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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)
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.
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
H2/SubstrateMixer
CatCart Heater
Bubble DetectorCatCartHolder
PressureDetector
Back-pressurevalve
Hydrogenation Process
t = 0t=2 min
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)
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
Catalyst Recycling
10% Pd/C, 60˚C, 1 barYield:>90%
Raney Ni, 80˚C, 80 barYield: 90%
10% Pd/C, RT, 1 barYield: 86-89%
Raney Ni, 70°C, 50 barYield:>85%
Validation reactions
01020
3040506070
8090
100
1 2 3 4 5 6 7 8Run #
% P
rodu
ct (U
V @
230
nm
)
0.1M ambient0.1M + 2% AcOH0.1M 75 C0.05M ambient0.05M 75C
prod s/m prod s/m prod s/m prod s/m prod s/m1 100 0 54 46 83 17 92 8 91 92 96 4 46 54 53 47 91 9 100 03 91 9 44 56 49 51 90 10 100 04 83 17 43 57 47 53 90 10 100 05 77 23 42 58 46 54 86 14 100 06 70 30 39 61 45 55 82 18 100 07 68 32 38 62 43 57 77 23 100 08 66 34 37 63 41 51 73 27 100 0
0.05M 75C0.05M ambient 0.1M ambient 0.1M + 2% Ac0H 0.1M 75C
NH
OH
O
tBuO
O
O
NH
OH
O
tBuO
O
OH
i.
i. 10% Pd/C CatCart30, [50:50] EtOH:EtOAc, ~ 1 bar.
Conditions: sequential 5 ml loop injection.
• 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
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
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