DESC:The following specification particularly describes the invention and the manner in
which it is to be performed.
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CROSS-REFERENCES TO RELATED APPLICATIONS
The present application claims benefit of Indian provisional patent application No.
201941033825 filed on 22 Aug 2019 and 202041004075 filed on 30 Jan 2020 which
are hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
Aspect of the present application relates to process for the preparation of
crystalline form of Apalutamide and process for the preparation of Apalutamide in
the presence of neutralizing agent.
BACKGROUND OF THE INVENTION AND DISCLOSURE OF PRIOR ART
The drug compound having the adopted name “Apalutamide” has chemical name:
4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro
[3.4]octan-5-yl)-2-fluoro-N-methylbenza-mide, has the following chemical
structure:
Apalutamide is approved in US as ERLEADA tablet for oral administration for the
treatment of patients with non-metastatic castration-resistant prostate cancer
(NM-CRPC). ERLEADA is available as 60 mg tablet and recommended daily dose
of 240 mg.
US8445507B2 discloses apalutamide, method for treating prostate cancer using
apalutamide and its pharmaceutical composition.
US8445507B2 discloses process for the preparation of apalutamide by reacting 5-
isothiocyanato-3-(trifluoromethyl)picolinonitrile with 4-(1-cyanocyclobutylamino)-2-
fluoro-N-methylbenzamide in microwave. The synthetic approach is very limited
for industrial application because microwave is not easy to apply in large scale
synthesis and results in higher costs. The synthetic approach is described below.
US9481663B2 discloses crystalline Form B of apalutamide and process for the
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preparation of crystalline Form B of apalutamide using water, ethyl acetate, tertbutyl
methyl ether (TBME), toluene, isopropylacetate, or methyl ethyl ketone
(MEK) as solvents.
WO2013184681A1 discloses crystalline Form A, Form B, Form C, Form D, Form
E, Form F, Form G, Form H, Form I and Form J of apalutamide.
WO2016124149A1 discloses crystalline Form I and Form II of apalutamide.
WO2018112001A1 discloses crystalline Form T2, Form T6, Form T11 and Form
T13 of apalutamide.
WO2019135254A1 discloses crystalline Form M4, Form M5, Form M6 of
apalutamide.
Comprehensive systematic polymorph screening in drug development and the
selection of the most suitable crystal form are one of the important research
contents that cannot be ignored. Identifying more cost effective and industrially
viable process of stable crystalline form of apalutamide also cannot be ignored.
Although approaches for preparing apalutamide have been disclosed as
discussed above, there is still an unmet need for a more environment friendly,
industrially practical, and economical process for preparation of apalutamide. The
present process disclosed herein address this need and other needs.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation
of apalutamide, the process comprising reacting formula III with formula IV in the
presence of neutralizing agent followed by treating with acid to obtain
Apalutamide. The synthetic approach is described below.
In second embodiment, the present invention provides a process for the
preparation of crystalline form of apalutamide characterized by a PXRD pattern
comprising peaks at about 12.1°, 16.0°, 16.7°,20.1°20.3°±0.1° 2?, comprising the
steps of:
a) providing apalutamide in solvent selected from n-butanol, methanol,
diisopropyl ether, isobutyl acetate, n-pentanol, methyl tert-butyl ether or mixture
4
thereof; and
b) isolating crystalline form of apalutamide.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous form of
apalutamide prepared by the method of example No 4.
Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline form of
apalutamide prepared by the method of example No 5.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation
of apalutamide, the process comprising reacting formula III with formula IV in the
presence of neutralizing agent followed by treating with acid to obtain
Apalutamide. The synthetic approach is described below.
In an aspect of the present invention, the condensation process can be carried
out in the presence of any suitable neutralizing agent including but not limited to:
triethylsilyl chloride, trimethylsilyl chloride zinc chloride, aluminium chloride, iron
chloride, borontriflouride etherate (BF3.OEt2), titanium isopropoxide, sodium
chloride, acetic acid or ammonium chloride or mixture thereof.
In an aspect of the present invention, the condensation process can be carried
out in any suitable solvent including but not limited to: toluene, N,N-dimethyl
acetamide(DMA), acetonitrile, ethyl acetate, dimethylformamide(DMF), dimethyl
sulfoxide(DMSO), 2-methyl tetrahydrofuran, Isopropyl acetate,
tetrahydrofuran(THF), chlorobenzene or mixture thereof.
In an aspect of the present invention, the condensation process can be carried
out in the presence of any suitable acids including but not limited to: hydrochloric
acid (HCl), hydrofluoric acid (HF), hydrobromic acid (HBr), hydroiodic acid
(HI),sulfuric acid (H2SO4), nitric acid (HNO3), phosphoric acid (H3PO4) or
mixture thereof.
In an aspect of the present invention, the condensation process can be carried
out at a temperature ranging from about 0°C to about 120°C. Preferably the
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condensation reaction is carried out at a temperature ranging from about 20°C to
about 70°C. The time required for the reaction may also vary widely, depending
on many factors, notably the reaction temperature and the nature of the reagents
and solvent employed. However, provided that the reaction is effected under the
conditions out lined above, a period of from about 10 minutes to about 48 hours
or longer.
During the condensation of Formula III with Formula IV, imine anion is generated
as an intermediate. This anion reacts with the 2nd molecule of Formula IV to
stabilize. This has the disadvantage of using up to 3 equivalents of Formula IV as
part of the process. During the process development it was unexpectedly
discovered that neutralizing agent is useful for reducing the equivalents of
Formula IV from 3 to 1.7
A specific process for the preparation of apalutamide by a method of present
application can be illustrated as given in below Schemes 1,2 and 3.
Scheme-1
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Scheme-2
Scheme-3
The starting materials (Formula II, III and IV) of apalutamide can be prepared by
any known method or by the process that is illustrated as given below in
schemes:
Synthetic scheme of Formula II
7
Synthetic scheme of Formula III
Synthetic scheme of Formula IV
Synthetic scheme of Formula IV
8
In an aspect, apalutamide may be prepared with or without isolation of
intermediates.
In second embodiment, the present invention provides process for the preparation
of crystalline form of apalutamide characterized by a PXRD pattern comprising
peaks at about 12.1°, 16.0°, 16.7°,20.1°20.3°±0.1° 2?, comprising the steps of:
a) providing apalutamide in solvent selected from n-butanol, methanol,
diisopropyl ether, isobutyl acetate, n-pentanol, methyl tert-butyl ether or mixture
thereof; and
b) isolating crystalline form of apalutamide.
In an aspect of the present invention, step a) may be carried out by dissolving
apalutamide in solvent or by taking the reaction mixture containing apalutamide
directly.
In an aspect of the present invention, a solution of apalutamide can be prepared
at any suitable temperatures, such as about 10°C to about the reflux temperature
of the solvent used. Stirring and heating may be used to reduce the time required
for the dissolution process.
In an aspect of the present invention, a solution of apalutamide may be filtered to
make it clear, free of unwanted particles.
In an aspect of the present invention, the obtained solution may be optionally
treated with an adsorbent material, such as carbon and/or hydrose, to remove
colored components, etc., before filtration.
In an aspect of the present invention, the seed crystals of apalutamide is optionally
added to the mixture of apalutamide and suitable solvent. When the seed crystals
are added, they are added in a quantity from about 0.1% w/w to about 50% w/w
over the weight of free base. Specifically, the seed crystals are added in a
quantity from about 0.5% to about 20% w/w and more specifically the seed
crystals are added in a quantity from about 1% to about 10% w/w.
In an aspect of the present invention, the solution of apalutamide may be cooled to
a suitable temperature before and / or after contacting with seed crystals.
In an aspect of the present invention, a solution of apalutamide may be
optionally contacted with an anti-solvent. Anti-solvent may include, but not
limited to n-hexane, n-heptane, cyclohexane, water or mixtures thereof.
In an aspect of the present invention, the anti-solvent may be contacted at
suitable temperature for the nucleation of solids and for sufficient time for
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the formation of solids. The anti-solvent may be contacted in sufficient quantity
to complete the formation of solids.
In an aspect of the present invention, the solution of aplutamide may be cooled to a
suitable temperature before and / or after contacting with anti-solvent.
In an aspect of the present invention, isolation of crystalline form of apalutamide
may be carried out by any methods known in the art or procedures described
in the present application. In an aspect of the present invention, crystalline Form
of apalutamide may be isolated by employing any of the techniques, but not
limited to: decantation, filtration by gravity or suction, centrifugation, adding
solvent to make slurry followed by filtration, or other techniques specific to the
equipment used and the like, and optionally washing with a solvent.
In an aspect of the present invention, drying crystalline Form of apalutamide may
be carried out at temperatures and times sufficient to achieve desired quality
of product. Drying may be carried out for any time period required for obtaining
a desired quality, such as from about 5 minutes to 10 hours or longer.
Starting materials used for the preparation of crystalline form of apalutamide may
be any crystalline or amorphous in nature. Further, these starting material may be
purified according to any of the method known in the art such as recrystallization,
slurrying, acid-base treatment i.e., salt making and breaking, chromatography,
fractional distillation or any other separation methods, before using. Apalutamide
that may be used as the input for the process of the present invention may be
obtained by the processes described in the art. For example apalutamide may be
prepared by the processes described in US8445507B2, US8987452B2 or
IN201941033825.
In another aspect, the present application provides crystalline form of
apalutamide having chemical purity may be more than 99% by HPLC or more
than 99.5% by HPLC or more than 99.9% by HPLC.
In another aspect, the present application provides crystalline form of
apalutamide having particle size (D90) may be less than 100 microns or less than
50 microns or less than 20 microns.
Certain specific aspects and embodiments of the present application will be
explained in greater detail with reference to the following examples, which are
provided only for purposes of illustration and should not be construed as limiting the
scope of the application in any manner. Variations of the described procedures, as
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will be apparent to those skilled in the art, are intended to be within the scope of the
present application.
Potential Impurities possible in apalutamide are described in the present
application and can have structures as illustrated below.
4-Amino-2-fluoro-N-methylbenzamide
4-((1-cyanocyclobutyl)amino)-2-fluoro-N-methylbenzamide
5-amino-3-(trifluoromethyl)picolinonitrile
4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-6,8-dithioxo-5,7-diazaspiro[3.4]octan-5-
yl)-2-fluoro-N-methylbenzamide
4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)-
2-fluoro-N-methylbenzamide
4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-
5-yl)-2-fluorobenzoic acid
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The possible impurities mentioned above are found to be less than 0.15% in
the apalutamide produced according to the process of the present application.
Apalutamide and its impurities can be analyzed using high performance liquid
chromatography (HPLC), such as with a liquid chromatograph equipped with variable
wavelength UV-detector and the method described below:
Column YMC Triart C18 150mm X 4.6mm, 3.0µm
Flow 0.9 mL/min
Load 10 µL
Column oven temp 45 °C
Detection 273 nm
Diluent Acetonitrile : Water 800 : 200 v/v
Elution Gradient
Sample concentration 0.5 mg/mL
Run time 70 min
Sample rack temperature 10 °C
Needle wash solution Diluent
Preparation of Mobile phase-A:
Water (900mL), Acetonitrile (100mL) and ortho-phosphoric acid (250µL) were mixed
and filtered through 0.45µ membrane filter.
Preparation of Mobile phase-B:
Acetonitrile (900mL) and water (100mL) were mixed and filtered through 0.45µ
membrane filter.
Gradient:
Time (min) % M.P-A % M.P-B
0 80 20
5 80 20
40 40 60
50 10 90
60 10 90
62 80 20
70 80 20
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EXAMPLES
Example-1: Preparation of 4-((1-cyanocyclobutyl)amino)-2-fluoro-Nmethylbenzamide.
4-amino-2-fluoro-N-methylbenzamide (20g) and acetonitrile (100mL) were
charged into a round bottom flask at 27oC. The reaction mass was stirred for 5
minutes. Cyclobutanone (9.59g) and zinc chloride (8.1g) were added to the
reaction mass at 27oC. The reaction mass was cooled to 2oC. Trimethylsilane
carbonitrile (TMSCN) (20.6g) was added to the reaction at 2oC. The reaction
mass was stirred for 8hrs at 5oC. The reaction mass was stirred for 3hrs at 26oC.
Water (200mL) was added to the reaction mass and stirred for 1hr. The reaction
mass was filtered and washed with water (40mL). The reaction mass was suck
dried for 10 minutes. Water (200mL) was added to the reaction mass and stirred
for 4hrs. The reaction mass was filtered and washed with water (40mL).The solid
was dried under vacuum at 58°C. Product weight: 24.2g; Yield: 82.31%; Purity by
HPLC: 99.39%
Example-2: Preparation of Apalutamide
4-((1-cyanocyclobutyl)amino)-2-fluoro-N-methylbenzamide (5 g), toluene(50mL),
5-isothiocyanato-3-(trifluoromethyl)picolinonitrile(9.27g), N,N-dimethyl acetamide
(10mL), triethylsilylchloride(9.14g) were charged into a round bottom flask at
25oC. The reaction mass was heated to 60oC. The reaction mass was stirred for
23hrs at 65oC. 2M HCl (15mL) was added to the reaction mass at 25oC. The
reaction mass was heated to 53oC. The reaction mass was stirred for 6hrs at
58oC. The reaction mass was evaporated under vacuum at 58°C. Isopropyl alcohol
(50mL) and apalutamide seed material (0.05g) were added to the reaction mass at
50oC. The reaction mass was stirred for 20 minutes at 50oC. Water (35 mL) was
added to the reaction mass and stirred for 9hrs at 28oC. The reaction mass was
filtered under vacuum and washed with Isopropyl alcohol (50mL). The reaction
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mass was suck dried for 30 minutes. Water (50mL) was added to the reaction mass
and stirred for 3hrs. The reaction mass was filtered and washed with water
(15mL).The solid was dried under vacuum at 65°C. The obtained apalutamide and
isopropyl alcohol (175mL) were charged into a round bottom flask at 25oC. The
reaction mass was heated to 72oC and stirred for 1hr. The reaction mass was
filtered to make it clear and free of unwanted particles. The reaction mass was
stirred for 12hrs at 28oC. The reaction mass was filtered under vacuum and
washed with Isopropyl alcohol (25mL). The reaction mass was suck dried for 30
minutes. The solid was dried under vacuum at 65°C. Product weight: 7.1g; Yield:
73.58%.
Example-3: Preparation for the purification of Apalutamide
Apalutamide (2g) and isopropyl alcohol (40mL) were charged into a round bottom
flask at 25oC. The reaction mass was heated to 75oC and stirred for 30 minutes.
The reaction mass was stirred for 4hrs at 28oC. The reaction mass was filtered
under vacuum and washed with Isopropyl alcohol (4mL). The solid was dried under
vacuum at 65°C. Product weight: 1.8g; Yield: 90%.Purity by HPLC:99.8%
Example-4: Preparation of amorphous form of Apalutamide
Apalutamide (30g) was dissolved in methanol (500 mL) at 52°C. The resulted
solution was filtered under vacuum to make particle free. The clear solution was
subjected to spray drying under nitrogen at a feed rate of 5g/min and feed
solution temperature was 30°C. Nitrogen was used as atomizing gas. Nitrogen
inlet temperature was kept at 85°C and the outlet temperature was kept at 45°C.
Thus obtained product was further dried under VTD at 30°C for 16 hours to obtain
the title compound. Yield: 69.6%.
Example-5: Preparation of crystalline Apalutamide
Crystalline Apalutamide (250g) was dissolved in n-Butanol (2500 ml) at 92°C. The
resulting solution was seeded with crystalline Apalutamide(2.5g). The reaction
mixture was stirred for 6 hours at 28°C. The reaction mixture was cooled to 4°C
and stirred for 3 hours.
The reaction mixture was filtered and washed with n-butanol (500 mL). The solid
was dried under vacuum at 65°C. Purity by HPLC:99.92%; Yield:90%
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Example-6: Preparation of crystalline Apalutamide
n-Butanol (25 ml) was added to crystalline Apalutamide (5g) at 28°C. The resulting
mixture was stirred for 16 hours at 28°C. The reaction mixture was filtered and
washed with n-butanol (10 mL). The solid was dried under vacuum at 60°C. Purity by
HPLC:99.86%; Yield:92%
Example-7: Preparation of crystalline Apalutamide
Apalutamide (5g) was dissolved in methanol (21.25ml) at 53°C. Water (50 mL)
was added to the resulting solution. The reaction mixture was stirred for 24 hours at
53°C. The reaction mixture was cooled to 26°C. The reaction mixture was filtered
and washed with water (12.50 mL). The solid was dried under vacuum at 65°C.
Yield:70%
Example-8: Preparation of crystalline Apalutamide
Crystalline Apalutamide (5g) was dissolved in diisopropyl ether (50ml) at 58°C.
The resulting reaction mixture was cooled to 28°C. The reaction mixture was
filtered. The solid was dried under vacuum at 60°C.
Example-9: Preparation of crystalline Apalutamide
Apalutamide (5g) was dissolved in isobutyl acetate (25ml) at 92°C. The reaction
mixture was cooled to 28°C and stirred for 2 hours. The reaction mixture was
filtered and washed with isobutyl acetate (5ml). The solid was dried under vacuum
at 65°C. Purity by HPLC:99.90%; Yield:70%
Example-10: Preparation of crystalline Apalutamide
Crystalline Apalutamide (5g) was dissolved in n-Butanol (50 ml) at 91°C. The
reaction mixture was cooled to 46°C and stirred for 1 hour. n-Heptane (50 mL)was
added to the reaction mass. The reaction mixture was stirred for 18 hours at 31°C.
The reaction mixture was filtered and washed with n-Heptane (5 mL). The solid was
dried under vacuum at 65°C. Purity by HPLC:99.88%; Yield:91%
Example-11: Preparation of crystalline Apalutamide
Crystalline Apalutamide (5g) was dissolved in n-pentanol (25 ml) at 90°C. The
15
reaction mixture was cooled to 28°C. The reaction mixture was filtered and washed
with n-pentanol (10 mL). The solid was dried under vacuum at 65°C. Purity by
HPLC:99.9%; Yield:80%
Example-:12 Preparation of crystalline Apalutamide
Crystalline Apalutamide (5g) was dissolved in methyl tert-butyl ether (MTBE) (25
ml) at 54°C. The reaction mixture was cooled to 28°C. The reaction mixture was
filtered and washed with MTBE (5 mL). The solid was dried under vacuum at 65°C.
Purity by HPLC:99.83%; Yield:92%
Example-13: Preparation of crystalline Apalutamide
Crystalline Apalutamide (5g) was dissolved in isobutyl acetate (25 ml) at 82°C.
The reaction mixture was cooled to 50°C. n-heptane (50 mL) was added to the
reaction mass at 50°C. The reaction mixture was cooled to 28°C. The reaction
mixture was filtered and washed with n-heptane (5 mL). The solid was dried under
vacuum at 65°C. Purity by HPLC:99.86%; Yield:91% ,CLAIMS:We claim:
1. A process for the preparation of apalutamide, the process comprising reacting formula III with formula IV in the presence of neutralizing agent followed by
treating with acid to obtain Apalutamide.
2. The process of claim 1, wherein neutralizing agent selected from triethylsilylchloride, trimethylsilyl chloride, zinc chloride, aluminium chloride, iron
chloride, sodium chloride, acetic acid, ammonium chloride or mixture thereof.
3. The process of claim 1, wherein acid selected from hydrochloric acid (HCl),hydrofluoric acid (HF), hydrobromic acid (HBr), hydroiodic acid (HI), sulfuric acid
(H2SO4), nitric acid (HNO3), phosphoric acid (H3PO4) or mixture thereof.
4. A process for the preparation of crystalline form of apalutamide characterized by a PXRD pattern comprising peaks at about 12.1°, 16.0°, 16.7°,20.1°20.3°±0.1° 2?,
comprising the steps of:
a) providing apalutamide in solvent selected from n-butanol, methanol,
diisopropyl ether, isobutyl acetate, n-pentanol or mixture thereof;and
b) isolating crystalline form of apalutamide.