Synthesis of potential impurities of bicalutamide

Article abstract of DOI:10.1080/00397910802519208

Bicalutamide is an oral nonsteroidal, anti-androgen drug used for prostate cancer. It binds to the androgen receptor. During the bulk synthesis of bicalutamide, various impurities are formed. The present work details the development of simple processes for the preparation of impurities of bicalutamide, viz bical-sulfoxides (6), bical-deshydroxy (10), bical-desfluoro (10a), bical-2-fluoro (10b), and bical-3-fluoro (10c). Copyright Taylor & Francis Group, LLC.

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Synthesis of Potential
Impurities of Bicalutamide
Nandu Baban Bhise a , Dhananjay Govind Sathe a ,
Tarur Radhakrishanan a & Raviraj Deore a
a CPRL, USV Limited , Mumbai, India
Published online: 02 Apr 2009.
To cite this article: Nandu Baban Bhise , Dhananjay Govind Sathe , Tarur
Radhakrishanan & Raviraj Deore (2009) Synthesis of Potential Impurities
of Bicalutamide, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:9, 1516-1526, DOI:
10.1080/00397910802519208
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Synthetic Communications1, 39: 1516–1526, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802519208
Synthesis of Potential Impurities of Bicalutamide
Nandu Baban Bhise, Dhananjay Govind Sathe,
Tarur Radhakrishanan, and Raviraj Deore
CPRL, USV Limited, Mumbai, India
Abstract: Bicalutamide is an oral nonsteroidal, anti-androgen drug used for
prostate cancer. It binds to the androgen receptor. During the bulk synthesis of
bicalutamide, various impurities are formed. The present work details the develop-
ment of simple processes for the preparation of impurities of bicalutamide, viz
bical-sulfoxides (6), bical-deshydroxy (10), bical-desfluoro (10a), bical-2-fluoro
(10b), and bical-3-fluoro (10c).
Keywords: Anti-androgen, bicalutamide, Casodex, impurities, non-steroidal
INTRODUCTION
Bicalutamide is described chemically as N-[4-cyano-3-(trifluoromethyl)-
phenyl]-3-(4-fluorophenyl)sulfonyl-2-hydroxy-2-methylpropanamide (1).
Bicalutamide and related acylanilides have been disclosed in the litera-
ture[1,2] as pharmaceutically active compounds possessing anti-androgenic
activity useful in the treatment of prostate cancer. Bicalutamide, the
pharmaceutical product, is approved worldwide under the brand name
Casodex (Astra Zeneca) (Fig. 1).
Bicalutamide has been prepared by reacting 3-trifluoromethyl-
4-cyanoaniline of formula 2 with methacryloyl chloride followed by
epoxidation of the resultant N-(3-trifluoromethyl-4-cyanophenyl)metha-
crylamide of formula 3. The formed epoxide 4 is opened with 4-fluorothio-
phenol to obtain the thioether 5, which on conversion to sulfone resulted in
bicalutamide of formula 1 as reported in the literature[3] (Scheme 1).
Received August 18, 2008.
Address correspondence to Nandu Baban Bhise, CPRL, BSD Marg, Govandi,
Mumbai 400088, India. E-mail: nandu.bhise@usv.co.in
1516

Bicalutamide Impurities
1517
Figure 1. Bicalutamide.
Bicalutamide, a nonsteroidal pharmaceutically active agent posses-
sing antiandrogenic properties, is generally used in treatment of prostate
cancer(i.e., forandrogen deprivationtreatment), althoughotherandrogen-
dependent conditions may also be treated. Bicalutamide is commercially
available in a pharmaceutical composition as a racemate under the brand
name Casodex, although one of the stereoisomers of bicalutamide has
been proposed in the literature[4] as being more beneficial than the
racemate. Several methods are known for making N-[4-cyano-3-(trifluoro-
methyl)
phenyl]-3-[(4-fluorophenyl)sulphonyl]-2-hydroxy-2-methyl-
propanamide (1) (i.e., bicalutamide) from its precursor N-[4-cyano-3-
(trimethyl)phenyl]-3-[(4-fluorophenyl)thio]-2-hydroxy-2-methyl-propan-
amide (5) using different oxidizing agents. The oxidation is reported to be
accomplished by using various peracids.[5,6] In our laboratory, it was
synthesized according to Scheme 1, with modifications (as compared
to prior literature) to make it simpler and commercially viable. Thus
N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]-2-hydroxy-
2-methyl propanamide (5) was oxidized to N-[4-cyano-3-(trifluoromethyl)-
phenyl]-3-[(4-fluorophenyl)sulphonyl]-2-hydroxy-2-methyl propanamide
(1), using sodium perborate tetrahydrate in acetic acid[7] (Scheme 2).
During analysis of laboratory batches of bicalutamide, five impurities
were detected by high-performance liquid chromatography (HPLC). The
presence of impurities in an active pharmacetical ingredient (API) can have
a significant impact on the quality and safety of the drug. Therefore, it is
necessary to study the impurity profile and limit the presence of
Scheme 1. Synthesis of bicalutamide using peracid.

1518
N. B. Bhise et al.
Scheme 2. Synthesis of bicalutamide using sodium perborate.
impurities in the final API during manufacturing of the drug substance.
International Conference on Harmonization (ICH) guidelines recommend
identifying and characterizing all impurities that are present at a level of
0.10% or more[8,9] in the final drug substance. To correctly quantify the
impurities present in the final drug substance, it is necessary to have
standards for these impurities. It was decided to make these impurities in
our laboratory because their detailed synthesis has not been reported in
the literature and they are not commercially available for purchase.
DISCUSSION
In this article, we present our work on the synthesis and characterization
of various potential impurities of bicalutamide. The present work
discloses a process for the synthesis of N-[4-cyano-3-(trifluoromethyl)-
phenyl]-3-(4-fluorophenyl)sulfinyl-2-hydroxy-2-methyl-propanamide (6),
N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluoro-phenyl)sulfonyl-2-methyl-
propanamide (8), N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(phenyl)-
sulfonyl-2-hydroxy-2-methylpropanamide (10a), N-[4-cyano-3-(trifluoro-
methyl) phenyl]-3-(2-fluorophenyl)sulfonyl-2-hydroxy-2-methyl-propan-
amide (10b), and N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(3-fluorophenyl)
sulfonyl-2-hydroxy-2-methyl-propanamide (10c). The invention discloses
a novel reagent (i.e., sodium perborate in presence of acetic acid) for
oxidation in the preparation of bicalutamide impurities.
Preparation of 4-cyano-3-(4-fluorophenylsulfinyl)-2-hydroxy-2-
methyl-3-(trifluoromethyl) propanamide [i.e., sulfoxide (6)] involves
oxidation of compound 5 with sodium perborate tetrahydrate in acetic
acid (Scheme 3). The mass spectrum (ESþ) of (6) showed (M þ Na) at
Scheme 3. Synthesis of bical-sulfoxide (6).

Bicalutamide Impurities
1519
437. The presence of –NH and –OH stretching (3437, 3358 cmꢀ1), aroma-
tic C-H stretching (3101 cmꢀ1), –CN stretching (2233 cmꢀ1),
1
and –C¼O stretching (1689) was evident in the infrared spectrum. H
NMR spectrum showed a broad signal at @ 10.53 for the –NH proton,
which disappeared on D2O exchange. The aromatic protons appeared
as a multiplet at @ 8.5, 8.27, 8.1, 7.71, and 7.43. The broad singlet at @
6.75 is due to the –OH proton, which disappeared upon D2O exchange.
The –CH2 protons appeared as a multiplet at @ 3.15–3.44, and the CH3
protons appeared as a multiplet at @ 1.56.
Preparation
of
4-cyano-3-(4-fluorophenylsulfonyl)-2-methyl-3-
(trifluoromethyl) propanamide [i.e., deshydroxy sulfone compound 8]
involves the addition reaction of 4-fluorothiophenol with compound 3
in the presence of a catalytic amount of a phase-transfer catalyst (PTC)
(i.e., tetrabutylammonium bromide) in a water–dioxan mixture to give
quantative yield of compound 7. The absence of PTC also works, but
1
the yield is less. H NMR spectrum showed multiplets at @ 7.97–8.27
and 7.15–7.57 due to the aromatic protons. The –CH proton appeared
as a multiplet at @ 4.04, –CH2 protons showed a multiplet at @
2.81–3.34, and the CH3 protons appeared as a doublet at @ 1.27.
Compound 7, on oxidation with sodium perborate tetrahydrate in
acetic acid, gave compound 8 (Scheme 4). The mass spectrum (ESþ) of 8
showed (M þ Na) at 437 and (ESꢀ) at 413. The presence of –NH and –
OH stretching (3340, 3298cmꢀ1), aromatic C-H stretching (2985 cmꢀ1), –
CN stretching (2225 cmꢀ1), and –C¼O stretching (1710) was evident in
1
the infrared (IR) spectrum. H NMR spectrum showed a broad signal at
@ 10.84 for –NH proton, which disappeared on D2O exchange. The aroma-
tic protons appeared as multiplets at @ 8.1, 7.92, 7.82, and 7.38. The –CH
proton appeared as a multiplet at @ 3.76–3.88, –CH2 protons showed a mul-
tiplet at @ 3.36–3.56, and the CH3 protons appeared as a doublet at @ 1.23.
Preparation of compounds 10a–c involves initial epoxide opening
reaction of compound 4 with corresponding thiophenol in the presence
of a base in tetrahydrofuran to obtain compounds 9a–c. 1H NMR
Scheme 4. Synthesis of bical-deshydroxy (8).

1520
N. B. Bhise et al.
Scheme 5. Synthesis of bical-desfluoro (10a), bical-2-fluoro (10b), and bical-3-
fluoro (10c).
spectrum of compound 9a showed a singlet at @ 10.53 for the –NH pro-
ton, which disappeared on D2O exchange. The aromatic eight protons
appeared as multiplets at @ 8.47, 8.24, 8.1, 7.88, and 7.57–7.65. The broad
singlet at @ 6.42 is due to –OH proton, which disappeared on D2O
exchange. The –CH2 protons appeared as a multiplet at @ 3.68–3.97,
and the CH3 protons appeared as a singlet at @ 1.48. The compounds
1
9b,c were also confirmed by H NMR spectrum. The compounds 9a–c,
on oxidation with sodium perborate tetrahydrate in acetic acid, gave
compounds 10a–c (Scheme 5). The mass spectrum (ESþ) of 10a showed
(M þ Na) at 435, and (ESꢀ) showed (Mꢀ1) at 411. The presence of –NH
and –OH stretching (3466, 3342 cmꢀ1), aromatic C-H stretching
(2966 cmꢀ1), –CN stretching (2229 cmꢀ1), and –C¼O stretching (1699)
1
was evident in the IR spectrum. H NMR spectrum showed a singlet at
@ 10.51 for –NH proton, which disappeared on D2O exchange. The aro-
matic eight protons appeared as multiplets at @ 8.47, 8.22, 8.05, and 7.11–
7.33. The singlet at @ 6.30 is due to the –OH proton, which disappeared
on D2O exchange. The –CH2 protons appeared as multiplets at @ 3.24–
3.48, and the CH3 protons appeared as a singlet at @ 1.42. Similarly com-
1
pounds 10b,c were confirmed by mass, IR, and H NMR spectra.
CONCLUSIONS
Information on the different possible potential impurities and their
synthetic routes is a prerequisite for better understanding of the impurity
formation pathway of the oral non-steroidal anti-androgen drug
bicalutamide. Keeping in view the regulatory importance of bicalutamide

Bicalutamide Impurities
1521
impurities, our efforts to synthesize and characterize them effectively
have proved to be benificial.
EXPERIMENTAL
General Remarks
All reagents were of commercial quality and were used as such unless
otherwise stated. Yields reported are isolated yields of the compounds.
All synthesized analogs were >95% pure based on thin-layer chromato-
graphy (TLC) and high-performance liquid chromatography (HPLC).
Melting points were recorded on a Buchi melting-point apparatus and
are uncorrected. 1H NMR and 13C NMR spectra were recorded on
Brucker 200-MHz FT NMR spectrometer, using dimethyl sulfoxide
(DMSO-d6) as solvent, unless otherwise mentioned. Chemical values
are expressed in parts per million (@ ppm) using tetramethylsilane
(TMS) as the internal standard. Electrospray ionization–mass spectro-
metry (ESI-MS) were recorded on Shimadzu LCMS-2010A instrument.
IR spectra were recorded as KBr wafers on a Shimadzu Fourier trans-
form (FT-IR 8300 spectrophotometer. TLC was performed on precoated
silica-gel aluminium plates containing a fluorescent indicator (1.0554,
silica gel 60 F254, Merck) technique using an appropriate solvent system
for development. Visualization of the components on TLC plates was
achieved either by exposure to iodine vapor or ultraviolet (UV) light.
Waters 2695 Alliance HPLC was used for analysis of bicalutamide’s
impurities.
N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)sulfinyl-2-
hydroxy-2-methyl-propanamide (6): Bical-sulfoxide
A solution of N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)-
thio]-2-hydroxy-2-methyl propanamide (5) (100 g, 252 mmol) in acetic
acid (800 ml) was stirred at room temperature. Then sodium perborate
tetrahydrate (34.4 g, 223 mmol) was added lotwise for 45 min at room
temperature. The reaction mixture was further stirred at room tempera-
ture for 2 h. The reaction mixture was poured into water and extracted
with ethyl acetate (2 ꢁ 300 ml). The ethyl acetate layer was separated,
washed with water, and concentrated under reduced pressure to obtain
crude 6 as an oil. Yield: 105 g. The crude compound was treated with tet-
rahydrofuran (200 ml) to get a clear solution. This solution was poured
into water, and a sticky solid was formed. The water was decanted from

1522
N. B. Bhise et al.
the flask, the sticky solid formed was treated with diisopropyl ether
(200 ml), and the solid formed was filtered, washed with diisopropyl
ether, and dried to obtain the title compound. Yield: 100 g. MP 140ꢀC.
ESI MS (ESþ) for C18H14F4N2O3S: calculated 414.37; found (M þ Na)þ
1
437. H NMR: @ 1.56 (d, 3H, –CH3); 3.15–3.44 (m, 2H, –CH2); 6.75 (b,
1H, –OH); 7.43 (m, 2H, Ar-H); 7.71 (m, 2H, Ar-H); 8.1 (m, 1H, Ar-H);
8.27 (m, 1H, Ar-H); 8.5 (m, 1H, Ar-H); 10.53 (b, 1H, –NH). IR: tmax
3437, 3358, 3101, 2233, 1689, 1587, 1525, 1493, 1186, 833 cmꢁ1
.
N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]-2-methyl
propanamide (7)
4-Fluorobenzenethiol (25.21 g, 197 mmol) was added dropwise to an aqu-
eous sodium hydroxide solution (7.9 g in 20 ml water) for 15 min at room
temperature. Then a solution of compound 3 (50 g, 197 mmol) in 1,4-
dioxan (500 ml) was added at room temperature followed by a catalytic
amount of tetrabutyl ammonium bromide. The reaction mixture was
refluxed for 3 h and cooled to room temperature, followed by addition
of 26% aqueous acetic acid. This mixture was extracted with ethyl acetate
(2 ꢂ 200 ml). The ethyl acetate layer was separated, washed with water,
and concentrated under reduced pressure to obtain crude 7 as an oil.
1
Yield: 70 g. H NMR: @ 1.27 (d, 3H, –CH3); 2.81–3.34 (m, 2H, –CH2);
4.04 (m, 1H, –CH); 7.15–7.57 (m, 5H, Ar-H); 7.97–8.27 (m, 2H, Ar-H).
N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)sulfonyl-2-
Methyl-propan-amide (8): Bical-deshydroxy
A solution of N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophe-
nyl)thio]-2-methyl-propanamide (7) (70 g, 194 mmol) in acetic acid
(490 ml) was stirred at room temperature. Then sodium perborate tetra-
hydrate (41 g, 266 mmol) was added at room temperature. The reaction
mixture was then heated at 55–60ꢀC for 2 h. The completion of reaction
was determined by TLC. After cooling to room temperature, the reaction
mixture was poured into water and extracted with ethyl acetate
(2 ꢂ 200 ml). The ethyl acetate layer was separated, washed with water,
and concentrated under reduced pressure to obtain crude 8. Yield: 75 g.
The crude 8 was crystallized from ethylacetate–hexane to obtain the title
compound (8) as an off-white solid. Yield: 70 g. Mp 154–156ꢀC. ESI MS
for C18H14F4N2O3S: calculated 414.37; (ESþ) found (M þ Na) 437; (ESꢁ)
1
found (Mꢁ1) ¼ 413. H NMR: @ 1.23 (d, 3H, –CH3); 3.36–3.56 (m, 2H,
–CH2); 3.76–3.88 (m, 1H, –CH); 7.38 (m, 2H, Ar-H); 7.82 (m, 1H,

Bicalutamide Impurities
1523
Ar-H); 7.92 (m, 2H, Ar-H); 8.1 (m, 2H, Ar-H); 10.84 (b, 1H, –NH).
13C NMR: 18.25, 36.30, 116.64, 121.95, 131.03, 131.24, 131.97, 135.24,
136.38, 143.27, 162.55, 167.57, 172.73; DEPT: (18.23, –CH3); (36.30,
116.20, 116.64, 121.95, 131.03, 131.24, 136.38, –CH); (57.19, –CH2). IR:
tmax 3340, 3298, 2985, 2225, 1710, 1591, 1533, 1140, 839 cmꢁ1
.
N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[phenylthio]-2-hydroxy-
2-methyl-propanamide (9a)
A solution of benzenethiol (21.82 g, 198 mmol) in terahydrofuran (THF;
50 ml) was added in a dropwise manner into a reaction flask containing
60% sodium hydride (9.33 g, 228 mmol) in THF (94 ml) at room tempera-
ture for 40 min under a nitrogen atmosphere. The mixture was stirred at
room temperature for 1 h, then a solution of N-[4-cyano-3-trifluoro-
methylphenyl]-2-methyloxiranecaboxamide (4) (50 g, 185 mmol) in THF
(213 ml) was added in a dropwise manner for 45 min at room tempera-
ture. The resulting reaction mixture was stirred at room temperature
for 2 h. The completion of reaction was determined by TLC. After com-
pletion of reaction, methanol (3.8 ml) was added dropwise into the reac-
tion mixture. The reaction mixture was acidified with aqueous acetic acid
(26.6 ml acetic acid in 1000 ml water) and extracted with hexane
(2 ꢂ 240 ml). The organic layer was separated and concentrated under
reduced pressure to obtain a residue. When this residue was treated with
hexane (188 ml), a solid appeared, which was filtered and dried to give
1
compound (9a). Yield: 70 g. H NMR: @ 1.48 (s, 3H, –CH3); 3.68–3.97
(m, 2H, –CH2); 6.42 (s, 1H, –OH); 7.57–7.65 (m, 3H, Ar-H); 7.85–90
(m, 2H, Ar-H); 8.1 (m, 1H, Ar-H); 8.23–8.28 (m, 1H, Ar-H); 8.47 (m,
1H, Ar-H); 10.43 (s, 1H, –NH).
N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-(phenyl)sulfonyl-2-hydroxy-
2-methyl-propanamide (10a): Bical-desfluoro
A solution of N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[phenylthio]-2-
hydroxy-2-methyl-propanamide (9a) (50 g, 132mmol) in acetic acid (358ml)
was stirred at room temperature, to which sodium perborate tetrahydrate
(41 g, 266mmol) was added at room temperature. The reaction mixture
was then heated at 55–60ꢀC for 6 h. The completion of the reaction
was determined by TLC. The reaction mixture was cooled to room tem-
perature, the solid formed was filtered, washed with water, and dried. This
solid was recrystallized from ethylacetate–hexane to obtain the title com-
pound (10a) as a white solid. Yield: 28 g. Mp 175–178ꢀC. ESI MS for

1524
N. B. Bhise et al.
C18H14F3N2O4S: calculated 412.39; (ESþ) found (M þ Na)þ 435; (ESꢀ)
1
found (M–1) 411. H NMR: @ 1.42 (s, 3H, –CH3); 3.24–3.48 (m, 2H,
–CH2); 6.30 (s, 1H, –OH); 7.11–7.33 (m, 5H, Ar-H); 8.05 (m, 1H, Ar-H);
8.22 (m, 1H, Ar-H); 8.47 (m, 1H, Ar-H); 10.51 (s, 1H, –NH). IR: tmax
3466, 3342, 2966, 2229, 1699, 1610, 1581, 1521, 1139, 844 cmꢀ1
.
N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(2-fluorophenyl)thio]-
2-hydroxy-2-methyl-propanamide (9b)
A solution of 2-fluorobenzenethiol (9.6 g, 75 mmol) in terahydrofuran
(20 ml) was added dropwise into a reaction flask containing 60% sodium
hydride (3.72 g, 93 mmol) in THF (45 ml) at room temperature, over a
period of 20 min under a nitrogen atmosphere. The mixture was stirred
at room temperature for 1 h, then a solution of N-[4-cyano-3-trifluoro-
methylphenyl]-2-methyloxiranecaboxamide (4) (20 g, 74 mmol) in THF
(80 ml) was added dropwise for 25 min at room temperature. The resul-
tant reaction mixture was stirred at room temperature for 2 h. The com-
pletion of the reaction was determined by TLC. After completion of the
reaction, methanol (1.6 ml) was added in a dropwise manner into the
reaction mixture. The reaction mixture was acidified with aqueous acetic
acid (10.6 ml acetic acid in 424 ml water) and extracted with hexane
(2 ꢁ 96 ml). The organic layer was separated and concentrated under
reduced pressure to obtain a residue. When this residue was treated with
hexane (75 ml), a solid appeared, which was filtered and dried to give
1
compound 9b. Yield: 26.2 g. H NMR: @ 1.49 (s, 3H, –CH3); 3.24–3.48
(m, 2H, –CH2); 6.34 (s, 1H, –OH); 7.08–7.18 (m, 3H, Ar-H); 7.45 (m,
1H, Ar-H); 8.08 (m, 1H, Ar-H); 8.24 (m, 1H, Ar-H); 8.46 (m, 1H,
Ar-H); 10.53 (s, 1H, –NH).
N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-(2-fluorophenyl)sulfonyl-
2-hydroxy-2-methyl-propanamide (10b): Bical-2-fluoro
A solution of N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(2-fluorophenyl)
thio]-2-hydroxy-2-methyl propanamide (9b) (23 g, 58 mmol) in acetic acid
(165 ml) was stirred at room temperature. Then sodium perborate tetra-
hydrate (18.86 g, 122 mmol) was added at room temperature. The reac-
tion mixture was heated at 55–60ꢂC for 6 h. The completion of the
reaction was determined by TLC. The reaction mixture was then cooled
to room temperature, and the formed solid was filtered, washed with
water, and dried. This was recrystallized from ethylacetate–hexane to
obtain the title compound (10b) as a white solid. Yield: 16.5 g. Mp

Bicalutamide Impurities
1525
160–164ꢂC. ESI MS for, C18H14F4N2O4S: calculated 430.38; (ESþ)
1
found (M þ Na)þ 453; (ESꢀ) found (Mꢀ1) ¼ 429. H NMR: @ 1.44 (s,
3H, –CH3); 3.74–4.10 (m, 2H, –CH2); 6.42 (s, 1H, –OH); 7.31–7.40
(m, 2H, Ar-H); 7.67–7.76 (m, 2H, Ar-H); 7.77 (m, 1H, Ar-H); 8.25 (m,
1H, Ar-H); 8.45 (m, 1H, Ar-H); 10.41 (s, 1H, –NH). IR: tmax 3433,
3317, 2980, 2233, 1697, 1610, 1581, 1524, 1124, 844 cmꢀ1
.
N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(3-fluorophenyl)thio]-
2-hydroxy-2-methyl Propanamide (9c)
A solution of 3-fluorobenzenethiol (9.6 g, 75 mmol) in THF (20 ml) was
added dropwise into a reaction flask containing 60% sodium hydride
(3.72 g, 93 mmol) in THF (45 ml), at room temperature, over period of
20 min under a nitrogen atmosphere. The mixture was stirred at room
temperature for 1 h, then a solution of N-[4-cyano-3-trifluoromethylphe-
nyl]-2-methyloxiranecaboxamide (4) (20 g, 74 mmol) in THF (80 ml) was
added dropwise over period of 25 min at room temperature. The resulting
reaction mixture was stirred at room temperature for 2 h. The completion
of reaction was determined by TLC. After completion of reaction, metha-
nol (1.6 ml) was added dropwise into the reaction mixture. The reaction
was acidified with aqueous acetic acid (10.6 ml acetic acid in 424 ml
water) and extracted with hexane (2 ꢁ 96 ml). The organic layer was sepa-
rated and concentrated under reduced pressure to obtain a residue. When
this residue was treated with hexane (75 ml), a solid appeared, which was
1
filtered and dried to give compound 9c. Yield: 26.5 g. H NMR: @ 1.5
(s, 3H, –CH3); 3.28–3.53 (m, 2H, –CH2); 6.34 (s, 1H, –OH); 6.9 (m,
1H, Ar-H); 7.13–7.27 (m, 3H, Ar-H); 8.10 (m, 1H, Ar-H); 8.24 (m, 1H,
Ar-H); 8.48 (m, 1H, Ar-H).
N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-(3-fluorophenyl)sulfonyl-
2-hydroxy-2-methyl-propanamide (10c): Bical-3-fluoro
A solution of N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(3-fluorophenyl)-
thio]-2-hydroxy-2-methyl propanamide (9c) (25 g, 63 mmol) in acetic acid
(179 ml) was stirred at room temperature. Then sodium perborate tetra-
hydrate (20.5 g, 133 mmol) was added at room temperature. The reaction
mixture was then heated at 55–60ꢂC for 6 h. The completion of reaction
was determined by TLC. The reaction mixture was cooled to room tem-
perature; the formed solid was filtered, washed with water, and dried.
The solid was further recrystallized from ethylacetate–hexane to obtain
the title compound (10c) as a white solid. Yield: 16.2 g. Mp 154–157ꢂC.

1526
N. B. Bhise et al.
ESI MS for C18H14F4N2O4S: calculated 430.38; (ESþ) found (M þ Na)þ
453; (ESꢀ) found (Mꢀ1) 429. 1H NMR: @ 1.43 (s, 3H, –CH3); 3.77–4.03
(m, 2H, –CH2); 6.45 (s, 1H, –OH); 7.47–7.75 (m, 4H, Ar-H); 8.1 (m, 1H,
Ar-H); 8.25 (m, 1H, Ar-H); 8.48 (m, 1H, Ar-H); 10.45 (s, 1H, –NH). IR:
tmax 3400, 3302, 2982, 2247, 1693, 1580, 1523, 1473, 1186, 843 cmꢀ1
.
ACKNOWLEDGMENTS
The authors thank the management of USV Ltd. for supporting this
work. We also thank Mr. S. V. Patil, Dr. V. Londe, and his group for
the analytical data.
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