cross-disciplinary working in the development of ... · pdf file2nd ed. h.-u. blaser,...
TRANSCRIPT
Cross-Disciplinary Working in the
Development of Sustainable
Pharmaceutical and Fine Chemical
Processes
John Blacker
Summary
• Supporting change in fine-chem and pharma sectors
• Cross disciplinary working for better processes
• Innovating better chemical and process technologies
• Academic support of the industry involved in making
complex organic products
Drivers for Change in Chemical Manufacture
Environmental (eg IPPC, REACH legislation)
Political (cost of drugs, food contamination, water quality)
Regulatory (especially pharmaceuticals – better control of properties)
Economic (intellectual property defence, time-to-market vs patent life)
Geographic (transfer of manufacture to low cost economies)
Industry Sector Annual Production
(tonnes)
Waste/Product
(E-factor)
Oil Refining 106 - 108 ca. 0.1
Bulk Chemicals 105 - 107 <1-5
Fine Chemicals 104 - 106 5 - 50
Pharmaceutical 10-103 25 - 100
Industry „gold standard‟
ViagraTM (E = 6)
Exemplar: waste issues in the industry
Pharma Product Lifecycle :
Volume/Time Profile
Pre-clinical
Launched
on-patent
growing
Pre-launch
stocking
Launched
on-patent
mature Off patent
Phase I II III
Generic product(s) launched
50%
28%
50%
Molecular Complexity of
Old and New Bioactive ProductsPharmaceuticals
Agrochemicals
Example of Process Improvement - Viagara
•1st generation route
• 2nd generation route
• Overall yield 7.5%
• Overall
yield 76%D. J. Dale, P. J. Dunn, C. Golightly, M. J. Hughes, P. C. Levett, A. K. Pearce, P. M. Searle, G. Ward, A. S. Wood
Org. Proc. Res. Dev., 2000, 4, 17-22
Former Process R+D Practices
•Success was measured by product yield and quality.
•This gives an incomplete picture of the process and is
missing information about:
Mass or energy inputs and outputs
Time
Material contacting
Equipment
Reproducibility
Robustness (tolerance to change)
Mechanism
•Multi-phase processes usually scale-up non-linearly
Synthetic organic
chemistry
Physical organic
chemistry
Chemical engineering
Statistical experimental
design
Physical science
Material science
Hazard studies
Analytical chemistry
Skills Required to Develop Complex
Organic Manufacturing Process
Process
Design
Route
design
Process
design
Isolation
design
Formulation
design ProductConcept/
candidate
Synthetic chemistry
Catalysis
Separation sci/eng
Crystallisation
Particle SciencePhysical organic chem.
Reaction engineering
The Need for Integrated Teams:
Chemist-Engineer Interface
Job of the process chemist
•Write chemical process description leading to process
instruction sheets
•Identify issues and problems that might cause problems in
scale-up
•Study safety, hazards, quality, raw materials costs, patents
•Support initial manufacture and provision of larger quantities
of material for human clinical or field trials
Job of the process engineer
•Draw chemical process flow sheet leading to plant design
•Identify issues and problems that might cause problems in
scale-up
•Study safety, hazards, mass-energy balance operational
and capital costs
•Support initial manufacture and provision of larger
quantities of material for human clinical or field trials
Measuring Process Performance
0
20
40
60
80
100
120
1 2 3 4 5
Yield (%)
Product Quality
Productivity
Waste
Cost
Batch failure rate
Time (years)
Rela
tive c
han
ge (
%)
Demands for New Technologies
•Thalidomide catastrophe - chiral chemistry
•Chiral molecules – biotransformations
•Complex molecules – catalysis
•More NCE‟s - parallel / robotic screening
•Volume of data analysis - statistical design
•Environmental impact - green / sustainable chemistry
•Genotoxicity - hydrogen borrowing
•Price pressure - continuous / intense processing
•Polymorph control - crystal science
•Bioavailability, drug delivery – nanoparticle science
• Diastereoselective ketone reduction of statin side chain at deca-tonne scale
• Regioselective primary alcohol protection
• Diastereoselective ketone reduction at tonne scale
• Biocatalyst gives kinetic diastereomer, chemo-catalysts give thermodynamic
• Ritter reaction with unusual retention of stereochemistry
Biotransformations : rosuvastatin and
dorzolamide intermediates at tonne scale
Biologists + Chemists + Engineers
Examples of New Technologies :
Asymmetric Transfer Hydrogenation
J. Takehara, S. Hashiguchi, A. Fujii, S. Inoue, T. Ikariya, R. Noyori, Chem.Commun. 1996, 233
A.J.Blacker, B.M.Mellor, WO9842643B2; A.J.Blacker, T. Ikariya, Acc.Chem.Res. 2007, 40(12), 1300-1308
CATHy™ CatalystsNoyori Catalysts
• Chiral alcohols and amines occur in >50%of
bioactive molecules
• Catalytic asymmetric transfer hydrogenation
of ketones and iminiums to make chiral
alcohols and amines is a green technology
solution
Asymmetric Transfer Hydrogenation
Yield 95%
EE >97%
S/C >1000/1
Concentration 5-15%
Cycle time <8hrs
• Economic
• Productive
• Reproducible Chemists + Engineers
Organic
Aqueous
Substrate /
Product /
Catalyst?
NaHCO2 /
Catalyst?
Biphasic reaction medium
• pH control
• Faster rates
• No off-gassing
Asymmetric Transfer Hydrogenation
Substrate
Reagent
Catalyst
Product
By-product
Catalyst
Batch reaction
Continuous reaction
• New ATH process E=<5
•Traditional resolution process E>10
Sun, X. Y.; Manos, G.; Blacker, J.; Martin, J.; Gavriilidis, A.,
Org. Proc. Res. Dev. 2004, 8, (6), 909-914J. Blacker, P. Thompson, Asymmetric Catalysis on Industrial Scale
2nd Ed. H.-U. Blaser, H.-J.Federsel , Wiley VCH, 2010, pp19-43
diltiazem
35
8
39
Resolution
Asymmetric
Chiral Pool
Opportunities For
Racemisation-Resolution Process•About 40% of chiral drugs are made by isomer resolution
•There is a sizeable waste stream of potentially useable drug /
intermediate
•Examples of generics made by resolution:
•Amine racemisation to enable use of waste isomer
R R'
NHR''
R R'
NR''
R R'
NHR'' catalyst catalyst
• Active Pharma Ingredient appx $110/kg
• 26% yield at final stage, 74% isomer waste
• To recover waste racemisation of both
chiral centres required
• Sertralone appx $12/kg
• Recycle needs to be <$12/kg !
• Iridium needs to be <10ppm in API
Sertraline Resolution Process
Sertraline
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
0 150 300 450 600 750 900 1050 1200
Time /mins
%d
e
Racemisation of amine centre
(0.1 mol%, 80‟C, 30 mins)
Chiral Amine Racemisation
Catalyst
ProductSubstrate Product
•Immobilised catalyst
for flow process
nanofiltration
membrane
SCRAM
Racemisation
Catalyst
Separation
Base
Racemisation Base
Catalyst
Base
Separation
Resolution
Process
Aqueous
Waste
Product
Salt
Sertraline
HCl
Pre-SCRAM
Preparation
Water
Resolving
Reagent
Racemic
Sertraline
• 100g scale
• 5 recycles - 35g / pass
• 175g >95% purity product
• <10ppm Iridium
• 0.1mol% catalyst
• 99% catalyst recovery
• <1kg waste/ kg product
Resolution – Racemisation Process
A. J. Blacker,S. Brown, B. Clique, B. Gourlay, C.E. Headley, S. Ingham, D. Ritson, T. Screen, M.J. Stirling, D. Taylor, G. Thompson, Org. Proc. Res. Dev. 2009, Chemists + Crystal Science + Engineers
Slowing Amine Dimerisation During
Racemisation
• Dropwise addition of amine
• Concurrent removal of desired enantiomer via enzymatic acylation
Amine
Enzyme +SCRAM
• [Amine] kept low throughout.
• Rate of : racemisation ≥ acylation > addition amine.
Biologists + Chemists + Physical Organic
Chiral Amine Dynamic Kinetic Resolution
• Primary amine DKR – yield doubled
• Secondary amine DKR – yield doubled
Blacker, A. J.; Stirling, M. J.; Page, M. I., Org. Proc. Res. Dev. 2007, 11, (3), 642-648
Stirling, M.; Blacker, J.; Page, M. I., Tet. Lett. 2007, 48(7), 1247-1250 Biologists + Chemists
• remarkably, selective transfer of secondary alkyl groups to amines which are capable of
being oxidised is also possible in very good yield:
• the origin of the selectivity is unclear: the alkylation substrates are oxidised; however, the
resulting oxidative dimer is also an alkylation substrate, suggesting a self-correcting process:
Hydrogen borrowing catalysis of
amines: alkylation
O. Saidi, A. J. Blacker, M. M. Farah, S. P. Marsden, J. M. J. Williams, Angew. Chem. Int. Ed., 2009, 48, 1-5
Hydrogen borrowing catalysis of amines:
alkylation• Beller has previously reported the use of the Shvo catalyst to promote selective cross-
coupling via hydrogen borrowing from amines, provided ONE of the coupling partners cannot
undergo oxidation (ie anilines, t-alkylamines)
• [Cp*IrI2]2 is also an effective catalyst for this process:
O. Saidi, A. J. Blacker, M. M. Farah, S. P. Marsden, J. M. J. Williams, Angew. Chem. Int. Ed., 2009, 48, 1-5
Hydrogen-transfer catalysis of amines:
benzoxazoles• [Cp*IrI2]2 is a highly effective catalyst for the “reagentless” homogeneous oxidative formation
of benzoxazoles, benzothiazoles from aldehydes and benzimimidazoles from alcohols:
• the reaction does not work with enolisable aliphatic aldehydes - enamine condensation
leading to 8-hydroxyquinolines competes
A. J. Blacker, M. M. Farah, M. Hall, S. P. Marsden, O. Saidi, J. M. J. Williams, Org. Lett., 2009, 11, 2039-2042Blacker, Farah, Marsden, Saidi , Williams Org. Lett., 2009, 11, 2039
Hydrogen-transfer catalysis of amines:
oxazolines• [Cp*IrI2]2 is also a highly effective catalyst for oxidative formation of non-aromatic
heterocycles such as oxazolines
• despite being a highly efficient amine-racemisation catalyst, no loss of stereochemistry is
seen in the oxazoline-forming reactions
A. J. Blacker, M. M. Farah, S. P. Marsden, O. Saidi, J. M. J. Williams, Tetrahedron Lett., 2009, 50
Hydrogen-transfer catalysis of amines:
2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles
Amine alkylation in water
O. Saidi, A. J. Blacker, G. W. Lamb, S. P. Marsden, J. E. Taylor, J. M. J. Williams, Org. Proc. Res. Dev., 2010, 10.1021/op100024j
Industry example – made in Asia J. A. Marsella, J. Organomet.Chem. 1991, 407, 97-105
Where will innovation
take place?
Industry already highly R&D intensive
(ca. 11% of sales)
Economic climate makes industry risk-averse
(only near-to-market or “critical path” activities)
Solution: partnering between industry and Universities
Mutually beneficial: industry spreads exposure to high risk/high return
activity; Universities increase power to benefit from IP generated
EU High Level Group on Competitiveness in European Chem. Industry:
“More should be done in improving the mechanisms of technology
transfer and the systemic links between public research and business”
Process Expertise in
Academia
•Poor awareness of process chemistry / manufacture
•Expertise fragmented and un-coordinated
•Organised in schools/departments with little cross-disciplinary
activity
•Funding aimed at research not development
•Measure of performance on publications not industrial impact
•Poor awareness of industry problems
•Industry seen as funders not collaborators
•Poor communication between industry / academia
•Few scale-up facilities, usually in chem.eng
The Institute of Process Research and Development is
established to support the fine chemical and pharmaceutical
industries by:
Working with companies to significantly improve manufacturing
processes (higher quality & productivity, lower cost, waste and energy)
Sustaining high-risk / high return projects by a leveraged combination of
industrial, public and academic resources
Inventing, understanding and developing new technology that can be
readily commercially applied
Improving mechanisms for industrial exploitation of academic creativity
Providing high quality trained process development chemists and
engineers – 2MSc courses in process R+D
Process Focused Cross
Disciplinary Centre
Huge demands on chemical industry to change and
compete
Industry can only afford short-term R+D with
commercial focus
Industry problems require multi-disciplinary teams
Academia can provide medium-long term sector-
wide support to help address problems
Academia needs to foster multi-disciplinary teams
Industry and academia need to build strong bridges
Summary
Acknowledgements
Prof. Stephen Marsden - Chemist
Prof. Jonathan Williams - Chemist
Prof. Kevin Roberts - Crystal Science
Prof. Mike Page - Phys Org
Prof. John Atherton - Phys Org
Dr John Cooksey - Chemist
Dr Mohamed Farrah - ChemistDr Steve Hatchett - EngineerDr Cat Headley - ChemistDr Chris Reeve – BiologistDr Matthew Stirling - Phys OrgDr Ourida Saidi – ChemistDr Peter Thompson - Chemist
EPSRC and TSB
Yorkshire Forward and EU
Avecia, Piramal Healthcare
Reaxa, AstraZeneca, Pfizer,
GSK, Merck, Syngenta,
Dr Reddys, Shasun,
BromChem DeDietrich,
DyeCat, Escubed