| WO/1997/010215 | FUNGICIDAL QUINOLINES |
| WO/2011/119701 | TRPV4 ANTAGONISTS |
| WO/2008/122395 | METHOD FOR THE CONTROL OF WEEDS IN TURF |
RATHNAKAR REDDY, Dasari (Hetero Research Foundation, Plot N°B-80 & 81A.P.I.E. Balanaga, Hyderabad 8 Hyderabad, 50001, IN)
MURALIDHARA REDDY, Dasari (Hetero Research Foundation, Plot N°B-80 & 81A.P.I.E. Balanaga, Hyderabad 8 Hyderabad, 50001, IN)
RAJI REDDY, Rapolu (Hetero Research Foundation, Plot N°B-80 & 81A.P.I.E. Balanaga, Hyderabad 8 Hyderabad, 50001, IN)
RAMAKRISHNA REDDY, Matta (Hetero Research Foundation, Plot N°B-80 & 81A.P.I.E. Balanaga, Hyderabad 8 Hyderabad, 50001, IN)
VAMSI KRISHNA, Bandi (Hetero Research Foundation, Plot N°B-80 & 81A.P.I.E. Balanaga, Hyderabad 8 Hyderabad, 50001, IN)
PARTHASARADHI REDDY, Bandi (Hetero Research Foundation, Plot N°B-80 & 81A.P.I.E. Balanaga, Hyderabad 8 Hyderabad, 50001, IN)
RATHNAKAR REDDY, Dasari (Hetero Research Foundation, Plot N°B-80 & 81A.P.I.E. Balanaga, Hyderabad 8 Hyderabad, 50001, IN)
MURALIDHARA REDDY, Dasari (Hetero Research Foundation, Plot N°B-80 & 81A.P.I.E. Balanaga, Hyderabad 8 Hyderabad, 50001, IN)
RAJI REDDY, Rapolu (Hetero Research Foundation, Plot N°B-80 & 81A.P.I.E. Balanaga, Hyderabad 8 Hyderabad, 50001, IN)
RAMAKRISHNA REDDY, Matta (Hetero Research Foundation, Plot N°B-80 & 81A.P.I.E. Balanaga, Hyderabad 8 Hyderabad, 50001, IN)
VAMSI KRISHNA, Bandi (Hetero Research Foundation, Plot N°B-80 & 81A.P.I.E. Balanaga, Hyderabad 8 Hyderabad, 50001, IN)
| We claim: 1. A process for the preparation of candesartan cilexetil substantially free of 2,3- dihydro-2-oxo-3-[[2'-(2H-tetrazol-5-yl)[l,l-biphenyl]-4-yl]methyl]-l- [ [(cyclohexyloxy)carbonyl] oxy] ethylester- 1 H-benzimidazole-7-carboxylate (des- candesartan cilexetil) impurity, which comprises: a. crystallizing candesartan cilexetil contaminated with des-candesartan cilexetil from methanol; b. isolating the solid obtained in step (a); c. crystallizing the isolated product obtained in step (b) from isopropyl alcohol; and d. isolating candesartan cilexetil substantially free of des-candesartan cilexetil as solid. 2. The process according to claim 1, wherein the candesartan cilexetil used in step (a) contains des-candesartan cilexetil above 0.1%. 3. The process according to claim 1, wherein the candesartan cilexetil contains des- candesartan cilexetil above 0.2%. 4. The process according to claim 1, wherein the candesartan cilexetil used in step (c) contains des-candesartan cilexetil below 1%. |
SUBSTANTIALLY FREE OF DES-CANDESARTAN CILEXETIL IMPURITY
Field of the Invention
The present invention provides a process for preparation of candeartan cilexetil substantially free of 2,3-dihydro-2-oxo-3-[[2'-(2H-tetrazol-5-yl)[l,l-biphenyl]-4- yl]methyl]-l-[[(cyclohexyloxy)carbonyl]oxy]ethylester-lH-ben zimidazole-7- carboxylate (des-candesartan cilexetil) impurity.
Background of the Invention
Candesartan cilexetil of formula I:
or 2-Ethoxy-l -[[2'-(l H-tetrazol-5-yl)[l ,l'-biphenyl]-4-yl]methyl]-lH-benzimidazole -7- carboxylic acid, l-[[(Cyclohexyloxy)carbonyl]oxy]ethylester is an antihyperten- sive agent and its therapeutic uses were disclosed in US 5,196,444.
Candesartan is an angiotensin II receptor antagonist used mainly for the treatment of hypertension. The prodrug candesartan cilexetil is marketed by AstraZeneca and Takeda Pharmaceuticals, commonly under the trade names Blopress, Atacand, Amias and Ratacand.
PCT publication no. WO 2005/1 11021 disclosed a process for the preparation of substantially pure candesartan cilexetil which comprises crystallizing the residue of candesartan cilexetil using methanol and toluene; and recrystallizing the crystalline candesartan cilexetil in methanol to yield a substantially pure candesartan cilexetil.
PCT publication no. WO 2006/015134 discloses the preparation of candesartan by deprotecting silyl protected candesartan by treatment with water or by deprotecting benzyl protected candesartan by hydrogenation of benzyl candesartan suspended in isopropyl alcohol and water.
PCT publication no. WO 2008/012372 disclosed a process for the preparation of candesartan cilexetil which comprises crystallization of candesartan cilexetil from isopropanol.
PCT publication no. WO 2009/157001 disclosed a process for the preparation of candesartan cilexetil, the said process comprises hydrogenating a solution of trityl candesartan cilexetil in an alcohol with hydrogen in the presence of a palladium catalyst.
PCT publication no. 2005/037821 disclosed a process for the preparation of crystalline candesartan cilexetil which comprises crystallizing the crude candesartan cilexetil using methanol or ethanol to obtain crystalline candesartan cilexetil.
Process for the preparation of candesartan cilexetil having a particle size which comprises dissolving candesartan cilexetil in methanol, cooling and isolating candesartan cilexetil was disclosed in PCT Publication no. WO 2005/123720.
2,3-Dihydro-2-oxo-3-[[2'-(2H-tetrazol-5-yl)[l,l-biphenyl]-4- yl]methyl]-l- [[(cyclohexyloxy)carbonyl]oxy]ethylester- 1 H-benzimidazole-7-carboxylate (herein after referred to as des-candesartan cilexetil) is potential impurity in candesartan cilexetil. Des-candesartan cilexetil may be represented by formula II.
It has been found that reduction of the des-candesartan cilexetil impurity is difficult and multiple crystallizations are required to reduce the des candesartan cilexetil impurity resulting in the loss of yield of the candesartan cilexetil.
It has been found that known purification method by crystallization either from methanol or isopropyl alcohol proved to be in-effective in reducing des-candesartan cilexetil impurity. Such known methods require multiple crystallizations to get pure candesartan cilexetil resulting in the loss of yield of the candesartan cilexetil. It has now been found that the purification method by crystallization of candesartan cilexetil from methanol and crystallization of the resulting candesartan cilexetil from isopropyl alcohol in sequence is effective in the purification of candesartan cilexetil.
An object of the present invention is to provide a process for preparation of candeartan cilexetil substantially free of 2,3-dihydro-2-oxo-3-[[2'-(2H-tetrazol-5-yl)[l,l- biphenyl]-4-yl]methyl]- 1 -[[(cyclohexyloxy)carbonyl]oxy]ethylester- 1 H-benzimidazole- 7-carboxylate (des-candesartan cilexetil) impurity.
Detailed Description of the Invention
According to an aspect of the present invention, there is to provided a process for the preparation of candesartan cilexetil substantially free of 2,3-dihydro-2-oxo-3-[[2'- (2H-tetrazol-5-yl)[l,l-biphenyl]-4-yl]methyl]-l-[[(cyclohexy loxy)carbonyl]oxy] ethylester-lH-benzimidazole-7-carboxylate (des-candesartan cilexetil) impurity, which comprises:
a) crystallizing candesartan cilexetil contaminated with des-candesartan cilexetil from methanol;
b) isolating the solid obtained in step (a);
c) crystallizing the isolated product obtained in step (b) from isopropyl alcohol; and d) isolating candesartan cilexetil substantially free of des-candesartan cilexetil as solid.
The term "candesartan cilexetil substantially free of 2,3-dihydro-2-oxo-3-[[2'-(2H- tetrazol-5-yl)[l ,l-biphenyl]-4-yl]methyl]-l-[[(cyclohexyloxy)carbonyl]oxy]et hylester- lH-benzimidazole-7-carboxylate (des-candesartan cilexetil) impurity" refers to candesartan cilexetil having the content of des-candesartan cilexetil impurity equal to or less than about 0.2% by weight, preferably equal to or less than about 0.1% by weight, more preferably equal to or less than about 0.05% by weight and still more preferably des-candesartan cilexetil is not detected. The contents of candesartan cilexetil and the impurities are determined by High performance liquid chromatography (HPLC).
HPLC conditions for analysis are:
Column : YMC Pack Pro C 18 RS, 150 x 4.6 mm, 3 μιη Buffer (Solvent A) : Dissolve 1.36 gm of potassium dihydrogen orthophosphate monohydrate in 1000 ml of Milli Q water. Adjust pH to 3.0 with dil. ortho phosphoric acid.
Elution Gradient (Solvent A : Solvent B)
Solvent A Degassed Buffer
Solvent B Acetonitrile : Water (90 : 10 v/v)
Diluent Solvent B
Flow rate 1.0 ml/minute.
Detector wavelength 210 nm
Column temperature
Injection volume 10 μΐ
Run time 65 minutes.
The solution of candesartan cilexetil in methanol (in step-a) can be obtained by dissolution of candesartan cilexetil in methanol.
Isolation of the solid in step (b) may preferably be carried out by the methods known such as filtration or centrifugation.
The solution of candesartan cilexetil in isopropyl alcohol (in step-c) can be obtained by dissolution of candesartan cilexetil in isopropyl alcohol.
Isolation of candesartan cilexetil substantially free of des-candesartan cilexetil as solid in step (d) may preferably be carried out by the methods known such as filtration or centrifugation.
The process of the present invention reduces or removes effectively des- candesartan cilexetil from candesartan cilexetil without much loss in the yield of pure candesartan cilexetil.
The invention will now be further described by the following examples, which are illustrative rather than limiting.
Examples
Example 1 :
Process for the preparation of methyl-3-amino-2-[[2'-cyanobiphenyl-4- y 1] methyl] amino] benzoate. 3-Nitro pthalic acid (100 gm) was dissolved in methanol (300 ml) and then added concentrated sulfuric acid (28 ml) for 45 minutes at room temperature. The temperature of the reaction mass was raised to 60 to 65°C and maintained for 24 hours. The reaction mass was distilled off the solvent completely under vacuum at below 50°C and then added ethyl acetate (500 ml) under stirring. The reaction mass was cooled to room temperature and then mass was pored into aqueous sodium carbonate solution at 10 to 15°C. Collect the aqueous layer and adjusted the pH to 1.0 with concentrated hydrochloric acid (165 ml). The reaction mass was stirred for 1 hour at 10°C, filtered. The solid obtained was dried at 55 to 60°C for 9 hours to obtain 92 gm of methyl-2- carboxy-3-nitro-benzoate.
Methyl-2-carboxy-3-nitro-benzoate (400 gm) was dissolved in toluene (1200 ml) and then added dimethylformamide (5 ml) at room temperature. The contents were heated to 75°C and stirred for 30 minutes to obtain solution. Thionyl chloride (200 ml) was added to the solution and maintained for 2 hours at 75°C. The reaction mass was distilled off the solvent completely under vacuum at below 50°C to obtain residue. To the residue was added dimethylformamide (200 ml) and toluene (800 ml) at room temperature. A mixture of sodium azide (400 gm), dimethylformamide (900 ml) and Tetra-n-butylammonium bromide (40 gm) under stirring cooled to -10°C was added to the above solution for 2 hours 30 minutes at -10°C. The reaction mass maintained for 1 hour 30 minutes at -5°C and then added water (2800 ml). The temperature of the reaction mass was raised to 10°C and the layers were separated. The organic layer was dried over sodium sulfate and then added tert-butyl alcohol (1320 ml) under stirring. The temperature of the reaction mass was raised to 80 to 85°C and maintained for 1 hour at 80 to 85°C. The reaction mass was distilled off the solvent completely under vacuum at below 60°C to obtain residue. To the residue was added diisopropyl ether (1000 ml) and stirred at reflux. The reaction mass cooled to room temperature and stirred for 4 hours and then cooled to 10°C. The reaction mass stirred for 2 hours at 10°C, filtered. The solid obtained was dried at 45 to 50°C for 5 hours to obtain 400 gm of 2-tert-butoxy carbonylamino-3-nitro benzoic acid methyl ester.
2-Tert-butoxy carbonylamino-3-nitro benzoic acid methyl ester (400 gm) was dissolved in toluene (2000 ml) and then added potassium carbonate (400 gm) at room temperature. 4-(2-cyanophenyl)benzyl bromide (400 gm) and Tetra-n-butylammonium bromide were added to the reaction mass. Gradually temperature raised to 80 to 85°C. The reaction mass maintained for 12 hours at 80 to 85°C. The reaction mass was cooled to room temperature and filtered on hiflo-bed. Collected the filtrate and concentrated to remove toluene. To the residue was added methanol (800 ml) and cooled to room temperature. The reaction mass was stirred for 4 hours at room temperature and filtered. Methanol (2900 ml) was added to the wet compound obtained and then added concentrated hydrochloric acid (725 ml) at room temperature. The reaction mass was heated to reflux and maintained for 3 hours at reflux. The reaction mass was further cooled to room temperature and filtered. Methanol (2900 ml) was added to the wet compound obtained and stirred for 45 minutes at room temperature. The separated solid was filtered and dried at 45 to 50°C for 6 hours to obtain 450 gm of 2-(2'-cyanobiphenyl- 4-yl-methylamino)-3-nitro benzoic acid methyl ester.
Ethyl acetate (3000 ml) was added to 2-(2'-cyanobiphenyl-4-yl-methylamino)-3- nitro benzoic acid methyl ester (500 gm) and then added tin(II) chloride (500 gm) for 1 hour at room temperature. The temperature of the reaction mass was raised to reflux and maintained for 1 hour 30 minutes at reflux. A solution of sodium hydroxide (500 gm) in water (6000 ml) was added to the reaction mass for 2 hours at -10°C. The reaction mass was stirred for 2 hours 30 minutes at 0°C and pH was adjusted to 1 1 to 12 with sodium hydroxide solution. To the reaction mass was added water (12 L) under stirring and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined the total organic layer was dried with sodium sulfate. The organic layer was concentrated and then added methanol (1500 ml), stirred for 30 minutes at reflux. The reaction mass was cooled to room temperature and stirred for 1 hour 30 minutes. The reaction mass was further cooled to 0°C and stirred for 1 hour 30 minutes, filtered. The solid obtained was dried at 45 to 50°C for 7 hours to obtain 375 gm of methyl-3-amino- 2-[[2'-cyanobiphenyl-4-yl]methyl]amino]benzoate.
Example 2:
Process for the preparation of l-(cyclohexyloxy carbonyIoxy)ethyl-2-ethoxy-l-[[2'- (lH-tetrazole-5-yl)biphenyl-4-yl] methyl] benzimidazole-7-carboxylate To the solution of Methyl-3-amino-2-[[2'-cyanobiphenyl-4-yl]methyl]amino] benzoate (100 gm) as obtained in example 1 in toluene (500 ml), tetraethyl ortho carbonate (125 gm) and acetic acid (20 gm) were added at room temperature and refluxed for 6 hours. Distilled off toluene under vacuum below 60°C, added methanol (300 ml) at 55°C, stirred for 20 minutes, cooled to room temperature, filtered and then washed with methanol (90 ml). Dried for 6 hours to yield 90 gm of methyl- l-[(2-cyano biphenyl-4-yl)methyl]-2-ethoxy benzimidazole-7-carboxylate.
To sodium azide (48 gm) was added water (500 ml), cooled to 0°C, tributyl tin chloride (240 gm) was added, maintained for 2 hours 30 minutes, added toluene (500 ml) and then allowed the temperature to rise to room temperature. Separated the layers, re-extracted using toluene (500 ml) and organic layer washed with 10% sodium chloride solution (480 ml). Methyl- l-[(2-cyanobiphenyl-4-yl)methyl]-2-ethoxy benzimidazole-7- carboxylate (100 gm) was added to above solution, refluxed for 100 hours, cooled to room temperature and then to 10°C. Methanol (400 ml), water (300),and acetic acid (320 ml) were added at 0°C. Stirred for 8 hours at room temperature, then cooled to 0°C, stirred for 3 hours, filtered, washed with toluene (400 ml) and dried the solid at 60°C to get 80 gm of methyl-2-ethoxy-l-[[2'-(lH-tetrazole-5-yl)biphenyl-4-yl]meth yl] benzimidazole-7-carboxylate.
Sodium hydroxide (30 gm) dissolved in water (600 ml) was added to Methyl-2- ethoxy- 1 -[[2'-( 1 H-tetrazole-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carbox ylate
(100 gm) in ethanol (600 ml) and refluxed for 3 hours 30 minutes then ethanol was removed by distillation and then water (600 ml) and ethyl acetate (600 ml) were added at room temperature, stirred for 30 minutes. Separated the layers, pH of the aqueous layer was adjusted to 4 by using acetic acid at 0°C, stirred for 3 hours, filtered, washed with water (200 ml) and dried to give 133 gm of Candesartan.
Triethylamine (45 gm) was added to the solution of Candesartan (100 gm) in methylene chloride (500 ml) at 0°C and then the solution of trityl chloride (85 gm) in methylene chloride (500 ml) was added drop wise at 0°C for 2 hours and further stirred for 6 hours at room temperature. Water (500 ml) was added to the reaction mass, stirred, separated the layers, and the aqueous layer was extracted with methylene chloride (400 ml). The combined organic layers were washed with water, then with IN hydrochloric acid solution at pH is 4, and with 10% sodium chloride solution (300 ml), dried and then distilled off the organic solvent to obtain a residue. Ethyl acetate (500 ml) and n-Hexane (600 ml) were added to the residue, stirred for 2 hours at room temperature, filtered and washed with mixture of ethyl acetate (50 ml) and n-hexane (50 ml) and then dried to get 1 10 gm of 2-ethoxy-l-[[2'-(N-triphenylmethyltetrazole-5-yl)biphenyl)-4 -yl]methyl]benz- imidazole-7-carboxilic acid.
Potassium carbonate (60 gm), 1-chloroethylcyclohexyl carbonate (60 gm) and potassium iodide (20 gm) were added to the solution of 2-Ethoxy-l-[[2'-(N- triphenylmethyltetrazole-5-yl)biphenyl)-4-yl]methyl]benzimid azole-7-carboxylic acid (100 gm) in dimethylformamide (500 ml) at room temperature. Raised the temperature to 75°C, stirred for 2 hours, cooled to room temperature and 5% sodium chloride solution (2000 ml) was added. Maintained for 15 minutes, ethyl acetate (400 ml) was added, stirred and separated the layers. Aqueous layer was extracted with ethyl acetate (400 ml), organic layer was taken, washed with 10% sodium chloride solution (400 ml), concentrated, and co-distilled with ethyl acetate (100 ml). Mixture of ethyl acetate (500 ml) and n-hexane (500 ml) were added to the residual mass, stirred for 6 hours at room temperature, cooled to 5°C, stirred for 1 hour, filtered, then washed with mixture of ethyl acetate (50 ml) and n-hexane (200 ml) and dried for 6 hours to obtain 1 10 gm of 1- (cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-l-[[2'-(lH-tetrazol e-5-yl)biphenyl-4-yl] methyl]benzimidazole-7-carboxylate.
Example 3 :
Preparation of candesartan cilexetil
Mixture of toluene (300 ml) and methanol (350 ml) was added to 1- (cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-l-[[2'-(N-triphenyl methyltetrazole-5-yl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (100 gm) as obtained example 2 and hydrogenated at room temperature with hydrogen at 3 atmospheric pressure in the presence of palladium on carbon (10%, 10 gm) until the hydrogen uptake was ceased. Filtered over celite bed, filtrate was collected and concentrated below 45°C. Cyclohexane (1000 ml) was added to the residue and stirred for 6 hours at room temperature. The separated solid was filtered and dried to get 80 gm of candesartan cilexetil contaminated with des candesartan cilexetil.
Candesartan cilexetil: 95%;
Des-candesartan cilexetil: 3.4%
Example 4:
Preparation of candesartan cilexetil
Mixture of toluene (1000 ml) and methanol (500 ml) was added to 1- (cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-l-[[2'-(N-triphenyl methyltetrazole-5-yl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (100 gm) and hydrogenated at room temperature with hydrogen at 3 atmospheric pressure in the presence of palladium on carbon (10%>, 20 gm) until the hydrogen uptake was ceased. Filtered over celite bed, washed the bed with a mixture of toluene and methanol, filtrate was collected and concentrated below 45°C. A mixture of acetone (200 ml) and n-hexane (900 ml) was added, stirred at room temperature for 2 hours, cooled to 0°C and stirred for 4 hours 30 minutes, filtered and dried to get 65 gm of candesartan cilexetil.
Candesartan cilexetil: 94%;
Des-candesartan cilexetil: 3.4%> Example 5:
Purification of candesartan cilexetil
Candesartan cilexetil contaminated with des-candesartan cilexetil (60 gm, HPLC Purity: 95%; 3.4% of des-candesartan cilexetil) as obtained example 3 was dissolved in methanol (480 ml) at room temperature and heated to 55 to 60°C, stirred for 30 minutes to obtain solution. Distilled off methanol until about 240 ml of solvent left under vacuum at 50°C and stirred for 2 hours at 40 to 45°C. The reaction mass was cooled to room temperature and stirred for 30 minutes. The reaction mass further cooled to 0°C and stirred for 1 hour, filtered. The solid obtained was dried at 50 to 55°C for 6 hours to obtain 56 gm of candesartan cilexetil.
Candesartan cilexetil: 98%;
Des-candesartan cilexetil: 0.9%. Example 6:
Purification of candesartan cilexetil
Candesartan cilexetil (56 gm, HPLC Purity: 98%; 0.9% of des-candesartan cilexetil) as obtained in example 5 was dissolved in isopropyl alcohol (480 ml) at room temperature. The contents were heated to 55 to 60°C and maintained for 1 hour. The reaction mass was cooled to room temperature and stirred for 1 hour. The reaction mass was further cooled to 0°C and stirred for 1 hour, and filtered. The solid obtained was dried at 50 to 55°C for 6 hours to obtain 46 gm of candesartan cilexetil.
Candesartan cilexetil: 99.8%;
Des-candesartan cilexetil: 0.03%.
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