Microwave Assisted Organic Synthesis Where do we go from here? · Microwave radiation was used for...
Transcript of Microwave Assisted Organic Synthesis Where do we go from here? · Microwave radiation was used for...
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Microwave Assisted Organic SynthesisWhere do we go from here?
Steve Jordan
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Escalating costs of drug discovery
$802m to bring a drug to market (Tufts Centre, 2001)
▪ 2.5 fold increase over the last decade!
▪ Costs largely associated with increasing clinical costs
▪ R&D expenditure ‘v’ marketable drugs
▪ False screening results
▪ Time for technology to realise its full potential!!
Hardware & informatics
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Evolution of Microwave Chemistry
Over 2000 publications on MAOS2005
Introduction of the first commercial single-mode microwave system for high throughput organic synthesis
2000
Gedye R. (Laurentian Univ. Canada); Majetich, G. (Univ. Georgia; USA) & Giguere, R. (Mercer Univ; USA) published papers relating to microwave radiation in chemical synthesis
1986
….????2006-2010
Microwave radiation was used for chemical analysis processes such as ashing, digestion and extraction
1983-85
Microwave radiation developed to dry organic materials1980-82
First microwave lab instrument developed to analyze moisture in solids
1978
First commercial domestic microwave oven1947
Microwave radiation was discovered as method of heating1946
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Microwave vs Conventional Heating
Microwave Heating Conventional Heating
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Advantages of Microwave Assisted Synthesis
• Shorter reaction times
Rapid testing of creative ideas
Increased productivity
Higher yields, improved purity
• Expanded reaction diversity
Some difficult reactions made possible
• Less reagents and solvents
• Less reactive reagents
• Reproducible results
• Scalable conditions
NH
NH
O
COOEt
N
NH
O OBa(OH)2 / DMF
Microwave Heating: 4 min; 90% yieldConventional Heating: 48 h; 54% yield
Hydantoin Synthesis
O
OH
NH2
NH4OH
Microwave Heating: 7 min; 93% yieldConventional Heating: 10 days; 13% yield
Epoxide Ring Opening
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Unusual Findings!
• Reactions conventionally done in ice-baths (0 oC)
• Reactions and substrates with perceived sensitivity to “heat”
Can be successful via microwave “flash”high temperature heating!
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Microwaves• 60°C, 10min• THF• Normal atmosphere
Br MgBr
89 %
Conventionally• 0°C, hours• Et2O• Inert atmosphere
Avoids the inconvenience of purging N2 and ice baths.
Preparation of Grignard reagent
Biotage Pathfinder data
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Ar X Ar MgX
OH
ArMg turnings / I2
THF100-170 oC / 1 hr
PhCHOH+ / H2O
100 oC / 30 min
51 - 99% (16 examples)
89 %
Grignard Reaction of Aryl Chlorides
Larhed, M. et al. Synlett., 2005, 1596
X = Cl, Br
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Microwave: 1 min, 190oC, 88 %
O
H
OH
OO
OO
O
H
O
OO
OO
+ BrNaH
CH3CN
Söderberg, E.; Westman, J.; Oscarsson, S. J. Carbohydrate Chem. 2001, 5, 397-410
Carbohydrate Chemistry
Microwave: 3 min, 150oC, 91 %
O
H
OH
OHOH
OHOH
O
H
OH
OO
OO
MeOH / H2O
K10 clay
1:1
Biotage Pathfinder data
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Safety. Use of Perchloric acid as catalyst
1. Optimized on Emrys™ Liberator: 70% yield2. Directly scaled up 30 X: 68 % yield (100% purity)
One-step, three-component synthesisof Imidazo[1,2-a] annulated Pyridine
N
N
BrNH
NO2
NBr
NH2
O
NO2
CN+ +
HClO4
EtOH170°C, 5min
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Solid Supported Reagents in
Solution Phase MAOS
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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 even greater with microwave chemistry
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Reduce cycle-time Fail Fast – Fail Cheaply
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:Reagents for Important Reaction Families
• Reductive Amination•30% of drugs in the Comprehensive Medicinal
Chemistry (CMC) database are tertiary amines1
• Common Reagents for Amide Synthesis•28% of compounds in the CMC database are
carboxamides1
• Oxidizing agents• Palladium Catalyst & Scavenger• Acids and Bases
1Ghose, A. K.; Viswanadhan, V. V.; Wendoloski, J. J. J. Comb. Chem. 1999, 1, 55-68.
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Incompatible with water, alcohols
• Swell in organic solvents • High loading
Polystyrene1 - 2 % cross linked(PS-)
Lower loading• Compatible with all solvents • Low swelling• Faster washing and drying
Macroporous Polystyrene(MP-)
LimitationsAdvantagesResin
Polymer Types
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Bound Reagent Solution Analog Application PS-TsCl p-toluenesulfonyl chloride Catch and Release
MP-TsOH p-toluenesulfonic acid Catch and Release
PS-DIEA Hindered tertiary amine Amine base
PS-NMM N-methylmorpholine Non-benzylic amine base
PS-TBD TBD Strong Base
PS-DMAP DMAP Catalyst, Catch and Release
MP-Carbonate Ammonium carbonate Base, Catch and Release
MP-Borohydride Sodium borohydride Reducing agent
MP-Cyanoborohydride Sodium cyanoborohydride Reductive amination
MP-Triacetoxyborohydride Sodium triacetoxyborohydride Reductive amination
MP-TsO-TEMPO TEMPO Oxidation of alcohols to carbonyls
PS-Carbodiimide DCC Coupling
PS-HOBt(HL) 1-hydroxybenzotriazole Active ester, amide synthesis
PS-Triphenylphosphine Triphenylphosphine Mitsunobu/Wittig/halogenations
PS-PPh3-Pd Triphenylphosphine Palladium (0) Palladium Catalyst
Biotage Polymeric Reagents
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Functional Group Stability StudyPS- and MP- resins
Collaboration with Argonaut Technologies (now Biotage)
• The stability PS- and MP- based resins upon microwave heating studied
• Three most commonly used solvents were selected: DCM, THF, DMF
• Temperatures were selected to be higher than what would be used in an actual application
• Heating time was 5 and 15 min
• The resins were evaluated for:Resin CapacityBead breaking/agglomerationVolatile and non-volatile leachable decomposition products
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Functional Group Stability Results forPS- and MP resins - SUMMARY
Collaboration with Argonaut Technologies (now Biotage)
• PS- and MP- behaved similarly; PS- type swelled and occupied more volume
• In general the resins were stable to microwave heating and did not break or agglomerate
• No volatile or non-volatile leachable decomposition products was found over the range of solvents studied (DCM, THF and DMF)
• The capacities of the PS and MP-isocyanate and MP-triacetoxyborohydrideresins was reduced by more than 70% This does not mean that they cannot be used with microwave heating because (a) the reaction would most probably be performed at a lower temp/time(b) the reaction rates maybe faster than the decomposition rates
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Functional Group Stability Results forPS- and MP resins
Collaboration with Argonaut Technologies (now Biotage)
1.11
3.86
pass
3.9
0.99
1.23
3.4
2.88
0.66
Resin Capacitymmol/g
04.5PS-trisamine8
01.15PS-Carbodiimide4
11PS-HOBt5
303.9PS-DIEA6
1.52MP-Triacetoxyborohydride1
02.8MP-Carbonate2
03.3MP-TsOH3
01.2PS-Benzaldehyde9
0passPS-PPh3Pd7
Resin Shape (% Broken)
Std Capacitymmol/g
Resin TypeNo
Condition: 1 g / 20 mL THF / 135 oC / 5 min
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Amide Formation
N
OHO
N
ON
R2
R1
NHR2
R1
+
1) PS-Carbodiimide HOBt, NMP 100 °C, 5 min
2) SPE (Si-Carbonate, elute with MeOH) 5 min
Sauer D.R. et al. Org. Lett. 2003, 5, 4721-4724.
HOBt scavenged via Si-carbonate SPE
Both synthesis and purification takes < 15 min
6 different amines were used
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Solid Supported Reagents Oxadiazole synthesis
OH
O
BnO
NH2
NOH BnO
N
NO
+
Wang, Y.; Miller, R.L.; Sauer, D. R. Djuric, S. W.; Org. Lett. 2005, 7(5), 925-928
[A] PS-Carbodiimide (3 equiv); HOBt (1 equiv); DIEA (3 equiv); CH3CN130 oC / 30 min (83% yield)
Conventional Heating:
OH
O
BnO
NH2
NOH
BnO
N
NOO
O
BnO
N
NH2
+
[A]
40 oC / 2 h
85 oC / 24 h
CH3CN
95 % 70 %
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Solid phase supported reagent. Heterogeneous solution
1. Developed & optimized on Emrys™ Liberator 2. Scaled up 30 times in Advancer; 92% yield (95% purity)
Solid Supported TriphenylphosphineOne-pot Wittig olefination
PPh
PhBrO
O
H
O
NN
Cl
O
O
NN
Cl+
K2CO3
MeOH150°C, 5 min
+
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Microwave Assisted Organic Synthesis (MAOS)Solid supported reagents Automated Flash purification
COMBINING
Shorten “compound production” time
Increase product purity
Increase productivity
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Simplified Workup & Purification“Catch and Release” purification of Tertiary Amines
150 μL NH3 in
MeOH is added
O
O
H
Hexane wash
removes DMF and aldehyde
N
O
CH 3
NHCH 3
TLC of Reaction mixture
Si N+Me3BH3CN
-
O
H
O
+NH
CH3 NCH3
O
Ghassemi, S. Biotage, Unpublished results
In situ catch & releaseSCX Samplet
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SP
Reaction Mixture(in DMF)
2
Simplified Workup & PurificationCatch/Release + Flash Technique
Ghassemi, S. Biotage, Unpublished results
Si SO3H
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Where do we go from here
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Drivers for change---
• HTC/HTS has put increased pressure down stream -----Process chemistry
• More compounds entering PRD ----need to respond quickly
• Many chemical routes now using MW technology
• Need to fail early----fail cheaply
• In the next 5 years many compounds come off patent
• A large number of API vendors now off-shore– 700 vs 3000
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FluoxetinePROZACTM
O
Cl
OH
Cl
O
Cl
CF3
O
NHMe
CF3
BH3/S(CH3)2 THF
p-(Trifluoromethyl)cresolPH3P / DEAD / THF
MeNH2 / MeOH /DMF
STEP 1 STEP 2 STEP 3
99 % 78 % 69 %
Overall Yield 53 % 51 % Total Reaction Time 12 min 20 sec 28 h
130 oC; 3 h150 oC; 5 minStep 3
23 oC; 18 h120 oC; 5 minStep 2
-25 oC; 7 h1100 oC; 2 min 20 secStep 1
Conventional SynthesisMicrowave Assisted Synthesis
* Ruda, K.; Katkevics, M.; Mutule, I; Ozola., V; Suna, E.(1) Brown, H.C. et al; J. Org. Chem. 1988, 53, 2916-2920
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What can we expect to see---
• More process chemistry done earlier and faster. Early scale-up group (1-5kg)
• Increasing use of MW technology in scale-up
• More Flow chemistry-----including MW/flow, Batch flow
• Use of solid support reagents, catalysts, scavengers in both the synthesis and purification
• New Polymer backbones
• Many new reagents/scavengers on Silica and Polymer supports
• API vendors /Pharma---looking towards MW technology in large scale production
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MP-TMT – New Palladium Scavenger
• Bound TMT ligand on macroporous resin• Scavenges Pd(II) and Pd(0), ligated
palladium• Effective in aqueous and non-aqueous
solutions• Useful for compound polishing• Reduces residual palladium to low ppm levels
S N
NN
SH
SH
Macroporous polystyrene-2,4,6-trimercaptotriazine
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Microwave Reaction Scale-up
0.2-5 ml 20 mL 300 ml mg-g 1-10g 10g-1kg
Initiator EXP Initiator EXP Advancer-Eight EXP - Eight EXP-Sixty EXP - Sixty EXP
Biotage™ Pathfinder
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SUMMARY
• MAOS is a versatile tool that speeds up the chemistry development process
• Adoption in to workflow simplifies and enhances the rate of discovery
• Allows access to reactions and conditions previously considered “impossible”
• Can be easily integrated with Solid Bonded Reagents and Automated Flash Chromatography eliminating the purification bottleneck
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• What is the top 5 troublesome reagents that you would like to see in bound form?
• What are your top 5 work-up/purification bottlenecks? (eg. solvents, byproducts, reagents etc..)
QUESTION TO YOU….????
Please drop of your list before leaving with a Biotage personnel
THANK YOU!!!