CN107056786B - 阿卡替尼的制备方法 - Google Patents
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Classifications
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
本发明揭示了一种可用于白血病治疗的新药阿卡替尼(Acalabrutinib)的制备方法，其制备步骤包括：以3‑氯‑2‑甲醛基吡嗪为原料，经缩合、酰化、环合和胺化等反应制得阿卡替尼。本发明涉及的阿卡替尼(Acalabrutinib)的制备方法具有原料易得，工艺简洁，经济环保等优点，适合大规模工业化生产。
Description
技术领域
本发明属于有机合成路线设计及其原料药和中间体制备技术领域，特别涉及一种可治疗白血病药物阿卡替尼(Acalabrutinib)的制备方法。
背景技术
Acalabrutinib(ACP-196)是由阿斯利康旗下Acerta Pharma公司开发的一种高度选择性和不可逆的第二代BTK抑制剂，该药物可以通过永久性结合BTK来发挥作用。通过阻断BTK来抑制癌细胞的生长信号，直至促进癌细胞死亡。2015年9月美国食品药品管理局(FDA)授予该药治疗套细胞淋巴瘤孤儿药资格；2016年3月欧洲药品管理局(EMA)授予该药治疗慢性淋巴细胞白血病/小淋巴细胞淋巴瘤、套细胞淋巴瘤以及淋巴浆细胞样淋巴瘤等三种适应症的孤儿药地位。由于Acalabrutinib还不具有标准的中文译名，故本申请人在此将其音译为“阿卡替尼”。
阿卡替尼的化学名为：4-[8-氨基-3-[(2S)-1-(1-氧代-2-丁炔-1-基)-2-吡咯烷基]咪唑并[1,5-a]吡嗪-1-基]-N-2-吡啶基苯甲酰胺，其结构式为：
国际专利WO2013010868报道了一种阿卡替尼及其母核的制备方法。其合成路线为：以3-氯-2-甲腈吡嗪为原料，经雷尼镍催化氢化还原将腈基还原成甲胺，其可与带有N-保护的脯氨酸或其酰氯发生酰化反应，所得产物在三氯氧磷作用下发生环合反应得到8-氯咪唑并[1,5-a]吡嗪衍生物；该衍生物依次通过咪唑环上的溴代反应、吡嗪环上氯的取代胺化反应得到8-氨基-咪唑并[1,5-a]吡嗪中间体；该中间体在钯催化剂作用下与侧链4-(吡啶-2-基-氨基羰基)苯硼酸发生Suzuki反应，所得产物通过脱除N-保护基以及与2-丁炔酸发生酰化反应，得到目标产物阿卡替尼。
由此看出，现有的阿卡替尼的制备方案存在反应步骤多和总收率低等问题，且受到成本、设备以及环保等诸多方面的限制，不易于工业化。所以，如何运用绿色化学合成理念，设计和开发出简易快捷、经济环保和便于工业化的新方法，对于该药物的经济技术发展具有重要意义。
发明内容
本发明的目的在于针对现有技术中的缺陷，开发出一条新的阿卡替尼的制备方法，该方法具有工艺简洁、经济环保且适合工业化生产等优点。
为实现上述发明目的，本发明采用了如下主要技术方案：一种阿卡替尼(Acalabrutinib)的制备方法，其包括以下步骤：
步骤S1：将原料3-氯-2-甲醛基吡嗪、4-(吡啶-2-基-氨基羰基)苯硼酸和氨在乙酰丙酮二羰基铑的催化剂下发生缩合反应制得4-[氨基(3-氯-2-吡嗪基)甲基]-N-(2-吡啶基)苯甲酰胺；
步骤S2：所述4-[氨基(3-氯-2-吡嗪基)甲基]-N-(2-吡啶基)苯甲酰胺与[1-(1-氧代-2-丁炔-1-基)]-L-脯氨酸酰氯在缚酸剂作用下发生酰化反应制得4-[1-(1-丁-2-炔酰基吡咯烷-2-基)甲酰氨基(3-氯-2-吡嗪基)甲基]-N-(2-吡啶基)苯甲酰胺；
步骤S3：所述4-[1-(1-丁-2-炔酰基吡咯烷-2-基)甲酰氨基(3-氯-2-吡嗪基)甲基]-N-(2-吡啶基)苯甲酰胺在三氯氧磷存在下发生环合反应制得4-[8-氯-3-[(2S)-1-(1-氧代-2-丁炔-1-基)-2-吡咯烷基]咪唑并[1,5-a]吡嗪-1-基]-N-2-吡啶基苯甲酰胺；
步骤S4：所述4-[8-氯-3-[(2S)-1-(1-氧代-2-丁炔-1-基)-2-吡咯烷基]咪唑并[1,5-a]吡嗪-1-基]-N-2-吡啶基苯甲酰胺与氨发生胺化反应制得阿卡替尼。
其中涉及的具体反应式过程可参看下式：
此外，本发明还提出如下附属技术方案：
在步骤S1中，所述原料3-氯-2-甲醛基吡嗪(II)、4-(吡啶-2-基-氨基羰基)苯硼酸(III)和氨发生缩合反应的投料摩尔比为1:1.0～2.5:5.0～15.0，优选1:1.5～2.0:10.0。
在步骤S1中，所述缩合反应的温度为50～150度，优选80～120度。
在步骤S1中，所述缩合反应的溶剂为四氢呋喃、二氧六环、二甲亚砜、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺，优选二氧六环。
在步骤S2中，所述酰化反应的缚酸剂为碳酸钠、碳酸钾、叔丁醇钠、叔丁醇钾、甲醇钠、三乙胺、乙二胺或二异丙基乙胺，优选碳酸钾或三乙胺。
在步骤S3中，所述环合反应的溶剂为乙腈、甲苯、二甲苯、二氧六环、二甲亚砜、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺，优选乙腈。
在步骤S3中，所述环合反应的温度60～150度，优选80～100度。
在步骤S4中，所述胺化反应的溶剂为乙醇、正丙醇、异丙醇、正丁醇、四氢呋喃、二氧六环或N,N-二甲基乙酰胺，优选异丙醇。
在步骤S4中，所述胺化反应的温度80～150度，优选100～120度。
相比于现有技术，本发明所涉及的一种新型的阿卡替尼的制备方法，具有工艺简洁和环保经济等优点，故而利于该原料药的工业化生产，促进其进行广为广泛的使用和发展。
具体实施方式
以下结合较佳实施例对本发明涉及的技术方案作进一步非限制性的详细说明。
本发明的一个实施方式提供了一种可用于白血病治疗药物的阿卡替尼(Acalabrutinib)的制备方法，其包括以下步骤：
步骤S1：
于压力反应器中加入3-氯-2-甲醛基吡嗪(II)(0.71g，5mmol)和二氧六环(20mL)，搅拌下通入氨气(1.7g，0.1mol)，再加入4-(吡啶-2-基-氨基羰基)苯硼酸(III)(2.42g，10mmol)、乙酰丙酮二羰基铑(0.26g，1mmol)和水4mL。将反应器密闭，逐步升温至80～90度，反应16-18小时，TLC检测，反应完成。减压浓缩，残余物用二氯甲烷溶解，饱和碳酸氢钠和水依次洗涤，无水硫酸钠干燥。浓缩，得到棕黄色油状物，用乙酸乙酯和石油醚(体积比1:2)柱层析得类白色固体4-[氨基(3-氯-2-吡嗪基)甲基]-N-(2-吡啶基)苯甲酰胺(IV)1.38g，收率81.2％；ESI-MS(m/z):340(M+H)。
步骤S2：
于反应器中加入[1-(1-氧代-2-丁炔-1-基)]-L-脯氨酸(1.09g，6mmol)和二氯亚砜(10mL)，滴加三乙胺4mL并升温至30～40度，反应2-4小时后，减压除去过量的二氯亚砜，残余物即为[1-(1-氧代-2-丁炔-1-基)]-L-脯氨酸酰氯(V)。将所得的[1-(1-氧代-2-丁炔-1-基)]-L-脯氨酸酰氯(V)用20mL二氯甲烷溶解，滴加至4-[氨基(3-氯-2-吡嗪基)甲基]-N-(2-吡啶基)苯甲酰胺(IV)(1.35g，4mmol)和三乙胺(0.6g，6mmol)的二氯甲烷(30mL)溶液中。滴毕，升温至30-50度，搅拌反应6～8小时，TLC检测，反应完成。降至室温，依次用饱和碳酸氢钠溶液、盐水和水洗涤，无水硫酸钠干燥。浓缩，得米黄色固体4-[1-(1-丁-2-炔酰基吡咯烷-2-基)甲酰氨基(3-氯-2-吡嗪基)甲基]-N-(2-吡啶基)苯甲酰胺(VI)1.8g，收率89.6％。ESI-MS(m/z):503(M+H)。步骤S3：
于反应瓶中加入4-[1-(1-丁-2-炔酰基吡咯烷-2-基)甲酰氨基(3-氯-2-吡嗪基)甲基]-N-(2-吡啶基)苯甲酰胺(VI)(1.0g,2mmol)、三氯氧磷(1.53g，10mmol)和乙腈(25mL)，搅拌下升温至80～100度，保持该温度下反应6～8小时，TLC检测反应完成。降至室温，将反应液倾入50mL浓度为8％的氨水中，加入乙酸乙酯，分出有机相，水相用乙酸乙酯萃取两次，合并有机相，用盐水和水洗涤，无水硫酸钠干燥。浓缩，所得残渣用用乙酸乙酯和石油醚(体积比2:1)柱层析，得类白色固体4-[8-氯-3-[(2S)-1-(1-氧代-2-丁炔-1-基)-2-吡咯烷基]咪唑并[1,5-a]吡嗪-1-基]-N-2-吡啶基苯甲酰胺(VII)0.85g，收率87.8％；EI-MSm/z:485[M+H]+。
步骤S4：
于压力反应器中加入4-[8-氯-3-[(2S)-1-(1-氧代-2-丁炔-1-基)-2-吡咯烷基]咪唑并[1,5-a]吡嗪-1-基]-N-2-吡啶基苯甲酰胺(VII)(0.48g,1mmol)和异丙醇(15mL)，降温至0度，通过剂量控制通入氨气(0.51g，30mmol)，关闭反应器，先升至室温，反应1小时，再不断提高反应温度至110～120度，保持该温度和压力下反应20～24小时，TLC检测反应完成。降至室温，缓慢放空，减压浓缩，所得残余物用乙酸乙酯溶解，饱和食盐水和水洗涤，无水硫酸钠干燥。浓缩，所得残渣用用乙酸乙酯和石油醚(体积比2:1)柱层析，得类白色固体阿卡替尼(I)0.40g，收率86.0％；1H NMR(DMSO-d6)1.63(m,1H),1.97(s,3H),2.02～2.12(m,1H),2.28～2.35(m,2H)；3.36～3.85(m,2H),5.47～5.49(m,1H),6.17～6.23(m,2H),7.12～7.20(m,2H),7.73～7.86(m,4H),8.16～8.25(m,3H),8.41(dd,1H),10.86(s,1H)；EI-MS m/z:466[M+H]+。
以上本发明涉及方法中采用的原料3-氯-2-甲醛基吡嗪(II)和4-(吡啶-2-基-氨基羰基)苯硼酸(III)，其制备方法可分别参考文献“Tetrahedron Letters,47(1),31-34；2006”和国际专利WO2013010868对相同化合物的制备方法。原料[1-(1-氧代-2-丁炔-1-基)]-L-脯氨酸酰氯(V)，在一个实施方式中，可以由已知化合物[1-(1-氧代-2-丁炔-1-基)]-L-脯氨酸的酰化制得。
需要指出的是，上述实施例仅为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。
Claims (6)
1.一种阿卡替尼(Acalabrutinib)的制备方法，其特征在于，其包括以下步骤：
步骤S1：将原料3-氯-2-甲醛基吡嗪、4-(吡啶-2-基-氨基羰基)苯硼酸和氨在乙酰丙酮二羰基铑的催化剂、于温度为50～150度下发生缩合反应制得4-[氨基(3-氯-2-吡嗪基)甲基]-N-(2-吡啶基)苯甲酰胺；
步骤S2：所述4-[氨基(3-氯-2-吡嗪基)甲基]-N-(2-吡啶基)苯甲酰胺与[1-(1-氧代-2-丁炔-1-基)]-L-脯氨酸酰氯在缚酸剂作用下发生酰化反应制得4-[1-(1-丁-2-炔酰基吡咯烷-2-基)甲酰氨基(3-氯-2-吡嗪基)甲基]-N-(2-吡啶基)苯甲酰胺；
步骤S3：所述4-[1-(1-丁-2-炔酰基吡咯烷-2-基)甲酰氨基(3-氯-2-吡嗪基)甲基]-N-(2-吡啶基)苯甲酰胺在三氯氧磷存在、于温度为60～150度下发生环合反应制得4-[8-氯-3-[(2S)-1-(1-氧代-2-丁炔-1-基)-2-吡咯烷基]咪唑并[1,5-a]吡嗪-1-基]-N-2-吡啶基苯甲酰胺；
步骤S4：所述4-[8-氯-3-[(2S)-1-(1-氧代-2-丁炔-1-基)-2-吡咯烷基]咪唑并[1,5-a]吡嗪-1-基]-N-2-吡啶基苯甲酰胺、于温度为80～150度下与氨发生胺化反应制得阿卡替尼。
2.根据权利要求1所述阿卡替尼的制备方法，其特征在于：在步骤S1中，所述3-氯-2-甲醛基吡嗪、4-(吡啶-2-基-氨基羰基)苯硼酸和氨发生缩合反应的投料摩尔比为1:1.0～2.5:5.0～15.0。
3.根据权利要求1所述阿卡替尼的制备方法，其特征在于：在步骤S1中，所述缩合反应的溶剂为四氢呋喃、二氧六环、二甲亚砜、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺。
4.根据权利要求1所述阿卡替尼的制备方法，其特征在于：在步骤S2中，所述酰化反应的缚酸剂为碳酸钠、碳酸钾、叔丁醇钠、叔丁醇钾、甲醇钠、三乙胺、乙二胺或二异丙基乙胺。
5.根据权利要求1所述阿卡替尼的制备方法，其特征在于：在步骤S3中，所述环合反应的溶剂为乙腈、甲苯、二甲苯、二氧六环、二甲亚砜、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺。
6.根据权利要求1所述阿卡替尼的制备方法，其特征在于：在步骤S4中，所述胺化反应的溶剂为乙醇、正丙醇、异丙醇、正丁醇、四氢呋喃、二氧六环或N,N-二甲基乙酰胺。
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