Improved Chemical SynthesisImproved Chemical Synthesis ...

Improved Chemical Synthesis Using Automated Microfluidic Platforms

Jonathan McMullen & Klavs F. Jensen

Department of Chemical Engineering Massachusetts Institute of Technology Cambridge, MA 02139 617 253 4589 kfjensen@mit.edu web.mit.edu/jensenlab

Chemistry classic science traditionally performed batchwise

~1900

~1750

~2000

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Continuous flow microsystems reduce cost of information per experiment and enable new operating conditions

Reactor 2 Separator Reactor 1

Integrated continuous, microreactors, separation and detection units in chemically compatible materials

High throughput, automated, and optimized synthesis Integrates analytics and workflow Less waste and better use of resources Platform for exploring new reaction chemistry and conditions not

easily accessed in batch

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Microreactor technology advantages Controlling mixing

Desired features:

? chemical compatibility (e.g., glass surfaces)

? controlled mixing

activator acceptor donor

D. Ratner, K.F. Jensen, P. Seeberger et al.,

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Chem Comm 2005, 24, 578

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Microreactor technology advantages Controlling mixing

Desired features:

? chemical compatibility (e.g., glass surfaces)

? controlled mixing

activator acceptor donor

DU. Rsaitnnegr, gK.aF.sJetnosemn,iPx. Seeberger et al.,

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Ch-emBlCaocmkmin2k00i5n,t2o4,w5a7t8er (S. Khan)

Microreactor technology advantages Controlling residence time and temperature

TE heater/ cooler

Desired features:

? chemical compatibility ? controlled mixing ? well defined reaction time

(residence time) ? ability to quench reaction ? temperature control (bath

or TE element) ? connections to fluid

handling

Heat sink fluid chamber

40 mm

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Microreactors can be fabricated for a variety of reactions

Chips customized for

? Gas ? liquid reaction ? Gas ? liquid ? solid

reaction ? Immobilized catalyst

Reactors integrated with

? Heaters ? Mixers ? Separators ? Temperature measurement ? Spectroscopy

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Continuous flow systems could revolutionize the development and production chain for fine chemicals and pharmaceuticals

Discovery

Laboratory

Plant

`

Biologists Chemists

Chemists Engineers

Different discovery, development and production platforms are slow and complicate scale-up

Integrated and automated continuous process platforms span across length scales and accelerate translation of

8 discoveries into development and production

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Combining continuous flow microreactors with liquid handling yields a reaction screening platform

? Set reaction temperature and residence time

? Withdraw reagents from sample well

? Inject samples into microfluidic flow system

? Detect reaction segment

? Collect reaction segment

? Perform analysis offline

Liquid handler

Flow inlets

Temp. control

UV/Vis

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To waste

Fraction collector

J.R. Goodell, J.P. McMullen, K.F. Jensen, J.A. Porco, A.B. Beeler, et al., J. Org. Chem (in press)

Combining continuous flow microreactors with liquid handling yields a reaction screening platform

reagents

O

O MeO

H

Ph Me 3H

Continuous screening of

reactions - building a library

A1+B, A1+C, ... A2+B, A2+C, ...

Ex: retro Dieckmann reaction analysis by UPLC

Compound libraries can be generated quickly

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J.R. Goodell, J.P. McMullen, K.F. Jensen, J.A. Porco, A.B. Beeler, et al., J. Org. Chem (in press)

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