FIELD OF INVENTION:
The present invention is related to the field of synthetic chemistry. It is related to process of synthesis of Azilsartan Medoxomil and its pharmaceutically acceptable salts. The present invention also relates to intermediates useful in the preparation of Azilsartan Medoxomil.
BACKGROUND:
The following discussion of the prior art is intended to present the invention in an appropriate
technical context and allow its significance to be properly appreciated. Unless clearly indicated
to the contrary, however, reference to any prior art in this specification should be construed as an
admission that such art is widely known or forms part of common general knowledge in the
field.
Azilsartan medoxomil is the adopted name of the drug compound chemically known as
(5Methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-
yl)biphenyl-4yl]methyl}-lH-benzimidazole-7-carboxylate salt and is represented by the
following structural Formula I:
O

Formula I
The drug substance used in the drug product formulation is the potassium salt of azilsartan medoxomil, also known by the US accepted name of azilsartan kamedoxomil and is chemically described as (5Methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4yl]methyl}-lH-benzimidazole-7-carboxylate monopotassium salt and its structural formula is:
2

>

Edarbi (Azilsartan medoxomil), a prodrug, is hydrolyzed to azilsartan in the gastrointestinal tract during absorption. Azilsartan is a selective ATI subtype angiotensin II receptor antagonist. Edarbi is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension to lower blood pressure.
Azilsartan was first disclosed in the year 1992 in EP 520423 Bl as angiotensin II antagonists. The patent discloses the synthesis of Azilsartan by reacting Methyl-l[[2'-cyanobiphenyl-4-yl] methyl]-2-ethoxybenzimidazole-7-carboxylate with hydroxyl amine hydrochloride in DMSO and 28% sodium methoxide to obtain Methyl 2-ethoxy-l-[[(2'-hydroxycarbamimidoyl)biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylate, which is added triethylamine in tetrahydrofuran and methylene chloride solution of ethylchloroformate to produce Methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol~3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate. This compound was dissolved in methanol followed by the addition of lithium hydroxide and 2N hydrochloric acid to produce Azilsartan. The following scheme depicts the above said synthesis:


Hydroxvlamiiie HC1 28%NaOMe
TEA/THF
■—»-
Ethyl chloroformafe

N J NH-OH
f y~o HN=
N

US patent 7,157,584 B2 (hereinafter US '584) on Azilsartan medoxomil discloses various methods for producing Azilsartan medoxomil.
3

^
The Method-(a) disclosed in US '584 involves reacting a reactive derivative (for example, a mixed acid anhydride, an acid halide and the like) of the compound represented by the formula (A) or a salt thereof with an alkylating agent such as (B) in the presence of a base to give a mixed anhydride and reacting the resulting compound with a corresponding alcohol of formula (C) in the presence of a base to allow esterification.



EtO
EtO
0*^0-Ri
O
X-LRI2
(B)

HO-Ri
(C)

(A) (0
wherein X is a halogen atom (chlorine, bromine, iodine etc.), Et is an ethyl, R12 is an alkyl (e.g., Ci.6 alkyl such as methyl, ethyl, propyl, t-butyl and the like), an alkoxy (e.g., Q.6 alkoxy such as methoxy, ethoxy, isobutyloxy and the like) or a phenyl optionally substituted by halogen atom, Ci-6 alkyl or nitro group and the like, Ri is a group represented by the formula
HO^, R2
V
o Wherein R2 a hydrogen atom or a Ci^ alkyl.
The Method-(b) comprises reacting a compound represented by the formula (A) or a salt thereof with thionyl chloride or oxalyl chloride in the presence of a catalyst such as DMF and the like to give an acid chloride, and reacting the acid chloride with a corresponding alcohol (C) in the presence of a base to allow esterification.


EtO
0-R1
EtO

<~o

SOCl2 or (COCrj2 HO-R1
*- >»
(C)

wherein R) is as defined above.
Method-(c) comprises reacting a compound represented by the formula (A) or a salt thereof (e.g., salt with alkali metal such as sodium, potassium and the like; salt with alkaline earth metal such as calcium, magnesium and the like; etc.) with an alkylating agent (X'—R1) as necessary in the presence of a base to allow esterification.



EtO^
EtO
O^ O-R1
X—R

wherein X* is a halogen atom (chlorine, bromine, iodine etc.) and R is as defined above. Method-(d) comprises reacting compound (A) with the corresponding alcohol (C) in the presence of a condensing agent to perform esterification.
EtO
EtO

O^OH
N-O.
"" condensing agent
HO-R
(A) 0)
wherein R1 is as defined above.
None of the above mentioned prior arts disclose the improved process according to the present invention. The present invention provides an improved, commercially viable and industrially advantageous process for the synthesis of Azilsartan medoxomil and its pharmaceutically acceptable salts. The intermediates and the final end products obtained through the improved processes of this invention are obtained in a superior yield and high purity.

SUMMARY OF THE INVENTION
The present invention relates to improved, commercially viable and industrially advantageous
processes for the synthesis of Azilsartan medoxomil and its pharmaceutically acceptable salts.
The present invention also relates to intermediates useful for the preparation of Azilsartan
Medoxomil.
In one embodiment, the present invention provides a process for the preparation of a compound
of Formula I


which comprises: (i) reacting a compound of Formula II

CH3 Formula I

Formula II
with a compound of Formula III

O-R

ci

Formula HI wherein R is selected from hydrogen or trialkylsilyl group to obtain a compound of formula (IV)


OR
Formula IV wherein R is as defined above; and
(ii) converting the compound of formula (IV) to compound of formula I. In another embodiment, the present invention provides a novel intermediate of formula (IV)

OR
Formula IV used in the preparation of azilsartan medoxomil.
In another embodiment, the present invention provides a process for the preparation of compound of formula I

CHS
Formula I which comprises reacting a compound of formula V
7

H*
o

0^ J3


NH / N

Formula V
with a compound of formula VI.

Formula VI In another embodiment, the present invention provides a process for the preparation of a compound of formula V

o
0^ JO
NH /
N
Formula V which comprises: a) protecting a compound of formula VII
o„ _o^
NH /
N
Formula VII with a boc anhydride to obtain a compound of formula VIII
1 Boc
ay-
Formula VIII
8

b) reacting the compound of formula (VIII) with a compound of formula IX
o
CI,
Formula IX to obtain a compound of formula X; and

Formula X c) deprotecting the compound of formula X. In another embodiment, the present invention provides a novel intermediate of formula V


o
0^ Jl
NH /
N
Formula V used in the preparation of azilsartan medoxomil.
In another embodiment, the present invention provides a process for the preparation of compounds of Formula VI
o
Br

Formula VI which comprises: (1) reacting a compound of formula (XI)
9

A

Formula XI with hydroxylamine hydrochloride to obtain a compound of formula (XII); and

^ ^ NH NH


OH

Formula XII (2) cyclizing the compound of formula (XII) to obtain a compound of formula (X). In another embodiment, the present invention provides a process for the preparation of a compound of formula I

CH3
Formula I
which comprises:
a. reacting a compound of formula XIII
NO,



with a compound of formula VI

Formula XIII
Formula VI 10

u
to obtain a compound of formula XIV; and

^1
Formula XIV b. converting the compound of formula XIV into compound of formula I. In yet another embodiment, the present invention provides a process for the preparation of the
compound of formula XIII
o
onr
N02
Formula XIII which comprises:
(1) reacting a compound of formula XV
Y~
Q
N02
Formula XV with ethylchloroformate to obtain a compound of formula XVI; and
or
N02
Formula XVI
(2) reacting the compound of formula XVI with a compound of formula IX.
11

0
CI
Formula IX
In yet another embodiment, the present invention provides a novel intermediate compound of
formula (XIII)
o

r
0 NO,
fr/

Formula XIII used in the preparation of azilsartan medoxomil
These and other features, aspects, and advantages of the present subject matter will become better understood with reference to the following description and appended claims. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to limit the scope of the claimed subject matter.
DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides a process for the preparation of a compound
of Formula I
o
CH3-^^°

CH3
which comprises:
Formula I 12

(i) reacting a compound of Formula II
o
Formula II
with a compound of Formula III
CU Jk ^O-R
Formula III
wherein R is selected from hydrogen or trialkylsilyl group; to obtain a compound of formula (IV)
o
N rq
OR
Formula IV wherein R is as defined above; and (ii) converting the compound of formula (IV) to compound of formula I.
Step (i) involves reacting the compound of formula (II) with the compound of formula (III) to
obtain the compound of formula (IV).
The compound of formula (II) used in step (i) is obtained according to»the process disclosed in
the patent number EP 0520423 B1.
Step (ii) involves converting the compound of formula (IV) to compound of formula (I).
The conversion involves two reaction steps, which are:
(a) deprotection of the hydroxy group; and
(b) cyclization of the resultant compound.
In step (a), the deprotection of the hydroxy group may be carried out in an acidic medium. In step (b), the cyclization reaction may be carried out using triphosgene or CDI.
13

>
In another embodiment, the present invention provides a novel intermediate of formula (IV)

OR
Formula IV used in the preparation of azilsartan medoxomil.
The general reaction scheme of the above embodiment of the instant invention can be schematically represented as scheme-A:
Scheme - A


O
f^ yo NHi
O
OR
CI
Formula III
*■
where R=H or Si(CH3)3
Formula II

*0 OR Formula IV
-o
Formula I
In another embodiment, the present invention provides a process for the preparation of compound of formula I

CH3
Formula I
which comprises: reacting a compound of formula V
14

J.
o
Formula V
with a compound of formula VI.

Br
o
NH ,N

Formula VI In another embodiment, the present invention provides a process for the preparation of a
compound of formula V
o

6^ J)
NH /
>—O
N
Formula V which comprises:
a) protecting a compound of formula VII
NH /
N
Formula VII
with a boc anhydride to obtain a compound of formula VIII;
o_o^
Boc
-N /
y<*
Formula VIII
b) reacting the compound of formula (VIII) with a compound of formula IX
15

o o
CI

o
A,

Formula IX
to obtain a compound of formula X; and

Formula X
c) deprotecting the compound of formula X.
In another embodiment, the present invention provides a novel intermediate compound of
formula V
o


Formula V used in the preparation of azilsartan medoxomil.

Formula VI
In another embodiment, the present invention provides a process for the preparation of compounds of Formula VI
which comprises:
16
(1) reacting a compound of formula (XI)

/

Formula XI with hydroxylamine hydrochloride to obtain a compound of formula (XII); and

NH NH

OH

Formula XII (2) cyclizing the compound of formula (XII) to obtain a compound of formula (VI) The cyclization reaction of step (2) may be carried out using ethyl chloroformate. The general reaction scheme of the above embodiment of the instant invention can be schematically represented as scheme-B:
Scheme - B


o_o

In another embodiment, the present invention provides a process for the preparation of a compound of formula I
17

J-

Formula I
which comprises:
a. reacting a compound of formula XIII
o
NH O
r
o
NO;
Formula XIII
with a compound of formula VI
o
.^ ^^ NH^ ^N
Formula VI to obtain a compound of formula XIV; and

"0
Formula XIV b.converting the compound of formula XIV into compound of formula I. The conversion reaction in step b involves the following reactions: Step 1. Reduction of the nitro group; and Step 2. Cyclization of the product of step 1.
18

J-
In yet another embodiment, the present invention provides a process for the preparation of the compound of formula XIII
o
r

NO;
Formula XIII which comprises: (1) reacting a compound of formula XV


N02
Formula XV with ethylchloroformate to obtain a compound of formula XVI; and
NH o
r
o
N0:
Formula XVI (2) reacting the compound of formula XVI with a compound of formula IX
o
CL

Formula IX In yet another embodiment, the present invention provides a novel intermediate compound of formula (XIII)
19

->

0
H
r
0^0

Formula XIII used in the preparation of azilsartan medoxomil
The general reaction scheme of the above embodiment of the instant invention can be schematically represented as scheme-C:
Scheme - C u

0
K
°^^0^ y
- ANHr° a^^
Formula IX
N02 Formula XIII 0
N02N Formula XIV
Formula I

In another embodiment, the present invention provides a process for the preparation of potassium salt of azilsartan medoxomil according to the scheme -D.
20


Scheme - D
N / NH-OH
■)— 0 NH = N

EXAMPLES:
Example 1: Preparation of Methyl 2-ethoxy-l-[[(2'-hydroxycarbamimidoyl) biphenyl-4-yl]
methyl]-lH-benzimidazole-7-carboxylate
a) 25% Potassium tertiary butoxide in methanol (17.0 ml) and hydroxylamine hydrochloride (0.422 g, 0.006 mol) are stirred in dimethylacetamide (5 ml). After 30 minutes, Methyl-1 [[2'-cyanobiphenyl-4-yl] methyl]-2-ethoxybenzimidazole-7-carboxylate (0.5 g, 0.0012 mol) was added and heated to 80-90°C for 29 hours. The reaction mass was cooled to 18-25°C and water was added and further cooled to 10-15°C. The reaction mass was stirred for 15-30 minutes and filtered and washed with water and dried to afford Methyl 2-ethoxy-l-[[(2'-hydroxycarbamimidoyl)biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylate (0.700 g); or;
b) Methyl-l[[2'-cyanobiphenyl-4-yl]methyl]-2-ethoxybenzimidazole-7-carboxylate (5.0 g, 0.0121 mol), trimethyl amine (21.84 ml, 0.123 mol) and hydroxylamine hydrochloride (8.68 g, 0.124 mol) are stirred in dimethylsulfoxide (37.5 ml): tetrahydrofuran (46.7 ml) for 30 minutes and heated to 70-75°C for 19 hours and the reaction mass is cooled to room temperature, followed by addition of water and extraction with ethylacetate, washed with water, brine dried oven sodium sulfate and the solvent was evaporated under reduced pressure
21

to afford Methyl 2-ethoxy-l-[[(2'-hydroxycarbamimidoyl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylate (4.1 g) as a solid; or;
c) Ammonium acetate (1.87 g, 0.0243 mol) and hydroxylamine hydrochloride (0.67 g, 0.0097 mol) were stirred in isopropanol (7.5 ml) and after 30 minutes Methyl-l[[2'-cyanobiphenyl-4-yl] methyl]-2-ethoxybenzimidazole-7-carboxylate (0.5 g, 0.0012 mol) was added and heated to 80 -85 °C for 29 hours. The reaction mass was cooled to room temperature, water was added and filtered and dried to afford Methyl 2-ethoxy-l-[[(2'-hydroxycarbamimidoyl) biphenyl-4-yl] methyl]-lH-benzimidazole-7-carboxylate (0.2 g) as a solid; or;
d) Sodium bicarbonate (6.0 g, 0.072 mol) and hydroxylamine hydrochloride (5.0 g, 0.072 mol) were stirred in isopropanol (40 ml) and after 30 minutes Methyl-l[[2'-cyanobiphenyl-4-yl] methyl]-2-ethoxybenzimidazole-7-carboxylate (1.0 g, 0.0024 mol) was added and heated to 80 -85 °C for 5 hours. The reaction mass was cooled to room temperature and water was added and filtered and dried to afford Methyl 2-ethoxy-l-[[(2'-hydroxycarbamimidoyl) biphenyl-4-yl] methyl]- lH-benzimidazole-7-carboxylate (0.6 g) as a solid; or;
e) Sodium bicarbonate (76.5 g, 0.91 mol) and hydroxylamine hydrochloride (21.06 g, 0.30 mol) were stirred in isopropanol (750 ml) and after 30 minutes Methyl-l[[2'-cyanobiphenyl-4-yl] methyl]-2-ethoxybenzimidazole-7-carboxylate (25.0 g ) was added and heated to 80-85°C for 74 hours. The reaction mass was cooled to room temperature, water was added filtered and dried to afford Methyl 2-ethoxy-l-[[(2'-hydroxycarbamimidoyl) biphenyl-4-yl] methyl]- 1H-benzimidazole-7-carboxylate (24.0 g) as a solid; or;
f) Sodium bicarbonate (154.0 g, 1.82 mol) and hydroxylamine hydrochloride (67.56 g, 0.972 mol) were stirred in isopropanol (1250 ml) and after 30 minutes Methyl-l[[2'-cyanobiphenyl-4-yl] methyl]-2-ethoxybenzimidazole-7-carboxylate (50.0 g, 0.121 mol) was added and heated to 80-85°C for 10 hours. The reaction mass was cooled to 40-50°C and 22.5 g of hydroxylamine hydrochloride was added and refluxed for 20hours. After completion of the reaction, the solvent was evaporated to minimum amount and cooled to 25-30°C and water was added and cooled to 10-15°C and stirred for 15-30 minutes and filtered, washed with water and dried to afford Methyl 2-ethoxy-l-[[(2'-hydroxycarbamimidoyl) biphenyl-4-yl] methyl]-lH-benzimidazole-7-carboxylate (54.2 g) as a solid.
22

Example 2: Preparation of Methyl 2-ethoxy-l-[[2-(2,5-dihydro-5-oxo-l,2,4-oxadiazol«3-yl)biphenyI-4-yl J methyl] benzimidazole-7-carboxylate
a) A solution of Methyl 2-ethoxy-l-[[(2'-hydroxycarbamimidoyl) biphenyl-4-yl] methyl]-lH-benzimidazole-7-carboxylate (19.0 g, 0.031 mol) and triethylamine (9.0 ml, 0.064 mol) in dichloromethane (280 ml) was cooled to 0-5°C and Ethylchloroformate (4.9 ml, 0.051 mol) was added and stirred at 18-25 C for 1 hour and water was added and the organic layer was separated, solvent was evaporated under reduced pressure, the residue was stirred in cyclohexane, filtered and dried to afford Methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol~3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (21.0 g) as a solid; or
b) A solution of Methyl 2-ethoxy-l-[[(2'-hydroxycarbamimidoyl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylate (1.0 g, 0.002 mol) and sodium bicarbonate (0.285 g, 0.003 mol) in ethylacetate (15 ml) was cooled to 0-5°C and Ethylchloroformate (0.259 ml, 0.002 mol) was added and stirred at 20-25°C for 2 hours, water was added and separated the organic layer, the organic layer was evaporated under reduced pressure, the residue was stirred in cyclohexane, filtered and dried to afford Methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol—3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.5 g) as a solid; or
c) A solution of Methyl 2-ethoxy-l-[[(2'-hydroxycarbamimidoyl) biphenyl-4-yl] methyl]- 1H-benzimidazole-7-carboxylate (1.0 g, 0.002 mol) and potassium carbonate (1.24 g, 0.008 mol) in acetone (15 ml) was cooled to 0-5°C and Ethylchloroformate (0.25 ml, 0.02 mol) was added and stirred at room temperature for 45 minutes then stirred at 60-65°C or 20 hours. After completion of the reaction solvent was evaporated under reduced pressure and water was added, acidified (pH 5-6) with aq.HCl stirred for 30 min and filtered, washed with water and recrystallized in isopropanol to afford Methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol—3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.89 g) as a solid.
Example 3: Preparation of Azilsartan
A suspension of Methyl 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol~3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (5.7 g, 0.012 mol) in water (57 ml) was cooled to 0°C and sodium hydroxide (1.94 g, 0.048 mol) in water (11.4 ml) was added, and stirred at room temperature and later stirred at 60-65°C for 20-22 hours. After completion of the reaction, the
23

reaction mass was cooled to 0°C and acidified (pH 2-3) with aq.HCl and stirred for 30 min and filtered, washed with water and dried to afford Azilsartan (3.7 g) as a solid.
Example 4: Preparation of Azilsartan medoxomil
a) A solution of Azilsartan (10.0 g, 0.021 mol), 4-Dimethylaminopyridine (DMAP) (0.535 g, 0.004 mol), Medoxomil alcohol (14.24 g, 0.109 mol) in Dimethylacetamide (DMAc) (110 ml) was cooled to 0-5 °C and p- Toluenesulfonyl chloride (p-TsCl) (6.26 g, 0.03 mol) and potassium carbonate (9.08 g, 0.06 mol) was added stirred at same temperature for lhour then stirred at 25-30 °C for 3-4 hours. After completion of the reaction, water (100 ml) was added and cooled to 10-15 °C and the pH was adjusted to 5-6 with 10 % aq.HCl, maintained for 10-15°C and filtered. The filtrate was extracted with ethylacetate and washed with water, brine, sodium bicarbonate solution and dried with sodium sulfate and the solvent was evaporated. The resulting residue and the above filtered solid were combined and stirred in petroleum ether and filtered to afford Azilsartan medoxomil (1.1 g) as a solid; or
b) A solution of Azilsartan (0.5 g, 0.001 mol), sodium bicarbonate (0.11 g, 0.001 mol) and Medoxomil chloride (0.162 ml, 0.001 mol) in DMAc (5 ml) were stirred at 50-55°C. Water was added and extracted with ethylacetate; washed with water, brine, dried with sodium sulfate and the solvent was evaporated, to afford Azilsartan medoxomil (1.1 g) as a solid.
Example 5: Preparation of potassium salt of Azilsartan medoxomil
A solution of Azilsartan medoxomil (0.1 g) in acetone (25 ml) under nitrogen was cooled to 0-5°C and a solution of potassium-2-ethyl hexanoate in acetone was added and allowed to stir at room temperature for 20-24 hours. The reaction mass was filtered and dried to afford potassium salt of Azilsartan medoxomil (0.013 g) as a solid.
Dated this 11* day of ^areJU, 2013

We Claim:
1. A process for the preparation of a compound of Formula I

which comprises:
(i) reacting a compound of Formula II
with a compound of Formula III

Formula I
o Formula II

o cu JL ^O-R
Formula III
wherein R is selected from hydrogen or trialkylsilyl group; to obtain a compound of formula
(IV)
o
N r oOR
Formula IV
wherein R is as defined above; and
(ii) converting the compound of formula (IV) to compound of formula I.
2. The process according to claim 1, wherein the step (ii) involves:
(a) deprotection of the hydroxy group;
25

JT

(b) cyclization of the resultant compound. 3. A novel intermediate of formula (IV)

o
N rqy-o NHi

OR
Formula IV wherein R is selected from hydrogen or tnalkylsilyl group. 4. A process for the preparation of compound of formula I


^v°
CH3

Formula I
which comprises: reacting a compound of formula V
o
Ko


Formula V
with a compound of formula VI.

Formula VI 5. A process for the preparation of a compound of formula V
26

o
VS
0^J>
,NH ,— —O
Formula V which comprises:
a) protecting a compound of formula VII
-NH /
Formula VII with a Boc anhydride to obtain a compound of formula VIII;
Boc
-N /
y