WO2011092666A1

WO2011092666A1 - An improved process for the preparation of candesartan cilexetil, polymorphic forms of n-trityl candesartan and their uses thereof

Info

Publication number: WO2011092666A1
Application number: PCT/IB2011/050400
Authority: WO
Inventors: Lakshmipathi V. Sanjeevi; Suresh Allada; Ashok Kumar; Kaptan Singh; Srinivasa Rao Guntu
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2010-01-29
Filing date: 2011-01-29
Publication date: 2011-08-04
Anticipated expiration: 2012-07-29

Abstract

The present invention provides an improved process for the preparation of candesartan cilexetil comprising the use of polymorphic Form A and Form B of N-trityl candesartan. Also, provided herein, new polymorphic Form A and Form B of N-trityl candesartan and the processes for their preparation.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF CANDESARTAN CILEXETIL, POLYMORPHIC FORMS OF N-TRITYL CANDESARTAN AND

THEIR USES THEREOF

Field of the Invention

The present invention provides an improved process for the preparation of candesartan cilexetil that includes the use of polymorphic Form A and Form B of N-trityl candesartan. Also provided herein are new polymorphic Forms A and Form B of N-trityl candesartan, and processes for their preparation.

Background of the Invention

Candesartan cilexetil (Atacand®) is a prodrug and is chemically described as (+)- 1 - [cyclohexyloxy)carbonyl] oxy] -ethyl-2-ethoxy- 1 - [ [2' -( 1 H-tetrazol-5-yl)- 1 , 1 ' biphenyl-4- yl]methyl-lH-benzimidazole-7-carboxylate. It is a selective angiotensin II receptor antagonist which is used for the treatment of hypertension and is represented by the following structural Formula I:

There are several patents/applications reported in literature related to process for the preparation of candesartan cilexetil, for example, U.S. Patent Nos. 5,578,733 and 7,345,072; WO 2005/021535; WO 2005/037821; WO 2007/074399; and WO

2007/042161 which are incorporated herein for reference only. However, the references do not provide enough disclosure related to different polymorphic forms of N-trityl candesartan and their use in the preparation of candesartan cilexetil.

U.S. Patent No. 5,196,444 describes preparation of crystals of trityl candesartan involving recrystallization of the crude crystals obtained from column chromatography using an ethyl acetate-benzene solvent mixture and having a melting point of about 168°C to 170°C. WO 2008/035360 provides a polymorphic form of the tritylated candesartan characterized by its XRD spectra and is prepared by reacting candesartan with trityl chloride and triethylamine in presence of acetone involving refluxing at 55°C to 60°C followed by cooling of the reaction mixture to room temperature.

The present inventors have now found two polymorphic forms of N-trityl candesartan which are stable and reproducible, do not require chromatographic purification and can be easily converted to candesartan cilexetil.

Summary of the Invention

An improved process for the preparation of candesartan cilexetil wherein the process comprises:

(i) preparing a polymorphic Form A or Form B of N-trityl candesartan; and

(ii) converting Form A or Form B N-trityl candesartan to candesartan cilexetil.

The process according to claim 1, wherein the preparation of polymorphic Form A or Form B of N-trityl candesartan further comprises involves isolation of the polymorphs.

The process according to claim 1, wherein the preparation of polymorphic Form A of N-trityl candesartan comprises the steps of:

(i) dissolving trityl candesartan in a polar organic solvent at ambient

temperature, optionally heating to dissolve the mixture;

(ii) stirring the reaction mixture followed by cooling if required; and

(iii) optionally, stirring the mixture obtained from step (ii) after cooling and

isolating polymorphic Form A.

The process according to claim 3, wherein the polar organic solvent is selected from the group comprising of methanol, ethanol, isopropanol, n-butanol, n-pentanol, n- heptanol, tert-butanol, diethylether, diisopropylether, ethylacetate, isopropylacetate, butyl acetate and/or mixtures thereof.

The process according to claim 3, wherein the heating of the reaction mixture is carried out from ambient temperature to about reflux temperature of the polar solvent.

The process according to claim 3, wherein the stirring of the reaction mixture obtained in step (i) is carried out from about 10 minutes to about 12 hours. The process according to claim 3, wherein the reaction mixture obtained after stirring in step (ii) is cooled to about 10°C to 30°C.

The process according to claim 7, wherein reaction mixture obtained after cooling is further stirred for about 1 hour to about 12 hours.

The process according to claim 3, further comprising drying of the isolated polymorphic Form A of the N-trityl candesartan under reduced pressure for about 1 hour to 2 hours and further in air for about 40 hours to 48 hours.

The process according to claim 9, wherein drying of the polymorphic Form A of the N-trityl candesartan is carried out at about 45°C to 55°C.

The process according to claim 1, wherein the preparation of polymorphic Form B of N-trityl candesartan comprises the steps of:

(i) dissolving trityl candesartan in a less polar or non-polar organic solvent at an ambient temperature;

(ii) stirring the reaction mixture; and

(iii) isolating polymorphic Form B.

The process according to claim 11, wherein the less polar or non-polar solvent is selected from the group comprising of methyltertiarybutyl ether, cyclopentane, cyclohexane, n-pentane, n-hexane, n-heptane, xylene, benzene, toulene and/or mixtures thereof.

The process according to claim 11, wherein the stirring of the reaction mixture is carried out from about 1 hour to about 5 hours.

The process according to claim 11, further comprising drying of the isolated polymorphic Form B of the N-trityl candesartan under reduced pressure for about 1 hour to 2 hours and further in air for about 40 hours to 48 hours at 45°C to 55°C.

The process according to claim 1, wherein the polymorphic Form A or Form B of

N-trityl candesartan has total impurities of not more than 0.8% and a level of desethyl candesartan cilexetil impurity less than 0.1%.

Substantially pure polymorphic Form A and Form B of N-trityl candesartan. The polymorphic Form A of N-trityl candesartan according to claim 16, wherein Form A has a chromatographic purity of between 90% and about 99%, when measured by HPLC area percentage.

The polymorphic Form B of N-trityl candesartan according to claim 16, wherein the Form B has chromatographic purity of greater than 86% when measured by HPLC area percentage.

The polymorphic Form A and Form B of N-trityl candesartan of claim 16, wherein the moisture content is less than 0.15%.

Polymorphic Form A of N-trityl candesartan comprising characteristic d-spacing (A⁰) values at 11.06, 7.58, 7.45, 7.36, 6.05, 5.06, 4.83, 4.59, 4.39, 4.33, 4.20, 4.12, 4.07, 3.77 or 3.58.

The polymorphic Form A of N-trityl candesartan of claim 20, further comprising X-ray diffraction peaks expressed in degrees two-theta at 5.82, 8.00, 8.75, 9.86, 10.32, 10.98, 11.68, 11.88, 12.03, 12.80, 12.92, 13.20, 14.18, 14.64, 15.21, 15.58, 16.06, 16.54, 17.08, 17.54, 17.76, 18.38, 19.36, 20.25, 20.52, 21.14, 21.59, 21.85, 22.13, 22.90, 23.63, 24.90, 25.72, 26.32, 26.93, 27.74, 28.36, 28.96, 29.42, 30.74, 31.21, 31.90, 33.04, 33.52, 33.97, 35.06, 36.03, 37.40 + 0.2.

Polymorphic Form A of the N-trityl candesartan of claims 20 and 21, further characterized by:

(i) an XRD having substantially the same pattern as depicted in Figure 1;

(ii) a TGA having substantially the same pattern as depicted in Figure 2; and/or

(iii) a DSC having substantially the same pattern as depicted in Figure 3, wherein the DSC shows the characteristics endotherm peak in the range from about 159.54°C to about 165.08°C

Polymorphic Form B of N-trityl candesartan comprising characteristic d-spacing

(A⁰) values at 19.03, 9.59, 7.14, 7.08, 6.82, 6.62, 6.34, 5.29, 4.82, 4.73, 4.63, 4.24, 4.07, 3.97 or 3.79. The polymorphic Form B of N-trityl candesartan of claim 23, further comprising X-ray diffraction peaks expressed in degrees two-theta at 4.64, 6.05, 6.50, 6.84, 7.76, 8.01, 8.51, 8.90, 9.22, 10.35, 10.72, 11.11, 11.66, 11.92, 12.40, 12.50, 12.98, 13.37, 13.97, 14.47, 14.73, 15.41, 16.11, 16.77, 17.31, 17.56, 17.81, 18.41, 18.78, 19.19, 20.03, 20.48, 20.96, 21.84, 22.41, 23.47, 24.21, 25.23, 26.65, 27.43, 28.42, 28.88, 31.61, 32.72, 35.32, 37.64 + 0.2.

Polymorphic Form B of the N-trityl candesartan of claims 23 and 24, further characterized by:

(i) an XRD having substantially the same pattern as depicted in Figure 4;

(ii) a TGA having substantially the same pattern as depicted in Figure 5; and/or

(iii) a DSC having substantially the same pattern as depicted in Figure 6, wherein the DSC shows first endothermal peak in the range from about 124.22°C to about 135.47°C and the second endothermal peak in the range from about 147.75°C to about 155.73°C.

Brief Description of the Drawings

Figure 1 : X-Ray Diffraction (XRD) pattern of Form A

Figure 2: Thermal Gravimetric Analysis (TGA) pattern of Form A

Figure 3: Differential Scanning Calorimetry (DSC) pattern of Form A

Figure 4: X-Ray Diffraction (XRD) pattern of Form B

Figure 5: Thermal Gravimetric Analysis (TGA) pattern of Form B

Figure 6: Differential Scanning Calorimetry (DSC) pattern of Form B

Table 1: XRD table for Form A

Table 2: XRD table for Form B

Detailed Description of the Invention

The present invention provides for an improved process for the preparation of candesartan cilexetil. The process includes:

(i) preparing polymorphic Form A or Form B of N-trityl candesartan; and (ii) converting N-trityl candesartan Form A or Form B to candesartan cilexetil.

The present invention also provides for substantially pure polymorphic Form A and Form B of N-trityl candesartan.

Polymorphic Form A of N-trityl candesartan exhibits characteristic d-spacing (A⁰) values at 11.06, 7.58, 7.45, 7.36, 6.05, 5.06, 4.83, 4.59, 4.39, 4.33, 4.20, 4.12, 4.07, 3.77 or 3.58. Polymorphic Form B of N-trityl candesartan exhibits characteristic d-spacing (A⁰) values selected at 19.03, 9.59, 7.14, 7.08, 6.82, 6.62, 6.34, 5.29, 4.82, 4.73, 4.63, 4.24, 4.07, 3.97 or 3.79.

The process for the preparation of polymorphic Form A of N-trityl candesartan includes the steps of:

(i) dissolving trityl candesartan in a polar organic solvent at ambient

temperature, optionally heating to dissolve the mixture;

(ii) stirring the reaction mixture, followed by cooling if required;

isolating polymorphic Form A.

The process for the preparation of polymorphic Form B of N-trityl candesartan includes the steps of:

(i) dissolving trityl candesartan in a less polar or non-polar organic solvent at ambient temperature;

(ii) stirring the reaction mixture; and

(iii) isolating polymorphic Form B.

Polymorphic Form A of the N-trityl candesartan of the present invention has d- spacing (A⁰) values at 15.18, 11.06, 10.10, 8.97, 8.57, 8.06, 7.58, 7.45, 7.36, 6.92, 6.85, 6.71, 6.25, 6.05, 5.82, 5.69, 5.52, 5.36, 5.19, 5.06, 5.00, 4.83, 4.59, 4.39, 4.33, 4.20, 4.12, 4.07, 4.02, 3.88, 3.77, 3.58, 3.46, 3.38, 3.31, 3.22, 3.15, 3.08, 3.04, 2.91, 2.87, 2.81, 2.71, 2.67, 2.64, 2.56, 2.49, 2.40 and the corresponding 2-theta values at 5.82, 8.00, 8.75, 9.86, 10.32, 10.98, 11.68, 11.88, 12.03, 12.80, 12.92, 13.20, 14.18, 14.64, 15.21, 15.58, 16.06, 16.54, 17.08, 17.54, 17.76, 18.38, 19.36, 20.25, 20.52, 21.14, 21.59, 21.85, 22.13, 22.90, 23.63, 24.90, 25.72, 26.32, 26.93, 27.74, 28.36, 28.96, 29.42, 30.74, 31.21, 31.90, 33.04, 33.52, 33.97, 35.06, 36.03, 37.40 + 0.2.

Polymorphic Form A of the N-trityl candesartan can also be characterized by: (i) XRD having substantially the same pattern as depicted in Figure 1; (ii) TGA having substantially the same pattern as depicted in Figure 2; and (iii) DSC having substantially the same pattern as depicted in Figure 3, wherein DSC shows the characteristics endotherm peak in the range from about 159.54°C to about 165.08°C.

Polymorphic Form B of the N-trityl candesartan of the present invention has d- spacing (A⁰) values at 19.03, 14.62, 13.60, 12.93, 11.40, 11.04, 10.40, 9.93, 9.59, 8.55, 8.26, 7.97, 7.59, 7.42, 7.14, 7.08, 6.82, 6.62, 6.34, 6.12, 6.01, 5.75, 5.50, 5.29, 5.12, 5.05, 4.98, 4.82, 4.73, 4.63, 4.43, 4.34, 4.24, 4.07, 3.97, 3.79, 3.68, 3.53, 3.35, 3.25, 3.14, 3.09, 2.83, 2.74, 2.54, 2.39 and the corresponding 2-theta values at 4.64, 6.05, 6.50, 6.84, 7.76, 8.01, 8.51, 8.90, 9.22, 10.35, 10.72, 11.11, 11.66, 11.92, 12.40, 12.50, 12.98, 13.37, 13.97, 14.47, 14.73, 15.41, 16.11, 16.77, 17.31, 17.56, 17.81, 18.41, 18.78, 19.19, 20.03, 20.48, 20.96, 21.84, 22.41, 23.47, 24.21, 25.23, 26.65, 27.43, 28.42, 28.88, 31.61, 32.72, 35.32, 37.64 + 0.2.

Polymorphic Form B of the N-trityl candesartan can also be characterized by: (i) XRD having substantially the same pattern as depicted in Figure 4; (ii) TGA having substantially the same pattern as depicted in Figure 5; and (iii) DSC having substantially the same pattern as depicted in Figure 6, wherein the DSC shows two characteristic endothermic peaks, first endothermal peak in the range from about 124.22°C to about 135.47°C and the second endothermal peak in the range from about 147.75°C to about 155.73°C.

The preparation of polymorphic Form A and Form B of the trityl candesartan may include one or more variants as described hereinafter.

"Trityl candesartan or N-Trityl candesartan" as used herein, may include trityl candesartan in any form, such as, solid (dry or wet), semi-solid or in the form of residue obtained from removal of organic layer involving its preparation under vacuum as per the process of the present invention or from any prior art process known to a person skilled in art, for example, the process described in U.S. Patent No. 5,196,444 or WO 2008/035360. Polar solvents for the preparation of Form A of trityl candesartan may include methanol, ethanol, isopropanol, n-butanol, n-pentanol, n-heptanol, tert-butanol, diethylether, diisopropylether, ethylacetate, isopropylacetate, butyl acetate, and the like.

Less polar or non-polar solvents used for the preparation of Form B of the trityl candesartan may include methyltertiarybutyl ether, cyclopentane, cyclohexane, n-pentane, n-hexane, n-heptane, xylene, benzene, toluene, and the like.

"Ambient temperature" used herein refers to a temperature range from about 25°C to about 30°C.

The reaction mixture containing trityl candesartan in polar solvent may be heated from ambient temperature to reflux temperature, wherein reaction mixture is heated up to reflux when ethyl acetate is used as one of the preferred polar solvent for the preparation of Form A. "Reflux" herein refers to the boiling of the suitable solvent used.

The solution containing trityl candesartan in suitable organic solvent may be stirred from about 10 minutes to about 12 hours for preparation of polymorphic Form A of the trityl candesartan and for about 1 hour to 5 hours for Form B.

"Suitable organic solvent" herein refers to solvent used for the preparation of polymorphic Form A or Form B of the trityl candesartan which has been described above.

The solution of trityl candesartan in polar organic solvent may be optionally cooled to about 10°C to 30°C; followed by the addition of a solvent and stirring. The stirring may be carried out from about 1 hour to about 12 hours to obtain Form A.

The isolation of the solid precipitated during/after stirring may be carried out through conventional techniques of filtration, washing and drying under air and/or vacuum for a certain period of time for example, for about 1 hour to 2 hours under reduced pressure followed by air drying for about 40 hours to 48 hours. The drying time can be varied depending on drying temperature; preferably drying is done at 45°C to 55°C.

The isolated crystalline solid refers to substantially pure polymorphic Form A or Form B of trityl candesartan depending upon the type of solvent (polar or less polar/non- polar) used for preparation of corresponding morph which have been confirmed by the XRD, DSC and TGA spectra. One embodiment of the present invention provides substantially pure polymorphic Form A or Form B of trityl candesartan.

"Substantially" herein refers to polymorphic Form A of trityl candesartan having purity greater than 90%, preferably greater than 97%. The suitable range is in between 90% to about 99%, as measured by HPLC area percentage. Polymorphic Form B of trityl candesartan should have a purity greater than 86%, suitably greater than 95%, more suitably in between 86% to about 97% as measured by HPLC area percentage, wherein HPLC parameters include column name Hypersil MOS, 5μ, 150 mm X 4.6 mm; Injection Volume: 20μί; Run time: 35 minutes, potassium dihydrogen ortho phosphate and potassium hydroxide (buffers), acetonitrile as mobile phase and mixture of methanol and dipotassium dihydrogen ortho phosphate (buffer) as diluent.

Polymorphic Form A or Form B of trityl candesartan, as obtained above, have a moisture content less than 0.15% as measured by Karl-Fisher analysis.

Polymorphic Form A or Form B of trityl candesartan can be further converted to candesartan cilexetil. The process includes conversion of polymorphic Form A or Form B of trityl candesartan to trityl candesartan cilexetil followed by detritylation with an organic acid to give candesartan cilexetil having total impurities not more than 0.8% and desethylcandesartan cilexetil less than 0.1%.

The reaction mixture containing Form A or Form B of N-trityl candesartan in a suitable organic solvent, in the presence of base and cilexetil chloride can be heated from about 55°C to about 65°C followed by stirring from about 1 hour to about 3 hours.

Examples of suitable organic solvents include dimethylformamide,

dimethylacetamide and the like. For example, dimethylformamide may be used.

Examples of bases include inorganic bases, such as carbonates and bicarbonates of alkali metals. For example, sodium and potassium carbonates and bicarbonates may be used.

The cooling of the above stirred mixture can be carried out from about 20°C to about 30°C followed by further cooling of the mixture, if required. The usual work-up of the reaction mixture containing trityl candesartan cilexetil may involve extraction with an organic solvent such as halogenated solvents, examples of which may include dichloromethane, chloroform and carbontetrachloride and/or mixtures thereof, followed by removal of solvent under reduced pressure at about 30°C to 35°C. To the residue, another organic solvent like cyclohexane, methyltertiarybutyl ether may be added, followed by stirring of the mixture for about 10 hours to about 15 hours.

The isolation of trityl candesartan cilexetil can be carried out by conventional techniques of filtration, washing and drying under air or vacuum for a certain period of time for example, for about 1 hour to 2 hours. To the isolated solid, an organic solvent, generally the halogenated solvent used in the previous step can be added. This is followed by heating of the reaction mixture to about 30°C to 35°C and then by layer concentration, optionally adding another organic solvents and stirring of the mixture to about 5 hours. Examples of optionally added organic solvent may include cyclohexane,

methyltertiarybutyl ether, and the like. The drying of the isolated solid can be carried out under vacuum for about 18 hours at about 35°C to 40°C. The usual process of re- dissolution of the trityl candesartan cilexetil in suitable solvent followed by isolation are well within the scope of the present invention and can be repeated or varied accordingly by a person skilled in art.

The trityl candesartan cilexetil obtained as per the present invention has purity greater than 98.8%, when measured by HPLC. The content of N-trityldesethylcandesartan cilexetil impurity in the trityl candesartan cilexetil obtained by the present invention is not more than 0.3%.

The preparation of candesartan cilexetil from trityl candesartan cilexetil, obtained above, include following variants as described thereinafter.

The reaction mixture containing trityl candesartan cilexetil and formic acid in suitable organic solvent or mixture of solvents can be heated from about 30°C to about 40°C, followed by stirring for about 5 hours to 7 hours. Examples of suitable organic solvent may include halogenated and alcoholic solvents which may be selected from a group comprising of dichloromethane, chloroform, carbontetrachloride, methanol, ethanol, n-propanol, iso-propanol and the mixtures thereof.

The isolation of the candesartan cilexetil involve usual steps of work-up involving extraction of the cooled mixture at 15°C to 20°C with a suitable solvent or its mixture with water, pH adjustment with solid inorganic base or its solution in water. This is followed by concentration of the organic layer under reduced pressure at about 25 °C to 30°C.

Examples of an extraction solvent include ethylacetate, propylacetate, or the like. Examples of inorganic bases include sodium and potassium bicarbonates and carbonates. After concentration and addition of organic solvent, preferably methylisobutyl ether, the organic layer can be stirred for about 3 hours to 5 hours at ambient temperature; followed by cooling of the reaction mixture to about 5°C to 15°C.

The isolation of candesartan cilexetil can be carried out by conventional techniques of filtration, washing and drying under air or vacuum for a certain period of time, for example, for about 1 hour to 18 hours at about 35°C to 40°C. The variants used in drying, i.e., drying temperature and drying hours can be changed accordingly by a skilled artisan within the scope of the invention.

The candesartan cilexetil obtained by the present invention has HPLC purity greater than 99.2% as measured by area percentage, wherein the HPLC parameters include column name: Hypersil BDS C - 18, 3μπι (100 mm X 4.6 mm); Temperature: 30°C; Flow rate: 1.5 mL/min; Injection Volume: 20 μί; Run time: 65 minutes, sodium acetate trihydrate (buffer), solvent mixture of acetonitrile and methanol as mobile phase and methanol as diluent.

Candesartan cilexetil obtained by the process of the present invention through the use of Form A or Form B of trityl candesartan has total impurity content of not more than 0.8% and desethylcandesartan cilexetil content of less than 0.1%; preferably 0.05%.

The candesartan cilexetil obtained by the present invention after purification is free of desethyl candesartan cilexetil impurity and has purity of 99.9%, when measured by HPLC area percentage, wherein HPLC parameters include column name: Hypersil BDS C - 18 , 3μπι (100 mm X 4.6 mm); Temperature: 30°C; Flow rate: 1.5 mL/min; Injection Volume: 20 μί; Run time: 65 minutes, sodium acetate trihydrate (buffer), solvent mixture of acetonitrile and methanol as mobile phase and methanol as diluent.

The candesartan cilexetil as obtained by the present invention can be used for the preparation of polymorphs, salts and solvates thereof. "Polymorphs" of candesartan cilexetil, as described herein, may include any crystalline or amorphous form known in the prior art including solvates and hydrates, preferably C-type crystal (Form I).

In the following section preferred embodiments are described by way of examples to illustrate the process. However, these are not intended in any way to limit the scope of the claims. Several variants of these examples would be evident to persons ordinarily skilled in the art.

EXAMPLES

Example 1: Preparation of Trityl Candesartan Step 1:

Candesartan (85 gm) was added to dichloromethane (680mL) at 25°C to 30°C followed by refluxing and azeotropic removal of dichloromethane (3 times) at the same temperature. The reaction mixture was cooled to 20°C to 30°C followed by addition of triethylamine (21.285 gm) and stirring of the mixture to get clear solution. Trityl chloride solution (59.716 gm in 85 mL dichloromethane) was added to the above solution in 45 minutes at 25°C to 30°C followed by heating of the reaction mixture to 30°C to 35°C.

The reaction mixture was stirred for 3 hours at the same temperature followed by cooling of the reaction mixture to 10°C to 15°C which was washed with ice cold de- ionized water twice (425 mL each) followed by collection of the organic layer which was divided into 10 equal parts for the isolation of polymorphic forms.

Step 2:

One part of the organic layer obtained from above step containing trityl candesartan was concentrated under vacuum at 30°C to 35°C to get trityl candesartan in the form of residue; methanol (8.5 mL) was added to the residue to remove traces of dichloromethane under vacuum. Different solvents employed for isolation of polymorphic forms as per the examples provided herein, are used for removing the traces of

dichloromethane under vacuum from trityl candesartan residue obtained by concentration of organic layer involving the similar conditions as mentioned above.

Step 3: Preparation of Form A of trityl candesartan: To the trityl candesartan residue (-13.2 gm) obtained from step 2 of Example 1, methanol (85 mL) was added at 25°C to 30°C to get suspension which was stirred for 1 hour at the same temperature. The precipitated solid was filtered, washed with methanol (8.5 mL) and dried under vacuum for 1 hour. The above crystalline solid was further air dried at 50°C to 55°C for 48 hours.

Yield: 91.61%

Chromatographic purity: 97.56%

Example 2: Preparation of Form A of Trityl Candesartan

To the trityl candesartan residue (-13.3 gm) obtained from step 2 of Example 1, isopropanol (40 mL) was added at 25 °C to 30°C to get clear solution which becomes sticky after 20 minutes of stirring followed by addition of isopropanol to the above reaction mixture (16 mL) and further cooling at 15°C to 20°C. The reaction mixture was stirred at the same temperature for 12 hours followed by precipitation of a solid which was filtered, washed with isopropanol (8.5 mL) and dried under the same conditions as described in step 3 of Example 1.

Yield: 76.5%

Chromatographic purity: 92.23%

Example 3: Preparation of Form A of Trityl Candesartan

A mixture of trityl candesartan residue (-13.3 gm) obtained from step 2 of Example 1 and tert-butanol (42.5 mL) was heated at 30°C to 35°C to get a suspension which was stirred at the same temperature for 12 hours; followed by filtration of isolated solid which was washed with tert-butanol (8.5 mL) and dried under the same conditions as discussed in step 3 of Example 1.

Yield: 82%

Chromatographic purity: 95.14%

Example 4: Preparation of Form A of Trityl Candesartan

Trityl candesartan residue (-13.2 gm) obtained from step 2 of the Example 1 and ethyl acetate (51 mL) was heated to reflux at 75°C to 78°C followed by stirring for 1 hour at the same temperature. The reaction mixture was cooled to 25°C to 30°C followed by further stirring for 1 hour. The precipitated solid was filtered, washed with ethyl acetate (8.5 mL) and dried under the same conditions as discussed in step 3 of Example 1.

Yield: 76.12%

Chromatographic purity: 94.55%

Example 5: Preparation of Form A of Trityl Candesartan

The trityl candesartan residue (-13.3 gm) obtained from step 2 of Example 1 and diisopropyl ether (40 mL) was stirred for 2 hours at 25 °C to 30°C. The precipitated solid was filtered, washed with diisopropyl ether (8.5 mL) and dried under the same conditions as mentioned in step 3 of Example 1.

Yield: 84.4%

Chromatographic purity: 91.69%

Similar experiment was performed with diethylether (-13.2 gm) to get Form A

Yield: 84.1%

Chromatographic purity: 90.11%

Example 6: Preparation of Form B of Trityl Candesartan

The trityl candesartan residue (-13.2 gm) obtained from step 2 of Example 1 and methyltertiary butyl ether (40 mL) was stirred for 2 hours at 25°C to 30°C. The precipitated solid was filtered, washed with methyltertiary butyl ether (8.5 mL) and dried under the same conditions as mentioned in step 3 of Example 1 to get Form B.

Yield: 83.8%

Chromatographic purity: 90.79%

Similar experiments were carried out with trityl candesartan residue (-13.2 gm each) using cyclohexane, xylene, n-pentane, n-heptane to get Form B.

Yield: 98.06% (cyclohexane)

Chromatographic purity: 86.54%

Yield: 82.6% (xylene) Chromatographic purity: 95.56%

Yield: 84.4% (n-pentane)

Chromatographic purity: 89.5%

Yield: 83.74% (n-heptane)

Chromatographic purity: 89.9%

Example 7: Preparation of Candesartan Cilexetil

Step I: Preparation of N-trityl candesartan cilexetil

A mixture of N-trityl candesartan (Form A: 120 gm), potassium carbonate (48.58 gm), cilexetil chloride (54.48 gm) and dimethyl formamide (180 mL) at ambient temperature was heated to 60°C to 65°C followed by stirring at the same temperature for 2 hours and 30 minutes. The reaction mixture was cooled to 25 °C to 30°C followed by addition of dichloromethane (600 mL) and ice cooled de-ionized water (1200 mL) at 10°C to 15°C to the reaction mass. The reaction was further stirred at 15°C to 20°C for 30 minutes followed by extraction of the aqueous layer with dichloromethane (120 mL) at 15°C to 30°C and washing with de-ionized water (2x600 mL) at ambient temperature.

The organic layer was concentrated completely under vacuum at 30°C to 35°C followed by removal of traces of dichloromethane with cyclohexane (120 mL) and the further addition of cyclohexane (360 mL) to the residue at the ambient temperature. The reaction mixture was stirred at the same temperature for 14 hours followed by filtration and washing of the solid with cyclohexane (120 mL) which was suck dried under vacuum for 1 hour. Dichloromethane was again added (360 mL) at ambient temperature to the isolated solid followed by heating and stirring of the reaction mass at 30°C to 35°C for 30 minutes. The organic layer was concentrated under vacuum at 30°C to 35°C, cyclohexane (300 mL) added and the reaction mass was stirred further for 5 hours at the same temperature. The solid was filtered, washed with cyclohexane (120 mL) and suck dried under vacuum for 1 hour followed by further drying under vacuum for 16 hours at 35°C to 40°C.

Chromatographic purity: 98.8%

N-trityl desethylcandesartan cilexetil- 0.28%

Step 2: Preparation of candesartan cilexetil A mixture of N-trityl candesartan cilexetil (120 gm) in dichloromethane (720 mL) and methanol (360 mL) was taken in a round botton flask at ambient temperature followed by addition of formic acid (120 gm) over 5 minutes. The reaction mixture was heated to 30°C to 35°C and stirred at the same temperature for 7 hours. The reaction mixture was cooled to 15°C, and ethyl acetate (480 mL) and de-ionized water (480 mL) were charged to the reaction mixture; this was followed by pH adjustment with 10% aqueous sodium bicarbonate (1750 mL) at 15°C to 20°C. Ethyl acetate (120 mL) and de-ionized water (120 mL) were charged to the reaction and stirred for 20 minutes at the same temperature. The aqueous layer was extracted with ethyl acetate (2 X 240 mL) and ethyl acetate (240 mL) was added to the combined organic layer which was further washed with 20% aqueous sodium chloride. The organic layer was concentrated completely under vacuum at 25 °C to 30°C and methyltertiarybutyl ether (120 mL) was added to remove the traces of ethyl acetate at the same temperature. Methyltertiarybutyl ether (480 mL) was added to the reaction mixture, stirred for 4 hours to 5 hours at ambient temperature, and cooled to 8°C to 12°C. The cooled reaction mixture was further stirred for 8 hours 12 hours, solid were filtered. The reaction mixture was washed with pre-cooled methyltertiarybutyl ether(120 mL) at 8°C to 12°C and dried under vacuum for 1 hour and further dried for 16 hours at 35°C to 40°C.

Yield: 84%

Chromatographic purity: 99.24%

Desethyl candesartan cilexetil- 0.05 %

Step 3: Purification of candesartan cilexetil

Crude candesartan cilexetil (50 gm) was suspended in acetone (350 mL) at ambient temperature and stirred for 30 minutes at the same temperature. The resulting solution was filtered to remove insoluble particles and the obtained filtrate was warmed to 35°C to 40°C and de-ionized water (150 mL) was added at the same temperature. The resulting mass was slowly cooled to 2°C to 6°C in 1.5 hours and further stirred for 5 hours at the same temperature. The solid obtained was filtered, washed with chilled mixture of acetone:de-ionized water (2 X (35+35 mL)) and dried under vacuum at 35°C to 40°C to give pure candesartan cilexetil.

Yield: 85% Chromatographic purity: 99.77%

Desethyl candesartan cilexetil -ND

The candesartan cilexetil (30 gm) obtained above was heated in methanol (270 mL) in a round bottom flask at 35°C to 40°C and then cooled to 13°C to 17°C in 1 hour. The reaction mixture was stirred further for 7 hours and the solid was filtered and further washed with chilled methanol (12 mL). This was finally dried under vacuum at 35°C to 40°C for 16 hours.

Yield : 88%

Chromatographic purity: 99.90%

Desethyl candesartan cilexetil -ND

Ethyl candesartan-0.076%

Claims

We claim:

1. An improved process for the preparation of candesartan cilexetil wherein the process comprises:

(i) preparing a polymorphic Form A or Form B of N-trityl candesartan; and (ii) converting Form A or Form B N-trityl candesartan to candesartan cilexetil.

2. The process according to claim 1, wherein the preparation of polymorphic Form A or Form B of N-trityl candesartan further comprises involves isolation of the polymorphs.

3. The process according to claim 1, wherein the preparation of polymorphic Form A of N-trityl candesartan comprises the steps of:

(iv) dissolving trityl candesartan in a polar organic solvent at ambient

temperature, optionally heating to dissolve the mixture;

(v) stirring the reaction mixture followed by cooling if required; and

(vi) optionally, stirring the mixture obtained from step (ii) after cooling and

isolating polymorphic Form A.

4. The process according to claim 3, wherein the polar organic solvent is selected from the group comprising of methanol, ethanol, isopropanol, n-butanol, n-pentanol, n- heptanol, tert-butanol, diethylether, diisopropylether, ethylacetate, isopropylacetate, butyl acetate and/or mixtures thereof.

5. The process according to claim 3, wherein the heating of the reaction mixture is carried out from ambient temperature to about reflux temperature of the polar solvent.

6. The process according to claim 3, wherein the stirring of the reaction mixture obtained in step (i) is carried out from about 10 minutes to about 12 hours.

7. The process according to claim 3, wherein the reaction mixture obtained after stirring in step (ii) is cooled to about 10°C to 30°C.

8. The process according to claim 7, wherein reaction mixture obtained after cooling is further stirred for about 1 hour to about 12 hours.

9. The process according to claim 3, further comprising drying of the isolated polymorphic Form A of the N-trityl candesartan under reduced pressure for about 1 hour to 2 hours and further in air for about 40 hours to 48 hours.

10. The process according to claim 9, wherein drying of the polymorphic Form A of the N-trityl candesartan is carried out at about 45°C to 55°C.

11. The process according to claim 1, wherein the preparation of polymorphic Form B of N-trityl candesartan comprises the steps of:

(iv) dissolving trityl candesartan in a less polar or non-polar organic solvent at an ambient temperature;

(v) stirring the reaction mixture; and

(vi) isolating polymorphic Form B.

12. The process according to claim 11, wherein the less polar or non-polar solvent is selected from the group comprising of methyltertiarybutyl ether, cyclopentane, cyclohexane, n-pentane, n-hexane, n-heptane, xylene, benzene, toulene and/or mixtures thereof.

13. The process according to claim 11, wherein the stirring of the reaction mixture is carried out from about 1 hour to about 5 hours.

14. The process according to claim 11, further comprising drying of the isolated polymorphic Form B of the N-trityl candesartan under reduced pressure for about 1 hour to 2 hours and further in air for about 40 hours to 48 hours at 45°C to 55°C.

15. The process according to claim 1, wherein the polymorphic Form A or Form B of N-trityl candesartan has total impurities of not more than 0.8% and a level of desethyl candesartan cilexetil impurity less than 0.1%.

16. Substantially pure polymorphic Form A and Form B of N-trityl candesartan.

17. The polymorphic Form A of N-trityl candesartan according to claim 16, wherein Form A has a chromatographic purity of between 90% and about 99%, when measured by HPLC area percentage.

18. The polymorphic Form B of N-trityl candesartan according to claim 16, wherein the Form B has chromatographic purity of greater than 86% when measured by HPLC area percentage.

19. The polymorphic Form A and Form B of N-trityl candesartan of claim 16, wherein the moisture content is less than 0.15%.

20. Polymorphic Form A of N-trityl candesartan comprising characteristic d-spacing (A⁰) values at 11.06, 7.58, 7.45, 7.36, 6.05, 5.06, 4.83, 4.59, 4.39, 4.33, 4.20, 4.12, 4.07, 3.77 or 3.58.

21. The polymorphic Form A of N-trityl candesartan of claim 20, further comprising X-ray diffraction peaks expressed in degrees two-theta at 5.82, 8.00, 8.75, 9.86, 10.32, 10.98, 11.68, 11.88, 12.03, 12.80, 12.92, 13.20, 14.18, 14.64, 15.21, 15.58, 16.06, 16.54, 17.08, 17.54, 17.76, 18.38, 19.36, 20.25, 20.52, 21.14, 21.59, 21.85, 22.13, 22.90, 23.63, 24.90, 25.72, 26.32, 26.93, 27.74, 28.36, 28.96, 29.42, 30.74, 31.21, 31.90, 33.04, 33.52, 33.97, 35.06, 36.03, 37.40 + 0.2.

22. Polymorphic Form A of the N-trityl candesartan of claims 20 and 21, further characterized by:

(i) an XRD having substantially the same pattern as depicted in Figure 1;

(ii) a TGA having substantially the same pattern as depicted in Figure 2; and/or (iii) a DSC having substantially the same pattern as depicted in Figure 3, wherein the DSC shows the characteristics endotherm peak in the range from about 159.54°C to about 165.08°C

23. Polymorphic Form B of N-trityl candesartan comprising characteristic d-spacing (A⁰) values at 19.03, 9.59, 7.14, 7.08, 6.82, 6.62, 6.34, 5.29, 4.82, 4.73, 4.63, 4.24, 4.07, 3.97 or 3.79.

24. The polymorphic Form B of N-trityl candesartan of claim 23, further comprising X-ray diffraction peaks expressed in degrees two-theta at 4.64, 6.05, 6.50, 6.84, 7.76, 8.01, 8.51, 8.90, 9.22, 10.35, 10.72, 11.11, 11.66, 11.92, 12.40, 12.50, 12.98, 13.37, 13.97, 14.47, 14.73, 15.41, 16.11, 16.77, 17.31, 17.56, 17.81, 18.41, 18.78, 19.19, 20.03, 20.48,

20.96,

21.84,

22.41,

23.47,

24.21, 25.23, 26.65, 27.43, 28.42, 28.88, 31.61, 32.72, 35.32, 37.64 + 0.2.

25. Polymorphic Form B of the N-trityl candesartan of claims 23 and 24, further characterized by:

(i) an XRD having substantially the same pattern as depicted in Figure 4;

(ii) a TGA having substantially the same pattern as depicted in Figure 5; and/or (iii) a DSC having substantially the same pattern as depicted in Figure 6, wherein the DSC shows first endothermal peak in the range from about 124.22°C to about 135.47°C and the second endothermal peak in the range from about 147.75°C to about 155.73°C.