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Rapid Chemical Space Exploration –p p pApplications from Discovery to Manufacturing
Neal SachSenior Principal Scientist10777 Science Centre DriveLa Jolla, CA 92121, [email protected]
ACS T h i l A hi t iACS Technical Achievements in Organic ChemistryPhiladelphia, USAAugust 22nd 2012August 22 2012
Contents
A I t d ti t R ti O ti i ti W kflAn Introduction to Reaction Optimization Workflows
Reaction Optimization in Process Chemistry
Adapting to Discovery Chemistry
Case Examples
Solving Chemistry Across the Portfolio
Discover Drugable Molecules S l D S b tSupply Drug SubstanceDevelop Commercial ProcessesTransfer Technology to Production
P P Supply ChainDiscovery ProcessResearch
ProcessDevelopment Manufacturing
Covalent Bonds Covalent BondsReaction Conditions
Covalent BondsReaction Conditions Reaction Conditions
How we do this in less time and at a lower cost?
Reaction Conditions Reaction ConditionsWork Up Conditions
Reaction ConditionsWork Up ConditionsVariations Variations
How we do this in less time and at a lower cost?
The First Reaction Optimization Tool
In 1998 a Process Research Technology Group was created with the aim of speeding Process Developmentthe aim of speeding Process DevelopmentThe SK233 was the first tool of its kind, 10 simultaneous reactions with integrated analytics 1g per reaction, 10 reactions, 10-50ml volume
100
59
76
90 9296
60708090
100OH ON
LiOH (10eq.)
14
43
1020304050
N N
Cl
NH2 NH2
N N
Cl
NH NH
LiOH (10eq.)
MeOH / H2O
0 00 0 0 0 0 1 2 2 3010
0 5 10 15Time
NH2 NH2NH2 NH2
UK-427,387 – The Tipping Point
Despite a few successes, the general adoption of the p , g pSK233 and reaction optimization technologies was slow… …but that was to change…gUK-427,387 was nominated as a follow up PDE5 inhibitor to Sildenafil (Viagra)( g )
UK-427,387 Pyrazole Alkylation
25kg Required for Phase 1 Parallel Synthesis Robot (PSR)250 ti 50 ti250mg per reaction, 50 reactions, 5-25ml volume
NH
N
O
NH2N
PhN
N
O
NH2
Na2CO3(1.1eq.)NaI (1.1eq.)THF / Water(9:1@5ml/g)80C / 7 days
NO2N
N
OMs
Ph Ph
NPh
NO2N
Issues (where to start?!)30% overall yieldy2:1 undesired : desired pyrazole7 days reaction time, complex conditions (4 solids 2 solvents)conditions (4 solids, 2 solvents)5-14% undesired alkylated isolated
UK-427,387 Pyrazole Alkylation
25kg Required for Phase 1 New ConditionsNa2CO3(1.1eq.)
BeforeN
PhN
N
O
NH2
N
NN
ONH2
O2N
PhPh
NH
N
O
NH2
O2N OMsN
Ph
PhN
N
O
NH2
O2N
NaI (1.1eq.)THF / Water(9:1@5ml/g)80C / 7 daysN
H
N
O
NH2
O2N OMsN
Ph
PhN
N
O
NH2
O2N
LiOtBu / MeCN80C / 6hrs
NH
N
O
NH2
O2N
NPhO2N
1:2 N1:N22
N
Ph Ph
Ph22
N
Ph Ph
Ph2
AfterScreen120 reactions run over 3 weeksResults30:1 selectivity achieved
AfterN
Ph
PhN
N
O
NH2
O2N
30:1 N1:N212 bases x 10 solventsStrong base required Lithi t i d d
y12hrs vs. 6 days reaction timeScaled to 32kg, 71% isolated yield of 99% purity
30
Lithium count-ion neededMeCN solvent found to be key
99% purityQ. Would this obscure hit have been found in the short time frame allowed without reaction screening technology?
Development of High Throughput Experimentation (HTE) Workflows 2002-2005( )
StatisticalMethods
SolidsDispensing
DataAnalysis
Reaction Execution
Data Capture andReactionRational
y
Reaction FastExecutionand Analysis
Capture and VisualisationPlatformDesign
ReactionPlatform
Fast Conclusions
Chemists LiquidsDispensing
DataMining
5Higginson, Paul D.; Sach, Neal W. High-Throughput Experimentation in Pharmaceutical Process R&D: Developing a New Software Workflow to Overcome Downstream Data-Analysis Bottlenecks and Improve Productivity. Organic Process Research & Development (2004), (8), 1009-1014.
2002-2005 Investment in Technology
By 2005 the HTE group in Process had expanded to 5 FTE’s with state of the art equipment at their disposalwith state of the art equipment at their disposal25mg per reaction, 50 reactions, 1-2ml volume
One 2 Many Weighing iChemExplorer Reaction Platform 2-4 minute HPLC l ti
2mlReactionVolume
Fast HPLC High-throughput
cycle-time per sample
Many 2 Many Weighing Gaseous Chemistry
Fast HPLCAnalysis Platform
High-throughput analytics and generic methods are critical to
HTE Modular Workflows
Application of High Throughput Chemistry WorkflowsAcross the Portfolio
Discovery Process Supply ChainDiscovery Development Supply Chain
ApplicationsApplications
Solubility Profiling
Solid Form Identification
Reaction Screening Start
Resolution ScreeningResolution Screening
Example Workflow - Resolution Screening
Scalable access to chiral molecules via diastereoisomeric salt formationdiastereoisomeric salt formation NH2
NH
O
O
OHOH
O
OH
OH
O
OH
O
OH
NN
CH 2HS R
S
SR
H
Resolution Coupling Protocol :96 Chiral Acids or Bases
1 Solvent
NH
OH
O
O
OH
NH
Ph
Ph
NH 2
OHS
OS
O
H
10-20mg per reaction : 2g Total0.5 FTE Days
1 Day Start to Finish per Solvent
O
OH
O
NH
OHNH 2
NH 2
O
HO
S
OHO
y p
O
OH
O
O
Cl
NH 2
OH
RS NH 2
S
POOH
O2
Example Results of Resolution Screens
R R
NH2
O NHNH2
OH
OH
OO
NR
O
Ar
OH
O
NR
O
Ar
OH
O
O
1st Crop : 92%ee2 d C t lli ti 99%
MeCN / H2O 13:140 Volumes
N
NH2NOH
OHOH
1st Crop : 98%eeYield : 45%
MeOH / Water 10:110 Volumes
2nd Crystallisation : 99%eeOverall yield : 32%
NH OHO
O
N OH
OHOH
OHOH
N
O O
OH
N N
OO
OH O
Tol Tol
O
O OOH 1st Crop 96%ee
Yield : 36%
MeOH / H2O 8:145 Volumnes
N
NHN
NHEtOH / MeOH 1:140 volumes
1st Crop : 99%eeYield : 31%
Zhou, Ru; Bi, Chris; He, Mingying; Hoffman, Robert; Jalaie, Mehran; Kath, John; Kupchinsky, Stan; Ling, Tony; Lu, Jihong; Marx, Matthew; Richardson, Paul; Sach, Neal; Tran, Khanh; Barbour, Nicole; Cho-Schultz, Su. Asymmetric synthesis of Pyrrolodino-pyridine based CXCR4. Abstracts of Papers, 240th ACS National Meeting, Boston, MA, United States, August 22-26, 2010 (2010)
Resolution screening is successful in 80% of cases
Example Workflow - Solubility ScreeningIsolating good quality material can be as difficult as forming the covalent bondsProblematic isolations may result in largeProblematic isolations may result in large quantities of organic and aqueous waste streams and loss of product Traditional Reaction SequenceTraditional Reaction Sequence
1.
Design Reaction
2.
Run Reaction
3.
Analyse Reaction
4.
Design Work-up
5.
Work-up Reaction
Reaction Solvent
Low Solubilityof Product
Bottom-up approach to Reaction Design
1.
Design Reaction
2.
Run Reaction
3.
Analyse Reaction
4.
Design Work-up
5.
Work-up Reaction
High Solubilityof Bi-products
Driven by solubility screening
Example Results of Solubility Screens
Objective: Solvent
Solubility of Impurity @ RT
Solubility of product @ RT
Map solubility of all synthetic intermediates in range of process solvents
HTE Workflow:
Solvent p y @mg/ml
p @mg/ml
Water <1 34Methanol 14.00 86Acetonitrile 61.00 15
20 solvents screened as standard chosen by chemistSolution saturated and liquors analysed
Ethanol 10.00 74Acetone >100 78Acetic acid >100 >1002-Propanol 7.00 152 B t 85 00 65Solution saturated and liquors analysed
Quantitative LC2-Butanone 85.00 65Tetrahydrofuran >100 34Ethylacetate 43.00 16Butyl Acetate 40.00 14t-amyl OH 4 00 17
Typically applied to entire synthesis250mg-1g per screen in 0.5 Day
t-amyl OH 4.00 17Dichloromethane >100 36Diisopropylether 5.00 12Toluene 22.00 8Heptane <1 3epta e 31M HCl >100 >201M NaOH <1 >201M NaHCO3 <1 <1
2007 - Bringing HTE to Discovery
Reaction Optimization Projects 2002-2007 Discovery 20071 FTE!!
LJ 2007-2011120
140
160
Process Projects2002-2006
1 FTE!!
Sandwich60
80
100
120
Projects
2002-20065 FTE’s
Sandwich2002-2006
0
20
40
60
02002 2003 2004 2005 2006 2007
Year
…the workflow was not designed for this throughput and was too slow…
Reaction Optimization in Process
Experimental Set-Up
x1x2X nExperiment
p
ReactionProject Team Answerx1x2X nExperiment
DesignReaction Analysis
Team Problem
Answer
Cycle 2 =Cycle 3 =Cycle 1 =Results
Interpretation Cycle 2 4 days
Cycle 3 6 days
Cycle 1 2 days
2007 - The Discovery Experience
Discovery chemists want answers…f d i l i l d i h d l…faster and using less material compared with process development
…and they have no product markers!
SDS – Screening / Designed Synthesis
LD – LeadDevelopment
CS – CandidateSeeking
ESD – ExploratoryScreen Development
Early Development
DiscoverySpeed █
Process DevelopmentScalable █Speed █
Diversity █Yield █
Scalable █Yield █Isolation █
Isolation █Scalable █
Speed █Diversity █
Speeding the Workflow
Challenge over the past three years has been to speed the workflow by removing the bottle necksthe workflow by removing the bottle necksWhere is the time spent?
Manual and slow
Semi-Automated
and fast
Semi-automated and slo
Reaction Reaction Analysis
and slow 50%
and fast20%
and slow30%
Design Executiony
andVisualisation
These steps needed addressing
Designing a Reaction Screen in Process
StatisticalStatisticalMethods Literature
Surveillance
Intelligent ReactionDesign
Chemistsand
Green Chemistry and
CeNChemistryPrincipals
Screening Chemical Space…searching the literature on a per screen basis helps us move into the
“correct” chemical space but if the chemistry doesn’t work in this initial screen we spend a lot of time searching or settling at local maximascreen we spend a lot of time searching or settling at local maxima…
…what if we moved to a more generic one-size fits all type template… that would save time but…the chemical space covered increases dramatically L R tidramatically…
Unchartered territory
Large Reaction Template
Cycle 1 = Bas
e
Literature Says
territory
Cycle 2 = Cycle 3 = 2 days
Catalyst
BLiterature Says Start Here 4 days6 days…besides...was we ever really comfortable excluding this space?
will you ever find something new?
Literature Misdirection161/161 references utilize Pd(Ph)4)3or Pd(P(Ph)3)Cl2
Sonogashira Reaction
BrSi
CatalystWhat have we really learnt?
Precedent (we knew that)N
N
N
Br
Ar
R N
N
NR
Ar
CatalystSolventBase
Project team report poor yields using standard conditions
%Area UV50%conditions
Literature SearchSi
50˚C 100˚CNN
Si
X 161 literature conditionsP P
PdClCl
ProductReactant/ReagentHNHN Mass Ion
CountPd-132Un-precendented
Increasing Chemical Screening Space vs. Material Demands
…discovery project teams cant afford >500mg of material for each screen, in-fact they would like to reduce the amounteach screen, in fact they would like to reduce the amount required…
WE NEED TO MINATURIZE (but without diluting)( g)
120uL1.2mlReactionVolume2007
to
ReactionVolume
to2011
20 Reactions=100mg 200 Reactions=100mg
Reducing Scale – Air/Moisture Sensitivity
8x30mm120uL
12x32mm1.2ml
Scale (400MW) 7.5mg, 0.02mmol 0.75mg, 0.002mmol
Catalyst (400MW 10mol%) 0 4mg 0 002mmol 0 04mg 0 0002mmolCatalyst (400MW, 10mol%) 0.4mg, 0.002mmol 0.04mg, 0.0002mmol
With just 0.04mg of catalyst present the workflow had to be moved into a glove box with a controlled O2 (<10ppm) and g 2 ( pp )H2O atmosphere (<20ppm)
Projects by Reaction Type
Buchwald12%
OtherReaction TypeReaction Type Templated :
Suzuki Couplings12%
Biotransformation0%
Oxidation0%
13%Other26%
p gBuchwald CouplingsAmide Couplings
Suzuki 17%
Flow Chemistry15%
Amide CouplingsHeck CouplingsCarbonylations
TemplatedBiotransformation
2%
Oxidation1%
yClassical Resol. Alkylations Hydrogenation
Sonogashira5%Heck
0%CH ActivationAmideResolution
Library Validation8%
Templated60%Flow Chemistry
9%
HydrogenationSonogashiraUllman Couplings0%CH Activation
3%Hydrogenation
8%Alkylation
11%Carbonylation
4%
Halogenation1%
Amide1%
Resolution0%Library Validation
3%
p gHalogenationsetc...
Speeding the Workflow
For templated chemistry (60%) the workflow is significantly fastersignificantly faster….…but analytical samples have increased by a magnitudemagnitude…
Semi Semi-Templated Chemistry
10%
Semi-Automated
and fast
Semi-Automated
but slow
ReactionDesign
Reaction Execution Analysis and
10% 30% 60%
Design Execution Visualisation
Data Analysis, Capture and Visualisation
Capturing data, identifying products, analysing trends and reaching quick conclusionsreaching quick conclusions
iChemExplorer Data Capture
Rapid Resolution 1200 LC/MSD
50-500 data points per
reaction screen.Email report
and then
Rapid Resolution 1200 LC/MSDPer sample cycle-time
dropped from 4 to 0.8minsreaction screen.
100 reactions take 1.5hrs
capture in CeN as well as in-
house reaction screening
Spotfire Visualization with Data Display
Data to knowledge in 1 hourscreening database
6Mathews, B. T.; Higginson, P. D.; Lyons, R.; Mitchell, J. C.; Sach, N. W.; Snowden, M. J.; Taylor, M. R.; Wright, A. G. Improving quantitative measurements for the evaporative light scattering detector.Chromatographia (2004), 60(11/12), 625-633.
Discovery Orientated Screening Workflow
…combining reaction templates with miniaturization and glove box technologies has enabled a reduction in materialglove box technologies has enabled a reduction in material demands and reduced screen cycle times leading to an increased applicability to Discovery Chemistry
317 35926.1
20 3 20 7
30400 Reaction Optimization Project 2002-2011
reen
158 195 24018.320.3
18.020.7
20200ro
jects
Projects
per S
cr
20 28 54 81 882.3 1.9 1.5 1.2 1.0
0
10
0
Pr Days per Screen
Day
s p
002002 2003 2004 2005 2006 2007 2008 2009 2010 2011
A templated reaction screen of >100 conditions is now turned around in 24hrs
Amide Bond Formation – A Discovery Problem
25% of all reactions in discovery involve amide couplingsy p g
Reaction Step detailsPiperidine formationMitsunobu couplingBuchwald amine arylation i f i
O-alkylationCarbon acylation
P lidi f ti
Large numbers of coupling agents are commercially availableTriazole formation
Buchwald amine arylation
Reduction aminationPurinone formation
Thiourea formationPyrazole formationPyridone formation
Pyrimidine formation
Nucleophilic addition
Enamime formationImidazole formation
Thermal decarboxylation
Pyrrolidinone formation
Buchwald ether coupling
Deprotection
Which one?Imine formation
Diketohydrazone formation
NO2 reduction
Imine cyclization
Boronic acid Mannich rearrangement
Urea formation
Sulfonamide formation
Dianiline 5 ring
N lk l tiWhich one?Reductive alkylation
N-alkylation
Nucleophilic substitution
Suzuki coupling
UgiQuinoline formation
Amide formation
Difficult Amide Bond Formations - Discovery
FSterically
70%1. T3P
60%1. Cyanuric Fluoride
ArCl
OH
OAr
Cl
NH
OR
NOH N
RR
NH
FF
F
FSelectivity
Stericallyhindered2. 1Cl2MPyI
1. Cyanuric Fluoride2. 2C-DMI-TFB
NAr
OH
NAr
NH
NH2
NH
OH
ONH RAmide Coupling Protocol :
36 Coupling Agents2 S l t 2 T t 1 Additi 50%
1. (COCl)22 CDMT
2 Solvents, 2 Temperatures, 1 Additive150 reactions = 90mg total (300MW)
0.5 FTE Days 2 D St t t Fi i h
60%1. TPTU 2. CDMT
3. iBuCOCl4. HATU
SO S
NR SO
OH
O
NH
Ar
NHO
Electron poor
amineSelectivity
2 Days Start to Finish2. TDBTU3. TOTT
R S
R Ar
OH NNR
R Ar
NHS
NN
NH2
ROH
Ar NN
NH2
NNH
R
The Amide Bond – Expanding Monomer Space
The amide bond remains a popular connection in drug di t l SARdiscovery to explorer SAR….
Ar O
OH
ANHCoupling AgentSolvent Core
Core
ArCOOH ArCl, Br, I, OTfAr1 O
NR3
Ar1
O
NHR3+
AcidAmide
Base
Amine Traditional Coupling
O l 725 (3 5%)
6441 14136
Ar1X
NH NAr1+
CatalystBaseSolvent
Core Core
but there are other way of making an amide bond and a
Overlap 725 (3.5%)R3N
R3OAmine Amide
X=Cl, Br, I, OTf Carboamidation Coupling
…but there are other way of making an amide bond and a monomer analysis reveals the advantages…
Carboamidation – Accessing New Chemical SpaceCarbonylation Screen
NH2N
N
NNH2
NN
NNH2
NN
NNH2CO Pressure
CatalystBaseS l t
H H
Details
NN
N
Br
N
ONH
N
ON O
NH
N N
SolventP
HHHH
Method required for primary, secondary and non-nucleophilic amines78 Conditions (0.005mmol, 1mg per reaction)
NH2NH2
N N
NH
( , g p )– 12 catalyst/ligand (combinations (all monomers)– 56 catalyst/ligand combinations (one monomer)– DMAc (0.03M), DIPEA (5eq.), 100C, 8Bar CO
NHTechnology NN
NNH2
ONH
NN
NNH2
O
O NH
O
Carbonylation Library ValidationCarbonylation Screen
N NNH2
NNH2
N NNH2CO Pressure
Catalyst
P
H H
HHHH
$73/gN
N
NNH2
Br
NN
N
ONH
NN
N
ON
N
ONH
N N
yBaseSolvent
ABS
P
NH2NH2
N N
NH
DetailsTake top eight ligands from initial screen and run under actual library conditions Conclusions
PFe$640/gN
run under actual library conditions78 Conditions (0.05mmol=10mg per reaction)
8 catalyst/ligand combinations3 monomers (3eq.)
ConclusionsLigand system works across all demonstration monomersLibrary 1 = 88 designed products
DMAc (0.1M), DIPEA (5eq.), 100C, 4Bar CO
CommentsSM is not soluble at this concentration at 25C.
Library 1 = 88 designed products82 / 88 achieved = 93% success rate @ 0.05mmol scale. How would acid compare?500 products have since been prepared
Solids weighing robot is used to weigh 80 x 10mg
500 products have since been prepared using these conditions (2 weeks)
Suzuki Optimization%Area UV
80% NN
ClCl
NF
F N
Br
R
NF
F
CatalystSolventBase
+
MeOH / CsF(aq.) /Pd-132 // 80C / 18hrsP P
PdClCl
Pd-132
Issue
FBOH OH
N
NH2
OR F
N
NH2
OROriginal
Conditions
Team tried DME / H2O / Pd(dppf)2Cl2/ 80°C but gave only 50% conversion after 2 days Results
Mass IonCounty
Screen Design96 conditions (0.003mmol, 1.13mg)
Results1/96 conditions gave >80% in-situ yieldMeOH, CsF and Pd-132 are critical. Three f t i t ti h d t fi d O f t
Product– 110mg for screen– 6 catalyst/ligand combinations– 4 bases and 4 solvents
factor interactions are hard to find. One factor at a time optimizations wont work here.Request to Results Cycle Time = 1day
– 80C, 18hrs, glove box Scaled to 200mg, 90% isolated yieldRequest to Registration Time = 2days
Des Bromo
Conclusions
1 / 100 / 10 / 1 / 0 05 /
20071998 2001 2004 2012
1g/rxnX 10
100mg/rxnX 50
10mg/rxnX 100
1mg/rxnX 200
0.05mg/rxn.X 1000
KNOWLEDGE PER GRAM PER UNIT TIME
20071998 2001 2004 2012
Maximize information per reactionMinimize material consumptionMinimize time to explore any given chemical space
Using HTE Workflows, optima within a given parameter g p g pspace can be quickly identified to focus resource at any stage across the portfolio
Acknowledgements
TechnologyC l B i
ChemistryKevin Bunker
Special ThanksSimon BaileyCarol Baines
David BernhardsonKlaus DressD id D
Kevin BunkerLaurence HarrisBob HoffmanPeter Huang
Simon BaileyRob CrookPeter DunnKlaus DressDavid Damon
Bill FarellStuart FieldSt F ll
Peter HuangSarah LewandowskiSacha NinkovicDan Richter
Klaus DressMartin EdwardsPaul HigginsonJennifer LafontaineSteve Fussell
Rob MaguireBen MatthewsAndre Morrell
Dan RichterHong ShenJohn TatlockJohn Tatlock
Jennifer LafontaineVan MartinIvan MarzianoSteve TrudelAndrew Morrell
Paul RichardsonSteve TrudelAle Wilder
John Tatlock Steve TrudelPaul RichardsonPete SpargoDavid WaiteAlex Wilder
Katie WilfordAlex Yanovsky
David WaiteMike WilliamsAlex Yanovsky