FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULES, 2003
PROVISIONAL SPECIFICATION [See section 10, rule 13]


An Improved Process For The Preparation Of Sartans
APPLICANT:
CALYX CHEMICALS AND PHARMACEUTICALS LTD. 2, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India
Indian Company incorporated under the Companies Act 1956
The following specification describes the invention


TITLE
An Improved Process for the Preparation of Sartans.
FIELD OF INVENTION
The present invention relates to an improved process for the preparation of Saltans of formula I and pharmaceutically acceptable salts thereof which are used as angiotensin-II antagonists

Formula I
wherein R is selected from the group (a), (b), (c), (d) or (e)



(d) (e)
The Sartans of formula I can identify specific angiotensin-II antagonist such as Losartan (wherein R is a), Irbesartan (wherein R is b), Valsartan (wherein R is c), Candesartan (wherein R is d) and Olmesartan (wherein R is e).
In particular, the present invention relates to an improved process for the preparation of tetrazole moiety of Sartans of formula I from the cyano compounds of formula II

BACKGROUND OF THE INVENTION
Sartans of formula I belongs to class of a non-peptide angiotensin-II antagonist (blocker). Angiotensin is an important participant in the rennin angiotensin-aldosterone system (RAAS) and has a strong influence on blood pressure. Sartans inhibits the action of angiotensin-II as its receptors and thus prevents the increase in blood pressure produced by the hormone-receptor interactions. It is therefore useful in the treatment of hypertension and heart failure.
3

Sartans of formula I comprises a common backbone of biphenyl-tetrazole. Sartans which show such biphenyl-tetrazole backbone include Losartan of formula la, Irbesartan of formula lb, Valsartan of formula Ic, Candesartan of formula Id and Olmesartan of formula Ie.

Several methods for the preparation of Sartans of formula I, are known in the literature. One of the important steps in preparing Sartans of formula I is the introduction of the
4

tetrazole group. The most common method for obtaining tetrazole group is by conversion of cyano moiety to tetrazole moiety in presence of organotin azides.
US 5,138,069 discloses a process for the preparation of tetrazole ring in which 2-[(butyl-4-chloro-5-(hydroxymethyI)~ 1 H-imidazol-1 -yl)methyl]biphenyl-2-carbonitrile is reacted with sodium azide in N,N-dimethylformamide in the -presence of lithium chloride or ammonium chloride for 13 days with 21% yield. Further 2-n-butyl-4-chloro-l-H-imidazolyl-5'methanol is coupled with 5-(4'-bromomethyl-l,r-biphenyl-2-yl)-2-triphenylmethyl-2H-tetrazole in N,N-dimethylformarnide to furnish trityl Losartan which is followed by deprotection to obtain Losartan.
Since the tetrazole formation takes 13 days and the yield is 21%, this process is unproductive and the content of impurities is very high. Besides, this method generates large amounts of by-products and is hampered by a risk of explosion of sublimable ammonium azide generated during the reaction. Also, since dimethylformamide is the solvent employed, higher temperature is required for the tetrazole ring formation and it is reported that dimethylformamide and azide at high temperature may lead to explosion.
EP 0578125, discloses a method for the preparation of Losartan using trioctadecyl or trioctyltin azide as a tetrazole forming agent.
WO 2007133040 and WO2007020654 describe the process for preparation of Losartan by reacting cyano compound with triethylamine hydrochloride and sodium azide in polar organic solvent such as N-methyl pyrrolidone, DMF, DMA etc.
EP 0454511 describes a process for the preparation of Irbesartan by the reaction of 2-n-
butyl-3-[[2'-cyanobiphenyl-4-yl]methyl]-l,3-diazaspiro[4.4]non-l-en-4-one with
5

tributyltin azide in xylene at reflux for 110 hrs. US patent no. 5,270,317 discloses reaction time of up to 210 hrs.
US 5,629,331 describes a process for the preparation of Irbesartan wherein the precursor 2-n-butyl-3-[[2'-cyanobiphenyl-4-yl]methyl]-l,3-diazaspiro[4.4]non-l-en-4-one is treated with sodium azide in presence of triethylamine hydrochloride in a polar aprotic solvent such as DMF and N-methyl pyrrolidone at temperature of 110-140 °C.
EP 459136 discloses the benzimidazole derivatives such as Candesartan and process for their preparation. The patent describes the process for formation of tetrazole compound from cyano compound using various azides such as trialkyltin azide, hydrogen azide and ammonium salt thereof and the like. The reaction is carried out in toluene or xylene at reflux temperature for 1-4 days when organotin azide is used. When sodium azide and ammonium chloride or tertiary amine is used the reaction is carried out in solvent such as DMF for about 1-4 days.
EP 796852 describes the process for preparing 5-substituted tetrazole by using inorganic azide salt in presence of amine salt and aromatic hydrocarbon as a solvent. The patent further discloses the process for preparing 1-(tetrazoylbiphenylmethyl)imidazole derivative i.e. Olmesartan by reacting cyano derivative with sodium azide in presence of triethylamine hydrochloride in aromatic hydrocarbon solvent such as toluene or xylene.
WO 2005051929 discloses the process for a conversion of aromatic nitriles to tetrazoles comprising reacting cyano compound with trialkyl tin chloride and sodium azide in the presence of phase transfer catalyst and solvent such as aromatic hydrocarbons, non-polar aprotic solvents and high boiling polar aprotic solvents. The process is claimed to be particularly useful in the preparation of Irbesartan, Candesartan, Losartan and Valsartan.
6

WO 2007054965 describes a process for the preparation of Sartans by reacting cyano compound with trialkyltin halide and metal azide in presence of a base like triethyl amine or isopropyl amine in solvent such as hydrocarbons, halogenated compounds, ethers, ketones etc.
All the processes explained above suffer from several drawbacks. Most of the processes use organotin azides which are toxic and environmentally hazardous chemicals. They are not safe to handle, difficult to isolate, requires special processes for their disposal and also they are costly. Also the prior art processes use polar aprotic solvents such as DMF, N-methyl pyrrolidinoe etc. These solvents are high boiling, non-recoverable and also expensive.
Moreover, the processes in prior art have the disadvantages of requiring a fairly extended reaction time at high temperatures which in turn results in relatively lower yields and purity.
Also these processes involve tedious workup procedures e.g. a large number of steps which include the protection and subsequent deprotection, and isolation of intermediates as well as separations by column chromatography results in excessive production times, which in turn renders the process more costly and less eco-friendly, hence the processes are not suitable for commercial scale up.
Hence there is a continuous need to develop an environment friendly and economical process for the preparation of Sartans of formula I in high yield and purity in a shorter period of reaction time.
The inventors of the present invention found out an improved, environment friendly, and economical process for the preparation of tetrazole moiety of Sartans of formula I from cyano compounds of formula II using sodium azide, trialkyl amine and trialkyl
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amine hydrochloride in an organic solvent such as substituted benzenes, ethers or ketones. The process provides the final product in good yield and high purity and also reduces the reaction time.
OBJECT OF THE INVENTION
An object of the present invention is to provide an improved process for the preparation Sartasns of formula I, such as Losartan of formula la, Irbesartan of formula lb, Valsartan of formula Ic, Candesartan of formula Id and Olmesartan of formula Ie and pharmaceutically acceptable salts thereof.
More particularly, an object of the present invention is to provide an improved process for the preparation of tetrazole moiety of Sartans of formula I from cyano compounds of formula II.
Another object of the present invention is to provide an environment friendly process for the preparation of tetrazole moiety of Sartans of formula I and pharmaceutically acceptable salts thereof by avoiding the use of toxic and hazardous tin azide.
Another object of the present invention is to provide an improved process for the preparation of tetrazole moiety of Sartans of formula I and pharmaceutically acceptable salts thereof in a shorter period of reaction time and thereby making the process cost effective.
Yet another object of the present invention is to provide an improved process for the preparation of Sartans of formula I and pharmaceutically acceptable salts thereof in good yield and with high purity.
8

SUMMARY OF THE INVENTION
According to an aspect of the present invention there is provided an improved process for the preparation of Sartans of formula I and pharmaceutically acceptable salts thereof
R


Formula I
wherein R is selected from the group (a), (b), (c), (d) or (e)

.a
comprising,
a) reacting cyano compounds of formula II
9


Formula II
wherein R is as defined above,
with sodium azide, trialkyl amine and trialkyl amine hydrochloride in an orgamc
solvent such as substituted benzenes, ethers or ketones at 60-130 °C.
b) continue heating of the the reaction mixture at 60-130 °C for 8-24 hrs.
c) isolating the product of formula I by usual workup procedure
d) optionally converting the product of formula I to its salts
In.particular, the present invention relates to an improved process for the preparation of tetrazole moiety of Sartans of formula I by reacting cyano compounds of formula II

wherein R is as defined above with sodium azide, trialkyl amine and trialkyl amine hydrochloride in an organic solvent such as substituted benzenes, ethers or ketones at 60-130 °C for 8-24 hrs.
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DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Saltans of
formula I and pharmaceutically acceptable salts thereof
R N=N
/
Formula I
wherein R is selected from the group (a), (b), (c), (d) or (e)

comprising,
a) reacting cyano compounds of formula II
11

R

Formula II
wherein R is as defined above,
with sodium azide, trialkyl amine and trialkyl amine hydrochloride in an orgamc
solvent such as substituted benzenes, ethers or ketones at 60-130 °C.
b) continue heating the reaction mixture at 60-130 °C for 8-24 hrs.
c) isolating the product of formula I by usual workup procedure
d) optionally converting the product of formula I to its salts
More particularly, the present invention is related to an improved process for the preparation of tetrazole moiety of Sartans of formula I and pharmaceutically acceptable salts thereof by reacting cyano compounds of formula II
R

Formula II
wherein R is selected from the group (a), (b), (c), (d) or (e)
12

with sodium azide, trialkyl amine and trialkyl amirie hydrochloride in an organic solvent such as substituted benzenes, ethers or ketones at 60-130 °C for 8-24 hrs.
The process of the present invention is as depicted in the scheme below.

wherein R is as defined above The cyano compounds of formula II are prepared by the well known prior art processes.
13

The product Saltans of formula I is optionally converted to its pharmaceutically acceptable salts such as Losartan potassium, Candesartan cilexetil or Olmesartan medoxomil by the well known prior art processes.
In an aspect of the present invention there is provided an improved process for the preparation of the Losartan of formula la and pharmaceutically acceptable salts thereof such Losartan potassium,

Formula la
by reacting cyano compound of formula II, as shown above, wherein R is (a), with sodium azide, trialkyl amine and trialkyl amine hydrochloride in an organic solvent such as substituted benzenes, ethers or ketones at 80-110 °C for 12-18 hrs.

Formula lb
14
In another aspect of the present invention there is provided an improved process for the preparation of the Irbesartan of formula lb

by reacting cyano compound of formula n, as shown above, wherein R is (b), with sodium azide, trialkyl amine and trialkyl amine hydrochloride in an organic solvent such as substituted benzenes, ethers or ketones at 80-110 °C for 12-20 hrs.
In another aspect of the present invention there is provided an improved process for the preparation of the Valsartan of formula Ic

Formula Ic
by reacting cyano compound of formula II, as shown above, wherein R is (c), with sodium azide, trialkyl amine and trialkyl amine hydrochloride in an organic solvent such as substituted benzenes, ethers or ketones at 60-130 °C for 8-24 hrs.
In yet another aspect of the present invention there is provided an improved process for the preparation of the Candesartan of formula Id and its pharmaceutically acceptable salt such as Candesartan cilexetil


COOH

Formula Id
by reacting cyano compound of formula II, as shown above, wherein R is (d), with sodium azide, trialkyl amine and trialkyl amine hydrochloride in an organic solvent such as substituted benzenes, ethers or ketones at 60-130 °C for 8-24 hrs.
15

In yet another aspect of the present invention there is provided an improved process for the preparation of the Ohnesartan of formula le and its pharmaceutically acceptable salt such as Olmesartan medoxomil

Formula le
by reacting cyano compound of formula II, as shown above, wherein R is (e), with sodium azide, trialkyl amine and trialkyl amine hydrochloride in an organic solvent such as halobenzenes, ethers or ketones at 60-130 °C for 8-24 hrs.
In an embodiment of the present invention, the organic solvent used in the reaction is selected from substituted benzenes, ethers or ketones, preferably substituted benzenes are selected form mono, di or tri-substituted benzenes such as toluene, xylenes or halobenzenes such as chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene; preferably ethers or ketones are selected from diphenyl ether or methyl isobutyl ketone, more preferably solvent used in the reaction is chlorobenzene or 1,2-dichlorobenzene.
The amount of organic solvent ranges from 3 to 8 volumes based on cyano compounds of formula II, preferably between 3 to 6 volumes.
In another embodiment of the present invention, the reaction is carried out at temperature between 60 -130 °C, preferably between 70 -120 °C.
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In yet another embodiment of the present invention the reaction time ranges from 8-24 hrs, preferably from 12-20 hrs.
In yet another embodiment of the present invention, sodium azide is employed in an amount ranging from 1 to 6 molar equivalents based on cyano compounds of formula II, preferably between 2.0 to 4.0 molar equivalents.
In further embodiment of the present invention, trialkyl amine and trialkyl amine hydrochloride is selected from trimethyl amine and trimethyl amine hydrochloride, or triethyl amine and triethyl amine hydrochloride, preferably triethyl amine and triethyl amine hydrochloride.
In yet another embodiment of the present invention triethyl amine hydrochloride is used in an amount ranging from 1 to 6 equivalents based on sodium azide preferably between 2.0 to 4.0 equivalents where as triethyl amine is employed in an amount ranging from 1 to 15 w/v based on cyano compounds of formula II, preferably between 5 to 10 w/v.
The experimental details for the preparation of tetrazole moiety of Losartan of formula la, by reacting cyano compound of formula 11, wherein R is (a), with sodium azide, triethylamine and triethylamine hydrochloride in various organic solvents are as given below in Table-L
Table-I:

Batch No. NaN3 (Mol. equiv.) Solvent Time
(hrs) %
conversion to Losartan
07/186/AZAR/45 2.5 Chlorobenzene 12 91.31
07/186/AZAR/45 2.5 Chlorobenzene 18 91.73
07/186/AZAR/46 3.5 Chlorobenzene 12 94.77
07/186/AZAR/46 3.5 Chlorobenzene 18 95.03
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07/186/AZAR/34 4 Chlorobenzene 12 90.93
07/186/AZAR/34 4 Chlorobenzene 18 95.97
07/186/AZAR/35 4.5 Chlorobenzene 12 92.64
07/186/AZAR/35 4.5 Chlorobenzene 18 96.1
07/186/AZAR/38 3.5 1,2-Dichlorobenzene 12 94.94
07/186/AZAR/38 3.5 1,2- Dichlorobenzene 18 97.69
07/186/AZAR/65 3 Methylisobutyl ketone 12 78.48
07/186/AZAR/65 3 Methylisobutyl ketone 18 84.76
07/186/AZAR/66 4 Methylisobutyl ketone 12 87.17
07/186/AZAR/66 4 Methylisobutyl ketone 18 91.83
07/173/AZAR/18 3 Diphenyl ether 12 64.27
07/173/AZAR/18 3 Diphenyl ether 18 80.22
07/186/AZAR/69 3 Toluene 12 77.23
07/186/AZAR/69 3 Toluene 18 91.25
Note: Molar equivalents of triethyl amine hydrochloride used are the same as of sodium azide, as shown in Table-I. Triethyl amine used is 10% w/v. The amount of the solvent used is 3-5 volumes based on compound of formula II. Reaction is carried out at a temperature of 100-106 °C.
The experimental details for the preparation of tetrazole moiety of Irbesartan of formula lb, by reacting cyano compound of formula II, wherein R is (b), with sodium azide, triethylamine and triethylamine hydrochloride in various organic solvents is as given below in Table-II.
Table-H:

Batch No. NaN3 (Mol. equiv.) Solvent Time
(hrs) %
conversion to Irbesartan
2008/027/BZAR/37 2.5 Chlorobenzene 12 88.26
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20O8/027/BZAR/37 2.5 Chlorobenzene 18 92.58
2008/027/BZAR/19 3.0 Chlorobenzene 12 92.82
2008/027/BZAR/19 3.0 Chlorobenzene 18 96.16
2008/027/BZAR/48 3.5 Chlorobenzene 6 93.34
2008/027/BZAR/48 3.5 Chlorobenzene 12 97.45
2008/027/BZAR/39 2.5 1,2-Dichlorobenzene 12 77.72
2008/027/BZAR/39 2.5 1,2-Dichlorobenzene 18 85.91
2007/173/BZAR/05 3.0 1,2-Dichlorobenzene 12 95.0
2007/173/BZAR/05 3.0 1,2-Dichlorobenzene 18 91.83
2008/027/BZAR/40 3.5 1,2-Dichlorobenzene 12 90.28
200.8/027/BZAR/40 3.5 1,2-Dichlorobenzene 18 93.51
2007/173/BZAR/02 3.0 1,3-Dichlorobenzene 12 88.8
2007/173/BZAR/02 3.0 1,3 -Dichlorobenzene 18 89.47
2007/173/BZAR/01 3.0 Toluene 12 84.90
2007/173/BZAR/01 3.0 Toluene 18 84.06
2008/027/BZAR/21 3.0 Methyl isobutyl ketone 12 72.7
2008/027/BZAR/21 3.0 Methyl isobutyl ketone 18 82.12
2008/027/BZAR/44 3.5 Methyl isobutyl ketone 12 88.98
2008/027/BZAR/44 3.5 Methyl isobutyl ketone 18 93.03
2008/027/BZAR/28 3.0 Anisole 12 87.1
2008/027/BZAR/28 3.0 Anisole 18 92.38
2007/173/BZAR/03 3.0 Diphenyl ether 12 91.83
2007/173/BZAR/03 3.0 Diphenyl ether 18 93.99
Note: Molar equivalents of triethyl amine hydrochloride used are the same as of sodium azide, as shown in Table-II. Triethyl amine used is 10% w/v. The amount of the solvent used is 3-5 volumes based on compound of formula II. Reaction is carried out at a temperature of 100-106 °C.
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The details of the invention provided in the following examples are given by the way of illustration only and should not be construed to limit the scope of the present invention.
Example I
2-Butyl-4-chloro-(l-{[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl}-l Himidazol-5-yl methanol (Losartan)
2-[(Bu1yl-4-chloro-5-(hydroxymemyI)-lH-imidazol-l-yl)methyl]biphenyl-2-carbonitrile (lOOg, 0.26 mole), triethylamine hydrochloride (126.8g, 0.921 moles), sodium azide (59.9g, 0.921 moles) were taken in chlorobenzene (500 ml, 5 volumes) and was stirred for 15 minutes. Triethyl amine (10 ml) was added and the reaction mixture was heated to 105 °C. The temperature was maintained at 100-105 °C for 15-18 hrs. (HPLC analysis of the reaction mixture after 18 hrs showed 95% conversion to the product.) After completion of the reaction, it was cooled to room temperature. Aqueous solution of sodium nitrite (75 g) was then added slowly over a period of 1.0 hr. and stirred for further 15 minutes. The pH of reaction mixture was then adjusted to 3.5 to 4 by using aq. hydrochloric acid and stirred for 3 hrs. Solid product precipitated in the solution was filtered out and washed with water. The wet cake was taken in water and was heated to 50 °C for 1 hour and filtered while hot and suck dried. Finally it was dried at 60-70 °C for 6-8 hrs. Yield: 101.5 g, (91.3%); HPLC Purity: >98 %
*H NMR in DMSO-ds (5ppm): 7.65-7.69 (dd, 2H, ArH), 7.51-7.59 (dd, 2H, ArH.), 7.02-7.09 (m, 4H, ArH.), 5.25 (s, 2H, CH2), 4.33 (s, 2H, CH2), 2.45-2.50 (m, 2H, CH2)1.40-1.47 (m, 2H, CH2), 1.18-1.27 (m, 2H, CH2), 0.77-0.81 (t, 3H, CH3)
IR (KBr): 3373.50, 3331.07, 3057.17, 2951.09, 2926.01, 2868.15, 2856.58, 2411.02, 2353.16, 1975.11, 1737.86, 1579.70,1469.76,1435.04,1411,89, 1363.67, 1323.17,
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1263.37,1230.58,1192.01,1087.85,1033.85,1008.77, 997.20, 763.81cm
Example II:
2-n-Butyl-3-[[2'-(lH-tetrazol-5-yl)[l,l,-biphenyl]-4-yl]methyl]-l^-diazaspiro[4.4] non-l-en-4-one (Irbesartan):
In a round bottom flask was taken 2-n-butyl-3-[[2,-cyanobiphenyl-4-yI]methyl]-l,3-diazaspiro-[4.4]non-l-en-4-one (lOOg, 0.2594 moles), sodium azide (54.2g, 0.834 moles), triethylamine hydrochloride (120g, 0.872 moles) and triethylamine (10 ml) in chlorobenzene (400 ml) and the mixture was gradually heated to 105-106 °C. Reaction mixture was continued heating at 105-106 °C for 12-18 hrs. After completion of the reaction, it was cooled to room temperature. Aqueous solution of sodium nitrite (65g) was then added slowly over a period of 1.0 hr and stirred further for 15 minutes. The pH of reaction mixture was then adjusted to 3.5 to 4.0 by using aq. HCI. The reaction mixture was stirred for 1 hrs. Solid product precipitated in the solution was filtered out and washed with water and dried under vacuum to obtain crude Irbesartan (1 lOg, HPLC purity = >95%). Crude product was crystallized using aqueous ethanol. Finally pure Irbesartan was dried under vacuum at 60-70 °C for 6-8 hours to yield white material.
Yield : 89g (80.0%), HPLC purity: 99.87%.
!H NMR in DMSO-d6 (5ppm): 87.69-7.64 (dd, 1H, ArH), 7.51-7.59 (dd, 1H, ArH), 7.08 (s,4H, ArH), 4.67 (s, 2H,-CH2), 2.25-2.30 (t, 2H,-CH2), 1.81-1.83 (t, 6H, J = 12Hz, -CH2), 1.65 (m, 2H, -CH2), 1.45 (m, 2H,-CH2), 1.25 (m, 2H,-CH2), 0.79 (t, 3H, -CH3).
13C NMR in DMSO-d6(8ppm): 8185.81, 161.31, 155.19, 141.19, 138.54, 136.47, 131.23, 130.76, 130.73, 129.43, 127.99, 126,43, 123.66, 75,97, 42.39, 38.87, 27.64, 26.74,25.61, 21.67,13.78.
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IR(KBr): 2958.80, 2873.94, 1732.08, 1614.42, 1556.55, 1435.04, 1408.04, 1336.67, 1238.30,1178.51, 939.33, 758.02, 665.44, 522.71 cm"1.
Dated this 9th day of July 2008
/OC¥AM /