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Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX pubs.acs.org/OPRD

Safe Scale-up of an Oxygen-Releasing Cleavage of Evans

Oxazolidinone with Hydrogen Peroxide
Andrew W. Glace,*,† Benjamin M. Cohen,† Darryl D. Dixon,† Gregory L. Beutner,† Dale Vanyo,‡
Fulya Akpinar,† Victor Rosso,† Kenneth J. Fraunhoffer,† Albert J. DelMonte,† Edgar Santana,‡
Christopher Wilbert,† Frank Gallo,‡ and William Bartels‡
†
Chemical and Synthetic Development and ‡Research and Development External Manufacturing, Bristol-Myers Squibb Company,
One Squibb Drive, New Brunswick, New Jersey 08903, United States
*
S Supporting Information
See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

ABSTRACT: In the pharmaceutical industry, H2O2-mediated oxidation reactions are commonly used in chemical syntheses
but they can also introduce unexpected safety hazards. Our labs recently reported on the discovery of oxygen evolution during
the LiOH/H2O2-mediated cleavage of Evans oxazolidinone. Faced with this previously unexpected hazard, the authors, herein,
Downloaded via 112.201.74.137 on January 16, 2020 at 03:16:51 (UTC).

report on the development and demonstration of a methodology for the safe scale-up of this O2-releasing reaction. It was found
that O2 in the headspace could be controlled by a combination of N2 sweeping and modulation of the LiOH addition rate. A
design of experiment study was used to probe the multivariate parameter space in order to minimize formation of the unstable
peracid intermediate, thus avoiding accumulation and subsequent risk of rapid and uncontrolled O2 release. To support scale-
up, the well-mixed vapor headspace assumption was tested using computational fluid dynamics, and it was found that N2
sparging is effective at reducing heterogeneity in the headspace. Condenser conditions were evaluated to balance recovery of
solventbecause of the high N2 sweepand avoid the risk of condenser freezingbecause of the presence of water in the
condensate. An additional fail safe was developed, using a pH buffer to rapidly halt the base-catalyzed reaction in the case of an
unexpectedly high headspace O2 concentration. The final process was validated and executed at up to 215 kg scale.
KEYWORDS: safety, hydrogen peroxide, oxygen, process analytical technology

■ INTRODUCTION
Oxidation reactions often play roles in syntheses of active
pharmaceutical ingredients (APIs) and chemical intermediates.
Depending on the desired products, oxidations can be carried
out with a variety of reagents, including pure oxygen (O2),
acids, hydrogen peroxide (H2O2), and air.1−4 If carried out
using common organic solvents, reactions involving these
reagents introduce the risk of fire and/or explosion. In typical
operations involving flammable or combustible liquids, the
main strategy to reduce the risk of fire is to control or eliminate
as many elements of the “fire triangle” (fuel, O2, and ignition
source) as possible. Primarily, this is accomplished through
eliminating or reducing the O2 concentration to below lower
explosive limit values and through selecting proper equipment
to eliminate sources of ignition. This strategy normally
materializes in the form of well-sealed, electrically classified
equipment, positively pressurized inert atmospheres, and
protocols to avoid air intrusion during material additions.5
The approach is coupled with appropriate electrical grounding
and bonding to reduce the risk of static accumulation and
dangerous discharge that could serve as an ignition source in
the event of inertion failure.6 While these protocols are
sufficient for most operations, additional consideration is
necessary when O2 is either purposely introduced or released
as a byproduct.
As part of the synthesis of a key pharmaceutical
intermediate, the authors dealt with the consequences of
previously unexpected O2 byproduct release in LiOH/H2O2-
mediated cleavage of Evans oxazolidinone. A common and
inexpensive oxidizing reagent, H2O2, is widely known for being
unstable and explosive in its pure form. Industrially, it is most
commonly used in dilute aqueous solution, stabilized with an
acid buffer to prevent natural degradation to O2 and water that
is accelerated under basic conditions. While H2O2 can release
O2 on its own, it can also participate in oxidative reaction
pathways, leading to the generation of stoichiometric amounts
of O2 with fast reaction kinetics. Such cases have been reported
in the literature.7−9 However, the risk of O2 release during the
LiOH/H2O2-mediated cleavage of the Evans oxazolidinone
was not widely known until our discovery during the
development of an API synthesis, utilizing this reaction.10
Given the stage of development, clinical supply delivery
timelines, and the lack of readily workable alternatives, we were
tasked with devising a means of safely scaling up the reaction.
Our previous publications describe the work done to
understand the mechanism for O2 formation, the use of
continuous reactors as a strategy to mitigate safety risks, and a
new methodology leveraging Lewis acid catalysis to obviate the
use of H2O2.10,11 In this paper, the authors instead focus on the
development of engineering controls put in place to ensure the
safe and effective scale-up of the LiOH/H2O2 cleavage of
Evans oxazolidinone from 1 (Figure 1) with semi-batch
processing. The development of a data-driven O2 control
Received: October 25, 2019

© XXXX American Chemical Society A DOI: 10.1021/acs.oprd.9b00462

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Figure 1. Production of 3 by cleavage of Evans oxazolidinone 5 using H2O2 and LiOH. 4 is the primary impurity generated.
strategy, attained via thorough understanding of parametric
effects, facilitated identification of a process amenable to
various equipment configurations and manufacturing facilities.
We developed a number of techniques generally applicable to
all O2-releasing processes, such as O2 identification and the use
of quantified gas flows to create computational fluid dynamics
(CFD) models. We also present plant-scale O2 release data and
contingency plans to ensure safe operations. Further, this work
reveals the magnitude and behavior of the O2 release
associated with the commonly executed cleavage of Evans
oxazolidinone using LiOH/H2O2.
■ SAFETY ASSESSMENT
The risk of O2 generation was originally identified during
development of this reaction, with the goal of improving
selectivity for 3 over the ring-opened impurity 4. From
reaction profiling, we found that the expected intermediate
lithium peracid 2 was not stable and was spontaneously
reduced to 3. The balanced reaction of the peracid reduction
indicated that O2 was a likely byproduct. Because this process
was planned for scale-up to multi-kg scale, safety testing was
performed to assess thermal hazards related to the reaction, as
well as the risk of O2 generation. A combination of traditional
and process analytical technology (PAT) tools was used,
including the Advanced Reactive System Screening Tool
(ARSST, Fauske & Associates, LLC), the CRC90 calorimeter
(Omnical, Inc.), mass flow meter (Brooks Instrument), the
RX-10 integrated lab interface (Mettler Toledo), the InPro
6850i G amperometric O2 sensor (Mettler Toledo), M800
multiparameter transmitter (Mettler Toledo), and the
SevenMulti pH meter and associated probes (Mettler Toledo).
The ARSST and CRC90 were used to establish off-gassing.
The other tools were used to characterize the reaction as a
function of process parameters and monitor O2 during
execution at larger scales.
The initial experiment identifying O2 release is shown in
Figure 2. In this small-scale lab experiment, the auxiliary
cleavage was carried out in a stirred reactor, with slight N2
positive pressure via a bubbler. 1 was dissolved in 7.5 L/kg
tetrahydrofuran (THF) to which was added 4.6 equiv of H2O2
followed by 1.6 equiv LiOH (7.9 wt % in water). Then, the
reaction was aged at 20 °C. An InPro 6850i G probe was
inserted into the reactor headspace, the O2 concentration was
read with the M800 transmitter, and the reaction conversion
was determined by high-performance liquid chromatography
(HPLC). This experiment confirmed that O2 was indeed
released concurrently with reaction conversion. We were very
surprised to find that the headspace reached 82% O2,
indicating that a significant amount of O2 was generated
during the reaction. Upon reaching this level of O2, the N2 flow
was increased to purge the system. Though this reaction was
B DOI: 10.1021/acs.oprd.9b00462
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Figure 2. Initial experiment resulting in detection of off-gassing. All of
the reagents were mixed instantaneously, and headspace O 2
concentration and reaction conversion were monitored.
conducted at small scale (15 g) in a fume hood with the sashes
closed, it is not recommended to repeat this experiment. The
high headspace oxygen concentration introduced a significant
challenge for controlling the “fire triangle” and an immense
flammability risk. The process could not be scaled-up as
originally run. Given the reaction performance with the all-in-
one approach, the team hypothesized that the LiOH flow rate
could control the O2 generation rate.
Using this hypothesis, the typical order of operations tested
in subsequent experiments was as follows: (1) dissolving 1 in
7.5 L/kg THF, (2) charging 4.6 equiv H2O2, and (3) adding
1.6 equiv of 7.9 wt % LiOH in water solution over a variable
time period. The target temperature was 25 °C throughout the
reaction. The order of reagent addition was set by the need to
achieve selectivity for the product 3 compared to the ring-
opened impurity 4. After the positive identification of O2, the
magnitude of O2 release was investigated with pressure
measurement experiments in the ARSST. These experiments
were conducted by charging the LiOH solution instanta-
neously, sealing the system, and monitoring the pressure
increase over time, as shown in Figure 3. The experiment was
run at room temperature. A control experiment, in the absence
of 1, was also performed. Both experiments showed a pressure
rise, indicating O2 generation, but was much greater in the
presence of 1, indicating two modes of O2 generation. The
large instantaneous spike early in the experiment with 1 was
attributed to the Evans cleavage while the slowly rising
pressure throughout the experiment was attributed to the
known decomposition of H2O2 under basic conditions.12 This
strong variation in the O2 release rate has been shown in other
basic systems as well.13 Scaling the pressure rises using the
ideal gas law and the amount of 1 input, it was calculated that
up to 52 L O2 per kg of 1 could be released. Considering
typical batch reactor sizes and the process volume, this amount
of O2 release would be sufficient to completely displace the
reactor headspace, creating a significant flammability risk.
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development Article

experiments 3 and 6 demonstrate that reduction of the LiOH

Figure 3. Pressure rise of the reaction system with and without
compound 1.
Several additional experiments were conducted with the
CRC90, which measures off-gassing by volume displacement.
The LiOH solution was added via a syringe pump to the
magnetically stirred test tube reaction vessel. The results of a
typical experiment are shown in Figure 4. A summary of all the
flow rate is an effective technique for reducing the maximum
O2 release rate. Also, experiments 4−6 show that reduction in
H2O2 equivalents is not effective at reducing the O2 release
rate or the total amount of O2 released. Finally, all of the
experiments show approximately 1 equiv of O2 is released in
each case, which provided corroborating evidence in our
understanding of the reaction pathway.10
Another component of the safety assessment was determin-
ing a maximum safe concentration of O2 in the reactor
headspace. The team tested the limiting O2 concentration
(LOC), defined as the minimum O2 concentration required for
combustion,14 for the THF−water solvent system in which the
reaction would take place. Both pure THF and THF−water
4.4:1 volumetric ratio mixture were evaluated by varying O2
headspace concentration and testing for ignition in a sealed
sphere.15 The results showed an LOC of 9.9% (by volume) for
THF and 10.1% for the THF−water mixture. These results are
in line with those for other solvents.16 With these results, we
decided to set an acceptable maximum limit of 5% O2 in the
headspace, with a target operating level of <2.5%.

Figure 4. Results of a typical CRC90 experiment. 1.6 equiv of LiOH
solution was charged over 1 h maintaining the test tube reactor in a 25
°C bath.
CRC90 experiments is shown in Table 1. These experiments
provide a number of valuable insights. For example, the
differences in maximum O2 release rate between experiments 1
and 2, which were replicates, suggest release rate variations
because of mixing effectiveness. Because of a small stir-bar size,
the reaction vessel in the CRC90 is likely to have poorly mixed
regions that could lead to unsteady reaction and O2 release.
For example, imperfect mixing could lead to a region with a
locally high ratio of peracid 3 to H2O2. This could lead to a
local dearth of reducing agent and longer lived peracid,
resulting in a higher O2 release rate later in the experiment.
Therefore, the variance between experiments 1 and 2 suggests
that vigorous mixing is a requirement for scale-up. Further,
■ REACTION CHARACTERIZATION
Following the safety assessment, the team considered various
possibilities to mitigate the O2 risk. Reducing the H2O2
equivalents resulted in impurity generation above tolerable
limits.10 Changing the order of addition was also investigated.
However, 1 in the presence of LiOH alone forms almost
exclusively the impurity 4. Premixing high amounts of H2O2
with LiOH and adding 1 was undesirable because of the
natural decomposition of H2O2 which would lead to a
continually increasing ratio of LiOH/H2O2, which harms
selectivity. These results are summarized in Table 2.
Table 2. Summary of Order Addition Change Experimentsa
LiOH (equiv) H2O2 (equiv) conversion 3:4 selectivity
a
2.0 0 >99 1.2:98.8
1.6b 1.7 >99 68.2:31.8
1.6b 4.6 >99 96.0:4.0
a
1 was mixed with THF and LiOH. bA solution of 1 in THF was
added to the mixture of LiOH and H2O2.
We also performed the reaction in a laboratory scale
continuous stirred tank reactor (CSTR). While proof-of-
concept was obtained with a different base (tetrabutylammo-
nium hydroxide), there was insufficient time to fully develop
the technique for scale-up.10 Another option using lanthanide-
based Lewis acids for Evans oxazolidinone cleavage developed
specifically to circumvent O2 generation was explored.11

Table 1. Summary of Gas Flow Data Collected Using the CRC90a

input H2O2 temperature LiOH addition time max O2 flow rate total O2 released total O2 released
experiment (ga) (equiv) (°C) (min) (L/min kga) (L/kga) (equiv)
1 0.85 4.6 25 60 2.5 61.6 1.12
2 0.85 4.6 25 60 1.6 59.9 1.09
3 0.85 4.6 25 240 0.5 61.6 1.12
4 0.85 2.5 25 60 1.7 58.3 1.06
5 0.85 3.5 25 60 1.7 62.3 1.13
6 0.85 2.5 25 240 0.3 46.5 0.85

a
Results are expressed on a mass basis of 1.

C DOI: 10.1021/acs.oprd.9b00462
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Figure 5. Experimental setup used to conduct parameter exploration experiments.
However, like the CSTR approach, time did not permit full
development and implementation to support the scale-up
timelines and program milestones. Therefore, the team focused
on developing the controls to safely scale-up the LiOH/H2O2
chemistry. To achieve this goal, the team needed to understand
the variables controlling O2 release and provide a robust
parameter operating space amenable to execution at a variety
of facilities.
The first step was to propose a control strategy involving
feedback control with PAT. In the lab, O2 monitoring was
accomplished with the InPro 6850i G probe in conjunction
with the reporting and control software of Mettler Toledo RX-
10. The laboratory setup diagram is shown in Figure 5. The
crucial aspect of this experimental setup was positioning the O2
probe downstream of the condenser in an empty reactor. This
was required because the O2 probe was found to give
inaccurate data if solvent droplets condense onto the probe
surface. Also, operation in a stirred tank reactor reduced the
risk of uncontrolled variations because of poor mixing. N2 was
supplied via a rotameter at a well-controlled flowrate to dilute
the O2 in the headspace to <5% at all times. LiOH solution was
delivered via a pump controlled by the RX-10.
Using this experimental setup, the initial objective was to
confirm whether O2 release could be controlled with the LiOH
solution charging rate. To test this phenomenon, the O2
content of the reactor headspace effluent was continuously
monitored while charging LiOH solution. The LiOH flow was
paused and restarted several times, resulting in concurrent
changes in headspace O2. The results are shown in Figure 6.
The reaction was found to be addition controlled, which then
formed the basis of our scale-up control strategy. The short lag
time between changes in the addition rate and the response in
the O2 trend is attributed to the void space between the reactor
and the probe. At the N2 flow rate used in this experiment, the
time required for the vapor to traverse the void space was
calculated at approximately 20 s. Also considered was the
solubility of O2 in the reaction mixture. Based on solubility
measurements in similar solvents,17 the solubility of O2 is likely
0.02−0.2 equiv. Therefore, saturation of the liquid phase with
O2 likely contributes to a portion of the time lag. This
D DOI: 10.1021/acs.oprd.9b00462
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Figure 6. Experiment demonstrating control of O2 release.
experiment confirmed that N2 sweep through the reactor was a
viable part of the O2 control strategy. Further experimentation
revealed that with LiOH addition time from 1 to 24 h, O2
generation consistently tracked with reaction conversion, and
the varying charge rate did not affect the final reaction purity
profile.
Once basic control of O2 was demonstrated, the team delved
further into the nuances of running the reaction with a
controlled LiOH addition. As shown in Figure 7, it was
observed that there was an induction period during which
some LiOH had been added but no O2 generation had yet
occurred. Note that this induction period, on the order of
minutes, was much longer than the period comprising the time
it takes for vapor to travel from the reaction vessel to the O2
detector, which was on the order of 20 s. To investigate the
longer induction period, we hypothesized that pH influences
the equilibria between LiOH, H2O2, LiOOH, and water.
Simultaneous pH, O2, and reaction conversion tracking
revealed this to be the case. The initial amount of LiOH was
added to the batch, resulting in a pH change from slightly
below 7 to approximately 10. Once the pH change occurred,
the O2 release began. It was later confirmed that our
commercial sources of 30 and 35 wt % aqueous H2O2 are
shipped with acidic stabilizers to maintain the pH slightly
below 7. Further, different manufacturers used varying
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Figure 7. Simultaneous monitoring of O2 release, reaction conversion, LiOH addition, and pH.
amounts of stabilizer, which required differing amounts of
LiOH to neutralize. The acidic stabilizers of H2O2 likely
account for the induction period observed at the start of the
reaction.
Another feature of the O2 generation profile is an initial peak
occurring near the start of the addition and then a second
broader peak near the end of the addition. In theory, a fully
dose-controlled reaction would result in a constant rate of O2
formation. However, our proposed reaction pathway did not
explain the variation in O2 off-gassing rate over the course of
the reaction. Nevertheless, the reaction purity profile did not
appreciably vary with differences in O2 release behavior. An
example is shown in Figure 8 and Table 3.
Therefore, although a theoretical explanation was not
forthcoming, the team instead elected to empirically explore
the parametric design space to understand the extent of O2
profile variation. This exploration would set the design space to
Figure 8. Variation in O2 release profiles with changes in scale, LiOH
addition time, and N2 flowrate. The same batch of 1 was used in each
experiment.
E DOI: 10.1021/acs.oprd.9b00462
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understand the maximum O2 level that is possible and to
adequately plan for the N2 flow requirements.
The experimental effort was achieved with a fractional
factorial design of experiments (DoEs). The design included
24 experimental runs and four center points. Eight of the
conditions were executed in the EasyMax (Mettler Toledo)
100 mL reactor. The remaining 16 and the four center points
were run in sealed 20 mL vials. The division of experiments
between the EasyMax and vials was done to (1) ensure that
sufficient data were collected in a well-mixed reactor design,
and (2) experimental time was minimized using lab
automation to execute the majority of the experiments. The
EasyMax experiments were conducted with N2 sweep and
condensers, whereas the vial experiments were not inerted
because of the small scale. The anticipated highest risk
scenarios were executed in the EasyMax to minimize
confounding with the possibility of poor mixing. Each mixture
was sampled at 1, 2, 4, 10, 14, 15, 20, and 21 h after the start of
LiOH addition. The parameter space covered and the key
results identified are shown in Table 4. The key impurities of
interest are shown in Figure 9.
Although in the DoE we did not measure O2 behavior, we
observed two variables that serve as surrogates of O2 behavior:
peracid intermediate content (2, Figure 9) and reaction
conversion. Our safety control strategy relies on rapid
decomposition of the peracid intermediate into 3 (see Figure
1) and O2. If significant levels of 2 are detected by HPLC, it
indicates buildup of stored O2 that could be released at a rate
faster than what is planned, resulting in a higher peak O2
concentration. The desired reaction is one in which there is no
detected 2 with a reaction conversion rate matching the rate of
LiOH addition. In order to maximize detectability of 2, all
samples were diluted by 20x, immediately analyzed, and then
quenched with a solution of sodium metabisulfite. In this DoE,
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Organic Process Research & Development
Table 3. Variable O2 Release Patterns of Experiments A to C Did Not Strongly Affect the Final Reaction Impurity Profile with
Respect to 1, 3, and 4
experiment 1 input (mmol) LiOH (equiv) H2O2 (equiv)
A 44.8 1.6 4.6
B 59.8 1.6 4.6
C 22.4 1.6 4.6
there were also two quality indicators: the N-oxide impurity (6,
Figure 9) and the ring-opened impurity (4, Figure 9). These
impurities were poorly removed in the crystallization, and the
team needed to limit their formation to assure purity of the
product 3. The treatment of the quality indicators is covered in
the Supporting Information.
The results from the DoE provided the team with valuable
information for scale-up. There was a single combination of
parameters that resulted in a maximum of 28% 2 detected at 1
h into the reaction. All of the other scenarios resulted in 6% or
less of 2. The 6% level of 2 was deemed manageable with a
combination of N2 flow rate safety margin and modulation of
the O2 release by controlling the LiOH addition rate. The
high-peracid scenario resulted from a run with high total water
content, the lowest H2O2 equivalents (4.0), and the lowest
temperature (15 °C). This result corresponds with earlier
experiments that identified longer peracid lifetime in high-
water and low-H2O2 conditions.10 Another safety finding was
the discovery of two scenarios with very slow reaction speed.
These two cases also had the lowest total water contents at <12
wt % each. It is suspected that slow reaction progress in these
cases was because of reduced solubility of LiOH. As a result of
the DoE experiments, the team identified the above multi-
variate combinations that should be avoided during scale-up.
However, multivariate deviations from planned operating
setpoints, that is, two or more parameters simultaneously
varying significantly from their center point values, are rare in a
typical good manufacturing practice facility. Consequently,
during the scale-up risk assessment, only single-point variations
are considered likely and assessed for their impact on process
safety. Under this framework, no single-point variations were
identified that would result in unexpectedly fast O2 release or
slow reaction conversion.
■ SCALE-UP ASSESSMENT AND EXECUTION
Prior to scale-up, the team investigated several additional safety
concerns. In particular, the O2 control strategy depends on the
assumption of a well-mixed headspace. If this assumption is not
correct, there is risk of O2 exceeding the LOC in local pockets
of the reactor. For instance, we anticipated a risk if the diluent
N2 bypassed the headspace and directly exited via the vent. To
evaluate this risk, we used COMSOL’s CFD package to model
the headspace of a 2000 L vessel. Representative liquid level
and N2 flow rate were based on batch input (60 kg), and a
source layer of O2 was applied at the top of the liquid surface,
corresponding to a reaction in which LiOH addition time is 4
h. The reactor riser was a 4-inch diameter pipe, and the reactor
itself was 48 in. in diameter with N2 introduced via the
headspace through a 1-inch inlet. In order to obtain
convergence in the gas-phase modeling, a ∼5× slower N2
flow rate was applied in the model than actually used at the
scale. Nevertheless, the model achieves the purpose of
identifying potential inhomogeneity in the reactor. The key
response from the model was the distribution of the ratio of O2
Article
Final impurity profile
N2 flowrate (SCFH) LiOH addition time (min) 1:3:4
0.2 480 0:97.1:2.9
0.6 360 0:98.2:1.8
0.6 240 0:96.9:3.1
partial pressure (PO2) to the O2 partial pressure that would be
achieved with a fully mixed headspace (PO* ). Ratios above 1
2
indicate areas in the headspace where O2 is enriched and
therefore present a risk.
In the first scenario evaluated, N2 was fed only through the
headspace pipe. Figure 10 shows vertical slices of the reactor in
both directions, and it can be seen that the N2 feed displaces
most of the released O2 to the riser side of the reactor. In
Figure 11, the histogram of PO2/PO*2 in the headspace shows a
long tail in which much of the reactor has significantly higher
O2 levels than the well-mixed assumption would indicate; in
some regions more than three times the expected O2 levels. In
the case of a planned maximum value of 2.5% O2, this could
result in some regions exceeding the safety limit of 5%. The
detection of such an excursion is a challenge because typical
instrumentation setup for measuring O2 concentration on-scale
occurs downstream of the reactor (Figure 12). With this risk in
mind, the team also modeled N2 sparging, where 10% of the
total N2 flow was directed through the liquid surface. With the
addition of sparging, the volume of headspace with PO2 above
the well-mixed value was significantly reduced, as shown in
Figure 10. This provided a strong basis to include N2 sparging
via a subsurface pipe in the technical requirements for the
process.
However, it is known that the high N2 flowrates to achieve
headspace O2 dilution can result in significant solvent loss from
the reactor.18 To understand this risk, the authors conducted
solvent recovery modeling19 to predict the thermodynamic
composition of the reactor vapor effluent and the degree of
solvent recovery afforded by the condenser. This model
assumes perfect heat transfer, meaning the condenser outlet
vapor and liquid streams are at the condenser coolant
temperature. The condenser temperature was initially selected
to be 5 °C to limit solvent loss while avoiding freezing because
of the presence of water in the vapor effluent. Freezing must be
avoided because it could impede gas flow out of the reactor,
leading to over-pressurization and/or higher than expected O2
content. For a batch size of 50 kg 1, a target N2 flow rate of 22
scfm was modeled. The condenser was a shell-and-tube design
with 88 tubes and a total heat transfer surface area of 90 ft2.
The model-predicted rate of solvent loss was 7.7 kg/h, while
the observed loss rate ranged from 11.0 to 14.1 kg/h over six
batches ranging from 40 to 57 kg input. The higher rate of
solvent loss was because of the short residence time of the
vapor effluent in the condenser, which in this case was likely
less than 5 s based on the high rate of N2 flow. Because of the
higher solvent loss rate, supplemental charges of THF were
periodically made to maintain batch volume.
Given the higher solvent loss rate than expected, it was then
investigated whether the condenser temperature could be
safely lowered to −5 to −10 °C without freezing. Vapor−liquid
equilibrium modeling was used to predict the condensate
F DOI: 10.1021/acs.oprd.9b00462
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 Table 4. Summary of Experiments Done in DoEa
maximum
peracid
final impurity profile detected
LiOH solution LiOH H2O2
input temperature concentration LiOH addition time concentration H2O2 THF conversion
experiment equipment of 1 (g) (°C) (wt %) (equiv) (h) (wt %) (equiv) (L/kg) (%) 3 (LC area %) 4 (LC area %) 6 (LC area %) 2 (LC area %)
1 EasyMax 10 35 5.5 1.9 1 25 4 10 100.0 77.8 4.2 ND 5.7
2 EasyMax 10 15 10.5 1.3 1 25 4 5 100.0 79.3 2.4 0.5 27.9
3 EasyMax 10 35 10.5 1.9 1 40 4 5 100.0 79.3 3.5 0.5 1.2
4 EasyMax 10 25 10.5 1.3 1 40 4 10 25.7 19.2 0.8 0.1 0.1
5 EasyMax 10 25 5.5 1.9 1 25 5.2 5 100.0 79.0 2.6 0.7 5.5
6 EasyMax 10 35 5.5 1.3 1 40 5.2 5 100.0 77.2 2.9 1.9 5.0
7 EasyMax 10 35 10.5 1.3 1 25 5.2 10 100.0 78.8 3.3 0.3 1.3
8 EasyMax 10 15 10.5 1.9 1 40 5.2 10 41.3 32.1 1.1 0.1 0.3
9 stir vial 1 15 5.5 1.9 7 25 4 5 99.9 80.5 2.3 0.2 0.7
Organic Process Research & Development

10 stir vial 1 35 5.5 1.3 7 40 4 5 100.0 77.2 3.7 0.5 0.3

11 stir vial 1 15 5.5 1.3 7 40 4 10 100.0 79.5 3.0 0.2 0.1
12 stir vial 1 35 5.5 1.3 7 40 4 10 100.0 78.2 4.0 0.4 0.3
13 stir vial 1 35 10 1.9 7 25 4 10 100.0 77.7 5.1 0.4 1.0
14 stir vial 1 15 10 1.9 7 40 4 5 100.0 80.2 2.2 0.3 0.1
15 stir vial 1 15 10 1.9 7 40 4 10 100.0 79.7 3.3 0.1 0.1

G
16 stir vial 1 35 5.5 1.9 7 25 5.2 10 100.0 77.8 4.1 0.5 2.7
17 stir vial 1 15 5.5 1.9 7 40 5.2 5 100.0 79.6 2.2 0.3 0.5
18 stir vial 1 15 5.5 1.3 7 40 5.2 10 100.0 79.9 2.7 0.2 0.1
19 stir vial 1 15 10 1.3 7 25 5.2 5 100.0 79.2 2.6 0.1 0.1
20 stir vial 1 35 10 1.3 7 40 5.2 5 100.0 78.7 3.0 0.5 0.2
21 stir vial 1 35 10 1.9 7 40 5.2 5 100.0 77.3 3.6 0.8 3.3
22 stir vial 1 15 5.5 1.3 <0.01 25 4 5 100.0 79.1 3.6 0.2 3.4
23 stir vial 1 35 10 1.3 <0.01 25 4 5 100.0 78.0 4.9 0.5 1.4
24 stir vial 1 15 10 1.3 7 25 5.2 10 100.0 80.0 2.7 0.1 0.1
Center stir vial 1 25 8 1.55 <0.01 30 4.6 7.5 99.8 77.1 4.4 0.2 0.5
Center stir vial 1 25 8 1.55 <0.01 30 4.6 7.5 99.9 78.0 3.8 0.3 0.3
Center stir vial 1 25 8 1.55 <0.01 30 4.6 7.5 99.9 78.1 3.2 0.3 0.3
Center stir vial 1 25 8 1.55 <0.01 30 4.6 7.5 99.9 77.4 4.1 0.3 0.5
a
Note that the desired product 3 in most cases accounted for ∼80% of the LC area. The remaining impurity mix consisted of ∼15% of 5 and another 5% distributed among the remaining impurities.
“ND” indicates a result below the detection limit of 0.05%. Samples labeled with <0.01 h addition time were charged with LiOH solution as a single bolus.
Article

Org. Process Res. Dev. XXXX, XXX, XXX−XXX

DOI: 10.1021/acs.oprd.9b00462
Organic Process Research & Development
Figure 9. Key impurities of interest in DoE.
Figure 10. CFD simulation of O2 partial pressure (PO2) in the reactor
compared to the partial pressure of O2 in a well-mixed headspace
(PO*2 ) when N2 is not sparged.
Figure 11. Histogram of relative O2 values for cases with and without
sparging. There is a significant reduction in heterogeneity with the
sparged case.
composition for a range of condenser-operating temperatures.
Then, the phase transition (melting/freezing) points were
measured at a range of condensate compositions. These data
were collected by rapidly cooling water−THF mixtures until
H DOI: 10.1021/acs.oprd.9b00462
Article
Figure 12. Schematic of typical O2 measurement during scale-up.
solids were observed and then slowly warming until all of the
solids were dissolved, which was considered the melting/
freezing point. The results and their comparison to previous
literature data by Hayduk are shown in Figure 13.20 Notably,
Figure 13. Condensate compositions of THF−water as a function of
condenser temperature and the corresponding freezing point data.
The operating space is delineated with the dashed red box.
there is a significant difference in melting/freezing points
between the literature and this study. This difference is because
of differences in experimental procedure. Hayduk measured
freezing point by detecting batch temperature plateaus during
controlled cooling. We took a more conservative approach
using visual detection of solids that resulted in our melting/
freezing point determinations to be higher than Hayduk’s. We
relied on the phase-transition data generated on our study for
scale-up purposes. The phase transition data and the modeled
condensate composition cross over at about −20 °C.
Operating a condenser below this temperature introduces a
significant risk of condensate freezing and therefore blocking
the vent path. The goal was to operate the condenser
temperature as low as possible for improved solvent recovery
but sufficiently above the freezing point of the condensate. We
found that operating at −10 to −5 °C afforded a good balance
between these goals. This temperature range was then selected
for future scale-ups. Although solvent loss data were not
tracked in future scale-ups, no condenser freezing occurred,
and supplemental THF charges to maintain batch volume were
reduced.
As noted above, the primary means for controlling
headspace O2 are a high flowrate N2 sweep and controlled
LiOH addition. However, the process hazard analysis for this
reaction indicated that an upset in either of these controls
could result in uncontrolled O2 levels. For example, control of
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
the LiOH addition could be lost or the N2 source could fail.
Therefore, there was a need to have a reaction quench to halt
O2 formation. Under normal conditions, the excess H2O2 is
quenched at the end of reaction with aqueous NaHSO3 (see
Experimental Section below). However, the quench is very
exothermic (ΔTadiabatic = +78 °C) and this solution can only be
added slowly over 1−3 h to avoid exceeding the thermal onset
temperature that varies from 66 to 190 °C, depending on how
much H2O2 is left in solution.
Thus, the team investigated alternatives to using the
NaHSO3 quench in an emergency. We discovered that adding
aqueous KH2PO4 buffered the reaction to a neutral pH (∼6.9),
which both halts the desired reaction and greatly slows the
peroxide decomposition by shifting the peroxide equilibrium
away from LiOOH to HOOH. Additionally, the ΔTadiabatic of
this neutralization was <5 °C, which allowed for its rapid
addition to the reactor. The effect of the KH2PO4 buffering
procedure was demonstrated using the CRC90 as shown in
Figure 14. In this experiment, the LiOH, H2O2, and 1 were
Figure 14. Demonstration of the emergency buffering with KH2PO4
solution.
mixed instantaneously. At approximately 25 min, the KH2PO4
solution was charged. This was detected as an instantaneous
increase in the gas flow rate because the liquid introduction
displaced gas from the reactor. Following the charge, no
additional gas flow occurs, indicating that the release of O2 has
stopped. After successful demonstration, the buffering
procedure was included in the scale-up plan in case of a
process upset. During each batch, a reactor loaded with 2.0
equiv of 6−10 wt % KH2PO4 in water was kept prepressurized
on standby for an emergency, such as loss of N2 service, loss of
power supply, or unexplained spike in headspace O2. As a
backup safety measure, another vessel was also held
prepressurized with N2 that could be sent to the reaction
vessel via a manual valve in the event of an emergency, buying
additional inertion time in the event of a process upset.
With the control strategy and contingency protocol in place,
the reaction was safely scaled up in three different plants and
ultimately validated for commercial production. The batch
scales ranged in size from 40 to 215 kg. In several runs,
headspace O2 and pH were monitored and compared to the
LiOH addition. In each implementation, the LiOH solution
was added in a series of timed portions, with a total addition
time varying 4−8 h. LiOH addition was paused periodically to
add THF via sprayballs in case of solvent loss, depending on
condenser performance. Headspace O2 was controlled to <5%
at all times, and the emergency KH2PO4 buffering was never
used. A typical profile of LiOH addition, O2, and pH is shown
I DOI: 10.1021/acs.oprd.9b00462
Article
for a scale-up batch in Figure 15. The O2 trend shows behavior
similar to that shown in Figure 7, with a higher O 2
Figure 15. Typical headspace O2, LiOH addition, and pH profiles for
a batch run in Facility 2 at 80 kg scale. The increasing level of O2 is
consistent with the laboratory experiment shown in Figure 8.
concentration level occurring in the second half of the reaction
compared to the first half. In this case, the N2 flow rate was
kept constant at 44 SCFM. The pH trend is also consistent
with the lab studies. Similar to Figure 7, approximately 0.2
equiv of LiOH was required to neutralize the H2O2 acidic
stabilizer followed by a sharp increase in pH that is maintained
throughout the reaction. A summary of scale-up performance
of O2 control is in Table 5. All batches achieved low-O2 levels
throughout the reaction, and all quality and yield targets were
met.
Table 5. Summary of Scale-Up Experience
total maximum O2 content
average 1 input 3 produced detected in headspace
facility batches per batch (kg) (kg) (%)
1 6 51 187 2.6
2 4 80 176 2.2
3 8 162 747 2.0
■
CONCLUSIONS
In summary, the authors were faced with a previously
unexpected release of O2 from cleavage of Evans oxazolidinone
with LiOH/H2O2. Because of a lack of workable alternatives,
the team was required to devise a means of safely scaling up
the reaction. To do this, the team returned to the fundamental
safety concept of the fire triangle (fuel, O2, and ignition) and
elected to remove the risk of fire and explosion by maintaining
a low-operating O2 level at all times. During reaction
characterization, the O2 release behavior proved to be complex.
However, the team devised a four-pronged approach to greatly
reduce the likelihood of O2 excursions above a target safety
limit of 2.5%: (1) controlled addition of LiOH along with N2
sweep, (2) understanding of the risks throughout the
parameter space via DoE, (3) N2 sparging to reduce vapor
heterogeneity according to CFD modeling, and (4) an
emergency stabilization procedure to instantaneously stop O2
release with very little exotherm. With these strategies in hand,
the process was successfully demonstrated in three different
facilities and has been used to supply commercial API
production. These results can be useful for researchers
considering O2-releasing processes in the future and should
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
lead to better safety considerations throughout the industry,
especially with oxidations involving H2O2.
■
EXPERIMENTAL SECTION
Batch Preparation of (R)-2-((1s,4S)-4-(6-Fluoroquino-
lin-4-yl)cyclohexyl)propanoic Acid (3). To a 1500 L glass-
lined carbon steel vessel preinerted with N2, 532.2 kg of THF
and 80.0 kg of (R)-3-((R)-2-((1s,4S)-4-(6-fluoroquinolin-4-
yl)cyclohexyl)propanoyl)-4-phenyloxazolidin-2-one (1) (LR)
were charged and stirred until dissolution. The vessel
condenser was set to −5 °C. N2 flow was introduced through
the vessel headspace and sparged through the reactor bottom
valve at a combined rate of 44 SCFM for the duration of the
reaction. The reactor vapor effluent was directed into the
condenser, and the O2 concentration detector was positioned
downstream of the condenser. H2O2 (80.1 kg, 35 wt % in
water) was charged followed by 2.0 kg of water, and the
temperature was controlled to 25 °C. Once the O2 reading was
<1%, 43.5 kg of 7.9 wt % LiOH in water solution was
transferred into the vessel at a rate of 14.5 kg/h. O 2
concentration was monitored continuously to ensure it was
<2.5% at all times. In the event of excursion above 2.5%, the
LiOH solution flow would be paused and N2 flow increased. If
O2 concentration increased above 5%, 488.0 kg of KH2PO4 10
wt % in water could be charged immediately to stop O2
generation. Following the LiOH solution transfer, 71.0 kg of
THF was charged via sprayballs to replace solvent lost via due
to N2 flow. LiOH (43.5 kg, 7.9 wt %) in water solution was
transferred at a rate of 14.5 kg/h, followed by a 10 kg water
rinse. THF (71.0 kg) was charged via sprayballs to ensure all 1
have been pushed into solution, and the batch was aged for 1
h. The batch was cooled to 5 °C, and a 28.0 wt % solution of
sodium metabisulfite in water was transferred at the rate
sufficient to maintain the batch temperature below 30 °C.
Water (80.0 kg) was charged as a rinse of the metabisulfite
solution. The mixture was agitated for 30 min at 25 °C and
then allowed for phase separation. The bottom aqueous phase
was discarded. N,N-dimethylacetamide (299.8 kg, DMAc) was
charged followed by polish filtration. THF (71.0 kg) was
charged as a rinse from the first vessel into the second. The
batch was distilled at 130 mbar until a reflux temperature of
70−72 °C. DMAc (37.5 kg) was charged via sprayballs. The
batch was heated to 70 °C, and 216.0 kg water was transferred
at 432.0 kg/h, maintaining the batch temperature above 65 °C.
The mixture was aged for 90 min. Water (88.0 kg) was charged
at a rate of 44.0 kg/h and aged for 90 min. The batch was
cooled from 70 to 20 °C over 6 h and aged for 8 h. The slurry
was filtered and washed with 155.2 kg of 1:1 DMAc/water
followed by 301.4 kg 3:1 water/acetonitrile. The cake was
dried at 50 °C under vacuum to afford 48.6 kg of 3 (90.0%
yield).
Computational Fluid Dynamics Modeling. The COM-
SOL CFD module, version 5.2a, was used to model a 2000L
Pfaudler reactor in the headspace heterogeneity investigation.
■
ASSOCIATED CONTENT
*
S Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.9b00462.
Statistical analysis of the quality-impacting responses in
the DoE experiments (PDF)
J DOI: 10.1021/acs.oprd.9b00462
■
Article
AUTHOR INFORMATION
Corresponding Author
*E-mail: andrew.glace@bms.com.
ORCID
Andrew W. Glace: 0000-0001-9789-4714
Benjamin M. Cohen: 0000-0002-7000-9292
Gregory L. Beutner: 0000-0001-8779-1404
Kenneth J. Fraunhoffer: 0000-0002-1771-3416
Albert J. DelMonte: 0000-0003-0645-3169
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
The authors acknowledge Jean Tom for advice and guidance
during manuscript writing, Douglas D. McLeod for encourag-
ing safety investigations, Mark Lindrud for emission calculation
assistance, and Brendan C. Mack for multivariate analysis
assistance. The BMS Chemical and Synthetic Development
senior leadership team is also acknowledged for their support.
■
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K DOI: 10.1021/acs.oprd.9b00462
Org. Process Res. Dev. XXXX, XXX, XXX−XXX