CN103288759B - 达克米替尼的制备方法 - Google Patents
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Abstract
本发明揭示了一种达克米替尼(Dacomitinib，I)的制备方法，包括如下步骤：4-氯-6-氨基-7-羟基喹唑啉(II)和硫酸二甲酯或碘甲烷发生醚化反应生成4-氯-6-氨基-7-甲氧基喹唑啉(III)，化合物(III)与4-(1-哌啶基)-2-丁烯酰氯进行酰化反应生成4-氯-6-[4-(1-哌啶基)-1-氧代-2-丁烯-1-基]氨基-7-甲氧基喹唑啉(IV)，化合物(IV)与4-氟-3-氯苯胺缩合制得达克米替尼(I)该制备方法工艺简洁、经济和环保，适合工业化放大的要求。
Description
本发明专利可参考本申请人同日递交的另外两件发明专利申请，其名称分别为“4-氯-6-氨基-7-羟基喹唑啉的制备方法”以及“一种4-氯-6-氨基-7-羟基喹唑啉的制备方法”。
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，特别涉及一种达克米替尼的制备方法。
背景技术
Dacomitinib是由美国辉瑞公司和沃尼尔·朗伯公司联合研发的一种多靶点小分子药物。因该药物在我国还未正式上市，还不具有标准的中文译名，故本申请人在此将其音译为“达克米替尼”。达克米替尼(dacomitinib)是一种泛人类表皮生长因子受体(pan-HER)抑制剂，主要用于应用一线化疗或酪氨酸激酶抑制剂(TKI)治疗进展后的患者，二线治疗非小细胞肺癌(NSCLC)显示，达克米替尼无进展生存期较厄洛替尼有所延长，并且生活质量有所提高。基于评估达克米替尼用于局部和转移性非小细胞肺癌对于pan-HER免疫活动的III期临床研究已经在亚洲和欧洲多个地区展开。
达克米替尼(Dacomitinib，I)，化学名为(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺。
沃尼尔·朗伯(Warner-Lambert)公司原研的世界专利第WO2005107758A1号报道了达克米替尼的制备方法：以母核7-氟喹唑啉-4-酮(V)为起始原料，先后通过7-位氟的取代形成甲氧基，6-位的硝化、还原和与4-(1-哌啶基)-2-丁烯酰氯的酰化反应，以及4-位和4-氟-3氯苯胺的缩合，制备得到达克米替尼(I)。
具体地，第一条合成路线的顺序为取代(甲氧基化)、硝化、氯化、缩合、还原和酰化，合计六步反应制得达克米替尼(I)。
第二条合成路线的顺序为硝化、氯化、缩合、取代(甲氧基化)、还原和酰化，也是六步反应制得达克米替尼(I)。
第三条合成路线的顺序为硝化、氯化、缩合、取代(同时进行氨基保护)、还原、酰化和脱保护，共七步反应制得达克米替尼(I)。
第四条合成路线的顺序为取代(甲氧基化)、硝化、氯化、缩合、保护、还原、酰化和水解脱保护，共八步反应制得达克米替尼(I)。
由此看出，达克米替尼制备技术的关键是喹唑啉母核的结构设计和三个侧链(4-位、6-位和7-位)链接时机的选择。目前达克米替尼的制备方法，是以7-氟-3，4-二氢喹唑啉-4-酮(V)为原料，经过取代、硝化、还原、氯化、缩合、保护和脱保护等反应来制备的。该方法步骤较多，总收率低，且多数步骤需要通过柱层析来分离和纯化，因而不适合产业化的要求。
发明内容
本发明的目的在于寻求新的制备途径，按照绿色化学的原子经济性合成理念，提供一种改进的达克米替尼的制备方法，该制备方法原料易得，工艺简洁，经济环保，利于工业化生产。
为了实现上述目的，本发明所提供的主要技术方案如下：4-氯-6-氨基-7-羟基喹唑啉(II)和硫酸二甲酯或碘甲烷发生醚化反应生成4-氯-6-氨基-7-甲氧基喹唑啉(III)，4-氯-6-氨基-7-甲氧基喹唑啉(III)与4-(1-哌啶基)-2-丁烯酰氯进行酰化反应生成4-氯-6-[4-(1-哌啶基)-1-氧代-2-丁烯-1-基]氨基-7-甲氧基喹唑啉(IV)，4-氯-6-[4-(1-哌啶基)-1-氧代-2-丁烯-1-基]氨基-7-甲氧基喹唑啉(IV)与4-氟-3-氯苯胺缩合制得达克米替尼(I)。
所述醚化反应的甲基化试剂为碘甲烷或硫酸二甲酯。
所述酰化反应的原料，4-氯-6-氨基-7-甲氧基喹唑啉(III)与4-(1-哌啶基)-2-丁烯酰氯的投料摩尔比为1∶1-2，优选1∶1.1-1.3。
所述酰化反应的缚酸剂为三乙胺、吡啶、N-甲基吗啡啉、二异丙基乙胺、氢氧化钠、甲醇钠、氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠或碳酸钾，优选三乙胺或碳酸钾。
所述缩合反应的原料4-氯-6-[4-(1-哌啶基)-1-氧代-2-丁烯-1-基]氨基-7-甲氧基喹唑啉(IV)与4-氟-3-氯苯胺的投料摩尔比为1∶1-2，优选1∶1.1-1.3。
所述缩合反应的缚酸剂为三乙胺、吡啶、N-甲基吗啡啉、二异丙基乙胺、氢氧化钠、甲醇钠、氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠或碳酸钾，优选三乙胺或吡啶。
所述缩合反应的溶剂为甲醇、乙醇、异丙醇、二氯甲烷、三氯甲烷、1，2，-二氯乙烷、乙腈、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、甲苯、二甲苯、乙醚、异丙醚、二氧六环、四氢呋喃或甲基叔丁基醚，优选异丙醇或甲苯。
相比于现有技术，本发明所涉及的达克米替尼的制备方法，其通过4-氯-6-氨基-7-羟基喹唑啉(II)和硫酸二甲酯或碘甲烷发生醚化反应生成4-氯-6-氨基-7-甲氧基喹唑啉(III)，化合物(III)再通过酰化和缩合反应即可制得达克米替尼，故而本发明达克米替尼的制备方法的优点主要是原料易得，工艺简洁，经济环保，利于工业化生产。
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。侧链4-(1-哌啶基)-2-丁烯酰氯可参见世界专利第WO2005107758A1号的制备方法描述。
实施例一：
室温下，于反应瓶中加入4-氯-6-氨基-7-羟基喹唑啉(II)(2.92g，15mmol)和50％氢氧化钠溶液20mL，加热至50-60℃，搅拌至无颗粒状物存在。缓慢降温至5℃，有沉淀产生。过滤、真空干燥，得浅红色固体。氮气保护下，将该固体加入到预先加有1-丁基-3-甲基咪唑四氟硼酸盐([Bmin]BF4)的反应瓶中，升温至80-90℃。逐滴加入碘甲烷(2.56g，18mmol)到上述反应体系中，滴加完备后，保温搅拌反应6小时。冷却，分出上层离子液体。下层用1，2，-二氯乙烷萃取，并用水洗涤两次。有机相用无水硫酸钠干燥，减压蒸馏回收溶剂，残余物用乙酸乙酯和重结晶，得类白色固体4-氯-6-氨基-7-甲氧基喹唑啉(III)2.85g，收率为90.8％。
实施例二：
于反应瓶中加入4-氯-6-氨基-7-甲氧基喹唑啉(III)(2.09g，10mmol)、三乙胺(1.0g，10mmol)和二氯甲烷50mL，升温至40-45℃，搅拌至体系溶解均一。降至10℃以下，缓慢滴加4-(1-哌啶基)-2-丁烯酰氯(2.24g，12mmol)的二氯甲烷15mL溶液，滴完后室温继续反应6小时，TLC检测反应结束。反应液分别用10％碳酸氢钠溶液和水洗涤，无水硫酸钠干燥。减压回收溶剂，剩余物用乙酸乙酯重结晶，得到白色固体4-氯-6-[4-(1-哌啶基)-1-氧代-2-丁烯-1-基]氨基-7-甲氧基喹唑啉(IV)3.16g，收率87.8％。
实施例三：
于反应瓶中加入4-氯-6-[4-(1-哌啶基)-1-氧代-2-丁烯-1-基]氨基-7-甲氧基喹唑啉(IV)(1.10g，3.0mmol)、三乙胺(0.45g，4.5mmol)和异丙醇20mL，搅拌至体系溶解均一。缓慢滴加4-氟-3-氯苯胺(0.48g，3.3mmol)的异丙醇10mL溶液，滴完后室温继续反应12小时，TLC检测反应结束。反应液倒入50mL冰水中，过滤。滤饼干燥后，用无水乙醇重结晶，得到白色固体达克米替尼(Dacomitinib，I)1.20g，收率85.7％。
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 (7)
1.一种达克米替尼的制备方法，所述达克米替尼的化学名为(2E)-N-[4-[(3-氯-4-氟苯基)氨基]-7-甲氧基-6-喹唑啉基]-4-(1-哌啶基)-2-丁烯酰胺(I)
其特征在于所述制备方法包括如下步骤：4-氯-6-氨基-7-羟基喹唑啉(II)和硫酸二甲酯或碘甲烷发生醚化反应生成4-氯-6-氨基-7-甲氧基喹唑啉(III)，所述4-氯-6-氨基-7-甲氧基喹唑啉(III)与4-(1-哌啶基)-2-丁烯酰氯进行酰化反应生成4-氯-6-[4-(1-哌啶基)-1-氧代-2-丁烯-1-基]氨基-7-甲氧基喹唑啉(IV)，所述4-氯-6-[4-(1-哌啶基)-1-氧代-2-丁烯-1-基]氨基-7-甲氧基喹唑啉(IV)与4-氟-3-氯苯胺发生缩合反应制得所述达克米替尼(I)，其中所述醚化反应采用离子液体1-丁基-3-甲基咪唑四氟硼酸盐为溶剂。
2.根据权利要求1所述达克米替尼的制备方法，其特征在于：所述醚化反应的甲基化试剂为碘甲烷或硫酸二甲酯。
3.根据权利要求1所述达克米替尼的制备方法，其特征在于：所述酰化反应的原料，4-氯-6-氨基-7-甲氧基喹唑啉(III)与4-(1-哌啶基)-2-丁烯酰氯的投料摩尔比为1:1-2。
4.根据权利要求1所述达克米替尼的制备方法，其特征在于：所述酰化反应的缚酸剂为三乙胺、吡啶、N-甲基吗啡啉、二异丙基乙胺、氢氧化钠、甲醇钠、氢氧化钾、碳酸钠、碳酸氢钠或碳酸钾。
5.根据权利要求1所述达克米替尼的制备方法，其特征在于：所述缩合反应的原料4-氯-6-[4-(1-哌啶基)-1-氧代-2-丁烯-1-基]氨基-7-甲氧基喹唑啉(IV)与4-氟-3-氯苯胺的投料摩尔比为1:1-2。
6.根据权利要求1所述达克米替尼的制备方法，其特征在于：所述缩合反应的缚酸剂为三乙胺、吡啶、N-甲基吗啡啉、二异丙基乙胺、氢氧化钠、甲醇钠、氢氧化钾、碳酸钠、碳酸氢钠或碳酸钾。
7.根据权利要求1所述达克米替尼的制备方法，其特征在于：所述缩合反应的溶剂为甲醇、乙醇、异丙醇、二氯甲烷、三氯甲烷、1,2,-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、甲苯、二甲苯、乙醚、异丙醚、二氧六环、四氢呋喃或甲基叔丁基醚。
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