FIELD OF INVENTION:
The present invention basically describes the demarcation between the processes disclosed in the basic product patent, several other patents for preparation of Candesartan Cilexetil as product (Candesartan Cilexetil) prepared using existing known processes in prior art, contains several impurities described in various pharmacopoeia like EP/USP/BP/JP etc. The present invention disclosed herein is not only capable of producing highly pure Candesartan Cilexetil (API) but it also capable of removing all major impurities if present in Candesartan cilexetil.

BACKGROUD OF INVENTION:
Various processes in prior art are elaborated in a concise manner in the section ‘background of invention’.
Candesartan cilexetil, 1-[[(Cyclohexyloxy)carbonyl]oxy]ethyl-2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) 1,1'-biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (Candesartan cilexetil) has the Formula Ia, as given below

(Formula Ia)
Candesartan is a potent, selective AT1 subtype angiotensin II receptor antagonist and used for treatment of hypertension. Due to poor absorption of Candesartan in body, the prodrug candesartan Cilexetil was developed. The Candesartan Cilexetil is rapidly and completely hydrolyzed to candesartan in gastrointestinal tract.
U.S. Pat. No. 5,196,444 or European patent 0459136 discloses the preparation of Candesartan Cilexetil via the formation of candesartan ethyl ester by reacting cyano compound with trimethyltin azide in toluene followed by purification of API with column chromatography to give a colorless powder which is recrystallized in ethanol yielding ‘C’ type crystals of Candesartan Cilexetil.
U.S. Pat. No. 5,703,110 describes the two step process which is a divisional of U.S. Pat. No. 5,196,444 claims candesartan acid, a pharmaceutically acceptable salt thereof, pharmaceutical compositions and method for antagonizing angiotensin II in a mammal by administering a therapeutically effective amount of candesartan or a pharmaceutically acceptable salt thereof.
U.S. Pat. No. 6,177,587 describes the preparation of candesartan involving candesartan methyl ester preparation by reacting cyano intermediate with trioctyltin azide in toluene followed by its hydrolysis in presence of caustic solution and the product candesartan acid thus formed, is washed with acetone and dried.
WO 2005/051929 discloses a process where cyano intermediate is reacted in toluene with tributyltin chloride in presence of sodium azide and tetrabutylammonium bromide at 110-115° C and isolating the product Candesartan methyl ester using toluene.
U.S. Pat. Application No. 2005/131027 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 gives Candesartan Cilexetil.
U.S. Pat. Application 2005/131027 further discloses the deprotection of Trityl candesartan cilexetil in methanol without an acid to give Candesartan Cilexetil.
The PCT publication WO 2005/021535 discloses the deprotection of Trityl candesartan cilexetil with neutral or slightly basic medium in alcohol.
PCT Publication WO 2006076710 A2 describes a process for preparing Candesartan cilexetil comprising heating a solution of trityl candesartan cilexetil in a water immiscible solvent in the presence of C1-C4 alcohol in two-phase system; and isolating Candesartan cilexetil.
PCT Publication WO 2009157001 A2 describes a process for preparing Candesartan cilexetil, the said process comprises hydrogenating a solution of trityl candesartan cilexetil in an alcohol Toluene mixture in the presence of a palladium catalyst until hydrogen uptake is ceased followed by isolation of Candesartan cilexetil in acetonitrile.
US Patent 7,884,212 B2 provides an improved synthesis for the manufacture of Candesartan and pharmaceutically acceptable salts and esters thereof as active ingredients of a medicament for the treatment of hypertension and related diseases and conditions which comprises the removal of the tetrazolyl protecting group in an organic solvent, and in the presence of a Lewis acid.
Chinese patent application CN102070617A provides the novel process for Candesartan cilexetil through absorption of active carbon, crystallization and adsorptive separation of macroporous absorption resin to achieve the purpose of refined purification and finally, the high-purity Candesartan cilexetil is obtained, thereby greatly improving the purity and content of the Candesartan cilexetil, improving the product quality of the preparation, reducing toxic and side effects and guaranteeing the clinical pharmacy safety of the Candesartan cilexetil in preparing anti-hypertension medicaments. The novel preparation method has the advantages of simple process, low cost and high yield, and is suitable for industrial production.
PCT Publication WO 2014088123 A1 provides Candesartan cilexetil preparation contains candesartan cilexetil and lauromacrogol. The lauromacrogol may be contained at a ratio of 2.4 parts by weight or less with respect to 100 parts by weight of the Candesartan cilexetil-containing preparation which may further contain at least one kind of pharmacologically acceptable additives among a diluent, a disintegrant and a binder.
Chem. Pharm. Bull. 47(2), 182-186 (1999) discloses two novel crystalline forms of Candesartan cilexetil, form-I and form-II.
PCT publication WO 04/085426 discloses Candesartan cilexetil 1,4-Dioxane solvate and two more crystalline forms, designated as form-III and form-IV. The disclosed process for preparation of form-III involves crystallization of Candesartan cilexetil in toluene whereas process for the ptreparation of form-IV involves crystallization in a mixture of methyl tert-butyl ether and methanol.
PCT publication WO2005123721 A1 describes a process for the preparation of two crystalline forms i.e. form A, form B and an amorphous form of Candesartan Cilexetil. The process disclosed hereinabove are tedious, time consuming and operationally difficult at industrial scale.
PCT publication WO2006048237 A1 describes a process for the preparation of form 5, form 6, form 7, form 8 and amorphous form of Candesartan Cilexetil. These forms are prepared by dissolving candesartan cilexetil in a chlorinated solvent, optionally concentrate thus obtain solution then liquid hydrocarbon is added to the solution to precipitate out these forms.
US Patent 7,692,023 B2 or PCT publication WO 2005/077941 of Teva discloses solvates of Candesartan Cilexetil along with a process for preparation of form-I (type-C). It cites as many as 21 polymorphic forms i.e. from form III to form XXIII along with amorphous form of Candesartan Cilexetil. However the patent has been granted just a novel process of making polymorphic form I of candesartan Cilexetil from its so called form XIV, XIV-I, XXII & XXIII.
PCT publication WO2008035360 A2 provides two novel crystalline forms of candesartan cilexetil which are designated as form G and form H and a novel crystalline form of candesartan, tritylated candesartan and tritylated candesartan cilexetil and process for their preparation thereof.
PCT publication WO 2005/077941 discloses several crystalline forms, solvates of Candesartan Cilexetil along with a process for preparation of form-I (type-C).
WO 2005/123721 processes for the preparation of amorphous Candesartan Cilexetil are provided, comprised of spray-drying and precipitation.
compounds such as palladium oxide. Preferably palladium on carbon may be used as catalyst.
The prior art disclosed methods for preparation of Candesartan Cilexetil involves purification of trityl candesartan and Candesartan Cilexetil by column chromatography or involves the use of strong acids like 1N HCl or the use of organic acids or without an acid in methanol for removal of trityl group from trityl candesartan Cilexetil. The major outcome of all the processes was that, it gives rise to Candesartan Cilexetil which often contains one or the other impurities which are difficult remove by these traditional methods. Furthermore, none of the above processes are capable of removing Candesartan acid (Impurity G) if present in the product. Therefore, there was a need for an improved process which is capable of producing high quality, highly pure Candesartan Cilexetil consistently by controlling or removing critical impurities from Candesartan cilexetil. This requirement paves way for our new invention which is described hereafter.

SUMMARY OF INVENTION:
The present invention discloses purification processes for crude Candesartan Cilexetil having high level of impurities to give highly pure Candesartan Cilexetil. The crude Candesartan Cilexetil used herein is prepared in accordance with various processes as disclosed in background / prior art. The crude candesartan Cilexetil thus prepared having various impurities in appreciable amount. Such as Impurity B (as described below), about 4-5%, Impurity A/ F / G / H about 1-2 % and many other unknown impurities. The present invention reports three different purification processes of converting this crude Candesartan Cilexetil to highly pure Candesartan Cilexetil. All the three processes are described in detail in next section.
All the processes as described in prior art / background of invention contains several impurities which are enlisted below:
S.No Impurity Code / Name Structure
1. Impurity A as per USP/EP or Candesartan Ethyl ester
Or Formula I

2. Impurity B as per USP/EP/ Desethyl Candesartan Cilexetil) or
Formula II
3. Impurity F in EP & Imp C in USP/ N2-Ethyl Candesartan Cilexetil or
Formula III
4. Impurity-G as per EP/ Candesartan acid Impurity
Formula IV
5. Impurity-H as per EP/ Trityl Candesartan Cilexetil
Formula V
6. Formula VI
/ Trityl Candesartan

DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, novel process of preparation/purification of crude Candesartan Cilexetil is disclosed which comprises:
a) Dissolving crude Candesartan Cilexetil in an organic nitrile
b) Addition of an organic amine.
c) Heating at 70-80°C
d) Stirring till complete dissolution.
e) Fine filtration of hot reaction mass via hyflo
f) Cooling of reaction mass to 30-40 °C
g) Stirring to ensure complete crystallization.
h) Further cooling reaction mass to 0-5 °C
i) Stirring
j) Filtration
k) Drying of product at 45-50 °C for 5-20 hours to give highly pure Candesartan Cilexetil.
According to one aspect of first embodiment, the aliphatic organic nitrile used in step (a) above is selected from acetonitrile, propionitrile or a mixture thereof.
According to another aspect of first embodiment, the aliphatic organic amine used in step (b) above is selected from N,N-diisopropyl ethylamine, triethylamine, tert butyl amine, dicyclohexylamine, cyclohexyl amine, dibenzylamine, phenylethylamine, di-n-propylamine, diisopropylamine, isopropylamine and a-methyl benzylamine.
According to the second embodiment of current invention, second novel process of preparation/purification of crude Candesartan Cilexetil is disclosed which comprises:
a) addition of crude candesartan Cilexetil in water
b) stirring
c) Addition of an organic amine.
d) Heating of reaction mass to 30-40°C
e) Stirring at this temperature for 30 to 60 minutes.
f) Isolation of resulting solid by filtration & drying at 45-50°C
g) Dissolving this wet cake in an aliphatic organic nitrile.
h) Heating & stirring of reaction mass to ensure complete dissolution.
i) Fine filtration of reaction mass via hyflow bed.
j) Cooling & stirring of reaction mass at 20-30 °C for 1-2 hours.
k) Further cooling to 0-5 °C & stirring for 2-3 hours.
l) Isolation of product by filtration and drying at 45-50 °C for 5-20 hours to give highly pure Candesartan Cilexetil.
According to one aspect of second embodiment, the tertiary organic amine used in step (c) above is selected from N,N-diisopropyl ethylamine, triethylamine, tert butyl amine, dicyclohexylamine, cyclohexyl amine, dibenzylamine, phenylethylamine, di-n-propylamine, diisopropylamine, isopropylamine and a-methyl benzylamine.
According to another aspect of second embodiment, the aliphatic organic nitrile used in step (g) above is selected from acetonitrile, propionitrile or a mixture thereof.
According to the third embodiment of current invention, third novel process of preparation/purification of crude Candesartan Cilexetil is disclosed which comprises:
a) Addition of crude candesartan Cilexetil to a halogenated hydrocarbon.
b) stirring & adding of water
c) Addition of an organic amine.
d) Continued stirring for 10-30 minute.
e) Layer separation & discarding the aqueous layer.
f) water washing of the organic layer with water thrice.
g) Isolating product by complete recovery of halogenated hydrocarbon under vacuum.
h) Dissolving this material in an aliphatic organic nitrile.
i) Heating & stirring of reaction mass to ensure complete dissolution.
j) Fine filtration of reaction mass via hyflo bed.
k) Cooling & stirring of reaction mass at 20-30 °C for 1-2 hours.
l) Further cooling to 0-5 °C & stirring for 2-3 hours.
m) Filtration
n) Drying of product at 45-50 °C for 5-20 hours to give highly pure Candesartan Cilexetil.
According to first aspect of third embodiment, the halogenated hydrocarbon used in step (a) is selected from methylene dichloride, chloroform, carbon tetrachloride or mixture thereof.
According to one aspect of second embodiment, the tertiary organic amine used in step (c) above is selected from N,N-diisopropyl ethylamine, triethylamine, tert butyl amine, dicyclohexylamine, cyclohexyl amine, dibenzylamine, phenylethylamine, di-n-propylamine, diisopropylamine, isopropylamine and a-methyl benzylamine.
According to the fourth embodiment of current invention, fourth novel process of preparation / purification of crude Candesartan Cilexetil is disclosed which comprises:
a) Took crude Candesartan Cilexetil solution in an halogenated hydrocarbon.
b) Addition of sodium bicarbonate solution having pH 6.5-8.5.
c) Stirring , settling & layer separation
d) Complete recovery of halogenated hydrocarbon under vacuum keeping temperature below 45 °C.
e) Re-dissolving crude thus obtained in cyclohexane
f) Heating to 40-45 °C.
g) Stirring for 12-14 hours.
h) Cooling of reaction mass to 25-30 °C.
i) Further stirring of reaction mass for 12-14 hours
j) Further cooling of reaction mass to 10-15 °C.
k) Stirring
l) Filtration
m) Drying of product at 45-50 °C for 5-20 hours to give highly pure Candesartan Cilexetil.
According to first aspect of fourth embodiment, the halogenated hydrocarbon used in step (a) is selected from methylene dichloride, chloroform, carbon tetrachloride or mixture thereof.
The above mentioned invention is supported by the following non limiting examples.

EXAMPLES:
Reference Example 1:
2-Ethoxy-1-[[(2'-(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]benzimidazole-7-carboxylic acid or trityl Candesartan Cilexetil (100 g) is taken in N,N-Dimethyl formamide (200 ml) & stirred. This is followed by addition of potassium carbonate (24 g) & Cyclohexyl-1-chloroethyl carbonate (36.2 g) at 20-30 °C. Now heated the reaction mass to 60-65 °C and stirred the reaction mass for 5-6 hours. After confirmation of reaction completion by HPLC/TLC, cooled the reaction mass to 20-25 °C. Then product was extracted in methylene chloride (400 ml) followed by layer separation. The aqueous layer was discarded and organic layer was given three water washings (200 ml). This was followed by complete recovery of methylene chloride. Again charged methylene dichloride (240 ml), methanol (470 ml) & water (20 ml) to it. Now heated reaction mass to 30-35 °C & stirred for 6-10 hour for reaction completion. After reaction completion water (200 ml) is charged followed by layer separation. The organic layer is heated & performed its recovery under vacuum keeping temperature below 40 °C. Now the residue is slurried in cyclohexane (400 ml) & stirred for 16-20 hours at 25-30 °C. The resulting mass is filtered & washing of wet cake in cyclohexane (50 ml) followed by water washing (500 ml) of wet cake at 40-45°C for 30 minutes & isolation of crude Candesartan cilexetil by filtration and drying at 45-50 °C to get crude Candesartan Cilexetil.
Yield = 0.80
Purity by HPLC = 93.66 %
Impurity B = 4.89 % (formula II).
Other Impurities = 0.54 % (Imp G), 0.25% (Imp F), 0.24% (Imp H) & 0.08% (Imp A).
Example 1:
Crude Candesartan Cilexetil (10g) as obtained in reference example 1, was dissolved in acetonitrile (50ml) in presence of N,N-diisopropylethyl amine (0.11 g) and heating to 70-80°C with stirring. After dissolution, the reaction mass is fine filtered via hyflow bed and allowed to cool to 30-40 with stirring till crystallization starts. Then temperature was further lowered to 0-5 °C to ensure complete crystallization. The product Candesartan Cilexetil is isolated by filtration and drying at 45-50 °C for 5-20 hours.
Yield = 6.70g
Purity by HPLC = 99.73%
Impurity B = 0.09%
Other major Impurities = 0.13% (Imp G).

Example 2:
Candesartan Cilexetil (10 g) as obtained from reference example 1, was added to water (50 ml) & N,N- Diisopropylethylamine (0.11 g). The reaction mass, thus obtained, was slurry washed at 30-40°C for 30-60 minutes. The product was isolated by filtration and drying followed by its dissolution in Acetonitrile (50 ml). After dissolution, the reaction mass is fine filtered via hyflow bed and allowed to cool to 30-40 with stirring till crystallization starts. Then temperature was further lowered to 0-5 °C to ensure complete crystallization. The product Candesartan Cilexetil is isolated by filtration and drying at 45-50 °C for 5-20 hours.
Yield = 8.0g
Purity by HPLC = 99.73%.
(Impurity B= 0.09%; Other major Impurity = 0.05 %(Imp G).

Example 3:
Crude Candesartan Cilexetil (10 g) as obtained in reference example 1, was dissolved in methylene chloride (40 ml). To this water (40ml) & N,N-diisopropylethylamine (0.11 g) were added. After stirring the reaction mass at ambient temperature layer separation was done. The aq layer was discarded & product containing organic layer was further given 3 consecutive washings with water (40 ml each). The solvent was recovered from organic layer to give residue which was further dissolved in Acetonitrile (50ml) at 70-80°C under stirring. The reaction mass was fine filtered via hyflo bed & the reaction mass cooled to Room temperature with stirring for 1-2 hours. The temperature was further lowered to 0-5 °C & stirred for 2-3 hours. The material, thus crystallized, was then filtered and dried at 45-50 °C for 5-20 hours to give pure Candesartan Cilexetil.
Yield = 7.0g
Purity by HPLC = 98.95%
Impurity B = 0.87%
Other major Impurity = 0.06 % (Imp G).

Example 4:
To a solution of Crude Candesartan Cilexetil (10 g) in methylene chloride (40 ml), aq. sodium bicarbonate solution (0.11 g in water; pH = 6.5-8.5) was added. After stirring the reaction mass at ambient temperature layer separation was done. The aq layer was discarded & product containing organic layer was further given 3 consecutive washings with water (40 ml each). The solvent was recovered from organic layer to give residue which was further dissolved in cyclohexane (50ml) at 35-45°C under stirring. The reaction mass was stirred for 10-15 hours at this temperature. The reaction mass was fine filtered via hyflo bed & the reaction mass cooled to Room temperature with stirring for 10-14 hours. The temperature was further lowered to 10-15 °C & stirred for 2-3 hours. The material, thus crystallized, was then filtered, given running washing with cyclohexane (10 ml) and dried at 45-50 °C for 5-20 hours to give pure Candesartan Cilexetil.
Yield = 7.8 g
Purity by HPLC = 98.95%
Impurity B = 0.77%
Other major Impurity = 0.15 % (Imp G).

CLAIMS:
1. A novel process of preparation of highly pure Candesartan Cilexetil comprises:
i) dissolving crude Candesartan Cilexetil in an organic nitrile which may be selected from acetonitrile, propionitrile or a mixture thereof;
ii) addition of an organic amine selected from N,N-diisopropyl ethylamine, triethylamine, tert butyl amine, dicyclohexylamine, cyclohexyl amine, dibenzylamine, phenylethylamine, di-n-propylamine, diisopropylamine, isopropylamine and a-methyl benzylamine or a mixture thereof;
iii) heating of reaction mass to 70-80°C;
iv) stirring till complete dissolution;
v) cooling of reaction mass to 30-40 °C;
vi) stirring to ensure complete crystallization;
vii) cooling reaction mass to 0-5 °C;
viii) stirring followed by isolation of product as wet cake by filtration;
ix) drying of product at 45-50 °C for 5-20 hours to give highly pure Candesartan Cilexetil.

2. A novel process of preparation of highly pure Candesartan Cilexetil comprises:
i) addition of crude candesartan Cilexetil in water;
ii) stirring;
iii) addition of an organic amine selected from N,N-diisopropyl ethylamine, triethylamine, tert butyl amine, dicyclohexylamine, cyclohexyl amine, dibenzylamine, phenylethylamine, di-n-propylamine, diisopropylamine, isopropylamine and a-methyl benzylamine or a mixture thereof;
iv) heating of reaction mass to 30-40°C;
v) stirring at this temperature for 30 to 60 minutes;
vi) isolation of resulting solid by filtration & drying at 45-50°C;
vii) re-dissolving this wet cake in an organic nitrile which may be selected from acetonitrile, propionitrile or a mixture thereof;
viii) heating & stirring of reaction mass to ensure complete dissolution;
ix) cooling & stirring of reaction mass at 20-30 °C for 1-2 hours;
x) cooling to 0-5 °C & stirring for 2-3 hours;
xi) stirring followed by isolation of product as wet cake by filtration;
xii) drying of product at 45-50 °C for 5-20 hours to give highly pure Candesartan Cilexetil.

3. A novel process of preparation of highly pure Candesartan Cilexetil comprises:
i) addition of crude candesartan Cilexetil to a halogenated hydrocarbon which may be selected from methylene dichloride, chloroform, carbon tetrachloride or mixture thereof;
ii) stirring & adding of water;
iii) addition of an organic amine selected from N,N-diisopropyl ethylamine, triethylamine, tert butyl amine, dicyclohexylamine, cyclohexyl amine, dibenzylamine, phenylethylamine, di-n-propylamine, diisopropylamine, isopropylamine and a-methyl benzylamine or a mixture thereof;
iv) continued stirring for 10-30 minute;
v) layer separation & discarding the aqueous layer;
vi) provided washing to the organic layer with water thrice;
vii) isolating product by complete recovery of halogenated hydrocarbon under vacuum;
viii) re-dissolving this material in an aliphatic organic nitrile which may be selected from acetonitrile, propionitrile or a mixture thereof;
ix) heating & stirring of reaction mass to ensure complete dissolution;
x) cooling & stirring of reaction mass at 20-30 °C for 1-2 hours;
xi) cooling to 0-5 °C & stirring for 2-3 hours;
xii) isolation of product as wet cake by filtration;
xiii) drying of product at 45-50 °C for 5-20 hours to give highly pure Candesartan Cilexetil.

4. A novel process of preparation of highly pure Candesartan Cilexetil comprises:
i) to a solution of crude candesartan Cilexetil in an halogenated hydrocarbon selected from methylene dichloride, chloroform, carbon tetrachloride or mixture thereof;
ii) adding aq. sodium bicarbonate solution having pH 6.5-8.5;
iii) stirring, settling & layer separation;
iv) complete recovery of halogenated hydrocarbon under vacuum keeping temperature below 45 °C;
v) re-dissolving crude in cyclohexane;
vi) heating to 40-45 °C;
vii) stirring for 10-15 hours;
viii) stirring for 10-12 hours at room temperature;
ix) cooling of reaction mass to 10-15 °C & stirring for 2-3 hours;
x) isolation of product as wet cake by filtration & given running washing with cyclohexane;
xi) drying of product at 45-50 °C for 5-20 hours to give highly pure Candesartan Cilexetil.