GSK3抑制剂的合成

Synthesis of GSK3 Inhibitor

4-甲酰基-2E-丁烯酸乙酯(8)经醛基保护、与2-氨基吡啶反应成环、加压氨化得到(11);5-氟-2-硝基苯甲醛(1)经醛基保护、Bartoli合成法制成吲哚、与乙醇胺反应并氢化、Boc保护、甲磺酰化、碱环合、与草酰氯甲醇钠反应制得(12);(11)与(12)对接、去保护、酰化得到目标化合物3-[9-氟2-(哌啶-1-羰基)-1,2,3,4-四氢-[1,4]-二氮杂卓艹并[6,7,1-hi]吲哚基-7]-4-咪唑并[1,2-a]吡啶基-3-吡咯-2,5-二酮.以化合物(1)为起始原料计算,共10步反应,总收率18%.

The intermediate（11） was prepared from（E） -ethyl 3-formylacrylate（ 8 ） via protection, cyclization and ammoniation under pressure; the key intermediate（12） was prepared by 5 -fluoro-2-nitrobenzaldehyde（ 1 ） via protection, Bartoli reaction, reduction, protection with Boc2O, methanesulfonylation, cyclization, treatment with oxalyl dichloride and sodium methoxide; the compound 3- [ 9 -Fluoro-2- （ piperidine- 1-carbonyl） - 1,2,3,4- tetrahydro- [ 1,4 ] diazepino [ 6,7,1-hi] indal-7- yl]-4-imidazo[ 1,2-a] pyridin-3-yl-pyrrole-2,5-dione was synthesized via cydization with intermediates（ 11 ）and（12）, and then deprotection, acylation with an overall yield of 18 % after 10 steps combined starting from compound（1）.