Microwave assisted organic synthesis and Solid supported reagents. A happy marriage? Dr Pelle Lidström Biotage

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1 Microwave assisted organic synthesis and Solid supported reagents A happy marriage? Dr Pelle Lidström Biotage 5/30/2007

2 Discovery Chemistry Tool-kit Synthesis Synthesis Microwave Synthesis Extremely fast reactions High yield and purity Enables impossible reactions Reproducible Work-up Work-up Solid-bound Reagent and Scavenger Simplifies purification Facilitates reaction chemistry Purification Purification Automated flash purification 1-10 cartridges in unattended operation TLC to gradient method development Evaporation Evaporation Vortex and Vacuum rapid evaporation rganic solvents & water Flexible formats Flow or batch mode Effective re-dissolution

3 Microwave Chemistry gives... Faster reactions Higher Yields Better purities ovel reactions

4 But it doesn t come automatically.. Experiment Positive Result egative Result Positive Result Experiment Hypothesis Positive Result Experiment Hypothesis egative Result Hypothesis Positive Result TIME SPET egative Result Positive Result Experiment Hypothesis Positive Result Experiment Hypothesis Positive Result Experiment Hypothesis Experiment egative Result Positive Result Experiment Hypothesis Experiment Positive Result Hypothesis Hypothesis egative Result Positive Result Experiment Hypothesis CVETIAL CHEMISTRY MICRWAVE-ASSISTED CHEMISTRY

5 Increased dynamic range # Rxns Ethanol Microwave Chemistry Temp rt

6 Adoption stage of microwave synthesis in discovery chemistry MAS in discovery chemistry? Innovators: Early Adopters: Early Majority: Already looking for the next thing! Has this been career changing technology? Show me the benefit and that it s easy!

7 Does Microwave Chemistry Enhance Productivity? Biology Chemistry Clinical trials Approval Purpose Time B Cost E x y

8 Choice of methodology Biology Chemistry Clinical trials Approval Purpose Likelihood of success yields robust reproducible well defined Time Cost y x B E Complexity hardware software synthetic procedure time to results

9 Productivity G chemist Complexity of synthetic procedure

10 = Productivity Likelihood of success Productivity Complexity of synthetic procedure

11 Microwave Chemistry Low complexity Low G # chemist Increased innovativeness High likelihood of success Solid supported reagents Multicomponent reactions Multi-step one-pot reactions Whole workflow

12 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 greater with microwave chemistry J. C. Hodges, Pfizer Inc. ACS Spring Meeting, San Diego, 2001

13 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 Real time reaction progress monitoring (TLC/LC-MS) Eliminate problems with small molecule reagents Toxicity, byproducts difficult to eliminate, odor Slow reaction kinetics

14 Functional Group Stability Results for PS- and MP resins 1 g / 20 ml THF / 135 o C/ 5 min o Resin Type Std Capacity mmol/g Resin Capacity mmol/g Resin Shape (% Broken) 1 MP-Triacetoxyborohydride MP-Carbonate MP-TsH PS-Carbodiimide PS-HBt PS-DIEA PS-P3Pd pass pass 0 8 PS-trisamine PS-Benzaldehyde Collaboration with Argonaut Technologies (now Biotage)

15 Solid-Bound Reagents & Scavengers Mode of Action Scvngr 1.5eq S1 S2 Rgt P 0.5eq S1 Rgt-spent Solution ase Synthesis Conventional Microwave-assisted Scvngr Rgt-spent S 1 Filtration Flash Chromatography Product

16 PS-P 3 -Pd & ISLUTE Si-Carbonate Rapid Suzuki Reaction & Workup Br 2 H B H 2 B H Cs 2 C 3 2 EtH / DME (1:1) µw 130 o C, 10 min P PdL n H (C 3 ) Si % Ghassemi, S. ACS, Atlanta, GA, March 2006

17 MP-CBH 3 ; Reductive Amination Ar H R R2 R3 2.5 eq CBH % AcH/DCM µw 110 o C / 5-7 min R2 R Ar R3 Amine Carbonyl Convn. Yield µw Yield H H 2 Me 79 % 91 % 98 % 85 % Conventional condition: (1) THF (2) room temp, 16 h H H 2 Me 39 % 63 % 77 % 79 % Microwave condition: (1) DCM (2) 110 o C, 5-7 min 69 % 73 % H 2 Pannagiotis,, P. www. biotagepathfinder.com

18 Purification Strategies Scenario 1 Scenario 2 Scenario 3 R Ar R3 R2 2 o or 3 o amine Product R3 R2 Excess Carbonyl Ar H R3 R2 2 o amine Product Ar H 2 Excess 1 o amine R R2 3 o amine Product Ar R3 Ar H R Excess 2 o amine S 3 H HC C Catch & Release Product H 3 S 3 - MP-TsH H 3 -MeH PS-Benzaldehyde Ar xs 1 o amine xs 2 o amine Ar R PS-Isocyanate MP-Isocyanate H Product R3 H 3 2 o or 3 o amine Product H Product H R2 2 o amine 3 o amine Excess Carbonyl

19 PS-Carbodiimide & ISLUTE Si-Carbonate Rapid Acylation & Purification of Amines I CH H 3 ts- =C= PS-Carbodiimide HBt, DIEA µw, 100 o C, 5 min I H HBt H I CH Unreacted acid AU HBt Acid Product Reaction Mixture (C 3 ) Si Minutes Product I AU Minutes H 99% yield 98 % Purity Ghassemi, S. ACS, Atlanta, GA, March 2006

20 PS-Carbodiimide; xadiazole synthesis Bn H H H % Bn 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),

21 PS-P3; xadiazole synthesis Bn H H H % Bn (i) PS-P 3 (3 equiv); CCl 3 C (1.5 equiv) 100 o C/ 5 min (ii) DIEA (2 equiv); Aldoxime; THF 150 o C/ 15 min Wang, Y.; Miller, R.L.; Sauer, D. R. Djuric, S. W.; rg. Lett. 2005, 7(5),

22 MP-Ts-TEMP xidation of Alcohols R H - Solvent S 3 Temp / Time R Alcohol Method Solvent Temp Time Yield H on-µw CH 3 C rt 16 h 95 % Br µw DCM 100 o C 10 min 100 % H on-µw CH 3 C rt 16 h 99 % H µw DCM 60 o C 2 h 100 % H on-µw CH 3 C rt 16 h 70 % H µw on-µw DCM DCM 60 o C rt 5 min 16 h 93% 70 % H µw on-µw DCM DCM 60 o C rt 1.5 min 16 h 100 % 100 % µw DCM 60 o C 2.5 min 100 % Lundin, R.

23 PS-P3; Wittig one-pot reaction Pol P Br Toluene 150C, 3min Pol P Br K 2 C 3 (aq) 125C, 5min Pol P H DMF 180C, 5min Jacob Westman, rganic Letters, accepted

24 PS-P3; Wittig one-pot reaction Pol P Pol Br Br P Toluene 150C, 3min H Pol P 1M Me - /MeH 150C, 5min Jacob Westman, rganic Letters, accepted

25 PS-P3; Wittig one-pot reaction Pol P Br H K 2 C 3 /MeH 150C, 5min Pol Pol Br P P Jacob Westman, rganic Letters, accepted

26 PS-Triphenylphosphine ne-pot Wittig olefination Cl H Br P K 2 C 3 MeH 150 C, 5 min Cl Developed & optimized on Emrys Liberator Scaled up 30 times in Advancer; 92% yield (95% purity)

27 Hear the wedding bells chime... MAS continues to be a versatile tool for accelerating synthesis Solid bonded Reagents and Scavengers can help in significantly reducing the work-up and purification bottleneck Combining MAS with Solid bonded Reagents and Scavengers can accelerate total compound production time