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Accelerating Your
Synthesis with
Flow Chemistry
Heather Graehl, MS, MBA
Director of Sales North America
ThalesNano North A...
Who	
  are	
  we?	
  

•  ThalesNano	
  is	
  a	
  technology	
  company	
  that	
  gives	
  chemists
	
  tools	
  to	
  p...
Customers	
  

• Flow	
  Chemistry	
  Market	
  Leader	
  
• Over	
  800	
  customers	
  worldwide	
  
What is flow
chemistry?
What	
  is	
  flow	
  chemistry?	
  

Performing	
  a	
  reacQon	
  conQnuously,	
  typically	
  on	
  small	
  scale,	
  
...
KineQcs	
  in	
  Flow	
  Reactors	
  
•  In	
  a	
  microfluidic	
  device	
  with	
  a	
  constant	
  flow	
  rate,	
  the
...
Improved	
  Mixing	
  Compared	
  to	
  Batch	
  

Flow	
  reactors	
  can	
  achieve	
  homogeneous	
  mixing	
  and	
  u...
Improved	
  Mixing	
  =	
  Faster	
  Rxn	
  Time	
  
Improved	
  mixing	
  can	
  lead	
  to	
  
improved	
  reac6on	
  6m...
Enhanced	
  Temperature	
  Control	
  
•  Microreactors	
  have	
  higher	
  surface-­‐to-­‐volume	
  raQo	
  than	
  macr...
Enhanced	
  Temperature	
  Control	
  
Batch
Larger solvent volume. Lower temperature
control.
Outcome:
More difficult rea...
Enhanced	
  Temperature	
  Control	
  
Batch	
  Heated	
  Rxns	
  
•  Safety	
  concerns,	
  especially	
  in	
  scale
	
 ...
Enhanced	
  Temperature	
  Control	
  
Exothermic Chemistry – LiBr Exchange

•  Batch experiment shows temperature increas...
SelecQvity	
  –	
  Residence	
  Time	
  Control	
  
Traditional Batch Method

Flow Method
Reactants

Gas inlet

H-Cube Pro...
SelecQve	
  AromaQc	
  Nitro	
  ReducQon	
  
Catalyst screening
Parameter scanning: effect of residence time to the
conver...
Survey	
  Conducted	
  

	
  

	
  Why	
  move	
  to	
  flow?	
  

Small	
  scale:	
  
§  Making	
  processes	
  safer	
  ...
Reactor	
  Pladorms	
  
H-Cube Pro & Gas Module:
Reagent gases

Phoenix Flow Reactor:
Endothermic chemistry

150°C, 100 ba...
H-Cube Catalysis Platform:
Making hydrogenations
safe, fast, and selective
H-­‐Cube	
  –	
  How	
  it	
  Works	
  

• 
• 
• 
• 

HPLC pumps continuous stream of solvent
Hydrogen generated from wate...
Water	
  Electrolysis	
  
Hydrogen generator cell
§  Solid Polymer Electrolyte

High-pressure regulating
valves

Water se...
Catalyst	
  System	
  -­‐	
  CatCarts	
  
• Benefits
•  Safety
•  No filtration necessary
•  Enhanced phase mixing
• Over ...
Simple	
  ValidaQon	
  ReacQons	
  (out	
  of	
  5,000)	
  

10% Pd/C, RT, 1 bar
Yield: 86 - 89%
Alternate reductions
Keto...
Simple	
  ValidaQon	
  ReacQons	
  (out	
  of	
  5,000)	
  

10% Pd/C, 60˚C, 1 bar
Yield: >90%
Batch reaction of {3-[(2-ca...
Difficult	
  Hydrogenatons	
  

Batch: 150°C, 80 bar, 3 days

Batch: 200°C, 200 bar, 48 hours
SelecQve	
  HydrogenaQons	
  
Selective reduction in presence of benzyl protected O or N
5% Pt/C, 75°C, 70 bar, 0,01M,
eth...
SelecQve	
  HydrogenaQons	
  
H-Cube® - Chemoselective hydrogenations

Selective hydrogenation of
the double-bond

Conditi...
SelecQve	
  HydrogenaQons	
  
H-Cube® - Chemoselective hydrogenations
Nitro group reduction in the
presence of a halogen

...
SelecQve	
  DehydrochlorinaQon	
  

Flow Pressure (bar) Temperatur Bubdet
o
rate
e ( C)
(mL/
min)
1
20 (∆p:5 bar)
110
50
1...
ParQal	
  SaturaQon	
  of	
  Heterocycles	
  

Optimised reaction parameters:
-  H-Cube Pro
-  Temperature: 100oC
-  Press...
Asymmetric	
  HydrogenaQon	
  

Chiral Phosphine-phosphoramidite ligands
packed in CatCart
DeuteraQon	
  
Substrate

Product

Isolated
yield / %

99

99

97

98

93

97

96

98

96

Mándity, I.M.; Martinek, T.A.; ...
H-­‐Cube	
  Family	
  
Which H-Cube is best for me?

• Original 2005 R&D100 award winner
• 20mg-10g/day
• Ambient to 100°C...
New	
  Sonware	
  with	
  H-­‐Cube	
  Pro	
  
• Touch Screen Interface
• Now can control hydrogen variability (0-60ml/min)...
H-­‐Cube	
  Pro	
  =	
  Higher	
  Throughput	
  

2 cells for higher hydrogen production: 60 mL/min

100% conversion

Comp...
H-­‐Cube	
  Pro	
  =	
  Higher	
  Temp	
  Capability	
  
H-­‐Cube	
  Pro	
  =	
  Lower	
  Temp	
  SelecQvity	
  

H-Cube
T (oC)

p (bar)

Flow rate (ml/min)

Conversion
(%)

B Sel...
H-­‐Cube	
  Midi	
  –	
  Reactor	
  for	
  Scale	
  Up	
  
Parameters:
-  p= 1-100 bar
-  T=10-150°C
Milligram
-  v=0.1-3 ...
H-­‐Cube	
  Autosampler	
  

Gilson 271 Liquid Handler
§ 
§ 
§ 
§ 
§ 
§ 

402 single Syringe pump (10 mL)
Direct GX ...
Expanding H-Cube
Beyond Hydrogenation
Coupling	
  ReacQons	
  
Heck C-C cross coupling:

CatCartTM: Pd (PPh3)4, TBAF, 2-propanol, 0.05M,
100oC, 1 bar, 0.2 ml/mi...
Coupling	
  ReacQons	
  
Suzuki-Miyaura C-C cross coupling:

NO 2

HO

B

OH

+
Br

NO 2
CatCartTM 70*4 mm Pd EnCatTM BINA...
SelecQve	
  Coupling	
  ReacQon	
  

The	
  condiQons	
  were:	
  

1	
  equivalent	
  of	
  2,6-­‐dichloroquinoxaline	
  ...
SelecQve	
  Coupling	
  ReacQon	
  
1	
  equivalent	
  of	
  2,6
-­‐dichloroquinoxaline
	
  with	
  1.2	
  equivalent	
  o...
Other	
  Reagent	
  Gases	
  
• 	
  Versa6le:	
  	
  
Compressed	
  Air,	
  O2,	
  CO,	
  C2H4,	
  SynGas,	
  
CH4,	
  C2H...
ApplicaQon	
  1:	
  CarbonylaQon	
  

Ø 
Ø 
Ø 
Ø 

Conditions: 100oC, 30 bar, CO gas, 0.5 ml/min liquid flow rate, 0.0...
ApplicaQon	
  2:	
  Green	
  OxidaQon	
  
Green	
  OxidaQon	
  OpQmizaQon	
  
Pressure

Selectivity

25

1 % Au/TiO2

0

–

65

1 % Au/TiO2

6.5

>85

40

25

1 % A...
AromiQzaQon	
  of	
  Heterocycles	
  

Reaction parameters were tested:
-  H-Cube Pro with and without GasModule
-  Oxidiz...
Ozonolysis	
  and	
  
Other	
  High	
  Energy	
  
Reac6ons	
  
What is ozonolysis?
•  Ozonolysis is a technique that cleaves double and
triple C-C bonds to form a C-O bond.

•  Currentl...
Workup Determines Product

Carboxylic Acid
(oxidative work-up)

Aldehyde/Ketone
(simple quenching)

Alcohol
(reductive wor...
Ozonolysis in Industry
Synthesis of Indolizidine 215F

Other major drug syntheses featuring ozonolysis includes:
(+)-Artem...
Why	
  ozonolysis	
  is	
  neglected?	
  
•  Highly	
  exothermic	
  reacQon,	
  high	
  risk	
  of	
  explosion	
  	
  
•...
Why	
  Ozonolysis	
  in	
  Flow?	
  
• 
• 
• 
• 
• 
• 
• 
• 

Highly effective oxidation
In line quenching of ozonide – SA...
Flow	
  Ozonolysis	
  of	
  Styrenes	
  

M.	
  Irfan,	
  T.	
  N.	
  Glasnov,	
  C.	
  O.	
  Kappe,	
  Org.	
  Ler.,
	
  
Flow	
  Ozonolysis	
  
Oxida6on	
  of	
  alkynes	
  

Oxida6on	
  of	
  amines	
  to	
  nitro	
  groups	
  

M.	
  Irfan,	...
Flow	
  Ozonolysis	
  Of	
  Thioanisole	
  

M.	
  Irfan,	
  T.	
  N.	
  Glasnov,	
  C.	
  O.	
  Kappe,	
  Org.	
  Ler.,
	...
IceCube	
  
Safe:	
  Low	
  reacQon	
  volume,	
  excellent	
  
temperature	
  control,	
  SW	
  controlled	
  –	
  includ...
IdenQfied	
  ApplicaQons	
  
Ozonolysis	
  
Azides	
  

Nitra6on	
  

Lithia6on	
  

Halogena6on	
  

Mul6step	
  reac6ons	...
ReacQon	
  Zones	
  

Water	
  inlet	
  and	
  outlet	
  

Reactor	
  Plate	
  
First	
  Reac6on	
  Zone	
   Second	
  Rea...
Single	
  or	
  MulQ-­‐Step	
  ReacQons	
  

A	
  

C	
  

B	
  
-­‐70-­‐+80ºC	
  
Reactor	
  

Pre-­‐cooler/Mixer	
  

Az...
Touch	
  Screen	
  Interface	
  

Welcome	
  screen	
  of	
  the	
  IceCube	
  

Ozonolysis	
  set-­‐up	
  

3	
  pump	
  ...
Modular	
  for	
  a	
  Variety	
  of	
  Chemistry	
  

Pump	
  Module	
  

• 	
  2pcs	
  rotary	
  piston	
  
pumps	
  	
 ...
ApplicaQon	
  Note	
  1:	
  Swern	
  OxidaQon	
  
0.45	
  M	
  alcohol,	
  0.14	
  M	
  
DMSO	
  in	
  DCM	
  
0.94	
  mL/...
Making	
  Azide	
  Chemistry	
  Safer	
  

TKX50

•  2 Step Azide Reaction in flow
•  No isolation of DAGL
•  Significantl...
ApplicaQon	
  Note	
  2:	
  DiazoiQzaQon	
  

Aniline	
  
HCl	
  sol.	
  

Pump	
  A	
  

NaNO2	
  	
  
sol.	
  

Pump	
  ...
Scaffolds	
  from	
  Explosive	
  Intermediates	
  
NitraQon	
  of	
  AromaQc	
  Alcohols	
  

Currently	
  invesQgaQng	
  ...
Coming	
  soon…	
  

•  LithiaQon	
  experiments	
  
•  HalogenaQons/FluorinaQons	
  
•  Low	
  temperature	
  selecQve	
 ...
Accessing New
Molecules or
Chemical Space
The	
  Quest	
  for	
  Novel	
  Heterocycles	
  

Heterocyclic rings of the future, J. Med. Chem., 2009, 52 (9), pp 2952–2...
High	
  Temp	
  Chemistry	
  –	
  In	
  Batch	
  

• 
• 

Standard benzannulation reaction
Good source of:
•  Quinolines
•...
Gould	
  Jacobs	
  ReacQon	
  -­‐	
  Overview	
  
• Replacement of diphenyl ether (b.p: 259°C) with
THF (b.p.: 66 °C)

Cyc...
Process	
  ExploraQon	
  
• Meldrum’s acidic route to pyridopyrimidones and to
hydroxyquinolines

Cyclization conditions:
...
New	
  Scaffold	
  GeneraQon	
  

5 novel bicyclic scaffolds generated-fully characterized.
Many more to follow
Phoenix	
  Flow	
  Reactor	
  
Powerful: Up to 450°C
Versatile: Heterogeneous and
homogeneous capabilities.
Fast: Reaction...
Phoenix	
  Homogeneous	
  ReacQons	
  
•  Choice of stainless steel, teflon, or
Hastelloy
•  Different length coils to var...
Phoenix	
  Heterogeneous	
  ReacQons	
  
•  Use same H-Cube Pro
or Midi CatCarts
•  Phoenix metal-metal
Catcarts for >250°...
Mitsunobu	
  ReacQon	
  not	
  Possible	
  in	
  Batch	
  

Ring closure on aryl NH : key step
•  Mitsunobu reaction or tr...
N-­‐AlkylaQon	
  with	
  RaNi	
  CatCart	
  
RaNi 70mm
200C, 80bar
0.5ml/min
AlkylaQon	
  of	
  2-­‐methyl-­‐indone	
  
Alkylation coupled with dehydrogenation

The total amount of dialkylated produc...
AlkylaQon	
  with	
  Diol	
  –	
  Ring	
  Closure	
  
Ring closuring of 2-methyl-indole with 1,3
-butanediol

Ring closure...
Fischer-­‐Indole	
  Synthesis	
  –	
  Scale	
  Out	
  

cf. MW reaction: Bagley, M. C.; et al. J. Org. Chem. 2005, 70 , 70...
VersaQle	
  Catalysis	
  System	
  
• Reactions from 10-450C and 1-100bar (1450 psi)
• Up to 13 different reagent gases
• ...
Free	
  Chemistry	
  Services	
  
Our chemistry team is full of flow chemistry
and catalysis experts
We aim to solve your ...
Onsite	
  Demos	
  &	
  Seminars	
  Available	
  
We can visit your site for chemistry demos
and seminars. Impress your co...
THANK YOU FOR YOUR ATTENTION!!
ANY QUESTIONS?
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Thales overview Feb 2014 Genentech

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Transcript of "Thales overview Feb 2014 Genentech"

  1. 1. Accelerating Your Synthesis with Flow Chemistry Heather Graehl, MS, MBA Director of Sales North America ThalesNano North America
  2. 2. 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.
  3. 3. Customers   • Flow  Chemistry  Market  Leader   • Over  800  customers  worldwide  
  4. 4. What is flow chemistry?
  5. 5. What  is  flow  chemistry?   Performing  a  reacQon  conQnuously,  typically  on  small  scale,   through  either  a  coil  or  fixed  bed  reactor.   OR   Pump   Reactor   CollecQon  
  6. 6. KineQcs  in  Flow  Reactors   •  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    
  7. 7. Improved  Mixing  Compared  to  Batch   Flow  reactors  can  achieve  homogeneous  mixing  and  uniform   hea6ng  in  microseconds  (suitable  for  fast  reac6ons)  
  8. 8. Improved  Mixing  =  Faster  Rxn  Time   Improved  mixing  can  lead  to   improved  reac6on  6mes,  especially   with  fixed  bed  reactors  
  9. 9. Enhanced  Temperature  Control   •  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  
  10. 10. Enhanced  Temperature  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.
  11. 11. Enhanced  Temperature  Control   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  
  12. 12. Enhanced  Temperature  Control   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
  13. 13. SelecQvity  –  Residence  Time  Control   Traditional Batch Method Flow Method Reactants Gas inlet H-Cube Pro™ Better surface interaction Controlled residence time Elimination of the products By-products By-products Reactants Products Products
  14. 14. SelecQve  AromaQc  Nitro  ReducQon   Catalyst screening Parameter scanning: effect of residence time to the conversion and selectivity Increase and decrease of residence time on the catalyst cannot be performed in batch 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
  15. 15. Survey  Conducted      Why  move  to  flow?   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  
  16. 16. Reactor  Pladorms   H-Cube Pro & Gas Module: Reagent gases Phoenix Flow Reactor: Endothermic chemistry 150°C, 100 bar (1450 psi) H2, CO, O2, CO/H2, C2H4, CO2. Reactions in minutes. Minimal work-up. 450°C, 100 bar (1450 psi) New chemistry capabilities. Chemistry in seconds. Milligram-kilo scale Solve Dead-end chemistry. Heterocycle synthesis IceCube: Exothermic Chemistry -70 - +80C O3, Li, -N3, -NO2 Safe and simple to use. Multistep synthesis. 2 step independant T control. Coming: fluorinations, low T selectivity
  17. 17. H-Cube Catalysis Platform: Making hydrogenations safe, fast, and selective
  18. 18. H-­‐Cube  –  How  it  Works   •  •  •  •  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) Hydro § N § N § H § D § P § R § H § I § D
  19. 19. Water  Electrolysis   Hydrogen generator cell §  Solid Polymer Electrolyte High-pressure regulating valves Water separator, flow detector, bubble detector
  20. 20. Catalyst  System  -­‐  CatCarts   • 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)
  21. 21. Simple  ValidaQon  ReacQons  (out  of  5,000)   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%
  22. 22. Simple  ValidaQon  ReacQons  (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
  23. 23. Difficult  Hydrogenatons   Batch: 150°C, 80 bar, 3 days Batch: 200°C, 200 bar, 48 hours
  24. 24. SelecQve  HydrogenaQons   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
  25. 25. SelecQve  HydrogenaQons   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 oxime Ürge, L.et al. submitted for publication
  26. 26. SelecQve  HydrogenaQons   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 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 Ürge, L.et al. submitted for publication Nitro group reduction in the presence of Cbz-group Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17s Results: 100% conversion, 100% yield
  27. 27. SelecQve  DehydrochlorinaQon   Flow Pressure (bar) Temperatur Bubdet o rate e ( C) (mL/ min) 1 20 (∆p:5 bar) 110 50 1 20 (∆p:3 bar) 110 50 1 20 (∆p:13 110 50 bar) 1 20 (∆p:10 110 50 bar) 1 20 (∆p:5 bar) 110 50 Catalyst Amount Amount Amount Amount A (%) B (%) C (%) D (%) 10% Pd/C 1% Pd/C 5% Rh/C 26.7% 61.5% 61,90% 29,40% 78.9% 5.1% - 7% 2,50% 9.2% 5% Pd/C 26.7% 60.9% - 6.7% 5% Pd/C(S) 25% 63.4% - 6.6% Objective: Match similar selectivity of 60% but without additives of CsF, S, K2CO3 and PPh3
  28. 28. ParQal  SaturaQon  of  Heterocycles   Optimised reaction parameters: -  H-Cube Pro -  Temperature: 100oC -  Pressure: 100 bar -  Hydrogen amount: Maximum Results: 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   •  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.
  29. 29. Asymmetric  HydrogenaQon   Chiral Phosphine-phosphoramidite ligands packed in CatCart
  30. 30. DeuteraQon   Substrate Product Isolated yield / % 99 99 97 98 93 97 96 98 96 Mándity, I.M.; Martinek, T.A.; Darvas, F.; Fülöp, F.; Tetrahedron Letters; 2009, 50, 4372–4374 Deuterium content(%) 99
  31. 31. H-­‐Cube  Family   Which H-Cube is best for me? • 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
  32. 32. New  Sonware  with  H-­‐Cube  Pro   • 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
  33. 33. H-­‐Cube  Pro  =  Higher  Throughput   2 cells for higher hydrogen production: 60 mL/min 100% conversion Compare to H-Cube SS where maximum concentration is 0.2M
  34. 34. H-­‐Cube  Pro  =  Higher  Temp  Capability  
  35. 35. H-­‐Cube  Pro  =  Lower  Temp  SelecQvity   H-Cube 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 H-Cube Pro Solvent Conc. Temp. (°C) Pressure (bar) Flow Rate (mL/ min) Product Distribution (%, GC-MS) A EtOH 0.1 M 10 10 1 B C 0 100 0
  36. 36. H-­‐Cube  Midi  –  Reactor  for  Scale  Up   Parameters: -  p= 1-100 bar -  T=10-150°C Milligram -  v=0.1-3 ml/min - c=0.01-0.1 M - H2 production = up to 60ml/min - CatCarts = 30x4mm or 70x4mm to Gram Scale Parameters: Half Kilogram -  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 Scale
  37. 37. H-­‐Cube  Autosampler   Gilson 271 Liquid Handler §  §  §  §  §  §  402 single Syringe pump (10 mL) Direct GX injector (Valco) Low-mount fraction collection (Bio-Chem) Septum-piercing needle Open vial collection Static drain wash station Collection through probe (into closed vial) Tubes, connectors, fittings
  38. 38. Expanding H-Cube Beyond Hydrogenation
  39. 39. Coupling  ReacQons   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
  40. 40. Coupling  ReacQons   Suzuki-Miyaura C-C cross coupling: NO 2 HO B OH + Br NO 2 CatCartTM 70*4 mm Pd EnCatTM BINAP 30, 2-propanol, TBAF, 80°C, 20 bar, 0.05M, 0.5 ml/min 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)
  41. 41. SelecQve  Coupling  ReacQon   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  
  42. 42. 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   Flow  rate  (ml/ min)   Pressure   (bar)   Temperature   o ( C)   0.8   20   100   0.3   20   100   0.8   20   100   0.8   20   100   0.8   20   100   0.8   20   100   0.5   20   50   0.5   20   100   0.2   20   100   0.2   20   100   0.2   20   100   Catalyst   Fibrecat  1007   (70mm)   Fibrecat  1007   (70mm)   Fibrecat  1035   (30mm)   Fibrecat  1029   (30mm)   Fibrecat  1048   (30mm)   10%  Pd/C   (30mm)   Fibrecat  1048   (30mm)   Fibrecat  1048   (30mm)   Fibrecat  1007   (70mm)   Fibrecat  1007   (70mm)   Fibrecat  1029   (30mm)   Base   3  ekv   3  ekv   2.5  ekv   2.5  ekv   2.5  ekv   2.5  ekv   2.5  ekv   2.5  ekv   2.5  ekv   2.5  ekv   2.5  ekv   Result   LC-­‐MS,  220nm   Conversion:  82%   SelecQvity:  48%   Conversion:  99%   SelecQvity:  48%   Conversion:  16%   SelecQvity:  100%   Conversion:  18%   SelecQvity:  100%   Conversion:  40%   SelecQvity:  100%   Conversion:  89%   SelecQvity:  14%   Conversion:17%   SelecQvity:  ~100%   Conversion:  35%   SelecQvity:  ~100%   Conversion:  93%   SelecQvity:  73%   Conversion:  93%   SelecQvity:  80%   Conversion:  12%   SelecQvity:  100%  
  43. 43. Other  Reagent  Gases   •   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™.  
  44. 44. ApplicaQon  1:  CarbonylaQon   Ø  Ø  Ø  Ø  Conditions: 100oC, 30 bar, CO gas, 0.5 ml/min liquid flow rate, 0.01 M in THF Catalyst: Polymer supported Pd(PPh3)4 Reaction was repeated Different gas flow rates were tested Observed reproducible conversion at each gas flow rate
  45. 45. ApplicaQon  2:  Green  OxidaQon  
  46. 46. Green  OxidaQon  OpQmizaQon   Pressure Selectivity 25 1 % Au/TiO2 0 – 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 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 Conversion 40 Very fast addition of alcohol to gold surface. Alkoxide formation. CatCart 40 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), Temp. (oC) 100 1 % Au /Fe2O3 31 7 100 • Area% of desired product in GC-MS / (100 – Area% of reactant in GC-MS)
  47. 47. AromiQzaQon  of  Heterocycles   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   The  catalyst  was  reacQvated   98%  aner  2  run   with  H2O2  between  the  runs.   O2  (10  ml/min)   Acetone   Au/TiO2   75   11   O2  (10  ml/min)   Acetone   Au/TiO2   150   11   95%   O2  (50  ml/min)   Acetone   Au/TiO2   150   20   >  98%   8%   Aner  10  minutes  the   conversion  was  dropped  to   50%  
  48. 48. Ozonolysis  and   Other  High  Energy   Reac6ons  
  49. 49. 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
  50. 50. Workup Determines Product Carboxylic Acid (oxidative work-up) Aldehyde/Ketone (simple quenching) Alcohol (reductive work-up)
  51. 51. Ozonolysis in Industry 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
  52. 52. 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.  
  53. 53. Why  Ozonolysis  in  Flow?   •  •  •  •  •  •  •  •  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
  54. 54. Flow  Ozonolysis  of  Styrenes   M.  Irfan,  T.  N.  Glasnov,  C.  O.  Kappe,  Org.  Ler.,  
  55. 55. Flow  Ozonolysis   Oxida6on  of  alkynes   Oxida6on  of  amines  to  nitro  groups   M.  Irfan,  T.  N.  Glasnov,  C.  O.  Kappe,  Org.  Ler.,  
  56. 56. Flow  Ozonolysis  Of  Thioanisole   M.  Irfan,  T.  N.  Glasnov,  C.  O.  Kappe,  Org.  Ler.,  
  57. 57. IceCube   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   Modular:  OpQon  for  Ozone  Module  or   more  pumps   Size:  Stackable  to  reduce  footprint   Mul6step  reac6ons:  2  reacQon  zones  in  1  system  
  58. 58. IdenQfied  ApplicaQons   Ozonolysis   Azides   Nitra6on   Lithia6on   Halogena6on   Mul6step  reac6ons   Swern  Oxida6on   Reac6ve  Intermediates  
  59. 59. ReacQon  Zones   Water  inlet  and  outlet   Reactor  Plate   First  Reac6on  Zone   Second  Reac6on  Zone   C   First  Reac6on  Zone   • 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   Second  Reac6on  Zone   A   B   D   -­‐70-­‐+80ºC   -­‐30-­‐+80ºC  
  60. 60. Single  or  MulQ-­‐Step  ReacQons   A   C   B   -­‐70-­‐+80ºC   Reactor   Pre-­‐cooler/Mixer   Azide,  nitra6on,  Swern  oxida6on   C   A   B   D   -­‐70-­‐+80ºC   -­‐30-­‐+80ºC   Applica6ons:  Azide,  Lithia6on,  ozonolysis,  nitra6on,  Swern  oxida6on   Ideal for reactive intermediates or quenching
  61. 61. Touch  Screen  Interface   Welcome  screen  of  the  IceCube   Ozonolysis  set-­‐up   3  pump  –  2  reactor  set-­‐up  
  62. 62. Modular  for  a  Variety  of  Chemistry   Pump  Module   •   2pcs  rotary  piston   pumps     •   2pcs  3-­‐way  inlet   valves   •   Flow  rate:  0.2  –  4.0   mL/min   •   Max  pressure:  6.9   bar   Cooling  Module   Ozone  Module   •   Main  reactor  block  temp:    -­‐70/50°C   •   ConQnuous  ozone  producQon   –  +80°C     •   Controlled  oxygen   introducQon   •   Main  reactor  volume  up  to  8  mL   •   Tubing:  1/16”  or  1/8”  OD  PTFE   •   Max.  100  mL/min  gas  flow   •   Secondary  reactor  block  temp.:     -­‐  30  –  +80°C   •   14%  Ozone  producQon   •   Secondary  reactor  volume  up  to  4   mL  
  63. 63. ApplicaQon  Note  1:  Swern  OxidaQon   0.45  M  alcohol,  0.14  M   DMSO  in  DCM   0.94  mL/min   Batch  reac6on:   Max.  -­‐60°C  to  avoid  side  reacQon   In  Flow:   0.45  M  in   DCM,  0.96   mL/min   *  Aner  purificaQon   3.6  M  in   MeOH,   0.76  mL/ min   Even  at  -­‐10°C  without  side  product   formaQon   When  compared  to  batch  condiQons,   IceCube  can  sQll  control  reacQons  at   warmer  temperatures  due  to  berer   mixing  and  more  efficient  heat   transfer.  
  64. 64. Making  Azide  Chemistry  Safer   TKX50 •  2 Step Azide Reaction in flow •  No isolation of DAGL •  Significantly reduced hazards
  65. 65. ApplicaQon  Note  2:  DiazoiQzaQon   Aniline   HCl  sol.   Pump  A   NaNO2     sol.   Pump  B   Entry   Vflow  (ml/min)   A  -­‐  B  -­‐  C   T  (°C)   1   2   0.4   0   2.12   3.33   91   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   Pump  C   Phenol     NaOH  sol.   τ  (1.  loop,   τ  (2.  loop,   min)   min)   Isolated   Yield  (%)   •  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  
  66. 66. Scaffolds  from  Explosive  Intermediates   NitraQon  of  AromaQc  Alcohols   Currently  invesQgaQng   selecQvity  at  lower   temperatures  on  IceCube   Pump  A   Flow  rate  (ml/ SoluQon   min)   ccHNO3   1.48g  NH4NO3/15ml   ccH2SO4   1.48g  NH4NO3/15ml   ccH2SO4   70%  ccH2SO4  30%   ccHNO3   70%  ccH2SO4  30%   ccHNO3   0.4   0.7   0.5   0.6   0.6   Pump  B   Temperature   Loop  size   Conversion   SelecQvity  (%)   Flow  rate  (ml/ (oC)   (ml)   (%)   SoluQon   min)   1g  PG/15ml   0  (different   0.4   5  -­‐  10   7   100   ccH2SO4   products)   1g  PG/15ml   0.5     5  -­‐  10   13   100   100   ccH2SO4   1g  PG/15ml   0.5     5  -­‐  10   13   50   80  (20%  dinitro)   ccH2SO4   1g  PG/15ml   0.5     5  -­‐  10   13  (3  bar)   100   100   ccH2SO4   1g  PG/15ml   70  (30%  dinitro   0.5     5  -­‐  10   13  (1  bar)   80   ccH2SO4   and  nitro)  
  67. 67. Coming  soon…   •  LithiaQon  experiments   •  HalogenaQons/FluorinaQons   •  Low  temperature  selecQve  reacQons,  not  necessarily  exothermic  nature   •  EpoxidaQons  
  68. 68. Accessing New Molecules or Chemical Space
  69. 69. 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
  70. 70. High  Temp  Chemistry  –  In  Batch   •  •  Standard benzannulation reaction Good source of: •  Quinolines •  Pyridopyrimidones •  Naphthyridines Disadvantages: • Harsh conditions • High b.p. solvents • Selectivity • Solubility → Important structural drug motifs W. A. Jacobs, J. Am. Chem. Soc.; 1939; 61(10); 2890-2895
  71. 71. Gould  Jacobs  ReacQon  -­‐  Overview   • 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 No THF polymerization! Quinoline Batch conditions: 2 hours
  72. 72. Process  ExploraQon   • 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 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. Lengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., 2012; 53; 738-743 72
  73. 73. New  Scaffold  GeneraQon   5 novel bicyclic scaffolds generated-fully characterized. Many more to follow
  74. 74. Phoenix  Flow  Reactor   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™.
  75. 75. Phoenix  Homogeneous  ReacQons   •  Choice of stainless steel, teflon, or Hastelloy •  Different length coils to vary residence time •  Easy to recoil
  76. 76. Phoenix  Heterogeneous  ReacQons   •  Use same H-Cube Pro or Midi CatCarts •  Phoenix metal-metal Catcarts for >250°C reactions H-Cube Pro CatCarts (30 or 70mm) Phoenix metal-metal CatCarts (125mm/250mm)
  77. 77. Mitsunobu  ReacQon  not  Possible  in  Batch   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.
  78. 78. N-­‐AlkylaQon  with  RaNi  CatCart   RaNi 70mm 200C, 80bar 0.5ml/min
  79. 79. AlkylaQon  of  2-­‐methyl-­‐indone   Alkylation coupled with dehydrogenation The total amount of dialkylated products was 18%. 79
  80. 80. AlkylaQon  with  Diol  –  Ring  Closure   Ring closuring of 2-methyl-indole with 1,3 -butanediol Ring closure is coupled with hydrogenation of double bond 80
  81. 81. Fischer-­‐Indole  Synthesis  –  Scale  Out   cf. MW reaction: Bagley, M. C.; et al. J. Org. Chem. 2005, 70 , 7003 Continuous Flow Results (4 mL or 16 mL Coil) In AcOH/2-propanol (3:1) (0.5M) 150 °C, 60 bars, 1.0 mL min-1 (4 min res. time) 88% isolated yield Scale-up 25 g indole/hour 200 °C, 75 bars, 5.0 mL min-1 (~3 min res. time) 96% isolated yield
  82. 82. VersaQle  Catalysis  System   • Reactions from 10-450C and 1-100bar (1450 psi) • Up to 13 different reagent gases • Heterogeneous or homogeneous catalysis Fully Automated system now available
  83. 83. Free  Chemistry  Services   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.
  84. 84. Onsite  Demos  &  Seminars  Available   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 heather.graehl@thalesnano.com
  85. 85. THANK YOU FOR YOUR ATTENTION!! ANY QUESTIONS?
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