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【结 构 式】

【药物名称】Eprosartan mesilate, SK&F-108566-J(?, SK&F-108566, Teveten SB, Navixen, Regulaten, Tevetenz, Teveten

【化学名称】3-[2-Butyl-1-(4-carboxybenzyl)-1H-imidazol-5-yl]-2-(2-thienylmethyl)-2(E)-propenoic acid mesylate
      (E)-alpha-[2-Butyl-1-(4-carboxybenzyl)-1H-imidazol-5-ylmethylene]-2-thiophenepropanoic acid mesylate

【CA登记号】144143-96-4, 133040-01-4 (monomesylate salt)

【 分 子 式 】C24H28N2O7S2

【 分 子 量 】520.62796

【开发单位】GlaxoSmithKline (Originator), Aventis Pharma (Licensee), Biovail (Licensee), Ferrer (Licensee), Juste (Licensee), Solvay (Licensee)

【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Angiotensin AT1 Antagonists

合成路线1

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.

1 Wittenberger, S.J.; Tasker, A.; Sorensen, B.K.; Donner, B.G.; 2-Butyl-4-iodoimidazole-5-carboxaldehyde: A versatile intermediate for the synthesis of highly functionalized imidazoles. Synth Commun 1993, 23, 22, 3231-48.
2 Merlos, M.; Casas, A.; Graul, A.; Castaner, J.; Eprosartan. Drugs Fut 1997, 22, 10, 1079.
3 Keenan, R.M.; Weinstock, J.; Finkelstein, J.A.; et al.; Potent nonpeptide angiotensin II receptor antagonists. 2. 1-(Carboxybenzyl)imidazole-5-acrylic acids. J Med Chem 1993, 36, 13, 1880-92.
4 Weinstock, J.; Keenan, R.M.; Samanen, J.; et al.; 1-(Carboxybenzyl)imidazole-5-acrylic acids: Potent and selective angiotensin II receptor antagonists. J Med Chem 1991, 34, 4, 1514-7.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 14558 2-butyl-1H-imidazole 50790-93-7 C7H12N2 详情 详情
(II) 14559 2-butyl-4,5-diiodo-1H-imidazole C7H10I2N2 详情 详情
(III) 14560 Benzyl chloromethyl ether; 1-[(chloromethoxy)methyl]benzene 3587-60-8 C8H9ClO 详情 详情
(IV) 14561 1-[(benzyloxy)methyl]-2-butyl-4,5-diiodo-1H-imidazole; benzyl (2-butyl-4,5-diiodo-1H-imidazol-1-yl)methyl ether C15H18I2N2O 详情 详情
(V) 14562 N-Methyl-n-(2-pyridyl)formamide; N-methyl-N-(2-pyridinyl)formamide 67242-59-5 C7H8N2O 详情 详情
(VI) 14563 1-[(benzyloxy)methyl]-2-butyl-4-iodo-1H-imidazole-5-carbaldehyde C16H19IN2O2 详情 详情
(VII) 14564 2-butyl-4-iodo-1H-imidazole-5-carbaldehyde C8H11IN2O 详情 详情
(VIII) 14565 methyl 4-(bromomethyl)benzoate 2417-72-3 C9H9BrO2 详情 详情
(IX) 14566 methyl 4-[(2-butyl-5-formyl-4-iodo-1H-imidazol-1-yl)methyl]benzoate C17H19IN2O3 详情 详情
(X) 14567 methyl 4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoate C17H20N2O3 详情 详情
(XI) 14568 methyl 3-(2-thienyl)propanoate 16862-05-8 C8H10O2S 详情 详情
(XII) 14569 methyl 4-([2-butyl-5-[1-hydroxy-3-methoxy-3-oxo-2-(2-thienylmethyl)propyl]-1H-imidazol-1-yl]methyl)benzoate C25H30N2O5S 详情 详情
(XIII) 14570 methyl 4-([5-[1-(acetoxy)-3-methoxy-3-oxo-2-(2-thienylmethyl)propyl]-2-butyl-1H-imidazol-1-yl]methyl)benzoate C27H32N2O6S 详情 详情
(XIV) 14571 methyl 4-([2-butyl-5-[(E)-3-methoxy-3-oxo-2-(2-thienylmethyl)-1-propenyl]-1H-imidazol-1-yl]methyl)benzoate C25H28N2O4S 详情 详情

合成路线2

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.

1 Wittenberger, S.J.; Tasker, A.; Sorensen, B.K.; Donner, B.G.; 2-Butyl-4-iodoimidazole-5-carboxaldehyde: A versatile intermediate for the synthesis of highly functionalized imidazoles. Synth Commun 1993, 23, 22, 3231-48.
2 Merlos, M.; Casas, A.; Graul, A.; Castaner, J.; Eprosartan. Drugs Fut 1997, 22, 10, 1079.
3 Keenan, R.M.; Weinstock, J.; Finkelstein, J.A.; et al.; Potent nonpeptide angiotensin II receptor antagonists. 2. 1-(Carboxybenzyl)imidazole-5-acrylic acids. J Med Chem 1993, 36, 13, 1880-92.
4 Weinstock, J.; Keenan, R.M.; Samanen, J.; et al.; 1-(Carboxybenzyl)imidazole-5-acrylic acids: Potent and selective angiotensin II receptor antagonists. J Med Chem 1991, 34, 4, 1514-7.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 14565 methyl 4-(bromomethyl)benzoate 2417-72-3 C9H9BrO2 详情 详情
(X) 14567 methyl 4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoate C17H20N2O3 详情 详情
(XIV) 14571 methyl 4-([2-butyl-5-[(E)-3-methoxy-3-oxo-2-(2-thienylmethyl)-1-propenyl]-1H-imidazol-1-yl]methyl)benzoate C25H28N2O4S 详情 详情
(XV) 13925 2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde 83857-96-9 C8H11ClN2O 详情 详情
(XVI) 14573 methyl 4-[(2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl]benzoate C17H19ClN2O3 详情 详情
(XVII) 14574 3-methoxy-3-oxo-2-(2-thienylmethyl)propionic acid C9H10O4S 详情 详情

合成路线3

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.

1 Wittenberger, S.J.; Tasker, A.; Sorensen, B.K.; Donner, B.G.; 2-Butyl-4-iodoimidazole-5-carboxaldehyde: A versatile intermediate for the synthesis of highly functionalized imidazoles. Synth Commun 1993, 23, 22, 3231-48.
2 Merlos, M.; Casas, A.; Graul, A.; Castaner, J.; Eprosartan. Drugs Fut 1997, 22, 10, 1079.
3 Weinstock, J.; Keenan, R.M.; Samanen, J.; et al.; 1-(Carboxybenzyl)imidazole-5-acrylic acids: Potent and selective angiotensin II receptor antagonists. J Med Chem 1991, 34, 4, 1514-7.
4 Keenan, R.M.; Weinstock, J.; Finkelstein, J.A.; et al.; Potent nonpeptide angiotensin II receptor antagonists. 2. 1-(Carboxybenzyl)imidazole-5-acrylic acids. J Med Chem 1993, 36, 13, 1880-92.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 14568 methyl 3-(2-thienyl)propanoate 16862-05-8 C8H10O2S 详情 详情
(XV) 14575 Dihydroxyacetone; 1,3-dihydroxyacetone 96-26-4 C3H6O3 详情 详情
(XVI) 14576 pentanimidamide 109-51-3 C5H12N2 详情 详情
(XVII) 13923 2-Butyl-5-hydroxymethylimidazole; (2-Butyl-1H-imidazol-5-yl)methanol 68283-19-2 C8H14N2O 详情 详情
(XVIII) 14578 (1-acetyl-2-butyl-1H-imidazol-5-yl)methyl acetate 136701-34-3 C12H18N2O3 详情 详情
(XIX) 14579 methyl 4-(hydroxymethyl)benzoate; Methyl 4-hydroxymethylbenzoate 6908-41-4 C9H10O3 详情 详情
(XX) 14580 methyl 4-([5-[(acetoxy)methyl]-2-butyl-1H-imidazol-1-yl]methyl)benzoate C19H24N2O4 详情 详情
(XXI) 14581 4-[[2-butyl-5-(hydroxymethyl)-1H-imidazol-1-yl]methyl]benzoic acid C16H20N2O3 详情 详情
(XXII) 14582 4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid C16H18N2O3 详情 详情
(XXIII) 14583 4-([2-butyl-5-[1-hydroxy-3-methoxy-3-oxo-2-(2-thienylmethyl)propyl]-1H-imidazol-1-yl]methyl)benzoic acid C24H28N2O5S 详情 详情
(XXIV) 14584 4-([5-[1-(acetoxy)-3-methoxy-3-oxo-2-(2-thienylmethyl)propyl]-2-butyl-1H-imidazol-1-yl]methyl)benzoic acid C26H30N2O6S 详情 详情
(XXV) 14585 4-([2-butyl-5-[(E)-3-methoxy-3-oxo-2-(2-thienylmethyl)-1-propenyl]-1H-imidazol-1-yl]methyl)benzoic acid C24H26N2O4S 详情 详情
Extended Information