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【结 构 式】 
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【分子编号】18410 【品名】N-[(3S)-2,5-dioxotetrahydro-3-furanyl]-2,2,2-trifluoroacetamide 【CA登记号】777-33-3 |
【 分 子 式 】C6H4F3NO4 【 分 子 量 】211.0973096 【元素组成】C 34.14% H 1.91% F 27% N 6.64% O 30.32% |
合成路线1
该中间体在本合成路线中的序号：(XV)The chiral intermediate 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-amine (IV) has also been obtained as follows: The Friedel Crafts condensation of anisole (XV) with N-trifluoroacetyl-L-aspartic acid anhydride (XVI) by means of AlCl3 in dichloromethane gives 4-(4-methoxyphenyl)-4-oxo-2(S)-(trifluoro-acetamido)butyric acid (XVII), which is hydrogenated with H2 over Pd/C in ethanol/H2SO4 yielding 4-(4-methoxyphenyl)-2(S)-(trifluoroacetamido)butyric acid (XVIII). The cyclization of (XVIII) by its reaction with PCl5, followed by a treatment with SnCl4 provides the tetralone (XIX), which is hydrogenated as before to give N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-yl)trifluoro-acetamide (XX). Finally, this compound is deacetylated with HCl in ethanol to provide the chiral intermediate the amine (IV).
| 【1】 Devocelle, M.; et al.; Alternative synthesis of the chiral atypical beta-adrenergic phenylethanolaminotetraline agonist SR58611A using enantioselective hydrogenation. Tetrahedron Lett 1999, 40, 24, 4551. |
| 【2】 Cecchi, R.; et al.; Synthesis and beta-adrenergic activity of atypical beta-adrenergic phenylethanolaminotetralin stereoisomers. Eur J Med Chem 1994, 29, 4, 259. |
| 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) | 32820 | (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine; (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine | C11H15NO | 详情 | 详情 | |
| (XV) | 18410 | N-[(3S)-2,5-dioxotetrahydro-3-furanyl]-2,2,2-trifluoroacetamide | 777-33-3 | C6H4F3NO4 | 详情 | 详情 |
| (XVI) | 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 |
| (XVII) | 32827 | (2S)-4-(4-methoxyphenyl)-4-oxo-2-[(2,2,2-trifluoroacetyl)amino]butyric acid | C13H12F3NO5 | 详情 | 详情 | |
| (XVIII) | 32828 | (2S)-4-(4-methoxyphenyl)-2-[(2,2,2-trifluoroacetyl)amino]butyric acid | C13H14F3NO4 | 详情 | 详情 | |
| (XIX) | 32829 | 2,2,2-trifluoro-N-[(2S)-7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl]acetamide | C13H12F3NO3 | 详情 | 详情 | |
| (XX) | 32830 | 2,2,2-trifluoro-N-[(2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]acetamide | C13H14F3NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Reaction of L-aspartic acid (I) with trifluoroacetic acid and trifluoroacetic anhydride afforded N-trifluoroacetyl-L-aspartic anhydride (II). Then, Friedel-Crafts acylation of 1,3-difluorobenzene (III) with this anhydride in the presence of AlCl3 gave ketone (IV). The reduction of the carbonyl group of (IV) was effected by catalytic hydrogenation in the presence of Pearlman's catalyst, and the resulting phenylbutyric acid (V) was converted to acid chloride on treatment with PCl5 in cold dichloromethane, and subsequently cyclized by addition of AlCl3 to yield tetralone (VI). Hydrogenolysis of (VI) in the presence of Pearlman's catalyst gave tetrahydronaphthalene (VII), and further hydrolysis of trifluoroacetamide with LiOH yielded (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl amine (VIII). Imidazole ring was then constructed by treatment of this amine with 1,3-dihydroxyacetone (IX) and potassium thiocyanate in acidic medium, and the hydroxyl group of the resulting X was substituted by a formamido group by either heating in formamide at 175 C or with ammonium formate. Finally, formamide (XI) was hydrolyzed in refluxing isopropanolic HCl.
| 【1】 Martinez, G.R.; Repke, D.B.; Teitelbaum, P.J.; Walker, K.A.M.; Gooding, O.W.; Whiting, R.L.; Bansal, R.P.; Muehldorf, A.V. (Syntex (USA), Inc.); Benzocycloalkylazolethione derivs.. JP 1997512269; US 5438150; WO 9529165 . |
| 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) | 13070 | L-Aspartic acid; (2S)-2-Aminobutanedioic acid | 56-84-8 | C4H7NO4 | 详情 | 详情 |
| (II) | 18410 | N-[(3S)-2,5-dioxotetrahydro-3-furanyl]-2,2,2-trifluoroacetamide | 777-33-3 | C6H4F3NO4 | 详情 | 详情 |
| (III) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (IV) | 18412 | (2S)-4-(2,4-difluorophenyl)-4-oxo-2-[(2,2,2-trifluoroacetyl)amino]butyric acid | C12H8F5NO4 | 详情 | 详情 | |
| (V) | 18413 | (2S)-4-(2,4-difluorophenyl)-2-[(2,2,2-trifluoroacetyl)amino]butyric acid | C12H10F5NO3 | 详情 | 详情 | |
| (VI) | 18414 | N-[(2S)-5,7-difluoro-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl]-2,2,2-trifluoroacetamide | C12H8F5NO2 | 详情 | 详情 | |
| (VII) | 18415 | N-[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-2,2,2-trifluoroacetamide | C12H10F5NO | 详情 | 详情 | |
| (VIII) | 18416 | (2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenylamine; (2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenamine | C10H11F2N | 详情 | 详情 | |
| (IX) | 14575 | Dihydroxyacetone; 1,3-dihydroxyacetone | 96-26-4 | C3H6O3 | 详情 | 详情 |
| (X) | 18418 | 1-[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-5-(hydroxymethyl)-1,3-dihydro-2H-imidazole-2-thione | C14H14F2N2OS | 详情 | 详情 | |
| (XI) | 18419 | [3-[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-2-thioxo-2,3-dihydro-1H-imidazol-4-yl]methylformamide | C15H15F2N3OS | 详情 | 详情 |