An improved kilogram-scale synthesis of 2-bromo-4-nitro-1H-imidazole: A key building block of nitroimidazole drugs

Article abstract of DOI:10.1021/op400095f

An efficient two-step method for the synthesis of 2-bromo-4-nitroimidazole, 6, a key building block for nitroimidazole drugs, has been developed. The synthesis involves dibromination of 4-nitroimidazole 10 followed by selective debromination using in situ reductive deiodination strategy. The reactions are facile, safe, and easy to scale up. The large-scale applicability of this improved method was tested by conducting the reactions on kilogram scale to produce the desired product in high yield and quality.

Full text of DOI:10.1021/op400095f

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Full Paper
An Improved Kilo-scale Synthesis of 2-Bromo-4-nitro-1H-
imidazole: A Key Building Block of Nitroimidazole Drugs
Srinivasa Rao Pedada, Vijay S. Satam, Pawan J. Tambade, Srinivas A. Kandadai,
Rama Mohan Hindupur, Hari Narayan Pati, Delphine Launay, and Denis Martin
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op400095f • Publication Date (Web): 15 Aug 2013
Downloaded from http://pubs.acs.org on August 16, 2013
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An Improved Kilo-scale Synthesis of 2-Bromo-4-nitro-1H-imidazole: A Key
Building Block of Nitroimidazole Drugs
Srinivasa Rao Pedada, Vijay S. Satam, Pawan J. Tambade, Srinivas A. Kandadai, Rama
Mohan Hindupur, Hari N. Pati*
Process Chemistry Division, Advinus Therapeutics Ltd., 21 & 22 Phase II, Peenya Industrial
Area, Bangalore ꢀ 560058, Karnataka, India.
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Delphine Launay, Denis Martin
Drugs for Neglected Diseases Initiative (DNDi), 15 Chemin Louis Dunant, 1202 Geneva,
Switzerland.
*
Corresponding author:
Hari N. Pati
Process Chemistry Division,
Advinus Therapeutics Ltd.,
1 & 22 Phase II, Peenya Industrial Area,
Bangalore ꢀ 560058, Karnataka, India.
eꢀmailꢀ hari.pati@advinus.com;
Tel No: (+91)9900212096
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TOC Graphic:
O N
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ABSTRACT: An efficient two steps method for the synthesis of 2ꢀbromoꢀ4ꢀnitroimidazole 6, a
key building block for nitroimidazole drugs, has been developed. The synthesis involves
dibromination of 4ꢀnitroimidazole 10 followed by selective debromination using in situ reductive
deiodination strategy. The reactions are facile, safe and easy to scaleꢀup. The largeꢀscale
applicability of this improved method was tested by conducting the reactions on kilogram scale
to produce the desired product in high yield and quality.
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INTRODUCTION
Nitroimidazole drugs are important therapeutic agents shown to be efficacious on a variety of
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protozoan and bacterial (anaerobic) infections of humans and animals. The antibiotic azomycin
2ꢀnitroimidazole 1, Figure 1), isolated from streptomycete species, was the first active
(
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nitroimidazole to be discovered. Nitroimidazoles have also been explored as promising
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scaffolds to develop drugs for the treatment of tuberculosis. The monocyclic 5ꢀnitroimidazole
derivative, metronidazole (2, Figure 1), and bicyclic 4ꢀnitroimidazole derivatives CGIꢀ17341 3,
PAꢀ824 4 and OPC 67683 5 (Figure 1) possess antitubercular activities and were developed as
6ꢀ9
treatments for tuberculosis.
N
N
N
O
CH3
O N
2
CH
3
NO2 O N
2
N
N
N
H
1
3
2
OH
O
N
N
O N
2
O
O
O
N
O N
2
N
N
CH3
O
5
F3CO
4
O N
2
O N
2
F3CO
N
N
O
O
Br
N
OCF3
N
H
CH3
6
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Figure 1. Structures of 2-nitroimidazole (1), metronidazole (2), CGI-17341 (3), PA-824 (4)
OPC 67683 (5), 2-bromo-4-nitro-1H-imidazole (6) and DNDI-VL-2098 (7)
One of the key building blocks of nitroimidazole drugs is 2ꢀbromoꢀ4ꢀnitroꢀ1Hꢀimidazole (6,
Figure 1). Despite the usefulness in the synthesis of many drug candidates and molecules for
various applications, no truly convenient process for its largeꢀscale production has been
published to the present day. In order to support preclinical and clinical development of a
nitroimidazoꢀoxazole based compound DNDIꢀVLꢀ2098 (7, Figure 1) as a candidate for oral
treatment of visceral leishmaniasis, our synthesis team initiated the development of a scalable
process to access its kilogram quantities. During the initial route selection process, it became
clear that we needed to ensure availability of 2ꢀbromoꢀ4ꢀnitroꢀ1Hꢀimidazole 6 in large quantities
as all retrosynthetic plans identified it as one of two key intermediates. Evaluation of literature
reports on the synthesis of 6 quickly led us to focus on development of the robust process for its
largeꢀscale production. While the synthesis of 6 is straightforward, several limitations in the
reported synthetic routes prevented their use for largeꢀscale production. In this communication,
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we wish to report an improved, robust and practical synthesis suitable for preparation of
multikilogram quantities of 2ꢀbromoꢀ4ꢀnitroꢀ1Hꢀimidazole 6.
ANTECEDENTS AND RESULTS
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Quite a few methods are reported in the literature for synthesis of 6 (Scheme 1).
However,
these methods have various disadvantages, and thus, are not suitable for largeꢀscale production.
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For example, in the method represented by Scheme 1a,
compounds 9 and 11 are formed as
intermediates. These compounds are chemically unstable, and there is a risk that these
compounds may explode due to impacts such as fall or friction. In addition, in this method, the
temperature (130 °C) applied to obtain compound 9 from compound 11 exceeds TNR
temperature of no return; maximum temperature at which compound can safely be handled in
chemical processing apparatus) of compound 11 (60ꢀ70 °C). Thus, it is extremely dangerous to
(
1
2
1
1
produce 6 using method described in Scheme 1a. Method described in Scheme 1b involves
nitration of 2ꢀbromoimidazole 12. However, this method is unsuitable for largeꢀscale production
as compound 6 is obtained in very low yield (25%). The four steps method as disclosed in
Scheme 1c requires additional protection/deprotection of NH group in 2,5ꢀdibromoꢀ4ꢀ
nitroimidazole 13. We felt that it was unwise to take up this lengthy method for scaleꢀup as the
additional protection/deprotection steps would lead to higher cost and cycle time. Moreover,
safety concerns were raised due to the use of sodium hydride in combination with DMF for the
preparation of compound 14. The alternative approach for the synthesis of 6, reported by
Takeshi and Shinhama, was found to be promising for scaleꢀup (Scheme 1d). The strategy
involved dibromination of relatively inexpensive 4ꢀnitroimidazole 10 followed by nucleophilic
substitution of bromine at position 5 of compound 13 with iodine to obtain 2ꢀbromoꢀ5ꢀiodoꢀ4ꢀ
nitroimidazole 16 which on reductive deiodination gave 2ꢀbromoꢀ4ꢀnitroimidazole 6. Since
removal of labile iodine was performed without protecting NH group in the imidazole ring, we
were inclined to adopt this strategy. Nevertheless, reproducibility of this synthesis to
multikilogram scale was very challenging. In the reported method, selective displacement of
bromo group at position 5 of 2,5ꢀdibromoꢀ4ꢀnitroimidazole 13 with iodo group was either
performed using hazardous hydriodic acid for a longer period (36 h) or using large quantity of
sodium iodide (10.0 equivalents) under harsh conditions. Moreover, reductive deiodination
reaction required use of very expensive platinum or palladium catalysts. Deiodination reactions
performed using sodium sulfite or other sulfur salts as reducing agents gave poor yields and
needed to be optimized. In this context and taking into account the requirement of a large
quantity of 6 to access DNDIꢀVLꢀ2098 7 for INDꢀenabling preclinical studies and the first
required batch of cGMP material, we decided to develop a robust process leading to 6, having a
purity of >99%, in multikilogram without performing chromatographic purifications.
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(CH CO) O
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O N
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O N
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N
HNO3
130 °C
HBr
NO2
Br
N
100 °C
N
(CH
3
CO)
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H
H
NO2
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10
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HNO3
H SO
Br
Br
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H
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c
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HCl
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Br
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O
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O
CH
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1d
PtO
or
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Pd on alumina
or
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N
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NaI or HI
N
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Br
Br
H O
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Br
N
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H
H
H
1
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16
1
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6
Scheme 1. Reported synthetic routes of 2-bromo-4-nitro-1H-imidazole 6
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First, the reported dibromination reaction of 4ꢀnitroimidazole 10 under the described conditions
was repeated. The reaction was carried out in water using bromine in the presence of sodium
bicarbonate. Although, the reaction was reproduced to obtain 2,5ꢀdibromoꢀ4ꢀnitroimidazole 13 in
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bromine, temperature, reaction time, etc. needed to be optimized before proceeding to largeꢀscale
synthetic efforts. Also, addition of bromine in the reaction mixture at ~25 °C resulted in
excessive foaming. This problem needed to be addressed as foaming caused dense bromine
fumes to escape resulting in poor conversion. Presumably, the foaming is due to carbon dioxide
gas produced from the reaction of sodium bicarbonate with hydrogen bromide formed during
5% yield several aspects of the synthesis such as molar equivalents of sodium bicarbonate and
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bromination. To overcome this problem, the bromination reaction was carried out using bases
other than sodium bicarbonate such as sodium hydroxide and disodium hydrogen phosphate.
Since sodium hydroxide and disodium hydrogen phosphate do not evolve any gas on reaction
with acid it was thought that bromination reaction using these bases would eliminate frothing.
However, reaction using sodium hydroxide gave the desired 2,5ꢀdibromoꢀ4ꢀnitroimidazole 13 in
only 48% yield and that using phosphate buffer did not proceed to completion. Hence, it was
decided to continue optimization efforts using sodium bicarbonate as acid scavenger and control
production of carbon dioxide gas by varying parameters like temperature and rate of addition of
bromine. Several experiments were performed in which addition of bromine was carried out at
different time intervals and at different temperatures ranging from 0ꢀ30 °C. It was observed that
foaming was less intense when bromine was added over a period of ~4 h at 0ꢀ5 °C. Hence, in the
subsequent optimization reactions addition of bromine was made over a period of 4ꢀ5 h
maintaining the temperature between 0 to 5 °C. The reaction mixture was stirred at 0ꢀ5 °C for 1.0
h and then at 65 °C for 6.0 h to ensure completion. During the course of heating the reaction
mixture at 65 °C no significant frothing was noticed. In order to determine the ratio of molar
equivalents of bromine and sodium bicarbonate to obtain optimum yield of 13, two sets of
experiments were performed on 10.0 g scale. In the first set of experiments, dibromination
reaction was carried out at 65 °C in water for 6.0 h by varying amount of bromine from 1.2 to 2.6
equivalents and keeping amount of sodium bicarbonate fixed to 2.0 equivalents. The results of
these reactions are displayed in Table 1. It was found that the yield of dibromo compound 13
increased with increase in amount of bromine up to 2.4 equivalents. At 2.4 equivalents of
bromine, compound 13 was obtained in 84% yield (Table 1, entry 6). Further increase in amount
of bromine did not result in any improvement in the yield of 13. In the second set of experiments,
reactions were repeated by keeping the amount of bromine unchanged to 2.4 equivalents and
varying amount of sodium bicarbonate from 1.5 to 2.5 equivalents. The results of these
experiments are presented in Table 1 (entries 8ꢀ13). It was found that at 2.3 equivalents of
sodium bicarbonate and 2.4 equivalents of bromine, compound 13 was obtained in 88% yield
after 6.0 h (Table 1, entry 10). The dibromination reactions carried out using same molar
equivalents of sodium bicarbonate and bromine gave compound 13 in 74% and 88% yield after 4
and 8 hours, respectively. It is clear from the data presented in Table 1 that compound 10
undergoes dibromination to give compound 13 in optimum yield of 88% after 6.0 h using
bromine and sodium carbonate in 2.4:2.3 molar ratio. It is noteworthy that no elaborate workup
is required to isolate the product. The dibromo compound 13 precipitates from the reaction
mixture. After adjusting the pH to 2ꢀ3 the yellow solid of 13 can be collected by filtration. This
optimized method gave 13 in excellent purity (~99% assay by HPLC) and was now ready for
scaleꢀup.
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Table 1. Results of dibromination reaction carried out at different Br and NaHCO3
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concentrations
O N
O N
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a
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Br
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Br2
equiv)
NaHCO3
(equiv)
Time
(h)
Yield
(%)
Entry
b
(
Dibromination using different molar equivalents of Br2
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Dibromination using different molar equivalents of NaHCO3
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2.4
2.4
2.4
2.4
2.4
1.5
2.0
2.3
2.5
2.3
2.3
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a
Reaction conditions: 4ꢀnitroimidazole 10 (10.0 g, 0.088 mol), water (50 mL), reaction
temperature 65 °C. Isolated yield.
b
Having optimized the first dibromination step, strategies were evaluated to carry out selective
debromination at position 5 of 2,5ꢀdibromoꢀ4ꢀnitroimidazole 13. After the study of various
debromination protocols, it occurred to us that the selective debromination at position 5 of the
compound 13 should be possible under mild conditions using sulfur salts as reducing agents in
the presence of nucleophilic iodide anion. The rationale behind this assumption was the presence
of strong electronꢀwithdrawing nitro group at position 4 which makes bromo group at position 5
in the compound 13 susceptible to nucleophilic substitution by iodide anion to afford 2ꢀbromoꢀ
ꢀiodoꢀ4ꢀnitroimidazole 16 which in turn could easily be deiodinated, owing to its labile nature,
using inexpensive sulfur salts. We felt that such a protocol would be advantageous as
deiodination could take place in situ making isolation of iodo compound 16 redundant.
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To validate this assumption, we examined the debromination reaction of compound 13 in acetic
acid using sodium iodide as the source of nucleophilic iodide anion and sodium sulfite as the
reducing agent. To our delight, the reaction gave desired 2ꢀbromoꢀ4ꢀnitroimidazole 6 in 42%
yield after 16 h. The reaction was performed on 10.0 g scale using 1.5 equivalents of sodium
iodide and 1.5 equivalents of sodium sulfite at 120ꢀ125 °C. Encouraged by the outcome, we
decided to optimize this reaction by using different iodide anion sources and sulfur containing
reducing agents. First, various iodine anion sources such as iodine, potassium iodide, tetraꢀnꢀ
butyl ammonium iodide (TBAI) were examined using sodium sulfite as a reducing agent. The
results of these selective debromination reactions are presented in Table 2 (entries 1ꢀ5).
Potassium iodide turned out to be the best iodide anion source as it gave product in excellent
isolated yield (64%, Table 2, entry 4). Other iodinating agents under similar reaction conditions
gave lower yields ranging from 25ꢀ42%. The reaction performed in the absence of iodide source
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did not give any product (Table 2, entry 5). This fact corroborated our assumption that the
reaction proceeds via formation of 2ꢀbromoꢀ5ꢀiodoꢀ4ꢀnitroimidazole 16 which on reductive
deiodination gives compound 6.
Next, several other sulfur salts such as Na S O , NaHSO , NaHS.xH O and Na SO were
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4
examined as reducing agents in the presence of potassium iodide. The results of these reactions
are displayed in Table 2 (entries 6ꢀ11). It is clear from these results that Na SO gave the desired
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3
debrominated product 6 in 64% yield which was highest compared to the yield obtained from
other reducing agents. Rest four reducing agents Na S O , NaHSO , NaHS.xH O and Na SO
4
gave lower yields (20%, 32%, 35% and 25%, respectively) of compound 6. The reaction
2
2
3
3
2
2
performed using potassium iodide in the absence of reducing agent gave 2ꢀbromoꢀ5ꢀiodoꢀ4ꢀ
1
13
nitroimidazole 16 instead of compound 6. The structure of 16 was confirmed by H NMR, C
NMR, IR spectroscopy and mass spectrometry. The formation of compound 16 confirms our
assumption that debromination reaction of compound 13 proceeds via formation of 2ꢀbromoꢀ5ꢀ
iodoꢀ4ꢀnitroimidazole 16 which then undergoes reductive deiodination in the presence of sodium
sulfite to afford 2ꢀbromoꢀ4ꢀnitroimidazole 6.
Before proceeding with largeꢀscale synthetic efforts, we turned our attention to other aspects of
the synthesis such as selection of solvent, reaction time and determination of molar equivalents
of potassium iodide and sodium sulfite to obtain optimum yield of 6. Different solvents such as
dimethylformamide (DMF), dimethylacetamide (DMA), Nꢀmethylꢀ2ꢀpyrrolidone (NMP), Nꢀ
methylmorpholine (NMM), acetic acid and water were screened. The experiments were
performed on 10.0 g scale at 120ꢀ125 °C using 1.5 equivalents each of potassium iodide and
sodium sulfite. The results of these experiments are presented in Table 2 (entries 12ꢀ19). The
debromination reaction in DMF progressed slowly to give 55% yield of compound 6 after 24 h.
While debromination reaction in DMA gave compound 6 in only 10% yield after 18 h, it did not
take place at all in NMP, NMM and water. Among the solvents screened, acetic acid emerged as
the solvent of choice. In the debromination reactions carried out in acetic acid, compound 6 was
obtained in 56%, 64% and 64% yields after 14, 16 and 18 hours, respectively. These results also
confirmed that optimum time for debromination reaction in acetic acid was 16 h. Class 3 solvent,
acetic acid, suits largeꢀscale synthesis as it is cost effective and nonꢀtoxic.
Table 2. Preliminary optimization of debromination reaction
O N
O N
2
2
N
N
a
Br
Br
Br
N
N
H
H
13
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Entry Iodinating
agent
Results of screen of different iodinating agents
Reducing
agent
Solvent
Time Temp
Yield
(%)
b
(h)
(°C)
1
2
3
4
5
NaI
TBAI
I2
KI
ꢀꢀꢀꢀ
Na SO
CH COOH
16
16
16
16
16
125
125
125
125
125
42
30
25
2
3
3
3
3
3
3
Na SO
CH COOH
2
3
Na SO
CH COOH
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Na SO
CH COOH
64
2
3
c
Na SO
CH COOH
2
3
Results of screen of different reducing agents
6
7
8
9
KI
KI
KI
KI
KI
KI
Na S O
CH COOH
16
16
16
16
16
16
125
125
125
125
125
125
20
32
35
25
2
2
3
3
NaHSO3
CH COOH
3
NaHS.xH O
CH COOH
2
3
Na SO
CH COOH
2
4
3
10
Na SO
CH COOH
64
2
3
3
d
11
ꢀꢀꢀ
CH COOH
3
Results of screen of different solvents
1
1
1
15
16
2
3
4
KI
KI
KI
KI
KI
Na SO
DMF
NMP
NMM
DMA
24
18
18
18
18
125
125
125
125
100
55
ꢀꢀꢀ
ꢀꢀꢀ
10
ꢀꢀꢀ
2
3
3
3
3
3
Na SO
2
Na SO
2
Na SO
2
Na SO
H O
2
2
1
7
KI
KI
KI
Na SO
CH COOH
14
16
18
125
125
125
56
64
64
2
3
3
3
3
18
Na SO
CH COOH
2
3
1
9
Na SO
CH COOH
2
3
a
Reaction conditions: 2,5ꢀdibromoꢀ4ꢀnitroimidazole 13 (10.0 g, 0.037 mol), solvent (50 mL),
iodinating agent (0.055 mol), reducing agent (0.055 mol). Isolated yield. No reaction. 2ꢀ
bromoꢀ5ꢀiodoꢀ4ꢀnitroimidazole 16 was isolated.
b
c
d
Two sets of experiments were designed to determine effect of molar equivalents of potassium
iodide and sodium sulfite on the reaction time and yield of compound 6. In the first set of
experiments, amount of potassium iodide was varied between 1.0 to 2.0 equivalents and amount
of sodium sulfite was kept unchanged to 1.5. The results presented in Table 3 (entry 1ꢀ4) showed
that the yield of monobromo compound 6 increased from 48% to 64% on increasing the amount
of potassium iodide from 1.0 to 1.5 equivalents. Further increase in the amount of potassium
iodide to 2.0 equivalents did not result in improvement in yield beyond 64%. The other set of
experiments was carried out by keeping molar equivalents of potassium iodide unchanged to 1.5
and varying molar equivalents of sodium sulfite from 1.0 to 2.0 (Table 3, entry 5ꢀ9). The yield of
compound 6 increased from 42% to 64% on increasing molar equivalents of sodium sulfite from
1
.0 to 1.5. Further increase in the amount of sodium sulfite to 2.0 equivalents did not result in
yield improvement. These results led us to conclude that 2,5ꢀdibromoꢀ4ꢀnitroimidazole 13 was
selectively and efficiently debrominated at position 5 to yield 2ꢀbromoꢀ4ꢀnitroꢀ1Hꢀimidazole 6
using 1.5 equivalents of potassium iodide and 1.5 equivalents of sodium sulfite in acetic acid at
20ꢀ125 °C after 16 h. The compound 6 was isolated in high purity after relatively easy work up.
Upon completion of reaction, acetic acid was recovered by vacuum distillation. The reaction
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mixture obtained after recovery of acetic acid was stirred in 5% aqueous sodium bisulfite
solution to quench excess iodide. Extraction of the reaction mixture in ethyl acetate followed by
concentration of the organic layer furnished compound 6 as yellow solid in >99% purity.
10
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13
14
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16
17
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45
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50
51
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53
54
55
56
57
58
59
60
Table 3. Results of debromination reaction carried out at different concentrations of KI
and Na SO
2
3
b
Entry
KI (equiv) Na SO (equiv)
Yield (%)
2
3
Debromination using different molar equivalents of KI
1
2
3
4
1.0
1.2
1.5
2.0
1.5
1.5
1.5
1.5
48
54
64
64
Debromination using different molar equivalents of Na SO3
2
5
6
7
8
9
1.5
1.5
1.5
1.5
1.5
1.0
1.2
1.5
1.7
2.0
42
56
64
64
64
a
Reaction conditions: 2,5ꢀdibromoꢀ4ꢀnitroimidazole 13 (10.0 g, 0.037 mol), CH COOH (50 mL),
3
b
reaction time (16 h), temperature (120ꢀ125 °C). Isolated yield.
This improved synthetic protocol (Scheme 2) to produce compound 6 was found to be superior
to all other protocols reported in the literature. In order to evaluate safety and operational issues,
both dibromination and debromination reactions were studied using reaction calorimetry.
Experiments were carried out in HEL (E188) calorimeter equipped with a 1.0 L glass vessel,
temperature sensor, calibration heater, and propeller stirrer. Figures 2 and 3 display calorimetric
curves of reactor temperature (green curve) and circular (jacket) temperature (red curve) (Yꢀaxis)
as a function of time (Xꢀaxis) for dibromination and debromination reactions, respectively. In the
case of dibromination reaction, calibration was performed before bromine feed and addition of
bromine was carried out over a period of 45 min instead of 4.0 h. Figure 2 shows a drop of about
1
0 °C in circular temperature during addition of bromine in the reaction mixture at 0ꢀ5 °C
indicating mild exothermic event. In order to maintain the reactor temperature at 0 °C, circular
temperature decreased by ~10 °C. The heat of reaction, as calculated from RC program (Win
ISO), was found to be low (488 kJ per kg of 10). Foaming caused due to evolution of carbon
dioxide was also moderate. The reaction progressed smoothly without any exothermic event after
bromine addition was completed. In the improved process of dibromination reaction, however,
bromine is added over a longer period (4.0 h), under such addition conditions the heat evolved
would be significantly lesser than 488 kJ/kg. The result suggests that cooling failure at any point
during the addition of bromine would not lead to significant gas evolution or any runaway
situation. Calorimetric curve obtained for debromination reaction (Figure 3) shows a clear
plateau indicating absence of any exothermic event during the course of heating the reaction
mass at 120ꢀ125 °C. From reaction calorimetry investigations, it is evident that the novel process
1
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developed for the synthesis of 2ꢀbromoꢀ4ꢀnitroꢀ1Hꢀimidazole 6 is safe, practical and suitable for
largeꢀscale production.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
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9
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 2. Reaction calorimetric curve of reactor and circular temperature as a function of
time associated with dibromination reaction of 4-nitroimidazole (10)
Figure 3. Reaction calorimetric curve of reactor and circular temperature as a function of
time associated with debromination reaction of 2,5-dibromo-4-nitroimidazole (13)
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To validate the largeꢀscale applicability of this improved synthesis of compound 6 (Scheme 2),
both dibromination and selective debromination reactions were performed in triplicate on 4.0 kg
and 5.0 kg scale, respectively. The reactions were monitored on HPLC. The results of scaleꢀup
batches are presented in Table 4. All scaleꢀup reactions exactly replicated optimized reactions to
provide consistent yields and purity of the desired monobromo compound 6. It is particularly
noteworthy that this synthetic protocol did not give even minute amount of 2ꢀbromoꢀ5ꢀiodoꢀ4ꢀ
nitroimidazole 16 or diꢀdebromoimidazole 10 as impurities.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
O N
O N
2
O N
2
2
N
N
N
2
KI/Na SO3
Br /NaHCO3
2
Br
Br
Br
H O,
N
CH COOH,
120-125 °C, 16 h
N
N
2
3
H
H
H
65 °C, 6 h
10
13
6
Scheme 2. An improved synthesis of 2-bromo-4-nitro-1H-imidazole 6
Table 4. Results of scale-up batches
a
Batch size
kg)
Output
(kg)
Yield
(%)
Purity by HPLC
(%)
Entry
(
Bromination of 4-nitroimidazole 10
1
2
3
4.0
8.44
8.15
8.26
88.00
85.00
86.13
99.2
99.1
98.9
4
.0
.0
4
Selective debromination of 2,5-dibromo-4-nitro-1H-imidazole 13
4
5
6
2.25
2.30
2.28
63.55
65.00
64.40
99.7
99.6
99.5
5.0
5
.0
.0
5
a
Assay purity analysis by HPLC on anhydrous basis
CONCLUSION
An improved and robust method for the synthesis of 2ꢀbromoꢀ4ꢀnitroꢀ1Hꢀimidazole 6, starting
from 4ꢀnitroimidazole 10, has been established by utilizing in situ reductive deiodination
strategy. This method is safe, cost effective, easy to scaleꢀup and hence superior to the other
methods that have been previously reported for the synthesis of compound 6. Largeꢀscale
applicability of this method was successfully tested by carrying out reactions on multikilogram
scale to obtain consistent yields and purity of 2ꢀbromoꢀ4ꢀnitroimidazole 6. With the employment
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of inexpensive, readily available reagents and environmentally benign solvents, this synthetic
method is suitable for industrial application.
EXPERIMENTAL SECTION
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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0
1
2
3
4
5
6
7
8
9
0
All raw materials were purchased from S. D. Fine Chem Ltd., India and used as it is without
1
13
further purification. The H NMR and C NMR spectra were recorded in DMSOꢀd using
6
VARIAN 400 MHz NMR spectrometer. The chemical shifts are reported as δ ppm relative to
tetramethylsilane. The FTIR spectra were obtained as a potassium bromide pellet using a
Spectrum 100 PerkinꢀElmer FTꢀIR spectrometer. Mass spectra were recorded on a QꢀTOF
Premier spectrometer, using electronꢀspray ionization. Melting points were determined on a
Buchi (Bꢀ545) melting point apparatus and are uncorrected. HPLC chromatographic purity was
determined on Waters HPLC using a Cosmosil Cꢀ18 column (250 × 4.6mm).
2,5-Dibromo-4-nitro-1H-imidazole 13. In a 100 L capacity AGLR (all glassꢀlined reactor)
equipped with a temperature probe, a condenser, and a mechanical stirrer was added water (20
L). To it was added 4ꢀnitroimidazole 10 (4.0 kg, 35.4 mol) at room temperature. The reaction
mixture was stirred and cooled to 0ꢀ5 °C. To the reaction mixture was added sodium bicarbonate
(6.8 kg, 81.3 mol) under stirring. Bromine (13.5 kg, 84.93 mol) was added slowly in the reaction
mixture over a period of 4.0 h maintaining temperature between 0 and 5 °C. After complete
addition of bromine, the reaction mixture was stirred vigorously at 0ꢀ5 °C for 1.0 h. The reaction
mixture was then stirred at 65 °C for 6.0 h. The progress of the reaction was monitored by HPLC
analysis. After completion, the reaction mixture was cooled to 0ꢀ5 °C. The pH of the reaction
mixture was adjusted to 2ꢀ3 by adding aqueous hydrochloric acid (6.0 N, 6.0 L). The reaction
mixture was stirred for 1.0 h at 0ꢀ5 °C and filtered. The compound 13 obtained as a pale yellow
solid was washed with water (12 L) and dried in air oven at 30ꢀ35 °C (8.44 kg, 88%). Mp 229ꢀ
1
13
2
31 °C; HPLC: 99.2% (assay); H NMR: (400 MHz, DMSOꢀd ) δ 7.98 (s, 1H); C NMR: (100
6
ꢀ1
MHz, DMSOꢀd ) δ 143.9, 119.9, 108.1; IR (KBr, cm ): 3208, 1548, 1513, 1454, 1393, 668;
6
+
Mass (m/z): 271.4 (M+1)
.
2-Bromo-4-nitro-1H-imidazole 6. In a dry 100 L capacity AGLR (all glassꢀlined reactor)
equipped with a temperature probe, a condenser, and a mechanical stirrer was added glacial
acetic acid (25 L). To it was added 2,5ꢀdibromoꢀ4ꢀnitroꢀ1Hꢀimidazole 13 (5.0 kg, 18.45 mol) at
room temperature under stirring. To the reaction mixture was added potassium iodide (4.60 kg,
27.67 mol) and sodium sulfite (3.48 kg, 27.67 mol) under stirring at room temperature. The
reaction mixture was heated at 120ꢀ125 ºC for 16 h (progress of the reaction was monitored by
HPLC). After completion of the reaction, acetic acid was distilled off under vacuum at 60ꢀ65 °C.
To the crude product obtained was added water (30 L). The reaction mixture was stirred for 10
min and to it was added aqueous sodium bisulfite solution (5%, 20 L) to quench excess iodide.
The reaction mixture was stirred for 30 min and then extracted in ethyl acetate (50 L). The
organic layer was separated. The aqueous layer extracted again in ethyl acetate (2 × 20 L). The
combined organic layer was then washed with water (2 × 25 L), dried over sodium sulphate and
concentrated under vacuum at 40ꢀ45 °C to obtain 2ꢀbromoꢀ4ꢀnitroimidazole 6 as a yellow solid.
The solid obtained was then dried under vacuum at 40ꢀ45 °C (2.3 kg, 65%). Mp 239ꢀ241 °C;
1
13
HPLC: 99.6% (assay); H NMR: (400 MHz, DMSOꢀd ) δ 14.15 (bs, 1H), 8.46 (s, 1H);
C
6
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ꢀ1
NMR: (100 MHz, DMSOꢀd ) δ 147.8, 122.6, 118.4; IR (KBr, cm ): 3208, 1548, 1513, 1454,
6
+
1
393, 668; Mass (m/z): 190.9 (M )
.
1
2
-Bromo-5-iodo-4-nitro-1H-imidazole 16. Yellow solid, Mp 190ꢀ193 °C; H NMR: (400 MHz,
DMSOꢀd ) δ 7.20 (s, 1H); C NMR: (100 MHz, DMSOꢀd ) δ 147.7, 122.5, 118.3; IR (KBr, cm
13
ꢀ
6
6
1
+
): 3208, 1548, 1513, 1454, 1393, 668; Mass (m/z): 316.7 (M )
.
10
11
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ACKNOWLEDGMENTS
Authors thank the Drug for Neglected Disease Initiative (DNDi) for financial aid to support this
research. Specific funding was obtained through DNDi from Bill & Melinda Gates Foundation,
USA with complementary core funding from Department for International Development (DFID),
UK; Dutch Ministry of Foreign Affairs (DGIS), The Nederlands; Federal Ministry of Education
and Research (BMBF), Germany; Spanish Agency for International Development Cooperation
(AECID), Spain; Swiss Agency for Development and Cooperation (SDC), Switzerland and
Médecins Sans Frontières (Doctors without Borders)/International. Authors also thank Advinus
Therapeutics Ltd., Bangalore, India for supporting this research.
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14) Takeshi, K.; Yuichi, I. Method for producing 2ꢀhaloimidazole compound. WO 2008120800,
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2
(
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