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【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
Extended Information