David Ford, Ph.D. Mettler Toledo Autochem Symposium June 21, 2017 Cambridge, MA

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1 David Ford, Ph.D. Mettler Toledo Autochem Symposium June 21, 2017 Cambridge, MA

2 Snapdragon Chemistry Snapdragon Chemistry was created to deliver complete flow chemistry solutions to clients. Using advanced continuous manufacturing technology, we are helping our clients to Improve access to existing molecules Reduce safety and environmental risks Enable new chemistries for manufacture Discover new molecules Process Development Technical Consulting Flow Chemistry CRO Custom Building Blocks Product Delivery 2

3 Batch vs. Flow Chemistry Flexible lots of installed capacity Difficult to scale from lab to plant Difficult to model computationally Significant safety risks Poor control over process parameters Limited range of temp & pressure Fixed output Purpose-built inexpensive (disposable reactor) for given reaction Easy to scale from lab to plant Can be modeled computationally Inherently safer Exquisite control over process parameters Broader range of temp & pressure Flexible output with same reactor 3

4 Is flow chemistry new? Flow chemistry is a new and exciting way to think about developing reactions! Chemical engineers have been running continuous processes since the dawn of time! 4

5 Continuous vs. flow chemistry Continuous production Always affords incremental efficiency gains compared to an analogous batch process Save time on start-up and shutdown Less material at risk Limited inventory of hazardous chemicals or reaction mixtures Compact apparatus Opportunity for excellent process control Flow chemistry Flow chemistry is chemistry that is only practical as a continuous process We use detailed knowledge of the chemical process to produce results that would be difficult to impossible to replicate in batch Mixing sensitivity Precise timing Extreme pressures and temperatures Very hazardous conditions The equipment of continuous production allows us to access new chemical space (i.e. flow chemistry)! Snapdragon works on projects in both categories! 5

6 Evolution from Simple to Complex Molecules 24 x8 x8 Acrylic acid production Decades old process Simple, 3 carbon molecule Prepared in one step from propylene feed >5 million tons per year Novartis-MIT Redline Project Reported in 2013 One drug product Integrated synthesis and formulation 3 chemical steps, isolations and formulation Angew. Chem. Int. Ed. 2013, 52, x2 x6 Darpa-MIT POD Reported in 2016 Seven drug products Integrated synthesis and formulation Multiple chemical steps, isolations and formulation Science, 2016, 6281,

7 Chemistry investment Evolution of flow chemistry toward general platforms Opportunity: rapid development with tools that are broadly applicable Pharma continuous manufacturing process (GMP) Minimal engineering investment to adapt to a new process Commodity chemical manufacturing Engineering investment 7

8 Snapdragon areas of expertise Ultrafast reactions Static Mixer Characterization Mixing time vs Total Flow Rate High temperature/high pressure reactions mixing completion time (ms) 1/8" mixer 5000 (100 g/h) 3/8" mixer (>5 kg/h) 500 1/4" mixer (1-5 kg/h) Operating range ( 200 ms) Flow rate (ml/min) Temp > 200 C Pressure > 1000 psi Gas/liquid reactions Flow Photochemistry ( 1 O 2, photoredox etc) Electrochemistry Fixed bed catalysis 8

9 Fast reactions Prototypical reactions are lithiations Batch processes often are often run at cryogenic temperatures. Why? Two major drivers: Mixing sensitivity Heat transfer Continuous processes can offer scalable mixing and heat transfer Added benefit: all of the other advantages of continuous processing! 9

10 Heat transfer Q = U A ΔT Heat transfer coeff (materials of construction) Surface area Temp. diff. across jacket As we scale up in a batch reactor, volume scales as r 3, but area only scales as r 2 decreasing surface area per unit volume for heat transfer In a tubular reactor, area and volume can scale together by using longer tubes or by using parallel tubes If we can t remove the heat quickly enough, we need to cool the reactor down to prevent the temperature from getting too high 10

11 Mixing sensitivity in batch RLi RLi SM Product Impurity RLi dosing High [RLi] SM in soln High [SM] Impurity formation Mixing rate needs to be faster than reaction rate! Solution: slow down the chemistry or speed up the mixing. We cool the reaction to buy ourselves time to mix. 11

12 Mixing sensitivity in flow RLi RLi SM Product Impurity SM in soln Smooth Fast mixing (static mixer) Smooth Slow mixing (laminar flow) Unsteady stoichiometry (pulsation) Trouble! RLi dosing 12

13 Where and how do we use FlowIR? Where: pretty much everywhere - Reagent stock solution stability - Gas dissolution in flow - Reactive intermediate stability and tracking - Tracking flow reaction steady state - Product process optimization and characterization How: Peel FlowIR multi-layer information - Chemometrics analysis of solvent composition - Quantification of starting material and product (IC Quant.) - Programmed FlowIR titration Starting materials intermediate product 13

14 Real-time reaction monitoring Need on-line PAT to gain reaction insight Low-maintenance and robust - No need for liquid nitrogen cooling: rarely turned off - No N 2 purge, no alignment - Small footprint Small sample size - 20 or 50 µl flow cell - Auxiliary flow cell heater and temp controlled - Microscale reaction in flow cell (sealed reactor) - stability studies - rapid reaction screening - reaction kinetics studies at variable temp 14

15 FlowIR Data Provides Diagnosis of Issues Chemometrics data processing Inconsistent results from aliquot sample and bulk collected sample Lower conversion found in bulk collected material FlowIR data shown repeated spiking pattern Chemometrics analysis enhanced the resolution 2.5 min intervals Glitch in Pump A delivery of n-buli explains observation of un-converted ArBr 15

16 Pressure (PSI) Pressure (PSI) Pump Performance Evaluation using Pressure Monitoring Pump A: reciprocating syringe pump with motor-driven switching valve Pressure Monitoring with Pump A Pump X: piston pump Pressure Monitoring with Pump X 30 8 ml/min 30 8 ml/min ml/min 20 6 ml/min 15 4 ml/min 15 4 ml/min ml/min difference drop (PSI) ml/min difference drop (PSI) Switching to pump X resolved the issue Smooth flow needs to be verified in the lab for mixing-sensitive reactions!

17 Case Study: A Practical Asymmetric Propargylation Original Chemistry: Boc H N Me O OMe Scale up of med chem process in batch failed Chiral epoxide synthesis required multiple steps, challenging chemistry TMS acetylene expensive raw material driving up cost of intermediate Snapdragon Proposal: BocHN Me O Li TMS Me 2 AlCl Boc H N Me OH TMS Project Goals: Ligand controlled propargylation using allene as starting material Scalable asymmetric process delivering better than 10:1 diastereoselectivity Hui Li, Jill Sheeran, Andy Clausen, Eric Fang, Matt Bio, Scott Bader Angew. Chem. Int. Ed. doi: /anie

18 Using FlowIR to Determine Gas Concentration in Pressurized Flow Reactor >2.5M solution in flow at 40 psi Allene saturated in THF at 1 atm RT 18

19 Ln [rel. Li-R] Stability of Lithium Allene? Decomposition follows 1 st order kinetics k = min -1, t 1/2 = C Organolithium Decay Kinetics y = x R² = Time (min) 19

20 Study of Lithiation Stoichiometry in Flow Efficient formation of lithioallene Precipitation risk beyond 0.7 equiv. HexLi 20

21 Importance of Mixing on Lithiation Static mixer was stable for short periods of time but failed due to precipitation of dilithioallene during extended operation Laminating mixers rapidly clogged 3D printed static mixer Laminating mixer Dynamic mixer gave stable performance without clogging for extended reaction times 21

22 Allenylzinc Screening and Optimization H N O H H C H ZnEt 2,R 2 N OH Li Chiral Ligands H H C H Zn O R 2 N Boc Me THF Boc H N Me OH 1-S,S + Boc H N Me OH 1-R,S N OH N L1, cinchonine N OH N L2, cinchonidine Ph NH 2 OH Ph L3 Me N OH Ph L4 N Me OH Ph Ph L5 Achiral Additives F 3 C OH A1 Me Me Me A2 OH O 2 N A3 OH Ph A4 OH A5 OH Me A6 OH Optimized conditions delivered 32:1 diastereoselectivity with 85% yield Li, H.; Sheeran, J.; Clausen, A. M.; Fang, Y.-Q..; Bio, M. M.; Bader, S. J. Angew. Chem. Int. Ed. 2017, in press 22

23 Optimized Propargylation Reactor Train 1905 cm -1 THF 1864 cm o C bath waste 1/8 OD tubing 30 mmol/hr = 15 grams/hr allene MFC FlowIR 20 psi BocHN Me CHO BocHN Me OH HexLi Zn* FlowIR CSTR Tube reactor Li Zn CSTR Tube Reactor 12.3 minutes 23

24 Optimized Propargylation Reactor Train Li Zn CSTR Tube Reactor 12.3 minutes 24

25 Case study: lithiation scale-up Challenge: lithiation reaction performed in batch with consistency issues, requires cryogenic conditions Evaluation in flow revealed that complete mixing in ~200 ms was required for acceptable product quality. Understanding the mixing allowed us to design and build a flow skid capable of performing the transformation at 1-2 kg/hour 25

26 Static mixers Static mixers provide efficient mixing without moving parts Characterized by Snapdragon using Bourne reactions and colorimetric readout of acid-base chemistry (publication forthcoming) Static mixers are critical for developing scalable processes with mixing-sensitive reactions! 26

27 Case Study: Rapid Scale-up by Design Lab to Plant by Calculation Static Mixer Characterization Mixing time vs Total Flow Rate mixing completion time (ms) 1/8" mixer (100 g/h) Flow rate (ml/min) 1/4" mixer (1-5 kg/h) Operating range ( 200 ms) 3/8" mixer (>5 kg/h) 27

28 Special opportunities afforded by fast reactions When we develop a process for a very fast reaction, the reactor can reach steady-state in just a few minutes It is practical to establish PAR and validate the process at full-scale using a modest amount of material In our case, ~15 minutes to establish stoichiometry PAR, and another ~15 minutes at the target conditions We can perform experiments using the unaltered >10 kg/day production process using only a few hundred grams of starting material! 28

29 Conclusions Continuous reactors afford us an exceptional degree of control over chemical processes, even in the most challenging cases Flow chemistry gives us the tools to reliably and safely perform chemistry that would be challenging or impossible in batch this allows chemists to think more creatively about new ways to assemble molecules PAT goes hand-in-hand with continuous: monitoring these processes gives valuable insights and in-process control Scale-up can be enabled through careful characterization of the reactor using model systems 29

30 Where do we go from here? Organic chemistry has lagged behind other fields in taking up new advances in data science One major challenge: we can t control batch processes well enough to collect good data! Continuous processes allow us the ability to precisely describe the conditions and collect high quality data Can we use this data combined with a deep understanding of our reactors to predictably and quickly scale up, scale down, and tech transfer? Can we leverage modern data science tools to develop chemical processes more rapidly? To lead us to better solutions? 30

31 Acknowledgements Matthew Bio Andrew Clausen Eric Fang Hui Li Jillian Sheeran Jade Nelson Scott Bader Adam Brown 31