An Efficient Scalable Route for the Synthesis of Enantiomerically Pure tert-Butyl-(1R,4S,6R)-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate

Maton, William; Stazi, Federica; Manzo, Angelo Maria; Pachera, Roberta; Ribecai, Arianna; Stabile, Paolo; Perboni, Alcide; Giubellina, Nicola; Bravo, Fernando; Castoldi, Damiano; Provera, Stefano; Turco, Lucilla; Simon, Bryant; Westerduin, Pieter; Profeta, Roberto; Nalin, Arnaldo; Miserazzi, Emanuele; Spada, Simone; Mingardi, Anna; Mattioli, M.; Andreotti, Daniele

doi:10.1021/op100164v

Cited by 6 publications

(6 citation statements)

References 29 publications

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“…The bromo precursor is available from HATU (1-[bis(dimethylamino) methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate)-mediated amide-coupling of the corresponding amine and carboxylic jpet.aspetjournals.org acid fragments (Alvaro et al, 2010;Maton et al, 2010;Verdelet et al, 2011), and its binding parameters (K d and B max ) for the human and rat OX1R were determined using conditions identical to those described for [ 3 H]SB-674042. The selectivity of compound 56 was evaluated in a large variety of ion channels, transporters, and receptor-binding assays.…”

Section: Methodsmentioning

confidence: 99%

A Selective Orexin-1 Receptor Antagonist Attenuates Stress-Induced Hyperarousal without Hypnotic Effects

Bonaventure

Yun

Johnson

et al. 2015

J Pharmacol Exp Ther

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Orexins (OXs) are peptides produced by perifornical (PeF) and lateral hypothalamic neurons that exert a prominent role in arousal-related processes, including stress. A critical role for the orexin-1 receptor (OX1R) in complex emotional behavior is emerging, such as overactivation of the OX1R pathway being associated with panic or anxiety states. Here we characterize a brain-penetrant, selective, and high-affinity OX1R antagonist, Although compound 56 did not alter spontaneous sleep in rats and in wildtype mice, its administration in orexin-2 receptor knockout mice selectively promoted rapid eye movement sleep, demonstrating target engagement and specific OX1R blockade. In a rat model of psychological stress induced by cage exchange, the OX1R antagonist prevented the prolongation of sleep onset without affecting sleep duration. In a rat model of panic vulnerability (involving disinhibition of the PeF OX region) to threatening internal state changes (i.e., intravenous sodium lactate infusion), compound 56 attenuated sodium lactate-induced panic-like behaviors and cardiovascular responses without altering baseline locomotor or autonomic activity. In conclusion, OX1R antagonism represents a novel therapeutic strategy for the treatment of various psychiatric disorders associated with stress or hyperarousal states.

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Section: Methodsmentioning

confidence: 99%

A Selective Orexin-1 Receptor Antagonist Attenuates Stress-Induced Hyperarousal without Hypnotic Effects

Bonaventure

Yun

Johnson

et al. 2015

J Pharmacol Exp Ther

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“…Other reagents such as BH 3 ·SMe 2 (stoichiometric)/NaBH 4 (catalytic), Zn(BH 4 ) 2 (prepared in situ from LiBH 4 and ZnCl 2 ), , borane (prepared in situ from LiBH 4 and BF 3 ·THF), LiBH 4 , (reactivity between LAH and NaBH 4 ; either commercial or prepared in situ from NaBH 4 and LiBr, , ), and Red-Al (Vitride, sodium bis(2-methoxyethoxy)aluminum hydride; 65–70 wt% in PhMe) have also been employed.…”

Section: Ester Reductionmentioning

confidence: 99%

“…Maton and co-workers at GlaxoSmithKline in Italy reported a dual ester/amide reduction for the preparation of Boc-protected piperidine 138 , a key intermediate to orexin antagonists 139 for the treatment of sleep disorders (Scheme ) . Amido ester 136 was obtained with high diastereomeric excess in two steps from tert -butyl ester 135 .…”

Section: Ester Reductionmentioning

confidence: 99%

Large-Scale Carbonyl Reductions in the Pharmaceutical Industry

Magano

Dunetz

2012

Org. Process Res. Dev.

402

309

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Herein we present a review on methods for carbonyl reductions on large scale (≥100 mmol) applied to the synthesis of drug candidates in the pharmaceutical industry. We discuss the most common and reliable methods for the reduction of aldehydes, ketones, carboxylic acids, esters, amides, imides, and acid chlorides. Representative examples illustrate detailed reaction and workup conditions and highlight the advantages and limitations of each reducing agent with special emphasis on safety, cost, and amenability to scale-up.

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“…Key intermediate 48 was synthesized using the CF 3 CO 2 ZnCH 2 I reagent and obtained as a single diastereomer in 70% yield (Scheme 17). 51 In 2011, Sherburn and coworkers synthesized a new class of hydrocarbon chains 51, termed "ivyanes", accessed by the cyclopropanation of the corresponding dendralenes 50. After screening various conditions for cyclopropanation, only the CF 3 CO 2 ZnCH 2 I reagent was able to provide complete conversion of the starting material in good to high yield, and the reaction was also amenable to gram scale (Scheme 18).…”

Section: Applications Of the Roznch 2 Y Cyclopropanation Reagentmentioning

confidence: 99%

A novel class of tunable cyclopropanation reagents (RXZnCH2Y) and their synthetic applications

Cornwall

Wong

et al. 2012

Org. Biomol. Chem.

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The Simmons-Smith cyclopropanation is a widely used method to synthesize cyclopropanes from alkenes using methylene iodide and a zinc reagent. A novel class of organozinc species, RXZnCH 2 Y, has been found to efficiently cyclopropanate alkenes, including traditionally unreactive unfunctionalized alkenes. The reactivity and selectivity of this class of organozinc reagents can be regulated by tuning the electronic and/or steric nature of the RX group attached to Zn. During recent years, this class of organozinc reagent has been widely used in organic synthesis as a reagent for cyclopropanation and other useful synthetic transformations. Catalytic, asymmetric versions of this reaction have been developed providing high enantiomeric excess for unfunctionalized olefins. On Lo AndreaWong was born in Hong Kong in 1981. She moved to Honolulu, Hawai'i in 1994 and received her B.Sc. degree in chemistry from the University of Hawai'i at Mānoa in 2003. She completed her doctoral dissertation in 2009 with Professor Yian Shi at Colorado State University. She is currently a postdoctoral fellow in Professor Christopher Ackerson's laboratory working on the synthesis of monodispersed thiolate-protected gold nanoparticles at Colorado State University.

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An Efficient Scalable Route for the Synthesis of Enantiomerically Pure tert-Butyl-(1R,4S,6R)-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate

Cited by 6 publications

References 29 publications

A Selective Orexin-1 Receptor Antagonist Attenuates Stress-Induced Hyperarousal without Hypnotic Effects

A Selective Orexin-1 Receptor Antagonist Attenuates Stress-Induced Hyperarousal without Hypnotic Effects

Large-Scale Carbonyl Reductions in the Pharmaceutical Industry

A novel class of tunable cyclopropanation reagents (RXZnCH2Y) and their synthetic applications

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