2015 05 thalesnano overview
TRANSCRIPT
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Flow Chemistry: A useful method for performing hazardous chemistry in a safer manner Heather Graehl, MS, MBA [email protected]
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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.
• Flow Chemistry Experience: 12 years • R&D 100 award winning instrument • Based Budapest, Hungary • 33 employees with R&D labs, chemists, and engineers
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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 reacRon conRnuously, through either a coil or fixed bed reactor.
OR
Pump Reactor
CollecRon
What is flow chemistry?
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Flow reactors can achieve homogeneous mixing and uniform hea6ng in microseconds
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 raRo 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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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
Exothermic ReacRons
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Batch Heated Rxns • Safety concerns, especially in scale
up • Microwave technology is fastest
way of heaRng solvent in batch
Flow 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, conRnuously
Endothermic ReacRons
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Where is flow chemistry applied best?
Exothermic Reactions • Very good temperature control • Accurate residence time control • Efficient mixing • Less chance for thermal run-away • Higher productivity per volume • High selectivity
Endothermic Reactions • Control over T, p and residence time • High selectivity • Accessing new chemistry • Higher productivity per volume • High atom efficiency
Reactions with gases • Accurate gas flow regulation • Increased safety • Easy catalyst recycling • High selectivity • Higher productivity per volume
Scale up
• Increased safety • Higher productivity per volume • Selectivity • Reproducibility
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Safe High Energy Reactions
Lithiation Ozonolysis
Nitration
-70 – + 80°C Inert Conditions
2 Reaction Zones Fast Optimization
Reactions with Gases Made
Simple
Hydrogenation Oxidation
Carbonylation
150°C,100 bar mg - Half a Kilo
13 Gases No Catalyst Handling
Synthesize Novel Compounds
Heterocycles C-H activation
Catalyst screening
450°C, 100 bar Microwave Scale Up Homogeneous and
Heterogeneous
Untapped Chemical Space
Cyclization Molecule cleavage
Free radicals
Vacuum to 400 bar RT to 1000°C
New Synthesis Routes Clean
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H-Cube Hydrogenation and Flow Catalysis Platform
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H-‐Cube Family
H-Cube®
H-Cube Pro™ H-Cube Mini™ H-Cube Midi™
Industry Hydrogenations and General Flow Platform
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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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Water Electrolysis
Hydrogen Tanks are Explosive and Severe Safety Hazard Hydrogen generator cell
§ Solid Polymer Electrolyte § Single Cell output:
30ml/min hydrogen
High-pressure regulating valves Water separator, flow detector, bubble detector
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• Benefits • Safety • No filtration necessary • Enhanced phase mixing – fast reaction times
• 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
• Pack your own with CatCart Packer
Catalyst System -‐ CatCarts
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NO2 NO2
Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17s Results: 100% conversion, 97% yield
O2N
O2N
NHO
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
SelecRve HydrogenaRons
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OO2N
Cl
OH2N
Cl
Conditions: 10% Pd/C, 70 bar, 0°C, residence time 16s Results: 100% conversion, 100% yield
HN
OOO
OO2NHN
OOO
OH2N
Conditions: 1% Pt/C, 70 bar, 30°C, residence time 11-17s Results: 100% conversion, 100% yield
O2N NO2OH
H2N NH2OH
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
SelecRve HydrogenaRons
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H-Cube: <5min Batch: 200°C, 200 bar, 48 hours
H-Cube: <5 min Batch: 150°C, 80 bar, 3 days
Difficult Hydrogenatons
10% Pd/C, 0.05M, EtOH, RT, 30 bar
10% Pt/C, 0.05 M EtOAc 100 °C, 100 bar
85% yield 92% yield
Partial or Full Reduction in <5min
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N
NO2
NH
NH2PtO2
N
NH2
+
A BNH
NH2
+
COptimised 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
ParRal SaturaRon of Heterocycles
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Radiochemistry applicaRon
• Model reaction:
18F t1/2 = 109.8 min
5 min
92% 90%
3 min
1 cartridge used 15 times – no degradation
Including purification 40 min process time
S. Liang, T. Collier, B. Rotstein, R. Lewis, M. Steck, and N. Vasdev.; Chem. Com., 2013; 49 (78); 8755 – 8757.
Harvard Medical School, Massachusetts General Hospital and Northeastern University
Positron emission tomography
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Chiral Phosphine-phosphoramidite ligands packed in CatCart
Asymmetric HydrogenaRon
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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
DeuteraRon
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New Sohware on H-‐Cube Pro Timer Hydrogen Variability
Valve control Data saving Chemistry Guide
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Increased ProducRon and Delivery of H2
2 hydrogen cells for higher hydrogen production: 60 mL/min
New hydrogen delivery algorithm • No more “controlled mode” (7% of 30ml/min) • Full H2 at at all pressures (100% 60ml/min) • Hydrogen control from 0-100% of 60ml/min
12g / hour!
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H-‐Cube Pro: Higher temperature
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H-‐Cube Pro: SelecRvity with lower temp
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
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• Installed with hundreds of H-Cubes • Flow Rates: 0.001 to 10ml/min • Stainless steel pump head
• Complaints • Loses prime frequently • Does not tolerate air bubbles • Difficult to maintain • Check valves are not robust • Poor performance at low flow rates, not advisable below 0.5ml/min „Knauer Pumps are the achiles heel of the H-Cube” – H-Cube Customer
New ThalesNano Micro HPLC Pump
Knauer Smartline HPLC Pump
• New pump for H-Cube and Phoenix • Ruby Ball/Saphire Seat Check Valves • More accurate • Tolerates air bubbles • Self flushing compartment • Less often and easier maintenance • Stainless Steel
New ThalesNano Mirco HPLC Pump
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• Versatile: Compressed Air, O2, CO, C2H4, SynGas, CH4, C2H6, He, N2, N2O, NO, Ar.
• Fast: Reactions with other gases complete in less than 10 minutes
• Powerful: Up to 100 bar capability.
• Robust: All high quality stainless steel parts.
• Simple: 3 button stand-alone control or via simple touch screen control on H-Cube Pro™.
Gas Module
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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
CarbonylaRons
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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 OxidaRon OpRmizaRon
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Powerful: Up to 450°C Versatile: Heterogeneous and homogeneous capabilities. Fast: Reactions in seconds or minutes. Safe – Software emergency shutoff and hardware pressure release valve
Phoenix Flow Reactor
Standalone Version Module Version Includes HPLC Pump and 200bar Valve Module
Requires HPLC Pump and BP Regulator from existing Thales Reactor (H-Cube, X-Cube, etc)
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Phoenix metal-metal CatCarts (125mm/250mm)
Max T 450°C+
H-Cube Pro CatCarts (30 or 70mm) Max T 250°C
Phoenix Heterogeneous ReacRons
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• Choice of stainless steel, teflon, or Hastelloy
• Different length coils to vary residence time
• Easy to recoil
Phoenix Homogeneous ReacRons
8ml loop w/ SS tubing
8ml loop holder
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SnAr in Flow – Rapid Optimization
Simplex optimalization
pointTemperature
Flow Rate mL/min
Equivalent Yield
1 180 0.5 1 402 200 0.5 2 603 200 1 2 354 220 1 2 505 250 1 2 806 250 1 4 807 250 0.7 2 888 270 0.5 2 999 250 0.5 2 98
Loop: 4 mL, concentration: 0.2M, residence time: 8 min
Simplex optimalization
pointTemperature
Flow Rate mL/min
Equivalent Yield
1 200 1 8 252 250 1 12 403 250 0.7 12 564 280 0.7 12 605 320 0.6 16 806 350 0.5 16 867 350 0.5 19 99
Loop:16 mL,concentration:0.05M, residence time: 32 min
CN
F F
NH
NMP + 6 %MeOH
CN
F N
2 eq.
CN
N N
NH
8-19eq.
NMP
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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
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 ReacRon -‐ Overview
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Merck & Phoenix Flow Reactor
• Optimal temperature at 220C • Des methyl quinoline ester observed
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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
VersaRle Flow Chemistry Plalorm
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IceCube for High Energy Reac6ons
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Halogena6on
Nitra6on Azides
Mul6step reac6ons
Reac6ve Intermediates
Lithia6on
Ozonolysis
Swern Oxida6on
IdenRfied ApplicaRons
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Set-up of the Ice Cube Modular System
Ozone Module: generates O3 from O2 100 mL/min, 14 % O3.
Pump Module – 2 Rotary Piston Pumps. Excellent chemical compatibility. Automation in progress.
Reactor Module: 2 Stage reactor. -70°C-+80°C. Teflon tubing.
A B
C
D -70-+80ºC -30-+80ºC
Potential Apps: Azide, Lithiation, ozonolysis, nitration, swern oxidation Teflon tubing for cheap and easy blockage removal.
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First Reac6on Zone Second Reac6on Zone
Water inlet and outlet
Reactor Plate • Aluminum blocks lined with teflon tubes • Easy to coil for desired pre-‐cooling and desired residence Rme aher mixing • Different mixers types available
A B
D
-‐70-‐+80ºC -‐30-‐+80ºC
C First Reac6on Zone Second Reac6on Zone
Cooling Module
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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.
• Safety problems: § Control of temperature. § Explosive decomposition
R1
R3 R4
R2
R4
R2R1
R3
O O
O
OR
H
OR
OH
R
OH
O3
Ozonide
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Flow Ozonolysis
O3(g)
Alkene Alcohol, Alehyde, Ketone 0ºC -‐0ºC
Quench First Reac6on Zone Second Reac6on Zone
• No ozonide is isolated • Exotherm controlled • Not just for Alkenes
§ Alkynes § Amine § Thiols
Org Let 2011 Vol. 13, No. 5 984–987
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Multistep Flow with Unconventional Quench
Ozonolysis Quenching with H-Cube®
T = -30 ºC CSM = 0.02 M (in EtOAc) O3 excess = 30 %
T = -30 ºC to r.t. p = 1 bar Cat: 10 % Pd/C
Mettler Flow IR™
O-Cube and ReactIR are trademarks of ThalesNano Inc. and Mettler Toledo International Inc., respectively, H-Cube is registered trademark of ThalesNano Inc.
ThalesNano lab based chemistry-unpublished Ozonide eluted into cool vial under N2
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Batch reac6on: Max. -‐60°C to avoid side reacRon In Flow: Even at -‐10°C without side product formaRon
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
* Aher purificaRon
When compared to batch condiRons, IceCube can sRll control reacRons at warmer temperatures due to beser mixing and more efficient heat transfer.
Swern OxidaRon
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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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Diazonium salts and diazo coupling
• Most aromatic diazonium salts are not stable at temperatures above 5°C
• The synthesis reaction to prepare the diazonium salt is typically exothermic, producing between 65 and 150 kJ/mole and is usually run industrially at sub-ambient temperatures
• Diazonium salts decompose exothermically, producing between 160 and 180 kJ/mole
• Many diazonium salts are shock-sensitive
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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 aromaRc 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-‐sensiRve
DioaziRzaRon
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• Reagent: BuLi
• Set-up: 3 pumps, 2 reactors. • Requires N2 atmosphere in the input vial. • It’s not necessary to cool the system down to -78 °C.
LithiaRon
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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?