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【结 构 式】 
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【药物名称】KB-5246 【化学名称】9,1-Epoxymethano-7-fluoro-8-(4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid hydrochloride 【CA登记号】119474-55-4, 119474-47-4 (free base) 【 分 子 式 】C18H17ClFN3O4S 【 分 子 量 】425.86929 |
【开发单位】Kanebo (Originator) 【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Quinolones |
合成路线1
A new synthesis for KB-5246 has been described: The reaction of 2,3,4-trifluoroaniline (I) with carbon disulfide (II) and triethylamine gives the corresponding dithiocarbamate (III), which by cyclization with 1-acetoxy-3-chloro-2-propanone (IV) in ethyl acetate yields 4-(acetoxymethyl)-3-(2,3,4-trifluorophenyl)thiazole-2(3H)-thione (V). The cyclization of (V) with potassium hydroxide in refluxing ethanol-water affords 6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazine-1-thione (VI), which is treated with trichloromethyl chloroformate in hot toluene to give the thiazolium chloride (VII), which is not isolated. The in situ reaction of (VII) with diethyl malonate by means of triethylamine in toluene gives (6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonic acid diethyl ester (IX), which is cyclized again with polyphosphoric acid (PPA) at 115 C to afford 7,8-difluoro-5-oxo-9,1-(epoxymethano)-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid ethyl ester (X). The hydrolysis of (X) with oleum gives the corresponding acid (XI), which is finally condensed with N-methylpiperazine (XII) in hot DMSO.
| 【1】 Kondo, H.; Tsukamoto, G.; Taguchi, M.; Jinbo, Y.; Kawahata, Y.; Sakamoto, F.; Inoue, Y.; Synthesis and antibacterial activity of new tetracyclic quinolone antibacterials. J Med Chem 1992, 35, 1, 94. |
| 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) | 13059 | 2,3,4-Trifluorophenylamine; 2,3,4-Trifluoroaniline | 3862-73-5 | C6H4F3N | 详情 | 详情 |
| (III) | 13060 | 2,3,4-trifluorophenylcarbamodithioate | C7H3F3NS2 | 详情 | 详情 | |
| (IV) | 13061 | 2-(chlorooxy)-2-oxoethyl acetate | C4H5ClO4 | 详情 | 详情 | |
| (V) | 13062 | [2-thioxo-3-(2,3,4-trifluorophenyl)-2,3-dihydro-1,3-thiazol-4-yl]methyl acetate | C12H8F3NO2S2 | 详情 | 详情 | |
| (VI) | 13063 | 6,7-Difluoro-4H-[1,3]thiazolo[4,3-c][1,4]benzoxazine-1-thione | C10H5F2NOS2 | 详情 | 详情 | |
| (VII) | 13064 | 1-Chloro-6,7-difluoro-4H-[1,3]thiazolo[4,3-c][1,4]benzoxazin-10-ium chloride | C10H5Cl2F2NOS | 详情 | 详情 | |
| (VIII) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (IX) | 13066 | diethyl 2-(6,7-difluoro-4H-[1,3]thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonate | C17H15F2NO5S | 详情 | 详情 | |
| (X) | 13067 | ethyl 5,6-difluoro-8-oxo-3H,8H-4-oxa-1-thia-9b-azacyclopenta[cd]phenalene-9-carboxylate | C15H9F2NO4S | 详情 | 详情 | |
| (XI) | 13068 | 5,6-Difluoro-8-oxo-3H,8H-4-oxa-1-thia-9b-azacyclopenta[cd]phenalene-9-carboxylic acid | C13H5F2NO4S | 详情 | 详情 | |
| (XII) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线2
The reaction of 2,3,4-trifluoroaniline (I) with carbon disulfide and triethylamine gives triethylammonium N-(2,3,4-trifluorophenyl)dithiocarbamate (II), which by reaction with ethyl chlorocarbonate in chloroform yields the corresponding isothiocyanate (III). The condensation of (III) with diethyl malonate (IV) by means of NaH in THF affords the sodium salt of diethyl [(2,3,4-trifluoroanilino)(mercapto)methylene]malonate (V), which is condensed with 1-acetoxy-3-chloroacetone in DMF to give the substituted thioester (VII). The cyclization of (VII) by means of sulfuric acid yields the thiazoline derivative (VIII), which is cyclized again by means of NaH in refluxing dioxane to afford diethyl (6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonate (IX). A final, new cyclization of (IX) by means of ethyl polyphosphate (PPE) at 138 C, followed by hydrolysis of the intermediate ester with sulfuric acid gives 7,8-difluoro-9,1-epoxymethano-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid (X). This compound is then condensed with 1-methylpiperazine (XI) in hot DMSO and treated with aqueous HCl.
| 【1】 Taguchi, M.; Kondo, H.; Inoue, Y.; Kawahata, Y.; Tsukamoto, G. (Kanebo Pharmaceuticals, Ltd.); Quinolinecarboxylic acid derivs., a compsns. comprising the same, process for preparing the same, and the use of the same for the manufacture of medicaments. EP 0286089; JP 1989199979; US 4808584 . |
| 【2】 Prous, J.; Castaner, J.; KB-5246. Drugs Fut 1989, 14, 6, 519. |
| 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) | 13059 | 2,3,4-Trifluorophenylamine; 2,3,4-Trifluoroaniline | 3862-73-5 | C6H4F3N | 详情 | 详情 |
| (II) | 20905 | N,N-dipropyl-1-propanaminium 2,3,4-trifluorophenylcarbamodithioate | C16H25F3N2S2 | 详情 | 详情 | |
| (III) | 20906 | 1,2,3-trifluoro-4-isothiocyanatobenzene; 2,3,4-trifluorophenyl isothiocyanate | 119474-40-7 | C7H2F3NS | 详情 | 详情 |
| (IV) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (V) | 20908 | sodium 3-ethoxy-2-(ethoxycarbonyl)-3-oxo-1-(2,3,4-trifluoroanilino)-1-propene-1-thiolate | C14H13F3NNaO4S | 详情 | 详情 | |
| (VI) | 20909 | 4-chloro-3-oxobutyl acetate | C6H9ClO3 | 详情 | 详情 | |
| (VII) | 20910 | diethyl 2-[[[2-(acetoxy)acetyl]sulfanyl](2,3,4-trifluoroanilino)methylene]malonate | C18H18F3NO7S | 详情 | 详情 | |
| (VIII) | 20911 | diethyl 2-[4-(hydroxymethyl)-3-(2,3,4-trifluorophenyl)-1,3-thiazol-2(3H)-ylidene]malonate | C17H16F3NO5S | 详情 | 详情 | |
| (IX) | 13066 | diethyl 2-(6,7-difluoro-4H-[1,3]thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonate | C17H15F2NO5S | 详情 | 详情 | |
| (X) | 13068 | 5,6-Difluoro-8-oxo-3H,8H-4-oxa-1-thia-9b-azacyclopenta[cd]phenalene-9-carboxylic acid | C13H5F2NO4S | 详情 | 详情 | |
| (XI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |