A process for the preparation of Candesartan and pharmaceutically acceptable salts and esters thereof
Field of the Invention
The present invention relates to a process for the preparation of candesartan and pharmaceutically acceptable sahs and esters thereof. Specifically the present invention relates to a process for the preparation of candesartan cilexitel by the process of deprotection of triphenylmethyl candesartan cilexetil.
Background of the Invention
Candesartan cilexetil an angiotensin ATI receptor blocker was developed by Astra Zeneca and Takeda. The drug was approved for hypertension and chronic heart failure in the E.U, US and other countries.
Candesartan cilexetil was disclosed in U.S. Patent No. 5,196,444 and chemically known as(±)-2-Ethoxy-l-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-lH-benzimidazoie-7-carboxylic acid l-(cyclohexyloxycarbonyIoxy)ethyl ester and can be represented by the Formula (I)
HX

Formula (I)
U.S. Pal. No. 5,196,444 discloses Candesartan cilexetil and a process for its preparation (shown below as scheme-I) by the reaction of 2-ethoxy-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyI]benzimidazole-7-carboxylic acid with trityl chloride in presence of triethyl amine in methylene chloride and purification by column chromatography gives 2-ethoxy-l-[[2'-(N-triphenylmethyltetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid, which upon condensation with cyclohexyl 1-iodoethyl carbonate in presence of
Pagel of 13

potassium carbonate in DMF followed by purification with column chromatography and recrystallization in ethanol yields Candesartan cilexetil.



CPh)j,CCI
TEft

^ccPhi

0 CH,
0 ^ ^0 ^1

1)K,C0,
2)HCI


Formula (I)
Scheme-I
WO 2005/051928 discloses a process for the preparation of candesartan cilexetil by removing the protective group from the corresponding tetrazole protected candesartan compound in the presence of organic acids. The main drawback of this reaction is yields of the desired compound are not higher that 60% and involves additional extractions and purifications where the yields of the desired compound further reduced.
U.S. Pat. Application No. 2005/131037 discloses a process for preparation of candesartan cilexetil by reaction of trityl candesartan with cilexetil halide and at least one base in a low boiling solvent in presence of phase transfer catalyst to give Trityl candesartan cilexetil, which upon deprotection with at least one organic acid in at least one organic solvent. U.S. Pat. Application 2005/131037 further discloses the deprotection of Trityl candesartan cilexetil in methanol without an acid.
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The PCT publication WO 2005/021535 discloses a process for the preparation of candesartan cilexetil by the deprotection of the trityl moiety in an alcohol. The main drawback of this reaction is incomplete reaction and low yield of the desired product. Another drawback of this reaction is longer reaction time and leads to decomposition of the compounds.
WO 2005/037821 describes the deprotection trity! candesartan cilexetil by the use of
organic acids in a mixture of toluene, methanol, and water. The drawbacks of this
reaction are that the deprotection reaction is not completed properly and the compound
obtained with contamination of impurities. Where the isolation of the desired compound
is difficult to isolate. ^
WO2007048361 describes the process for the removal of the triphenylmethane protecting group from the precursors of antihypertensive drugs including candesartan cilexitel using only water in a suitable solvent without using acids. However, the product obtained according to this process associated with impurities, additional steps like purification or recrystallization have to be performed to get the desired product with acceptable purity, which leads this process not economical.
EP1945629 describes an improved synthesis of Candesartan cilexetil by removal of the tetrazolyl protecting group in an organic solvent, and in the presence of a Lewis acid. The disadvantage of this reaction is using of Lewis acids in the acid sensitive reactions is not preferable as decomposition of ester group from the candesartan cilexitel takes place along with removal of tritylgroup, leading the formation of impurities along with desired compound.
The prior art references disclosed several methods for preparation of Candesartan cilexetil, all these process have some disadvantages/drawback like involves purification of Trityl candesartan and Candesartan cilexetil by column chromatography or involves the use of strong acids like IN HCl or the use of organic acids or without an acid in
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methanol for detrytilation of trityl candesartan cilexetil. Thus, there is a need to develop a process for the preparation of Candesartan cilexitel without involving strong or mineral acids and no need to perform purification by column chromatography.
Summary of the Invention
The present invention provides an improved process for the synthesis of candesartan and pharmaceutically acceptable salts and esters thereof comprising the removal of the tetrazolyl protecting group from the corresponding candesartan compound in mixture of solvents with out involving any acid or base.
The embodiment of the present invention provides an improved process for the deprotection of protecting groups like triphenylmethyl (trityl), tributyltin, trimethylsilyl, triethylsilyl,substituted or unsubstituted benzyl derivatives from the protected candesartan and pharmaceutical ly acceptable salts and esters thereof
In accordance with one preferred embodiment of the present invention, there is provided a process for the preparation of candesartan cilexitel free from impurities.
The main embodiment of the invention preparation of candesartan cilexetil by the process of removal of the triphenylmethane (trityl) protecting group from the tetrazolyl moiety of candesartan cilexetil, in a mixture of organic solvents.
Detailed Description of the Invention
The disclosed embodiment of the present invention involves a process for producing substantially pure candesartan cilexetil in a mixture of solvents.
The main embodiment of the invention, there is provided a process for preparation of candesartan cilexetil which yields pure candesartan cilexetil without containing any impurities in high percentage where by no need to perform purification by column chromatography and limiting further steps like multiple extractions, crystallization and purifications.
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Candesartan cilexetil obtained according to the present invention is in tact substantially pure, and in particular substantially free from all possible impurities. The expression "substantially pure" means a purity degree equal to or higher than 99% and having a impurities equal to or lower than 5 ppm.
The process for the preparation of candesartan cilexetil (I) developed by the present invention can be shown below Scheme -II.

Ph
Ph

^\ M^s J-P

r ^^ > V r
0 CH,

Scheme-II
According to the present invention, the process for the preparation of candesartan cilexetil comprises refluxing the compound of Formula (II) in the presence of a solvent which are partially or completely miscible with water.
The process of the present invention which is detritylation of trityl candesartan cilexetil of Formula II, can be carried in solvents which are miscible with water and at least one of the solvent is dipolar aprotic solvent. The other solvent used in the process of the present invention comprising an C1-C5 alcohol, halogenated hydrocarbon solvent and aromatic hydrocarbon solvent.
The other solvent used in the process of the present invention is preferably C1-C5 alcohol, most preferably methanol.
The dipolar aprotic solvent used in the process of the present invention is selected from dimethylsulfoxide, dimethylformamide, acetonitrile, or acetone.
The dipolar aprotic solvent used in the process of the present invention is preferably dimethyl formamide.
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According to the present invention the reaction is carried out preferably at 50 tol 10 C temperature, most preferably the reaction can be carried out at reflux temperature of the mixture of solvents used.
The main embodiment of the present invention which provides a process for preparing candesartan cilexetil (I) comprising:
a) stirring trityl candesartan cilexetil of Formula (II) in a mixture of suitable solvents for complete dissolution;
b) stirring the reaction solution of step (a) at reflux temperature for about 15-25 hours;
c) distilling off the solvents from the reaction solution of step (b) under reduced pressure;
d) stirring the residue obtained in step (c) in a solvent selected from a group of an aromatic hydrocarbon solvent;
e) distilling off the solvent from the reaction solution of step (d) under reduced pressure;
f) stirring the residue obtained in step (e) in a solvent selected from a group of an aromatic hydrocarbon solvent;
g) stirring the reaction solution of step (f) at 25-30*^0 for about 10-20 minutes;
h) adding low polar solvent to the solution of step (g) and stirring for 30 minutes;
i) cooling the solution of step (h) to O-S'^C and stirring for 1-3 hours;
j) filtering the separated solid from step (i) and washing with a low polar solvent
used in step (h); and k) drying the obtained solid of step (j) at 40-55'^C under reduced pressure for a
suitable period .
The trityl candesartan cilexetil of Formula (II) used in above step (a) is the form of solid or residue.
The residue of trityl candesartan cilexetil of Formula (II) used in step (a) can be prepared by dissolving the solid of trityl candesartan cilexetil in a mixture of an halogenated
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hydrocarbon solvent and water, separating the organic layer and distilling off the solvent completely under reduced pressure.
The suitable solvents of the above step (a) selected from dipolar aprotic or protic solvents.
At least one of the solvent used in step (a) is dipolar aprotic solvent.
The dipolar aprotic solvent used in step (a) is selected from dimethylsulfoxide, dimethylformamide, acetonitrile, or acetone.
The other solvent used in above step (a) is selected from a group comprising an C1-C5 alcohol, halogenated hydrocarbon solvent and aromatic hydrocarbon solvent.
The aromatic hydrocarbon solvent of step (d) is selected from benzene, toluene, xylene, preferably toluene.
The aromatic hydrocarbon solvent of step (f) is same as used in step (d).
The low polar solvent of step (h) is selected from pet-ether, isopropyl ether, methyl propyl ether preferably pet-ether.
The drying period of step (k) is from 3-8 hours, preferably 4-6 hour most preferably 4-5 hours.
The solid obtained in step (k) optionally crystallized from a solvent selected from an aromatic hydrocarbon solvent preferably toluene or an alcohol preferably methanol or acetone with or without water or mixture thereof
The invention is fiirther demonstrated in the following examples. The examples, which illustrate the improvement of the method according to the invention, are of an illustrative nature only and do not limit the extent of the invention in any respect.
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Example 1
Preparation of candesartan cilexetil (I)
A mixture of trityl candesartan cilexetil (11,100 g), dimethylformamide (500 ml), and methanol (500 ml) was refluxed for 24 h. Then, distilled off the solvents completely from the reaction mixture, the concentration residue was cooled to 25-30'^C and toluene (200 ml) was added. The toluene solution was stirred for 15 minutes at 25-30^C followed by pet-ether (300 ml) was added and stirred for 30 minutes. Then, the solution was cooled to 0-5^^0 and stirred for 2 hours. The separated solid was filtered and washed with pet-ether (50 ml). The obtained solid was dried at 50 C to get candesartan cilexitel (73 g). The solid was dissolved in a mixture of acetone (370 ml) and water (225 ml) cooled to 0-5^C and stirred for 2 hours. The separated solid was filtered and washed with mixture of chilled acetone (50 ml) and water (50ml), to get candesartan cilexetil (65 g) with HPLC purity of 99.90%.
Example 2
Preparation of candesartan cilexetil (I)
A mixture of trityl candesartan cilexetil (11,100 g), dimethylformamide (500 ml), and methanol (500 ml) was refluxed for 24 h. Then, distilled off the solvents completely from the reaction mixture, the concentration residue was cooled to 25-30^C and toluene (200 ml) was added. The toluene solution was stirred for 15 minutes at 25-30°C followed by pet-ether (300 ml) was added and stirred for 30 minutes. Then, the solution was cooled to 0-5 C and stirred for 2 hours. The separated solid was filtered and washed with pet-ether (50 ml). The obtained solid was dried at SO^C to get candesartan cilexetil (77 g).
Recrystallization -1:
The solid obtained in Example 2, stirred with toluene (275 ml) at reflux temperature for about 15 minutes. The solution was cooled at 0-5*^C and stirred for 2 hours. The separated
T>r.no 9 nf ^'^i

solid was filtered and washed with toluene(50 ml). Dried the solid at 45-50^C under reduced pressure for about 3-5 hours to get candesartan cilexetil (67 g).
Recrystallization -2:
The solid obtained in Example 2, stirred with methanol (500 ml) at reflux temperature for about 15 minutes. The solution was cooled at 0-5*^0 and stirred for 2 hours. The separated solid was fdtered and washed with methanol (50 ml). Dried the solid at 45-50°C under reduced pressure for about 3-5 hours to get candesartan cilexetil (67 g).

We Claim
1. A process for the preparation of candesartan cilexetil of Formula (I),


/ hi =— /

Formula (I)
comprising:
a) stirring trityl candesartan cilexetil of Formula (II) in a mixture of suitable solvents for complete dissolution;

H,C M , _p^

Formula (11)
b) stirring the reaction solution of step (a) at reflux temperature for about 15-25 hours;
c) distilling off the solvents from the reaction solution of step (b) under reduced pressure;
d) stirring the residue obtained in step (c) in a solvent selected from a group of an aromatic hydrocarbon solvent;
e) distilling off the solvent from the reaction solution of step (d) under reduced pressure;
f) stirring the residue obtained in step (e) in a solvent selected from a group of an aromatic hydrocarbon solvent;
g) stirring the reaction solution of step (f) at 25-30°C for about 10-20 minutes;
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h) adding low polar solvent to the solution of step (g) and stirring for 30
minutes; i) cooling the solution of step (h) to 0-5^C and stirring for 1-3 hours; j) filtering the separated solid from step (i) and washing with a low polar
solvent used in step (h); and k) drying the obtained solid of step (j) at 40-55^C under reduced pressure for
a suitable period.
2. The process of claim 1 in step a) wherein at lease one of the solvent is selected from a group of dipolar aprotic solvent.
3. The process of claim 2 wherein the dipolar aprotic solvent is selected from dimethyl sulfoxide, dimethylformamide, acetonitrile, or acetone.
4. The process of claim 3 wherein the dipolar aprotic solvent is dimethylformamide.
5. The process of claim 1 in step d) wherein the aromatic hydrocarbon solvent of is selected from benzene, toluene, xylene.
6. The process of claim 5 wherein the aromatic hydrocarbon solvent is toluene.
7. The process of claim 1 in step h) wherein the low polar solvent is pet-ether.
8. The process of claim 1 in step k) wherein the drying period is from 3-8 hours.
9. The process of claim 8 wherein the drying period is 5 hours.
10. The process for the preparation candesartan cilexetil of Formula (I) from trityl candesartan cilexetil of Formula (II) as shown by below scheme.

J^/ _ \_ DMF/MeOH
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