Scale-up prospects
The automated lab reactor platforms EasyMax 102 and 402 (Mettler-Toledo AG, AutoChem, Switzerland) were utilised by Merck for the reaction scale-up of Islatravir synthesis. The EasyMax reactors contained integrated measurement probes for pH and temperature, FireStringO2 dissolved oxygen sensors (Pyro-Science GmbH, Germany) and the EasySampler 1210 automated sampling system.
Tentative equipment list for manufacturing
EasyMax 102 and 402 equipped with FireStringO2 sensors and the EasySampler 1210 system.
A thermal gas flow controller (Aalborg, USA) to monitor and control oxidation air-gas flow to the reactor, with a suitable compressed air-source.
Reactions at the 1L scale should be conducted using the Optimal 1001 automated lab reactor platform (Mettler-Toledo) or equivalent, alongside a sintered steel frit for improved 1L gas distribution for the oxidation reactions.
Manufacturing
Several synthetic chemical processes describing the manufacture of ISL have been published, with each approach containing around twelve and eighteen steps. However, it should be noted that these approaches have proved to be complex and highly inefficient, with marked difficulty in controlling 2’-deoxyribonucleoside anomer stereochemistry and the requirement for several protecting-group manipulations. To counter these issues, Merck developed a highly innovative and extraordinarily efficient approach utilising directed evolution to create a novel three-step biocatalytic cascade for ISL synthesis
Specific analytical instrument required for characterization of formulation
400 MHz Briker AVANCE III and 500MHz Bruker Ultrashield spectrometer (or equivalent) for 1H, 19F, 31P and 13C NMR.
An Accurate-Mass Time-of-Flight (TOF) high resolution mass spectrometer.
Molecular Devices plate reader Spectra Max Plus for Spectrophotomeric analyses, alongside a Perkin Elmer polarimeter with a PCB 1500 water Peltier system for optical rotation measurements.
Aglient 7890A instrument for gas chromatography.
UPLC via Agilent Technologies 1290 Infinity II series or HPLC through Agilent 1100 Series.
Corona Ultra RS detector by Dionex for supercritical fluid chromatography.
