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【结 构 式】 
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【分子编号】14568 【品名】methyl 3-(2-thienyl)propanoate 【CA登记号】16862-05-8 |
【 分 子 式 】C8H10O2S 【 分 子 量 】170.2322 【元素组成】C 56.45% H 5.92% O 18.8% S 18.84% |
合成路线1
该中间体在本合成路线中的序号：(XI)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
该中间体在本合成路线中的序号：(XI)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 |