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【结 构 式】

【分子编号】15937

【品名】5-methyl-1-benzofuran-2-ylboronic acid

【CA登记号】

【 分 子 式 】C9H9BO3

【 分 子 量 】175.97966

【元素组成】C 61.43% H 5.15% B 6.14% O 27.27%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(II)

1) The reaction of 5-methylbenzofuran (I) with triisopropyl borate by means of butyllithium and tetramethylethylenediamine (TMEDA) in ethyl ether gives 5-methylbenzofuran-2-boronic acid (II), which is condensed with methyl 2-bromobenzoate (III) by means of tetrakis(triphenylphosphine)palladium yielding 2-(5-methylbenzofuran-2-yl)benzoic acid methyl ester (IV). The bromination of (IV) with Br2 in CCl4 affords 2-(3-bromo-5-methylbenzofuran-2-yl)benzoic acid methyl ester (V), which is hydrolyzed with NaOH in refluxing methanol to the corresponding benzoic acid (VI). The reaction of (VI) with diphenylphosphoryl azide (DPPA) and tert-butanol in dioxane gives N-[2-(3-bromo-5-methylbenzofuran-2-yl)phenyl]carbamic acid tert-butyl ester (VII), which is brominated with N-bromosuccinimide (NBS) and benzoyl peroxide to the corresponding bromomethyl derivative (VIII). The condensation of (VIII) with 4-cyclopropyl-2-ethylimidazole-5-carboxylic acid ethyl ester (IX) by means of K2CO3 in DMF affords 1-[3-bromo-2-[2-(tert-butoxycarbonylamino)phenyl]benzofuran-5-ylmethyl]-4-cyclopropyl-2-ethylimidazole-5-carboxylic acid ethyl ester (X), which is treated with trifluoroacetic acid to eliminate the carbamate group, yielding compound (XI) with a free amino group. Acylation of (XI) with trifluoromethanesulfonic anhydride in dichloromethane gives the sulfonamide (XII), which is treated with NaOH in hot aqueous methanol to hydrolyze the ethyl ester group and isolate the carboxylic acid (XIII). Finally, this compound is treated first with carbonyldiimidazole (CDI) in THF and then with ethanolic ammonia. 2) The intermediate imidazole (IX) is obtained by reaction of ethyl 3-cyclopropyl-3-oxopropanoate (XIV) with NaNO2 and acetic acid, followed by hydrogenation with H2 over Pt/C in ethanol to give ethyl 2-amino-3-cyclopropyl-3-oxopropanoate (XV), which is then cyclized with propionimidic acid ethyl ester (XVI) by means of triethylamine in ethanol.

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
(I) 15936 5-methyl-1-benzofuran C9H8O 详情 详情
(II) 15937 5-methyl-1-benzofuran-2-ylboronic acid C9H9BO3 详情 详情
(III) 15938 methyl 2-bromobenzoate 610-94-6 C8H7BrO2 详情 详情
(IV) 15939 methyl 2-(5-methyl-1-benzofuran-2-yl)benzoate C17H14O3 详情 详情
(V) 15940 methyl 2-(3-bromo-5-methyl-1-benzofuran-2-yl)benzoate C17H13BrO3 详情 详情
(VI) 15941 2-(3-bromo-5-methyl-1-benzofuran-2-yl)benzoic acid C16H11BrO3 详情 详情
(VII) 15942 tert-butyl N-[2-(3-bromo-5-methyl-1-benzofuran-2-yl)phenyl]carbamate C20H20BrNO3 详情 详情
(VIII) 15943 tert-butyl N-[2-[3-bromo-5-(bromomethyl)-1-benzofuran-2-yl]phenyl]carbamate C20H19Br2NO3 详情 详情
(IX) 15944 ethyl 4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate C11H16N2O2 详情 详情
(X) 15945 ethyl 1-[(3-bromo-2-[2-[(tert-butoxycarbonyl)amino]phenyl]-1-benzofuran-5-yl)methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate C31H34BrN3O5 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
(XII) 15947 ethyl 1-[[3-bromo-2-(2-[[(trifluoromethyl)sulfonyl]amino]phenyl)-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate C27H25BrF3N3O5S 详情 详情
(XIII) 15948 1-[[3-bromo-2-(2-[[(trifluoromethyl)sulfonyl]amino]phenyl)-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylic acid C25H21BrF3N3O5S 详情 详情
(XIV) 15949 3-Cyclopropyl-3-oxo-propionic acid ethyl ester; ethyl 3-cyclopropyl-3-oxopropanoate 24922-02-9 C8H12O3 详情 详情
(XV) 15950 ethyl 2-amino-3-cyclopropyl-3-oxopropanoate C8H13NO3 详情 详情
(XVI) 15951 ethyl propanimidoate C5H11NO 详情 详情
Extended Information