A batch process was developed to produce 1-(azidomethyl)-3,5-bis-(trifluoromethyl)benzene, 1, in 94% yield by an efficient nucleophilic substitution reaction between 3,5-bis-(trifluoromethyl)benzyl chloride, 4, and sodium azide. Hydrazoic acid (HN3), a toxic volatile compound with explosive properties, can be formed in the reactor headspace during conventional batch processing that requires significant engineering controls. In order to improve the overall safety profile, the process to produce azide 1 was optimized for operation in a microcapillary tube reactor. In addition, azide 1 was prepared in a simple biphasic solvent system using phase-transfer catalysis which results in an overall low e-factor. The product was purified via wiped film evaporation (WFE) technology.
This paper presents a case study
in establishing the operation
space of a Grignard reaction in a continuous stirred tank reactor
(CSTR). The operation space is the multivariate space with the boundary
defined by the proven acceptable range of every CSTR process parameter
such as flow rates and temperature. The mapping of the operation space
was conducted by a thorough understanding of reaction kinetics, magnesium
(Mg) sequestration efficiency, equipment characterization, and the
impact of process disturbances has on steady state. A fit-for-use
reaction kinetics model was developed to parametrize the kinetics
and mass transfer rates of the batch Grignard reaction across different
scales from 250 mL to 500 gallons. The reaction kinetics model was
applied to design the Mg recharge frequency accounting operational
variability to ensure a state of control can be maintained. Furthermore,
reactor temperature was determined to be suitable to detect process
failures to ensure process safety and product quality at manufacturing
scale. Computational fluid dynamics (CFD) models were also applied
to aid equipment design to maximize Mg sequestration in the CSTR.
Based on the optimal equipment design, the unit operation was scaled-down
to test the sequestration efficiency. The resulting process understanding
enabled the team to define the final operation strategy to ensure
a safe and robust commercial process.
A commercial synthesis was developed for the production of (4benzylmorpholin-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 I 2 and DIBAL-H for the initiation. In addition, the Grignard reagent formation was monitored by ReactMax calorimetry, and proofof-concept studies were completed, demonstrating that the Grignard step could potentially be run as a continuous process with magnesium recycling.
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.
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