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Process Requirements for the Development of Asymmetric Hydrogenation Reactions: From the Bench to Kilogram Scale Ian C. Lennon Dowpharma, Cambridge, UK.

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Presentation on theme: "Process Requirements for the Development of Asymmetric Hydrogenation Reactions: From the Bench to Kilogram Scale Ian C. Lennon Dowpharma, Cambridge, UK."— Presentation transcript:

1 Process Requirements for the Development of Asymmetric Hydrogenation Reactions: From the Bench to Kilogram Scale Ian C. Lennon Dowpharma, Cambridge, UK

2 Outline of Talk – Known Asymmetric Hydrogenation Processes – Process Requirements – Screening Methodology for 2-Methylenesuccinamic Acid – Optimisation Studies for 2-Methylenesuccinamic Acid – Case Studies (Candoxatril, Pregabalin, 4-F-Acetophenone) – Imine Hydrogenation (Thiadiazine) – Conclusions Process Requirements for the Development of Asymmetric Hydrogenation Reactions: From the Bench to Kilogram Scale

3 2001 BCMS 2001 Corporate NBD 2002 Dow pharma Dow pharma Formation CMS 1995 Marion Merrell Dow

4 Early Applications of Asymmetric Hydrogenation

5 Some of the First Applied Phosphine Ligands

6 Noyori’s Binap Complexes

7 Largest Scale Industrial Asymmetric Hydrogenation

8 Rh-DuPhos Asymmetric Hydrogenation  The substrate binds to the metal  The substrate carbonyl group controls the orientation of hydrogenation DuPhos licensed from DuPont since 1995: license now assigned to Dow Mechanism:

9 M. J. Burk Acc. Chem. Res. 2000, 33, 363 Scope of the DuPhos / BPE Hydrogenation

10 Asymmetric Hydrogenation & Biocatalysis combined LD 1. Rh-(S,S)-DuPhos, H 2 2. L-aminoacylase 1. Rh-(R,R)-DuPhos, H 2 2. D-aminoacylase Unnatural Amino Acids Combination of technologies provides an efficient process 100’s kg of several amino acids made this way Asymmetric Catalysis on Industrial Scale Eds Blaser and Schmidt. Page 269.

11 Amino Acids Prepared Using Chemo/Biocatalysis

12  -Branched  -Amino Acids  Combination of asymmetric hydrogenation and amino acid oxidase provides access to all four diastereoisomers of  -branched  -amino acids In Collaboration with Nick Turner J. Am. Chem. Soc. 2004, 126, 4098

13 Process Requirements  Choice of Catalyst Complex  Synthesis and Purity of Substrate  Solvent  Temperature  Pressure  Concentration  Enantiomeric Excess  Substrate to Catalyst Ratio (Activity of the catalyst)  Removal of spent catalyst from the product  Availability of the Chosen Catalyst (Security of Supply)

14 Screening for Asymmetric Hydrogenation Ligand collection for asymmetric hydrogenation screening

15 Time 0 0 30 15 99.4 % e.e ml Heller’s Findings “….the use of NBD precatalyst in the asymmetric hydrogenation has significant advantages over the application of the usually sold and applied COD complexes” “…..the frequently used COD complexes do not imply optimal activity in the catalysis, at least for five-membered chelates, and cannot therefore be regarded very economically” COD Versus NBD Precatalysts Borner & Heller, Tetrahedron Lett., 2001, 42, 223 challenges economy of use of COD precatalyst - but at S/C 100:1.

16 Methyl acetamidocinnamate (R,R)- COD + (S,S)- NBD At S/C = 2,000 e.e. = 23% At S/C = 5,000 e.e. = 7% Competition reactions: % Hydrogen uptake Time (min)

17 Candoxatril Precursor % Hydrogen uptake Time (min) Reactor stirring efficiency: (1)(2) (1) (2) Hydrogen availability more important than COD vs NBD ChiroTech publication: Tetrahedron Letters, 2001, 42, 7481

18 Applications of Rh-Me-DuPhos Catalyst Reviews: Synthesis 2003,1639 Curr. Opin. Drug Discovery Dev. 2003, 6, 855

19 [(Me-DuPhos)Rh(COD)]BF 4 Manufacture Multiple Kilogram quantities produced Using a scaleable process

20 Security of Supply  Dowpharma manufactures a number of catalyst systems on a multi-kilogram, kilogram and multi-100 g scale  Dowpharma offer manufacturing operational excellence, based on a history rooted in the manufacture of pharmaceuticals  We have developed secure and robust supply chains for important intermediates  All catalysts are manufactured to a precise specification and are subject to a use test prior to dispatch  Dowpharma has the ability to manufacture catalysts at a variety of sites in Europe and North America. In addition, we have the capability to increase capacity as required  We offer tailored commercial terms for licensing and supply agreements  Dowpharma has a well defined intellectual property position on all catalyst systems See: Chimica oggi, December 2003, 63-67

21 Substrate Synthesis: Manufacture of  -Amino Acids Asymmetric Catalysis on Industrial Scale Eds Blaser and Schmidt. Page 269. Key Issues  Use of Erlenmeyer reaction is preferable to Horner-Emmons chemistry, which can give low level of phosphorus impurities that poison catalysis  Erlenmeyer route is scaleable and cost effective  Conditions for the DuPhos Hydrogenation are mild and scaleable  Many 100’s kg of product have been made using this route

22 Substrate Synthesis: Manufacture of  -Amino Acids Key Issues  Competitive binding to the pyridyl group made the catalysis inefficient  The optimum substrate was the methyl ester-HBF 4 salt  >200 Kg produced

23 Activity of Catalysts: Ph-BPE Enhanced selectivity and activity over alkyl BPE ligands Dowpharma Paper: Org. Lett. 2003, 5, 1273

24 Fast Reaction Rates with Ph-BPE Ligand Rates of asymmetric hydrogenation of methyl acetamidocinnamate

25 Optimizing the catalysis: Argonaut Endeavor

26 A New Approach to Acyl Enamides

27 4-Amino-2-methyl butanol and 4-hydroxy-3-methyl-butyronitrile Chiral building blocks for several biologically active compounds

28 Substrate Synthesis: Methylenesuccinamic acid  Substrate synthesis from readily available materials  Scaleable process  Substrate contains ~ 1 mol % of a chloride containing impurity

29 Asymmetric Hydrogenation of Methylenesuccinamic acid

30

31 Substrate to Catalyst Ratio (S/C) Performance of Et-DuPhos holds at higher S/C

32 Temperature and Pressure Enantioselectivity is retained at higher temperatures and pressures

33 Concentration and Effect of NEt 3 NEt 3 increases the reaction rate, but reduces enantioselectivity

34 Solvent Screen

35 Effect of Chloride Contaminant Removal of Cl - increases rate by a factor of 30

36  Complete conversion with 96 % e.e. at S/C 100,000:1 (w/w ~21,400)  Chloride impurity identified that limited S/C to 1000:1  Upgraded to 99.5 % e.e. with a single reslurry (MeOH)  Rh content reduces from 9.0 ± 0.4 ppm to 0.88 ± 0.05 ppm (36 ± 1 ppm to 9.8 ± 0.4 ppm for S/C 20,000) Asymmetric Hydrogenation of Methylenesuccinamic acid Dowpharma paper: Org. Process Res. Dev. 2003, 7, 407.

37 Pfizer’s Candoxatril for Congestive Heart Failure Substrate Synthesis: Tetrahedron Letts. 1999, 40, 2187

38 Pfizer’s Candoxatril: Original Route Pfizer Patent: EP 0342850

39 New Asymmetric Hydrogenation Route M. Bulliard et al. Org. Process Res. Dev. 2001, 5, 438

40 Screen for Asymmetric Hydrogenation Catalyst

41 Candoxatril: Me-DuPHOS-Rh-Catalysed Process Cationic (R,R)-Me-DuPHOS-Rh Found to be Superior S/C Ratio = 3500/1 (5000/1 readily obtainable) Reaction Time = 3 h Conversion = 100% (No Isomerization) Isolated Crude Yield = 97% Demonstrated on 12 kg Scale in Pfizer Pilot Plant Joint Publication: J. Org. Chem. 1999, 64, 3290

42 Asymmetric Hydrogenation Route to Pregabalin Pregabalin is a potent anticonvulsant in late stage clinical trials A resolution route, that uses (S)-mandelic acid, has been reported (Org. Process Res. Dev. 1997, 1, 26).

43 Classical Resolution Route to Pregabalin (Org. Process Res. Dev. 1997, 1, 26). 15 MT made for clinical trials Overall yield of 25% at best 4 isolated solids, 2 for resolution

44 Pregabalin – Substrate Synthesis J. Org. Chem. 2003, 68, 5731

45 Successful Hydrogenation: Pregabalin Reduction in cost of goods and waste over resolution route Improvement in throughput (Bill Kissel MPPCC, 2001) Resolution route 25% yield, hydrogenation 50% overall yield Collaborative Project Carried out with Pfizer, Holland, Michigan Joint Paper J. Org. Chem. 2003, 68, 5731

46 Alternative Substrates: Pregabalin

47 Noyori / Ikariya Hydrogenation Technology  Licensed obtained in Dec 2000 from the Japan Science and Technology Corporation TRANSFER HYDROGENATION PRESSURE HYDROGENATION

48 Mechanism of Noyori Hydrogenation  The substrate does not bind to the metal  Chiral environment created by both diphosphine and diamine R. Noyori et al. J. Am. Chem. Soc. 2003, 125, 6510

49 Kilogram Scale Reactions  PhanePhos-based ligand best  Substrate distilled before use  S/C 100,000 : 1 achieved  Catalyst removed by short path distillation  Another example at 100s kgs scale Org. Lett. 2000, 2, 4173 and Org. Process Res. Dev. 2003, 7, 89

50 Dynamic Ketone Hydrogenation  Catalyst loading of 200,000 demonstrated  Xyl-MeOBIPHEP gave 79% ee at S/C 1,000,000  9 Kg of product produced  Overall yield of route using asymmetric hydrogenation was 53%.  Discovery synthesis 3.5% overall yield Roche, Org. Process Res. Dev. 2003, 7, 418

51 Asymmetric Hydrogenation of 2-Methylquinoxaline [(S)-HexaPHEMP.RuCl 2.(S,S)-DACH]:69% ee, >99% Conv. [(S)-BINAP.RuCl 2.(S,S)-DACH]:61% ee, >99% Conv. Patent: US 652868 and Adv. Synth. Catal., 2003, 345, 195-201.

52 Reduction of Imines

53 Customer Example - Thiadiazine Dowpharma/Oril Joint Publication: Tetrahedron Asymmetry 2003, 14, 3431

54 Ligands and Catalysts Available from Strem Many Dowpharma ligand and catalyst systems are available from the Strem Chemical Catalogue for Research use only.

55 Conclusions  A number of asymmetric hydrogenation processes have been carried out on a manufacturing scale over the last 30 years  Despite these successes, the technology is still not routinely used for the manufacture of pharmaceutical intermediates  With a greater number of catalyst systems available and a better understanding of the process issues surrounding asymmetric hydrogenation technology, we are starting to see increased applications for this technology  In this talk we have reviewed several case studies of successful applications of asymmetric hydrogenation  With a good understanding of catalyst selection, substrate purity, solvent, temperature and pressure variables, it is relatively straightforward to develop a successful process  Security of supply of the catalyst is of paramount importance

56 Acknowledgements Pieter de Koning Ray McCague Christophe Malan Graham Meek Paul Moran Justine Peterson Chris Pilkington Jim Ramsden Simon Watkins Andy Wildsmith Antonio Zanotti Ulrich Berens Frank Bienewald Mark Burk David Chaplin Lee Boulton Guy Casy Chris Cobley Will Hems Julian Henschke Daniela Herzberg Nick Johnson Analytical Team Natasha Cheeseman Paul Harrison Catherine Hill Jon Hill Brendan Mullen PfizerSteve Challenger Nick Thomson Tom Mulhern Bill Kissel Oril Jean-Pierre Lecouve

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