|
【结 构 式】 
|
【药物名称】 【化学名称】5(R)-[2-(4-Methoxyphenyl)ethyl]-4(S)-methyl-3-methylenetetrahydrofuran-2-one 【CA登记号】364335-55-7 (undefined stereoch.) 【 分 子 式 】C15H18O3 【 分 子 量 】246.30891 |
【开发单位】CSIC (Originator), Industrial Farmacéutica Cantabria (Originator), Universidad de Alcalá (Originator), Universidad del Bio-Bio (Originator), Universidad Palmas de Gran Canaria (Originator) 【药理作用】Oncolytic Drugs, Apoptosis Inducers |
合成路线1
4-Hydroxybenzaldehyde (I) was acetylated using Ac2O in pyridine. The resultant 4-(acetyloxy)benzaldehyde (II) was then subjected to a Wadsworth-Emmons condensation with trimethyl phosphonoacetate to afford methyl 4-(acetyloxy)cinnamate (III). After catalytic double bond hydrogenation, the resultant saturated ester (IV) was reduced by LiAlH4 to furnish 3-(4-hydroxyphenyl)-1-propanol (V) –alternatively (V) can be obtained by reduction with LiAlH4 of the propionic acid derivative (VI) (isolated from Asplenium onopteris)-. Methylation of the phenolic hydroxyl group of (V) with iodomethane and K2CO3 in acetone gave the methyl ether (VII). Then, oxidation of alcohol (VII) to 3-(4-methoxyphenyl)propanal (VIII) was accomplished by means of pyridinium chlorochromate.
| 【1】 Gonzalez, A.G.; et al.; Synthesis and antiproliferative activity of a new compound containing an alpha-methylene-gamma-lactone group. J Med Chem 2002, 45, 12, 2358. |
| 【2】 Bermejo Barrera, J.; Hernandez Silva, M.; Alvarez de Mon, M.; Pivel Ranieri, J.P. (CSIC (Consejo Superior de Investigaciones Cientificas)); Derivs. of p-hydroxy phenyl propionic acid as antiproliferative agents. ES 2160093; WO 0172733 . |
| 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) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (II) | 56432 | 4-Acetoxybenzaldehyde; p-Acetoxybenzaldehyde; p-Formylphenyl acetate | 878-00-2 | C9H8O3 | 详情 | 详情 |
| (III) | 56433 | methyl (E)-3-[4-(acetyloxy)phenyl]-2-propenoate | C12H12O4 | 详情 | 详情 | |
| (IV) | 56434 | methyl 3-[4-(acetyloxy)phenyl]propanoate | C12H14O4 | 详情 | 详情 | |
| (V) | 56435 | 3-(4-Hydroxyphenyl)-1-propanol | C9H12O2 | 详情 | 详情 | |
| (VI) | 25691 | 3-(4-hydroxyphenyl)propionic acid | 501-97-3 | C9H10O3 | 详情 | 详情 |
| (VII) | 56436 | 3-(p-Methoxyphenyl)propanol; 3-(4-Methoxyphenyl)propanol | 5406-18-8 | C10H14O2 | 详情 | 详情 |
| (VIII) | 56437 | 3-(4-methoxyphenyl)propanal | C10H12O2 | 详情 | 详情 |
合成路线2
Condensation of acetaldehyde with methyl acrylate (VIII) under Bayliss-Hillmann conditions gave rise to the allylic alcohol (IX). Bromination of (IX) using N-bromosuccinimide and dimethyl sulfide proceeded with rearrangement to the allyl bromide (X). This was then coupled with aldehyde (VII) in the presence of metallic tin and catalytic amounts of HOAc to produce, after acid-catalyzed cyclization, the target methylene butyrolactone derivative.
| 【1】 Gonzalez, A.G.; et al.; Synthesis and antiproliferative activity of a new compound containing an alpha-methylene-gamma-lactone group. J Med Chem 2002, 45, 12, 2358. |
| 【2】 Bermejo Barrera, J.; Hernandez Silva, M.; Alvarez de Mon, M.; Pivel Ranieri, J.P. (CSIC (Consejo Superior de Investigaciones Cientificas)); Derivs. of p-hydroxy phenyl propionic acid as antiproliferative agents. ES 2160093; WO 0172733 . |