H-Cube – The next generation in Hydrogenation

H-Cube – The next generation in Hydrogenation Asynt Ltd.

H-Cube – Continuous Flow Hydrogenator • Reaction Cube Concept • Integrated compact flow reactors designed to have FOUR main advantages over conventional reactors. • Improved Safety • Faster Optimization • Continuous Flow Automation • Reduced Size Developed by Thales Nanotechnology(Partner company of Comgenex)

Product H-Cube – Continuous Flow System • HPLC pump flows a continuous stream of solvent into reactor. • Hydrogen generated from electrolysis of water • Hydrogen is mixed with sample, heated and passed through a catalyst cartridge. Up to 100°C and 100 bar. (1 bar=14.5 psi) • Hydrogenated product emerges continuously into reaction vial.

H-Cube System-Monitoring Screen • Touch Screen operated • Easy setting of pressure and temperature • Control flow rate of HPLC pump • Displays safety messages • No lengthy set-up/shut down procedure

Pressure Detector CatCart Holder Bubble Detector H2/Substrate Mixer Back -pressure valve CatCart Heater Hydrogenation Process t=2 min t = 0

Catalyst System • Catalyst contained in sealed disposable cartridges • No scale-up issues • No filtration necessary • 10mg to 100 g scale • Catalysts used: • 10% Pd/C , 5% Pd/C • Raney Nickel / Raney Cobalt • 20% Pd(OH)2/C • 10% Pt/C , 5% Pt/C Sulfided • 5% Rh/C , 5% Rh/Al2O3 • 5% Pd/CaCO3 with lead (Lindlar’s Catalyst) 30mm

How does H-Cube compare to Batch Reactor? • Nitro reduction tried on H-Cube and batch reactor. • 2 minutes reaction time • 100% conversion with H-Cube vs. <2% with batch reactor • Higher active surface with packed column cartridges

Reaction Examples • Reductions • Nitro group • Nitrile group • Imine • Heterocycle • C=C bond • Alkyne • Dehalogenation • Desulphurization • Oxime • Deprotection • N-benzyl • O-benzyl • cBz • Deuteration

Reaction Conditions • 0.05M – 0.2M Solution in organic solvent, acetic acid or NH3/MeOH • Choose CatCart (Catalyst and size) • Set flow rate between 1ml/min and 3ml/min • Set Pressure 1bar – 100bar • Set Temperature 25-100 C • Set Mode • Controlled mode • Full H2 mode • No H2 mode (introduce a different gas) • How much throughput? • If RMM = 200 • Worst case 1ml/min, 0.05M, 3mmol/hour (600mg) • Best Case 3ml/min, 0.2M, 36mmol/hour (7.2g)

Catalyst Recycling H-Cube conditions: 0.1M, [50:50] EtOAc:EtOH, ~1 bar, 30 oC, 1 mL/min; Total material processed = 30x 10 fractions = 30 mmol = 4.85 g with 140mg Pd/C

10% Pd/C, RT, 1 bar Yield: 86-89% Raney Ni, 70°C, 50 bar Yield:>85% 10% Pd/C, 60˚C, 1 bar Yield:>90% Raney Ni, 80˚C, 80 bar Yield: 90% Validation reactions

O-Debenzylation using the Thales H-Cube: a study of catalyst capacity & deactivation

Automated High-throughput Hydrogenation • H-Cube integrated into CAVRO work station • Automated injection and collection • Timed injections, link to UV detector possible

H-Cube vs Traditional Batch Systems

Advantages of H-Cube • Safer… • No hydrogen cylinders necessary • Uses deionised water • No filtration of catalyst necessary • Only µmolar quantities react at any one time • Smaller… • H-Cube footprint is less than 0.3m3 • Easy storage • Scaleable reactions from mg to 100g • Faster… • Monitor reaction progress after 2 minutes! • 30 reaction conditions can be validated in less than a half day. • Simple to use, minimal training required

Acknowledgements Richard Jones, Thales Nanotechnology Mark Ladlow, GSK Cambridge

H-Cube – The next generation in Hydrogenation