A comprehensive assessment of a Ru-catalyzed direct asymmetric reductive amination (DARA) reaction for producing an intermediate for an active pharmaceutical ingredient (API) was carried out. Experiments were conducted to investigate the impact of process parameters (such as reaction temperature, time, concentration, pressure, Ru-catalyst concentration, acid catalyst, and reagent stoichiometry) on chemo-and stereo-selectivity, and yield. An analysis of experimental data led to the development of a mechanistic mathematical model that was mathematically consistent with data from laboratory development and manufacturing campaigns. A combinatory approach outlined herein could be used to provide the optimum conditions for the DARA process. Furthermore, the feasible operating region was mapped out, which highlighted the complexity of the investigated chemistry and aided in developing the control strategy and regulatory submission package pertinent to this reaction. The efforts allowed the process to be successfully validated and scaled using a plug flow reactor (PFR) to manufacture 3200 kg of (S)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b] azepin-5-amine under current Good Manufacturing Practice (cGMP).

• Eli Lilly & Co
• Takasago International Corporation

• API

1. API
2. asymmetric synthesis
3. cGMP
4. DARA process
5. reductive amination
6. Research Article
7. scaled up