1381802-56-7Relevant academic research and scientific papers
Regioisomerism in the synthesis of a chiral aminotetralin drug compound: Unraveling mechanistic details and diastereomer-specific in-depth NMR investigations
Schuisky, Peter,Federsel, Hans-Juergen,Tian, Wei
, p. 5503 - 5514 (2012/09/07)
During chemical process development of a novel 2-aminotetralin derivative intended for use as an antidepressant, scrutiny of the byproduct present in the drug molecule revealed a set of regioisomers. Detailed studies showed that this impurity issue origin
Optimization and scale-up of a Pd-catalyzed aromatic C-N bond formation: A key step in the synthesis of a novel 5-HT1B receptor antagonist
Federsel, Hans-Juergen,Hedberg, Martin,Qvarnstroem, Fredrik R.,Tian, Wei
, p. 512 - 521 (2013/01/03)
Searching for the best synthetic route for a given target molecule is a complex task and, by the same token, a key deliverable from a process R&D department. In this vein the challenge for our group was to identify a sustainable manufacturing process for a chiral compound, AR-A2, to be developed for the treatment of certain neurological disorders. Besides designing a method for assembling the core (R)-2-aminotetralin nucleus, a key feature in the overall synthesis was to provide a robust procedure for creating a new C-N bond between an aromatic ring and a heterocyclic moiety. The methodology employed a Buchwald-Hartwig coupling, and a highly efficient catalytic process was developed using Pd(OAc)2 as precatalyst, with loadings as low as 0.47 mol % (in laboratory trials one order of magnitude lower) together with (R)-BINAP as ligand. Optimizing the reaction conditions allowed a virtually quantitative conversion of the brominated aromatic substrate after heating to 110-115 °C in toluene for 4 h. Telescoping this step with a succeeding catalytic hydrogenation to effect an N-debenzylation, followed by precipitation of the benzoate salt offered an overall yield for the two consecutive steps of 88% at 125-kg batch size, combined with excellent stereochemical product purity of 98% ee.
