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【结 构 式】 
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【分子编号】42975 【品名】ethyl (1S)-6-fluoro-1-(fluoromethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate 【CA登记号】 |
【 分 子 式 】C19H21F2N3O3S 【 分 子 量 】409.4569664 【元素组成】C 55.73% H 5.17% F 9.28% N 10.26% O 11.72% S 7.83% |
合成路线1
该中间体在本合成路线中的序号：(XVII)Treatment of 3,4-difluoroaniline (I) with CS2 and Et3N gives triethylammonium dithiocarbamate (II), which reacts with ethyl chloroformate in chloroform to yield (III). Isothiocyanate (III) is converted into the potassium salt (IV) by reaction with diethyl malonate and KOH in dioxane, and then transformed into methoxymethyl thioether (VI) by means of reagent (V) and Et3N in toluene. Cyclization of (VI) by heating in diphenyl ether affords quinoline (VII), which is then converted into (IX) by means of benzoyl chloride (VIII) in pyridine. Benzoyloxy derivative (IX) is converted into (X) by means of HCl in EtOH, and its reaction with 1-bromo-2-fluoroethane (XI) and NaHCO3 yields compound (XII). Chlorination of (XII) with SO2Cl2 in hexane provides (XIII), which by simultaneous hydrolysis and intramolecular cyclization by means of Et3N /H2O in THF provides the mixture of isomers (XIV). (-)-(XV) is then obtained by HPLC chromatography on a chiral stationary phase. Treatment of (-)-(XV) with 1-methylpiperazine (XVI) in DMF provides ethyl ester (-)-(XVII), which is finally hydrolyzed by means of H2SO4 in H2O.
| 【1】 Segawa, J.; Matsuoka, M.; Tomii, Y. (Nippon Shinyaku Co., Ltd.); Quinolinecarboxylic acid deriv. and process for producing the same. EP 0675127; WO 9414819 . |
| 【2】 Kise, M.; Amimoto, I.; Kitano, M.; Segawa, J.; Tomii, Y.; Matsuoka, M.; Masui, Y.; Synthesis and antibacterial activity of novel 7-substituted-6-fluoro-1-fluoromethyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid derivatives. Chem Pharm Bull 1999, 47, 12, 1765. |
| 【3】 Segawa, J.; Kitano, M.; Kazuno, K.; Matsuoka, M.; Shirahase, I.; Ozaki, M.; Matsuda, M.; Tomii, Y.; Kise, M.; Studies on pyridonecarboxylic acids. 1. Synthesis and antibacterial evaluation of 7-substituted-6-halo-4-oxo-4H-[1,3]thiazeto[3, 2-a]quinoline-3-carboxylic acids. J Med Chem 1992, 35, 25, 4727. |
| 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) | 13451 | 3,4-Difluoroaniline; 3,4-Difluorophenylamine | 3863-11-4 | C6H5F2N | 详情 | 详情 |
| (II) | 42953 | 3,4-difluorophenylcarbamodithioic acid | C7H5F2NS2 | 详情 | 详情 | |
| (III) | 13453 | 1,2-Difluoro-4-isothiocyanatobenzene; 3,4-difluorophenyl isothiocyanate | 113028-75-4 | C7H3F2NS | 详情 | 详情 |
| (IV) | 42954 | potassium 1-(3,4-difluoroanilino)-3-ethoxy-2-(ethoxycarbonyl)-3-oxo-1-propene-1-thiolate | C14H14F2KNO4S | 详情 | 详情 | |
| (V) | 18319 | Chloro(methoxy)methane; Chloromethyl methyl ether | 107-30-2 | C2H5ClO | 详情 | 详情 |
| (VI) | 13455 | diethyl 2-[(3,4-difluoroanilino)[(methoxymethyl)sulfanyl]methylene]malonate | C16H19F2NO5S | 详情 | 详情 | |
| (VII) | 13456 | ethyl 6,7-difluoro-4-hydroxy-2-[(methoxymethyl)sulfanyl]-3-quinolinecarboxylate | C14H13F2NO4S | 详情 | 详情 | |
| (VIII) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (IX) | 42955 | ethyl 4-(benzoyloxy)-6,7-difluoro-2-[(methoxymethyl)sulfanyl]-3-quinolinecarboxylate | C21H17F2NO5S | 详情 | 详情 | |
| (X) | 42956 | ethyl 4-(benzoyloxy)-6,7-difluoro-2-sulfanyl-3-quinolinecarboxylate | C19H13F2NO4S | 详情 | 详情 | |
| (XI) | 28769 | 1-bromo-2-fluoroethane | 762-49-2 | C2H4BrF | 详情 | 详情 |
| (XII) | 42957 | ethyl 4-(benzoyloxy)-6,7-difluoro-2-[(2-fluoroethyl)sulfanyl]-3-quinolinecarboxylate | C21H16F3NO4S | 详情 | 详情 | |
| (XIII) | 42958 | ethyl 4-(benzoyloxy)-2-[(1-chloro-2-fluoroethyl)sulfanyl]-6,7-difluoro-3-quinolinecarboxylate | C21H15ClF3NO4S | 详情 | 详情 | |
| (XIV) | 42959 | ethyl 6,7-difluoro-1-(fluoromethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C14H10F3NO3S | 详情 | 详情 | |
| (XV) | 42971 | octyl 2-[6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate | C21H25F2NO4S | 详情 | 详情 | |
| (XVI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (XVII) | 42975 | ethyl (1S)-6-fluoro-1-(fluoromethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C19H21F2N3O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)Alternatively, (-)-(XVII) can be obtained as follows: Treatment of (X) with 1-acetoxy-2-bromoethane (XVIII) in DMF in the presence of NaHCO3 yields derivative (XIX), which is then chlorinated by means of SO2Cl2 in CH2Cl2 to provide (XX). Simultaneous hydrolysis and intramolecular cyclization of (XX) by means of Et3N /H2O in THF affords (XXI), which is then converted into octyl ester derivative (XXII) by treatment with refluxing octanol (A). Resolution of the racemic mixture (XXII) by treatment with Liposyme IM in vinyl acetate followed by chromatographic separation provides alcohol (+)-(XXIII) and acetoxy (-)-(XXIV). Hydrolysis of (-)-(XXIV) with hot H2SO4/EtOH gives alcohol (-)-(XXV), which then reacts with 1-methylpiperazine (XVI) in DMF to yield derivative (-)-(XXVI). Finally, treatment with (diethylamino)sulfur trifluoride (DAST) in CH2Cl2 provides fluoro derivative (-)-(XVII). Alternatively, (-)-(XXV) can be obtained by conversion of (XXI) into butyl ester (XXVII) by means of refluxing butanol (B), followed by its enantiomer enzymatic resolution with Lipase PL in vinyl acetate and chromatographic separation to afford (+)-(XXVIII) and (-)-(XXIX). Finally, hydrolysis of (-)-(XXIX) with hot H2SO4/EtOH yields (-)-(XXV). An analogous procedure comprising enantiomer separation and subsequent hydrolysis can be performed from ethyl esters (XX) or (XXI) by treatment with the corresponding lipases in an appropriate solvent.
| 【1】 Segawa, J.; Matsuoka, M.; Tomii, Y. (Nippon Shinyaku Co., Ltd.); Quinolinecarboxylic acid deriv. and process for producing the same. EP 0675127; WO 9414819 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 | |
| (A) | 12970 | (8R,9S,10R,13S,14R)-14-Hydroxy-3-methoxy-10,13-dimethyl-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C20H28O3 | 详情 | 详情 | |
| (B) | 29766 | butanol; n-butanol; 1-butanol | 71-36-3 | C4H10O | 详情 | 详情 |
| (X) | 42956 | ethyl 4-(benzoyloxy)-6,7-difluoro-2-sulfanyl-3-quinolinecarboxylate | C19H13F2NO4S | 详情 | 详情 | |
| (XVI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (XVII) | 42975 | ethyl (1S)-6-fluoro-1-(fluoromethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C19H21F2N3O3S | 详情 | 详情 | |
| (XVIII) | 33463 | 2-bromoethyl acetate | 927-68-4 | C4H7BrO2 | 详情 | 详情 |
| (XIX) | 42962 | ethyl 2-[[2-(acetoxy)ethyl]sulfanyl]-4-(benzoyloxy)-6,7-difluoro-3-quinolinecarboxylate | C23H19F2NO6S | 详情 | 详情 | |
| (XX) | 42963 | ethyl 2-[[2-(acetoxy)-1-chloroethyl]sulfanyl]-4-(benzoyloxy)-6,7-difluoro-3-quinolinecarboxylate | C23H18ClF2NO6S | 详情 | 详情 | |
| (XXI) | 42964 | ethyl 1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C16H13F2NO5S | 详情 | 详情 | |
| (XXII) | 42971 | octyl 2-[6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate | C21H25F2NO4S | 详情 | 详情 | |
| (XXIII) | 42973 | octyl 2-[(1R)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate | C21H25F2NO4S | 详情 | 详情 | |
| (XXIV) | 42972 | octyl 2-[(1S)-1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate | C23H27F2NO5S | 详情 | 详情 | |
| (XXV) | 42976 | ethyl (1S)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C14H11F2NO4S | 详情 | 详情 | |
| (XXVI) | 42977 | ethyl (1S)-6-fluoro-1-(hydroxymethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C19H22FN3O4S | 详情 | 详情 | |
| (XXVII) | 42965 | butyl 6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C16H15F2NO4S | 详情 | 详情 | |
| (XXVIII) | 42967 | butyl (1R)-1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C18H17F2NO5S | 详情 | 详情 | |
| (XXIX) | 42966 | butyl (1S)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C16H15F2NO4S | 详情 | 详情 |