244081-36-5Relevant articles and documents
Process development of a scaleable route to (2R)-[3-(2-Aminopropyl)-1H- indol-7-yloxy]-N,N-diethylacetamide: A key intermediate for AJ-9677, a potent and selective human and rat β3-adrenergic receptor agonist
Harada, Hiroshi,Fujii, Akihito,Odai, Osamu,Kato, Shiro
, p. 238 - 245 (2004)
(2R)-[3-(2-Aminopropyl)-1H-indol-7-yloxy]acetic acid (2) is the left-hand side segment of AJ-9677, which is a potent and selective human and rat β3-adrenergic receptor agonist. Herein, we describe the process development of a scaleable synthetic route to the corresponding N,N-diethylacetamide derivative 3 of 2 from 7-benzyloxy-1H-indole (4). Reaction of the indole Grignard reagent 12 generated from 4 and methylmagnesium bromide with the N-Fmoc-D-alanyl chloride 22, followed by reduction of the resulting crude 3-acylindole 26 with NaBH4 in a mixture of MeCN and 2-PrOH at refluxing temperature and subsequent treatment with oxalic acid gave the oxalate of the N-deprotected product, (2R)-3-(2-aminopropyl)-7-benzyloxy-1H- indole [(R)-7] as a crystalline material in 60% yield. After N-protection of the (R)-7 by Boc group, the (2R)-3-[2-(Boc-amino)propyl]-1H-indole 30 was hydrogenated to provide the (2R)-3-(2-aminopropyl)-7-hydroxy-1H-indole 31, which was subsequently alkylated with ClCH2CONEt2 to give 32 in 91% yield. Finally, treatment of 32 with oxalic acid afforded the desired 3 in 79% in >99% ee.
