EP1778650A1 - Process for preparing candesartan cilexetil - Google Patents

Process for preparing candesartan cilexetil

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Publication number
EP1778650A1
EP1778650A1 EP05778344A EP05778344A EP1778650A1 EP 1778650 A1 EP1778650 A1 EP 1778650A1 EP 05778344 A EP05778344 A EP 05778344A EP 05778344 A EP05778344 A EP 05778344A EP 1778650 A1 EP1778650 A1 EP 1778650A1
Authority
EP
European Patent Office
Prior art keywords
methyl
ethoxy
formula
benzimidazole
biphenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05778344A
Other languages
German (de)
French (fr)
Other versions
EP1778650A4 (en
Inventor
Sundaram Plot No. 141 Flat No. 202 VENKATARAMAN
Padi Pratap House No. 4-7-17/5/2 Plot 5-A REDDY
Gade Srinivas Plot 04 Vivekananda Enclave REDDY
Sanikommu S. House No. 48-53/4 REDDY
Harikeerthi Plot No. 11 NARASIMHA MURTHY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
Original Assignee
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
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Application filed by Dr Reddys Laboratories Ltd, Dr Reddys Laboratories Inc filed Critical Dr Reddys Laboratories Ltd
Publication of EP1778650A1 publication Critical patent/EP1778650A1/en
Publication of EP1778650A4 publication Critical patent/EP1778650A4/en
Withdrawn legal-status Critical Current

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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

Definitions

  • the present invention relates to a process for the preparation of ( ⁇ )-1- Hydroxyethyl 2-ethoxy-1-[p-(o-1 H-tetrazol-5-ylphenyl)benzyl]-7- benzimidazolecarboxylate, cyclohexyl carbonate (ester), or 1- (cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1 -[[2'-(1 H-tetrazol-5-yl)biphenyl-4.- yl]methyl] benzimidazole-7-carboxylate, having Formula I and the adopted name "candesartan cilexetil.”
  • Candesartan cilexetil is being sold in pharmaceutical products for treating hypertension, using the trademark ATACAND.
  • candesartan cilexetil is hydrolyzed to candesartan by removal of the cyclohexylcarbonate moiety, cleavage occurring at the bond indicated by an arrow in Formula I; candesartan is a selective ATi subtype angiotensin Il receptor antagonist.
  • a process for preparing candesartan cilexetil comprises a) reacting 2-ethoxy-1 -[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]- methyl]benzimidazole-7-carboxylic acid with a trialkylsilyl halide to form a 2- ethoxy-i-P'-CN-trialkylsilyltetrazol-S-ylJbiphenyl ⁇ -ylJmethyQbenzimidazole-T- carboxylic acid; b) condensing the product of a) with 1 -chloroethylcyclohexylcarbonate to form ( ⁇ )-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1-trialkylsilyl-1 H- tetrazol-5-yl)biphenyl-4-yl]methyl]benzimid
  • a process for preparing candesartan cilexetil comprises:
  • Fig. 1 is a schematic representation of a process for preparing candesartan cilexetil.
  • An aspect of the present invention provides a process for the preparation of the compound, (+) HCyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1- [[2'-(1 H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate of Formula-1 comprising the steps of: a. reaction of alkyl 1-[(2'-cyanobiphenyl-4-yl) methyl]-2-ethoxy- benzimidazole-7-carboxylate of formula V, wherein R is C 1 -C 4 alkyl, preferably methyl
  • Step a involves the reaction of alkyl 1-[(2'-cyanobiphenyl-4-yl) methyl]-2- ethoxy-benzimidazole-7-carboxylate of formula V, wherein R is C 1 -C 4 alkyl, with trialkyltin azide in the presence of aromatic hydrocarbon solvent such as toluene or xylene at a reflux temperature to form alkyl 2-ethoxy-1- [[2'-(1 H-tetrazol-5-yl) biphenyl-4-yl]-methyl] benzimidazole-7-carboxylate of formula Vl wherein R is C-i- C 4 alkyl.
  • aromatic hydrocarbon solvent such as toluene or xylene
  • trialkyltin azide such as trimethyltinazide, triethyltinazide, tributyltinazide in presence of xylene or toluene at reflux temperature
  • Step b involves the hydrolysis of alkyl 2-ethoxy-1- [[2'-(1 H-tetrazol-5-yl) biphenyl-4-yl]-methyl] benzimidazole-7-carboxylate of formula Vl wherein R is C-i- C 4 alkyl in the presence of base and aqueous organic solvent to form the 2- ethoxy-1- [[2'-(1 H-tetrazolyl-5-yl) biphenyl-4-l] methyl] benzimidazole-7-carboxylic acid of formula VII.
  • Step c may or may not be a one pot reaction wherein protection of 2- ethoxy-1- [[2'-(1 H-tetrazolyl-5-yl) biphenyl-4-l] methyl] benzimidazole-7-carboxylic acid of formula VII to form compound of formula Vila, wherein Ri is trialkyl silyh benzyl.
  • Step c involves protection of 2-ethoxy-1- [[2'-(1 H-tetrazolyl-5-yl) biphenyl- 4-l] methyl] benzimidazole-7-carboxylic acid of formula VII with benzyl halide or trialkyl silyl halid in presence of organic solvent and a base.
  • the compound 2- ethoxy-1- [[2'-(1 H-tetrazolyl-5-yl) biphenyl-4-l] methyl] benzimidazole-7-carboxylic acid of formula VII can be protected with a protecting groups such as trialkyl silyl halide like trimethylsilylchloride, trimethylsilylbromide, trimethylsilyliodide, triethylsilylchloride, trimethylsilylbromide, triethylsilyliodide, tributylsilylchloride, tributylsilylbromide, tributylsilyliodide or benzyl alkyl halides like benzylchloride, benzyl bromide, benzyl iodide and the like.
  • a protecting groups such as trialkyl silyl halide like trimethylsilylchloride, trimethylsilylbromide, trimethyls
  • a preferred protecting agent is benzyl bromide or tributylsilylchloride.
  • the bases include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, organic base such as triethylamine, tributylamine, methylamine, dimethylamine and the like.
  • the reaction is carried out in an organic solvent such as alcoholic solvents like methanol, ethanol, isopropylacohol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethylmethylketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propylacetate, n-butylacetate, tertiary-butylacetate and the like; ether solvents such as diethylether, dimethylether, di-isopropylether, methyltertiarybutylether and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile and the like; or mixtures thereof.
  • a preferred halogenated solvent is chloroform.
  • Compound of formula Vila of step c may or may not be isolated which on condensation with 1-chloroethylcyclohexylcarbonate in step d to afford compound of formula VIIb, wherein Ri is described above.
  • the bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, tributylamine, methylamine, and dimethylamine.
  • organic solvents such as alcoholic solvents like methanol, ethanol, isopropylacohol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethylmethylketone, methylisobutylketone and the like; esters such as ethylacetate, n-propylacetate, n- butylacetate, t-butylacetate and the like; ether solvents such as diethylether, dimethylether, di-isopropylether, methyltertiarybutylether, tetrahydrofuran, 1 ,4- dioxane and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile, butylronitrile and the like; aprotic polar solvent such as N
  • Compound of formula Vila wherein R1 is tributylsilyl - may or may not be isolated wherein the reaction is carried out in presence of base such as triethylamine in presence of organic solvents include but are not limited to halogenated solvent such as chloroform.
  • base such as triethylamine
  • organic solvents include but are not limited to halogenated solvent such as chloroform.
  • base such as potassium carbonate in presence of organic solvents include but are not limited to N, N dimethylformamide.
  • Compound of formula VIIb of Step d may or may not be isolated which involves deprotection of compound of formula VIIb, wherein Ri is described above to afford the (+) HCyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1- [[2'-(1H-tetrazol- 5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate of formula I.
  • Compound of formula VIIb wherein R1 is tributylsilyl may or may not be isolated wherein deprotection can be carried out by using water.
  • deprotection can be carried out in presence of catalytic transfer hydrogenation with ammonium formate and catalysts such as palladium- carbon, platinum dioxide, Raney nickel, and the like.
  • a preferred deprotecting agent is palladium-carbon in organic solvents such as alcoholic solvents like methanol, ethanol, isopropyl alcohol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethylmethylketone, methylisobutylketone and the like; esters such as ethylacetate, n-propylacetate, n-butylacetate, t-butylacetate and the like; ether solvents such as diethylether, dimethylether, di-isopropylether, methyltertiarybutylether, tetrahydrofuran, 1 ,4-
  • Candesartan cilexetil can be prepared from 3-nitrophthalic acid as a starting material.
  • An embodiment of a complete process comprises: a) reaction of 3-nitrophthalic acid in the presence of thionyl chloride and a lower alkyl alcohol such as methanol or ethanol at reflux temperatures to give the corresponding ester, alkyl 2-carboxyl-3-nitrobenzoate; b) conversion of the ester of step a) to an acid chloride in the presence of a haloalkane solvent, such as methylene chloride, with dimethyl formamide as a catalyst, and subsequent reaction with an azide compound such as sodium azide to form the corresponding acyl azide, and further conversion to an isocyanate followed by hydrolysis with aqueous hydrogen chloride in the presence of a lower alkyl alcohol, such as terf-butanol to yield the alkyl 2-amino-3-nitrobenzoate; c) conversion of the compound produced in step b) to an alkyl 2,3-
  • Step a involves reaction of 3-nitrophthalic acid in the presence of esterifying agent and alcohol at reflux temperature to give the corresponding ester, alkyl 2-carboxyl-3- nitrobenzoate of formula II, wherein R is lower alkyl.
  • esterifying agents include but are not limited to concentrated sulfuric acid, thionyl chloride, mixtures of formaldehyde and formic acid and the like. Thionyl chloride is a preferred esterifying agent.
  • Suitable organic solvents for this reaction include but are not limited to alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-butanol, t-butyl alcohol, and the like. Methanol, ethanol, isopropyl alcohol are preferred organic solvents with methanol being the most preferred.
  • Step b is preferably a one pot reaction, which involves conversion of compound of formula Il to acid chloride of formula Na in the presence of organic solvents with a suitable catalyst.
  • Step b involves a suitable organic solvent such as but not limited to alcoholic solvents like methanol, ethanol, isopropyl alcohol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethylmethyl ketone, methylisobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ether solvents such as diethyl ether, dimethylether, di-isopropylether, methyltertiarybutyl ether, tetrahydrofuran, 1 ,4- dioxane and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile and the like;
  • Halogenated solvents such as dichloromethane, 1 ,2- dichloroethane, chloroform, carbon tetrachloride are preferred in the presence of a catalyst such as N.N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N, N- dimethylacetamide (DMA), preferably DMF.
  • a catalyst such as N.N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N, N- dimethylacetamide (DMA), preferably DMF.
  • Step c involves reaction of the acid chloride of formula Na with a reducing agent to form the corresponding acyl azide of formula lib.
  • the resultant compound is subsequently reduced with reducing agents such as sodium azide, sodium amide, sodium hydride and the like, preferably sodium azide to form the corresponding acyl azide of formula lib.
  • reducing agents such as sodium azide, sodium amide, sodium hydride and the like, preferably sodium azide to form the corresponding acyl azide of formula lib.
  • Acyl azide of formula lib may or may not be isolated.
  • Step d involves hydrolysis of formula Il b to yield the alkyl 2-amino-3- nitrobenzoate of formula III.
  • the hydrolysis is carried out in the presence of an organic solvent such as for example alcoholic solvents like methanol, ethanol, isopropyl alcohol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethylmethyl ketone, methylisobutyl ketone and the like; esters such as ethylacetate, n-propylacetate, n-butylacetate, t-butylacetate and the like; ether solvents such as diethylether, dimethylether, di-isopropylether, methyltertiarybutyl ether and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, pro
  • Step e is preferably a one pot reaction which involves reduction of the alkyl 2-amino-3-nitrobenzoate of formula III to alkyl 2,3-diamino benzoate of formula Ilia by reducing the nitro group either catalytic hydrogenation or with stannous chloride at acidic conditions preferably catalytic hydrogenation.
  • Reducing agents can be but are not limited to Raney nickel, palladium-carbon, platinum dioxide, and stannous chloride and the like, preferably hydrogenation catalysts like Raney nickel, palladium-carbon, platinum dioxide.
  • the reaction is carried out in the presence of an organic solvent such as for example alcoholic solvents like methanol, ethanol, isopropylacohol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethylmethylketone, methyl isobutylketone and the like; esters such as ethylacetate, n-propylacetate, n-butylacetate, t-butylacetate and the like; ether solvents such as diethylether, dimethylether, di-isopropylether, methyltertiarybutylether and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile and the like; or mixtures thereof.
  • an organic solvent such as for example alcoholic solvents like methanol, ethanol, isopropy
  • Preferred ester solvents include ethylacetate, n-propylacetate, n-butylacetate, t-butylacetate and the like; more preferably ethyl acetate in acidic medium.
  • the alkyl 2,3-diamino benzoate of formula Ilia of step e may or may not be isolated.
  • Step f involves cyclization of alkyl 2,3-diamino benzoate of formula IHa to yield the alklyl 2-ethoxy benzimidazole-7-carboxylate of formula IV using suitable cyclizing agents such as polyphosphoric acid, tetraalkylorthocarbonate such as tetraethylorthocarbonate, and phosphorous pentoxide, preferably tetraethylorthocarbonate in an acidic medium.
  • suitable cyclizing agents such as polyphosphoric acid, tetraalkylorthocarbonate such as tetraethylorthocarbonate, and phosphorous pentoxide, preferably tetraethylorthocarbonate in an acidic medium.
  • Step g involves condensation of its precursor key intermediate 2-ethoxy- 3H-benzoimidazole-4-carboxylic acid methylester compound of Formula (IV), with 4'-Bromomethyl-biphenyl-2-carbonitrile in presence of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, trimethylamine, dimethylamine, methylamine and the like preferably potassium carbonate in an organic solvent such as alcoholic solvents like methanol, ethanol, isopropylacohol, n-butanol, tert-butanol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethylmethylketone, methylisobutylketone and the like; ester solvents such as ethyl acetate, n-propyl acetate, n-
  • alcoholic solvents like methanol, ethanol, isopropylacohol, n-butanol, tert-butanol and the like; more preferably methanol.
  • wanted isomer compound of Formula V and the unwanted isomer compound of Formula Va formed are in the ratio of about 8:1
  • a lower alkyl group i.e., a branched or unbranched alkyl group having 1 to about 6 carbon atoms. Where there is more than one R group on a molecule, the individual groups can be different lower alkyl groups.
  • a lower alkyl alcohol is an alcohol having the formula ROH, where the R group is defined above.
  • the present invention further provides a one pot process for the preparation of compound of Vila comprising conversion of methyl 1-[(2'-cyanobiphenyl-4-yl) methyl]-2-ethoxy-benzimidazole-4-carboxylate compound of formula V into 3-[2'(N-Benzyl-1 H-tetrazol-5-yl)-biphenyl-4-ylmethyl]- 2-ethoxy-3H-benzimidazole-4-carboxylicacid methyl ester compound of formula IX by treating it with reducing agents such as sodium azide, sodamide, sodium hydride and the like; preferably sodium azide in an organic solvent such as alcoholic solvents like methanol, ethanol, isopropylacohol, n-butanol, tert-butanol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethyl-
  • hydrocarbon solvents such as like toluene, xylene and the like; more preferably xylene, and protecting the corresponding compound with protecting groups such as trialkyl silyl halides like trimethylsilylchloride, trimethylsilylbromide, trimethylsilyliodide, triethylsilylchloride, triethylsilylbromide, triethylsilyliodide, tributylsilylchloride, tributylsilylbromide, tributylsilyliodide and the like; benzyl alkyl halides such as benzylchloride, ben ⁇ ylbromide, benzyliodide and the like, preferably benzyl bromide and subsequent hydrolysis of the resultant compound with suitable hydrolyzing agent such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like
  • 3-Nitrophthalic acid 500 g, 2.37 moles was added to 2500 ml of methanol and 260 ml of thionyl chloride below ambient temperature. The mixture was heated at reflux for about 24 hours and then was concentrated under reduced pressure, followed by expelling the excess thionyl chloride under nitrogen. 1500 ml of toluene was mixed with the residue, and then filtered. The obtained solid was dried at 60-70 0 C to get 522.0 grams (98%) of methyl 2-carboxyl-3- nitrobenzoate, which was substantially free from 3-nitrodimethylphthalate.
  • Methyl 2-carboxyl-3-nitrobenzate (200 grams, 0.88 moles) was added to 1000 ml of methylene chloride and 20 ml of N,N-dimethylformamide.
  • Thionyl chloride 120 ml was added under nitrogen atmosphere with stirring. The mixture was stirred at ambient temperature for about 10-12 hours, and 1000 ml of 16.7% aqueous sodium carbonate solution was added at below 2O 0 C. The aqueous layer was separated and extracted with 2 x 200 ml of methylene chloride. The organic layers were combined, and the combined organic layer was added to 320 ml of N,N-dimethylformamide containing 80 grams of sodium azide, at ambient temperature.
  • Solvent was completely evaporated by distillation at about 45-80 0 C for about 4-6 hours and residue was cooled to about 25-30 0 C. 135 ml of water was added under stirring to the residue and was maintained under stirring for about 30-60 minutes. Separated solid was filtered and washed with 100 ml of water. Solid obtained was dried at about 55- 65 0 C for about 10-15 hours to yield 154.5 grams of 2-amino-3-nitro-benzoic acid methylester of formula III.
  • Methyl 2-amino-3-nitrobenzoate (150.0 grams, 0.765 moles) was placed in an autoclave vessel and 1000 ml of ethyl acetate and 75 grams of Raney nickel were added to the vessel and stirred under a 2-3 kg/cm 2 hydrogen pressure for 12-15 hours. The catalyst was removed by filtration, and the ethyl acetate was evaporated under reduced pressure. Acetic acid (170 ml) was added to the residue, and 180 grams of tetraethylorthocarbonate was slowly added at 25-35°C. The reaction mass was stirred for 2-3 hours, and water (750 ml) was added after the reaction mass was cooled to 10 0 C. The solid was filtered, washed with 150 ml of water, and dried at 50-60°C to get 140 grams (83.1 %) of methyl 2- ethoxybenzimidazole-7-carboxylate.
  • reaction mass 150 grams of 2-Amino-3-nitro-benzoic acid methylester, Raney nickel (75 grams), ethyl acetate (1 litre) were charged in an autoclave vessel. 3.0kg/cm 2 of dry hydrogen gas was passed into the reaction suspension for about 20-25 hours under agitation. Reaction mass was filtered on celite, followed by washing the celite with 150 ml of ethyl acetate. Solvent was removed completely from the filtrate at about 45-50 0 C by distillation. 171 ml of acetic acid was charged and tetraethylorthocarbonate (180 grams) was added over about 30-45 minutes. Reaction mass was maintained for about 1-3 hours and was cooled to about 0- 5 0 C.
  • the wet solid was washed with 370 ml of hot ethyl acetate, and then dried at 50-60 0 C to get 105.0 grams of methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy- benzimidazole-7-carboxylate, substantially free from methyl 1-[(2'-cyanobiphenyl- 4-yl)methyl]-2-ethoxy-benzimidazole-4-carboxylate.
  • the mixture was slowly heated to reflux and maintained for 24 hours, and then the solvent was evaporated under reduced pressure.
  • the residue was dissolved in 225 ml of methanol and 225 ml of water followed by the addition of 91.3 grams of sodium nitrite and 75 ml of ethyl acetate.
  • the pH of the resulting solution was adjusted to 3 with aqueous hydrochloric acid.
  • the upper liquid layer was decanted and 225 ml of ethyl acetate was added.
  • reaction mass was cooled to 57°C and 25.8 grams (1.1 moles) of 1- chloroethylcyclohexylcarbonate and 46 grams of triethylamine were added simultaneously, and the resulting mixture was stirred for 24 hours.
  • the reaction mass was washed with aqueous saturated sodium bicarbonate solution followed by water, and the chloroform layer was separated and evaporated under reduced pressure.
  • diisopropyl ether was added and stirred to form a complete solution.
  • the ether solution was dried over magnesium sulfate and the solvent was evaporated under reduced pressure.
  • Reaction mass was cooled to about 25-30 0 C followed by addition of 41.6 g of benzyl bromide and 33.5 g of potassium carbonate. Reaction mass was heated to about 90-95 0 C and was maintained for about 5-8 hours. Reaction mass was cooled to about 25-30 0 C and 375 ml of n-heptane, 150 ml of water were added under stirring followed by cooling to about 0-10 0 C and was maintained for about 1-2 hours. Separated solid was filtered and the solid was washed with 50 ml of n- heptane.
  • the wet solid was charged to a mixture of sodium hydroxide (17 g), water (425 ml) and methanol (50 ml) followed by heating to about 80-85 0 C and was maintained for about 12-15 hours. Reaction mass was cooled to about 25- 30 0 C and the separated solid was filtered, washed with 25 ml of water. Filtrate was charged in a round bottom flask and was cooled to about 0-10 0 C and pH was adjusted to about 2-3 and was maintained for about 45-90minutes with 20% sulphuric acid solution. Reaction mass was extracted with 2x200 ml of dichloromethane and then with 100 ml again followed by distillation of solvent completely at about 45-60 0 C.

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Abstract

A process for preparing candesartan cilexetil.

Description

PROCESS FOR PREPARING CAMDESARTAiM CILEKETIL
INTRODUCTION TO THE INVENTION
The present invention relates to a process for the preparation of (±)-1- Hydroxyethyl 2-ethoxy-1-[p-(o-1 H-tetrazol-5-ylphenyl)benzyl]-7- benzimidazolecarboxylate, cyclohexyl carbonate (ester), or 1- (cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1 -[[2'-(1 H-tetrazol-5-yl)biphenyl-4.- yl]methyl] benzimidazole-7-carboxylate, having Formula I and the adopted name "candesartan cilexetil."
Formula 1
Candesartan cilexetil is being sold in pharmaceutical products for treating hypertension, using the trademark ATACAND. In the body, candesartan cilexetil is hydrolyzed to candesartan by removal of the cyclohexylcarbonate moiety, cleavage occurring at the bond indicated by an arrow in Formula I; candesartan is a selective ATi subtype angiotensin Il receptor antagonist.
Processes and intermediates for preparing candesartan cilexetil are described in the following U.S. Patents: 5,196,444; 5,703,110; 5,705,517; 6,355,808; and 6,608,210.
SUMMARY OF THE INVENTION
In one embodiment, a process for preparing candesartan cilexetil comprises a) reacting 2-ethoxy-1 -[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]- methyl]benzimidazole-7-carboxylic acid with a trialkylsilyl halide to form a 2- ethoxy-i-P'-CN-trialkylsilyltetrazol-S-ylJbiphenyl^-ylJmethyQbenzimidazole-T- carboxylic acid; b) condensing the product of a) with 1 -chloroethylcyclohexylcarbonate to form (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1-trialkylsilyl-1 H- tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate; and c) reacting the product of b) with an aqueous material to form candesartan cilexetil.
In another embodiment, a process for preparing candesartan cilexetil comprises:
1 ) reacting 3-nitrophthalic acid with thionyl chloride and a lower alkyl alcohol, to form alkyl 2-carboxyl-3-nitrobenzoate;
2) converting the product of 1 ) to an acid chloride, and reacting the acid chloride with an azide to form the acyl azide, converting the azide to an isocyanate, and then hydrolyzing to form an alkyl 2-amino-3-nitrobenzoate;
3) reducing the nitro group of the product of 2) and cyclizing to form an alkyl-2-ethoxybenzimidazole-7-carboxylate;
4) reacting the product of 3) with 4-bromomethyl-2'-cyanobiphenyl to form alkyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-benzimidazole-7- carboxylate;
5) reacting the product of 4) with trialkyltin azide to form alkyl-2-ethoxy- 1 -[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate; and
6) hydrolyzing the product of 5) to form 2-ethoxy-1 -[[2'-(1 H-tetrazolyl-5- yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid;
7) reacting the product from 6) with a trialkylsilyl halide to form a 2- ethoxy-1-[[2'-(N-trialkylsilyltetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7- carboxylic acid;
8) condensing the product of 7) with 1 -chloroethylcyclohexylcarbonate to form (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1 -[[2'-(1 -trialkylsilyl-1 H- tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate; and
9) reacting the product of 8) with an aqueous material to form candesartan cilexetil. BRIEF DESCRIPTION OF THE DRAWING
Fig. 1 is a schematic representation of a process for preparing candesartan cilexetil.
DETAILED DESCRIPTION
An aspect of the present invention provides a process for the preparation of the compound, (+) HCyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1- [[2'-(1 H- tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate of Formula-1 comprising the steps of: a. reaction of alkyl 1-[(2'-cyanobiphenyl-4-yl) methyl]-2-ethoxy- benzimidazole-7-carboxylate of formula V, wherein R is C1-C4 alkyl, preferably methyl
with trialkyltin azide in the presence of aromatic hydrocarbon solvent at reflux temperature to form alkyl 2-ethoxy-1-[[2'-(1 H-tetrazol-5-yl) biphenyl-4-yl]- methyl]benzimidazole-7-carboxylate of formula Vl;
b. hydrolysis of alkyl 2-ethoxy-1- [[2'-(1 H-tetrazol-5-yl) biphenyl-4-yl]-methyl] benzimidazole-7-carboxylate of formula Vl in the presence of strong base and aqueous organic solvent to form the 2-ethoxy-1- [[2'-(1 H-tetrazolyl-5-yl) biphenyl-4-l] methyl] benzimidazole-7-carboxylic acid of formula VII;
c. protection of 2-ethoxy-1- [[2'-(1 H-tetrazolyl-5-yl) biphenyl-4-l] methyl] benzimidazole-7-carboxylic acid of formula VII to form compound of formula Vila, wherein R1 is trialkyl silyl, preferably tertiary-butyldimethylsilyl, or benzyl.
d. condensation of compound of formula Vila with 1- chloroethylcyclohexylcarbonate to afford compound of formula Vllb,wherein Ri is described above.
e. deprotection of compound of formula VIIb, wherein Ri is described above to afford the (+) 1 -(Cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1- [[2'-(1H-tetrazol-
5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate of formula I.
Step a involves the reaction of alkyl 1-[(2'-cyanobiphenyl-4-yl) methyl]-2- ethoxy-benzimidazole-7-carboxylate of formula V, wherein R is C1-C4 alkyl, with trialkyltin azide in the presence of aromatic hydrocarbon solvent such as toluene or xylene at a reflux temperature to form alkyl 2-ethoxy-1- [[2'-(1 H-tetrazol-5-yl) biphenyl-4-yl]-methyl] benzimidazole-7-carboxylate of formula Vl wherein R is C-i- C4 alkyl. The reaction of alkyl 1 -[(2'-cyanobiphenyl-4-yl) methyl]-2-ethoxy- benzimidazole-7-carboxylate of formula V, wherein R is methyl with trialkyltin azide such as trimethyltinazide, triethyltinazide, tributyltinazide in presence of xylene or toluene at reflux temperature to form alkyl 2-ethoxy-1- [[2'-(1 H-tetrazol- 5-yl) biphenyl-4-yl]-methyl] benzimidazole-7-carboxylate of formula Vl wherein R is methyl.
Step b involves the hydrolysis of alkyl 2-ethoxy-1- [[2'-(1 H-tetrazol-5-yl) biphenyl-4-yl]-methyl] benzimidazole-7-carboxylate of formula Vl wherein R is C-i- C4 alkyl in the presence of base and aqueous organic solvent to form the 2- ethoxy-1- [[2'-(1 H-tetrazolyl-5-yl) biphenyl-4-l] methyl] benzimidazole-7-carboxylic acid of formula VII. Hydrolysis of alkyl 2-ethoxy-1- [[2'-(1 H-tetrazol-5-yl) biphenyl- 4-yl]-methyl] benzimidazole-7-carboxylate of formula Vl wherein R is methyl in the presence of base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride and the like and aqueous organic solvent such as methanol, ethanol or acetone to form the 2-ethoxy-1- [[21- (1 H-tetrazolyl-5-yl) biphenyl-4-l] methyl] benzimidazole-7-carboxylic acid of formula VII wherein R is methyl.
Step c may or may not be a one pot reaction wherein protection of 2- ethoxy-1- [[2'-(1 H-tetrazolyl-5-yl) biphenyl-4-l] methyl] benzimidazole-7-carboxylic acid of formula VII to form compound of formula Vila, wherein Ri is trialkyl silyh benzyl. Step c involves protection of 2-ethoxy-1- [[2'-(1 H-tetrazolyl-5-yl) biphenyl- 4-l] methyl] benzimidazole-7-carboxylic acid of formula VII with benzyl halide or trialkyl silyl halid in presence of organic solvent and a base. The compound 2- ethoxy-1- [[2'-(1 H-tetrazolyl-5-yl) biphenyl-4-l] methyl] benzimidazole-7-carboxylic acid of formula VII can be protected with a protecting groups such as trialkyl silyl halide like trimethylsilylchloride, trimethylsilylbromide, trimethylsilyliodide, triethylsilylchloride, trimethylsilylbromide, triethylsilyliodide, tributylsilylchloride, tributylsilylbromide, tributylsilyliodide or benzyl alkyl halides like benzylchloride, benzyl bromide, benzyl iodide and the like. A preferred protecting agent is benzyl bromide or tributylsilylchloride. The bases include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, organic base such as triethylamine, tributylamine, methylamine, dimethylamine and the like. The reaction is carried out in an organic solvent such as alcoholic solvents like methanol, ethanol, isopropylacohol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethylmethylketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propylacetate, n-butylacetate, tertiary-butylacetate and the like; ether solvents such as diethylether, dimethylether, di-isopropylether, methyltertiarybutylether and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile and the like; or mixtures thereof. A preferred halogenated solvent is chloroform.
Compound of formula Vila of step c may or may not be isolated which on condensation with 1-chloroethylcyclohexylcarbonate in step d to afford compound of formula VIIb, wherein Ri is described above. The bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, tributylamine, methylamine, and dimethylamine. The reaction is conducted in organic solvents such as alcoholic solvents like methanol, ethanol, isopropylacohol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethylmethylketone, methylisobutylketone and the like; esters such as ethylacetate, n-propylacetate, n- butylacetate, t-butylacetate and the like; ether solvents such as diethylether, dimethylether, di-isopropylether, methyltertiarybutylether, tetrahydrofuran, 1 ,4- dioxane and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile, butylronitrile and the like; aprotic polar solvent such as N,N-dimethylformamide (DMF), Dimethylsulfoxide (DMSO), N,N-Dimethylacetamide (DMA) or their mixtures. Compound of formula Vila wherein R1 is tributylsilyl -, may or may not be isolated wherein the reaction is carried out in presence of base such as triethylamine in presence of organic solvents include but are not limited to halogenated solvent such as chloroform. Whereas compound of formula Vila wherein R1 is benzyl -, the reaction is carried out in presence of base such as potassium carbonate in presence of organic solvents include but are not limited to N, N dimethylformamide. Compound of formula VIIb of Step d may or may not be isolated which involves deprotection of compound of formula VIIb, wherein Ri is described above to afford the (+) HCyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1- [[2'-(1H-tetrazol- 5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate of formula I. Compound of formula VIIb wherein R1 is tributylsilyl, may or may not be isolated wherein deprotection can be carried out by using water. Whereas compound of formula VIIb wherein Ri is benzyl, deprotection can be carried out in presence of catalytic transfer hydrogenation with ammonium formate and catalysts such as palladium- carbon, platinum dioxide, Raney nickel, and the like. A preferred deprotecting agent is palladium-carbon in organic solvents such as alcoholic solvents like methanol, ethanol, isopropyl alcohol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethylmethylketone, methylisobutylketone and the like; esters such as ethylacetate, n-propylacetate, n-butylacetate, t-butylacetate and the like; ether solvents such as diethylether, dimethylether, di-isopropylether, methyltertiarybutylether, tetrahydrofuran, 1 ,4-dioxane and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile, butylronitrile and the like; or their mixtures. Preferred alcoholic solvents are methanol, ethanol, and isopropylacohol; more preferably isopropylalcohol. The reaction is carried out under basic conditions at pH values about 7 to 14, or pH 7.
Candesartan cilexetil can be prepared from 3-nitrophthalic acid as a starting material. An embodiment of a complete process comprises: a) reaction of 3-nitrophthalic acid in the presence of thionyl chloride and a lower alkyl alcohol such as methanol or ethanol at reflux temperatures to give the corresponding ester, alkyl 2-carboxyl-3-nitrobenzoate; b) conversion of the ester of step a) to an acid chloride in the presence of a haloalkane solvent, such as methylene chloride, with dimethyl formamide as a catalyst, and subsequent reaction with an azide compound such as sodium azide to form the corresponding acyl azide, and further conversion to an isocyanate followed by hydrolysis with aqueous hydrogen chloride in the presence of a lower alkyl alcohol, such as terf-butanol to yield the alkyl 2-amino-3-nitrobenzoate; c) conversion of the compound produced in step b) to an alkyl 2,3- diaminobenzoate by reducing the nitro group using catalytic hydrogenation, or using stannous chloride under acidic conditions, and further cyclization with a tetraalkylorthocarbonate in an acidic medium to yield the aikyl-2- ethoxybenzimidazole-7-carboxylate; d) reaction of the product of step c) with 4-bromomethyl-2'- cyanobiphenyl in the presence of a base and an organic solvent such as a lower alkyl alcohol, dimethylformamide, acetone, a hydrocarbon such as toluene, or a haloalkane, to yield alkyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy- benzimidazole-7-carboxylate; e) reaction of the compound produced in step d) with trialkyltin azide in the presence of a hydrocarbon aromatic solvent at reflux temperatures to form alkyl-2-ethoxy-1-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7- carboxylate; f) hydrolysis of the compound produced in step e) in the presence of a strong base and an aqueous organic solvent to form 2-ethoxy-1-[[2'-(1 H-tetrazolyl- 5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid; and g) reaction of the product of step f) with a trialkylsilyl halide in the presence of a haloalkane and an organic base to form the 2-ethoxy-1-[[2'-(N-tert- alkyldimethylsilyltetrazol-δ-yObiphenyl^-ylJmethyπbenzimidazole-T-carboxylic acid, followed by the in situ condensation with 1-chloroethylcyclohexylcarbonate to yield (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1-f-butyldimethylsilyl- 1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate, and finally removing the f-butyldimethyl silyl protecting moiety by treating the reaction mass with an aqueous material to generate (±)-1-(Cyclohexyloxycarbonyloxy)ethyl-2- ethoxy-1-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate. Step a involves reaction of 3-nitrophthalic acid in the presence of esterifying agent and alcohol at reflux temperature to give the corresponding ester, alkyl 2-carboxyl-3- nitrobenzoate of formula II, wherein R is lower alkyl. Suitable esterifying agents include but are not limited to concentrated sulfuric acid, thionyl chloride, mixtures of formaldehyde and formic acid and the like. Thionyl chloride is a preferred esterifying agent.
Suitable organic solvents for this reaction include but are not limited to alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-butanol, t-butyl alcohol, and the like. Methanol, ethanol, isopropyl alcohol are preferred organic solvents with methanol being the most preferred. Step b is preferably a one pot reaction, which involves conversion of compound of formula Il to acid chloride of formula Na in the presence of organic solvents with a suitable catalyst. Step b involves a suitable organic solvent such as but not limited to alcoholic solvents like methanol, ethanol, isopropyl alcohol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethylmethyl ketone, methylisobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ether solvents such as diethyl ether, dimethylether, di-isopropylether, methyltertiarybutyl ether, tetrahydrofuran, 1 ,4- dioxane and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile and the like; or mixtures thereof in various proportions. Halogenated solvents such as dichloromethane, 1 ,2- dichloroethane, chloroform, carbon tetrachloride are preferred in the presence of a catalyst such as N.N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N, N- dimethylacetamide (DMA), preferably DMF.
The acid chloride of formula Ha of step b may or may not isolated. Step c involves reaction of the acid chloride of formula Na with a reducing agent to form the corresponding acyl azide of formula lib. The resultant compound is subsequently reduced with reducing agents such as sodium azide, sodium amide, sodium hydride and the like, preferably sodium azide to form the corresponding acyl azide of formula lib. Acyl azide of formula lib may or may not be isolated.
Step d involves hydrolysis of formula Il b to yield the alkyl 2-amino-3- nitrobenzoate of formula III. The hydrolysis is carried out in the presence of an organic solvent such as for example alcoholic solvents like methanol, ethanol, isopropyl alcohol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethylmethyl ketone, methylisobutyl ketone and the like; esters such as ethylacetate, n-propylacetate, n-butylacetate, t-butylacetate and the like; ether solvents such as diethylether, dimethylether, di-isopropylether, methyltertiarybutyl ether and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile and the like; or their mixtures thereof, preferably alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-butanol, t-butanol and the like; more preferably t-butanol in acidic conditions using hydrochloric acid .acetic acid and the like.
Step e is preferably a one pot reaction which involves reduction of the alkyl 2-amino-3-nitrobenzoate of formula III to alkyl 2,3-diamino benzoate of formula Ilia by reducing the nitro group either catalytic hydrogenation or with stannous chloride at acidic conditions preferably catalytic hydrogenation. Reducing agents can be but are not limited to Raney nickel, palladium-carbon, platinum dioxide, and stannous chloride and the like, preferably hydrogenation catalysts like Raney nickel, palladium-carbon, platinum dioxide. The reaction is carried out in the presence of an organic solvent such as for example alcoholic solvents like methanol, ethanol, isopropylacohol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethylmethylketone, methyl isobutylketone and the like; esters such as ethylacetate, n-propylacetate, n-butylacetate, t-butylacetate and the like; ether solvents such as diethylether, dimethylether, di-isopropylether, methyltertiarybutylether and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile and the like; or mixtures thereof. Preferred ester solvents include ethylacetate, n-propylacetate, n-butylacetate, t-butylacetate and the like; more preferably ethyl acetate in acidic medium. The alkyl 2,3-diamino benzoate of formula Ilia of step e may or may not be isolated.
Step f involves cyclization of alkyl 2,3-diamino benzoate of formula IHa to yield the alklyl 2-ethoxy benzimidazole-7-carboxylate of formula IV using suitable cyclizing agents such as polyphosphoric acid, tetraalkylorthocarbonate such as tetraethylorthocarbonate, and phosphorous pentoxide, preferably tetraethylorthocarbonate in an acidic medium.
Step g involves condensation of its precursor key intermediate 2-ethoxy- 3H-benzoimidazole-4-carboxylic acid methylester compound of Formula (IV), with 4'-Bromomethyl-biphenyl-2-carbonitrile in presence of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, trimethylamine, dimethylamine, methylamine and the like preferably potassium carbonate in an organic solvent such as alcoholic solvents like methanol, ethanol, isopropylacohol, n-butanol, tert-butanol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethylmethylketone, methylisobutylketone and the like; ester solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ether solvents such as diethyl ether, dimethylether, di-isopropylether, methyltertiarybutylether, tetrahydrofuran, 1 ,4-dioxane and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile, butyronitrile and the like; aprotic polar solvents such as N.N-dimethylformamide, dimethylsulfoxide, N, N- dimethylacetamide and the like; or their mixtures thereof. Preferably alcoholic solvents like methanol, ethanol, isopropylacohol, n-butanol, tert-butanol and the like; more preferably methanol. In which the wanted isomer compound of Formula V and the unwanted isomer compound of Formula Va formed are in the ratio of about 8:1
The above-described process is shown schematically in Fig. 1. In Fig. 1 , the symbol "R" is used to represent a lower alkyl group, i.e., a branched or unbranched alkyl group having 1 to about 6 carbon atoms. Where there is more than one R group on a molecule, the individual groups can be different lower alkyl groups. As used herein, a lower alkyl alcohol is an alcohol having the formula ROH, where the R group is defined above.
In another embodiment, the present invention further provides a one pot process for the preparation of compound of Vila comprising conversion of methyl 1-[(2'-cyanobiphenyl-4-yl) methyl]-2-ethoxy-benzimidazole-4-carboxylate compound of formula V into 3-[2'(N-Benzyl-1 H-tetrazol-5-yl)-biphenyl-4-ylmethyl]- 2-ethoxy-3H-benzimidazole-4-carboxylicacid methyl ester compound of formula IX by treating it with reducing agents such as sodium azide, sodamide, sodium hydride and the like; preferably sodium azide in an organic solvent such as alcoholic solvents like methanol, ethanol, isopropylacohol, n-butanol, tert-butanol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethylmethylketone, methylisobutylketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ether solvents such as diethylether, dimethylether, di-isopropylether, methyltertiarybutylether, tetrahydrofuran, 1 ,4- dioxane and the like; hydrocarbon solvents such as like toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile, butyronitrile and the like; or their mixtures thereof. Preferably hydrocarbon solvents such as like toluene, xylene and the like; more preferably xylene, and protecting the corresponding compound with protecting groups such as trialkyl silyl halides like trimethylsilylchloride, trimethylsilylbromide, trimethylsilyliodide, triethylsilylchloride, triethylsilylbromide, triethylsilyliodide, tributylsilylchloride, tributylsilylbromide, tributylsilyliodide and the like; benzyl alkyl halides such as benzylchloride, ben∑ylbromide, benzyliodide and the like, preferably benzyl bromide and subsequent hydrolysis of the resultant compound with suitable hydrolyzing agent such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like; preferably sodium hydroxide in an organic solvent such as alcoholic solvents like methanol, ethanol, isopropylacohol, n-butanol, tert-butanol and the like; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketonic solvents such as acetone, ethylmethylketone, methylisobutylketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ether solvents such as diethylether, dimethylether, di- isopropylether, methyltertiarybutylether, tetrahydrofuran, 1 ,4-dioxane and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile, butyronitrile and the like; or their mixtures thereof. Preferably alcoholic solvents like methanol, ethanol, isopropylacohol, n-butanol, tert-butanol and the like; more preferably methanol.
An embodiment of this synthetic pathway is depicted in the following scheme.
Formula -V Formula -IXa
Formula -Vila Certain aspects of the invention will be further illustrated by the following examples, which are not intended to limit the scope of the claimed invention.
EXAMPLE 1
PREPARATION OF METHYL 2-CARBOXYL-3-NITROBENZOATE (Formula II)
3-Nitrophthalic acid (500 g, 2.37 moles) was added to 2500 ml of methanol and 260 ml of thionyl chloride below ambient temperature. The mixture was heated at reflux for about 24 hours and then was concentrated under reduced pressure, followed by expelling the excess thionyl chloride under nitrogen. 1500 ml of toluene was mixed with the residue, and then filtered. The obtained solid was dried at 60-700C to get 522.0 grams (98%) of methyl 2-carboxyl-3- nitrobenzoate, which was substantially free from 3-nitrodimethylphthalate.
EXAMPLE 1A
PREPARATION OF 3-NITROPHTHALIC ACID-1-METHYLESTER (FORMULA II) 500 g of 3-Nitrophthalic acid, and methanol (2.5 I) were charged in a round bottom flask followed by cooling to about 5-100C. 259.5 ml of thionyl chloride was added under stirring for about 60-90 minutes followed by heating to about 60- 650C and was maintained for about 20-25 hours. Solvent was distilled completely at about 60-650C; 1500 ml of toluene was added and stirred for about 5-6 hours under nitrogen atmosphere. Separated solid was filtered and washed with 500ml of toluene, followed by drying the solid at about 55-650C for about 5-10 hours to afford 525 grams of 3-nitrophthalic acid-1-methylester compound of Formula (II).
EXAMPLE 2
PREPARATION OF METHYL 2-AMINO-3-NITROBENZOATE. (Formula III)
Methyl 2-carboxyl-3-nitrobenzate (200 grams, 0.88 moles) was added to 1000 ml of methylene chloride and 20 ml of N,N-dimethylformamide. Thionyl chloride (120 ml) was added under nitrogen atmosphere with stirring. The mixture was stirred at ambient temperature for about 10-12 hours, and 1000 ml of 16.7% aqueous sodium carbonate solution was added at below 2O0C. The aqueous layer was separated and extracted with 2 x 200 ml of methylene chloride. The organic layers were combined, and the combined organic layer was added to 320 ml of N,N-dimethylformamide containing 80 grams of sodium azide, at ambient temperature. The resulting mixture was stirred for about 2 hours, water (1000 ml) was added, and the organic layer was separated. The aqueous layer was extracted with 2 x 200 ml of methylene chloride. The organic layers were combined and washed with water. Tertiary-butanol (400 ml) and 4N HCI were added to the organic layer, and the reaction mass was heated to reflux temperature. The solvent was distilled off under reduced pressure. Water was added to the residue, and then stirred for 2 hours, filtered and the solids washed with water. The solids were dried at 60-700C to get 125.0 grams (71.8%) of methyl 2-amino-3-nitrobenzoate.
EXAMPLE 2A
PREPARATION OF 2-AMINO-3-NITRO-BENZOIC ACID METHYL ESTER (FORMULA III) 200 grams of 3-nitro-phthalic acid-1-ethylester, N, N-dimethylformamide
(20 ml) and dichloromethane (1 liter) were charged in a round bottom flask and stirred for 10-15 minutes. 120ml of thionyl chloride was added over about 10-30 minutes followed by stirring for about 10-15 hours. 1 liter of water and 167 grams of sodium carbonate were charged in another round bottom flask, followed by cooling to about 15-200C. Reaction solution was added over about 20-45 minutes followed by allowing resultant solution to a temperature of about 25-3O0C. Stirred the reaction mixture for about 1-3 hours. Organic and aqueous layers were separated and the aqueous layer was extracted with 2x200 ml of dichloromethane. 80 grams of sodium azide, 320 ml of N, N-dimethylformamide were charged in another round bottom flask followed by stirring for about 5-20 minutes.Organic layer was added over about 30-90 minutes under stirring and stirred for another 1-2 hours.The reaction was quenched with 1 liter of water. Organic and aqueous layers were separated followed by extracting the aqueous layer with 2x200 ml of dichloromethane. Total organic layer was washed with 1 litre of water. Separated the organic layer and aqueous layer. Organic layer and tributylamine (200 ml) were charged in a round bottom flask followed by addition of 4N hydrochloric acid over about 15-30 minutes. Solvent was completely evaporated by distillation at about 45-800C for about 4-6 hours and residue was cooled to about 25-300C. 135 ml of water was added under stirring to the residue and was maintained under stirring for about 30-60 minutes. Separated solid was filtered and washed with 100 ml of water. Solid obtained was dried at about 55- 650C for about 10-15 hours to yield 154.5 grams of 2-amino-3-nitro-benzoic acid methylester of formula III.
EXAMPLE 3
PREPARATION OF METHYL 2-ETHOXYBENZIMIDAZOLE-7-CARBOXYLATE (Formula IV)
Methyl 2-amino-3-nitrobenzoate (150.0 grams, 0.765 moles) was placed in an autoclave vessel and 1000 ml of ethyl acetate and 75 grams of Raney nickel were added to the vessel and stirred under a 2-3 kg/cm2 hydrogen pressure for 12-15 hours. The catalyst was removed by filtration, and the ethyl acetate was evaporated under reduced pressure. Acetic acid (170 ml) was added to the residue, and 180 grams of tetraethylorthocarbonate was slowly added at 25-35°C. The reaction mass was stirred for 2-3 hours, and water (750 ml) was added after the reaction mass was cooled to 100C. The solid was filtered, washed with 150 ml of water, and dried at 50-60°C to get 140 grams (83.1 %) of methyl 2- ethoxybenzimidazole-7-carboxylate.
EXAMPLE 3A
PREPARATION OF 2-ETHOXY-3H-BENZOIMIDAZOLE-4-CARBOXYLIC ACID METHYL ESTER (FORMULA IV)
150 grams of 2-Amino-3-nitro-benzoic acid methylester, Raney nickel (75 grams), ethyl acetate (1 litre) were charged in an autoclave vessel. 3.0kg/cm2 of dry hydrogen gas was passed into the reaction suspension for about 20-25 hours under agitation. Reaction mass was filtered on celite, followed by washing the celite with 150 ml of ethyl acetate. Solvent was removed completely from the filtrate at about 45-500C by distillation. 171 ml of acetic acid was charged and tetraethylorthocarbonate (180 grams) was added over about 30-45 minutes. Reaction mass was maintained for about 1-3 hours and was cooled to about 0- 50C. 750 ml of water was added over about 15-30 minutes and the separated solid was filtered and washed with 150 ml water, followed by 150 ml of ethyl acetate. Solid obtained was dried at about 55-65°C for about 10-12 hours to yield 140 grams of 2-Ethoxy-3H-benzoimidazole-4-carboxylic acid methylester compound of Formula (IV).
EXAMPLE 4
PREPARATION OF METHYL 1-[(2'-CYANOBIPHENYL^-YL) METHYL]-2- ETHOXY-BENZIMIDAZOLE-7-CARBOXYLATE (Formula V) To 80.0 grams (0.363 moles) of methyl 2-ethoxybenzimidazole-7- carboxylate were added 400 ml of methanol, 99 grams of potassium carbonate and 94 grams of 4-bromomethyl-2'-cyanobiphenyl, and the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mass was quenched with chilled 2400 ml of water, filtered and washed with 160ml of water. The wet solid was washed with 370 ml of hot ethyl acetate, and then dried at 50-600C to get 105.0 grams of methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy- benzimidazole-7-carboxylate, substantially free from methyl 1-[(2'-cyanobiphenyl- 4-yl)methyl]-2-ethoxy-benzimidazole-4-carboxylate.
EXAMPLE 5
PREPARATION OF METHYL 2-ETHOXY-1-[[2'-(1 H-TETRAZOL-5- YL)BIPHENYL-4-YL]-METHYL]BENZIMIDAZOLE-7-CARBOXYLATE. (Formula Vl) To 75.0 grams of methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy- benzimidazole-7-carboxylate were added 375 ml xylene and 2.5 moles of tri-n- butyltin azide, which was prepared with sodium azide and tri-n-butyltin chloride in the presence of water and extracted with methylene chloride. The mixture was slowly heated to reflux and maintained for 24 hours, and then the solvent was evaporated under reduced pressure. The residue was dissolved in 225 ml of methanol and 225 ml of water followed by the addition of 91.3 grams of sodium nitrite and 75 ml of ethyl acetate. The pH of the resulting solution was adjusted to 3 with aqueous hydrochloric acid. The upper liquid layer was decanted and 225 ml of ethyl acetate was added. The solid was filtered, washed with ethyl acetate, and dried at 50-600C to get 82.0 grams (98%) of methyl 2-ethoxy-1-[[2'-(1 H- tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate.
EXAMPLE 6
PRODUCTION OF 2-ETHOXY-1-[[2'-(1 H-TETRAZOLYL-5-YL)BIPHENYL-4-YL]
METHYL] BENZIMIDAZOLE-Z-CARBOXYLIC ACID (Formula VII)
To 80.0 grams (0.176 moles) of methyl 2-ethoxy-1-[[2'-(1 H-tetrazol-5- yl)biphenyl-4-yl]-methyl] benzimidazole-7-carboxylate, were added 265 ml of methanol, 535 ml of water, and 21.1 grams of sodium hydroxide, below 100C, and the mixture was heated to 700C and maintained until the reaction completed. The methanol was distilled off completely under reduced pressure, and the residue was cooled to 100C. The pH of the residue was adjusted to 2 with aqueous hydrochloric acid solution. The precipitated compound was filtered, washed with water and dried at 60-70°C to get 70.0 grams (90%) of 2-ethoxy-1 -[[2'-(1 H- tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylic acid.
EXAMPLE 7
PRODUCTION OF (+)-1 -(CYCLOHEXYLOXYCARBONYLOXY)ETHYL 2- ETHOXY-1 -[[2'-(1 H-TETRAZOL-5-YL)BIPHENYL-4-YL]METHYL] BENZIMIDAZOLE-7-CARBOXYLATE (Formula I).
To 50.0 grams (0.113 moles) of 2-ethoxy-1-[[2'-(1 H-tetrazol-5-yl)biphenyl-4- yl]-methyl]benzimidazole-7-carboxylic acid were added 250 ml of dry chloroform and 46 grams of triethylamine. Then, a solution of 25.5 grams tert- butyldimethylchlorosilane in dry chloroform was slowly added to the resulting solution at ambient temperature and the mixture was stirred for 3 hours. The reaction mass was cooled to 57°C and 25.8 grams (1.1 moles) of 1- chloroethylcyclohexylcarbonate and 46 grams of triethylamine were added simultaneously, and the resulting mixture was stirred for 24 hours. The reaction mass was washed with aqueous saturated sodium bicarbonate solution followed by water, and the chloroform layer was separated and evaporated under reduced pressure. To the residue, diisopropyl ether was added and stirred to form a complete solution. The ether solution was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The precipitated solid was filtered and dried at 6O0C to get the product (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.
EXAMPLE 8
PREPARATION OF 3-[2'-(N-BENZYL-I H-TETRAZOL-S-YL)-BIPHENYL^- YLMETHYL]-2-ETHOXY-3H-BENZIMIDAZOLE-4-CARBOXYLIC ACID (FORMULA VIIa: Ri IS BENZYL)
70 grams of 3-[2'-(1 H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-2-ethoxy-3H- benzoimidazole-4-carboxylic acid, chloroform (350 ml) were charged in a round bottom flask. 24.1 grams of triethylamine and 27.1 grams of benzyl bromide were charged. Reaction mass was heated to about 55-600C and was maintained for about 3-5 hours. Cooled the reaction mass to about 25-35°C and 10% sodium bicarbonate solution (2x140 ml) was added. Organic and aqueous layers were separated and solvent was evaporated from the organic layer by distillation at about 50-600C. Mixture of sodium hydroxide (7.56 grams) and water (210 ml) was added to the residue and washed with dichloromethane (3x210 ml). Organic and aqueous layers were separated and 20% sulfuric acid was added to the aqueous layer over about 15-30 minutes. Aqueous layer was extracted with dichloromethane (2x210 ml) and solvent was distilled to a minimum volume under vacuum at about 40-450C. 700 ml of n-heptane was charged in another round bottom flask. Residual solution was added over about 30-45 minutes under stirring. The resultant suspension was stirred for about 1-5 hours.the separated solid was filtered and washed with 35 ml of n-heptane. Dried the solid obtained at about 25-30°C for about 3-5 hours to yield 52.5 grams of 3- [2'-(1 -benzyl-1 H- tetrazol-δ-yO-biphenyl^-ylmethylj^-ethoxy-SH-benzimidazole^-carboxylic acid compound of Formula Vila. EXAMPLE 9
PREPARATION OF 1 -(CYCLOHEXYLOXYCARBONYLOXY) ETHYL- 2- ETHOXY-1- [[2'-(I H-TETRAZOL-S-YL) BIPHENYL-4-YL] METHYL] BENZIMIDAZOLE-7-CARBOXYLATE (CANDESARTAN CILEXETIL OF FORMULA I)
3-[2'-(1-Benzyl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-2-ethoxy-3H- benzoimidazole-4-carboxylic acid (19.5 grams) potassium carbonate (7.5 grams) and N, N-dimethylformamide (39 ml) were charged in a round bottom flask. 1- chlorbethylcyclohexylcarbonate (8.4 grams) was added followed by heating the reaction suspension to about 60-650C and was maintained for about 2-3 hours. The resultant reaction mixture was cooled to about 25-3O0C and was quenched with 10% sodium chloride solution (390 ml) and was extracted with 2x98 ml of dichloromethane. Organic and aqueous layers were separated and organic layer was washed with 4x98 ml of water. Organic and aqueous layers were separated and organicjayer was distjHed completely. Residue was cooled to about 25-3O0C followed by charging isopropyl alcohol (60 ml), water (40 ml), palladium-carbon (6.4 grams), and ammonium formate (11.6 grams). The resultant reaction suspension was heated to about 55-600C and maintained for about 12-15 hours. The reaction mass was cooled to about 25-300C and was filtered on celite, washed the celite with isopropyl alcohol (20 ml). 585 ml of water was charged in another round bottom flask and the filtrate was charged. pH was adjusted to about 4-5 with 33 ml of acetic acid over about 30-45 minutes. Separated solid was filtered and washed with 25 ml of water followed by slurrying in 200 ml of water. Solid was filtered and washed with 25 ml of water. Wet solid was slurried in 78 ml of toluene and filtered, washed with 20 ml of toluene. Solid obtained was dried at about 50-600C under vacuum for about 3-5 hours to yield 14.2 grams of title compound of Formula (I).
EXAMPLE 10
ALTERNATIVE PREPARATION OF 3-[2'-(N-BENZYL-I H-TETRAZOL-5-YL)- BIPHENYL-4-YLMETHYL]-2-ETHOXY-3H-BENZIMIDAZOLE-4-CARBOXYLIC ACID, (FORMULA VIIa: R1 IS BENZYL) FROM METHYL 2-ETHOXY- 1-[[2'- 1 H- TETRAZOL-5-YL) BIPHENYL-4-YL]-METHYL] BENZIMIDAZOLE-7- CARBOXYLATE (FORMULA V)
50 grams of methyl 2-ethoxy- 1-[[2'- (1 H-tetrazol-5-yl) biphenyl-4-yl]-methyl] benzimidazole-7-carboxylate, 100 ml of N, N-dimethylformamide, 22.6 grams of benzylbromidθ and 45.7 grams of potassium carbonate were charged in a round bottom flask. The reaction mass was heated to about 60-650C and stirred for about 1-3 hours followed by cooling to about 25-3O0C. Reaction mass was quenched with a mixture of sodium chloride (100 grams) and water (1 litre) under stirring. Reaction mass was extracted with 2x250 ml and was washed with 2x250 ml water. Organic and aqueous layers were separated and evaporated the solvent completely by distillation at about 35-400C. Residue was cooled to about 25-300C and 50 ml methanol, mixture of sodium hydroxide (15.4 grams) and water (400 ml) were charged. Reaction mass was heated to about 80-850C for about 1-3 hours and cooled to about 25-300C followed by filtration of the reaction mass on celite. pH of the filtrate was adjusted to about 2-3 and was stirred for about 15-60 minutes. Separated solid was filtered and washed with 50 ml of water. Wet solid was slurried in 1 litre of water and washed with 950 ml of water. Solid obtained was dried at about 55-600C for about 10-15 hours to yield 51.5 grams of the title compound of Formula Vila.
EXAMPLE 11
ALTERNATIVE PREPARATION OF 3-[2'-(N-BENZYL-I H-TETRAZOL-5-YL)- BIPHENYL-4-YLMETHYL]-2-ETHOXY-3H-BENZIMIDAZOLE-4-CARBOXYLIC ACID, (FORMULA VIIa: Ri IS BENZYL) FROM METHYL 1-[(2'- CYANOBIPHENYL^-YLJ METHYLj^-THOXY-BENZIMIDAZOLE^- CARBOXYLATE COMPOUND (FORMULA IXa)
20 g of sodium azide and 50 ml water were charged in a round bottom flask followed by cooling to about -5 to 0°C. 99g of tributyltin chloride was added over about 30-45 minutes and resultant reaction mass was maintained for about 1-2 hrs. Reaction mass was extracted with 2x200 ml of xylene and the organic layer was added to 50 g of methyl 1-[(2'-cyanobiphenyl~4-yl) methyl]-2-thoxy- benzimidazole-4-carboxylate followed by heating the resultant reaction mixture to about 140-1500C and was maintained under stirring for about 12-15 hours. Reaction mass was cooled to about 25-300C followed by addition of 41.6 g of benzyl bromide and 33.5 g of potassium carbonate. Reaction mass was heated to about 90-950C and was maintained for about 5-8 hours. Reaction mass was cooled to about 25-300C and 375 ml of n-heptane, 150 ml of water were added under stirring followed by cooling to about 0-100C and was maintained for about 1-2 hours. Separated solid was filtered and the solid was washed with 50 ml of n- heptane. The wet solid was charged to a mixture of sodium hydroxide (17 g), water (425 ml) and methanol (50 ml) followed by heating to about 80-850C and was maintained for about 12-15 hours. Reaction mass was cooled to about 25- 300C and the separated solid was filtered, washed with 25 ml of water. Filtrate was charged in a round bottom flask and was cooled to about 0-100C and pH was adjusted to about 2-3 and was maintained for about 45-90minutes with 20% sulphuric acid solution. Reaction mass was extracted with 2x200 ml of dichloromethane and then with 100 ml again followed by distillation of solvent completely at about 45-600C. 150 ml of n-heptane was charged to the residue and stirred for about 30-60 minutes and separated solid was filtered, washed. Solid obtained was dried at about 25-3O0C for about 1-2 hours to yield 54.5 g of the title compound of Formula (Vila)
EXAMPLE 12
PREPARATION OF 3-(2'-CYANO-BIPHENYL-4-YLMETHYL)-2-ETHOXY-3H- BENZOIMIDAZOLE-4-CARBOXYLIC ACID METHYL ESTER (FORMULA V) 15O g of 2-ethoxy-3H-benzoimidazole-4-carboxylic acid methyl ester, 750 ml. of methanol, 231.8 g of 4'-Bromomethyl-biphenyl-2-carbonitrile and 235.2 g of potassium carbonate were charged in a four neck round bottom flask equipped with a half moon shaped Teflon type blade. The reaction mixture was heated to about 50-550C and was maintained under stirring for about 3-4 hours. Cooled the reaction mixture to about 25-35°C. Charged 6 liters of water in a four neck round flask followed by cooling to about 0-5°C.The reaction mass was added to the water under stirring over about 10-30 minutes under stirring and was stirred further for about 1-2 hours. Separated solid was filtered and washed with 300 ml. of water. The wet compound was charged in a four neck round bottom flask followed by charging 2250 ml of ethyl acetate. Reaction suspension was heated to about 70-750C and was stirred for about 30-45 minutes. Reaction suspension was cooled to about 0-50C and was stirred for about 1-2 hours. Separated solid was filtered and washed with 150 ml of ethyl acetate. Solid obtained was dried at about 60-650C for about 3-5 hours to yield 177 g of title compound of Formula (V)

Claims

CLAIMS:
1. A process for preparing candesartan cilexetil, comprising: a) reacting 2-ethoxy-1 -[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]- methyl]benzimidazole-7-carboxylic acid with a trialkylsilyl halide to form a 2- ethoxy-i-f^'-CN-trialkylsilyltetrazol-δ-yObiphenyl^-yljmethylJbenzimidazole-Z- carboxylic acid; b) condensing the product of a) with 1-chloroethylcyclohexylcarbonate to form (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1-trialkylsilyl-1 H- tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate; and c) reacting the product of b) with an aqueous material to form candesartan cilexetil.
2. The process according to claim 1 , wherein a trialkylsilyl halide comprises terf-butyldimethylchlorosilane.
3. The process according to claim 1 , wherein the reaction of a) occurs in the presence of a haloalkane and an organic base.
4. The process according to claim 1 , wherein the aqueous material is water.
5. The process of claim 1 , wherein 2-ethoxy-1-[[2'-(1 H-tetrazol-5-yl)biphenyl- 4-yl]-methyl]benzimidazole-7-carboxylic acid is prepared by a process comprising:
1 ) reacting 3-nitrophthalic acid with thionyl chloride and a lower alkyl alcohol, to form alkyl 2-carboxyl-3-nitrobenzoate;
2) converting the product of 1 ) to an acid chloride, and reacting the acid chloride with an azide to form the acyl azide, converting the azide to an isocyanate, and then hydrolyzing to form an alkyl 2-amino-3-nitrobenzoate;
3) reducing the nitro group of the product of 2) and cyclizing to form an alkyl-2-ethoxybenzimidazole-7-carboxylate;
4) reacting the product of 3) with 4-bromomethyl-2'-cyanobiphenyl to form alkyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-benzimidazole-7- carboxylate; 5) reacting the product of 4) with trialkyitin azide to form alkyl-2-ethoxy- 1 -[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate; and
6) hydrolyzing the product of 5) to form 2-ethoxy-1 -[[2'-(1 H-tetrazolyl-5- yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid.
6. The process according to claim 1 , wherein 2-ethoxy-1 -[[2'-(1 H-tetrazol-5- yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylic acid is prepared by a process comprising:
1) reacting a CrC4 alkyl 1-[(2'-cyanobiphenyl-4-yl) methyl]-2-ethoxy- benzimidazole-7-carboxylate with a trialkyitin azide, to form an alkyl 2-ethoxy-1- [[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]-methyl] benzimidazole-7-carboxylate;
2) hydrolyzing the product of 1 ) to form 2-ethoxy~1 -[[2'-(1 H-tetrazolyl-5- yl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid;
3) reacting the product of 2) with a trialkylsilyl halide or benzyl halide to form a compound having the formula:
where Ri is a trialkylsilyl or benzyl protecting group;
4) condensing the product of 3) with 1-chloroethylcyclohexylcarbonate to form a compound having the formula:
where Ri is as defined in 3); and
5) removing the Ri group.
7. The process according to claim 6, wherein R1 is a trialkylsilyl group and removing in 5) comprises reacting with an aqueous material.
8. The process according to claim 6, wherein Ri is a benzyl group and removing in 5) comprises hydrogenation or reacting with formate.
9. The process according to claim 6, wherein any one or more of 2) through 5) is conducted without isolating the previous product.
10. A process for preparing a compound having the formula
comprising:
1 ) reacting a compound having the formula
with a reducing agent and then with a benzyl halide, to form a compound having the formula
and
2) hydrolyzing the product of 2); without isolating an intermediate product.
11. The compound having the formula wherein Ri is a trialkyl silyl or benzyl group.
12. The compound having the formula
wherein Ri is a trialkyl silyl or benzyl group.
13. The compound having the formula
wherein R is a lower alkyl group.
EP05778344A 2004-07-28 2005-07-28 Process for preparing candesartan cilexetil Withdrawn EP1778650A4 (en)

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WO2008044244A2 (en) * 2006-10-10 2008-04-17 Matrix Laboratories Ltd One pot process for the preparation of candesartan
EP2303870A4 (en) * 2008-06-24 2011-07-20 Hetero Research Foundation Process for preparation of candesartan cilexetil
CN102766138B (en) * 2012-07-23 2017-10-24 温州市人民医院 A kind of preparation method of Azilsartan
CN103922948A (en) * 2014-05-04 2014-07-16 青岛雪洁助剂有限公司 Preparation method of 2-amino-3-nitrobenzoic acid
CN104876877B (en) * 2015-06-24 2018-03-09 峨眉山宏昇药业股份有限公司 A kind of synthetic method of the carboxylate methyl ester of 2 ethoxybenzoimidazole 7
WO2018212162A1 (en) * 2017-05-17 2018-11-22 株式会社トクヤマ Method for producing diaminobenzene compound
CN107089972B (en) * 2017-06-23 2021-05-18 浙江华海药业股份有限公司 Preparation method of candesartan cilexetil
AU2019292883A1 (en) 2018-06-28 2021-01-14 Tokuyama Corporation Method for producing α-azidoaniline derivative or α, α'-diazide derivative
CN116332913A (en) * 2021-12-22 2023-06-27 浙江华海药业股份有限公司 Preparation method of high-purity losartan

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