Catalysis in the Pharmaceutical Industry : Catalysis in the Pharmaceutical Industry : Catalysis in the Pharmaceutical Industry : Catalysis in the Pharmaceutical Industry : Challenges and Approaches Challenges and Approaches Challenges and Approaches Challenges and Approaches Challenges in Catalysis for Pharmaceuticals and Fine Chemicals London Nov. 2, 2016 Yi Hsiao Catalyst R&D Group Chemical Development Catalyst R&D Group, Chemical Development Bristol-Myers Squibb
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Catalysis in the Pharmaceutical Industry :Catalysis in the Pharmaceutical Industry :Catalysis in the Pharmaceutical Industry :Catalysis in the Pharmaceutical Industry :Challenges and ApproachesChallenges and ApproachesChallenges and ApproachesChallenges and Approaches
Challenges in Catalysis for Pharmaceuticals and Fine ChemicalsLondon Nov. 2, 2016
Yi HsiaoCatalyst R&D Group Chemical DevelopmentCatalyst R&D Group, Chemical Development
Bristol-Myers Squibb
OutlineOutlineIntroductionIntroduction
OutlineOutline
1. The power of Parallel Experimentation
2. Complex parameters and local optimization
3. The mechanism of catalyst activation and its impact on3. The mechanism of catalyst activation and its impact on
process robustness
Opportunities and Challenges of Catalytic ReactionsOpportunities and Challenges of Catalytic Reactions
IntroductionIntroduction
Opportunities and Challenges of Catalytic ReactionsOpportunities and Challenges of Catalytic Reactions
Diversity of Transformationsy Asymmetric hydrogenation, C–C cross-coupling, C–X couplings, Heck,
Sensitivity to Reaction ConditionsEff t f i d i t l t b / id dditi t l t ti Effects of air and moisture, solvents, base/acid additives, catalyst ratios, pressure, temperature
There is No Magic Bullet! >4000 phosphine ligands, along with thousands of other ligands, metal
complexes, organocatalysts, enzymes
To develop a robust catalytic process, large number of experiments are inevitableare inevitable
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A “ShotgunA “Shotgun”” HTP Screening Approach Will FailHTP Screening Approach Will Fail
IntroductionIntroduction
A ShotgunA Shotgun HTP Screening Approach Will FailHTP Screening Approach Will Fail
Significant parameters of a catalytic reaction:Significant parameters of a catalytic reaction:
Discrete parameters: Identity of pre-catalyst, ligand, base/additive, solvent
Continuous parameters: Loading of substrate, pre-catalyst, additive, solvent,
water, L/M ratio, temperature, time ate , / at o, te pe atu e, t e
Total: 12 parameters (4 discrete, 8 continuous)
If only two of each parameters are investigated: 212 = 4096
Slightly expanding the number of ligands, additives and solvents:
HTP experimentation must be conducted in a RATIONAL manner!
Moseley et al, Org. Process Res. Dev. 2013, 17, 40-464
Strategic and Iterative HTP Experiment DesignStrategic and Iterative HTP Experiment Design
IntroductionIntroduction
Strategic and Iterative HTP Experiment DesignStrategic and Iterative HTP Experiment Design
An initial round of HTP experiments should cover as much “chemical space” as possible (i.e., evaluating discrete variables); generally ligands and solvents have the most dramatic effects
Subsequent rounds of experiments should explore the regions of chemical space around the
Moseley et al, Org. Process Res. Dev. 2013, 17, 40-46
top hits and then begin to asses the impact of continuous variables
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Substrate Specificity: There is No Magic Bullet!Substrate Specificity: There is No Magic Bullet!
Parallel ExperimentationParallel Experimentation
Substrate Specificity: There is No Magic Bullet!Substrate Specificity: There is No Magic Bullet!
5 mol % Pd(OAc)210 mol % ligand
2.4 equiv 1 M K3PO4solvent, 50 °C,
Challenge: A key Suzuki coupling was low yielding, even with high cat. loading of XPhos-Pd-G1S l ti A i l 96WP i t id tifi d th diff t li d th t 60AP
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Solution: A single 96WP experiment identified three very different ligands that gave >60AP coupled product – under the same conditions, X-Phos gave <15AP regardless of base or solvent!
AsymmetricAsymmetric Hydrogenation of theHydrogenation of the DiketoneDiketone
Parallel ExperimentationParallel Experimentation
AsymmetricAsymmetric Hydrogenation of the Hydrogenation of the DiketoneDiketone
• Rh(R-binapine)(COD)BF4 is the best from the 1st
screening• >99.5%ee, 100% regioselectivity• Works best in DCM, as well as Methanol, EtOAc
The TelescopedThe Telescoped ProcessProcess
Parallel ExperimentationParallel Experimentation
The TelescopedThe Telescoped ProcessProcess
Telescoped Process
80-85 % overall yield~200 Kg prepared
• Selected DCM for hydrogenation reaction, excellent selectivity • Allows for direct telescope of TIPS-protection• Considerably more cost effective than the enzymatic process
• Over 2000 catalytic conditions screened• Primary metal included Rh, Ru, Pd, and Ir• Rh showed complete conversion in many cases with excellent chemoselectivity
– Five Rh/ligand combinations showed >95% e.e.
• HTP screening is a powerful tool to avoid premature decisions and quickly identify a viable solution
Looking Forward 7 Tons of Alumina?Looking Forward 7 Tons of Alumina?
Global OptimizationGlobal Optimization
Looking Forward…7 Tons of Alumina?Looking Forward…7 Tons of Alumina?
Upcoming Campaigns:
70-80% In process yield56-65% Isolated yield
Upcoming Campaigns:
Requirement of ~850 kg of BMS’710 Another 400-900 kg needed soon after
Challenges to Address:
Low isolated yields (56-65%) Strongly basic conditions lead to both BMS’853 and BMS’710 decomposition Strongly basic conditions lead to both BMS 853 and BMS 710 decomposition Tedious and time-consuming alumina treatment required (8 kg/kg) Cycle time per batch: 14 days
Need better catalytic conditions
Development of 2Development of 2ndnd Generation Pd CatalystGeneration Pd Catalyst
Global OptimizationGlobal Optimization
Development of 2Development of 2 Generation Pd CatalystGeneration Pd Catalyst
CC––O Coupling with Aliphatic AlcoholsO Coupling with Aliphatic Alcohols
Global OptimizationGlobal Optimization
CC––O Coupling with Aliphatic AlcoholsO Coupling with Aliphatic Alcohols
Challenges: Low yields at the end of the synthesis were non-ideal – improved yield desiredCost and availability of RockPhos were both issues – cheaper, more available ligand needed
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Large excess of Boc-leucinol made isolation challenging – lower equiv of Boc-leucinol desired
CC––O Coupling : New Ligand HitsO Coupling : New Ligand Hits
Global OptimizationGlobal Optimization
CC––O Coupling : New Ligand HitsO Coupling : New Ligand Hits
A single catalyst/ligand survey identified 3 new ligands that were effective for this couplingCs2CO3 and K3PO4 were both found to be effective bases, and Toluene and CPME both gave
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2 3 3 4 , ggood results
Lactam Substrate: Comparison of Top LigandsLactam Substrate: Comparison of Top LigandsLactam Substrate: Comparison of Top LigandsLactam Substrate: Comparison of Top Ligands
P(t-Bu)2Me
MeMeMe
P(t-Bu)2( )2iPr
iPr
iPr
tB4Me-XPhos
( )2iPr
iPr
iPr
tB-XPhostB4Me-XPhos89AP
tB-XPhos88AP
At lower temperature, lower catalyst loading and shorter reaction times, tB4Me-XPhos significantly outperforms RockPhos, tB-BrettPhos and Mor-DalPhos
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tB-XPhos, which was not part of the original ligand survey but has wide commercial availability, also gave excellent performance
CC––O Coupling : Reduction of O Coupling : Reduction of LeucinolLeucinol LoadingLoading
Boc-L-leucinol charge can be lowered to 1.2 equiv with tB4Me-XPhos or tB-XPhos while still giving high AP of the desired aryl ether significantly facilitating the workup process
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giving high AP of the desired aryl ether, significantly facilitating the workup process
Isolation of Isolation of MonoligatedMonoligated Pd(II) ComplexPd(II) ComplexPd(II) Reduction by Base in the Presence of ArBr :
Air stable, crystalline solid
2 4x More reactive2-4x More reactive than Pd(PCy3)2
Wei, C. S.; Davies, G. H. M.; Soltani, O.; Albrecht, J.; Gao, Q.; Pathirana, C.; Hsiao, Y.; Tummala,S.; Eastgate, M. D. Angew. Chem. Int. Ed. 2013, 52, 5822.
Catalyst Activation in CCatalyst Activation in C--H H ArylationArylation and Suzukiand SuzukiCase of bidentate Ligands
Ji, Y.; Plata, R. E.; Regens, C. S.; Hay, M.; Schmidt, M.; Razler, T.; Qiu, Y.; Geng, P.; Hsiao, Y.;Rosner, T.; Eastgate, M. D.; Blackmond, D. G. J. Am. Chem. Soc. 2015, 137, 13272.
SummarySummarySummarySummaryTo effectively develop a robust catalytic process:
HTP screening is a powerful TOOL,
To effectively develop a robust catalytic process:
To avoid local optimization, HTP screenings are best conducted
in a parallel e perimentation approachin a parallel experimentation approach
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