Development of a small volume continuous process that used a combination of batch and flow unit operations to manufacture the small molecule oncolytic candidate merestinib is described. Continuous ...processing was enabled following the identification and development of suitable chemical transformations and unit operations. Aspects of the nascent process control strategy were evaluated in the context of a 20 kg laboratory demonstration campaign, executed in walk-in fume hoods at a throughput of 5–10 kg of active pharmaceutical ingredient per day. The process comprised an automated Suzuki–Miyaura cross-coupling reaction, a nitro-group hydrogenolysis, a continuous amide bond formation, and a continuous deprotection. Three of the four steps were purified using mixed-suspension, mixed-product removal crystallizations. Process analytical technology enabled real-time or nearly real-time process diagnostics. Findings from the demonstration campaign informed a second process development cycle as well as decision making for what steps to implement using continuous processing in a proximate manufacturing campaign, which will be described in part 2 of this series.
A fully automated fill/empty reactor system for liquid–liquid biphasic Suzuki couplings is described. The system was capable of charging reactant and catalyst solutions to a heated vessel, heating ...reagent solutions by flow heat exchanger on the way into the reactor, allowing the reaction to occur, monitoring reaction completion, discharge of the product solution, and initiation of another cycle in a repeating fashion. A unique noncontact colorimetric method was used to monitor reaction completion. The reactor system exhibits many of the characteristics of a fully continuous reactor such as (1) high productivity from a small process footprint, (2) a large number of volume turnovers each day, (3) higher heat transfer area per unit volume compared to batch because the reactor is 50× smaller, and (4) rapid heat up and cool down of process streams enabled by heat exchangers. Downstream unit operations that are intended for eventual integrated end-to-end continuous production included a batch metal removal step and a continuous antisolvent crystallization to isolate the product in high yield and purity.
The hazard assessment of a telescoped Miyaura borylation and Suzuki coupling reaction employing bis(pinacolato)diboron (BisPin), used in the developmental synthesis of an intermediate for ...abemaciclib, led to the observation of hydrogen being generated. Quantitative headspace GC and solution 11B NMR were used to show that the rapid decomposition of the excess BisPin from the borylation under the aqueous basic conditions of the Suzuki reaction was responsible for H2 generation. The moles of H2 observed were found equal to the BisPin excess, which is rationalized by mass balance and a stoichiometric reaction. The possible generation of the stoichiometric levels of H2 should be considered in hazard assessments of this class of reaction. Kinetic and process modeling was used to minimize the risk upon scale-up, and results for commercial manufacturing batches are presented, which showed good agreement with the lab scale data. Furthermore, the hydrogen evolution potentials of other common borylating agents including bisboronic acid (BBA) and pinacol borane were demonstrated.
Technology transfer of a small volume continuous (SVC) process and Current Good Manufacturing Practices (cGMP) manufacturing of merestinib are described. A hybrid batch-SVC campaign was completed at ...a contract manufacturing organization under cGMP. The decision process by which unit operations were selected for implementation in flow for the cGMP campaign is discussed. The hybrid process comprised a Suzuki–Miyaura cross-coupling reaction, a nitro-group hydrogenolysis, a continuous amide bond formation, and a continuous deprotection. A continuous crystallization using two mixed suspension, mixed product removal (MSMPR) crystallizers and a filtration with in situ dissolution were employed for purification between the two SVC steps. Impurity levels were monitored using both online process analytical technology (PAT) and offline measurements. The continuous processing steps operated uninterrupted for 18 days to yield the drug substance in solution at a throughput of 12.5 kg/day. Crystallization in batch mode afforded 183 kg of the drug substance in specification. Success of the campaign was attributed to robustness of the control strategy and to the multiyear partnership in continuous manufacturing between the development organization and the contract manufacturer. Key learnings are offered from the perspectives of both the development organization and the contract manufacturer.
Boronic esters and acids are potential intermediates in the manufacture of many active pharmaceutical ingredients (API). Accurate quantitation of the intermediate is necessary to assure the ...stoichiometry of the reaction. The analysis of these compounds is challenging due to their labile nature. For example, the boronic ester can hydrolyze to the acid during storage, when exposed to moisture in the air, during sample preparation and analysis, and thus give erroneous ester results. Traditional analytical techniques like gas chromatography (GC), normal phase chromatography (NPLC), hydrophilic interaction chromatography (HILIC), and reversed phase liquid chromatography (RPLC) have been utilized but with noted limitations such as poor peak shape, variation in retention times, and evidence of hydrolysis. All of these limitations impact accurate quantitation needed for selected situations. For the proprietary boronic ester evaluated here, these traditional techniques were insufficient for the accurate determination of assay and residual boronic acid. Non-aqueous capillary electrophoresis (NACE) is an accurate quantitative technique that can be used to analyze boronic esters and their corresponding acids without the limitations noted for traditional analytical techniques. The present study describes the development of methodology for the determination of the potency of a proprietary boronic ester as well as methodology for the determination of residual boronic acid in the ester. In addition, nine model boronic ester and acid pairs with a range in polarity, based on the electronic properties of the attached side group, were tested to evaluate and demonstrate the general applicability of these conditions. Under the conditions used for potency, all ten pairs had a resolution between the boronic ester and acid of greater than 1.5, acceptable peak shape for the boronic ester (tailing factor of less than 2.0), and a run time of less than 3min. In addition, this work describes the development of methodology to determine residual levels of boronic acids in the corresponding boronic ester. Using the ten boronic ester and acid pairs, eight of the ten pairs were shown to have acceptable sensitivity (S/N of 10 or better at 0.5%) and spike recoveries (within the range of 80–120%). The potential for hydrolysis during analysis was also addressed by using a subset of the ten boronic ester and acid pairs and spiking water into the diluent. There was no observed conversion of the ester to the acid. The lack of hydrolysis during analysis and the high success in separating and validating these methods for the boronic ester and acid pairs supports the utility of NACE as a technique for the analysis of boronic esters and acids.
A commercial synthesis was developed for the production of (4-benzylmorpholin-2-(S)-yl)-(tetrahydropyran-4-yl)methanone mesylate, 1a, a key starting material for a phase 2, new investigational drug ...candidate at Eli Lilly and Company. The target compound was produced in the clinical pilot plant by the combination of two key steps: resolution of a morpholine amide intermediate to install the S-morpholino stereocenter in 35% yield and a high-yielding (89%) Grignard reaction to generate the title compound 1a, isolated as a mesylate salt. The Grignard reaction was found to proceed optimally when using a combination of I2 and DIBAL-H for the initiation. In addition, the Grignard reagent formation was monitored by ReactMax calorimetry, and proof-of-concept studies were completed, demonstrating that the Grignard step could potentially be run as a continuous process with magnesium recycling.
A pilot-plant scale desymmetrization of the cyclic meso-epoxide 4b, using a chiral lithium amide prepared from symmetrical diamine 17, was designed and implemented to provide allylic alcohol 3b in ...high yield and greater than 99% ee. This chiral alcohol was converted to ketone 2b, a key intermediate in a new asymmetric synthesis of LY459477. Chiral diamine 17 was prepared from a readily available chiral precursor, (R)-α-methylbenzylamine, and could be recovered from the reaction mixture and reused. Studies performed to probe the mechanism of the rearrangement reaction of epoxide 4b showed that diamine 17 provided an optimal combination of selectivity and scaleability for this process.
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