The advantages of applying flow synthesis towards hydrogenation from laboratory to process scale Richard Jones Product Manager Increased Mixing Efficiency • Batch heating is limited by non uniform heating and mixing. • Flow reactors can achieve homogeneous mixing and uniform heating in microseconds Increased Rates of Reaction, Yields and Selectivities Rapid heat transfer and mixing speeds up reactions O OSiMe3 + O OH TBAF H Br Br Time needed to Reach 100% Conversion Flow: 20 minutes Batch 24 hours Wiles, C.; Watts, P.; Haswell, S. J.; Pombo-Villar, E. Lab Chip 2001,1, 100. Precise temperature control can lead to selective chemistries O O HO MgCl + A B Optimized Conditions: 78% Yield Regioisomer Ratio: 95:5 A:B Taghavi-Moghadam, S.; Kleemann, A.; Golbig, K. G. Org. Process Res. DeV. 2001, 5, 652. Accessiblity of Exothermic and Runaway Reactions Flow reactors typically have high heat transfer properties OH OH OH NO2 HNO3 + NO2 • Yield of mononitrate mixture increased from 55% to 75% • Purity increased from 56% to 78% • Polymeric byproducts reduced by a factor of 5 • Exotherms eliminated Ducry, L.; Roberge, D. M. Angew. Chem., Int. Ed. 2005, 44, 7972. Improved Safety Small volumes undergo reaction at any one time. Highly exothermic or toxic reagents may be used safely O 10% F2 in N2 O OEt O O Formic acid, 5°C OEt F 99% Conversion, 73% Yield Jahnisch, K.; Baerns, M.; Hessel, V.; Ehrfeld, W.; Haverkamp, V.; Lowe, H.; Wille, C.; Guber, A. J. Fluor. Chem. 2000, 105, 117. Increased Efficiency Flow reactors can also run reactions at higher concentrations due to higher heat transfer Less solvent and less byproducts from a reaction creates significantly less waste Solvent-Free Paal-Knorr Reaction O + H2N O OH 65°C N OH Taghavi-Moghadam, S.; Kleemann, A.; Golbig, K. G. Org. Process Res. Dev. 2001, 5, 652. Other advantages • • • • • Fast Optimization On-line reaction monitoring Automation Smoother transition to scale-up Potential for multi-step flow synthesis Why improve hydrogenation? Accounts for 10-15% of reactions in the chemical industry Current batch reactor technology has many disadvantages: Time consuming and difficult to set up Expensive – separate laboratory needed! Catalyst addition and filtration is hazardous Analytical sample obtained through invasive means. Mixing of 3 phases inefficient - poor reaction rates H-Cube™ Overview O2N H2N N H • HPLC pump flows a continuous stream of solvent into reactor • Hydrogen generated from water inside of the instrument • 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. N H H-Cube Reaction Line Pressure Detector CatCart Holder Bubble Detector H2/Substrate Mixer Back -pressure valve CatCart Heater Catalyst System-CatCart™ •Catalyst contained in sealed disposable cartridges •No filtration necessary •Enhanced phase mixing 30 mm Filter Smallest catalysts can reduce 10mg-5g of substrate Largest CatCarts up to 100g •Over 50 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 H-Cube vs. Batch Comparison O2N 10% Pd/C H2N Methanol, RT, 1 bar N H N H Product Conversion (%) Batch vs Flow 100 80 60 batch 40 flow 20 0 0 3 6 9 time 12 15 Conventional Batch and Continuous Flow Mode Starting material Gap Gas introduction Side-product Starting material Product Product Debenzylation before catalyst poisoning 1 R N S N 2 R i. H-Cube, 10% Pd/C CatCart30 low dilution, conditions. 1 N R S HN 2 R • Requires high catalyst:substrate loading for efficient conversion in the presence of the thiazole • Very difficult transformation as a batch process. •Performed by Mark Ladlow and his team at GSK lab in the University of Cambridge How long can a CatCartTM be reused? H-Cube™ conditions: 0.1M, [50:50] EtOAc:EtOH, ~1 bar, 30 oC, 1 mL/min; Total material processed = 30x 1mmole fractions = 30 mmoles = 4.85 g with 140 mg Pd/C Product PRODUCT STARTING MATERIAL Starting Material Simple Validation Reactions (out of 5,000) O O 10% Pd/C, RT, 1 bar Yield: 86 - 89% Batch reference: Reagent: water, catalyst: Pd on active carbon, 250 °C, 40-50 bar, yield: 64% Matsubara, Seijiro; Yokota, Yotaka; Oshima, Koichiro; Org. Lett.; EN; 6; 12; 2004; 2071-2074 N MeO NH2 MeO Raney Ni, 70°C, 50 bar 2M NH3 in MeOH Yield: >85% No batch reference Simple Validation Reactions (out of 5,000) 10% Pd/C, 60˚C, 1 bar Yield: >90% O H N NH2 O N H N H 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% N OH NH2 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 Validation Reactions (out of 5,000) O N OH N 10% Pt/C, RT, 70 bar, 0,05M, ethanol, LC-MS result: 95% without purification, full conversion Batch reference: Reagent: NaBH4, Solvent: MeOH, reaction time: 10 min, 0° C Yield: 83 % Pitts, Michael R.; Harrison, Justin R.; Moody, Christopher J.; JCSPCE; J. Chem. Soc. Perkin Trans. 1; EN; 9; 2001; 955-977 D D D D D-source is D2O Conditions: Toluene, 30°C, 1 bar (full H2 mode), 10% Pt/C Purity after evaporation: 98% (NMR) Yield: 90% Batch reference deuteration of trans-propenyl-benzene: Reagent: D2, Catalyst: Wilkinson catalyst, Solvent: Benzene Yield: 20 % Heesing, Albert; Leue, Hans-joachim; CHBEAM; Chem. Ber.; GE; 119; 4; 1986; 1232-1243 H-CubeTM Complex Reactions Examples Example: a dangerous reaction in batch reactor N3 O 10% Pd/C BOC2O, EtOAc O CO2Et BocHN O O CO2Et 1.0 ml/min, 0.1M 50oC, 1 atm „2-step-1 flow” reaction Highly exothermic in batch reactor(inhouse experience) In H-CubeTM: - Small quantities reacted at any one time – safer! - Effective temperature control - Good yield (< 40% in batch) (76%, 1.1g) Chemoselective hydrogenations O O OH O O 5% Pt/C, 75°C, 70 bar, 0,01M, ethanol,no byproduct Yield: 75% O 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 O O OH O 2-Hydroxy-[1,4]naphthoquinone OH route A O route B Route A: Raney Ni, abs. EtOH, 0,01 M, 70 bar, 25°C. Yield: 80% O Route B: Raney Ni, abs. EtOH, 0,01 M, 70 bar, 100°C. Yield: 85% O No batch reference Faster Optimization Monitor reaction progress after 4 minutes! Temperature can be changed during the reaction 50 reaction conditions can be validated in a day. Product Collection Example for fast optimization cis-stilbene H2 / cat. + H2 / cat. 1,2-diphenylethane diphenyl-acetylene trans-stilbene • Batch reactions gave results after 4 hours! H. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446 Hydrogenation of diphenylacetylene, one day optimization, %f(T) [RuCl2(mTPPMS)2]/Molselect DEAE • 80 diphenylethane cis-stilbene trans-stilbene conversion 60 % 40 20 0 30 40 50 60 70 80 0 T ( C) • • • p(H2) = 30 bar, [S] = 0.1 M Solvent: toluene/ethanol 1/1 24 experiments, total operation time is one day H. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446 University of Cambridge-Prof. Steven Ley N R1 H2O Entry R3 R R1 R2 electrolysis (%) R3 R2 Catalyst H2 (g) Yield Purity Imine HN (%) Entry Imine OH 1 MeO N MeO Yield Purity (%) (%) 96 85 92 >95 quant. 90 quant. 90 OH quant. >95 5 93 >95 6 N OH 2 N N OH N 3 N quant. 95 7 quant. 84 8 N OH 4 N NC O O H O N N S. Saaby, K.R. Knudsen, M. Ladlow and S.V. Ley, J. Chem. Soc., Chem. Commun., 2005, 2909. Flow Synthesis of Oxomaritidine catch, react, release NMe3N3 HO HO (1) Br MeCN:THF (1:1), 70 oC N3 HO Ph(nBu)2P (2) rt to 55 oC N MeO OH NMe3RuO4 OMe O MeO MeO OMe OMe electrolysis O F3C HO 10% Pd/C, THF O O H2 (g) H2O Flow hydrogenation CF3 HO 80 oC N O MeO N H CF3 OMe MeO OMe O rt MeOH / H2O (4:1) PhI(O2CX3)2 O NMe3OH MeO MeO H MeO N CF3 O 35 oC MeO N (±)-oxomaritidine I.R. Baxendale, J. Deeley, C.M. Griffith-Jones, S.V. Ley, S. Saaby, G. Tranmer, J. Chem. Soc., Chem. Commun., 2006, 2566. Production of a primary amine library with no protection/deprotection O2N O H2N O R N H Conditions: 10% Pd/C Methanol, 1 bar (Full H2 mode), 30 ºC Injection time: 6 min/25 mg R N H Result: 50 compounds/ 5 hours LC-MS purity above 90%, without purification in most cases Model Library O O Pd/C O O Full H2 H H 60°C EtOAc/EtOH N N NH2 NO2 5-10 mg/mL R = Cl, dehalogenation R R O O Ra-Ni O O Full H2 6 examples 95% - Quant. H H N 30°C R1 = H, R2 = Cl N NH 2 NO 2 Quantitative R1 = Cl, R2 = H 5-10 mg/mL EtOAc/EtOH R1 R1 R2 R2 Sauer, D. R., Recent advances in high-throughput organic synthesis for drug discovery, Application of Modern Tools in Organic Synthesis, Edinburgh University Summer Program Edinburgh, July 2426, 2007 Abbott automated debenzylation CatCart Changer™ with H-Cube™ • Line can be directed between 6 catalysts • Individually changeable temperature • Software control • No stop between changes • Rapid optimization The H-Cube Midi Hydrogenation Scale up Reactor Flow Scale up Advantages Problems associated with Batch Scale up Time consuming-new optimzation Handling of hazardous reagents and/or solvents Catalyst handling is problematic Temperature control Reaction with materials of batch reactors Gas production Reproduction H-Cube Midi Flow Scale up Low amount of optimzation Reproducibility-no unexpected side reactions High level of temperature control Hazardous chemicals reacted in small amounts continuously Gas production not a problem-system not sealed Parameters, such as Time, vs Cost, can be selected flexibly based on the project need and status 30 25 20 t /min 15 Flow Batch 10 5 0 Aldoxim reduction Aldehyde reduction H-Cube Midi™ Touch Screen Panel Heating Unit With MidiCart™ Exchangable for different CC Outlet Bubble Detector Inlet Bubble Detector System Pressure Sensor Mixer Unit Inlet Pressure Sensor System Pressure Valve Pump Outlet Valve Switch Inlet Valve Switch Heat Exchanger Preheating Unit Scale-up of cartridge CatCart® for the H-Cube® 30 × 4 mm MidiCart™ for the H-Cube Midi™ 90 × 9,5 mm 90 x 14 mm 90 x 22 mm Difference between a normal hydrogenation reactor and the H-Cube Midi™ Normal Hydrogenation Reactor H-Cube Midi™ Scale-up from mg to Kg in one day Old method in batch 6-8 weeks One day H-Cube® H-Cube Midi™ Optimization Procedure • • • • Optimize reaction on small scale on H-Cube Take temperature and pressure and apply it to Midi Start with 0.15M and 10mL/min flow rate Take first sample and then increase flow rate during reactions. • Go back to original flow rate and increase temperature and/or pressure by 20ºC or 20 bar and increase flow rates. • All parameters can be increased on the fly! • Reactions may be optimized in less than 1 hour! Effect of the flow rate and the concentration I. O O OCH3 OCH3 H2 NH 2 NO 2 Parameters: 120 5% Pd/C P = 70 bars T = 70°C c = 0,2-0,1 M Flow rate = 20-2,5 mL/min Conversion (%) MeOH 100 0,2M 80 0,17M 60 0,15M 0,12M 40 0,1M 20 0 0 5 10 15 Flow rate (mL/min) 20 25 Effect of the flow rate and the concentration II. O Parameters: MeOH P = 50 bars T = 100°C c = 0,2 – 0,4 M 100% Conversion (%) 10% Pd/C (2,45 g) 120% 80% 60% 40% 20% 0% 0 5 10 15 20 25 Flow rate (mL/min) Flow rate: 2,5-20 mL/min 0,4M 0,35M 0,3M 0,25M 0,2M Industrial Experience Example 1 N NH2 Conditions Catalyst Temperature Pressure Flow-Rate Concentration Conversion Production Rate H-Cube 20% Pd(OH)2/C 60ºC 50 bar 1mL/min 0.05M 100% 300mg/hour H-Cube Midi 20% Pd(OH)2/C 60ºC 50 bar 12mL/min 0.15M 100% 10g/hour Industrial Experience Example 2 O Conditions Catalyst Temperature Pressure Flow-Rate Concentration Conversion Production Rate H OH H-Cube Raney Ni 60ºC 50 bar 1mL/min 0.05M 100% 300mg/hour H-Cube Midi Raney Ni 60ºC 50 bar 12mL/min 0.15M 100% 10g/hour Industrial Hydrogenation Example 3 HO N R Conditions Catalyst Temperature Pressure Flow-Rate Concentration Conversion Production Rate H N HN R H-Cube Raney Ni 60ºC 50 bar 1mL/min 0.05M 100% 500mg/hour H N H-Cube Midi Raney Ni 60ºC 50 bar 7mL/min 0.15M 100% 10g/hour Conclusion Starting Material Product O Reaction Conditions OH O OH O O OH OH H2 N O2 N OH OH O Calc. Amount for 8 hours Yield Flow-rate: 10 mL/min Temperature: 40°C Pressure: 70 bar Solvent: methanol Catalyst: 10% Pd/C (2,9 g) Concentration: 0.35 M 71 g in 3 hours 190g 72% Flow-rate: 25 mL/min Temperature: 40°C Pressure: 70 bar Solvent: methanol Catalyst:10% Pd/C (10,84 g) Concentration: 0.35 M 74,2 g in 80 min 445,2 74% Flow-rate: 30 mL/min Temperature: 30°C Pressure: 30 bar Solvent: methanol Catalyst: 10% Pd/C (2,81 g) Concentration: 0.05 M 46,2 g in 3 hours 123g 90% Flow-rate: 10 mL/min Temperature: 90°C Pressure: 10 bar Solvent: ethanol Catalyst: Raney Cu (17,4 g) Concentration: 0.2 M 92 g in 6 hours 122.66 82% Flow-rate: 10 mL/min Temperature: 60°C Pressure: 50 bar Solvent: ethanol Catalyst: 10% Pd/C (3,1 g) Concentration: 0.05 M 13.9 g in 1.5 hours 74g 95% NH 2 HN O Ph N H Amount Processed/Time N H X-Cube Flash for High T Reactions Tmax. = 350°C pmax. = 200 bars • Extends the boundaries of lab synthesis • Match microwave reaction rates • Offers viable alternative for microwave scale up Diels-Alder reaction in batch and MW conditions Activation Extended heating Microwave Medium T / °C t/h Yield / % Toluene 250 24 60 No solvent No solvent No solvent 150 150 150 3 24 3 19 44 (40) 64 (62) Products 1-a:1-b = 65:35 1-a 1-a 1-a Using Flash reactor: 350°C, 1 mL/min, 8 min residence time, 80 bar 98% conversion, 100% selectivity: 1-a Loupy, A. et al, Tetrahedron, 2004, 60, 1683-1691 Alkylation of triazole with trichloroacetophenone in batch and MW conditions Activation Microwave Conventional heating Microwave Conventional heating Microwave Conventional heating Microwave Conventional heating Medium Pentanol DMF o-xylene No solvent Conversion / % 90 N1/N4/N1,4 95 / 5 / 0 90 95 / 5 / 0 90 95 / 5 / 0 90 95 / 5 / 0 82 100 / 0 / 0 95 32 / 28 / 40 92 100 / 0 / 0 100 36 / 27 / 27 Loupy, A.; Perreux, L.; Liagre, M.; Burle, K.; Moneuse, M. Pure Appl. Chem. 2001, 73, 161. Alkylation of triazole with trichloroacetophenone in Flash reactor T (°C) Conversion % Selectivity % (N1,4) Selectivity % (N1) Selectivity % (N4) 140 2 0 100 0 170 20 30 70 0 200 25 25 75 0 210 31 23 78 0 220 35 20 80 0 230 35 0 100 0 240 37 0 100 0 250 40 0 100 0 260 75 0 100 0 270 92 0 100 0 Reaction optimization using Flash reactor: T= 140 – 350 °C P= 80 bar v= 0,5 mL/min – residence time: 16 min c= 0,1 M (acetonitril) 100 90 100 0 94 5 290 100 0 81 12 300 100 0 62 38 310 100 0 43 44 320 100 0 40 49 330 100 0 30 56 340 100 0 21 77 350 100 0 15 80 70 Selectivty 280 80 60 50 N1,4 40 N4 30 N1 20 10 350 330 N1,4 340 320 300 290 270 310 Temperature 280 250 260 240 220 230 200 210 140 170 0 Serial link of flow reactors •Flow reactors may be linked sequentially •H-Cube and X-Cube may be linked for multistep synthesis Chemistry using coupled reactors Step 2a: Reduction of azide group in H-Cube : N3 Step 1: Organic Azide formation in X-Cube : Br Azide CatCartTM •0.4mL/min, 100°C, 20 bar, 0.1M •Immobilized azide in CatCartTM •Quantitative conversion NH2 •1.0 mL/min, RT, 70 bar, 0.05M, 10% Pt/C •Quantitative conversion N3 Step 2b: Triazole synthesis in X-Cube: N3 O + O N N N •0.2 mL/min, 200°C, 40 bar, 0.1M, K2CO3 •Yield: 82% (from crude azide) O O-CubeTM Overview O-Cube can eliminate almost all disadvantages of current ozonolysis: • Ozonolysis difficult to carry out • Ozonide is unstable and explosive! • The ozone source is water • Continuous-flow method with effective reaction heat dissipation . • Reactions performed on room temperature • Reactions may be performed under pressure • Reaction parameters-pressure, temperature, • concentration, flow rate etc. are easy to control. O-CubeTM Room Temperature Reactions Examples Cl O-CubeTM OH OH Cl O DCM, RT, Atm. N H collected in 40% NaBH4 MeOH + Cl NH2 N H Conversion 80% 0,05 M, 1,0 ml/min No batch reference OH OH O-CubeTM + DCM, RT, Atm. N H collected in 40% NaBH4 MeOH N H O NH2 Conversion 100% 0,05 M, 1,0 ml/min No batch reference O O-CubeTM HO DCM, RT, Atm. HO collected in 40% NaBH4 MeOH N N O 0,05 M, 1,0 ml/min Batch reference: 0°C, DCM, 10% NaOH, O3, H2O2, 4 h Yield: 40% Conversion: 85 % Thank you to the ThalesNano Chemistry team in Budapest, Hungary for their hard work and results! Thank you for your attention! Any questions?