Nitration Using Fuming HNO3 in Sulfolane: Synthesis of 6-Nitrovanillin in Flow Mode

Article abstract of DOI:10.1021/acs.oprd.8b00020

We report herein an improved synthesis of 6-nitrovanillin, an important building block used in pharmaceuticals and agrochemicals. The key step in this sequence is the nitration of O-Bn vanillin, which was carried out using fuming HNO₃. Sulfolan

Full text of DOI:10.1021/acs.oprd.8b00020

Article
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Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Nitration Using Fuming HNO3 in Sulfolane: Synthesis of
6‑Nitrovanillin in Flow Mode
Souvik Rakshit,† Thirumalai Lakshminarasimhan,† Sivakrishna Guturi,† Kishorekumar Kanagavel,†
Umamaheswara Rao Kanusu,† Ankita G. Niyogi,† Somprabha Sidar,† Michael R. Luzung,‡
Michael A. Schmidt,‡ Bin Zheng,‡ Martin D. Eastgate,‡ and Rajappa Vaidyanathan*,†
†Chemical Development and API Supply, Biocon Bristol-Myers Squibb Research and Development Center, Biocon Park,
Jigani Link Road, Bommasandra IV, Bangalore 560099, India
‡Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States
ABSTRACT: We report herein an improved synthesis of 6-nitrovanillin, an important building block used in pharmaceuticals
and agrochemicals. The key step in this sequence is the nitration of O-Bn vanillin, which was carried out using fuming HNO3.
Sulfolane emerged as the solvent of choice for this transformation due to its high stability toward strongly acidic and oxidizing
conditions. The specific hazards of this reaction were studied, and the nitration was efficiently and safely conducted leveraging
flow conditions.
the absence of remaining starting material) only when fuming
HNO3 (98%) was used (entries 1 and 2, Table 1). In both of these
cases, the desired nitro product 3 was observed in ∼75−80 area %
(by HPLC), along with ∼20 area % of the ipso substitution
product 4,8 presumably formed via nitration para to the −OBn
substituent, followed by deformylation. Most other nitrating
agents such as KNO3 (entry 3), NaNO3 (entry 4), and dilute
versions of HNO3 (entries 5, 6, and 7) provided incomplete
conversions. Interestingly, the use of concentrated HNO3 (70%)
with sulfuric acid or trifluoroacetic acid9 led to complete decom-
position of the starting material 2 (entries 8 and 9). This initial
screen led us to conclude that fuming HNO3 was the best
nitrating agent out of those studied. However, the documented
incompatibility of nitric acid with most organic solvents (e.g.,
acetic acid) was an issue preventing further scale up.10
Our initial approach to synthesize small quantities (<10 g) of
1 for evaluation of subsequent transformations utilized 2 equiv of
fuming HNO3 in MeCN at ∼55 °C (Scheme 3).11 While this was
a reasonable approach for accessing lab scale quantities, both
ARSST (Figure 2) and DSC (Figure 3) studies indicated sig-
nificant thermal events in the vicinity of the operating temper-
ature (55 °C). As seen from the DSC thermograms in Figure 3,
the reaction mass with 2 equiv of fuming HNO3 exhibited an
onset temperature of ∼71 °C, with an energy release of 464 J/g
(Figure 3a). We hypothesized that we may be able to lower the
reaction temperature (and therefore widen the safety margin
for the process) by increasing the stoichiometry of the nitric
acid, cognizant of the potential for greater energy release due to
the presence of excess oxidant in the system. While the reac-
tion proceeded to ca. 65% conversion at room temperature with
8−10 equiv of fuming HNO3, the increase in nitric acid also
lowered the onset temperature, with the expected increase in
decomposition energy (Figure 3b and 3c), negating any potential
safety advantages.
INTRODUCTION
■
6-Nitrovanillin (1)1 is a valuable building block that can be uti-
lized to construct several biologically active natural products and
pharmaceutical ingredients (some examples shown, Figure 1).2−4
Despite its potential as a key intermediate, to the best of our
knowledge there are no reports that detail the preparation of this
molecule on a large-scale. In a recent program, we were required
to synthesize multiple kilograms of 6-nitrovanillin (1) for further
elaboration; this warranted the development of a robust process
for its production.
Direct nitration of vanillin is known to afford 5-nitrovanillin.5
However, protection of the hydroxyl group redirects the selec-
tivity of the process to produce 6-nitrovanillin.4,6 Previous reports
demonstrated that benzylation followed by nitration and deben-
zylation affords 6-nitrovanillin (Scheme 1).6 The key step in this
sequence was the nitration of O-Bn vanillin 2 using fuming nitric
acid. While it may appear straightforward, this reaction was
fraught with liabilities which required systematic investigation
and resolution before the reaction could be conducted on-scale.
For instance, the use of fuming nitric acid with organic solvents
mandated a thorough interrogation of their mutual compatibility.
Furthermore, the reaction mass containing excess nitrating agent
and a potentially energetic product can pose a thermal risk, which
can be exacerbated by the presence of polynitrated byproducts,
which are likely to form due to the electron-rich nature of the
substrate under these conditions.7
RESULTS AND DISCUSSION
■
The benzylation reaction was effected cleanly by treating vanillin
with benzyl bromide and K2CO3 in acetonitrile (Scheme 2). The
resulting O-Bn vanillin 2 was subjected to the nitration reaction
under a variety of conditions.
The nitration of O-Bn vanillin 2 is known in the literature and
has been reported on a small scale in several solvents such as
dichloroethane, acetic acid, and water, all providing the nitrated
product in modest yields.6 A rapid screen of nitrating agents
revealed that the reaction went to completion (as designated by
Received: January 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.8b00020
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Figure 1. Some bioactive molecules derived from 6-nitrovanillin.
Scheme 1. Known Synthesis of 6-Nitrovanillin
should be miscible with HNO3, should preferably solubilize
the starting material, and should allow for easy isolation of the
product. DSC analysis of mixtures of fuming HNO3 in aceto-
nitrile, dichloromethane,12 N-methylpyrrolidone, and sulfolane
(10% w/w) was carried out. It was found that the mixture of
fuming HNO3 and sulfolane showed a relatively high onset of
decomposition (∼153 °C) and a significantly lower decompo-
sition energy (∼250 J/g) when compared to other mixtures as
depicted in Figure 4.
Sulfolane is a highly stable and attractive alternative to com-
mon dipolar aprotic solvents such as DMSO, DMF, DMAc, and
NMP.13,14 Because of its high stability toward strong acids and
oxidizing agents, as well as its thermal stability, sulfolane is a
solvent that can be utilized under a wide range of reaction con-
ditions. Sulfolane has been used as a solvent for aromatic nitration
reactions using nitronium tetrafluoroborate ([NO2]BF4) as a
nitrating reagent.15 However, to the best of our knowledge, there
are no reports of the use of sulfolane in combination with con-
centrated or fuming HNO3.
Scheme 2. Benzylation of Vanillin
Thus, treatment of 2 with 3 equiv of fuming HNO3 in sulfolane
at 35 °C led to complete conversion of starting material within
3 h (entry 1, Table 2). The reaction time could be decreased to
1 h using 5 equiv of fuming HNO3 to achieve similar conversion
(entry 2, Table 2). In both of these instances, the ipso product
4 was formed to the same extent (∼22%), which was effectively
purged in the downstream operations (vide infra). The high
miscibility of sulfolane in water enabled direct precipitation of
The incompatibility of fuming HNO3 with acetonitrile as well
as with alcohols, ethers, ketones, haloalkanes, and DMSO is well-
documented10 and prompted the quest for a solvent that would
be compatible with this challenging reagent. The ideal solvent
would have to be inert under the reaction conditions (i.e., it
should not be prone to oxidation or trigger thermal events),
Table 1. Screening of Reaction Conditions for the Nitration Reaction
b
IPC (HPLC area %)
a
entry
conditions
2
3
4
1
2
3
4
5
6
7
8
9
Fuming HNO3 (5 equiv), AcOH (5 vol), 23 °C, 8 h
Fuming HNO3 (5 equiv), CH3CN (5 vol), 55 °C, 1 h
KNO3 (2 equiv), AcOH (8 vol), 0 °C, 16 h
NaNO3 (2 equiv), AcCl (1 equiv), DMF (8 vol), 23 °C, 20 h
Conc. HNO3 (10 vol), neat, 0 °C, 2 h
Conc. HNO3 (25 equiv), DCM (5 vol), 0 °C, 2 h
Conc. HNO3 (5 equiv), AcOH (8 vol), 23 °C, 8 h
Conc. HNO3 (2 equiv), H2SO4 (8 vol), 0 °C, 2 h
0.2
79.3
75.0
ND
0.1
17.0
19.4
ND
ND
3.4
0.2
99.3
32.1
59.0
56.8
24.2
ND
0.9
25.2
34.2
59.2
ND
25.3
6.9
12.9
ND
ND
Conc. HNO3 (2 equiv), TFA (8 vol), 23 °C, 2 h
a
b
All reactions were performed on a 100 mg scale. In-process control (IPC) area % was determined by HPLC at 210 nm.
Scheme 3. Nitration Using Fuming HNO3 with MeCN
B
DOI: 10.1021/acs.oprd.8b00020
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Figure 2. ARSST runReaction mixture containing 3 with fuming HNO3 (2.5 equiv) in MeCN.
Figure 3. DSC thermograms of reaction mixture containing 3 with fuming HNO3 in MeCN.
Figure 4. DSC thermograms of fuming HNO3 in various solvents (10% w/w).
the product by quenching the reaction mass in water, obviating
the need for an extractive workup.
In preparation for scale-up of this process in batch mode, we
to perform best with 10 mL of sulfolane per gram of 2. This
concentration was achieved by dissolving 2 in 7 vol of sulfolane
and by utilizing the remaining 3 vol of sulfolane to prepare a
25% w/w solution of nitric acid (5 equiv of fuming HNO3).
conducted preliminary safety assessments. The reaction seemed
C
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Table 2. Optimization of Equiv of Fuming HNO3 for Nitration Reaction
a
b
conditions
IPC (area %)
entry
equiv of HNO3
time (h)
2
3
4
1
2
3
5
3
1
ND
ND
70.9
76.7
21.4
22.1
a
b
All reactions were performed on a 100 mg scale. In-process control (IPC) area % was determined by HPLC at 210 nm.
Figure 5. DSC thermogram of nitration reaction mass.
Figure 6. Temperature and self-heating profile of nitration reaction mass in ARSST.
Dilution of fuming HNO3 using sulfolane was found to be
exothermic (RC1e) with an adiabatic temperature rise of 35 °C.
The HNO3/sulfolane solution was charged dropwise into the
solution of starting material 2 in sulfolane while maintaining the
reaction temperature below 38 °C. As expected, the nitration was
found to be exothermic (energy of −160 kJ/mol) with an adia-
batic temperature rise of 31 °C. The reaction was found to be
dose controlled, with 80% of the total heat evolved during the
addition. The thermal stability of the reaction mass was evaluated
by DSC and ARSST, and onset of a significant exotherm was
observed around 80 °C (Figure 5a and the green lines in Figure 6)
with an energy release of 406 J/g (adiabatic temperature rise
(ΔTad) of ∼270 °C).
Kinetic analysis of the heat data from DSC using AKTS
software16 predicted the ADT2417,18 to be 45 °C (Figure 7),
which was in close agreement with the estimated ADT24 using
the self-heating data from the ARSST19 run (42 °C). This
relatively low ADT24 suggested a high probability of decom-
position or a thermal runaway reaction in the case of loss of
temperature control (either due to loss of control on external
cooling, or addition rate) during the reaction. This could possibly
trigger secondary decomposition reactions (MTSR > ADT24),
D
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Figure 7. Thermal stability diagram of reaction mass after the formation of 3.
Figure 8. DSC thermograms of fuming HNO3−sulfolane solution at various concentrations.
and the process would fall into Stoessel Criticality Class 5,18
indicating severe risks. A safety review of the process indicated
that batch mode would not be a viable long-term option due to
the narrow thermal operating window, and thus, we explored the
feasibility of carrying out the nitration reaction in flow mode.20,21
The fact that the nitration reaction in sulfolane was homoge-
neous was a major advantage that made it amenable for execution
in flow. However, the relatively long reaction time using 5 equiv
of fuming HNO3 (∼1 h) could limit this option (Table 2). In an
effort to increase the reaction rate, the process was attempted
using 8 equiv of fuming HNO3 on a small scale in the laboratory.
Gratifyingly, the reaction reached complete conversion within
15 min at 40 °C. Encouraged by these results, we evaluated the
thermal stability of the fuming HNO3−sulfolane solution (8 equiv
of fuming HNO3 in 3 vol of sulfolane per g of 2, which translates to
∼33% w/w fuming HNO3 in sulfolane). DSC analysis of varying
concentrations of HNO3 in sulfolane revealed that while the onset
temperature did not vary significantly with increasing concen-
trations (remaining close to ∼160 °C), the severity of decom-
position, i.e. energy released, increased significantly, as seen
previously. As depicted in Figure 8, a solution of 10% w/w
fuming HNO3 in sulfolane shows an energy of ca. 250 J/g, while
the 33% w/w solution exhibits an energy of 1683 J/g.22
data using AKTS software (ADT24 = 91 °C).23 Samples of
reaction mixtures containing excess nitric acid (8−10 equiv used
for the reaction) were tested in DSC and ARSST and were found
to exhibit onset of severe exotherm/self-heating at ∼80 °C
(Figure 5b and the brown lines in Figure 6). The 1 h Time to
Maximum Rate (TMRad) was found to be 55−65 °C by kinetic
analysis of self-heating data from ARSST and DSC heat data by
AKTS software, indicating that the mass was stable in the flow
conditions as the residence time in the flow reactor was expected
to be no more than 15 min.
With these data in hand, a set of screening experiments was
performed using the flow reactor (Hastelloy C22, id 0.18 cm, and
length 9.1 m). Two inlet streams, namely a 1 M solution of 2 in
sulfolane, and a ∼33% w/w solution of fuming HNO3 in sulfo-
lane, were passed through the coiled reactor at a specific temper-
ature (Figure 9; for actual set up, see Experimental Section).
The sulfolane solution of 2 was maintained at 35 °C,24 while the
solution of fuming HNO3 in sulfolane was maintained at room
temperature. The outlet stream was quenched by allowing it to
flow directly into a vessel containing chilled water (0−5 °C), and
the resultant crystalline product was isolated by filtration.
In these screening experiments, it was found that a resi-
dence time of 11.3 min at 35 °C led to very good conversions
(entry 1, Table 3). Attempts to shorten the residence time by
increasing the reaction temperature alone were not successful
The 33% w/w fuming HNO3-sulfolane mixture was found to
be stable in the operating conditions by kinetic analysis of DSC
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Figure 9. Nitration of 2 in continuous flow mode.
CONCLUSION
Table 3. Screening Experiments for the Nitration in
Continuous Flow Mode
■
In conclusion, we have developed a safe, robust, and scalable
protocol for the synthesis of 6-nitrovanillin. The key step in this
sequence was the nitration of O-Bn vanillin on large-scale to
selectively afford the 6-nitro analog. The best reagent for this
transformation was fuming nitric acid; however, the incompat-
ibility of this reagent with various organic solvents was a serious
limitation that needed to be overcome prior to scale-up. Sulfolane
emerged as the solvent of choice for this transformation: it was
stable under the reaction conditions, provided good solubility
of the starting material, and allowed for easy isolation of the
product. The process safety hazards associated with the use of
fuming nitric acid on large-scale were overcome by carrying out
the transformation in flow mode. To the best of our knowledge,
this is the first report of the successful use of sulfolane in con-
junction with nitric acid.
a
IPC (HPLC area %)
Rt
temp
equiv of fuming
HNO3
entry (min)
(°C)
2
3
4
1
2
3
4
11.3
3.4
35
40
40
45
8.0
8.0
8.0
8.7
1.9
15.5
13.9
1.3
76.1
66.8
67.0
77.1
21.0
17.1
18.4
21.6
4.3
8.5
a
In-process control (IPC) area % was determined by HPLC at 210 nm.
(entries 2 and 3, Table 3). However, increasing both the temper-
ature and the stoichiometry of HNO3 led to high conversions and
shortened the residence time to 8.5 min (entry 4, Table 3). These
conditions were validated on a 2 kg scale (Figure 9) and afforded
the product in ∼70% assay corrected yield at a satisfactory
production rate of ∼110 g/h (see Experimental Section).
The solids isolated after filtration were washed with water to
remove traces of sulfolane and dried in a vacuum tray dryer at
45−50 °C. Compound 3 thus isolated was found to be energetic,
displaying an onset of a major exotherm at ∼226 °C (energy =
1246 J/g), by DSC but was found not to be shock or friction
sensitive.25 The compound was found to be stable in the oper-
ating conditions (AKTS software predicted an ADT24 of 158 °C,
which is well above the drying temperature of 45−50 °C required
for complete removal of water).
Crude 3 isolated from the nitration reaction contained ca. 20%
of the ipso impurity 4. Treatment of this mixture with trifluo-
roacetic acid (2.5 vol) in CH2Cl2 (1 vol) at 40 °C for 16 h afforded
the debenzylated product 1 in >98 area % purity after crys-
tallization from MTBE. Isolated 1 displayed onset of a severe
event around 195 °C with an average energy of 1977 J/g. Although
the compound was energetic, it was found isolable as it was not
sensitive to impact and friction.25 The overall process is depicted in
Scheme 4. The benzylation−nitration−debenzylation sequence
was accomplished on a multikilogram scale to provide 1 in 62%
yield and >98% purity.
EXPERIMENTAL SECTION
■
General. All reactions were performed under a nitrogen atmo-
sphere. Commercial reagents were used as received. Anhydrous
fuming nitric acid (98%) was procured from Avra. Sulfolane
(LR grade) was procured from Spectrochem. Chemical shifts for
protons are reported in parts per million downfield from tetra-
methylsilane and are referenced to residual proton in the NMR
solvent ((CD3)2SO = δ 2.50). Chemical shifts for carbons are
reported in parts per million downfield from tetramethylsilane
and are referenced to the carbon resonances of the solvent
((CD3)2SO = δ 39.5).
4-Hydroxy-3-methoxybenzaldehyde (2). Acetonitrile (1.6 L)
was charged to a reactor and heated to 40 °C. Vanillin (4.0 kg,
26.3 mol) was charged to the solvent at 40 °C under nitrogen
atmosphere. Potassium carbonate (4.0 kg, 28.9 mol) was charged
lot wise by maintaining the temperature of the reaction at 40−45 °C.
Benzyl bromide (3.4 L, 28.9 mol, 1.1 equiv) was added dropwise
over 15−20 min under nitrogen. After the addition was com-
plete, the reaction mass was heated to 50 °C and maintained at
the same temperature for 12−14 h. After reaction completion,
Scheme 4. Overall Scheme for the Synthesis of 6-Nitrovanillin (1)
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the reaction mass was cooled to 0−5 °C and chilled water (40 L)
was slowly added to it (white crystalline product precipitated out).
The resulting slurry was stirred at 0−5 °C for ∼2 h, filtered and
the cake was washed with purified water (20 L), followed by
n-heptane (20 L). The isolated solid was dried at 40 °C under
vacuum to provide 6.0 kg (94% yield) of 2 as a white crystalline
solid. 1H NMR (300 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.54 (dd,
J = 8.4, 1.8 Hz, 1H), 7.49−7.35 (m, 6H), 7.27 (d, J = 8.1 Hz, 1H),
5.22 (s, 2H), 3.84 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
δ 191.3, 153.2, 149.4, 136.3, 129.8, 128.4, 128.0, 127.9, 125.8,
112.6, 109.8, 70.0, 55.5.
reduced pressure to provide 2.1 kg of 1 (97.5% potency, 94%
assay corrected yield) as a yellow solid. H NMR (400 MHz,
DMSO-d6) δ 11.01 (brs, 1H), 10.16 (s, 1H), 7.50 (s, 1H), 7.35
(s, 1H), 3.95 (s, 3H): 13C NMR (75 MHz, DMSO-d6) δ 188.2,
151.8, 150.9, 143.7, 123.4, 111.0, 110.6, 56.3.
1
AUTHOR INFORMATION
Corresponding Author
*E-mail: vaidy@bms.com.
■
ORCID
Michael R. Luzung: 0000-0001-9729-2211
Michael A. Schmidt: 0000-0002-4880-2083
Bin Zheng: 0000-0002-5466-174X
Martin D. Eastgate: 0000-0002-6487-3121
Rajappa Vaidyanathan: 0000-0002-2236-5719
Nitration of O-Bn vanillin (2) with fuming HNO3 in continuous
flow mode using a plug flow reactor. A solution of O-Bn vanillin
2 (1.0 kg, 4.1 mol, 1.0 equiv) in sulfolane (4.0 L) was prepared in
an all-glass reactor (Reactor-1), and maintained at 30−35 °C.24
In another similar reactor (Reactor-2), fuming nitric acid (2.3 kg,
36.0 mol, 8.7 equiv) was charged slowly to sulfolane (3.5 L)
maintained at 30−35 °C (during the mixing of fuming HNO3
and sulfolane, a 5−10 °C exotherm was observed). These two
solutions were pumped via an FMI-Ceramic pump (Ceram pump),
and then through a plug flow reactor (C-22 Hastelloy coil)26
equipped with a temperature sensor (Hastelloy C) and a pressure
gauge. The coil was immersed in a water bath maintained at
45−50 °C. The flow rate of each of the solutions was adjusted to
630 mL/h (10.5 mL/min each). The outlet stream from the plug
flow reactor was drained into a glass quenching vessel containing
chilled water (20 L) maintained at 5−10 °C. The solid that
precipitated in the quenching vessel was filtered, and the filter
cake was washed with water (5 L). The solid was unloaded and
suspended in a fresh reactor with water (10 L) and stirred for 1 h
at 30−35 °C (Note: this reslurry protocol was used to remove
traces of sulfolane).27 The yellow solid mass was filtered, washed
with water (5 L) and dried in vacuo at 50−55 °C for 16 h to
provide 1.1 kg (71% assay corrected yield) of 3 as a pale yellow
solid. The material also contained ∼20% of ipso product 4.
A total of 4.8 kg of crude 3 was synthesized using this protocol at
a production rate of ∼110 g/h.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Jayaprakash Karamil and Sabuj Mukherjee for their
contributions. Analytical support was provided by Saravanan
Natarajan, Periyasamy Palanisamy, and Hemant Bhutani. We
thank Simon Leung and Dhinesh Selvam for their assistance with
process safety data. Scale-up support from the Bristol-Myers
Squibb Chemical Development Laboratory operating staff is
gratefully acknowledged. Our sincere thanks are extended to
David Kronenthal and Robert Waltermire for their support of
this work.
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■
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column chromatography for characterization purposes (SiO2, eluent:
n-heptane:EtOAc 9:1 → 1:1).
4-(Benzyloxy)-5-methoxy-2-nitrobenzaldehyde (or O-Bn-
1
6-nitrovanillin) 3. H NMR (400 MHz, DMSO-d6) δ 10.21
(s, 1H), 7.84 (s, 1H), 7.50−7.48 (m, 2H), 7.45−7.42 (m, 2H),
7.40−7.38 (m, 2H), 5.33 (s, 2H), 3.97 (s, 3H); 13C NMR
(75 MHz, DMSO-d6) δ 188.4, 152.8, 150.8, 143.3, 135.6, 128.5,
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(d, J = 8.8 Hz, 1H), 5.26 (s, 2H), 3.90 (s, 3H); 13C NMR
(75 MHz, DMSO-d6) δ 153.6, 148.8, 140.8, 135.9, 128.5, 128.2,
127.9, 117.4, 112.0, 106.4, 70.4, 55.9.
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ichart, J.-P. Bioorg. Med. Chem. 2004, 12,
4-Hydroxy-5-methoxy-2-nitrobenzaldehyde (or 6-nitrova-
nillin) 1. CH2Cl2 (3.9 L) was charged to a reactor followed by
crude 4-(benzyloxy)-5-methoxy-2-nitrobenzaldehyde 3 (3.9 kg
with 80.7% assay, 13.5 mol assay corrected) and trifluoroacetic
acid (9.7 L, 14.6 kg, 128.3 mol). After completion of addition, the
reaction mixture was stirred at 40−45 °C for 14−16 h. After
reaction completion, the mixture was cooled to 0−10 °C. MTBE
(27 L) was charged slowly into the mass over 2 h, maintaining the
temperature at 0−10 °C. The resulting slurry was stirred for 1 h
at 0−10 °C, filtered, and the cake was washed with chilled MTBE
(2 × 7.8 L) at 0−10 °C. The solid was deliquored for 6 h under
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DOI: 10.1021/acs.oprd.8b00020
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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(22) Negative results were observed in six trials at an impact energy of
60 J, as well as in six trials at a friction force of 240 N (although
inflammation was observed at 360 N). As a result, the material is not
considered to be impact or friction sensitive.
(23) The Self-Accelerating Decomposition Temperature (SADT) of
this solution was predicted to be 74 °C, providing a reasonable thermal
window for storage.
(24) The solution of 2 in sulfolane was maintained at 35 °C to prevent
the freezing of sulfolane (mp = 28 °C).
(25) Negative results were observed in six trials at an impact energy of
40 J (although crackling was observed at an impact energy of 60 and 50
J), as well as in six trials at a friction force of 360 N. As a result, the
material is not considered to be impact or friction sensitive.
(26) Fuming HNO3 is compatible with Hastelloy, C. See:McConville,
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(27) The mother liquors after the filtration were neutralized with
NaOH prior to disposal.
H
DOI: 10.1021/acs.oprd.8b00020
Org. Process Res. Dev. XXXX, XXX, XXX−XXX