2005-11-14 Welcome Biotage 2005 User Group Meeting
Biotage AB Corporate Headquarters, Uppsala Sweden USA Headquarters, Charlottesville, Virginia Biotage is a global company and leading supplier of tools and technology for Medicinal and Analytical Chemistry, Process Development and Applied Genetic Analysis.
Building the business Recent Acquisitions: Argonaut Technologies June 2005 Complimentary products include the Argonaut reagents and scavengers. These products combined with Biotage microwave synthesizers and flash chromatography products, offer a complete solution from synthesis through purification. An expanded ChemDev product line with a range of reaction screening instruments that simulate and replicate conditions seen in larger production reactors. ew markets with a broad range of Analytical SPE products used for ADME-Tox screening and bioanalysis.
Drug Discovery today HTC chemists Medicinal Chemists Larger scale flash/ scavengers HTS HIT ID H2L L Process Chemists EDC Solid supported reagents/scavengers Flash/Large,small Microwave and Process instrumentation PRE CLI Bio-Analytical tools Phase 1 CLI Bio-Analytical Bio-Analytical
Global presence USA Charlottesville Boston Discovery Chemistry Biotage AB UK Hertford Cardiff Biosystems Sweden Uppsala Six major international offices with direct sales and service. Distribution partners in over 40 countries. Japan Tokyo EU direct sales France Germany Italy Swiss
DCG Prorata Sales History DCG Prorata Sales $60.00 $50.00 Millions USD $40.00 $30.00 $20.00 AGT ld Biotage PC $10.00 $0.00 2000 2001 2002 2003 2004 Year
Company Mission To help its global customers meet the enormous pressures of time, cost and innovation with better tools that successfully lead chemists into the next era of research, discovery and development.
Achieving our mission We will achieve success through collaboration with our industry partners. Industrial Advisory Boards User Group Meetings n-site Market Research Customer test-drives
Biotage IAB 2005 Biotage Industrial Advisory Board members: Abbott Laboratories AstraZeneca R&D Boston CombiPure Eisai Co., Ltd. Glaxo SmithKline Pfizer Karl-Franzens University Graz Lilly Research Laboratories Merck & Co., Inc. University of Cambridge Mitsubishi Pharma Corp. Deciphera Shionogi & Co., Ltd. Vertex Pharmaceuticals University of Texas, El Paso Bend Technologies
2004 User Group Meetings ver 460 customers and prospects of Biotage synthesis and purification products participated in our 2004 User Group Meetings. Select speakers presented technical talks (58 in total) at eight different meetings throughout Europe and the United States. Presentations are available at www.biotage.com
2005-11-14 THAK YU to today s Speakers & Attendees!
Microwave Assisted rganic Synthesis Where do we go from here? Steve Jordan 2005-11-14
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 Late stage Tox issues Time for technology to realise its full potential!! Hardware & informatics
Evolution of Microwave Chemistry 1946 Microwave radiation was discovered as method of heating 1947 First commercial domestic microwave oven 1978 First microwave lab instrument developed to analyze moisture in solids 1980-82 Microwave radiation developed to dry organic materials 1983-85 Microwave radiation was used for chemical analysis processes such as ashing, digestion and extraction 1986 Gedye R. (Laurentian Univ. Canada); Majetich, G. (Univ. Georgia; USA) & Giguere, R. (Mercer Univ; USA) published papers relating to microwave radiation in chemical synthesis 2000 Introduction of the first commercial single-mode microwave system for high throughput organic synthesis 2005 ver 2000 publications on MAS 2006-2010.????
Microwave vs Conventional Heating Microwave Heating Conventional Heating
Advantages of Microwave Assisted Synthesis Shorter reaction times Hydantoin Synthesis Rapid testing of creative ideas Increased productivity Higher yields, improved purity H H CEt Ba(H) 2 / DMF H Expanded reaction diversity Some difficult reactions made possible Less reagents and solvents Less reactive reagents Reproducible results Scalable conditions Microwave Heating: 4 min; 90% yield Conventional Heating: 48 h; 54% yield Epoxide Ring pening H 4 H Microwave Heating: 7 min; 93% yield Conventional Heating: 10 days; 13% yield H H 2
Unusual Findings! Reactions conventionally done in ice-baths (0 o C) Reactions and substrates with perceived sensitivity to heat Can be successful via microwave flash high temperature heating!
Preparation of Grignard reagent Br MgBr 89 % Conventionally 0 C, hours Et 2 Inert atmosphere Microwaves 60 C, 10min THF ormal atmosphere Avoids the inconvenience of purging 2 and ice baths. Biotage Pathfinder data
Grignard Reaction of Aryl Chlorides Mg turnings / I 2 Ar X Ar MgX THF 100-170 o C / 1 hr X = Cl, Br PhCH H + / H 2 100 o C / 30 min 89 % Ar H 51-99% (16 examples) Larhed, M. et al. Synlett., 2005, 1596
Carbohydrate Chemistry Microwave: 1 min, 190 o C, 88 % H H + Br ah CH 3 C H Microwave: 3 min, 150 o C, 91 % H H K10 clay MeH / H 2 1:1 H H H H H H Söderberg, E.; Westman, J.; scarsson, S. J. Carbohydrate Chem. 2001, 5, 397-410 Biotage Pathfinder data
ne-step, three-component synthesis of Imidazo[1,2-a] annulated Pyridine Br + + H 2 2 C HCl 4 EtH 170 C, 5min Br H 2 Safety. Use of Perchloric acid as catalyst 1. ptimized on Emrys Liberator: 70% yield 2. Directly scaled up 30 X: 68 % yield (100% purity)
2005-11-14 Solid Supported Reagents in Solution Phase MAS
What slows down drug discovery? 1. Target and Synthesis Design 2. Reaction 3. Work-up - usually extraction & evaporation 4. Purification - usually chromatography 5. Spectral Analysis Registration Bottlenecks (3) and (4) become even greater with microwave chemistry J. C. Hodges, Pfizer Inc. ACS Spring Meeting, San Diego, 2001
Reduce cycle-time Fail Fast Fail Cheaply
: Reagents for Important Reaction Families Reductive Amination 30% of drugs in the Comprehensive Medicinal Chemistry (CMC) database are tertiary amines 1 Common Reagents for Amide Synthesis 28% of compounds in the CMC database are carboxamides 1 xidizing agents Palladium Catalyst & Scavenger Acids and Bases 1 Ghose, A. K.; Viswanadhan, V. V.; Wendoloski, J. J. J. Comb. Chem. 1999, 1, 55-68.
Polymer Types Resin Advantages Limitations Polystyrene 1-2 % cross linked (PS-) Swell in organic solvents High loading Incompatible with water, alcohols Macroporous Polystyrene (MP-) Compatible with all solvents Low swelling Faster washing and drying Lower loading
Biotage Polymeric Reagents Bound Reagent Solution Analog Application PS-TsCl p-toluenesulfonyl chloride Catch and Release MP-TsH p-toluenesulfonic acid Catch and Release PS-DIEA Hindered tertiary amine Amine base PS-MM -methylmorpholine on-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-Ts-TEMP TEMP xidation of alcohols to carbonyls PS-Carbodiimide DCC Coupling PS-HBt(HL) 1-hydroxybenzotriazole Active ester, amide synthesis PS-Triphenylphosphine Triphenylphosphine Mitsunobu/Wittig/halogenations PS-PPh 3 -Pd Triphenylphosphine Palladium (0) Palladium Catalyst
Functional Group Stability Study PS-and MP-resins 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 Capacity Bead breaking/agglomeration Volatile and non-volatile leachable decomposition products Collaboration with Argonaut Technologies (now Biotage)
Functional Group Stability Results for PS- and MP resins - SUMMARY 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 o 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-triacetoxyborohydride resins 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 Collaboration with Argonaut Technologies (now Biotage)
Functional Group Stability Results for PS- and MP resins o Resin Type Std Capacity mmol/g Resin Capacity mmol/g Resin Shape (% Broken) 1 MP-Triacetoxyborohydride 2 0.66 1.5 2 3 4 5 6 7 8 9 MP-Carbonate MP-TsH PS-Carbodiimide PS-HBt PS-DIEA PS-PPh3Pd PS-trisamine PS-Benzaldehyde 2.8 3.3 1.15 1 3.9 pass 4.5 1.2 2.88 3.4 1.23 0.99 3.9 pass 3.86 1.11 0 0 0 1 30 0 0 0 Condition: 1 g / 20 ml THF / 135 o C/ 5 min Collaboration with Argonaut Technologies (now Biotage)
Amide Formation H + R1 H R2 1) PS-Carbodiimide HBt, MP 100 C, 5 min 2) SPE (Si-Carbonate, elute with MeH) 5 min R1 R2 HBt scavenged via Si-carbonate SPE Both synthesis and purification takes < 15 min 6 different amines were used Sauer D.R. et al. rg. Lett. 2003, 5, 4721-4724.
Solid Supported Reagents xadiazole synthesis H Bn + H Bn H 2 [A] PS-Carbodiimide (3 equiv); HBt (1 equiv); DIEA (3 equiv); CH 3 C 130 o C/ 30 min (83% yield) Conventional Heating: Bn Bn + H H H 2 [A] 40 o C / 2 h 95 % H 2 85 o C / 24 h CH 3 C 70 % Bn Wang, Y.; Miller, R.L.; Sauer, D. R. Djuric, S. W.; rg. Lett. 2005, 7(5), 925-928
Solid Supported Triphenylphosphine ne-pot Wittig olefination Cl H + Br + Ph P Ph K 2 C 3 MeH 150 C, 5 min Cl Solid phase supported reagent. Heterogeneous solution 1. Developed & optimized on Emrys Liberator 2. Scaled up 30 times in Advancer; 92% yield (95% purity)
CMBIIG Microwave Assisted rganic Synthesis (MAS) Solid supported reagents Automated Flash purification Shorten compound production time Increase product purity Increase productivity
Simplified Workup & Purification Catch and Release purification of Tertiary Amines H + H CH 3 Si + - Me 3 BH 3 C In situ catch & release SCX Samplet CH 3 TLC of Reaction mixture H 150 µl H 3 in MeH is added CH 3 Hexane wash removes DMF and aldehyde CH 3 H Ghassemi, S. Biotage, Unpublished results
Simplified Workup & Purification Catch/Release + Flash Technique Si S 3 H Reaction Mixture (in DMF) SP Ghassemi, S. Biotage, Unpublished results 2
2005-11-14 Where do we go from here
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 eed 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
Fluoxetine PRZAC TM STEP 1 STEP 2 STEP 3 CF 3 CF 3 Cl BH 3 /S(CH 3 ) 2 THF H Cl p-(trifluoromethyl) cresol PH 3 P / DEAD / THF Cl MeH 2 / MeH / DMF 99 % 78 % 69 % HMe Microwave Assisted Synthesis Conventional Synthesis Step 1 100 o C; 2 min 20 sec -25 o C; 7 h 1 Step 2 120 o C; 5 min 23 o C; 18 h Step 3 150 o C; 5 min 130 o C; 3 h verall Yield 53 % 51 % Total Reaction Time 12 min 20 sec 28 h * Ruda, K.; Katkevics, M.; Mutule, I; zola., V; Suna, E. (1) Brown, H.C. et al; J. rg. Chem. 1988, 53, 2916-2920
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 ew Polymer backbones Many new reagents/scavengers on Silica and Polymer supports API vendors /Pharma---looking towards MW technology in large scale production
MP-TMT ew Palladium Scavenger SH S Macroporous polystyrene-2,4,6-trimercaptotriazine Bound TMT ligand on macroporous resin Scavenges Pd(II) and Pd(0), ligated palladium Effective in aqueous and non-aqueous solutions SH Useful for compound polishing Reduces residual palladium to low ppm levels
Microwave Reaction Scale-up 0.2-5 ml 20 ml 300 ml mg-g 1-10g 10g-1kg Biotage Pathfinder Initiator EXP Initiator EXP Advancer -Eight EXP - Eight EXP -Sixty EXP - Sixty EXP
SUMMARY MAS 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
QUESTI T YU.???? 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..) Please drop of your list before leaving with a Biotage personnel THAK YU!!!