2014 08 ThalesNano Overview Presentation

Flow Chemistry: Enabling Safer and Novel Chemistry

Heather Graehl, MS, MBA Director of Sales N. America [email protected]

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.

• Flow Chemistry Market Leader • Over 800 customers worldwide

Customers

What is flow chemistry?

Performing a reacQon conQnuously, typically on small scale, through either a coil or fixed bed reactor.

OR

Pump Reactor CollecQon

What is flow chemistry?

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 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

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

Exothermic ReacQons

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

Endothermic ReacQons

Discovery Scale: !  Making processes safer !  Accessing new chemistry

!  Speed in synthesis and workup

!  AutomaQon

Process Scale: !  Making processes safer !  Reproducibility-‐less batch to batch variaQon

!  SelecQvity !  Green

Why move to flow?

Survey Conducted

Where is flow chemistry applied best?

Exothermic Reactions • Very good temperature control • Accurate residence time control • Efficient mixing • Less chance for thermal run-away • Higher productivity per volume • High selectivity

Endothermic Reactions • Control over T, p and residence time • High selectivity • Accessing new chemistry • Higher productivity per volume • High atom efficiency

Reactions with gases

• Accurate gas flow regulation • Increased safety • Easy catalyst recycling • High selectivity • Higher productivity per volume

Scale up

• Increased safety • Higher productivity per volume • Selectivity • Reproducibility

Safe High Energy Reactions

Lithiation Ozonolysis

Nitration

-70 – + 80°C Inert Conditions

2 Reaction Zones Fast Optimization

Reactions with Gases Made

Simple

Hydrogenation Oxidation

Carbonylation

150°C,100 bar mg - Half a Kilo

13 Gases No Catalyst Handling

Synthesize Novel Compounds

Heterocycles C-H activation

Catalyst screening

450°C, 100 bar Microwave Scale Up Homogeneous and

Heterogeneous

Untapped Chemical Space

Cyclization Molecule cleavage

Free radicals

Vacuum to 400 bar RT to 1000°C

New Synthesis Routes Clean

H-Cube Hydrogenation and Flow Catalysis Platform

•  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)

Hydrogenation reactions: ! Nitro Reduction ! Nitrile reduction ! Heterocycle Saturation ! Double bond saturation ! Protecting Group hydrogenolysis ! Reductive Alkylation ! Hydrogenolysis of dehydropyrimidones ! Imine Reduction ! Desulfurization

H-‐Cube – How it Works

Water Electrolysis

Hydrogen Tanks are Explosive and Severe Safety Hazard

Hydrogen generator cell !  Solid Polymer Electrolyte !  Single Cell output:

30ml/min hydrogen

High-pressure regulating valves

Water separator, flow detector, bubble detector

• Benefits •  Safety •  No filtration necessary •  Enhanced phase mixing – fast reaction times

• 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

• Pack your own with CatCart Packer

Catalyst System -‐ CatCarts

ReacQon Time

Reaction Guide is preloaded with recommended pressure, temperature, flow rate, and catalyst for each reduction type.

1.  Load Method 2.  Insert Catalyst 3.  Press Start Optional: Use Reaction Timer

Increased Reaction Times

30 seconds residence time on 30mm CatCart @ 1ml/min liquid flow rate

<5 minutes single pass through H-Cube Pro @ 1ml/min liquid flow rate

If more product is desired, run continuously.

H-Cube Pro: 1-2 grams/hour

Reactants

Products

By-products

Traditional Batch Method

Gas inlet

Reactants

Products

By-products

Batch vs. Flow

Better surface interaction Controlled residence time Elimination of the products

Flow Method

H-Cube Pro™

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

SelecQve HydrogenaQons

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

SelecQve HydrogenaQons

H-Cube: <5min Batch: 200°C, 200 bar, 48 hours

H-Cube: <5 min Batch: 150°C, 80 bar, 3 days

Difficult Hydrogenatons

10% Pd/C, 0.05M, EtOH, RT, 30 bar

10% Pt/C, 0.05 M EtOAc 100 °C, 100 bar

85% yield 92% yield

Partial or Full Reduction in <5min

Optimised reaction parameters: -  H-Cube Pro -  Temperature: 100oC -  Pressure: 100 bar -  Hydrogen amount: Maximum

Results:

•  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.

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

ParQal SaturaQon of Heterocycles

Radiochemistry application

•  Model reaction:

18F t1/2 = 109.8 min

5 min

92% 90%

3 min

1 cartridge used 15 times – no degradation

Including purification 40 min process time

S. Liang, T. Collier, B. Rotstein, R. Lewis, M. Steck, and N. Vasdev.; Chem. Com., 2013; 49 (78); 8755 – 8757.

Harvard Medical School, Massachusetts General Hospital and Northeastern University

Positron emission tomography

Chiral Phosphine-phosphoramidite ligands packed in CatCart

Asymmetric HydrogenaQon

Substrate Product Deuterium content(%)

Isolated yield / %

99 99

97 98

93 97

96 98

96 99

Mándity, I.M.; Martinek, T.A.; Darvas, F.; Fülöp, F.; Tetrahedron Letters; 2009, 50, 4372–4374

DeuteraQon

Selective Suzuki coupling (Cl, Cl)

The condiQons were:

Various FibreCat CatCarts Screened

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

Selective Suzuki coupling (Cl, Cl)

Flow rate (ml/min)

Pressure Temperature Catalyst Base

Result (bar) (oC) LC-‐MS, 220nm

0.8 20 100 Fibrecat 1007

(70mm) 3 ekv

Conversion: 82% SelecQvity: 48%

0.3 20 100 Fibrecat 1007

(70mm) 3 ekv


0.8 20 100 Fibrecat 1035

2.5 ekv Conversion: 16%

(30mm) SelecQvity: 100%

0.8 20 100 Fibrecat 1029

(30mm) 2.5 ekv


0.8 20 100 Fibrecat 1048

(30mm) 2.5 ekv


0.8 20 100 10% Pd/C



0.5 20 50 Fibrecat 1048

2.5 ekv Conversion:17%

(30mm) SelecQvity: ~100%

0.5 20 100 Fibrecat 1048


(30mm) SelecQvity: ~100%

0.2 20 100 Fibrecat 1007



0.2 20 100 Fibrecat 1007



0.2 20 100 Fibrecat 1029



• 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

H-‐Cube Family

• 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

H-Cube®

H-Cube Pro™ H-Cube Mini™ H-Cube Midi™

Industry Hydrogenations and General Flow Platform

H-‐Cubes Compared

H-Cube Mini (academia only)

H-Cube SS (refurbished only)

H-Cube Pro (current generation)

Temperature Ambient - 100°C Ambient - 100°C 10°C - 150°C

Liquid Flow 0.3-3ml/min 0.3-3ml/min 0.3-3ml/min

Throughput 20mg-10g/day 20mg-10g/day 20mg-50g/day

Starting Material Introduction

Manual Inlet Manual Inlet Automated through valves

Hydrogen Drying External DryCart Built in H2O separator Built in H2O separator

Hydrogen Flow 0ml/min OFF or 25ml/min ON

Controlled Mode ~7% of 30ml/min, 30ml/min at 1 bar, or H2 off

Full control of H2 flow from 0ml/min to 60ml/min

Module Control (Gas Module and Phoenix)

Standalone operation Standalone Operation Automated through touch screen

• Installed with hundreds of H-Cubes • Flow Rates: 0.001 to 10ml/min • Stainless steel pump head

• Complaints • Loses prime frequently • Does not tolerate air bubbles • Difficult to maintain • Check valves are not robust • Poor performance at low flow rates, not advisable below 0.5ml/min

„Knauer Pumps are the achiles heel of the H-Cube” – H-Cube Customer

New ThalesNano Micro HPLC Pump

Knauer Smartline HPLC Pump

• New pump for H-Cube and Phoenix • Ruby Ball/Saphire Seat Check Valves • More accurate • Tolerates air bubbles • Self flushing compartment • Less often and easier maintenance • Stainless Steel

New ThalesNano Mirco HPLC Pump

•  Versatile: Compressed Air, O2, CO, C2H4, SynGas, CH4, C2H6, He, N2, N2O, NO, Ar.

•  Fast: Reactions with other gases complete in less than 10 minutes

•  Powerful: Up to 100 bar capability.

•  Robust: All high quality stainless steel parts.

•  Simple: 3 button stand-alone control or via simple touch screen control on H-Cube Pro™.

Gas Module

"  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

CarbonylaQons

Pressure Temp. (oC) CatCart Conversion Selectivity

40 25 1 % Au/TiO2 0 – 40 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 0 100 100 1 % Au

/Fe2O3 31 7 100 • Area% of desired product in GC-MS / (100 – Area% of reactant in GC-MS)

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),

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

Very fast addition of alcohol to gold surface. Alkoxide formation.

Green OxidaQon OpQmizaQon

Powerful: Up to 450°C

Versatile: Heterogeneous and homogeneous capabilities.

Fast: Reactions in seconds or minutes.

Safe – Software emergency shutoff and hardware pressure release valve

Phoenix Flow Reactor

Standalone Version Module Version Includes HPLC Pump and 200bar Valve Module

Requires HPLC Pump and BP Regulator from existing Thales Reactor (H-Cube, X-Cube, etc)

Phoenix metal-metal CatCarts (125mm/250mm)

Max T 450°C+

H-Cube Pro CatCarts (30 or 70mm) Max T 250°C

Phoenix Heterogeneous ReacQons

•  Choice of stainless steel, teflon, or Hastelloy

•  Different length coils to vary residence time

•  Easy to recoil

Phoenix Homogeneous ReacQons

8ml loop w/ SS tubing

8ml loop holder

Heck Chemistry (MW / Flow) – Homogeneous Catalysis with Pd(OAc)2

Entry Conditions Pd(OAc)2 [mol%] Temp [°C] / Time [min]

Conversion [%, GC-FID]

Selectivity P/D/H [%, GC-FID]

1 Batch/MW 0.4 150 / 2 >99 89 / 5 / 6

2 Batch/MW 0.1 150 / 2 >99 93 / 2 / 5

3 Batch/MW 0.05 150 / 5 >99 98 / 1 / 1

4 Batch/MW 0.01 150 /25 >99 99 / <1 / 0

5 Batch/MW 0.01 170 / 10 >99 99 / <1 / 0

6 Batch/MW 0.001/ 10 mol% TBAB 190 / 15 >99 99 / <1 / 0

7 Batch/OB 0.01 150 / 25 >99 99 / <1 / 0

(94%)

Aryl Iodide

Scalable C-‐C Couplings

Conditions: p = 70 bar T = 270°C v = 0.4 mL/min c = 0.04 M (NMP) Result: 82% yield

Kappe, O. C. et al. Eur. J. Org. Chem., 2009, 9, 1321-1325.

Kolbe Synthesis Conditions: p = 60 bar T = 180°C v = 4 mL/min Residence time: 440 s c = 0.49 M (H2O) Best result: 51% conversion

Kappe, O. et al. Chem. Eng. Technol. 2009, 32(11), 1-16.

SNAr reaction

High Temperature ReacQons

•  Standard benzannulation reaction •  Good source of:

•  Quinolines •  Pyridopyrimidones •  Naphthyridines

→ Important structural drug motifs

Disadvantages: • Harsh conditions • High b.p. solvents • Selectivity

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 ReacQon -‐ Overview

Merck & Phoenix Flow Reactor

• Optimal temperature at 220C • Des methyl quinoline ester observed

• Reactions from 10-450C and 1-100bar (1450 psi) • Up to 13 different reagent gases • Heterogeneous or homogeneous catalysis

Fully Automated system available

VersaQle Flow Chemistry Planorm

IceCube for

High Energy

Reac6ons

Halogena6on

Nitra6on Azides

Mul6step reac6ons

Reac6ve Intermediates

Lithia6on

Ozonolysis

Swern Oxida6on

IdenQfied ApplicaQons

Set-up of the Ice Cube Modular System

Ozone Module: generates O3 from O2 100 mL/min, 14 % O3.

Pump Module – 2 Rotary Piston Pumps. Excellent chemical compatibility. Automation in progress.

Reactor Module: 2 Stage reactor. -70°C-+80°C. Teflon tubing.

A B

C

D -70-+80ºC -30-+80ºC

Potential Apps: Azide, Lithiation, ozonolysis, nitration, swern oxidation Teflon tubing for cheap and easy blockage removal.

First Reac6on Zone Second Reac6on Zone

Water inlet and outlet

Reactor Plate • Aluminum blocks lined with teflon tubes • Easy to coil for desired pre-‐cooling and desired residence Qme aoer mixing • Different mixers types available

A B

D

-‐70-‐+80ºC -‐30-‐+80ºC

C First Reac6on Zone Second Reac6on Zone

Cooling Module

Ozonolysis •  Ozonolysis is a technique that cleaves double and triple C-C bonds to form a C-O bond.

•  Safety problems: !  Control of temperature. !  Explosive decomposition

O3

C=C Product (alcohol, ketone, or acid)

-‐70-‐+80ºC -‐30-‐+80ºC

First Reac6on Zone Second Reac6on Zone Quench

IceCube™ – H-Cube® - ReactIR™ ozonolysis of decene

Ozonolysis Quenching with H-Cube®

T = -30 ºC CSM = 0.02 M (in EtOAc) O3 excess = 30 %

T = -30 ºC to r.t. p = 1 bar Cat: 10 % Pd/C

Mettler Flow IR™

O-Cube and ReactIR are trademarks of ThalesNano Inc. and Mettler Toledo International Inc., respectively, H-Cube is registered trademark of ThalesNano Inc.

ThalesNano lab based chemistry-unpublished Ozonide eluted into cool vial under N2

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

In Flow:

Even at -‐10°C without side product formaQon

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

* Aoer purificaQon

When compared to batch condiQons, IceCube can sQll control reacQons at warmer temperatures due to beuer mixing and more efficient heat transfer.

Swern OxidaQon

•  2 Step Azide Reaction in flow •  No isolation of DAGL •  Significantly reduced hazards

TKX50

Making Azide Chemistry Safer

Diazonium salts and diazo coupling

•  Most aromatic diazonium salts are not stable at temperatures above 5°C

•  The synthesis reaction to prepare the diazonium salt is typically exothermic, producing between 65 and 150 kJ/mole and is usually run industrially at sub-ambient temperatures

•  Diazonium salts decompose exothermically, producing between 160 and 180 kJ/mole

•  Many diazonium salts are shock-sensitive

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 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

DioaziQzaQon

•  Reagent: BuLi

•  Set-up: 3 pumps, 2 reactors. •  Requires N2 atmosphere in the input vial. •  It’s not necessary to cool the system down to -78 °C.

LithiaQon

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 08 ThalesNano Overview Presentation

Science

Transcript of 2014 08 ThalesNano Overview Presentation