FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
A PROCESS FOR PREPARATION OF ANTIANDROGEN COMPOUND
SUN PHARMACEUTICAL INDUSTRIES LIMITED
A company incorporated under the laws of India having their office at ACME PLAZA,
ANDHER1-KURLA ROAD, ANDHERI (E), MUMBA1-400059, MAHARASHTRA, INDIA.

The following specification particularly describes the invention and the manner in
which it is to be performed.

The present invention relates to a process for the preparation of an antiandrogen
compound. Particularly the present invention provides a process for preparation of N-[4-
cyano-3-(trifluoromethyl)phenyl]-3-[(4-florophenyl)sulfonyl]-2-hydroxy-2-
methylpropanamide, a compound of formula 1, known as bicalutamide.

Formula 1
Bicalutamide is an effective non-steroidal antiandrogen, the racemic form of which is
marketed for use in the treatment of advanced prostate cancer.
United States Patent No. 4636505 (equivalent Indian reference not available and Tucker
et al. J. Med. Chem., 31, page 954, 1988) teach thai the compound of formula 1, viz.
bicalutamide, can be prepared by reacting 4-cyano-3-trifluoromethylaniline with
methacryloyl chloride, followed by epoxidation of the resultant N-(3-trifluoromethyl-4-
cyanophenyl)methacrylamide to form the epoxide compound of formula 2, viz., N-[4-
cyano-3-(trif!uoron7ethyl)phenyl]-2-methyloxirane-2-carboxamide. The compound of
formula 2 is reacted with 4-fluorothiophenol, a compound of formula 3, in
letrahydrofuran (THF) in presence' of sodium hydride (NaH), to form N-[4-cyano-3-
(trifluoromethyl)phenyl]-3-[(4-nuorophenyl)thio]-2-hydroxy-2-methylpropanamide, viz.,
the compound of formula 4, which is then oxidized using meta-chloroperbenzoic acid
(MCPBA) in dichloromethane to form the compound of formula 1 (as depicted in
Scheme 1).
2


However, THF is an expensive solvent and NaH is hazardous for large-scale operations,
MCPBA is an expensive rengem and handling and transportation on large scale can pose
hazards and also a large excess of dichloromethane (470 volumes) has been used.
The PCT application WO 0224638 (equivalent Indian reference not available, equivalent
United States Patent No. 6562994) prepares the compound of formula 4 by reacting the
epoxide compound of formula 2 with 4-fluorothiophenol in THF in presence of NaH.
Then the compound of formula 4 is isolated and oxidized to form the compound of
formula 1 using hydrogen peroxide in dichloromethane.
The PCT application WO 03053920 (equivalent Indian reference not available,
equivalent United States Patent No. 6740770) prepares the compound of formula 4 by
reacting the epoxide compound of formula 2 with 4-fluorotbiopheno! iji THF in presence
of NaH or NaOH. Then the compound of formula 4 is isolated and oxidized to form the
compound of formula 1 using mono-perphthalic acid in ethyl acetate. The reagent mono-
perphthalic acid is expensive, and isolation of compound of formula 4 is not without
3

problems as the unreacted 4-fluorothiophenol has an offensive odour and on large scale
operations it can be inconvenient.
A one-pot preparation method, wherein the compound of formula 4 is generated in-situ
and oxidized further to obtain the compound of formula 1 would therefore be convenient
and advantageous.
The reagents used for oxidizing the compound of formula 4 to the compound of formula
1. in the prior art like hydrogen peroxide/acetic acid can form peracids, which are
potentially explosive and hazardous. In ether solvents, hydrogen peroxide can form
explosive mixtures. In presence of a base, hydrogen peroxide can react with the nitrile
group present in the compound to form perimidates, which can decompose to amides,
generating side products.
There is thus a need (o improve the synthetic process for bicalutamide, which is
economical, less hazardous, operationally convenient and environmentally safe.
The present invention provides a convenient one-pot preparation of the compound of
formula 1 by reacting the compound of formula 2 with the compound of formula 3 to
form the compound of formula 4 iu-sitn, which is then efficiently oxidized to form the
compound of formula 1 using a permanganate reagent.
There is no teaching of use of a permanganate for preparation of a compound of formula
1 by oxidation of a compound of formula 4 in the prior an.
We have found a simple method for preparation of bicaJutamide without the need to
isolate the intermediate compound of formula 4 and obviating the use of hazardous
oxidizing agents like peracids or the peroxides. The compound of formula 1 prepared by
the process of the present invention is devoid of the sulfoxide impurities that can result
from incomplete oxidation of the compound of formula 4.
4

SUMMARY OF THE INVENTION
The present invention provides a process for preparation of an antiandrogen compound,
N-[4-cyano-3-(trifluoromethyl)pheny1]-3-[(4-nLiofopheny])sulfonyl]-2-hydroxy-2-
methylpropanamide, a compound of formula 1,

Formula 1
comprising:
a) reacting N-[4-cyano-3-(trifluoroniethyl)phenyl]-2-methyloxirane-2-carboxamide, a
compound of formula 2 with 4-fIuorothrophenol, a compound of formula 3, in presence
of a phase transfer catalyst to form N-[4-cyano-3-(tri:fluoromethyl)phenyl]-3-[(4-
fluorophenyl)thio]-2-hydroxy-2-melhylpropanamide, a compound of fomnula 4,

b) adding a permanganate reagent to the reaction mixture to afford the compound of
formula 1.
5

In one aspect, (he present invention provides a process for preparation of N-[4-cyano-3-
(trifluoromethyl)phenyl}-3-[(4-:nuoroplienyl)lhio]-2-liydroxy-2-methy]propanamide, a
compound of formula 4

Formuta 4
comprising reacting N-[4-cyano-3-(triflLioromelhyl)phenyl]-2~methyloxirane-2-
carboxamide, a compound of formula 2 with 4-fluorothiophenol, a compound of formula

in presence of a phase transfer catalyst.
In one aspect the present invention provides a process for preparation of an antiandrogen
compound N-[4-cyano-3-(trifluoromethy])phenyl]]-3-[(4-f]iioropheny])sulfony]]-2-
hydroxy-2-methylpropanamide, a compound of formula 1,

Formula 1
comprising reacting N-[4-cyano-3-(trinuoromethyl)phenyl]-3-[(4-fluorophenyl)thio]-2-
hydroxy-2-methylpropanamide. a compound represented by formula 4,
6


with a permanganate reagent.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a simple process for preparation of bicalutamide starting
from a compound of formula 2. The compound of formula 2 may be prepared by a
method known in the art, for example by epoxidation of N-(3-lrifluoromethyl.-4-
cyanophenyl)melhacrylamide, such as in United Stales Palent No. 4636505 incorporated
herein by reference.
Optical isomers of compound of formula 1 may be obtained by carrying out the
epoxidation step under asymmetric conditions to give chiral compounds. For example,
epoxidation can be carried out with a chiral dioxirane to form a chirai epoxide and then to
form a chiral sulfide, which can be oxidized to form optical isonier of compound of
formula 1,
As biclutamide has a chiral carbon it can form two enanliomeric forms, viz., R and S
isomers. The bicahitamide prepared by the process of (he present invention can be
racemic or an enriched optical isomer including a pure or substantially pure optical
isomer. As used herein enriched means greater than about 60% optically pure and
substantially pure means greater than about 90% optically pure. The enriched optical
isomer of compound of formula 1 can be obtained by using enriched optical isomer of
compound of formula 4. The enriched optical isomer of compound of formula 4 may be
prepared from enriched epoxide compound of formula 2.
7

The enriched optical isomers or the substantially pure optical isoiners can be prepared by
using chiral reagents or by separation methods afier formation of racemic compounds.
Suitable separation methods are known in the art like derivatization with a chiral
substrate and resolution of the derivative, fractional crystallization of a salt with a chiral
substrate, chromalography separation using a chiral stationary phase etc.
In one embodiment, the compound of formula 2 in a single enantiomeric form is reacted
with a compound of formula 3 in a biphasic system in presence of a phase transfer
catalyst and a suitable organic or inorganic base to form a compound of formula 4 in a
single enantiomeric form, which is then further oxidized by treatment with a
permanganate reagent to obtain the compound of formula 1 in a single enanliomeric
form.
l.n one embodiment, the compound of formula 2 in racemic form is reacted with a
compound of formula 3 in a biphasic system in presence of a phase transfer catalyst and a
suitable organic or inorganic base to form a compound of formula 4 in a racemic form,
which is the further oxidized by treatment with a permanganate reagent to obtain the
compound of formula 1 in a racemic form.
The biphasic system can be formed by using water and a water-immiscible solvent.
Examples of the solvent usable for forming the biphasic system are ester solvents such as
ethyl acetate, methyl acetate, isopropy! acetate, tert-butyl acetate and the like; ether
solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether; hydrocarbon or
halogenated hydrocarbon solvents such as benzene, toluene, chlorobenzene, methylene
chloride, elhylene dichloride, chloroform and the like.
Examples of inorganic bases that may be used are hydroxides, carbonates, or fluorides of
alkali or alkaline earth metals. The organic base may be selected from secondary or
tertiary amines, which may be cyclic or acyclic. Preferably, the base is selected from
hydroxide of an alkali metal.
S

To the resultant compound of formula 4, a permanganate reagent is added, preferably an
alkali metal permanganate tike potassium permanganate, sodium permanganate or lithium
permanganate. A permanganate reagent can be added to the reaction mixture containing
the compound of formula 4 or if so desired, the compound of formula 4 may be isolated
from the reaction mixture and then oxidized lo the compound of formula 1 by using a
permanganate reagent. The amount of the permanganate reagent that may be
conveniently used is about 1.5 to 4 mole equivalent, preferably 2 to 3 mole equivalent
with reference to compound of formula 2 or compound of formula 4.
The phase transfer catalyst that may be used in the process of the present invention are
not particularly limited and is exemplified by quaternary ammonium salt or a
tetralkylphosphonium salt; for example tetrabuiylammonium hydrogen sulfate, tetrabutyl-
ammonium bromide, tetrabulylphosphonium bromide, benzyltriethylammonium chloride,
cetvJtri a lkyl ammonium sails; Tweens (nolyoxyeihylene sorbitan esters) such as
Tween®20, Tween®40, Tween®60, Tween®80, Tweeir 85; crown ethers, for example, 18-
Crown-6; alkylated polyethylene glycols, for example, poly(ethylene glycol)dimethyl
ether. The amount of the phase transfer catalyst that may be conveniently used is about
0.01 to 0.25 mole equivalent, preferably 0,1 to 0.2 mole equivalent with reference to
compound of formula 2.
It is also possible to carry out the reaction of compound of formula 2 with a compound of
formula 3 in anhydrous biphasic conditions by using solid permanganate, in aprotic
organic solvents in presence of a phase transfer catalyst, cited above. Any suitable aprotic
organic solvent, for example acetonitrile, ethyl acetate, 1,2-dimethoxyethane, diisopropyl
ether, tetrahydrofuran, 1,4-dioxane can be used,
The reaction of compound of formula 2 with a compound of formula 3 may be carried out
at a temperature between the range of about 0°C to about 100°C, preferably at about
20°C to about 30°C for a suitable reaction time, generally for about 2 to about 3 hours.
To the reaction mixture containing the resultant compound of formula 4, the
permanganate reagent may be added and reaction continued further at temperature
9

between the range of about 0°C to about 100°C, preferably at about 20°C to 30°C for a

suitable period, for example, about 2 to about 3 hours to obtain the compound of formula -
In a general work up procedure, the reaction mixture may be washed with aqueous
sodium metabisulfite, filtered, washed with dilute acid and the compound of formula 1
may be isolated after removal of organic solvent by concentration, cooling, evaporation
and/or crystallization techniques.
If desired, the isolated compound of formula 1 may be further purified by
recrystallization from a suitable organic solvent or a solvent mixture. For example, a
prolic solvents such as methanol, ethanol, isopropanol, and aprotic solvents such as ethyl
acetate, dichloromethane, acetonitrile, or a solvent mixture such as ethyl acetate-ethanol,
aelonhrile-methanol etc.
In another aspect, the present invention provides a process for preparation of the
compound of formula 4 comprising reacting a compound represented by the formula 2
with a compound represented by the formula 3, in presence of a phase transfer catalyst.
The reaction may be preferably earned out in a biphasic system as described earlier in
presence of a suilable organic or inorganic base, at a temperature in the range of 0 to
100°C. preferably at 20-30°C, for a suitable lime, generally for about 2 to about 3 hours.
The amount of the phase transfer catalyst that may be conveniently used is about 0.01 to
0.25 mole equivalent, preferably 0.1 to 0.2 mole equivalent with reference lo compound
of formula 2.
In another aspect, the present invention provides a process for preparation of the
compound of formula 1 by reacting the compound of formula 4 with a permanganate
reagent. The reaction may be preferably carried out in a biphasic system in presence of a
phase transfer catalyst cited above, at a temperature in the range of 0 to 100°C, preferably
at 20-30°C, For a suitable time, generally for about 2 to about 3 hours. The amount of the
phase transfer catalyst that may be conveniently used is about 0.01 to 0.25 mole
10

equivalent, preferably 0.1 lo 0.2 mole equivalent wilh reference to compound of formula
4.
The present invention is illustrated by examples and not to be construed as limiting.
11

EXAMPLES
Example 1: Preparation of hicalutamide from compound of formula 4
A biphasic mixture of compound of formula 4 (250.Og, 0.627mol), potassium
permanganate (253.Og, 1.56mol), ethyl acetate (1500ml), water (2500ml) and
tetrabutylammonium hydrogen sulfate (21.28g, 0.0627mol) was stirred for 2.5 hours at
25-30°C. A solution of sodium metabisulfite (750g) in water (1500ml) was then added,
followed by ethyl acetate (1000ml). The mix lure stirred for ) hour, the insoluble inorganic
material is filtered, and (he upper organic layer containing product was separated. The
organic layer was washed sequentially with 5% HC1 solution and water, concentrated and
degassed under vacuum lo obtain bicalutamide, 270g (100% yield).
Purification: A suspension of bicalutamide (376g) in 2-propanol (3.761it) was heated to
reflux for 2 hours, and then gradually cooled lo ambient temperature. The resultant slurry
was filtered, washed with 2-propanol and dried at about 50°C lo obtain bicalutamide of
HPLC purity 99.79%.
Example 2: Process for one-pot preparation of bicalutamide from compound of
formula 2
A biphasic mixture of compound of formula 2 (lO.Og, 0.037mole), 4-ftuorothiophenol
(4.33ml, 0.041mol), sodium hydroxide (0.74g, O.O18mol), tetrabulylammonium hydrogen
sulfate (l.SSg, 5.5mmol), ethyl acetate (100ml) and water (20ml) was stirred at 25-30°C
for 3 hours. Potassium permanganate (17.54g, 0.11 Imol) and water (80ml) was then
added to the reaction mixture and stirring was continued for further 2.5 hours. A solution
of sodium metabisulfite (45g) in water (90ml) was added to the reaction mixture and
stirred at about 50°C for I hour. The insoluble inorganic material was filtered, and the
upper organic layer containing product was separated. The organic layer was washed
sequentially with 2% HC1 solution and water, concentrated and degassed under vacuum
to obtain bicalutamide, 15.5g (97.3% yield).
12

A suspension of bicalutamide (15.5g) in 2-propanol (100ml) was heated to reflux for 1
hour, and then gradually cooled to ambient temperature. The resultant slurry was filtered,
washed with 2-propanol, and dried at about 50°C to obtain bicalutamide of HPLC purity
99.16%.
13

CLAIMS:
1) A process for preparation of an antiandrogen compound, N-[4-cyano-3-
(trifluoromelhy])phenyl]-3-[(4-fluorophenyl)siiironyl]-2-hydroxy-2-methylpropanamide,
a compound of formula I.

formula 1
comprising:
a) reacting N-[4-cyano-3-(trifluorome(hy!)phenyl]-2-me[hyloxirane-2-carboxamide a
compound of formula 2 with 4-fluorothiophenol, a compound of formula 3, in presence
of a phase transfer catalyst lo form N-(4-cyano-3-(trjfluoromethy])pbeny]]-3-[(4-
fluorophenyl)thio]-2-hydroxy-2-melhyIpropananiide, a compound of fonnula 4,

Formula 4
b) adding a permanganate reagent to the reaction mixture to afford the compound of
fonnula 1.
14

2) The process as claimed in claim 1. wherein the permanganate reagent is an alkali metal
permanganate.
3) The process as claimed in claim 2, wherein the alkali metal permanganate is potassium
permanganate.
4) The process as claimed in claim 1, wherein ihe reaction of compound 2 and compound
3 is carried out in a biphasic system comprising water and organic solvent.
5) A process for preparation of N-[4-cyano-3-(trifluoromethy])phenyl]-3-[(4-
:fluorophenyl)thio]-2-hydroxy-2-methylpropanamide, a compound of formula 4

Formula 4
comprising reacting A'-[4-cyano-3-(trinuoiomethyl)phenyl]-2-methy!oxirane-2-
carboxamide, a compound of formula 2 with 4-fluorothiophenol, a compound of formula



in presence of a phase transfer catalyst.

6) The process as claimed in claim 5, wherein the reaction of compound 2 and compound
3 is earned out in a biphasic system comprising water and organic solvent.
15

7) A process for preparation of an antiandrogen compound, N-[4-cyano-3-
(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide,
a compound of formula 1,

Formula 1
comprising reacting N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluoropheny])thio]-2-
hydroxy-2-methylpropanamide, a compound represented by formula 4,

Formula 4
with a permanganate reagent.
8) The process as claimed in claim 7, wherein the permanganate reagent is an alkali metal
permanganate.
9) The process as claimed in claim 8, wherein the alkali metal permanganate is potassium
permanganate.
16
Dated this 10th day of April, 2006