New route investigation and process development in the synthesis of GSK221149

Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2015
Thesis identifier
  • T16144
Person Identifier (Local)
  • 201099718
Qualification Level
Qualification Name
Department, School or Faculty
  • This thesis describes the development of a novel synthetic route to the Oxytocin antagonist GSK221149 developed by GlaxoSmithKline for the treatment of pre-term labour. The case for investigating new synthetic routes is made and retrosynthetic analysis allows the prioritisation of a route employing an asymmetric reductive amination as the key step. The investigation and development of the prioritised route is then described. The synthetic methods and processes for the synthesis of an α-keto amide using a modification of an existing literature procedure and the application of Lewis acidic conditions to facilitate the synthesis of a challenging imine is detailed. The novel application of a 1st generation Noyori type ruthenium catalyst to the asymmetric hydrogenation of a sterically encumbered and densely functionalised imine is shown and the newly developed route is scaled up to provide material meeting clinical specification. A detailed comparison of the cost and manufacturability implications versus the existing chemistry is then performed. The final section of the thesis describes the investigations to understand the origin of reactivity in, and scope of, the newly discovered asymmetric hydrogenation reaction. A number of alternate imine substrates are hydrogenated leading to the proposition of a 5-membered ruthenacycle as a key intermediate in the catalytic cycle.
Advisor / supervisor
  • Percy, Jonathan M.
Resource Type
  • Please note the confidentiality statement on each page of this thesis DOES NOT apply.
  • Previously held under moratorium in Chemistry Department (GSK) from 4 June 2015 until 18 June 2021.