8/3/2019 Paul Whittles et al- A Comparitive Study Between Microwave and Microfluidic Reactivity to Offer Up Microreactors a

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H-Cube - Continuous-flow

Hydrogenation

A flow of substrate is pumped into the reactor where it is combined with hydrogen,produced by the electrolysis of water

The substrate/hydrogen mixture is heated and/or pressurized, up to 100C and100 bars (1450 psi) respectively, and then passed through a catalyst cartridge(CatCart)

The reaction takes place on the catalyst and the generated product elutescontinuously into a collection vial.

EXPERIMENTALS

Paul Whittles, Niesz Krisztian, Richard Jones, Laszlo rge, Ferenc Darvas

ThalesNano, Inc., Zahony u. 7., Budapest, Hungary H-1031 paul.whittles@thalesnano.comwww.thalesnano.com

SummaryThe above reactions demonstrate that the continuous-flow technology, H-Cube for hydrogenation and X-Cube for different type of chemical reactions can offer a viablesolution to the microwave scale up problem. These microreactors open the door to the new generation of reactions and scale-up applications combining the elavetedtemperature and pressure with the continuous-flow of reactants resulting higher yield than it can be achieved in microwave reeactors.

References: (1) Leadbeater, N. E.; Smith, R. J.; Org. Lett.; 2006; 8(20); 4589 - 4591. (2) Varma, R. S.; Dahiya, R.; Tetrahedron; 54 (23); 1998; 6293 - 6298.(3) Firoz, M. M.; Khakshoor O; Ghaffarzadeh M; J. Chem. Res. Synop. 12;

2001; 525-527, (4) Ju, Y.; Kumar, D.; Varma, R. S; J. Org. Chem.; 2006; 71(17); 6697 - 6700. (5) Gupta, R,; Paul, S.; Nanda, P.; J. Indian Chem. Soc.; 2005; 82(6); 573 - 574.

A Comparitive Study Between Microwave and Microfluidic Reactivityo Offer Up Microreactors as a Scale Up Alternative to Microwaves

The hydrogenation reactor, H-Cube, is acompact continuous-flow reactor whichperforms high pressure hydrogenationsthrough the use of a microfluidic reactionline, in-situ hydrogen generation and acatalyst cartridge system (CatCart).

INTRODUCTIONThe pharmaceutical and chemical industry is continuously searching for technologies that make synthesis easier and faster in large scale.

Microflow technology has many advantages highly efficient heat exchange is one of the most important. The flow of material through the

reactors is only a matter of minutes, so results can be achieved in a very short space of time. At ThalesNano Nanotechnology Inc., we havedeveloped a series continuous-flow reactors for organic synthesis. Below is a description of the H-Cube, a hydrogenation reactor, and the

X-Cube reactor for different type of organic reactions. The microreactors reactions can also be scaled-up easily by running many smallscale reactions in parallel, and/or for a longer time. With the microwave technology scale up is extremely difficult and fraught withcomplications. Therefore microreactors can offer a viable solution to the microwave scale up problem. The following reactions will

demonstrate that different type of reactions can be performed with the similar results as can achieve using microwave irradiation.

X-Cube - Continuous-flow organic reactions

Many application can prove theadvantages of the microwave assistedorganic synthesis. Using microwaveenergy the results of the reactions aregenerally better than in case ofconventional heating which means thathigher yields can be achieved because ofthe direct, focused heating if the reactionmixture instead of the vessel. The scale-up procedure eighter in bach or inmicrowave reactors is complicated

NHN

NH2

O

+

1. 2.

Reaction

No.Mode Catalyst/Reagent Conditions

Yield /

%

1 Microwave 1. Montmorillonte K10 clay

2. NaBH4-clay

MW irradiation

65C, MW irradiation

89

1 Flow 1% Ir/C Solvent: EtOH

c = 0,01 M

T = 70 C;

p = 70 bars

Flow rate: 0,5 mL/min

93

2 Microwave Triethylammonium

formate, formic acid

MW irradiation81

2 Flow FibreCat Ir Solvent: EtOH

C = 0,01 M

T = 100 C

p = 70 barsFlow rate: 0,3 mL/perc

94

NH

NH2

O

+

N NH

Reaction No. ModeCatalyst/Rea

gentConditions Yield / %

Azid synthesis Microwave NaN3 Solvent: H2O

120C 95Azid synthesis Flow Azid on

AmberlyteSolvent: Acetonitrilp = 40 barsT = 110CFlow rate: 0,2 mL/minc = 0,1 M

96

N-formylation Microwave Basic

alumina, H2O

36-38C

81

N-formylation Flow Titanium Solvent: EtOH:-HCOOH= 5:1p = 50 barsT = 200CFlow rate: 0,2 mL/minc = 0,1 M

90

Suzuki coupling Microwave DBU,Pd(OAc)2

Solvent: EtOH, H2O150C

55

Suzuki coupling Flow FibreCat1007;

Base: TBAF;Solvent: IPA;c= 0,01 M

p = 10 barsT = 80 C;

Flow rate: 0,3 mL/min;

70

Br N3

NH

N

O

B

HO OH

+

Br

O

O

The X-Cube allows organic reactions to beperformed in a flow manner, combining the use oftemperatures and pressures up to 200C and 150bars (2176 psi) respectively and acatalyst/reagent cartridge system (CatCart). Acontinuous-flow of reaction mixture may be fed by

a dual pump system or injected into the reactordirectly. All reagents are heterogeneous includingmany polymer bound reagents and catalysts.

The two reaction zones can be heated independently and multistep synthesis canbe carried out in one flow.

The high pressure/high temperature capability means many reactions progress tocompletion in minutes

Regulated gas can be introduced into the instrument from an external gas source toperform industrially important triphasic reactions.

Scale-up: Present and Future Perspective

Easier scale-upwith

similar results

Step 1.

Easier scale-upwith

similar results

Step 2.

BACKGROUND

The following reactions demonstrate that

different reactions can be performed withthe similar results can be achieved usingmicrowave irradiation, but the scale-upusing continuous flow mode is easierand have 3 ways

increasing the time of reactions

increasing the flow rate

using the soon available H-CubeMidi, Scale-up Hydrogenation Reactor

Reaction 1. (Microwave mode) Reaction 1. (Flow mode)

Reaction 2.

FibreCat is a trademark of Reaxa Ltd,.