Cobimetinib消旋体的合成
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摘要
以3-羟基氮杂环丁烷盐酸盐为原料,经Cbz保护和氧化反应制得1-苄氧羰基氮杂环丁烷-3-酮(3);3与N-亚硝基哌啶发生亲核反应后与2,3-二氟-(2-氟-4-碘氨基)苯甲酸发生缩合反应,最后经氯化氢脱亚硝基和碱化合成了Cobimetinib消旋体,其结构经1H NMR和HR-MS(ESI)确证。
Benzyl 3-oxoazetidine-1-carboxylate( 3) was obtained by Cbz protection and oxidation,using 3-hydroxyazetidine hydrochloride as raw material. Racemate of Cobimetinib was synthesized by nucleophilic reaction with N-nitrosopiperidine,then followed by a condensation reaction with 3,4-difluoro-2-[( 2-fluoro-4-iodophenyl) amino]benzoic acid and finally deprotection with hydrochloric acid gas and alkalization. The structure was confirmed by1 H NMR and HR-MS( ESI).
Benzyl 3-oxoazetidine-1-carboxylate( 3) was obtained by Cbz protection and oxidation,using 3-hydroxyazetidine hydrochloride as raw material. Racemate of Cobimetinib was synthesized by nucleophilic reaction with N-nitrosopiperidine,then followed by a condensation reaction with 3,4-difluoro-2-[( 2-fluoro-4-iodophenyl) amino]benzoic acid and finally deprotection with hydrochloric acid gas and alkalization. The structure was confirmed by1 H NMR and HR-MS( ESI).
引文
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[3]田红,肖桂芝,田苗,等.黑色素瘤治疗药物的研究进展[J].现代药物与临床,2015,30(07):890-896.
[4]张莹,刘波,胡金成,等.抗黑色素瘤新药cobimetinib[J].中国新药杂志,2016,25(21):2401-2404.
[5]晁颖颖,艾斌,柯会星.新药Cobimetinib的药理作用与临床评价[J].药品评价,2016,13(18):15-19.
[6]RICE K D,AAY N,ANAND N K,et al.Novel carboxamide-based allosteric MEK Inhibitors:Discovery and optimization efforts toward XL518(GDC-0973)[J].Acs Medicinal Chemistry Letters,2012,3(5):416-421.
[7]李朝平,曹志华,王广勇,等.一种3-(哌啶-2-基)-氮杂环丁烷-3-醇的衍生物的合成方法及其用途:CN 104725352A[P].2015.
[8]ENDERS D,PIETER R,RENGER B,et al.Nucleophilicα-sec-aminoalkylation:2-(Diphenylhydroxymethyl)pyrrolidine[J].Organic Syntheses,1978,58:113-117.
[9]SEEBACH D,ENDERS D.Lithiierte methylnitrosamine nucleophileα-sek-aminomethylierung[J].European Journal of Inorganic Chemistry,1975,108(4):1293-1320.
[10]ZHANG J,JIANG J W,LI Y L,et al.Iodide-catalyzed synthesis of nitrosamines via C—N cleavage of nitromethane[J].The Journal of Organic Chemistry,2013,(78):11366-11372.
[11]PETER B,LEE W K.α-Lithioamine synthetic equivalents:Syntheses of diastereoisomers from the Boc-piperidines[J].The Journal of Organic Chemistry,1990,55(9):2578-2580.
[12]TOMOHIKO O,MOTOKO M,HARUKO T,et al.Structural features of aliphatic N-nitrosamines of 7-aza bicyclo[2.2.1]heptanes that facilitate N—NO bond cleavage[J].Journal of the American Chemical Soc iety,2001,123(42):10164-72.
[13]LIU B,FAN Y,GAO Y,et al.Rhodium(III)-catalyzed N-nitroso-directed C—H olefination of arenes:High-yield,versatile coupling under mild conditions[J].Journal of the American Chemical Society,2013,135(1):468-471.
[14]SEEBACH D,WYKYPIEL W.Safe one-pot carboncarbon bond formation with lithiated nitrosamines including denitrosation by sequential reduction with lithium aluminium hydride and Raney-nickel[J].Synthesis,1979(06):423-424.
[15]GEORGE W H,DANIEL S,SAROJ K V.Reversible interconversion of N-nitroso(2-methylamino)acetonitrile and 3-methyl-5-amino-1,2,3-oxadiazolium chloride and related reactions[J].The Journal of Organic Chemistry,1978,43(9):1671.