Chemical Assembly Systems From Fundamental Flow Chemistry to Affordable Drugs. Peter H. Seeberger

Transcription

1 Chemical Assembly Systems From Fundamental Flow Chemistry to Affordable Drugs

2 Current Pharmaceutical Manufacturing is Costly and Wasteful Patented Medicine Costs R&D Marketing & Sales Profit Manufacturing Operating Costs Generic Medicine Costs R&D Marketing & Sales Profit Manufacturing Operating Costs Industry Annual Output (MT) Kg Waste/kg product Oil Refining Bulk Chemicals <1-5 Fine Chemicals >50 Pharmaceuticals 10 - > >

3 Batch and Continuous Manufacturing Comparison Pharmaceuticals made In Batch All other mass-produced items made Continuously Enables wide variation Hard to monitor Large batch to batch variations $ Produce high value items Precludes wide input variation* Enables combination of steps Easy to monitor Very low defect rates $ Produce low margin items

4 Why Continue to Do Flow Chemistry in 2016? 1) Automated reaction optimization 2) Reproducibility 3) Do chemistry otherwise not possible 4) Discover new chemistry 5) Make drugs affordable Major intellectual hurdles have been overcome Potential societal impact immense

5 Studying Glycosylations Quickly and Reliably Automated system for glycosylation optimization with inline detection Identify intermediates and final products using inline spectroscopy and multivariate evaluation Insights into glycosylation mechanism Automated analysis of glycosylation kinetics Chatterjee, Moon, Gilmore, Seeberger in preparation

6 Automated Reaction Optimizer LabView

7 Factors Affecting Glycosylation Selectivity

8 Example: Temperature Dependence BnO BnO BnO O BnO O BnO NH HO TMSOTf (0.2 eq) BnO O BnO O O CCl 3 + BnO BnO BnO O toluene BnO BnO BnO OMe 45 s BnO OMe BnO BnO BnO O BnO O BnO BnO O BnO OMe Chatterjee, Moon, Gilmore, Seeberger in preparation

9 Effect of Sterics of the Acceptor on a/b Selectivity Chatterjee, Moon: Unpublished

10 Mechanistic Hypotheses * S/E = sterics and electronics

11 Predicted Beta (%) Predicting Glycosylations (Glucose/Galactose Schmidt Donor in DCM) Key Parameters for a/b Selectivity: (thus far) - Stereoelectronic Interactions of Donor - Solvent - Temperature - Sterics and Electronics of Acceptor R² = Chatterjee, Moon: Unpublished Measured Beta (%)

12 Chemical Assembly Systems (CAS)

13 Singlet Oxygen ( 1 O 2 ) Excited state of dioxygen Greenest and cheapest oxidant Unstable (lifetime micro seconds) -- generated in-situ. Dye-sensitized photoexcitation of oxygen generates 1 O 2 K. I. Salokhiddinov, I. M. Byteva, G. P. Gurinovich, Zh. Prikl. Specktrosk., 1981, 34,

14 Photochemical Singlet Oxygen Generation Improve singlet oxygen productivity: Increase light irradiation Improve mass transfer of oxygen

15 L A M P Photochemistry in Flow is Scalable Minimized path length improves illumination I/I 0 l Batch Channel Continuous product removal prevents secondary reactions Org. Lett. 2011, 13,

16 Influence of the Flow Rate Entry Concentration of Citronellol Flow Rate Solution (ml/min) Flow Rate O 2 (ml/min) Eq. of O 2 Residence Time Conversion M min 78% M min 95% M min 57% M min 80% Faster flow rates shorter residence time better conversion Org. Lett. 2011, 13,

17 Importance of the Flow Pattern Plug Flow Specific interfacial area (a) 3500 m 2 m -3 Slug Flow Liquid Phase Gas Phase (O 2(g) ) m 2 m -3 Annular Flow Thin Film of Liquid m 2 m -3 Fick s Law d[ 3 O 2(sol) ]/dt = K L a([ 3 O 2(sol) ] sat [ 3 O 2(sol) ]) Org. Lett. 2011, 13,

18 MAKING DRUGS FROM WASTE

19 40% of ACT Malaria Medication in Africa are Fake!

20 Malaria is a Disease of Poverty Prevention and treatment too expensive for the poorest!

21 Artemisinin: Our Best Weapon Against Malaria Artemisinin Traditional Chinese Medicine since 200 BC Artemisia annua 1972: isolation and structure elucidation (Tu Youyou) 2001: WHO recommends artemisinin-based combination therapy (ACTs) 2009: 159 mio ACT treatments 2013: 330 mio ACT treatments required Artemisinin demand / year: about 250 t

22 Current Treatments for Malaria First line treatment: Artemisinin Combination Therapies (ACTs) Coartem (Novartis): Artemether (20 mg) Coarsucam (Sanofi): Artesunate (100 mg) Eurartesim, Artekin, Duo-Cotecxin (sigma-tau, Chongqing Holley) Dehydroartemisinin (40 mg) Treatment for severe malaria: Intravenous or intramuscular injection of artesunate

23

24 Engineered Yeast: Alternative Source of Artemisinin? Engineered yeast produces 100 mg/l of artemisinic acid or dihydroartemisinic acid. No enzyme known to convert artemisinic acid to artemisinin Last three steps to be done chemically on large scale. Ro, D.K. et al. Nature, 2006, 440, 940. Zhang, Y. et al. J. Biol. Chem. 2008, 283,

25 Making Drugs from Waste Traditional Extraction Biotech+ Chemistry Artemisia annua GM Yeast % 200 t/a Artemisinin Artemisinic acid??? 450 US$ / kg 30 t/a Artesunate /Artemether / Dehydroartemisinin

26 Conversion of Dihydroartesiminic Acid to Artemisinin Step 1 Step 2 Step 3 Y. Li, Y.-L. Wu, Cur. Med. Chem. 2003, 10, R. K. Haynes, S. C. Vonwiller, Acc. Chem. Res. 1997, 30,

27 Utilizing Singlet Oxygen for the Continuous Production of Artemisinin Productivity: 150 g/d artemisinin Lévesque ACIE 2012, 51, Kopetzki Chem. Eur. J. 2013, 19,

28 Towards Anti-Malarial APIs

29 Towards Anti-Malarial APIs: Literature Precedent Established Batch Reaction Established Batch Reaction LiHBEt 3 in flow: OPRD 2012, 16, 1039 fully continuous synthesis Telescoping from Artemisinin using NaBH 4 previously unsuccessful due to observed detrimental selectivity of epimeric ratio. Stringham & Teager, OPRD. 2012, 16,

30 Telescoping Reduction and Etherification Entry Hydride Source Intermediate Wash β:α 1 Superhydride (LiHEt 3 ) none 50:50 2 Superhydride (LiHEt 3 ) H 2 O 50:50 3 Superhydride (LiHEt 3 ) H 2 O/ethanolamine (3/1, v/v) 80:20 4 NaBH 4 Column none 75:25 5 NaBH 4 Column H 2 O 81:19 6 NaBH 4 Column H 2 O/ethanolamine (3/1, v/v) 82:

31 Overall Process for Anti-Malarial APIs Gilmore et al. Chem. Comm. 2014, 50,

32 Incorporating Continuous Purification Gilmore et al. Chem. Comm. 2014, 50,

33 S. Pneumoniae: Artemisinin-Produktion DISTRIBUTION OF SEROTYPES Traditional Extraction Continuous Chemistry Batch Chemistry Artemisia annua Extract DHAA GM Yeast Extraction Artemisinin Artemisinic Acid % 230 US$ / kg 200 T/a 65% < 200 US$ / kg??? 450 US$ / kg 30 T/a

34 Increasing the Efficiency of Chemical Syntheses

35 Non-iterative Chemical Assembly Goal: Take advantage of all layers of control to develop a convergent and divergent chemical assembly system, made up of interchangeable flow reaction modules, capable of producing a variety of APIs of multiple structural classes in a continuous fashion. Develop reaction modules for oxidation, olefination, Michael addition, hydrogenation, and hydrolysis

36 Non-iterative Chemical Assembly Goal: Take advantage of all layers of control to develop a convergent and divergent chemical assembly system, made up of interchangeable flow reaction modules, capable of producing a variety of Active Pharmaceutical Ingredients of multiple structural classes in a continuous fashion. Develop reaction modules for oxidation, olefination, Michael addition, hydrogenation, and hydrolysis

37 Non-iterative Chemical Assembly Goal: Take advantage of all layers of control to develop a convergent and divergent chemical assembly system, made up of interchangeable flow reaction modules, capable of producing a variety of Active Pharmaceutical Ingredients of multiple structural classes in a continuous fashion. Develop reaction modules for oxidation, olefination, Michael addition, hydrogenation, and hydrolysis

38 Oxidation of Amines Ushakov, et al. ACIE 2014, 53,

39 Oxidative Strecker Ushakov, et al. ACIE 2014, 53,

40 Temperature Control Reactivity Control Ushakov, et al. ACIE 2014, 53,

41 Module 1: Biphasic Bleach/TEMPO Oxidation - No Byproducts: Biphasic system, aqueous layer separated using modified Jensen extractor - Flexible: Multiple organic solvents tolerated - Selective: No over-oxidation detected Angew. Chem. Int. Ed. 2015, 54,

42 Module 2: Olefination: Knoevenagel/HWE Change in reagent diverts outcome to either b or g pathway

43 Module 3: Nitromethane Michael Addition Solvent for Assembly System Dictated: Reason: Reaction fails in presence of methanol, which is added in module 2 to dissolve salts Solution: Methanol efficiently removed by inline workup when toluene is organic solvent

44 Module 4: Hydrogenation Module 5: Hydrolysis Versatile: Commercial H-Cube used with metal catalyst cartridges to effect nitro, nitrile, and olefin reductions. Clean: Upon hydrolysis, product in aqueous layer. All byproducts remain in organic phase. Acidification and inline back-extraction provide product solution

45 CAS Synthesis of b-amino Acids Angew. Chem. Int. Ed. 2015, 54,

46 CAS Synthesis of g-lactams Rolipram: Anti-inflammatory Angew. Chem. Int. Ed. 2015, 54,

47 CAS Synthesis of g-amino Acids Phenibut: Anxiolytic Effects Gabapentin: Epilepsy Baclofen: Spasticity Pregabalin (Lyrica): Anticonvulsant and general anxiety disorder All 5 APIs USD/yr = >5 billion ACIE 2015, 54,

48 Short Route to Efavirenz Efavirenz HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor (NNRTI), used in combination therapy Semi-continuous flow synthesis Overall yield: 45% Total reaction time: < 2 hours Correia, Gilmore, McQuade, Seeberger, Angew. Chem. Int. Ed. 2015, 54,

49 Conclusions Flow reactors are routine laboratory tool Rapid reaction optimization on small amounts of material kinetic, mechanistic data for process development Applicable to liquid, gas, solids, nanoparticles and crystallization Scale-up of complex syntheses possible Cost savings for generics impact in low income countries Chemical Assembly Systems (CAS) provide straightforward access to common cores Challenge: Find truly new chemistry

50 Acknowledgements Dr. Kerry Gilmore S.-Y. Moon Matthew Plutschack Stella Vukelić Dr. Sourav Chatterjee Dr. Anna Chernova Dr. Bartholomäus Pieper Dr. Francois Levesque (Merck/USA) Dr. Camille Correia (Merck/KGaA) Dr. Dmitry B. Ushakov (Merck/KGaA) Dr. Gouzhi Xiao (Penn State) Dr. Diego Ghislieri (BASF) Collaborators: Prof. Koksch (FU) Prof. Seidel-Morgenstern (MPI) Zoltan Horváth (MPI) Elena Horosanskaia (MPI) Ju-Weon Lee (MPI)

51 Thank You!