Cross-Disciplinary Working in the

Development of Sustainable

Pharmaceutical and Fine Chemical

Processes

John Blacker

j.blacker@leeds.ac.uk

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