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High-pressure asymmetric hydrogenation in a customized flow reactor and its application in multi-step flow synthesis of chiral drugs

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Abstract

Asymmetric homogeneous hydrogenation under high pressure in continuous flow was achieved with a slug flow reactor. High hydrogen pressure enabled iridium-catalyzed asymmetric hydrogenation of acetophenone with a turn-over-frequency (TOF) of up to 274,000 h−1. An operando infrared tool was used to provide in-situ monitoring of the reaction. The effect of gas-liquid ratio and speed of slug flow in the microchannel were studied. The multi-step flow synthesis of active pharmaceutical ingredients, in which asymmetric hydrogenation is a key step, was successfully demonstrated, with subsequent reactions carried out under longer residence times within a cascade of CSTRs.

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Acknowledgements

F.G. thanks the joint PhD program of SUStech with the University of Leeds. This project was financially supported by the National Natural Science Foundation of China (21801118) and the Science, Technology and Innovation Commission of Shenzhen (KQTD20150717103157174).

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Authors and Affiliations

  1. Department of Chemistry, Southern University of Science and Technology, 1088 Xueyuan Rd, Shenzhen, 518055, Guangdong, China

    Fanfu Guan, Jialin Wen & Xumu Zhang

  2. Institute of Process Research and Development, Faculty of Engineering and Physical Sciences, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK

    Fanfu Guan, A. John Blacker, Brendan Hall & Nikil Kapur

  3. Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, 1088 Xueyuan Rd, Shenzhen, 518055, Guangdong, China

    Jialin Wen

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Appendix

Appendix

Experimental

High TON AH of acetophenone in flow

To a 5-mL vial was added the catalyst precursor [Ir(COD)Cl]2 (1.4 mg, 0.002 mmol), f-amphox (2.3 mg, 0.0042 mmol) and anhydrous iPrOH (1.0 mL) in an argon-filled glovebox. This vial was sealed and mixed for 2 h at room temperature. tBuOK (89.8 mg, 0.8 mmol) was dissolved in 10 mL anhydrous iPrOH. 0.5 mL catalyst solution was firstly mixed with 10 mL base solution and then acetophenone (9.6 g, 9.4 mL, 80 mmol). The resulting mixture was filtered and the filtrate was added into a flask.

The process diagram was shown in Fig. S7 and Scheme S1. Fig. S8 showed the remote control app and real time IR analysis. The process was washed by anhydrous and degassed iPrOH at a liquid flow rate of 4 mL/min and gas flow rate of 5 sccm (avoid back flow of liquid to gas flow meter) for 5 min and then pressurized the BPR. After the reactor was pressurized to 70 bar and heated to 90 °C, the aforehand reaction medium was pumped instead of solvent. Liquid flow rate was set at 0.23 mL/min and gas flow rate 0.9 mL/min (45 sccm). The reactor system could achieve steady state in 5 reaction volumes. Samples were collected every 15 min in an empty vial. The conversion and ee were analyzed by NMR and HPLC. When reaction finished, system was depressurized by releasing the gas of Equilibar BPR slowly, and washed the whole system by pumping iPrOH for 10 min.

Multi-step flow synthesis of 5

To a 20-mL vial was added the catalyst precursor [Ir(COD)Cl]2 (16.8 mg, 0.025 mmol), f-amphox (31.0 mg, 0.055 mmol) and anhydrous iPrOH (10.0 mL) in an argon-filled glovebox. The solution was mixed for 2 h under room temperature. CsOH•H2O (83.5 mg, 0.5 mmol) was dissolved in 10.0 mL anhydrous iPrOH. 10.0 mL catalyst solution was sequentially mixed with 10.0 mL base solution and 3 (12.5 g, 25 mmol) in 25.0 mL toluene. The resulting mixture was filtrated and clear solution was added into a 50-mL volumetric flask. Then, 5.0 mL iPrOH was added to prepare a 50.0 mL reaction solution.

Deprotection module consisting of 9 fReactors (15.3 mL) were installed after the high-pressure slug flow reactor. The fReactors were filled with 750 mg 10% Pd/C in total. The frit-in-ferrule was installed before the BPR to hold the solid catalyst in the reactor. The hydrogenation module with a residence time of 6.5 min was pressurized to 100 bars and heated to 60 °C. After it reached steady state, the gas liquid flow was directed to the deprotection module without separation. The fReactor module was heated to 80 °C. Two step yield of ezetimibe was 84%. 272 mg product was obtained in 15 min with 95% de.

Multi-step flow synthesis of (R)-9

Medium for module 1

To a 20.0 mL vial was added the catalyst precursor [Ir(COD)Cl]2 (16.8 mg, 0.025 mmol), f-amphol (38.0 mg, 0.055 mmol) and anhydrous iPrOH (10.0 mL) in the argon-filled glovebox. The medium was mixed for 2 h under room temperature. tBuONa (120.0 mg, 1.25 mmol) was dissolved in 5.0 mL catalyst medium. The resulting medium was mixed with 6 (5.2 g, 25 mmol) in anhydrous and degassed 25.0 mL DCM. The resulting medium was filtrated by filter paper and added into a 50 mL volumetric flask. Then, 15.0 mL iPrOH was added to prepare a 50 mL reaction medium.

Medium for module 2

37.5 mL acetic anhydride and 12.5 mL NEt3 were mixed in a 100 mL volumetric flask. 133.0 mg DMAP was dissolved in the medium.

Medium for module 3

Was neat ClSO2NCO.

The module 1 was washed by anhydrous and degassed iPrOH by a liquid flow rate of 4 mL/min and gas flow rate of 5 sccm (avoid back flow of liquid to gas flow meter) for 5 min and then pressurized the BPR. After the pressure and temperature was elevated to 90 bar and 80 °C, the aforehand reaction medium was pumped instead of solvent. Liquid flow rate was 0.46 mL/mins and gas flow rate was 44 sccm. The reaction was monitored by TLC analysis. After it reached steady state with full conversion, the product medium was collected in the gas liquid separator (Schlenk tube in this process). Module 2 consisting of 5 fReactors (8.5 mL) was installed and filled with dry DCM. The medium for module 2 was taken by a 50 mL syringe that was installed on a PhD Ultra syringe pump. Then it was pumped by a flow rate of 0.26 mL/min. The liquid in gas liquid separator was pumped into module 2 by a flow rate of 0.23 mL/min. The hotplate was heated to 70 °C to have a liquid temperature of 60 °C. The residence time of module 2 was 17 mins. The reaction was monitored by TLC analysis. After it reached steady state with full conversion, the outlet was connected to cooling part of the module 3. Neat ClSO2NCO was pumped by a flow rate of 0.069 mL/min and mixed with medium from module 2 in a T-junction. Tubes of module 3 were in a room temperature water bath. The final product was connected in a beaker that has 20 mL water to quench the solution. There was HCl gas generated in module 3. Thus, the calculated residence time was 2.7 min that was longer than batch reaction time that was 1 min. The biphasic medium was left stirring for 1 h. Organic phase was separated. 5 ml DCM was added to wash the aqueous phase for two times. Organic layer was combined and washed with water (5 mL). The solvent was evaporated at 40 °C under reduced pressure. The crude materials were purified by column chromatography. (60 mL 50% ethyl acetate in petroleum ether, then 100 mL 80% ethyl acetate in petroleum ether). In the first run, 320.0 mg eslicarbazepine acetate with 76% yield and 98% ee in 13 min. In the second run, 2.7 g eslicarbazepine acetate with 81% yield and 98% ee in 100 min.

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Guan, F., Blacker, A.J., Hall, B. et al. High-pressure asymmetric hydrogenation in a customized flow reactor and its application in multi-step flow synthesis of chiral drugs. J Flow Chem 11, 763–772 (2021). https://doi.org/10.1007/s41981-021-00143-8

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