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【结 构 式】 
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【分子编号】22822 【品名】3-bromodihydro-2(3H)-furanone 【CA登记号】5061-21-2 |
【 分 子 式 】C4H5BrO2 【 分 子 量 】164.9865 【元素组成】C 29.12% H 3.05% Br 48.43% O 19.39% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of methyl-5-acetylsalicylate (I) with alpha-bromo-gamma-butyrolactone (II) by means of K2CO3 in refluxing acetone gives alpha-[(2-methoxycarbonyl-4-acetylphenyl)oxy]-gamma-butyrolactone (III), which is hydrolyzed with NaOH in methanol yielding alpha-[(2-carboxy-4-acetylphenyl)oxy]-gamma-butyrolactone (IV). The cyclization of (IV) with refluxing acetic anhydride affords 5-acetyl-4',5'-dihydrospiro[benzofuran-2(3H),3'(2'H)-furan]-2',3-dione (V), which is finally treated at 155 C in dimethylsulfoxide containing NaCl.
| 【1】 Hirosada, S.; Watanabe, M.; Mitsuru, K.; Isuke, I. (Takeda Chemical Industries, Ltd.); Spirobenzofuranone compounds, processes for their preparation and their use as medicines. CA 1113467; DE 2861651; EP 0003084; ES 476330; ES 8102114; JP 54098752; ZA 7807296 . |
| 【2】 Blancafort, P.; Castaner, J.; Serradell, M.N.; AG-629. Drugs Fut 1983, 8, 2, 92. |
| 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) | 30753 | methyl 5-acetyl-2-hydroxybenzoate | 16475-90-4 | C10H10O4 | 详情 | 详情 |
| (II) | 22822 | 3-bromodihydro-2(3H)-furanone | 5061-21-2 | C4H5BrO2 | 详情 | 详情 |
| (III) | 30754 | methyl 5-acetyl-2-[(2-oxotetrahydro-3-furanyl)oxy]benzoate | C14H14O6 | 详情 | 详情 | |
| (IV) | 30755 | 5-acetyl-2-[(2-oxotetrahydro-3-furanyl)oxy]benzoic acid | C13H12O6 | 详情 | 详情 | |
| (V) | 30756 | 5-Acetyl-2,2',3,3',4',5'-hexahydrospiro[benzofuran-2,2'-furan]-3,3'-dione | C13H10O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The title compound was prepared by condensation of the carbothioic acid (I) with alpha-bromo-gamma-butyrolactone (II) in the presence of K2CO3 in DMF.
| 【1】 Biggadike, K.; Procopiou, P.A. (Glaxo Wellcome plc); Lactone derivs. of 17beta-carboxy, carbothio and amide androstane derivs.. JP 1999501675; US 6197761; WO 9724365 . |
| 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) | 14478 | (6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carbothioic S-acid | C24H30F2O5S | 详情 | 详情 | |
| (II) | 22822 | 3-bromodihydro-2(3H)-furanone | 5061-21-2 | C4H5BrO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)Nitration of 5-bromoisoquinoline (I) using KNO3 in H2SO4 gave 5-bromo-8-nitroisoquinoline (II), which upon methylation with dimethyl sulfate was converted to the isoquinolinium salt (III). Subsequent reduction of (III) with NaBH4 in AcOH provided tetrahydroisoquinoline (IV). This was coupled with phenylboronic acid (V) in the presence of Pd(PPh3)4 and NaHCO3 to yield the 5-phenylisoquinoline (VI). Further reduction of the nitro group of (VI) by catalytic hydrogenation over Pd/C afforded amine (VII). The pyrroloisoquinoline (VIII) was then formed by condensation of (VII) with chloral and hydroxylamine in boiling water, followed by cyclization of the intermediate (oxymino)acetamide in methanesulfonic acid at 120 C. After chlorosulfonation of (VIII), the sulfonyl chloride (IX) was condensed with dimethylamine in THF to afford sulfonamide (X). Hydroxylamine derivative (XIV) was prepared by O-alkylation of N-hydroxyphthalimide (XI) with alpha-bromo-gamma-butyrolactone (XII), followed by hydrolysis of the phthalimide (XIII) in boiling 1 M HCl. Hydroxylamine derivative (XIV) was then condensed with sulfonamide (X) to furnish oxime (XV). Finally, hydrolysis of the butyrolactone group of (XV) with aqueous NaOH gave the title compound.
| 【1】 Watjen, F.; Drejer, J. (NeuroSearch A/S); Novel indole-2,3-dione-3-oxime derivs.. EP 0869958; JP 2000501432; US 6124285; WO 9814447 . |
| 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) | 22811 | 5-bromoisoquinoline | C9H6BrN | 详情 | 详情 | |
| (II) | 22812 | 5-bromo-8-nitroisoquinoline | C9H5BrN2O2 | 详情 | 详情 | |
| (III) | 22813 | 5-bromo-2-methyl-8-nitro-2lambda(5)-isoquinoline | C10H8BrN2O2 | 详情 | 详情 | |
| (IV) | 22814 | 5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline | C10H11BrN2O2 | 详情 | 详情 | |
| (V) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (VI) | 22816 | 2-methyl-8-nitro-5-phenyl-1,2,3,4-tetrahydroisoquinoline | C16H16N2O2 | 详情 | 详情 | |
| (VII) | 22817 | 2-methyl-5-phenyl-1,2,3,4-tetrahydro-8-isoquinolinylamine; 2-methyl-5-phenyl-1,2,3,4-tetrahydro-8-isoquinolinamine | C16H18N2 | 详情 | 详情 | |
| (VIII) | 22818 | 8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione | C18H16N2O2 | 详情 | 详情 | |
| (IX) | 22819 | 4-(8-methyl-2,3-dioxo-2,3,6,7,8,9-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-5-yl)benzenesulfonyl chloride | C18H15ClN2O4S | 详情 | 详情 | |
| (X) | 22820 | N,N-dimethyl-4-(8-methyl-2,3-dioxo-2,3,6,7,8,9-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-5-yl)benzenesulfonamide | C20H21N3O4S | 详情 | 详情 | |
| (XI) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (XII) | 22822 | 3-bromodihydro-2(3H)-furanone | 5061-21-2 | C4H5BrO2 | 详情 | 详情 |
| (XIII) | 22823 | 2-[(2-oxotetrahydro-3-furanyl)oxy]-1H-isoindole-1,3(2H)-dione | C12H9NO5 | 详情 | 详情 | |
| (XIV) | 22824 | 3-(aminooxy)dihydro-2(3H)-furanone | C4H7NO3 | 详情 | 详情 | |
| (XV) | 22825 | N,N-dimethyl-4-(8-methyl-2-oxo-3-[[(2-oxotetrahydro-3-furanyl)oxy]imino]-1,2,6,7,8,9-hexahydro-3H-pyrrolo[3,2-h]isoquinolin-5-yl)benzenesulfonamide | C24H26N4O6S | 详情 | 详情 |