Developing NonProprietary Pd Catalysts for Industrial Processes

1
Developing Non-Proprietary Pd Catalysts for
Industrial Processes

• Robert Singer
• Pfizer Global Research and Development
• Groton Labs
• Chemical Research and Development

2
Pd Catalysis in Industry

• Med Chem Discovery Applications
• Need broad scope for a reliable process
  (Libraries)
• Small scale application with chromatographic
  purification (facile Pd removal and cleanup)
• Process Chemistry Applications
• Optimize process for specific target
• Desire minimal side products and high yield
• Require facile isolations and ability to remove
  Pd
• Must be scalable process and commercially
  available materials
• Need Freedom to Operate

3
Current Pfizer Process Preparation of
Varenicline RSM

• Inexpensive commodity chemicals used, including
  supporting ligand (PCy3) for Pd
• Tandem processing steps with key isolations for
  clean up

4
Case Study Pd-Catalyzed Amination Reaction

• Vast Discovery Applications for traditional Med
  Chem and Library screening
• Recent Process Challenges
• Needed commercial development for Step 1 in
  Torcetrapib
• Applications of chloropyridine couplings in early
  candidates

5
Mechanistic Pitfalls of the Pd-Catalyzed
Amination Reaction
6
Modern Phosphine Ligands
7
Why the Buchwald Catalyst is Effective
8
Evolution of Pfizer Phosphine Ligands
9
Substrate Scope for Di-tert-butyl Pyrazole
Phosphine

• This ligand is not very effective with primary
  amines!
• Ligand is not compatible with Pd(OAc)2 and forms
  inactive complexes

10
Next Generation of Ligands
11
Scope of Naphthyl-Pyrazole Ligand

• Issues in Preparation cross-coupling may be
  required
• and intermediate can not be purified easily since
  it is an oil

12
Design of Next Generation Ligand - Bippyphos

• Modular Design
• No Cross-Couplings, only simple alkylations or
  condensations
• Facile lithiation
• Now Commercially Available (Bippyphos)

13
Substrate Scope of Bippyphos
14
Other Substrate Types
15
Case Study Optimization of Chloropyridine
Couplings

• Discovery is currently preparing various families
  of drug candidates by Pd-catalyzed couplings
  possessing the 2-amino-pyridine moiety

16
Screen of Base in Pyridine Couplings

• KOH or NaOH work equally well as NaOtBu
• Some water is tolerated, but excess water has
  inhibition effect

17
Solvent Screen of Couplings

• Excellent Reactivity with alcohols but coupling
  side reactions with primary or secondary alcohols
  for activated aryl halides

18
Pyridines in Pd-Catalyzed Amination
19
Pyridine coupling alpha to carbonyls

• Demonstrate couplings of malonates with
  halo-pyridines

20
Streamlined Synthesis of Bippyphos

• Shorter reaction times for each step with
  optimization
• Important to avoid isolation of reactive
  intermediates
• Alternatives to Bromine available in Step 1
  NBS!

21
Additional Ligands in the Bippyphos Family

• Wanted to probe if alcohol functionality improves
  performance in same way as solvent effect
• Wanted to prepare less hindered ligand

22
Suzuki-Miyaura Couplings

• Pd(OAc)2 is more effective than Pd2(dba)3
• Hindered substrates can be coupled
• 31 Ligand to Pd ratio preserves the catalyst

23
Acknowledgements

• Michael Dore
• Greg Withbroe
• Janice Sieser
• Norma Tom
• Stephane Caron
• Ruth McDermott
• Martin Berliner
• Nga Do

24
Back up slides
25
(No Transcript)
26
(No Transcript)