PROCESS FOR THE PREPARATION OF ENZALUTAMIDE
Field of the Invention
The present invention provides a process for the preparation of enzalutamide.
Background of the Invention
Enzalutamide is chemically described as 4-(3-[4-cyano-3-(trifluoromethyl)phenyl]-5,3-
dimethyl-4-0x0-2-sulfanylideneimidazolidin1-- y l) -2-fluoro-N-methylbenzamide of Formula I.
NHMe
FORMULA I
Processes for the preparation of enzalutamide are described in U.S. Publication Nos.
200710004753 and 200710254933 and PCT Publication Nos. WO 2007/1270 10, WO
200611241 18, and WO 201 l/l06570.
PCT Publication No. WO 201 11106570 discloses that the processes described in U.S.
Publication Nos. 200710004753 and 200710254933 result in a 25% yield of enzalutamide in the
final step, which accounts for a 15% overall yield. PCT Publication No. WO 201 1/106570
further discloses that the known processes for preparing enzalutamide involve the use of
extremely toxic reagents, for example, acetone cyanohydrin. .
Acetone cyanohydrin is toxic and therefore its use as a reagent should be avoided for
industrial production of a pharmaceutical ingredient. Thus, there is a need in the art to develop a
process for the preparation of enzalutamide that avoids the use of acetone cyanohydrin as a
reagent.
Summary of the Invention
The present invention provides a process for the preparation of enzalutamide that does
not involve the use of any toxic reagents and, at' the same time, results in a higher yield of
enzalutamide.
" ,..
. . 3 . Detailed Description of the Invention
. . .. . . I . . . . . . The.ten "about9'.,as used herein, refers to any value which-lies within the range defined
. - by a number up .to *lo% of the value.
A first aspect of the present invention provides a process for the preparation of
enzalutamide of Formula I,
FORMULA I
which comprises:
a) . reacting a compound of Formula I1
FORMULA I1
with a compound of ~orrnulaI1 1
FORMULA I11
to prepare a compound of Formula IV;
F 0
FORMULA IV
b) -reacting the coinpound of Formula IV obtained in step a) with a compound of
Formula V; and
FORMULA V
c) . isolating enzalutamide of Formula I .from the .reaction mixture of step b)
I wherein X is methyl, ethyl, or benzyl.
I A second aspect of the present invention provides a process for the preparation of a
compound of Formula IV,
FORMULA IV
comprising reacting a compound of Formula I1
FORMULA I1
with a compound of Formula 111,
FORMULA I11
wherein X is methyl, ethyl,, or benzyl.
A third aspect of the present invention provides a compound of Formula IV, wherein X
is methyl, ethyl, or benzyl.
FORMULA IV
A fourth aspect of present invention provides the use of a compound of Formula I1 or a
compound of Formula IV for the preparation of enzalutamide.
. ,
I The compound of Formula I1 can be prepared by reducing a compound of Formula VI.
FORMULA VI
The reduction of the compound of Formula VI is performed in the presence of a reducing
agent and a solvent. Examples of reducing agents include hydrogen gas in the presence of
palladiudcarbon, palladium hydroxidelcarbon, or platinum dioxide. Preferably, the reducing
agent is hydrogen gas in the presence of palladiudcarbon. The solvent is selected fro111 the
group comprising alcohols, halogenated hydrocarbons, esters, hydrocarbons, ethers, and
mixtures thereof. Examples of alcohol solvents include methanol, ethanol, and n-butanol. An
example of a halogenated hydrocarbon is dichloromethane. Examples of ether solvents include
tetrahydrofuran and diisopropyl ether. Examples of ester solvents include ethyl acetate, butyl
acetate, and isopropyl acetate. Examples of hydrocarbon solvents include hexane and heptane.
Preferably, the solvent used for the reduction of a compound of Formula VI is methanol.
The compound of Formula VI, which is used for the preparation of the compound of
Formula 11, can be obtained by reacting a compound of Formula VII
FORMULA VII
with methylamine hydrochloride in the presence of a coupling agent and a solvent. Examples of
'. hydrochloride, dicyclohexyl carbodiimide, O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU), - and 0-(benzotriazol- 1-y1)-N,N,N',N1-tetramethyluronium
hexafluorophosphate (HBTU). The preferred coupling agent is hydroxybenzotriazole. The
solvent is selected fiom the group consisting of alcohols, halogenated hydrocarbons, esters,
hydrocarbons, ethers, and mixtures thereof. Examples of alcohol solvents include methanol,
ethanol, and n-butanol. An example of a halogenated hydrocarbon is dichloromethane.
Examples of ether solvents include tetrahydrofuran and diisopropyl ether. Examples of ester
solvents include ethyl acetate, butyl acetate, and isopropyl acetate. Examples of hydrocarbon
solvents include hexane and heptane. The preferred solvent is dichloromethane.
The compound of Formula VII can be prepared by any method known in the art, for
example, PCT Publication Nos. WO 200711270 10 and WO 20061124 1 18.
In an embodiment of the present invention, the reaction of a compound of Formula I1
with a compound of Formula I11 is carried out in the presence of a base and a solvent.
The base can be an organic or an inorganic base. Examples of organic bases include
ethyl amine, diisopropyl amine, diisopropyl ethyl amine, and mixtures thereof. Examples of
inorganic bases include hydroxides, carbonates, and bicarbonates of an alkali or an alkaline
metal, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Preferably, the base is
diisopropyl ethyl amine.
The solvent used during the reaction of a compound of Formula I1 with a compound of
Formula I11 is selected from the group comprising water, ethers, esters, alcohols, hydrocarbons,
halogenated hydrocarbons, and mixtures thereof. Examples of ether solvents include
tetrahydrofuran and diisopropyl ether. Examples of ester solvents include ethyl acetate, butyl
acetate, and isopropyl acetate. Examples of alcohol solvents include methanol, ethanol, and nbutanol.
Examples of hydrocarbon solvents include hexane and heptane. An example of a
halogenated hydrocarbon is dichloromethane. Preferably, the solvents used are tetrahydrofuran,
ethyl acetate, water, or mixtures thereof.
In'another embodiment of the present invention, the reaction of a compound of Formula
I1 with a compound of Formula I11 is carried out in the presence of a p.h ase. transfer catalyst.
Examples of phase transfer catalysts include . tetrabutylammonium iodide,
tetrabutylammonium bromide, tetrabutylammonium fluoride, and mixtures thereof. Preferably,
the phase transfer catalyst used is tetrabutylammonium iodide.
The reaction of a compound of Formula I1 with a.compound of Formula 111 is carried out
for about 10 hours to about 18 hours, for example, from about 12 hours to about 14 hours. -
In another embodiment of the present invention, the reaction of a compound of Formula
I1 with a compound of Formula I11 is carried out at a .temperature of about 10°C to about 100°C,
for example, about 20°C to about 80°C.
The compound of Formula IV, obtained by the reaction of a compound of Formula I1
with a compound of Formula 111, may optionally be isolated by employing one or more
techniques selected from the group consisting of filtration, decantation, extraction, distillation,
evaporation, chromatography, precipitation, centrifugation, and recrystallization.
The compound of Formula V can be prepared by reacting a compound of Formula VIII
with thiophosgene.
FORMULA VIII
The compound of Formula VIII can be prepared by the methods known in the art, for
example, PCT Publication Nos. WO 200711270 1.0 .and WO 20061124 1 18.
In another embodiment of the present invention, the reaction of a compound of Formula
IV with a compound of Formula V is carried out in the presence of a solvent.
The solvent used during the reaction of a compound of Formula IV with a compound of
Formula V is selected fiom the group consisting of water, dimethyl sulfoxide, esters, ethers,
alcohols, hydrocarbons, halogenated hydrocarbons, or mixtures thereof. Examples of ester
solvents include ethyl acetate, butyl acetate, and isopropyl acetate. Examples of alcohol solvents
include methanol, ethanol, and n-butanol. Examples of hydrocarbon solvents include hexane
and heptane. Examples of ether solvents include tetrahydrofuran and diisopropyl ether. An
example of a halogenated hydrocarbon is dichloromethane. Preferably, a mixture-of dimethyl
sulfoxide, isopropyl acetate, methanol, and water is used as a solvent.
The reaction of a compound of Formula IV with a compound of Formula V is carried out
for. about 10 hours to .about 1 8 hours, for example, fiom about 12 hours to about 14 hours.
In another embodiment of the present invention, the reaction of a compound of Formula
IV with the compound of Formula V is carried out at a temperature of about 10°C to about
100°C, for example, about 20°C to about 80°C.
In another embodiment of the present invention, the compound of Formula I obtained by
the reaction of a compound of Formula IV with a compound of Formula V is isolated by
employing one or more techniques selected from the group consisting of filtration, decantation,
extraction, 'distillation, evaporation, chromatography, precipitation, centrifugation, and
recrystallization.
Methods:
The IR spectrum was recorded using a ~ e r k i n ~ l mSepre~ct rum One FT-IR spectrometer.
The Mass spectrum was recorded using an API 2000 LC/MS/MS system.
The NMR spectrum was recorded using a ~ r u k eArv~a nce I11 400 MHz NMR
spectrometer.
While the present invention has been described in terms of its specific embodiments,
certain modifications and equivalents will be apparent to those skilled in the art and are intended
to be included within the scope of the present invention.
EXAMPLES
Example 1 : Process for the preparation of 2-flouro-4-nitro benzoic acid ormu mu la VII)
Method 1 :
2-Flouro-4-nitro toluene (20 g) and sodium bromide (26.6 g) were added to de-ionized
water (600 mL). Concentrated sulfuric acid (14 mL) was added to the reaction mixture and it
was heated to 80°C to 85°C. A solution of potassium bromate (21.6 g) in de-ionized water (400
mL) was added to the reaction mixture over 3 hours. The reaction mixture was stirred for 24
hours and cooled to 20°C to 25°C. Ethyl acetate (300 mL) was added to the reaction mixture
and it was stirred for 15 minutes. The layers obtained were separated. ' A solution of sodium
hydroxide (10 g) in de-ionized water (300 mL) was added to the organic layer and it was stirred
/
for 30 minutes. The layers obtained were separated and the aqueous layer was further washed
with ethyl acetate (300 mL) to remove any undesired organic impurities. The aqueous layer was
hrther acidified with concentrated hydrochloric acid (-26 mL). Ethyl acetate (300 mL) was
. . added to the aqueous layer. The ethyl acetate layer obtained was concentrated to obtain the title
compound.
Yield: 15.4 g.
Method 2:
2-Flouro-4-nitro toluene (20.g) was added to de-ionized water (600 mL) and heated to
50°C. Potassium permanganate (62 g) was added to the reaction mixture at 80°C to 90°C over 3
hours. The reaction mixture was stirred at 80°C to 90°C for 7 hours to 10 hour's. The mixture
was cooled to 20°C to 25OC, filtered through celite, and washed with de-ionized water (600 mL)
and ethyl acetate (600 mL)'. The reaction.mixture was stirred for 30 minutes and the layers
obtained were separated. The ethyl acetate layer was acidified using concentrated hydrochloric
acid to bring the pH to 1-2, then stirred for 10 minutes. The layers obtained were separated and
dichloromethane (400 mL) was added to the aqueous layer over 30 minutes. The layers
obtained were further separated. The ethyl acetate and dichloromethane layers obtained were
combined and concentrated to obtain the title compound.
Yield: 7.2 g.
Example 2: Process for the preparation of N-methvl2-flouro-4-nitro benzamide (Formula VI)
from 2-flouro-4-nitro benzoic acid (Formula VII)
2-Flouro-4-nitro benzoic acid (Formula VII; 13 g) was added to dichloromethane (130
mL) and cooled to OPC to . 5OC. A solution of methyl amine hydrochloride (9.48 g),
hydroxybenzotriazole (9.49 g), and carbodiimide hydrochloride (17.5 g) in triethyl amine (34.3
mL) was added to the reaction mixture at O°C to 5OC over 30 minutes. The reaction mixture was
heated to 20°C to 25OC and stirred for 5 hours. De-ionized water (65 mL) was added to the
reaction mixture. The layers obtained were separated and dichloromethane (65 mL) was added
to the aqueous layer. Both of the organic layers were collected, combined, and washed with 1M
hydrochloric acid.solution (40 mL) for 10 minutes. The layers obtained were separated and the
organic layer, was washed with 5% (wlv) aqueous sodium bicarbonate solution for 15 minutes.
The layers obtained were separated and the organic layer was further dried over sodium
sulphate. The organic layer was filtered through a cogon plug and washed with
dichloromethane (26 mL). The solution obtained was concentrated under reduced pressure to
obtain the title compound.
Yield: 13.8 g.
Example 3 : Process for the preparation' of N-methvl2-flouro 4-amino benzamide (Formula 11)
, fi0m.N-methyl2-flouro 4-nitro benzamide -(Formula VI)
N-Methyl 2-flouro-4-nitro benzamide (Formula VI; 13 g) was added to methanol (260
mL) followed by the addition of 10% (wlw) palladiumlcarbon (1.3 g) at 27OC and hydrogen gas
at 2 ~ ~ / c mto *2. 5 ICg/cm2 pressure for 2 hours to 4 hours. The reaction mixture was filtered
through celite and washed with methanol (40 mi). The solution obtained was concentrated
under reduced pressure at 30°C to 35°C for 1 hour to 2 hours to obtain the title compound.
Yield: 10.5 g.
Exam~le4 : Process for the preparation of ethyl N-.[3-fluoro-4-(methylcarbamo~1)phenyll-2-
methylalaninate (Formula IV) from N-methyl2-flouro 4-amino benzamide (Formula 11):
I N-Methyl 2-flouro-4-amino benzamide (Formula 11; 2 g) was added to ethyl 2-bromo
I isobutyrate (Formula 111; 4 mL) and tetrahydrofuran (4 mL), followed by the addition of
diisopropylethyl amine (2 mL) and tetrabutyl ammonium iodide (4 g). The reaction mixture was
heated to 80°C to 85°C and a mixture of ethyl 2-bromo isobutyrate (2 mL) and diisopropyl ethyl
amine (2 mL x 4) was added to the reaction mixture over 8 hours. The reaction mixture was
cooled to 20°C to 25°C followed by the addition of ethyl acetate (100 mL) and de-ionized water
(100 mL). The reaction mixture was stirred for 30 minutes and the layers obtained were
separated. The organic layer was separated and concentrated to obtain a residue which was
hrther purified using silica gel column to obtain the title compound.
Yield: '1.5 g.
'H NMR (400 MHz, CDC13), 6 (in ppm): 7.9(t, j=9.04 Hz, lH), 6.39(dd, j=2.32 Hz; 8.72 Hz,
lH), 6.2(dd, j=2.36 Hz; 15.16 Hz, lH), 4.19(q, j=7.12 Hz, 2H), 2.99(d, 3H), 1.55(6H, s), 1.2(t,
j=7.12 Hz, 3H).
Mass: [M + H]+=283.5; MSIMS: 283, 251.9, 224.1, 209.2, 178.1, 169.3, 152.1, 138, 112.1,
87.1,58.1:
IR in KBr, (in cm-'): 3348,2980,2936, 1730, 1G24, 1607, 1551, 1517, 1407, 1384, 1343, 1315,
1299, 1268, 1223, 1179, 1146, 1108, 1019, 852, 832, 772, 755, 646, 619, '568, 527, 554, 466,
433.
Example 5: Process for the preparation of 4-isothiocyanato 2-(triflouromethvl) benzonitrile
- JFormula V) from 4-amino 2-(triflouromethvl) benzonitrile (Formula VIII)
4-Amino-2-(triflouromethy1)-benzonitrile (Formula VIII; 20 g) was added to de-ionized
water (1 00 mL)' under stirring followed by the addition of thiophosgene (1 0 mL). The reaction
mixture was stirred for 3 hours. Hexane (200 mL) was added to the reaction mixture and it was
stirred for 30 minutes. The organic layer was concentrated to obtain the title compound.
Yield: 16.2 g.
Example 6: Process for the meparation of Enzalutamide (Formula I)
Ethyl N - [ 3 - f l u o r o - 4 - ( m e t h y l c a r b a m o y 1 ) - p h e n y l l - 2 (Formula IV; 0.2 g)
and 4-isothiocyanato 2-(triflouromethy1)-benzonitrile (Formula V; 0.33 g) were added to
dimethyl sulfoxide (0.2 m ~an)d isopropyl acetate (0.4 mL) and heated to 90°C to 95OC. The
reaction mixture was cooled to 70°C followed by the addition of methanol (0.4 mL). The
reaction mixture was stirred for 2 hours. Isopropyl acetate (4 mL) was added to the reaction
mixture followed by washing with water (4 mL). The organic layer was concentrated at 3'5OC
under vacuum to obtain an oily residue which was further purified using silica gel column to
obtain the title compound.
Yield: 0.2 g

claim
1. A process for the preparation of enzalutamide of Formula I,
FORMULA I
which comprises:
a) reacting a compound of Formula I1
. .
FORMULA I1
with a compound of Formula I11
FORMULA I11
to prepare a compound of Formula IV;
FORMULA IV
b) reacting the compound of Formula IV-obtained in step a) with a compound of
FORMULA V
c) isolating enzalutamide of Formula I from the reaction mixture of step b)
wherein X is methyl, ethyl, or benzyl.
A process for the preparation of a compound of Formula IV,
F 0
FORMULA IV
comprising reacting a compound of Formula 11
FORMULA I1
with a compound of Formula 111,
wherein X is methyl, ethyl, or benzyl.
I ..-
': 3:. ': ~,A.c,ompounodf Formula IV, wherein X is methyl, ethyl, or benzyl group.
FORMULA IV
4. The process according to claim 1 or claim 2, wherein the reaction of the compound of
Formula I1 with the.compound of Formula I11 is carried out in the presence of a base and
a solvent.
" '5. The process according to claim 4, wherein the base is an organic or an inorganic base.
6. The process according to claim 4, wherein the solvent is selected from the group
consisting of water, ethers, esters, alcohols, hydrocarbons, halogenated hydrocarbons,
and mixtures thereof.
7. The process according to claims 1 or 2, wherein the reaction of the compound of
Formula I1 with the compound of Formula I11 is carried out in the presence of a phase
transfer catalyst..
8. The process according to claim 1, wherein the reaction of the compound of Formula IV
. with the compound of Formula V is carried out in the presence of a solvent.
9. The process according to claim 8, wherein the solvent is selected from the group
consisting of water, dimethyl sulfoxide, esters, ethers, alcohols, hydrocarbons, '
halogenated hydrocarbons, or mixtures thereof.
10. Use of a compound of Formula I1 or a compound of Formula IV for the preparation of
enzalutamide.