Process Aspects of Asymmetric Hydrogenation SCI Process Development Symposium 5 th -7 th December 2007

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1 rocess Aspects of Asymmetric ydrogenation SCI rocess Development Symposium 5 th -7 th December 007 Dr Ian C. Lennon Dowpharma, Cambridge, UK Service Mark of The Dow Chemical Company TM Trademark of The Dow Chemical Company

2 utline of resentation Some rocess Aspects of Asymmetric ydrogenation Introduction and overview rocess requirements Catalyst Screening recatalyst Manufacture Substrate Synthesis Scale-up Issues

3 Early Applications of Asymmetric ydrogenation C hcl-l 3 C 15% ee r L = : W.S. Knowles and M. J. Sabacky Chem. Commun., 1968, 1445 L. orner et al. Angew. Chem., Int. Ed. Engl. 1968, 7, 94 h C 3 Monsanto L-DA process Ac Me C Ac [(,)-Me-DIAM-h(CD)] Me Ac Me C Ac 95% ee DIAM = Me W.S. Knowles Angew. Chem., Int. Ed. 00, 41, 1998

4 Some of the First Applied hosphine Ligands C Ac Ligand % ee Ligand % ee Ligand % ee r C 3 h 8% Me Me 95% h h 95% DIAM CIAS C 3 Me 88% h h 87% h BC h 91% CAM hone-oulenc BM h h 83% h h h h 94% Fe Me h h 93% DI W.S. Knowles Acc. Chem. es. 1983, 16, 106 BFA

5 Some of the 3,000 Known hosphine Ligands Me Me Me Me Me Me Me C 3 t Bu t Me Me Bu t t Bu t Bu Bu h Cl Me F S Ar F Ar h h h Me h h Me h h Ar Ar h h F Me h Me h h Ar Ar h h h h Ar Ar F S Cl Me h Me Me S h Me h h Me Ar h Me h Ar Ar Ar Fe h h Me Ar Ar Me h Ar Me Ar h S Me h Me Me h Me Me h S h h ' ' Me ' ' Me h h h h ' ' ' ' Me S Me Me Me Ar Me Me h h ' Me Me h h Fe X Me Me Fe Fe Fe Fe Fe Fe C 3 Fe h h Y Me h Me Z Me Me Me Me h C 3 ' Ar C Fe Me Fe 3 Fe Fe h Fe Me Fe h Fe Me Me Ar h Me h h h h h h h h h h h Fe h h h Me h h h Me S Me h h h h h h h h h h h h BC h h h h Xyl

6 oyori s Binap Complexes Me CC 6 5 [ucl (()-Binap)] Et 3 Me CC 6 5 TBDMS Ac Binap = h h 100% Conv. 98% ee, syn:anti =94:6 10 tonnes per year Carbapenem intermediate Asymmetric Catalysis in rganic Synthesis,. oyori John Wiley & Sons, 1994 Me [()-u-(binap)cl ].Et 3 S/C 3, mol% Cl, Me 40 psi, 40 o C >98% ee Me S. A. King et al J. rg. Chem. 199, 57, 6689

7 Largest Scale Industrial Asymmetric ydrogenation C 3 Ir / Xyliphos 50 o C, 100 psi C 3 C 3 Cl 80% ee ton,000,000; tof 400,000 h -1 Metolachlor Xyliphos = Fe Xyl h >0,000 tonnes per year Laboratory work Josihos first reported First roduction batch ans-ulrich Blaser Adv. Synth. Catal. 00, 344, 17

8 M. J. Burk Acc. Chem. es. 000, 33, 363 Scope of the Duhos / BE ydrogenation 1 C 1 C h Ar Ac Ac C Me C 1 Boc C Duhos/BE C Me C C C 1 C 1 C C Me C t-bu C C

9 Applications of h-me-duhos Catalyst Me Me Me h Me Me + - BF 4 h Candoxatril C 3 S C CF 3 Tipranavir [(,)-Me-Duhos h (CD)]BF 4 eviews: Synthesis 003,1639; Curr. pin. Drug Discovery Dev. 003, 6, 855 C regabalin

10 FDA Approved Drugs and Asymmetric ydrogenation BIA-u 1400 psi, Me ozerem Takeda, Launched-005, insomnia CF 3 CF 3 F F F Josihos-h 0.3 wt% F F F Sitagliptin Merck, Launched-006, diabetes C Walhos-h and Monohos-h Aliskiren ovartis, Launched 007, hypertension

11 rocess equirements Choice of Catalyst Complex screening Availability of the Chosen Catalyst (Security of Supply) Synthesis, urity and Selection of Substrate Substrate to Catalyst atio (Activity of the catalyst) Enantiomeric Excess Choice of Solvent Concentration, Temperature, ressure emoval of spent catalyst from the product eactor Configuration, e.g. Agitation

12 rocess equirements Choice of Catalyst Complex screening Availability of the Chosen Catalyst (Security of Supply) Synthesis, urity and Selection of Substrate Substrate to Catalyst atio (Activity of the catalyst) Enantiomeric Excess Choice of Solvent Concentration, Temperature, ressure emoval of spent catalyst from the product eactor Configuration, e.g. Agitation

13 Screening for Asymmetric ydrogenation DuS BE Cy h Fe ()-(S)-JSIS Fe DiFc Fe 5-Fc Ar Ar Ar = h ()-BIA Ar = 4MeC 6 4 ()-TolBIA Et Et h ()-EthenylLAE h Fe FerroTAE h "Since achieving 95 % e.e. only involves energy differences of about kcal, which is no more than the barrier encountered in a simple rotation of ethane, it is unlikely that before the fact one can predict what kind of ligand structures will be effective" Cl Me Me Cl h h h h h W.S. Knowles, 1983 ()-Cl-Me-BIE ()-QUIA (,3)-S (S,S)-DI h h h h h h h BC h h h h h CABS (S,S)-CIAS BM ()-hosphinooxazoline ()-hanehos ()-exaem Ligand collection for asymmetric hydrogenation screening

14 Dowpharma Asymmetric ydrogenation Screening More than 400 rhodium, ruthenium and iridium catalysts are available roprietary ligands based on four major classes: hospholanes (Duhos, BE, 5-Fc) Fe hosphetanes (FerroTAE) Ar Ar aracyclophane ligands (hanes) Ar Ar Biaryl phosphines (exaem) (exclusive licence from Duont) (ChiroTech patent) (Licence from Merck) (ChiroTech patent) roduction of unnatural aminoacids (rhodium catalysis combined with biocatalysis) C C roduction of peptidomimetics (rhodium catalysis) C C roduction of chiral alcohols (ruthenium catalysis / JST technology) roduction of chiral β-hydroxyesters and diols (ruthenium catalysis) C C Ac C >99% e.e. C >98% e.e. >98% e.e. >98% e.e.

15 Thiadiazine ydrogenation - Unbiased Catalyst Screening h h Cl u Cl h h S [()-Binap ucl (,)-DE] S/C =,500 (550 wt / wt ) S t-buk, i- r, Toluene 60 psi, 60 o C 97% Yield, 87% ee Substrate inert to all other asymmetric hydrogenation reactions Best system identified was not proprietary to Dowpharma An equivalent of base required for full conversion. roduct crystallises to >99% ee Dowpharma/ril Joint ublication: Tetrahedron Asymmetry 003, 14, 3431

16 Joint ublication Tetrahedron Lett. 007, 48, Asymmetric ydrogenation Screen for ZD-616 Enamide (S)-irFerroTAE u(methallyl) S/C = 1000 (450 wt / wt ) Me, 65 o C, 10 psi ZD616 Enamide 18-4 h (S)-ZD616 henol Catalyst S/C ee ()- i r-duhos-h % (S)- t Bu-FerroTAE-h % ()-(S)-JosiS-h % ()-Me-Duhos-u % (S)- i r-ferrotae-u % roject carried out with AstraZeneca, Macclesfield. ver 100 h, u and Ir catalysts screened. Suitable h and u catalysts were identified, based on the FerroTAE ligand

17 See Dowpharma atent Application W 006/1773 Catalyst Screen for Diphenylalanine Ac C Me hodium-catalyst S/C = 50 Ac C Me Me, (140 psi) recatalyst t 1/ Temp ee [(,)-Me-BE h CD]BF 4 1 h 5 m 60 o C 70% [(,)-hanehos h CD]BF 4.5 m 60 o C 88% [(,)-Me-BE h CD]BF 4 3 h 9 m 50 o C 76% [(,)-hanehos h CD]BF 4 3 m 50 o C 88% [(,)-Me-FerroTAE h CD]BF 4 13 m 50 o C 7% [(,)-Me-5-Fc h CD]BF 4 m 50 o C 75% [(,)-h-be h CD]BF 4 3 h 3 m 50 o C 94% [(,)-Bis * h CD]BF 4 5 h 17 m 50 o C 51% [(,)-Et-Duhos h CD]BF 4 nd 50 o C 53% hanehos provides the most active catalyst system Diphenylalanine derivatives have been manufactured on a ton scale

18 rocess equirements Choice of Catalyst Complex screening Availability of the Chosen Catalyst (Security of Supply) Synthesis, urity and Selection of Substrate Substrate to Catalyst atio (Activity of the catalyst) Enantiomeric Excess Choice of Solvent Concentration, Temperature, ressure emoval of spent catalyst from the product eactor Configuration, e.g. Agitation

19 Commercial Scale recatalyst Manufacture Dowpharma has >1 years of asymmetric hydrogenation experience >10 precatalysts made on a Kg+ scale [Me-Duhos h( CD)]BF 4 available on a multi-10 s kg scale h-hanehos precatalyst produced on a multi-kilogram scale Many metric tons of chiral products are manufactured using our asymmetric hydrogenation technology

20 Catalyst Scale-Up Batch Variation [Me-Duhos h (CD)]BF 4 A istorical erspective BF 4 h BF 4 Et Alcoholic solvent 1,5-Cyclooctadiene _ h BF 4 Me-Duhos - CD Anti-solvent h Insoluble intermediate Low recovery Low volume efficiency Unpredictable product form

21 Catalyst Scale-Up Soluble & reactive intermediate igh volume efficiency ~.5kg from 0L vessel Uniform granular product form T react reduced from 78ºC to 55ºC roduct isolated at T roductivity increased ~100% / volume ecovery increased from 75 to 96% ew route BF 4 h BF 4 Et Ethereal/alcoholic solvent _ h solv. solv. BF 4 Me-Duhos - x solv. h

22 Catalyst Scale-Up: Test-ig eactions h 1. [h(cd)acac] in ethereal solvents

23 Catalyst Scale-Up: Test-ig eactions h solv. solv. BF 4 1. [h(cd)acac] in ethereal solvents. Add acid in alcoholic solvent

24 Catalyst Scale-Up: Test-ig eactions h BF 4 1. [h(cd)acac] in ethereal solvents. Add acid in alcoholic solvent 3. Add ligand in ethereal solvent

25 Catalyst Scale-Up: Isolated Catalyst h BF 4 1. [h(cd)acac] in ethereal solvents. Add acid in alcoholic solvent 3. Add ligand in ethereal solvent 4. Isolate robust material in high yield 5. ptional recrystallisation

26 Catalyst Scale-Up: Extending the Scope 31 -M Isolated material at 5 ºC multi-kg, > 99% purity, 97% yield BF 4 h

27 Catalyst Scale-Up: Extending the Scope Isolated material >Kg, > 99% purity, 9.0% yield BF 4 h

28 Catalyst Scale-Up: Extending the Scope Isolated Catalysts roduct form comparisons BF 4 BF 4 h h h BF 4 h BF 4

29 Catalyst Scale-Up: Extending the Scope BF 4 BF 4 BF 4 BF 4 h h h Fe h 95% 97% 96.4% 97% h BF 4 h h h h h BF 4 Fe h BF 4 h h h BF 4 94% 97.5% 91% 95% W Widely applicable to typical phosphine ligands 10 proprietary systems operated at Kg scale Largely compatible with analogous iridium complexes

30 rocess equirements Choice of Catalyst Complex screening Availability of the Chosen Catalyst (Security of Supply) Synthesis, urity and Selection of Substrate Substrate to Catalyst atio (Activity of the catalyst) Enantiomeric Excess Choice of Solvent Concentration, Temperature, ressure emoval of spent catalyst from the product eactor Configuration, e.g. Agitation

31 Substrate Synthesis: Manufacture of α-amino Acids F C 1. C Ac Ac, aac. a F C Ac [(S,S)-Me-Duhos-h] + S/C = 1400 (500 wt / wt ) 40 o C, 100 psi 69% Th Me F C 1. L-Acylase F C Ac. Boc, Me Boc Key Issues 69% Th over three steps >99% ee, >98% purity Use of Erlenmeyer reaction is preferable to orner-emmons chemistry, which can give low level of phosphorus impurities that poison catalysis Erlenmeyer route is scaleable and cost effective Conditions for the Duhos ydrogenation are mild and scaleable Many 100 s kg of product have been made using this route Asymmetric Catalysis on Industrial Scale Eds Blaser and Schmidt. age 69.

32 Asymmetric Catalysis on Industrial Scale Eds Blaser and Schmidt. age 69. Substrate Synthesis: Manufacture of α-amino Acids 1. C Ac C Ac, aac C 1. Esterify. a Ac. BF 4 BF C Me Ac [(S,S)-Et-Duhos-h] + 30 o C, 90 psi C Me Ac Key Issues Me 98% ee Competitive binding to the pyridyl group made the catalysis inefficient The optimum substrate was the methyl ester-bf 4 salt >00 Kg produced

33 Diphenylalanine Substrate Synthesis Ac Me Ac Me Ac Me i) BS, C Cl ii) Et 3 Br d(ac), a C 3 hb(), Et 89% Yield ~1.3 : 1 75% Yield Substrate synthesized according to Burk et al. Tetrahedron Lett. 1997, 38,1309, using the Suzuki conditions of Deng et al. Synthesis 003, 337 Commercially available dehydroamino acid and boronic acid Both steps good yield Alternative substrate synthesis devised

34 Diphenylalanine- Alternative Substrate Synthesis CC C Et, base C Et Ac C Et Ac, y K C 3, Me Ac Et Synthesis of the -Formyl intermediate followed procedures reported in Bioorg. Med. Chem. Lett. 199,, 1085 Commercially available ketone and isocyanide -protecting group exchange required, -formyl is a poor hydrogenation substrate

35 Substrate Selection: Directing Groups h C Me h-di, S/C psi, Me, T h C Me Group t/ Conversion ee = = C 3 = h = Bn - 15 min 16 min 50 min % 83% 68% 33% = t Bu 60 min 100 9% = CF % Tetrahedron 1979, 35, 381; Tetrahedron: Asymm. 1993, 4, 047

36 Tetrahedron: Asymm. 1993, 4, 047 Substrate Selection: Directing Groups h C Me h-catalyst, S/C psi, Me, T h C Me h Boc BM h ir h h ropraphos Group t/ ee t/ ee = C 3 = h = tbu 16 min 15 min 80 min 93% 80% 8% = Bn 60 min 87% 16 min 10 min 50 min 10 min 86% 90% 93% 88%

37 Syntheses of Enamide Substrates ' ' Fe powder, Ac Ac (3 eq.) Toluene, 75 o C ()Ac ' E/Z Mixture Chirotech aper: Burk et al. J. rg. Chem. 1998, 63, 6084 Tf Ac Ac C Et 3, DMF, d(ac) D, 100 o C C Dowpharma aper: Meek et al. Tetrahedron Lett. 004, 45, Ac F C MeMgBr F Ac F or MeLi or AcCl Burk et al. J. Am. Chem. Soc. 1996, 118, 514 (supporting info.)

38 Enamide Substrate Synthesis eck Coupling Tf Ac Ac Catalyst Ac C Et 3, DMF, d(ac) D, 100 o C C (150 psi), Me 40 C, S/C 1,000 C ef: J. rg. Chem., 199, 57, 3558 h h h BF 4 Ac Ac Ac h h C Cl C Me (S,S)-h-BE 99.4% ee 99.1% ee 98.3% ee Et Et h BF 4 - Ac Cl Ac Et Et (S,S)-Et-Duhos Cl 97.9% ee 97.5% ee Dowpharma aper: Tetrahedron Lett. 004, 45, 977

39 Merck Enamide ydrogenation Cl Me Me h Me Me + BF 4 - Cl Boc [(S,S)-Me-BE h (CD)]BF 4 S/C = 500, Et, Boc Substrate synthesised using the Benzonitrile method urification of the substrate was found to be important to obtain a robust process umerous ligands screened, best results with BE, Binaphane and Duhos BE gave the best catalyst loadings (See W 006/057904) 88% ee, 100% assay yield Me-BE-h catalysts are relatively low molecular weight, S/C 500 = 345 wt / wt recatalyst supplied by Dowpharma

40 fizer & Dowpharma aper: rg. Lett., 005, 7, 1931 rocess Issue - Choice of Technology 1. Quinidine, t BME/EtAc 50 o C to 0 o C. a, C Cl / 35%, 98% ee Boc C Boc C Diastereoisomeric salt resolution gave the product in good e.e. The nature of a resolution, the yield is low, but a quick solution eed a higher yielding route to meet manufacturing requirements d/c C C oute to racemic imidazole is via d/c reduction

41 fizer & Dowpharma aper: rg. Lett., 005, 7, 1931 rocess Issue Selecting the ight Substrate C Me 60% conv. 14% e.e. [()-Binap ucl ] CF 3 C - + C 100% conv. 83% e.e. [(,)-i-r-duhos u (CCF 3 ) ] Boc C 0% conv. 40% e.e. [(,)-i-r-ferrotae u (methallyl) ] Boc C 100% conv. 6% e.e. [(,)-i-r-duhos u (CCF 3 ) ] Boc 93% conv. o assay available [(,)-i-r-be u (methallyl) ] Ts - + Boc C 95% conv. 77% e.e. [()-Tol-Binap u (C 6 6 )Cl]Cl (loss of Boc group) C 100% conv. 56% e.e. [(S,S)-i-r-FerroTAE u (methallyl) ]

42 fizer & Dowpharma aper: rg. Lett., 005, 7, 1931 ptimised rocess for a δ-amino Acid i r BF 4 - Fe i r i r h i r [(,)-ir-5-fc h(cd)]bf 4 Boc C S/C = 5000 (3900 wt / wt ) Me, 150 psi 76 % yield Boc C 98 % de After an extensive screen of 8 substrates and >100 catalysts we found that the quinidine salt could be hydrogenated in good de. We chose the most active and not the most selective catalyst for this process Compared with the classical resolution we were able to double the yield of product. fizer made >0 Kg by this route.

43 rocess equirements Choice of Catalyst Complex screening Availability of the Chosen Catalyst (Security of Supply) Synthesis, urity and Selection of Substrate Substrate to Catalyst atio and urity of Substrate Enantiomeric Excess Choice of Solvent Concentration, Temperature, ressure emoval of spent catalyst from the product eactor Configuration, e.g. Agitation

44 Substrate urity for Ketone ydrogenation Xyl Xyl Cl h u Cl h Xyl Xyl 109 mg (S)-(,)-precatalyst, F 1.38 Kg S/C = 100,000/1 i-r, 1 mol% t-buk psi h F 1.31 Kg after distillation urity 99.3% by GC 98.3 % e.e. hanehos-based ligand best Substrate distilled before use. o reaction with commercial substrate S/C 100,000 : 1 achieved (13,000/1 wt / wt ) Several other examples at 100s kg scale rg. Lett. 000,, 4173 and rg. rocess es. Dev. 003, 7, 89

45 Chiral Alcohols: Asymmetric ydrogenation Single enantiomer alcohols made using ketone hydrogenation F 3 C F 99% ee 98% ee 70% ee 98% ee 99% ee 99% ee Cl F F 3 C 3 C 3 C Br Cl 99% ee 97% ee 98% ee 97% ee 99% ee 99% ee CF 3 C 3 Me Br 94% ee 96% ee Fe 98% ee 96% ee S 94% ee 99% ee 98% 9% 98% ee 78% ee 99% ee 96% ee Dowpharma apers: rg. Lett. 000,, 4173 and rg. rocess es. Dev. 003, 7, 89

46 Large Scale Asymmetric Ketone ydrogenation n n Cl etar Catalyst Cl etar Aims >95% de >95% chemical purity >80% overall yield Minimal reduction of the olefin

47 Catalyst Screen and Loading n Cl etar re-catalyst K t Bu/ t Bu (1M, 1. eq), i-r (10 psi), 40 C, 150 mg/ml n etar re-catalyst S/C Time a (min) Conv. (%) ver-reduction (%) de (%) [()-exaem ucl (,)-DE] 10, [()-exaem ucl (,)-DE] 50, [(S)-hanehos ucl (,)-DE] 10, exaem provided the best de and least olefin reduction Starting material contains 0.9% olefin-reduced material

48 Manufacturing Campaigns Mirfield, UK S/C , 5 mol% K t Bu/ t Bu (1M) re-catalyst added as a solid >97% de produced in all batches Four campaigns making >500 Kg product apid implementation of the process from the laboratory to the plant

49 rocess equirements Choice of Catalyst Complex screening Availability of the Chosen Catalyst (Security of Supply) Synthesis, urity and Selection of Substrate Substrate to Catalyst atio and urity of Substrate Enantiomeric Excess Choice of Solvent Concentration, Temperature, ressure emoval of spent catalyst from the product eactor Configuration, e.g. Agitation

50 Case Study: Methylenesuccinamic acid ydrogenation F 3 C C F 3 C TAK-637 Itaconic anhydride Asymmetric C ydrogenation C Substrate readily made from Itaconate anhydride by reaction with 4 eaction was quenched with Cl according to literature preparation

51 Screen of h recatalysts C [Diphosphine h CD]BF 4 S/C h, 60 psi Me (0.1-0.M), 5 ºC C * %ee Me Et i-r Me Et Me Et i-r t-bu i-r Me Et i-r i-r Xyl MeXyl Fe Duhos 0 FerroTAE 5-Fc Duhos BE hanehos exaem FerroTAE Chloride containing substrate Chloride free substrate

52 Temperature & ressure C [Diphosphine h CD]BF 4 S/C 1,000 * Me (0.3M), C recatalyst Temp (ºC) ressure (psi) TF (h -1 ) Conv. (%) ee (%) [(S,S)-Et-Duhos h CD]BF () > () > () > () > () [(S,S)-Et-FerroTAE h CD]BF > () > 98 7 () > () Enantioselectivity is retained at higher temperatures and pressures for Et-Duhos-h catalyst

53 Solvent Screen C [(S,S)-Et-Duhos h CD]BF 4 S/C = 1,000 Solvent (0.3 M), 5 ºC 16 h, 140 psi C * Solvent Conv. (%) ee (%) Solvent Conv. (%) Me > () EtAc 1 Et () C Cl i-r () Acetone 9 CF 3 C 5 - Toluene 0 TF 4 17 (S) α,α,αtrifluorotoluene 0 Alcoholic solvents are generally the best for asymmetric hydrogenation Methanol is probably the most commonly used solvent This is very much substrate and type of hydrogenation dependant For example [Diphosphine ucl Diamine] hydrogenations require i r

54 Effect of Chloride Ions C [(S,S)-Et-Duhos h CD]BF 4 Me (1.0 M) 45 ºC, 140 psi C S/C Substrate Input TF (h -1 ) Time Conv. (%) ee (%) 1, g h 57 min > () 1, g min > () 1, g min > (S) 5, g min > () 10, g min > () 0, g h 4 min > () 50, g h min > () 100, g h 7 min > () emoval of chloride increases rate by factor of 30 This effect was reproduced by preparing the precatalyst from [hcl(cd)] & eq. of (,)-Et-Duhos

55 Asymmetric ydrogenation of Methylenesuccinamic acid [(S,S)-Et-Duhos h CD]BF 4 S/C 100,000 C Chloride impurity identified that limited S/C to 1000:1 Synthesis of substrate from itaconic anhydride was modified Complete conversion with 96 % e.e. at S/C 100,000:1 ( w / w ~1,400) Upgraded to 99.5 % e.e. with a single reslurry (Me) h 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 0,000) Me (1.0 M), 45 ºC C ~8 h, 140 psi Dowpharma paper: rg. rocess es. Dev. 003, 7, % ee >99.5% ee after solvent slurry

56 rocess equirements Choice of Catalyst Complex screening Availability of the Chosen Catalyst (Security of Supply) Synthesis, urity and Selection of Substrate Substrate to Catalyst atio and urity of Substrate Enantiomeric Excess Choice of Solvent Concentration, Temperature, ressure emoval of spent catalyst from the product eactor Configuration, e.g. Agitation

57 rocess Issue eactor Configuration Me [Me-Duhos h (CD)]BF 4 S/C = 4,00 Me t-bu C C a 70 psi, Me, T t-bu C * C a 10 0 % ydrogen uptake (1) () eactor stirring efficiency: (1) () Time (min) ydrogen availability is a critical process parameter on-optimal stirring and hydrogen absorption can lead to slow/failed reactions

58 Large Scale Asymmetric ydrogenation of DMI Me h Me + - BF 4 Me Me Me Me [(,)-Me-Duhos h CD]BF 4 S/C 0,000 Me, 5 o C Me Me -3 h, 35 psi Ton-scale manufacture (Molar S/C 0,000 = 5,00 wt / wt ) Consistent >97 ee obtained over multiple runs eaction time typically -3 hours Commercial Manufacture carried out in Midland, Michigan

59 Conclusions There has been an increasing number of asymmetric hydrogenation processes carried out on a manufacturing scale over the last 4 decades Asymmetric hydrogenation technology is now 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, there are increased applications for this technology e.g. Tipranavir, ozerem, Sitagliptin and Aliskiren Dowpharma technology is available for customers to use in their own, preferred third party suppliers or Dowpharma facilities Security of supply of the catalyst is of paramount importance

60 Acknowledgments Lee Boulton David Chaplin Chris Cobley Martin Fox Mark Jackson ick Johnson Graham Meek aul Moran Justine eterson Jim amsden Dowpharma/Chirotech Colleagues ast & resent