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【结 构 式】 
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【分子编号】15129 【品名】ethyl 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate 【CA登记号】 |
【 分 子 式 】C15H11ClF3NO3 【 分 子 量 】345.7051896 【元素组成】C 52.12% H 3.21% Cl 10.26% F 16.49% N 4.05% O 13.88% |
合成路线1
该中间体在本合成路线中的序号：(V)The condensation of 3-chloro-2,4,5-trifluorobenzoylacetic acid ethyl ester (I) with (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) and ethyl orthoformate (II) in hot acetic anhydride gives (1R,2S)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(2-fluorocyclopropylamino)acrylic acid ethyl ester (IV). The cyclization of (IV) by means of NaH yields the quinolone (V), which is hydrolyzed with HCl to the free acid (VI). The condensation of (VI) with 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (VII) by means of triethylamine in refluxing acetonitrile affords the protected final product (VIII), which is finally deprotected with trifluoroacetic acid and anisole.
| 【1】 Hayakawa, I.; Kimura, Y. (Daiichi Pharmaceutical Co., Ltd.); Optically active pyridone carboxylic acid derivs. AU 8933702; EP 0341493; JP 1990231475; JP 1995300416; JP 1999124367; JP 1999124380; US 5587386; US 5767127 . |
| 【2】 Castaner, J.; Graul, A.; Prous, J.; DU-6859. Drugs Fut 1994, 19, 9, 827. |
| 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) | 11681 | ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate | 101987-86-4 | C11H8ClF3O3 | 详情 | 详情 |
| (II) | 11927 | 5-Sulfanyl-1,3,4-thiadiazol-2-ylhydrosulfide; 1,3,4-Thiadiazole-2,5-dithiol | 1072-71-5 | C2H2N2S3 | 详情 | 详情 |
| (III) | 15127 | tert-butyl N-[(1R,2S)-2-fluorocyclopropyl]carbamate | 127199-16-0 | C8H14FNO2 | 详情 | 详情 |
| (IV) | 15128 | ethyl (E)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-[[(1R,2S)-2-fluorocyclopropyl]amino]-2-propenoate | C15H12ClF4NO3 | 详情 | 详情 | |
| (V) | 15129 | ethyl 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C15H11ClF3NO3 | 详情 | 详情 | |
| (VI) | 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 |
| (VII) | 15131 | N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamic acid tert-butyl ester | 127199-45-5 | C11H20N2O2 | 详情 | 详情 |
| (VIII) | 15132 | 7-[(7S)-7-(carboxyamino)-5-azaspiro[2.4]hept-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C20H18ClF2N3O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)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 |