Van batch naar flow: paradigmaverschuiving in de organische synthese

Transcription

1 Van batch naar flow: paradigmaverschuiving in de organische synthese Floris Rutjes Instituut voor Moleculen en Materialen Radboud Universiteit Nijmegen Labanalyse oktober 2009

2 An old hobby: rowing The Macon blade became popular in the 1960s and was the most widely used blade type for thirty years. Introduced in 1991, its asymmetric design and increased surface area create a bigger "shovel". The latest design offers the greatest potential for increasing boat speed.

3 Organic synthesis over the years > 230 yrs Antoine Lavoisier Anno ~1770 Modern lab Anno 2007 Our aim: Development of a microreactor system Focus on optimization and screening

4 2003: Microreactor project Kaspar Koch Pieter Nieuwland Intterreg-III (Euregio) subsidized collaborative project between Radboud University Nijmegen (van Hest, Rutjes), Wageningen University (Sudholter, Boom) and Fraunhofer IMS in Duisburg (Germany)

5 Definition microreactor A microreactor or microstructured reactor or microchannel reactor is a device in which chemical reactions take place in a confinement with typical lateral dimensions below 1 mm; the most typical form of such confinement are microchannels. [1] Rapid mixing Smaller footprint Heat/masstransfer Industry 0.06 cm 2 /cm 3 Lab 1 cm 2 /cm 3 Microreactor 200 cm 2 /cm 3 [1] P Watts, C Wiles Chem Commun 2007,

6 Traditional versus flow chemistry Traditional batch wise Major drivers Flowchemistry: Safer, cleaner Outscalable Coupling Oxidation Deprotection Hydrolysis Centrifuge Dryer Continuous flow Continuous flow microreactors Translation Coupling Oxidation Deprotection Hydrolysis Centrifuge Dryer Microreactor: Rapid mixing Heat/masstransfer Industry 0.06 cm 2 /cm 3 Lab 1 cm 2 /cm 3 Microreactor 200 cm 2 /cm 3 Smaller footprint

7 Examples

8 Microreactors are highly scalable µl / min ml/ min W. P. Bula, G. E. Gardeniers et al, Lab on a Chip 2007, 7, L / min Micronit Microfluidics CPC, Velocys, Siemens H Pennemann, P Watts, SJ Haswell, V Hessel, H Lowe, Org Proc Res Dev 2004, 8, 422.

9 Initial bottlenecks µm Fluid handling Microreactor Quench Image of microchannel HPLC GC Interpretation Analysis

10 Evolution of chipholder V1.0 (sept 2004) - Leakage at in- and outlets - Time consuming to connect Commercial source (jan 2004) - No heating - Leakage at in- and outlets - Time consuming to connect V1.1 (sept 2005) - Time consuming to connect - No commercial connectors V2.0 (june 2005) - No heating - No commercial connectors V2.1 (dec 2005) - No heating V2.2 (oct 2006) V2.3 final version

11 The microreactor setup Patent application PCT/EP/2006/010299

12 Microreactor setup Offline analysis GC / HPLC Online analysis NMR* / MS / Raman K. Koch et al, Biotechnol. Bioeng., 2008, 99, Patent application PCT/EP/2006/ *Collaboration with prof. Kentgens (RU) and prof. Gardeniers (UT)

13 The microreactor platform A Plug and Play microreactor platform has been established Hardware Patented chipholder Control box (i.e. temperature, flow) Multiple microreactor designs Software Control over flow and temperature Automated screening of reaction parameters Automated feedback to/from analysis devices Applications and experience Organic reactions Separation Extraction Collaboration with Prof. J. van Hest (Radboud University) and Fraunhofer IMS (Germany)

14 Access to enantiopure cyanohydrins OH (S)-HNL,pH 4.5 O (R)-HNL,pH4.5 OH HCN, H 2 O/MTBE HCN,H 2 O/MTBE NC CO 2 Me H CO 2 Me NC CO 2 Me Hevea brasiliensis Prunus amygdalum (rubbertree) (almonds) 91%, 94%ee 95%, 93%ee Enzymes are produced via a recombinant Pichia pastoris PluGbug strain (DSM, The Netherlands), but are also commercially available Review on HNL-catalyzed reactions: MH Fechter, H Griengl, In Enzyme catalysis in organic synthesis; K Drauz, H Waldmann, Eds.; Wiley-VCH: Weinheim, 2002; Vol II, pp

15 Schematic setup 0.23 M HCN, (R)-PaHNL Chiral HPLC Internal volume 1.3 µl Length channel 0.7 meter! 1 M HCl [quench] collect sample ( 1 min) 0.23 M benzaldehyde

16 Formation of mandelonitrile K Koch, RJF van den Berg, PJ Nieuwland, R Wijtmans, MG Wubbolts, HE Schoemaker, FPJT Rutjes, JCM van Hest, Chem Eng J 2008, 135S, S89 S92.

17 PMP deprotection Cl N O N Cl O N Cl TCCA O Chlorine Maxi Tablets 10kg R O NH 3 Cl % OMe 0.5 equiv TCCA O NH 3 Cl or 1equiv H 5 IO 6 Laccase frome.g. O HN R 1equiv H 2 SO 4 Trametesversicolor then extraction R or R 1 Agaricusbisporus R 1 R 1 (mediator) 50-90% Deprotection with TCCA or periodic acid: JMM Verkade, LJC van Hemert, PJLM Quaedflieg, PL Alsters, FL van Delft, FPJT Rutjes, Tetrahedron Lett 2006, 47, Deprotection with laccase: JMM Verkade, LJC van Hemert, PJLM Quaedflieg, HE Schoemaker, M Schürmann, FL van Delft, FPJT Rutjes, Adv Synth Catal 2007, 349, 1332.

18 Optimization of the deprotection Step 1: Translation Quenching H 5 IO 6 NaOH H 2 SO 4 Step 2: Selection of the factors Three factors were investigated: q Temperature (60 90 ) q Reaction time (0.1 6 min) q Stoichiometry (1 4) Analysis Advanced design-of-experiments (D optimal) With IMM chemometrics group (H.R.M.J. Wehrens)

19 D-optimal: flexible, versatile, robust D-optimal allows to work in irregular experimental domains (very flexible) +1 x 2 +1 D-optimal selection -1 x 1-1 Ideal for experimental designs which are non-linear x 1 response response response factor factor factor Tutorial: P. F. de Aguiar, B. Bourguignon et al. 1995, Chemom. Intell. Lab. Syst.,