Diastereoselective synthesis of cis-N-Boc-4-aminocyclohexanol with reductive ring opening method using continuous flow
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The N-protected cis-4-aminocyclohexanol derivatives have proven to be valuable intermediates in the syntheses of active pharmaceutical ingredients (APIs). A novel continuous flow process for hydrogenation of N-protected 2-oxa-3-azabicyclo[2.2.2]oct-5-ene cycloadducts to the corresponding cis-4-aminocyclohexanols has been reported using H-Cube Pro. A > 99% selectivity towards the desired product was obtained using Raney nickel catalyst cartridge. Under carefully selected hydrogenation parameters the reduction could stop at the also valuable 2-oxa-3-azabicyclo[2.2.2] octane intermediate, with a selectivity of >99%. The N-protected 2-oxa-3-azabicyclo[2.2.2]oct-5-ene producing nitroso hetero-Diels–Alder cycloaddition was also accomplished in a flow system using an Omnifit column packed with MnO2. The two flow reactions were successfully merged in a system, thus the product was obtained in a multistep flow synthesis without any isolation or purification steps. Compared with the previously reported batch processes, the present multistep procedure facilitates an efficient cis selective preparation of numerous synthetically valuable 4-aminocyclohexanol derivatives.
KeywordsFlow chemistry Reductive ring opening Diastereomer selective Nitroso-Diels-Alder cycloaddition
B.Sz. thanks Gedeon Richter Talentum and the Pro Progressio Foundations for financial support. This work was performed in the frame of FIEK_16-1-2016-0007 project, implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the FIEK_16 funding scheme.
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