Post on 08-Mar-2021
transcript
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!