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【结 构 式】 
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【分子编号】19649 【品名】1-vinylbenzene 【CA登记号】100-42-5 |
【 分 子 式 】C8H8 【 分 子 量 】104.15152 【元素组成】C 92.26% H 7.74% |
合成路线1
该中间体在本合成路线中的序号：(X)In an alternative synthesis, 2,4,6-triaminopyrimidine (VI) was condensed with bromomalonaldehyde (VII) under acidic conditions to give pyridopyrimidine (VIII), which was protected with pivaloyl anhydride in pyridine, yielding the bispivaloylamide (IX). Palladium-catalyzed Heck coupling of (IX) with styrene (X) afforded (XI). Subsequent ozonolysis of the styryl derivative (XI), followed by reductive workup with dimethyl sulfide gave aldehyde (XII). Reduction of (XII) to the corresponding alcohol with NaBH4, followed by bromination with PPh3 and Br2 provided bromide (XIII). The N-methyl aniline (XIV) was synthesized by direct alkylation of 3,4,5-trimethoxyaniline (IV) with methyl iodide. Nucleophilic displacement of the bromide (XIII) with aniline (XIV) afforded the tertiary amine (XV). The pivaloyl protecting groups of (XV) were finally removed by treatment with methanolic NaOMe.
| 【1】 Gangjee, A.; et al.; Synthesis and dihydrofolate reductase inhibitory activities of 2,4-diamino-5-deaza and 2,4-diamino-5, 10-dideaza lipophilic antifolates. J Med Chem 1997, 40, 4, 470. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 31545 | 3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine；3,4,5-Trimethoxybenzenamine；[3,4,5-Tris(methyloxy)phenyl]amine | 24313-88-0 | C9H13NO3 | 详情 | 详情 |
| (VI) | 28977 | 2,6-diamino-4-pyrimidinylamine | 1004-38-2 | C4H7N5 | 详情 | 详情 |
| (VII) | 14278 | 2-Bromomalonaldehyde | C3H3BrO2 | 详情 | 详情 | |
| (VIII) | 31547 | 6-bromopyrido[2,3-d]pyrimidine-2,4-diamine; 2-amino-6-bromopyrido[2,3-d]pyrimidin-4-ylamine | C7H6BrN5 | 详情 | 详情 | |
| (IX) | 31548 | N-[6-bromo-2-[(2,2-dimethylpropanoyl)amino]pyrido[2,3-d]pyrimidin-4-yl]-2,2-dimethylpropanamide | C17H22BrN5O2 | 详情 | 详情 | |
| (X) | 19649 | 1-vinylbenzene | 100-42-5 | C8H8 | 详情 | 详情 |
| (XI) | 31549 | N-[2-[(2,2-dimethylpropanoyl)amino]-6-[(E)-2-phenylethenyl]pyrido[2,3-d]pyrimidin-4-yl]-2,2-dimethylpropanamide | C25H29N5O2 | 详情 | 详情 | |
| (XII) | 31550 | N-[2-[(2,2-dimethylpropanoyl)amino]-6-formylpyrido[2,3-d]pyrimidin-4-yl]-2,2-dimethylpropanamide | C18H23N5O3 | 详情 | 详情 | |
| (XIII) | 31554 | 3-bromo-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C11H11BrO | 详情 | 详情 | |
| (XIV) | 31552 | 3,4,5-trimethoxy-N-methylaniline; N-methyl-N-(3,4,5-trimethoxyphenyl)amine | C10H15NO3 | 详情 | 详情 | |
| (XV) | 31553 | N-(2-[(2,2-dimethylpropanoyl)amino]-6-[[3,4,5-trimethoxy(methyl)anilino]methyl]pyrido[2,3-d]pyrimidin-4-yl)-2,2-dimethylpropanamide | C28H38N6O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The asymmetric dihydroxylation of styrene (I) by means of K3Fe(CN)6 and OsO4, catalyzed by 1,4-bis(dihydroquinin-9-O-yl)phthalazine ((DHQ)2PHAL)in tert-butanol/water gives the 1(R)-phenylethane-1,2-diol (II), which is treated with Ts-Cl and pyridine in dichloromethane to yield the monotosylate (III). The reaction of (III) with NaCN in Et-OH/water affords 3(R)-hydroxy-3-phenylpropionitrile (IV), which is reduced by means of BH3/Me2S in refluxing THF to provide the corresponding amine (V). The O-alkylation of (V) with 4-(trifluoromethyl)chlorobenzene (VI) by means of NaH in hot DMSO gives 3(R)-phenyl-3-[4(trifluoromethyl)phenoxy]propylamine (VII), which is treated with methyl chloroformate (VIII) and K2CO3 in dichloromethane to yield the carbamate (IX) Finally, this compound is reduced by means of LiAlH4 in THF to provide the target (R)-fluoxetine.
| 【1】 Pandey, R.K.; et al.; An asymmetric dihydroxylation route to enantiomerically pure norfluoxetine and fluoxetine. Tetrahedron Lett 2002, 43, 25, 4425. |
| 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) | 19649 | 1-vinylbenzene | 100-42-5 | C8H8 | 详情 | 详情 |
| (II) | 57175 | R(-)-1-Phenyl-1,2-ethanediol R(-)-Phenylethylene glycol | C8H10O2 | 详情 | 详情 | |
| (III) | 57176 | (2S)-2-hydroxy-2-phenylethyl 4-methylbenzenesulfonate | C15H16O4S | 详情 | 详情 | |
| (IV) | 57177 | (3R)-3-hydroxy-3-phenylpropanenitrile | C9H9NO | 详情 | 详情 | |
| (V) | 57178 | (1R)-3-amino-1-phenyl-1-propanol | C9H13NO | 详情 | 详情 | |
| (VI) | 11973 | 1-Chloro-4-(trifluoromethyl)benzene; 4-Chlorobenzotrifluoride | 98-56-6 | C7H4ClF3 | 详情 | 详情 |
| (VII) | 57179 | (3R)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylamine; (3R)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-1-propanamine | C16H16F3NO | 详情 | 详情 | |
| (VIII) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (IX) | 57180 | methyl (3R)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylcarbamate | C18H18F3NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The bromination of styrene (II) with N-bromosuccinimide in the presence of cyanamide (I) provided 2-bromo-1-phenylethylcyanamide (III). Further addition of MeOH to (III) in the presence of HCl, followed by Na2CO3-promoted cyclization, produced the methoxyimidazoline (IV). Acylation of indoline (V) with trifluoroacetic anhydride and pyridine gave amide (VI) and subsequent chlorosulfonation yielded sulfonyl cloride (VII). This acid chloride was coupled to imidazoline (IV) in the presence of NaHCO3 in aqueous acetone to furnish a mixture of sulfonyl imidazolines (VIII) and (IX). The major isomer (IX) was isolated by column chromatography, and then, hydrolysis with HCl in MeOH at r.t. provided imidazolidinone (X). The trifluoroacetamide group of (X) was further hydrolyzed by treatment with NaOH in aqueous MeOH to give (XI). Subsequent condensation of (XI) with 4-nitrobenzoyl chloride (XII) in the presence of pyridine yielded 4-nitrobenzamide (XIII), which was finally reduced to the aminobenzamide by hydrogenation using Raney-nickel as the catalyst.
| 【1】 Jung, S.-H.; Lee, H.S.; Song, J.S.; Kim, H.M.; Han, S.B.; Lee, C.W.; Lee, M.; Choi, D.R.; Lee, J.A.; Chung, Y.H.; Yoon, S.J.; Moon, E.Y.; Hwang, H.S.; Seong, S.K.; Lee, D.K.; Synthesis and antitumor activity of 4-phenyl-1-arylsulfonyl imidazolidinones. Bioorg Med Chem Lett 1998, 8, 12, 1547. |
| 【2】 Yoon, S.J.; Chung, Y.H.; Lee, M.S.; Choi, D.R.; Lee, J.A.; Lee, H.S.; Yun, H.R.; Lee, D.K.; Moon, E.Y.; Hwang, H.S.; Choi, C.H.; Jung, S.H. (Dong-Wha Pharmaceuticals Industry Co. Ltd); Arylsulfonylimidazolone derivs. as an antitumor agent. EP 1021437; JP 2000505096; US 5929103; WO 9807719 . |
| 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) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (II) | 19649 | 1-vinylbenzene | 100-42-5 | C8H8 | 详情 | 详情 |
| (III) | 19650 | 2-bromo-1-phenylethylcyanamide | C9H9BrN2 | 详情 | 详情 | |
| (IV) | 19651 | methyl 5-phenyl-4,5-dihydro-1H-imidazol-2-yl ether; 2-methoxy-5-phenyl-4,5-dihydro-1H-imidazole | C10H12N2O | 详情 | 详情 | |
| (V) | 19652 | indoline | 496-15-1 | C8H9N | 详情 | 详情 |
| (VI) | 19653 | 1-(2,3-dihydro-1H-indol-1-yl)-2,2,2-trifluoro-1-ethanone | C10H8F3NO | 详情 | 详情 | |
| (VII) | 19654 | 1-(2,2,2-trifluoroacetyl)-5-indolinesulfonyl chloride | C10H7ClF3NO3S | 详情 | 详情 | |
| (VIII) | 19655 | 2,2,2-trifluoro-1-[5-[(2-methoxy-5-phenyl-4,5-dihydro-1H-imidazol-1-yl)sulfonyl]-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C20H18F3N3O4S | 详情 | 详情 | |
| (IX) | 19656 | 2,2,2-trifluoro-1-[5-[(2-methoxy-4-phenyl-4,5-dihydro-1H-imidazol-1-yl)sulfonyl]-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C20H18F3N3O4S | 详情 | 详情 | |
| (X) | 19657 | 4-phenyl-1-[[1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]sulfonyl]-2-imidazolidinone | C19H16F3N3O4S | 详情 | 详情 | |
| (XI) | 19658 | 1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-4-phenyl-2-imidazolidinone | C17H17N3O3S | 详情 | 详情 | |
| (XII) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (XIII) | 19660 | 1-[[1-(4-nitrobenzoyl)-2,3-dihydro-1H-indol-5-yl]sulfonyl]-4-phenyl-2-imidazolidinone | C24H20N4O6S | 详情 | 详情 |