In-line Monitoring of Continuous and Segmented Flow Processes

Transcription

1 In-line Monitoring of Continuous and Segmented Flow Processes Catherine Carter, The Ley Group, Department of Chemistry, University of Cambridge

2 Introduction Why do flow chemistry? Safety Why do we need in-line monitoring? Early examples from our group -IR -UV Quality Durability/ Robustness In-line monitoring for process control - Third stream addition - Azide scavenging - Gas concentrations The future of in-line monitoring Cost Environmental Impact Zhang, T. Y., Chem. Rev.2006, 106, 2583.

3 Introduction Advantages of flow chemistry - Control over reaction parameters leads to reproducibility - Pressurized system allows superheating of solvents superior reaction profiles - Increased process safety through containment of hazardous or malodorous substances - In-line purification methods minimise manual handling and lessens waste - Ability to continuously process machine-assisted 24/7 working Baxendale, I. R.; Hayward, J. J.; Lanners, S.; Ley, S. V. and Smith, C. D., in Microreactors in Organic Synthesis and Catalysis, ed. T. Wirth, WileyVCH, Weinheim, 2008, ch. 4.2, pp

4 In-line monitoring - Control over a closed system - A problem can be detected immediately, not after the residence time of the reactor - Reactive intermediates - Monitoring of hazardous components - Process safety, control and timing - System is not interrupted by off-line processing

5 UV monitoring: Synthesis of Gleevec - Cheap and established (fraction collector control in HPLC systems) - Small footprint -Used in the continuous flow synthesis of Gleevec Cl O 9(1equiv.) Cl CH 2 Cl ml/min DIPEA(1.1 equiv.) 1mL,0.2M QP-DMA/QP-SA (1:1, 4.5 equiv.) Br CH 2 Cl ml/min 1mL,0.2M rt,5ml, 12.5 min 100 PSI HN O Cl Br NH 2 (1equiv.) Hopkin, M. D.; Baxendale, I. R.; Ley, S. V., Chem. Commun. 2010, 46,

6 UV monitoring: Synthesis of Gleevec - Cheap and established (fraction collector control in HPLC systems) - Small footprint -Used in the continuous flow synthesis of Gleevec Cl O 9(1equiv.) Cl CH 2 Cl ml/min DIPEA(1.1 equiv.) 1mL,0.2M QP-DMA/QP-SA (1:1, 4.5 equiv.) UV 100 PSI 1mL,0.2M rt,5ml, 12.5 min N CH 2 Cl ml/min Br Fraction Collector N H (2equiv.) DMF (10 ml) NH 2 (1equiv.) Hopkin, M. D.; Baxendale, I. R.; Ley, S. V., Chem. Commun. 2010, 46,

7 UV monitoring: Synthesis of Gleevec Cl O (1.5 equiv.) Cl PS-DMAP (3equiv.) QP-DMA (3equiv.) Waste CH 2 Cl ml/min 1mL,0.3M UV 100 PSI then CH 2 Cl ml/min 1mL,0.2M Br (1equiv.) NH 2 SS-SA (0.2 mmol) PS-NCO (3equiv.) CaCO 3 (3.5 g) Exhaust N 2 Waste 100 PSI 80 C 0.1 ml/min N Br HN N N O 80% (47%over2steps) 2.0MNH 3 inmeoh 5mL then MeOH 0.5 ml/min Fraction Collector/ Autosampler N H (2equiv.) DMF (4mL) Hopkin, M. D.; Baxendale, I. R.; Ley, S. V., Chem. Commun. 2010, 46,

8 IR monitoring - Body: ReactIR TM 45m, fitted with a Mercury Cadmium Telluride (MCT) detector. - Flow cell: Attenuated Total Reflectance (ATR) diamond and silicon sensors - Full infrared spectral region from 650 to 4000 cm 1 - icir 4.2 software for system operation and data analysis Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Wittkamp, B.; Goode, J. G.; Gaunt, N. L., Org. Process Res. Dev. 2010, 14, ;

9 IR monitoring - Body: ReactIR TM 45m, fitted with a Mercury Cadmium Telluride (MCT) detector. - Flow cell: Attenuated Total Reflectance (ATR) diamond and silicon sensors - Full infrared spectral region from 650 to 4000 cm 1 - icir 4.2 software for system operation and data analysis Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Wittkamp, B.; Goode, J. G.; Gaunt, N. L., Org. Process Res. Dev. 2010, 14, ;

10 IR monitoring: Fluorinations Baumann, M.; Baxendale, I. R.; Martin, L. J.; Ley, S. V. Tetrahedron 2009, 65, ; Baumann, M.; Baxendale, I. R.; Ley, S. V. Synlett 2008,

11 IR monitoring: Fluorinations

12 IR monitoring: Fluorinations

13 IR monitoring: Fluorinations

14 IR monitoring: Fluorinations

15 IR monitoring: Curtius rearrangement OH O HO NEt 3 MeCN 0.5 ml/min MeCN 0.5 ml/min 10mL rt-120 C IR 10mL 120 C 10mL 120 C 100 PSI QP-SA/QP-DMA rt N H O O 84% purity 93% O P PhO N 3 PhO Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D.; Tierney, J. P. Org. Biomol. Chem.2008, 6,

16 IR monitoring: Curtius rearrangement

17 IR monitoring: Curtius rearrangement N 3 O IR 10mL 40 C 20mL 120 C

18 The Third Stream Problem

19 First solution: Off-line modelling and automated pumping Prediction based on dispersion model Can t take into account polymer supported reagents Not based on live information, doesn t account for incomplete conversion Simple on/off pumping wastes excess material Flow Commander available from Vapourtec

20 Second solution: In-line monitoring and manual pumping 0.5 M "Third Stream" Manual Reagent D 0.5M 0.1 ml/min Solvent Solvent 0.1 ml/min Reagent A 1M Reagent B 1M XmL XmL 10mL C IR Product E 0.5 M 0.5 M 2XmL YmL Can take into account dispersive effects of polymer supported reagents increased accuracy Based on live information, but still doesn t account for incomplete conversion Simple on/off pumping wastes excess material Qian, Z. Z.; Baxendale, I. R.; Ley, S. V., Chem. Eur. J. 2010, 16,

21 Third solution: In-line monitoring and automated pumping Lange, H.; Carter, C. F.; Hopkin, M. D.; Burke, A.; Goode, J. G.; Baxendale, I. R.; Ley, S. V., Chem. Sci. 2011, 2,

22 Third solution: In-line monitoring and automated pumping Desired number of equivalents Flow rate of reaction stream Absorption coefficient of C in reaction solvent Concentration of D Absorbance of C in IR (peak height) Correlation factor Lange, H.; Carter, C. F.; Hopkin, M. D.; Burke, A.; Goode, J. G.; Baxendale, I. R.; Ley, S. V., Chem. Sci. 2011, 2,

23 Software development Can we control a pump based on a live read out of concentration from the ReactIR? National Instruments LabVIEW application written Obtain live peak height from Excel Multiply by conversion factor Can resulting flow rate be delivered by the pump? NO YES Set flow rate to 0 or a defined maximum Convert into a string of type Fxxxx Send command to pump Repeat every 1 s

24 Software Development Can we control a pump based on a live read out of concentration from the ReactIR? National Instruments LabVIEW application written Obtain live peak height from Excel Multiply by conversion factor Can resulting flow rate be delivered by the pump? NO YES Set flow rate to 0 or a defined maximum Convert into a string of type Fxxxx Send command to pump Repeat every 1 s

25 Accurate Reagent Addition: Proof-of-concept y = x R² = Concentration (M) FR = (( )/0.0833) A = 6630 A Peak Height

26 Accurate reagent addition: Proof-of-concept 75PSI First cell shows dispersion curve of intermediate

27 Accurate reagent addition: Proof-of-concept 75PSI Second cell shows the trace of the second compound accurately matched with the first compound Each annotation represents a vial collected every 90 seconds 1 H NMR ratio calculated Ratio of the integrations of the absolute absorptions also calculated

28 Accurate reagent addition: Proof-of-concept 2 Addition of a Third Stream with 1:1 Stoichiometry Ratio between components :21:36 0:24:29 0:27:22 0:30:14 0:33:07 0:36:00 0:38:53 0:41:46 0:44:38 0:47:31 0:50:24 Reaction time (hh:mm:ss) NMR IR Third stream successfully added with 1:1 stoichiometry for >97% of the material Limitation at the ends of the dispersion curves arises from inaccuracy of piston pumps at very low flow rates

29 Application to polyketide synthesis 75PSI No manual handling of sensitive aldehyde intermediate Application in complex molecule synthesis Much faster than the corresponding batch processes Carter, C. F.; Lange, H.; Sakai, D.; Baxendale, I. R.; Ley, S. V., Chem. Eur. J. 2011, 17,

30 Application to polyketide synthesis 75PSI No manual handling of sensitive aldehyde intermediate Application in complex molecule synthesis Much faster than the corresponding batch processes

31 IR monitoring: Azide chemistry Smith, C. J.; Nikbin, N.; Ley, S. V.; Lange, H.; Baxendale, I. R., Org. Biomol. Chem. 2011, 9,

32 IR monitoring: Azide chemistry

33 IR monitoring: Azide chemistry Kopach, M. E.; Murray, M. M.; Braden, T. M.; Kobierski, M. E.andWilliams, O.L.Org. Process Res. Dev.2009, 13, ; Feigl, F. and Anger, V. Spot Tests in Inorganic Analysis, trans. R. E. Oesper, Elsevier, Amsterdam, 6th English edn, 1972, p. 357.

34 IR monitoring: Azide chemistry

35 IR monitoring: Gas reactions CRD CO 0.6 ml/min (7 bar) R I NEt3 PhMe/MeOH/DMF (45:45:10) 0.1 ml/min O QP-TU 75 PSI PhMe/MeOH/DMF (45:45:10) 0.1 ml/min 100 PSI R OMe 30 ml 100 C Xantphos (3 mol%) PdOAc2 (2.5 mol%) Koos, P; Polyzos, A.; O Brien, M.; Baxendale, I. R.; Ley, S. V. J. Am. Chem. Soc. 2011,in press.

36 IR monitoring: Gas reactions CRD CO (X bar) 100PSI IR 75PSI PhMe+CO XmL/min PhMe SiComp

37 IR monitoring: Gas reactions GPR GPR

38 Outlook: The lab of the future Goals: - Controlled continuous chromatography - Fourth and fifth streams - Remote monitoring and control - Full In-line analysis of new compounds Hopkin, M. D.; Baxendale, I. R. and Ley, S. V. Chim. Oggi./Chemistry Today, 2011, 29,

39 Acknowledgements Professor Steven Ley The Ley Group AstraZeneca MettlerToledo, Merck, Advion, GlaxoSmithKline, AstraZeneca, Syngenta, Novartis, Pfizer, Thales, Biotage, CEM, Syrris, Vapourtec, Uniqsis, Cambridge Reactor Design EPSRC