Development and Scale Up of a Continuous Reaction for Production

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Development and Scale Up of a Continuous Reaction for Production of an API Intermediate Jonathan McMullen, Christopher H. Marton, Benjamin D Sherry, Glenn Spencer, Joseph Kukura, and Natalie S. Eyke Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00192 • Publication Date (Web): 06 Aug 2018 Downloaded from http://pubs.acs.org on August 6, 2018

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Organic Process Research & Development

Development and Scale Up of a Continuous Reaction for Production of an API Intermediate Jonathan P. McMullen*, Christopher H. Marton, Benjamin D. Sherry, Glenn Spencer, Joseph Kukura, Natalie S. Eyke Process Research and Development, Merck & Co., Inc., P.O. Box 2000, Rahway, NJ 07065, United States. Keywords: Flow chemistry, mixing sensitive reaction, scale up.

Abstract

Examples of continuous flow reactions in the laboratory setting are becoming commonplace in pharmaceutical

drug

substance

research.

Developing

these

processes

commercialization and identifying the scale up parameters remains a challenge.

for

robust

An aldol

reaction in the formation of an API intermediate was developed in flow at milliliter scale. Research focused on identifying conditions that led to robust and stable operating conditions. Desired reaction performance was achieved in various mixers across reactor scales by identifying conditions that led to similar flow regimes. Conditions from the lab were transferred to the pilot plant to successfully process ~200 kg of the starting material.

Background

ACS Paragon Plus Environment

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Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Continuous flow reactors are enabling the pharmaceutical industry to utilize syntheses that have long been considered too challenging or unsafe to reliably scale up for commercialization.16

In comparison to batch reactors, the enhanced mixing and heat transfer rates inherent to flow

reactors can lead to improved yield and selectivity of reactions with rapid kinetics.7-9 Moreover, the ability to tune the residence time in flow reactors facilitates reaction optimization for systems with short-lived, unstable intermediates.10,

11

These features are particularly appealing to

chemical systems that involve enolates.12 As flow chemistry research continues to expand through impressive demonstrations of pharmaceutically relevant reactions in flow,1, 13, 14 the need to establish scale up principles and process guidelines for commercialization becomes more critical. Scaling up any continuous reaction can be riddled with challenges and complexity. In particular, mixing sensitive reactions that operate at fast flow rates require high confidence in the process robustness and scale up protocol; otherwise, a significant portion of the batch can be processed before realizing that the reaction is not behaving as intended. Here, we describe one approach to designing a flow reaction with line of sight to manufacturing. Recently, our group described a continuous flow process for the aldol formation (Scheme 1) of a key intermediate in the synthesis of doravirine.15 We expand upon that initial lab development to generate a robust, transferable flow process for commercialization.


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Scheme 1: Aldol chemistry of ethyl ester (1) and enone (2) to form aldolate (3) with subsequent elimination and cyclization to generate pyridine (5).

Experimental The initial laboratory flow process, illustrated in Figure 1, involved combining a stream of ethyl ester (1) and enone (2) in toluene with a stream of commercially available 1.7 M potassium tert-amylate (KOtAm) in toluene. Because the reaction performance is enhanced at cooler temperatures, each stream was pre-cooled prior to entering the reaction zone. A 0.6 M ethyl ester in toluene solution approaches its solubility limit at -10⁰C; therefore, it was chosen to precool the combined starting material solution to -8⁰C to avoid plugging the flow reactor. 1/16 inch stainless steel tubing that was coiled within a 3/4 inch straight tube was used as a tube-in-shell heat exchanger to pre-cool this starting material stream. The KOtAm solution, on the other hand, could be cooled to lower temperatures without observing any precipitation. This base solution passed through a section of 1/8 inch FEP tubing that was submerged in a cooling fluid at -30⁰C. After pre-cooling, these two reagent streams were combined in a T-mixer (Idex, 0.05 inch thru hole) to produce the aldolate (3). The resulting aldolate stream was then cooled in the same jacketed flask mentioned above and then charged to a receiving vessel at -10⁰C in a semi-continuous manner along with triethylamine (TEA) and trifluoroacetic anhydride (TFAA) to afford the diene (4). Using this flow reactor system, typical lab experiments were performed using 25 g of 1 with a total flow rate through the reactor of 11.2 mL/min, providing a residence time of 15 s. This is a conservative residence time for this


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process as the reaction rate is rapid and is complete in less than 1 s under suitable mixing conditions. Subsequently, the diene was then cyclized to the pyridone (5) through the use of gaseous ammonia in a pressurized batch-reactor, followed by crystallization and isolation of the API intermediate.

Figure 1: The initial flow process involved pre-cooling the starting material solution in a tube-in-shell heat exchanger and pre-cooling the KOtAm base solution by submerging a section of tubing in a jacketed flask at -30 oC. Streams were then combined in a mixer before entering the reaction zone. The resulting product solution was charged to a receiving vessel with TEA and TFAA. The KOtAm pre-cooling loop, mixer, and reaction zone were temperature controlled in the same jacketed flask.

Results This innovative process quickly achieved proof-of-concept and led to a streamlined synthesis of 5. Directly transferring these conditions to the pilot plant, however, resulted in several processing concerns. Ingress of water resulted in a thick gel, likely due to hydrolysis of the base, and caused plugging in the base feed line and the reactor. These solids also contributed to fouling of the KOtAm heat exchanger. Fouling along the walls of the heat exchanger decreased the overall heat transfer rate and resulted in a gradual increase in the observed reaction temperature as shown in the pilot plant temperature profiles of Figure 2. Upward drifts in the temperature profiles corresponded with similar upward trends measured with the in-line pressure gauges.


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These two measurements, combined with flow controller valve position, were used to monitor line plugging and served as an indicator as to when to shut down and purge the reactor outlet to waste. A variety of techniques were employed during this campaign to address these solids. The production train was flushed with solvent and purged with nitrogen to remove residual water. An inline 10 µm PTFE filter was placed upstream of the KOtAm heat-exchanger, but required frequent cleaning and replacement. Additionally, solids that were present in the KOtAm source vessel were removed from the process via decanting; however, with sufficient time the decanted solution would also produce additional solids that led to line plugging. These approaches aided flow operations for short periods of time, but flushing plugged lines to waste was a common necessity. Although this campaign generated sufficient amounts of quality material to meet clinical and program needs, lab development opportunities existed to improve process robustness by identifying reaction conditions that minimized plugging and maximized yield.


5


40 30 20

Temperature [C]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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10 0 -10 -20 -30 -40 0

5

10

Pre-cooled Ethyl Ester Stream

15

20

Time [hr] Pre-cooled KOtAm stream

25

30

35

Reaction Stream

Figure 2: Pilot plant temperature profile of the pre-cooled ethyl ester stream, the pre-cooled base stream, and the flow reaction stream. Note, the reaction stream is always elevated in comparison to the mixing cup average of the two inlet streams due to the fast, adiabatic nature of this aldol reaction. Gaps in measured reaction stream correspond to shutdown periods when reactor lines were purged to waste to remove solid build-up.

There are numerous techniques to handle solids in flow reactors in the lab and manufacturing environment.16, 17 Rather than relying on engineering controls to address the solid formation, cosolvents were screened to improve the solubility of the base hydrolysis by-product.18 This small screen suggested that tetrahydrofuran (THF), even at relatively low amounts, could significantly improve the solubility of KOH in the reaction system and reduce the risk of plugging. However, the overall level of impurities increased as the amount of THF increased in the reaction system. Simplified flow reactions with 0%, 10%, and 20% v/v THF in the base solution were performed and the resulting product purity and assay yields are given in Table 1.19 In each of these experiments, the base stream and the ester/enone stream were cooled to -30⁰C and -8 ⁰C,


6

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respectively, and the mixer/reactor were submerged in a bath at -30⁰C. Based on these results, using 10% THF co-solvent was deemed an acceptable balance between yield, purity, and sustainable operations. This assessment was then verified by performing a prolonged flow experiment in the lab. This experiment resulted in the anticipated purity profile and yield without any signs of plugging or pressure increase after two hours of operations, at which point the feed solutions were exhausted.

As a benchmark for comparison, the majority of lab

development runs were 20 minutes and plugging was commonly observed in the first 10 minutes when it occurred. Table 1: Impact of THF co-solvent level on purity and yield in aldol formation flow reaction.

THF v/v% in KOtAm solution 0 10 20

Aldol purity (LC area %)

Aldol assay yield (%)

85.9 84.5 84.0

78 76 73

After resolving the concerns around plugging, the impact of mixing on the reaction performance was investigated in the lab. Previous publications have characterized the mixing intensity in a variety of commercially available micromixers.20 Based on this review, the arrowhead mixer (U-466S, Idex) seemed to be the ideal tool for this specific application as it balanced material requirements (e.g. minimal flow rate for ideal mixing), cost, and availability. This 2.2 µL mixer uses a stainless steel frit to mix two reagent streams. Although this frit promotes good mixing of the inlet streams, it also produces an appreciable pressure drop across the device. High-pressure piston pumps can be used to provide steady flow of the reaction streams through the arrowhead mixer in laboratory experiments, but this type of mixer in the manufacturing environment would require specialized capital equipment to overcome the large pressure drop associated with production-level flow rates. As such, it was preferable to use a


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Page 8 of 21

different mixer design in the scale up such that lower pressure drop could be achieved at production-level flow rates. For this reason, directly mapping mixing intensity to the flow rate through the arrowhead mixer would not provide useful scaling information. Therefore, we applied a dimensionless analysis approach to relate aldol reaction performance to mixing intensity in the arrowhead. As the reaction conditions (reagent concentrations, temperature) were relatively fixed, the fluid dynamics were considered the most relevant scaling parameter. A common approach used to characterize the fluid dynamics of a stream is to calculate the Reynolds number and compare the value with known thresholds for laminar, transitional, and turbulent flow. The terms involved in the Reynolds number calculation and the value at which flow regimes transition from one to the next vary with the geometry. For example, the Reynolds number through a porous medium similar to that of the arrowhead mixer is given by Eq. 1, where Us is the superficial velocity, k is the permeability coefficient of the frit, and ν is the kinematic viscosity. Flow through this medium is laminar for Refrit < 1, transitional for 1 < Refrit < 10, and turbulent for Refrit > 10.21 The Reynolds number through an empty tube, however, is defined by Eq. 2 and characterizes flow as laminar for Retube < 2,100, transitional for 2,100 < Retube < 4,000, and turbulent for Retube > 4,000. Consequently, matching flow regime rather than a specific Re value is a more transferrable approach to matching flow patterns across different mixer styles and scales. ܴ݁௙௥௜௧ = ܴ݁௧௨௕௘ =

௎ೞ ௞ బ.ఱ

(Eq. 1)

ν

௎஽

(Eq. 2)

ν

The impact of mixing on the aldol flow reaction performance was assessed by monitoring the reaction profile at various flow rates through the arrowhead mixer and calculating the Refrist value for these flow rates as given by Eq 1.22 Post mixing, the reaction stream passed through a


8

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residence time unit23 before being quenched by a phosphate solution in a second arrowhead mixer to produce the aldol. This quenched stream was analyzed via UPLC for ester starting material, aldol product, and two key process impurities referred to as Impurity A and Impurity B. The reaction conversion as a function of Refrit is given in Figure 3 and the corresponding experimental conditions with associated reaction purity profile detailed in Table 2. As these results illustrate, incomplete conversion is observed in the laminar flow regime where Refrit < 1. This incomplete conversion is suspected to be a result of stratified flow in the residence time unit where a portion of the ester/enone solution never contacts the base solution. Impurity levels are also elevated in this laminar regime, potentially due to concentration gradients across the reaction mixture. Once the flow regime becomes transitional, the reaction becomes less sensitive to mixing and the targeted aldol conversion is achieved. This analysis suggests that sufficient mixing can be achieved in any mixing platform given that the flow rates afford the transitional flow regime at a minimum.


9


100 90 80 70

Ester and Aldol LCAP

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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60 Aldol 50

Ester

40 30 20 10 0 0

0.5

1 1.5 Reynolds Number (frit)

2

2.5

Laminar (RefritRefrit>10), Turbulent (Refrit> 10) Figure 3: Impact of mixing on ethyl ester conversion to aldol product as a function of Refrit. Table 2: Impact of conversion and selectivity as a function of Refri. Reported values are averaged over 2 runs.

Entry

Refrit

Ester (LCAP)

Aldol (LCAP)

1

Flow rate (mL/min) 20

Impurity Impurity A B (LCAP) (LCAP) 0.67 0.09

1.93

10.50

85.30

2

16

1.55

7.32

86.73

0.88

0.12

3

12

1.16

4.50

87.37

0.80

0.16

4

10

0.97

4.09

86.48

1.31

0.23

5

6

0.58

19.36

74.52

2.65

1.06

6

2

0.19

28.28

66.72

2.28

1.35

7

1

0.10

34.16

60.73

2.07

2.27

Previous investigations on scale-up methods for mixing sensitive reactions have shown that a variety of parameters, such as mixing time scales, turbulent energy dissipation, or residence time,


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can be used as scaling factors.24, 25 Selecting the most appropriate scaling factor is application specific. For this aldol reaction, the conversion steadily increased before plateauing at the onset of transitional flow. Beyond this transition, providing additional mixing intensity to the reaction stream did not lead to an enhancement in the conversion or selectivity. Consequently, matching flow regime behavior is appropriate when the reaction exhibits this asymptotic behavior and can be more straightforward for commercial tech transfer purposes. After understanding the impact of mixing on the reaction performance, we evaluated the robustness of the flow process to reaction temperature. As will be discussed later, the pilot plant flow reactor consisted of a Y-mixer and a jacketed residence time unit. Because the mixer is not jacketed, the initial reaction temperature is dictated by the temperatures of the incoming streams and the heat of reaction. However, the reaction spends only a short amount of time in this mixer before being cooled in the downstream residence time unit. For rapid, exothermic reactions, this arrangement results a reaction stream that approaches the adiabatic temperature rise in the mixer before quickly decaying to the target temperature in the residence time unit. It is difficult to simulate the dynamic temperature profile of the pilot plant flow reactor in the lab due to the disparate surface area to volume ratios between the two setups. Rather than try to mimic this exact temperature profile in the lab, we decided to explore the reaction sensitivity to temperature by adjusting the bath temperature that cooled the KOtAm stream and the flow reactor while maintaining the starting material stream at -8⁰C. Investigated temperatures and reaction results are listed in Table 3 and indicate the desired reaction is enhanced at cooler temperature. Furthermore, the purity profile obtained over the range of temperatures explored satisfied the quality requirements of the process, giving us more confidence that the flow reaction would be robust to the anticipated temperature profile in the plant. When comparing the


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results in Table 3 with those in Figure 3, it should be noted that the UPLC analytical method was being evolved during lab development and that the modified method resulted in a change in the relative response factors of the impurities. This modified analytical method was used throughout this report going forward. Table 3: Impact of reaction conversion and purity profile as a function of temperature.a

KOtAm stream and flow reactor temperature -25

Assay Yield [%]

Reaction purity for compounds of interest Aldol Ethyl Ester Impurity Impurity (3) (1) 6 7 [LCAP] [LCAP] [LCAP] [LCAP]

-

82.67

N.D.

9.10

4.92

-10

75

83.24

N.D.

9.69

3.57

0

70

81.53

0.45

10.50

3.24

a– LCAP measurements are average of three samples. Reaction temperature was modified by adjusting cooling jacket fluid temperature on KOtAm stream and flow reactor. Experiment was performed at total flow rate of 11.2 mL/min (residence time 15 s). Lastly, we explored the impact of extended residence time on reaction conversion and selectivity. Given that the plant environment may require additional hold-up volume to transfer material from the point of mixing to the receiving vessel, it is paramount to ensure that this will not lead to product degradation. A series of lab reactions were performed at various residence times to determine if any process instabilities existed. To decouple the impact of mixing on these results, the flow rates of the reactant streams were fixed and the residence time was varied by using tubing of increasing lengths. Residence times between 24 and 50 seconds at -30⁰C were explored, and as shown in Figure 4 have little impact on yield or purity.


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Figure 4: Impact of prolonged residence time on reaction conversion and selectivity at -30⁰C ⁰C. ⁰C

After achieving lab development goals around operations stability and robustness, the flow reaction was scaled up to the pilot plant to process ~200 kg of ethyl ester. The pilot plant flow reactor used modular (skid-based) technology to integrate flow chemistry components with existing batch equipment.

To minimize back-flow, a Y-mixer fabricated from 1/4 inch

Hastelloy-C SCH-40 pipe (9.2 mL for mixed stream volume) was selected for this scale up process. As the process flow diagram in Figure 5 illustrates, the ester/enone and KOtAm solutions were prepared in vessels ST-1 and ST-2, respectively. The ester/enone solution in ST1 was cooled to -8 oC to promote stability of the enone, while the base solution was held at 20oC. Both solutions were pressure-transferred (via nitrogen at 90 psig or less) to the receiver vessel ST-3 via the flow reactor. In-line filters were used as a precaution to prevent unintended solids from entering the flow reactor skid. Dual controlling mass meters controlled the flow rates of the starting material streams, and commercial dual-tube heat exchangers (DTC-HC2/SSD-8-1-1X, Sentry Equipment Corp., 0.49 L internal volume and 0.23 m2 heat transfer area) were used to


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control fluid temperature during the transfer (HE1 and HE2) and the reactor (HE3). Inline reaction monitoring of the aldolate stream was possible through the integration of Fouriertransform infrared spectroscopy (FTIR) prior to the diene formation in ST-3. Figure 6 highlights the flow reactor elements of the pilot plant skid.

Figure 5: Pilot plant process flow diagram for continuous aldol formation with subsequent diene formation. Not all fluidic connections (e.g. valves, tees) are shown for the sake of clarity.


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(a)

(b)

Figure 6: Flow reactor equipment that was used in the piloting of the aldol flow chemistry. (a) The tube-in-shell heat exchangers were used to control stream temperature upstream and downstream of the (b) Y-mixer. Valves and ports on Y-mixer enabled flushing of lines and incorporation of inline thermocouples.

The targeted total flow rate through the Y-mixer was set such that the flow regime was transitional to achieve a similar mixing intensity as what was seen in the laboratory mixer. Therefore, the minimum flow rate through the Y-mixer is one that provides a Retube of 2100. To be slightly conservative, we chose a total flow rate of 1.6 L/min (1.0 L/min ester/enone stream, 0.6 L/min base stream) giving a Reynolds number through the Y mixer of ~3300. At this flow rate, the residence time through HE3 was 19 s. Higher flow rates could have been achieved with the equipment. However, for a fixed lot size as in this application, faster flow rates also result in shorter overall processing times. This increases the burden on the analytical resources for immediate reaction performance feedback and increases the risk of unknown reaction


15


performance for a significant portion of the batch. Therefore, we considered this flow rate of 1.6 L/min to be a good balance between the mixing requirements and the process risks. In addition to slip stream samples, a variety of inline measurements were used to assess the sustainability of the flow operations. Similar to the previous campaign, inline thermocouples and pressure transducers were used to monitor the starting material and reaction streams. Although the recent lab development described above appeared to have resolved the issues around solid formation and line plugging, a conservative pilot plant reactor design was employed where multiple tees were installed to act as local flush points in the unexpected event that a line did clog. Fortunately, the process improvements identified at the lab scale transferred well to the pilot plant and no degradation of flow performance, such as plugging or fouling, was observed as indicated by the temperature trends shown in Figure 7. 30

20

10

Temperature [C]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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0

-10

-20

-30

-40 0

5

Pre-cooled Ethyl Ester Stream

10 Time [hr] Pre-cooled KOtAm stream

15

20 Reaction Stream

Figure 7: Temperature profile of the pre-reaction starting material stream (cooled ester), the pre-reaction base solution (cooled base), and the flow reaction stream (hot rxn) with the improvements from lab development implemented.


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Besides ensuring stable flow operations, the FTIR also provided key information on the reactor dynamics and the time required to reach steady-state. The FTIR trend in Figure 8 captures the dynamics of the system start-up. Initially, the process lines from vessels ST-1 and ST-2 to the Y-mixer were primed with reagent material by diverting a small portion of the streams to waste via a three-way valve. At t = 0 min on the x-axis of Figure 8, these three-way valves were turned and the ester/enone and KOtAm solutions were pumped through the Y-mixer, the downstream heat exchanger (HX-3), and pipe that connects the flow reactor system to the FTIR and ST-3. As Figure 8 illustrates, stable conversion through this overall flow system was achieved in roughly six minutes after starting the flow of the starting materials through the Ymixer. This transient time is a small fraction of the overall processing time of 6-8 hours and confirmed that the reaction material collected during the start-up and shut-down periods had insignificant impact on product quality and yield.

Figure 8: Process start-up trend obtained by monitoring aldol formation at flow reactor outlet.

Overall, this second pilot plant flow reaction campaign processed over 200 kg of ethyl ester in three segments, each lasting 6-8 hours.

Processing was divided into these segments to

accommodate vessel fit or lot definition, rather than due to challenges associated with the flow


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reaction. The isolated yield of ethyl ester to the pyridone was 68% which is in excellent agreement with laboratory data. Additionally, slip stream samples obtained downstream of HE3 showed that the aldol reaction stream had purity profile comparable to lab data. The inclusion of inline PAT provided a data-rich pilot plant campaign for this flow chemistry step and has been used to enhance process understanding and to support tech transfer to the validation sites. Conclusions A flow chemistry process for sustainable operations was developed by utilizing THF as a cosolvent to improve the solubility of the reagent degradants. Process robustness was further established by understanding the impact of mixing, residence time, and solvent composition on reaction performance.

Identifying a suitable flow regime via the Reynolds number was

identified as the scaling parameter for this flow reaction, and used to scale the flow reaction from 20 mL/min in the lab to 1.6 L/min in the production environment. A modular flow reactor skid was fabricated for facile integration of flow chemistry components with existing batch equipment and was used to process 200 kg of starting material.

AUTHOR INFORMATION Corresponding Author * [email protected] ACKNOWLEDGMENT We gratefully acknowledge Zhihao Lin’s support in developing an IR method to monitor ethyl ester and base levels for the pilot plant campaign. We also acknowledge Chunli Huang, Feng Tan, Irina Schwartzburg, Robert Hartman, and Jinjian Zheng for analytical support. We are grateful for technical discussions with Marguerite Mohan and Donald Gauthier. We would like


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to thank the production and operation staff of the Small Scale Organic pilot plant, especially Mark Morgan, Adam Lukaszewski, John Arena, Scott Cheeseman, Keith O’Neil, and Ruben Perez.

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13. Tsubogo, T.; Oyamada, H.; Kobayashi, S., Multistep continuous-flow synthesis of (R)and (S)-rolipram using heterogeneous catalysts. Nature 2015, 520, (7547), 329-332. 14. Thaisrivongs, D. A.; Naber, J. R.; McMullen, J. P., Using Flow To Outpace Fast Proton Transfer in an Organometallic Reaction for the Manufacture of Verubecestat (MK-8931). Organic Process Research & Development 2016, 20, (11), 1997-2004. 15. Gauthier, D. R.; Sherry, B. D.; Cao, Y.; Journet, M.; Humphrey, G.; Itoh, T.; Mangion, I.; Tschaen, D. M., Highly Efficient Synthesis of HIV NNRTI Doravirine. Organic Letters 2015, 17, (6), 1353-1356. 16. Noel, T.; Naber, J. R.; Hartman, R. L.; McMullen, J. P.; Jensen, K. F.; Buchwald, S. L., Palladium-catalyzed amination reactions in flow: overcoming the challenges of clogging via acoustic irradiation. Chemical Science 2011, 2, (2), 287-290. 17. Laue, S.; Haverkamp, V.; Mleczko, L., Experience with Scale-Up of Low-Temperature Organometallic Reactions in Continuous Flow. Organic Process Research & Development 2016, 20, (2), 480-486. 18. Hydrolysis screens were performed by adding cosolvent to base solution and spiking water at various levels to determine if any solids precipitated. 19. Experiments were performed at standard 25 g ethyl ester scale and at standard total flow rate 11.2 mL/min, but aldolate stream was quenched with aquesous acid to stop the reaction at the adol, rather than carrying forward through to the pyridone. 20. Schwolow, S.; Hollmann, J.; Schenkel, B.; Roder, T., Application-Oriented Analysis of Mixing Performance in Microreactors. Organic Process Research & Development 2012, 16, (9), 1513-1522. 21. Lorenzi, A., Laminar, turbulent, and transition flow in porous sintered media. In 1975; Vol. 10, pp 75-77. 22. Each experiment in this study involved pre-cooling the base stream and the ester/enone stream to -25 deg. C and -8 deg. C, respectively. The mixer/reactor was submerged in a bath at 25 deg. C. Superficial velocity was caluclated using frit diameter of 0.062 in. Kinematic viscosity of the solution was estimated to be that of toluene at 0 deg. C. Permeability coefficient was estimated to be approximately 5E-11 squared meters. 23. Residence time unit corresponds to a section of FEP tubing that was 4' long and had an inner diameter of 0.04”. 24. Taylor, R. A.; Penney, W. R.; Vo, H. X., Scale-up Methods for Fast Competitive Chemical Reactions in Pipeline Mixers. Industrial & Engineering Chemistry Research 2005, 44, (16), 6095-6102. 25. Levesque, F.; Rogus, N. J.; Spencer, G.; Grigorov, P.; McMullen, J. P.; Thaisrivongs, D. A.; Davies, I. W.; Naber, J. R., Advancing Flow Chemistry Portability: A Simplified Approach to Scaling Up Flow Chemistry. Organic Process Research & Development Article ASAP doi: 10.1021/acs.oprd.8b00063.


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Development and Scale Up of a Continuous Reaction for Production

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