2014 02 cepheid presentation - midi, phoenix, icecube

Enabling Your Synthesis with Flow Chemistry Heather Graehl, MS, MBA Director of Sales North America ThalesNano 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 reacRon conRnuously, typically on small scale, through either a coil or fixed bed reactor.

OR

Pump Reactor CollecRon

What is flow chemistry?

•  In a microfluidic device with a constant flow rate, the concentraRon of the reactant decays exponenRally with distance along the reactor.

•  Thus Rme in a flask reactor equates with distance in a flow reactor

X

A

dX/dt > 0

dA/dt < 0

KineRcs in Flow Reactors

Flow reactors can achieve homogeneous mixing and uniform hea6ng in microseconds (suitable for fast reac6ons)

Improved Mixing Compared to Batch

Improved mixing can lead to improved reac6on 6mes, especially with fixed bed reactors

Improved Mixing = Faster Rxn Time

•  Microreactors have higher surface-‐to-‐volume raRo 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

Enhanced Temperature Control

Lower reaction volume. Closer and uniform temperature control

Outcome:

Safer chemistry. Lower possibility of exotherm.

Batch

Flow

Larger solvent volume. Lower temperature control.

Outcome:

More difficult reaction control. Possibility of exotherm.


Batch Heated Rxns •  Safety concerns, especially in scale

up

•  Microwave technology is fastest way of heaRng 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, conRnuously


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


Reactants

Products

By-products

Traditional Batch Method

Gas inlet

Reactants

Products

By-products

Better surface interaction Controlled residence time Elimination of the products

Flow Method

H-Cube Pro™

SelecRvity – Residence Time Control

Catalyst screening

Parameter scanning: effect of residence time to the conversion and selectivity

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

SelecRve AromaRc Nitro ReducRon

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)

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 GeneraRon

• 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 • 90x9.5mm

• Ability to pack your own CatCarts • CatCart Packer (with vacuum) • CatCart Closer (no vacuum)

Catalyst System -‐ CatCart

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%

Simple ValidaRon ReacRons

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

Simple ValidaRon ReacRons

Batch: 200°C, 200 bar, 48 hours

Batch: 150°C, 80 bar, 3 days

Difficult HydrogenaRons

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

SelecRve HydrogenaRons

Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17s Results: 100% conversion, 97% yield


Conditions: Au/TiO2, 70 bar, 30°C, residence time 17s Results: 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


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


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


Analysis by GC-MS At the same substrate: catalyst ratio 0.125 mol substrate was reduced

Reaction parameters

Batch in house H-Cube Midi™

Catalyst C (M)

Flow rate (mL/min) T (°C)

p (bar) Conversion(%)

Selectivity(%)

360 mg RaNi 0.05 (60 cm3)

- 30 20

100 95

After 120 min 0.003 mol compound was reduced

15.02 g RaNiEtOH 0.2

12.5 30 20

100 95

After 1.2 min 0.003 mol compound was reduced

Conversion (%

)

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

OpRmizaRon on H-‐Cue 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

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.

HydrogenaRon Challenge

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

SelecRve DehydrochlorinaRon

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%)

SelecRve Nitro ReducRon: Sanofi

●  Genzyme needed 1.2 kg of Zavesca for an internal study, which was priced at 47K USD per 100 g.

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

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

Gould Jacobs ReacRon -‐ Overview

5 novel bicyclic scaffolds generated-fully characterized. Many more to follow

New Scaffold GeneraRon

•  Choice of stainless steel, teflon, or Hastelloy

•  Different length coils to vary residence time

•  Easy to recoil

Phoenix Homogeneous ReacRons

•  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 ReacRons

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 ReacRon not Possible in Batch

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 Energy

Reac6ons

Safe: Low reacRon volume, excellent temperature control, SW controlled – including many safety control points

Simple to use: easy to set up, default reactor structures, proper system construcRon

Powerful: -‐70°C to +80°C

Versa6le chemistry: Ozonolysis, nitraRon, lithiaRon, azide chemistry, diazoRzaRon

Versa6le reactors: Teflon loops for 2 reactors with 1/16” and 1/8” loops

High Chemical resistance: Teflon weped parts

Mul6step reac6ons: 2 reacRon zones in 1 system Modular: OpRon for Ozone Module or more pumps

Size: Stackable to reduce footprint

IceCube

First Reac6on Zone Second Reac6on 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 Rme aqer mixing • Different mixers types available

A B

D

-‐70-‐+80ºC -‐30-‐+80ºC

C First Reac6on Zone Second Reac6on Zone

ReacRon Zones

A

B C

A B

C

D

Pre-‐cooler/Mixer Reactor

-‐70-‐+80ºC

-‐70-‐+80ºC -‐30-‐+80ºC

Applica6ons: Azide, Lithia6on, ozonolysis, nitra6on, Swern oxida6on

Azide, nitra6on, Swern oxida6on

Ideal for reactive intermediates or quenching

Single or MulR-‐Step ReacRons

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

Carboxylic Acid (oxidative work-up)

Aldehyde/Ketone (simple quenching)

Alcohol (reductive work-up)

Workup Determines Product

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

Ozonolysis in Industry

Why ozonolysis is neglected?

•  Highly exothermic reacRon, high risk of explosion

•  Normally requires low temperature: -‐78°C. •  In addiRon, the batchwise accumulaRon of ozonide is associated again with risk of explosion

•  There are alternaRve oxidizing agents/systems: •  Sodium Periodate – Osmium Tetroxide (NaIO4-‐OsO4)

•  Ru(VIII)O4 + NaIO4

•  Jones oxidaRon (CrO3, H2SO4)

•  Swern oxidaRon •  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. Lep.,

Flow Ozonolysis of Styrenes

Batch reac6on: Max. -‐60°C to avoid side reacRon

In Flow:

Even at -‐10°C without side product formaRon

0.45 M in DCM, 0.96 mL/min

0.45 M alcohol, 0.14 M DMSO in DCM 0.94 mL/min

3.6 M in MeOH, 0.76 mL/min

* Aqer purificaRon

When compared to batch condiRons, IceCube can sRll control reacRons at warmer temperatures due to beper mixing and more efficient heat transfer.

ApplicaRon 1: Swern OxidaRon

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 91

2 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

Aniline HCl sol. Pump A

Pump B NaNO2 sol.

Pump C

Phenol NaOH sol. • Most aromaRc 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-‐sensiRve

DioaziRzaRon and Azo Coupling

Pump A Pump B Temperature (oC)

Loop size (ml)

Conversion (%)

SelecRvity (%)

SoluRon Flow rate (ml/

min) SoluRon Flow rate (ml/

min)

ccHNO3 0.4 1g Ph/15ml ccH2SO4 0.4 5 -‐ 10 7 100

0 (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)

NitraRon of AromaRc Alcohols

•  LithiaRon experiments

•  HalogenaRons/FluorinaRon experiments

•  ExpoxidaRon experiments, asymmetric

•  Very low temperature experiments, where batch

condiRons 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, MBA Director of Sales North America

Based in sunny San Diego [email protected]

Onsite Demos & Seminars Available

THANK YOU FOR YOUR ATTENTION!!

ANY QUESTIONS?

2014 02 cepheid presentation - midi, phoenix, icecube

Technology