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【结 构 式】

【分子编号】15944

【品名】ethyl 4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate

【CA登记号】

【 分 子 式 】C11H16N2O2

【 分 子 量 】208.26032

【元素组成】C 63.44% H 7.74% N 13.45% O 15.36%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(IX)

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

合成路线2

该中间体在本合成路线中的序号:(IX)

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3

该中间体在本合成路线中的序号:(XXXIII)

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
Extended Information