Synthesis of a Histamine H-3 Receptor Antagonist-Manipulation of Hydroxyproline Stereochemistry, Desymmetrization of Homopiperazine, and Nonextractive Sodium Triacetoxyborohydride Reaction Workup
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 th...
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Published in | Journal of organic chemistry Vol. 75; no. 13; pp. 4463 - 4471 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
WASHINGTON
Amer Chemical Soc
02.07.2010
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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ISSN: | 0022-3263 1520-6904 |
DOI: | 10.1021/jo100629z |