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【结 构 式】 
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【分子编号】65946 【品名】7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 【CA登记号】 |
【 分 子 式 】C14H8ClFN2O3 【 分 子 量 】306.6803032 【元素组成】C 54.83% H 2.63% Cl 11.56% F 6.19% N 9.13% O 15.65% |
合成路线1
该中间体在本合成路线中的序号：(I)Coupling of 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (I) with (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazine (II) in the presence of triethylamine in acetonitrile and subsequent treatment of the resulting adduct (III) with hydrochloric acid in water gives finafloxacin hydrochloride (1, 2). Alternatively, condensation of the ethyl ester (IV) with the Boc-protected pyrrolo-oxazine (V) by means of DIPEA in dimethylphthalate (DMP) at 100 °C gives adduct (VI), which is hydrolyzed with lithium hydroxide to yield the corresponding free carboxylic acid (VII). Finally, acid (VII) is deprotected by treatment with hydrochloric acid in ethanol/ether (3). Scheme 1.
| 【1】 Matzke, M., Petersen, U., Schenke, T. et al. (Bayer Healthcare AG). Use of 7-(2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-quinolone carboxylic acid and naphthyridon carboxylic acid derivatives for the treatment of Helicobacter pylori infections and associated gastroduodenal diseases. CA 2274894, DE 19652239, EP 0946176, JP 200351781, JP 2000514825, US 6133260, US 6432948, WO 1998026779. |
| 【2】 Wohlert, S.E., Jaetsch, T., Gallenkamp, B. et al. New fluoroquinolone finafloxacin HCI (FIN): Route of synthesis, physicochemical characteristics and activity under neutral and acid conditions. 48th Annu Intersci Conf Antimicrob Agents Chemother (ICAAC) Infect Dis Soc Am (IDSA) Annu Meet (Oct 25-28, Washington, D.C.) 2008, Abst F1-2036. |
| 【3】 Hong, J., Zhang, Z., Lei, H. et al. A novel approach to finafloxacin hydrochloride (BAY35-3377). Tetrahedron Lett 2009, 50(21): 2525-8. |
| 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) | 65946 | 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid | C14H8ClFN2O3 | 详情 | 详情 | |
| (II) | 65947 | (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazine | C6H12N2O | 详情 | 详情 | |
| (III) | 65948 | C20H19FN4O4 | 详情 | 详情 | ||
| (IV) | 65949 | C16H12ClFN2O3 | 详情 | 详情 | ||
| (V) | 65950 | C11H20N2O3 | 详情 | 详情 | ||
| (VI) | 65951 | C27H31FN4O6 | 详情 | 详情 | ||
| (VII) | 65952 | C25H27FN4O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)3,5-Dimethylfluorobenzene (VIII) is treated with chlorine in the presence of anhydrous FeCl3 in either solvent-free conditions or in 1,2-dichloroethane to yield the 2,4-dichlorobenzene derivative (IX). Photochemical chlorination of compound (IX) affords 2,4-dichloro-3-(dichloromethyl)-1-fluoro-5-(trichloromethyl)benzene (X), which is further oxidized with concentrated sulfuric acid at 70 °C to give 2,4-dichloro-5-fluoro-3-formylbenzoic acid (XI) (1, 2). Aldehyde (XI) is next condensed with hydroxylamine hydrochloride (XII) in either an ethanolic NaOH basic media at 60 °C (1, 2) or in formic acid (2) to afford aldoxime (XIII) and the 3-cyanobenzoic acid derivative (XIV), respectively. Treatment of either of the two condensation products (XIII) and (XIV) with refluxing thionyl chloride affords the 3-cyanobenzoyl chloride derivative (XV) (1, 2), which is coupled with ethyl 3-(dimethylamino)acrylate (XVI) by means of DIEA in dichloromethane at 50 °C (1, 2) or triethylamine in toluene at 60-80 °C (3) to produce the 1,3-ketoester (XVII). Tertiary dimethylenamine (XVII) is converted to the secondary cyclopropylenamine (XIX) by treatment with cyclopropylamine (XVIII) in the presence of acetic acid in dichloromethane/water (1, 2) or in a mixture of ethanol/ether (3). Without isolation, intermediate (XIX) undergoes cyclization in the presence of potassium carbonate in N-methylpyrrolidone at 60-70 °C (1, 2) or in acetonitrile (3), affording the ethyl ester (IV). Compound (IV) is hydrolyzed in the presence of sulfuric acid in refluxing AcOH/water to yield the free carboxylic acid (I) (1, 2). Scheme 2.
An alternative pathway for the synthesis of intermediate (XV) proceeds as follows. Friedel-Craft’s acylation of 2,4-dichloro-1-fluorobenzene (XX) with acetyl chloride in the presence of AlCl3 and subsequent oxidation with sodium hypochlorite in 1,4-dioxane gives 2,4-dichloro-5-fluorobenzoic acid (XXI), which is nitrated with HNO3/H2SO4 to give the nitrobenzoic acid (XXII). Esterification of compound (XXII) by means of thionyl chloride in methanol followed by hydrogenation in the presence of Raney-Ni in methanol yields amino ester (XXIII), which is subjected to a Sandmayer reaction with CuCN in the presence of 2-methyl-2-nitropropane (t-BuNO2) in DMF at 60 °C. The intermediate thus obtained is then treated with lithium hydroxide in THF/water and the resulting carboxylic acid is finally chlorinated with thionyl chloride in toluene to afford acyl chloride (XV) (3). Scheme 2.
| 【1】 Matzke, M., Petersen, U., Schenke, T. et al. (Bayer Healthcare AG). Use of 7-(2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-quinolone carboxylic acid and naphthyridon carboxylic acid derivatives for the treatment of Helicobacter pylori infections and associated gastroduodenal diseases. CA 2274894, DE 19652239, EP 0946176, JP 200351781, JP 2000514825, US 6133260, US 6432948, WO 1998026779. |
| 【2】 Wohlert, S.E., Jaetsch, T., Gallenkamp, B. et al. New fluoroquinolone finafloxacin HCI (FIN): Route of synthesis, physicochemical characteristics and activity under neutral and acid conditions. 48th Annu Intersci Conf Antimicrob Agents Chemother (ICAAC) Infect Dis Soc Am (IDSA) Annu Meet (Oct 25-28, Washington, D.C.) 2008, Abst F1-2036. |
| 【3】 Hong, J., Zhang, Z., Lei, H. et al. A novel approach to finafloxacin hydrochloride (BAY35-3377). Tetrahedron Lett 2009, 50(21): 2525-8. |
| 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) | 65946 | 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid | C14H8ClFN2O3 | 详情 | 详情 | |
| (IV) | 65949 | C16H12ClFN2O3 | 详情 | 详情 | ||
| (VIII) | 65953 | 1-Fluoro-3,5-dimethylbenzene; 3,5-Dimethylfluorobenzene; 1,3-Dimethyl-5-fluorobenzene; 5-Fluoro-m-xylene | 461-97-2 | C8H9F | 详情 | 详情 |
| (IX) | 65954 | 2,4-Dichloro-1-Fluoro-3,5-Dimethylbenzene | 214774-61-5 | C8H7Cl2F | 详情 | 详情 |
| (X) | 65955 | C8H2Cl7F | 详情 | 详情 | ||
| (XI) | 65956 | 2,4-Dichloro-5-fluoro-3-formylbenzoic acid | 214774-58-0 | C8H3Cl2FO3 | 详情 | 详情 |
| (XII) | 65957 | Hydroxylamine hydrochloride; Hydroxylammonium chloride; Oxammonium hydrochloride | 5470-11-1 | H3NO.HCl | 详情 | 详情 |
| (XIII) | 65958 | C8H4Cl2FNO3 | 详情 | 详情 | ||
| (XIV) | 65959 | 2,4-Dichloro-3-cyano-5-fluorobenzoic acid | 117528-58-2 | C8H2Cl2FNO2 | 详情 | 详情 |
| (XV) | 65960 | 2,4-Dichloro-3-cyano-5-fluorobenzoyl chloride | 117528-59-3 | C8HCl3FNO | 详情 | 详情 |
| (XVI) | 65961 | ethyl (Z)-3-(dimethylamino)-2-propenoate; Ethyl cis-3-dimethylaminoacrylate | C7H13NO2 | 详情 | 详情 | |
| (XVII) | 65962 | (Z)-ethyl 2-(2,4-dichloro-3-cyano-5-fluorobenzoyl)-3-(dimethylamino)acrylate | C15H13Cl2FN2O3 | 详情 | 详情 | |
| (XVIII) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (XIX) | 65963 | C16H13Cl2FN2O3 | 详情 | 详情 | ||
| (XX) | 65964 | 1,3-Dichloro-4-fluorobenzene; 2,4-Dichloro-1-fluorobenzene; 2,4-Dichlorofluorobenzene | 1435-48-9 | C6H3Cl2F | 详情 | 详情 |
| (XXI) | 65965 | 2,4-Dichloro-5-fluorobenzoic acid | 86522-89-6 | C7H3Cl2FO2 | 详情 | 详情 |
| (XXII) | 65966 | 2,4-Dichloro-5-fluoro-3-nitrobenzoic acid; 2,4-Dichloro-3-nitro-5-fluorobenzoic acid | 106809-14-7 | C7H2Cl2FNO4 | 详情 | 详情 |
| (XXIII) | 65967 | 3-Amino-2,4-Dichloro-5-Fluorobenzoic Acid | 115549-13-8 | C7H4Cl2FNO2 | 详情 | 详情 |