From Dream to Production Process

Transcription

1 (S)-Metolachlor From Dream to Production Process Hans-Ulrich Blaser, SLVIAS AG, Basel Switzerland Uni Rostock, Gastvorlesung Asymmetrische Katalyse, Dez. 2007

2 utline Background The Molecule, the situation, possible approaches In Search of the Ideal Catalyst Moving in a Labyrinth (in the Fog) The Technical Process Ligand Scale-up, Imine Synthesis, Choice of Reactor,

3 Metolachlor The Molecule Cl (R,S) Herbicide for maize > t/y H 3 C nly (S)-enantiomers active Ca. 35% less loading for enriched form

4 The Four Stereoisomers of Metolachlor CH 2 Cl CH 2 Cl CH 2 Cl CH 2 Cl R,1'S S,1'S R,1'R S,1'R 2 active stereoisomers 2 inactive stereoisomers H. Moser, G. Rihs, H.P. Sauter 1982

5 Herbicidal Activity of Metolachlor Stereoisomers R,1'S S,1'S rac-metolachlor S,1'R R,1'R 100% H 3 C Cl 80% H 60% 40% 20% 0% application rate (g/ha) H. Moser, G. Rihs, H.P. Sauter 1982

6 The History of rac-metolachlor and (S)-Metolachlor 1970 Discovery of biological activity 1978 Full-scale plant > t/y 1982 Bioactivity of (S) enantiomers detected 1983 First attempts to make (S)-metolachlor 1985 Rh - cycphos (UBC Vancouver) 1987 Ir - diphosphine (F. Spindler; J.A. sborn) 1993 Ir - ferrocenyl diphosphine catalysts 1993/4 Patents of rac. metolachlor expired 1995/6 Pilot results: e.e. 79%, ton , tof > /h 16. ov First production batch

7 Metolachlor: The Problem Production process for racemate H 2 H CH 2 Cl CH 2 Cl H 2 - Pt/C AA ClCCH 2 Cl ar,1'r as,1'r inactive stereoisomers + H 2? CH 2 Cl CH 2 Cl + ClCCH 2 Cl ar,1's as,1's active stereoisomers

8 (S)-Metolachlor The Challenge Enantioselectivity Catalyst productivity (ton) Catalyst activity (tof) Space-time yield Production process - >1'000'000 (70 recycles) >4000/h at 50 C, 5 bar very high Minimum requirements ee >80% >50'000 (s/c ratio) >10'000/h high

9 Moving in the "ee ton" Space 100 ee >80% ton > '000 10' '000 1'000'000

10 Moving in the "ee ton" Space A Labyrinth! 100 ee >80% ton > '000 10' '000 1'000'000

11 Development Phases for EPC Synthesis Phase 1: Design and assessment of synthetic routes Phase 2: Demonstrating chemical feasibility Phase 3: ptimizing the key (catalytic) reaction(s) Phase 4: ptimizing the over-all process

12 Routes to (S)-Metolachlor Hydrogenation of enamide (isomers) Hydrogenation of imine (isomers) CCH 2 Cl or CCH 2 Cl chiral cat + H 2? + H 2 chiral cat? Hydrogenation / substitution Direct alkylation? 1. H 2, chiral cat M e 2. T sx R = H or C CH 2 Cl H Ts + R Me? H Me + H 2 chiral cat?

13 (S)-Metolachlor Route Assessment route enamide substitution imine direct alkylation catalytic step close analogy ee >90% weak analogy ee >80% weak analogy ee <30% no precedent

14 (S)-Metolachlor: Route Assessment route catalytic step other steps enamide substitution imine direct alkylation close analogy ee >90% weak analogy ee >80% weak analogy ee <30% no precedent enamide synthesis difficult substitution difficult as in current process as in current process

15 (S)-Metolachlor: Route Assessment route catalytic step other steps cost (ecology) priority enamide close analogy ee >90% enamide synthesis difficult high (medium) 1 substitution weak analogy ee >80% substitution difficult high (bad) 2 imine weak analogy ee <30% as in current process medium (good) 3 direct alkylation no precedent as in current process low (very good) 4

16 Development Phases for EPC Synthesis Phase 1: Design and assessment of synthetic routes Phase 2: Demonstrating chemical feasibility Phase 3: ptimizing the key (catalytic) reaction(s) Phase 4: ptimizing the over-all process

17 The Enamide Route The Analogy: L-Dopa Rh-dipamp (Monsanto) CH H ee 96% ton Me Me The Result: (All) available Rh/P^P (up to 20 bar / 50 C) activity at all!! Me Me Me Me CCH Cl 2 or CCH 2 Cl or CCH 2 Cl CCH 2 Cl H.U. Blaser, F. Spindler 1983

18 From Dream to Process Important Milestones (1983) 100 ee >80% enamide ton > '000 10' ' 000 1'000' 000

19 Substitution Route Heterogeneous Hydrogenation The Analogy: Pt/Al23-Cinchonidine (rito, 1979) The Result: Pt/Al23-Cinchonidine ee >85% activity ok ee 0%!! ee 12%!! H.U. Blaser, H.P. Jalett 1983

20 From Dream to Process Important Milestones (1983) 100 ee >80% enamid 20 Pt/cinch ton > '000 10' ' 000 1'000' 000

21 Imine Hydrogenation??????? H

22 Enantioselective C= Reduction State of the Art Around 1982 ee (%) 100 o report on -aryl imine hydrogenation Rh / diop Hydrosilylation Kagan et al. JMC 90 (1975) mostly heterogeneous catalysts Hydrogenation Levi et al. CC (1975)

23 Industry s Approaches for Solving Difficult Problems Do-it-yourself utsource to a specialized department utsource to a specialized company (Solvias!) Collaboration with universities UBC Vancouver (Cullen, Fryzuk, James, Kutney et al.) Search for a catalyst ULP Strasbourg (J.A. sborn) Investigate Ir-diphosphine catalysts (active species, deactivation behavior)

24 UBC: Rh-Cycphos A First Success H H 2 PPh 2 R h-p P H Ph 2 P D M A-im in e (R)-cycphos s/c Temperature t Conv. tof ee [ C] [hrs.] [%] [h-1] [%] Cullen, Fryzuk, James, Kutney, et al. UBC Vancouver

25 From Dream to Process Important Milestones (1985) 100 ee >80% Rh/cycphos enamid Pt/cinch ton > '000 10' ' 000 1'000' 000

26 ew Idea: Ir - P^P Complexes Ligand tof (4h) tof (24h) ee diop subst-diop bppm ( tbume) 6 79 bppm (MeH) 30 6 dipamp 19 7 bppfoh bdpp p(me) 2 -bdpp 31 rac C, bar, conversion: 17-96% R H R' P R P R H R' R substituted diop 2 2 H H Fe PPh 2 PPh 2 bppfoh P Ph Ph dipamp P PPh 2 Ph 2 P PPh 2 CH 2 PPh 2 C-t-Bu bdpp (skewphos) bppm F. Spindler 1986

27 Why Iridium? [Ir(cod)(py)(Pcy 3 )]PF 6 : Extremely active catalysts for olefin hydrogenation lefin maximum tof (1/h) Drawback: Very fast deactivation via dimerization R. Crabtree et al. J. rganomet. Chem. 141 (1977) 205

28 1997: Chiral Iridium P Catalysts: Effective for C=C Hydrogenation R 1 R 2 Ir + / P / X - R 1 R 2 R' R 3 ee up to >99% ton >5000 tof 1250 h -1 R' R 3 R 1 P R 2 R 3 R 1 R 1 PPh 2 R 2 R3 A. Pfaltz Review: A. Pfaltz, W.J. Drury, Proc. at. Acad. Sci. USA 101 (2004) 5723

29 Iridium: Best Results after ptimization Ir - P^P, iodide H PPh 2 CH 2 PPh 2 PPh 2 CH 2 PPh 2 bdpp diop bdpp ee 84% ton 100 (at 0 C) diop ee 52% ton 10'000 (at 30 C) PRBLEM CATALYST DEACTIVATI (Dimerization??) F. Spindler, B. Pugin 1986

30 From Dream to Process Important Milestones ee >80% Ir/bdpp Rh/cycphos Ir/diop enamid Pt/cinch ton > '000 10' ' 000 1'000' 000

31 Fighting Catalyst Deactivation Understanding ature of active species: Collaboration with JA Stabilizing Additives Avoid dimerization by complexation Immobilization Avoid dimerization by site-isolation

32 Fighting Deactivation Immobilization of Ir - bppm soluble catalyst; ee = 38% imine [%] P P Ir H H Ir P P 20 inactive dimer??? B. Pugin raction time [h]

33 Fighting Deactivation Immobilization of Ir - bppm P Ir P P P H P Ir Ir H P inactive dimer Ir P P tof ee dilution Si Si Loading (mmol Ir/g) 0 B. Pugin 1988

34 Fighting Deactivation Homogeneous Ir bppm Catalyst 120 imine [%] soluble catalyst; ee = 38% Immob. catalyst; ee >50% B. Pugin raction time [h]

35 From Dream to Process Important Milestones ee >80% Ir/bdpp Rh/cycphos Ir/diop enamid 0 0 Pt/cinch Ir/bppm immob ton > '000 10' ' 000 1'000' 000

36 Intermezzo : Project stopped by Agro Division A. Togni: Ligands for Au-Aldol reaction Enlargement of ligand library Systematic immobilization studies Technical ligands syntheses Various process developments

37 A. Togni Ligands Studies: Josiphos SAc RR' Ac Fe PPh 2 Fe PPh 2 Fe PPh 2 PPh 2 PCy 2 PPh 2 X Fe PPh 2 first Josiphos ligands for Au-Aldol X = H, PPh 2 H ( ) 2 ( ) 2 PR' 2 Fe a) BuLi Fe PR 2 HPR' 2 Fe PR 2 b) ClPR 2 AcH A. Togni, F. Spindler, B. Pugin Modular, tunable ligands

38 The Final Breakthrough Ir Xyliphos / AcH / Iodide Best results (laboratory) R = p-tbu-phenyl ee 87% low tof at -15 C Fe PR' 2 PPh 2 R = 3,5-xylyl ee 76-80% ton ; tof ca. 30'000 h -1 BUT: only on presence of acid AD iodide!! F. Spindler, H.P. Jalett, H.P. Buser 1992

39 Ir - Xyliphos: Effect of Solvent S olvent t (100% ) (h) initial rate thf C H 2 C l (C H 3 ) 3 C C H aceto ne toluene i-pr H t-b u H C H 3 C Et no ne C H 3 C H R eaction conditions: M EA-Im ine; s/c: 800; 150 m g T BAI; solvent: 2 m l; 25 bar H 2 ; 30 C. ee H.P. Jalett, F. Spindler HH69

40 Why Acetic Acid Pt/Al cinchona H H R CEt R = and PhCH 2 CH 2 + H 2 R R-hydroxyester CEt solvent ee EtH 82% toluene 87% acetic acid 92-94% H.P. Jalett, H.U. Blaser, Wiehl 1991

41 Ir - Xyliphos Effect of AcH and I - TF ee H P Fe P(C 6 H 5 ) Xyliphos General acid effect: - CF 3 CH AcH Iodide --- Iodide AcH 0 - H 2 S 4 H.P. Jalett, F. Spindler 1993

42 From Dream to Process Important Milestones ee 80% ton > tof >10 000/h ee (%) Ir/bdpp Ir/PPF-P Rh/cycphos Ir/diop Ir/xyliphos Acid / iodide Ir/bppm immob enamid Pt/cinch ton '000 10' ' 000 1'000' 000

43 Reductive Alkylation of MEA Ir-xyliphos, AcH: Solvent Effect H 2 + H 2 Ir-PP s/c 10'000 MEA MA S-AA H H Solvent Time Rate Conv. ee [h] [mmol/min] [%] [%] none phases Cyclohex (10 ml) phases EtH (10 ml) phase Reaction conditions: 0.1 mol MEA; 0.12 mol MA (dry); AcH: 2.5 ml; 20 mg TBAI; 80 bar H 2 ; 50 C. H.U. Blaser, H.P. Jalett

44 Functionalization of Xyliphos Me 2 1) BuLi BuLi /TMEDA Me 2 H-Pxyl 2 Pxyl 2 Fe Cl 2) mixture of Cl-PPh 2 and Si Cl Fe PPh 2 Si xyl= (60-70%) Fe PPh 2 Si (53%) Cl Cl Gabriel (90%) Fe PPh 2 Si Pxyl 2 Immobilization B. Pugin, H. Landert 1995

45 Metolachlor: Recycling?? homogeneous free extractable immobilized silicagel heterogeneous immobilized polystyrene P(xyl) 2 Fe PPh 2 P(xyl) 2 Fe PPh 2 P(xyl) 2 Fe PPh 2 P(xyl) 2 Fe PPh 2 -C Si C- Si H Si Silicagel H H H H H Polystyrene S/C 50' ' '000 50' '000 50'000 time 1h 2.1h 3h 8h 10h 30h ee 79% 80% 79% 78% 78% 74% separation distillation extraction > 90% filtration 95% B. Pugin, H. Landert, F. Spindler, H.U. Blaser, Adv. Synth. Catal. 344 (2002) 974 filtration 95%

46 Hydrogenation of Imine Best Ir / Xyliphos Systems 14'000 Homogeneous Reductive alkylation Immobilized ' '000 tof 8'000 6'000 4'000 2'000 o acid s/c 2'000'000 AcH s/c 10'000 s/c 100' ee (%) 0 0 F. Spindler, B. Pugin, H.U. Blaser, H.P. Jalett

47 Development Phases Metolachlor Imine Route Phase 1: Assessing synthetic routes Phase 2: Demonstrating chemical feasibility Phase 3: ptimizing the key (catalytic) reaction(s) Phase 4: ptimizing the over-all process

48 Process ptimization Ligand fine tuning ptimization of reaction conditions Strategy for the development of the over-all process The Production of the MEA Imine in the Required Quality Technical Ligand Synthesis Choice of Reactor Technology Scale up Work-up Separation of the Catalyst from the Product

49 Fine Tuning (S)-Metolachlor Process Ir - PP H MEA imine (S) -AA Catalyst: [Ir(CD)Cl] 2, ai, H 2 S 4, (R)-(S)-R 2 PF-PR 2 ; p(h 2 ), 80 bar, 50 C P Fe P H F 3 C P Fe P H P Fe P H P Fe H P F 3 C ee % ton tof [h -1 ] > F. Spindler

50 Ligand Finetuning: Substituents at Xylyl Group Fe H PR 2 P(C 6 H 5 ) 2 e.e.: 76% rate: 26 mmol/min e.e.: 80% rate: 25 mmol/min e.e.: 83% rate: 1 mmol/min F. Spindler, H.P. Buser 1994 e.e.: 69% rate: 10 mmol/min e.e.: 76% rate: 2 mmol/min e.e.: 82% rate: 0.5 mmol/min

51 Reaction Conditions Effect of H 2 Pressure r max (mmol H2/min) ee: 75-76% Pressure (bars) F. Spindler, H.P. Jalett 1994

52 Development Phases for EPC Synthesis Phase 1: Design and assessment of synthetic routes Phase 2: Demonstrating chemical feasibility Phase 3: ptimizing the key (catalytic) reaction(s) Phase 4: ptimizing the over-all process

53 Process Development Ligand fine tuning ptimization of reaction conditions Strategy for the development of the over-all process The Production of the MEA Imine in the Required Quality Technical Ligand Synthesis Choice of Reactor Technology Scale up Work-up Separation of the Catalyst from the Product

54 Imine Production H + H 2 Me + H 2 + Simple chemistry BUT Scale up difficult due to thermal instability of the imine Fast removal of water neccessary Significant catalyst deactivation High purity required

55 Effect of MEA Concentration Ir/xyliphos, Acetic Acid, TBAI inital rate (mmol H2/min) t(100%): 0.5 h ee not affected! MEA (%) MEA imine H 2 MEA t(100%): 18 h F. Spindler, H.P. Jalett

56 Imine Production: Water Separators

57 Process Development Ligand fine tuning ptimization of reaction conditions Strategy for the development of the over-all process The Production of the MEA Imine in the Required Quality Technical Ligand Synthesis Choice of Reactor Technology Scale up Work-up Separation of the Catalyst from the Product

58 Technical Ligand Synthesis Fe Fe Fe H enzymatic kinetic resolution Fe + Fe H Fe PPh 2 P H 2 Fe PPh 2 Me 2 Fe Me 2 Ugi amine 30 Kg scale unproblematic

59 Process Development Ligand fine tuning ptimization of reaction conditions Strategy for the development of the over-all process The Production of the MEA Imine in the Required Quality Technical Ligand Synthesis Choice of Reactor Technology Scale up Work-up Separation of the Catalyst from the Product

60 Choice of Reactor Technology Issues High pressure (80 bar) -> high investment Fast exothermic reaction -> heat removal important Sensitive catalyst -> handling and loading Alternatives Stirred tank reactor Loop reactor

61 Coice of Reactor pump stirred tank loop reactor

62 Coice of Reactor cooling pump

63 Process Development Ligand fine tuning ptimization of reaction conditions Strategy for the development of the over-all process The Production of the MEA Imine in the Required Quality Technical Ligand Synthesis Choice of Reactor Technology Scale up Work-up Separation of the Catalyst from the Product

64 16. ovember 1996 Happy End: First Production Batch H H Pxyl 2 H Fe PPh 2 amount mol MEA-imine 10'000 kg 48'700 [Ir(CD)Cl] 2 34 g 0.05 Ligand 68 g 0.11 ai 92.5 g 0.6 H 2 S g 0.5 reaction time 2h conversion 99.6% ee 79%. Pericles, R. Hanreich

65 From Dream to Process Important Milestones ee 80% ton > tof >10 000/h ee (%) Ir/bdpp Ir/PPF-P Rh/cycphos Ir/diop Ir/xyliphos Acid / iodide Ir/bppm immob enamid Pt/cinch ton '000 10' ' 000 1'000' 000

66 Some Lessons Enantioselectivity is not always the major problem ton and tof can be just as critical!! Success often depends on availability of ligands Modular ligands are an optimal solution Solvias Ligand Kit Screening capabilities are crucial Parallel screening equipment SUCCESS WITHUT TP EXPERTISE

67 The Key Players B. Pugin F. Spindler H.P. Jalett

68 Think catalytic!