Synthesis of a Histamine H-3 Receptor Antagonist-Manipulation of Hydroxyproline Stereochemistry, Desymmetrization of Homopiperazine, and Nonextractive Sodium Triacetoxyborohydride Reaction Workup

• Published in: Journal of organic chemistry Vol. 75; no. 13; pp. 4463 - 4471
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 02.07.2010
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; ORGANIC-SYNTHESIS; KETONES; ALPHA,BETA-ENONES; BILN-2061; (2S,4R)-4-HYDROXYPROLINE; HCV PROTEASE INHIBITOR; ALDEHYDES; (+)-APHANORPHINE; REDUCTIVE AMINATION; EPOXIDATION
• DOI: 10.1021/jo100629z
• ISSN: 0022-3263

We have recently completed the synthesis of 1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-Buoro-phenoxy)-pyrrolidin-1-yl]-ethanone, a hydroxyproline-based H-3 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 target's core, which necessitated an inversion at both stereogenic centers. The inversions were accomplished through strategic employment of La Rosa's 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.