Field of the Invention
The present invention relates to a process for the preparation of Fimasartan potassium
trihydrate. The present invention more specifically relates to a process for the preparation of
Fimasartan comprising thioamidation and detritylation of a compound of Formula II in the
presence of a mixture of water and solvent.
Background of the Invention
Fimasartan potassium trihydrate, chemically 2-n-butyl-5-dimethylaminothio
carbonylmethyl-6-methyl-3-[[2’-(1H-tertazol-5-yl)biphenyl-4-yl]methyl]-pyrimidin-4(3H)-
one, represented by Formula I.
N
N
O
H3C
S
N
CH3
H3C
CH3
N
-
N
N N
K
+
. 3H2O
Formula I
Fimasartan is a non-peptide angiotensin II receptor antagonist (ARB) used for the
treatment of hypertension and heart failure.
2-n-Butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-[[2’-(Ntriphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl-pyrimidin-4(3H)-one of Formula II, is one
of the key intermediate used in the preparation of Fimasartan.
N
N
O
H3C
O
N
CH3
H3C
CH3
N N
N N
CPh3
Formula II
3
U.S. Patent No. 6,294,542 discloses a process for the preparation of Fimasartan
comprising thioamidation followed by detritylation of the compound of Formula II using 4M
hydrochloric acid solution.
U.S. Patent No. 7,309,788 discloses a process for the preparation of Fimasartan
comprising thioamidation followed by detritylation of the compound of Formula II using
alcoholic reagent. The present inventors have observed that Fimasartan as per reported
processes has low yield and purity.
Therefore, there is a need for an industrially advantageous process for the preparation
of Fimasartan having high yield and purity.
Summary of the Invention
The present invention relates to a process for the preparation of Fimasartan potassium
trihydrate. The present invention more specifically relates to a process for the preparation of
Fimasartan comprising thioamidation and detritylation of a compound of Formula II in the
presence of a mixture of water and solvent.
The present invention provides an environmentally friendly, cost-effective, and
industrially advantageous process for the preparation of Fimasartan. The present invention
provides Fimasartan having yield above 80% and purity above 95%.
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.
The term “room temperature,” as used herein, refers to a temperature in the range of
about 25°C to about 35°C.
The term “reaction mixture,” as used herein, refers to suspension, solution, emulsion,
or precipitate.
A first aspect of the present invention provides a process for the preparation of
Fimasartan potassium trihydrate of Formula I comprising
4
N
N
O
H3C
S
N
CH3
H3C
CH3
N
-
N
N N
K
+
. 3H2O
Formula I
a) thioamidation of a compound of Formula II
N
N
O
H3C
O
N
CH3
H3C
CH3
N N
N N
CPh3
Formula II
to obtain a compound of Formula III;
N
N
O
H3C
S
N
CH3
H3C
CH3
N N
N N
CPh3
Formula III
b) detritylation of the compound of Formula III in the presence of a mixture of water and
solvent to obtain Fimasartan base; and
c) converting Fimasartan base to Fimasartan potassium trihydrate of Formula I.
A second aspect of the present invention provides a process for the preparation of
Fimasartan potassium trihydrate of Formula I comprising
5
N
N
O
H3C
S
N
CH3
H3C
CH3
N
-
N
N N
K
+
. 3H2O
Formula I
a) detritylation of a compound of Formula III
N
N
O
H3C
S
N
CH3
H3C
CH3
N N
N N
CPh3
Formula III
in the presence of a mixture of water and solvent to obtain Fimasartan base; and
b) converting Fimasartan base to Fimasartan potassium trihydrate of Formula I.
The compound of Formula II used for the preparation of Fimasartan may be prepared
by any method provided in the art, for example, the methods as disclosed in U.S. Patent Nos.
6,294,542 or 7,309,788.
The thioamidation of the compound of Formula II to obtain the compound of Formula
III is carried out using Lawesson’s reagent in a solvent.
Lawesson’s reagent, chemically designated as 2,4-bis(4-methoxyphenyl)-1,3,2,4-
dithiadiphosphetane-2,4-disulfide, represented by Formula IV.
S
S
P P
S
S
O
CH3
O
H3C
Formula IV
6
The solvent used for the thioamidation of the compound of Formula II is selected from
aromatic hydrocarbons, halogenated hydrocarbons, ethers, alcohols, and mixtures thereof.
Examples of aromatic hydrocarbons include benzene, toluene, chlorobenzene, and xylene.
Examples of halogenated hydrocarbons include dichloromethane, dichloroethane, carbon
tetrachloride, and chloroethane. Examples of ethers include tetrahydrofuran, ethyl methyl
ether, diethyl ether, and di-isopropyl ether. Examples of alcohols include methanol, ethanol, npropanol, isopropanol, n-butanol, and tert-butanol.
The thioamidation of the compound of Formula II is carried out for about 10 hours to
about 24 hours. In an embodiment, the thioamidation of the compound of Formula II is carried
out for about 12 hours to about 22 hours. In another embodiment, the thioamidation of the
compound of Formula II is carried out for about 15 hours to about 20 hours. In yet another
embodiment, the thioamidation of the compound of Formula II is carried out for about 17 hours
to about 19 hours.
The thioamidation of the compound of Formula II is carried out at a temperature of
about 60C to about 85C. In an embodiment, the thioamidation of the compound of Formula
II is carried out at a temperature of about 65°C to about 80°C. In another embodiment, the
thioamidation of the compound of Formula II is carried at a temperature of about 68°C to about
78°C. In yet another embodiment, the thioamidation of the compound of Formula II is carried
out at a temperature of about 70°C to about 75°C.
The compound of Formula III may be isolated or used as such without isolation for the
next step.
The compound of Formula III may be isolated by filtration, decantation, extraction,
distillation, evaporation, chromatography, precipitation, concentration, crystallization,
centrifugation, and recrystallization. The compound of Formula III may be dried using
conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying,
air drying, or agitated thin film drying.
The detritylation of the compound of Formula III to obtain Fimasartan base is carried
out in the presence of a mixture of water and solvent.
7
The solvent used for the detritylation of the compound of Formula III is aprotic polar
solvent. The aprotic polar solvent is selected from ethers, ketones, nitriles, and mixtures
thereof. Examples of ethers include tetrahydrofuran, ethyl methyl ether, diethyl ether, and diisopropyl ether. Examples of ketones include acetone, methyl ethyl ketone, methyl isobutyl
ketone, and butanone. An example of nitrile includes acetonitrile.
The detritylation of the compound of Formula III to obtain Fimasartan base is carried
out for about 10 hours to about 24 hours. In an embodiment, the detritylation of the compound
of Formula III is carried out for about 12 hours to about 22 hours. In another embodiment, the
detritylation of the compound of Formula III is carried out for about 15 hours to about 20 hours.
In yet another embodiment, the detritylation of the compound of Formula III is carried out for
about 17 hours to about 19 hours.
The detritylation of the compound of Formula III is carried out at a temperature of about
60C to about 85C. In an embodiment, the detritylation of the compound of Formula III is
carried out at a temperature of about 65°C to about 80°C. In another embodiment, the
detritylation of the compound of Formula III is carried at a temperature of about 68°C to about
78°C. In yet another embodiment, the detritylation of the compound of Formula III is carried
out at a temperature of about 70°C to about 75°C.
Fimasartan may be isolated by filtration, decantation, extraction, distillation,
evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and
recrystallization. Fimasartan may be dried using conventional techniques, for example, drying,
drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
Fimasartan may be converted to Fimasartan potassium trihydrate of Formula I by the
process known in the art, for example, Korean. Patent No. KR100521980000.
While the present invention has been described in terms of specific aspects and
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.
Method
Chromatographic purity was determined using HPLC, Agilent® Technologies 1260
Infinity- II. The column used was Zorbax SB-Phenyl [250X4.6] mm.
8
The following examples are for illustrative purposes only and should not be construed
as limiting the scope of the invention in any way.
EXAMPLES
Reference Example: Preparation of 2-n-butyl-5-dimethylaminothiocarbonylmethyl-6-
methyl-3-[[2’-(1H-tertazol-5-yl)biphenyl-4-yl]methyl]-pyrimidne-4(3H)-one
(Fimasartan) (as per procedure disclosed in U.S. Patent No. 7,309,788)
2-n-Butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-[[2’-(Ntriphenylmethyltetrazol-5-yl) biphenyl-4-yl]methyl-pyrimidin-4(3H)-one (Formula II, 20 g),
Lawesson’s reagent (10.90 g) and toluene (100 mL) were charged to a round bottom flask to
obtain a reaction mixture. The reaction mixture was heated to a temperature of 80°C for 6
hours. After completion, the reaction mass was cooled to room temperature and then
concentrated and degassed for 30 minutes to obtain a residue. Methanol (60 mL) was added to
the residue and refluxed for 3 hours. After completion, the reaction mass was concentrated and
dissolved in a mixture of ethyl acetate (45 mL) and distilled water (45 mL). The solid obtained
was filtered and washed with ethyl acetate: distilled water (30 mL), and then dried for 5 hours
to 8 hours at 50°C to 55°C to obtain title compound.
Yield: 48%
Chromatographic purity: 94.75%
Example 1: Preparation of 2-n-butyl-5-dimethylaminothio carbonylmethyl-6-methyl-3-
[[2’-(1H-tertazol-5-yl)biphenyl-4-yl]methyl]-pyrimidne-4(3H)-one (Fimasartan)
2-n-Butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-[[2’-(Ntriphenylmethyltetraol-5-yl)biphenyl-4-yl]methyl-pyrimidin-4(3H)-one (Formula II, 30 g),
Lawesson’s reagent (16.64 g) and toluene (150 mL) were charged to a round bottom flask to
obtain a reaction mixture. The reaction mixture was heated at a temperature of 50°C to 55°C
for 12 hours. After completion of the reaction, tetrahydrofuran was added and stirred at 50°C
to 55°C for 30 minutes. Distilled water was added to the reaction mixture and heated at 70°C
to 75°C. After completion, reaction mass was distilled and degassed for 30 minutes to obtain
a residue. Dichloromethane was added to the residue followed by pH adjustment to neutral
using aqueous potassium hydroxide. The organic layer was separated and distilled under
vacuum to obtain a residue. Ethyl acetate (30 mL) was added to the residue and stirred to obtain
9
a solid. The solid was filtered and washed with ethyl acetate, suck dried and then dried to obtain
title compound.
Yield: 80 %
Chromatographic purity: 95.51%

Claims
1. A process for the preparation of Fimasartan potassium trihydrate of Formula I comprising
N
N
O
H3C
S
N
CH3
H3C
CH3
N
-
N
N N
K
+
. 3H2O
Formula I
a) thioamidation of a compound of Formula II
N
N
O
H3C
O
N
CH3
H3C
CH3
N N
N N
CPh3
Formula II
to obtain a compound of Formula III;
N
N
O
H3C
S
N
CH3
H3C
CH3
N N
N N
CPh3
Formula III
b) detritylation of the compound of Formula III in the presence of a mixture of water and
solvent to obtain Fimasartan base; and
c) converting Fimasartan base to Fimasartan potassium trihydrate of Formula I.
2. A process for the preparation of Fimasartan potassium trihydrate of Formula I comprising
11 N
N
O
H3C
S
N
CH3
H3C
CH3
N
-
N
N N
K
+
. 3H2O
Formula I
a) detritylation of a compound of Formula III
N
N
O
H3C
S
N
CH3
H3C
CH3
N N
N N
CPh3
Formula III
in the presence of a mixture of water and solvent to obtain Fimasartan base; and
b) converting Fimasartan base to Fimasartan potassium trihydrate of Formula I.
3. The process according to claim 1 or 2, wherein thioamidation of the compound of Formula
II is carried out using Lawesson’s reagent in a solvent.
4. The process according to claim 1 or 2, wherein the detritylation of the compound of Formula
III is carried out in the presence of a mixture of water and solvent.
5. The process according to claim 4, wherein the solvent used for the detritylation of the
compound of Formula III is aprotic polar solvent.
6. The process according to claim 5, wherein the aprotic polar solvent is selected from ethers,
ketones, nitriles, and mixtures thereof.
7. The process according to claim 6, wherein the ether solvent is selected from
tetrahydrofuran, ethyl methyl ether, diethyl ether, and di-isopropyl ether.
8. The process according to claim 6, wherein the ketones solvent is selected from acetone,
methyl ethyl ketone, methyl isobutyl ketone, and butanone.
9. The process according to claim 6, wherein the nitrile solvent is acetonitrile