Application of Predictive Tools to
Solve Synthetic Challenges in
Drug Discovery and Development
Tobias Rein
Chemnotia AB
powered by InfoChem GmbH
Contents
• Brief history of Computer-Assisted
Synthesis Design (CASD)
• The ICSYNTH tool
• Retrosynthetic analysis
• Forward reaction prediction
• Summary
My Background
• Synthetic chemist
• Academic research
• AstraZeneca R&D
• Part of collaboration with
InfoChem since 2008
• Chemnotia AB started 2012
Computer-Assisted Synthesis Design – History
Retrosynthetic analysis:
Software tools (Corey, then others, late 60’s =>):
OCSS
LHASA
SYNCHEM
SYNGEN
SYNSUP
CHIRON
WODCA
OSET
and several others...
What Became of This?
• In industry, declining interest from the late 80’s
• Searchable reaction databases became favored tools
• But recently, renewed interest in CASD tools
InfoChem – AZ collaboration:
• A tool for idea generation
in retrosynthetic analysis
ICSYNTH – the Basis
Prerequisites for developing ICSYNTH:
Algorithms / software
Atom-atom-mapping
Reaction center id
Reaction classification
Fast search engine
Extensive reaction
databases
e.g., SPRESI:
>4 M reactions
Computer hardware
Powerful
Inexpensive
Networked
Secure
ICSYNTH Today
by
• Currently InfoChem – Chemnotia collaboration
• An idea generator:
• transforms hard to spot by manual analysis
• also unusual or unconventional reactions
• based on precedented, conceptual chemistry
• stimulates the creativity of the user!
Transforms Hard To Spot – Example
Key drug intermediate
Transforms Hard To Spot – Example
Key drug intermediate
• Sequential cycloadditions / rearrangements
• Potentially a one-pot cascade process over
two or three steps
How ICSYNTH Works – Transform Generation
Database reaction (red bond = changed during the reaction)
Reagent template
(2-bond)
Product template
(2-bond)
Transform
• The transform describes the structural change
(but not the mechanism)
Transform Application, Ranking of Output
1) Check for matching
product template
2) Transform application
Target
Precursor
Precursors and routes are ranked by a set of parameters, e.g.:
• Number of new bonds formed
• Number & size of precursor
molecules
• Branching site
• Stereocenter
•
•
•
•
•
Bond type (C-C, C-X ...)
Number of precedent rxns
Best literature yield
Commercial availability
etc ...
Applying Unusual Reactions – Example
Key intermediate for LO program:
Complex mixture
<10% yield
• Known compound; previously published route
used for first preparation
• Poor overall yield, difficult separations, reagents
unsuitable for scale-up
Applying Unusual Reactions – Example
A non-intuitive
retrosynthetic option:
New key step suggested
by ICSYNTH:
S(VI)
New synthesis:
• Overall yield increased to 32%
• Purification by crystallization
S(IV)
”Reversing the engine”:
ICSYNTH Forward Reaction Prediction
ICSYNTH FRP – Applications
• ICSYNTH suggests different products that can be
obtained from a given precursor
• Different outputs obtained by tailoring the query
FRP
Query Molecule
• Lead compound
• Molecule with labile
functionalities
• Patent core intermediate
Suggested Products
• New test compounds
one synthetic step away
• Molecules with possible
bioisosteres
• New compounds not
included in the patent
Scaffold Modification – Example
Diazepam
Library Design – Example
Identifying possible bioisosteres:
Metiamide
Reaction center
Based on analogy, not on exact match:
Cimetidine
(Tagamet)
Other Tools Currently Being Developed
A new approach :
Network of Organic Chemistry
Reaction vectors;
Evotec
Summary
•ICSYNTH is a highly useful idea generator
– will make an experienced chemist
even more creative
•Supports both retrosynthetic analysis
and design of new compounds
Manuscript in preparation; will be submitted to Org. Proc. Res. Dev.
Acknowledgements
Heinz Saller
Christoph Oppawsky
Mike Hutchings
Hans Kraut
Peter Löw
Valentina Eigner-Pitto
Josef Eiblmaier
Stephanie North
Anders Bøgevig
Fernando Huerta
Hans-Jürgen Federsel
Thomas Langer
Thank you!
... and: please come for a look
at ICSYNTH at our booth!
Backup
ICSYNTH – Future Development
Some key areas:
• Chemoselectivity
• Tautomers
• Workflow integration
Why is Synthesis Important in Drug
Discovery and Development?
• How can this novel compound be synthesized?
• The next study requires 2 kgs of API –
a new route is needed for scale-up!
• Can I confirm the
structure of this
trace impurity by
synthesizing it?
ICSYNTH Retrosynthesis Mode – Example 3
Key intermediate for a development project:
Initial route
Mulholland et al., Org. Proc. Res. Dev. 2013, 17 (9), 1117 and 1123
Example 3 (Continued)
New synthetic route suggested by ICSYNTH:
based on an unusual degenerate ring transformation
Example 3 (Continued)
Alternative routes suggested in brainstorming:
Spiroketone Ring Closure / Mechanism
ICSYNTH FRP – Applications
• ICSYNTH suggests different products that can be
obtained from a given precursor
• Different outputs obtained by tailoring the query
Reactivity
mapping
Overview of
side chain
modifications
Core Structure
Library synthesis
Modifications at
a given position
Scaffold modification
Core changes
Reactivity Mapping – Example
Scaffold Modification (Continued)
After processing:
New “virtual” molecules show similar
properties to the known ones
ICSYNTH FRP – Example
Project challenge:
How can the CH3 group in this
compound be modified?
Background:
Ideal
Good
Tedious
Very
unpleasant
Direct lithiation / addition of an electrophile did not work:
ICSYNTH FRP Example (Continued)
ICSYNTH query:
Identified analogy:
Reaction center
…and it did work in practice: 
34
• Both designed for retrosynthetic analysis
• Both based on transforms (rules) derived from published
chemistry
• Differences
• Approaches to “strategies”
• Output display formats
• Transforms algorithmic; shellbased  chemistry
• Rules capture key chemistry
• Transforms optionally derived
from as few as 1 lit example:
unexpected solutions
• Rules based on 10 lit examples,
tried-and-tested chemistry only
• Only limited stereochemistry yet
• Enantioselective chemistry