Development of an acyl sulfonamide anti-proliferative agent, ly573636 ? na

Article abstract of DOI:10.1021/op800210x

The synthesis of 5-bromo-thiophene-2-sulfonic acid 2,4-dichlo- robenzoylamide sodium salt on multikilogram scale is described. The initial clinical supplies were made using carbonyl diimidazole to converge the two fragments. A more efficient acid chloride process has been developed, which also provides better control of impurities and color throughout the synthesis.

Full text of DOI:10.1021/op800210x

Organic Process Research & Development 2009, 13, 255–262
Development of an Acyl Sulfonamide Anti-Proliferative Agent, LY573636 · Na†
Matthew H. Yates,* Neil J. Kallman, Christopher P. Ley, and Jeffrey N. Wei
Eli Lilly and Company, Chemical Product Research and DeVelopment DiVision, Indianapolis, Indiana 46285, U.S.A.
Abstract:
short synthesis and simple structure of the API and related
substances made it difficult to separate impurities during
processing so minimization at their introduction/generation was
essential. Below is described the development of each of the
steps with special attention to impurity generation and fate.
2.1. Preparation of Sulfonyl Chloride 2. 2-Bro-
mothiophene 1 is a bulk commodity chemical which can be
processed under well established conditions2 to give the
corresponding sulfonyl chloride 2, as shown in Scheme 2.
Impurities seen in 2 from either route included some that
originated from the quality of the bromothiophene, as well as
the bis-thiophene sulfone, and sulfonic acid. The sulfonylchlo-
ride 2 is a low-melting solid that can be distilled under reduced
pressure or crystallized from alkanes.
The synthesis of 5-bromo-thiophene-2-sulfonic acid 2,4-dichlo-
robenzoylamide sodium salt on multikilogram scale is described.
The initial clinical supplies were made using carbonyl diimidazole
to converge the two fragments. A more efficient acid chloride
process has been developed, which also provides better control of
impurities and color throughout the synthesis.
1. Introduction
The acyl sulfonamide LY573636·Na has been recently
reported1 as having potent antitumor activity against a variety
of tumor xenografts in animal models including: colon, lung,
breast, ovary and prostate. These encouraging results led to the
need for more material for clinical trials. Initial supplies were
met using the chemistry outlined in Scheme 1.
Scheme 2. Preparation of sulfonyl chloride 2
Handling concerns and cost of 1,1′-carbonyldiimidazole
(CDI) were seen as a liability in such a simple coupling,
especially since there was neither stereochemistry to preserve
nor delicate functionality on the acid. In this case CDI is more
expensive than the carboxylic acid being coupled. The develop-
ment of this synthesis focused on minimization and control of
impurities, and reduction in environmental impact.†
Scheme 1. Initial synthesis of LY573636 ·Na
2.2. Preparation of Sulfonamide 3. Initially the sulfonyl
chloride was dissolved in 2 volumes of THF, and ammonium
hydroxide was added to the solution. This resulted in ∼3-5%
of the dimer impurity 9, which is only partially rejected during
the isolation and therefore carried through the synthesis
(Scheme 3).
Scheme 3. Preparation of sulfonamide 3
Surprisingly, inverse addition (sulfonyl chloride into am-
monium hydroxide) did not reduce the levels of 9. At 2 volumes
of THF, the reaction mixture is biphasic. The formation of this
impurity is dependent on the solubility of the product and
miscibility of the solvent in the aqueous ammonium hydroxide.
As the reaction progressed, the sulfonamide quickly saturated
the organic layer but could be easily deprotonated and taken
into the aqueous phase, where it competed with the ammonia.
2. Results and Discussion
The initial synthesis of LY573636 as outlined in Scheme 1
is very straightforward but a requirement for tight impurity
control led to further process optimization at each step. The
† This paper is dedicated to the memory of our friend and former colleague
Dr. Christopher R. Schmid.
* Author for correspondence. E-mail: yatesmh@lilly.com.
10.1021/op800210x CCC: $40.75
Published on Web 01/12/2009
2009 American Chemical Society
Vol. 13, No. 2, 2009 / Organic Process Research & Development
•
255

Scheme 5. Formation and decomposition of symmetrical
anhydride
At 6 volumes of THF, the level of the dimer 9 was reduced
from 4% to 2%. Switching solvents to an ester greatly reduced
the level of dimer seen to <0.5% in EtOAc or iPAc.
Unfortunately the degradation of both solvents was seen, which
gave >1% of acetamide in reaction mixtures. Since residual
acetamide needs to be controlled to the ppm level,3 these
solvents were considered undesirable. 2-Methyl tetrahydrofuran
was stable to the ammonium hydroxide conditions and behaved
like the ester solvents, thus minimizing the dimer 9 formation
to <0.5%.
The initial isolation involved the addition of water followed
by distillation to remove 2-methyltetrahydrofuran. Variability
in the dimer levels was due to varying levels of ammonia
remaining after the solvent distillation. To achieve more
consistent ammonia removal, the aqueous layer was separated
after neutralization of the excess ammonium hydroxide with
HCl. The product was then crystallized by adding water to the
final organic phase and distilling off the organic solvent. Since
impurity 9 is sufficiently more acidic than the desired product
3, it can be selectively removed by adding sodium bicarbonate
to the slurry of product 3 in water. This process resulted in
pure (>99.9%) sulfonamide in 96% yield.
2.3. Preparation of Acyl Sulfonamide 6. An acid chloride
process was developed to replace the CDI process for the
activation of the benzoic acid, as a separate step Via thionyl
chloride in toluene. Using thionyl chloride is advantageous in
comparison to using CDI on the basus if synthetic simplicity,
cost,4 and preferred liquid handling versus a hygroscopic solid
(Scheme 4).
dride as a soluble source of chloride,5 since DMF formed new
impurities (Figure 1). Toluene was selected as the solvent for
the acid chloride formation, since it is compatible with the
reagents and product 10 and because 6 could be easily isolated
from toluene/heptane. After the reagents were combined and
heated, the mixture was distilled to remove excess thionyl
chloride, resulting in a toluene solution of the acid chloride in
essentially quantitative yield.
Scheme 4. Preparation of acyl sulfonamide 6
During the acid chloride formation, the symmetrical anhy-
dride was formed in ∼5% yield (Scheme 5). Pyridine was
preferred as the catalyst to decompose the symmetrical anhy-
Figure 1. New impurities formed when DMF was used as the
catalyst.
(1) (a) De Dios, A.; Grossman, C. S.; Hipskind, P. A.; Lin, H. S.; Lobb,
K. L.; Lopez De Uralde Garmendia, B.; Lopez, J. E.; Mader, M. M.;
Richett, M. E.; Shih, C. WO Patent 2003/035629, 2003. (b) Lobb,
K. L.; Hipskind, P. A.; Aikins, J. A.; Alvarez, E.; Cheung, Y.;
Considine, E. L.; De Dios, A.; Durst, G. L.; Ferritto, R.; Grossman,
C. S.; Giera, D. D.; Hollister, B. A.; Huang, Z.; Iversen, P. W.; Law,
K. L.; Li, T.; Lin, H.-S.; Lopez, B.; Lopez, J. E.; Martin Cabrejas,
L. M.; McCann, D. J.; Molero, V.; Reilly, J. E.; Richett, M. E.; Shih,
C.; Teicher, B.; Wikel, J. H.; White, W. T.; Mader, M. J. Med. Chem.
2004, 47, 5367–5380. (c) Mader, M.; Shih, C.; Considine, E.; De Dios,
A.; Grossman, C.; Hipskind, P.; Lin, H.; Lobb, K.; Lopez, B.; Lopez,
J.; Cabrejas, L.; Richett, M.; White, W.; Cheung, Y.; Huang, Z.; Reilly,
J.; Dinn, S. Bioorg. Med. Chem. Lett. 2005, 15, 617–620.
Online mass spectrometry data were acquired during the
development and scale-up of the acid chloride using thionyl
chloride. Gas evolution was found to be an indicator of reaction
progress and degassing, as SO2 and HCl are byproducts. Upon
scale-up, gas removal rates were slower, even when N2 was
(3) Acetamide is listed by IARC as a Level IIb compound “sufficient evidence
in experimental animals for the carcinogenicity of acetamide”. IARC
Monographs on the EValuation of Carcinogenic Risks to Humans ; 1999;
Vol. 71, p 1211.
(4) Aldrich prices for the largest standard package is $71/mol for CDI,
$15/mol for oxalylchloride, and $14/mol for 2,4-dichlorobenzoic acid.
(5) (a) Cason, J.; Reist, E. J. Org. Chem. 1958, 23, 1492–1496. (b) Wirth,
D. In Encyclopedia of Reagents for Organic Synthesis; Wiley: New
York, 1995; Vol. 7, pp 4873-4876.
(2) (a) Sone, T.; Abe, Y.; Sato, N.; Ebina, M. Bull. Chem. Soc. Jpn. 1985,
58, 1063–1064. (b) Igarashih, Y.; Nobeshima, H. Japanese Patent JP-
143060, 2004. (c) Chan, M. F.; Kois, A.; Verner, E. J.; Raju, B. G.;
Castillo, R. S.; Wu, C.; Okun, I.; Stavros, F. D.; Balaji, V. N. Bioorg.
Med. Chem. 1998, 6, 2301–2316.
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Scheme 7. Benzamide formation
purged through the reactor. The formation of an insoluble scum
in the reactor was attributed to the poor removal of reactive
byproducts such as SO2.6 Additionally, the acid chloride
solutions were golden in color, unlike the colorless solutions
prepared in the laboratory. Although the initial scale-up of this
chemistry used thoinyl chloride, future preparations of the acid
chloride 10 will use oxalyl chloride since the byproducts (CO
and CO2) are expected to be more innocuous.
With the acid chloride solution in hand, various base/solvent
combinations were tried. Scho¨tten-Baumann conditions with
1.3 equiv of acid chloride failed to go to completion, due to
the relative rate of hydrolysis vs coupling at room temperature.
More equivalents of acid chloride 10 would have overcome
the hydrolysis issue, yet would have resulted in larger amounts
of benzoic acid 4 to reject in the workup and isolation.
Initial results using solid sodium carbonate in refluxing iPAc
appeared promising. This approach was later abandoned due
to variability in reaction completeness. Careful analysis showed
that water level in the reaction mixture was critical. For example,
if the reaction was too dry (200 ppm water), no reaction
occurred because no Na2CO3 was in solution; if the reaction
mixture was too wet (0.4% water), hydrolysis of acid chloride
competed with the desired coupling.
Alkyl tertiary amines resulted in complete consumption of
3 without the level of competing hydrolysis as seen in the other
approaches. Therefore, a toluene solution of acid chloride 10
was added to an iPAc solution of sulfonamide 3 with 2.5 equiv
of alkyl tertiary amine at 70-80 °C. Triethylamine (TEA) was
preferred over Hu¨nig’s base for ease of workup. In both cases
the initial product formed is the amine salt of 6. With TEA,
the amine salt of 6 is soluble in warm solvent, allowing removal
of some of the benzoic acid 4 by an initial water wash.
With these conditions, a new amidine impurity 12 was seen,
at 1-4%, which was not removed in the isolation. It is proposed
that this impurity originates from diacylated product 11 (Scheme
6). The addition of catalytic pyridine minimized the formation
of the amidine impurity 12, presumably through decomposition
of the diacylated product 11.7
crystallization at the expense of yield. Color was seen in the
reaction mixtures at the end of the acid chloride addition, which
was attributed to the reaction of the acid chloride with the
tertiary amine.
Combining just tertiary amines with the acid chloride showed
that more color was seen with ethyl amines and much less color
with methyl or aromatic amines. Therefore, dimethylbutylamine
and pyridine were compared in the coupling reaction. Dimeth-
ylbutylamine resulted in improvement in color but contained
large amounts (0.35%) of benzamides (Scheme 7). Pyridine,
which is a weaker base, in place of triethylamine resulted in
less color, no benzamides, but incomplete reactions.
Triethylamine with catalytic pyridine resulted in low ben-
zamides and amidines and reaction completeness, but the
products were colored. Alternative acylation catalysts were
explored as a way to increase the rate of the reaction and
minimize color formation (Table 1). To quantitate the level of
color, the product was assayed at 400 nm. Catalytic 4-dim-
ethylaminopyridine (DMAP)8 resulted in the ability to perform
the reaction at a lower temperature (55 °C, the temperature at
which the amine salt of 6 was soluble), resulting in white to
off-white products in higher yields.
The workup consisted of a water wash, two aqueous acid
washes, and another water wash. The final organic phase was
distilled to result in a toluene concentrate of the product. After
seeding and cooling, heptane was added, resulting in a 91- 93%
isolated yield and 99.8% purity.9
There is limited literature on the formation of acyl
sulfonamides with acid chlorides;10 we wanted to see if
this chemistry could be generalized across the class.
Several substrates were screened, and the results are shown
in Table 2. This process provides consistently high yields
Color is an important attribute for a parenteral product;
however, the sulfonamide 6 from the original process was
consistently yellow to tan. Color could be removed in the
Scheme 6. Formation of amidine impurity
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Table 1. Use of acylation catalysts at 1 mol % in the formation of acylsulfonamide 6 at 55 °C
catalyst
product color
area at 400 nm
318.2
% sulfonamide 3 remaining
area % amidine 12
pyridine
light yellow
light yellow
white
white
light yellow
0.08
1.87
0.02
0.03
0.00
0.33
4.39
0.11
0.04
0.02
2-methoxypyridine
N-methylimidazole
4-dimethylaminopyridine
4-methoxypyridine
50.2
22.5
48.9
Table 2. Preparation of acyl sulfonamides
across a variety of functional groups on both coupling
partners, proving to be a more general method than those
in previous communications.11
2.4. Salt Formation. The final step to make the API is
sodium salt formation (Scheme 8). Since impurity control has
been maintained at each step, there was no need for a
recrystallization if the correct form could be made directly. A
screen of several conditions indicated that IPA/n-heptane would
consistently give the desired stable form. As a parenteral
oncolytic, there were several additional challenges to making
Scheme 8. Preparation of sodium salt 7
(6) SO2 is very corrosive to Hastelloy and stainless steel. The insoluble
scum and colored acid chloride solutions are thought to be related to
the presence of SOx byproducts. Trace levels of sulfuryl chloride in
thionyl chloride will lead to the formation of SO3. There are some
spectroscopic data in support of the reaction of symmetrical anhydrides
with SO3 at low temperature. Montoneri, E.; Giuffre, L.; Cassago,
M.; Tempesti, E.; Fornaroli, M. Can. J. Chem. 1977, 55, 355–359.
Montoneri, E.; Tempesti, E.; Giuffre, L.; Cassago, M.; Castoldi, A.
J. Chem. Soc., Perkin Trans. 2 1980, 662–667.
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this API: control of trace levels of color and containment to
limit exposure to the product. The sulfonamide proton is quite
acidic,12 and any number of sodium bases can make the salt.
However, sodium alkoxide solutions are colored due to
unknown impurities, and the solids are hygroscopic. Sodium
hydroxide is not only effective at making the salt but also brings
in enough water to increase the solubility allowing for polish
filtration. The water could then be removed by distillation with
IPA, resulting in crystallization of the API.
Since the API is dissolved and then lyophilized in the drug
product, particle size is not critical for clinical performance.
Instead it was desirable to control particle size for processing
performance: filtration rate, drying profile, and handling (static
and dust). To this end, xonce the product crystallized from IPA,
n-heptane was added to boost recovery. The slurry was ripened
with a slow heating and cooling cycle, favoring crystal growth
and a gradual increase in the average particle size (Figure 2).
These larger particles processed well with an estimated cake
flux13 of >3000 L/min per m2 and a drying time of <20 h at
∼15 kg scale. The material was free flowing without any need
to delump or process further.
of the reactions to be predictive of scale-up results, even for
the crystallizations. The noticeable exception was the formation
of the scum in the reactor during the acid chloride formation
which was attributed to poor vapor-liquid mass transfer which
is a common “scale-up effect” that is difficult to model. The
final process is summarized in Scheme 9.
4. Experimental Section
Described below are the preferred conditions to make
LY573636·Na; unfortunately, some of these developments took
place after the pilot-plant scale-up, using slightly different
conditions (pyridine as the coupling catalyst instead of DMAP
and thionyl chloride for the preparation of the acid chloride).
These alternative procedures, at multikilogram scale, can be
found in the Supporting Information.
5-Bromothiophene-2-sulfonamide (3). Sulfonyl chloride 2
(200.36 g, 766.1 mmol) and 2-methyltetrahydrofuran (1.2 L)
were combined under N2, forming a light-yellow solution. The
solution was chilled to 0-5 °C. Concentrated aq NH4OH
(384.29 g, 3.07 mol) was added dropwise to the reaction over
0.5 h. The reaction was allowed to warm to room temperature,
and DI water (600 mL) was added. The pH of the reaction
mixture was adjusted to pH ∼2 using 37% conc. aq HCl (484.1
g, 4.85 mol). The phases were separated, the aqueous layer was
back extracted with 2-methyltetrahydrofuran (200 mL), and the
organic layers were combined. DI water (1 L) was added to
the organic layer, and the mixture was distilled at atmospheric
pressure until the reactor temperature reached 99 °C. A total
of 1475 mL of distillate was collected. The mixture was allow
to cool to room temperature, during which time a slurry of
sulfonamide 3 formed. Once at room temperature, solid sodium
bicarbonate (19.65 g, 233.9 mmol) was added, and the slurry
was stirred for 90 min. The product was filtered, and the
wetcake was washed with DI water (600 mL). The product was
dried in Vacuo at 45 °C overnight, resulting in 178.54 g (734.9
mmol, 95.9% yield) of off-white product, containing nonde-
(7) Diacylated product 11 has been prepared and isolated. When 11 was
combined with sulfonamide 3 and Et3N, amidine 12 was formed. When
11 was combined with pyridine, 6 and 4 were formed. In the coupling
to form 6, no 11 was seen in the isolated 6.
(8) Hasegawa, T.; Yamamoto, H. Bull. Chem. Soc. Jpn. 2000, 73, 423–
428.
(9) Most of the impurities that result are impurities derived from the quality
of benzoic acid 4.
(10) (a) Cremlyn, R. J.; Swinbourne, F. J.; Yung, K.-M. J. Heterocycl.
Chem. 1981, 18, 997–1006. (b) Kazhemekaite, M.; Stumbryavichyute,
Z.; Astrauskas, V. Khim.-Farm. Zh. 1997, 31, 37–39. (c) Kondo, K.;
Sekimoto, E.; Miki, K.; Murakami, Y. J. Chem. Soc., Perkin Trans.
1 1998, 2973–2974. (d) Kondo, K.; Sekimoto, E.; Nakao, J.;
Murakami, Y. Tetrahedron 2000, 56, 5843–5856. (e) Ishizuka, N.;
Matsumura, K.; Hayashi, K.; Sakai, K.; Yamamori, T. Synthesis 2000,
784–788.
Figure 2. Changes to particle size of acylsulfonamide sodium
salt during thermocycles.
(11) For methods using anhydrides see:(a) Kravchenya, N. A. Khim.-Farm.
Zh. 1990, 24, 49–50. (b) Martin, M.; Roschangar, F.; Eaddy, J.
Tetrahedron. Lett. 2003, 44, 5461–5463. (c) Singh, D.; Singh, P.;
Samant, S. Tetrahedron. Lett. 2004, 45, 4805–4807. For a catalytic
rhodium method see: (d) Chan, J.; Baucom, K. D.; Murry, J. A. J. Am.
Chem. Soc. 2007, 129, 14106–14108. High yields have been reported
using carbodiimides: (e) Matassa, V. G.; Brown, F. J.; Bernstein, P. R.;
Shapiro, H. S.; Maduskuie, T. P.; Cronk, L. A.; Vacek, E. P.; Yee,
Y. K.; Snyder, D. W.; Krell, R. D.; Lerman, C. L.; Maloney, J. J.
J. Med. Chem. 1990, 33, 2621–2629. (f) Johnson, D. C., II.; Widlanski,
T. S. Tetrahedron Lett. 2001, 42, 3677–3679.
3. Conclusion
A robust process that can produce high-quality API has been
developed and demonstrated. A complete understanding of
impurity generation and control was critical to improving the
efficiency of the process while achieving an overall yield of
77%. A simple calculation of process mass intensity (kg in/kg
out) shows a 45% reduction in environmental impact over the
original process. We found our small-scale (∼20 g) modeling
(12) A pKa of 2.2 was determined experimentally via titration.
(13) Flux is calculated by dividing the flow rate (L/min) by the filter area
(π·(filter diameter/2))2.
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259

Scheme 9. Final acyl sulfonamide
tectable levels of dimer 9. 1H NMR (d6-DMSO, 400 MHz): δ
7.79 (s, 2H); 7.38 (d, J ) 4.0 Hz, 1H); 7.30 (d, J ) 4.0 Hz,
1H). 13C NMR (d6-DMSO, 100 MHz): δ 146.6, 130.9, 130.6,
116.8.
(21.43 g, 24.6 mL), and distilling to 23.5 g. This resulted
in a mixture with low levels of iPAc and TEA. The
mixture was cooled to 45-55 °C, seeded with acylsul-
fonamide 6 (5 mg), and held at this temperature for 1 h,
before cooling to 20-25 °C over at least 1 h. After
reaching 25 °C, n-heptane (60 mL) was added over 2 h.
The white slurry was stirred at 20-25 °C for at least 1 h
before the slurry was filtered. The wet cake was washed
with 10 mL of 2:1 n-heptane/toluene, followed by 10 mL
of n-heptane. The product was dried at 45 °C in Vacuo
with N2 purge. This resulted in acyl sulfonamide product
6 (8.07 g, 19.39 mmol, 93.9% yield), <0.3% impurities,
2,4-Dichlorobenzoyl chloride (10). Benzoic acid 4 (17.41
g, 91.2 mmol) was combined with toluene (102.7 mL) and
pyridine (0.225 g, 2.84 mmol), and heated to 60 °C. Oxalyl
chloride (14.95 g, 117.8 mmol) was added over 15-30 min.
The mixture was held at 60 °C for at least 1 h. The solution
was distilled at atmospheric pressure; after 52 mL of distillate
was collected, 68.0 mL of fresh toluene was added back, and
an additional 65 mL was distilled. This resulted in 70.05 g of
a solution of 26.02 wt % acid chloride 10 (87.02 mmol, 95.5%
yield). Cooling below RT, the trace of pyridine-HCl that was
present precipitated.
N-(5-Bromothiophen-2-ylsulfonyl)-2,4-dichlorobenza-
mide (6). Sulfonamide 3 (5.02 g, 20.65 mmol) was
combined with isopropylacetate (45 mL), triethylamine
(5.24 g, 51.8 mmol), and DMAP (13.3 mg, 108.5 umol)
under N2, forming a light-yellow solution. The mixture
was heated to 55 °C, before the toluene solution of acid
chloride 10 (1.64 M, 13.59 g, 22.31 mmol) was added
over 1 h, maintaining the temperature at 50-60 °C. During
the addition, the amine salt precipitated, forming an off-
white slurry. The container from which the acid chloride
was added was rinsed with toluene (5 mL), and this rinse
was added to the reaction mixture. After the addition was
complete, the mixture was maintained at 50-60 °C for
1 h.
DI water (30.55 g) was added, and the mixture was
heated to 45-55 °C, dissolving the salts and resulting in
two phases. The lower aqueous phase was drawn off and
discarded. While still at 45 -55 °C, the mixture was
washed with 0.7 M HCl (35.91 g, 24.9 mmol). The layers
were separated, and the aqueous phase was discarded. The
organic phase was washed (at RT) with 0.7 M HCl (35.64
g, 24.7 mmol), followed by DI water (25.1 g).
The washed organic phase was transferred to a flask
with iPAc (4.93 g, 5.66 mL) and atmospherically distilled,
collecting 33.63 g of distillate, diluting with toluene (22.07
g, 25.3 mL), distilling to 18.7 g, diluting with toluene
1
that is white in color. H NMR (d6-DMSO, 400 MHz): δ
7.74 (d, J ) 2.4 Hz, 1H); 7.71 (d, J ) 4.8 Hz, 1H); 7.58
(d, J ) 8.4 Hz, 1H); 7.51 (dd, J ) 8.4, 2.0 Hz, 1H); 7.42
(d, J ) 4.0 Hz, 1H). 13C NMR (d6-DMSO, 100 MHz): δ
164.5, 139.9, 136.2, 135.1, 132.4, 131.3, 131.2, 130.6,
129.5, 127.5, 121.1.
Sodium (5-Bromothiophen-2-ylsulfonyl)(2,4-dichloroben-
zoyl)amide (7). Acyl sulfonamide 6 (18.335 kg, 44.17 mol),
isopropyl alcohol (185 L), 51% aqueous NaOH solution
(3.350 kg, 42.71 mol, 0.967 equiv), and DI water (2.215
kg) were combined under N2. The slurry was stirred at
25 °C until it became a clear solution. This solution was
passed through a carbon filter followed by filtering through
a 0.45 µm filter, followed by a 0.22 µm filter, and was
collected in the crystallization vessel, rinsing the initial
vessel and filters with IPA (90 L).
The filtered solution was atmospherically distilled until
55 L of solution remained in the crystallization vessel.
The concentrated solution was cooled to 25 °C, seeded
with acyl sulfonamide sodium salt 7 (0.178 kg), and stirred
for at least 30 min. n-Heptane (127.5 L) was added,
causing the product to crystallize. The resulting slurry was
stirred at 25 °C for at least 30 min. The diluted slurry
was thermally cycled from 25 to 60 °C at a rate of 0.5
°C/min three times. After ripening, the slurry was cooled
at 0.5 °C/min to -5 °C and stirred for at least 1 h before
it was filtered. The wetcake was washed with a 95:5
n-heptane/IPA mixture (92.5 L of n-heptane, 5 L IPA)
precooled to -5 °C. Finally, the wet cake was dried in
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1
Vacuo at 40 °C with N2 purge. This resulted in acyl
sulfonamide sodium salt product 7 (16.838 kg, 38.52 mol,
87.2% yield), that is white in color. H NMR (d6-DMSO,
400 MHz): δ 7.53 (d, J ) 8.4 Hz, 1H); 7.49 (d, J ) 1.6
Hz, 1H); 7.35 (dd, J ) 8.4, 1.6 Hz, 1H); 7.31 (d, J ) 4.0
Hz, 1H); 7.14 (dd, J ) 4.0, 0.8 Hz, 1H). 13C NMR (d6-
DMSO, 100 MHz): δ 169.9, 148.7, 138.7, 132.9, 131.4,
131.0, 129.3, 129.2, 129.0, 126.6, 114.6.
N-(4-Methoxyphenylsulfonyl)benzamide (1c): H NMR
(d6-DMSO, 400.00 MHz): δ 12.38 (s, 1H); 7.95 (d, J ) 8.4
Hz, 2H); 7.85 (d, J ) 7.2 Hz, 2H); 7.61 (d, J ) 6.4 Hz, 1H);
7.48 (d, J ) 14.4 Hz, 1H); 7.48 (s, 1H); 7.16 (d, J ) 7.6 Hz,
2H); 3.85 (s, 3H). 13C NMR (d6-DMSO, 100.00 MHz): δ 165.2,
163.1, 133.1, 131.5, 130.8, 130.1, 128.5, 128.3, 114.2, 55.7.
HRMS calcd for C14H13NO4S m/z 292.0638 (MH+), Found:
292.06442.
1
N-(4-Nitrophenylsulfonyl)benzamide (1d): 1H NMR (d6-
DMSO, 400.00 MHz): δ 8.45 (dd, J ) 8.8, 1.2 Hz, 2H); 8.25
(dd, J ) 8.8, 1.6 Hz, 2H); 7.87 (d, J ) 8.4 Hz, 2H); 7.66-7.62
(m, 1H); 7.50 (t, J ) 7.2 Hz, 2H), 3.43 (s, 1H). 13C NMR (d6-
DMSO, 100.00 MHz): δ 165.9, 150.1, 144.9, 133.4, 131.3,
129.3, 128.6, 128.5, 124.4. HRMS calcd for C13H10N2O5S m/z
307.0383 (MH+), Found: 307.03840.
General Procedure for the Preparation of Acyl Sulfona-
mides. Into a 100 mL vessel containing a stir bar were
added ( under N2) sulfonamide (5 mmol, limiting reagent),
iPAc (10.90 mL), triethylamine (2.5 equiv for primary
sulfonamides, 1.5 equiv for secondary sulfonamides), and
DMAP (0.5 mol %), forming a clear solution. The solution
was heated under a N2 atmosphere.
In a vial was added acid chloride (1.10 equiv) and
toluene (3.65 mL). This solution was drawn up into a 5
mL syringe and added to the sulfonamide/iPAc solution
at 55 °C over 1 h via syringe pump, rinsing the syringe
and vial with toluene (1.20 mL). After the addition was
complete, the mixture was stirred for at least 1 h at 55
°C. In all cases the reaction was complete after 1 h, but
additional time at 55 °C was not detrimental to the
reaction.
After cooling to room temperature, the residual acid
chloride was quenched with DI water (1.1 mL), and 0.7
M HCl (16.90 mL) was added, dissolving the amine salts.
The aqueous phase was drawn off and assayed. If
necessary, the aqueous phase was extracted with iPAc.
The organic phases were combined and stripped to
dryness, resulting in a solid (except 2 entry 5, which were
oils). The product was dried at 50 °C in Vacuo with N2
purge.
In the case of 2 entries 1d, 4, and 8c, a solid resulted
upon the addition of aq HCl. In those cases, the solid was
filtered off, and the organic phase was separated and
concentrated to dryness, resulting in two crops of product.
In some cases, if residual reagents (i.e., TEA/HCl) were
seen by 1H NMR, the crude product was purified by
passing through a plug of silica gel with EtOAc to obtain
analytically pure material.
1H and 13C NMR and HRMS for 22 compounds in Table 2
are given below (copies of spectra are available in the
Supporting Information).
N-(Phenylsulfonyl)benzamide (1a): 1H NMR (d6-DMSO,
400.00 MHz): δ 12.55 (s, 1H); 8.02 (d, J ) 8.0 Hz, 2H); 7.86
(d, J ) 8.0 Hz, 2H); 7.75-7.58 (m, 4H); 7.49 (t, J ) 6.8 Hz,
2H). 13C NMR (d6-DMSO, 100.00 MHz): δ 165.4, 139.4, 133.6,
133.2, 131.4, 129.1, 128.5, 128.3, 127.6. HRMS calcd for
C13H11NO3S m/z 262.0532 (MH+), Found: 262.05350.
N-(4-Chlorophenylsulfonyl)benzamide (1b): 1H NMR (d6-
DMSO, 400.00 MHz): δ 12.64 (s, 1H); 8.02 (dd, J ) 8.4, 0.8
Hz, 2H); 7.87 (d, J ) 8.0 Hz, 2H); 7.72 (dd, J ) 8.4, 0.8 Hz,
2H); 7.64-7.60 (m, 1H); 7.49 (t, J ) 7.2 Hz, 2H). 13C NMR
(d6-DMSO, 100.00 MHz): δ 165.5, 138.6, 138.2, 133.3, 131.3,
129.6, 129.3, 128.6, 128.4. HRMS calcd for C13H10ClNO3S m/z
296.0413 (MH+), Found: 296.04137.
N-(4-Methylphenylsulfonyl)benzamide (1e): 1H NMR (d6-
DMSO, 400.00 MHz): δ 12.46 (s, 1H); 7.89 (dd, J ) 8.8, 7.2
Hz, 3H); 7.85 (s, 1H); 7.64-7.60 (m, 1H); 7.49 (d, J ) 14.0
Hz, 1H); 7.46 (dd, J ) 13.2, 8.4 Hz, 3H); 2.40 (s, 3H). 13C
NMR (d6-DMSO, 100.00 MHz): δ 165.3, 144.2, 136.5, 133.2,
131.4, 129.5, 128.5, 128.3, 127.7, 21.0. HRMS calcd for
C14H13NO3S m/z 276.0689 (MH+), Found: 276.06881.
1
N-(2,4,6-Triisopropylphenylsulfonyl)benzamide (2): H
NMR (d6-DMSO, 400.00 MHz): δ 12.66 (s, 1H); 7.90 (d, J )
8.0 Hz, 2H); 7.61 (t, J ) 6.8 Hz, 1H); 7.49 (t, J ) 7.6 Hz,
2H); 7.26 (s, 2H); 4.36 (dd, J ) 13.2, 6.4 Hz, 2H); 2.94-2.90
(m, 1H); 1.20 (dd, J ) 6.8, 2.8 Hz, 18H). 13C NMR (d6-DMSO,
100.00 MHz): δ 165.6, 153.0, 150.4, 133.0, 129.2, 128.5,128.5,
128.1, 123.6, 33.3, 28.3, 24.3, 23.3. HRMS calcd for
C22H29NO3S m/z 388.1941 (MH+), Found: 388.19438.
N-(Methylsulfonyl)benzamide (3a): 1H NMR (d6-DMSO,
400.00 MHz): δ 12.13 (s, 1H); 7.94 (d, J ) 7.6 Hz, 2H);
7.65-7.63 (m, 1H); 7.53 (d, J ) 16.0 Hz, 1H); 7.52 (d, J )
6.8 Hz, 1H); 3.37 (d, J ) 4.4 Hz, 3H). 13C NMR (d6-DMSO,
100.00 MHz): δ 166.4, 133.2, 132.9, 131.7, 129.2, 128.6, 128.4,
41.4. HRMS calcd for C8H9NO3S m/z 200.0375 (MH+), Found:
200.03810.
N-(tert-Butylsulfonyl)benzamide (3b): 1H NMR (d6-
DMSO, 400.00 MHz): δ 12.94 (s, 1H minor); 11.55 (s, 1H
major); 7.95 (dd, J ) 8.0, 1.6 Hz, 1H); 7.88 (d, J ) 8.0 Hz,
1H); 7.62 (t, J ) 7.6 Hz, 1H); 7.51 (s, 1H); 7.51 (d, J ) 14.4
Hz, 1H); 1.41 (s, 9H major); 1.269 (s, 1H minor). 13C NMR
(d6-DMSO, 100.00 MHz): δ 167.3, 165.8,132.8, 132.7, 130.7,
129.2, 128.5, 128.5, 128.4, 128.4, 128.4, 61.1, 57.0, 24.1, 24.0.
HRMS calcd for C11H15NO3S m/z 264.0664 (MNa+), Found:
264.06660.
1
N-(Thiophen-2-ylsulfonyl)benzamide (4): H NMR (d6-
DMSO, 400.00 MHz): δ 12.68 (s, 1H); 8.07-8.05 (m, 1H);
7.89 (d, J ) 6.4 Hz, 1H); 7.88 (d, J ) 8.8 Hz, 1H); 7.87 (d, J
) 2.4 Hz, 1H); 7.66-7.61 (m, 1H); 7.50 (d, J ) 15.6 Hz, 1H);
7.49 (d, J ) 6.8 Hz, 1H); 7.24-7.21 (m, 1H). 13C NMR (d6-
DMSO, 100.00 MHz): δ 165.5, 139.7, 134.8, 134.4, 133.3,
131.5, 128.6, 128.4, 127.5. HRMS calcd for C11H9NO3S2 m/z
268.0096 (MH+), Found: 268.01000.
1
N-Methyl-N-(phenylsulfonyl)benzamide (5a). H NMR
(d6-DMSO, 400.00 MHz): δ 7.99 (dd, J ) 6.8, 1.2 Hz, 2H);
7.79-7.75 (m, 1H); 7.69-7.60 (m, 2H); 7.58 (dd, J ) 3.2, 1.2
Hz, 1H); 7.56 (d, J ) 1.6 Hz, 1H); 7.50 (d, J ) 1.6 Hz, 1H);
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7.48 (d, J ) 4.8 Hz, 1H); 7.46 (d, J ) 2.0 Hz, 1H); 3.25 (s,
3H). 13C NMR (d6-DMSO, 100.00 MHz): δ 170.6, 138.2, 134.1,
133.9, 132.0, 129.3, 128.5, 128.1, 127.9, 35.9. HRMS calcd
for C14H13NO3S m/z 276.0688 (MH+), Found: 276.06980.
) 9.6, 8.4 Hz, 4H); 7.85 (d, J ) 8.0 Hz, 2H); 7.73 (t, J ) 7.2
Hz, 1H); 7.69 (d, J ) 17.2 Hz, 1H); 7.64 (dd, J ) 7.2, 1.6 Hz,
2H). 13C NMR (d6-DMSO, 100.00 MHz): δ 166.2, 164.6, 139.3,
135.4, 133.8, 133.1, 132.8, 132.5, 132.2, 130.1, 129.4, 129.2,
128.1, 127.7, 125.6, 125.5, 125.5, 125.5, 124.9, 122.3, 119.6.
HRMS calcd for C14H10F3NO3S m/z 330.0406 (MH+), Found:
330.04080.
1
N-Methyl-N-tosylbenzamide (5b): H NMR (d6-DMSO,
400.00 MHz): δ 7.86 (d, J ) 6.8 Hz, 1H); 7.85 (s, 1H); 7.57
(d, J ) 6.0 Hz, 1H); 7.56 (t, J ) 4.0 Hz, 1H); 7.49 (d, J ) 1.2
Hz, 1H); 7.46 (d, J ) 8.0 Hz, 4H); 3.24 (d, J ) 2.0 Hz, 3H);
2.42 (s, 3H). 13C NMR (d6-DMSO, 100.00 MHz): δ 170.6,
144.8, 135.2, 134.0, 132.0, 129.7, 128.4, 128.1, 128.0, 35. 9,
21.1. HRMS calcd for C15H15NO3S m/z 290.0845 (MH+),
Found: 290.08360.
1
N-(Phenylsulfonyl)acetamide (9a): H NMR (d6-DMSO,
400.00 MHz): δ 12.09 (s, 1H); 7.92 (d, J ) 9.6 Hz, 1H); 7.91
(d, J ) 2.4 Hz, 1H); 7.71-7.69 (m, 1H); 7.63 (t, J ) 7.2 Hz,
1H); 7.61 (d, J ) 7.2 Hz, 1H); 1.92 (s, 3H). 13C NMR (d6-
DMSO, 100.00 MHz): δ 169.2, 144.6, 139.8, 134.0, 132.2,
129.5, 129.3, 127.9, 126.0, 23.7. HRMS calcd for C8H9NO3S
m/z 200.0375 (MH+), Found: 200.03770.
N-(Phenylsulfonyl)pivalamide (9b): 1H NMR (d6-DMSO,
400.00 MHz): δ 11.70 (s, 1H); 7.89 (d, J ) 10.0 Hz, 1H);
7.88 (s, 1H); 7.71-7.59 (m, 3H); 1.05 (s, 9H). 13C NMR
(d6-DMSO, 100.00 MHz): δ 176.7, 139.5, 133.4, 129.0,
127.3, 39.6, 25.9. HRMS calcd for C11H15NO3S m/z
242.0845 (MH+), Found: 242.08481.
2,2,2-Trichloro-N-(phenylsulfonyl)acetamide (9c): 1H NMR
(d6-DMSO, 400.00 MHz): δ 13.18 (s, 1H); 7.90-7.83 (m, 2H);
7.60 (dt, J ) 7.2, 2.4 Hz, 1H); 7.57 (d, J ) 1.2 Hz, 1H); 7.54
(dd, J ) 6.8, 1.6 Hz, 1H). 13C NMR (d6-DMSO, 100.00 MHz):
δ 162.008, 144.1, 141.2, 132.6, 131.9, 129.0, 128.7, 127.2,
125.6, 94.9. HRMS calcd for C8H6Cl3NO3S m/z 301.9206
(MH+), Found: 301.92110.
N-(Methylsulfonyl)pivalamide (10a): 1H NMR (d6-
DMSO, 400.00 MHz): δ 11.26 (s, 1H); 3.22 (s, 3H); 1.14
(s, 9H). 13C NMR (d6-DMSO, 100.00 MHz): δ 177.8, 40.9,
39.7, 26.1. HRMS calcd for C6H13NO3S m/z 180.0688
(MH+), Found: 180.06890.
N-(Methylsulfonyl)-N-phenylbenzamide (6): 1H NMR (d6-
DMSO, 400.00 MHz): δ 7.51 (d, J ) 1.6 Hz, 1H); 7.49 (t, J )
1.6 Hz, 1H); 7.42-7.26 (m, 8H); 3.54 (dd, J ) 10.4, 1.6 Hz,
3H). 13C NMR (d6-DMSO, 100.00 MHz): δ 170.3, 136.6, 133.7,
131.6, 130.4, 129.1, 128.7, 128.1, 40.6. HRMS calcd for
C14H13NO3S m/z 276.0688 (MH+), Found: 276.06930.
N-[(1S)-(-)-2,10-Camphorsultam]benzamide (7): 1H NMR
(d6-DMSO, 400.00 MHz): δ 7.65 (d, J ) 1.2 Hz, 1H); 7.61
(dd, J ) 16.4, 1.2 Hz, 2H); 7.48 (s, 1H); 7.48 (d, J ) 14.8 Hz,
1H); 4.13-4.10 (m, 1H); 3.84 (d, J ) 14.0 Hz, 1H); 3.64 (d,
J ) 14.0 Hz, 1H); 1.89 (d, J ) 7.2 Hz, 3H); 1.84 (d, J ) 10.8
Hz, 2H); 1.54-1.48 (m, 1H); 1.31 (d, J ) 8.4 Hz, 1H); 1.25
(d, J ) 11.6 Hz, 3H); 0.98 (s, 3H). 13C NMR (d6-DMSO, 100.00
MHz): δ 169.2, 133.9, 132.4, 128.94, 128.0, 65.0, 52.6, 48.0,
47.3, 44.6, 40.1, 37.9, 32.1, 25.9, 21.1, 19.5. HRMS calcd for
C17H21NO3S m/z 320.1315 (MH+), Found: 320.13192.
4-Methoxy-N-(phenylsulfonyl)benzamide (8a): 1H NMR
(d6-DMSO, 400.00 MHz): δ 12.38 (s, 1H); 8.07 (d, J ) 13.2
Hz, 1H); 8.05 (d, J ) 12.4 Hz, 1H); 7.92 (d, J ) 11.6 Hz, 1H);
7.88 (s, 1H); 7.66 (dd, J ) 18.0, 6.8 Hz, 2H); 7.62 (d, J ) 7.6
Hz, 1H); 7.00 (d, J ) 8.4 Hz, 2H); 3.79 (s, 3H). 13C NMR
(d6-DMSO, 100.00 MHz): δ 164.7, 163.2, 139.7, 133.5, 130.6,
129.1, 127.7, 123.5, 113.9, 55.5. HRMS calcd for C14H13NO4S
m/z 292.0638 (MH+), Found: 292.06400.
N-(tert-Butylsulfonyl)pivalamide (10b): 1H NMR (d6-
DMSO, 400.00 MHz): δ 10.63 (s, 1H); 1.32 (s, 9H); 1.15 (s,
9H). 13C NMR (d6-DMSO, 100.00 MHz): δ 176.4, 61.1, 56.9,
40.3, 26.1, 24.0, 24.0. HRMS calcd for C9H19NO3S m/z
222.1158 (MH+), Found: 222.11590.
1
4-Methyl-N-(phenylsulfonyl)benzamide (8b): H NMR
(d6-DMSO, 400.00 MHz): δ 12.46 (s, 1H); 8.03 (d, J )
6.4 Hz, 1H); 8.01 (s, 1H); 7.78 (d, J ) 8.8 Hz, 1H); 7.77
(s, 1H); 7.73-7.62 (m, 3H); 7.28 (d, J ) 7.6 Hz, 2H);
2.34 (s, 3H). 13C NMR (d6-DMSO, 100.00 MHz): δ 165.2,
143.7, 139.6, 133.6, 129.1, 129.1, 128.6, 128.5, 127.7,
21.1. HRMS calcd for C14H13NO3S m/z 276.0688 (MH+),
Found: 276.06830.
Acknowledgment
We thank Kurt Lorenz and Marv Hansen for helpful
discussions and Edward Sheldon for HRMS support.
1
Supporting Information Available
4-Chloro-N-(phenylsulfonyl)benzamide (8c): H NMR
Pilot-plant procedures for compounds 3, 6, and 10, experi-
mental procedures and characterization of impurities 11, 12,
and 13, and spectra of the 22 compounds in Table 2. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(d6-DMSO, 400.00 MHz): δ 12.65 (s, 1H); 8.00 (dd, J )
8.4, 0.8 Hz, 2H); 7.89 (t, J ) 1.6 Hz, 1H); 7.87 (t, J )
2.0 Hz, 1H); 7.71-7.56 (m, 3H); 7.54 (d, J ) 4.4 Hz,
1H); 7.53 (d, J ) 2.8 Hz, 1H). 13C NMR (d6-DMSO,
100.00 MHz): δ 164.7, 139.7, 138.0, 133.502, 130.7,
130.3, 129.0, 128.6, 127.6. HRMS calcd for C13H10ClNO3S
m/z 296.0143 (MH+), Found: 296.01460.
Received for review August 29, 2008.
OP800210X
N-(Phenylsulfonyl)-4-(trifluoromethyl)benzamide (8d): 1H
NMR (d6-DMSO, 400.00 MHz): δ 12.95 (s, 1H); 8.05 (dd, J
262
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