Eprosartan has been obtained by several different ways: 1) The iodination of 2-butylimidazole (I) with I2 and Na2CO3 in dioxane/water gives 2-butyl-4,5-diiodoimidazole (II), which is treated with benzyl chloromethyl ether (III) and K2CO3 in DMF yielding the imidazole derivative (IV). The condensation of (IV) with N-methyl-N-(2-pyridyl)formamide (V) by means of butyllithium in THF affords 1-(benzyloxymethyl)-2-butyl-4-iodoimidazole-5-carbaldehyde (VI), which is deprotected with concentrated HCl ethanol to give 2-butyl-4-iodoimidazole-5-carbaldehyde (VII). The acylation of (VII) with methyl 4-(bromomethyl)benzoate (VIII) by means of K2CO3 in hot DMF yields 4-(2-butyl-5-formyl-4-iodoimidazol-1 ylmethyl)benzoic acid methyl ester (IX), which is deiodinated by hydrogenation with H2 over Pd/C in methanol affording compound (X). The condensation of (X) with methyl 3-(2-thienyl)propionate (XI) by means of lithium diisopropylamide (LDA) in THF gives (XII), which is acylated with acetic anhydride and dimethylaminopyridine (DMAP) in dichloromethane yielding the corresponding acetate (XIII). Elimination of acetic acid from (XIII) with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in hot toluene affords the expected propenoic ester (XIV), which is finally saponified with NaOH or KOH in ethanol/water.

2) The condensation of 2-butyl-4-chloroimidazole-5-carbaldehyde (XV) with methyl 4-(bromomethyl)benzoate (VIII) by means of K2CO3 in DMF yields 4-(2-butyl-4-chloro-5-formylimidazol-1-ylmethyl)benzoic acid methyl ester (XVI), which is dechlorinated by hydrogenation with H2 over Pd/C in methanol affording compound (X). The condensation of (X) with 2-(2-thienylmethyl)malonic acid monomethyl ester (XVII) by means of piperidine/pyridine in toluene gives the previously described compound (XIV), which is finally saponified with KOH in ethanol.

3) The cyclization of 1,3-dihydroxyacetone (XV) with pentanamidine (XVI) in liquid ammonia gives 2-butyl-5-(hydroxymethyl)imidazole (XVII), which is acetylated with acetic anhydride yielding 5 (acetoxymethyl)-1-acetyl-2-butylimidazole (XVIII). The condensation of (XVIII) with methyl 4-(hydroxymethyl)benzoate (XIX) by means of trifluoroacetic anhydride and diisopropylethylamine in dichloromethane affords 4-[5-(acetoxymethyl)-2-butylimidazol-1-ylmethyl)benzoic acid methyl ester (XX), which is hydrolyzed with NaOH in methanol/water giving 4-[2-butyl-5-(hydroxymethyl)imidazol-1-ylmethyl)benzoic acid (XXI). The controlled oxidation of (XXI) with activated MnO2 in toluene/dichloromethane yields the corresponding aldehyde (XXII), which is condensed with methyl 3-(2-thienyl)propionate (XI) with LDA in THF affording (XXIII). The acetylation of (XXIII) with acetic anhydride and DMAP gives the corresponding acetate (XXIV), which is treated with DBU as before yielding the propenoate (XXV). Finally, this compound is hydrolyzed with NaOH as already described.

Eprosartan has been obtained by several different ways: 1) The iodination of 2-butylimidazole (I) with I2 and Na2CO3 in dioxane/water gives 2-butyl-4,5-diiodoimidazole (II), which is treated with benzyl chloromethyl ether (III) and K2CO3 in DMF yielding the imidazole derivative (IV). The condensation of (IV) with N-methyl-N-(2-pyridyl)formamide (V) by means of butyllithium in THF affords 1-(benzyloxymethyl)-2-butyl-4-iodoimidazole-5-carbaldehyde (VI), which is deprotected with concentrated HCl ethanol to give 2-butyl-4-iodoimidazole-5-carbaldehyde (VII). The acylation of (VII) with methyl 4-(bromomethyl)benzoate (VIII) by means of K2CO3 in hot DMF yields 4-(2-butyl-5-formyl-4-iodoimidazol-1 ylmethyl)benzoic acid methyl ester (IX), which is deiodinated by hydrogenation with H2 over Pd/C in methanol affording compound (X). The condensation of (X) with methyl 3-(2-thienyl)propionate (XI) by means of lithium diisopropylamide (LDA) in THF gives (XII), which is acylated with acetic anhydride and dimethylaminopyridine (DMAP) in dichloromethane yielding the corresponding acetate (XIII). Elimination of acetic acid from (XIII) with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in hot toluene affords the expected propenoic ester (XIV), which is finally saponified with NaOH or KOH in ethanol/water.

2) The condensation of 2-butyl-4-chloroimidazole-5-carbaldehyde (XV) with methyl 4-(bromomethyl)benzoate (VIII) by means of K2CO3 in DMF yields 4-(2-butyl-4-chloro-5-formylimidazol-1-ylmethyl)benzoic acid methyl ester (XVI), which is dechlorinated by hydrogenation with H2 over Pd/C in methanol affording compound (X). The condensation of (X) with 2-(2-thienylmethyl)malonic acid monomethyl ester (XVII) by means of piperidine/pyridine in toluene gives the previously described compound (XIV), which is finally saponified with KOH in ethanol.

3) The cyclization of 1,3-dihydroxyacetone (XV) with pentanamidine (XVI) in liquid ammonia gives 2-butyl-5-(hydroxymethyl)imidazole (XVII), which is acetylated with acetic anhydride yielding 5 (acetoxymethyl)-1-acetyl-2-butylimidazole (XVIII). The condensation of (XVIII) with methyl 4-(hydroxymethyl)benzoate (XIX) by means of trifluoroacetic anhydride and diisopropylethylamine in dichloromethane affords 4-[5-(acetoxymethyl)-2-butylimidazol-1-ylmethyl)benzoic acid methyl ester (XX), which is hydrolyzed with NaOH in methanol/water giving 4-[2-butyl-5-(hydroxymethyl)imidazol-1-ylmethyl)benzoic acid (XXI). The controlled oxidation of (XXI) with activated MnO2 in toluene/dichloromethane yields the corresponding aldehyde (XXII), which is condensed with methyl 3-(2-thienyl)propionate (XI) with LDA in THF affording (XXIII). The acetylation of (XXIII) with acetic anhydride and DMAP gives the corresponding acetate (XXIV), which is treated with DBU as before yielding the propenoate (XXV). Finally, this compound is hydrolyzed with NaOH as already described.

Eprosartan has been obtained by several different ways: 1) The iodination of 2-butylimidazole (I) with I2 and Na2CO3 in dioxane/water gives 2-butyl-4,5-diiodoimidazole (II), which is treated with benzyl chloromethyl ether (III) and K2CO3 in DMF yielding the imidazole derivative (IV). The condensation of (IV) with N-methyl-N-(2-pyridyl)formamide (V) by means of butyllithium in THF affords 1-(benzyloxymethyl)-2-butyl-4-iodoimidazole-5-carbaldehyde (VI), which is deprotected with concentrated HCl ethanol to give 2-butyl-4-iodoimidazole-5-carbaldehyde (VII). The acylation of (VII) with methyl 4-(bromomethyl)benzoate (VIII) by means of K2CO3 in hot DMF yields 4-(2-butyl-5-formyl-4-iodoimidazol-1 ylmethyl)benzoic acid methyl ester (IX), which is deiodinated by hydrogenation with H2 over Pd/C in methanol affording compound (X). The condensation of (X) with methyl 3-(2-thienyl)propionate (XI) by means of lithium diisopropylamide (LDA) in THF gives (XII), which is acylated with acetic anhydride and dimethylaminopyridine (DMAP) in dichloromethane yielding the corresponding acetate (XIII). Elimination of acetic acid from (XIII) with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in hot toluene affords the expected propenoic ester (XIV), which is finally saponified with NaOH or KOH in ethanol/water.

2) The condensation of 2-butyl-4-chloroimidazole-5-carbaldehyde (XV) with methyl 4-(bromomethyl)benzoate (VIII) by means of K2CO3 in DMF yields 4-(2-butyl-4-chloro-5-formylimidazol-1-ylmethyl)benzoic acid methyl ester (XVI), which is dechlorinated by hydrogenation with H2 over Pd/C in methanol affording compound (X). The condensation of (X) with 2-(2-thienylmethyl)malonic acid monomethyl ester (XVII) by means of piperidine/pyridine in toluene gives the previously described compound (XIV), which is finally saponified with KOH in ethanol.

3) The cyclization of 1,3-dihydroxyacetone (XV) with pentanamidine (XVI) in liquid ammonia gives 2-butyl-5-(hydroxymethyl)imidazole (XVII), which is acetylated with acetic anhydride yielding 5 (acetoxymethyl)-1-acetyl-2-butylimidazole (XVIII). The condensation of (XVIII) with methyl 4-(hydroxymethyl)benzoate (XIX) by means of trifluoroacetic anhydride and diisopropylethylamine in dichloromethane affords 4-[5-(acetoxymethyl)-2-butylimidazol-1-ylmethyl)benzoic acid methyl ester (XX), which is hydrolyzed with NaOH in methanol/water giving 4-[2-butyl-5-(hydroxymethyl)imidazol-1-ylmethyl)benzoic acid (XXI). The controlled oxidation of (XXI) with activated MnO2 in toluene/dichloromethane yields the corresponding aldehyde (XXII), which is condensed with methyl 3-(2-thienyl)propionate (XI) with LDA in THF affording (XXIII). The acetylation of (XXIII) with acetic anhydride and DMAP gives the corresponding acetate (XXIV), which is treated with DBU as before yielding the propenoate (XXV). Finally, this compound is hydrolyzed with NaOH as already described.

Eprosartan has been obtained by several different ways: 1) The iodination of 2-butylimidazole (I) with I2 and Na2CO3 in dioxane/water gives 2-butyl-4,5-diiodoimidazole (II), which is treated with benzyl chloromethyl ether (III) and K2CO3 in DMF yielding the imidazole derivative (IV). The condensation of (IV) with N-methyl-N-(2-pyridyl)formamide (V) by means of butyllithium in THF affords 1-(benzyloxymethyl)-2-butyl-4-iodoimidazole-5-carbaldehyde (VI), which is deprotected with concentrated HCl ethanol to give 2-butyl-4-iodoimidazole-5-carbaldehyde (VII). The acylation of (VII) with methyl 4-(bromomethyl)benzoate (VIII) by means of K2CO3 in hot DMF yields 4-(2-butyl-5-formyl-4-iodoimidazol-1 ylmethyl)benzoic acid methyl ester (IX), which is deiodinated by hydrogenation with H2 over Pd/C in methanol affording compound (X). The condensation of (X) with methyl 3-(2-thienyl)propionate (XI) by means of lithium diisopropylamide (LDA) in THF gives (XII), which is acylated with acetic anhydride and dimethylaminopyridine (DMAP) in dichloromethane yielding the corresponding acetate (XIII). Elimination of acetic acid from (XIII) with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in hot toluene affords the expected propenoic ester (XIV), which is finally saponified with NaOH or KOH in ethanol/water.

2) The condensation of 2-butyl-4-chloroimidazole-5-carbaldehyde (XV) with methyl 4-(bromomethyl)benzoate (VIII) by means of K2CO3 in DMF yields 4-(2-butyl-4-chloro-5-formylimidazol-1-ylmethyl)benzoic acid methyl ester (XVI), which is dechlorinated by hydrogenation with H2 over Pd/C in methanol affording compound (X). The condensation of (X) with 2-(2-thienylmethyl)malonic acid monomethyl ester (XVII) by means of piperidine/pyridine in toluene gives the previously described compound (XIV), which is finally saponified with KOH in ethanol.

3) The cyclization of 1,3-dihydroxyacetone (XV) with pentanamidine (XVI) in liquid ammonia gives 2-butyl-5-(hydroxymethyl)imidazole (XVII), which is acetylated with acetic anhydride yielding 5 (acetoxymethyl)-1-acetyl-2-butylimidazole (XVIII). The condensation of (XVIII) with methyl 4-(hydroxymethyl)benzoate (XIX) by means of trifluoroacetic anhydride and diisopropylethylamine in dichloromethane affords 4-[5-(acetoxymethyl)-2-butylimidazol-1-ylmethyl)benzoic acid methyl ester (XX), which is hydrolyzed with NaOH in methanol/water giving 4-[2-butyl-5-(hydroxymethyl)imidazol-1-ylmethyl)benzoic acid (XXI). The controlled oxidation of (XXI) with activated MnO2 in toluene/dichloromethane yields the corresponding aldehyde (XXII), which is condensed with methyl 3-(2-thienyl)propionate (XI) with LDA in THF affording (XXIII). The acetylation of (XXIII) with acetic anhydride and DMAP gives the corresponding acetate (XXIV), which is treated with DBU as before yielding the propenoate (XXV). Finally, this compound is hydrolyzed with NaOH as already described.