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H-Cube – The next generation in Hydrogenation

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Presentation on theme: "H-Cube – The next generation in Hydrogenation"— Presentation transcript:

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

2 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)

3 H-Cube – Continuous Flow System
Product 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.

4 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

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

6 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

7 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

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

9 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 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)

10 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

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

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

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

14 H-Cube vs Traditional Batch Systems
Parameter H-Cube Batch Systems Time to set-up reaction 10 minutes 30 minutes Catalyst Separation None required Filtration- Hazardous Reaction analysis 2 minutes After reaction Time taken to set up new reaction 5 minutes 60 minutes High-throughput library capability Potential for automated system Not possible Specialist Lab Required? Can use in normal laboratory Separate hydrogenation laboratory

15 Advantages of H-Cube Safer… Smaller… Faster…
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

16 Acknowledgements Richard Jones, Thales Nanotechnology
Mark Ladlow, GSK Cambridge

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