WO2011092666A1 - Procede ameliore de preparation de candesartan cilexetil, formes polymorphes de n-trityl candesartan et leurs utilisations - Google Patents

Procede ameliore de preparation de candesartan cilexetil, formes polymorphes de n-trityl candesartan et leurs utilisations Download PDF

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WO2011092666A1
WO2011092666A1 PCT/IB2011/050400 IB2011050400W WO2011092666A1 WO 2011092666 A1 WO2011092666 A1 WO 2011092666A1 IB 2011050400 W IB2011050400 W IB 2011050400W WO 2011092666 A1 WO2011092666 A1 WO 2011092666A1
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candesartan
polymorphic form
trityl candesartan
trityl
process according
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PCT/IB2011/050400
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English (en)
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Lakshmipathi V. Sanjeevi
Suresh Allada
Ashok Kumar
Kaptan Singh
Srinivasa Rao Guntu
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Ranbaxy Laboratories Limited
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Publication of WO2011092666A1 publication Critical patent/WO2011092666A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

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  • 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.
  • 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:
  • 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.
  • An improved process for the preparation of candesartan cilexetil wherein the process comprises:
  • step (iii) optionally, stirring the mixture obtained from step (ii) after cooling and
  • 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.
  • step (i) wherein the stirring of the reaction mixture obtained in step (i) is carried out from about 10 minutes to about 12 hours.
  • step (ii) wherein the reaction mixture obtained after stirring in step (ii) is cooled to about 10°C to 30°C.
  • reaction mixture obtained after cooling is further stirred for about 1 hour to about 12 hours.
  • drying of the polymorphic Form A of the N-trityl candesartan is carried out at about 45°C to 55°C.
  • 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.
  • 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 are substantially pure polymorphic Form A and Form B of N-trityl candesartan.
  • Polymorphic Form A of N-trityl candesartan comprising characteristic d-spacing (A 0 ) 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.
  • 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.
  • Table 1 XRD table for Form A
  • the present invention provides for an improved process for the preparation of candesartan cilexetil.
  • the process includes:
  • 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 (A 0 ) 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 (A 0 ) 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:
  • step (iii) optionally, stirring the mixture obtained from step (ii) after cooling and
  • the process for the preparation of polymorphic Form B of N-trityl candesartan includes the steps of:
  • Polymorphic Form A of the N-trityl candesartan of the present invention has d- spacing (A 0 ) 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
  • 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 (A 0 ) 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
  • 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 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.
  • 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.
  • 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, 5 ⁇ , 150 mm X 4.6 mm; Injection Volume: 20 ⁇ ; 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%.
  • 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.
  • Suitable organic solvents include dimethylformamide,
  • dimethylacetamide and the like.
  • dimethylformamide may be used.
  • bases include inorganic bases, such as carbonates and bicarbonates of alkali metals.
  • 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.
  • 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.
  • another organic solvent like cyclohexane, methyltertiarybutyl ether may be added, followed by stirring of the mixture for about 10 hours to about 15 hours.
  • 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.
  • 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.
  • organic solvent generally the halogenated solvent used in the previous step
  • 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 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.
  • 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.
  • an extraction solvent examples include ethylacetate, propylacetate, or the like.
  • inorganic bases include sodium and potassium bicarbonates and carbonates.
  • 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, 3 ⁇ (100 mm X 4.6 mm); Temperature: 30°C; Flow rate: 1.5 mL/min; Injection Volume: 20 ⁇ ; Run time: 65 minutes, sodium acetate trihydrate (buffer), solvent mixture of acetonitrile and methanol as mobile phase and methanol as diluent.
  • HPLC parameters include column name: Hypersil BDS C - 18, 3 ⁇ (100 mm X 4.6 mm); Temperature: 30°C; Flow rate: 1.5 mL/min; Injection Volume: 20 ⁇ ; 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 , 3 ⁇ (100 mm X 4.6 mm); Temperature: 30°C; Flow rate: 1.5 mL/min; Injection Volume: 20 ⁇ ; Run time: 65 minutes, sodium acetate trihydrate (buffer), solvent mixture of acetonitrile and methanol as mobile phase and methanol as diluent.
  • HPLC parameters include column name: Hypersil BDS C - 18 , 3 ⁇ (100 mm X 4.6 mm); Temperature: 30°C; Flow rate: 1.5 mL/min; Injection Volume: 20 ⁇ ; Run time: 65 minutes, sodium acetate trihydrate (buffer), solvent mixture of acetonitrile and methanol as mobile phase and methanol as
  • 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).
  • 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.
  • 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 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.
  • Step I Preparation of N-trityl candesartan cilexetil
  • N-trityl candesartan 120 gm
  • potassium carbonate 48.58 gm
  • cilexetil chloride 54.48 gm
  • dimethyl formamide 180 mL
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

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Abstract

L'invention concerne un procédé amélioré de préparation de candesartan cilexetil consistant à utiliser des formes polymorphes A et B de N-trityl candesartan. L'invention concerne également de nouvelles formes A et B de N-trityl candesartan et leurs procédés de préparation.
PCT/IB2011/050400 2010-01-29 2011-01-29 Procede ameliore de preparation de candesartan cilexetil, formes polymorphes de n-trityl candesartan et leurs utilisations WO2011092666A1 (fr)

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WO2005037821A2 (fr) 2003-10-16 2005-04-28 Teva Pharmaceutical Industries Ltd. Preparation de candesartan cilexetil
WO2007042161A1 (fr) 2005-10-07 2007-04-19 Krka, D.D. Novo Mesto Procédé de préparation de candésartan cilexétil
WO2007074399A2 (fr) 2005-06-06 2007-07-05 Medichem, S.A. Procede de preparation de composes tetrazolyle
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WO2008035360A2 (fr) 2006-06-13 2008-03-27 Alembic Limited Nouvelles formes cristallines
WO2009007986A1 (fr) * 2007-07-11 2009-01-15 Alembic Limited Procédé amélioré pour la préparation de candésartan cilexétil
WO2009157001A2 (fr) * 2008-06-24 2009-12-30 Hetero Research Foundation Procédé de préparation de candésartan cilexétil

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5196444A (en) 1990-04-27 1993-03-23 Takeda Chemical Industries, Ltd. 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof
US5578733A (en) 1994-01-28 1996-11-26 Takeda Chemical Industries, Ltd. Process for the production of tetrazolyl compounds
WO2005021535A2 (fr) 2003-08-27 2005-03-10 Zentiva, A.S. Procede d'extraction du groupe protecteur de triphenylmethane
WO2005037821A2 (fr) 2003-10-16 2005-04-28 Teva Pharmaceutical Industries Ltd. Preparation de candesartan cilexetil
US7345072B2 (en) 2003-11-28 2008-03-18 Dipharma S.P.A. Phenyltetrazole compounds
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WO2007094015A1 (fr) * 2006-02-15 2007-08-23 Matrix Laboratories Ltd Procédé amélioré pour la préparation de candésartan cilexetil
WO2008035360A2 (fr) 2006-06-13 2008-03-27 Alembic Limited Nouvelles formes cristallines
WO2009007986A1 (fr) * 2007-07-11 2009-01-15 Alembic Limited Procédé amélioré pour la préparation de candésartan cilexétil
WO2009157001A2 (fr) * 2008-06-24 2009-12-30 Hetero Research Foundation Procédé de préparation de candésartan cilexétil

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