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]-535-
dimethyl-4-oxo-2-sulfanylideneimidazolidin-^^
CH3
FORMULA I
Processes for the preparation of enzalutamide are described in U.S. Publication Nos.
2007/0004753 and 2007/0254933; and PCT Publication Nos. WO 2007/127010, WO 2006/124118,
and WO 2011/106570.
PCT Publication No. WO 2011/106570 discloses that the processes described in U.S.
Publication Nos. 2007/0004753 and 2007/0254933 result in a 25% yield of enzalutamide in the
final step, which accounts for a 15% overall yield. PCT Publication No. WO 2011/106570 further
discloses that the known processes for preparing enzalutamide involve the use of extremely toxic
reagents, for example, acetone cyanohydrin.
Therefore, 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 results in a higher yield of enzalutamide.
DELHI 2 9 - 0 - 8 - 2 . 0 1 6 I B ' - 41
Detailed Description of the Invention
The term "about," as used herein, refers to any value which lies within the range defined by
a number up to ± 10% of the value.
A first aspect of the present invention provides a process for the preparation of
enzalutamide of Formula I
F,C
NHMe
which comprises:
FORMULA I
a) reacting a compound of Formula II
H,N
NHMe
FORMULA II
with a compound of Formula III
CI CH3
CI—\ i—OH
CI CH3
FORMULA III
in the presence of a compound X-OH, to prepare a compound of Formula IV
NHMe
FORMULA IV
wherein X is methyl, ethyl, isopropyl, -t-butyl, phenyl, or benzyl; and
CD
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Q.
CD
CN
E
o
LL
m
CN
o>
CN o
CO
o
CN
CO
CN
CO
O
CO
CO
o
CN
G)
o>
CN
b) . reacting the compound of Formula IV obtained in step a) with a compound of Formula
V.
F*C
FORMULA V
A second aspect of the present invention provides a process for the preparation of a
compound of Formula IV
NHMe
FORMULA IV
comprising reacting a compound of Formula II
HoN
NHMe
FORMULA II
with a compound of Formula III
CI CH3
CI—\ /—OH
CI CH3
FORMULA III
in the presence of a compound X-OH, wherein X is methyl, ethyl, isopropyl, t-butyl, phenyl, or
benzyl.
The compounds of Formula II and Formula V can be prepared by any of the methods
known in the art, for example, the methods disclosed in PCT Publication Nos. WO 2007/127010,
WO 2006/124118 and WO 2011/106570.
8 • - 2
In one embodiment of the present invention, the reaction of the compound of Formula II
and the-compound of Formula III is carried out in a solvent in the presence of a compound X-OH
and optionally in the presence of a base.
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.
The solvent is selected from the group consisting of water, ethers, esters, 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 hydrocarbon solvents include hexane and heptane. An
example of a halogenated hydrocarbon solvent is dichloromethane.
The compound of Formula X-OH is selected from the group comprising methanol, ethanol,
isopropanol, t-butanol, phenol, or benzyl alcohol.
The reaction of the compound of Formula II with the compound of Formula III is carried
out for about 1 hour to about 18 hours, for example, for about 1 hour to about 14 hours.
The reaction of the compound of Formula II with the compound of Formula III is carried
out at a temperature of about -20°C to about 50°C, for example, at about 0°C to about 30°C.
The compound of Formula IV may optionally be isolated by employing one or more
techniques selected from the group consisting of filtration, decantation, extraction, distillation,
evaporation, chromatography, precipitation, centrifugation, concentration, and recrystallization.
In another embodiment of the present invention, the reaction of the compound of Formula
IV with the compound of Formula V is carried out in a solvent. The solvent can be selected from
the group consisting of water, dimethyl sulfoxide, esters, alcohols, hydrocarbons, halogenated
hydrocarbons, and 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. An example of a halogenated
hydrocarbon solvent is dichloromethane.
The reaction of the compound of Formula IV with the compound of Formula V is carried
out for about 2 hours to about 18 hours, for example, for about 4 hours to about 14 hours.
DE LB J . 2 9 - 0 8 - 2 0 1 6 16 : 4A.
The reaction of the compound of Formula IV with the compound of Formula V is carried
out at a temperature of about 10°C to about 100°C,4br example, at about 20°C to about 95°C;
The-enzalutamide compound of Formula 1 can be isolated by employing one or more
techniques selected from the group consisting of filtration, decantation, extraction, distillation,
evaporation, chromatography, precipitation, centrifiigation, concentration, and recrystallization.
A third aspect of the present invention provides a process for the preparation of
enzalutamide of Formula I
F,c
NHMe
FORMULA I
which comprises:
a) reacting a compound of Formula II
HoN
NHMe
FORMULA II
with chloroform, acetone, and a compound X-OH to prepare a compound of Formula
IV,
NHMe
FORMULA IV
wherein X is methyl, ethyl, isopropyl, t-butyl, phenyl, or benzyl; and
b) reacting the compound of Formula IV obtained in step a) with a compound of Formula
V.
- 2
F*C
FORMULA V
A fourth aspect of the present invention provides a process for the preparation of a
compound of Formula IV
NHMe
FORMULA IV
comprising reacting a compound of Formula II
NHMe
><^ J
H2N
FORMULA II
with chloroform, acetone, and a compound X-OH to prepare a compound of Formula IV, wherein
X is methyl, ethyl, isopropyl, t-butyl, phenyl, or benzyLgroup.
In an embodiment of the present invention, the compound of Formula II is reacted with
chloroform, acetone, and a compound X-OH in a solvent and optionally in the presence of a base.
The base is selected from organic or inorganic bases. 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.
The solvent used for the reaction of a compound of Formula II with chloroform and acetone
is selected from the group consisting of 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 hydrocarbon solvents include hexane and heptane. An example of a
halogenated hydrocarbon solvent is dichloromethane.
The compound of Formula X-OH is selected from the group comprising methanol, ethanol,
isopropanol, t-butanol, phenol, or benzyl alcohol.
In. another embodiment of the present invention, the reaction of a compound of Formula II
with chloroform and acetone is carried out in the presence of a phase transfer catalyst.
Examples of phase transfer catalysts include tetrabutylammonium iodide,
tetrabutylammonium bromide, tetrabutylammonium fluoride, or mixtures thereof.
The reaction of the compound of Formula II with chloroform and acetone is carried out for
about 48 hours to about 70 hours, for example, for about 48 hours to about 65 hours.
The reaction of the compound of Formula II with chloroform and acetone is carried out at a
temperature of about -20°C to about 50°C, for example, at about 0°C to about 30°C.
The compound of Formula IV may optionally be isolated by employing one or more
techniques selected from the group consisting of filtration, decantation, extraction, distillation,
evaporation, chromatography, precipitation, centrifugation, concentration, and recrystallization.
The reaction of the compound of FormulaTV with the compound of Formula V may be
carried out as described above in earlier aspects of the present invention.
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 Ethyl iV-r3-fluoro-4-(methylcarbamoyOphenyl1-2-
methylalaninate (Formula IV, when X = ethyl) from 1J J-trichloro-2-methylpropan-2-ol (Formula
III}
l,l,l-Trichloro-2-methylpropan-2-ol (100 g, Formula III) was added to dichloromethane
(120 mL) and the reaction mixture was cooled to 0°C to 5°C. Sodium hydroxide (50 g) was added
to the reaction mixture and the mixture was stirred for 30 minutes. JV-Methyl 2-flouro-4-amino
benzamide (10 g) and ethanol (30 mL),were added to the reaction mixture at 0°C to 5°C over 1
minute. The reaction mixture was stirred at 0°C to 5°C for 60 minutes. The reaction mixture was
heated at 20°C to 25°C for 2 hours to 3 hours. Water (100 mL) and dichloromethane (100 mL)
were added to the reaction mixture and the mixture was stirred for 15 minutes. The layers obtained
were separated, and then the organic layer was concentrated at 45 °C to 50°C over 1 hour to 2 hours
to obtain the title compound.
Yield: 12 g.
Example 2: Process for the preparation of Ethyl AM3-fluoro-4-fmethylcarbamoyl)phenyl]-2-
methylalaninate (Formula IV, when X = ethyl)
TV-Methyl 2-flouro-4-amino benzamide (0.3 g), chloroform (0.3 mL), acetone (2 mL), and
tetrabutylammonium iodide (0.001 g) were added to dichloromethane (4 mL) and ethanol (0.4 mL).
The reaction mixture was cooled to 0°C to 5°C and a solution of sodium hydroxide (0.36 g) in
water (0.7 mL) was added to the reaction mixture. The reaction mixture was stirred at 0°C to 5°C
for 48 hours. A mixture of water (10 mL) and dichloromethane (10 mL) was added to the reaction
mixture and the mixture was stirred for 15 minutes. The layers obtained were separated, and then
the organic layer was concentrated to obtain the residue. The residue obtained was purified using a
silica gel column to obtain the title compound.
Yield: 0.15 g.
Example 3: Process for the preparation of Enzalutamide (Formula I)
Ethyl 7V-(3-fluoro-4-(methylcarbamoyl)-phenyl]-2-methylalaninate (0.2 g, Formula IV,
when X = ethyl) and 4-isothi6cyanato-2-(triflouromethyl)-benzonitrile (0.33 g, Formula V) were
added to dimethyl sulfoxide (0.2 mL) and isopropyl acetate (0.4 mL) and the mixture was heated to
90°C to 95°C. 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, and the mixture was washed with water {4 mL). The layers obtained were
separated, and the organic layer was concentrated at 35°C under vacuum to obtain an oily residue.
The oily residue obtained was purified using a silica gel column to obtain the title compound.
Yield:.0.2 g

WE CLAIM:
1. A process for the preparation of enzalutamide of Formula I
F,C
NHMe
which comprises:
FORMULA I
a) reacting a compound of Formula II
H,N
NHMe
FORMULA II
with a compound of Formula III
CI CH3
CI—J 1—OH
CI CH3
FORMULA III
in the presence of a compound X-OH, to prepare a compound of Formula IV
NHMe
FORMULA IV
wherein X is methyl, ethyl, isopropyl, t-butyl, phenyl, or benzyl; and
b) reacting the compound of Formula IV obtained in step a) with a compound of Formula
. V.
X Z 9 - G 8 - 2 G 1 6 1 6 : 4 1.
F,C
FORMULA V
2. A process for the preparation of a compound of Formula IV
NHMe
FORMULA IV
wherein X is methyl, ethyl, isopropyl, t-butyl, phenyl, or benzyl group
comprising reacting a compound of Formula II
H,N
NHMe
FORMULA II
with a compound of Formula III
CI CH3
CI—j /—OH
CI CH3
FORMULA III
in the presence of X-OH, wherein X is methyl, ethyl, isopropyl, t-butyl, phenyl, or benzyl.
3. The process according to claim 1 or claim 2, wherein the reaction of the compound of
Formula II with the compound of Formula III is carried out in a solvent.
4. The process according to claim 1 or claim 2, wherein the reaction of the compound of
Formula II with the compound of Formula III is carried out in the presence of a base.
5. A process for the preparation of enzalutamide of Formula I
L H I . 2 8- - 2
F,C
NHMe
FORMULA I
which comprises:
a) reacting a compound of Formula II
H,N
NHMe
FORMULA II
with chloroform, acetone, and X-OH to prepare a compound of Formula IV
NHMe
FORMULAIV
wherein X is methyl, ethyl, isopropyl, t-butyl, phenyl or benzyl; and
b) reacting the compound of Formula IV obtained in step a) with a compound of Formula
V.
F,C
FORMULA V
6. A process for the preparation of a compound of Formula IV
9 8 -
NHMe
FORMULA IV
wherein X is methyl, ethyl, isopropyl, t-butyl, phenyl or benzyl
comprising reacting a compound of Formula II
HoN
NHMe
FORMULA II
with chloroform, acetone, and a compound X-OH to prepare the compound of Formula IV, wherein
X is methyl, ethyl, isopropyl, t-butyl, phenyl, or benzyl.
7. The process according to claim 5 or claim 6, wherein the compound of Formula II is reacted
with chloroform, acetone, and the compound X-OH in a solvent.
8. The process according to claim 5 or claim 6, wherein the compound of Formula II is reacted
with chloroform, acetone, and the compound X-OH in the presence of a base.
9. The process according to claim 5 or claim 6, wherein the reaction of the compound of
Formula II with chloroform and acetone is carried out in the presence of a phase transfer catalyst.
10. The process according to claim 1 or claim 5, wherein the reaction of the compound of
Formula IV with the compound of Formula V is carried out in a solvent.