CN107556226B - 一种拉曲替尼中间体的制备方法 - Google Patents
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Abstract
本发明揭示了一种拉曲替尼中间体(R)‑2‑(2,5‑二氟苯基)四氢吡咯烷的制备方法,其包括如下步骤:以手性诱导试剂以(7aS,12R)‑12‑苯基‑7a,8,9,10‑四氢‑12H‑萘酚[1,2‑e]吡咯并[2,1‑b][1,3]噁嗪为原料,与格氏试剂2,5‑二氟苯基溴化镁经加成和脱苄基反应制得拉曲替尼中间体(R)‑2‑(2,5‑二氟苯基)四氢吡咯烷。与现有技术相比,该制备方法工艺简洁、条件温和、副反应少和成本较低,适应工业化生产,可促进该原料药的经济技术的发展。
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,特别涉及一种拉曲替尼中间体的制备方法。
背景技术
拉曲替尼(Larotrectinib)是由一家位于美国斯坦福的生物医药公司LoxoOncology开发的强效、口服、选择性原肌球蛋白受体激酶(TRKs)抑制剂。2017年5月美国食品药品管理局(FDA)授予该实验性药物治疗携带NTRK基因融合的实体瘤的孤儿药地位。
拉曲替尼的化学名为(S)-N-((R)-2-(2,5-二氟苯基)四氢吡咯烷-1-基)吡唑[1,5-a]并嘧啶-3-基)-3-羟基四氢吡咯烷-1-甲酰胺,其化学结构为:
拉曲替尼的制备方法已有报道,国际专利WO2010/048314和WO2016/077841报道了拉曲替尼的制备方法,并给出其重要中间体(R)-2-(2,5-二氟苯基)四氢吡咯烷(I)的制备方法。
从上述合成路线可以看出,该方法涉及手性配体、金属锂/锌试剂、贵金属钯试剂以及四氟硼酸三正丁基磷等原料或催化剂,同时涉及低温、无氧、无水等苛刻的反应条件,且步骤繁多,不利于工业化生产。
虽然US2016/0168156、US2015/0368238和CN104672121等专利还报道了该化合物的一些合成方法,由于使用了手性亚砜或其他拆分试剂,使制备工艺的原子经济性降低。所以有必要寻求一种原料易得、操作方便、条件温和且能减少副反应和环境污染的新的拉曲替尼中间体(R)-2-(2,5-二氟苯基)四氢吡咯烷(I)的制备方法。
发明内容
本发明的目的在于提供一种新的拉曲替尼中间体(R)-2-(2,5-二氟苯基)四氢吡咯烷的制备方法,通过以手性贝蒂碱(Betti base)为母核的手性诱导试剂与格氏试剂进行加成反应,所得产物通过脱苄基反应制得目标产物。该方法使得目标产物的制备步骤更加简洁,且原料易得,副反应少,适合工业化生产。
为实现上述发明目的,本发明采用了如下主要技术方案:一种拉曲替尼中间体(R)-2-(2,5-二氟苯基)四氢吡咯烷(I)的制备方法,
其特征在于所述制备方法包括如下步骤:以(7aS,12R)-12-苯基-7a,8,9,10-四氢-12H-萘酚[1,2-e]吡咯并[2,1-b][1,3]噁嗪(II)为原料,与2,5-二氟苯基溴化镁(III)发生加成反应得到1-[(R)-[(2R)-2-(2,5-二氟苯基)-1-四氢吡咯烷基]苯基甲基]-2-萘酚(IV),所得1-[(R)-[(2R)-2-(2,5-二氟苯基)-1-四氢吡咯烷基]苯基甲基]-2-萘酚(IV)经脱苄基反应制得拉曲替尼中间体(R)-2-(2,5-二氟苯基)四氢吡咯烷(I)。
此外,本发明还包括如下附属技术方案:
所述加成反应原料(7aS,12R)-12-苯基-7a,8,9,10-四氢-12H-萘酚[1,2-e]吡咯并[2,1-b][1,3]噁嗪(II)与2,5-二氟苯基溴化镁(III)的投料摩尔比为:1.0∶1.0~2.0,优选1.0∶1.4~1.6。
所述加成反应的温度为0~60℃,优选25~35℃。
所述加成反应的溶剂为甲苯、***、异丙醚、二氯甲烷、1,2-二氯乙烷、2-甲基四氢呋喃或四氢呋喃,优选四氢呋喃。
所述脱苄基反应的反应体系为催化加氢还原体系或硝酸铈铵氧化体系。
所述脱苄基反应的反应体系为催化加氢还原体系时,其催化加氢的催化剂为钯炭、雷尼镍、氢氧化钯炭或铂炭,优选钯炭。
所述脱苄基反应的反应体系为催化加氢还原体系时,其脱苄基反应的溶剂为甲醇、乙醇、异丙醇、二氯甲烷、乙酸乙酯或乙酸异丙酯,优选甲醇或乙醇。
所述脱苄基反应的反应体系为硝酸铈铵氧化体系时,其脱苄基反应的溶剂为乙腈/水、二氯甲烷/水或四氢呋喃/水,优选乙腈/水;其体积比为1~5∶1,优选2∶1。
相比于现有技术,本发明的优点在于:采用手性诱导试剂,通过经典的加成和脱苄基等反应简单快捷地制得目标产物。与现有的该产品的制备方法相比,缩短了反应过程,减少了贵金属催化剂和其它昂贵试剂,避免使用无氧、无水等苛刻反应条件,提高了反应收率和操作可控性,使拉曲替尼中间体(I)的生产更加可控,成本降低,促进该原料药的经济技术的发展。
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。其中手性诱导试剂(7aS,12R)-12-苯基-7a,8,9,10-四氢-12H-萘酚[1,2-e]吡咯并[2,1-b][1,3]噁嗪(II)的制备可参见“Synlett(2004),(1),122-124”或“Tetrahedron:Asymmetry(2004),15(3),475-479”对相同化合物的制备方法。
实施例一:
氮气氛下,于干燥反应瓶中加入(7aS,12R)-12-苯基-7a,8,9,10-四氢-12H-萘酚[1,2-e]吡咯并[2,1-b][1,3]噁嗪(II)(3.0g,10mmol)和干燥的四氢呋喃30mL,降温至0℃,滴加2,5-二氟苯基溴化镁(III)(3.2g,15mmol)的四氢呋喃溶液30mL。升温至25~35℃,保持该温度搅拌反应3-5小时,TLC检测反应完成。用饱和氯化铵25mL淬灭反应,二氯甲烷萃取三次,合并有机相,依次用水和饱和食盐水洗涤,无水硫酸钠干燥。浓缩,残留物用乙酸乙酯重结晶,得类白色固体1-[(R)-[(2R)-2-(2,5-二氟苯基)-1-四氢吡咯烷基]苯基甲基]-2-萘酚(IV)3.5g,收率84.3%,FAB-MS m/z:416[M+H]+。
实施例二:
于氢化反应瓶中加入1-[(R)-[(2R)-2-(2,5-二氟苯基)-1-四氢吡咯烷基]苯基甲基]-2-萘酚(IV)(2.1g,5mmol)、10%钯炭(Pd/C)(0.32g,0.3mmol)和甲醇25mL,室温和常压下通入氢气,至氢气不再被吸收,停止通氢气。过滤回收催化剂,减压回收溶剂,得微红色油状物(R)-2-(2,5-二氟苯基)四氢吡咯烷(I)0.79g,收率86.3%;1H NMR(CDCl3)δ7.24(m,1H),6.94(m,1H),6.85(m,1H),4.40(t,J=7.6Hz,1H),3.16(m,1H),3.04(m,1H),2.21-2.30(m,1H),1.77-1.95(m,3H),1.57-1.67(m,1H);EI-MS m/z:184[M+H]+。
实施例三:
于反应瓶中加入1-[(R)-[(2R)-2-(2,5-二氟苯基)-1-四氢吡咯烷基]苯基甲基]-2-萘酚(IV)(2.1g,3mmol)、硝酸铈铵(4.1g,7.5mmol)和乙腈和水(体积比2∶1)的混合溶剂60mL,室温搅拌5-7小时,TLC检测反应结束。过滤,滤液中加入碳酸氢钠溶液,并用二氯甲烷萃取三次,合并有机相,无水硫酸钠干燥。减压浓缩,得微红色油状物(R)-2-(2,5-二氟苯基)四氢吡咯烷(I)0.76g,收率83.0%;1H NMR(CDCl3)δ7.24(m,1H),6.94(m,1H),6.85(m,1H),4.40(t,J=7.6Hz,1H),3.16(m,1H),3.04(m,1H),2.21-2.30(m,1H),1.77-1.95(m,3H),1.57-1.67(m,1H);EI-MSm/z:184[M+H]+。
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 (8)
2.根据权利要求1所述拉曲替尼中间体的制备方法,其特征在于:所述加成反应原料(7aS,12R)-12-苯基-7a,8,9,10-四氢-12H-萘酚[1,2-e]吡咯并[2,1-b][1,3]噁嗪与2,5-二氟苯基溴化镁的投料摩尔比为:1.0:1.0~2.0。
3.根据权利要求1所述拉曲替尼中间体的制备方法,其特征在于:所述加成反应的温度为0~60℃。
4.根据权利要求1所述拉曲替尼中间体的制备方法,其特征在于:所述加成反应的溶剂为甲苯、***、异丙醚、二氯甲烷、1,2-二氯乙烷、2-甲基四氢呋喃或四氢呋喃。
5.根据权利要求1所述拉曲替尼中间体的制备方法,其特征在于:所述脱苄基反应的反应体系为催化加氢还原体系或硝酸铈铵氧化体系。
6.根据权利要求5所述拉曲替尼中间体的制备方法,其特征在于:所述脱苄基反应的反应体系为催化加氢还原体系时,其催化加氢的催化剂为钯炭、雷尼镍、氢氧化钯炭或铂炭。
7.根据权利要求5所述拉曲替尼中间体的制备方法,其特征在于:所述脱苄基反应的反应体系为催化加氢还原体系时,其脱苄基反应的溶剂为甲醇、乙醇、异丙醇、二氯甲烷、乙酸乙酯或乙酸异丙酯。
8.根据权利要求5所述拉曲替尼中间体的制备方法,其特征在于:所述脱苄基反应的反应体系为硝酸铈铵氧化体系时,其脱苄基反应的溶剂为乙腈/水、二氯甲烷/水或四氢呋喃/水;其中乙腈、二氯甲烷或四氢呋喃与水的体积比为1~5:1。
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