1234176-08-9Relevant academic research and scientific papers
Synthesis of a histamine H3 receptor antagonist - Manipulation of hydroxyproline stereochemistry, desymmetrization of homopiperazine, and nonextractive sodium triacetoxyborohydride reaction workup
Pippel, Daniel J.,Young, Lana K.,Letavic, Michael A.,Ly, Kiev S.,Naderi, Bita,Soyode-Johnson, Aki,Stocking, Emily M.,Carruthers, Nicholas I.,Mani, Neelakandha S.
scheme or table, p. 4463 - 4471 (2010/10/02)
(Figure presented) We have recently completed the synthesis of 1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy) -pyrrolidin-1-yl]-ethanone, a hydroxyproline-based H3 receptor antagonist, on 100 g scale. The synthesis proceeds through four steps and route selection was driven by a desire to minimize the cost-of-goods. Naturally occurring trans-4-hydroxy-L-proline was chosen as the precursor to the targets core, which necessitated an inversion at both stereogenic centers. The inversions were accomplished through strategic employment of La Rosas lactone and a late-stage Mitsunobu reaction. A first generation synthesis that employed N-Boc-homopiperazine was improved in a second generation approach wherein homopiperazine was directly desymmetrized. Finally, the water solubility of a key intermediate necessitated the development of a nonextractive workup for the sodium triacetoxyborohydride reduction.
