on TM 2012 KinetiChem, Inc. Irvine, CA Jeffrey C. Raber, Ph.D.

Transcription

1 Synthetr Synthetron TM on TM Flow Reactor Technology 2012 KinetiChem, Inc. Irvine, CA Jeffrey C. Raber, Ph.D.

2 Flow chemistry offers significant advantages Current flow reactor technology does not meet all possible reaction needs: Precipitate and plugging concerns Shortened diffusion path is not enough Simple, rapid scale-up is most desired Smaller plant footprint desirable The Synthetron platform was conceived to overcome these limitations

3 The Synthetron incorporates two innovations 1. Line Contacting Formation of thin flowing films of reagents US Patents 7,125,527 & 7,534,404

4 The Synthetron incorporates two innovations 2. FUMI Forced Uniform Molecular Interdiffusion Molecular clusters, groups of the same molecules together in solution, slow down and impede potential reaction rates Disruption of molecular clusters enables more molecules to be immediately available for reaction participation

5 Molecular Clusters in Solutions

6 Ideal flow reaction

7 The Synthetron incorporates two innovations 1. Line Contacting Formation of thin flowing films of reagents 2. FUMI Forced Uniform Molecular Interdiffusion

8 Synthetron S3 Reactor

9 Synthetron S3T1 Reactor Easy to clean Easy to assemble and inspect Easy to re-machine the surfaces

10 Broad material capabilities PLASTICS METALS CERAMICS PEEK Hastelloy SiC* 1 Watt/M - K 22 Watt/M - K 100 Watt/M - K Can mix and match materials Flexibility of creating the right tool for the job Options for making disks out of unique materials *not currently implemented

11 Flexible and Scalable Technology Platform Wide Range of Flow Rates are Possible From 0.5 ml/min up to 400 ml/min on same device Current Capabilities of Kilos-Per-Hour Demonstrated with a 2.5 disk diameter Scalability is based on increasing disk diameter As disk diameter increases, reactive surface area increases as a square function disk diameter = 16 5!

12 High Flow Rates = Production Capabilities Broad Flow Rate Ranges Demonstrated 0.5 Kg/hr up to 8.0 Kg/hr in SAME DEVICE! Tremendous Throughput 0.5 Kg/hr = 4Kg in 8 hour shift 8 Kg/hr = 64 Kg in 8 hour shift KILO LAB IN A FUME HOOD! Space and Time Savings Energy Efficient

13 High Flow Rates = New Options Handling of precipitate formations Particle Size Controls Tremendous Throughput Multiple Kg s per hour possible with a reaction volume of 0.2 ml Enabling New Directions New Applications New Chemical Possibilities

14 The Frequency Factor Impact

15 Impacting a SLOW Reaction - ODS Reactivity complementary to HDS zero-levels not achieved Oxidation occurs through peroxo-acid Catalytic amounts of acid are required Requires an aqueous oxidant to act on a substrate in the organic phase Translates into hours stirring at elevated temperatures! How to improve and adapt this reaction to the Synthetron platform? Otsuki, S. et al Energy & Fuels 2000, 14, Kong, L. et al Catal. Lett. 2004, 92, García-Gutiérrez, J. L. et al Appl. Catal A: General 2006, 305, 15-20

16 Optimize Conditions with DOE Parameter FR (ml/min) Low 0.3 High Shear Rate (sec-1) 2.0 gap size (µm) RPM org:aq 1 10 % formic acid temperature ( C) Residence Time (sec) 1 53 Resolution IV experiment - Included 1 fold-over for a total of 29 trials - 5 replicates of center point included Bottom line: Discovered conditions that lead to ~60% removal with a residence time of 80 seconds at only 10 C The same reaction with vigorous traditional stirring took over 8 hours to reach the same extent conversion at 70 C

17 Further Optimization Efforts Percent deulfurization Series 2 = smaller much higher shear rates with lower oxidant ratios Seies 1 Series Pass Number Higher flow rates were found to be effective Residence Time is NOT an independent parameter Recirculation = further ODS Could use multiple reactors in-line as well

18 Reaction Examples Traditional methods provided product in only 57% yield and required difficult purification How to improve and adapt this reaction to the Synthetron platform?

19 Reaction Examples First Approach Feed 1 = Aniline/LHMDS Feed 2 = Nitroarene Second Approach Feed 1 = Nitroarene/Aniline Feed 2 = LHMDS First Flow Rate = 60% First Flow Rate = 94% Faster Flow Rate = 62% Faster Flow Rate = 96%

20 Reaction Examples Batch Add aniline to flask and cool to 0 Dropwise addition of LHMDS Maintain 0, slowly add Nitroarene Warm to r.t. over 12 hours Synthetron Equilibrate reactor at 25 Pump reagents as needed Produce at 22.6 g/min or 1.36Kg/hr 57% Crude Yield 96% Crude Yield Chromatography, Recrystallize recrystallization or direct use

21 Reaction Examples: Organometallics 2.0M, r.t. 2.0M, r.t. Process Temp = 0 C Batch Synthetron 30% Yield 98% Yield Multiple side products 2 Kg/hr

22 Reaction Examples: Organometallics Batch CPC CLSmicroreactor Synthetron 76% Yield 90% Yield 98% Yield 50 g/hr 1.5 Kg/hr

23 Reaction Examples: Gas-Liquid Efficiencies Synthetron Process: 96.2% 292 g/hr (unoptimized) 2.7% Biphenyl, 90% Isolated Yield Only 1.75 equivalents of gas utilized!

24 Reaction Examples: Precipitates Complete Conversion of N-Boc-Phe 2880 g/h Observed very small and fine particles Others are studying particle formation

25 Reaction Examples: Halogen/Lithium Exchange Batch Synthetron 97% Yield 98% Yield Variable results at scale 2.7 Kg/hr Feed reagent concentrations of 2.0M, lithium products were quenched with TMSCl and analyzed by GC. Tet. Lett., 2010, 51, p

26 Reaction Examples: Halogen/Lithium Exchange Batch Synthetron 85% Yield 92% Yield Selectivity: 10 : 1 Selectivity: 104 : 1 Variable results at scale 3.5 Kg/hr Feed reagent concentrations of 2.0M, lithium products were quenched with TMSCl and analyzed by GC.

27 Reaction Examples: Halogen/Lithium Exchange Tet. Lett., 2010, 51, p Synthetron Process: 94% Conv., 2466 g/hr 400g produced in ~ 10 min reaction time. A 50g batch process required ~40 min of reagent addition time!

28 Reaction Examples: Halogen/Lithium Exchange Synthetron Process: 93% Conv., 1569 g/hr Overall combined flow rate = 400 ml/min Highly flexible synthetic platform for the creation of diverse fine chemical building blocks

29 Reaction Examples: Halogen/Lithium Exchange Synthetron Process: 96% Conv., 2135 g/hr Overall flow rate of 250 ml/min Both solutions at 1.0M

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31 Comparisons O + 3 mol% + PhCH 2 OH HCl (conc.) Neat O O Ph CPC CLS-microreactor Synthetron 100% Yield 97% Yield 177 g/hr 8602 g/hr 1.36 mol/hr 44.8 mol/hr* Using Ethanol, *Unoptimized Results, THP-Ether yield based on crude 1H NMR

32 Comparisons NH 2 O O O Toluene + N O H CPC CLS-microreactor Synthetron 80% Yield 98% Yield 24 g/hr 2250 g/hr mol/hr mol/hr* Using Propylamine, *Unoptimized Results, Yield based on crude 1H NMR

33 Capabilities NC CN OH O O O Neat, + O O DMAP (10 mol%) 96% 8.25 Kg/hr + O EtOH CN CN 90% 5.24 Kg/hr NH 2 + O Neat N 98% 2.85 Kg/hr

34 1. High Throughput Line contacting Forced Uniform Molecular Interdiffusion 2. Flexible Gas/Liquid reactions Precipitates 3. Easy to use Take apart and clean Re-surface A forgiving reactor