Development of safe, scalable nitric acid oxidation using a catalytic amount of NaNO2 for 3-bromo-2,2-bis(bromomethyl)propanoic acid: An intermediate of S-013420

Article abstract of DOI:10.1021/op1003133

A safe, scalable process was developed for nitric acid oxidation of 3-bromo-2,2-bis(bromomethyl)propan-1-ol (2) to give 3-bromo-2,2-bis(bromomethyl) propanoic acid (3), an intermediate in the synthesis of S-013420 (1). The key points are the use of a catalytic amount of NaNO₂ and addition of the starting material in portions. We achieved 3,000 L scale pilot production.

Full text of DOI:10.1021/op1003133

ARTICLE
pubs.acs.org/OPRD
Development of Safe, Scalable Nitric Acid Oxidation Using a Catalytic
Amount of NaNO2 for 3-Bromo-2,2-bis(bromomethyl)propanoic Acid:
An Intermediate of S-013420
Hiroshi Osato,* Mikio Kabaki, and Sumio Shimizu
Chemical Development Center, CMC Development Laboratories, Shionogi & Co., Ltd., 1-3, Kuise Terajima 2-Chome, Amagasaki,
Hyogo 660-0813, Japan
S Supporting Information
b
ABSTRACT: A safe, scalable process was developed for nitric acid oxidation of 3-bromo-2,2-bis(bromomethyl)propan-1-ol (2) to
give 3-bromo-2,2-bis(bromomethyl)propanoic acid (3), an intermediate in the synthesis of S-013420 (1). The key points are the use
of a catalytic amount of NaNO2 and addition of the starting material in portions. We achieved 3,000 L scale pilot production.
Scheme 1
’ INTRODUCTION
Nitric acid is a strong oxidant that has been widely used for a
long time.1 However, other mild oxidants such as DessÀMartin
periodinane,2 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO),3
2-iodoxybenzoic acid (IBX),4 RuCl3ÀNaIO4,5 and tetrapropyl
ammonium perruthenate (TPAP)6 have been used more often
than nitric acid because the strong acidic nature of nitric acid
causes decomposition of unstable substrates and sometimes
produces nitro aromatic compounds. In addition, oxidizing
specific parts of compounds with nitric acid is difficult, and
oxidation using nitric acid has sometimes resulted in a thermal
runaway reaction.7 However, if the oxidation product is stable in
strong acid and the reaction heat and gases can be safely
controlled, nitric acid oxidation can be valuable, especially in
the chemical industry, because nitric acid is inexpensive and has
no toxic potential. Such an oxidation procedure would be simple,
easy, and environmentally friendly because the side products are
gases such as oxides of nitrogen. In addition, nitric acid oxidation
is a clean direct method of converting alcohols to carboxylic acids
in contrast to other methods such as Jones oxidation (CrO3,
H2SO4, acetone)8 and KMnO4 oxidation,9 which require very
toxic reagents and can cause environment pollution. For these
reasons, we chose nitric acid as an oxidant for the process of
manufacturing the starting material methylene diol (4) for
S-013420 (1), a novel bicyclolide (bridged bicyclic macrolide).10
The route to intermediate 4 is illustrated in Scheme 1. The
reaction conditions of the oxidation (2 f 3) were optimized, and
a detailed safety evaluation study was conducted. The pilot
manufacturing was successful on a 3,000 L scale. Here we report
the details of safe, practical oxidation with nitric acid for scale-up
manufacturing and also discuss the reaction mechanism.
there is an induction period before the reaction starts, (2) the
reaction mixture has two phases from the beginning to the end,
and (3) the generation of reaction heat and gases cannot be
controlled as it is a full batch reaction. To overcome these
problems, starting material 2 was dissolved in acetic acid, and
this solution was added to 68% nitric acid containing a catalytic
amount of NaNO2 in accordance with the literature.1f As a result,
the induction period was shortened, and the generation of
reaction heat and gases also seemed to be controllable.
Safety Evaluation of Nitric Acid Oxidation. The calories and
the generation of NOx gases were measured by RC1e as shown
in Figure 1 and Table 1. The solution of starting material 2 in
acetic acid (1 vol) was added to a mixture of 68% nitric acid (8.0
equiv) and NaNO2 (1.0 mol %) dropwise over 2 h at 65 °C. The
’ RESULTS AND DISCUSSION
Preliminary Experimental Study and Optimization of
Nitric Acid Oxidation. At first, oxidation of 2 using 68% nitric
acid was carried out at 90 °C and gave the desired product 3 in 80%
yield. However, there were three issues for scale-up production: (1)
Received: November 29, 2010
Published: March 16, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/op1003133 Org. Process Res. Dev. 2011, 15, 581–584
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Figure 1. Reaction heat and gas generation 1.
Table 1. Result of RC1e Experiment 1
accumulation of the reaction heat and NOx gases generation
were observed in the early stages (when 25% of starting material
2 in acetic acid was added, only 14% heat and 7% gases
generation were observed), further investigation was necessary
to ensure safety.
specific heat of
ΔHreact
(kJ/mol)a
dropwise addition
time (min)b
reaction mass
(J/(g K))
ΔTad (K)
3
Consideration of the Reaction Mechanism of Nitric Acid
Oxidation. The following reaction mechanism is proposed in
the literature1a as shown in Figure 2. First, NaNO2 is converted
to HNO2 in the acidic condition and HNO2 reacts with nitric
acid to form NO2. Alcohol reacts with NO2 and becomes an
alkyl radical, which is oxidized by NO2 to form alkyl nitrite (R-
CH(OH)-OdN-O). This alkyl nitrite reacts with nitric acid in
the acidic condition and becomes diol, which is immediately
converted to aldehyde. Further oxidation by nitric acid leads to
carboxylic acid 3. According to this mechanism, the rate of
reaction depends on the concentration of NO2, and thus the
initial rate of the reaction in the previous condition is slow
because only a small amount of NO2 is present in the initial
reaction mixture. When a small portion of starting material 2 is
added as an initiator, enough NO2 would be generated and the
rate of the reaction would be greater from the beginning. On the
basis of this idea, further investigation was conducted.
216.0
120
2.60
113.8
a Based on charged 2. b Dropwise addition of a solution of 2 in
acetic acid.
Investigation for Safer Nitric Acid Oxidation and Safety
Evaluation. The amount of the starting material for the initiation
was set at 10% because the adiabatic temperature rise calculated
from previous data was approximately 11 K, and MTSR would be
76.0 °C, which is lower than the boiling point of the solvents
(nitric acid 83 °C, water 100 °C, and acetic acid 118 °C). To
initiate the reaction, 10% starting material 2 in acetic acid was
added, and after using HPLC to confirm that all of the starting
material had been consumed, the remaining 90% of starting
material 2 in acetic acid was added dropwise over 3 h. The
RC1e result is shown in Figure 3 and Table 2. The adiabatic
temperature rise (ΔTad2) of the initiation by dosing 10% starting
material 2 was 10.0 K, and ΔTad3 of the reaction by dosing the
Figure 2. Plausible reaction mechanism.
total reaction calorie level was 216.0 kJ/mol, and the adiabatic
temperature rise (ΔTad1) was 113.8 K. The instantaneous
maximum reaction heat was 35 W when 33% of starting material
2 was added. The maximum temperature of the synthetic
reaction (MTSR) by this ΔTad1 is 178.8 °C. As the
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Figure 3. Reaction heat and gas generation 2.
Table 2. Result of RC1e Experiment 2
ΔHreact (kJ/mol)a
dropwise addition time (min)b
specific heat of reaction mass (J/(g K))
ΔTad (K)
3
10% 2 and acetic acid
90% 2 and acetic acid
18.3
18
2.51
2.50
10.0
218.3
180
109.6
a Based on charged 2. b Dropwise addition of a solution of 2 in acetic acid.
Table 3. Results of DSC Experimenta
Tonset (°C)
enthalpy (J/g)
Tonset at mp (°C)
enthalpy at mp (J/g)
alcohol 2
alcohol 2 in aceteic acidb
92.52
À58.46
249.84
269.83
23.57
22.61
carboxylic acid 3
120.13
À35.91
a Heating rate; 10 °C/min. b Alcohol 2/acetic acid = 1:1 (w/w).
remaining 90% of starting material 2 was 109.6 K. The instanta-
neous maximum reaction heat was 10 W, and the reaction heat
could be safely controlled by the dropwise addition of the
remaining 90% reactant,11 which also controlled the NOx gases
generation from the early period as expected. The exothermic heat
of starting material 2, a solution of 2 in acetic acid, and product 3 was
measured by DSC. The results are summarized at Table 3. The
significant exothermic peak was not observed at all samples. This
procedure was much safer than the previous one and was adapted
for pilot plant manufacturing.
Application in a Manufacturing Facility. Pilot manufactur-
ing using this oxidation was carried out with a 3,000 L glass-lined
reactor. Hydrolysis of NOx gases was carried out in an alkali
scrubber. At 20 min after addition of 10% of the starting material
in one portion as an initiator, an increase in temperature of
approximately 2 K was observed, and in-process testing by
HPLC12 showed that all of starting material 2 had been
consumed. The reaction heat and the gas generation were well
controlled by gradual addition of the remaining starting material
2 from the beginning to the end, and no leakage of acidic gases
from the alkali scrubber was observed. The purity of the obtained
crystals from the manufacturing run was comparable to that of
the lab run.
’ CONCLUSION
Safe, scalable nitric acid oxidation using a catalytic amount of
NaNO2 was applied to pilot manufacturing of 3-bromo-2,2-
bis(bromomethyl)propanoic acid (3), which is an intermediate
of S-013420 (1). Initiation was successfully conducted with 10%
starting material, and the reaction heat and gas generation could
be successfully controlled. This led to successful scale-up manu-
facturing on a scale of 425 kg.
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’ EXPERIMENTAL SECTION
(7) Van Woezik, B. A. A.; Westerterp, K. P. Chem. Eng. Process. 2002,
41, 59.
NMR spectra were measured on a Varian MERCURY-300VX.
High performance liquid chromatographic (HPLC) analysis was
carried out using a Shimadzu LC-10ADVP. DSC measurements
were conducted on a METTLER TOLEDO SDC822e.
(8) (a) Petersen, Q. R.; Cambie, R. C.; Russell, G. B. Aust. J. Chem.
1993, 46, 1961. (b) Kim, H.; Lee, J. B. Arch. Toxicol. 2004, 78, 363.
(9) (a) John, R. R. Organic Synthesis; Wiley: New York, 1943;
Collect. Vol. II, p 315. (b) Casale, R. J.; LeChevallier, M. W.; Pontius,
F. W. Proceedings - Annual Conference, American Water Works Association;
AWWA: Denver, CO, 2001; p 193.
(10) (a) Revill, P.; Bolos, J.; Serradell, N. Drugs Future 2006, 31, 479.
(b) Guoyou, X.; Datong, T.; Yonghua, G.; Guoqiang, W.; Heejin, K.;
Zhigang, C.; Ly, T. P.; Yat, S. O.; Zhe, W. Org. Process. Res. Dev. 2010,
14, 504.
Procedure for Manufacturing Acid 3 in a Pilot Plant.
NaNO2 (0.9 kg, 13 mol) was dissolved in 68% nitric acid
(992.6 kg, 10712 mol), and the mixture was heated to 65 °C.
Alcohol 2 (425.0 kg, 1308 mol) was dissolved in acetic acid
(425.0 kg), and 10% of this solution was added to the nitric acid
solution at 65 °C. After the complete consumption of alcohol 2
had been confirmed by HPLC, the remaining 90% of alcohol 2 in
acetic acid was added dropwise over 3 h, and the whole mixture
was stirred for 1 h. After completion of the reaction had been
confirmed by HPLC, the reaction mixture was cooled to 32 °C,
and the product was observed to precipitate. The mixture was
stirred for 1 h at the same temperature. After 1148.0 kg of water
(2.7 vol) was added, the slurry was aged for 3 h, cooled to 5 °C,
and stirred for 1 h at the same temperature. The crystals were
filtrated on a Nutsche plate filter, washed with water (1148.0 kg,
2.7 vol), and dried using a double-cone dryer under reduced
pressure at 55 °C. By this procedure, 394.1 kg of acid 3 was
obtained (isolated yield 88.9%). Mp 98À99 °C, lit.12 mp
(11) The Qr line has some dents because the feeder was changed five
times during the reagent addition.
(12) (a) Carnmalm, B.; Gyllander, J.; Jonsson, N. A.; Mikiver, L. Acta
Pharm. Suec. 1974, 11, 161; Chem. Abstr. 1967 66, 75713f.
’ NOTE ADDED AFTER ASAP PUBLICATION
This paper was published on the Web on March 16, 2011.
Changes were made to the Acknowledgment and the corrected
version was reposted on March 25, 2011.
1
98À100; H NMR (300 MHz, CDCl3) δ 3.76 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 32.50, 53.24, 174.29.
’ ASSOCIATED CONTENT
1
Supporting Information. Copies of H NMR and 13C
S
b
NMR of compound 3; copies of RC1e, DSC, and HPLC results.
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: hiroshi.oosato@shionogi.co.jp.
’ ACKNOWLEDGMENT
The authors thank Takashi Oda, Yuki Endo, and Toshimasa
Hamada in Nissan Chemical Industries, Ltd. for their process
development study and helpful discussion and Dr. Yoshitaka
Araki and Dr. Takemasa Hida in Shionogi CMC Development
Laboratories for helpful discussion on safety evaluation study.
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