Efficient large-scale synthesis of 2-amino-5- methanesulfonylaminobenzenesulfonamide

Article abstract of DOI:10.1080/00397910801997512

A novel synthesis of 2-amino-5-methanesulfonylaminobenzenesulfonamide is described. This preparation begins with readily available 4-nitroaniline and proceeds through five steps (isolations) in 41% overall yield. The described chemistry is conducted on a 50- to 100-g scale and does not require extractive workup procedures or chromatographic purifications. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910801997512

1
Synthetic Communications , 38: 1909–1916, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801997512
Efficient Large-Scale Synthesis of 2-Amino-
5
-methanesulfonylaminobenzenesulfonamide
Peter S. Dragovich, Douglas E. Murphy, Chinh V. Tran,
and Frank Ruebsam
Anadys Pharmaceuticals, San Diego, California, USA
Abstract: A novel synthesis of 2-amino-5-methanesulfonylaminobenzenesulfon-
amide is described. This preparation begins with readily available 4-nitroaniline
and proceeds through five steps (isolations) in 41% overall yield. The described
chemistry is conducted on a 50- to 100-g scale and does not require extractive
workup procedures or chromatographic purifications.
Keywords: 2-Amino-5-methanesulfonylaminobenzenesulfonamide; Friedel–Crafts
acylation; Sulfonamide
INTRODUCTION
During the course of our efforts to develop novel antiviral agents, we
often required the use of large (>20 g) quantities of 2-amino-5-methane-
sulfonylaminobenzenesulfonamide (1, Scheme 1). Unfortunately, existing
methods for the synthesis of 1 require the generation of ammonia gas in
[
1]
sealed reaction vessels under high temperature and pressure conditions.
We therefore sought to develop an alternate preparation of 1 that avoids
the potential safety hazards associated with the existing routes to the
compound. To facilitate the large-scale synthesis of 1, we also wished
to employ inexpensive and readily available reagents in our alternate
method and to avoid extractive workup procedures and chromatographic
purifications. Here, we describe a new preparation of 2-amino-5-
methanesulfonylaminobenzenesulfonamide (1) that achieves all of these
objectives.
Received in the USA January 16, 2008.
Address correspondence to Peter S. Dragovich, Anadys Pharmaceuticals,
San Diego, CA, USA. E-mail: pdragovich@anadyspharma.com
1
909

1910
P. S. Dragovich et al.
ꢀ
Scheme 1. Reagents and conditions: (a) MsCl, pyridine, CH CN, 23 C, 19 h,
3
ꢀ
8
9%; (b) H , Pd on C, THF, 23 C, 4 d, 95%; (c) O=C=NSO Cl, EtNO ,
2
2
2
ꢀ
ꢀ
ꢀ
ꢁ
20 C, 2 h, then AlCl
e) MsCl, pyridine, CH
3
, 110 C, 1 h, 81%; (d) 9.0 M H
ꢀ
2
SO
4
, 130 C, 2.5 h, 75%;
(
3
CN, 23 C, 15 h, 80%.
RESULTS AND DISCUSSION
Our new synthesis of 2-amino-5-methanesulfonylaminobenzenesulfon-
amide is depicted in Scheme 1 and begins with readily available 4-nitro-
aniline (ca. $70=kg). This material was sulfonylated by treatment with
methanesulfonylchloride in the presence of a slight excess of pyridine.
The resulting product (2) was precipitated from the reaction mixture by
the addition of water and was isolated in 89% yield by vacuum fil-
[
2]
tration. Reduction of the nitro group present in 2 proceeded smoothly
at room temperature over several days using Pd=C and hydrogen gas
(latex balloons). The extended reaction time was likely due to the dif-
ficulty of introducing large hydrogen volumes into the reaction flask
using simple balloons. [No attempt was made to perform the reduction
of 2 using more elaborate hydrogenation equipment. For an alternate
synthesis of N-(4-aminophenyl)methanesulfonamide, see Ref. 2a.] The
1
catalyst was removed via filtration through Celite , and the reduction
product (3) was isolated in 95% yield by partial evaporation of the
filtrate and precipitation with heptane.
We then employed a three-step literature procedure to intramolecu-
[
3,4]
larly introduce a second sulfonamide moiety into compound 3.
Thus,
adding a nitroethane solution of 3 to a cold solution of chlorosulfonyl-
isocyanate in the same solvent afforded the corresponding urea (not
shown). This entity was then transformed via an aluminum chloride-
mediated intramolecular Friedel–Crafts acylation into compound 4. This
product was isolated in 81% yield by vacuum filtration following

2
-Amino-5-methanesulfonylaminobenzenesulfonamide
1911
addition of water to the Friedel–Crafts reaction mixture. The urea moiety
present in compound 4 was subsequently hydrolyzed by exposure to
[5]
9
.0 M H SO at elevated temperature. Care was needed when conduct-
2 4
ing this reaction on more than a 20-g scale because the liberated CO2
caused significant foaming of the suspended reaction mixture. This issue
could be effectively controlled through the use of slow heating=stirring
and oversize reaction vessels and was most problematic during the early
part of the transformation (the aminobenzene-sulfonamide products are
soluble in acidic media). Unfortunately, the acidic reaction conditions
also resulted in partial hydrolysis of the methanesulfonamide moiety
present in 4, and the described transformation therefore afforded a mix-
ture of the desired 2-amino-5-methanesulfonylaminobenzenesulfonamide
1
and 2,5-diaminobenzene-sulfonamide (5) in 75% yield after isolation by
filtration (ca. 1.5:1.0 ratio). [Several other reagents and reaction con-
ditions were examined to effect the transformation of 4 to 1 at elevated
temperature (e.g., 6.0 M HCl, 12.0 M HCl, 6.0 M H SO , 50% H PO ,
2
4
3
4
6
.0 M KOH). None were found to be superior to the method described
in this work.] However, this mixture was easily converted to pure 1 by
treatment with methanesulfonylchloride in the presence of a slight excess
of pyridine (stoichiometry of reagents based on the quantities of 5 pre-
1
sent in the mixture as determined by H NMR). Compound 1 prepared
in this manner was isolated by vacuum filtration in 80% yield following
partial concentration of the reaction mixture and dilution with EtOAc.
SUMMARY
In this work, we describe a novel and efficient synthesis of 2-amino-5-
methanesulfonylaminobenzenesulfonamide (1) from 4-nitroaniline. This
method proceeds in 41% overall yield through five steps (isolations)
and does not require extractive workup procedures or chromatographic
purifications. We have utilized this synthesis on several occasions to
prepare 1 in quantities greater than 50 g.
EXPERIMENTAL
General Considerations
All reactions were performed in septum-sealed flasks under a slight posi-
tive pressure of dry nitrogen. All commercial reagents were used as
received from their respective suppliers. Reagent-grade nitroethane was
purchased from Aldrich and was used without additional purification.

1912
P. S. Dragovich et al.
All other solvents were purchased from EMD in anhydrous form and
1
13
were used without additional purification. H NMR and C NMR spec-
tra were recorded at 400 and 100 MHz, respectively. Chemical shifts are
reported in parts per million (d) using internal solvent signals as refer-
ences, and coupling constants (when given) are reported in hertz (Hz).
N-(4-Nitrophenyl)methanesulfonamide (2)
A solution of methanesulfonylchloride (47.1 mL, 0.61 mol, 1.05 equiv) in
CH CN (160 mL) was added via addition funnel over 40 min to a solution
3
of 4-nitroaniline (80.0 g, 0.58 mol, 1.0 equiv) and pyridine (70.2 mL,
ꢀ
0
neck flask. The mixture was stirred at 23 C for 19 h, and then water
.87 mol, 1.5 equiv) in CH CN (400 mL) at 23 C in a 2000-mL single-
ꢀ
3
ꢀ
(
3
800 mL) was added. The resulting suspension was stirred at 23 C for
0 min, and then was vacuum-filtered through medium paper using a
B u¨ chner funnel. The collected solid was washed with water (2 ꢂ 150 mL)
and air dried overnight to give 2 (111.4 g, 89%) as a yellow-brown solid:
ꢀ
1
mp ¼ 180–182 C; H NMR (DMSO-d ) d: 3.17 (3H, s), 7.32–7.36
6
1
3
(
2H, m), 8.18–8.22 (2H, m), 10.69 (1H, s); C NMR (DMSO-d ) d:
6
41.0, 118.2, 126.1, 142.8, 145.5. Anal. calcd. for C H N O S: C, 38.88;
7 8 2 4
H, 3.73; N, 12.96. Found: C, 39.08; H, 3.75; N, 13.36.
N-(4-Aminophenyl)methanesulfonamide (3)
Palladium on carbon (11.1 g, 5%, wet, Alfa-Aesar) was added to a
ꢀ
solution of 2 (111.4 g, 0.52 mol) in THF (900 mL) at 23 C in a 2000-mL
single-neck flask. The atmosphere above the resulting suspension was
replaced with hydrogen gas, and the reaction mixture was maintained
ꢀ
under an atmosphere of hydrogen at 23 C for 4 days (three standard-size
latex balloons full of H were simultaneously attached to the reaction
2
flask via separate 18-ga needles; these balloons were replaced with newly
filled ones every 8–12 h until the reaction was complete). The mixture was
1
then filtered through Celite , and the Celite was washed with THF
(
3 ꢂ 100 mL). The combined filtrate and washings were concentrated
under reduced pressure to approximately 300 mL and heptane (500 mL)
was added dropwise via addition funnel over 45 min at 23 C with vigor-
ous stirring. The resulting suspension was stirred for an additional 45 min
at 23 C, and then was vacuum-filtered through medium paper using a
B u¨ chner funnel. The collected solid was washed with heptane
ꢀ
ꢀ
(
1 ꢂ 150 mL) and was air dried to give 3 (90.7 g, 95%) as a pale green
ꢀ
6
1
solid: mp ¼ 116–117 C; H NMR (DMSO-d ) d: 2.79 (3H, s), 5.00
1
3
(
2H, s), 6.48–6.51 (2H, m), 6.85–6.89 (2H, m), 8.87 (1H, s); C NMR

2
-Amino-5-methanesulfonylaminobenzenesulfonamide
1913
(
C H N O S: C, 45.15; H, 5.41; N, 15.04. Found: C, 45.39; H, 5.42;
DMSO-d ) d: 39.1, 114.8, 125.5, 126.7, 147.3. Anal. calcd. for
6
7
10
2
2
N, 15.30.
6
N-(1,1,3-Trioxo-1,2,3,4-tetrahydro-1k -benzo[1,2,4]thiadiazin-7-yl)-
methanesulfonamide (4)
Compound 3 (90.7 g, 0.49 mol, 1.0 equiv) was dissolved in warm
ꢀ
nitroethane (900 mL, 40 C) in a large Erlenmeyer flask with vigorous
stirring. Separately, a 3000-mL three-necked flask equipped with (1)
an addition funnel, (2) a mechanical stirrer, and (3) a thermocouple
was charged with chlorosulfonylisocyanate (50.6 mL, 0.54 mol, 1.1 equiv)
ꢀ
and nitroethane (150 mL). This solution was cooled to ꢁ20 C, and the
ꢀ
nitroethane solution of 3 (cooled to 23 C) was added dropwise via
addition funnel over 1.5 h with vigorous mechanical stirring. The result-
ꢀ
ing suspension was stirred at ꢁ20 C for 30 min, and then aluminum
chloride (77.9 g, 0.58 mol, 1.18 equiv) was added in portions over 1 min.
The resulting brown solution was allowed to warm to 23 C, and the
addition funnel was replaced with a reflux condenser. The reaction mix-
ꢀ
ꢀ
ture was then heated to 110 C and was maintained at that temperature
for 1 h (considerable gas evolution was noted during this time). After
ꢀ
cooling to ꢁ5 C, the reflux condenser was replaced with an addition
funnel. Water (300 mL) was added dropwise to the mixture over
1
5 min, followed by the rapid addition of a larger volume of water
ꢀ
(
700 mL). The resulting suspension was allowed to warm to 23 C, vigor-
ously stirred for 30 min, and then vacuum-filtered through medium paper
using a B u¨ chner funnel. The collected solid was washed with water
(
1 ꢂ 300 mL) and air dried to give 4 (115.2 g, 81%) as a tan solid:
ꢀ
6
1
mp ¼ 288 C (decomp.); H NMR (DMSO-d ) d: 3.00 (3H, s), 7.22
(
1H, d, J ¼ 8.4), 7.46 (1H, dd, J ¼ 2.3, J ¼ 8.5), 7.51 (1H, d,
1
2
1
3
J ¼ 2.4), 9.93 (1H, s), 11.20 (1H, s); C NMR (DMSO-d ) d: 113.5,
6
1
solvent). Anal. calcd. for C H N O S : C, 32.98; H, 3.11; N, 14.42.
19.1, 123.6, 126.9, 132.0, 134.5, 151.4 (NHSO CH signal coincided with
2 3
8
9
3
5 2
Found: C, 32.62; H, 2.92; N, 14.47.
2
2
-Amino-5-methanesulfonylaminobenzenesulfonamide (1) and
,5-Diaminobenzenesulfonamide (5)
A 3000-mL three-necked flask equipped with (1) an addition funnel, (2)
a mechanical stirrer, and (3) a thermocouple was charged with 18 M
H SO (250 mL). Water (250 mL) was added via addition funnel over
2
4
2
0 min with external cooling such that the internal temperature did not

1914
P. S. Dragovich et al.
ꢀ
rise to more than 80 C. The addition funnel was replaced with a powder
funnel, and compound 4 (115.2 g, 0.40 mol) was added rapidly in several
portions over 2 min. The powder funnel was then replaced with a reflux
ꢀ
condenser, and the resulting tan suspension was heated to 130 C for
2
.5 h. [Significant foaming is likely to occur during the first 30–60 min
of the hydrolysis of 4 and may threaten to expel reaction materials from
the vessel when conducted on a scale of more than 20 g. This behavior
can be controlled by (1) slowly heating the reaction mixture to the desired
temperature, (2) periodically pausing the heating, and (3) slowing or halt-
ing the stirring of the reaction. As a result of this foaming, some reaction
materials may become dispersed along the sides of the vessel above any
contained liquid. Such material should be periodically washed back into
the reaction mixture with small amounts of water.] The resulting brown
ꢀ
solution was cooled to 0 C, and the condenser was replaced with an
addition funnel. An aqueous solution of sodium hydroxide (351 g in
7
50 mL water; ca. 11.7 M) was added over 45 min, and the pH of the reac-
tion mixture was subsequently adjusted to approximately 7.0 by the drop-
wise addition of 3.0 M aqueous sodium carbonate (mild gas evolution
was noted during this addition). The resulting suspension was warmed
ꢀ
to 23 C, stirred for 1 h, and then vacuum-filtered through medium paper
using a B u¨ chner funnel. The collected solid was washed with water
ꢀ
(
(
1 ꢂ 300 mL) and was dried in a vacuum oven at 50 C to give 1 and 5
1
1.5:1.0 ratio as determined by H NMR, 70.0 g, 75%) as a brown solid.
Compound 5: H NMR (DMSO-d ) d: 4.54 (2H, bs), 4.97 (2H, bs), 6.55–
1
6
6.60 (2H, m), 6.86 (1H, d, J ¼ 2.2), 6.99 (2H, bs). Analytical data for
compound 1 are provided later.
2
-Amino-5-methanesulfonylaminobenzenesulfonamide (1)
A solution of methanesulfonylchloride (8.2 mL, 0.11 mol, 1.05 equiv
based on amount of 5) in CH CN (100 mL) was added over 15 min to
a solution of compounds 1 and 5 (1.5:1.0 ratio, 60.0 g) and pyridine
3
(
(
12.0 mL, 0.15 mol, 1.5 equiv based on amount of 5) in CH CN
3
500 mL) at 23 C. The mixture was stirred at 25 C for 15 h, and then
ꢀ
ꢀ
was concentrated under reduced pressure to approximately 300 mL
volume. EtOAc (300 mL) was added, and the resulting suspension was
ꢀ
stirred at 23 C for 10 min and vacuum-filtered through medium paper
using a B u¨ chner funnel. [Water can be added to the reaction mixture
instead of EtOAc with minimal impact on the isolated yield of 1. How-
ever, the appearance of 1 may vary (purple or grey solid) depending on
the workup employed.] The collected solid was washed thoroughly with
ꢀ
water (2 ꢂ 200 mL) and was dried in a vacuum oven at 50 C to give 1

2
-Amino-5-methanesulfonylaminobenzenesulfonamide
1915
ꢀ
1
(
2
54.0 g, 80%) as a grey solid: mp ¼ 203–204 C; H NMR (DMSO-d ) d:
6
.86 (3H, s), 5.77 (2H, bs), 6.76 (1H, d, J ¼ 8.6), 7.11 (1H, dd, J ¼ 2.4,
1
1
3
J ¼ 8.6), 7.25 (2H, s), 7.43 (1H, d, J ¼ 2.1), 9.16 (1H, s); C NMR
2
(
for C H N O S : C, 31.69; H, 4.18; N, 15.84. Found: C, 32.02; H, 4.23;
DMSO-d ) d: 39.3, 118.1, 123.5, 124.8, 126.1, 129.6, 144.0. Anal. calcd.
6
7
11
3
4 2
N, 15.83.
ACKNOWLEDGMENT
The authors thank Drs. David Kucera, Jerry (Lijian) Chen, and David
Ellis for many helpful discussions during the course of this work.
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2
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3
4
. Girard, Y.; Atkinson, J. G.; Rokach, J. A new synthesis of 1,2,4-benzothia-
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1916
P. S. Dragovich et al.
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