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·950· 精细化工 FINE CHEMICALS 第 36 卷

由表 8 可以看出，在相同溶剂中，Osimertinib 常温下即可快速反应完全，不仅避免了文献方法合
与甲磺酸投料物质的量比的不同会生成不同性状的 成步骤较多以及成本较高等缺陷，奥斯替尼甲磺酸
奥斯替尼磺酸盐。当 n(Osimertinib)∶n(甲磺酸)= 盐的收率也得到了较大提升。各中间体及目标产物均
1.0∶1.0 时，生成浅黄色固体，熔点为 247~250 ℃。 经核磁和质谱进行了表征，以期为奥斯替尼甲磺酸盐
由于熔点范围较小，可初步判定产物较纯，经核磁 的国产化提供实验数据支持。
氢谱确认为奥斯替尼的单甲磺酸盐； 当
参考文献：
n(Osimertinib)∶n(甲磺酸)=1.0∶2.0 时，生成亮黄色
[1] He Heng (何珩), Huang Lu (黄璐), Xu Yong (许勇). Osimertinib: a
固体，熔点为 263~265 ℃，熔点范围也较小，故可
new drug for non-small cell lung cancer[J]. Chinese Journal of New
初步判定产物较纯，经核磁氢谱确认为奥斯替尼的 Drugs (中国新药杂志), 2016, 25(16): 1801-1806.
双甲磺酸盐；当 n(Osimertinib)∶n(甲磺酸)=1.0∶1.5 [2] Astra Zeneca P. TAGRISSOTM (osimertinib) tablet, for oral use
时，生成物为黄色固体，但其熔点具有一个较大的 Initial US[EB/OL]. 2015-11-13. http://www.accessdata.fda.gov/
drugsatfda_docs/label/2015/208065s000lbl.pdf.
熔程，为 249~264 ℃，结合单甲磺酸盐和双甲磺酸 [3] Kang Fangyuan (康芳圆), Pang Xuehai (庞学海), Wang Yingwei (王
盐状态和熔点，可判断该固体为单甲磺酸盐和双甲 颖伟), et al. Synthesis of deuterated AZD9291[J]. Chinese Journal of
磺酸盐共存；当 n(Osimertinib)∶n(甲磺酸)=1.0∶2.5 Synthetic Chemistry (合成化学), 2016, 24(3): 263-265.
[4] Finlay M, Anderton M, Ashton S, et al. Discovery of a potent and
时，生成产物的状态和熔点与 n(Osimertinib)∶n(甲 selective EGFR inhibitor (AZD9291) of both sensitizing and T790M
磺酸)=1.0∶2.0 时相同，可知生成物为 Osimertinib resistance mutations that spares the wild type form of the receptor[J].
双甲磺酸盐，并没有生成多甲磺酸盐。 Journal of Medicinal Chemistry, 2014, 57(20): 8249-8267.
[5] Cross D, Ashton S, Ghiorghiu S, et al. AZD9291, an irreversible
EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors
3 结论 in lung cancer[J]. Cancer Discovery, 2014, 4(9): 1046- 1061.
[6] Peters S, Zimmermann S, Adjei A. Oral epidermal growth factor
以 3-(2-氯嘧啶-4-基)-1-甲基吲哚为原料，经取 receptor tyrosine kinase inhibitors for the treatment of non-small cell
代、缩合、还原和酰胺化以及成盐 4 步反应，得到 lung cancer: comparative pharmacokinetics and drug–drug
interactions [J]. Cancer Treatment Reviews, 2014, 40(8): 917-926.
目标化合物奥斯替尼甲磺酸盐。在目标化合物的合
[7] Butterworth S, Finlay M, Ward R, et al. 2-(2,4,5-substituted-anilino)
成过程中，对每一步反应的关键参数进行了优化， pyrimidine derivatives as egfr modulators useful for treating cancer:
得到了一条快速、高效的合成路线，总收率为 WO2013014448[P]. 2013-1-31.
41.9%。在化合物Ⅴ合成 Osimertinib 的过程中，引 [8] Ji Min (吉民), Li Yuan (李元), Liu Haidong (刘海东), et al. The
synthesis of an anti-cancer drug: CN104817541B[P]. 2017-06-16.
入一锅法不仅减少了中间体的分离、纯化等步骤， [9] Liu Haidong, Lv Yongfeng, Li Yuan, et al. A novel and efficient
有效控制了副产物的产生，很好地解决了中间产物 synthesis of anti-cancer agent, mereletinib[J]. Journal of Chemical
不稳定的问题，且由化合物Ⅴ合成 Osimertinib 的产 Research, 2015, 39(6): 318-320.
[10] Chen Ning, Xu Jiaxi. Facile synthesis of various substituted taurines,
率也由文献的 33%提升到了 61%；在该过程中以廉 especially syn- and anti-1, 2-disubstituted taurines, from nitroolefins[J].
价丙烯酸代替丙烯酰氯直接与中间产物进行反应， Tetrahedron, 2012, 68(11): 2513-2522.

（上接第 939 页） production from low-grade oils and fats[J]. Catalysis Today, 2012,
195(1): 44-53.
[13] Zhu Y Z, Jaenicke S, Chuah G K. Supported zirconium propoxide- [18] Yang L, Yang X, Tian E, et al. Mechanistic insights into the
aversatile heterogeneous catalyst for the Meerwein Ponndorf Verley production of methyl lactate by catalytic conversion of carbohydrates
reduction[J]. Journal of Catalysis, 2003, 218(2): 396-404. on mesoporous Zr-SBA-15[J]. Journal of Catalysis, 2016, 333: 207-216.
[14] Zhu Y Z, Chuah G K, Jaenicke S. Chemo-andregios elective [19] Tan Ying (谈瑛), Li Yongfei (李勇飞), Wei Yuanfeng (魏元峰), et al.
Meerwein-ponndorf-verley and Oppenauer reactions catalyzed by High selective synthesis of orthoisomer of bisphenol F catalyzed by
Al-free Zr-zeolite beta[J]. Journal of Catalysis, 2004, 227(1): 1-10. Zr-SBA-15[J]. CIESC Journal (化工学报), 2016, 67(5): 1900-1906.
[15] Lou Xinyue (娄馨月), Chen Xihui (陈希慧), Ren Lifeng (任利锋). [20] Maria D G, Alina M B, Juan M C, et al. Evidences of the in situ
Catalyzing activity of ZrO 2/SiO 2 samples in Meerwein–Ponndorf– generation of highly active Lewis acid species on Zr-SBA-15[J].
Verley reduction of citral[J]. Journal of Guangxi University: Natural Applied Catalysis A: General, 2009, 371: 85-91.
Science Edition (广西大学学报: 自然科学版), 2009, 34(6): 740-743. [21] Yang Xiyao (杨锡尧). Research methods of solid catalysts. Chapter
[16] Zhao D, Feng J, Huo Q, et al. Triblock copolymer syntheses of 13 temperature-programming analysis techniques (below)[J].
mesoporous silica with periodic 50 to 300 angstrom pores[J]. Petrochemical (石油化工), 2002, 31 (1): 63-73.
Science, 1998, 279(5350): 548-552. [22] Tabe Hiromi, Misonoo Cheng, Ono Kami, et al. New solid acid and
[17] Melero J A, Bautista L F, Iglesias J, et al. Zr-SBA-15 acid catalyst: bases: their catalytic properties, Second Edition[M]. Beijing:
optimization of the synthesis and reaction conditions for biodiesel Chemical Industry Press(化学工业出版社), 1992: 89.