0
Accessing new chemical   space with flow chemistryHeather Graehl, MS, MBADirector of Sales North America
Agenda•    Company Background•    Intro to Flow Chemistry•    H-Cube Pro Overview•    Reaction Examples•    Gas Module for...
Who	  are	  we?	  •  ThalesNano	  is	  a	  technology	  company	  that	  gives	  chemists   	  tools	  to	  perform	  nove...
Customers (>800 worldwide)              §  20 out of 20 top pharmaceutical              §  Top 3 agrochemical companies ...
Number of Publications on ThalesNano Instruments                                             142 in 7 years          20   ...
What is flowchemistry?
What is flow chemistry?Performing a reaction continuously by pumping fluid through a  coil or fixed bed reactor. Coil/Glas...
Heating Control  Batch                  Larger solvent volume. Lower temperature                  control.                ...
Heating ControlLithium Bromide Exchange                                                       Batch                       ...
Batch vs. Flow    Traditional Batch Method           Flow Method                                       Reactants          ...
Catalyst System - CatCart®                             • Benefits                                  •  Safety              ...
Other Advantages•  Fast Optimization   §  Analytical sample after 5 min to change parameters•  Safety   §  Generate H2 o...
IndustryPerspective
The innovation gap
Closing the Innovation Gap•  Companies are actively looking at new techniques to:    §  Decrease reaction times → Faster ...
Survey	  Conducted	             	         	  Why	  move	  to	  flow?	  Small	  scale:	                            Large	  s...
Survey Conducted  What chemistries are of interest?  Difficult to perform chemistries  •  Low temperature exothermic react...
Catalysis reactor: Modular: H-Cube Pro    Phoenix Module    450°C                                           Automated inje...
H-Cube Pro
H-Cube Pro Overview      •    HPLC pumps continuous stream of solvent      •    Hydrogen generated from water electrolysis...
In Situ H2 ProductionNo more H2 Tanks or costly bomb roomsSafe hydrogenations up to 1450 PSI!!Hydrogen generator cells    ...
H-Cube Pro OverviewHydrogenation                Reactions  Reactions                  without H2 § Nitro Reduction       ...
H-Cube Pro - Higher temperature capability
Lower temperature capability-more selectiveH-Cube                                                                Conversio...
Simple Validation Reactions (out of 5,000)                                             10% Pd/C, RT, 1 bar                ...
Simple Validation Reactions (out of 5,000)                                       10% Pd/C, 60˚C, 1 bar                    ...
H-Cube® Reaction Examples                     Batch: 150°C, 80 bar, 3 days                    Batch: 200°C, 200 bar, 48 ho...
Chemoselective hydrogenations                                Selective reduction in presence of benzyl protected O or N   ...
Hydrogenations in a simplified manner  H-Cube® - Chemoselective hydrogenations                                            ...
Hydrogenations in a simplified manner  H-Cube® - Chemoselective hydrogenations          Nitro group reduction in the      ...
Hydrogenations in a simplified manner   H-Cube® - Dethionation                                                            ...
Deuteration                      Substrate                                      Product                     Deuterium    I...
Sample reactions  Suzuki-Miyaura C-C cross coupling:   NO 2                HO       OH                     B           +  ...
Selective Suzuki coupling (Cl, Cl) Flow	  rate	  (ml/   Pressure	       Temperature	                                      ...
Sample reactions  Heck C-C cross coupling:                            CatCartTM: Pd (PPh3)4, TBAF, 2-propanol, 0.05M,     ...
Sample reactions  In-situ organic azide synthesis: Conversion: complete Purity (crude azide product): 95-100% (TLC) Batch ...
Faster OptimizationMonitor reaction progressafter 5 minutes!Temperature can be changed during the reaction50 reaction cond...
Example for fast optimization                           •    Batch reactions gave results after 4 hours! H. H., Horváth; G...
Hydrogenation of diphenylacetylene, one day optimization, %f(T)                             •     [RuCl2(mTPPMS)2]/Molsele...
Hydrogenation of diphenylacetylene, one day optimization, %f(pressure)                                    [RuCl2(mTPPMS)2]...
University of Graz-Prof. Oliver Kappe                                        Prof. Oliver Kappe,                          ...
Catalysis reactor: Modular: H-Cube Pro     Phoenix Module     450°C                                                Automat...
H-Cube Pro Modules Expanding Chemistry Capability of H-Cube and     H-Cube Pro
Gas Module
Gas	  Module	                      • 	  Versa7le:	  	                               Compressed	  Air,	  O2,	  CO,	  C2H4,	...
Use of Gas Module Attached to the H-Cube Pro™   Gas Module               HPLC pump           H-Cube Pro™          Filter i...
Alcohol oxidation: Optimization                                                               Temp.                       ...
Aromatization of heterocyclesReaction parameters were tested:-  H-Cube Pro with and without GasModule-  Oxidizing agent: H...
Aminocarbonylation      Ø    Conditions: 100oC, 30 bar, CO gas, 0.5 ml/min liquid flow rate, 0.01 M in THF      Ø    Cat...
Phoenix Module
Phoenix Flow Reactor High Temperature Synthesis                               Powerful & New Parameter Space              ...
Catalyst Cartridges (Heterogenous Rxns)Type	                                                         Volume	              ...
Loop-Reactor Options (homogenous rxns)•  Control Residence/Rxn Time by   Length/Volume of Coil.•  Materials and Sizes   §...
Places dedicated for connection of Phoenix                                                     2.                         ...
Back from Heat Exchanger To Heat ExchangerTo Heat ExchangerBack from Heat Exchanger                            Heat exchan...
The quest for novel heterocycles Heterocyclic rings of the future, J. Med. Chem., 2009, 52 (9), pp 2952–2963. • 3000 poten...
Our focus: 2 main cyclization routes • Gould-Jacobs-reaction • Meldrum’s acid variation                                   ...
Gould-Jacobs Cyclization                                                       Condensation                               ...
• Gould-Jacobs-reaction      §  Replacement of diphenyl ether with THF                                                   ...
Pyrolysis of Meldrums Acid                                                           ketene•    Meldrum’s acid is more aci...
Process exploration • Meldrum’s acidic route to pyridopyrimidones and to  hydroxyquinolines                               ...
• Extension to the synthesis of naphthol and phenyl-substituted salicylic acid-derivatives• Formal mechanism:             ...
Thermal cyclisation of amino-flavon  • Solution Phase Flow Thermolysis method                                             ...
Going supercritical:350°C<T>500°C
Transesterification           Conditions:                                                                            85% y...
Esterification in supercritical methanol   - Suppression of side reactions by increasing the pressure and flow rate   - Me...
Thank you for your attention
Upcoming SlideShare
Loading in...5
×

Thales nano reactor overview jan 2013

534

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
534
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
15
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Transcript of "Thales nano reactor overview jan 2013"

  1. 1. Accessing new chemical space with flow chemistryHeather Graehl, MS, MBADirector of Sales North America
  2. 2. Agenda•  Company Background•  Intro to Flow Chemistry•  H-Cube Pro Overview•  Reaction Examples•  Gas Module for H-Cube Pro•  Phoenix Module for H-Cube Pro
  3. 3. Who  are  we?  •  ThalesNano  is  a  technology  company  that  gives  chemists  tools  to  perform  novel,  previously  inaccessible  chemistry  safer,  faster,  and  simpler.  •  Market  leader:  800  customer  install  base  on  6  conDnents.  •  10  years  old-­‐most  established  flow  reactor  company.  •  33  employees  with  own  chemistry  team.  •  Headquarters  in  Budapest  •  R&D  Top  100  Award  Winner.
  4. 4. Customers (>800 worldwide) §  20 out of 20 top pharmaceutical §  Top 3 agrochemical companies §  Petrochemical emerging
  5. 5. Number of Publications on ThalesNano Instruments 142 in 7 years 20 18 16 14 2005 12 10 2006 8 2007 6 4 2008 2 2009 0 2010 2011
  6. 6. What is flowchemistry?
  7. 7. What is flow chemistry?Performing a reaction continuously by pumping fluid through a coil or fixed bed reactor. Coil/Glass Chip Column Homogeneous: Liquid-Liquid Homogeneous: Liquid-Liquid (inert column) Heterogeneous: Liquid-Solid Heterogeneous: Liquid-Solid-Gas
  8. 8. Heating Control Batch Larger solvent volume. Lower temperature control. Outcome: More difficult reaction control. Possibility of exotherm. Flow Lower reaction volume. Closer and uniform temperature control Outcome: Safer chemistry. Lower possibility of exotherm.
  9. 9. Heating ControlLithium Bromide Exchange Batch Flow •  Batch experiment shows temperature increase of 40°C. •  Flow shows little increase in temperature. Ref: Thomas Schwalbe and Gregor Wille, CPC Systems
  10. 10. Batch vs. Flow Traditional Batch Method Flow Method Reactants Gas inlet H-Cube Pro™ Better surface interaction Controlled residence time Elimination of the products By-products By-productsReactants Products Products
  11. 11. Catalyst System - CatCart® • 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 Wilkinsons 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)
  12. 12. Other Advantages•  Fast Optimization §  Analytical sample after 5 min to change parameters•  Safety §  Generate H2 on demand, no tanks §  CatCart system ideal pyrophoric catalysts•  Automation•  Selectivity §  Residence time on catalyst controlled, not possible batch•  Speed §  Better mass transfer, high temp, high pressure §  Optimize for single pass 100% conversion for under 10min reactions
  13. 13. IndustryPerspective
  14. 14. The innovation gap
  15. 15. Closing the Innovation Gap•  Companies are actively looking at new techniques to: §  Decrease reaction times → Faster to market §  Cut down on number steps→Lower cost §  Increase yields→Less purification downstream §  Reduce solvent/waste → Cost savings §  Re-examine industry wide untouchable chemistries→novel molecules→competitive edge•  Flow chemistry is one of these techniques being investigated.
  16. 16. Survey  Conducted      Why  move  to  flow?  Small  scale:   Large  scale:   §  Making  processes  safer   §  Making  processes  safer   §  Accessing  new  chemistry   §  Reproducibility-­‐less  batch §  Speed  in  synthesis  and  to  batch  variaDon    analysis   §  SelecDvity   §  AutomaDon  
  17. 17. Survey Conducted What chemistries are of interest? Difficult to perform chemistries •  Low temperature exothermic reactions •  Reactions with gases •  Very slow reactions or unaccessible chemistry •  Reactions with selectivity issues Approx. 30% of reactions!
  18. 18. Catalysis reactor: Modular: H-Cube Pro Phoenix Module 450°C Automated injection Novel heterocycles & collection. Optimization H-Cube Pro H2 Generation 150°C, 100 bar Hydrogenation Selective C-C coupling H-Cube Midi Gas Module H2 Generation 12 Extra gases 150°C, 100 bar 100 bar Scale Up
  19. 19. H-Cube Pro
  20. 20. H-Cube Pro Overview •  HPLC pumps continuous stream of solvent •  Hydrogen generated from water electrolysis •  Sample heated and passed through catalyst •  Up to 150°C and 100 bar (almost 1500 psi!)
  21. 21. In Situ H2 ProductionNo more H2 Tanks or costly bomb roomsSafe hydrogenations up to 1450 PSI!!Hydrogen generator cells §  Solid Polymer ElectrolyteHigh-pressure regulating valvesWater separator, flow detector, bubble detectorNew on H-Cube Pro: •  Double H2 production •  Full H2 mode at any pressure up to 100bar!
  22. 22. H-Cube Pro OverviewHydrogenation Reactions Reactions without H2 § Nitro Reduction No Modules § Nitrile reduction § Suzuki Reaction § Heterocycle Saturation § Heck Reaction § Double bond saturation § Catalysis § Protecting Group (homogeneous or hydrogenolysis heterogeneous) § Reductive Alkylation § Hydrogenolysis of With Adding Modules dehydropyrimidones § Carbonylation § Imine Reduction § Oxidation § Desulfurization § Diels Alder § Rearrangements § Supercritical fluids
  23. 23. H-Cube Pro - Higher temperature capability
  24. 24. Lower temperature capability-more selectiveH-Cube Conversion T (oC) p (bar) Flow rate (ml/min) B Selectivity (%) (%) 20 1, controlled 1 37 99 20 1, controlled 2 65 93 20 1, controlled 3 87 77H-Cube Pro Product Distribution (%, GC-MS) Pressure Flow Rate (mL/ Solvent Conc. Temp. (°C) (bar) min) A B C EtOH 0.1 M 10 10 1 0 100 0
  25. 25. Simple Validation Reactions (out of 5,000) 10% Pd/C, RT, 1 bar Yield: 86 - 89% Raney Ni, 70°C, 50 bar, 2M NH3 in MeOH, Yield: >85%
  26. 26. Simple Validation Reactions (out of 5,000) 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
  27. 27. H-Cube® Reaction Examples Batch: 150°C, 80 bar, 3 days Batch: 200°C, 200 bar, 48 hours
  28. 28. Chemoselective hydrogenations 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
  29. 29. Hydrogenations in a simplified manner H-Cube® - Chemoselective hydrogenations Selective hydrogenation of the double-bond 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 Selective hydrogenation of the double-bond Conditions: Au/TiO2, 70 bar, 30°C, residence time 17s Results: 100% conversion, 100% yield Selective hydrogenation to afford oximeÜrge, L.et al. submitted for publication
  30. 30. Hydrogenations in a simplified manner H-Cube® - Chemoselective hydrogenations Nitro group reduction in the presence of a halogen Conditions: 10% Pd/C, 70 bar, 0°C, residence time 16s Results: 100% conversion, 100% yield Nitro group reduction in the presence of Cbz-group Conditions: 1% Pt/C, 70 bar, 30°C, residence time 11-17s Results: 100% conversion, 100% yield Nitro group reduction without retro-Henry as a side-reaction Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17s Results: 100% conversion, 100% yieldÜrge, L.et al. submitted for publication
  31. 31. Hydrogenations in a simplified manner H-Cube® - Dethionation Conditions: Raney Ni Full H2 mode T = 40°C v = 1 mL/min c = 0,012M (25 mL, MeCN) Result: Yield: 95%Kappe, O.C. et al. J. Comb. Chem., 2005, 7, 641-43 Conditions: H-Cube® - Formyl group reduction 10% Pd/C p = 40 bar T = 50°C v = 0.5 mL/min c = 10 mg/mL (MeOH) Result: Quantitative reaction (was used in the following reaction step without further purificationPorco, J.A. et al. Angew. Chem. Int. Ed., 2009, 48 (8), 1494-1497
  32. 32. Deuteration Substrate Product Deuterium Isolated content(%) yield / % 99 99 97 98 93 97 96 98 96 99Mándity, I.M.; Martinek, T.A.; Darvas, F.; Fülöp, F.; Tetrahedron Letters; 2009, 50, 4372–4374
  33. 33. Sample reactions Suzuki-Miyaura C-C cross coupling: NO 2 HO OH B + NO 2 CatCartTM 70*4 mm Pd EnCatTM BINAP 30, 2-propanol, TBAF, 80°C, 20 bar, 0.05M, 0.5 ml/min BrConversion: 90-95% (TLC)Purity: 70% (LC-MS) without work-upBatch parameters: K3PO4, TBA-Br, Pd(OAc)2, DMF, 2 hours, 130 °CReference:(Zim, Danilo; Monteiro, Adriano L.; Dupont, Jairton; Tetrahedron Lett.; EN; 41; 43; 2000;8199-8202)
  34. 34. Selective Suzuki coupling (Cl, Cl) Flow  rate  (ml/ Pressure   Temperature   Result   o Catalyst   Base   min)   (bar)   ( C)   LC-­‐MS,  220nm   Fibrecat  1007   Conversion:  82%   0.8   20   100   3  ekv   (70mm)   SelecDvity:  48%   Fibrecat  1007   Conversion:  99%   0.3   20   100   3  ekv   (70mm)   SelecDvity:  48%   Fibrecat  1035   Conversion:  16%   0.8   20   100   2.5  ekv   (30mm)   SelecDvity:  100%   0.8   The  condiDons  were:   1029   20   100   Fibrecat   2.5  ekv   Conversion:  18%   (30mm)   SelecDvity:  100%   0.8   20   1  equivalent  of  2,6-­‐dichloroquinoxaline  with 100   Fibrecat  1048   2.5  ekv   Conversion:  40%   (30mm)   SelecDvity:  100%    1.2  equivalent  of  o-­‐Tolylboronic  acid     10%  Pd/C   Conversion:  89%   0.8   20   100   2.5  ekv   ConcentraDon  set  to  0.02M   (30mm)   Fibrecat  1048   SelecDvity:  14%   Conversion:17%   0.5   20   50   2.5  ekv   Solvent:  Methanol   (30mm)   SelecDvity:  ~100%   Fibrecat  1048   Conversion:  35%   0.5   20   100   2.5  ekv   Base:  NaOH   (30mm)   SelecDvity:  ~100%   Fibrecat  1007   Conversion:  93%   0.2   20   100   2.5  ekv   AnalyDcs:  GC-­‐MS   (70mm)   SelecDvity:  73%   Fibrecat  1007   Conversion:  93%   0.2   20   100   2.5  ekv   (70mm)   SelecDvity:  80%   Fibrecat  1029   Conversion:  12%   0.2   20   100   2.5  ekv   (30mm)   SelecDvity:  100%  
  35. 35. Sample reactions Heck C-C cross coupling: CatCartTM: Pd (PPh3)4, TBAF, 2-propanol, 0.05M, 100oC, 1 bar, 0.2 ml/min.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
  36. 36. Sample reactions In-situ organic azide synthesis: Conversion: complete Purity (crude azide product): 95-100% (TLC) Batch reference: (Saxon, Eliana; Luckansky, Sarah J.; Hang, Howard C.; Yu, Chong; Lee, Sandy C.; Bertoyyi, Carolyn R.; J. Am. Chem. Soc. EN; 124; 5`; 2002; 14893-14902) Parameters: NaN3, DMF, 12 hours, 20 °C; Yield: 91%
  37. 37. Faster OptimizationMonitor reaction progressafter 5 minutes!Temperature can be changed during the reaction50 reaction conditions canbe validated in a day.
  38. 38. Example for fast optimization •  Batch reactions gave results after 4 hours! H. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446
  39. 39. Hydrogenation of diphenylacetylene, one day optimization, %f(T) •  [RuCl2(mTPPMS)2]/Molselect DEAE •  p(H2) = 30 bar, [S] = 0.1 M •  Solvent: toluene/ethanol 1/1 •  24 experiments, total operation time is one dayH. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446
  40. 40. Hydrogenation of diphenylacetylene, one day optimization, %f(pressure) [RuCl2(mTPPMS)2]/Molselect DEAE T = 50 oC, [S] = 0.1 M Solvent: toluene/ethanol 1/1 26 experiments, total operation time is one dayH. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446
  41. 41. University of Graz-Prof. Oliver Kappe Prof. Oliver Kappe, University of Graz, B. Desai, D. Dallinger, C. O. Kappe, Tetrahedron, 2006, 62, 4651-4664.
  42. 42. Catalysis reactor: Modular: H-Cube Pro Phoenix Module 450°C Automated injection Novel heterocycles & collection. Optimization H-Cube Pro H2 Generation 150°C, 100 bar Hydrogenation Selective C-C coupling H-Cube Midi Gas Module H2 Generation 12 Extra gases 150°C, 100 bar 100 bar Scale Up
  43. 43. H-Cube Pro Modules Expanding Chemistry Capability of H-Cube and H-Cube Pro
  44. 44. Gas Module
  45. 45. Gas  Module   •   Versa7le:     Compressed  Air,  O2,  CO,  C2H4,  SynGas,   CH4,  C2H6,  He,  N2,  N2O,  NO,  Ar.   •   Fast:     ReacDons  with  other  gases  complete  in   less  than  10  minutes   •   Powerful:     Up  to  100  bar  capability.   •   Robust:     All  high  quality  stainless  steel  parts.   •   Simple:     3  bubon  stand-­‐alone  control  or  via  simple   touch  screen  control  on  H-­‐Cube  Pro™.  
  46. 46. Use of Gas Module Attached to the H-Cube Pro™ Gas Module HPLC pump H-Cube Pro™ Filter included Check valve included
  47. 47. Alcohol oxidation: Optimization Temp. Pressure (oC) CatCart Conversion Selectivity 40 25 1 % Au/TiO2 0 – 40 65 1 % Au/TiO2 6.5 >85 1 % Au 40 25 /Fe2O3 0 –General conditions: H-Cube Pro with Gas Module, 1 % Au50 mL/min oxygen gas, 1 mL/min liquid flow rate 40 65 /Fe2O3 12.7 0(0.05M in acetone, 20 mL sample volume), 5 % RuCatCart: 70mm., 1 % Au/TiO2 (cartridge: 70mm, 40 25 /Al2O3 2.8 ~100THS 01639), 5 % Ru 40 65 /Al2O3 3.6 ~100 5 % Ru Very fast addition of alcohol to gold surface. 100 65 /Al2O3 2.7 ~100 Alkoxide formation. 5 % Ru 100 100 /Al2O3 8.5 ~100 5 % Ru 100 140 /Al2O3 15.5 ~100 100 65 1 % Au/TiO2 5.6 84 Batch ref.: Oxygen; perruthenate modified 100 100 1 % Au/TiO2 47.2 93 mesoporous silicate MCM-41 in toluene 1 % Au 100 140 /TiO2 ~100 93 T=80°C; 24 h; Bleloch, Andrew; et al. Chemical Communications, 1999 , 8,1907 - 1908 1 % Au 100 65 /Fe2O3 4 0 1 % Au 100 100 /Fe2O3 31 7 100 • Area% of desired product in GC-MS / (100 – Area% of reactant in GC-MS)
  48. 48. Aromatization of heterocyclesReaction 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   Temperature   Pressure   agent   Solvent   Catalyst   (oC)   (bar)   Conversion   Comment   MnO2   Acetone   MnO2   60   20   82%   Blockage  afer  10  minutes   Acetone  -­‐  H2O2   68%  afer  1  run   H2O2   (4-­‐1)   Au/TiO2   70   20   78%  afer  2  run   Acetone  -­‐  H2O2   68%  afer  1  run   The  catalyst  was  reacDvated   H2O2   (4-­‐1)   Au/TiO2   100   30   98%  afer  2  run   with  H2O2  between  the  runs.   O2  (10  ml/min)   Acetone   Au/TiO2   75   11   8%   Afer  10  minutes  the   conversion  was  dropped  to   O2  (10  ml/min)   Acetone   Au/TiO2   150   11   95%   50%   O2  (50  ml/min)   Acetone   Au/TiO2   150   20   >  98%  
  49. 49. Aminocarbonylation 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 Results HC-­‐Pro  with  gas  module  (CO  flow  rate)   ReacDon   10 ml/ 30  ml/ 30  ml/ 30  ml/ 60  ml/ 60  ml/ 60  ml/ 60  ml/ min min   min   min   min   min   min   min   Conversion   %   60   65   62   66   79   79   79   82   Reproducible Conversion for Each Flow Rate
  50. 50. Phoenix Module
  51. 51. Phoenix Flow Reactor High Temperature Synthesis Powerful & New Parameter Space Up to 450°C, 100 bar Versatile: Cartridges for Heterogeneous and loops homogeneous capabilities. Fast: Reactions in seconds or minutes. Chemical Resistance: Stainless steel, Hastelloy, and teflon options Innovative: Validated procedure to generate novel bicyclic compounds Scale Up: Different size CatCarts, MidiCart, Loops Simple: 3 button stand-alone control or via simple touch screen control on H-Cube Pro™.
  52. 52. Catalyst Cartridges (Heterogenous Rxns)Type   Volume   Max.  T/p  (100  bar   Comment   unDl  it  is  indicated   otherwise)   H-­‐Cube  Pro  Type  CatCarts  30  mm   0.38  mL   250°C   Packed  by   ThalesNano  70  mm     0.76  mL   250°C   Packed  by   ThalesNano   Metal-­‐Metal  Sealing  High  T  CatCarts    125  mm  (1/4  SS  id  3  mm)   0.9  mL   450  °C   User  can  fill  125  mm  (1/4  SS  id  3.8  mm)   1.3  mL   450  °C   User  can  fill  125  mm  (1/2  SS  id  9.4mm)   9  mL   450  °C   User  can  fill,  filters   are  needed  250  mm  (1/4  SS  id  3mm)   1.8  mL   450  °C   User  can  fill,  filters   are  needed  250  mm  (1/4  SS  id  3.8  mm)   2.6  mL   450  °C    User  can  fill,  filters   are  needed  250  mm  (1/2  SS  id  9.4mm)   18  mL   450  °C   User  can  fill,  filters   are  needed   H-­‐Cube  Midi  Type  MidiCarts  MidiCart   7.6  mL   150  °C   Packed  by   ThalesNano  
  53. 53. Loop-Reactor Options (homogenous rxns)•  Control Residence/Rxn Time by Length/Volume of Coil.•  Materials and Sizes §  Stainless steel (1 – 16 mL) – up to 450oC and 100bar •  Coil (1/16” 4-16 ml) •  Short coil (1/16” 1-4ml) •  Static mixer (3/8”, 32ml) •  Acidity limit §  Hastelloy (4 – 16 ml) – up to 450oC and 100bar •  Less sensitive to acid though more expensive than stainless steel §  PTFE coil (4 – 16 ml) – up to 150oC or 20bar•  Easy to recoil•  Versatile
  54. 54. Places dedicated for connection of Phoenix 2. 1. 1.) reaction in the Phoenix Flow Reactor, followed by a reaction in the H-Cube Pro 2.) reaction in the H-Cube Pro, followed by a reaction in the Phoenix Flow Reactor i.) if inert CatCart is placed into the H-Cube Pro: reaction in the Phoenix Flow Reactor only ii.) engineering: forget about the H-Cube Pro CatCart place
  55. 55. Back from Heat Exchanger To Heat ExchangerTo Heat ExchangerBack from Heat Exchanger Heat exchanger and release valve (140 bar)
  56. 56. The quest for novel heterocycles 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
  57. 57. Our focus: 2 main cyclization routes • Gould-Jacobs-reaction • Meldrum’s acid variation 57 Curran, T.T. in Named reactions in Heterocyclic Chemistry; Li, J.-J., Corey, E. J. Eds. Wiley Interscience: New York, 2005, pp423-436
  58. 58. Gould-Jacobs Cyclization Condensation Cyclization methylenemalonic ester Saponification Decarboxylation•  Standard benzannulation reaction Disadvantages:•  Good source of: • Harsh conditions •  Quinolines • High b.p. solvents •  Pyridopyrimidones • Selectivity •  Naphthyridines • Solubility•  Important structural drug motifs W. A. Jacobs, J. Am. Chem. Soc.; 1939; 61(10); 2890-2895
  59. 59. • Gould-Jacobs-reaction §  Replacement of diphenyl ether with THF 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 Batch conditions: 2 hours No THF polymerization! 59Lengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., (accepted for publishing)
  60. 60. Pyrolysis of Meldrums Acid ketene•  Meldrum’s acid is more acidic than malonic ester=easier synthesis of adduct•  Decomposition needs no purification•  Lower temperature reactions
  61. 61. Process exploration • 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 minThe 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. 61Lengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., (accepted for publishing)
  62. 62. • Extension to the synthesis of naphthol and phenyl-substituted salicylic acid-derivatives• Formal mechanism: 62Lengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., (accepted)
  63. 63. Thermal cyclisation of amino-flavon • Solution Phase Flow Thermolysis method 50% Yield 95% NMR purity In collaboration with the Patonay Group from Debrecen University 63
  64. 64. Going supercritical:350°C<T>500°C
  65. 65. Transesterification Conditions: 85% yield p = 180 bar T = 350°C Remark: little or no reaction below 200°C v = 0.5 mL/min c = 0.05 M (MeOH) Under supercritical conditions Esterification Conditions: MeOH and EtOH p = 120 bar 87% yield act as an acidic T = 300°C catalyst Remark: 3 passes v = 1.0 mL/min little or no reaction below 200°C c = 0.33 M (EtOH)Razzaq, T.;, Glasnov, T.N.; Kappe, O. C., Continuous-Flow Microreactor Chemistry under High-Temperature/Pressure Conditions,Eur. J. Org. Chem., 2009, 9, 1321-1325
  66. 66. Esterification in supercritical methanol - Suppression of side reactions by increasing the pressure and flow rate - MeOH: Tcr = 239.4°C, pcr = 80.8 bar - Concentration: 0.05M Temp.  (°C)   Pressure  (bar)   Residence  7me  (sec)   Calc.  yield  (%)*   300   150   30   15   425   117   18   9   450   118   7,2   38   450   118   12   25   450   109   12   27   460   140   9   55   460   144   9   54   Rapid optimization 460   135   9   59   436   137   9   74   460   137   9   76   481   137   9   76   496   137   6,9   76   483   137   5   80   - Isolated yield 60%, NMR 98% 483   137   3,3   80   475   137   2,6   74   475   137   2,9   79  * By calibration curve, loop size 1.5 mL
  67. 67. Thank you for your attention
  1. A particular slide catching your eye?

    Clipping is a handy way to collect important slides you want to go back to later.

×