the advantages of applying flow synthesis towards hydrogenation from laboratory … · 2012. 1....

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


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


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


Solvent: methanol Catalyst:10% Pd/C (10,84 g)


74,2 g in 80 min 445,2 74%

O2N

O

OH

H2N

O

OH


Solvent: methanol Catalyst: 10% Pd/C (2,81 g)


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


NH

NH2

OH

NH

OH

O+


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!

the advantages of applying flow synthesis towards hydrogenation from laboratory … · 2012. 1....

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