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