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【结 构 式】 
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【分子编号】13451 【品名】3,4-Difluoroaniline; 3,4-Difluorophenylamine 【CA登记号】3863-11-4 |
【 分 子 式 】C6H5F2N 【 分 子 量 】129.1092464 【元素组成】C 55.82% H 3.9% F 29.43% N 10.85% |
合成路线1
该中间体在本合成路线中的序号：(I)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：(I)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：(I)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4
该中间体在本合成路线中的序号：(VII)Acylation of 3,4-difluoroaniline (VII) with Ac2O and Et3N afforded acetanilide (VIII). Subsequent condensation of (VIII) with the Vilsmeier reagent produced the quinolinecarbaldehyde (IX), which was reduced to alcohol (X) using NaBH4. Coupling of (X) with pyridinone (VI) under Mitsunobu conditions yielded adduct (XI). Finally, intramolecular Heck reaction in the presence of palladium diacetate and triphenylphosphine provided the desired pentacyclic compound.
| 【1】 Demarquay, D.; Lavergne, O.; Bailly, C.; et al.; Topoisomerase I-mediated antiproliferative activity of enantiomerically pure fluorinated homocamptothecins. J Med Chem 2000, 43, 11, 2285. |
| 【2】 Cazaux, J.-B.; Manginot, E.; Lavergne, O.; Le Breton, C.; Bigg, D. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Optically pure camptothecin analogues, optically pure synthesis intermediate and method for preparing same. EP 1007527; FR 2768431; WO 9911646 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 33100 | (5R)-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C11H13NO4 | 详情 | 详情 | |
| (VII) | 13451 | 3,4-Difluoroaniline; 3,4-Difluorophenylamine | 3863-11-4 | C6H5F2N | 详情 | 详情 |
| (VIII) | 25472 | N-(3,4-difluorophenyl)acetamide | 458-11-7 | C8H7F2NO | 详情 | 详情 |
| (IX) | 25473 | 2-chloro-6,7-difluoro-3-quinolinecarbaldehyde | C10H4ClF2NO | 详情 | 详情 | |
| (X) | 25474 | (2-chloro-6,7-difluoro-3-quinolinyl)methanol | C10H6ClF2NO | 详情 | 详情 | |
| (XI) | 33101 | (5R)-8-[(2-chloro-6,7-difluoro-3-quinolinyl)methyl]-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C21H17ClF2N2O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The condensation of 3,4-difluoroaniline (I) with 3-chloropropionyl chloride (II) and pyridine in hot acetone give the anilide (III), which is cyclized by means of AlCl3 at 110?C, yielding 6,7-difluoro-1,2,3,4-tetrahydroquinolin-2-one (IV). The reaction of (IV) with POCl3 and dimethylformamide affords the carbaldehyde (V), which is oxidized and aromatized by means of KMnO4 and KOH in water, providing 2-chloro-6,7-difluoroquinoline-3-carboxylic acid (VI). The reaction of (VI) with SOCl2 in chloroform gives the corresponding acyl chloride (VII), which is condensed with the magnesium salt of the malonic acid monoethyl ester (VIII) in THF to yield the 3-oxopropanoate (IX). The reaction of (IX) with dimethylformamide dimethylacetal (DMF) in hot ethyl acetate affords the 3-(dimethylamino)acrylate (X), which is cyclized by means of methylamine in ethanol to provide 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[g][1,8]naphthyridine-3-carboxylic acid ethyl ester (XI). The hydrolysis of (XI) with HCl in hot HOAc gives the corresponding carboxylic acid (XII) (1), which is condensed with 1-(4-fluorophenyl)piperazine (XIII) by heating at 90?C to yield the adduct (XIV). Finally, this compound is treated with choline hydroxide (XV) in methanol to afford the target choline salt.
| 【1】 Tabart, M.; et al.; Synthesis and biological evaluation of benzo[b]naphthyridones, a series of new topical antibacterial agents. Bioorg Med Chem Lett 2001, 11, 7, 919. |
| 【2】 Tabart, M.; et al.; Synthesis and biological evaluation of RP60556A, a new topical antibacterial agent. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1512. |
| 【3】 Wentzler, S.; Desconclois, J.-F.; Girard, P.; Picaut, G.; Tabart, M. (Aventis Pharma SA); 1,8-Benzonaphthyridine derivs.. FR 2787452; WO 0037467 . |
| 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) | 18936 | 3-chloropropanoyl chloride | 625-36-5 | C3H4Cl2O | 详情 | 详情 |
| (III) | 46274 | 3-chloro-N-(3,4-difluorophenyl)propanamide | C9H8ClF2NO | 详情 | 详情 | |
| (IV) | 46275 | 6,7-difluoro-3,4-dihydro-2(1H)-quinolinone | C9H7F2NO | 详情 | 详情 | |
| (V) | 46276 | 2-chloro-6,7-difluoro-1,4-dihydro-3-quinolinecarbaldehyde | C10H6ClF2NO | 详情 | 详情 | |
| (VI) | 46277 | 2-chloro-6,7-difluoro-3-quinolinecarboxylic acid | C10H4ClF2NO2 | 详情 | 详情 | |
| (VII) | 46278 | 2-chloro-6,7-difluoro-3-quinolinecarbonyl chloride | C10H3Cl2F2NO | 详情 | 详情 | |
| (VIII) | 46279 | C6H9MgO4 | 详情 | 详情 | ||
| (IX) | 46280 | propyl 3-(2-chloro-6,7-difluoro-3-quinolinyl)-3-oxopropanoate | C15H12ClF2NO3 | 详情 | 详情 | |
| (X) | 46281 | propyl (Z)-2-[(2-chloro-6,7-difluoro-3-quinolinyl)carbonyl]-3-(dimethylamino)-2-propenoate | C18H17ClF2N2O3 | 详情 | 详情 | |
| (XI) | 46282 | propyl 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate | C17H14F2N2O3 | 详情 | 详情 | |
| (XII) | 46283 | 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid | C14H8F2N2O3 | 详情 | 详情 | |
| (XIII) | 12143 | 1-(4-Fluorophenyl)piperazine | 2252-63-3 | C10H13FN2 | 详情 | 详情 |
| (XIV) | 46284 | 7-fluoro-8-[4-(4-fluorophenyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid | C24H20F2N4O3 | 详情 | 详情 | |
| (XV) | 46285 | 2-hydroxy-N,N,N-trimethyl-1-ethanaminium hydroxide | C5H15NO2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Diazotization of 3,4-difluoroaniline (I), followed by reduction with SnCl2 gives rise to hydrazine (II). This is then condensed with mucobromic acid (III) in refluxing AcOH to produce the pyridazinone (IV). Selective displacement of the 4-bromo of (IV) with the sodium alkoxide of 3-methyl-1,3-butanediol (V) yields ether (VI). 4-(Methylsulfanyl)benzeneboronic acid (VIII) is prepared by metalation of 4-bromothioanisole (VII) with butyl lithium, followed by reaction with trimethyl borate, and aqueous work-up. Suzuki coupling of boronic acid (VIII) with bromopyridazinone (VI) furnishes the 5-(methylsufanylphenyl)pyridazinone (IX). Finally, the sulfide group of (IX) is oxidized to the target sulfone by using peracetic acid in cold dichloromethane.
| 【1】 Stewart, A.O.; Black, L.A.; Basha, A.; Patel, M.V.; Kolasa, T.; Coghlan, M.J.; Liu, H.; Kort, M.E.; McCarty, C.M.; Rohde, J.J. (Abbott Laboratories Inc.); Prostaglandin endoperoxide H synthase biosynthesis inhibitors. EP 1124804; JP 2003512292; WO 0024719 . |
| 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) | 61025 | 1-(3,4-difluorophenyl)hydrazine | C6H6F2N2 | 详情 | 详情 | |
| (III) | 22280 | (Z)-2,3-dibromo-4-oxo-2-butenoic acid | 21577-50-4 | C4H2Br2O3 | 详情 | 详情 |
| (IV) | 61026 | 4,5-dibromo-2-(3,4-difluorophenyl)-3(2H)-pyridazinone | C10H4Br2F2N2O | 详情 | 详情 | |
| (V) | 61027 | 3-methyl-1,3-butanediol | C5H12O2 | 详情 | 详情 | |
| (VI) | 61028 | 5-bromo-2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-3(2H)-pyridazinone | C15H15BrF2N2O3 | 详情 | 详情 | |
| (VII) | 19266 | 4-bromophenyl methyl sulfide; 1-bromo-4-(methylsulfanyl)benzene | 104-95-0 | C7H7BrS | 详情 | 详情 |
| (VIII) | 18561 | 4-(methylsulfanyl)phenylboronic acid | 98546-51-1 | C7H9BO2S | 详情 | 详情 |
| (IX) | 61029 | 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(methylsulfanyl)phenyl]-3(2H)-pyridazinone | C22H22F2N2O3S | 详情 | 详情 |