Post on 20-May-2015
description
Challenges in scale-up:Developing a process for the large scale manufacture of a pharmaceutical intermediate
Greg Briner
Introduction to AstraZeneca
A multi-national pharmaceutical company
Formed in 1999
Zoladex (cancer), Seroquel (schizophrenia), Bricanyl (asthma)
Process Research & Development
Role in product timeline:
Introduction to PR&D
Target Identification
Hit Identification
Lead Identification
Lead Optimisation
CD Prenomination
Concept Testing
Development for Launch
Launch Phase
Product Maintenance
PR&D
PR&D at Macclesfield
Analytical Chemistry
Process Chemistry
Process Safety Group
Process Engineering
Process Chemistry
http://www-bioc.rice.edu/
Safe Robust Commercially viable
Process Chemistry
AstraZeneca Products
Respiratory andInflammation
Neuroscience
Infection
Gastrointestinal
Cardiovascular
Cancer
Therapy Areas
AZD2171
A vascular endothelial growth factor (VEGF) signalling inhibitor
Phase II / III trials for lung cancer and colorectal cancer
AZD2171
AZD2171 Reaction Scheme
AZD2171 Chloropyrrolidine free base
N Cl
N
N
O
RO
BnO
Ar
AZD2171 BQ Indole
N
N
O
RO
O
Ar
N
AZD2171 Crude
H2 / Pd
NMP K2CO3
N
N
O
RO
OH
Ar
AZD2171 Indolphenol
NH
+Cl
R
AZD2171 Chloropyrrolidine salt
Pyrrolidine
RH
Br Cl MTBEN
AZD2171 Chloropyrrolidine salt
NH
+Cl
R
AZD2171 Chloropyrrolidine salt
Pyrrolidine
RH
Br ClN
20 g 200 g
Reaction scaled-up
Heat:
17°C exotherm observed
L
Volume L3
Surface Area L2
∞
∞
NH
+Cl
R
AZD2171 Chloropyrrolidine salt
Pyrrolidine
RH
Br ClN
AZD2171 Chloropyrrolidine salt
AZD2171 Reaction Scheme
AZD2171 Chloropyrrolidine free base
N Cl
N
N
O
RO
BnO
Ar
AZD2171 BQ Indole
N
N
O
RO
O
Ar
N
AZD2171 Crude
H2 / Pd
NMP K2CO3
N
N
O
RO
OH
Ar
AZD2171 Indolphenol
NH
+Cl
R
AZD2171 Chloropyrrolidine salt
Pyrrolidine
RH
Br Cl MTBEN
AZD2171 Reaction Scheme
AZD2171 Chloropyrrolidine free base
N Cl
N
N
O
RO
BnO
Ar
AZD2171 BQ Indole
N
N
O
RO
O
Ar
N
AZD2171 Crude
H2 / Pd
NMP K2CO3
N
N
O
RO
OH
Ar
AZD2171 Indolphenol
NH
+Cl
R
AZD2171 Chloropyrrolidine salt
Pyrrolidine
RH
Br Cl MTBEN
AZD2171 Crude Work-up
AZD2171 Chloropyrrolidine free base
N Cl
N
N
O
RO
O
Ar
N
AZD2171 Crude
K2CO3
N
N
O
RO
OH
Ar
AZD2171 Indolphenol
Anti-solvents:
Different volumes of water
Water / Methanol
Water / Acetonitrile
AZD2171 Crude Work-up
1:1 Water / Methanol Anti-solvent
Liquors
Product
Conclusions
AZD2171 Chloropyrrolidine free base
N Cl
N
N
O
RO
BnO
Ar
AZD2171 BQ Indole
N
N
O
RO
O
Ar
N
AZD2171 Crude
H2 / Pd
NMP K2CO3
N
N
O
RO
OH
Ar
AZD2171 Indolphenol
NH
+Cl
R
AZD2171 Chloropyrrolidine
salt
Pyrrolidine
RH
Br Cl MTBEN
Acknowledgements
Mike Senior
Matt Evans
Martin Jones