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【结 构 式】 
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【分子编号】15957 【品名】ethyl 1-[[3-bromo-2-(2-nitrophenyl)-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate 【CA登记号】 |
【 分 子 式 】C26H24BrN3O5 【 分 子 量 】538.39778 【元素组成】C 58% H 4.49% Br 14.84% N 7.8% O 14.86% |
合成路线1
该中间体在本合成路线中的序号：(XXII)3) The condensation of 2-hydroxy-5-methylbenzaldehyde (XVII) with 2-nitrobenzyl alcohol (XVIII) by means of methanesulfonyl chloride and K2CO3 in dioxane/dimethylacetamide gives 5-methyl-2-(2-nitrobenzyloxy)benzaldehyde (XIX), which is cyclized by means of NaOMe in dimethylacetamide, yielding 5-methyl-2-(2-nitrophenyl)benzofuran (XX). The bromination of (XX) with Br2 and azobis(isobutyronitrile) (AIBN) in 1,1,1-trichloroethane affords 3-bromo-5-(bromomethyl)-2-(2-nitrophenyl)benzofuran (XXI), which is condensed with 4-cyclopropyl-2-ethylimidazole-5-carboxylic acid ethyl ester (IX) (already obtained in the preceding Scheme) by means of K2CO3 in dimethylacetamide to give 1-[3-bromo-2-(2-nitrophenyl)benzofuran-5-ylmethyl]-4-cyclopropyl-2-ethylimidazole-5-carboxylic acid ethyl ester (XXII). The reduction of (XXII) with Fe in ethanol/acetic acid yields the corresponding amino derivative (XI) already described, which is converted into the final product as described in Scheme 19090801a. 4) [13C]-Labeled saprisartan has been synthesized as follows: The decarboxylative iodination of 1-[3-bromo-2-(2-nitrophenyl)benzofuran-5-ylmethyl]-4-cyclopropyl-2-ethylimidazole-5-carboxylic acid ethyl ester (XXII) (already described in Scheme 2) by hydrolysis with NaOH in refluxing methanol, followed by reaction with iodine yields the corresponding 5-iodoimidazole derivative (XXIII), which is treated with [13C]-labeled potassium cyanide and copper iodide in DMF to afford the labeled imidazole-5-carbonitrile derivative (XXIV). The reduction of the nitro group of (XXIV) with iron filings in acetic acid/water yields the corresponding amino derivative (XXV), which is acylated with trifluoromethanesulfonic anhydride and triethylamine to give the sulfonamide (XXVI). Finally, the cyano group of (XXVI) is selectively hydrolyzed with aqueous ammonia and hydrogen peroxide to afford saprisartan labeled at the carboxamide group. 5) [14C]-Labeled saprisartan has been synthesized by the same synthetic sequence described previously for the [13C]-labeled compound.
| 【1】 Carr, R.M.; Cable, K.M.; Newman, J.J.; Sutherland, D.R.; Synthesis of isotopically labelled angiotensin II antagonist GR138950X. J Label Compd Radiopharm 1996, 38, 5, 453. |
| 【2】 Robinson, K.A.; Robinson, C.P.; Castaner, J.; Saprisartan. Drugs Fut 1996, 21, 11, 1129. |
| 【3】 Ross, B.C.; Middlemiss, D.; Scopes, D.I.C.; Jack, T.I.M.; Cardwell, K.S.; Dowle, M.D.; Judd, D.B.; Watson, S.P. (Glaxo Wellcome plc); 1H-Imidazol-1-yl-methyl benzofuran derivs. with the imidazolyl moiety being substd. by a cycloalkyl group. EP 0514198; JP 1994211846; US 5498722; WO 9220674 . |
| 【4】 Judd, D.B.; Dowle, M.D.; Middlemiss, D.; et al.; Bromobenzofuran-based non-peptide antagonists of angiotensin II: GR138950, a potent antihypertensive agent with high oral bioavailability. J Med Chem 1994, 37, 19, 3108-20. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 15944 | ethyl 4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate | C11H16N2O2 | 详情 | 详情 | |
| (XI) | 15946 | ethyl 1-[[2-(2-aminophenyl)-3-bromo-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate | C26H26BrN3O3 | 详情 | 详情 | |
| (XVII) | 15952 | 2-hydroxy-5-methylbenzaldehyde | 613-84-3 | C8H8O2 | 详情 | 详情 |
| (XVIII) | 15953 | (2-nitrophenyl)methanol; 2-Nitrobenzyl alcohol | 612-25-9 | C7H7NO3 | 详情 | 详情 |
| (XIX) | 15954 | 5-methyl-2-[(2-nitrobenzyl)oxy]benzaldehyde | C15H13NO4 | 详情 | 详情 | |
| (XX) | 15955 | 5-methyl-2-(2-nitrophenyl)-1-benzofuran | C15H11NO3 | 详情 | 详情 | |
| (XXI) | 15956 | 3-bromo-5-(bromomethyl)-2-(2-nitrophenyl)-1-benzofuran | C15H9Br2NO3 | 详情 | 详情 | |
| (XXII) | 15957 | ethyl 1-[[3-bromo-2-(2-nitrophenyl)-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate | C26H24BrN3O5 | 详情 | 详情 | |
| (XXIII) | 15958 | 1-[[3-bromo-2-(2-nitrophenyl)-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-5-iodo-1H-imidazole | C23H19BrIN3O3 | 详情 | 详情 | |
| (XXIV) | 15959 | 1-[[3-bromo-2-(2-nitrophenyl)-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carbonitrile | C24H19BrN4O3 | 详情 | 详情 | |
| (XXIV) | 45287 | 1-[[3-bromo-2-(2-nitrophenyl)-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carbonitrile | C24H19BrN4O3 | 详情 | 详情 | |
| (XXV) | 15960 | 1-[[2-(2-aminophenyl)-3-bromo-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carbonitrile | C24H21BrN4O | 详情 | 详情 | |
| (XXV) | 45288 | 1-[[2-(2-aminophenyl)-3-bromo-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carbonitrile | C24H21BrN4O | 详情 | 详情 | |
| (XXVI) | 15961 | N-(2-[3-bromo-5-[(5-cyano-4-cyclopropyl-2-ethyl-1H-imidazol-1-yl)methyl]-1-benzofuran-2-yl]phenyl)(trifluoro)methanesulfonamide | C25H20BrF3N4O3S | 详情 | 详情 | |
| (XXVI) | 45289 | N-(2-[3-bromo-5-[(5-cyano-4-cyclopropyl-2-ethyl-1H-imidazol-1-yl)methyl]-1-benzofuran-2-yl]phenyl)(trifluoro)methanesulfonamide | C25H20BrF3N4O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXIV)6) Mass labeled saprisartan has been obtained as follows: The Wittig condensation of cyclopropylcarbonyl chloride (XXVII) with ethoxycarbonylmethylene triphenylphosphorane (XXVIII) by means of bis(trimethylsilyl)acetamide in dichloromethane gives 3-cyclopropyl-3-oxo-2-(triphenylphosphoranylidene)propionic acid ethyl ester (XXIX), which is oxidized with potassium peroxymonosulfate to the dicarbonyl compound (XXX). The cyclization of (XXX) with [all-13C]-propionaldehyde (XXXI) (obtained by hydrogenation of the corresponding acyl chloride (XXXII) with H2 over Pd/C in THF containing 2,6-lutidine) and [15N]-ammonium acetate by means of triethylamine in THF yields 4-cyclopropyl-2-[1,2-13C]-ethyl-[1,3-15N,2-13C]imidazole-5-carboxylic acid ethyl ester (XXXIII). The condensation of (XXXIII) with the benzofuran (XXI) (already described in Scheme 2) by means of K2CO3 in dimethylacetamide affords 1-[3-bromo-2-(2-nitrophenyl)benzofuran-5-ylmethyl]-4-cyclopropyl-2-[1,2-13C]-ethyl-[1,3-15N,2-13C]imidazole-5-carboxylic acid ethyl ester (XXXIV), which is finally treated sequentially with Fe and acetic acid to reduce the nitro group, with trifluoromethanesulfonic anhydride to acylate the amino group, with NaOH to hydrolyze the ester group, and with carbonyldiimidazole and ammonia to generate the amide group, thus obtaining mass labeled saprisartan. This sequence has already been described in Scheme 19090802a for the unlabeled compound.
| 【1】 Carr, R.M.; Cable, K.M.; Newman, J.J.; Sutherland, D.R.; Synthesis of isotopically labelled angiotensin II antagonist GR138950X. J Label Compd Radiopharm 1996, 38, 5, 453. |
| 【2】 Robinson, K.A.; Robinson, C.P.; Castaner, J.; Saprisartan. Drugs Fut 1996, 21, 11, 1129. |
| 【3】 Ross, B.C.; Middlemiss, D.; Scopes, D.I.C.; Jack, T.I.M.; Cardwell, K.S.; Dowle, M.D.; Judd, D.B.; Watson, S.P. (Glaxo Wellcome plc); 1H-Imidazol-1-yl-methyl benzofuran derivs. with the imidazolyl moiety being substd. by a cycloalkyl group. EP 0514198; JP 1994211846; US 5498722; WO 9220674 . |
| 【4】 Judd, D.B.; Dowle, M.D.; Middlemiss, D.; et al.; Bromobenzofuran-based non-peptide antagonists of angiotensin II: GR138950, a potent antihypertensive agent with high oral bioavailability. J Med Chem 1994, 37, 19, 3108-20. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 15956 | 3-bromo-5-(bromomethyl)-2-(2-nitrophenyl)-1-benzofuran | C15H9Br2NO3 | 详情 | 详情 | |
| (XXVII) | 14061 | Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride | 4023-34-1 | C4H5ClO | 详情 | 详情 |
| (XXVIII) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (XXIX) | 15964 | ethyl 3-cyclopropyl-3-oxo-2-(triphenyl-lambda(5)-phosphanylidene)propanoate | C26H25O3P | 详情 | 详情 | |
| (XXX) | 15965 | ethyl 3-cyclopropyl-2,3-dioxopropanoate | C8H10O4 | 详情 | 详情 | |
| (XXXI) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
| (XXXI) | 45291 | propionaldehyde | C3H6O | 详情 | 详情 | |
| (XXXII) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (XXXII) | 45290 | propanoyl chloride | C3H5ClO | 详情 | 详情 | |
| (XXXIII) | 15944 | ethyl 4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate | C11H16N2O2 | 详情 | 详情 | |
| (XXXIII) | 15968 | ethyl 4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate | C11H16N2O2 | 详情 | 详情 | |
| (XXXIV) | 15957 | ethyl 1-[[3-bromo-2-(2-nitrophenyl)-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate | C26H24BrN3O5 | 详情 | 详情 | |
| (XXXIV) | 15969 | ethyl 1-[[3-bromo-2-(2-nitrophenyl)-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate | C26H24BrN3O5 | 详情 | 详情 |