chemical assembly systems from fundamental flow chemistry ... · peter h. seeberger micro/nano 2016...

13.12.2016 | 1 Peter H. Seeberger Micro/Nano 2016 – Amsterdam

Chemical Assembly Systems – From Fundamental Flow Chemistry

to Affordable Drugs

Peter H. Seeberger


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


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


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


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


Automated Reaction Optimizer

LabView


Factors Affecting Glycosylation Selectivity


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


Effect of Sterics of the Acceptor on a/b Selectivity

Chatterjee, Moon: Unpublished Results


Mechanistic Hypotheses

* S/E = sterics and electronics


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


Chemical Assembly Systems (CAS)


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


Photochemical Singlet Oxygen Generation

Improve singlet oxygen productivity:

Increase light irradiation

Improve mass transfer of oxygen


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


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


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.


MAKING DRUGS FROM WASTE


40% of ACT Malaria Medication in Africa are Fake!


Malaria is a Disease of Poverty

Prevention and treatment too expensive for the poorest!


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


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


http://www.nature.com/news/2010/100803/full/466672a.html


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?


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


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


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


Towards Anti-Malarial APIs


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


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


Gilmore et al. Chem. Comm. 2014, 50, 12652

Overall Process for Anti-Malarial APIs


Gilmore et al. Chem. Comm. 2014, 50, 12652

Incorporating Continuous Purification


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


Increasing the Efficiency of Chemical Syntheses


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


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.




Ushakov, et al. ACIE 2014, 53, 557.

Oxidation of Amines



Oxidative Strecker



Temperature Control Reactivity Control


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


Change in reagent diverts

outcome to either b or g pathway

Module 2: Olefination: Knoevenagel/HWE


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


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.



CAS Synthesis of b-Amino Acids



Rolipram: Anti-inflammatory

CAS Synthesis of g-Lactams


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


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


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


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


[email protected] www.peter-seeberger.de Twitter @peterseeberger

Thank You!

mailto:[email protected]

http://www.peter-seeberger.de



chemical assembly systems from fundamental flow chemistry ... · peter h. seeberger micro/nano 2016...

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