2014 02 flow chemistry and scale up presentation (gilead)
TRANSCRIPT
Enabling Your Synthesis with Flow Chemistry
Heather Graehl, MS, MBADirector of Sales North AmericaThalesNano North America
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.• 12 years old-most established flow reactor company.• R&D Top 100 Award Winner.
•Flow Chemistry Market Leader•Over 800 customers worldwide
Customers
What is flow
chemistry?
Performing a reaction continuously, typically on small scale, through either a coil or fixed bed reactor.
OR
PumpReactor Collection
What is flow chemistry?
• In a microfluidic device with a constant flow rate, the concentration of the reactant decays exponentially with distance along the reactor.
• Thus time in a flask reactor equates with distance in a flow reactor
X
A
dX/dt > 0
dA/dt < 0
Kinetics in Flow Reactors
Flow reactors can achieve homogeneous mixing and uniform heating in microseconds (suitable for fast reactions)
Improved Mixing Compared to Batch
Improved mixing can lead to improved reaction times, especially with fixed bed reactors
Improved Mixing = Faster Rxn Time
• Microreactors have higher surface-to-volume ratio than macroreactors, heat transfer occurs rapidly in a flow microreactor, enabling precise temperature control.
Yoshida, Green and Sustainable Chemical Synthesis Using FlowMicroreactors, ChemSusChem, 2010
Enhanced Temperature Control
Lower reaction volume. Closer and uniformtemperature control
Outcome:
Safer chemistry. Lower possibility of exotherm.
Batch
Flow
Larger solvent volume. Lower temperature control.
Outcome:
More difficult reaction control. Possibility of exotherm.
Enhanced Temperature Control
Batch Heated Rxns• Safety concerns, especially in scale
up• Microwave technology is fastest
way of heating 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, continuously
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
Enhanced Temperature Control
Reactants
Products
By-products
Traditional Batch Method
Gas inlet
Reactants
Products
By-products
Better surface interactionControlled residence timeElimination of the products
Flow Method
H-Cube Pro™
Selectivity – Residence Time Control
Catalyst screening
Parameter scanning: effect of residence time to the conversion and selectivity
0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0 2,2
85
90
95
100
105
110
Conversion Selectivity
%
Flow rate / mLmin-1
1% Pt/C (V) catalyst at 0,02 concentration of 4-bromo-nitrobenzene
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
Increase and decrease of residence time on the catalyst cannot be performed in batch
Selective Aromatic Nitro Reduction
150°C, 100 bar (1450 psi)
H2, CO, O2, CO/H2, C2H4, CO2.
Reactions in minutes.
Minimal work-up.
-70 - +80C
O3, Li, -N3, -NO2
Safe and simple to use.
Multistep synthesis.
2 step independant T control.
450°C, 100 bar (1450 psi)
New chemistry capabilities.
Chemistry in seconds.
Milligram-kilo scale
Solve Dead-end chemistry.
H-Cube & Gas Module:
Reagent gases
Phoenix Flow Reactor:
Endothermic chemistry IceCube:
Exothermic Chemistry
Reactor Line
H-Cube Midi Scale Up Flow Hydrogenation
Parameters:- p= 1-100 bar- T=10-150°C- v=0.1-3 ml/min-c=0.01-0.1 M-H2 production = up to 60ml/min-CatCarts = 30x4mm or 70x4mm
Parameters:- p= 1-100 bar- T=RT-150°C- v=5-25 ml/min-c=0.05-0.25 M-H2 production = up to 125ml/min-CatCarts = 90x9.5mm
Milligram to Gram Scale
Half Kilogram Scale
H-Cube Midi – For Scale Up
• 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)
NH
O2N
NH
NH2
H-Cube Midi Overview
System overview of the H-Cube Midi™
• 500 g product/24 hours• Standard lab compatible • Temperature: RT-150°C • Pressure: 1 bar- 100 bar• Flow Rate: 3 -25 mL/min• In-situ hydrogen generation•Built-in pump with software control• Two-step heating• Easy control using the touch screen
Pump
Mixer Unit
Touch Screen Panel
Outlet Bubble Detector
System Pressure Sensor
System Pressure Valve
Outlet Valve Switch Inlet Valve Switch
Inlet Pressure Sensor
Inlet Bubble Detector
Heating Unit With MidiCart™
Heat Exchanger Preheating Unit
H-Cube Midi
4 Hydrogen generator cells Solid Polymer Electrolyte
High-pressure regulating valves
Water separator, flow detector, bubble detectors
In Situ Hydrogen Generation
•Benefits• Safety• No filtration necessary • Enhanced phase mixing
•Over 100 heterogeneous andImmobilized homogeneous catalysts
10% Pd/C, PtO2, Rh, Ru on C, Al2O3
Raney Ni, Raney CoPearlmans, Lindlars CatalystWilkinson's RhCl(TPP)3
Tetrakis(TPP)palladiumPd(II)EnCat BINAP 30
•Different sizes•30x4mm•70x4mm•90x9.5mm
•Ability to pack your own CatCarts•CatCart Packer (with vacuum)•CatCart Closer (no vacuum)
Catalyst System - CatCart
10% Pd/C, RT, 1 barYield: 86 - 89%Alternate reductionsKetone: Pt/CAromatic: Ru/O2
Raney Ni, 70°C, 50 bar, 2M NH3 in MeOH, Yield: >85%
Simple Validation Reactions
10% Pd/C, 60˚C, 1 barYield: >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 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
Simple Validation Reactions
N
O
OEt
Ar
NH
O
OEt
Ar
Acetic Acid
20% Pd(OH)2/C, 70 bar, 70oC
70% Yield, 5g
RuO2, 100 C
100 bar, 1 mL/min
99% Conversion
Batch: 200°C, 200 bar, 48 hours
Batch: 150°C, 80 bar, 3 days
Difficult 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
Selective Hydrogenations
NO2 NO2
Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17sResults: 100% conversion, 97% yield
O2N
O2N
NHO
Conditions: 1% Pt/C, 70 bar, 30°C, residence time 17sResults: 100% conversion, 100% yield
Conditions: Au/TiO2, 70 bar, 30°C, residence time 17sResults: 100% conversion, 100% yield
H-Cube® - Chemoselective hydrogenations
Ürge, L.et al. submitted for publication
Selective hydrogenation of the double-bond
Selective hydrogenation to afford oxime
Selective hydrogenation of the double-bond
Selective Hydrogenations
OO2N
Cl
OH2N
Cl
Conditions: 10% Pd/C, 70 bar, 0°C, residence time 16sResults: 100% conversion, 100% yield
HN
OOO
OO2N HN
OOO
OH2N
Conditions: 1% Pt/C, 70 bar, 30°C, residence time 11-17sResults: 100% conversion, 100% yield
O2N NO2
OHH2N NH2
OH
Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17sResults: 100% conversion, 100% yield
Ürge, L.et al. submitted for publication
H-Cube® - Chemoselective hydrogenations
Nitro group reduction in the presence of a halogen
Nitro group reduction in the presence of Cbz-group
Nitro group reduction without retro-Henry as a
side-reaction
Selective Hydrogenations
Analysis by GC-MSAt the same substrate: catalyst ratio 0.125 mol substrate was reduced
N
N
NH
HN
Reaction parameters
Batch in house H-Cube Midi™
CatalystC (M)
Flow rate (mL/min)T (°C)
p (bar)Conversion(%)
Selectivity(%)
360 mg RaNi0.05 (60 cm3)
-3020
10095
After 120 min 0.003 mol compound was reduced
15.02 g RaNiEtOH0.2
12.53020
10095
After 1.2 min 0.003 mol compound was reduced
Co
nversio
n (%
)
Flow rate (mL/min)
C = 0.20 M c = 0.25 M c = 0.30 M c = 0.35 M c = 0.40 M
Quinoxaline reduction
Optimization on H-Cube Midi
Problem: Cyclopropylcarbinol cleavage with Pd/C
H-Cube®-screening suggested better catalysts: Pt/C, Raney nickel, Pd/CaCO3....
Selective hydrogenation of alkenes in the presence of cyclopropylcarbinols Transfer to batch conditions: Scalable Synthesis of Pashminol
OH
1
catalyticheterogeneous
hydrogenation
OH
2
OH
Pashminol™+
run cartridge T / p cyclopropane cleavage to 2
substrate 1
product Pashminol
a 10% Pd/C 25 °C / 1 bar 5 3 73
b 5% Pd/Al2O3 25 °C / 1 bar 15 17 53
c 5% Pt/C 25 °C / 1 bar 0 1 84
d Raney nickel 80 °C / 1 bar 1 2 87
e 5% Pd/CaCO3 25 °C / 1 bar 1 1 83
Table: H-Cube® hydrogenation of 1. GC-conversion. Selected examples.
Hydrogenation Challenge
Ar
F
F
Cl Ar
F
F
H Ar
F
H
H Ar
H
H
H
A B C D
Flow rate
(mL/min)
Pressure (bar)Temperature (oC)
Bubdet Catalyst Amount A (%)
Amount B (%)
Amount C (%)
Amount D (%)
1 20 (∆p:5 bar) 110 50 10% Pd/C 26.7% 61.5% - 7%1 20 (∆p:3 bar) 110 50 1% Pd/C 61,90% 29,40% - 2,50%1 20 (∆p:13
bar)110 50 5% Rh/C 78.9% 5.1% - 9.2%
1 20 (∆p:10 bar)
110 50 5% Pd/C 26.7% 60.9% - 6.7%
1 20 (∆p:5 bar) 110 50 5% Pd/C(S) 25% 63.4% - 6.6%
Solvay Objective: Match similar selectivity of 60% but without additives of
CsF, S, K2CO3 and PPh3
Selective Dehydrochlorination
Flow rate(ml/min)
Pressure(bar)
Temp(oC)
Catalyst H2 amount Result
2 12(∆p:8) 120 1% Au/TiO2 80(48%) Conversion: 48%Selectivity: 99%(Z-isomer: 81%)
1 12(∆p:5) 120 1% Au/TiO2 68(51%) Conversion: 99%Selectivity: 99%(Z-isomer: 84%)
2 12(∆p:5) 120 1%Pt/C(V) 80(48%) Conversion: 63%Selectivity: 99%(Z-isomer: 62%)
1 12(∆p:7) 120 1%Pt/C(V) 68(51%) Conversion: 99%Selectivity: 99%(Z-isomer: 64%)
Ar
Ar NO2
Ar
Ar NH2
Selective Nitro Reduction: Sanofi
N
OH
OHHO
OH
● Genzyme needed 1.2 kg of Zavesca for an internal study, which was priced at 47K USD per 100 g.
N
OH
OHHO
OH
HN
OH
OHHO
OH
H2 / Pd(OH)2 on C
O
H
Saved~ 500K as opposed to purchasing it. It assayed with higher purity than previous commercial lots. Kilo scale.
Genzyme Chemistry
Cooper, C., Nivororozhkin, V., Process Development of a Potent Glucosylceramide Synthase Inhibitor, OPRD, 2012
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™.
Phoenix Flow Reactor
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
The Quest for Novel Heterocycles
• Standard benzannulation reaction
• Good source of:
• Quinolines
• Pyridopyrimidones
• Naphthyridines
→ Important structural drug motifs
Disadvantages:
•Harsh conditions
•High b.p. solvents
•Selectivity
•Solubility
W. A. Jacobs, J. Am. Chem. Soc.; 1939; 61(10); 2890-2895
NH2
RO2C CO2R
OR''R'
+NH
R'
CO2RRO2C
Heat, -R''OH
R = alkylR' = alkyl, aryl, or HR" = alkyl or H
Heat
N R'
CO2R
OH
N R'
CO2H
OH
OH- Heat
methylenemalonic ester
CyclizationSaponification Decarboxylation
Condenzation
N R'
OH
High Temp Chemistry – In Batch
•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 Quinoline
No THF polymerization!
Batch conditions: 2 hours
Y
CO2Et
OEtX NH2
R
R'
X NH Y
R
CO2EtR'Batch Flow
1a-c 2a-c
3a-c
a: R=H, R'=H, X=N, Y=CO2Etb: R=H, R'=H, X=N, Y=CNc: R=H, R'=H, X=CH, Y=CN
+THF
3a (70%) 3b (75%) 3c (73%)
N
N
O
CO2EtN
N
O
CN
N
CN
OH
Gould Jacobs Reaction - Overview
5 novel bicyclic scaffolds generated-fully characterized.
Many more to follow
New Scaffold Generation
• Choice of stainless steel, teflon, or Hastelloy
• Different length coils to vary residence time
• Easy to recoil
Phoenix Homogeneous Reactions
• Use same H-Cube Pro or Midi CatCarts
• Phoenix metal-metal Catcarts for >250°C reactions
Phoenix metal-metal CatCarts (125mm/250mm)
H-Cube Pro CatCarts (30 or 70mm)
Phoenix Heterogeneous Reactions
HN
N
R
O
R
HO
HN
OR
HN R
Phoenix
T3P, 300C80 bar, THF
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.
Mitsunobu Reaction not Possible in Batch
NHNH2
O
NH
+AcOH/2-propanol (3:1) (0.5 M)
200°C, 75 bar, 5.0 mL min-1
96 %
cf. MW reaction: Bagley, M. C.; et al. J. Org. Chem. 2005, 70 , 7003
In AcOH/2-propanol (3:1) (0.5M)150 °C, 60 bars,
1.0 mL min-1 (4 min res. time) 88% isolated yield
Continuous Flow Results (4 mL or 16 mL Coil)
Scale-up 200 °C, 75 bars,
5.0 mL min-1 (~3 min res. time) 96% isolated yield
25 g indole/hour
Fischer-Indole Synthesis – Scale Out
High EnergyReactions
Safe: Low reaction volume, excellent temperature control, SW controlled – including many safety control points
Simple to use: easy to set up, default reactor structures, proper system construction
Powerful: -70°C to +80°C
Versatile chemistry: Ozonolysis, nitration, lithiation, azide chemistry, diazotization
Versatile reactors: Teflon loops for 2 reactors with 1/16” and 1/8” loops
High Chemical resistance: Teflon wetted parts
Multistep reactions: 2 reaction zones in 1 systemModular: Option for Ozone Module or more pumps
Size: Stackable to reduce footprint
IceCube
First Reaction Zone Second Reaction Zone
Water inlet and outlet
Reactor Plate•Aluminum stackable plates•Teflon tubing for ease in addressing blockage•Easy to coil for desired pre-cooling and desired residence time after mixing•Different mixers types available
AB
D
-70-+80ºC -30-+80ºC
CFirst Reaction Zone Second Reaction Zone
Reaction Zones
A
BC
AB
C
D
Pre-cooler/Mixer Reactor
-70-+80ºC
-70-+80ºC -30-+80ºC
Applications: Azide, Lithiation, ozonolysis, nitration, Swern oxidation
Azide, nitration, Swern oxidation
Ideal for reactive intermediates or quenching
Single or Multi-Step Reactions
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
R1
R3 R4
R2
R4
R2R1
R3
O O
O
OR
H
OR
OH
R
OH
O3
Ozonide
Carboxylic Acid(oxidative work-up)
Aldehyde/Ketone(simple quenching)
Alcohol(reductive work-up)
R3
R1 R2
R4
OR
OH
OR
H
OHR
Workup Determines Product
Synthesis of Indolizidine 215F
Other major drug syntheses featuring ozonolysis includes:
(+)-ArtemisininD,L-Camptothecin L-IsoxazolylalanineProstaglandin endoperoxides.
Van Ornum, S.G., Champeau, R., Pariza, R., Chem. Rev. 2006, 106, 2990-3001
Ozonolysis in Industry
Why ozonolysis is neglected?
• Highly exothermic reaction, high risk of explosion • Normally requires low temperature: -78°C.• In addition, the batchwise accumulation of ozonide is
associated again with risk of explosion• There are alternative oxidizing agents/systems:
• Sodium Periodate – Osmium Tetroxide (NaIO4-OsO4)
• Ru(VIII)O4 + NaIO4
• Jones oxidation (CrO3, H2SO4)• Swern oxidation
• Most of the listed agents are toxic, difficult, and/or expensive to use.
• 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
Why Ozonolysis in Flow?
M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,
Flow Ozonolysis of Styrenes
Batch reaction:Max. -60°C to avoid side reaction
In Flow:
Even at -10°C without side product formation
0.45 M in DCM, 0.96 mL/min
0.45 M alcohol, 0.14 M DMSO in DCM0.94 mL/min
3.6 M in MeOH, 0.76 mL/min
* After purification
When compared to batch conditions, IceCube can still control reactions at warmer temperatures due to better mixing and more efficient heat transfer.
Application Note 1: Swern Oxidation
Entry Vflow (ml/min)
A - B - C
T (°C) τ (1. loop, min)
τ (2. loop,
min)
Isolated Yield (%)
1 0.4 0 2.12 3.33 912 0.9 0 0.94 1.48 913 0.6 0 1.42 2.22 854 0.9 10 0.94 1.48 855 1.5 10 0.56 0.88 866 1.5 15 0.56 0.88 987 1.2 15 0.71 1.11 848 1.8 15 0.47 0.74 86
NH2 N N+ Cl-NaNO2
HCl
O-
NaOH
N N
OH
AnilineHCl sol. Pump A
Pump BNaNO2 sol.
Pump C
Phenol NaOH sol. • Most aromatic diazonium salts
are not stable at temperaturesabove 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-sensitive
Dioazitization and Azo Coupling
OH OH
NO2
NO2
O2N
Phenol
Pump A Pump BTemperature
(oC)Loop size
(ml)Conversion
(%) Selectivity (%)Solution
Flow rate (ml/min) Solution
Flow rate (ml/min)
ccHNO3 0.41g Ph/15ml
ccH2SO4 0.4 5 - 10 7 1000 (different products)
1.48g NH4NO3/15ml ccH2SO4 0.7
1g Ph/15ml ccH2SO4 0.5 5 - 10 13 100 100
1.48g NH4NO3/15ml ccH2SO4 0.5
1g Ph/15ml ccH2SO4 0.5 5 - 10 13 50 80 (20% dinitro)
70% ccH2SO4 30% ccHNO3 0.6
1g Ph/15ml ccH2SO4 0.5 5 - 10 13 (3 bar) 100 100
70% ccH2SO4 30% ccHNO3 0.6
1g Ph/15ml ccH2SO4 0.5 5 - 10 13 (1 bar) 80
70 (30% dinitro and nitro)
Nitration of Aromatic Alcohols
• Lithiation experiments
• Halogenations/Fluorination experiments
• Epoxidation experiments, asymmetric
• Very low temperature experiments, where batch
conditions required liquid nitrogen temperature or
below
Coming soon…
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.
Free Chemistry Services
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, MBADirector of Sales North America
Based in sunny San [email protected]
Onsite Demos & Seminars Available
THANK YOU FOR YOUR ATTENTION!!
ANY QUESTIONS?