Development and a practical synthesis of nepafenac intermediate via modified gassman reaction

Article abstract of DOI:10.2174/157017812802139582

Modification of nepafenac intermediate synthesis (5A) via Gassman specific ortho-substitution is reported. According to the process, 2-aminobenzophenone (1A) and 2-(methylthio)acetamide (2) were reacted in the convenient temperature conditions, in the presence of N-chlorophthalimide (3) or 1,3-dichloro-5,5- dimethylhydantoin (4), to activate the formation of azasulfonium salt and rearrangement thereof to pure 2-amino-3-benzoyl-α-(methylthio) phenylacetamide (5A). The procedure appears to be suitable for a reaction carried out in a large scale.

Full text of DOI:10.2174/157017812802139582

Letters in Organic Chemistry, 2012, 9, 461-464
461
Development and a Practical Synthesis of Nepafenac Intermediate via
Modified Gassman Reaction
Marcin Cybulski*, Adam Formela, Mariola Mucha, Karolina Kꢀos, Jacek Roszczyꢁski and Jerzy
Winiarski
Pharmaceutical Research Institute, 8 Rydygiera Street, 01-793 Warsaw, Poland
Received January 23, 2012: Revised March 27, 2012: Accepted May 07, 2012
Abstract: Modification of nepafenac intermediate synthesis (5A) via Gassman specific ortho-substitution is reported. Ac-
cording to the process, 2-aminobenzophenone (1A) and 2-(methylthio)acetamide (2) were reacted in the convenient tem-
perature conditions, in the presence of N-chlorophthalimide (3) or 1,3-dichloro-5,5-dimethylhydantoin (4), to activate the
formation of azasulfonium salt and rearrangement thereof to pure 2-amino-3-benzoyl-ꢀ-(methylthio)phenylacetamide
(5A). The procedure appears to be suitable for a reaction carried out in a large scale.
Keywords: Gasmann reaction, Nepafenac, N-chlorophthalimide.
INTRODUCTION
phenylacetamide (5A) intermediate. Recently, the improved
process for preparing 5A with halogenosuccinic acid imide
has been disclosed [9]. The two above mentioned procedures
for the preparation of 2-amino-3-benzoyl-ꢀ-(methylthio)
phenylacetamide (5A) require low temperature and dry, inert
atmosphere. In the final step of nepafenac synthesis, the
nickel sponge desulfurization of 5 gave the final compound.
Nepafenac (0.1% ophthalmic suspension) non-steroidal
anti-inflammatory drug (NSAID) has been introduced for
commercial use in the US and EU [1]. Originally, nepafenac
was synthesized using Gassman's procedure for the prepara-
tion of indole ring [2-5]. Gassman’s indole synthesis in-
volves a one-pot process in which a hypohalite and a ꢁ-
carbonyl sulfide are added sequentially to substituted aniline
to form an azasulfonium salt. Then the salt is treated with
base to cause Sommelet-Hauser-type rearrangement, to pro-
vide 3-thioalkoxyindoles [6]. The selection of reagent addi-
tion sequence seems to be connected with the effect of sub-
stituent on the aniline ring. In the presence of electron-
donating group, which destabilizes the N-chloroaniline in-
termediate, the enhanced synthetic strategy is a formation of
chlorosulfonium salt followed by reaction with appropriate
aniline (Scheme 1). Wright et al. have developed a modifica-
tion of the Gassman synthesis that affords the improved
yields in many cases [7]. The key feature of the modification
was the formation of the chlorosulfonium salt from sulfoxide
and oxalyl chloride. The reaction was successful for a num-
ber of substrates that are particularly sensitive to halogena-
tions, and for which the use of the ethyl (methylthio)acetate/
chlorine or tert-butyl hypochlorite condition was unsuitable,
although it required low temperature and dry, inert atmos-
phere. Firstly described nepafenac intermediate (5A) synthe-
sis was carried out in a one-pot sequence in the presence of
tert-butyl hypochlorite [8]. 2-aminobenzophenone (1A) was
reacted with a 2-(methylthio)acetamide to give an azasulfo-
nium salt (Scheme 1), followed by triethylamine addition to
cause rearrangement to 2-amino-3-benzoyl-ꢀ-(methylthio)
RESULTS AND DISCUSSION
In the present paper we report a modification of the
Gassman reaction that makes it convenient to scale-up the
process. At the beginning, the preparation described by
Walsh [8] was examined using HPLC for determining the
purity of final 2-amino-3-benzoyl-phenyl)-ꢂ-(methylthio)
phenylacetamide (5A). The best results, achieved by the ad-
dition of rearrangement agent at -70ºC, yielded about 54%
with only 58% HPLC purity after crystallization. The main
impurities, extremely difficult to remove from the final 5A
by common purification techniques, were two chlorination
by-products i.e. 2-amino-5-chlorobenzophenone [10] (major;
1B) and 2-amino-3-benzoyl-5-chloro-ꢂ-(methylthio)-phenyl
acetamide (5B). Both compounds were synthesized for our
HPLC studies. It’s worth noticing that the direct para-
substitution of 2-aminobenzophenone (1A) with tert-butyl
hypochlorite, leading to 1B, has never been reported before.
Moreover, there is no analytical data for 5B in literature. As
a result of our examination, two chlorination agents - N-
chlorophthalimide (3) or 1,3-dichloro-5,5-dimethylhydantoin
(4) were selected for the studies of a new modified Gassman
procedure. The most important criteria for our choice were
common availability of proposed compounds and the sim-
plicity of by-product (i.e. phthalimide) detection.
In our work we evaluated the influence of the amount of
the chlorinating agent and temperature on the purity of 5A,
in the condensation produced by N-chlorophthalimide (Table
1). In addition, the suitability of 1,3-dichloro-5,5-
*Address correspondence to this author at the Pharmaceutical Research
Institute, 8 Rydygiera Street, 01-793 Warsaw, Poland; Tel: +48 22 456 39
28; Fax: +48 22 456 39 00;
E-mail: m.cybulski@ifarm.eu
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

462 Letters in Organic Chemistry, 2012, Vol. 9, No. 7
Cybulski et al.
O
O
N-Cl
N-Cl
O
N
Cl
S+
or
O
O
O
HN
R
NH2
O
NH2
3
4
O
S
CH2Cl2/TEA
NH2
R
1A (R=H)
1B (R=Cl)
sulfonium ion
O
NH2
O
NH2
S
NH2
Raney's type Ni
NH2
1. TEA
O
O
2. KOHaq
R
nepafenac
R
5A (R=H)
5B (R=Cl)
Scheme 1. Synthesis of 5.
Table 1. The Obtaining of 5A with N-chlorophthalimide (3) Activation, in Various Reaction Conditions
Starting Temperature
[ºC]
3
[eq.]
Yield
g [%]
HPLC Purity of Crude Product
5A
Content of Substrate 1A in Crude
Product
-50:-45
-50:-45
-50:-45
-30:-25
-20:-15
-5:0
1
1,2
1,4
1
89.8%
96.0%
96.0%
90.8%
90.0%
92.0%
89.6%
78.59 %
79.07 %
66.72%
78.86%
82.47%
77.11%
61.80%
17,64%
10,37%
9,73%
19,73%
15,80%
21,89%
35,75%
1
1
+10:+15
1
dimethylhydantoin in Gassman rearrangement was checked.
The use of N-chlorophthalimide was quite effective in a
wide range of temperatures i.e. from -50ºC to 15ºC. All re
actions were carried out under normal atmospheric condi-
tions. It seems that inert and dry atmosphere was not essen-
tial. The purity varied from about 62% to 82% of 5A in
crude product. The best results were observed in tempera-
tures -20ºC to -15ºC. The quantity increase of 3 (from 1 to
1,4 molar eq.) did not significantly affect the amount of the
expected product; however, it led to a negative change in
purity profile of 5A. Instead of an easy removable substrate
1A, new undefined impurities were formed. In the case of N-
chlorophthalimide (with molar ratio 1:1) to promote the re-
action, there was no need to isolate a formed azasulfonium
salt before the rearrangement to methylthiophenylacetamides
5A and 5B. The crude products were easily purified by stan-
dard crystallization from 2-propanol. The reactions with 1,3-
dichloro-5,5-dimethylhydantoin were not optimized. The
enhanced purity of 5A was achieved in the work-up with the
isolation of azasulfonium salt before organic base addition.
Compound 5B was obtained by the crystallization of crude
product, which had been isolated after quenching the reac-
tion mixture with triethylamine.
EXPERIMENTAL
Materials and Instruments
Reagent and solvents were purchased from common
commercial suppliers and were used without further purifica-
tion. NMR spectra were recorded on a Varian VNMRS 600
spectrometer (at 298 K) in DMSO-d6. Melting points were
determined from DSC experiments using Mettler- Toledo
822e with an intercooler. Chromatographic studies were per-
formed on a Waters Alliance® (2695 Separations Module)
HPLC system. Reverse-phase C18 column (2.6 μ particles
size, 250 mmx4.5mm) and mobile phase (A: 10mM ammo-
nium formate, adjusted to pH 4 with formic acid; B: acetoni-
trile) with gradient elution were used for separation.
2-amino-5-chloro-benzophenone (1B)
Tert-butyl hypochlorite [11] (5,4 mL; 0,045 mol) was
added dropwise to
benzophenone (8,88 g; 0,045 mol) in methylene chloride
(135 mL). The temperature rose from 20ºC to 35ºC and the
mixture was stirred for 10 min. The organic solution was
washed twice with water (2x50 mL), dried over anhydrous
a stirred solution of 2-amino-

Development and a Practical Synthesis of Nepafenac
Letters in Organic Chemistry, 2012, Vol. 9, No. 7 463
magnesium sulfate, and evaporated in vacuo to give a brown
solid. The crude product was purified by column chromatog-
raphy on silica-gel (eluent: hexanes and ethyl ace-
tate/hexanes 9:1) and crystallization (ethyl acetate/hexanes).
Yield 5,09 g (48,8%). HPLC purity 99,74%. M. p. 98 °C
while the temperature was maintained in the range -20 - -
15ºC. The obtained mixture was stirred in -20 - -15ºC for 30
min, then allowed to warm up to - 5 ºC within 150 min.
Triethylamine (5,4 mL; 38,8 mmol) was added. Then the
organic solution was washed with 1M potassium hydroxide
(3x85 mL) and water (3x85 mL), dried over anhydrous mag-
nesium sulfate, and evaporated in vacuo. The crude product
was purified by crystallization from methylene chlo-
ride/hexanes. The formed yellow crystals were filtered and
air dried. Yield 4,35 g (36,5%). HPLC purity 99,22%. M.p.
191°C.1H NMR (600 MHz; DMSO) 2.04 (s, 3H), 4.79 (s,
1H), 7.18 (d, J1=2.4 Hz,1H), 7.22 (br, 2H), 7.46 (br, 1H),
7.53–7.56 (m, 2H), 7.58–7.62 (m, 2H), 7.61–7.64 (m, 1H),
7.71 (br, 1H); 13C NMR (600 MHz; DMSO) 14.4, 49.9,
117.0, 118.4, 124.1, 128.4, 128.7, 131.6, 132.01, 134.1,
139.1, 147.8, 170.5, 197.2.
1
(95-99 °C [5]). H NMR, 13C NMR data and melting point
corresponded with those reported in literature [5].
2-amino-3-benzoyl-ꢀ-(methylthio)phenylacetamide (5A)
Preparation with N-chlorophthalimide (3)
A stirred suspension of 2-amino-benzophenone (1A)
(7,02 g; 35,6 mmol) and 2-(methylthio)acetamide [12] (3,74
g; 35,6 mmol) in methylene chloride (160 mL) was cooled
down to -20 -15ºC.
A
solution of 95% (T) N-
chlorophthalimide (3) (6,63 g; 36,5 mmol) in methylene
chloride (215 mL) was added dropwise during 30 min.,
while the temperature was maintained in the range -20 -
15ºC. The obtained mixture was stirred in -20 -15ºC for 30
min, then allowed to warm up to - 5 ºC within 150 min.
Triethylamine (5,4 mL; 38,8 mmol) was added. Then the
organic solution was washed with 1M potassium hydroxide
(3x85 mL) and water (3x85 mL), dried over anhydrous mag-
nesium sulfate, and evaporated in vacuo. The crude product
was purified by crystallization from 2-propanol. The formed
yellow crystals were filtered and air dried. Yield 6,75 g
(63,1%). HPLC purity 99,22%. M.p. 159 °C (153°-155 °C
[8]).
1H NMR (600 MHz; DMSO) 2.03 (s, 3H), 4.76 (s, 1H),
6.57 (dd, J1=J2=7.8 Hz), 7.22–7.30 (m, 1H), 7.26 (br, 2H),
7.39 (br, 1H), 7.46–7.51 (m, 1H), 7.48–7.53 (m, 2H), 7.53–
7.58 (m, 2H), 7.56–7.60 (m, 1H), 7.67 (br, 1H); 13C NMR
(600 MHz; DMSO) 14.5, 50.7, 113.9, 117.4, 122.1, 128.2,
128.6, 131.1, 133.9, 134.9, 140.0, 149.3, 171.0, 198.4.
Preparation with 1,3-dichloro-5,5-dimethylhydantoin
A stirred suspension of 2-amino-5-chloro-benzophenone
(1B) (1,92 g; 8,3 mmol) and 2-(methylthio)acetamide [12]
(0,87 g; 8,3 mmol) in methylene chloride (37 mL) was
cooled to -20 -15ºC. A solution of min. 68% (T) 1,3-
dichloro-5,5-dimethylhydantoin (4) (1,45 g) in methylene
chloride (20 mL) was added dropwise during 15 min., while
the temperature was maintained between -20 - -15ºC. The
obtained mixture was stirred in -20 - -15ºC for 30 min, then
allowed to warm to - 5 ºC within 120 min. Triethylamine
(1,25 mL; 9,0 mmol) was added. After work-up a crystalliza-
tion as described above, yellow crystals were filtered and air
dried. Yield 0,90 g (32,4%). M.p. 191°C. HPLC purity
99,82%. NMR confirmed.
CONCLUSIONS
Preparation with 1,3-dichloro-5,5-dimethylhydantoin (4)
The present procedures offer an alternative to the work
with tert-butyl hypochlorite which is unstable and not easy
to handle in bulk. The most important advantage of the new
chlorinating agents was good purity and the yield of
nepafenac intermediate, in comparison to the original
method. The activation by N-chlorophthalimide (3) and 1,3-
dichloro-5,5-dimethylhydantoin (4) in Gassman-type ortho-
substitution results in mild reaction conditions, the ease of
manipulation and selectivity. The use of N-chlorophtha-
limide (3) is quite effective in a wide range of temperatures
(up to 15ºC), under normal atmospheric conditions. Our pro-
cedure not only gives nepafenac intermediate with no chlori-
nation by-products but also enables an easy detection of re-
sidual phthalimide as opposed to the synthetic method which
generates succinimide impurity. Additionally, the use of N-
chlorophthalimide (3) significantly improves the workup and
purification process of the post-reaction mixture, using the
extraction with an aqueous inorganic base to remove the
impurity as a phthalate.
A stirred suspension of 2-amino-benzophenone (1A)
(1,64 g; 8,3 mmol) and 2-(methylthio)acetamide [12] (0,87
g; 8,3 mmol) in methylene chloride (37 mL) was cooled
down to -20 - -15ºC. A solution of min. 68% (T) 1,3-
dichloro-5,5-dimethylhydantoin (4) (1,45 g) in methylene
chloride (20 mL) was added dropwise during 15 min., while
the temperature was maintained in the range -20 - -15ºC. The
obtained mixture was stirred in -20 - -15ºC for 30 min, then
allowed to warm up to - 5 ºC within 120 min and the formed
salt was collected by filtration. The precipitate was sus-
pended in methylene chloride (20 mL) and triethylamine
(1,25 mL; 9,0 mmol) was added. After work-up and crystal-
lization as described above, yellow crystals were filtered and
air dried. Yield 0,90 g (36,1%). M.p. 159 °C (153°-155 °C
[8]). HPLC purity 99,73%. NMR confirmed.
2-amino-3-benzoyl-5-chloro-ꢀ-(methylthio)phenylaceta-
mide (5B)
Preparation with N-chlorophthalimide
ACKNOWLEDGEMENTS
A stirred suspension of 2-amino-5-chloro-benzophenone
(1B) (8,25 g; 35,6 mmol) and 2-(methylthio)acetamide [12]
(3,74 g; 35,6 mmol) in methylene chloride (160 mL) was
cooled down to -20 - -15ºC. A solution of 95% (T) N-
chlorophthalimide (3) (6,63 g; 36,5 mmol) in methylene
chloride (215 mL) was added dropwise during 30 min.,
This work was supported by the European Union under
The Innovative Economy Operational Programme 2007-
2013 (OP IE); “Innovative technologies of ophthalmic medi-
cines of special therapeutic and social importance” UDA-
POIG.01.03.01-14-068/08-04.

464 Letters in Organic Chemistry, 2012, Vol. 9, No. 7
Cybulski et al.
[7]
[8]
Wright, S.W.; McClure, L.D.; Hageman, D.L. A Convenient
Modification of the Gassman Oxindole Synthesis. Tetrahedron Let-
ters, 1996, 37(27), 4631-4634.
Walsh, D.A.; Moran, H.W.; Shamblee, D.A.; Welstead, W.J.;
Nolan, J.C.; Sancilio, L.F.; Graff G. Antiinflammatory agents. 4.
Syntheses and biological evaluation of potential prodrugs of 2-
CONFLICT OF INTEREST
The author(s) confirm that this article content has no con-
flicts of interest.
amino-3-benzoylbenzeneacetic
chlorobenzoyl)benzeneacetic acid. J. Med. Chem., 1990, 33, 2296-
2304.
Tojo Suarez, G.; Gavalda Escude, A. Process for preparing a ben-
zoylbenzeneacetamide derivative Pat. Appl. US2009/0312575 A1,
December 17, 2009.
Mannam, S.; Sekar, G. An enantiopure galactose oxidase model:
synthesis of chiral amino alcohols through oxidative kinetic resolu-
tion catalyzed by a chiral copper complex. Tetrahedron: Asymme-
try, 2009, 20(4), 497-502.
acid
and
2-amino-3-(4-
REFERENCES
[1]
EMEA/H/C/818, European Public Assessment Report (EPAR),
Nevanac.
[9]
[2]
Gassman, P.G.; Gruetzmacher, G.; Van Bergen, T.J. Use of halo-
gen-sulfide complexes in the synthesis of indoles, oxindoles, and
alkylated aromatic amines. JACS., 1973, 95(19), 6508
Gassman, P.G.; van Bergen, T.J.; Gilbert, D. P.; Cue, Jr., B. W.
General method for the synthesis of indoles. JACS., 1974, 96(17),
5495-5508.
[10]
[3]
[11]
[12]
Mintz, M.J.; Walling, C. t-Butyl Hypochlorite. Org. Synth., 1973,
coll. vol. 5, 184-197.
[4]
[5]
Gassman, P.G.; Van Bergen, T.J. Oxindoles. New, general method
of synthesis. JACS., 1974, 96(17), 5508ꢀ5512.
Mori, Y.; Fujiwara, S.; Miyachi, T.; Kitanishi, H.; Oya, M.; Ya-
mamoto, K.; Suzuki, M. Mass Spectrometry of 2-Alkylthio-2-
Methylpropanoic Acid and Amides. Structural and Steric Effects
on the McLafferty Rearrangement. Chem. Pharm. Bull., 1983, 31,
1505-1517.
Gassman, P.G.; Gruetzmacher, G.; Van Bergen, T.J. Generation of
azasulfonium salts from halogen-sulfide complexes and anilines.
Synthesis of indoles, oxindoles, and alkylated aromatic amines
bearing cation stabilizing substituents. JACS., 1974, 96(17), 5512-
5517.
[6]
Li, J.J. In: Name Reactions, A Collection of Detailed Mechanisms
and Synthetic Applications; Fourth Expanded Edition, Springer
Dordrecht Heidelberg London New York, 2009, pp. 251-252.