chemical assembly systems from fundamental flow chemistry ... · peter h. seeberger micro/nano 2016...
TRANSCRIPT
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13.12.2016 | 1 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Chemical Assembly Systems – From Fundamental Flow Chemistry
to Affordable Drugs
Peter H. Seeberger
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13.12.2016 | 2 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
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 106-108 0.1
Bulk Chemicals 104-106 <1-5
Fine Chemicals 102-104 5 - >50
Pharmaceuticals 10 - >103 25 - >100
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13.12.2016 | 3 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Batch and Continuous Manufacturing Comparison
Pharmaceuticals made In Batch
• Enables wide variation • Hard to monitor • Large batch to batch variations
$ Produce high value items
All other mass-produced items made Continuously
• Precludes wide input variation* • Enables combination of steps • Easy to monitor • Very low defect rates
$ Produce low margin items
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13.12.2016 | 4 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
1) Automated reaction optimization
2) Reproducibility
3) Do chemistry otherwise not possible
4) Discover new chemistry
5) Make drugs affordable
Why Continue to Do Flow Chemistry in 2016 ?
Major intellectual hurdles have been overcome
Potential societal impact immense
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13.12.2016 | 5 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
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
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13.12.2016 | 6 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Automated Reaction Optimizer
LabView
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13.12.2016 | 7 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Factors Affecting Glycosylation Selectivity
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13.12.2016 | 8 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Example: Temperature Dependence
OBnO
BnO
BnO
BnOTMSOTf (0.2 eq)
OBnO
BnO
HO
BnO
OMe
O
NH
CCl3 + OBnO
BnO
O
BnO
OMe
OBnO
BnO
BnO
BnO
toluene45 s
OBnO
BnO
O
BnO
OMe
OBnO
BnO
BnO
BnO
Chatterjee, Moon, Gilmore, Seeberger in preparation
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13.12.2016 | 9 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Effect of Sterics of the Acceptor on a/b Selectivity
Chatterjee, Moon: Unpublished Results
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13.12.2016 | 10 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Mechanistic Hypotheses
* S/E = sterics and electronics
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13.12.2016 | 11 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Predicting Glycosylations
R² = 0.9802
20
30
40
50
60
70
80
90
20 30 40 50 60 70 80 90
(Glucose/Galactose Schmidt Donor in DCM)
Measured Beta (%)
Pred
icte
d B
eta
(%
)
Key Parameters for a/b Selectivity: (thus far) - Stereoelectronic Interactions of Donor - Solvent - Temperature - Sterics and Electronics of Acceptor
Chatterjee, Moon: Unpublished
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13.12.2016 | 12 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Chemical Assembly Systems (CAS)
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13.12.2016 | 13 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Singlet Oxygen (1O2)
Excited state of dioxygen
Greenest and cheapest oxidant
Unstable (lifetime micro seconds) -- generated in-situ.
K. I. Salokhiddinov, I. M. Byteva, G. P. Gurinovich, Zh. Prikl. Specktrosk., 1981, 34, 892.
Dye-sensitized photoexcitation of oxygen generates 1O2
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13.12.2016 | 14 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Photochemical Singlet Oxygen Generation
Improve singlet oxygen productivity:
Increase light irradiation
Improve mass transfer of oxygen
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13.12.2016 | 15 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Photochemistry in Flow is Scalable
Minimized path length improves illumination
Continuous product removal prevents secondary reactions
l
I/I0
Batch Channel
L A
M P
Org. Lett. 2011, 13, 5008
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13.12.2016 | 16 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Influence of the Flow Rate
Entry Concentration of Citronellol
Flow Rate Solution (mL/min)
Flow Rate O2
(mL/min) Eq. of O2
Residence Time
Conversion
1 0.25 M 0.09 0.91 1.6 5.0 min 78%
2 0.25 M 0.23 2.27 1.6 2.0 min 95%
3 0.50 M 0.09 0.91 0.8 5.0 min 57%
4 0.50 M 0.23 2.27 0.8 2.0 min 80%
Org. Lett. 2011, 13, 5008.
Faster flow rates → shorter residence time → better conversion
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13.12.2016 | 17 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Importance of the Flow Pattern
Plug Flow
Slug Flow Liquid Phase Gas Phase (O2(g))
Thin Film of Liquid Annular Flow
Specific interfacial area
(a)
25300 m2m-3
18700 m2m-3
3500 m2m-3
Fick’s Law
d[3O2(sol)]/dt = KLa([3O2(sol)]sat –[3O2(sol)])
Org. Lett. 2011, 13, 5008.
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13.12.2016 | 18 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
MAKING DRUGS FROM WASTE
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13.12.2016 | 19 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
40% of ACT Malaria Medication in Africa are Fake!
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13.12.2016 | 20 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Malaria is a Disease of Poverty
Prevention and treatment too expensive for the poorest!
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13.12.2016 | 21 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Artemisinin: Our Best Weapon Against Malaria
Artemisinin
Artemisia
annua
Traditional Chinese Medicine since 200 BC
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
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13.12.2016 | 22 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
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
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13.12.2016 | 23 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
http://www.nature.com/news/2010/100803/full/466672a.html
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13.12.2016 | 24 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
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, 21501.
Engineered Yeast: Alternative Source of Artemisinin?
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13.12.2016 | 25 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Making Drugs from Waste
??? 450 US$ / kg
30 t/a
GM Yeast
Biotech+ Chemistry
Artemisinic acid
0.4 – 1.2 % 200 t/a
Artemisinin
Artemisia annua
Traditional Extraction
Artesunate /Artemether /
Dehydroartemisinin
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13.12.2016 | 26 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Conversion of Dihydroartesiminic Acid to Artemisinin
Y. Li, Y.-L. Wu, Cur. Med. Chem. 2003, 10, 2197. R. K. Haynes, S. C. Vonwiller, Acc. Chem. Res. 1997, 30, 73.
Step 1 Step 2
Step 3
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13.12.2016 | 27 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Lévesque ACIE 2012, 51, 1706.
Kopetzki Chem. Eur. J. 2013, 19, 5450.
Productivity: 150 g/d artemisinin
Utilizing Singlet Oxygen for the Continuous Production of Artemisinin
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13.12.2016 | 28 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Towards Anti-Malarial APIs
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13.12.2016 | 29 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Telescoping from Artemisinin using NaBH4 previously unsuccessful due to “observed detrimental selectivity” of epimeric ratio.
LiHBEt3 in flow: OPRD 2012, 16, 1039
Established Batch Reaction Established Batch Reaction
Stringham & Teager, OPRD. 2012, 16, 764
fully continuous synthesis
Towards Anti-Malarial APIs: Literature Precedent
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13.12.2016 | 30 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Entry Hydride Source Intermediate Wash β:α
1 Superhydride® (LiHEt3) none 50:50
2 Superhydride® (LiHEt3) H2O 50:50
3 Superhydride® (LiHEt3) H2O/ethanolamine (3/1, v/v) 80:20
4 NaBH4 Column none 75:25
5 NaBH4 Column H2O 81:19
6 NaBH4 Column H2O/ethanolamine (3/1, v/v) 82:18
Telescoping Reduction and Etherification
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13.12.2016 | 31 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Gilmore et al. Chem. Comm. 2014, 50, 12652
Overall Process for Anti-Malarial APIs
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13.12.2016 | 32 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Gilmore et al. Chem. Comm. 2014, 50, 12652
Incorporating Continuous Purification
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13.12.2016 | 33 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
S. Pneumoniae: DISTRIBUTION OF SEROTYPES Artemisinin-Produktion
DHAA
Continuous Chemistry
65%
< 200 US$ / kg
Extract
Artemisinin
Artemisia annua
Traditional Extraction
0.4 – 1.2% ≈ 230 US$ / kg
200 T/a
Extraction
GM Yeast
Batch Chemistry
??? 450 US$ / kg
30 T/a
Artemisinic Acid
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13.12.2016 | 34 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Increasing the Efficiency of Chemical Syntheses
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13.12.2016 | 35 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
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
Non-iterative Chemical Assembly
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13.12.2016 | 36 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
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
Non-iterative Chemical Assembly
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13.12.2016 | 37 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
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
Non-iterative Chemical Assembly
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13.12.2016 | 38 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Ushakov, et al. ACIE 2014, 53, 557.
Oxidation of Amines
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13.12.2016 | 39 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Ushakov, et al. ACIE 2014, 53, 557.
Oxidative Strecker
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13.12.2016 | 40 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Ushakov, et al. ACIE 2014, 53, 557.
Temperature Control Reactivity Control
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13.12.2016 | 41 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Angew. Chem. Int. Ed. 2015, 54, 678
- No Byproducts: Biphasic system, aqueous layer separated using modified Jensen extractor
- Flexible: Multiple organic solvents tolerated
- Selective: No over-oxidation detected
Module 1: Biphasic Bleach/TEMPO Oxidation
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13.12.2016 | 42 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Change in reagent diverts
outcome to either b or g pathway
Module 2: Olefination: Knoevenagel/HWE
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13.12.2016 | 43 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
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
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13.12.2016 | 44 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
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.
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13.12.2016 | 45 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
Angew. Chem. Int. Ed. 2015, 54, 678
CAS Synthesis of b-Amino Acids
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Angew. Chem. Int. Ed. 2015, 54, 678
Rolipram: Anti-inflammatory
CAS Synthesis of g-Lactams
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ACIE 2015, 54, 678
Phenibut: Anxiolytic Effects
Gabapentin: Epilepsy
Baclofen: Spasticity
Pregabalin (Lyrica): Anticonvulsant and general anxiety disorder
CAS Synthesis of g-Amino Acids
All 5 APIs USD/yr = >5 billion
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Short Route to Efavirenz
•Semi-continuous flow synthesis
•Overall yield: 45% •Total reaction time: < 2 hours
Correia, Gilmore, McQuade, Seeberger, Angew. Chem. Int. Ed. 2015, 54, 4945
Efavirenz
HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor (NNRTI), used in combination therapy
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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
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13.12.2016 | 50 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
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)
Acknowledgements
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13.12.2016 | 51 Peter H. Seeberger Micro/Nano 2016 – Amsterdam
[email protected] www.peter-seeberger.de Twitter @peterseeberger
Thank You!