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Continuous Liquid Vapor Reactions Part 1: Design and Characterization of a Reactor for Asymmetric Hydroformylation Martin David Johnson, Scott A May, Joel Calvin, Gordon Lambertus, Prashant B Kokitkar, Clark R. Landis, Bradley R. Jones, Martha Leigh Abrams, and James Stout Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00407 • Publication Date (Web): 31 Mar 2016 Downloaded from http://pubs.acs.org on April 5, 2016

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Organic Process Research & Development

Continuous Liquid Vapor Reactions Part 1: Design and Characterization of a Reactor for Asymmetric Hydroformylation Martin D. Johnson,†,* Scott A. May,† Joel R. Calvin,† Gordon R. Lambertus,† Prashant B. Kokitkar,† Clark R. Landis,‡ Bradley R. Jones,‡‡, M. Leigh Abrams,‡ ‡, James R. Stout# †

‡

Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, Unites States Department of Chemistry, University of Wisconsin—Madison, 1101 University Avenue, Madison Wisconsin

53706, United States #

D&M Continuous Solutions, LLC, Greenwood, IN 46143, United States

ACS Paragon Plus Environment


TOC Graphic

360 L liquid in reactor

8 mL liquid in reactor

To 43 more pipes

45,000X

To 18 more pipes

1 mm

Scale Down

8 mm

5.3 mm

53 mm

3.7 m

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Gas and Liquid In Gas Bubbles Gas and Liquid In

4.27 m of tubing (4.57 mm id) between pipes

Liquid slug: 0.1 – 10 mL, 25-50 cm/s


3.7 m of tubing (0.56 mm id) between pipes

Gas Bubbles

Liquid slug: ~0.001 mL, 1-3 cm/s

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Abstract A research scale continuous reactor system was designed and developed for high pressure asymmetric hydroformylation (AHF) reactions with 8 hour reaction time. The continuous reactor achieved high kla, low axial dispersion, and 8 mL liquid holdup volume. The reactor consisted of 20 vertical bubble flow pipes-in-series, connected by small diameter tubing jumpers. This type of continuous reactor is proven to be scalable up to 360 L in our GMP pharmaceutical manufacturing plant for high pressure hydrogenation. The continuous reactor was used for the AHF of styrene and 2-vinyl-6-methoxynaphthalene catalyzed by rhodium(bisdiazaphospholane) (BDP) complexes. The CSTRs-in-series numerical model fit the experimental data better than the plug flow with dispersion model. Samples were taken along the length of the continuous reactor and used for kinetic data modeling. Vapor liquid mass transfer rate constants were about 3 orders of magnitude higher than reaction rate constants.

Key words continuous reaction, plug flow reactor, pipes in series, hydroformylation



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Introduction Part 2 of this work (companion paper) documents the results of an asymmetric hydroformylation (AHF) in a plug flow reactor1. That paper describes the efficient enantioselective synthesis of (S)-Naproxen via asymmetric hydroformylation of 2-vinyl-6methoxynaphthalene with Rh-BDP. Continuous reactors are advantageous for high pressure hydroformylation reactions in the pharmaceutical industry because of safety, cost,2 and consistent quality. There are many examples of reduced cost and improved safety and quality of continuous reactions compared to batch.3 Hydrogen is an explosion hazard4 and carbon monoxide has high toxicity.5 They both have relatively low solubility in many organic solvents at atmospheric pressure and therefore often require high reactor pressures, which increases the risk of gas releases and the amount of gas that could be released. The manufacturing scale vertical bubble flow pipes in series reactors are designed to operate more than 98% liquid filled, which minimizes the mass of hazardous reagent gas that could be released in the event of a leak or rupture. Furthermore, continuous reactors made of pipes and tubing are relatively low cost for achieving high pressure rating and sufficient heat and mass transfer rates, with low internal gas volume. One of the main challenges for this work was to design and develop a research scale continuous hydrofomylation reactor capable of high pressures (60 bar), long reaction times (2 to 20 hours residence time), small reactor liquid volume (less than 10 ml), intermediate sample points along the length or the reactor, optional catalyst pre-activation in flow prior to mixing in substrate, very low liquid flow rates (0.02 ml/min or less), and high vapor liquid mass transfer rates (kla about 0.1 s-1). Specifically, the desired research scale continuous reactor would meet the design criterial listed in Table 1. The reason for the long reaction times was to achieve high


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substrate to catalyst ratio and minimize the quantity6 and removal burden of precious metals.7 While vertical bubble flow pipes in series is an effective reactor design of choice for continuous high pressure hydrogenation reactions using homogeneous catalysts, it is difficult to scale this type of reactor down to research scale and maintain high vapor liquid mass transfer rates, and also meet all 13 of the design requirements in Table 1. Table 1. Design criteria for research scale continuous hydroformylation reaction system 1. Flows

τ Volume Pressure

Heat and mass transfer

2. 3. 4.

Mass flow metering of reagent gas with redundant measurements of gas flow for different ratios of H2 and CO mass flow metering of substrate solution and catalyst/ligand solution Mean hydraulic residence time (τ) adjustable Small reactor volume to minimize material usage in development.

5.

Reactor pressure control.

6.

High vapor liquid mass transfer rates.

7.

High heat transfer rates so that reaction is isothermal along entire length of continuous reactor.

8. 9.

Extra capabilities

Low axial dispersion. Intermediate sample points along the length of the PFR, to generate conversion versus time data. 10. Ability to significantly change syngas equivalents or reactor pressure without significantly changing τ.

0.05 to 1.0 mmol/min, +/- 5% of setpoint 0.001 to 0.1 ml/min, +/- 2% 2 to 20 hours < 10 mL liquid holdup 1 to 70 bar, +/- 0.1% of setpoint kla > 0.01/s Within 2 °C of desired reaction temperature for >99% of reactor length. D/uL < 0.025

11. Optional Pre-activation in flow for catalyst/ligand mixing with syngas at reaction pressure and elevated temperature.

12. O2 free system. Inert transfers of catalyst/ligand solution into feed containers/pumps in an inert fashion. 13. Scalable to commercial volume of >1000L a Constant pressure +/- 0.1%. facilitates constant, accurate, precise reagent gas flow through the entire reactor. This is necessary to establish the segmented flow needed for high vapor/liquid mass transfer.

The continuous membrane reactors developed by Ley and co-workers are a good option for research scale experimental continuous gas/liquid reactions8. Reagent gas diffuses into a liquid filled tube from the pressurized gas-filled shell side through permeable tubing. The tubein-tube semi-permeable membrane-based gas reactor has been used for continuous homogeneously catalyzed hydrogenations8,9 and continuous reactions with CO.10 However, the



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desire was to develop a reactor that could be scaled to >1000 L at manufacturing scale. The larger volumes are needed for the longer residence times to reduce catalyst loading. Continuous asymmetric hydrogenation reactions have also successfully been run in a helicoidal single channel falling film micro reactor11, and a micro channel mixer followed by tube reactor12. A recent review of continuous flow reactions at research scale using reagent gas was provided by Baxendale, in which examples using CO, H2, and syngas were described.13 In addition, see Cossar et al for a review of continuous hydrogenation reactions highlighting safety and performance advantages of flow.14 Continuous hydrogenation with heterogeneous catalysts in a packed bed, for example the Thales Nano H-Cube®, often require short reaction times for example less than 5 minutes.15 Furthermore, many continuous reactions with CO gas have been done in microfluidic devices with fast reaction times on the order of 2 to 15 minutes.16 However, one of the design criteria in this work was to enable flow chemistry with 2-20 hour reaction times. We have run continuous gas/liquid reactions in coiled tube reactors with 12 hours reaction time, and scaled these reactors up to 73 L. 17 However, the coiled tube reactors are not practically scalable to volumes larger than about 200 L due to fabrication and heating/cooling challenges. Instead, a vertical pipes in series reactor design was envisaged, where the liquid and gas flow co-currently up through larger diameter bubble flow pipes and down through smaller diameter jumper tubing, with 15 to 45 pipes in series.18 Compared to the coiled tube reactors, this reactor type is scalable to larger volumes, it operates at higher percent liquid filled, it has higher vapor liquid mass transfer rate in the small diameter jumpers, and the internal surfaces of the straight pipes and jumpers are more easily inspected after cleaning. Continuous processing is gaining importance in pharmaceutical development, manufacturing, and academic research.19 Quality control advantages of continuous processing


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can be achieved because of steady state operation and real-time product quality information by on-line process analytical technology. Real time adjustments can be made to keep product quality high at all times. This aligns with quality by design principles, and implementation of continuous processes is supported by the FDA.20 ICH Q8 is a guide to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The guideline explains that a process is designed to consistently meet product critical quality attributes, and that the process is continually monitored and updated to assure consistent quality over time. A steady state process (continuous) with on-line analytical is more intrinsically suited for consistency than a transient process (batch). In this manuscript and the Supporting Information, a custom on-line HPLC system is described, which was developed and used to convert a standard off-line HPLC into a fully automated on-line system.

Results and Discussion First generation coiled tube reactor system suffered from poor mass transfer The first generation coiled tube reactor system gave slower reaction rates than batch. Continuous AHF of styrene was run using a coiled tube reactor similar to the lab scale reactor that we reported in a previous study for asymmetric hydrogenation of an enone.17 The coiled tube reactor was 68 ml, made from a coil of 1.75 mm i.d. stainless steel tubing. The reactor used standard 1/8-inch o.d. commercially available 316L stainless steel tubing, high pressure pumps, and a commercially available back pressure regulator.21 A picture of the coiled tube reactor and the constant temperature oil bath used to submerge the reactor is shown in Figure 1.



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a

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b

Figure 1. Picture of (a) 68 mL coiled tube continuous reactor and (b) constant temperature oil bath. The two continuous feed solutions were 2.01 M styrene in toluene and 7.766 mM catalyst in toluene. Reagent gas was 50:50 CO:H2. The reaction schematic is shown in Figure 2. Rh(CO) 2(acac), (S, S)-Ph-BPE S/C 2000

O

O O

CO/H 2 (200 psi) Toluene, 80 °C Ph Ph P

(S)-2-phenylpropionaldehyde

(R)-2-phenylpropionaldehyde

3-phenylpropionaldehyde

(S)-Branched

(R)-Branched

Linear

P

Ph Ph (S, S)-Ph-BPE

Figure 2. Asymmetric Hydroformylation of Styrene with Rh-(S,S)-Ph-BPE Two sets of flow conditions were used in the continuous AHF experiments, as listed in Table 2. Conversion versus time is shown in Figure 3, and B/L ratio and ee versus time are shown in Figure 4. With 2 hour τ, conversion was about 47%, and with 4 hour τ, conversion was about 65%. The data in the figures was generated using an on-line GC platform, as described in the experimental section.


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Table 2. AHF of styrene in first generation coiled tube continuous reactor at 80 oC and 200 psig Syngas. styrene mean solution residence catalyst flow conversion B/L ee flow time, τ rate 0.0987 0.0128 352 hour 47% 45-50% mL/min mL/min 45 0.0493 0.00638 4 hours 65% 15 35% mL/min mL/min Gas/liquid volumetric flow rate was about 5/1 but not consistently controlled.

80

4 hour residence time

70 60 Conversion

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2 hour residence

50 40 30 20 10 0 0.00

5.00

10.00

15.00

20.00

Reaction Time (hours)

Figure 3. Conversion of styrene in first generation continuous AHF reactor.


25.00

30.00


50

70

2 hour residence 45 time

60

40 50

35

4 hour residence time

30

40 ee

B/L ratio

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25 30

20

B/Lratio ee

15

20

10 10

5 0 0.00

5.00

10.00

15.00

20.00

25.00

0 30.00

Reaction Time (hours)

Figure 4. B/L ratio and ee for styrene asymmetric AHF in first generation flow reactor. For comparison, the reaction was run batch in an Endeavor® reactor at 80 °C and 100, 200, 300 psig, using the same feeds solutions as the continuous reactions.22 The batch reactions achieved 100% conversion in 4 hours. The continuous flow conversion versus time did not match batch. Furthermore, low selectivity in flow pointed to poor vapor liquid mixing. One problem was poor control of gas mass flow rate and reactor pressure. The commercially available back pressure regulator was allowing the pressure to vary between about 198-202 psig. This resulted in liquid and gas segments that were very long, causing low vapor/liquid interfacial surface area. Some liquid segments were 0.24 mL volume. The smallest liquid segments were about 0.01 mL. Vapor liquid mass transfer would be much better if all liquid segments were about 0.01 mL because interfacial surface area in the reactor would be much higher. This was verified visually by changing the first 3 feet of the reactor tube from stainless steel to transparent PFA, so that the bubble lengths and liquid slug lengths could be directly observed. The large internal diameter of the tubing (1.75 mm) was another reason for larger liquid segment volume in the tubes and thus lower gas/liquid interfacial surface area. Linear velocity in the tube reactor


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was only about 24 cm/min at 2 h τ and 12 cm/min at 4 h τ. Data in the Supporting Information shows that gas/liquid mass transfer rate is higher for higher linear velocities. Therefore, we sought a reactor with higher gas/liquid interfacial surface area and higher linear velocities, which should lead to higher gas/liquid mass transfer rates. Second generation coiled tube reactor system had better gas+liquid mixing The second generation coiled tube reactor system was designed for better pressure control, better gas mass flow rate control, and smaller diameter tubing. Takebayashi et al had shown that changing to smaller i.d. tubing, 0.5 mm versus 1.0 mm, made a dramatic improvement in reaction efficiency for segmented flow with CO reagent gas,23 reasoning that it was because of the increased surface area of CO interface per unit reactor volume. Likewise, our second generation coiled tube reactor achieved about 10-300X smaller liquid segment size and thus much higher interfacial surface area for gas/liquid mass transfer. Changes to the reactor inlet and outlet side flow control and pressure control resulted in less oscillations in pressures and gas flow rate, and much smaller and more consistent liquid slug length and gas bubble length. The re-designed method of pressure control allowed the reactor outlet pressure to be held very close to setpoint, with less than 0.1% variation, for example 200.0 psig ± 0.2 psig. A pressure versus time trend is shown in the Supporting Information. No pressure regulators were used for pressure control, only sequenced automated block valves, finite volume chambers, and pressure transmitters. This is described in more detail in the experimental section and Supporting Information. Using the revised reactor system design, a hydroformylation reaction with styrene was run in a 14.3 mL reactor made from standard 1/16-inch o.d. 316L stainless steel tubing. The



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reactor tube was 0.56 mm i.d. and 58 m long, coiled and submerged inside a constant temperature bath. Conversion versus time matched closely between the second generation continuous coiled tube reactor and the batch reactor. The reaction scheme was shown in Figure 2. Flow conditions for the styrene AHF reaction were 80 °C, 200 psig pressure, 2.03 M styrene in toluene, S/C = 2000, total liquid flow rate of 0.02 ml/min, gas feed rate 0.13 mmol/min at 50:50 CO:H2, and about 60 minutes τ. Conversion was 60%, ee was 60-70% (rising with time from about 60% after one reactor turnover to about 70% after 10 turnovers), and B/L was ∼40. With the same styrene and catalyst solutions used in the continuous reactor, a batch reaction which was run for 16 hours and achieving 100% conversion resulted in ee of 61% and the B/L was 42. The ee and B/L results were almost identical to the continuous results. Five batch reactions were done using an Endeavor, using 2 mL of the styrene solution and 0.25 mL of the catalyst solution in each reactor (S/C 2000). Various pressure and temperatures were screened. Results for the 16 hour reactions are shown in Table 3. Table 3. Batch AHF of styrene with Rh-(S,S)-BPE. Entry 1 2 3 4 5

temp (oC) 60 60 80 80 80

pressure conversion (psig) (%) 100 93 400 52 100 100 200 100 400 98

B/L

ee (%)

55.5 50.7 33.4 42.2 40.6

89.5 90.9 59.2 60.9 63.8

In the batch reactions, ee was higher (∼90%) and the B/L ratio also increased to > 50 at 60 °C and 400 psig. However, the conversion was lower at 60 °C with the 100 psi reaction reaching only 93% conversion after 16 hours and the 400 psi only 52%. At 80 °C the ee was ~ 60% and the B/L ratio was between 33-42. Reaction rate was faster at lower pressure.


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Conversion after 60 minutes in the continuous reactor was as high as conversion after 120 minutes batch, and B/L ratio and ee were similar. As described in the companion paper1, it has been shown that regio- and enantioselectivity of styrene hydroformylation as catalyzed by rhodium(bisdiazaphospholane) complexes are sensitive to the CO partial pressure, with low partial pressures giving low selectivity.24 The Endeavor provides exceptional mixing (high kLA) and therefore maximum selectivity would be expected25. The selectivity from the continuous run matched that observed in the batch run, thus evidence that vapor liquid mixing rate was sufficient to maintain high CO concentration in solution. While improvement to gas flow control and smaller diameter tubing in the 2nd generation coiled tube allowed for much better results in flow, both the 1st and 2nd generation reactors fail to meet design criteria 3, 9, 10, 11, and 13 listed in Table 1. Notably, it was difficult to achieve desired residence time accurately with the coiled tube design. In order to achieve a desired τ, the % liquid filled must be known and maintained. τ depends on conversion, and conversion depends on τ, because % liquid filled depends on how much of the gas reacts. Thus, we sought a reactor design for which liquid τ was not so significantly impacted by gas flow rate or reaction conversion. Measurement of vapor/liquid mass transfer rates in small diameter tubing One of the challenges in flow reactors is quantifying vapor/liquid mass transfer rates, especially at research scale. It is difficult to make direct measurements of dissolved gas concentration as a function of time in micro tube reactors at low flow rates. In batch, the gas uptake is measured by change in pressure versus time. As gas dissolves, pressure decreases. This is not possible in the flow tube reactors. In the continuous reactors, pressure does not change. There have been several examples of research scale gas/liquid reactions with high mass



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transfer rates, on the order of 0.1 to 15 s-1. Ley and co-workers measured gas/liquid mass transfer rates in membrane reactors using total liquid flow rates of about 1-2 ml/min. 8 Mass transfer rate was measured indirectly, by measuring how much gas was evolved from the liquid during degassing. A research group at University of Huddersfield measured vapor liquid mass transfer rates in small scale bubble columns.26 In 3 mL bubble flow reactors, kla was on the order of 0.1 s-1. Hessel and co-workers have used falling film micro reactors at research scale and achieved kla 3 s-1 to 8 s-1 .27 Flow rate range was 0.5 to 3 mL/min and reactor pressure was 1 to 6 bar. A microchannel device with sequestered heterogeneous catalyst was used by Jensen and co-workers for the hydrogenation of cyclohexene, where kla was determined to be 5 s-1 to 15 s1 28

.

A reason for their high kla was the high vapor/liquid interfacial area in the micro structured

reactor. We also sought to achieve 0.1 s-1 or greater in this present work, but to sustain the high kla for longer τ (8 h) in the flow reactor, using 1000L

Therefore, design changes were made to achieve these goals while retaining the previous criteria. We had previously developed a pipes-in-series reactor platform29 that was capable of achieving the design criteria proven at scales up to 360 L, but a small research scale version (volume 98% liquid filled even if overall gas/liquid volumetric ratio is 1:1; (ii), high vapor liquid mass transfer rates in the down-jumpers, and (iii) minimize surging. The pipes are vertical rather than horizontal because it results in higher vapor liquid mass transfer rate, lower axial dispersion, and smaller plant footprint. All these aspects will be described and quantified in a different paper.18 The research scale version of this rector is not geometrically similar. At research scale, percent of reactor volume in the jumper tubes was about 80X larger than production scale, in order to improve vapor liquid mass transfer at research scale. The research scale reactor only operated about 33% liquid filled by design. At the sub-mm scale, vapor and liquid segments move through the reactor tubing at approximately the same linear velocity. This means that the research scale continuous reactor was higher % vapor-filled than the production scale. The height to diameter ratio of the vertical pipes was about 80X smaller in the research scale reactor. This is because diameter must be large enough for vapor to bubble up through liquid without


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pushing it out the top. The length to diameter ratio of the small diameter connecting tubes was about 7X higher at research scale to allow more time for gas/liquid mass transfer. Table 9. Comparison of research scale versus production scale pipes in series reactor dimensions. volume each tube, mL

length each tube, m

Tubing i.d., mm

Number in series

Total volume all tubes(mL)

volume% of reactor

24 mL reactor upflow pipes

0.3

0.0073

8.0

20

6.0

25%

24 mL reactor connecting tubes

0.9

3.66

0.56

20

17.8

75%

380L reactor upflow pipes

7989

3.69

52.5

45

360,000

99.1%

360L reactor downflow connecting tubes

70

4.27

4.57

45

3,150

0.9%

One reason why the manufacturing reactor was designed to run almost completely liquid filled was to minimize vapor space for safety. More importantly, manufacturing reactor operated outside the walls of the building, which greatly lowered the safety hazard. Reagent and catalyst feeds were prepared inside, pumped outside through sealed piping, mixed with reagent gas, and flowed through the sealed reactor. After stripping excess reagent gas and depressurizing outside, the product solutions flowed continuously back inside the manufacturing building for workup and isolation. This greatly improved the safety of handling hazardous gas reagents, and will be an important aspect of using CO in the manufacturing scale reactor. Conclusions A research scale continuous pipes in series reactor was developed for high pressure asymmetric hydroformylation reactions with about 8 h reaction times. The reactor was designed for low liquid flow rates, low liquid volume, high gas/liquid mass transfer rates, low axial dispersion, the ability to take samples along the length of the reactor to study kinetics, and the



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option for pre-activation of the catalyst in flow. The first generation coiled tube reactor system gave slower reaction rates than batch for styrene AHF, likely due to poor gas/liquid mass transfer. The second generation coiled tube reactor system, with improvements to pressure control and gas mass flow rate control, gave the same reaction rates as batch for styrene AHF, but did not achieve all design criteria. Gas/liquid mass transfer rates were measured in the reactor, and kla was calculated to be 0.1 s-1. The third generation reactor system achieved additional design criteria by using 20 vertical bubble flow pipes in series, connected by small diameter tubing jumpers. It was used for the AHF of 2-vinyl-6-methoxynaphthalene catalyzed by rhodium(bisdiazaphospholane) complexes. Axial dispersion and mean residence time were quantified in the continuous reactor via nonreactive solvent tracer runs. The reactor was modeled numerically as (1) a non-ideal plug flow with dispersion reactor with D/uL 0.015, and (2) 36 equal volume CSTRs in series. The CSTRs in series model fit the experimentally measured RTD data better. Model fits to the experimental data were used to quantify reaction rate constants for each of the hydroformylation reaction experiments, which ranged from 0.5 h-1 to 1.2 h-1. On-line HPLC was valuable for observing transitions from one steady state to the next after each step change in process parameters, and for verifying steady state. A custom system was designed and implemented for on-line HPLC, to convert an off-line LC to an on-line LC. Experimental Section See companion paper for experimental procedures on pre-catalyst preparation, olefin preparation, 2-vinyl-6-methoxynapthalene synthesis, method for flow with 2-vinyl-6methoxynapthalene substrate, and sample monitoring.1 Method for flow with styrene substrate. Reagent feed solution was 2.03 M concentration styrene in toluene. The catalyst solution was prepared by mixing 40.7 mg of Rh complex and


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103.52 mg of Ph-BPE in a 75 mL pressure bottle and diluting with 20 mL toluene. Concentration was 7.885 mM catalyst in toluene. The continuous reaction was done at 200 psig pressure, S/C = 2000, and temperature = 80 °C. Catalyst solution feed rate was 0.0023 ml/min, styrene solution feed rate was 0.0177 mL/min, and syngas (50:50 CO:H2) feed rate was 0.18 mmol/min. On-line GC. An Agilent Model 6850 GC (Agilent Technologies, Santa Clara, California) was converted to an online instrument using a heated, pressurized liquid injection system (Transcendent Enterprises Inc., Edmonton, AB). The online GC system was fluidically integrated directly to the outlet of the reactor such that, after depressurization, all of the reaction product solution passed through the online GC assembly. A solenoid valve controlled through the GC software actuated a moving piston with a 0.5uL etched groove, which served as the sample loop to inject neat reaction solution into the conventional split/splitless GC inlet. Operated in this manner, no sample preparation is required, and sample dilution is accomplished through control of the column and split vent flows in the GC inlet. The analytical method was 20 minutes long, utilized a temperature ramp with a thin film Cyclo-β-dextrin stationary phase coated column, with the GC cycling as frequently as possible throughout the process run (limited on the backend of the analytical method by the cool down time of the GC oven). Hydrogen was used as the carrier gas and fuel for the flame ionization detector. Automated sampling for off-line sample analysis. Experimental F-curve data was collected using an automated sampling device (FloPro Sampler from Global FIA, Fox Island, Washington) integrated to the process downstream of the depressurization pots at the outlet of the reactor. Due to low liquid volumetric flow rates the volume of material delivered to the sample point was quite small. In order to provide adequate material for representative samples,



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an additional constant flow of 2x THF was mixed with the reactor effluent and sent to the sampling reservoir. Cycling of the automated sampler was completed every ∼20 minutes, and was set to match the cycle time of the back end of the reactor cart. To reduce sample-to-sample carryover, every sample was programmed to pull a volume of material large enough to completely empty the liquid from the sampling reservoir. Samples were manually diluted and analyzed using offline GC. Pressure and gas flow control in second and third generation continuous reactors. Custom design and automation were used to control reactor pressure, gas mass flow into the reactor, gas and liquid mass flow out of the reactor, and gas/liquid separation. Reactor pressure was controlled within 0.1% of setpoint. Mass feed rate of gas was accurate over a wide range of flow rates, as low as 0.05 mmol/min at 800 psig. The custom system was designed to not use any regulators for reactor back pressure or supply gas, because commercially available regulators were not able to achieve the desired accuracy and precision. A detailed description of the control system is provided in the Supporting Information. On-line HPLC. On-line HPLC was achieved by converting an off-line Agilent 1100 HPLC into an on-line HPLC by implementing a custom built and automated sampling/diluting/parking system. Conversion of a typical offline, benchtop LC to an online instrument simply begins with bypassing the autosampler module in the LC stack and reconfiguring the 6-port, 2-position column switching valve to be used as an injection valve. By using an appropriately sized sample loop and writing the instrument method to actuate the valve with the correct timing, online samples are routinely injected onto the LC via the switching valve. Once the analytical sample is on-column, the separation, analysis, and data reporting mirrors its offline counterpart. Sample delivery to the online LC requires careful consideration


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of a number of factors, including the amount of material available for analysis, sample preparation requirements, frequency of analysis, location of the instrumentation relative to the reactor, and integration and automation of all related components. Sample preparation began with continuous dilution of the reaction product flowing out of the continuous reactor by mixing with 20X volume of toluene. The 20X diluted solution was pushed intermittently with nitrogen gas from the reactor to an automated sampling/dilution cart which was located on the other side of the lab. Total length of 0.79 mm i.d. tubing between the reactor and the sampling cart was about 20 m. Average time for the diluted sample to reach the automated sampling cart was about 1 minute. The automated sampling/dilution/parking system is described in the Supporting Information. This unit took a 0.33 mL sample from the intermittently flowing process stream of the 20X diluted reaction product, diluted it 30X, mixed the diluted sample, then pushed the diluted sample to an on-line HPLC, through about 10 m of 1.8 mm i.d. tubing. At the on-line HPLC, the sample was parked in an automated injection loop. Average total delay time from the time the sample exited the continuous reactor to the time it was injected on the Agilent HPLC was 15 minutes. Supporting Information: In the SI, measurement of vapor/liquid mass transfer rates in small diameter tubing is described in greater detail. Data for gas uptake in the liquid is shown. Axial dispersion and mean residence time are quantified in the continuous reactor via nonreactive solvent tracer runs, and the transition curve data is shown. Engineering drawings and automation sequences are given for pressure and gas flow control in second and third generation continuous reactors. Pressure trends versus time are presented in graphs. Our custom automated sampling/dilution/parking



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system used for On-line HPLC is described with engineering drawing, automation sequence, and procedure. This material is available free of charge via the Internet at http://pubs.acs.org Author Information: corresponding author *email: [email protected] Funding Sources: This research was supported through the Eli Lilly LRAP program. Acknowledgements: We thank Paul Milenbaugh, Ed Deweese, Ed Plocharczyk, Morgan Rosemeyer, and Jonathan Adler from D and M Continuous Solutions. Paul Milenbaugh and Ed Deweese constructed the reactor systems and custom dilution cart for online HPLC. Ed Plocharczyk advised the engineering. Morgan assisted with the axial dispersion testing and provided engineering drawings. Jonathan provided engineering drawings. We thank Richard Cope for assisting with the continuous reaction experiments. Wei-Ming Sun was co-inventor and automation engineer for the custom sampling/dilution/parking system that enabled on-line HPLC. We thank the LRAP program for financial support. Brian Haeberle did the first generation continuous reactor development work. Luke Webster did the heat transfer modeling. We thank Bret Huff for leading and sponsoring the continuous reaction design and development work at Eli Lilly and Company.


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There are operational cost advantages as well as capital avoidance advantages. With respect to capital avoidance a

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de Bellefon, C.; Pestre, N.; Lamouille, T.; Grenouillet, P.; Hessel, V. Adv. Synth. Catal. 2003, 345, 190.

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Cossar, P. J.; Hizartzidis, L.; Simone, M. I.; McCluskey, A.; Gordon, C. P. Org. Biomol. Chem. 2015, 13, 7119-

7130 15

Baumann, M.; Baxendale, I. R.; Hornung, C. H.; Ley, S. V.; Rojo, M. V.; Roper, K. A. Molecules 2014, 19, 9736-

9759. 16

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Jennings, L. E.; deMello, A. J.; Gee, A. D.; Long, N. J.; Vilar, R. Adv. Synth. Catal. 2009, 351, 3260-3268. (c) Gong, X.; Miller, P. W.; Gee, A. D.; Long, N. J.; de Mello, A. J.; Vilar, R. Chem. - Eur. J. 2012, 18, 2768-2772. (d) Fukuyama, T.; Totoki, T.; Ryu, I. Org. Lett. 2014, 16, 5632-5635. (e) Takebayashi, Y.; Sue, K.; Yoda, S.; Furuya, T.; Mae, K. Chem. Eng. J. 2012, 180, 250-254. (f) Fukuyama, T.; Totoki, T.; Ryu, I. Green. Chem. 2014, 16, 20422050. 17

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Manuscript in preparation regarding the development of the vertical pipes in series platform

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J. Pharm. Innov. 2015, 1. (b) Allison, G.; Cain, Y. T.; Cooney, C.; Garcia, T.; Bizjak, T. G.; Holte, O.; Jagota, N.; Komas, B.; Korakianiti, E.; Kourti, D.; Madurawe, R.; Morefield, E.; Montgomery, F.; Nasr, M.; Randolph, W.; Robert, J.-L.; Rudd, D.; Zezza, D., Journal of Pharmaceutical Sciences 2015, 104, 803-812. 21

Equilibar® dome-loaded diaphragm style regulator.

22

The Endeavor was run in a glovebox to avoid oxygen. 3.4 mL of the Styrene solution and 0.44 mL of the catalyst

solution were charged into 4 Endeavor tubes. 23

Takebayashi, Y.; Sue, K.; Yoda, S.; Furuya, T.; Mae, K. Chem. Eng. J. 2012, 180, 250-254.

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ACS Catalysis 2013, 3, 2905-2909. 25

We have measured kla in the Biotage Endeavor® with hydrogen and methanol, filling 2 to 5 ml solvent in each

reactor tube. kla was 0.04 to 0.09 s-1 at stir rate 750 rpm, 0.02-0.07 s-1 at 500 rpm, and 0.01-0.04 s-1 at 250 rpm. 26

Atherton, J.H.; Elmekawy, A.; Hall, A.; Williams, H. Org. Process Res. Dev., 2015, 19, 1159–1163.

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Manuscript in preparation.

30

We know that there is not a problem with dead zones because we measured residence time distribution as shown

in the Supporting Information in figures S7 through S14. 31

May, S. A.; Johnson, M. D.; Braden, T. M.; Calvin, J. R.; Haeberle, B. D.; Jines, A. R.; Miller, R. D.;

Plocharczyk, E. F.; Rener, G. A.; Richey, R. N.; Schmid, C. R.; Vaid, R. K.; Yu, H., Org. Process Res. Dev. 2012, 16, 982–1002. 32

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system H2 +CO2 + toluene from 305 to 343K and 1.2 to 10.5MPa 33

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36

A high pressure homogeneous reductive amination reaction was run in manufacturing in a 360L pipes-in-series

reactor. A manuscript describing this chemistry is in preparation.


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Continuous Liquid Vapor Reactions Part 1: Design ... - ACS Publications

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