【结 构 式】 |
【药物名称】Helioxanthin, ACH-126447 【化学名称】10-(1,3-Benzodioxol-5-yl)furo[3',4':6,7]naphtho[1,2-d]-1,3-dioxol-7(9H)-one 【CA登记号】18920-47-3 【 分 子 式 】C20H12O6 【 分 子 量 】348.31504 |
【开发单位】Yale University (Originator), Achillion (Licensee) 【药理作用】Anti-Hepatitis B Virus Drugs, Anti-Hepatitis C Virus Drugs, Anti-Hepatitis Virus Drugs, ANTIINFECTIVE THERAPY, Antiviral Drugs |
合成路线1
The condensation of 4-iodo-1,3-benzodioxole-5-carbaldehyde (I) with dimethyl succinate (II) by means of NaOMe in aqueous methanol gives the benzylidene derivative (III), which is condensed with 1,3-benzodioxole-5-carbaldehyde (IV) by means of NaOMe in methanol, affording the bis-benzylidene hemiester (V). The selective reduction of (V) with LiEt3BH, followed by lactonization with ethyl chloroformate and TEA in THF, yields the lactone (VI), which is finally cyclized by means of Pd(OAc)2 and K2CO3 at 110 C through the nonisolated intermediate (VII), providing the target compound.
【1】 Mizufune, H.; et al.; The first regiospecific synthesis of helioxanthin by novel palladium-catalyzed benzannulation reaction of alpha,beta-bisbenzylidene-gamma-lactone. Tetrahedron Lett 2001, 42, 3, 437. |
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) | 46632 | 4-iodo-1,3-benzodioxole-5-carbaldehyde | C8H5IO3 | 详情 | 详情 | |
(II) | 41056 | dimethyl succinate | 106-65-0 | C6H10O4 | 详情 | 详情 |
(III) | 46633 | dimethyl 2-[(E)-(4-iodo-1,3-benzodioxol-5-yl)methylidene]succinate | C14H13IO6 | 详情 | 详情 | |
(IV) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
(V) | 46634 | (E)-4-(1,3-benzodioxol-5-yl)-2-[(E)-(4-iodo-1,3-benzodioxol-5-yl)methylidene]-3-(methoxycarbonyl)-3-butenoic acid | C21H15IO8 | 详情 | 详情 | |
(VI) | 46635 | 4-[(E)-1,3-benzodioxol-5-ylmethylidene]-3-[(E)-(4-iodo-1,3-benzodioxol-5-yl)methylidene]dihydro-2(3H)-furanone | C20H13IO6 | 详情 | 详情 | |
(VII) | 46636 | [(10S)-10-(1,3-benzodioxol-5-yl)-7-oxo-7,10-dihydrofuro[3',4':6,7]naphtho[1,2-d][1,3]dioxol-9(9H)-yl](iodo)palladium | C20H13IO6Pd | 详情 | 详情 |
合成路线2
Alternatively, the condensation of 1,3-benzodioxole-5-carbaldehyde ethylene ketal (VIII) with carbaldehyde (V) by means of n-BuLi gives the hydroxy ketal (IX), which is treated with Ac2O, HOAc and maleic anhydride (XI) at 140 C to perform a Diels-Alder cyclization between the nonisolated isobenzofuran (X) (a reactive diene) and the maleic anhydride (the dienophile), giving rise to the cyclic anhydride (XII). Finally, this compound is reduced with NaBH4 to the target compound along with some structural isomer (XIII) that is separated by chromatography.
【1】 Urasaki, Y.; et al.; Activity of a novel camptothecin analogue, homocamptothecin, in camptothecin-resistant cell lines with topoisomerase I alterations. Cancer Res 2000, 60, 23, 6577. |
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) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
(VIII) | 46637 | 5-(1,3-dioxolan-2-yl)-1,3-benzodioxole | C10H10O4 | 详情 | 详情 | |
(IX) | 46638 | 1,3-benzodioxol-5-yl[5-(1,3-dioxolan-2-yl)-1,3-benzodioxol-4-yl]methanol | C18H16O7 | 详情 | 详情 | |
(X) | 46639 | 8-(1,3-benzodioxol-5-yl)furo[3,4-e][1,3]benzodioxole | C16H10O5 | 详情 | 详情 | |
(XI) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
(XII) | 46640 | 10-(1,3-benzodioxol-5-yl)furo[3',4':6,7]naphtho[1,2-d][1,3]dioxole-7,9-dione | C20H10O7 | 详情 | 详情 | |
(XIII) | 46641 | 10-(1,3-benzodioxol-5-yl)furo[3',4':6,7]naphtho[1,2-d][1,3]dioxol-9(7H)-one | C20H12O6 | 详情 | 详情 |