Development of an organometallic flow chemistry. reaction at pilot plant scale for the manufacture of

Transcription

1 Supporting Information Development of an organometallic flow chemistry reaction at pilot plant scale for the manufacture of verubecestat David A. Thaisrivongs*, John R. Naber*, Nicholas J. Rogus, and Glenn Spencer Process Research and Development, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey, USA 1

2 Pilot plant equipment summary Jacketed stainless steel flexible metal hose This was used to keep the anion solution at 20 C from the outlet of feed tank to inlet of dual mass flow controller. Figure S1. Jacketed stainless steel flexible metal hose 2

3 Dual mass flow controller This was used to regulate the mass flow of the two feed solutions to the flow mixer, using two E&H Coriolis flow meters, 3/8 and 1/4. The system also contains two control valves, 1/2 and 1/4", respectively, with pneumatic actuators and electro-pneumatic positioners to control the valve position and outlet pressure. The control valves open or close to maintain the desired flow rate. Figure S2. Dual mass flow controller and specifications 3

4 Heat exchangers This was used to cool the feed solutions to the desired set point immediately upstream of the flow reactor. Each coil was designed as a double-pipe heat exchanger with 20 of 1/2 tubing inside 1 tubing. Table S1. Heat exchanger specifications Inner tube Outer tube Tube size 1/2 O.D. x AW 1 O.D. x AW Tube length Nominally Nominally 19-1 Design pressure 3000 PSIG & Full vacuum 2300 PSIG & Full vacuum Heat transfer area m m 2 Volume 0.49 L 1.56 L Residence time at 1 L/min 30 s N/A 4

5 Flow mixers Flow reactor A was constructed out of regular 1/4 Schedule 40 stainless steel pipe. The ID of ¼ schedule 40 pipe is The static mixer is a Koflo unit designed to fit inside a 1/4" pipe so it is basically an interference fit. We have found that the static mixer is a very tight fit in some ¼ piping due to manufacturing tolerances, so we have had to lightly clean up the pipe section with a file or abrasive cloth to get the mixer to slide in smoothly. Figure S3. Flow mixers 5

6 Flow reactor B was constructed out of 1/4 tubing and used the Koflo Stratos Tube mixer model 1/4-21. Figure S4. Flow reactor B static mixer specifications 6

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8 Flow reactor C was constructed out of 1/4 pipe and used the Koflo mixer model 1/ Figure S5. Flow reactor C static mixer specifications 8

9 Table S2. Flow reactor summary information Pilot plant representative batch summary Stage 1 Preparation of 3 feed solution kg of THF (2.58 kg THF/assay kg 3) was charged to reactor R1 via the 1 above surface charge line using a 1 sandpiper pump. A sample was taken from R1 and the KF was measured as 40 ppm kg of 3 (91 wt% purity) was charged to R1 with agitator at 50% of scale (113 rpm). 5 kg of THF (0.07 kg THF/assay kg 3) was charged to R1 via the PSL sprayball using a 1 sandpiper pump. R1 was then purged five times to psig using nitrogen, venting to <1 psig between purges. 15 kg of THF (0.20 kg THF/assay kg 3) was then charged to R1 via the vessel sprayball using a 1 sandpiper pump. The solution of 3 in THF was then held in R1 at C for 16 hours until the start of the flow chemistry reaction. Stage 2 Preparation of 4 feed solution kg of THF (3.80 kg THF/assay kg 3) was charged to R2 via the 1 above surface charge line using a 1 sandpiper pump. A sample was taken from R2 and KF was measured as 85 ppm (the target was <l00 ppm). The THF was cooled to 23.7 C in approximately 1.5 hours kg of 2 (100 wt%, to make up 2% excess anion) were then charged with the agitator at 35% of scale (82 rpm). 5 kg of THF (0.07 kg THF/kg 3) was charged via the PSL sprayball using a 1 9

10 sandpiper pump and R1 was then purged five times using psig nitrogen, venting to <1 psig between purges. 15 kg of THF (0.20 kg THF/ kg 3) was then charged via the vessel sprayball using a 1 sandpiper pump. The solution of 2 in THF was then held at 23 to 24 C until the start of the n-hexyllithium charge. Note: The anion was made up in 2% excess for this batch to allow for physical loss during startup and to simplify the shutdown procedure, so that we did not have two transfer lines going empty at the same time. It is not recommended to makeup the anion in less than a 2% excess. A total of kg of 33 wt% n-hexyllithium in hexanes (1.73 equiv vs 3) was charged to R2 over 4.25 hours using nitrogen pressure and a 3/8 driptube, maintaining batch temperature between 10 and 22 C. The maximum batch temperature during the charge was 12 C kg of n-hexyllithium solution was charged from the first cylinder over 4 hours and 10 minutes, followed by 8.6 kg of solution charged in 10 minutes from a second cylinder. The n-hexyllithium addition is exothermic. The vessel jacket temperature during the charge was 23 C. The batch is metastable at the end of the n-hexyllithium addition and during all pilot plant batches, a thick slurry formed at the very end of the charge (see pictures below). Figure S6. Heat profile for the n-hexyllithium charge to 2 in THF in R2 10

11 Figure S7. Solution of 4 in THF (9:22 AM, agitator on) Figure S8. Slurry of 4 in THF (9:38 AM, agitator on) After a 2 kg n-heptane line flush was performed, the lithium anion in R2 was cooled 22 C and aged for 5 minutes. Note: This is not a stable hold point. Do not age the batch for longer than necessary. Visual inspection showed that solids were present in R kg of DMPU (1.79 equivalents vs 3) was charged to R2 via the vessel sprayball using a 1 sandpiper pump, maintaining batch temperature between 15 and 24 C. Visual inspection showed that the lithium anion in R2 was not in solution, so the batch was warmed to 12 C. 11

12 Figure S9. Slurry of 4 in THF immediately after DMPU charge ( 24 C, agitator off) After warming the batch from 23 to 12 C in 25 minutes, there were noticeably less solids out of solution, but the batch was not completely transparent (the bottom of the vessel was not visible). Figure S10. Solution of 4 in THF after DMPU charge ( 12 C, agitator off) The batch in R2 was then immediately cooled back to 22 C in 1 hour in preparation for the flow chemistry reaction. At 22 C, the batch was not completely transparent (the impeller was not visible). There was no change in visual appearance of the batch at 12 C versus 22 C. 12

13 Figure S11. Solution of 4 in THF before flow reaction ( 22 C, agitator off) Note: A total of 9 hours elapsed from the start of the n-hexyllithium charge to the start of the flow chemistry reaction. Stage 3 Flow reaction startup Glycol services at 21 C were started to the R2 anion jacketed flexible metal hose bottom transfer line and to the heat exchanger which was used to maintain the temperature of the anion supplied to the flow reactor at 20 C. The Huber temperature bath was then started to supply 37 C syltherm to the heat exchanger which was used to cool the 3 solution from 15 C in the supply tank to 22 C at the inlet of the flow reactor. The solution of 4 in R2 was degassed by reducing pressure to 100 mm Hg and agitating at 100% of scale (174 rpm) for 5 minutes. After 5 minutes under max agitation, the agitator was turned off and the batch was held for approximately 2 minutes. R2 was then pressurized to 35 psig using regulated nitrogen. The solution of 3 in R1 was degassed by reducing pressure to 200 mm Hg and agitating at 100% of scale (192 rpm) for 5 minutes. After 5 minutes under max agitation, the agitator was turned off and the batch was held for approximately 2 minutes. R1 was then pressurized to 35 psig using regulated nitrogen. The 3 feed solution transfer line between R1 and the B-side of the mixer was primed by opening all manual valves upstream of the final manual valve at the mixer and the bottom valve of R1. 13

14 The flow control valve on the B-side of the dual mass flow controller was put in manual at 100% output, the R1 bottom valve was opened and then the drain valve at the inlet to the B-side of the mixer was opened to bleed gas from the line until 3 feed solution was observed in the sample bottle. Once flow was observed, the drain valve was closed and the line was left full and pressurized with the final manual valve at the mixer closed. The 4 feed solution transfer line between R2 and the A-side of the mixer was primed by opening all manual valves upstream of the final manual valve at the mixer and the bottom valve of R2. The flow control valve on the A-side of the dual mass flow controller was put in manual at 100% output, the R2 bottom valve was opened and then the drain valve at the inlet to the A-side of the mixer was opened to bleed gas from the line until anion was observed in the sample bottle (the sample bottle was pre-filled with 1M acetic acid in 9:1 THF:water buffer solution). Once flow was observed, the drain valve was closed and the line was left full and pressurized with the final manual valve at the mixer closed. The A-side (4) of dual mass flow controller was set in manual mode at 85% output and a set point of kg/h was entered. The B-side (3) of the dual mass flow controller was set in manual at 90% output and a set point of 85.7 kg/h was entered. While keeping the final manual valves on the A and B side of the mixer closed, all valves between the mixer and receiving vessel were opened. The manual valve on the A-side (4) of the mixer was opened to begin flow from R2 in manual mode. The A-side of the mass flow controller was then switched from manual to automatic flow control and we waited approximately 30 seconds for the flowrate to stabilize. The manual valve on the B-side (3) was then opened to begin flow from R1 in manual mode. The B-side of the mass flow controller was then switched from manual to automatic flow control. Stage 4 Flow reaction At 45 minute intervals, slipstream samples of the reaction were taken from a tee at the 3/8 driptube to the receiving vessel. A 100 ml flush sample was taken into a 500 ml Pyrex bottle containing 100 ml of 1M acetic acid in 9:1 THF:water. A 100 ml batch sample was then taken into a 500 ml Pyrex bottle containing the same volume of buffer solution. Table S3. Summary of slipstream sample results for the flow reaction sample mixer total flow 4 to mixer 3 to mixer post- Mixer conversion dr (kg/h) (L/min) ( C) ( C) ( C) 1 A :8.4 2 A :9.2 3 A :8.5 4 A :8.3 14

15 Stage 5 Flow reaction shutdown After 3.5 hours of continuous flow, R1 emptied and the flow rate of the solution of 3 stopped at the mass flow controller. The line was blown clear with nitrogen and then the manual valve at the mixer was closed. The flow control valve on the A-side (4) was then put in manual at 100% output and all remaining anion in R2 was transferred into the receiving vessel. When R2 went empty, the transfer line was blown clear with nitrogen and then the manual valve at the mixer was closed. 25 kg of THF was charged as a rinse to R2 via the vessel sprayball, using a 1 sandpiper pump. The rinse was cooled to 10 to 20 C and then transferred via pressure through the A side of dual mass flow controller, the heat exchanger, the mixer, and the FTIR flow cell and then into the receiving vessel There is no need to rinse the 3 solution makeup vessel and transfer line at the end of the flow reaction. There was no residual solution in the vessel at the end of the transfer. As shown in the graphic below, there were no upsets during the 3.5 hour flow chemistry reaction. With steady pressure in the two feed tanks, the flow control valve output for the 4 and 3 feed solutions was very steady during the run. The pressure at the inlet of the 3 solution mass flow control valve was steady at 44 psig and the pressure at the outlet of the control valve was 18 psig. The pressure at the outlet of the 4 mass flow control valve was 20 psig during the 3.5 hour run. 15

16 Figure S12. In-process flow rate and pressure data In between batches, three separate flushes were performed on R2 and associated transfer line through the A-side of the mass flow controller, the heat exchanger, and the FTIR flow cell with 1M acetic acid to remove any residual anion, THF to remove any residual acetic acid, and THF to dry out equipment. 16