Thales overview march 2014
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Accelerating Your Synthesis with Flow Chemistry Heather Graehl, MS, MBA Director of Sales North America ThalesNano North America
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Who are we?
• ThalesNano is a technology company that gives chemists tools to perform novel, previously inaccessible chemistry safer, faster, and simpler.
• Based Budapest, Hungary • 33 employees with own chemistry team. • 11 years old-‐most established flow reactor company.
• R&D Top 100 Award Winner.
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• Flow Chemistry Market Leader • Over 800 customers worldwide
Customers
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What is flow chemistry?
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Performing a reacQon conQnuously, typically on small scale, through either a coil or fixed bed reactor.
OR
Pump Reactor CollecQon
What is flow chemistry?
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• In a microfluidic device with a constant flow rate, the concentraQon of the reactant decays exponenQally with distance along the reactor.
• Thus Qme in a flask reactor equates with distance in a flow reactor
X
A
dX/dt > 0
dA/dt < 0
KineQcs in Flow Reactors
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Flow reactors can achieve homogeneous mixing and uniform hea6ng in microseconds (suitable for fast reac6ons)
Improved Mixing Compared to Batch
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Improved mixing can lead to improved reac6on 6mes, especially with fixed bed reactors
Improved Mixing = Faster Rxn Time
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• Microreactors have higher surface-‐to-‐volume raQo than macroreactors, heat transfer occurs rapidly in a flow microreactor, enabling precise temperature control.
Yoshida, Green and Sustainable Chemical Synthesis Using Flow Microreactors, ChemSusChem, 2010
Enhanced Temperature Control
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Lower reaction volume. Closer and uniform temperature control
Outcome:
Safer chemistry. Lower possibility of exotherm.
Batch
Flow
Larger solvent volume. Lower temperature control.
Outcome:
More difficult reaction control. Possibility of exotherm.
Enhanced Temperature Control
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Batch Heated Rxns • Safety concerns, especially in scale
up
• Microwave technology is fastest way of heaQng solvent in batch
Flow Chemistry Heated Rxns • Flow mimics microwave’s rapid
heat transfer
• Solvent is not limited to dipole
• Higher pressures and temperatures possible
• High pressures allow use of low boiling point solvents for easy workup
• Safety improvement as small amount is reacted, conQnuously
Enhanced Temperature Control
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Exothermic Chemistry – LiBr Exchange
• Batch experiment shows temperature increase of 40°C. • Flow shows little increase in temperature.
Ref: Thomas Schwalbe and Gregor Wille, CPC Systems
Enhanced Temperature Control
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Reactants
Products
By-products
Traditional Batch Method
Gas inlet
Reactants
Products
By-products
Better surface interaction Controlled residence time Elimination of the products
Flow Method
H-Cube Pro™
SelecQvity – Residence Time Control
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Catalyst screening
Parameter scanning: effect of residence time to the conversion and selectivity
Catalyst Flow rate / mL/
min
Residence time / sec
Conc. / mol/dm3
Conv. / %
Sel. / %
IrO2 2 9 0,2 52 69
Re2O7 2 9 0,2 53 73
(10%Rh 1% Pd)/C
2 9 0,2 79 60
RuO2 (activated)
2 9 0,2 100 100
1 18 0,2 100 99
0,5 36 0,2 100 98
Ru black 2 9 0,2 100 83
1% Pt/C doped with Vanadium
2 9 0,2 100 96
1 18 0,2 100 93
0,5 36 0,2 100 84
Conditions: 70 bar, EtOH, 25°C
Increase and decrease of residence time on the catalyst cannot be performed in batch
SelecQve AromaQc Nitro ReducQon
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Small scale: § Making processes safer § Accessing new chemistry
§ Speed in synthesis and workup
§ AutomaQon
Large scale: § Making processes safer § Reproducibility-‐less batch to batch variaQon
§ SelecQvity § Green
Why move to flow?
Survey Conducted
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150°C, 100 bar (1450 psi) H2, CO, O2, CO/H2, C2H4, CO2. Reactions in minutes. Minimal work-up.
-70 - +80C O3, Li, -N3, -NO2
Safe and simple to use. Multistep synthesis. 2 step independant T control. Coming: fluorinations, low T selectivity
450°C, 100 bar (1450 psi) New chemistry capabilities. Chemistry in seconds. Milligram-kilo scale Solve Dead-end chemistry. Heterocycle synthesis
H-Cube Pro & Gas Module: Reagent gases
Phoenix Flow Reactor: Endothermic chemistry
IceCube: Exothermic Chemistry
Reactor Pladorms
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H-Cube Catalysis Platform: Making hydrogenations safe, fast, and selective
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• HPLC pumps continuous stream of solvent • Hydrogen generated from water electrolysis • Sample heated and passed through catalyst • Up to 150°C and 100 bar. (1 bar=14.5 psi)
Hydrogenation reactions: § Nitro Reduction § Nitrile reduction § Heterocycle Saturation § Double bond saturation § Protecting Group hydrogenolysis § Reductive Alkylation § Hydrogenolysis of dehydropyrimidones § Imine Reduction § Desulfurization
H-‐Cube – How it Works
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Hydrogen generator cell § Solid Polymer Electrolyte
High-pressure regulating valves
Water separator, flow detector, bubble detector
Water Electrolysis
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• Benefits • Safety • No filtration necessary • Enhanced phase mixing
• Over 100 heterogeneous and Immobilized homogeneous catalysts
10% Pd/C, PtO2, Rh, Ru on C, Al2O3 Raney Ni, Raney Co Pearlmans, Lindlars Catalyst Wilkinson's RhCl(TPP)3 Tetrakis(TPP)palladium Pd(II)EnCat BINAP 30
• Different sizes • 30x4mm • 70x4mm (longer residence time or scale up)
• Ability to pack your own CatCarts • CatCart Packer (with vacuum) • CatCart Closer (no vacuum)
Catalyst System -‐ CatCarts
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10% Pd/C, RT, 1 bar Yield: 86 - 89% Alternate reductions Ketone: Pt/C Aromatic: Ru/O2
Raney Ni, 70°C, 50 bar, 2M NH3 in MeOH, Yield: >85%
Simple ValidaQon ReacQons (out of 5,000)
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10% Pd/C, 60˚C, 1 bar Yield: >90%
Batch reaction of {3-[(2-carbazol-9-yl-acetylamino)-methyl]-benzyl}-carbamic acid benzyl ester Reagent: H2, catalyst: 10% Pd/C, EtOH, 1 atm, Yield: 76 % Conn, M. Morgan; Deslongchamps, Ghislain; Mendoza, Javier de; Rebek, Julius; JACSAT; J. Am. Chem. Soc.; EN; 115; 9; 1993; 3548-3557.
Raney Ni, 80˚C, 80 bar Yield: 90%
Batch reference: Reagent: HCOONH4, catalyst: 10% Pd/C, solvent: MeOH, Reaction time: 30 min, 1 atm. Yield: 78 % Kaczmarek, Lukasz; Balicki, Roman; JPCCEM; J. Prakt. Chem/Chem-Ztg.; EN; 336; 8; 1994; 695-697
Simple ValidaQon ReacQons (out of 5,000)
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Batch: 200°C, 200 bar, 48 hours
Batch: 150°C, 80 bar, 3 days
Difficult Hydrogenatons
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Selective reduction in presence of benzyl protected O or N 5% Pt/C, 75°C, 70 bar, 0,01M, ethanol,no byproduct Yield: 75%
Batch reference: Reagent: aq. NaBH4, Solvent: THF; 0°C, Yield: 76,1 % Nelson, Michael E.; Priestley, Nigel D.; JACSAT; J. Am.
Chem. Soc.; EN; 124; 12; 2002; 2894-2902
Route A: Raney Ni, abs. EtOH, 0,01 M, 70 bar, 25°C. Yield: 80%
Route B: Raney Ni, abs. EtOH, 0,01 M, 70 bar, 100°C. Yield: 85%
No batch reference
SelecQve HydrogenaQons
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Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17s Results: 100% conversion, 97% yield
Conditions: 1% Pt/C, 70 bar, 30°C, residence time 17s Results: 100% conversion, 100% yield
Conditions: Au/TiO2, 70 bar, 30°C, residence time 17s Results: 100% conversion, 100% yield
H-Cube® - Chemoselective hydrogenations
Ürge, L.et al. submitted for publication
Selective hydrogenation of the double-bond
Selective hydrogenation to afford oxime
Selective hydrogenation of the double-bond
SelecQve HydrogenaQons
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Conditions: 10% Pd/C, 70 bar, 0°C, residence time 16s Results: 100% conversion, 100% yield
Conditions: 1% Pt/C, 70 bar, 30°C, residence time 11-17s Results: 100% conversion, 100% yield
Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17s Results: 100% conversion, 100% yield
Ürge, L.et al. submitted for publication
H-Cube® - Chemoselective hydrogenations
Nitro group reduction in the presence of a halogen
Nitro group reduction in the presence of Cbz-group
Nitro group reduction without retro-Henry as a
side-reaction
SelecQve HydrogenaQons
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Flow rate
(mL/min)
Pressure (bar) Temperature (oC)
Bubdet Catalyst Amount A (%)
Amount B (%)
Amount C (%)
Amount D (%)
1 20 (∆p:5 bar) 110 50 10% Pd/C 26.7% 61.5% - 7% 1 20 (∆p:3 bar) 110 50 1% Pd/C 61,90% 29,40% - 2,50% 1 20 (∆p:13
bar) 110 50 5% Rh/C 78.9% 5.1% - 9.2%
1 20 (∆p:10 bar)
110 50 5% Pd/C 26.7% 60.9% - 6.7%
1 20 (∆p:5 bar) 110 50 5% Pd/C(S) 25% 63.4% - 6.6%
Objective: Match similar selectivity of 60% but without additives of CsF, S, K2CO3 and PPh3
SelecQve DehydrochlorinaQon
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Optimised reaction parameters: - H-Cube Pro - Temperature: 100oC - Pressure: 100 bar - Hydrogen amount: Maximum
Results:
• Generate new non-planar molecules from existing stocks. • New molecules have new Log P and other characteristics.
• Cheap • Clean • Quick • Only on H-Cube: High P + Selective control.
Flow rate (ml/min) Conversion % of A % of B % of C 0.3 100% 100 0 0 0.5 100% 92 8 0 1.0 100% 86 14 0
ParQal SaturaQon of Heterocycles
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Chiral Phosphine-phosphoramidite ligands packed in CatCart
Asymmetric HydrogenaQon
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Substrate Product Deuterium content(%)
Isolated yield / %
99 99
97 98
93 97
96 98
96 99
Mándity, I.M.; Martinek, T.A.; Darvas, F.; Fülöp, F.; Tetrahedron Letters; 2009, 50, 4372–4374
DeuteraQon
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• Original 2005 R&D100 award winner • 20mg-10g/day • Ambient to 100°C • Limited H2 control: Full H2 mode (30ml/min), Controlled H2 mode, No H2
• Improved H-Cube • 20mg-50g/day • -10°C to 150°C • H2 production variability from 0ml/min – 60ml/min (selectivity!) • Reaction timer with auto switching valves • Software for logs, graphs, reaction guide, module control
• High throughput • Larger MidiCart Catalysts • 20mg-500g/day • Ambient to 150°C • H2 production variability from 0ml/min – 125ml/min • Reaction timer with auto switching valves
Which H-Cube is best for me?
H-‐Cube Family
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• Touch Screen Interface • Now can control hydrogen variability (0-60ml/min) for selectivity • Suggested reaction parameters for each functional group • Reaction Timer with automatic valve switching • Logs and graphs for viewing achieved reaction parameters
New Sonware with H-‐Cube Pro
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2 cells for higher hydrogen production: 60 mL/min
Compare to H-Cube SS where maximum concentration is 0.2M
100% conversion
H-‐Cube Pro = Higher Throughput
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H-‐Cube Pro = Higher Temp Capability
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T (oC) p (bar) Flow rate (ml/min) Conversion (%) B Selectivity (%)
20 1, controlled 1 37 99 20 1, controlled 2 65 93 20 1, controlled 3 87 77
Solvent Conc. Temp. (°C) Pressure (bar)
Flow Rate (mL/min)
Product Distribution (%, GC-MS)
A B C EtOH 0.1 M 10 10 1 0 100 0
H-Cube
H-Cube Pro
H-‐Cube Pro = Lower Temp SelecQvity
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Parameters: - p= 1-100 bar - T=10-150°C - v=0.1-3 ml/min - c=0.01-0.1 M - H2 production = up to 60ml/min - CatCarts = 30x4mm or 70x4mm
Parameters: - p= 1-100 bar - T=25-150°C - v=5-25 ml/min - c=0.05-0.25 M - H2 production = up to 125ml/min - CatCarts = 90x9.5mm
Milligram to Gram Scale
Half Kilogram Scale
H-‐Cube Midi – Reactor for Scale Up
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Gilson 271 Liquid Handler § 402 single Syringe pump (10 mL) § Direct GX injector (Valco) § Low-mount fraction collection (Bio-Chem) § Septum-piercing needle § Static drain wash station § Tubes, connectors, fittings
Open vial collection Collection through probe (into closed vial)
H-‐Cube Autosampler
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Expanding H-Cube Beyond Hydrogenation
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Purity (LCMS): 63%
Batch parameters: Pd(OAc)2, PPh3, TEA, DMF, 3 days, 110°C, yield: 70% Reference: J. Chem. Soc. Dalton Trans., 1998, 1461-1468 J. Chem. Soc. Dalton Trans., 1998, 1461-1468
Heck C-C cross coupling:
CatCartTM: Pd (PPh3)4, TBAF, 2-propanol, 0.05M, 100oC, 1 bar, 0.2 ml/min.
Coupling ReacQons
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Conversion: 90-95% (TLC) Purity: 70% (LC-MS) without work-up
Batch parameters: K3PO4, TBA-Br, Pd(OAc)2, DMF, 2 hours, 130 °C Reference: (Zim, Danilo; Monteiro, Adriano L.; Dupont, Jairton; Tetrahedron Lett.; EN; 41; 43; 2000; 8199-8202)
Suzuki-Miyaura C-C cross coupling:
Br
N O 2 B
O H O H
N O 2 CatCart TM 70*4 mm Pd EnCat TM BINAP 30, 2-propanol, TBAF, 80°C, 20 bar, 0.05M, 0.5 ml/min
+
Coupling ReacQons
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The condiQons were:
1 equivalent of 2,6-‐dichloroquinoxaline with 1.2 equivalent of o-‐Tolylboronic acid
ConcentraQon set to 0.02M
Solvent: Methanol
Base: NaOH
AnalyQcs: GC-‐MS
SelecQve Coupling ReacQon
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Flow rate (ml/min)
Pressure Temperature Catalyst Base
Result (bar) (oC) LC-‐MS, 220nm
0.8 20 100 Fibrecat 1007
(70mm) 3 ekv Conversion: 82% SelecQvity: 48%
0.3 20 100 Fibrecat 1007
(70mm) 3 ekv Conversion: 99% SelecQvity: 48%
0.8 20 100 Fibrecat 1035
2.5 ekv Conversion: 16%
(30mm) SelecQvity: 100%
0.8 20 100 Fibrecat 1029
(30mm) 2.5 ekv Conversion: 18% SelecQvity: 100%
0.8 20 100 Fibrecat 1048
(30mm) 2.5 ekv Conversion: 40% SelecQvity: 100%
0.8 20 100 10% Pd/C
2.5 ekv Conversion: 89%
(30mm) SelecQvity: 14%
0.5 20 50 Fibrecat 1048
2.5 ekv Conversion:17%
(30mm) SelecQvity: ~100%
0.5 20 100 Fibrecat 1048
2.5 ekv Conversion: 35%
(30mm) SelecQvity: ~100%
0.2 20 100 Fibrecat 1007
2.5 ekv Conversion: 93%
(70mm) SelecQvity: 73%
0.2 20 100 Fibrecat 1007
2.5 ekv Conversion: 93%
(70mm) SelecQvity: 80%
0.2 20 100 Fibrecat 1029
2.5 ekv Conversion: 12%
(30mm) SelecQvity: 100%
SelecQve Coupling ReacQon 1 equivalent of 2,6
-‐dichloroquinoxaline with 1.2 equivalent of o-‐Tolylboronic acid
ConcentraQon set to 0.02M
Solvent: Methanol, Base: NaOH
AnalyQcs: GC-‐MS
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• Versa6le: Compressed Air, O2, CO, C2H4, SynGas, CH4, C2H6, He, N2, N2O, NO, Ar.
• Fast: ReacQons with other gases complete in less than 10 minutes
• Powerful: Up to 100 bar capability.
• Robust: All high quality stainless steel parts.
• Simple: 3 buron stand-‐alone control or via simple touch screen control on H-‐Cube Pro™.
Other Reagent Gases
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Ø Conditions: 100oC, 30 bar, CO gas, 0.5 ml/min liquid flow rate, 0.01 M in THF Ø Catalyst: Polymer supported Pd(PPh3)4 Ø Reaction was repeated Ø Different gas flow rates were tested
Observed reproducible conversion at each gas flow rate
ApplicaQon 1: CarbonylaQon
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ApplicaQon 2: Green OxidaQon
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Pressure Temp. (oC) CatCart Conversion Selectivity
40 25 1 % Au/TiO2 0 – 40 65 1 % Au/TiO2 6.5 >85 40 25 1 % Au
/Fe2O3 0 – 40 65 1 % Au
/Fe2O3 12.7 0 40 25 5 % Ru
/Al2O3 2.8 ~100 40 65 5 % Ru
/Al2O3 3.6 ~100 100 65 5 % Ru
/Al2O3 2.7 ~100 100 100 5 % Ru
/Al2O3 8.5 ~100 100 140 5 % Ru
/Al2O3 15.5 ~100 100 65 1 % Au/TiO2 5.6 84 100 100 1 % Au/TiO2 47.2 93 100 140 1 % Au
/TiO2 ~100 93 100 65 1 % Au
/Fe2O3 4 0 100 100 1 % Au
/Fe2O3 31 7 100 • Area% of desired product in GC-MS / (100 – Area% of reactant in GC-MS)
General conditions: H-Cube Pro with Gas Module, 50 mL/min oxygen gas, 1 mL/min liquid flow rate (0.05M in acetone, 20 mL sample volume), CatCart: 70mm., 1 % Au/TiO2 (cartridge: 70mm, THS 01639),
Batch ref.: Oxygen; perruthenate modified mesoporous silicate MCM-41 in toluene T=80°C; 24 h; Bleloch, Andrew; et al. Chemical Communications, 1999 , 8,1907 - 1908
Very fast addition of alcohol to gold surface. Alkoxide formation.
Green OxidaQon OpQmizaQon
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Reaction parameters were tested: - H-Cube Pro with and without GasModule - Oxidizing agent: Hydrogen-peroxide and Oxygen - Catalyst: MnO2, Amerlyst 36, Au/TiO2 - Solvent: Acetone/H2O2, Acetone - Temperature 60-150oC, pressure 20-50 bar, flow rate 1 ml/min, concentration: 0.05 mmol/ml
Oxidizing agent Solvent Catalyst
Temperature (oC)
Pressure (bar) Conversion Comment
MnO2 Acetone MnO2 60 20 82% Blockage aner 10 minutes
H2O2 Acetone -‐ H2O2
(4-‐1) Au/TiO2 70 20 68% aner 1 run 78% aner 2 run
H2O2 Acetone -‐ H2O2
(4-‐1) Au/TiO2 100 30 68% aner 1 run 98% aner 2 run
The catalyst was reacQvated with H2O2 between the runs.
O2 (10 ml/min) Acetone Au/TiO2 75 11 8%
O2 (10 ml/min) Acetone Au/TiO2 150 11 95%
Aner 10 minutes the conversion was dropped to
50%
O2 (50 ml/min) Acetone Au/TiO2 150 20 > 98%
AromiQzaQon of Heterocycles
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Accessing New Molecules or Chemical Space
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Heterocyclic rings of the future, J. Med. Chem., 2009, 52 (9), pp 2952–2963.
• 3000 potential bicyclic systems unmade • Many potential drug like scaffolds Why? • Chemists lack the tools to expand into new chemistry space to access these new compounds. • Time • Knowledge
The Quest for Novel Heterocycles
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• Standard benzannulation reaction • Good source of:
• Quinolines • Pyridopyrimidones • Naphthyridines
→ Important structural drug motifs
Disadvantages: • Harsh conditions • High b.p. solvents • Selectivity • Solubility
W. A. Jacobs, J. Am. Chem. Soc.; 1939; 61(10); 2890-2895
High Temp Chemistry – In Batch
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• Replacement of diphenyl ether (b.p: 259°C) with THF (b.p.: 66 °C)
Cyclization conditions: a: 360 °C, 130 bar, 1.1 min b: 300 °C, 100 bar, 1.5 min c: 350 °C, 100 bar, 0.75 min
Pyridopyrimidinone Quinoline
No THF polymerization!
Batch conditions: 2 hours
Gould Jacobs ReacQon -‐ Overview
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The nature of the substituents is critical because they increase or decrease the nucleophilicity of the ring: Electron donating groups increase yields, Electron withdrawing groups decrease yields.
52
• Meldrum’s acidic route to pyridopyrimidones and to hydroxyquinolines
Cyclization conditions: a: 300 °C, 160 bar, 0.6 min b: 300 °C, 100 bar, 0.6 min c: 360 °C, 100 bar, 1 min d: 350 °C, 130 bar, 4 min e: 300 °C, 100 bar, 1.5 min
Lengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., 2012; 53; 738-743
Process ExploraQon
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5 novel bicyclic scaffolds generated-fully characterized. Many more to follow
New Scaffold GeneraQon
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Powerful: Up to 450°C
Versatile: Heterogeneous and homogeneous capabilities.
Fast: Reactions in seconds or minutes.
Innovative: Validated procedure to generate novel bicyclic compounds
Simple: 3 button stand-alone control or via simple touch screen control on H-Cube Pro™.
Phoenix Flow Reactor
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• Choice of stainless steel, teflon, or Hastelloy
• Different length coils to vary residence time
• Easy to recoil
Phoenix Homogeneous ReacQons
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• Use same H-Cube Pro or Midi CatCarts
• Phoenix metal-metal Catcarts for >250°C reactions
Phoenix metal-metal CatCarts (125mm/250mm)
H-Cube Pro CatCarts (30 or 70mm)
Phoenix Heterogeneous ReacQons
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Ring closure on aryl NH : key step • Mitsunobu reaction or traditional heating with T3P did not
furnish the bicyclic heterocycle. • Reaction proceeded smoothly in Phoenix reactor at 300oC with
65% yield despite requirement for the cis amide conformer in transition state.
Mitsunobu ReacQon not Possible in Batch
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RaNi 70mm 200C, 80bar 0.5ml/min
N-‐AlkylaQon with RaNi CatCart
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59 The total amount of dialkylated products was 18%.
Alkylation coupled with dehydrogenation
AlkylaQon of 2-‐methyl-‐indone
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60
Ring closure is coupled with hydrogenation of double bond
Ring closuring of 2-methyl-indole with 1,3-butanediol
AlkylaQon with Diol – Ring Closure
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cf. MW reaction: Bagley, M. C.; et al. J. Org. Chem. 2005, 70 , 7003
In AcOH/2-propanol (3:1) (0.5M) 150 °C, 60 bars,
1.0 mL min-1 (4 min res. time) 88% isolated yield
Continuous Flow Results (4 mL or 16 mL Coil) Scale-up
200 °C, 75 bars, 5.0 mL min-1 (~3 min res. time)
96% isolated yield
25 g indole/hour
Fischer-‐Indole Synthesis – Scale Out
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• Reactions from 10-450C and 1-100bar (1450 psi) • Up to 13 different reagent gases • Heterogeneous or homogeneous catalysis
Fully Automated system available
VersaQle Catalysis System
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High Energy
Reac6ons
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What is ozonolysis?
• Ozonolysis is a technique that cleaves double and triple C-C bonds to form a C-O bond.
• Currently neglected oxidation technique • Highly exothermic, ozonide accumulation is dangerous
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Carboxylic Acid (oxidative work-up)
Aldehyde/Ketone (simple quenching)
Alcohol (reductive work-up)
Workup Determines Product
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Synthesis of Indolizidine 215F
Other major drug syntheses featuring ozonolysis includes:
(+)-Artemisinin D,L-Camptothecin L-Isoxazolylalanine Prostaglandin endoperoxides.
Van Ornum, S.G., Champeau, R., Pariza, R., Chem. Rev. 2006, 106, 2990-3001
Ozonolysis in Industry
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Why ozonolysis is neglected?
• Highly exothermic reacQon, high risk of explosion
• Normally requires low temperature: -‐78°C. • In addiQon, the batchwise accumulaQon of ozonide is associated again with risk of explosion
• There are alternaQve oxidizing agents/systems: • Sodium Periodate – Osmium Tetroxide (NaIO4-‐OsO4)
• Ru(VIII)O4 + NaIO4
• Jones oxidaQon (CrO3, H2SO4)
• Swern oxidaQon • Most of the listed agents are toxic, difficult, and/or expensive to use.
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• Highly effective oxidation • In line quenching of ozonide – SAFETY • Efficient cooling for exotherm control - SAFETY • The reactions typically go cleanly in high yield and
conversion with little by products • Gas is used as a reagent, so work up is less labor
intensive • Can be used in non-aqueous condition • Ozonolysis is fast and atom efficient • Ease in Scale Up
Why Ozonolysis in Flow?
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M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Ler.,
Flow Ozonolysis of Styrenes
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Oxida6on of alkynes
Oxida6on of amines to nitro groups
Flow Ozonolysis
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Ler.,
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Flow Ozonolysis Of Thioanisole
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Ler.,
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Safe: Low reacQon volume, excellent temperature control, SW controlled – including many safety control points
Simple to use: easy to set up, default reactor structures, proper system construcQon
Powerful: Down to -‐50°C/-‐70°C, up to 80°C
Versa6le chemistry: Ozonolysis, nitraQon, lithiaQon, azide chemistry, diazoQzaQon
Versa6le reactors: Teflon loops for 2 reactors with 1/16” and 1/8” loops
High Chemical resistance: Teflon wered parts
Mul6step reac6ons: 2 reacQon zones in 1 system Modular: OpQon for Ozone Module or more pumps
Size: Stackable to reduce footprint
IceCube
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Halogena6on
Nitra6on Azides
Mul6step reac6ons
Reac6ve Intermediates
Lithia6on
Ozonolysis
Swern Oxida6on
IdenQfied ApplicaQons
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First Reac6on Zone Second Reac6on Zone
Water inlet and outlet
Reactor Plate • Aluminum stackable blocks • Teflon tubing for ease in addressing blocks • Easy to coil for desired pre-‐cooling and desired residence Qme aner mixing • Different mixers types available
A B
D
-‐70-‐+80ºC -‐30-‐+80ºC
C First Reac6on Zone Second Reac6on Zone
ReacQon Zones
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A
B C
A B
C
D
Pre-‐cooler/Mixer Reactor
-‐70-‐+80ºC
-‐70-‐+80ºC -‐30-‐+80ºC
Applica6ons: Azide, Lithia6on, ozonolysis, nitra6on, Swern oxida6on
Azide, nitra6on, Swern oxida6on
Ideal for reactive intermediates or quenching
Single or MulQ-‐Step ReacQons
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Welcome screen of the IceCube
Ozonolysis set-‐up 3 pump – 2 reactor set-‐up
Touch Screen Interface
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• 2pcs rotary piston pumps
• 2pcs 3-‐way inlet valves
• Flow rate: 0.2 – 4.0 mL/min
• Max pressure: 6.9 bar
• Main reactor block temp: -‐70/50°C – +80°C
• Main reactor volume up to 8 mL
• Tubing: 1/16” or 1/8” OD PTFE
• Secondary reactor block temp.: -‐ 30 – +80°C
• Secondary reactor volume up to 4 mL
Cooling Module
• ConQnuous ozone producQon
• Controlled oxygen introducQon
• Max. 100 mL/min gas flow
• 14% Ozone producQon
Pump Module Ozone Module
Modular for a Variety of Chemistry
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Batch reac6on: Max. -‐60°C to avoid side reacQon
In Flow:
Even at -‐10°C without side product formaQon
0.45 M in DCM, 0.96 mL/min
0.45 M alcohol, 0.14 M DMSO in DCM 0.94 mL/min
3.6 M in MeOH, 0.76 mL/min
* Aner purificaQon
When compared to batch condiQons, IceCube can sQll control reacQons at warmer temperatures due to berer mixing and more efficient heat transfer.
ApplicaQon Note 1: Swern OxidaQon
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• 2 Step Azide Reaction in flow • No isolation of DAGL • Significantly reduced hazards
TKX50
Making Azide Chemistry Safer
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Entry Vflow (ml/min) A -‐ B -‐ C
T (°C) τ (1. loop, min)
τ (2. loop, min)
Isolated Yield (%)
1 0.4 0 2.12 3.33 91
2 0.9 0 0.94 1.48 91
3 0.6 0 1.42 2.22 85
4 0.9 10 0.94 1.48 85
5 1.5 10 0.56 0.88 86
6 1.5 15 0.56 0.88 98
7 1.2 15 0.71 1.11 84
8 1.8 15 0.47 0.74 86
Aniline HCl sol. Pump A
Pump B NaNO2 sol.
Pump C
Phenol NaOH sol. • Most aromaQc diazonium salts
are not stable at temperatures above 5°C • Produces between 65 and 150 kJ/mole and is usually run industrially at sub-‐ambient temperatures • Diazonium salts decompose exothermically, producing between160 and 180 kJ/mole. • Many diazonium salts are shock-‐sensiQve
ApplicaQon Note 2: DioaziQzaQon
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NitraQon of AromaQc Alcohols
Pump A Pump B Temperature (oC)
Loop size (ml)
Conversion (%)
SelecQvity (%)
SoluQon Flow rate (ml/
min) SoluQon Flow rate (ml/
min)
ccHNO3 0.4 1g PG/15ml ccH2SO4 0.4 5 -‐ 10 7 100
0 (different products)
1.48g NH4NO3/15ml ccH2SO4 0.7
1g PG/15ml ccH2SO4 0.5 5 -‐ 10 13 100 100
1.48g NH4NO3/15ml ccH2SO4 0.5
1g PG/15ml ccH2SO4 0.5 5 -‐ 10 13 50 80 (20% dinitro)
70% ccH2SO4 30% ccHNO3 0.6
1g PG/15ml ccH2SO4 0.5 5 -‐ 10 13 (3 bar) 100 100
70% ccH2SO4 30% ccHNO3 0.6
1g PG/15ml ccH2SO4 0.5 5 -‐ 10 13 (1 bar) 80
70 (30% dinitro and nitro)
Currently invesQgaQng selecQvity at lower temperatures on IceCube
Scaffolds from Explosive Intermediates
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• LithiaQon experiments
• HalogenaQons/FluorinaQons
• Low temperature selecQve reacQons, not necessarily
exothermic nature
• EpoxidaQons
Coming soon…
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Our chemistry team is full of flow chemistry and catalysis experts
We aim to solve your challenging chemistry in flow!
Phoenix Flow Reactor - High temperature and pressure reactor for novel heterocycle and compound synthesis (up to 450C)
H-Cube Pro and Gas Module - for gas reagent chemistry from hydrogenation to oxidation
IceCube - for low temperature and high energy reactions
Free chemistry services on Thalesnano flow platforms for up to a week. No strings attached.
Ship us your compound or visit our labs in Budapest, Hungary. CDAs and NDAs are approved quickly.
Free Chemistry Services
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We can visit your site for chemistry demos and seminars. Impress your colleagues and bring flow chemistry to your lab.
Phoenix Flow Reactor - High temperature and pressure reactor for novel heterocycle and compound synthesis (up to 450C)
H-Cube Pro and Gas Module - for gas reagent chemistry from hydrogenation to oxidation
H-Cube Midi – scale up H-Cube for 10-500g/day hydrogenations
IceCube - for low temperature and high energy reactions
Heather Graehl, MS, MBA Director of Sales North America
Based in sunny San Diego [email protected]
Onsite Demos & Seminars Available
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THANK YOU FOR YOUR ATTENTION!!
ANY QUESTIONS?