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【结 构 式】

【分子编号】13456

【品名】ethyl 6,7-difluoro-4-hydroxy-2-[(methoxymethyl)sulfanyl]-3-quinolinecarboxylate

【CA登记号】

【 分 子 式 】C14H13F2NO4S

【 分 子 量 】329.3243664

【元素组成】C 51.06% H 3.98% F 11.54% N 4.25% O 19.43% S 9.74%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(VI)

The reaction of 3,4-difluoroaniline (I) with carbon disulfide and triethylamine gives triethylammonium N-(3,4-difluorophenyl)dithiocarbamate (II), which by reaction with ethyl chloroformate and triethylamine in chloroform is converted into 3,4-difluorophenyl isothiocyanate (III). The reaction of (III) with diethyl malonate and KOH in dioxane affords the potassium salt (IV), which is treated with chloromethyl methyl ether in DMF to give the corresponding methoxymethylsulfanyl compound (V). The cyclization of (V) at 240 C in diphenyl ether affords 6,7-difluoro-4-hydroxy-2-(methoxymethylsulfanyl)quinoline-3-carboxylic acid ethyl ester (VI), which by treatment with HCl in ethanol gives the corresponding mercapto compound (VII). The cyclization of (VII) with 1,1-dibromoethane by means of K2CO3 and KI in hot DMF yields 5,6-difluoro-1-methyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid ethyl ester (VIII), which is condensed with piperazine (IX) in DMF to afford the corresponding piperazino-derivative (X). The hydrolysis of (X) with KOH in hot tert-butanol gives the corresponding free acid (XI) , which is finally condensed with 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (XII) by means of KHCO3 in DMF.

1 Tracy, M.; Castaner, J.; Prulifloxazin < Prop INN >. Drugs Fut 1996, 21, 8, 805.
2 Kise, M.; Kitano, M.; Ozaki, M.; Kazuno, K.; Matsuda, M.; Shirahase, I.; Segawa, J. (Nippon Shinyaku Co., Ltd.); Quinolinecarboxylic acid derivs. AU 8824673; EP 0315828; JP 1989294680 .
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) 13452 N,N-diethyl-1-ethanaminium 3,4-difluorophenylcarbamodithioate C13H20F2N2S2 详情 详情
(III) 13453 1,2-Difluoro-4-isothiocyanatobenzene; 3,4-difluorophenyl isothiocyanate 113028-75-4 C7H3F2NS 详情 详情
(IV) 13454 2-(3,4-Difluorophenylamino)-2-sulfanylethylene-1,1-dicarboxylic acid diethyl ester potassium salt C14H14F2KNO4S 详情 详情
(V) 13455 diethyl 2-[(3,4-difluoroanilino)[(methoxymethyl)sulfanyl]methylene]malonate C16H19F2NO5S 详情 详情
(VI) 13456 ethyl 6,7-difluoro-4-hydroxy-2-[(methoxymethyl)sulfanyl]-3-quinolinecarboxylate C14H13F2NO4S 详情 详情
(VII) 13457 ethyl 6,7-difluoro-4-hydroxy-2-sulfanyl-3-quinolinecarboxylate C12H9F2NO3S 详情 详情
(VIII) 13458 ethyl 6,7-difluoro-1-methyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C14H11F2NO3S 详情 详情
(IX) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(X) 13460 ethyl 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C18H20FN3O3S 详情 详情
(XI) 13461 6-Fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid C16H16FN3O3S 详情 详情
(XII) 13462 4-(Bromomethyl)-5-methyl-1,3-dioxol-2-one 80715-22-6 C5H5BrO3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VII)

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 then reacts with benzoyl chloride (VIII) in pyridine to furnish (IX). 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 obtained by HPLC chromatography of (XIV) 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) 42960 ethyl (1R)-6,7-difluoro-1-(fluoromethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C14H10F3NO3S 详情 详情
(XVI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(XVII) 42961 ethyl (1R)-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3

该中间体在本合成路线中的序号:(VII)

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
Extended Information