环十二烷
化学
特里斯
衍生工具(金融)
对映体过量
组合化学
药物化学
立体化学
对映选择合成
有机化学
催化作用
生物化学
经济
金融经济学
作者
Stuart G. Levy,Vincent Jacques,Kevin Li Zhou,Shirley Kalogeropoulos,Kelly K. Schumacher,John C. Amedio,J. Scherer,Steven R. Witowski,R J Lombardy,Karsten J. Koppetsch
摘要
A process for the multigram asymmetric synthesis of the chiral tetraazamacrocycle 2-(R)-2-(4,7,10-tris tert-butylcarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)-pentanedioic acid, 1-tert-butyl ester ((R)-tert-Bu4-DOTAGA, 4) has been devised and demonstrated. The nine-step synthesis features an improved synthesis of 2-(S)-5-oxotetrahydrofuran-2-carboxylic acid, tert-butyl ester 8, the precursor to the novel alkylating agent (S)-5-benzyl 1-tert-butyl 2-(methylsulfonyloxy)pentanedioate 12, which was used to introduce an orthogonally protected chiral glutarate arm to the 1,4,7,10-tetraazacyclododecane (cyclen) nucleus in high optical purity. Cyclen derivative (R)-t-Bu4-DOTAGA, 4, a key intermediate for the manufacture of a magnetic resonance imaging (MRI) candidate, was produced with high chemical (≥95%) and optical (ee ≥ 97%) purity. The process developed was successfully applied to the kilogram-scale cGMP synthesis of (R)-t-Bu4-DOTAGA.
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