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