Diastereoselective synthesis of cis-N-Boc-4-aminocyclohexanol with reductive ring opening method using continuous flow

Balázs Szabó, Bálint Tamás, F. Faigl, János Éles, István Greiner

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)13-17
Number of pages5
JournalJournal of Flow Chemistry
Volume9
Issue number1
DOIs
Publication statusPublished - Mar 15 2019

Fingerprint

Hydrogenation
Derivatives
Cycloaddition
Azabicyclo Compounds
Drug products
Purification
Nickel
Catalysts
Pharmaceutical Preparations
4-aminocyclohexanol

Keywords

  • Diastereomer selective
  • Flow chemistry
  • Nitroso-Diels-Alder cycloaddition
  • Reductive ring opening

ASJC Scopus subject areas

  • Chemistry (miscellaneous)
  • Fluid Flow and Transfer Processes
  • Organic Chemistry

Cite this

Diastereoselective synthesis of cis-N-Boc-4-aminocyclohexanol with reductive ring opening method using continuous flow. / Szabó, Balázs; Tamás, Bálint; Faigl, F.; Éles, János; Greiner, István.

In: Journal of Flow Chemistry, Vol. 9, No. 1, 15.03.2019, p. 13-17.

Research output: Contribution to journalArticle

Szabó, Balázs ; Tamás, Bálint ; Faigl, F. ; Éles, János ; Greiner, István. / Diastereoselective synthesis of cis-N-Boc-4-aminocyclohexanol with reductive ring opening method using continuous flow. In: Journal of Flow Chemistry. 2019 ; Vol. 9, No. 1. pp. 13-17.
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