WO2011080684A1

WO2011080684A1 - Process for the preparation of candesartan cilexetil

Info

Publication number: WO2011080684A1
Application number: PCT/IB2010/056066
Authority: WO
Inventors: Kaptan Singh; Lakshmipathi V. Sanjeevi; Krishnarao Tukaram Shirsath; Sanjeev Kumar Arora; Ashok Kumar; Suresh Allada
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2009-12-31
Filing date: 2010-12-23
Publication date: 2011-07-07
Also published as: WO2011080684A4; WO2011080684A9

Abstract

The present invention provides an improved process for the preparation of candesartan and pharmaceutically acceptable salts and esters thereof for use in the treatment of hypertension and related diseases. Specifically, it refers to the deprotection of tetrazolyl -protecting group of candesartan or its derivative in the presence of iodine in one or more alcoholic solvents.

Description

PROCESS FOR THE PREPARATION OF CANDESARTAN CILEXETIL

Field of the Invention

The present invention provides an improved process for the preparation of

candesartan and pharmaceutically acceptable salts and esters thereof for use in the treatment of hypertension and related diseases.

Background of the Invention

Candesartan cilexetil of Formula I is a prodrug and is chemically described as (±)-l- Hydroxyethyl-2-ethoxy- 1 - [p-(o- lHtetrazol-5-ylphenyl)benzyl] -7-benzimidazole carboxylate, cyclohexyl carbonate (ester). It is a selective angiotensin II receptor antagonist and is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents and is represented by the structural Formula I as shown below.

Formula I

U.S. Patent Nos. 5,196,444 and 5,578,733 describe the removal of a trityl protecting group of the N-protected tetrazolyl compounds using methanol in the presence of a mineral acid, such as hydrochloric acid, which requires complex extractions or chromatographic purification to produce pure candesartan cilexetil.

U.S. Patent No. 7,345,072 describes the deprotection of tetrazolyl compounds, including candesartan cilexetil, in the presence of an anhydrous mineral acid or aqueous mineral acid at a concentration higher than 20% w/w. The strong acidic conditions produce more decomposition products and thereby reduces the overall purity of the final product.

WO 05/021535 discloses the preparation of candesartan cilexetil by the deprotection of trityl moiety at a reflux temperature in the presence of anhydrous Ci to C₅ alcohol under neutral or slightly basic conditions involving longer reaction time (for e.g. stirring for several hours, such as 18-24 hours); this is followed by removal of the triphenylmethylether moiety precipitated as a solid, and thereby increases the number of reaction steps. WO 05/037821 describes the deprotection of the trityl candesartan cilexetil by the use of methane sulphonic acid, p-toluene sulphonic acid, formic and trifluoroacetic acid in solvent mixture or by refluxing candesartan cilexetil in mixture of toluene, water, and methanol. The initial product obtained by these procedures is mostly a viscous oil or a semi solid, which is difficult to handle.

WO 07/074399 and WO 07/042161 disclose the preparation of candesartan cilexetil from trityl candesartan cilexetil involving Lewis acids such as boron trifluoride, zinc chloride, aluminium trihalide, or titanium tetrachloride which are costly and thus are not commercially viable.

The present inventors have now found an improved process for the preparation of candesartan or its derivatives which is simple, convenient to operate, and uses readily available raw materials.

Summary of the Invention

In one general aspect, the present invention provides for a process for the preparation of candesartan or its derivatives. The process includes:

(a) removing a tetrazolyl-protecting group of candesartan or its derivative in the presence of iodine in one or more alcoholic solvents;

(b) optionally adding a second solvent;

(c) heating the reaction mixture; and

(d) isolating candesartan or its derivative.

Embodiments of this aspect may include one or more of the following features. For example, the alcoholic solvent used in step (a) may include methanol, ethanol, n-propanol, n- butanol, n-pentanol, n-hexanol, n-heptanol, n-octanol and/or mixtures thereof. The second solvent may be chloroform, dichloromethane, carbon tetrachloride, ethylene dichloride and/or mixtures thereof.

The heating of the reaction mixture is carried out at the temperature from about 35°C to about reflux temperature. The stirring of the reaction mixture is carried out from about 1 hour to about 10 hours. The isolation of the solid obtained in step (d) involves purification from a suitable organic solvent that includes the heating of the mixture at the temperature from about 25°C to about 45°C. The suitable organic solvent may be either ethers and/or hydrocarbon solvents. The ether may be methyl tertiary butyl ether, tetrahydrofuran, 1,4-dioxane and/or mixtures thereof. The hydrocarbon solvent may be pentane, hexane, n-heptane, n-octane,

cyclopentane, cyclohexane, benzene, toluene or o, m, p- xylenes.

The drying of the solid is carried out in air at a temperature from about 30°C to about 60°C. The purification from a ketonic solvent or a mixture with water involves heating from about 35°C to about 50°C. The ketonic solvent is selected from the group of acetone, 2- butanone, 2-pentanone, 3-pentanone, 2-hexanone, 2-heptanone, 2-octanone and/or mixtures thereof.

The isolation of the solid includes the cooling of the reaction mixture from about 0°C to about 15°C. The isolation may further include drying the solid in air at the temperature from about 30°C to about 50°C.

In another general aspect, the present invention includes a process for the preparation of candesartan or its derivatives. The process includes:

(a) treating trityl candesartan cilexetil having the structure of Formula II

Formula II

with iodine in an alcoholic solvent or mixtures;

(b) optionally adding a second solvent;

(c) heating the reaction mixture; and

(d) isolating candesartan cilexetil.

Embodiments of this aspect may include one or more of the following features. For example, the alcoholic solvent used in step (a) may be methanol, ethanol, n-propanol, n- butanol, n-pentanol, n-hexanol, n-heptanol, n-octanol and/or mixtures thereof. The second solvent includes chloroform, dichloromethane, carbon tetrachloride, ethylene dichloride and/or mixtures thereof.

The heating of the reaction mixture is carried out at the temperature from about 35°C to about reflux temperature. The stirring of the reaction mixture is carried out from about 1 hour to about 10 hours. The isolation of the solid obtained in step (b) involves purification from a suitable organic solvent that includes the heating of the mixture at the temperature from about 25 °C to about 45 °C. The suitable organic solvent may be ethers and/or hydrocarbon solvents. The ether may be methyl tertiary butyl ether, tetrahydrofuran, 1,4- dioxane and/or mixtures thereof. The hydrocarbon solvent may be pentane, hexane, n- heptane, n-octane, cyclopentane, cyclohexane, benzene, toluene or o, m, p- xylenes.

The purification from a ketonic solvent or its mixture with water involves heating from about 35°C to about 50°C. The ketonic solvent is selected from the group of acetone, 2- butanone, 2-pentanone, 3-pentanone, 2-hexanone, 2-heptanone, 2-octanone and/or mixtures thereof.

The isolation of the solid includes the cooling of the reaction mixture from about 0°C to about 15°C. The process further includes drying the solid in air at the temperature from about 30°C to about 50°C.

In another general aspect, the present invention provides for candesartan cilexetil comprising HPLC purity greater than 99% and desethyl impurity content less than 0.2%.

Detailed Description of the Invention

The present invention provides for a process for the preparation of candesartan or its derivatives, which includes the steps of:

(a) removing the tetrazolyl-protected group of candesartan or its derivative in the presence of iodine, in one or more alcoholic solvents;

(b) optionally adding a second solvent; and heating the reaction mixture; and

(c) isolating candesartan or its derivative.

The alcoholic solvent can be selected from methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n-heptanol, n-octanol or a mixture thereof. The second solvent in step (b) can be selected from chloroform, dichloromethane, carbontetrachloride, ethylene dichloride and/or mixtures thereof.

The present invention also included candesartan or its derivatives as obtained above, including candesartan cilexetil containing a desethyl impurity content less than 0.6%, preferably less than 0.5% and a purity greater than or equal to about 98% when measured by HPLC area percentage. Candesartan or its derivatives may be purified from a ketonic solvent or their mixtures and/or a mixture with water.

"Derivatives of candesartan" herein refers to pharmaceutically acceptable salts and esters.

The reaction mixture containing a tetrazolyl protected derivative of candesartan in an alcoholic solvent or their mixtures in the presence of iodine can be heated from about 35°C to about reflux temperature followed by stirring.

As used herein, the term "about" when used in reference to defined parameter like temperature, indicates inherent variability in, for example, measuring the parameter or achieving the parameter and refers to variation by +5°C.

"Reflux temperature" herein refers to the temperature at which solvent/solvent mixture starts boiling.

The term "tetrazolyl protecting group" as used herein may include, but is not limited groups including optionally substituted multiphenylmethyl groups (e.g., triphenylmethyl (trityl), 4-methoxy triphenylmethyl, 4,4'-dimethoxytriphenylmethyl, 4,4',4"- trimethoxytriphenyl methyl, 4,4'-dimethoxydiphenyl methyl and the like), 2- nitrobenzenesulfenyl and benzhydryl.

The solution of iodine in an alcoholic solvent or mixtures thereof can be prepared at room temperature (25 °C to 30°C) or by heating.

Alcoholic solvent may include Ci-C₈ straight or branched chain alcohols which can be primary, secondary, tertiary, comprising of methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, ter-butanol, n-pentanol, n-hexanol, n-heptanol, n-octanol and the like.

The second solvent used herein is a halogenated solvent which may be optionally added to the alcoholic mixture of tetrazolyl-protected candesartan and iodine, examples of which may include chloroform, dichloromethane, carbontetrachloride, ethylene dichloride and/or mixtures thereof. It is generally observed that the addition of the second solvent helps in increasing the final purity of the candesartan or its derivatives including candesartan cilexetil. The stirring of the above reaction mixture containing the tetrazolyl protected derivative of candesartan and iodine in an alcoholic solvent may be carried out for about 1 hour to about 10 hours to get a clear solution at the same temperature. Stirring time may be changed accordingly, depending upon the temperature used for heating by a person of ordinary skill in the art.

The solvent/solvent mixture may be removed to get the residual solid material. The removal of the solvent/solvent mixture may be carried out by any means known to a person of ordinary skill in the art, including for example concentration, evaporation or distillation.

The residual solid material can be further dissolved in a halogenated solvent followed by washing with an aqueous sodium thiosulfate solution and de-ionized water. Examples of halogenated solvents are as described above.

The organic layer so obtained may be dried over sodium sulfate and concentrated under reduced pressure and/or optionally charcolized with active carbon. This is followed by filtration over hyflobed to get solid mass, which then may be further dissolved in a suitable organic solvent, for purification from about ambient temperature to about 45 °C and stirred for about 7 hours to about 15 hours at the same temperature.

"Ambient temperature" herein refers to room temperature (25°C to 30°C).

Examples of suitable organic solvents may include ethers, such as, methyl tertiary butyl ether, tetrahydrofuran, 1,4-dioxane or aliphatic, alicyclic and aromatic hydrocarbons, such as, pentane, hexane, n-heptane, n-octane, cyclopentane, cyclohexane, benzene, toluene, o, m, p-xylenes and the like.

The product obtained after stirring can be isolated by any conventional means known to a person of ordinary skill in the art including decantation, filtration or centrifugation.

The isolated solid can be dried under vacuum and/or air or by any other drying means known in the prior art. The drying of the solid can be carried out in air at a temperature from about 30°C to about 60°C or can be changed accordingly depending on the drying parameters (drying hours and drying temperature) used by a person of ordinary skill in the art.

The candesartan or its derivatives, including candesartan cilexetil, as obtained by the process described above contains the desethyl impurity at a content of less than 0.6%, preferably less than 0.5% , additionally, the purity is greater than or equal to about 98% when measured by HPLC area percentage.

The candesartan derivatives obtained above can be further purified in a ketonic solvent and/or a mixture with water under heat.

Examples of ketonic solvent may include acetone, 2-butanone, 2-pentanone, 3- pentanone, 2-hexanone, 2-heptanone, 2-octanone and/or mixtures thereof.

The heating of the above solution may be carried out at a temperature of from about 35°C to about 50°C and is followed by the addition of water, optionally at the same temperature. The reaction mixture may be slowly cooled to a temperature range of about 0°C to about 15°C and is stirred for several hours, for example 2 hours to 5 hours.

The product obtained during or after stirring can be isolated through conventional means known to a person of ordinary skill in the art including decantation, filtration or centrifugation. The solid so obtained can be further purified in a mixture of a ketonic solvent and water as mentioned above.

The isolated solid can be dried under a vacuum, air or by any other drying means known in the art. The drying of the solid can be carried out in air at a temperature from about 30°C to about 50°C.

The candesartan or its derivatives, including candesartan cilexetil as obtained above after purification, has a desethyl impurity content of less than 0.2%, preferably less than 0.1%; and has a purity greater than 99% when measured by HPLC area percentange.

The present invention also provides a process for the preparation of candesartan cilexetil including the steps of:

(a) treating trityl candesartan cilexetil with iodine in an alcoholic solvent;

(b) optionally adding a second solvent and heating the reaction mixture; and

(c) isolating candesartan cilexetil.

The present invention also provides for candesartan cilexetil having a desethyl impurity content of less than 0.4%, and preferably less than 0.05%. The present invention also provides candesartan cilexetil having purity greater than 99%, preferably greater 99.7%

The candesartan cilexetil obtained as per the present invention can be further purified in an alcoholic solvent. The process includes the heating of the reaction mixture from about 35°C to about reflux temperature followed by the cooling of the reaction mixture to a temperature range of about 5°C to about 20°C, stirring for about 4 hours to 8 hours, isolation of the solid using conventional means, for example, decantation, filtration, centrifugation or evaporation and drying under vacuum and/or air. The final product obtained as per the procedures of the present invention is in any crystalline or amorphous form, preferably in C- type crystal.

The present invention provides candesartan cilexetil having purity greater than 99%, more preferably greater than 99.6%, most preferably greater than 99.7% when measured by HPLC area percentage. 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 min, sodium acetate trihydrate (buffer), solvent mixture of acetonitrile and methanol as mobile phase and methanol as diluent.

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 Candesartan Cilexetil Step I:

Trityl candesartan cilexetil (10 gm, 0.0117moles) was added to a mixture of methanol (100 mL) and iodine (0.3gm, 0.001181 moles) in a round bottom flask and the resulting solution was stirred for 15 minutes at ambient temperature to get a clear solution. The mixture was heated to 57°C to 58°C and stirred for 4 hours to 5 hours at the same

temperature, followed by removal of the methanol under reduced pressure, to get the residual mass. The residual mass so obtained was dissolved in dichloromethane (60mL) and washed with a 5% aqueous sodium thiosulfate (lOOmL) solution followed by washing of the organic layer with de-ionized water (40 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get the residual mass. This was followed by the addition of cyclohexane (lOOmL) and subsequent stirring for 12 hours at ambient

temperature. The solid obtained was filtered, washed with cyclohexane (20mL) and air dried at 40°C to get crude candesartan cilexetil.

Yield: 7.45 gm

Step II:

Purification of candesartan cilexetil:

Crude candesartan cilexetil (7gm) was suspended in acetone (60mL) at ambient temperature and stirred for 15 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. This was followed by the addition of de-ionized water (22mL) at the same temperature. The resulting mass was slowly cooled to 2°C to 6°C and stirred for a further for 3 hours to 3.5 hours. The wet solid was again suspended in a mixture of acetone (47 mL) and de-ionized water (20 mL) at 35°C to 40°C. The resulting mass was slowly cooled to 8°C to 12°C and stirred further for 4 hours. The solid obtained was filtered, washed with chilled mixture of acetone:de-ionized water (20 mL, 1:1) and air dried at 40°C to give pure candesartan cilexetil.

Yield: 3.97gm

Chromatographic purity: 99.34%

Desethyl candesartan cilexetil: 0.29%

Example 2: Preparation of Candesartan Cilexetil

Trityl candesartan cilexetil (lOgm) was added to a mixture of iodine (0.3gm, 0.00118 moles), methanol (100 mL) and dichloromethane (lOmL) at ambient temperature. The resulting mixture was heated to 57°C to 58°C and stirred for 90 to 120 minutes at the same temperature to get the clear solution. This was followed by the removal of the solvent mixture under reduced pressure to get residual mass. The residual mass was dissolved in

dichloromethane (lOOmL), washed with 5% aqueous sodium thiosulfate (40mL) solution, and washed with de-ionized water twice (2 X 20 mL). The organic layer was dried over sodium sulfate and charcoalized with activated carbon (0.25gm) followed by filtration over hyflo bed. The obtained filtrate was concentrated under reduced pressure to get the residual mass. Cyclohexane (lOOmL) was added and the resulting reaction mixture was stirred for 12 hours at ambient temperature. The solid obtained was filtered, washed with cyclohexane (20mL) and air dried at 40°C to 45°C to get crude candesartan cilexetil.

Yield: 7.2 gm

The solid (7.0 gm) as obtained above was purified involving Step II of the Example 1 to provide pure candesartan cilexetil.

Yield: 5.68g

Chromatographic purity: 99.72%

Desethyl candesartan cilexetil: 0.01%

Example 3: Preparation of Candesartan Cilexetil Step I:

Methanol (20mL) and iodine (0.2966gm) were stirred in a round bottom flask for 15 minutes at 25°C to 30°C to get clear solution. This was followed by the addition of N-trityl candesartan cilexetil (lOgm) and dichloromethane (40mL). The reaction mixture was heated to reflux at 38°C to 40°C for 9 hours, followed by concentration of the reaction mass under vacuum at 30°C to 35°C to get the dark brown colour residue. To the obtained residue dichloromethane (lOOmL) was added, and the mixture was stirred to get clear solution followed by washing with 5% aqueous sodium thiosulphate (2.5gm in 50mL of de-ionized water). The reaction mixture was further stirred at 25 °C to 30°C for 30 minutes, the layers were separated and the organic layer was washed with de-ionized water twice (2 X 20mL). This was followed by the removal of the solvent under vacuum at 30°C to 32°C. Methyl tertiarybutyl ether (50mL; MTBE) was added at 25 °C to 30°C, the reaction mixture was stirred for 14 hours, the solid was filtered and washed with the same solvent (lOmL) and dried under vacuum at 35°C to 40°C for 8 hours to 12 hours.

Dry Weight: 5.4 gm

Yield: 0.54 w/w

Chromatographic Purity: 98.92% Desethyl candesartan cilexetil: 0.18%

The solid (4.0 gm) as obtained above was purified involving Step II of the Example 1 to provide pure candesartan cilexetil.

Dry weight: 3.4g Yield: 0.85 w/w

Chromatographic purity: 99.32%

Desethyl candesartan cilexetil: 0.04%

Step II:

Candesartan cilexetil (2.5gm) obtained from Step 1 was heated in methanol (22.5mL) in a round bottom flask at 35°C to 40°C followed by the cooling of the reaction mixture to 13°C to 17°C over 40 minutes. The reaction mixture was stirred further for 6.5 hours and then filtrated wherein the solid was washed with chilled methanol (ImL) and dried under vacuum at 35°C to 40°C for 12 hours.

Dry weight: 2.2 gm

Yield: 0.88 w/w

Chromatographic purity: 99.79%

Desethyl candesartan: 0.018%

Example 4:

Step I of the Example 3 was repeated using cyclohexane instead of methyl tertiarybutyl ether for the isolation of the crude candesartan cilexetil (5.2 gm) which was further purified as per description provided in Example 3 to provide pure candesartan cilexetil.

Dry weight: 1.32 gm

Yield: 0.88 w/w

Chromatographic purity: 99.15%

Desethyl candesartan cilexetil: 0.19%

Claims

RI-WO 2011/080684 PCT/IB2010/056066 12 We claim:

1. A process for the preparation of candesartan or its derivatives, the process

comprising:

(b) optionally adding a second solvent;

(c) heating the reaction mixture; and

(d) isolating candesartan or its derivative.

2. The process according to claim 1, wherein the alcoholic solvent used in step (a)

comprises methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n- heptanol, n-octanol and/or mixtures thereof.

3. The process according to claim 1, wherein the second solvent comprises chloroform, dichloromethane, carbon tetrachloride, ethylene dichloride and/or mixtures thereof.

4. The process according to claim 1, wherein the heating of the reaction mixture is

carried out at the temperature from about 35°C to about reflux temperature.

5. The process according to claim 1, wherein the stirring of the reaction mixture is

carried out from about 1 hour to about 10 hours.

6. The process according to claim 1, wherein the isolation of the solid obtained in step (d) involves purification from a suitable organic solvent comprising the heating of the mixture at the temperature from about 25 °C to about 45 °C.

7. The process according to claim 6, wherein the suitable organic solvent comprises ethers and/or hydrocarbon solvents.

8. The process according to claim 7, wherein the ether comprises methyl tertiary butyl ether, tetrahydrofuran, 1,4-dioxane and/or mixtures thereof.

9. The process according to claim 7, wherein the hydrocarbon solvent comprises

pentane, hexane, n-heptane, n-octane, cyclopentane, cyclohexane, benzene, toluene or o, m, p- xylenes.

10. The process according to claim 7, wherein the drying of the solid is carried out in air at a temperature from about 30°C to about 60°C.

11. The process according to claim 7, wherein the purification from a ketonic solvent or a mixture with water involves heating from about 35°C to about 50°C. ^RI-WO 2011/080684 PCT/IB2010/056066

13 12. The process according to claim 11, wherein the ketonic solvent is selected from the group comprising of acetone, 2-butanone, 2-pentanone, 3-pentanone, 2-hexanone, 2- heptanone, 2-octanone and/or mixtures thereof.

13. The process according to claim 1, wherein the isolation of the solid comprises cooling of the reaction mixture from about 0°C to about 15°C.

14. The process according to claim 13, further comprising drying the solid in air at the temperature from about 30°C to about 50°C.

15. A process for the preparation of candesartan or its derivatives, the process

comprising:

(a) treating trityl candesartan cilexetil having the structure of Formula II

Formula II

with iodine in an alcoholic solvent or mixtures;

(b) optionally adding a second solvent;

(c) heating the reaction mixture; and

(d) isolating candesartan cilexetil.

16. The process according to claim 15, wherein the alcoholic solvent used in step (a) comprises methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n- heptanol, n-octanol and/or mixtures thereof.

17. The process according to claim 15, wherein the second solvent comprises chloroform, dichloromethane, carbon tetrachloride, ethylene dichloride and/or mixtures thereof.

18. The process according to claim 15, wherein the heating of the reaction mixture is carried out at the temperature from about 35°C to about reflux temperature.

19. The process according to claim 15, wherein the stirring of the reaction mixture is carried out from about 1 hour to about 10 hours.

20. The process according to claim 15, wherein the isolation of the solid obtained in step (b) involves purification from a suitable organic solvent comprising the heating of the mixture at the temperature from about 25°C to about 45°C. ^RI-WO 2011/080684 PCT/IB2010/056066

14 21. The process according to claim 20, wherein the suitable organic solvent comprises ethers and/or hydrocarbon solvents.

22. The process according to claim 21, wherein the ether comprises methyl tertiary butyl ether, tetrahydrofuran, 1,4-dioxane and/or mixtures thereof.

23. The process according to claim 21, wherein the hydrocarbon solvent comprises

24. The process according to claim 20, wherein the purification from a ketonic solvent or its mixture with water involves heating from about 35°C to about 50°C.

25. The process according to claim 24, wherein the ketonic solvent is selected from the group comprising of acetone, 2-butanone, 2-pentanone, 3-pentanone, 2-hexanone, 2- heptanone, 2-octanone and/or mixtures thereof.

26. The process according to claim 15 , wherein the isolation of the solid comprises the cooling of the reaction mixture from about 0°C to about 15°C.

27. The process according to claim 26, further comprising drying the solid in air at the temperature from about 30°C to about 50°C.

28. Candesartan cilexetil comprising a HPLC purity greater than 99% and desethyl

impurity content less than 0.2%.