够与obinutuzumab、idelalisib、ibrutinib匹敌，有望成为第一个上市的Bcl-2抑制剂，目前ABT-199正在进行III期临床研究。
ABT-199的化合物CAS号为1257044-40-8，化合物结构如下：
专利WO2012058392、WO2012071336、WO2010138588等公开了ABT-199的制备方法，以5-溴-1H-吡咯[2，3-b]吡啶为原料经保护羟基化、取代后得到化合物5，在与化合物6反应、水解得到化合物9，化合物9与化合物10缩合得到ABT-199，具体路线如下：
该方法在制备化合物5时，由于化合物4有两个F，都可以参与反应，导致生成化合物5的产率很低，且无法纯化，往下反应生成2位取代和4位取代的混合物；在反应过程中脱除TIPS保护基，导致底物中-OH与自身另外一分子N反应，导致产率很低。因此，该路线存在种种弊端。
(三)发明内容
本发明提供了一种新的合成方法，能够克服前人路线中的缺点，产率高，操作简便，合成成本低。
为了达到上述要求，本发明使用2-氟-4-硝基苯甲酸甲酯(A)为原料，与5-羟基-7-氮杂吲哚(B)取代，还原，生成化合物(D)，化合物(D)经环合后与化合物(H)取代，水解，生成化合物(J)，再与化合物(K)反应得到ABT-199。
具体路线如下：
有益效果：
(1)发明原料价廉，步骤简单；
(2)避免了WO2012058392中多取代产率低，不好纯化的缺点。
(3)化合物A与未经TIPS的化合物(B)反应，通过控制反应条件，降低自身取代的几率，从而增加反应的收率。
(四)具体实施方式
下面通过具体实施例对该发明作进一步的描述。
实施例一 化合物(F)的制备
第一步：合成化合物(C)
在1L三口瓶中加入2-氟-4-硝基苯甲酸甲酯50.0g，用N’N-二甲基甲酰胺250ml溶解，顺次加入5-羟基-7-氮杂吲哚33.6g，碳酸钾34.7g，反应液氮气保护下加热50度反应2小时，后倒入2L冰水中，加入乙酸乙酯萃取三次，有机相经饱和氯化钠干燥后旋干，得到化合物(C)粗品82.0g，粗品不经纯化直接投下一步反应。
第二步：合成化合物(D)
将上一步化合物(C)的粗品用甲醇400ml溶解，加入10％钯碳4.0g，常压下通氢气反应，TLC检测反应结束后旋去溶剂，得到化合物(D)粗品73.2g，粗品不经纯化直接投下一步反应。
第三步：合成化合物(F)
取上一步化合物(D)粗品20.0g，依次加入叔丁醇150ml，化合物(E)10.g，碳酸钾9.7g，加完反应体系回流48小时后冷却反应液，加入乙酸乙酯稀释，用水洗三次，合并水相用乙酸乙酯再萃取一次，合并两次乙酸乙酯相，经无水硫酸钠干燥后旋去溶剂，得到的粗品经硅胶柱层析纯化得到13.9g，三步总产率57.4％。
实施例二 化合物(H)的制备
取化合物(G)(按照WO2012058392中方法制备)5.0g，用二氯甲烷50ml溶解，加入三乙胺5.6ml，反应液搅拌冷却至0-5度，滴加甲基磺酰氯2.7g，加完反应液升至室温反应过夜，TLC检测反应结束后加水淬灭反应，有机相经无水硫酸钠干燥后旋去溶剂，硅胶柱层析纯化得到化合物(H)6.5g，产率99％。
实施例三 ABT-199的制备
第一步：合成化合物(I)
在100ml三口瓶中依次加入化合物(F)2.5g，化合物(H)2.3g，碳酸钾1.9g，N’N-二甲基甲酰胺15ml，氮气保护下加入50度反应，TLC检测反应结束后反应液倒入冰水，加入乙酸乙酯萃取两次，乙酸乙酯相经无水硫酸钠干燥后旋干，硅胶柱层析纯化后得到化合物(I)3.6g，产率88％。
第二步：合成化合物(J)
在10ml单口瓶中加入化合物(I)1.0g，依次加入水5ml，乙醇5ml，四氢呋喃5ml，氢氧化钠136mg，反应液室温搅拌反应，TLC检测反应结束后加入乙酸乙酯稀释，用1N盐酸调节pH4-5，乙酸乙酯萃取三次，经无水硫酸钠干燥后旋干得到化合物(J)907mg，产率93％。
第二步：合成ABT-199
在25ml单口瓶中加入化合物(J)100mg，EDCI67mg，二氯甲烷10ml，反应液搅拌30分钟后，加入化合物(K)(按照WO2012058392中方法制备)55mg，最后加入催化量DMAP，加完反应液搅拌反应过夜，TLC检测反应结束后旋去溶剂，经制备HPLC纯化得到ABT-199纯品98mg，产率65％。
Claims (4)
1.一种Bcl-2抑制剂ABT-199的合成方法，其路线如下：
该方法以2-氟-4-硝基苯甲酸甲酯(A)为原料，与5-羟基-7-氮杂吲哚(B)取代，还原，生成化合物(D)，化合物(D)经环合后与化合物(H)取代，水解，生成化合物(J)，再与化合物(K)反应得到ABT-199。
2.一种制备Bcl-2抑制剂ABT-199的所需中间体(I)的制备方法，其路线如下：
该方法以2-氟-4-硝基苯甲酸甲酯(A)为原料，与5-羟基-7-氮杂吲哚(B)取代，还原，生成化合物(D)，化合物(D)经环合后与化合物(H)取代生成所需中间体(I)。
3.根据权利要求2所述的制备Bcl-2抑制剂ABT-199的所需中间体(I)的制备方法，其特征在于化合物(A)与化合物(B)生成化合物(C)的反应温度是45-55度，反应时间为1.5-3小时，化合物(A)与化合物(B)的摩尔比为1∶0.9-1∶1.2。
4.根据权利要求2所述的制备Bcl-2抑制剂ABT-199的所需中间体(I)的制备方法，其特征在于化合物(D)与化合物(E)经环合生成化合物(F)，所用的条件为化合物(D)与化合物(E)的当量比为1∶0.5-1∶2.0，所用的碱为碳酸钾，所用的溶剂为叔丁醇。
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