CN103304545B - 5-氨基-1,4-二取代基-1,2,3-三氮唑及其制备方法 - Google Patents
5-氨基-1,4-二取代基-1,2,3-三氮唑及其制备方法 Download PDFInfo
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Abstract
本发明揭示了一种5-氨基-1，4-二取代基-1，2，3-三氮唑(I)及其制备方法，该化合物(I)是替卡格雷等具有1，2，3-三氮唑结构的药物制备的关键中间体，其制备方法包括如下步骤：通过叠氮化合物(II)与氰基衍生物(III)发生环合反应，得到5-氨基-1，4-二取代基-1，2，3-三氮唑(I)。该制备方法原料易得，条件温和，收率高。
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，特别涉及一种新型的中间体5-氨基-1，4-二取代基-1，2，3-三氮唑及其制备方法。
背景技术
1，2，3-三氮唑是重要的三氮芳杂环，由于易形成氢键、配位键等，可发挥多种非共价键相互作用，因而广泛用于构筑高分子材料、新型催化剂、药物及其超分子药物等多种类型的功能分子。近年来，尤其在医药领域，1，2，3-三唑母环被广泛用于设计新药物分子，迄今已有多种含有1，2，3-三氮唑母环的化合物进入临床实验或已用于临床，涉及抗细菌、抗真菌、抗结核、抗病毒、抗肿瘤、抗凝血及其它心血管疾病等多个治疗领域。
替卡格雷(Ticagrelor)是由阿斯利康公司研发的一种新型的、具有选择性的小分子抗凝血药，也是第一个可逆的结合型口服P2Y12腺苷二磷酸受体拮抗剂。对ADP引起的血小板聚集有明显的抑制作用，能有效改善急性冠心病患者的症状。分析替卡格雷的分子结构，可以看出，其核心结构之一就是与嘧啶并环[4，5-d]的1，2，3-三氮唑母环。
已经公开的替卡格雷的制备文献，尽管工艺路线和制备方法多种多样，但其核心方法均是在阿斯利康公司的原研技术基础上所做的各种改进。总结这些合成路线和方法，发现其大多数是以三个中间体(A，B和C)为起始原料，在先构建嘧啶环(中间体A)的基础上，再通过嘧啶环上的氨基亚硝化，与另一邻位氨基(由中间体C提供)一起形成1，2，3-三氮唑母环结构，继而制备得到替卡格雷。
到目前为止，尚未见有先构建1，2，3-三氮唑环，再构建[4，5]并嘧啶环从而制备替卡格雷的方法。如能实现此构思，对于简化该类化合物的制备、提高产品质量和收率定会产生突破性进展。为此，本发明设计并制备了一种可用于替卡格雷新合成路线的重要中间体5-氨基-1，4-二取代基-1，2，3-三氮唑(I)。
发明内容
本发明的目的在于按照绿色化学的合成理念，提供一种新型中间体5-氨基-1，4-二取代基-1，2，3-三氮唑(I)及其制备方法，该制备方法简便、经济和环保，手性纯度和化学收率均较高，适用于含有1，2，3，-三氮唑母环结构的原料药如替卡格雷等的工业化生产。
为了实现上述目的，本发明所提供的主要技术方案如下：一种如式(I)所示的5-氨基-1，4-二取代基-1，2，3-三氮唑：
此外，本发明还提供如下附属技术方案：
所述5-氨基-1，4-二取代基-1，2，3-三氮唑的制备方法包括如下步骤：通过叠氮化合物(II)与 氰基衍生物(III)发生环合反应，得到5-氨基-1，4-二取代基-1，2，3-三氮唑(I)。
所述式(I)化合物中R基团为氢(H)、1-6个碳原子的烷基、2-6个碳原子的链烯基和2-6个碳原子的链炔基、3-10个碳原子的环烷基或芳基或杂环基、1-5个碳原子(n＝1-5)的端酯基[-(CH2)nCO2R1]或1-5个碳原子(n＝1-5)的端烷氧基[-(CH2)nOR2]。
所述R基团为1-5个碳原子(n＝1-5)的端酯基[-(CH2)nCO2R1]时，其R1为1-6个碳原子的烷基或6-10个碳原子的芳基或取代芳基；
所述R基团为1-5个碳原子(n＝1-5)的端烷氧基[-(CH2)nOR2]时，其R2为氢(H)、1-6个碳原子的烷基、2-6个碳原子的链烯基和2-6个碳原子的链炔基、苄基或取代苄基、三甲基硅烷基、三苯基甲基或取代的三苯基甲基、四氢吡喃基或取代四氢吡喃基或烷氧羰基。
所述R3基团为甲酰胺基(-CONH2)、甲酸基(-COOH)、腈基(-CN)或甲酸烷基酯基(-COOR4)。
所述R3基团为甲酸烷基酯基(-COOR4)时，其R4基团为甲基、乙基、丙基、丁基、烯丙基、苯基、取代苯基、苄基或取代苄基。
所述式(I)化合物中的四个潜手性碳原子可以分别为单一R构型、单一S构型或其消旋体。
所述原料氰基衍生物(III)为2-氰基乙酰胺(IIIa)、2-腈基乙酸(IIIb)、丙二腈(IIIc)或2-腈基乙酸烷基酯(IIId)。
所述环化反应的原料叠氮化合物(II)和腈基衍生物(III)的投料摩尔比为1∶1-5，优选1∶1.1-1.3。
所述环化反应所使用的碱促进剂为氢化钠、甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、碳酸钾、三乙胺(TEA)、吡啶、2，6-二甲基吡啶、4-二甲氨基吡啶(DMAP)、N-甲基吗啉(NMM)、 N-乙基吗啉(NEM)、二异丙基乙胺(DIEA)、1，5-二氮杂二环[4.3.0]-壬-5-烯(DBN)、1，8-二氮杂双环[5.4.0]-十一-7-烯(DBU)或1，4-二氮杂二环[2.2.2]辛烷(DABCO)，优选叔丁醇钾或乙醇钠。
所述环化反应的所使用的溶剂为二氯甲烷、三氯甲烷、1，2-二氯乙烷、甲苯、乙腈、四氢呋喃、甲醇、乙醇、异丙醇、1，2-二氧六环或四氢呋喃，优选乙醇或四氢呋喃。
本发明所涉及的替卡格雷中间体5-氨基-1，4-二取代基-1，2，3-三氮唑及其制备方法，其优点主要是制备方法简单，反应条件温和易控，原料廉价易得，产品收率及产品纯度高，有利于简化含有1，2，3，-三氮唑母环结构的原料药如替卡格雷等的整个合成工艺，适合大规模工业化生产。
具体实施方式
以下结合数个较佳实施例对本发明技术方案作进一步非限制性的详细说明。其中原料叠氮化合物(II)的合成方法可参见本申请人的第2013102513642号的发明专利申请。
实施例一：
0-5℃和氮气氛下，于反应瓶中加入2-腈基乙酰胺(IIIa)(1.0g，12mmol)、乙醇钠(1.0g，15mmol)和绝对乙醇20mL，反应30分钟后，滴加[3aR-(3aα，4α，6α，6aα)]-6-叠氮基-2，2-二甲基-四氢-4H-环戊二烯并-1，3-二氧杂环戊-4-醇(II)(2.0g，10mmol)的20mL乙醇溶液。缓慢升温至同流，并保持回流反应5小时，TLC检测反应完成。降至室温，过滤除去固体。剩余物加水后有沉淀析出，过滤，固体用乙醇和乙酸乙酯重结晶，得1-[3aR-(3aα，4α，6α，6aα)-[2，2-二甲基-四氢-4H-环戊二烯并-1，3-二氧杂环戊-4-醇]-6-基]-5-氨基-4-甲酰胺基-1，2，3-三氮唑(I)2.4g，收率84.8％。
实施例二：
0-5℃和氮气氛下，于反应瓶中加入2-腈基乙酰胺(IIIa)(1.0g，12mmol)、甲醇钠(0.8g， 15mmol)和无水甲醇20mL，反应30分钟后，滴加[3aR-(3aα，4α，6α，6aα)]-[6-叠氮基-2，2-二甲基-四氢-4H-环戊二烯并-1，3-二氧杂环戊-4-氧基]乙醇(II)(2.4g，10mmol)的20mL甲醇溶液。缓慢升至窒温，并保持室温反应24小时，TLC检测反应完成。过滤除去固体，剩余物加水后有沉淀析出，过滤，机品用异丙醇和乙酸乙酯重结晶，得1-[3aR-(3aα，4α，6α，6aα)-[[2，2-二甲基-四氢-4H-环戊二烯并-1，3-二氧杂环戊-4-氧基]乙醇]-6-基]-5-氨基-4-甲酰胺基-1，2，3-三氮唑(I)2.6g，收率79.5％。
实施例三：
0-5℃和氮气氛下，于反应瓶中加入丙二腈(IIIc)(0.8g，12mmol)、叔丁醇钾(1.8g，15mmol)和干燥的四氢呋喃溶剂25mL，反应30分钟后，滴加[3aR-(3aα，4α，6α，6aα)]-[6-叠氮基-2，2-二甲基-四氢-4H-环戊二烯并-1，3-二氧杂环戊-4-氧基]乙酸甲酯(II)(2.7g，10mmol)的四氢呋喃30mL溶。缓慢升至同流，并保持回流反应6小时，TLC检测反应完成。过滤除去固体，剩余物加水后有沉淀析出，过滤，粗品用乙醇和乙酸乙酯重结晶，得1-[3aR-(3aα，4α，6α，6aα)-[[2，2-二甲基-四氢-4H-环戊二烯并-1，3-二氧杂环戊-4-氧基]乙酸甲酯]-6-基]-5-氨基-4-腈基-1，2，3-三氮唑(I)2.9g，收率86.1％。
需要指出的是，上述较佳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)
1.一种如式(I)所示的5-氨基-1,4-二取代基-1,2,3-三氮唑
其中所述式(I)化合物中R基团为氢、1-6个碳原子的烷基、2-6个碳原子的链烯基和2-6个碳原子的链炔基、3-10个碳原子的环烷基或芳基或杂环基、n＝1-5的端酯基[-(CH2)nCO2R1]或n＝1-5的端烷氧基[-(CH2)nOR2]，而所述R基团为n＝1-5的端酯基[-(CH2)nCO2R1]时，其R1为1-6个碳原子的烷基或6-10个碳原子的芳基；所述R基团为n＝1-5的端烷氧基[-(CH2)nOR2]时，其R2为氢、1-6个碳原子的烷基、2-6个碳原子的链烯基和2-6个碳原子的链炔基、苄基、三甲基硅烷基、三苯基甲基、四氢吡喃基或烷氧羰基；
所述R3基团为-CONH2、-COOH、-CN或-COOR4，其中所述R3基团为COOR4时，其R4基团为甲基、乙基、丙基、丁基、烯丙基、苯基或苄基。
2.根据权利要求1所述5-氨基-1,4-二取代基-1,2,3-三氮唑，其特征在于：所述式(I)化合物中的四个潜手性碳原子分别为单一R构型、单一S构型或其消旋体。
3.根据权利要求1所述5-氨基-1,4-二取代基-1,2,3-三氮唑的制备方法，其特征在于其包括如下步骤：通过叠氮化合物与氰基衍生物发生环合反应，得到5-氨基-1,4-二取代基-1,2,3-三氮唑(I)。
4.根据权利要求3所述5-氨基-1,4-二取代基-1,2,3-三氮唑的制备方法，其特征在于：所述原料氰基衍生物为2-氰基乙酰胺、2-腈基乙酸、丙二腈或2-腈基乙酸烷基酯。
5.根据权利要求3所述5-氨基-1,4-二取代基-1,2,3-三氮唑的制备方法，其特征在于：所述环合反应的原料叠氮化合物和腈基衍生物的投料摩尔比为1:1-5。
6.根据权利要求3所述5-氨基-1,4-二取代基-1,2,3-三氮唑的制备方法，其特征在于：所述环合反应所使用的碱促进剂为氢化钠、甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、碳酸钾、三乙胺、吡啶、2,6-二甲基吡啶、4-二甲氨基吡啶、N-甲基吗啉、N-乙基吗啉、二异丙基乙胺、1,5-二氮杂二环[4.3.0]-壬-5-烯、1,8-二氮杂双环[5.4.0]-十一-7-烯或1,4-二氮杂二环[2.2.2]辛烷；以及所述环合反应所使用的溶剂为二氯甲烷、三氯甲烷、1,2-二氯乙烷、甲苯、乙腈、甲醇、乙醇、异丙醇、1,2-二氧六环或四氢呋喃。
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