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【结 构 式】 
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【分子编号】15949 【品名】3-Cyclopropyl-3-oxo-propionic acid ethyl ester; ethyl 3-cyclopropyl-3-oxopropanoate 【CA登记号】24922-02-9 |
【 分 子 式 】C8H12O3 【 分 子 量 】156.18148 【元素组成】C 61.52% H 7.74% O 30.73% |
合成路线1
该中间体在本合成路线中的序号：(XIV)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：(LV)6) Synthesis of the quinoline (XXI): Anthranilic acid (LI) is tolylated with tosyl chloride and treated with PCl5 in 1,2-dichloroethane to give the corresponding acyl chloride (LII), which is submitted to a Friedel Crafts condensation with fluorobenzene (LIII)/AlCl3 yielding 2-amino-4'-fluorobenzophenone (LIV). The cyclization of (LIV) with ethyl 2-(cyclopropylcarbonyl)acetate (LV) [obtained by condensation of cyclopropyl methyl ketone (LVI) and diethyl carbonate (LVII) with H2SO4] by means of p-toluenesulfonic acid yields 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carboxylic acid ethyl ester (LVIII), which is submitted to a decarboxylative iodination with I2 and acetyl peroxide to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI). 7) Synthesis of the quinoline (XXXVII): The reduction of the quinolinecarboxylate (LVIII) with LiAlH4 in THF gives the corresponding methanol derivative (LIX), which is then treated with diphenyl disulfide (LX) and tri-butylphosphine in pyridine to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-(phenylsulfanylmethyl)quinoline (XXXVII).
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
| 【2】 Kamikubo, T.; Takano, S.; Sugihara, T.; Suzuki, M.; Ogasawara, K.; Enantioconvergent synthesis of a promising HMG-CoA reductase inhibitor NK-104 from both enantiomers of epichlorohydrin. Tetrahedron Asymmetry 1993, 4, 2, 201-4. |
| 【3】 Iwasaki, H.; Miyachi, N.; Yanagawa, Y.; Ohara, Y.; Hiyama, T.; A novel synthetic method of HMG-CoA reductase inhibitor NK-104 via a hydroboration-cross-coupling sequence. Tetrahedron Lett 1993, 34, 51, 8267-70. |
| 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) | 17435 | 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline | C18H13FIN | 详情 | 详情 | |
| (XXXVII) | 17451 | [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methyl phenyl sulfide; 2-cyclopropyl-4-(4-fluorophenyl)-3-[(phenylsulfanyl)methyl]quinoline | C25H20FNS | 详情 | 详情 | |
| (LI) | 11661 | 2-Aminobenzoic acid;Anthranilic acid; o-Aminobenzoic acid | 118-92-3 | C7H7NO2 | 详情 | 详情 |
| (LII) | 17465 | 2-aminobenzoyl chloride | C7H6ClNO | 详情 | 详情 | |
| (LIII) | 17466 | Fluorobenzene | 462-06-6 | C6H5F | 详情 | 详情 |
| (LIV) | 17467 | (2-aminophenyl)(4-fluorophenyl)methanone | C13H10FNO | 详情 | 详情 | |
| (LV) | 15949 | 3-Cyclopropyl-3-oxo-propionic acid ethyl ester; ethyl 3-cyclopropyl-3-oxopropanoate | 24922-02-9 | C8H12O3 | 详情 | 详情 |
| (LVI) | 12435 | Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone | 765-43-5 | C5H8O | 详情 | 详情 |
| (LVII) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (LVIII) | 17471 | ethyl 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarboxylate | C21H18FNO2 | 详情 | 详情 | |
| (LIX) | 17472 | [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methanol | C19H16FNO | 详情 | 详情 | |
| (LX) | 17473 | diphenyl disulfide; 1-(phenyldisulfanyl)benzene; diphenyldisulfide | 882-33-7 | C12H10S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Malonic acid monoethyl ester (I) is converted into beta-ketoester (III) by formation of the corresponding trimethylsilyl ester with TMSCl and pyridine in ether followed by deprotonation with n-BuLi and acylation with cyclopropanecarbonyl chloride (II) in DME. Treatment of (III) with refluxing N,N-dimethylformamide dimethyl acetal (IV) affords enamine (V). Quinoline-5-amine (VI) is first subjected to diazotation by treatment with NaNO2 in H2O/HCl, reduced with SnCl2.2H2O in HCl and isolated as the corresponding dihydrochloride salt (VII) by treatment with HCl. Condensation of enamine (V) with hydrazine (VII) in the presence of Et3N in refluxing EtOH yields pyrazole ester (VIII), which is converted into acylguanidine (X) either by direct heating with guanidine (IX) in EtOH or by first transformation into the corresponding carboxylic acid (XI) by saponification with NaOH in refluxing MeOH, followed by treatment with refluxing thionyl chloride and reaction with guanidine hydrochloride (XII) under Schotten-Baumann conditions in refluxing THF/NaOH. Finally, treatment of the free base (X) with HCl in THF allows isolation of the corresponding monohydrochloride-monohydrate salt .
| 【1】 Wester, R.T.; Allen, M.C.; Guzman-Perez, A.; et al.; Discovery of zoniporide: A potent and selective sodium-hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility. Bioorg Med Chem Lett 2001, 11, 6, 803. |
| 【2】 Guzman-Perez, A.; Ruggeri, R.B.; Wester, R.T.; Hamanaka, E.S.; Mularski, C.J. (Pfizer Inc.); N-[(Substd. five-membered di- or triaza diunsaturated ring)carbonyl] guanidine derivs. for the treatment of ischemia. EP 1056729; WO 9943663 . |
| 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),(XII) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (I) | 15086 | 3-ethoxy-3-oxopropionic acid | 1071-46-1 | C5H8O4 | 详情 | 详情 |
| (II) | 14061 | Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride | 4023-34-1 | C4H5ClO | 详情 | 详情 |
| (III) | 15949 | 3-Cyclopropyl-3-oxo-propionic acid ethyl ester; ethyl 3-cyclopropyl-3-oxopropanoate | 24922-02-9 | C8H12O3 | 详情 | 详情 |
| (IV) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (V) | 48913 | ethyl (Z)-3-amino-2-(cyclopropylcarbonyl)-2-propenoate | C9H13NO3 | 详情 | 详情 | |
| (VI) | 26799 | 5-Aminoquinoline; 5-quinolinamine | 611-34-7 | C9H8N2 | 详情 | 详情 |
| (VII) | 48914 | 5-hydrazinoquinoline | C9H9N3 | 详情 | 详情 | |
| (VIII) | 48915 | ethyl 5-cyclopropyl-1-(5-quinolinyl)-1H-pyrazole-4-carboxylate | C18H17N3O2 | 详情 | 详情 | |
| (X) | 48917 | N''-[[5-cyclopropyl-1-(5-quinolinyl)-1H-pyrazol-4-yl]carbonyl]guanidine | C17H16N6O | 详情 | 详情 | |
| (XI) | 48916 | 5-cyclopropyl-1-(5-quinolinyl)-1H-pyrazole-4-carboxylic acid | C16H13N3O2 | 详情 | 详情 |