丙二酸环异丙酯依次与原甲酸三乙酯和对溴苯胺缩合、环合、硝化、氯代生成3- 硝基-4- 氯-6- 溴喹啉( 7)。对硝基苯乙腈与碘甲烷经烷基化、还原生成2-(4- 氨基苯基)-2- 甲基丙腈(10)，与7 发生取代反应，得到2-[4-[(6- 溴-3-硝基喹啉-4- 基) 氨基] 苯基] -2- 甲基丙腈，再经还原、环合、甲基化、Suzuki 偶联反应制得PI3K/mTOR 双重抑制剂NVP-BEZ235，总收率为6％ ( 以丙二酸环异丙酯计算)，纯度为99.1％，并经1H NMR、MS 确证结构。该路线原料价廉易得、操作简便、反应条件温和，适合较大规模制备。
Abstract
6-Bromo-4-chloro-3-nitroquinoline (7) was synthesized from 2,2-dimethyl-1,3-dioxane-4,6-dione by substitution with triethoxymethane, condensation with 4-bromoaniline, cyclization, nitrification and chlorination. NVP-BEZ235, the PI3K/mTOR inhibitor, was synthesized from 2-(4-nitrophenyl)acetonitrile via alkylation with iodomethane and reduction to give 2-(4-aminophenyl)-2-methylpropanenitrile (10), followed by substitution with 7 to obtain 2-[4-[(6-bromo-3-nitroquinolin-4-yl)amino]phenyl]-2-methylpropanenitrile, which was subjected to reduction, cyclization, alkylation and Suzuki-coupling reaction with an overall yield of 6％(based on 2,2-dimethyl-1,3-dioxane-4,6- dione) and purity of 99.1％. The structure of the target product was confirmed by 1H NMR and MS. This method started with cheap raw materials was of simple experimental operation and mild reaction conditions. It was suitable for largescale pilot study.
关键词
PI3K/mTOR 双重抑制剂 /
NVP-BEZ235 /
合成 /
工艺优化
{{custom_keyword}} /
Key words
PI3K/mTOR inhibitor /
NVP-BEZ235 /
synthesis /
process optimization
{{custom_keyword}} /
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] Maira SM, Stauffer F, Brueggen J, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamyein inhibitor with potent in vivo antitumor activity [J]. Mol Cancer Ther, 2008, 7(7): 1854—1863.
[2] Serra V, Markman B, Scaltriti M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations [J].
Cancer Res, 2008, 68(19): 8023—8030.
[3] Roper J, Richardson MP, Wang WV, et al. The dual PI3K and mTOR inhibitor NVP-BEZ235 induce tumor regression in a genetically engineered mouse model of PIK3CA wild-type
colorectal cancer [J]. PloS One, 2011, 6(9): e25132.
[4] 王 娟, 周 雪, 陈秀华, 等. PI3K/mTOR 信号通路及双重抑制剂NVP-BEZ235 的开发[J]. 世界临床药物, 2013,34(3): 172—176.
[5] Roulin D, Waselle L, Dormond-Meuwly A, et al. Targeting renal cell carcinoma with NVP-BEZ235, a dual PI3K/mTOR inhibitor, in combination with sorafenib [J]. Mol Cancer, 2011, 10(7): 90—95.
[6] Manara MC, Nicocetti G, Zambelli D, et al. NVP-BEZ235 as a new therapentic option for sarcomas [J]. Clin Cancer Res, 2010, 16(2): 531—540.
[7] Kim A, Park S, Lee JE, et al. The dual PI3K and mTOR inhibitor NVP-BEZ235 exhibits anti-proliferative activity and overcomes bortezomib resistance in mautle cell lymphoma cells [J]. Leak Res, 2012, 36(7): 912—920.
[8] Awasthi N, Yen PL, Schwarz MA, et al. The efficacy of a novel, dual PI3K/mTOR inhibitor NVP-BEZ235 to enhance chemotherapy and antiangiogenic response in pancreatic cancer [J]. J Cell Biochem, 2012, 113(3): 784—791.
[9] Seixas JD, Luengo-Arratta SA, Diaz R, et al. Establishment of a structure-activity relationship of 1H-Imidazo[4,5- c]quinoline-based kinase inhibitor NVP-BEZ235 as a lead for African sleeping sickness [J]. J Med Chem, 2014, 57(11): 4834—4848.
[10] Zhang WJ, Li Z, Zhou M, et al. Synthesis and biological evaluation of 4-(1,2,3-triazol-1-yl)coumarin derivatives as potential antitumor agents [J]. Bioorg Med Chem Lett, 2014, 24(3): 799—807.
[11] Ch e n L, Ch e n SQ, Lo u J P, e t a l . Th i a z o l i n o n e 4-monosubstituted quinolines: US, 20060063805 [P] . 2006-03-23.
[12] Liu Y, Li LS, Chan K, et al. Heterocyclic compounds and uses thereof: WO, 20120116237A2 [P]. 2012-08-30.
[13] Stauffer F, Maira SM, Furet P, et al. Imidazo[ 4,5- c]quinolines as inhibitors of the PI3K/PKB-pathway [J]. Bioorg Med Chem Lett, 2008, 18(3): 1027—1030.
[14] Vannucchi A, Bogani C, Niccolo B. JAK PI3K/mTOR combination therapy: WO, 2013023119A1 [P]. 2013-02-14.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
基金
国家自然科学基金项目(81460527)、江西省自然科学基金项目(20142BAB215020)
{{custom_fund}}
PDF(6374 KB)
