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

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
Hydrogenation Process
Pressure
Detector
CatCart
Holder
Bubble Detector
H2/Substrate
Mixer
Back
-pressure
valve
t=2 min
CatCart Heater
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
30mm
•10% Pt/C , 5% Pt/C Sulfided
•5% Rh/C , 5% Rh/Al2O3
•5% Pd/CaCO3 with lead (Lindlar’s
Catalyst)
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
Validation reactions
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%
• O-Debenzylation using the Thales H-Cube: a study of catalyst capacity & deactivation
i.
O
t
BuO
N
H
O
OH
t
BuO
O
N
H
OH
O
i. 10% Pd/C CatCart30, [50:50] EtOH:EtOAc, ~ 1 bar.
Conditions: sequential 5 ml loop injection.
0.1M ambient
0.1M + 2% AcOH
0.1M 75 C
0.05M ambient
0.05M 75C
% Product (UV @ 230 nm)
OH
O
100
90
80
70
60
50
40
30
20
10
0
1
2
3
4
5
6
7
Run #
1
2
3
4
5
6
7
8
0.05M ambient
prod
s/m
100
96
91
83
77
70
68
66
0
4
9
17
23
30
32
34
0.1M ambient
prod
s/m
54
46
44
43
42
39
38
37
46
54
56
57
58
61
62
63
0.1M + 2% Ac0H
prod
s/m
83
17
53
47
49
51
47
53
46
54
45
55
43
57
41
51
0.1M 75C
prod
s/m
92
91
90
90
86
82
77
73
8
9
10
10
14
18
23
27
0.05M 75C
prod
s/m
91
100
100
100
100
100
100
100
9
0
0
0
0
0
0
0
8
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
FiltrationHazardous
Reaction analysis
2 minutes
After reaction
Time taken to set up 5 minutes
new reaction
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