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【结 构 式】 
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【分子编号】15181 【品名】1-[2-(bromomethyl)-1,3-dioxolan-2-yl]-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide 【CA登记号】 |
【 分 子 式 】C16H20BrNO3 【 分 子 量 】354.24374 【元素组成】C 54.25% H 5.69% Br 22.56% N 3.95% O 13.55% |
合成路线1
该中间体在本合成路线中的序号：(XLIII)b) The intermediate 7(S)-(tert-Butoxycarbonylamino)-5-azaspiro[2.4]heptane (VII) can also be obtained as follows: 2) The reaction of 1-acetylcyclopropane-1-carboxylic acid ethyl ester (XXXIII) with (R)-alpha-methylbenzylamine (XIII) by means of NaOH and ethyl chloroformate gives the corresponding amide (XLI), which by reaction with ethylene glycol and p-toluenesulfonic acid is converted into the ethylene ketal (XLII). The bromination of (XLII) with Br2 in dioxane affords the bromomethyl dioxolane (XLIII), which is finally cyclized to 5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione (XXXV), already obtained as an intermediate in the preceding synthesis.
| 【1】 Castaner, J.; Graul, A.; Prous, J.; DU-6859. Drugs Fut 1994, 19, 9, 827. |
| 【2】 Sato, K.; Saito, T.; Hayakawa, I.; Sato, M.; Yafune, T.; Atarashi, S.; Une, T.; Kimura, Y.; Kawakami, K.; Design and structure-activity relationship of new N1-cis-2-fluorocyclopropyl quinolones. 31st. 31st Intersci Conf Antimicrob Agents Chemother (Sept 29-Oct 2, Chicago) 1991, Abst 1504. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XXXIII) | 15171 | ethyl 1-acetylcyclopropanecarboxylate | C8H12O3 | 详情 | 详情 | |
| (XXXV) | 15173 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione | C14H15NO2 | 详情 | 详情 | |
| (XLI) | 15179 | 1-acetyl-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C14H17NO2 | 详情 | 详情 | |
| (XLII) | 15180 | 1-(2-methyl-1,3-dioxolan-2-yl)-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C16H21NO3 | 详情 | 详情 | |
| (XLIII) | 15181 | 1-[2-(bromomethyl)-1,3-dioxolan-2-yl]-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C16H20BrNO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)2) The reaction of 1-acetylcyclopropane-1-carboxylic acid (XIII) with 1(R)-phenylethylamine (IV) by means of ethyl chloroformate and triethylamine gives the corresponding amide (XIV), which is treated with ethylene glycol and p-toluenesulfonic acid, yielding the dioxolane (XV). The bromination of (XV) with Br2 in dioxane affords the bromomethyl-dioxolane (XVI), which is cyclized by means of NaH in DMF to give 5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione 7-ethyleneketal (XVII). Opening of the ketal ring with 1N HCl in refluxing acetone yields the free diketone (XVIII), which by reaction with hydroxylamine and triethylamine in ethanol affords the monooxime (XIX). The reduction of (XIX) with H2 over RaNi in methanol gives the aminoketone (XX) as a diastereomeric mixture, which is separated by column chromatography yielding 7(S)-amino-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptan-4-one (XXI). The reduction of (XXI) with LiAlH4 in THF affords the amine (XXII), which is protected with 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile in THF to give 7(S)-(tert-butoxycarbonylamino)-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane (XXIII). Finally, this compound is hydrogenolyzed with H2 over Pd/C in ethanol, yielding the desired chiral spiro compound (II).
| 【1】 Kimura, Y.; Atarashi, S.; Kawakami, K.; Hayakawa, I.; Sato, K.; (Fluorocyclopropyl)quinolones. 2. Synthesis and stereochemical structure-activity relationships of chiral 7-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-(2-fluorocyclopropyl)quinolone antibacterial agents. J Med Chem 1994, 37, 20, 3344. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 | |
| (IV) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XIII) | 15194 | 1-acetylcyclopropanecarboxylic acid | C6H8O3 | 详情 | 详情 | |
| (XIV) | 15179 | 1-acetyl-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C14H17NO2 | 详情 | 详情 | |
| (XV) | 15180 | 1-(2-methyl-1,3-dioxolan-2-yl)-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C16H21NO3 | 详情 | 详情 | |
| (XVI) | 15181 | 1-[2-(bromomethyl)-1,3-dioxolan-2-yl]-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C16H20BrNO3 | 详情 | 详情 | |
| (XVII) | 15198 | 10-[(1R)-1-phenylethyl]-5,8-dioxa-10-azadispiro[2.0.4.3]undecan-11-one | C16H19NO3 | 详情 | 详情 | |
| (XVIII) | 15173 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione | C14H15NO2 | 详情 | 详情 | |
| (XIX) | 15174 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione 7-oxime | C14H16N2O2 | 详情 | 详情 | |
| (XX) | 63961 | 7-amino-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one | C14H18N2O | 详情 | 详情 | |
| (XXI) | 15176 | (7S)-7-amino-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one | C14H18N2O | 详情 | 详情 | |
| (XXII) | 15177 | (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-7-amine; (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-ylamine | C14H20N2 | 详情 | 详情 | |
| (XXIII) | 15204 | tert-butyl N-[(7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-yl]carbamate | C19H28N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The cyclopropanation of ethyl acetoacetate (I) with 1,2-dibromoethane and K2CO3 in DMF, followed by hydrolysis with NaOH gives 1-acetylcyclopropane-1-carboxylic acid (II), which is condensed with 1(R)-phenylethylamine (A) by means of butyl chloroformate in dichloromethane yielding the chiral amide (III). The protection of the acetyl group with ethylene glycol and p-toluenesulfonic acid affords the cyclic acetal (IV), which is brominated with Br2 in dioxane to give the bromomethyl compound (V). The cyclization of (V) by means of NaH in THF affords the spirocyclopropane derivative (VI), which is deprotected with HCl providing the spiro pyrrolidinedione (VII). The reaction of (VII) with hydroxylamine affords the oxime (VIII), which is reduced with H2 over RaNi in methanol and crystallized with l-tartaric acid to give the desired chiral 7(R)-amino-5-(1(R)-phenylethyl)-5-azaspiro[2.4]heptan-4-one (IX). The reduction of the ketonic group of (IX) with LiAlH4 yields the chiral amine (X), which is protected with tert-butoxycarbonyl anhydride to the carbamate (XI). The hydrogenation of (XI) with H 2 over Pd/C affords the spiropyrrolidine (XII) with its NH group free, which is condensed with the quinolizine (XIII) by means of triethylamine in DMF providing intermediate (XIV). Finally, this compound is deprotected and hydrolyzed to the target compound with LiOH in ethanol.
| 【1】 Armiger, Y.L.; Chu, D.T.W.; Fung, A.K.L.; et al.; The discovery of A-165753 and A-170568, two potent broad-spectrum antimicrobial agents. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-86. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (I) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (II) | 15194 | 1-acetylcyclopropanecarboxylic acid | C6H8O3 | 详情 | 详情 | |
| (III) | 15179 | 1-acetyl-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C14H17NO2 | 详情 | 详情 | |
| (IV) | 15180 | 1-(2-methyl-1,3-dioxolan-2-yl)-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C16H21NO3 | 详情 | 详情 | |
| (V) | 15181 | 1-[2-(bromomethyl)-1,3-dioxolan-2-yl]-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C16H20BrNO3 | 详情 | 详情 | |
| (VI) | 15198 | 10-[(1R)-1-phenylethyl]-5,8-dioxa-10-azadispiro[2.0.4.3]undecan-11-one | C16H19NO3 | 详情 | 详情 | |
| (VII) | 15173 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione | C14H15NO2 | 详情 | 详情 | |
| (VIII) | 15174 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione 7-oxime | C14H16N2O2 | 详情 | 详情 | |
| (IX) | 15176 | (7S)-7-amino-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one | C14H18N2O | 详情 | 详情 | |
| (X) | 15177 | (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-7-amine; (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-ylamine | C14H20N2 | 详情 | 详情 | |
| (XI) | 15204 | tert-butyl N-[(7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-yl]carbamate | C19H28N2O2 | 详情 | 详情 | |
| (XII) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 | |
| (XIII) | 16831 | ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C16H15ClFNO3 | 详情 | 详情 | |
| (XIV) | 26950 | ethyl 8-[(7S)-7-[(tert-butoxycarbonyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C27H34FN3O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)The cyclopropanation of ethyl acetoacetate (I) with 1,2-dibromoethane and K2CO3 in DMF, followed by hydrolysis with NaOH gives 1-acetylcyclopropane-1-carboxylic acid (II), which is condensed with 1(R)-phenylethylamine (A) by means of butyl chloroformate in dichloromethane yielding the chiral amide (III). The protection of the acetyl group with ethylene glycol and p-toluenesulfonic acid affords the cyclic acetal (IV), which is brominated with Br2 in dioxane to give the bromomethyl compound (V). The cyclization of (V) by means of NaH in THF affords the spirocyclopropane derivative (VI), which is deprotected with HCl providing the spiro pyrrolidinedione (VII). The reaction of (VII) with hydroxylamine affords the oxime (VIII), which is reduced with H2 over RaNi in methanol and crystallized with l-tartaric acid to give the desired chiral 7(R)-amino-5-(1(R)-phenylethyl)-5-azaspiro[2.4]heptan-4-one (IX). The reduction of the ketonic group of (IX) with LiAlH4 yields the chiral amine (X), which is protected with tert-butoxycarbonyl anhydride to the carbamate (XI). The hydrogenation of (XI) with H 2 over Pd/C affords the spiropyrrolidine (XII) with its NH group free, which is condensed with the quinolizine (XIII) by means of triethylamine in DMF providing intermediate (XIV). This compound is methylated by means of methyl iodide and sodium bis(trimethylsilyl)amide yielding the methylamino derivative (XV), which is finally deprotected and hydrolyzed to the target compound with LiOH in ethanol.
| 【1】 Armiger, Y.L.; Chu, D.T.W.; Fung, A.K.L.; et al.; The discovery of A-165753 and A-170568, two potent broad-spectrum antimicrobial agents. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-86. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (I) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (II) | 15194 | 1-acetylcyclopropanecarboxylic acid | C6H8O3 | 详情 | 详情 | |
| (III) | 15179 | 1-acetyl-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C14H17NO2 | 详情 | 详情 | |
| (IV) | 15180 | 1-(2-methyl-1,3-dioxolan-2-yl)-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C16H21NO3 | 详情 | 详情 | |
| (V) | 15181 | 1-[2-(bromomethyl)-1,3-dioxolan-2-yl]-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C16H20BrNO3 | 详情 | 详情 | |
| (VI) | 15198 | 10-[(1R)-1-phenylethyl]-5,8-dioxa-10-azadispiro[2.0.4.3]undecan-11-one | C16H19NO3 | 详情 | 详情 | |
| (VII) | 15173 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione | C14H15NO2 | 详情 | 详情 | |
| (VIII) | 15174 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione 7-oxime | C14H16N2O2 | 详情 | 详情 | |
| (IX) | 15176 | (7S)-7-amino-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one | C14H18N2O | 详情 | 详情 | |
| (X) | 15177 | (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-7-amine; (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-ylamine | C14H20N2 | 详情 | 详情 | |
| (XI) | 15204 | tert-butyl N-[(7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-yl]carbamate | C19H28N2O2 | 详情 | 详情 | |
| (XII) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 | |
| (XIII) | 16831 | ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C16H15ClFNO3 | 详情 | 详情 | |
| (XIV) | 26950 | ethyl 8-[(7S)-7-[(tert-butoxycarbonyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C27H34FN3O5 | 详情 | 详情 | |
| (XV) | 26951 | ethyl 8-[(7S)-7-[(tert-butoxycarbonyl)(methyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C28H36FN3O5 | 详情 | 详情 |