Development of a Scalable and Safer Synthesis of Diazeniumdiolates

Article abstract of DOI:10.1021/acs.oprd.0c00067

Although diazeniumdiolates (DAZDs) and the synthetic methods to access DAZDs were discovered over 50 years ago, the current methodology is not safe, has a limited substrate scope, and is not amenable to large-scale production. For example, a recent investigation utilizing the standard methodology to prepare DAZDs resulted in two unexpected explosions, highlighting the need for safer and more practical chemistry. Recently, we have reported a general, scalable, safer, and high-yielding methodology adaptable to large-scale synthesis of diazeniumdiolates in water using a calcium hydroxide base. Herein, we report the full account for the development of the reaction. The merit of this strategy is evidenced by the highly efficient and safer preparation of a key DAZD intermediate, on the kilogram scale, needed for the preparation of MK-8150 (1), a novel O2-alkylated diazeniumdiolate NO donor under investigation as a potent and significant blood-pressure-lowering drug candidate.

Full text of DOI:10.1021/acs.oprd.0c00067

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Full Paper
Development of a Scalable and Safer Synthesis of Diazeniumdiolates
Yong-Li Zhong, Daniel J. Muzzio, Mark Weisel, Li Zhang,
Guy R. Humphrey, Kevin M. Maloney, and Kevin R Campos
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00067 • Publication Date (Web): 11 Aug 2020
Downloaded from pubs.acs.org on August 11, 2020
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Development of a Scalable and Safer Synthesis of
Diazeniumdiolates
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Yong-Li Zhong,* Daniel J. Muzzio, Mark Weisel, Li Zhang, Guy R. Humphrey, Kevin M.
Maloney and Kevin R. Campos
Process Research and Development, MRL, Merck & Co., Inc., Rahway, New Jersey 07065, Unite States
*yongli_zhong@merck.com
RECEIVED DATE (to be automatically inserted after your manuscript is accepted)
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NO (250 psi)
Ca(OH)2, water
O
N
O
N
H
20 C, 160 h
N
O
O
N
N
Ca
N
N
95%
100 L (6 kg scale)
Safer
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ABSTRACT: Although diazeniumdiolates (DAZDs) and the synthetic methods to access DAZDs were
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discovered over 50 years ago, the current methodology is not safe, has a limited substrate scope, and is not
amenable to large scale production. For example, a recent investigation utilizing the standard methodology to
prepare DAZDs resulted in two unexpected explosions, highlighting the need for safer and more practical
chemistry. Recently, we have reported a general, scalable, safer, and high yielding methodology adaptable to
large scale synthesis of diazeniumdiolates in water using a calcium hydroxide base. Herein, we report the full
account for the development of the reaction. The merit of this strategy is evidenced by the highly efficient and
safer preparation of a key DAZD intermediate, on the kilogram scale, needed for the preparation of MK-8150 (1),
a novel O2-alkylated diazeniumdiolate NO donor under investigation as a potent and significant blood-pressure
lowering drug candidate.
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KEYWORDS: NO-donors, nitric oxide, nitrous oxide, diazeniumdiolate calcium salts, MK-8150
INTRODUCTION
Nitric oxide (NO) is a signaling molecule and plays a key role for all living systems.1-7 Many pathological and
physiological processes are implicated due to the NO deficiency.8-13 Diazeniumdiolate (DAZD)-based NO-donors,
which are able to release two equivalents of nitric oxide under either physiological or metabolized conditions,
indicate the bioactivity for the treatment of cardiovascular diseases.14-22 Seeking to further optimize the
pharmacokinetic profile, medicinal chemists at Merck & Co., Inc., Kenilworth, NJ, USA, have discovered MK-8150
(1),23-24 a novel O2-alkylated diazeniumdiolate NO donor, as a potent and significant blood-pressure lowering
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drug candidate in humans. As shown in Figure 1, DAZD (2) is a key intermediate for the synthesis of 1. We have
previous reported a novel and scalable synthesis of the intermediate and the application to the preparation of 1.25
Herein, we report the full account of the development of the reaction.
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O
OH
O
N
O
N N
N
N
+
N
H
N
N OH
N
N
NC
1: MK-8150
2
3
NC
Figure 1. Structure and synthetic analysis of MK-8150 (1). High energy compound DAZD (2) is a key synthetic
intermediate for the preparation of 1.
As shown in Figure 2, the medicinal chemistry route for the preparation of DAZD employing sodium
methoxide in methanol and NO gas at 250 psi, gave desired product A in 9-19% yield with 50-60 wt% purity.26-27
During optimization, two unexpected explosions occurred in a 500-mL autoclave reactor (during venting) due to
the rapid depressurization of high-pressure nitric oxide (NO) from the headspace through Teflon-lined steel-
braided tubing to the atmospheric pressure.28 The magnitude of the energy released in these events was
substantial as shown from the damage of the high pressure hose. The explosive energy of the event caused the
stainless-steel braided Teflon hose to break apart in not just one but multiple places (Figure 2). Fortunately, no
one was injured in the events and damage was contained within the appropriate barricaded hood. Similarly,
Drago reported an explosion over 50 years ago when aniline DAZD was attempted to be prepared through the
reaction of aniline with NO in ether at high pressure.29 The heat generated melted the high pressure tubing used
in their system.
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R
N N
O
R
NH
1
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6
NO (200-350 psi)
Na
N O
NaOMe (1 equiv), MeOH
9-19%
A
R = CH2=CHCH2, Et
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Figure 2. The medicinal chemistry route afforded low yield and low purity of the DAZD sodium salt. Two
unexpected violent explosions occurred in a 500-mL autoclave reactor. The pictures of destroyed equipment: On
the left, the ruptured valve metal bellows. In contrast, a new pristine bellows is shown in middle photo. On the far
right, the metal braided hose ruptured by the reaction. Normal working pressure for the hose is 2500 psi and
maximum burst pressure is 10,000 psi. The multiple breaks in the hose demonstrate this was a detonation and
not merely an over-pressure event.
RESULTS AND DISCUSSION
According to a previous report by Muzzio and coworkers,28 the cause of the explosions was likely due to
the large amount of nitrous oxide (N2O) formed during the reaction. While venting the gas at the end of reaction,
the methanol vapor and nitrous oxide rushing through the Teflon-lined tubing created optimal conditions to create
brush static electricity of sufficient energy to ignite the highly combustible vapor. It is well documented that N2O is
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a strong oxidizing reagent, similar to hydrogen peroxide, and much stronger than oxygen gas.30 Thus, the
minimization of N2O formation during the reaction will be a key factor for safe preparation of DAZD. After careful
analysis of the reaction mechanism for DAZD formation, we summarized the possible side reactions in which
formation of nitrous oxide could occur as shown in Figure 3. The reaction of NO with carbanions in the presence
of sodium methoxide to prepare carbon-bound DAZDs was discovered over 100 years ago,31 however, the side
reaction of NO with sodium methoxide to generate sodium formate and potentially hazardous nitrous oxide was
just recently identified by Hrabie (Figure 3, equation-2).32 The NO gas can undergo a relatively quick
disproportionation reaction that can lead to significant N2O and NO2 production in a short period of time. It is
estimated 0.5 mol% of this impurity mixture is formed every 10 days under typical commercial pressures (450-500
psi).33 Schoenfisch and coworkers discovered that nitrosamines could form competitively with DAZDs in
anaerobic reactions of NO with polyamines, which could lead to the formation of nitrous oxide.34 Thus, tert-
butylamine could be oxidized to nitrosamines and nitrous oxide (Figure 3, equation-1). NO is also an oxidant that
could oxidize methanol solvent in the presence of a base, leading to the formation of nitrous oxide (Figure 3,
equation-3). In addition, base/acid swings and hydrolysis of sodium methoxide to sodium hydroxide in the
presence of water is certain (Figure 3, equation-4 to 6). Lastly, sodium hydroxide can react with NO, leading to
the formation of nitrous oxide and sodium nitrite (Figure 3, equation-7).
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NO
H
1
2
3
N
N
+ 4 NO
2
+ H2O
+
N2O
(equation-1)
2
R
R
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(equation-2)
(equation-3)
CH3ONa + 4 NO
CH3OH + 4 NO
HCO2Na + H2O
HCO2H + H2O
+
+
2 N2O
2 N2O
H2O
(equation-4)
(equation-5)
CH3ONa +
CH3OH
CH3OH
+ NaOH
+ HCO2Na
HCO2H
CH3ONa +
H2
N
H
N
R
HCO2H
(equation-6)
+
R
HCO2
2 NaNO2 + H2O
2 NaOH + 4 NO
+
N2O (equation-7)
Figure 3. Problems with diazeniumdiolate scale up by the medicinal chemistry route.
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As stated above, several challenges remain for scaling up the preparation of DAZD by the literature
reported chemistry. Recently, we have reported a general, scalable, safer, and high yielding methodology
adaptable to large scale synthesis of diazeniumdiolates in water using a calcium hydroxide base.25 To gain an
understanding of the reaction, we initially conducted control experiments in the absence of the starting material
organic amines. Three experiments were performed in 1.76 N NaOMe/MeOH, 1.76 N NaOH/water, and a slurry
–
of Ca(OH)2 (equal to 1.76 N OH) in water. All reactions were run under 250 psi NO gas at 20-25 °C. As
expected, all the three control experiments showed the generation of N2O during the agitation of the basic
solution under the pressure of NO (Figure 4) but with dramatically different rates. In the NaOH/water system, N2O
was rapidly generated and reached the unsafe zone, over the limited fraction N2O/NO (0.25), associated with
hydrogen or flammable organic solvents/compounds35-36 within ~ 450 min after the reaction started. After 1300
min reaction time, the fraction N2O/NO reached 0.659 and the reaction was depressurized and terminated (Figure
4, a). In the NaOMe/MeOH solution, the generation of N2O was slower than in the NaOH/water system. It
required around ~ 2500 min to reach the unsafe zone. However, the fraction N2O/NO got as far as 1.15 after
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8500 min. The fraction N2O/NO increased impressively to 2.38 after depressurizing the reaction to 5 psi (Figure 4,
b). Formation of N2O was much slower from the slurry of Ca(OH)2 in water, which generated only around 0.012
fraction of N2O/NO after stirring 10000 min (Figure 4, c). The plot clearly showed that the Ca(OH)2/water reaction
system didn’t build up dangerous levels of N2O gas. These results were consistent with the analysis of the anion
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-
-
concentration of nitrite (NO2 ) and formate (HCO2 ) in the reaction mixture by ion chromatography (IC). 70.9 mol%
and 22.8 mol% of nitrite were generated in the reaction of NaOH/water and NaOMe/MeOH, respectively.
Furthermore, large amounts of the formate (10.4 mol%) were detected in the NaOMe/MeOH reaction system. As
expected, the Ca(OH)2/water reaction system generated very low level of nitrite (< 3 mol%). Therefore, the
Ca(OH)2 water system should be the safest out of the methods we explored for the production of DAZD, based
on our understanding of combustion for the N2O/NO system. It was noteworthy to note that the fraction of
N2O/NO in the headspace dramatically increased after depressurizing from 250 psi to 5 psi (Figure 4, b) This was
likely due to the higher solubility of N2O than NO in solvents under high pressure. This finding clearly explained
the two previous unexpected explosions that occurred during the rapid depressurization (venting) of high-
pressure nitric oxide (NO).
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Figure 4. Plots of the ratio of N2O to NO sampled from the headspace of high pressure NO reaction systems over
time: Background control reaction (without organic amines) for N2O generation from the bases and solvents with
NO gas. a, 0.422 g NaOH (10.6 mmol) in degassed deionized (D.I.) water (6 mL) in a 15 mL reactor was agitated
with NO gas (250 psi) at 20 °C. b, 0.600 g NaOMe (95%, 10.6 mmol) in MeOH (6 mL) in a 15 mL reactor was
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–
agitated with NO gas (250 psi) at 20 °C. c, 0.412 g Ca(OH)2 (95%, equal to 10.6 mmol OH) in degassed D.I.
water in a 15 mL reactor was agitated with NO gas (250 psi) at 20 °C.
Finally, N-(tert-butyl)allylamine was converted to the corresponding DAZD calcium salt 5 under 250 psi of
nitric oxide in 95% isolated yield (Scheme 1). Monitoring the fraction of N2O/NO in the headspace of the real
reaction, we found that the fraction of N2O/NO in the headspace was less than 0.015 after the end of the reaction
and less than 0.03 after depressurizing from 250 psi to 5 psi (Figure 5, b). Both these numbers are well below the
safety guideline limit of 0.25 in the headspace. It clearly showed that the DAZD calcium salt formation didn’t build
up dangerous levels of N2O gas. Analysis of the aqueous solution in the reaction mixture by IC showed the
concentrations of nitrite and formate were 3.0 mol% and 0.29 mol%, respectively. The stability tests for the
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ending reaction mixture were conducted in 20 °C, 50 °C and 95 °C, respectively. We found that there were no
pressure building up both at 20 °C and 50 °C after agitation for 10 days. It suggested that the reaction mixture is
stable at ≤ 50 °C. However, we observed 13 psi net pressure increase after agitation at 95 °C over 168 h, which
corresponded to around 7.1% of calcium t-butyl allyl DAZD salt 5 decomposition. The preparation of 5 was
successfully carried out in multiple batches on multiple kilogram scale and was achieved in 95% isolated yield
and high purity by direct isolation from the reaction batch.
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Scheme 1. Preparation of DAZD Calcium salt 5
NO (250 psi)
O
O
N
H
Ca(OH)2, water
N
N
O
O
N
N
Ca
N
N
20 C, 160 h
4
5
95%
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Figure 5. Plots of the ratio of N2O to NO sampled from the headspace of high pressure NO reaction systems over
time: Comparison of the Ca(OH)2/water reaction system with or without the organic amine substrate. a, 0.412 g
Ca(OH)2 (95%, equal to 10.6 mmol –OH) in degassed D.I. water (6 mL) in a 15 mL reactor was agitated with NO
–
gas (250 psi) at 20 °C. b, 0.412 g Ca(OH)2 (95%, equal to 10.6 mmol OH) and 1.03 g tert-butylallylamine (8.80
mmol) in degassed D.I. water (6 mL) in a 15 mL reactor was agitated with NO gas (250 psi) at 20 °C.
DSC data showed that the dried calcium t-butyl allyl DAZD salt 5 is stable below 110 °C and has no
exothermic decomposition below 200 °C (Figure 6) and is not shock sensitive by drop weight testing (impact 300
kg/cm, 6 of 6 negative). It does undergo a large endothermic decomposition at ~150 °C. Although not specifically
studied, this decomposition is probably associated with a large gas release from the decomposition of DAZD. On
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the other hand, sodium salt 6 showed a thermal profile with the main exotherm being ~ 418 joule/gram initiating at
~165 °C, confirming the improved safety profile of the calcium salt 5 compared to the sodium salt 6.
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O
N
N
O
N
N
N
N
Ca
N
N
O
O
O
N
O
Na
5
6
Figure 6. DSC data for the DAZD calcium salt 5 and sodium salt 6.
With key intermediate 5 in hand, a robust process for the synthesis of MK-8150 (1) was developed and
was achieved in high purity (> 99.5 LCAP) and 85.6% isolated yield to MK-8150 (1) in two steps from 3a and 5.25
OR
O
N
O
N
N
2 steps
O
N
N
N
NH
N
N
Ca
+
N
O
O
O
85.6%
overall
N
N
NC
N
NC
3
5
1: MK-8150
: R = H
85%
-
3a
: R = 4-CF3PhSO2
Figure 7. Application of DAZD calcium 4 for the successful synthesis of MK-8150 (1) in kilogram-scale.
CONCLUSION
A practical, efficient, and safer methodology for the synthesis of diazeniumdiolate calcium salt 5 was
developed. This novel synthetic method has demonstrated several advantages over previous methods such as
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significantly improved yields, and easy isolation. The isolated diazeniumdiolate calcium salt has no exothermic
decomposition below 200°C, and is not shock sensitive, which is convenient for handling. More significantly, the
use of less soluble Ca(OH)2 as a base and water as solvent resulted in the controlled release of hydroxide to
suppress the formation of hazardous nitrous oxide, which was identified as a key factor in causing previous
explosions for the preparation of diazeniumdiolate using literature method. Additional safeguards were employed
by backfilling the vent line with an insert gas at reaction pressure prior to venting the reaction. Also re-configured
the control system to perform a much slower reaction vent at the end of the reaction. Monitoring the fraction of
N2O/NO in the headspace of the real reaction through FT-IR, we detected that the fraction of N2O/NO in the
headspace is less than 0.015 after the end of the reaction and less than 0.03 after venting. Both these numbers
are far below the safety guideline limit 0.175 in the headspace, a significant improvement over traditional
methodology that has been used for the past 50 years. Based on the safety data, the preparation of 5 was
successfully carried out in multiple batches on multiple kilograms scale and was achieved in 95% isolated yield
and high purity by direct isolation to support the MK-8150 NO-donor program at Merck & Co., Inc., Kenilworth,
NJ, USA. It is worthwhile to mention that anyone who uses this chemistry does so at their own risk and need to
generate their own safety data.
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EXPERIMENTAL SECTION
General Information. Nuclear magnetic resonance (NMR) spectra were recorded for 1H NMR at 500 MHz
or 400 MHz, for 13C NMR at 125 MHz or 100 MHz. Chemical shifts were reported in ppm (δ), and coupling
1
constants were reported in Hz. H resonances were relative to the residual deuterated solvent peaks for CDCl3
(7.26 ppm), CD3OD (3.34 ppm), D2O (4.79 ppm), or DMSO-d6 (2.54 ppm). 13C resonances were reported relative
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to the residual deuterated solvent peaks for CDCl3 (77.0 ppm), CD3OD (49.8 ppm), or DMSO-d6 (39.5 ppm). 19F
1
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resonances were relative to CFCl3 (δ = 0.0 ppm). Splitting patterns for H NMR signals are designated as: s
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(singlet), d (doublet), t (triplet), q (quartet), quint (quintuplet), broad singlet (br s) or m (multiplet). HPLC analysis
was performed on either (method 1) a Zorbax Eclipse Plus C18 50 mm x 4.6 mm, 1.8 μm, standard gradient: 10%
B to 95% B (A = 0.1% H3PO4, B = acetonitrile), 1 min hold, 2 min post, 1.5 mL/min, UV at 210 nm, 30 °C, 8 min
run time or (method 2) XBridge C18 15 cm x 4.6 mm, 3.5 μm, gradient: 5% B to 90% B (A = 10 mM
trimethylammonium hydroxide and adjust the pH with H3PO4 to 10.5, B = acetonitrile), 2 min hold, 5 min post, 1.0
mL/min, UV at 210 nm, 25 °C, 16 min run time. Ion chromatography (IC) was performed on a Dionex IonPac
AG194 x 250 mm (anion exchange) analytical column with IonPac4 x 50 mm guard column, mobile phase A with
100% de-ionized water, gradient: 5 mM potassium hydroxide to 25 mM, 5 min hold, 2 min post, 1.0 mLmin
(isocratic from mobile phase A), column temperature 30 °C, suppressor ASRS 300_4mm, P/N#064554,
conductivity detector cell temperature 35 °C, suppressor_current 62 mA. High resolution mass spectrometry
(HRMS) data were obtained using electrospray ionization technique either in positive or negative mode (ESI+ or
ESI-). Melting points were measured in open capillaries and are uncorrected. Water content (KF) was determined
by Karl Fisher titration on a Metrohm 737 KF coulometer. Room temperature (rt) is defined as 20-25 °C. The
fraction of N2O/NO was measured in Matrix MG01 FT-IR spectrometer. The wavenumbers (vmax) of N2O and NO
are 2100-2300 cm-1 and 1800-1950 cm-1, respectively. Differential Scanning Calorimetry (DSC) data were
collected using DSC Q2000 V24.4 Build 116.
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All reagents were of commercial grade and were used without further purification unless noted otherwise.
All solvents were purchased from Sigma Aldrich or Fisher Scientific as anhydrous and used without further
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purification unless otherwise noted. Acetonitrile and water (HPLC grade) were purchased from Fisher Scientific.
For reactions run in water (H2O), deionized and degassed water was used unless stated otherwise.
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General Procedure of the Reactions and Results of IC Analysis for Figures 4 and 5. All reactions in
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Figures 4 and 5 were run in an Endeavor Stirred Reactor.
Experiment in Figure 4: a, To a 15 mL Endeavor stirred reactor was charged NaOH (0.422 g, 10.6 mmol)
and degassed deionized (D.I.) water (6 mL). The reaction mixture was depressurized and pressurized with
nitrogen 3 times, with nitric oxide 3 times and then was pressurized with nitric oxide to 250 psi ± 2.5 psi while
maintaining the temperature at 20 °C. Each gas sample was taken 4 psi from the headspace of high pressure
NO reaction systems over time and diluted with nitrogen to 50 psi. The fraction of N2O/NO was obtained by FT-
IR. After stirring for 1300 min, the vessel was slowly depressure and then purged with nitrogen. The resulting
mixture was a homogenous solution. The concentration of formate, nitrite and nitrate in the solution (diluted by
10000X) was analyzed by IC.
Experiment in Figure 4: b, To a 15 mL endeavor stirred reactor was charged NaOMe (0.600 g, 95 wt%,
10.6 mmol) and methanol (6 mL). The reaction mixture was depressurized and pressurized with nitrogen 3 times,
with nitric oxide 3 times and then was pressurized with nitric oxide to 250 psi ± 2.5 psi while maintaining the
temperature at 20 °C. Each gas sample was taken
4 psi from the headspace of high pressure NO reaction
systems over time and diluted with nitrogen to 50 psi. The fraction of N2O/NO was obtained by FT-IR. After
stirring for 8500 min, the vessel was slowly depressure and then purged with nitrogen. The resulting mixture was
a homogenous solution. The methanol solution was concentrated to dry and the resulting solid was dissolved in
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D.I. water (6 mL). The concentration of formate, nitrite and nitrate in the solution (diluted by 1000X) was analyzed
by IC.
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Experiment in Figure 4: c, To a 15 mL endeavor stirred reactor was charged Ca(OH)2 (0.412 g, 95%,
equal to 10.6 mmol OH-) and degassed D.I. water (6 mL). The reaction mixture was depressurized and
pressurized with nitrogen 3 times, with nitric oxide 3 times and then was pressurized with nitric oxide to 250 psi ±
2.5 psi while maintaining the temperature at 20 °C. Each gas sample was taken 4 psi from the headspace of
high pressure NO reaction systems over time and diluted with nitrogen to 50 psi. The fraction of N2O/NO was
obtained by FT-IR. After stirring for 10000 min, the vessel was slowly depressure and then purged with nitrogen.
The resulting mixture was a light slurry. The solid [Ca(OH)2] was filtered off through solka flock bed. The
concentration of formate, nitrite and nitrate in the filtrate (diluted by 500X) was analyzed by IC.
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Experiment in Figure 5: b, To a 15 mL endeavor stirred reactor was charged Ca(OH)2 (0.412 g, 95%,
equal to 10.6 mmol OH-), tert-butylallylamine (1.03 g, 8.80 mmol) and degassed D.I. water (6 mL). The reaction
mixture was depressurized and pressurized with nitrogen 3 times, with nitric oxide 3 times and then was
pressurized with nitric oxide to 250 psi ± 2.5 psi while maintaining the temperature at 20 °C. Each gas sample
was taken 4 psi from the headspace of high pressure NO reaction systems over time and diluted with nitrogen
to 50 psi. The fraction of N2O/NO was obtained by FT-IR. After stirring for 10000 min, the vessel was slowly
depressure and then purged with nitrogen. The resulting mixture was a slurry. The solid (compound 30, typical
95% yield) was filtered off. The concentration of formate, nitrite and nitrate in the filtrate (diluted by 250X) was
analyzed by IC.
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1 - LZ_MK8150_20190308_1 #10 [modif ied by watersadmin]
0187A 500x
0187B 250x
0188A 1000x
0188B 10000x
CD_1
CD_1
CD_1
CD_1
2 - LZ_MK8150_20190308_1 #11 [modif ied by watersadmin]
3 - LZ_MK8150_20190308_1 #15 [modif ied by watersadmin]
4 - LZ_MK8150_20190308_1 #13 [modif ied by watersadmin]
µS
1
8.09
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9
7.00
6.00
5.00
4.00
3.00
2.00
1.00
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0.00
min
-0.95
0.3
2.0
4.0
6.0
8.0
10.0
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16.0
18.0
20.0
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24.0
26.0
28.0
30.0
32.0
34.8
-
-
Reaction Formate (HCO2 )
Nitrite (NO2-) conc. Nitrate (NO3 ) conc.
conc. mg/mL (mol%)
0.01 (0.012)
0.23 (0.29)
mg/mL (mol%)
1.77 (2.2)
mg/mL (mol%)
0.11 (0.10)
0.17 (0.16)
0.21 (0.19)
1.7 (1.6)
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4
2.42 (3.0)
8.25 (10.4)
18.51 (22.8)
57.63 (70.9)
0.01 (0.012)
Figure 8. IC analysis of the aqueous solution of the reactions
Experiment in Figure 6 for DSC data collection: a) for DAZD calcium salt 5, compound 5 (4.10 mg, 90
wt%) was charged to a 40 µL of tantalum-lined pressure-tight crucibles and was run at a scan rate of 5K/min. b)
for DAZD sodium salt 6, compound 5 (5.80 mg, 70 wt%) was charged to a 40 µL of tantalum-lined pressure-tight
crucibles and was run at a scan rate of 5K/min.
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Calcium 1(3-Allyl-3-(tert-Butyl))Diazen-1-Ium-1,2-Diolate (5).25
NO (250 psi)
Ca(OH)2, water
O
N
O
N
H
N
O
O
N
N
Ca
N
N
20 C, 160 h
4
5
95%
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To 100 L vessel-1 was charged degassed deionized water (50 L), tert-butylallyl amine (99 wt%, 5.000 kg, 43.73
mol) and Ca(OH)2 (96 wt%, 2.000 kg, 25.91 mol) while maintaining the batch temperature at 20-30 °C. The batch
in vessel-1 was purged with nitrogen for 3 times and was transferred to a 100 L autoclave (vessel-2). The vessel-
1 was rinsed with degassed deionized water (25 L), which was transferred to vessel-2. The batch in vessel-2 was
purged with nitric oxide for 3 times and then was pressurized with nitric oxide to 250 psi while maintaining the
temperature at 20-30 °C. The reaction mixture was stirred while maintaining the NO pressure at 250 ± 40 psi until
no further nitric oxide consumption was detected. The batch was cooled to 10-25 °C. The vessel-2 was vented
slowly over 2-4 h, then purged with nitrogen. The batch in vessel-2 was transferred to a filter pot for filtration. The
vessel-2 was rinsed with 0.01 M Ca(OH)2 aqueous solution (15 L x 2). The rinsed solutions were transferred to
the filter pot. The solid in filter pot was washed with 0.01 M Ca(OH)2 (10 L x 1), dried under vacuum with nitrogen
sweep at 30-40 °C. The desired product 30 was obtained in 8.050 kg (95% yield), m.p. 150 °C (decompose). IR
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1
(KBr) νmax 2974, 1603, 1481, 1416, 1392, 1376, 1361, 1236, 1185, 1079, 1002, 983, 947, 925 cm-1; H NMR (400
MHz, CD3OD)  5.81 (ddt, J = 17.2, 10.2, 6.4 Hz, 1H), 5.25 (d, J = 17.2, 1.7 Hz, 1H), 5.06 (m, 1H), 3.71 (d, J =
6.4 Hz, 2H), 1.28 (s, 9H); 13C NMR (100 MHz, CD3OD)  136.1, 119.4, 60.8, 50.8, 28.1; HRMS (ESI-TOF): [M +
OH] calcd for C14H29CaN6O5 401.1825, found 401.1810.
ASSOCIATED CONTENT
Supporting Information
The supporting information is available free of charge on the ACS Publications website at DOI:
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Experimental ignition tests and results, experimental stability tests of reaction mixture and results and 1H
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and 13C NMR spectra of 5 (PDF).
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: yongli_zhong@merck.com
ORCID®
Yong-Li Zhong: 0000-0001-9701-3630
Notes
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
The authors acknowledge T.P. Vickery (Merck & Co., Inc., Rahway, NJ, USA) for DSC data collections.
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