Continuous Flow Asymmetric Hydrogenation with Supported Ionic

Research Article Cite This: ACS Catal. 2018, 8, 3297−3303

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Continuous Flow Asymmetric Hydrogenation with Supported Ionic Liquid Phase Catalysts Using Modified CO2 as the Mobile Phase: from Model Substrate to an Active Pharmaceutical Ingredient Daniel Geier,† Pascal Schmitz,† Jędrzej Walkowiak,† Walter Leitner,*,†,‡ and Giancarlo Franciò*,† †

Institut für Technische und Makromolekulare Chemie, RWTH Aachen University, Worringerweg 2, 52074 Aachen, Germany Max-Planck-Institut für Chemische Energiekonversion, Stiftstraße 34-36, 45470 Mülheim an der Ruhr, Germany

‡

S Supporting Information *

ABSTRACT: The continuous flow asymmetric hydrogenation of (hetero)aromatic enamides has been realized using a Rh-Quinaphos catalyst immobilized in a supported ionic liquid phase (SILP) and employing supercritical CO2 modified with toluene (modCO2) as the mobile phase. This approach allows expansion of the scope of the original SILP/scCO2 system to nonvolatile substrates with poor solubility in pure CO2. The potential of a SILP catalyst in combination with modCO2 was demonstrated for an industrial case study using the continuous flow hydrogenation for the synthesis of a key intermediate of an active pharmaceutical ingredient (API) from AstraZeneca’s portfolio. Toluene was selected as the most promising modifier, and the influence of the ratio of modifier to CO2 was evaluated in detail. The catalyst support was found to play a major role for maintaining constant performance and the use of hydrophobic fluorous reverse-phase silica (FRP-SiO2) instead of dehydroxylated silica strongly enhanced the long-term stability under continuous flow operation. Virtually a single enantiopure product was obtained over a prolonged time-on-stream of 90 h (quantitative single-pass conversion, ee > 99%) reaching a total turnover number of 10 300 at a space−time yield (STY) of 24 g L−1 h−1. No metal contamination was detected in the product solutions, indicating effective catalyst retention. KEYWORDS: continuous flow synthesis, asymmetric hydrogenation, SILP catalysts, carbon dioxide, catalyst immobilization, rhodium, quinaphos

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INTRODUCTION Continuous flow techniques have been attracting increasing attention as a promising technology for sustainable production of fine chemicals and pharmaceuticals.1,2 For transition metalcatalyzed reactions, the catalyst immobilization method plays a crucial role for the realization of an integrated continuous flow process, ideally achieving high selectivity and productivity at minimized metal contamination in the product.3 Preferred approaches are noncovalent immobilization strategies4 which allow the use of off-the-shelf catalysts and can lead to a catalyst retention comparable to that achieved with the more tedious and time-demanding covalent anchoring procedures.5 Moreover, covalent immobilization strategies lead in most cases to a depletion of activity and selectivity performances of the immobilized catalyst as compared to the original molecular catalyst. This drawback is much less pronounced by noncovalent immobilization approaches where the catalyst structure is maintained.6 Among noncovalent immobilization strategies, the supported ionic liquid phase (SILP) method is a straightforward approach where the medium, in which the catalyst is dissolved, is immobilized.7 A prerequisite for efficient continuous flow reactions with SILP catalysts is the preservation of the solvent film on the support. Several © XXXX American Chemical Society

examples show that this requirement is met if both substrates and products are in the gas phase, as ionic liquids have extremely low volatility (Figure 1).8−10 With the aid of a controlled evaporation mixing device using helium as carrier gas

Figure 1. Selected examples of continuous flow reactions using SILP catalysts. Received: January 17, 2018 Revised: March 6, 2018

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DOI: 10.1021/acscatal.8b00216 ACS Catal. 2018, 8, 3297−3303

Research Article

ACS Catalysis and methanol, also relatively high boiling compounds like methyl pyruvate (bp 135 °C) and methyl acetoacetate (bp 169 °C) could be used as substrates.11,12 The delivery of nonvolatile substrates containing functional groups in the gas phase, however, is not a suitable option in most cases. In particular, when the targeted reaction is an asymmetric transformation, the high temperatures required to generate a gas phase can be beyond the thermal stability of the substrates or products, or lead to reduced chemo- or enantioselectivity. Highly enantioselective continuous flow asymmetric catalysis with SILP catalysts involving medium volatile substrates have been achieved using supercritical CO2 (scCO2) as the mobile phase, as this medium effectively combines gas-phase transport properties with liquid-like solvation properties.13−18 Sufficient solubility of substrates and products in the scCO2 phase is an indispensable requirement for the realization of such processes. Functionalized substrates of medium polarity and low volatility, which are common in the fine-chemical and pharma industry, do often not possess useful solubilities, however, hampering a broad applicability of this methodology. In this work, we present a significant extension of the original scope of SILP catalysis to substrates with no appreciable solubility in scCO2. This was achieved using a strategy widely applied in supercritical fluid chromatography (SFC), i.e., mixing scCO2 with a cosolvent, a so-called entrainer or modifier.23 The use of modified scCO2 (modCO2) results in a mobile phase with higher solvent strength for the solutes, yet maintaining the compatibility with SILP catalysts as demonstrated by stable catalyst performance over 90 h on stream in the continuous flow Rh-catalyzed asymmetric hydrogenation of enamides with excellent enantioselectivities of >99% ee. The mobile phase is characterized by medium polarity and low viscosity and hence does neither dissolve nor strip the IL film from the support, allowing for effective IL/catalyst retention. Factors controlling the long-term catalyst stability have been investigated, and finally, this strategy has been successfully applied in the asymmetric hydrogenation of a real industrial case study, an active pharmaceutical ingredient (API) of AstraZeneca’s portfolio.

Scheme 1. Asymmetric Hydrogenation of 1

therefore seemed an ideal case study to explore the possibility to adapt the SILP/scCO2 system for these kinds of substrates. In preliminary experiments, we used N-(1-phenylvinyl)acetamide (1a) as a model substrate possessing a structure similar to the actual target molecule of this investigation, N-(1(5-fluoropyrimidin-2-yl)vinyl)acetamide (1b). Enamides 1a and 1b are polar solids with a melting point of 89 and 123 °C, respectively. Both substrates have a negligible solubility of 99% (Table 1, entry 5). Again, no IL-leaching could be detected under these conditions. Building up on these promising results, a series of continuous flow experiments was carried out using a computer-controlled in-house built setup.35 A stainless steel tube with a volume of 8 mL (diameter = 8.5 mm; length = 14 cm) containing the SILPcatalyst material (2.07 g, 3.3 μmol) was used as the reactor, and the flow rates were adjusted as follows: V̇ (tol) = 0.037 mL min−1, V̇ (H2) = 18 mLN min−1, and V̇ (CO2) = 60 mLN min−1. The temperature was set to 50 °C and the (total) pressure to 150 bar. Before starting the experiment, the system was flushed

thus fulfilling the basic requirement. The same behavior was observed at lower substrate concentrations, whereas a saturated methanol solution (4.7 M) remained biphasic even at a pressure of up to 360 bar. Using DCM (1 mL) as a modifier, the system became monophasic at a pressure above 100 bar if the concentration was ≤0.25 M. At higher concentrations of 1a, DCM formed a single phase with compressed CO2 at pressures in the range of 200 bar, but the enamide precipitated. The best compromise between substrate concentration and processing window was obtained when toluene was used as a modifier. At an initial volume of 0.5 mL of a saturated solution of 1a in toluene (0.25 M), the system became monophasic at a pressure of 85 bar, but a precipitation of 1a was observed at a pressure of 110 bar. When using 1.0 mL of a 0.25 M solution, this phenomenon was not observed and the system stayed monophasic up to a pressure of 200 bar, defining a broad operating window. The maximum solubility of the industrial case study substrate 1b in toluene is 0.2 mol L−1 and thus in the same range as that of 1a. The phase behavior was tested for 1.0 and 2.0 mL of a 0.18 M solution of 1b in toluene. Both systems became monophasic at around 100 bar, and neither precipitation nor phase separation occurred up to a pressure of 200 bar. In the next set of experiments, the solvents toluene, DCM, and methanol were tested as modifier in the batch-wise asymmetric hydrogenation of 1 (Scheme 2) under conditions ensuring homogeneity of the modCO2 phase according to Figure 2. As molecular catalyst in the SILP system, we chose Rh-Quinaphos,33,34 a very effective catalyst for highly enantioselective transformations, including the asymmetric hydrogenation of enamides.34 This catalyst has already been successfully immobilized using the SILP strategy for highly enantioselective asymmetric hydrogenation under a continuous flow with pure scCO2 as a mobile phase.17,18 The SILP catalyst Rh-Quinaphos@SiO2-[EMIM][NTf2] was prepared according to a literature procedure.17 Dehydroxylated SiO2 was used as support material, dried and degassed 1-ethyl3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM][NTf2]) as IL, and [Rh(cod){(Sa ,Rc )-1-NaphQuinaphos}][NTf 2 ] or [Rh(cod){(Ra,Sc)-1-NaphQuinaphos}][NTf2]34 as catalyst precursor (Scheme 1). The immobilization was done via wet impregnation with DCM as a 3299

DOI: 10.1021/acscatal.8b00216 ACS Catal. 2018, 8, 3297−3303

Research Article

ACS Catalysis Table 1. Batch Hydrogenation of 1 with Rh-Quinaphos@SiO2-[EMIM][NTf2] in modCO2a

a

entry

modifier (mL)

ptotal bar

sub

sub/cat mol/mol

conv. %

TOF h−1

ee %

IL leaching %b

1 2 3 4 5

methanol (0.4) methanol (1.0) DCM (0.8) toluene (1.8) toluene (1.8)

200 200 150 150 150

1a 1a 1a 1a 1b

350 350 925 925 925

35 81 62 85 90

7 16 32 44 46

31 62 98 91 >99

16 39 34 98 10 (THF) 0 10 rt 399 99 30 (toluene) 140 150 50 24 99% ee were achieved over 90 h on stream, resulting in a tTON of 10 300 at a STYmax of 24 g L−1 h−1. The metal leaching in the product solutions was below the detection limit (1 ppm), indicating effective catalyst retention. Thus, the new modCO2/ SILP process virtually generated a single enantiomeric product without detectable rhodium impurities fully satisfying the requirements of the pharmaceutical industry for the manufacture of an API. Comparison of the Rh-Quinaphos/SILP/modCO2 catalytic system with other process options reveals distinct advantages for continuous-flow processes. The choice of the preferred immobilization technique for a given transformation depends critically on the compatibility of the molecular chiral catalyst and the support material as demonstrated for Rh-Quinaphos/ SILP and Rh-EtDuphos/Al2O3/phosphotungstic acid in the present case study. Progressing the development of such systems from heuristic planning to rational design still requires a deeper understanding of the underlying interactions on the molecular and the mesoscale. The potential advantages of flow systems for cost-effective and environmentally benign production certainly can serve as motivation for corresponding research at the interface of molecular and material science.

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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/acscatal.8b00216. Description of reactors and procedures used for solubility experiments and preliminary hydrogenation reactions in batch, description of catalyst preparation and continuous flow setup, data and conditions of continuous flow experiments, analytic details (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Walter Leitner: 0000-0001-6100-9656 Giancarlo Franciò: 0000-0002-1546-4858 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the European Union (FP-7 integrated project SYNFLOW) for financial support (NMP2009-3.2-1 no. 246461). We thank Dr. Philipp Oczipka and Dr. Christian Schmitz (both ITMC) for preparation of a large batch of Quinaphos, Dr. Amara Zacharias (The University of Nottingham) for fruitful discussion, Dr. Rebecca E. Meadows and Dr. Robert Woodward (AstraZeneca) for valuable insight into the industrial process and for providing substrate 1b, and Heike Bergstein (ITMC) for ICP-OES measurements.

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REFERENCES

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