|
【结 构 式】 
|
【分子编号】15193 【品名】tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate 【CA登记号】 |
【 分 子 式 】C11H20N2O2 【 分 子 量 】212.29208 【元素组成】C 62.24% H 9.5% N 13.2% O 15.07% |
合成路线1
该中间体在本合成路线中的序号：(II)A new synthesis of DU-6859 has been described: This compound is obtained by condensation of 8-chloro-6,7-difluoro-1-[2(S)-fluoro-1(R)-cyclopropyl]-4-oxo-1,4-dihydr oquinoline-3-carboxylic acid (I) with 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (II) by means of triethylamine in refluxing acetonitrile, followed by deprotection with 35% aqueous HCl. The starting compounds (I) and (II) are obtained as follows: 1) The reaction of (+/-)-cis-2-fluorocyclopropane-1-carboxylic acid (III) with 1(R)-phenylethylamine (IV) by means of N,N'-carbonyldiimidazole (CDI) gives the corresponding amide (V) as a mixture of diastereomers, which is submitted to preparative HPLC yielding 2(S)-fluorocyclopropane-1(R)-carboxylic acid 1(R)-phenylethylamide (VI). Hydrolysis of (VI) with hot 35% HCl affords the corresponding free acid (VII), which by reaction with diphenyl phosphorazidate in tert-butanol is converted to 1(R)-(tert-butoxycarbonylamino)-2(S)-fluorocyclopropane (VIII). The deprotection of (VIII) with trifluoroacetic acid gives the corresponding free amine as trifluoroacetate (IX), which is condensed with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (X) by means of triethylamine in dichloromethane to yield the chiral 3-aminoacrylate (XI). The cyclization of (XI) by means of NaH in dioxane affords 8-chloro-6,7-difluoro-1-[2(S)-fluoro-1(R)-cyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (XII), which is finally saponified to the desired acid (I) with hot 35% HCl.
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 15130 | 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | 127199-27-3 | C13H7ClF3NO3 | 详情 | 详情 |
| (II) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 | |
| (III) | 15140 | (1S,2S)-2-fluorocyclopropanecarboxylic acid | C4H5FO2 | 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 |
| (V) | 15139 | (1S,2S)-2-fluoro-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C12H14FNO | 详情 | 详情 | |
| (VI) | 15139 | (1S,2S)-2-fluoro-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C12H14FNO | 详情 | 详情 | |
| (VII) | 15140 | (1S,2S)-2-fluorocyclopropanecarboxylic acid | C4H5FO2 | 详情 | 详情 | |
| (VIII) | 15127 | tert-butyl N-[(1R,2S)-2-fluorocyclopropyl]carbamate | 127199-16-0 | C8H14FNO2 | 详情 | 详情 |
| (IX) | 15146 | (1R,2S)-2-Fluorocyclopropanamine; (1R,2S)-2-Fluorocyclopropylamine | C3H6FN | 详情 | 详情 | |
| (X) | 11682 | ethyl (Z)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxy-2-propenoate | C14H12ClF3O4 | 详情 | 详情 | |
| (XI) | 15190 | ethyl (E)-2-(3-chloro-4,5-difluorobenzoyl)-3-[[(1R,2S)-2-fluorocyclopropyl]amino]-2-propenoate | C15H13ClF3NO3 | 详情 | 详情 | |
| (XII) | 15129 | ethyl 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C15H11ClF3NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)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：(XI)An efficient synthesis of 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XI), a key intermediate in the synthesis of DU-6859a, via an asymmetric microbial reduction has been described: The reaction of N-benzylglycine (I) with tert-butoxycarbonyl anhydride gives N-benzyl-N-(tert-butoxycarbonyl)glycine (II), which is condensed with the potassium salt of ethyl hydrogen malonate (III) by means of carbonyldiimidazole (CDI) in THF yielding 4-[N-benzyl-N-(tert-butoxycarbonyl)amino]-3-oxobutyric acid ethyl ester (IV). The cyclopropanation of (IV) with 1,2-dibromoethane (V) by means of K2CO3 in refluxing acetone affords the cyclopropane derivative (VI), which is cyclized by means of trifluoroacetic acid in dichloromethane to give 5-benzyl-5-azaspiro[2.4]heptane-4,7-dione (VII). The enantioselective microbial reduction of (VII) by means of Phaeocreopsis sp. JCM 1880 in a complex medium containing glucose and polypeptone yields 5-benzyl-7(R)-hydroxy-5-azaspiro[2.4]heptan-4-one (VIII), which by reaction with triphenylphosphine, diethyl azodicarboxylate and diphenylphosphoryl azide (DPPA) followed by reduction with LiAlH4, is converted into 7(S)-amino-5-benzyl-5-azaspiro[2.4]heptane (IX). The protection of (IX) with tert-butoxycarbonyl anhydride as usual gives the protected amine (X), which is finally debenzylated by hydrogenation with H2 over Pd/C in ethanol affording the desired 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XI).
| 【1】 Yukimoto, Y.; Imura, A.; Satoh, K.; Kanai, K.; Miyadera, A.; An efficient synthesis of a key intermediate of DU-6859a via asymmetric microbial reduction. Chem Pharm Bull 1998, 46, 4, 587. |
| 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) | 27895 | N-(benzylamino)acetic acid; N-Benzylglycine; 2-(benzylamino)acetic acid | 17136-36-6 | C9H11NO2 | 详情 | 详情 |
| (II) | 27846 | 2-[benzyl(tert-butoxycarbonyl)amino]acetic acid | C14H19NO4 | 详情 | 详情 | |
| (III) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (IV) | 27896 | ethyl 4-[benzyl(tert-butoxycarbonyl)amino]-3-oxobutanoate | C18H25NO5 | 详情 | 详情 | |
| (V) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (VI) | 27897 | ethyl 1-[2-[benzyl(tert-butoxycarbonyl)amino]acetyl]cyclopropanecarboxylate | C20H27NO5 | 详情 | 详情 | |
| (VII) | 27898 | 5-benzyl-5-azaspiro[2.4]heptane-4,7-dione | C13H13NO2 | 详情 | 详情 | |
| (VIII) | 27899 | (7R)-5-benzyl-7-hydroxy-5-azaspiro[2.4]heptan-4-one | C13H15NO2 | 详情 | 详情 | |
| (IX) | 27900 | (7S)-5-benzyl-5-azaspiro[2.4]hept-7-ylamine | C13H18N2 | 详情 | 详情 | |
| (X) | 27901 | tert-butyl (7S)-5-benzyl-5-azaspiro[2.4]hept-7-ylcarbamate | C18H26N2O2 | 详情 | 详情 | |
| (XI) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XV)Nitration of 2,4,5-trifluoro-3-methylbenzoic acid (I) with H2SO4 and HNO3 provides nitrobenzoic acid derivative (II), which is then converted into the nitrobenzoyl chloride derivative (III) by reaction with oxalyl chloride in CH2Cl2 in the presence of DMF. Condensation of (III) with diethyl malonate (IV) by means of Mg in EtOH in the presence of CCl4 yields diethyl (2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)malonate (V), which is then treated with p-toluene sulfonic acid in refluxing H2O to furnish ethyl acetate derivative (VI). Reaction of (VI) with ethyl orthoformate and acetic anhydride at reflux affords ethyl acrylate derivative (VII), which is then treated with cyclopropylamine (VIII) in EtOH to give compound (IX). Cyclization of (IX) is then induced either by treatment with NaH in 1,4-dioxane or with 18-crown-6-ether and K2CO3 in THF to provide quinolone derivative (X), whose nitro group is reduced by hydrogenation over Ni Raney in HOAc to give amino derivative (XI). Hydrolysis of the ethyl ester moiety of (XI) is performed by refluxing with HCl/HOAc to furnish carboxylic acid (XII), which is then treated with boron trifluoride etherate to give boron chelate (XIII). Finally, condensation of (XIII) with (S)-7-trifluoroacetylamino-5-azaspiro[2.4]heptane hydrochloride (XIV) by means of Et3N in DMSO, followed by deprotection with KOH in H2O and treatment with MeSO3H affords the desired compound. Alternatively, the target product can also be synthesized from the Boc protected derivative (XVI) obtained either by coupling of boron chelate (XIII) with (S)-7-Boc-amino-5-azaspiro[2.4]heptane hydrochloride (XIV) by means of DIEA in DMSO (or Et3N in MeOH) or by reaction between carboxylic acid (XII) and compound (XV) by heating in DMSO. Finally, the Boc protecting group of (XVI) is removed with HCl and the corresponding methanesulfonate salt formed by treatment with MeSO3H.
| 【1】 Yoshida, T.; et al.; Studies on quinolone antibacterials.V. Synthesis and antibacterial activity of chiral 5-amino-7-(4-substituted-3-amino-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acids and derivatives. Chem Pharm Bull 1996, 44, 7, 1376. |
| 【2】 Ito, Y.; Kato, H.; Yasuda, S.; Kado, N.; Yoshida, T.; Yamamoto, Y. (Hokuriku Seiyaku Co., Ltd.); 5-Amino-8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid deriv.. CA 2126118; EP 0641793; JP 1995309864; US 5547962 . |
| 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) | 51094 | 2,4,5-trifluoro-3-methylbenzoic acid | C8H5F3O2 | 详情 | 详情 | |
| (II) | 51095 | 2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid | C8H4F3NO4 | 详情 | 详情 | |
| (III) | 51096 | 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride | C8H3ClF3NO3 | 详情 | 详情 | |
| (IV) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (V) | 51097 | diethyl 2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)malonate | C15H14F3NO7 | 详情 | 详情 | |
| (VI) | 51098 | ethyl 3-oxo-3-(2,4,5-trifluoro-3-methyl-6-nitrophenyl)propanoate | C12H10F3NO5 | 详情 | 详情 | |
| (VII) | 51099 | ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)-2-propenoate | C15H14F3NO6 | 详情 | 详情 | |
| (VIII) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (IX) | 51100 | ethyl (Z)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)-2-propenoate | C16H15F3N2O5 | 详情 | 详情 | |
| (X) | 51101 | ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-5-nitro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C16H14F2N2O5 | 详情 | 详情 | |
| (XI) | 51102 | ethyl 5-amino-1-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C16H16F2N2O3 | 详情 | 详情 | |
| (XII) | 51103 | 5-amino-1-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C14H12F2N2O3 | 详情 | 详情 | |
| (XIII) | 51104 | C14H11BF4N2O3 | 详情 | 详情 | ||
| (XIV) | 51105 | N-[(7S)-5-azaspiro[2.4]hept-7-yl]-2,2,2-trifluoroacetamide | C8H11F3N2O | 详情 | 详情 | |
| (XV) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 | |
| (XVI) | 51106 | 5-amino-7-[(7S)-7-[(tert-butoxycarbonyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C25H31FN4O5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XII)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6
该中间体在本合成路线中的序号：(XII)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 |
合成路线7
该中间体在本合成路线中的序号：(XIV)The reaction of 3-chlorotetrafluoropyridine (I) with sodium tert-butoxide in THF gives 4-(tert-butoxy)-3-chloro-2,5,6-trifluoropyridine (II), which is dechlorinated with H2 over Pearlman's catalyst in methanol yielding 4-(tert-butoxy)-2,3,6-trifluoropyridine (III). The methylation of (III) with methyl iodide and lithium diethylamide (LDA) in THF affords 4-(tert-butoxy)-2,3,6-trifluoro-5-methylpyridine (IV), which is treated with hydrazine in refluxing propanol to give 4-(tert-butoxy)-2,5-difluoro-3-methylpyridine (V). The condensation of (V) with 2-bromo-2-cyclopropylacetopnitrile (VI) by means of LDA in THF yields the expected condensation product (VII), which is treated with TFA to eliminate the tert-butyl protecting group and with POCl3 in DMF to afford the 4-chloropyridyl derivative (VIII). The hydrolysis of the nitrile group of (VIII) with HCl in ethanol gives the corresponding acetate ester (IX), which is reduced with LiAlH4 in THF to the alcohol (X). The oxidation of (X) with oxalyl chloride in DMSO/dichloromethane yields the aldehyde (XI), which is cyclized with diethyl malonate (XII) by means of piperidine in refluxing acetic acid, followed by heating at 220 C C in Dowtherm to afford 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (XIII). The condensation of (XIII) with 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XIV) by means of triethylamine in DMF gives the expected condensation product (XV), which is methylated with methyl iodide and sodium hexamethyldisylazane (Na-HMDS) in THF yielding the N-methyl derivative (XVI). The hydrolysis of the ester group of (XVI) with LiOH in THF/water provides the corresponding free acid (XVII), which is finally deprotected with HCl in acetic acid. The synthesis of the intermediate 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XIV) has already been described in the first synthesis of compound no. 268134 (see scheme 26813401a).
| 【1】 Or, Y.S.; Armiger, Y.-L.; Fung, A. (Abbott Laboratories Inc.); Pyridone antibiotic with improved safety profile. US 5977133; WO 0010998 . |
| 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) | 16189 | (2R)-2-(1-benzothiophen-5-yl)-2-hydroxyethanoic acid | C10H8O3S | 详情 | 详情 | |
| (II) | 16820 | 4-(tert-butoxy)-3-chloro-2,5,6-trifluoropyridine; tert-butyl 3-chloro-2,5,6-trifluoro-4-pyridinyl ether | C9H9ClF3NO | 详情 | 详情 | |
| (III) | 16821 | 4-(tert-butoxy)-2,3,6-trifluoropyridine; tert-butyl 2,3,6-trifluoro-4-pyridinyl ether | C9H10F3NO | 详情 | 详情 | |
| (IV) | 16822 | tert-butyl 2,3,6-trifluoro-5-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,3,6-trifluoro-5-methylpyridine | C10H12F3NO | 详情 | 详情 | |
| (V) | 16823 | tert-butyl 2,5-difluoro-3-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,5-difluoro-3-methylpyridine | C10H13F2NO | 详情 | 详情 | |
| (VI) | 31629 | 2-bromo-2-cyclopropylacetonitrile | C5H6BrN | 详情 | 详情 | |
| (VII) | 16825 | 2-[4-(tert-butoxy)-5-fluoro-3-methyl-2-pyridinyl]-2-cyclopropylacetonitrile | C15H19FN2O | 详情 | 详情 | |
| (VIII) | 16826 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetonitrile | C11H10ClFN2 | 详情 | 详情 | |
| (IX) | 16827 | ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetate | C13H15ClFNO2 | 详情 | 详情 | |
| (X) | 31627 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropyl-1-ethanol | C11H13ClFNO | 详情 | 详情 | |
| (XI) | 16828 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetaldehyde | C11H11ClFNO | 详情 | 详情 | |
| (XII) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 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) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 | |
| (XV) | 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 | |
| (XVI) | 16951 | (1R)-1-[(4S,5R)-2,2-dimethyl-5-[(E)-1-tetradecenyl]-1,3-dioxolan-4-yl]-2-(trityloxy)-1-ethanol | C40H54O4 | 详情 | 详情 | |
| (XVII) | 31628 | 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-carboxylic acid | C26H32FN3O5 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(IX)The reaction of 2,4,5-trifluoro-3-methoxybenzoic acid (I) with SOCl2 in toluene gives the corresponding acyl chloride (II), which is condensed with 3-(dimethylamino)acrylic acid ethyl ester (III) by means of TEA to yield 3-(dimethylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)acrylic acid ethyl ester (IV). The cyclization of (IV) with 2-fluorocyclopropylamine (V) by means of TEA and K2CO3 in DMF affords the quinolone-3-carboxylate (VI), which is hydrolyzed with HCl in HOAc to provide the carboxylic acid (VII). The reaction of (VII) with BF3/Et2O in diethyl ether gives the boronic ester (VIII), which is condensed with the spiropyrrolidine (IX) by means of TEA in ethanol. Finally, the boronic ester of (IX) is hydrolyzed with HCl to afford the target quinolone-3-carboxylic acid.
| 【1】 Kawakami, K.; et al.; DK-570k, a new 8-methoxyquinolone: Synthesis and biological evaluation of 7-[(3-amino-4-substituted)pyrrolidin-1-yl] derivatives. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-546. |
| 【2】 Suzuki, T.; Takahashi, H.; Hayakawa, I.; Takemura, M.; Ohtani, T.; Kawakami, K.; Itoh, M.; Miyauchi, R.; Sekiguchi, M. (Daiichi Pharmaceutical Co., Ltd.); Quinolonecarboxylic acid deriv.. WO 0172738 . |
| 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) | 12258 | 2,4,5-Trifluoro-3-methoxybenzoic acid | 112811-65-1 | C8H5F3O3 | 详情 | 详情 |
| (II) | 12259 | 2,4,5-Trifluoro-3-methoxybenzoyl chloride | C8H4ClF3O2 | 详情 | 详情 | |
| (III) | 16000 | ethyl (E)-3-(dimethylamino)-2-propenoate; Ethyl trans-3-dimethylaminoacrylate | 1117-37-9 | C7H13NO2 | 详情 | 详情 |
| (IV) | 53193 | ethyl (Z)-3-(dimethylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate | n/a | C15H16F3NO4 | 详情 | 详情 |
| (V) | 15146 | (1R,2S)-2-Fluorocyclopropanamine; (1R,2S)-2-Fluorocyclopropylamine | C3H6FN | 详情 | 详情 | |
| (VI) | 53194 | ethyl 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate | n/a | C16H14F3NO4 | 详情 | 详情 |
| (VII) | 53195 | 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | n/a | C14H10F3NO4 | 详情 | 详情 |
| (VIII) | 53196 | 3-{[(difluoroboryl)oxy]carbonyl}-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4(1H)-quinolinone | n/a | C14H9BF5NO4 | 详情 | 详情 |
| (IX) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 | |
| (X) | 53197 | tert-butyl (7S)-5-{3-{[(difluoroboryl)oxy]carbonyl}-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydro-7-quinolinyl}-5-azaspiro[2.4]hept-7-ylcarbamate | n/a | C25H28BF4N3O6 | 详情 | 详情 |