Development of a Commercial Flow Barbier Process for a

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Development of a Commercial Flow Barbier Process for a Pharmaceutical Intermediate Timothy M. Braden, Martin David Johnson, Michael E Kopach, Jennifer McClary Groh, Richard D Spencer, Jeffrey Lewis, Michael R Heller, John P Schafer, and Jonathan J Adler Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00373 • Publication Date (Web): 30 Jan 2017 Downloaded from http://pubs.acs.org on February 1, 2017

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Organic Process Research & Development

Development of a Commercial Flow Barbier Process for a Pharmaceutical Intermediate

Timothy M. Braden, †,* Martin D. Johnson, † Michael E. Kopach, † Jennifer McClary Groh, † Richard D. Spencer, †† Jeffrey Lewis, ††† Michael R. Heller, ††† John P. Schafer, ††† Jonathan J. Adler †††

†

Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, USA

††

Eli Lilly SA, Dunderrow, Kinsale, Co Cork, Ireland

†††

D&M Continuous Solutions, LLC, Greenwood, IN 46143, USA

*email: [email protected]

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ABSTRACT A flow Barbier process was developed to produce a key intermediate in the Edivoxetine.HCl registered sequence. The control strategy was developed based on a critical understanding of integrated parameters and design space requirements for a continuous stirred tank reactor (CSTR) process. In this flow Barbier process, the Grignard reagent formation and reaction occurs in a single CSTR, with quenching of the resulting tetrahedral intermediate in a second CSTR. Real time PAT monitoring was used to assist process development and understanding. The post quench liquid-liquid separation was continuous, and the quenched intermediate flowed directly into a neutralization CSTR to minimize epimerization potential of the quenched intermediate. The optimized process was run for 80 consecutive hours in 2L CSTR’s where magnesium was re-charged every four hours for the first half of the continuous campaign and every eight hours for the second half with no quantifiable differences in performance. The Barbier process delivered in situ >99% ee which is sufficient for telescoping into the next step. The process development is intended to support a Quality by Design (Qbd) regulatory submission. Keywords: Grignard, Barbier, Continuous, Edivoxetine.



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INTRODUCTION It is widely recognized that the Grignard reaction is one of the most important methods for forming carbon–carbon bonds and has widespread synthetic applications in modern organic chemistry. Less common is the Barbier variant where metal insertion and reaction occurs concurrently.1 The Barbier approach often works well in cases where the Grignard reagent is unstable, and in cases where the Grignard reagent and product can be produced at the same temperature. The Barbier-Grignard -type reactions are most commonly developed and scaled using batch conditions. However, the acute hazards of this reaction class make it one of the more challenging processes to develop and to bring to commercial scale. These hazards include: 1) strongly exothermic magnesium metal activation; 2) heterogeneous reactions with potential difficulties suspending and mixing; 3) operational hazards posed by solvents with low vapor pressures; and 4) hydrogen liberation during quench of excess Mg. For these reasons the pharmaceutical industry has often moved away from Barbier-Grignard -type reactions even if it means adding several steps to a synthesis. A potentially attractive option to mitigate the aforementioned hazards are reactions in continuous stirred tank reactors (CSTRs). For the Barbier-Grignard -type reactions the CSTR strategy minimizes hazards by operating at a small reaction volume, and potentially performing metal activation only once per campaign.

A detailed discussion of the benefits of flow Grignard processes operated in CSTRs

relative to other continuous approaches was recently reported.2 Despite the numerous drivers and upsides for developing CSTR processes, there appears to have been limited uptake for manufacture of multi- kilogram quantities of pharmaceutical intermediates or API. Possible reasons for the limited progress include lack of understanding of cGMP requirements for flow processes, and inconsistent expectations from the FDA and EMA regulatory authorities. In addition, the lack of a historical track record has likely resulted in a hesitancy for organizations to file continuous processes. Previously we


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disclosed the synthesis of compound 1 by a batch Grignard process.3 Unfortunately, the Grignard reagent formation and reaction were not robust on scale, with complete racemization occurring in the plant. Key issues included a highly sensitive initiation, an insoluble Grignard reagent and an unstable tetrahedral intermediate. To address these issues, a flow Barbier process was developed to produce intermediate 1 (Scheme 1) which was demonstrated at a 250 mL CSTR scale.4 While the proof-ofconcept was successful, significant development was still needed. In order to completely understand the critical process parameters toward commercial manufacturing, some aspects of the process required additional research and development including: 1) optimal reaction solvent system; 2) system response to perturbations and return to steady state; 3) magnesium charging strategy amenable to commercial manufacturing; 4)online monitoring of reaction conversion and hydrogen present in the headspace; 5) simplification of the process; 6) improving Mg sequestering devices and methods. It is intended that the results from these studies will help catalyze the pharma industry to routinely develop organometallic CSTR processes and for the Regulatory authorities to embrace these processes which offer enhanced process control.

Scheme 1. Barbier process to produce compound 1.

RESULTS AND DISCUSSION At the conclusion of the previously disclosed proof of concept work we set about development of the continuous flow Barbier process for use in commercial manufacturing. Two of the side-products of the originally developed process were poorly rejected by the crystallization. These impurities were toluene based impurities 4 and 5 (Scheme 2). Larger excesses of Mg in the CSTR resulted in increased 4 by5 ACS Paragon Plus Environment


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product, which is consistent with direct metal insertion into toluene. In addition, both the Grignard reagent and tetrahedral intermediate are sufficiently basic to promote these type of side reactions.

Scheme 2. Toluene based side reactions.

These results led us to explore replacement of toluene which had been used primarily to solubilize the tetrahedral intermediate. 2-Me-THF is a solvent which is available from renewable sources5 and has found significant utility in organometallic chemistry such as Grignard reactions.6 We found 2-MeTHF to be equivalent to toluene in the freebasing of the methanesulfonate salt 6 to produce 3 (Scheme 3).

Scheme 3. . Freebasing of Methanesulfonate salt 6

After aqueous work-up and azeotropic drying by distillation, the result was a dry solution (< 500 ppm water) of 3 in 2-MeTHF suitable for use in the Barbier reaction. In the previously disclosed process compound 2 was used as a solution in THF. We initially hoped to accomplish a single solvent reaction system in the Barbier reaction by also replacing this THF with 2-MeTHF. However, the reaction in pure 2-MeTHF led to unpredictable loss of magnesium activity and an inconsistent reaction rate. The dull 6 ACS Paragon Plus Environment

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color of the magnesium metal turnings in these reactions led us to conclude that solubility of one or more species was lower in this solvent system leading to solids coating of the magnesium and deactivation. It was found, however, that a mixed 2-MeTHF/THF system, using a solution of 3 in 2MeTHF and a solution of 2 in THF alleviated this issue. As anticipated, the toluene related impurities 4 and 5 were completely eliminated (Table 1, Figure 1).Conversion was slightly lower but still acceptable, and a second finishing CSTR was not needed. In addition, all by-products were lower and no new impurities were detected at levels > 0.05%. Consequently, this mixed THF/2-MeTHF system was adopted into the process.

O

H

O solution in toluene or 2-MeTHF

N

1)

O

N 3 Cl

O

Mg DIBAL, I2 THF 55°C

O

MgCl

O

O

O

N

2) AcOH

2

Solvent system toluene/THF 2-MeTHF/THF

H

1

1 96.0 96.9

3 1.2 1.7

4 0.23 0

5 0.06 0

8 0.29 0.19

Table 1. Barbier Solvent System Impurity profiles Comparison (HPLC Area %)

Figure 1. Barbier reaction by products



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One aspect of continuous flow process development that differs from batch is that the vast majority of the resources are used preparing for the flow run. Designing and setting up the equipment, leak testing and performing solvent runs to ensure they are adequate to the needs of the process takes time and planning. Feed stream preparation and characterization (concentration, water content and other key quality attributes) must be assessed. In addition, start-up of continuous flow processes, particularly ones with multiple simultaneous flow unit operations, can demand additional personnel until the system reaches steady state. Once the system reaches steady state the effort required to sustain and monitor the process is greatly reduced relative to a batch process. Because of this high up-front effort and the lower required effort at steady state, our preferred strategy for development of a flow process is to carefully plan an extended run on a scale that is representative of what can be expected in manufacturing. This is accomplished using three CSTR’s in series where it is easy to stop and restart flows without requiring fresh Mg activation or significant start-up and restart procedures. This makes 24 hour a day operations unnecessary during development, although that option may be preferred in commercial manufacturing. A current trend in the pharmaceutical industry is towards more potent drugs which require lower doses. As a consequence Lilly’s small molecule development portfolio is moving towards more lower volume products (99%) from the start, and the initial flows out of the Grignard CSTR had very high conversion. The quench CSTR and the carbonate wash CSTR began with the aqueous phase at minimum stir volume and gradually filled once flows began to enter them. Running in this manner resulted inall of the product meeting specifications with the amount of extra dilution during startup minimized. There are alternative methods to do the startup transition. The quench CSTR and carbonate CSTR and both gravity decanters could have started liquid filled with solvent and representative volumes of aqueous phase. This would have resulted in higher dilution during start up transition before reaching steady-state concentrations, but it would have been operationally simpler. Steady-State Operation Figure 4 shows the Barbier Grignard reaction with magnesium stirring inside the 2 liter CSTR, and the settling pipe for sequestering magnesium. The four vertical flat baffles helped with the Mg solid suspension. The ½ inch OD, 0.376 inch ID settling pipe was angled at 30° from horizontal and it extended 11 ACS Paragon Plus Environment


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out the side of the reactor. The ¼ inch OD, 0.125 inch ID suck tube was inserted part way into the settling pipe. The suck tube did not go all the way to the bottom of the second pipe; rather, it went down to the desired liquid level in the reactor. It allowed about 30 seconds τ for the liquid flowing up the settling pipe. As the Grignard product solution moved up the settling pipe to get to the suck tube, the magnesium particles settled by gravity and moved back down into the reactor. The top of the settling pipe headspace was connected back to the headspace of the reactor to equalize pressures and also to prevent gas from bubbling up the settling pipe which would have disturbed the Mg fines settling. This has proven to be an extremely effective way of keeping magnesium sequestered in the reactor until each particle is completely consumed by the reaction.

Figure 4. Barbier Grignard reaction with magnesium stirring inside 2 liter CSTR. Settling pipe for sequestering magnesium is shown on the left side of the CSTR.

Figure 5 shows the top of Grignard CSTR with magnesium trap and magnesium charging device. Reaction product solution from the settling pipe flowed directly up and into the glass magnesium trap (cross piece shown in the picture). Directly below the trap was a valve shown in the picture with a blue


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handle. The plan was to periodically open this valve to allow magnesium fines to gravity drain back down into the reactor. However, in reality, the settling pipe did such a good job sequestering magnesium that almost no magnesium fines made it up to the trap. Particulate magnesium was never seen in the transfer line leading to the magnesium trap. The specialized magnesium charge port shown on the left side of the picture was made from Teflon. It allowed contained solids charging while maintaining an inert atmosphere in the reactor.

Figure 5. Top of Grignard CSTR showing magnesium trap with magnesium fines return to CSTR on the right and magnesium charging device on the left.

Figure 6 shows two of the 80 L pressurized stainless steel feed vessels on data logging floor balances in the laboratory. These feed vessels are pressurized to about 10 psig. The feed solution flows out the bottom valve and through tubing to a Micro Motion Coriolis mass flow meter and an automated research flow control valve. The DeltaV™ automation system uses feedback control for the mass flow rate. The change in mass of the feed vessel on the weigh scale serves as a secondary check of mass flow rate. 13 ACS Paragon Plus Environment


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Figure 6. 80 L pressurized stainless steel feed vessels on data logging floor balances in the laboratory.

Magnesium Recharge strategy Rather than using a complicated continuous solids addition device to continually add magnesium metal to the Grignard CSTR, Mg was added intermittently. The small amount of Grignard reagent that is always present in the CSTR at steady state and mechanical collisions of the Mg particles effectively activates the newly charged magnesium, so no additional iodine or DIBAL-H activation is required after start-up. Figure 8 describes the intermittent charging of solid magnesium reagent to the Grignard formation CSTR during the continuous campaign. On average, there were about nine molar equivalents of magnesium in the reactor relative to total moles of substrate. This is shown with the green triangles in Figure 8. More than 99% of the substrate in the reactor was converted to product at steady-state, therefore you can also think of this as moles magnesium per mole product in the reactor. The molar ratio of elemental magnesium to unreacted 2 in the reactor was extremely high at all times, because it was such a high loading of magnesium in the reactor and because the amount of unreacted 2 was


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extremely low at steady state. This served to minimize the Wurtz coupled by-product 9 (Figure 7), and additional advantage of continuous processing for a Grignard process.

Figure 7. Wurtz-coupled by-product

At the very beginning of the campaign, the reactor started with 12 molar equivalents of magnesium. For the next 25 hours, 4 eq. of magnesium were added once every four hours. Then, for the remainder of the campaign, 8 eq. of magnesium were added once every eight hours. Near the end of the campaign, only two molar equivalents were added, and the magnesium in the reactor was allowed to run down until it was almost gone. This can be seen by the blue diamonds and the redline in Figure 8. By the end of the campaign, overall magnesium used was close to 1.0 molar equivalent. This is another advantage of continuous processing instead of batch for the Grignard process: There is less excess Mg to quench at the end of the reaction, resulting in less hydrogen liberation during the quench. This strategy represents a significant improvement for magnesium charging relative to prior art.2



14.00

120.00

12.00

100.00

10.00

80.00

8.00 60.00 6.00 40.00

4.00

Mg Charge (g)

Mg Supply to Barbier Grignard Equivalents of Mg/tamide

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20.00

2.00 0.00

0.00 0

10

20

30

40

50

60

70

80

Flow (hrs) Equ Mg

Avg Equ Mg.

Mg Charges

Figure 8. Intermittent charging of solid magnesium reagent to the Grignard formation CSTR during the continuous campaign.

Online HPLC Analytical sample burden is high during these long duration development runs, so PAT is utilized extensively for as many unit operations as possible to ensure that appropriate data is collected. In accordance with this strategy, an extended run with extensive utilization of PAT was executed at a scale allowing for production of >5 Kg of 1 per day. Figure 9 shows a picture of an automated sampling and dilution cart used for online HPLC. This is one of three automated sampling and dilution carts used in this process. This custom built automated system is described in detail in the Supporting Information section of another manuscript.8


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Figure 9. Automated sampling and dilution cart used for online HPLC.

This automated sampling and quench technique is rapid, consistent, and inert, therefore it gives consistent HPLC analytical results for the unquenched tetrahedral intermediate. A 0.33 mL of the unquenched tetrahedral intermediate sample was taken from the overflow Tee at the exit of the Barbier Grignard reactor. The sample zone was the space between two standard 3/8” block valves.9 A vertical dilution solvent zone fills from the bottom up, and is emptied from top down. This ensured that it was completely filled, and subsequently completely emptied. The diluted sample was mixed in a mixing chamber and then pushed by nitrogen pressure to a vapor liquid separator near the HPLC. From the vapor liquid separator, a portion of the diluted sample was parked on the HPLC injection loop using a series of sequenced automated valves. The vapor/liquid separator vessel (V6) served to make sure there was no gas bubbling through the HPLC sample injection loop. This is all described in detail in the other manuscript. The sample was injected on column from the loop by switching valve. HPLC data from this automated sampling cart placed at the exit of the Barbier Grignard reactor is shown in Figure 10. Since this CSTR was started up by a semi-batch addition, conversion was high from the start and



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stayed steady through the campaign. The only change in the conversion occurred at approximately 43 hours into the run when the feed was switched to a different lot of starting material. The only known difference with the two feeds is that the second can had slightly less water. It is not clear if this is the cause of the change in conversion.

Figure 10: Conversion in Barbier Rxn CSTR

Two additional automated sampling and dilution systems were used for online HPLC of the product solution downstream from continuous carbonate wash, taking the sample from the organic product stream flowing out of the gravity decanter after the aqueous sodium carbonate wash. These systems were used in tandem. The first system automatically sampled 2.6 mL product solution from the continuous process stream and diluted the sample by 10 times. The second system diluted the sample by 20 times. This way, less dilution solvent was used overall. The first system parked the diluted sample in the overflow Tee above the second system [8].


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HPLC data from these automated sampling and “double-dilution” systems is shown in Figure 11. The same step change in conversion is noted after the change of the starting material feed at the 43 h point in the run, though the response is delayed as would be expected by the broader residence time distribution (RTD) at this point in the process train. Less easily explained; however, is the fact that while residual starting material 3 was steady from the start, the area % product 1 started out around 95% which is significantly lower than what was seen in the Barbier CSTR. The area % product 1 slowly increased to about 99% over 10 hours. A possible explanation between the difference in behavior in the post-quench sample when compared with the reaction CSTR is that, in the former, the analysis relies on higher dilution sample prep which is more consistent. In the acid quench CSTR the reaction is quenched with a large excess of acid, which ultimately levels off at three equivalents after several volume turnovers. The higher level of acid results initially in enriched partitioning of product in the aqueous layers until steady state levels of acid are achieved.

Figure 11. HPLC Data after the Na2CO3 wash



To monitor the headspace for H2, micro-GC was used during the campaign. A valve was installed to allow operations personnel to switch between the two headspaces. Figure 12 shows hydrogen concentration and the headspace of the quench CSTR during the 72 hour continuous production campaign. For most of the experiment, the Grignard CSTR head space was monitored. The near-zero readings correspond to the times when the instrument was switched to the Barbier Grignard CSTR to monitor oxygen levels. On average, 250 ppm of hydrogen was liberated during the run with a reactor nitrogen sweep rate of 0.1 SCFH. This equals a H2 liberation rate of 32 µmol/hour in the quench CSTR (5mg of H2 was liberated for the entire run). This corresponds to an average inlet Mg concentration of 0.81ppm flowing into the quench CSTR. In summary, the Mg sequestering system performed exceptionally well at preventing elemental Mg from flowing out of the Grignard CSTR and into the downstream quench. The low H2 generation during the quench reaction is another safety advantage of continuous processing compared to batch. 500 400 H2 (ppmv)

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300 200 100 0 0:00

12:00

24:00

36:00

48:00

60:00

72:00

Elapsed time (hours)

Figure 12. Hydrogen concentration and the headspace of the quench CSTR during the 72 hour continuous production campaign measured by micro GC.

Product Analysis


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The organic layer from the gravity decanter was collected in a series of 4L collection bottles over the course of the campaign. Total campaign time was 77.5 hrs, including 2.9 hrs for initiation, 69.0 hrs for flow, and 5.6 hrs for final push- out. The average conversion of amide 3 was 99.2% in the Barbier CSTR and 99.1% at the post wash sample location. The first product collection bottle was slightly lower in concentration due to start-up dilution, but the remaining bottles showed consistent concentration of product 1 throughout the run (Figure 13). The average % ee for all of the collection bottles was 99.2% (Figure 14). The consistently high ee was a key differentiator between flow and batch, as it allowed the potential to telescope 1 into the next processing step without isolation, a prospect not feasible with the less consistent batch reaction .

Figure 13. Product concentration in collection bottles



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Figure 14. % ee in product collection bottles

A portion of these collection bottles were subjected to work-up and isolation in 5 different batches. In total, 59.4 Kgs of the product 1 solution was water washed and solvent exchanged into isopropanol via two evaporations to dryness with isopropanol add-backs. Methanesulfonic acid was added to isolate 5.75 Kg of the product as an IPA solvate of its methanesulfonic acid salt 7 in 89.6% overall yield (Scheme 4). HPLC Potency, total impurities and % ee data are summarized in Table 2. The potencies are lower than 100% due to the product being isolated as an isopropanol solvate.

Scheme 4. Formation of Methanesulfonate salt 7

Batch

Wt. (g)

1

1329

Potency (%) 95.1

2

1367

3

1371

Impurities (%) ee (%) 0.64

99.8

93.6

0.60

99.5

93.5

0.49

99.3


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4

1361

93.4

0.32

99.5

5

322

96.1

0.51

99.8

Total / Avg.

5750 (86.5%)

94.4

0.51

99.6

Table 2. Isolated methanesulfonate salt data

Shut-down of the Process Shut down transition was done in reverse manner. After the reagent feed ran out, the Grignard CSTR was gradually emptied at the same rate the as the steady-state outlet pumping rate. The quench CSTR and carbonate CSTR and the gravity decanters were gradually emptied to get almost all the product out by lowering height of the adjustable dip tubes. In this manner, there was very little shut down transition waste and there was no extra dilution during shutdown. This could also have been done differently. If extra solvent dilution was deemed to be acceptable, then we could have continued running the entire process at normal operating levels but switched over to solvents instead of reagents and run long enough for the product to be pushed out. This would have required more time and more solvent because of the residence time distribution in CSTRs, but it would have been simpler for the operators and we would not have needed to adjust the height of the tubes for pumping out of each of the vessels. CONCLUSIONS A viable commercial process was developed to produce ketone 1, a key intermediate for production of edivoxetine·HCl in continuous flow. The process results in a solution of 1 which is > 99% purity by HPLC and > 99% in situ ee and is suitable for telescoping into the next synthetic step without the need for isolation. Key impurities were eliminated as a result of a solvent system change. The consistent quality of the product is due in large part to steady state control and the ability to quickly quench and base wash the unstable tetrahedral intermediate, thus avoiding epimerization. Custom designed automated systems were used to enable on-line HPLC for the Barbier Grignard CSTR and the neutralization CSTR. Development was done on a scale that would represent commercial manufacturing throughput for 23 ACS Paragon Plus Environment


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many continuous drug substance processing steps which increases process confidence prior to tech transfer to manufacturing. EXPERIMENTAL All of the reagents and solvents for the Grignard reaction were pre-combined into a single feed solution. Unless otherwise specified water levels in solvent streams are controlled to < 500 ppm of water. Commercial grade 1/8 – 3/16” magnesium turnings (Elektron Magnesium, 99.8% minimum purity) was used. THF suppliers were Superior and Lyondell MFG. No reaction takes place without magnesium. This made the control of stoichiometry between amide 3 and 2 in the continuous reactor much simpler. The target molar ratio of 2to 3 was 1.35. The reagent feed was a mixture of the amide in 2-MeTHF, compound 2, and THF. The amide was first prepared as a solution in 2-MeTHF in 2 batches. The amide mesylate was first freebased to make the solution. Freebasing was done with 3.5 kg of the amide mesylate ,10.5 L of 2-MeTHF, and 10.55 L of Na2CO3 solution (1.25 kg Na2CO3) per batch. The mixture was stirred for 1 hour. The layers were separated and the aqueous layer discarded. The organic layer was washed with 3.5 L water. The layers were separated and the aqueous layer discarded. The organic layer was stripped to an oil and 17.5 L toluene was added. The solution was stripped to an oil and 17.5 L 2-MeTHF was added. The solution was stripped to an oil again and 12.3 L 2-MeTHF was added. Total solution volume was 14.3 L. This was repeated to make two sections of the amide solution. This resulted in an amide stream (Section A) of 7.71 wt% with 291ppm of residual water content, and another amide stream (Section B) of 7.76 wt% with 125 ppm of residual water content. A 50 L reactor was inerted with nitrogen. The reactor was rinsed with 1.1 kg of 2-MeTHF. A sample was taken from this rinse solution and analyzed for KF. The result was 106 PPM water, which was sufficiently lower than the required 300 ppm. 9.177 kg of the amide solution was added to the 50 L reactor. The agitator was turned on. 13.0 kg of tetrahydrofuran was added. The reactor was stirred for five minutes. 1.028 kg of compound 2was added. The reactor was stirred for five minutes and the contents were 24 ACS Paragon Plus Environment

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transferred from the 50 liter reactor into a stock solution feed vessel. 500 g of THF was used to rinse the residual from the 50 liter reactor into the stock vessel. The stock vessel was kept in art with the nitrogen head pressure. Acetic acid quench solution was made for the campaign with 3.26 kg acetic acid diluted to 15.9 L. Na2CO3 wash solution was made for the campaign with 1.92 kg Na2CO3 diluted to 36.3 L. The Barbier Grignard reaction was initiated in the 2 L reactor and started in batch mode before any flows were started. 100g of Elektron magnesium was charged into the 2 L reactor (CSTR1) in preparation for the run. The magnesium was tripled rinsed with THF. The final THF rinse was analyzed for residual water content via KF assay. The final water analysis was 137 ppm, which is well below the 300ppm limit. The mixed reagent feed, acetic acid solution, and sodium carbonate solution were charged to their respective feed vessels in preparation for the continuous campaign. 850mL of THF was charged to CSTR1 contents and agitation was started at 300 rpm. An iodine/THF solution (3.97 g of I2 in 44.42 g of THF) was added to CSTR1 contents to activate the magnesium (Note: If left to stand for extended periods, I2 will catalyze polymerization of THF, resulting in thick, un-pourable polymer). This solution should be used soon after preparation) A temperature exotherm of 2°C was observed with the addition. 15mL of DIBAL solution was added to CSTR1 contents to activate the magnesium. A temperature exotherm of 0.9°C was observed with the addition. Heating was started in CSTR1 to bring contents to 55°C in preparation for the Grignard initiation, and then the reactor stirred for 30 minutes after reaching temperature. The 30 minute stir used post magnesium activation ensured a trouble free Grignard activation where6mL of compound 2was added to CSTR1 contents to initiate the Grignard reaction. Color of the solution in CSTR1 transitioned form milky gray to darker milky gray and then because a clear dark solution. A temperature exotherm of 3.9°C was observed with the initiation. CSTR1 contents were cooled to 35°C for the Barbier-Grignard continuous reaction.



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The feed lines were filled to the CSTRs. This included the mixed reagent feed to CSTR1, the quench acid feed to CSTR2, and the carbonate wash feed to CSTR3. The feed of mixed reagent was started to CSTR1 at 15.65g/min. This was controlled by a pressurized feed vessel a mass flow meter, a control valve, and feedback control via the DeltaV DCS system. The feed vessel was on a data logging balance for a secondary measure of mass feed rate. The feed delivery system of pressurized feeds cans with mass flow meters and control valves controlled by the DCS worked very well. The feeds were very consistent and responsive. CSTR1 contents were kept at temperature of 35°C. The quench CSTR chiller set-point was set to 0°C in preparation for the acetic acid quench reaction, and the quench CSTR was pre-filled with 47g of acetic acid solution (minimum stir volume) from the acetic acid feed can. Likewise, the carbonate wash CSTR was prefilled with 272 g of sodium carbonate solution (minimum stir volume) from the sodium carbonate feed can. The peristaltic pumps for pumping material out of each CSTR were started. The suction tubes from the CSTRs to the peristaltic pump were set at the desired liquid levels, therefore no solution started pumping out until the CSTRs reached desired operating levels. Once Grignard product solution started pumping from CSTR1 to the quench CSTR, feed of acetic acid solution started at 3.74g/min. Once the quench CSTR reached the dip tube level it started pumping to the continuous gravity decanter. After the gravity decanter filled, the aqueous layer continuously flowed by gravity to a waste container and the organic layer was continuously pumped to the sodium carbonate wash CSTR. The sodium carbonate solution feed was started at 8.78 g per minute. After the sodium carbonate wash CSTR filled to the dip tube level, the two phase, liquid-liquid mixture pumped continuously to the second continuous gravity decanter. After the gravity decanter filled, the aqueous layer continuously flowed to waste and organic layer continuously flowed to product collection vessels. Mg was added to the Grignard CSTR periodically throughout the continuous campaign. It was charged once every 4 hours for the first half of the campaign, and once every 8 hours for the second half of the campaign. Automated sampling for online HPLC was done in the flowing stream at the outlet from the


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Grignard CSTR and at the outlet of the carbonate wash CSTR. At the end of the campaign when the reagent feeds ran out, the CSTRs and gravity decanters were gradually emptied in sequential order using the same pumping rates between vessels. The total campaign time was 77.5 hrs. This time included 2.9 hrs for initiation, 69.0 hrs for flow, and 5.6 hrs for final push-out. The average amide conversion was 99.2% and 99.1% in the Barbier CSTR and post wash sample locations, respectively. The average ee for all of the collection bottles was 99.2%. The flow total material balance closure was 99%. The magnesium remaining in the system at the conclusion of the process was calculated to be 3.55 g. A total of 568.75g of magnesium was charged; therefore, 565.20g of magnesium (99.4%) was consumed during the run. Analysis of the two aqueous waste layers indicated very minimal product loss. The quench aqueous layer contained only 1.2g of the product (0.01 wt%), and the wash aqueous layers contained a total of 11.2g of product (0.03 wt%).Work-up and isolation of some of the product solution containers from the continuous process was done batch. Water wash was done with 2.80 L/kg amide feed basis. The layers were separated and the aqueous layer was discarded. The organic layer was stripped to an oil and then IPA was added (7.2 L per kg amide feed). The solution was stripped to and oil again and then IPA was added (7.2 L per kg amide). The solution was stripped to an oil again and then IPA was added (7.2 L per kg amide). The solution was heated to 70°C. Methanesulfonic acid was added (1.0 equivalent). The solution was cooled and the product was isolated and washed with IPA. The solid was vacuum dried at 45°C to yield 5.7 kg of 1 (MSA salt) in 86.5% overall yield. AUTHOR INFORMATION Corresponding Author *email: [email protected] Notes The authors did not receive any funding sources and declare no competing financial interests. REFERENCES



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(1) a) Barbier, P. Compt. Rend., 1899, 128, 110. b) Urban, F. J.; Jasyz, J. V. Org. Process Res. Dev. 2004, 8, 169. (2) Kopach, M. E; Cole, HK. P.; Pollock, P. M.; Johnson, M. D.; Braden, T. M.; Webster, L. P.; McClary Groh, J.; McFarland, A. D.; Schafer, J. P.; Adler, J. J. and Rosemeyer, M. Org. Process Res. Dev., 2016, 20, 1581. (3) Kopach, M. E.; Singh, U. K.; Kobierski, M. E.; Trankle, W. G.; Murray, M.M.; Pietz, M. A.; Forst, M. A.; Stephenson, G. A.; Mancuso, V.; Giard, T.; Vanmarsenille, M. and DeFrance, T. Org. Process Res. Dev.,2009, 13, 209. (4) Kopach, M. E.; Roberts, D. J.; Johnson, M. D.; McClary Groh, J.; Adler, J. J.; Schafer, J. P.; Kobierski, M. E.; Trankle, W. G. Green Chem. 2012, 14 (5), 1524–1536. (5) a) Frenzel, S.; Peters, S. ; Rose, T.; Kunz, , M. Sustainable Solutions for Modern Economies, ed. R. Hofer, RSC Green Chemistry Series, Cambridge, 2009, vol. 4, pp264-299. b) Comanita, B. 2-MeTHF for Greener Processes, htttp://www.pennakem.com/pdfs/MeTHFPennGreenChemistry.pdf. (6) a) Aycock, D. Org. Process Res. Dev., 2007, 11, 156. b) Clarke, M. I.; Milton, E. J. Green Chem., 2010, 12, 381. (7) Houlton, S. D.; Bottomley, K. Pharmaceutical Trends and Investment Opportunities in 2013, http://resultshealthcare.com/wp-content/uploads/2015/08/Pharmaceutical-Manufacturing.pdf (8) Figure S25 contained in the Supporting Information for the following document is a detailed process and instrumentation diagram of the invention, and Table S5 describes the automated sequence in detail: 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 (5), pp 888–900. (9) The inside dimension of standard 3/8” ball valves was large enough for self-venting, which means that liquid flowed down into the 0.33 mL zone by gravity and displaced vapor bubbled up and out through the overflow Tee.


Development of a Commercial Flow Barbier Process for a

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