Development and Scale-Up of a Continuous Aerobic Oxidative Chan

Article Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Development and Scale-Up of a Continuous Aerobic Oxidative Chan−Lam Coupling Alison Campbell Brewer,*,† Philip C. Hoffman,† Joseph R. Martinelli,† Michael E. Kobierski,† Nessa Mullane,‡ and David Robbins† †

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Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States ‡ Eli Lilly Kinsale Limited, Dunderrow, Kinsale, P17 NY71 Co. Cork, Ireland ABSTRACT: Despite the benefits of high atom economy and low cost, aerobic oxidations have found limited use in the synthesis of active pharmaceutical ingredients (APIs) because of safety concerns and poor selectivity. In this report, the design, development, and scale-up of a continuous, high pressure aerobic oxidation to produce the penultimate of an API are described. The identification of robust homogeneous conditions for the oxidative C−N coupling of interest and the use of diluted air allowed for the process to be safely and selectively carried out on manufacturing scale as a continuous process using a vertical pipes-in-series reactor to prepare high-quality material. KEYWORDS: continuous manufacturing, aerobic oxidation, GMP, homogeneous catalysis, Chan−Lam coupling

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INTRODUCTION Oxidation reactions are important transformations in organic chemistry because they can increase chemical complexity and heteroatom functionality in organic molecules. Molecular oxygen (O2) is the ideal oxidant for these transformations due to its low cost, high abundance, and lack of toxic byproducts when undergoing reactions, making it well aligned to the “green chemistry” priorities of industry.1 Despite the strong economic and environmental advantages of O2, aerobic oxidations are used infrequently in the pharmaceutical industry due to the historically poor activity and selectivity of oxidation methods on complex heterocyclic molecules. Furthermore, there are significant safety and practical concerns surrounding the use of molecular oxygen in the presence of organic solvents, particularly in the multipurpose batch tanks commonly employed by the pharmaceutical industry.2 Recent work has begun to address the safety concerns associated with the use of O2 in the scale-up of aerobic oxidation reactions, making these transformations viable options for pharmaceutical synthesis.3,4 Continuous flow reactors have been demonstrated as safer and more practical alternatives to largescale batch reactors in handling reactive gases, including O2,5 and understanding the limiting oxygen concentration (LOC)6 for reaction solvents has been described to allow for safe operation by designing for conditions which cannot sustain a flame.3d,7 Additionally, significant work in the past decade has greatly improved the selectivity of oxidation methods, increasing their synthetic utility in the preparation of complex molecules.8 One such class of reactions is the copper-mediated coupling of Nnucleophiles with boronic acids, first reported in 1998 by Chan and Lam.9 Since the initial reports, the Chan−Lam coupling has been extensively studied, and mild conditions using catalytic copper and O2 as the terminal oxidant have emerged. In the course of developing a synthetic route to an active pharmaceutical ingredient (API) of interest, we identified the © XXXX American Chemical Society

Chan−Lam coupling of pyrazole 1 and cyclopropylboronic acid (2) as an efficient means of generating 3, the penultimate of the API (Scheme 1).10 Initial conditions developed for the oxidative Chan−Lam coupling mirrored common literature conditions9 and used stoichiometric copper acetate in combination with sodium carbonate in 1,2-dichloroethane under an atmosphere of air (21% O2 in N2) (Scheme 1, conditions A). There are two regioisomers that can form in the cross-coupling reaction depending on which nitrogen in the pyrazole ring is functionalized. When bipyridine was used as the ligand, formation of the desired regioisomer 3 was favored in a 10:1 ratio over 4. These conditions served as a proof-of-concept for the use of a Chan− Lam coupling to construct the key C−N bond, but prior to scaleup of the chemistry, several concerns needed to be addressed. Dichloroethane is a very undesirable solvent in manufacturing,11 and efforts were undertaken to eliminate it from the process. More significantly, addressing concerns related to the safe use of O2 as the terminal oxidant was crucial to running on kilogram scale. Both of these concerns were initially overcome by using a mixture of NMP and water as the reaction solvent. A 2:1 mixture of NMP/H2O exhibited no flash up to 150 °C under 1 atm of air. Because the reaction operated at >25 °C below the flash point of the mixture, the use of bubbling air as the oxidant could be used without the risk of an ignition event, and these conditions were implemented in a 25 kg manufacturing campaign to prepare 19 kg of 3 (Scheme 1, conditions B). Although flammability concerns over the use of O2 were addressed by the NMP/H2O conditions, there were still a number of challenges with the process. The transformation was Special Issue: Honoring 25 Years of the Buchwald-Hartwig Amination Received: March 21, 2019

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DOI: 10.1021/acs.oprd.9b00125 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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Scheme 1. Cu-Catalyzed Chan−Lam Coupling To Form 3

Table 1. Summary of Screening Conditions for the Oxidative Coupling of 1 and 2

entry

ligand

solvent

additivea

yield 3 (%)

3:4

homogeneous?

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18b

bipy bipy bipy bipy bipy bipy pyridine 4,4′-OMe2bipy 4,4′-tBu2bipy bipy bipy 4,4′-tBu2bipy 4,4′-tBu2bipy bipy bipy 4,4′-tBu2bipy 4,4′-tBu2bipy bipy

DMF DMSO acetone NMP THF 2-MeTHF 2-MeTHF 2-MeTHF 2-MeTHF THF 2-MeTHF 2-MeTHF THF THF/DMSO (1:1) 2-MeTHF/DMSO (1:1) THF/DMSO (1:1) 2-MeTHF/DMSO (1:1) THF/DMSO (1:1)

− − − − − − − − − myrisitc acid myrisitc acid myrisitc acid myrisitc acid myrisitc acid myrisitc acid myrisitc acid myrisitc acid myrisitc acid

91 62 85 74 53 43 83 30 84 48 48 63 68 41 47 34 32 89

13.1 11.2 13.3 13.0 12.0 12.0 6.6 13.3 12.3 12.8 13.2 11.9 12.8 14.6 15.0 13.8 14.5 14.9

yes no no no no no no no no no no no no yes no yes no yes

The reaction was run at 75 °C. b2 equiv relative to Cu(OAc)2.

a

scale sensitive and required significantly higher catalyst loadings to achieve high conversion at larger scale. The 25 kg campaign was carried out in a series of continuous stirred tank reactors (CSTRs) to minimize this scale-up effect but still required almost stoichiometric Cu catalyst (0.8 equiv). The reaction mixture was heterogeneous due to poor solubility of the Cu catalyst in the solvent matrix and the use of inorganic base, and 3 was prone to forming an oil layer as the reaction progressed. The

heterogeneity of the reaction mixture led to clogging in transfer lines between the CSTRs on both 1.5 and 25 kg scales. Because of the challenges detailed above, we sought an alternative approach to the design and implementation of the Chan−Lam coupling. In particular, we were focused on designing a process that allowed for safe use of O2 while improving robustness and eliminating scale sensitivity. Although the NMP/H2O solvent system did allow for the safe use of air as B



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a source of O2,12 the presence of water in the system was a liability due to the tendency of 3 to phase separate as an oil. Typically, the use of air in the presence of organic solvents represents a significant safety hazard due to the risk of combustion; however, operating below the LOC of the reaction solvent by using diluted air (e.g., 5% O2 in N2) is a practical approach to safe operation.7 The use of diluted air typically requires elevated pressures and constant gas flow to ensure adequate levels of O2 are present throughout the process. Continuous processing is well-suited to accommodating these pressure and gas flow requirements, and previous experience with vertical vapor−liquid pipes-in-series continuous reactors led us to believe this class of reactors would be well-suited to this case. Herein, we report the development and scale-up of a continuous aerobic copper-catalyzed C−N coupling.

increasing solubility of the copper catalyst in organic solvents. Envisioning that this strategy might improve solubility in our system, we carried out a series of reactions using 2 equiv of myristic acid relative to copper. The solubility of the reaction was significantly improved, and the combination of Cu(OAc)2 with 4,4′-tBu2bipy and myristic acid in 2-MeTHF using iPr2NEt as the base led to a fully homogeneous starting reaction mixture and a good reaction profile (Table 1, entry 12). However, when the reaction was scaled up, the formation of a green precipitate was observed at the end of the reaction. The green precipitate was isolated and, by high resolution mass spectroscopy, was found to be consistent with a [(4,4′-tBu2bipy)Cu(OAc)] complex. The complex was only sparingly soluble in most organic solvents but was found to have appreciable solubility in DMSO. Although DMSO alone had been previously determined to be unsuitable as a solvent for the coupling reaction,18 combinations of DMSO with either THF or 2-MeTHF were explored. Using a 1:1 mixture of THF/DMSO allowed for a fully homogeneous solution at both the beginning and the end of the reaction (Table 1, entry 14). Additionally, 4,4′-tBu2bipy, which is expensive and poorly purged in the workup, could be replaced with bipy and full solubility maintained. The addition of DMSO did slow conversion, so the reaction temperature was increased to 75 °C which improved the rate without a detrimental effect on the reaction profile (Table 1, entry 18). The reaction was scaled up to 1 g in a 100 mL autoclave using 1000 psi of 6.25% O2/N2 as the oxygen source, and the reaction was monitored by online HPLC; full conversion of 1 was achieved in 12 h (Figure 1).

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RESULTS AND DISCUSSION Initial Flow Considerations. Because the vertical pipes-inseries reactor has been shown to accommodate both development- and manufacturing-scale vapor−liquid reactions that require elevated temperatures and long residence times,13 we sought to develop homogeneous reaction conditions for the Chan−Lam coupling that would be amenable to this reactor type. The development of homogeneous reaction conditions required identifying a reaction solvent that fully dissolved the starting materials and product as well as the copper catalyst; additionally, the heterogeneous carbonate base needed to be replaced with a soluble organic base. The solubility of 1, 2, and 3 was measured in a series of solvents, and all species were determined to have high solubility (>250 mg/mL) in NMP, DMF, DMSO, THF, 2-MeTHF, and acetone. These solvents were prioritized for the initial reaction screening which also included several bases that were expected to be soluble in the reaction solvent. In addition to conversion and the ratio of 3 to 4, having a fully homogeneous reaction mixture over the course of the reaction was also prioritized as a key variable (Table 1). Reactions were run in an autoclave pressurized to 900 psi with 6.25% O2 diluted with N2.14 On small scale, this provided a safe way to screen reaction conditions in the presence of a large excess of O2. Amine bases were found to be a suitable, soluble replacement for the K2CO3 used in earlier conditions.15 The combination of DMF and i Pr 2 NEt gave good conversion and a fully homogeneous reaction mixture, providing proof-of-concept for a fully homogeneous Chan−Lam coupling (Table 1, entry 1). However, because DMF is included on the REACH substance of very high concern list,16 it was viewed as an undesirable option. Other solvents, while showing some reactivity and sufficient selectivity for the desired product, did not produce a homogeneous reaction mixture and therefore were not suitable for the pipes-in-series reactor (Table 1, entries 2−6). Several ligands were explored in addition to bipyridine (bipy). The use of pyridine as a ligand led to deterioration in the regioselectivity (Table 1, entry 7). Both 4,4′-OMe2bipy and 4,4′-tBu2bipy showed similar regioselectivity to bipy (Table 1, entries 8 and 9); 4,4′-tBu2bipy also led to improved Cu solubility which may have been reflected in the improved conversion, but the system was still not fully homogeneous. In a 2001 report, Buchwald and co-workers demonstrated that the addition of myristic acid to copper-catalyzed couplings of boronic acids and amines increased the reaction rate.17 The authors propose that this enhancement may be due to coordination of the myristic acid to the copper center, thereby

Figure 1. Reaction kinetics for the conversion of 1 to 3 using Cu(OAc)2/bipy/myristic acid catalyst system.

Reaction Description. After preliminary screening in batch mode (vide supra), we wanted to demonstrate the current optimal conditions in a vertical pipes-in-series continuous reactor. A schematic of the pipes-in-series reactor is shown in Figure 2. Vapor and liquid travel through the reactor in the same direction, up through the large diameter pipes and down through the smaller diameter jumper tubes. There are two flow regimes in this design: segmented flow in the small-diameter tubing connects the vertical pipes which operate as bubble flow. This reactor design provides several practical and safety advantages: 1. The reactor allows for the use of high pressures and flow rates of diluted O2 in N2 so that the reaction can readily be C



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Figure 2. Pipes-in-series reactor design schematic.

Figure 3. Setup of vapor−liquid pipes-in-series reactor.

4. The reactor operates at a higher level of liquid fill than a batch reactor while maintaining oxygen saturation. From a safety perspective, this decreases risk by decreasing the amount of oxygen in the system should an event occur. First-Generation Continuous Runs. With homogeneous coupling conditions in hand, we first explored the transformation in a 75 mL research-scale vertical pipes-in-series reactor. The two continuous feeds used were (1) 1 and 2 in THF/DMSO and (2) Cu(OAc)2, bipyridine, myristic acid, and i Pr2NEt in THF/DMSO. The oxygen source was 8% O2 in N2.19

run below the LOC of the solvent while maintaining an excess of O2. 2. The pipes-in-series reactor design can be readily and reliably scaled from small-volume lab scale (22 mL) up to large-volume manufacturing scale (>300 L).13 This enables rapid development and implementation of aerobic oxidation processes into manufacturing. 3. The configuration of the pipes-in-series reactor allows for excellent vapor/liquid mass-transfer rates, even at low liquid flow rates. D



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Figure 4. Online HPLC data trend for continuous run with 12 h tau at 75 °C using 3 equiv of O2 under 400 psig 8% O2/N2.

Figure 5. Reaction kinetics in the 75 mL pipes-in-series reactor compared to a 100 mL Parr batch reactor.

The block flow diagram for the reaction is shown in Figure 3. The output from the reactor was monitored by online HPLC.20 Based on the reaction rate observed in batch reactions, flow rates were chosen to give a 12 h reaction time (tau). The initial results in the pipes-in-series reactor were consistent with batch experiments. Using 400 psi of 8% O2/ N2 and a gas flow rate to deliver 3 equiv of O2, the reaction reached steady state at 99% conversion and produced 3 in a 15:1 ratio relative to regioisomer 4 at 75 °C (Figure 4). In the continuous reactor, the reaction kinetics can be obtained by sampling at several points along the reactor; in this case, intermediate samples were taken from pipes 11, 21, and 31, with the final reaction sample taken after pipe 40 and the vapor− liquid separator. Because a 12 h tau was used, the sample taken at pipe 11 represented a 3 h tau, the sample taken at pipe 21 represented a 6 h tau, and the sample taken at pipe 31 represented a 9 h tau. The samples at these intermediate points were all taken at the same time after the reactor reached steady state so they are analogous to sampling at different times in a batch reaction. The kinetic profile observed in flow was consistent with that observed in batch runs (Figure 5). A series of pressures and O2 stoichiometries were explored. For the sake of being able to easily compare the reaction rates, the particular pairings of pressures and O2 equivalents were chosen to ensure equal gas volume flow rates and therefore no variation in the actual liquid residence times. Surprisingly, there was minimal effect of different combinations of O2/N2 pressures and flow rates on the reaction rate. Aerobic oxidation reactions are often sensitive to O2 partial pressure and mixing, but these

conditions appeared to be nearly independent of O2 pressure and not mass transfer limited.21 In fact, the observed reaction rate was actually slightly faster with lower O2 pressure and stoichiometry,22 but it appeared to slow after ca. 9 h, and full conversion was not quite achieved in 12 h (97.7%). For additional screening work in the 75 mL pipes-in-series reactor, 400 psi and 3.0 equiv of O2 were chosen going forward because of the reproducibly high steady-state conversion observed. To continue reaction optimization, a series of reaction conditions was examined in flow. A range of reaction temperatures was explored, and the reaction was found to be sensitive to temperature and considerably faster at 90 °C as compared to 75 °C, with minimal change to the impurity profile of the crude reaction mixture (Figure 6A).23 Efforts to reduce the stoichiometry of 2 were not successful at either 75 or 90 °C with the reaction stalling at either temperature when only 2 equiv of 2 was used (Figure 6B). Copper-catalyzed deborylation of boronic acids is known,24 and background deborylation of 2 to produce cyclopropane was found to be competitive with the desired reaction.25 Interestingly, the reaction rate was unaffected by reducing the catalyst loading from 25 mol% to 12.5 mol% (Figure 6C) although follow-up reactions in both batch and flow showed that full conversion was not achieved when the catalyst loading was reduced further.26 Using 12.5 mol% Cu(OAc)2 in combination with 18.75 mol% bipyridine, 25 mol% myristic acid, and 3 equiv of iPr2NEt in 20 vol THF/DMSO (50/50), 3 was formed with a 92% in situ yield in less than 6 h. Process Optimization. Given the preliminary success in carrying out a selective oxidative coupling between 1 and 2 in a E



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Figure 6. Reaction kinetics plots of (A) temperature effect on conversion, (B) stoichiometry of 2 on conversion at 75 and 90 °C, and (C) effect of catalyst loading on conversion at 75 and 90 °C.

of myristic acid in EtOH/H2O mixtures led to poor rejection in the crystallization. Given the importance of myristic acid in achieving a fully homogeneous catalyst system, other long chain carboxylic acid were explored as alternative additives. The addition of 2 equiv of valeric acid relative to Cu(OAc)2 was similarly able to affect copper solubility and led to a comparable reaction profile (Figure 7).27 Because valeric acid has significantly higher water

continuous reactor, we next turned our attention to the reaction workup conditions. It became quickly evident that purging the myristic acid would be problematic. Myristic acid has poor water solubility, even as a carboxylate salt, and could not be removed from 3 using aqueous washes. Attempts to purge the myristic acid by crystallization were also unsuccessful. The use of an EtOH/H2O crystallization solvent had significant advantages to the impurity control strategy (vide infra), and the low solubility F



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Figure 7. Comparison of coupling with myristic acid or valeric acid additives at 75 or 90 °C. i

solubility as compared to myristic acid, it could be readily separated from 3 by aqueous washes.28 Additional reaction optimization demonstrated that the reaction rate was not dependent on the concentration of i Pr2NEt which could be reduced to 1.5 equiv with no change in the reaction profile. The stoichiometry of 2 could be reduced from 3 equiv to 2.75 equiv without reaction stalling but in the interest of maximizing process robustness, we chose to continue using 3 equiv of 2 relative to 1 going forward. As described previously, the reaction rate is unaffected by copper loadings in the range of 12.5−25 mol%. Both the reaction rate and regioselectivity were found to be sensitive to the concentration of bipyridine, with higher ratios of bipyridine relative to Cu giving slower reactions and slightly higher selectivity (Table 2). To maximize both rate and selectivity, we

Pr2NEt, valeric acid, and DMSO from the organic layer, but residual copper remained in the organic layer with 3 which complicated the crystallization. Aqueous solutions which are commonly used to remove copper salts such as NH4Cl, NH4OH, and EDTA were unsuccessful in this case. To address copper removal, treatment of the washed organic solution with a series of copper scavenger resins was explored. Most of the resins tested were able to successfully lower the concentration of copper in the solution, and QuadraSil TA, which contains a diethylenetriamine functional group, looked especially promising. Given the miscibility of diethylenetriamine with water, we hypothesized that it might be possible to use an aqueous solution of diethylenetriamine to extract copper from the organic product solution into the aqueous layer; this approach would be less expensive and more operationally straightforward than a resin treatment. To test the hypothesis, the crude reaction mixture was diluted with 10 volumes of 2-MeTHF and subsequently washed with 10 volumes each of 15 wt% aqueous diethylenetriamine, 1 N HCl, and 5 wt% aqueous NaHCO3. After the diethylenetriamine wash, the concentration of copper in the organic phase was below the limit of detection, and the color of the solution was notably lighter than solutions which had not been subjected to the amine wash. Using this series of aqueous washes, residual diethylenetriamine, iPr2NEt, valeric acid, and DMSO were not detected in the resulting 2-MeTHF solution of 3. The workup proved to be very robust across a range of scales and always resulted in solutions of 3 with Cu levels below the limit of detection (Table 3).30 The ethanol/water crystallization used in the previous campaign exhibited excellent rejection of regioisomer 4 and proved successful in this case as well. The 2-MeTHF solution of 3 could be solvent exchanged with ethanol and diluted with water to give a solution of 3 in 3 volumes of ethanol and 1 volume of water at 45 °C. Slow addition of an additional 3.5 volumes of water, seeding with 1% 3 at 45 °C, cooling to 5 °C, and filtering the resulting slurry afforded 3 in good yield and high purity with

Development and Scale-Up of a Continuous Aerobic Oxidative Chan

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