Huters Alexander D, Stambuli James, Klix Russell C, Matulenko Mark A, Chan Vincent S, Simanis Justin, Hill David R, Reddy Rajarathnam E, Towne Timothy B, Bellettini John R, Kotecki Brian J, Cardinal-David Benoit, Ji Jianguo, Voight Eric A, Shou Minshan, Balaraman Selvakumar, Ashok Abhishek, Ghosh Soma
Anthem Biosciences, No. 49 Canara Bank Road, Bommasandra Industrial Area, Bangalore 560 099, Karnataka, India.
J Org Chem. 2022 Feb 18;87(4):1986-1995. doi: 10.1021/acs.joc.1c00905. Epub 2021 Jul 19.
Foslevodopa (FLD, levodopa 4'-monophosphate, ) and foscarbidopa (FCD, carbidopa 4'-monophosphate, ) were identified as water-soluble prodrugs of levodopa (LD, ) and carbidopa (CD, ), respectively, which are useful for the treatment of Parkinson's disease. Herein, we describe asymmetric syntheses of FLD () and FCD () drug substances and their manufacture at pilot scale. The synthesis of FLD () employs a Horner-Wadsworth-Emmons olefination reaction followed by enantioselective hydrogenation of the double bond as key steps to introduce the α-amino acid moiety with the desired stereochemistry. The synthesis of FCD () features a Mizoroki-Heck reaction followed by enantioselective hydrazination to install the quaternary chiral center bearing a hydrazine moiety.
福司左旋多巴（FLD，左旋多巴4'-单磷酸酯）和福司卡比多巴（FCD，卡比多巴4'-单磷酸酯）分别被鉴定为左旋多巴（LD）和卡比多巴（CD）的水溶性前药，它们可用于治疗帕金森病。在此，我们描述了FLD（）和FCD（）原料药的不对称合成及其中试规模生产。FLD（）的合成采用霍纳尔-沃兹沃思-埃蒙斯烯烃化反应，随后对双键进行对映选择性氢化作为关键步骤，以引入具有所需立体化学的α-氨基酸部分。FCD（）的合成特点是米佐罗基-赫克反应，随后进行对映选择性肼化以安装带有肼部分的季碳手性中心。
