1. Stereoselective synthesis of (2S,3R)- and (2R,3S)-iodoreboxetine; potential SPECT imaging agents for the noradrenaline transporter
Nicola K. Jobson, Rosemary Spike, Andrew R. Crawford, Andrew Sutherland*. Org. Biomol. Chem., 2008, 6, 2369–2376
A typical compound used in such studies is reboxetine, the well-known, selective noradrenaline re-uptake inhibitor. Reboxetine is commercially available under the names Edronax, Prolift,Vestra and Norebox for the treatment of depressive disorder and, while the drug ismarketed as a racemicmixture of (2R,3R)- and (2S,3S)-enantiomers, it is (2S,3S)-reboxetine that has the best afﬁnity and selectivity for NAT. Using this information, the groups of Saji and Tamagnan have recently designed and synthesised a range of iodinated analogues of (2S,3S)-reboxetine for the SPECTimaging of NAT. Testing of these compounds showed one compound in particular, iodo-analogue to have excellent afﬁnity (Ki 2.47 nM), good selectivity and signiﬁcant potential as an imaging agent for NAT.
2. Co(III)(salen)-catalyzed HKR of two stereocentered alkoxy- and azido epoxides: a concise enantioselective synthesis of (S,S)-reboxetine and (+)-epi-cytoxazone
R. Santhosh Reddy, Pandurang V. Chouthaiwale, Gurunath Suryavanshi, Vilas B. Chavan, Arumugam Sudalai*. Chem. Commun., 2010, 46, 5012–5014
A wide range of synthetic applications of this HKR procedure is readily envisaged and is amply illustrated in the short synthesis of (S,S)-reboxetine, a selective norepinephrine reuptake inhibitor (NRI), and (+)-epi-cytoxazone, a cytokine modulator. For (S,S)-reboxetine, chiral epoxide was chosen as the starting material. Regiospeciﬁc opening of epoxide 4a with 30%NH4OH gave amino alcohol 16 in 83% yield, which was condensed with chloroacetyl chloride under basic conditions to aﬀord imide in 72% yield. Alcohol was obtained in 88% yield by a standard sequence of reactions. The transformation of alcohol to (S,S)-reboxetine was achieved in 98% ee.
3. The use of environmental metrics to evaluate green chemistry improvements to the synthesis of (S,S)-reboxetine succinate
Georges Assaf, Graham Checksﬁeld, Doug Critcher, Peter J. Dunn, Laurence J. Harris*. Green Chem., 2012, 14, 123–129
(±)-Reboxetine mesylate is a selective norepinephrine uptake (NRI) inhibitor which is marketed as the racemate, under the trade name EdronaxTM, for the treatment of depression, in more than 60 countries. The (S,S)-enantiomer is signiﬁcantly more active than the racemate in a number of studies and has undergone clinical evaluation as the succinate salt 2 for a number of indications in the pain therapeutic area. The chemical development program for (S,S)-reboxetine succinate was very much inﬂuenced by the unusual history of the compound. Pharmacia had manufactured 15000 kg of (±)-reboxetine mesylate or late stage intermediates, such as 3 in readiness for a US approval of EdronaxTM. When this approval did not occur it was clear that only a small proportion of the stock would be required to support the other markets and the remainder was“written off” and made available to the research organisation. Not surprisingly the large stock pile ofmaterialwas initially used as a starting point for the synthesis of (S,S)-reboxetine succinate, the single enantiomer which was being developed for new indications in the pain area. The development work was being carried out at a time when the discipline ofGreen Chemistry was becoming more established in the pharmaceutical industry. As such, in this article we focus on the environmental (and cost) improvements that were achieved through process development and synthetic route design coupled with rigorous measurement and analysis of Green Chemistry metrics.
4. Synthesis of morpholine or piperazine derivatives through gold-catalyzed cyclization reactions of alkynylamines or alkynylalcohols
Liang-Feng Yao, Yuan Wang, Kuo-Wei Huang*. Org.Chem. Front., 2015, 2, 721-725
Morpholine and piperazine derivatives have attracted considerable attention owing to their occurrence in biologically active natural products and pharmaceuticals, such as antivertigo/ antiemetic agent Buclizine, antibacterial agent Grepafloxacin hydrochloride, gyrase and topoisomerase IV inhibitor Gatifloxacin, and antidepressant drug Reboxetine. They also serve as versatile building blocks in organic synthesis. While various methodologies have been established on the synthesis of morpholine and piperazine derivatives, there are still several challenges to overcome, including the limitation of starting materials, harsh reaction conditions, low eﬃciency, poor selectivity, etc. Only very few literature reports exist to provide a mild and highly regioselective access to functiona-lized-morpholine and piperazine derivatives. Alkynylamines and alkynylalcohols can be used to assemble various heterocyclic compounds and can serve as precursors for morpholine and piperazine derivatives. They typically undergo two diﬀerent pathways to aﬀord endo-or exo-cyclization products