Sequential α-lithiation and aerobic oxidation of an arylacetic acid - continuous-flow synthesis of cyclopentyl mandelic acid
The development of a multistep continuous-flow process, consisting of a direct α-lithiation stage and subsequent hydroxylation by aerobic oxidation, is reported. The protocol is applied to the synthesis of cyclopentylmandelic acid (CPMA), the main building block for the anticholinergic glycopyrronium bromide (glycopyrrolate). We demonstrate the safe utilization of organolithium reagents and molecular oxygen in combination by using a continuous-flow protocol. The first stage involves the formation of a di-lithium enolate intermediate, which was either pre-formed in batch or formed in flow by using n-hexyllithium as a cost-effective and industrially safe base. The subsequent hydroxylation stage utilized molecular oxygen under homogeneous and mild conditions (atmospheric pressure and room temperature) to give the desired product. A diluted form of oxygen gas, consisting of less than 10% O2 in N2 (“synthetic air”), is used in pharmaceutical batch manufacturing to effectively address safety concerns when handling molecular oxygen. The telescoped flow process afforded the target intermediate in 65% solution NMR yield (50% isolated yield after re-crystallization). The continuous-flow process opens up new opportunities for the manufacture of CPMA, with a protocol which can safely handle pure O2, and compares favorably with existing Grignard-based batch processes.
KeywordsGlycopyrrolate (glycopyrronium bromide) Cyclopentyl mandelic acid (CPMA) Continuous-flow Gas-liquid transformations Molecular oxygen Organometallics
There are two further methods that are less likely to be used at industrial scales due to safety concerns and the very low reaction temperatures employed (routes E and F). Dichloromethane is deprotonated by n-butyllithium (n-BuLi) at −100 °C and reacted with phenyl-cyclopentyl ketone, which is subsequently hydrolyzed and oxidized with potassium permanganate to give 1 (route E) . The highest yielding reported protocol utilizes molecular oxygen for the hydroxylation of cyclopentyl phenyl acetic acid (route F). Adam and Cueto described the formation of lithium carboxylate 17 at −60 °C by an equivalent of n-BuLi, and after 60 min the second equivalent of n-BuLi formed the di-lithium enolate 18 at −40 °C. Oxygen was then bubbled through the α-lithiocarboxylate solution at room temperature . CPMA (1) was prepared by the procedure described by Adam and Cueto in a remarkable 85% isolated yield . However, the authors noted that “the system was very sensitive to reaction conditions and required particular attention, in the presence of excess n-BuLi (equivalent ratio 0.9:1), to the exposure of the base and to the bubbling oxygen.” The inverse addition of di-lithiated carboxylic acid to a solution with bubbling oxygen at low temperature (−78 °C) afforded the α-hydroperoxy acids . Moersch and Zwiesler were the first to report a procedure for the synthesis of α-hydroxycarboxylic acids from their corresponding carboxylic acids by using air as the oxygen source . Air was bubbled through a solution of the di-lithiated carboxylic acid at room temperature over a prolonged time (18 h) to prepare the α-hydroxycarboxylic acids in low to moderate yields.
Molecular oxygen is highly abundant, environmentally benign, inexpensive and easy to separate from product mixtures. However, it is underutilized in organic synthesis due to safety concerns, particularly at large scales . Historically, the pharmaceutical industry has used batch processes for the manufacture of active pharmaceutical ingredients (APIs). Within a batch reactor, high concentrations of oxygen/organic vapor would exist within the headspace when using O2 gas, which is a large inventory of a potentially flammable mixture. A common strategy applied in pharmaceutical manufacturing is to operate below the limiting oxygen concentration (LOC) value by using a diluted form of oxygen gas, consisting of less than 10% O2 in N2 (“synthetic air”) . The LOC value is defined as “the minimum partial pressure of oxygen that supports a combustible mixture”. Operating below the LOC value ensures the oxygen/organic vapor never enters the explosive regime. However, there can be limitations in terms of process efficiency, including reaction rate and product selectivity, in using diluted air in comparison to pure air. Alternatively, the recent transition from batch to continuous processing in pharmaceutical manufacturing has enabled the safe handling of hazardous chemistry , including the ability to handle liquid-phase aerobic oxidations, even at large scales . The precise temperature control and the small channel dimensions of continuous-flow reactors provide a high surface-to-volume ratio enabling the generated heat to be dissipated quickly. With sufficient understanding of a reaction system and adequate process design to address safety concerns and mitigate risks, aerobic oxidations utilizing pure molecular oxygen can be adopted at large scales through the utilization of appropriate continuous-flow processing systems . In addition, pioneering work by Yoshida and others have demonstrated organometallic reagents can be handled at higher temperatures than the standard cryogenic conditions applied under batch conditions when using continuous-flow reactors . Based on the success reported by our group and others for liquid-phase oxidations using continuous-flow reactors, we were encouraged to explore the development of a continuous-flow process for route E as a safe and cost-effective alternative to the existing synthesis strategies. We herein report the development of a multistep continuous-flow protocol for CPMA (1) synthesis via the hydroxylation of cyclopentylphenylglycolic acid by using organolithium reagents and molecular oxygen.
We commenced our studies by examining the critical parameters in batch experiments. The di-lithium enolate 18 formation by reaction of cyclopentylphenylglycolic acid (16) with n-BuLi, and the subsequent hydroxylation of the di-lithium enolate by using O2 were studied separately. α-Phenylcyclopentylacetic acid (16) was reacted with n-BuLi and then trapped by deuterium oxide (D2O) with the optimal base equivalents and temperature evaluated (Table S1). D2O is a liquid at room temperature and therefore was easier to handle than O2 gas for preliminary studies. Conditions were sought that kept the lithium species in solution to ensure the reaction was amenable to flow processing. The lithium carboxylate intermediate 17 was identified to be particularly prone to precipitation when using THF/hexanes in 50/50 ratio. The monolithium intermediate precipitation was avoided by adding the n-BuLi as a single portion, rather than as two separate portions, and by using a solvent composition ratio of THF/hexanes ≥77/23. The batch experiments showed that the di-lithium enolate was successfully formed after trapping with D2O in 87% yield with 3 equivalents of n-BuLi at 25 °C and a reaction time of 5 min.
Preliminary batch investigation of hydroxylation by using molecular oxygena
Continuous-flow optimization for hydroxylation step using a pre-formed enolate with HexLia
Continuous-flow optimization for sequential α-lithiation using HxLi and aerobic oxidation
In conclusion, a continuous-flow protocol was developed for the synthesis of cyclopentylmandelic acid (CPMA, 1), an important intermediate in the synthesis of glycopyrronium bromide (glycopyrrolate). The two reaction steps were investigated separately in batch and in flow to identify the critical parameters. The system was very sensitive to changes in the reaction conditions and equipment configuration. The process was developed to utilize n-hexyllithium as an industrially suitable base. O2 gas could be dosed continuously in a safe and accurate manner using a mass-flow controller for the aerobic oxidation step. It was identified that low equivalents of O2, atmospheric pressure and room temperature favored the desired product. On the other hand, high concentrations of oxygen, high pressure and low temperatures favored the undesired oxidative decarboxylation pathway to form a ketone side product. The lithiation reaction proceeded with 5 min residence time and the aerobic oxidation with 18 min residence time to give the target compound in 65% solution NMR yield (50% isolated yield after re-crystallization) under the optimal reaction conditions . This yield is superior to the yields obtained applying traditional Grignard-based protocols (Scheme 2).
Representative procedure for the preparation of CPMA  using continuous-flow conditions (Table 3, entry 4)
Flow experiments were performed using the continuous-flow setup depicted in Table 3. A 2.3 M solution of n-hexyllithium in hexane was introduced through a sample loop. The liquid feed containing n-hexyllithium in hexane was pumped using a syringe pump (Syrdos) with a flow rate of 119 μL/min, using THF as a carrier solvent. A 0.19 M solution of α-phenylcyclopentylacetic acid (16) in THF (anhydrous) was pumped directly through the second syringe pump (Syrdos) with a flow rate of 481 μL/min. The two streams were mixed using a T-piece into a tubular reactor (3 mL, 0.8 mm internal diameter, PTFE coil) to provide 5 min residence time. The T-piece and reactor were submerged within an ultrasound bath at 25 °C to avoid lithium salt precipitation within the channel. On formation of the di-lithium enolate within the solution an intense dark red color was observed. The third feed consisted of O2 gas and was dosed at a flow rate of 1.28 mLn/min with a calibrated mass flow controller (EL-Flow, Bronkhorst). The gas flow rate was measured in units of mLn/min (n represents measurement under standard conditions: Tn = 0 °C, Pn = 1.01 bar). The enolate solution and molecular oxygen were mixed using a Y-mixer into a tubular reactor (11 mL, 0.8 mm internal diameter, PTFE coil) at room temperature to give a homogeneous solution and providing 18 min residence time. The pressure was maintained at 1 bar by using a back pressure regulator (Zaiput). The output material was collected for one residence time worth of material (23 min) within a round bottom flask containing MeOH (4 mL) under N2. The solution obtained was then evaporated under reduced pressure. Crystallization was achieved with hexane/chloroform (9:1). The chloroform was removed under reduced pressure which resulted in product precipitation. Subsequent filtration afforded pure CPMA (1) (230 mg, 1.05 mmol, 50% yield). 1H-NMR (300 MHz, CDCl3) δ: 7.68 (2H, d, J 8.1 Hz), 7.42–7.3 (3H, m), 2.95 (1H, q, J 8.2 Hz), 1.76–1.28 (8H, m). 13C-NMR (75 MHz, CDCl3) δ: 180.64, 141.13, 128.36, 127.90, 126.02, 79.30, 47.32, 27.08, 26.56, 26.44, 26.03.
Open access funding provided by University of Graz.
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