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Development and Manufacturing GMP Scale-Up of a Continuous IrCatalyzed Homogeneous Reductive Amination Reaction Scott A. May,* Martin D. Johnson,* Jonas Y. Buser, Alison N. Campbell, Scott A. Frank, Brian D. Haeberle,‡ Philip C. Hoffman, Gordon R. Lambertus, Adam D. McFarland, Eric D. Moher, and Timothy D. White Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States

D. Declan Hurley,* Aoife P. Corrigan, Olivia Gowran, Niall G. Kerrigan, Marie G. Kissane, Regina R. Lynch, Paul Sheehan, and Richard D. Spencer Eli Lilly SA, Dunderrow, Kinsale, Cork, Ireland

Shon R. Pulley§ and James R. Stout D&M Continuous Solutions, LLC, Greenwood, Indiana 46113, United States S Supporting Information *

ABSTRACT: The design, development, and scale up of a continuous iridium-catalyzed homogeneous high pressure reductive amination reaction to produce 6, the penultimate intermediate in Lilly’s CETP inhibitor evacetrapib, is described. The scope of this report involves initial batch chemistry screening at milligram scale through the development process leading to full-scale production in manufacturing under GMP conditions. Key aspects in this process include a description of drivers for developing a continuous process over existing well-defined batch approaches, manufacturing setup, and approaches toward key quality and regulatory questions such as batch definition, the use of process analytics, start up and shutdown waste, “in control” versus “at steady state”, lot genealogy and deviation boundaries, fluctuations, and diverting. The fully developed continuous reaction operated for 24 days during a primary stability campaign and produced over 2 MT of the penultimate intermediate in 95% yield after batch workup, crystallization, and isolation. KEYWORDS: Evacetrapib, continuous manufacturing, flow chemistry, hydrogenation, hydrogen, reductive amination, GMP, lot genealogy, deviation boundaries, start up and shutdown transitions, homogeneous catalysis, iridium, [Ir(COD)Cl]2, process analytical technologies, steady state, state of control, LY2484595, online HPLC

■

INTRODUCTION

emphasis on catalytic methods and minimizing environmental impact. However, a detailed analysis between the Pt/C and STAB processes revealed that the STAB route was preferred from an overall cost perspective. This was primarily driven by higher cycle time, lower yield, and insufficient hydrogenation capacity to support peak demand projections for the Pt/C process. Investment decisions regarding specialty equipment at a pharmaceutical manufacturing site are especially challenging since these investments are often made prior to product approval. Further, the size of this investment is also complex given uncertainties around peak demand of the product. This is one reason that the pharmaceutical industry has long favored unit operations designed for standard multiuse batch equipment. Continuous processing technologies nicely address some of these issues in that the infrastructure is smaller and capital investment is lower than batch. There is also a modular aspect of flow that lends itself to become a more generally utilized

LY2484595 is a cholesteryl ester transfer protein (CETP) inhibitor that was recently in phase III clinical trials for the prevention of cardiovascular events in patients with high-risk vascular disease (HRVD).1 Step 2 in the proposed registered sequence for evacetrapib drug substance is a reductive amination reaction between secondary amine 3 and transaldehyde 5 to produce tertiary amine 6 (Scheme 1).2 Two separate approaches to this transformation had been previously developed and scaled up to 2000 gallon batch equipment. The first approach used the stoichiometric reducing agent sodium triacetoxyborohydride (STAB),2 while a second generation approach employed a heterogeneous catalytic hydrogenation with Pt/C.3 The use of STAB as a long-term manufacturing route was not appealing for several reasons including handling, dispensing and storage of STAB, poor atom economy, and hydrogen evolution during reaction and workup. The Pt/C method was developed as a greener and more efficient method to accomplish this transformation. Indeed this approach does hit on several green chemistry principals4 including the © XXXX American Chemical Society

Received: April 23, 2016

A

DOI: 10.1021/acs.oprd.6b00148 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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Scheme 1. Synthesis of Evacetrapib Drug Substance via STAB or Pt/C Processes

Scheme 2. Background Reduction and Formation of cis-Impurity 8

bulk catalyst. This scenario is not viable in flow, where the stability of the fixed bed over time is essential to reaction performance. Attempts were made to modify the existing Pt/C chemistry such that it could be run in flow; however, these efforts did not deliver acceptable results. Low conversion and high levels of the cis impurity 8 were consistently observed in flow. Low conversion was associated with high background reduction of aldehyde 5 to form alcohol 10 (Scheme 2). The cis impurity (8) was formed as a result of epimerization of 5 to cisaldehyde 7 which reacts competitively in step 2, an issue observed in all step 2 methods studied. The control of cisimpurity 8 was essential since this material is converted in step 3 to the corresponding cis-acid 9, an impurity in the API. An inprocess target of >99% conversion with 98 >98 >98 >98 >99

99:1 9:1 98:1 35:1 >100:1

1000

400

>99

94:1

process and to a lesser extent in the STAB process as well. Under well controlled, inert workup conditions this impurity does not form at an appreciably high level, but in screening at laboratory scale this impurity forms at higher level as seen in the tables.13 Iminium 11 can open to amino aldehyde 12, which is subject to further oligomerization and degradation. Fortunately, these impurities are well-rejected in the crystallization of 6, but they do impact yield. A positive pressure effect had been seen in an early screen so this was further examined along with reaction temperature (Table 2). The data showed that pressure was indeed a positive

6:8

Table 2. Screen of Pressure and Temperature

phosphine ligands, which are typically used to enhance reactivity and selectivity and stabilize the metal, inhibited the reaction (entry 1).10 In control reactions (entry 2) without a ligand, very good reactivity and selectivity were observed, and further work was conducted using [Ir(COD)Cl]2 as the catalyst of choice.11 Toluene was initially examined as the solvent since this had previously been used to form aldehyde 5 from bisulfite adduct 4 (Scheme 1). When the S/C was increased 5×, high conversion could still be maintained through increased hydrogen pressure (entry 3). However, this also resulted in a 10× reduction in trans:cis selectivity. A solvent change to THF (entries 4 and 5) did allow for better results, but at a practical catalyst loading (S/C 1000; entry 5) the selectivity was not acceptable. Building off information from the Pt/C batch chemistry, water and acetic acid were added as additives. This was extremely helpful as full conversion and excellent trans:cis selectivity could be achieved at S/C 500 (entry 6) and acceptable selectivity could be achieved at S/C 1000 (entry 7). It is important to note that trans:cis selectivity is a crude marker for the reaction rate. In slower reactions increased amounts of cis aldehyde 7 form over time, resulting in increased cis impurity 8. Importantly, trans product 6 does not epimerize to give 8 under reaction conditions. The quality of the starting bisulfite adduct 4 also played a role, and some variability was also observed in early development as a result. The screening results above served as directional guidance for more detailed development work. The screening revealed that there was a significant pressure effect upon the reaction, but the equipment used in the screening could not operate above 400 psig. Increased understanding of the low level impurities formed in the reaction allowed for a more complete understanding of reaction performance. These are captured largely as “other” in the following tables; however, iminium

entry

T (°C)

H2 (psig)

3 (%)

6 (%)

8 (%)

11 (%)

other (%)

1 2 3 4 5 6a

25 25 25 15 5 25

400 600 800 400 400 400

0.07 0.11 0.04 0.09 0.08 0.94

97.46 97.37 98.37 96.42 95.97 97.21

1.04 0.74 0.64 1.16 1.6 0.81

0.81 1.18 0.36 1.75 1.8 0.57

0.62 0.6 0.59 0.58 0.55 0.47

a

1.4 equiv of 5 was used.

influence, resulting in a steady decrease in 8 (entries 1−3). The full benefit of this trend could not be determined due to equipment pressure limitations. The data also indicated that decreasing the temperature from 25 to 5 °C led to slower rates and higher cis impurity 8. Finally entry 6 showed that decreasing aldehyde equivalents down to 1.4 led to slower reaction rate (entry 6 vs entry 1). The use of 1.4 equiv of 5 was important since that was the stoichiometry used in the STAB process and higher levels would impact the economics. If the Ir process was going to be cost-competitive, these lower amounts needed to be used. The amount of time between adding AcOH to the reaction and the timing of hydrogen introduction was important because aldehyde epimerization is accelerated in the presence of both amine and acetic acid (Table 3). As expected, increased isomerization was observed with increased mixing time (entries 5 and 6). Control of addition time during scale up is something difficult to do in batch since addition times increase as scale increases. In continuous processing, however, the mixing times of a specific feed can be maintained from research to manufacturing scale easily. Increasing the amount of water C



Article

of the conversion trends (Figure 1). The initial rates of the reactions shown in Figure 1 do show the positive impact on pressure; however, these reactions all failed to go to completion suggesting some type of deactivation or change in reaction mechanism. While the batch Parr scale up efforts did not exactly replicate the batch screening results (Table 1, Table 2, Table 3), modeling the initial reaction rates in the Parr reactor provided an estimated reaction rate to base the residence time (τ14) on in the continuous plug flow reactor (PFR) system. First-Generation Continuous Runs. This chemistry was intended for scale-up in a continuous reactor from the beginning, but most of the design and development was done in batch mode. Throughout development batch reactions were used for determining reaction rate measurements, screenings for solvent, reagent, catalyst, and ligand, impact of order of addition, kinetics of secondary reactions with respect to impurity profile, impact of temperature, pressure, and stoichiometry on rate and impurities, impact of inerting, materials of construction, effect of mixing rate, and reaction safety testing. There are instances15 where some of these items could be done in flow, in some cases faster, but for vapor liquid reactions of this type batch tools are effective to design and develop for flow. Reactor Design. Previously we scaled up an asymmetric hydrogenation in plug flow reactors (PFRs) that were a coiled tube design (Figure 2A).5a However, for this homogeneous vapor−liquid reaction, a pipes-in-series style continuous reactor was used (Figure 2B). The coiled tube PFR had been used with great success on other projects, but this design is limited to ∼150 L because it is difficult to construct larger coiled tube reactors and the agitated constant temperature baths for submerging the coiled tubes. Bending of tubing larger than 3/ 4″ diameter is also difficult. This volume limitation becomes an issue with high volume products with longer residence times.18 A crude schematic of the pipes-in-series reactor is shown below in Figure 3.16 Vapor and liquid travel through the reactor concurrently, up through the larger diameter pipes and down through the smaller diameter downflow tubes. There are two distinct flow regimes in this design. Vapor and liquid first enter the bottom of the first vertical upflow pipe. The linear velocity of the vapor in this regime is significantly faster than that of the liquid. This allows the vapor to bubble through the solution and gives flexibility in the hydrogen flow rate used in the process. As the liquid and vapor reach the top of the vertical pipe, it transitions into a much smaller diameter downflow tube through which liquid and vapor travel down to the bottom of the next pipe in series. In this regime the flow is segmented, and the linear velocities of the vapor and liquid are approximately equal. This sequence is repeated for the specified number of pipes prior to exiting the reactor. The vapor/liquid mass transfer rate is higher in the small diameter downflow tubes than in the upflow bubble pipes.17 Another reason why the downflow tubes are small diameter is to minimize surging. The larger the number of pipes in series, the lower the overall reactor axial dispersion number and the higher the overall vapor/liquid mass transfer. At the reactor outlet the pressure will be reduced first via a diaphragm style back pressure regulator; then the pressure will be further reduced to atmospheric through the vapor liquid separator. The vapor liquid separator consists of expansion chambers in series and a continuous stirred tank reactor (CSTR) stripping vessel. The expansion chambers in series function to step down the pressure, separate vapor from liquid, and strip H2 gas using N2

Table 3. Screen of Water Stoichiometry and Premixing Time

entry

water (μL)

time (min)

3 (%)

6 (%)

8 (%)

11 (%)

other (%)

1 2 3 4 5 6

55 110 220 330 110 110

8 8 8 8 23 60

0 0 0.05 0.03 0.01 0.01

98.34 98.91 98.91 98.89 98.8 98.58

1.08 0.44 0.38 0.41 0.59 0.77

0.3 0.38 0.35 0.37 0.31 0.36

0.28 0.27 0.31 0.3 0.29 0.28

from 0.35 volumes to 0.7 volumes based on 3 improved the selectivity, but increasing to 1.05 volumes gave no further improvement (entries 1−4). The amount of water could be limited by the solubility in THF at the high end. In all of the screens up to this point aldehyde 5 was prepared as a solution in either toluene or 2-MeTHF; then the solvent was removed and THF was added for the screen. This is not practical on scale and was a potential source of variability in the aldehyde during screening. The next series of reactions probed the effect of various levels of 2-MeTHF. A process would need to be developed such that the 5 solution from step 2a could be used directly in step 2b without solvent exchange. The data indicated that about 20% of 2-MeTHF could be tolerated in the reaction. This data would later influence the step 2a conditions. A second aspect to this screen was a brief probe of acetic acid stoichiometry (Table 4, entries 7 and 8). Increasing from 2 to 3 equiv led to an increase in 8 (0.52 → 0.82%) content, while decreasing to 1.5 equiv slightly reduced the 8 from 0.52% to 0.45%. Table 4. Reaction Tolerance to 2-MeTHF and HOAc Content

entry % 2-MeTHF 1 2 3 4 5 6 7 8

100 0 20 40 60 80 0 0

ACOH (equiv)

3 (%)

6 (%)

8 (%)

11 (%)

other (%)

2 2 2 2 2 2 1.5 3

0.01 0.01 0 0.02 0 0.01 0.03 0.01

97.59 98.41 98.57 98.29 98.12 97.95 98.77 98.28

1.48 0.52 0.58 0.83 0.92 1.08 0.45 0.82

0.53 0.78 0.54 0.52 0.59 0.6 0.5 0.63

0.39 0.28 0.31 0.34 0.37 0.36 0.25 0.26

Once conditions were refined using small scale screening tools (∼300 mg of amine per reaction), larger batch Parr reactors were used to gain experience at increased scale (gram scale) as well as increased pressure ranges. Some variability was observed during scale up resulting in stalled reactions which was difficult to understand. Various cleaning efforts did improve the following runs; however, none of the scale up runs went to completion as quickly as those run at small screening scale. Hydrogen pressures of 400, 1000, and 1675 psig were examined, and the following figure contains the rate information obtained from these runs along with a model fit D



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Figure 1. Step 2b initial Parr rate information.

high anticipated demand for this product, the production scale reactor could be on the order of 1000 L. This reactor type could be practically and economically18 scaled from research to production scale, while maintaining the same temperature (−25−125 °C) and pressure (>80 Barg) capabilities. This enables high pressure vapor−liquid reactions with τ on the order of 4−16 h in commercial manufacturing of pharmaceuticals. 3. The vertical bubble flow pipes in series reactors have higher vapor liquid mass transfer rates for the same H2 equivalents used, because mass transfer rates are higher in the downflow tubes than in coiled tube reactors with larger diameter tubing. A description of all seven pipes-in-series continuous reactors used in this work along with the main design criteria can be found in the Supporting Information. A separate manuscript describes the engineering development of this new reactor class16 along with a third manuscript describing development of the smallest research scale version of this reactor.19 First-Generation Continuous Run in Pipes in a Series Reactor. Research scale versions of the reactor described in Figure 3 were used in all research scale flow hydrogenations. These all utilized the same design which used bubble flow and segmented flow regimes. The first reactor was 412 mL and consisted of 15 vertical stainless steel pipes connected in series by smaller diameter downflow tubes (see Supporting Information). The block flow diagram for this reaction setup is shown in Figure 4. In this experiment hydrogen combined in flow with a mixture of aldehyde and amine followed by catalyst then finally by acetic acid to minimize epimerization. Various step changes (Table 5) were planned after steady state was established. Both residence time and catalyst loading were investigated during the course of the run. Under initial conditions (A) the reaction conversion was high (∼98%), which was unexpected for this residence time. The reactor was

Figure 2. Coiled tube (A) and pipes-in-series (B) design PFR reactors.

and pressure cycling. Hydrogen is removed to a safe level (150 L) reactor volumes. Due to the E



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Figure 3. Pipes-in-series reactor design schematic.

Figure 4. Initial setup for 412 and 48 mL pipes-in-series reactors.

One of the initial theories was reactor contamination, and this led to a second experiment in a new 48 mL reaction under identical start-up conditions. The reaction profile for this 100 h run was variable, and overall performance was worse than in the 412 mL reactor. Conversion never approached the 98% observed previously, and a true state of control was never achieved over the 100 h run time. At this point it became apparent that the poor performance of the reaction was not due to contamination from a previous run but rather a fundamental problem with the chemistry. Both the 48 mL reactor and the 412 mL reactors were disassembled and visually inspected. Both showed a fine black coating within the reactor tubes and fittings. This coating was most prominent in the feed lines from catalyst addition up to the reactor and in the initial reactor tubes. A slight coating was still visible in the final reactor tube; however, the initial tube visibly had the highest levels of coating. It was reasonable to suspect that this material was Ir(0) which formed under the reaction conditions and deposited on the metal surface. It was not clear at that time why the precipitate was forming, but order of addition was something that needed to be examined. In a concurrent effort to understand the reaction mechanism and kinetics, experiments were being conducted using flow NMR.20 Using flow NMR as a tool for watching and characterizing the reaction provided an analytically unique

Table 5. Step Changes during First Step 2b Flow Run in 412 mL Pipes-in-Series PFR

conditionsa

S/C

residence time (h)

3 (%)

8 (%)

6 (%)

11 (%)

A B C D

500 500 1000 500

4 >18 6 6

2.09 0.06 14.16 19.82

1.52 1.32 1.02 0.34

94.43 97.26 83.73 78.26

1.10 0.89 0.64 0.60

a

13 equiv of H2 were used in this experiment.

held overnight such that the residence time was effectively 18 h (B) resulting in nearly full conversion. Halfway through the run the conversion was at 86% with a 1000:1 S/C (C). Increasing the catalyst loading back to S/C 500 (D) did not increase conversion as was expected, but rather decreased conversion of 80%. This was confusing since these conditions should have led to results comparable to condition A. The origin of the problem was not entirely clear at this time as both reactor and feed solutions were suspects for the failure. Overall, however, the data were encouraging as high conversion was maintained for 20+ hours in these experiments. F



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Figure 5. First flow NMR run for step 2b.

During the order of addition experiments between the catalyst and H2 charges, the NMR flow tube had become coated with a black residue (Figure 6). This coating on the interior of

way to monitor all components in the reaction at the same time without perturbing the reaction. All NMR spectra are collected at pressure in a closed loop system. In this case the NMR also allowed simultaneous observation and rates of formation for all of the key components of the reaction. This included aldehyde 5, amine 3, hydrogen, product 6, and alcohol 10. Since the aldehyde, alcohol, and hydrogen are all species that lack a UV chromaphore, 1H NMR represents a superior analytical technique for reaction understanding. While each of these components can be independently measured by other methods (HPLC, GC, and gas uptake) it is unlikely that all will be online for a single experiment. Additionally, the NMR is a direct measurement in real time, unlike HPLC or GC. This method was leveraged in this project extensively and helped promote the reaction understanding and focus efforts. In the initial flow NMR run, the Parr reactor was started under the standard batch conditions wherein the aldehyde and amine were added along with solvent, followed by HOAc/water and then catalyst. This was typically done in the glovebox under inert conditions. The reactor was then transported to the NMR lab where hydrogen (100 psig) was added. The time course data for this NMR run is shown in Figure 5. The reaction proceeded very slowly after H2 introduction, and after approximately 2 h a second catalyst charge was added (see annotation in Figure 5). An important point to note is that, although the system was allowed to depressurize, dissolved H2 still remained in solution as indicated by the resonance in the 1H NMR spectrum. Immediately following the second charge, the formation of desired product occurred at a much faster rate than was previously observed, and the reaction proceeded to near completion approximately 6 h. It was clear that the initial charge of catalyst was inactive and only after second charge was any product observed. To eliminate the possibility of a setup error, this same experiment was repeated which confirmed the result. Based on these observations, it appeared as though catalyst was deactivating and should be introduced last with H2.

Figure 6. Flow NMR tubes used (A) and new (B).

the tube was not able to be cleaned with simple solvent flushes. This is consistent with what was observed previously in some batch Parr experiments and in the initial flow runs in PFRs. A reasonable hypothesis was that this was Ir(0) and this was responsible for the observed rapid reduction of aldehyde starting material.21 A series of experiments were conducted to test this theory. First, a control flow NMR run was conducted using a new NMR tube without any catalyst under otherwise standard conditions. NMR spectra were taken every 5 min, and the flow was stopped for the duration of this experiment. There was some initial aldehyde reduction in this experiment, but levels of the alcohol remained constant throughout the run and did not increase even with persistent levels of hydrogen and aldehyde. This small amount of aldehyde reduction is believed to be associated with Ir(0) build up either in the feed lines or in the Parr reactor.22 Iridium appears to deposit strongly to metal G



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Figure 7. Graphical results from the flow run with a catalyst added last in the 412 mL reactor.23

Table 6. Results from the Flow Run 412 mL Reactor with the Catalyst Added Last entry

aldehyde (equiv)

τ (h)

pressure (psig)

6 (%)

3 (%)

8 (%)

excess equiv 5

excess equiv 10

1 2 3 4 5 6

1.75 2.5 2.5 1.75 1.75 1.75

8 4 2 2 4 2

400 400 400 400 400 1000

94.52 98.16 96.45 94.16 94.86 92.28

3.81 0.74 2.70 4.69 4.21 7.01

1.08 0.68 0.48 0.37 0.55 0.25

trace 0.27 0.53 ND 0.06 0.16

0.63 0.92 0.61 ND 0.58 0.54

surfaces, with a dependence on surface finish. Once plated on the surface, Ir is extremely difficult to clean while accumulation on glass is both less prominent and much easier to clean. This observation helped explain why the small scale screening runs in glass lined tubes did not match scale-up reactions in Parr vessels. In the second portion of this experiment, the new NMR tube was removed and the coated NMR tube inserted. The flow was then turned on and allowed to circulate for several minutes to ensure that new material from the reactor had entered the flow tube. The flow was then stopped again, and proton spectra were again collected every 1 min. The results dramatically differed as the alcohol formed rapidly in conjunction with a decrease in the dissolved H2 levels. The reduction of aldehyde ceased with the disappearance of the dissolved H2. In a flow system where H2 is constantly replenished, the aldehyde could be steadily consumed and short the reaction. Once the proper order of addition was determined, another reaction was done in flow with the following addition order: amine 3, aldehyde 5, water/HOAc, hydrogen, and finally a catalyst. This was done in flow by using a series of mixing tees and specific lengths of 0.559 mm ID tubing between the tees for sufficient diffusion mixing time. Also, with the understanding that Ir plating could competitively reduce the aldehyde, GC was used to monitor the levels of these at each steady state. Figure 7 shows the graphical data and where specific conditions were varied. The specific conditions along

with the impurity profile for each steady state are shown in Table 6. Overall this experiment was much better than previous runs, yielding the highest steady state conversion up to that point in development (>99% conversion). There are several key observations from this run that informed the future experiments. First, under condition 1, steady state was achieved at 96% conversion; however, GC indicated that there was no excess aldehyde at the end of the reaction. This indicated that a significant amount of background reduction was occurring which is not unexpected since this was the same 412 mL reactor used in the previous two flow runs and likely coated with iridium. In the second set of conditions the aldehyde equivalents were increased to 2.5, and the residence time was halved to 4 h. Gratifyingly this results in >99% conversion, and excess aldehyde was detected by GC at the outlet of the reactor. Halving the residence time to 2 h (condition 3) showed some dip in conversion but also an increase in unreacted aldehyde indicating that the ideal residence time was between 2 and 4 h for these conditions. Reducing the aldehyde equivalents back down to 1.75 equiv resulted in lower conversion and no aldehyde at the outlet. Increasing pressure did not improve conversion which was concerning and suggested that the reactor was becoming more plated with Ir over time. Trying to replicate this in the 48 mL reactor, pipes in series reactor were not successful as low conversion, and the high background aldehyde reduction was observed. The results from the batch and flow run with optimized order of addition were H



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and LiI additives were effective at preventing formation of black residues, but the reaction rate was significantly reduced resulting higher levels of cis impurity 8. In the case of TBAI, incomplete conversion was observed even after reacting under 400 psig of hydrogen for 20 h. Examination of equivalents revealed that TBAI appeared to be a much more effective reagent than LiI. When 0.5 equiv of TBAI was added relative to iridium, the reaction went to completion, and cis isomer 8 was just 0.64% by HPLC. In contrast 2.5 equiv of LiI was required to afford similar catalyst stability, and this resulted in almost twice the level of 8. All of the screening discussed above was performed in glass Endeavor reactors. Previous experience with batch and continuous runs in stainless steel, prior to the incorporation of TBAI, highlighted the propensity for the Ir to plate on stainless surfaces when compared to glass. With this in mind the next important step was to examine the TBAI conditions (0.5 equiv relative to Ir) in a stainless Parr reactor prior to running in a pipes in series reactor. Table 8 describes a series of step 2 reactions that were all conducted in a 25 mL stainless steel Parr reactor. The first reaction (Table 8, entry 1) resulted in good conversion and an acceptable crude impurity profile with respect to 8. The kinetics with TBAI are slower than without the additive; however, there was no evidence of plating or black particles at the end of the reaction. A key aspect to a successful process would be the ability to repeat the chemistry in this same reactor with only solvent rinsing as a cleanout. The repeat reaction in the same reactor was important information for future flow runs, and we were pleased to observe equivalent results (entry 2). Decreasing the catalyst loading to the target level of S/C 1000 led to slower kinetics but an acceptable final product profile. Further increasing the S/C to 1500 (entry 4) led to incomplete conversion even after 27 h. The conditions shown in entry 5 replicated those in entry 3 except with reduced 5 (1.75 → 1.20 equiv). This resulted in ∼99% conversion after 19 h but was slower than the conditions with excess aldehyde as highlighted by increased 8 and residual 3. Previous screening had shown the benefit of acetic acid on rate, but acetic acid also contributes to epimerization of the aldehyde. Entry 6 tested the importance of acetic acid and once again verified that substoichiometric levels led to slow

encouraging yet not reproducible. Based on this data, the prospect of running this process for long durations at steady state without chemistry modification were low. The tendencies toward formation of Ir(0) under reaction conditions led the team to conclude that this was not scalable in its current state. Additive Screening. Based on the previous results, it was clear that there needed to be a chemistry advance to enable the flow step 2 process. The tendency of the Ir(I) catalysts to form Ir(0) under hydrogenation conditions suggested that some type of stabilization of the metal would be required. The challenge with this approach was that the traditional phosphine ligands had already been shown to suppress the desired reaction. This limited the scope of the additive one could choose. Literature precedent suggested that additives could help stabilize the [IrClCOD]2 catalyst system once the COD ligands are quickly reduced24 to avoid the formation of Ir(0) species in the presence of hydrogen.25 Among the options investigated were alternative phosphine-based ligands and iodide sources. All of the phosphine-based additives that were investigated shut down the reaction almost entirely under the conditions that were investigated. The uses of lithium iodide and tetrabutylammonium iodide (TBAI) were more promising. A screen comparing these two reagents and then examining equivalents of these additives revealed that TBAI provided a beneficial stabilization effect on the catalyst system (Table 7). Both TBAI Table 7. Screening Iodide Equivalents entry

additive a

1 2

control control without degassing 0.25 equiv LiI/Ir 0.5 equiv LiI/Ir 2.5 equiv LiI/Ir 5 equiv LiI/Ir 0.25 equiv TBAI/Ir 0.5 equiv TBAI/Ir 2.5 equiv TBAI/Ir 5 equiv TBAI/Ir

3 4 5 6 7 8 9 10

observation

3

6

8

ND 38.75

98.52 54.79

0.36 5.64

black ring black ring

ND ND ND 0.18 ND ND ND 1.98

98.54 98.78 98.58 97.73 98.57 98.71 98.5 94.3

0.41 0.55 1.14 1.46 0.45 0.64 1.15 3.12

black ring faint black ring no black solids no black solids no black solids no black solids no black solids no black solids

a

5 (1.4 equiv), 3 (300 mg), [Ir(COD)Cl] (S/C 500), THF/2MeTHF, HOAc (2eq), water (0.7%), 20 h, RT.

Table 8. Summary of Step 2 Screening Conditions in the 25 mL Parr Reactor

entry 1 2 3 4 5 6 7 8 9 a

H2 (PSIG) 400 400 400 400 400 400 1000 1000 400

S/C

time (hr)

HOAc (equiv)

5 (equiv)

3 (%)

11 (%)

6 (%)

500 500 1000 1500 1000 1000 1000 1000 1000

a

2 2 2 2 2 0.1 0.1 2 2

1.75 1.75 1.75 1.75 1.20 1.20 1.20 1.20 1.20

0.63 0.15 0.03 7.22 1.16 35.63 49.54 12.3 14.19

1.12 0.81 1.09 2.13 1.22 0.07 0.04 0.47 0.87

96.69 96.47 98.39 90.26 97.30 63.85 49.56 86.51 84.46

6 6.4 18 27 19 23 22.5 22.5 19

After 22 h this reaction contained just 0.05% 3 and >98% 6. The 6 h time data is shown for direct comparison to the repeat run in entry 2. I



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Figure 8. TBAI titration experiment by NMR.

Figure 9. Assignment of anionic Ir(I) complexes.

reaction rate. The final two entries examined increased hydrogen pressure. In entry 7 increased pressure was used in an attempt to offset the reduced rate with 0.1 equiv of acetic acid. This did not work, in fact the rate appeared to be compromised. Entry 8 is a repeat of entry 5, but at 1000 psig hydrogen. Once again conversion was low suggesting that a plating event may have taken place under these more forcing conditions. An examination of the crude reaction mixture showed no aldehyde remained, suggesting the high pressure had decomposed the catalyst resulting in the plated Ir. Returning to the original conditions in this now plated reactor showed significant aldehyde reduction (entry 9). Overall, this set demonstrated reproducibility in a Parr reactor for the first time. It also provided good understanding of the stability the TBAI catalyst system especially as it relates to sensitivity to increased hydrogen pressure. Increasing the TBAI to 1 equiv with respect to iridium provided additional protection against iridium plating, but at the cost of slightly reduced rate. Mechanism. There is a distinct benefit of using TBAI to prevent plating of Ir(0), but it was not clear how TBAI was

functioning with respect to the catalyst. To help understand this, a TBAI titration experiment was done in the NMR (Figure 8). In Figure 8, TBAI is added to a solution of [Ir(COD)Cl]2 in THF. As TBAI is added, the 1H NMR spectrum changes up to the point where equimolar TBAI is present with respect to iridium. No changes are observed beyond this point. An analysis of region between 3.2 and 4.2 ppm resulted in the identification of three new anionic iridium(I) complexes (Figure 9). These were identified by a combination of NMR (1H and HSQC-TOCSY) and mass spectroscopy. Of these three anionic complexes only the dichloro species has been reported in the literature.26 The presence of TBAI appears to hold the Ir(I) in a more stable anionic form which is less prone to degradation under reaction conditions. This is still an equilibrium process so the desired chemistry can take place through a neutral Ir(I) species. TBAI functions like a weakly coordinating ligand which does attenuate the reactivity, but not such that the desired reaction is compromised. If a large excess of TBAI were used this would push the equilibrium further toward the anionic species and J



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Figure 10. Possible catalytic cycle.

test that can differentiate the two.29 This reaction does display some of the indicators such as minimal ligand effects, metallic precipitate,30 and the use of special additives.31 However, it does not require forcing conditions such as high temperature or display sigmoidal kinetics which are also indicators of heterogeneous processes. Interestingly reaction filtrates held under inert conditions for over a month retain catalytic activity and remain as clear solutions. This indicates that the active catalyst is appreciably stable. The exact mechanism is not clear, and further work is needed to elucidate the nature of the active catalyst. Testing New Step 2 Conditions with TBAI in PFRs. The modified reaction conditions32 were retested in a new 48 mL reactor.33 The new 48 mL reactor was constructed identical to the first with 25 small vertical pipes in series. Prior to the main reaction, a background aldehyde test (no amine present) was conducted, and minimal aldehyde reduction was observed. The reaction was carried out for 5 days before being shut down for the weekend. Four different conditions were tested through deliberate step changes over the course of this run, and the associated steady-state results are summarized in Table 9.

slow the reaction further. This is evident in the additive screening data shown in Table 7. A possible homogeneous catalytic cycle is shown below in Figure 10. Recognize that the COD group in the precatalyst is reduced and unspecified ligands (L) are used generically. Additionally the metal may also coordinate to solvent or other substrates (S) during the catalytic cycle. Figure 10 shows a mechanistic possibility via direct reduction of the aminol (14) which is assisted by the acetic acid. There is also an option where the reduction is via the iminium (not pictured), but this would require the Ir-iminium complex which seems less likely. Since these intermediates cannot be easily observed by NMR we can only speculate on the which may be operating. There may also be crossover between the two mechanisms, and both may be participating. It is also not clear what other compounds may be stabilizing the metal center during the catalytic cycle once the COD groups are reduced. Certainly TBAI is a possibility, but the reaction still does function without this additive. If aldehyde 5 is left out of the reaction, immediate iridium plating is observed (black suspension); however, under reaction conditions where 5 is present, iridium(0) formation is greatly reduced. In control reactions without amine 3 formation, black heterogeneous mixtures were not observed. This suggests that 5 plays a role in the stability of the Ir species in the mechanism. The coordination of carbonyl compounds to metal centers is wellestablished. The coordination of aldehydes to metal centers is known27 and may take the form of either η1 (16) or η2 complexes.28 Metal coordination (18) with the hydrated aldehyde (13) remains a possibility given that 13 is observed by 1H NMR. Coordination could also take place on the ester (17), the most Lewis basic site on the molecule.

Table 9. Average Steady-State Results and Conditions for 48 mL Reactor Run entrya

S:C

H2 (psig)

5 (equiv)

3 (%)

8 (%)

6 (%)

5 (equiv)

1 2 3 4

500 1000 1000 1000

400 400 400 750

1.75 1.87 1.4 1.4

0.21 0.80 5.61 0.53

1.54 1.92 2.13 1.94

98.00 97.03 91.98 97.24

0.7 0.8 0.37 0.37

a

Acid premix time 20 min.

The first step change was a reduction in catalyst loading (S/ C 1000:1), and this had a slight impact on conversion. Dropping the aldehyde loading to 1.4 equiv resulted in a significant decrease in rate (94.5% conversion). To compensate for this decreased rate, the pressure was increased to 750 psig which improved rate back to the level seen in condition 2 and justified increasing the baseline conditions to 750 psig. The overall high content of cis impurity 8 can be attributed to a long premix time (20 min) with acetic acid. A 300 h run was then conducted in the same 48 mL reactor with comparable results.

The case for a homogeneous mechanism has been suggested; however in ligandless systems under reducing conditions, it is possible that the primary reaction could be promoted heterogeneously through Ir(0) nanoparticles or colloids. Distinguishing heterogeneous from homogeneous reaction mechanisms is not straightforward, and there is no singular K



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Both of these flow runs used 0.5 equiv of TBAI with respect to iridium(I) monomer as these results worked well in batch screening and scale up experiments. While these flow runs delivered excellent results at up to 300 h of run time, there was some evidence of iridium plating when the fittings of the reactor were examined. When TBAI was introduced as a catalyst additive, flow runs showed a visible decrease in the amount of black coating observed in the reactor. This can be clearly seen in Figure 11

transitions were always excellent when the background test was done first. However, when starting a reaction with a solvent filled reactor (no background test) there was evidence of Ir plating and nonideal start-up transitions. In this case all pumps were being started simultaneously which led to segments of solution that contained just catalyst, acid, and hydrogen. This results in a portion of time during start-up (T1 + T2 + T3 in Figure 12) where catalyst and hydrogen mix without any aldehyde or amine. This results in plating of iridium during the start-up transition which is halted only after the aldehyde and amine solutions reach the catalyst mixing tee. This scenario results in the poor start-up transition; however, given time the system recovers and reaches the desired reaction profile. In earlier runs it was speculated that elevated levels of the cis impurity 8 in the product could be attributed to epimerization of aldehyde in the reaction feeds. Two main parameters were known to effect cis levels in the product, both the mixing time of the 3 and 5 along with the mixing time of that stream with the H2O/AcOH stream. To determine if this would have a major impact on the impurity profile of the continuous product, each of these mixing times were shortened by replacing the mixing loop with a smaller volume loop (Table 10).

Figure 11. Post-reaction pictures of fittings for 0.5 and 1 equiv of TBAI.

Table 10. Impact of Feed Mixing Time on the Product Profile

where discoloration is seen in pipe 1 of the 48 mL reactor. Iridium coating was not seen in the downstream pipes beyond pipe 2. The same coating effect is also shown for the 412 mL reactor when 0.5 equiv of TBAI is used. This gradual accumulation of iridium over time could compromise the step during long duration runs that would be expected in commercial manufacturing. After increasing the TBAI to 1 equiv there was no visible coating on the initial reactor tube as shown in the 77 mL reactor (far right picture). The affinity for coating only the initial tubes allowed for easy replacement of only a small portion of the reactor prior to development of a cleaning method. Risk mitigation for a scale-up reactor for future use could include a bypass of an initial section of tubes such that if a plating incident occurred the contaminated portion of the reactor could be taken offline. A second important observation in these experiments was the timing of the feed pumps. In the first few flow runs with TBAI, a background test was always conducted such that the reactor started up with all components except for the amine. Start-up

entry

T1 mixing time (min)

T2 mixing time (min)

S/C

3 (%)

8 (%)

6 (%)

1 2 3 4

30.6 30.6 1.1 1.1

33.0 5.8 5.8 5.8

1000 1000 1000 500

0.91 0.13 98% liquid filled to minimize the quantity of hazardous gas in the vessel. It was designed for H2 stripping at the reactor outlet, so that liquid flowing into the product collection tank had almost no hydrogen. Hydrogen stripping was accomplished in the VLS (vapor−liquid separation) expansion chambers in series at the reactor outlet separated by automated block valves. In these chambers, the reaction product solution and excess gas were safely depressurized to atmospheric pressure, and the automated sequence of the chambers effectively removed H2 by pressure cycles and purges with nitrogen. A detailed description of how the expansion chambers in series operated and how the pressure was controlled is given in the Supporting Information for another paper.16 The reactor was designed with the option of operating outside the manufacturing building, so that H2 feed, reactor, and H2 stripping operations would not be inside the building. A picture of the shell is in Figure 18, along with a picture of the bottom of the pipes and tubing connectors. A picture of the reactor mounted in place outside the 250 gallon processing area is in Figure 19. While continuous reaction has safety advantages compared to batch for high pressure hydrogenations, it is important to remember the safety precautions that pertain to continuous processes. A summary of key safety guidelines for continuous processes and applies to all scales from research and development to manufacturing can be reviewed in the Supporting Information. Solution Feed Stability. Critical questions that must be answered prior to running a continuous process are the stability of the solution feeds and understanding of stable hold points throughout the process. The stability of the primary solution feeds was excellent as indicated in Table 14. The ability to mix feeds is also critical as it could simplify equipment require-

Manual handling of STAB for the batch process increases safety risk and potential operator exposure to a known water reactive and irritant substance. For a single 2000 gallon batch reaction (75% liquid fill), 320 kg of STAB (up to 30 bags) is added to every reaction. Furthermore, this amount of STAB could liberate 3500 L of hydrogen at STP and has the potential to generate in excess of 140 psig in the batch reactor. The use of STAB also impacts the environmental profile since 99.9% of the hydrogen used does not enter the manufacturing building. All feed vessels were paired in a duty/ standby arrangement such that one could be refilled, while the other delivered solution and maintained a continuous supply to the reactor. Bulk feed solutions for aldehyde 5 and amine 3 were prepared in a 2000 gallon batch tank building and transported via intermediate bulk containers (IBCs) as needed for refilling tanks in the 250 gallon tank building. Collection of reaction solution was also achieved in a duty/standby arrangement such that one tank could be emptied while the other collected solution and maintain continuous collection from the reactor. Online HPLC data was collected on the product solution stream before it reached the collection tank. The collection tanks were capable of collecting 24 h of continuous reactor flow for the campaign. Once a product collection tank was filled, the collection was switched to the R



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feeds were kept separated to maintain flexibility in the process. The downside to that approach is that additional feeds add complexity to the process and the risk of equipment failure. In the case of evacetrapib step 2, the feeds were kept separate for this campaign. This was justified on the basis of epimerization risk when the amine and aldehyde are combined (entries 3, 4, 6). The aldehyde did show stability in the presence of acetic acid (entry 5), but this combination was not pursued in this campaign. The crude reaction solution stability is >1 month. If, however, the product solution is not kept inert, considerable oxidative degradation takes place leading to iminium 11 and then to other impurities. Analytical. The continuous process end of reaction was sampled between the VLS and the collection tank in the 250 gallon building via an automated quantitative sampling and dilution cart39 that pushed diluted product solution to an online HPLC. Online HPLC data were used to monitor the process, while offline samples from the homogeneous collection tank were tested for forward processing decisions. The lag time from the automated sampling to the time HPLC analysis was done was about 45 min; therefore, the online data was not instantaneous or real time but sufficient for this continuous section with 13.6 h τ. A detailed description of how the custom automated systems accomplish sampling, dilution, mixing, and transport to the online HPLC is given in the Supporting Information section of another paper.40 The trending from the online HPLC data could be used to make slight adjustments to flow rates within predefined ranges in the manufacturing ticket. The online HPLC data could also trigger additional offline testing such as GC samples for evaluation of aldehyde to alcohol ratio in the case of a process upset. The decision to sample from the collection tank was made to minimize the analytical burden of approving all online HPLC data. This decision comes with some risk since a failed in-process assay would have resulted in loss of the entire 24 h segment, 4% of the overall yield.41 A more conservative approach could have been chosen where a smaller surge vessel was used (less material at risk), but this would result in more offline analytical sampling. The allowable levels for starting material (NMT 10.0%) and the cis impurity (NMT 2.3%) also reduced the risk of failure due to reaction performance. These limits are a result of excellent rejection efficiency in the downstream workup and crystallization. The cumulative online HPLC data for in-process sampling, the forward processing samples, and the final analysis of the isolated solids will be discussed later in the campaign results section. The parallel 24 h collection tanks addressed the issue of diverting nonconforming material and minimizing the impact of such material on the larger product batch. If one of the 24 h collection tanks did not meet specification, then the plan was to transfer it to waste. Thus, from one point of view, all of the material from the continuous section was diverted to the parallel collection tanks, and only the material that met in process specifications was forward-processed, which was 100% of the material for the campaign. This was also a robust and reliable strategy for diverting nonconforming material if that situation arose. Start-up and Shutdown Transitions. Start-up and shutdown transitions involve portions of product solutions that are not at steady state with respect to concentration. For example, in start-up the reactor starts solvent filled. As the reaction solution progresses through the PFR, it pushes the solvent out of the reactor. In this transition from solvent to steady state product, the product concentration first emerges from the

Figure 18. Reactor shell (A) and pipes and tubing connectors (B).

Figure 19. Continuous reactor and infrastructure outside the processing module.

Table 14. Feed Solution Stability and Stable Hold Points entry 1 2

5 − feed solution 5 − feed solution

3

5 + 3 combined feed

4

5 + 3 combined feed

5

5 + HOAc + water combined feed 5 + 3 + HOAc + water combined feed 3 − feed solution [Ir(COD)Cl]2, TBAI feed solution crude product solution

6

7 8 9

a

potential combination or hold point

solvent

T (°C)

degassed 2-MeTHF degassed THF/2MeTHF (20%) nondegassed THF/ 2-MeTHF (40%)

0−5 rt

>5 months >4 months

rt

>25% cis aldehyde after 3 days 6.5% cis aldehyde after 6 days no isomerization in 48 ha 26% cis aldehyde after 65 ha

stability

degassed THF/2MeTHF (10%) THF

rt

THF

rt

THF (degassed) THF (degassed)

rt rt

>3 months >3 months

reaction composition (degassed)

rt

>1 month

rt

Based on NMR.

ments/manufacturing operations; thus, the stability of mixed solution feeds must be established. These stability studies help drive decisions on the frequency of feed makeup and also to determine the number of feeds. In many individual reaction S



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Figure 20. Online HPLC data for step 2.

Table 15. Residual Starting Amine 3 in 24 h Sections and Combined Batch Composites collection day starting material collection day starting material collection day starting material collection day starting material

3 (%) in 24 h tank 3 (%) in 24 h tank 3 (%) in 24 h tank 3 (%) in 24 h tank

1 1.90 7 0.12 13 0.23 19 0.21

2 0.08 8 0.20 14 0.19 20 0.27

3 0.10 9 0.20 15 0.15 21 0.23

4 0.08 10 0.17 16 0.11 22 0.16

5 0.10 11 0.16 17 0.16 23 0.14

6 0.09 12 0.22 18 0.23 24 0.33

combined 0.39 combined 0.18 combined 0.18 combined 0.22

input Batch 1 average (%) input Batch 2 average (%) input Batch 3 average (%) input Batch 4 average (%)

starting material present for “end of reaction material” inputted into Batch 1 was 0.39% and into Batch 4 was 0.22%, both far below the requirement of 10%, even though area % starting material was above 10% temporarily during the dilute startup transition (Table 15). This decision also led to slightly lower product concentrations in Batches 1 and 4. The additional dilution was inconsequential, required no modification to the batch workup, and did not impact product yield and quality. The campaign online HPLC monitoring data is shown below. Figure 20 exaggerates the impact of lower conversion during start-up and shutdown transitions because it shows area % rather than weight %. Although conversion is lower during these time periods, the actual weight % unreacted starting material in solution is low because of the dilution. Another reason why area % starting material was high during startup transition was because the catalyst flow was deliberately started several minutes later than the reagents. This was done to minimize the potential for Ir plating on the tubing walls during startup. Continuous Reductive Amination Campaign Analysis. Overall, the step 2b reaction ran for 24 consecutive days. The cumulative HPLC data is shown in Figure 21. The online

reactor dilute, and it reaches full strength over a time dictated by the extent of axial dispersion of the PFR. Likewise, during a shutdown transition from steady state product to solvent, the solvent pushes the reaction solution out of the reactor resulting in a drop in concentration that can be calculated if axial dispersion for the reactor is known. The start-up transition curve created from HPLC area % of product for the API6 manufacturing campaign are shown above (Figure 20). To minimize this transition time the PFR used in the campaign was designed for very low axial dispersion. The dispersion was measured from start-up transition campaign HPLC data, and the numerical model fit to the data gave D/μL = 0.0009, confirming that axial dispersion was very low. An isolated batch contains about 144 h of collected product. The F-curve transition is only 3.8 h (2:1 in favor of the aldehyde throughout. Since the reaction is essentially operating at 100% conversion, this represents the percentage of excess aldehyde (0.4 equiv) that has been reduced to alcohol.43 This does, however, warrant further investigation since increases in alcohol have correlated with iridium plating scenarios. Some plating was observed in the tubing leading into the first pipe, but no plating was observed in the first pipe or in any of the downflow tubes when they were examined with a borescope. A final point on the campaign relates to the response to the online HPLC data. In the case of residual amine starting material 3, high conversion was expected in this step (>99% step 2 product). While the process tolerance for residual amine was 10%, our lab experience suggested that if steady state conversion trended down below 99% there was a possible issue that could lead to a deviation if left unchecked. Before the campaign, predefined decision guidelines were developed to ensure a consistent response. The precampaign plan called for investigation of possible causes such as flow rate, pressure or other variations that could be confirmed with offline HPLC and GC data. If no obvious root cause existed, then the issue would be escalated. A full process stop for further investigation could be considered or parameter adjustments within predefined ranges for pump flows, pressure, and temperature. Adjustments within the acceptable operating process ranges allow for process corrections before the trend goes out of control. Process optimization due to new data can also be managed in this manner. Larger changes in conversion or trending below 90% would require a process stop, a full investigation and a deviation. These decisions were made by the responsible scientists and the process team in the manufacturing plant. While the conversion never dropped below 99.0% by online HPLC, the offline data from the 24 h collection tanks was the defining data supporting forward processing decisions and process optimization changes. Two times during the campaign, minor adjustments to the catalyst pump rate were made to achieve the target catalyst loading with a given feed tank concentration. A typical continuous processing question is whether or not a process must be at steady state to collect and forward process product. Overall, the process was in control and running as planned the entire campaign, and thus all the material was forward processed as planned. The transitions and the fluctuations during the campaign were not at steady state, but they were in control and within specification limits. A conclusion is that the continuous process did not need to be at a true steady state in order to forward process the product solution in GMP manufacturing. Furthermore, the instantaneous area % starting material did not need to be less than 10% during startup transition in order for the first 24 h batch collection tank to be less than 10%; therefore, the plan to forward process 100% of the material was justified.

Automated feedback control was heavily used in the manufacturing plant for the continuous process. This included feedback control based on mass flow, temperature, pressure, and liquid level measurements. Feedback control with online analytical was not necessary for this process but is expected to be beneficial and implemented in the future. Workup, Crystallization, and Isolation. Four workup, crystallization, and isolation batches were performed in 2000 gallon batch manufacture equipment. These unit operations performed very well overall despite some known variability due to the process, analytical assay, and equipment. As discussed above, batches 1 and 4 input from the continuous reactor were more dilute than steady state material available for batches 2 and 3. A standard charge quantity of 10% sodium carbonate was used for all four batches regardless of the concentration or amount of input “end of reaction” solution; this resulted in some variability on the levels of water in the carbonate washed “end of reaction” solution. An assay was used to estimate the amount of expected product and estimated distillation end point; assay variability from theoretical was up to 3.4%. Load cells were used on the 2000 gallon batch reactors to determine the distillation end point which have a ±50 kg tolerance; this is 3.2% considering a typical end point of 1550 kg. However, the process performed robustly, and the variability in the washed “end of reaction” solution and the distillation end point had very little impact on the crystallization performance. More careful control of the distillation end point and composition will be a future focus point. The process distillate can be recycled and used in the preparation of step 2a aldehyde process feed with appropriate solvent and water input adjustments to the step 2a aldehyde preparation. Stabilizer BHT will need to be added to this tetrahydrofuran recycle stream to maintain safety levels at 150−400 ppm. The crystalline product was dry after centrifugation as evident from the fast drying temperature profiles and the LOD measurement of centrifuge wet sample of batch 4 at 0.23% LOD (LOD specification LT 0.5%). Step 2 product was difficult to remove from the dryer as it blocked the chute to the bagging head and required nitrogen chute blows and vibration to get the bag off the product. The API 6 product has smaller particles than API 5. FBRM data shows that the cord length for the four batches was on average 34−38 μm during slurry feed circulation to the centrifuge. The smaller particle sizes may have contributed to difficulties with off loading the dryer. Overall, the centrifuge operation ran very smoothly, and high yields with high quality were achieved. However, control of the crystallization will require attention to avoid long cycle time for dryer discharge. Overall the campaign delivered 2054 kg of 6 over four batches in 95% yield (Table 17). All four batches of material were within the specification limits for all quality attributes. The yield of the first batch was somewhat lower due to a higher than expected heel in the filter and a small product slurry loss due to a clogged recirculation line during the crystallization process. W



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Figure 25. Representation of batch genealogy and boundaries for aldehyde 5 through the continuous system, all four batches.

Lot Genealogy/Traceability for the Step 2b Continuous Section. One of the important aspects of running a continuous process under GMP conditions is the clear determination of lot genealogy.44 Understanding lot genealogy is an expectation from regulatory agencies since this relates not just to traceability of individual lots of starting material but also to defining deviation boundaries. In the reductive amination reaction, four feed solutions (starting materials, reagents, and catalyst) were combined with hydrogen by continuously mixing together at the inlet of the plug-flow reactor as shown in the process flow diagram (Figure 17). Product (6) solution continuously exited the reactor and was accumulated in a collection tank. When the product collection tank was filled with the preplanned amount of material, product collection was switched to a parallel tank, and the filled tank of product solution was subjected to batch mode workup and isolation unit operations. The reaction and hydrogen stripping unit operations ran continuously, while the batch unit operations were conducted at repeating cycles as required to satisfy the campaign’s material supply goals. The logging of the dates and times for the switching of these feed lots and product solution batches in the batch record was a key component to building the batch history. In addition to knowing when the various feed lot and product batch solution switches occurred over the course of a campaign, an understanding of residence time (τ) and residence time distribution (RTD) also informed the overall lot genealogy. RTD was determined through measurement of axial dispersion along the length of the continuous section. The axial dispersion number for the continuous section was very low, estimating D/μL = 0.0009. This means that the material entering the continuous section at time = 0 exited from the continuous section at 0.1% of full concentration after 0.86 volume turnovers and 99.9% of full concentration after 1.14 volume turnovers. One volume turnover is defined as Q*t/Vl = 1, where Q is the volumetric flow rate corrected for thermal expansion, t is time, and Vl is the volume of the continuous section corrected for % liquid filled. Furthermore, given D/μL

= 0.0009, 99.9% of the material in the reactor at time = 0 was pushed out after 1.07 volume turnovers of the continuous section. Practically speaking, axial dispersion was so low in the real plant reactor system, that if one assumed it to be zero it would result in less than 0.18% error with respect to the calculation of lot genealogy. Nevertheless the calculations accounted for the impact of axial dispersion. This firstprinciples understanding and characterization of fluid dynamics and axial dispersion allowed us to know RTD and maintain integrity of lot genealogy for batch identification. Campaign Derived Example: Aldehyde (5) Feed Solution. During the primary stability campaign, reagent feed lot solutions were fed to the continuous reactor for 577 h, representing 42.4 reactor volume turnovers. The total liquid volume in the continuous section45 was about 407 L; therefore, one volume turnover was 407 L total liquid flow through the continuous section. The mean residence time in the continuous section was 13.6 h. The aldehyde feed solution switches during continuous run are listed below and are represented as vertical dotted lines in Figure 25. 1. Start feeding 5 reagent feed lot 1 at time = 0. 2. Switch from 5 reagent feed lot 1 to feed lot 2 at 16.7 turnovers. 3. Switch from 5 reagent feed lot 2 to feed lot 3 at 29.0 turnovers. 4. Stop feeding 5 reagent feed lot 3 at 42.4 turnovers. Switch to THF solvent only feeding the continuous section for product push out. The product 6 batch switches during the continuous run are listed below and are also depicted as solid vertical lines in Figure 25: 1. Start collecting product at 0.75 volume turnovers. 2. Switch from collecting product batch 1 to product batch 2 at 11.6 volume turnovers. 3. Switch from collecting product batch 2 to product batch 3 at 22.2 volume turnovers. X



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Figure 26. Expanded view of batch 2.

Figure 27. Lot genealogy for all four feeds used in the primary stability campaign.

In this example calculation, the switches between different product batches did not occur in the transition regime. Therefore, impact of axial dispersion was negligible in the calculations. However, if it did, then the straightforward calculations account for the impact of D/μL. The example described for aldehyde 5 can be applied to all of the solution feeds used in the continuous section to provide a holistic understanding of the batch genealogy for the process. Each feed used in the campaign can be traced back to individual lots of starting materials, and the precise amounts of each can be accurately traced as described for the aldehyde (Figure 27). The lot genealogy for the evacetrapib step 2 drug substance process (batch and continuous operations) is readily available from the feed input and product collection times recorded in the batch record along with the known τ for one turnover and residence time distribution of the continuous section. In turn, if a deviation occurs during the continuous processing, the batches affected can be bracketed by examination of this data. Thus, it is not necessary to synchronize feed lot introductions and product lot collections on a one-to-one basis in order to readily determine the drug substance batch genealogy.

4. Switch from collecting product batch 3 to product batch 4 at 32.8 volume turnovers. 5. Stop collecting product batch 4 at 43.7 volume turnovers. The blue, red, and green curves plotted in Figure 25 represent product tracking from aldehyde 5 reagent feed lots 1, 2, and 3, respectively. These were generated from the known axial dispersion number and the model calculations for residence time distribution. The midpoint of the transition occurs 1 volume turnover after a switch in reagent feed lot. This is illustrated in Figure 26. Since the dates and times for the switching of these feed and product solution batches was logged in the batch record and the mean residence time and axial dispersion measured, calculating lot genealogy for the aldehyde 5 feed lots in the 6 product batches was straightforward. The results of the calculations for the aldehyde 5 feed are as follows: 1. Batch 1 derives from 100% reagent aldehyde 5 lot 1. 2. Batch 2 derives from 57.5% reagent aldehyde 5 lot 1 and 42.5% reagent aldehyde 5 lot 2. 3. Batch 3 derives from 73.6% reagent aldehyde 5 lot 2 and 26.4% reagent aldehyde 5 lot 3. 4. Batch 4 derives from 100% reagent aldehyde 5 lot 3. Y



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Post Campaign Cost Analysis. Cost Comparison of Reducing Agents (STAB vs Ir2(COD)2Cl2). The overall cost benefit of the iridium catalyzed route can be viewed in several ways. The first analysis is a direct comparison to the cost of the reducing agent (STAB vs H2/Ir2(COD)2Cl2). Internal cost calculations over the projected lifecycle of evacetrapib are represented in Figure 28 and Figure 29. There are many

many implications with respect to transport, storage, and waste stream management (waste boron). Cost Per Kilogram API Savings. While the cost associated with the reducing agent is an important consideration, it does not reflect other aspects of total API cost which includes yield, operational expense, and cycle time.46 When comparing the two processes using cost estimation tools, the breakdown of savings/kg of API is shown in Table 19. Table 19. Breakdown of Cost Savings between STAB and Ir2(COD)2Cl2 cost contributor

Figure 28. Yearly cost of reducing agent.

cost savings

comment

starting material costs reducing agent cost solvent cost

$0

The same stoichiometry between amine and aldehyde can be used.47

$78/kg

STAB vs Ir2(COD)2Cl2.

$4/kg

operating cost total

$0 $82/kg

Recycle of THF/water from workup demonstrated.48 Conversion costs, rig time, and FTEs. Estimate based on process including reduced aldehyde use and THF recycle.

As expected, the bulk of the cost savings is associated with the replacement of stoichiometric reducing agent STAB with a catalytic method. The operating cost was projected as identical between the two processes. Solvent cost (THF vs toluene) shows a slight difference and assumes that THF would be recycled. Solvent recycle was demonstrated in the laboratories where the distillate from the workup (THF/water mixture) was used directly in the salt break step 2a (Scheme 4). The total Scheme 4. Step 2a Formation of Aldehyde 5 Figure 29. Lifespan accumulated costs.

assumptions built into this analysis. Peak volume estimates of the drug were provided by internal Lilly estimates; bulk catalyst and STAB cost were obtained through an Lilly external sourcing group. The recycling estimates were based on estimated Ir available for recovery from the reaction filtrate and recovery and refining costs obtained from a catalyst supplier. While there is uncertainty in these calculations, the difference in cost of the reducing agent is significant on a yearly basis and has a long-term accumulated cost savings of at least 50% for iridium catalyst vs STAB. Building in the recycle of iridium would further differentiate the processes with respect to the cost of reducing agents. The projected reduction in quantity of material used over the lifecycle of the product is also striking by comparison (Table 18). The use of STAB over the lifecycle of the program was calculated to exceed 1.1 million kilograms compared to 2500 kg of [Ir(COD)Cl2]2 without recycle or 336 kg assuming iridium recovery. The amount of STAB is physically large, which has

estimated saving was $82/kg, a substantial sum considering the large peak volume estimates for this product. It is important to note that the realized cost savings must also account for the capital investment in the high pressure infrastructure. This investment will reduce the overall cost/kg savings. High Pressure Infrastructure Cost. The cost of installing flow infrastructure for high-pressure vapor liquid reactions must be evaluated vs installation of batch autoclaves. The 360 L flow reactor and supporting infrastructure were installed with a total capital cost of approximately €2.5 million. The 360 L reactor itself was a small component of the overall cost at €120,000. This opens up the possibility of dedicating the reactor to a specific chemistry application or metal catalyst, something not practical in the batch case. The total capital cost of a batch reactor with comparable throughput was estimated at €30 million. The capital avoidance is massively in favor of the flow option. The inherent safety of the flow reactor directly links to capital savings. Additionally, the depreciation of the asset over the next 20 years is much less. This project also utilized existing feed skids which were purchased as part of another continuous

Table 18. Projected Accumulated Mass Reduction compound

kg (lifecycle)

STAB [Ir(COD)Cl2]2 [Ir(COD)Cl2]2, recycle

1110460 2514 336 Z



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process underscoring the flexibility in the use of the equipment (These were included in the €2.5 million total capital cost for the continuous part of the process even though they had been previously purchased for another project). The infrastructure installed for this project can be used in the future for vapor liquid reactions of any type49 and can support homogeneous or heterogeneous (packed bed) systems. Additionally, this same infrastructure could accommodate a 900 L reactor50 which would allow for production of up to 1.5 bMT of product per week.51 The flexibility in product throughput from this infrastructure is important since peak volumes of product are notoriously difficult to predict as is the rate of uptake. Installing this infrastructure of this type, at comparatively low cost to the batch, allows for the deferral of large at-risk capital expense.

organic layer to appropriate container, and degas for 30−90 min with nitrogen. Assay for weight % and KF of 5, typically 10.9 wt % and 5.8% water. Step 2b Reaction (Batch). To an inerted pressure vessel charge a degassed solution of 3 (24.4 wt % in THF). Charge a degassed solution of aldehyde 5 (1.4 equiv, typically a 10.9 wt % solution from step 2a) as prepared above. The overall solvent volume is 8 volumes based on 3 (≤20% 2-MeTHF in THF). Charge a degassed solution of acetic acid in water (1.05 equiv of acetic acid based on 3). The volume of water should be such that, when in combination with the amount of water in the aldehyde solution, the total is 1 volume based on 3. Immediately purge the vessel with hydrogen, and pressurize the reactor to 750 psig hydrogen. Extended stir time without hydrogen will result in epimerization of the aldehyde and increased cis content in the product. Stir the contents of the reactor for 3−5 min at pressure, then vent the reactor, and charge a stock solution of degassed catalyst solution in THF54 such that S/C = 1000 (typically delivered as a 0.0043 M solution) while maintaining an inert atmosphere in the reactor. It is important to charge the catalyst solution directly into the reaction solution not allowing the catalyst solution to wet the interior surface of the reactor. Catalyst solution on the wall of the reactor can lead to Ir plating once hydrogen pressure is reapplied. Stir under hydrogen pressure for 12−20 h. Once the reaction is completed by HPLC55 ( [Ir(COD)2]BARF. (12) Crude reaction solutions have been helped under inert conditions for extended periods of time with no observable degradation. (13) Sampling for HPLC analysis is a source of oxygen introduction. Depending upon the sampling technique and time the sample is held prior top dilution iminium can form to greater or lesser extents. (14) Mean hydraulic residence time is also referred to as tau or τ. (15) Notably reactions with very fast reaction kinetics with extremely short residence times. (16) Johnson, M. D.; May, S. A.; Haeberle, B.; Lambertus, G.; Pulley, S. R.; Stout, J. Org. Process Res. Dev. 2016, 20 (7), 1305−1320. (17) Johnson, M. D.; May, S. A.; Haeberle, B.; Lambertus, G. R.; Pulley, S. R.; Stout, J. R. Org. Process Res. Dev. 2016, 20, 1305−1320. (18) The reactor designs consist of a series of SS piping and tubing which is inexpensive even at commercial scale. Further, the commercial design resemble shell in tube heat exchangers which provides options with respect to fabricators. (19) Johnson, M. D.; May, S. A.; Calvin, J. R.; Lambertus, G.; Kokitkar, P.; Landis, C.; Jones, B.; Abrams, M.; Stout, J. Org. Process Res. Dev. 2016, 20, 888−900. Also see Abrams, M. L.; Buser, J. Y.; Calvin, J. R.; Johnson, M. D.; Jones, B. R.; Lambertus, G. R.; Landis, C. R.; Martinelli, J. R.; May, S. A.; McFarland, A. D.; Stout, J. R. Org. Process Res. Dev. 2016, 20 (5), 901−910. (20) Buser, J. Y.; McFarland, A. D. Chem. Commun. 2014, 50 (32), 4234−4237. (21) The reduction of aldehydes to alcohol by heterogeneous catalysis is well-known. Examples with Pd/C, Ru/C, and Pt/C are prolific in the literature. There are fewer examples of Ir(0) which is likely due to the lower cost alternatives mentioned above. The following publication represents one example of aldehyde reduction with heterogeneous Ir(0). This reference also speaks to the potential function of Ir nanoparticles, a topic addressed later in this manuscript. Wang, Z.; Huang, L.; Geng, L.; Chen, R.; Xing, W.; Wang, Y.; Huang, J. Catal. Lett. 2015, 145, 1008−1013. (22) The equipment setup including the feed lines and Parr reactor can be found in the Supporting Information. (23) 13 equiv of H2 in flow.

with 2.0 volumes (6 basis) of cold 4:1 3A ethanol−water. Vacuum dry at 50 °C to provide 6 (93−95% yield based on reaction wt % assay).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.6b00148. A summary of the reactors used in this manuscript including reactor dimensions, characteristics, and flow conditions. The 32 L scale-up reactor design and vapor− liquid separator design are also described. Finally a section on safety guidance for operating a continuous vapor liquid reaction is included (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail (Scott A. May): [email protected]. *E-mail: (Martin D. Johnson): [email protected]. *E-mail: (Declan D. Hurley): [email protected]. Present Addresses ‡

D.H.: Synergy Industrial Corporation, Brookfield, Wisconsin 53005, United States. § S.R.P.: Elanco Animal Health, 2500 Innovation Way, Greenfield, Indiana 46141, United States. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We would like to acknowledge the following individuals from Lilly Research Laboratories (Indianapolis, IN, USA): Vaidyaraman Shankarraman for contributions to cost models, Michael O. Frederick for helpful discussions relating to the Pt/C work, William D. Diseroad for preliminary crystallization studies, Lars Magnusson for analytical testing strategies, Todd D. Maloney for contributions to online HPLC, Jeremy M. Merritt for modeling support, Amélie Dion for help with use tests, and Jeffrey D. Hofer for help on the DOE design. We would also like to acknowledge the following individuals from Lilly Manufacturing (Kinsale, Ireland): Luke Bollard for analytical testing, Hossam Moursy for PAT work associated with FBRM, Maria T. G. Perez for centrifuge expertise, Kenneth Desmond for support of online HPLC, Jim Cashman for contributions to quality and regulatory strategy, and Humphrey Moynihan for helpful discussions relating to deviation management and failure mode analysis. We thank Bret Huff for initiating, leading, and sponsoring the continuous reaction design and development work at Eli Lilly and Company.

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REFERENCES

(1) Details on the evacetrapib ACCELERATE phase III clinical trial can be found online at www.clinicaltrials.gov. (2) Chen, X.; Frank, S. A.; Remick, D. M.; Pedersen, S. W. U.S. Pat. Appl. Publ. US 20100331309 A1 20101230, 2010. (3) Frederick, M. O.; Frank, S. A.; Vicenzi, J. T.; LeTourneau, M. E.; Berglund, K. D.; Edward, A. W.; Alt, C. A. Org. Process Res. Dev. 2014, 18, 546−551. (4) A list of the 12 Principals of Green Chemistry may be found on the ACS website: http://www.acs.org/content/acs/en/ greenchemistry/what-is-green-chemistry/principles/12-principles-ofgreen-chemistry.html. (5) (a) Johnson, M. D.; May, S. A.; Calvin, J. R.; Remacle, J.; Stout, J. R.; Diseroad, W. D.; Zaborenko, N.; Haeberle, B. D.; Sun, W.-M.; AB



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(24) Hopmann, K. H.; Bayer, A. Organometallics 2011, 30, 2483− 2497. (25) Dieguez, M.; Pamies, O.; Claver, C. Top. Organomet. Chem. 2011, 34, 11−29. Crabtree, R. Acc. Chem. Res. 1979, 12, 331−337. (26) Ozerov, O. V. Organometallics 2005, 24, 3487. (27) Huang, Y.-H.; Gladysz, J. A. J. Chem. Educ. 1988, 65, 298. (28) Hartwig, J. F. Organotransition metal chemistry: from bonding to catalysis; Univ. Science Books: 2010; p 53. (29) (a) Crabtree, R. H. Chem. Rev. 2012, 112, 1536−1554. (b) Widegren, J. A.; Finke, R. G. J. Mol. Catal. A: Chem. 2003, 198, 317−341. (30) Since the aldehyde is reduced by the deposited Ir(0) rapidly, it is possible that the main reaction is primarily a homogenously catalyzed mechanism while the background reaction is heterogeneous. (31) Tetraalkylammonium salts are known to stabilize iridium nanoclusters. (32) 400 psig hydrogen, 17−23 °C (RT), 6 h residence time, 1.75 equiv of aldehyde, 500:1 catalyst loading, 2 equiv of acetic acid, and 0.5 equiv of TBAI (w.r.t. Ir). (33) Like the previous reactor, the 48 mL reactor was constructed with 25 vertical pipes in series each 40 mm tall, 9.53 mm OD, 7.75 mm ID. Connecting tubes were 1.59 mm OD, 0.559 mm ID. (34) A common practice in asymmetric hydrogenation reactions. (35) The 12 L reactor was constructed with 15 vertical pipes in series each 1.83 m tall, 25.4 mm OD, 22.1 mm ID. Downflow tubes were each 2.13 m long, 3.18 mm OD, 1.75 mm ID. See the Supporting Information for complete reactor details. (36) See Supporting Information for a schematic of the 32 L setup and discussion. (37) While not known at this time, some of the infrastructure used in this reaction was also used on two other flow processes. (38) Chatterjee, S. FDA Perspective on Continuous Manufacturing, presented at IFPAC Annual Meeting, Baltimore, MD, January 2012. http://www.fda.gov/downloads/AboutFDA/CentersOffices/ OfficeofMedicalProductsandTobacco/CDER/UCM341197.pdf. (39) ATEX rated for plant use (40) Johnson, M. D.; May, S. A.; Calvin, J. R.; Lambertus, G. R.; Kokitkar, P. B.; Landis, C. R.; Jones, B. R.; Abrams, M. L.; Stout, J. R. Org. Process Res. Dev. 2016, 20, 888−900. (41) The overall process ran for 24 days; therefore 1/24th represents 4.1% of the overall theoretical yield. (42) The reactor can be held with no liquid flow at pressure for days and restart to produce acceptable material. (43) The average background reduction of excess aldehyde (0.4 equiv) was 34%. This correlates to 0.136 equivalents of alcohol or ∼10% overall background reduction. (44) Allison, G.; Cain, Y. T.; Cooney, C.; Garcia, T.; Bizjak, T. G.; Holte, O.; Jagota, N.; et al. Regulatory and quality considerations for continuous manufacturing. May 20−21, 2014 Continuous Manufacturing Symposium. J. Pharm. Sci. 2015, 104 (3), 803−812. (45) This includes the volume of the feed lines, pipe-in-series reactor, and the VLS system. (46) Actual life cycle savings are calculated as the net present value discounted using RARR (risk adjusted return rate) and probablized using pTS. (47) In the manufacturing campaign 1.4 equiv of aldehyde was used where the STAB process operated with 1.22 equiv. Reduced stoichiometry (as low as 1.1 equiv) was successfully demonstrated in flow runs after the campaign. (48) Fully continuous reaction quench, washes, and distillation with solvent recycle was demonstrated in the flow after the manufacturing campaign. This account for a total of $16/kg of cost savings. Only the cost reduction associated with the solvent recycle was considered. (49) These include carbonylation with CO, hydroformylation with synthesis gas, aerobic oxidation, or amination with ammonia to name a few. (50) The cost estimate from a supplier for this reactor was €180,000. (51) This assumes 98% liquid fill, 8 volume equivalents of solvent based on product, and 95% isolated yield. This is a very conservative

estimate since the reaction time can be reduced by operating at higher temperatures. (52) This stoichiometry accounts for losses in step 2a and potency of 4. The output will result in the desired 1.40 equiv of 5. (53) This is a fast separation at lab scale (

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