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Rapid Compound Production:Microwave-Assisted Synthesis, Workup and Purification
Farah Mavandadi, Ph.D.Product Manager
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Topics
• Microwave Assisted Organic Synthesis – Advantages
• Role of Solid-Supported Reagents & Scavengers in Solution Phase Chemistry
• Advantages of Solid-Supported Reagents & Scavengers
• Supported Reagents/Scavengers in Microwave Assisted Multi-step Synthesis:
Sulfahydantoin & Unsymmetrical Sulfamides
Substituted Biaryls
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Microwave Assisted Organic Synthesis (MAOS)
Uses Less Energy
Uses Less Solvent
Enables Difficult Compound Synthesis
Increases Reaction Rate
Rapid Reaction Optimization
Rapid Analog Synthesis
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Microwave Assisted Sulfonylation of7-Azaindolyl-1-yl acetonitriles
N N
N
ArSO OCl N N
N
S ArOO
+
Conventional: 125 oC / 18-20 h /11-18% yield
tmw = tconv x 0.5[(Tmw-Tconv)/10 oC]
tmw = 1440 min x 0.5[(200 oC - 120 oC)/10 oC]
tmw = 5.6 min
Microwave: 200oC / 5 min / 30-40% yield
S. Haydar et al. 33rd Microwave Symposium, Philadelphia, PA, Oct 2006Bioorg. Med. Chem. Lett. In Press
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Microwave Assisted Sulfonylation of7-Azaindolyl-1-yl acetonitriles
N N
N
ArSO OCl
N N
N
S ArOO
+
S. Haydar et al. 33rd Microwave Symposium, Philadelphia, PA, Oct 2006Bioorg. Med. Chem. Lett. In Press
Traditional: 125 oC/ 18-20h / 11-18%
Microwave: 200 oC / 5 min / 30-40%
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Microwave Assisted Sulfonylation of7-Azaindolyl-1-yl acetonitriles
N N
N
ArSO OCl N N
N
S ArOO
+200oC / 5 min
S. Haydar et al. 33rd Microwave Symposium, Philadelphia, PA, Oct 2006Bioorg. Med. Chem. Lett. In Press
PhNO2
DMA(CH3)2CHCN
Sc(OTf)3
Sn(OTf)2
Fe(mont)Y(OTf)3Cu(OTf)2
FeCl3Sm(OTf)3La(OTf)3
AlCl3Dy(OTf)3Yb(OTf)3
InBr3Zn(OTf)2Bi(OTf)3
In(OTf)3Ho(OTf)3AgOTf
FailedNot IsolatedSucceed
Reagents
Solvents
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Microwave Assisted Sulfonylation of7-Azaindolyl-1-yl acetonitriles
S. Haydar et al. 33rd Microwave Symposium, Philadelphia, PA, Oct 2006Bioorg. Med. Chem. Lett. In Press
• Rapid Optimization of Reaction Conditions
• 45 sulfonylations in ~ 4 h (vs 18-20 h)
• Moderate 18-76% Yields vs 11-18% conventional
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What slows down drug discovery?
1. Target and Synthesis Design2. Reaction
J. C. Hodges, Pfizer Inc. ACS Spring Meeting, San Diego, 2001
3. Work-up - usually extraction & evaporation4. Purification - usually chromatography
5. Spectral Analysis Registration
Bottlenecks (3) and (4) become greater with microwave chemistry
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Purification Techniques
Flash Chromatography
HPLC
Solid phase extraction (SPE)
Solid-supported liquid extraction
Solid-bound reagents
Solid-bound scavengers
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Solid Supported Organic Synthesis
A-B M M A M A-B
M
Filter
B (XS)
B Filter Filter
A (XS)
A
• Excess reagents help drive reactions to completion
• Minimal workup is needed, usually by filtration
• Extra steps of anchoring and cleaving the target molecule to the resin
• Difficulty in real time monitoring of the reaction progress
• Slow reaction kinetic
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Solid-Bound Reagents & ScavengersMode of Action
Rgt1.5eq S1 + S2
R gt-sp e nt
P + 0 .5 e q S 1
Scvngr
ScvngrRgt-spent S1
Product
Solution Phase Synthesis• Conventional• Microwave-assisted
• Filtration• Flash Chromatography
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Biotage Resin Reagents
Catch & Releasep-toluenesulfonic acidMP-TsOH
Catch & Releasep-toluenesulfonyl chloridePS-TsCl
ApplicationSolution AnalogBound Reagent
Catalyst, Catch & ReleaseDMAPPS-DMAP
Strong BaseTBDPS-TBD
Base, Catch & ReleaseAmmonium carbonateMP-Carbonate
Non-benzylic baseN-methyl morpholinePS-NMM
Amine baseHindered tertiary aminePS-DIEA
Reducing agentSodium triacetoxy borohydrideMP-Triacetoxyborohydride
Reducing agentSodium cyanoborohydrideMP-Cyanoborohydride
Reducing AgentSodium borohydrideMP-Borohydride
Oxidizing AgentTEMPOMP-TsO-TEMPO
Coupling agentHOBtPS-HOBt (HL)
Coupling AgentDCCPS-CarbodiimidePalladium CatalystTriphenylphosphine Pd(0)PS-PPh3-Pd
Mitsunobu/Wittig/HalogenationTriphenylphosphinePS-Triphenylphosphine
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Biotage Polymeric Scavengers
Pd (0)MP-TMTMetal
Amines, AnilinesMP-Tosic acid
Anilines, AlcoholsPS-Tosyl chloride
1o aminesPS-Benzaldehyde
1o, 2o amines, hydrazinePS-IsocyanateMP-Isocyanate
Nucleophile
Alkyl halidesPS-Triphenylphosphine
Alkylating agentsPS-Thiophenol
Ti(IV), Sn(IV), Boronic acids
MP-DEAM
Aldehydes, KetonesPS-Tosylhydrazide
Carboxylic acids, PhenolsMP-Carbonate
Acyl halides, Sulfonylhalides, Isocyanates
PS-TrisamineMP-Trisamine
Electrophile
NCO
H
O
S ClO O
S OHO O
NH
N
NH2
NH2
NEt3+ (CO3
2- )0.5
S NHNH2
O O
NH
OSH
P
S N
NN
SH
SH
NOHOH
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Solution Phase Resins: Introductory Kit
Contains resin samples for:
AmidationPS-Carbodiimide (3g; 1.1-1.3 mmol/g)PS-HOBt(HL) (3g; (0.9-1.0 mmol/g)Rgt-ACTU (3g)MP-TsOH(65) (3g; 3.5-4.5 mmol/g)MP-Carbonate (3g, 2.5-2.8 mmol/g)
Reductive AminationMP-Triacetoxyborohydride (3g; 1.8-2.0 mmol/g)MP-Cyanoborohydride (3g; 2.0-2.3 mmol/g)MP-TsOH(65) (3g; 3.5-4.5 mmol/g)PS-Isocyanate (3g, 1.1-1.4 mmol/g)MP-Isocyanate (3g, 0.9-1.3 mmol/g)PS-Benzaldehyde (3g, 1.1-1.3 mmol/g)
CouplingPS-Triphenylphosphine (3g; 1.8-2.2 mmol/g); PS-PPh3-Pd (1g, 0.08-0.1 mmol/g)MP-TsOH(65) (3g; 3.5-4.5 mmol/g)MP-Carbonate (3g, 2.5-2.8 mmol/g) PS-DEAM (3g; 1.5-1.8 mmol/g)
OxidationMP-TsO-TEMPO (3g; 0.8-1.0 mmol/g)
NEW! Launched Sept 18, 2006NEW! Launched Sept 18, 2006
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ISOLUTE® Si-Triamine
BIOTAGE INTRODUCESBIOTAGE INTRODUCESSilicaSilica--supported Reagents/Scavengerssupported Reagents/Scavengers
ISOLUTE® Si-Carbonate
ISOLUTE® Si-Ts-Hydrazine
ISOLUTE® Si-Thiol
ISOLUTE® Si-Propylsulfonic acid (SCX-2)
ISOLUTE® Si-EthylPhenyl sulfonic acid (SCX-3)
N+ (CO3)-20.5Si
SHSi
NH
HN
NH2Si
S
O
O
NHNH2
Si
SSiO
O
O-
S
O
O
O-Si
NEW!NEW!
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In the Laboratory
•Use standard lab equipment
•Shaking, overhead or magnetic
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Advantages of Solid-supported Reagents/Scavengers
Drive reaction to completion using excess reagents
Remove spent and excess reagent by filtration
Perform one-pot multi-step reactions
Mix “incompatible” functionalities
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R1 R2
ON
NH
R2
R11) NH2NH2
70 °C, 3h2) PS-CHO
N-Substituted Pyrazoline Libraries
Chalcones used as templates for pyrazoline library
Bauer, U. et al. Tetrahedron Lett. 2000, 41, 2713-2717
Synthesis1, R3COCl, PS-DIEA; 2, R3NCO; 3, R3SO2Cl, PS-DIEA; 4, R3OCOCl, PS-DIEA
PurificationPS-Trisamine, PS-Isocyanate cocktail
NN
R2
R1
NN
R2
R1
NNS
R2
R1
NN
R2
R1
R3
HN
O
O
O R3
O R3
OO
R3
1
2
3
4
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Advantages of Solid-supported Reagents/Scavengers
Drive reaction to completion using excess reagents
Remove spent and excess reagent by filtration
Perform one-pot multi-step reactions
Real time reaction progress monitoring (TLC/LC-MS)
Mix “incompatible” functionalities
Eliminate problems with the free reagent
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Amide Coupling Reagents
Use:One-step amide synthesis
Advantage over DCCUrea Byproduct Resin bound and easily removed
Use:Two-step amide synthesisAmine = limiting reagent in acylation
Advantage over HOBt:Active Ester intermediate resin bound; Isolatable & Storable
NN
O2S
NH
NOH
PS-HOBt
O N=C=N
PS-Carbodiimide
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PS-Triphenylphosphine-Pd(0)
Use:Palladium catalyzed C-C couplingPd catalyzed reductive cleavage of protecting groups eg Alloc
Advantage over Tetrakis palladiumStable to air, light and moistureNo “Hot Spot” – minimizes vial breakage in MAOSShelf-stable at room temperature Simplified product isolationLow Pd levels in product (< 100ppm)
P PdLn
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PS-Triphenylphosphine
P
R2
R3 R1
R1 O R2CN
R
ClO
Cl
R1
R2
P R
Wittig Chemistry Alkene Synthesis
Mitsunobu Chemistry Ether Synthesis
Palladium Catalyzed ReactionsC-C coupling
Pd(OAc)2
DEAD, DIAD
ChlorinationFormation of acid chlorides & alkyl halides
Cl3CCN or CCl4
Scavengingof Alkyl Halides+ X-
Advantage over Triphenylphosphine:
Phosphines and oxide byproducts are resin bound
and easily removed
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Use:Reductive amination under ‘Neutral’ conditions
Advantage over Na(OAc)3BHDoes not require acid catalyst; can be used with acid-sensitive groups: ketals, acetalsWorkup = Filtration; eliminates aqueous extraction
NEt3 (OAc)3BH
2 mmol/ g
Bound Reagents Reductive Amination
MP-Triacetoxyborohydride
NEt3 (CN)BH3
2-3 mmol/ g
Use:Reductive amination under acidic conditions
Advantages over NaCNBH3:Eliminates Aqueous extractions post-reactionMasked toxicityVery little pressure build up with MAOS
MP-Cyanoborohydride
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SO O
OH
Bound Acid: MP-TsOHISOLUTE® Si-TsOH
Scavenger for amines & basic compoundsCatch and Release purifications
UseAcid catalystCleavage of acid sensitive groups eg BOC-
S
O
O
O-Si
MP-TsOH ISOLUTE® Si-TsOH
Advantages over p-Toluenesulfonic acid:
Eliminates Aqueous extractions post-reactionCan perform Catch-and-Release purification of amines via filtrationSilica bound form compatible with Flash Chromatography
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Advantages of Solid-supported Reagents/Scavengers
Drive reaction to completion using excess reagents
Slow reaction kinetics
Remove spent and excess reagent by filtration
Perform one-pot multi-step reactions
Real time reaction progress monitoring (TLC/LC-MS)
Mix “incompatible” functionalities
Eliminate problems with the free reagent
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Supported Reagents in Microwave-Assisted
Multi-Step Organic Synthesis
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• Sulfahydantoin compounds have broad biological activity
O NH
SO2N
R1 R
I
Pka comparable to carboxylic
acid ~ 4
Sulfahydantoin
• General scheme for sulfahydantion1. Reductive alkylation (1 day)2. Sulfamide synthesis (2 days)3. Cyclitive cleavage (1 day)
Total time: ~4 Days
• These conditions are not convenient for rapid High Throughput Synthesis
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Two-Step One-PotMicrowave-Assisted Reductive Amination
Step I
O NH2
O
OMe
HO
DIEA, MeOH+ µW
90 ºC / 2 minImine
O
N
O
OMe
Total time for synthesis: 5 min Total time for synthesis + purification: 10-15 mins (vs 1 day)
Ghassemi, S. 2005 ACS, San Diego
Amine
O
NH
O
OMe
µW80 ºC / 3 min
(CN)BH3
MeOH is important for stereoselectivityEtOH or CH3CN result in racemization
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Microwave-Assisted Reductive AminationRacemization study
• Extent of racemization was studied by comparing 1H-NMR (500 MHz) of the LL and DL diastereomers
+
• No racemization was detected
NHBoc
O
NH
O
Et
LL
NHBoc
O
NH
O
Et
DL
Ghassemi, S. 2005 ACS, San Diego
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Microwave-Assisted Reductive AminationComparison of Cyanoborohydide reagents
O
ONH
NH
OO
O
NHO
O
NH
O
CF3
O
NHO
O
O
NH
O
ClCl
NHO
O
OMe
NH
CF3
O
OBrNHO
ONH
Cl
O
O
Cl
Method A 84% 68%83%79%
75%88%88%89%85%Method A
Method A: 2 eq. 1 M NaCNBH3
Method B 79%74% 85% 63%
73%78%80%84%79%Method B
Method B: 2 eq. Silica-CNBH3
Method C: 2 eq. Polymer-CNBH3
Method C 80%72% 73% 59%
65%81%77%80%80%Method C
Ghassemi, S. 2005 ACS, San Diego
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Microwave-Assisted Sulfamide Synthesis
Step II
H OH
O+ S
O
OCl NH2S
O
OCl NCO µW
90 ºC / 1 min
Total time for synthesis: 5 min Total Synthesis+Purification: 25-30 mins (vs 2 days)
O
N
O
OMeSO2NH2
Et3N, DCM
µW 80 ºC / 4 min
O
NH
O
OMe
Ghassemi, S. 2005 ACS, San Diego
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Microwave-Assisted Cyclitive CleavageStep III
Total time for synthesis: 5 min Total Synthesis + Purification: 25-30 mins (vs 1 day)
O
N SO2
NH
MeO
O
N
O
OMeSO2NH2
NaOMe / MeOH
µW
100 ºC / 5 min
Ghassemi, S. 2005 ACS, San Diego
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SulfahydantoinIn Summary
Conventional Synthesis
4 days
Microwave-assisted organic synthesis+ Solid Supported reagents
+ Flash Chromatography
1 – 1.5 hours
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Unsymmetrical Sulfamides
Amine or
Aniline
µW80 °C,5 min
SOO
NO
O
R1
NR
H
R3-OHPh3PDEAD
SOO
NO
O
R1
NR
R3
THF µW80 °C
1-4 min
SO
OO
-SOO
NR1
N+R
R3
H HSi
µW
100 °C / 5 min
MeCN:DCM
SiSO
OO
H
NH3/MeOH
SOO
NR1
NR
R3
H
* Ghassemi, S. et al. Molecular Diversity, 2005, 9, 295-299
SCl
OO
NCO DCM0° C
SCl
O O
NH O
OOH Helium
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Substituted Biaryls
COOHN
O
R2R1
R1NHR2
BrBr
BOH
OH R3N
O
R1
R2
R3
Ghassemi, S. ACS, Atlanta, GA, March 2006
Step I: Amide Coupling Step II: Suzuki Coupling
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Step I: AmidationPS-DIEA, Si-Carbonate, Si-TsOH
COOHBrN
O
R2R1
BrR1NHR2
+PS-DIEA, HATU
µW, 110-150 oC 6-12 min
NiPr
iPrPS
Ghassemi, S. ACS, Atlanta, GA, March 2006
N+ (CO3)-20.5Si
57-99% yield>97 % Purity
N
O
R2R1
Br
SO O
O-
Si
Catch & Release
59150oC, 12 min6
57150oC, 12 min5
90110oC, 6 min4
97110oC, 6 min3
91110oC, 6 min2
99110oC, 6 min1
% YieldConditionR1NHR2
NH
NH
N NH
NH
O
EtO
NH
NH
R1NHR2
+
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Step II: Suzuki Coupling PS-PPh3-Pd, Si-Carbonate
Ghassemi, S. ACS, Atlanta, GA, March 2006
N
O
R2R1
Br
BOH
OH R3N
O
R1
R2
R3
PPh3-Pd CsCO3
µW 130 oC, 10 min
EtOH:DME (1:1)
N+ (CO3)-20.5Si
85-99% yield>97 % Purity
O
NO2N
O
NNO2N
O
NCH3O2N O
OEt
O
NO2N
O
NO2N
O
NO2N
O
N
MeO
O
NN
CH3
99 %
89 %
85 %
96 %
99 %
99 %
97%
95%
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SUMMARY
• MAOS is a versatile tool for accelerating synthesis
• Solid bonded Reagents and Scavengers significantly reduces the work-up and purification bottleneck
• Combining MAOS with Solid bonded Reagents and Scavengerscan accelerate total compound production time
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Thank You for Your Attention!