The advantages of applying flow synthesis towards hydrogenation from laboratory to process scale Richard Jones Product Manager
The advantages of applying flow synthesis towards hydrogenation from laboratory to process scale
Richard JonesProduct 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
OSiMe3O
H
Br
OH
Br
O
+TBAF
Time needed to Reach 100% ConversionFlow: 20 minutes Batch 24 hours
Optimized Conditions: 78% YieldRegioisomer Ratio: 95:5 A:B
OMgCl
O OH
+
A B
Rapid heat transfer and mixing speeds up reactions
Precise temperature control can lead to selective chemistries
Wiles, C.; Watts, P.; Haswell, S. J.; Pombo-Villar, E. Lab Chip 2001,1, 100.
Taghavi-Moghadam, S.; Kleemann, A.; Golbig, K. G. Org. Process Res. DeV. 2001, 5, 652.
Accessiblity of Exothermic and Runaway Reactions
OH OH
NO2
OHNO2
+HNO3
Flow reactors typically have high heat transfer properties
• 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
OEt
OO
OEt
OO
F
10% F2 in N2
Formic acid, 5°C
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
O
NH2
OHN
OH+
65°C
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 upExpensive – separate laboratory needed!Catalyst addition and filtration is hazardousAnalytical sample obtained through invasive means.Mixing of 3 phases inefficient - poor reaction rates
H-Cube™ Overview
• 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.
NH
O2N
NH
NH2
H-Cube Reaction Line
Bubble Detector
H2/SubstrateMixer
CatCartHolder
CatCart Heater
PressureDetector
Back-pressurevalve
•Catalyst contained in sealeddisposable cartridges
•No filtration necessary•Enhanced phase mixing
•Over 50 heterogeneous andImmobilized homogeneous catalysts
10% Pd/C, PtO2, Rh, Ru on C, Al2O3Raney Ni, Raney CoPearlmans, Lindlars CatalystWilkinson's RhCl(TPP)3Tetrakis(TPP)palladiumPd(II)EnCat BINAP 30
Filter
30 m
m
Catalyst System-CatCart™
Smallest catalysts can reduce10mg-5g of substrateLargest CatCarts up to 100g
H-Cube vs. Batch Comparison
NH
O2N
NH
NH210% Pd/C
Methanol, RT, 1 bar
Batch vs Flow
0
20
40
60
80
100
0 3 6 9 12 15
time
Prod
uct C
onve
rsio
n (%
)
batch
flow
Starting material
Product
Side-product
Starting material
Product
Conventional Batch and Continuous Flow Mode
Gas introduction
Gap
NN
R2
R1
S
NHN
R2
R1
S
i. H-Cube, 10% Pd/C CatCart30
low dilution, conditions.
• 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
Debenzylation before catalyst poisoning
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 with140 mg Pd/C
STARTING MATERIAL
PRODUCT
Starting Material
Product
Simple Validation Reactions (out of 5,000)
O O
MeO
N
MeO
NH2
10% Pd/C, RT, 1 barYield: 86 - 89%
Batch reference: Reagent: water, catalyst: Pd on activecarbon, 250 °C, 40-50 bar, yield: 64%Matsubara, Seijiro; Yokota, Yotaka; Oshima, Koichiro; Org. Lett.; EN; 6; 12; 2004; 2071-2074
Raney Ni, 70°C, 50 bar 2M NH3 in MeOHYield: >85%
No batch reference
Simple Validation Reactions (out of 5,000)
10% Pd/C, 60˚C, 1 barYield: >90%
Batch reaction of {3-[(2-carbazol-9-yl-acetylamino)-methyl]-benzyl}-carbamic acid benzyl esterReagent: 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.
NH
NH
O
O
NH
NH2
NOH NH2
Raney Ni, 80˚C, 80 barYield: 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
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° CYield: 83 %Pitts, Michael R.; Harrison, Justin R.; Moody, Christopher J.;
JCSPCE; J. Chem. Soc. Perkin Trans. 1; EN; 9; 2001; 955-977
N
O
N
OH
Simple Validation Reactions (out of 5,000)
D
D
D
D
D-source is D2OConditions: Toluene, 30°C, 1 bar(full H2 mode), 10% Pt/CPurity after evaporation: 98% (NMR)Yield: 90%
Batch reference deuteration of trans-propenyl-benzene:Reagent: D2, Catalyst: Wilkinson catalyst, Solvent:
BenzeneYield: 20 %Heesing, Albert; Leue, Hans-joachim; CHBEAM; Chem.
Ber.; GE; 119; 4; 1986; 1232-1243
H-CubeTM Complex Reactions Examples
OON3 CO2Et
OOBocHN CO2Et
10% Pd/C BOC2O, EtOAc
1.0 ml/min, 0.1M 50oC, 1 atm
(76%, 1.1g)
Example: a dangerous reaction in batch reactor
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)
„2-step-1 flow” reaction
Chemoselective hydrogenations
O
OO
O
OOH
5% Pt/C, 75°C, 70 bar, 0,01M,ethanol,no byproductYield: 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
OHO
O
OHO
O
O
O
route A
route B2-Hydroxy-[1,4]naphthoquinone
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
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
• Batch reactions gave results after 4 hours!
H2 / cat.+
diphenyl-acetylene
cis-stilbene
trans-stilbene
1,2-diphenylethane
H2 / cat.
H. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446
30 40 50 60 70 800
20
40
60
80
diphenylethane cis-stilbene trans-stilbene conversion%
T (0C)
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
S. Saaby, K.R. Knudsen, M. Ladlow and S.V. Ley, J. Chem. Soc., Chem. Commun., 2005, 2909.
MeO
MeON
OH
N
OH
NN
OH
NC
N
OH
1
2
3
4 quant.
quant.
quant.
93
>95
>95
95
84
Yield(%)
Purity(%)
ImineEntry
N
OH
N
N
OO
NH
NO
5
6
7
8 quant.
92
96 85
>95
90
90
quant.
EntryYield(%)
Purity(%)
Imine
RN
R2R1
R3
H2O H2 (g)electrolysis
HN
R2R1
R3
Catalyst
University of Cambridge-Prof. Steven Ley
MeO
MeO
(±)-oxomaritidine
NH
O
Br
HO NMe3N3
N3
HO
MeCN:THF (1:1), 70 oC
O
MeOOMe
(1)
(2)
catch, react, release
MeO
OMe
N
HO
rt to 55 oC
Ph(nBu)2P
H2OH2 (g)electrolysis
Flow hydrogenation
10% Pd/C, THF
MeOOMe
NH
HO
O
F3C O
O
CF3
MeOOMe
N
HO
CF3O
80 oC
NMe3RuO4OH
MeOOMe
PhI(O2CX3)2rt
NMeO
MeO
CF3
O
OMeOH / H2O (4:1)
NMe3OH
35 oC
I.R. Baxendale, J. Deeley, C.M. Griffith-Jones, S.V. Ley, S. Saaby, G. Tranmer, J. Chem. Soc., Chem. Commun., 2006, 2566.
Flow Synthesis of Flow Synthesis of OxomaritidineOxomaritidine
Production of a primary amine library with no protection/deprotection
Conditions:
10% Pd/CMethanol, 1 bar (Full H2 mode), 30 ºCInjection time: 6 min/25 mg
NH
OO2N
RNH
ONH2
R
Result:
50 compounds/ 5 hoursLC-MS purity above 90%, without purification in most cases
Model Library
N
O
O
H
NO2
R
N
O
O
H
NH2
R
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 24-26, 2007
N
O
O
H
NO2
R1
R2
N
O
O
H
NH2
R1
R2
R1 = H, R2 = Cl
R1 = Cl, R2 = H
6 examples95% - Quant.
R = Cl, dehalogenation
Pd/C
Full H2
60°C
5-10 mg/mL
EtOAc/EtOH
Ra-Ni
Full H2
30°C
5-10 mg/mL
EtOAc/EtOH
Quantitative
Abbott automated debenzylation
CatCart Changer™ with H-Cube™
• Line can be directed between6 catalysts
• Individually changeable temperature
• Software control
• No stop between changes
• Rapid optimization
The H-Cube MidiHydrogenation Scale up
Reactor
Flow Scale up Advantages
Problems associated with Batch Scale upTime consuming-new optimzationHandling of hazardous reagents and/or solventsCatalyst handling is problematic Temperature controlReaction with materials of batch reactorsGas productionReproduction
H-Cube Midi Flow Scale upLow amount of optimzationReproducibility-no unexpected side reactionsHigh level of temperature controlHazardous chemicals reacted in small amounts continuouslyGas production not a problem-system not sealedParameters, such as Time, vs Cost, can be selected flexibly based on the project need and status
Aldoxim reductionAldehyde reduction
0
5
10
15
20
25
30
t /m
in
FlowBatch
H-Cube Midi™
Pump
Mixer Unit
Touch Screen Panel
Outlet BubbleDetector
System PressureSensor
System PressureValve
Outlet ValveSwitch Inlet Valve Switch
Inlet Pressure Sensor
Inlet Bubble Detector
Heating Unit With MidiCart™
Exchangable for different CC
Heat Exchanger Preheating Unit
Scale-up of cartridge
CatCart® for the H-Cube®
MidiCart™ for the H-Cube Midi™ 90 × 9,5 mm
90 x 14 mm
90 x 22 mm
30 × 4 mm
Difference between a normal hydrogenation reactor andthe H-Cube Midi™
NormalHydrogenationReactor
H-Cube Midi™
Scale-up from mg to Kg in one day
H-Cube® H-Cube Midi™
Old method in batch
6-8 weeks
One day
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!
NO2
OCH3O
NH2
OCH3O
H2
0
20
40
60
80
100
120
0 5 10 15 20 25
Flow rate (mL/min)
Con
vers
ion
(%) 0,2M
0,17M0,15M0,12M0,1M
Parameters:
5% Pd/C
MeOH
P = 70 bars
T = 70°C
c = 0,2-0,1 M
Flow rate = 20-2,5 mL/min
Effect of the flow rate and the concentration I.
Effect of the flow rate and the concentration II.
0%
20%
40%
60%
80%
100%
120%
0 5 10 15 20 25
Flow rate (mL/min)
Con
vers
ion
(%)
0,4M 0,35M 0,3M 0,25M 0,2M
O
Parameters:
10% Pd/C (2,45 g)
MeOH
P = 50 bars
T = 100°C
c = 0,2 – 0,4 M
Flow rate: 2,5-20 mL/min
Industrial Experience Example 1
NNH2
10g/hour300mg/hourProduction Rate100%100%Conversion0.15M0.05MConcentration12mL/min1mL/minFlow-Rate50 bar50 barPressure60ºC60ºCTemperature20% Pd(OH)2/C20% Pd(OH)2/CCatalystH-Cube MidiH-CubeConditions
Industrial Experience Example 2
HO OH
10g/hour300mg/hourProduction Rate100%100%Conversion0.15M0.05MConcentration12mL/min1mL/minFlow-Rate50 bar50 barPressure60ºC60ºCTemperatureRaney NiRaney NiCatalystH-Cube MidiH-CubeConditions
Industrial Hydrogenation Example 3
10g/hour500mg/hourProduction Rate100%100%Conversion0.15M0.05MConcentration7mL/min1mL/minFlow-Rate50 bar50 barPressure60ºC60ºCTemperatureRaney NiRaney NiCatalystH-Cube MidiH-CubeConditions
HNOH
NR
HNH
NR
Conclusion
Starting Material
Product Reaction Conditions Amount Processed/Time
Calc. Amount for 8 hours
Yield
O
OH
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%
O
OH
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%
O2N
O
OH
H2N
O
OH
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%
OH
OH
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%
NH
HNO
O
Ph
NH
NH2
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%
X-Cube Flash for High T Reactions
Tmax. = 350°Cpmax. = 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
Loupy, A. et al, Tetrahedron, 2004, 60, 1683-1691
Activation Medium T / °C t / h Yield / % Products
Toluene 250 24 60 1-a:1-b = 65:35
No solvent 150 3 19 1-a Extended heating
No solvent 150 24 44 (40) 1-a Microwave No solvent 150 3 64 (62) 1-a
Using Flash reactor: 350°C, 1 mL/min, 8 min residence time, 80 bar98% conversion, 100% selectivity: 1-a
Alkylation of triazole with trichloroacetophenone in batch and MW conditions
Loupy, A.; Perreux, L.; Liagre, M.; Burle, K.; Moneuse, M. Pure Appl. Chem. 2001, 73, 161.
Activation Medium Conversion / % N1/N4/N1,4
Microwave Pentanol 90 95 / 5 / 0 Conventional
heating 90 95 / 5 / 0
Microwave DMF 90 95 / 5 / 0 Conventional
heating 90 95 / 5 / 0
Microwave o-xylene 82 100 / 0 / 0 Conventional
heating 95 32 / 28 / 40
Microwave No solvent 92 100 / 0 / 0 Conventional
heating 100 36 / 27 / 27
Alkylation of triazole with trichloroacetophenone in Flash reactor
Reaction optimization using Flash reactor:
T= 140 – 350 °CP= 80 barv= 0,5 mL/min – residence time: 16 minc= 0,1 M (acetonitril)
80150100350
77210100340
56300100330
49400100320
44430100310
38620100300
12810100290
5940100280
0100092270
0100075260
0100040250
0100037240
0100035230
0802035220
0782331210
0752525200
0703020170
010002140
Selectivity % (N4)
Selectivity % (N1)
Selectivity % (N1,4)
Conversion %
T (°C)
140
170
200
210
220
230
240
250
260
270
280
290
300
310
320
330
340
350
N1,4
0
10
20
30
40
50
60
70
80
90
100
Sel
ectiv
ty
Temperature
N1,4N4N1
Serial link of flow reactors
•Flow reactors may be linked sequentially
•H-Cube and X-Cube may be linked for multi-step synthesis
Step 1: Organic Azide formation in X-Cube :
Step 2a: Reduction of azide group in H-Cube:
•0.4mL/min, 100°C, 20 bar, 0.1M•Immobilized azide in CatCartTM
•Quantitative conversion
•1.0 mL/min, RT, 70 bar, 0.05M, 10% Pt/C•Quantitative conversion
N3Br Azide CatCartTM
N3 NH2
Step 2b: Triazole synthesis in X-Cube:
N3OO NN
NO+
•0.2 mL/min, 200°C, 40 bar, 0.1M, K2CO3•Yield: 82% (from crude azide)
Chemistry using coupled reactors
O-CubeTM Overview
• The ozone source is water• Continuous-flow method with effective reaction heatdissipation .• Reactions performed on room temperature • Reactions may be performed under pressure
O-Cube can eliminate almost all disadvantages ofcurrent ozonolysis:• Ozonolysis difficult to carry out• Ozonide is unstable and explosive!
• Reaction parameters-pressure, temperature, • concentration, flow rate etc. are easy to control.
O-CubeTM Room Temperature Reactions Examples
NH
Cl
NH
ClOH
ONH2
ClOH
+O-CubeTM
DCM, RT, Atm. collected in 40% NaBH4 MeOH
N
OHOH N
O
O
O-CubeTM
DCM, RT, Atm. collected in 40% NaBH4 MeOH
NH
NH2
OH
NH
OH
O+
DCM, RT, Atm. collected in 40% NaBH4 MeOH
O-CubeTM
Batch reference: 0°C, DCM, 10% NaOH, O3, H2O2, 4 hYield: 40%
No batch reference
No batch reference
Conversion 100%
Conversion 80%
0,05 M, 1,0 ml/min
0,05 M, 1,0 ml/min
0,05 M, 1,0 ml/min
Conversion: 85 %
Thank you for your attention!
Any questions?
Thank you to the ThalesNanoChemistry team in Budapest, Hungary for their hard work and results!