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【结 构 式】 
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【药物名称】Hydroxymethylacylfulvene, Irofulven, NSC-683863, 6-HMAF, HMAF, MGI-114 【化学名称】6'(R)-Hydroxy-3'-(hydroxymethyl)-2',4',6'-trimethyl-6',7'-dihydrospiro[cyclopropane-1,5'-[5H]inden]-7'-one 【CA登记号】158440-71-2 【 分 子 式 】C15H18O3 【 分 子 量 】246.30891 |
【开发单位】MGI (Orphan Drug), MGI (Originator), Dainippon Pharmaceutical (Licensee), M.D. Anderson Cancer Center (Codevelopment), National Cancer Institute (Codevelopment) 【药理作用】Brain Cancer Therapy, Breast Cancer Therapy, Colorectal Cancer Therapy, Leukemia Therapy, Liver Cancer Therapy, Lung Cancer Therapy, Melanoma Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Ovarian Cancer Therapy, Pancreatic Cancer Therapy, Prostate Cancer Therapy, Renal Cancer Therapy, Solid Tumors Therapy, Apoptosis Inducers |
合成路线1
The cyclization of the diacyl cyclopropane (I) with cyclopentenone (II) gives the tricyclic epoxide (III), which is converted into the unsaturated epoxydione (IV). Hydroxylation of the double bond of (IV) affords the diol (V), which is protected as cyclic ketal, with simultaneous ring opening of the epoxide and methylation of one ketonic group to give intermediate (VI). Elimination of the ketal group and simultaneous acetylation yields the monoacetoxytetrahydroindenone (VII), which is converted into the dihydroindenone (VIII). Finally, this compound is hydroxymethylated with paraformaldehyde.
| 【1】 McMorris, T.C.; Discovery and development of sesquiterpenoid derived hydroxymethylacylfulvene: A new anticancer drug. Bioorg Med Chem 1999, 7, 5, 881. |
| 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) | 26682 | 1-(1-Acetylcyclopropyl)-2-diazo-1-ethanone | C7H8N2O2 | 详情 | 详情 | |
| (II) | 26683 | (4S,5R)-4-(1-methoxy-1-methylethoxy)-5-methyl-2-cyclopenten-1-one | C10H16O3 | 详情 | 详情 | |
| (III) | 26684 | (2R,3S,3aS,4R,7S,7aS)-4,7-Epoxy-3-(1-methoxy-1-methylethoxy)-2,7-dimethylspiro[perhydroindane-6,1'-cyclopropane]-1,5-dione; (2R,3S,3aS,4R,7S,7aS)-4,7-Epoxy-3-(1-methoxy-1-methylethoxy)-2,7-dimethylspiro[perhydroindane-6,1'-cyclopropane]-1,5-dione | C17H24O5 | 详情 | 详情 | |
| (IV) | 26685 | (3aR,4R,7S,7aS)-4,7-Epoxy-2,7-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-spiro[indene-6,1'-cyclopropane]-1,5-dione; (3aR,4R,7S,7aS)-4,7-Epoxy-2,7-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-spiro[indene-6,1'-cyclopropane]-1,5-dione | C13H14O3 | 详情 | 详情 | |
| (V) | 26686 | (2R,3R,3aR,4R,7S,7aS)-4,7-Epoxy-2,3-dihydroxy-2,7-dimethylperhydrospiro[indene-6,1'-cyclopropane]-15-dione | C13H16O5 | 详情 | 详情 | |
| (VI) | 26687 | (3aR,5R,8aR)-4,5-Dihydroxy-2-methoxy-5,7,8a-trimethyl-3b,4,5,6,8,8a-hexahydro-3aH-spiro[indeno[1,2-d][1,3]dioxole-6,1'-cyclopropan]-8-one | C16H22O6 | 详情 | 详情 | |
| (VII) | 26688 | (3aR,5R)-4-Acetoxy-5-hydroxy-2,5,7-trimethyl-3a,4,5,6-tetrahydro-1H-spiro[indene-6,1'-cyclopropan]-1-one | C16H20O4 | 详情 | 详情 | |
| (VIII) | 26689 | 6(R)-6-Hydroxy-2,4,6-trimethyl-6,7-dihydro-5H-spiro[indene-5,1'-cyclopropan]-7-one; 6(R)-6-Hydroxy-2,4,6-trimethyl-6,7-dihydro-5H-spiro[indene-5,1'-cyclopropan]-7-one | C14H16O2 | 详情 | 详情 |
合成路线2
Racemic compound.- The reaction of 1,1-diacetylcyclopropane (I) with the disilylated propargyl alcohol (II) by means of tert-butyllithium gives the monocondensation compound (III), which is treated with ethynylmagnesium bromide (IV) and CeCl3 to yield the bis acetylenic diol (V). The acylation of (V) with acetic anhydridde affords the monoacetate (VI), which is isomerized by means of [CuH(PPh3]6 to provide the allene compound (VII). The selective deprotection of (VII) gives the terminal acetylene (VIII), which is cyclized with Mo(CO)6 in refluxing DMSO/toleuene to afford the tricyclic ketone (IX). The methyletion of (IX) with CH3Li gives the monosilylated tricyclic diol (X), which is deprotected with TBAF yielding the diol (XI). The oxidation of the secondary alcohol of (XI) with Dess Martin periodinane (DMP) provides the tricyclic ketone (XII), which is finally hydroxymethylated with formaldehyde and sulfuric acid to afford the target compound as a racemic mixture.
| 【1】 Brummond, K.M.; Lu, J.; A short synthesis of the potent antitumor agent (±)-hydroxymethylacylfulvene using allenic pauson-khand type cycloaddition. J Am Chem Soc 1999, 121, 21, 5087. |
| 【2】 Brummond, K.M.; et al.; A rapid synthesis of hydroxymethylacylfulvene (HMAF) using the allenic Pauson - Khand reaction. A synthetic approach to either enantiomer of this illudane structure. J Am Chem Soc 2000, 122, 20, 4915. |
| 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) | 27116 | 1-(1-acetylcyclopropyl)-1-ethanone | C7H10O2 | 详情 | 详情 | |
| (II) | 27117 | tert-butyl(dimethyl)silyl 3-(trimethylsilyl)-2-propynyl ether | C12H26OSi2 | 详情 | 详情 | |
| (III) | 27118 | 1-[1-[2-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-1-methyl-4-(trimethylsilyl)-3-butynyl]cyclopropyl]-1-ethanone | C19H36O3Si2 | 详情 | 详情 | |
| (IV) | 17778 | ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium | 4301-14-8 | C2HBrMg | 详情 | 详情 |
| (V) | 27119 | 3-[[tert-butyl(dimethyl)silyl]oxy]-2-[1-(1-hydroxy-1-methyl-2-propynyl)cyclopropyl]-5-(trimethylsilyl)-4-pentyn-2-ol | C21H38O3Si2 | 详情 | 详情 | |
| (VI) | 27120 | 1-[1-[2-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-1-methyl-4-(trimethylsilyl)-3-butynyl]cyclopropyl]-1-methyl-2-propynyl acetate | C23H40O4Si2 | 详情 | 详情 | |
| (VII) | 27121 | 3-[[tert-butyl(dimethyl)silyl]oxy]-2-[1-(1-methyl-1,2-propadienyl)cyclopropyl]-5-(trimethylsilyl)-4-pentyn-2-ol | C21H38O2Si2 | 详情 | 详情 | |
| (VIII) | 27122 | 3-[[tert-butyl(dimethyl)silyl]oxy]-2-[1-(1-methyl-1,2-propadienyl)cyclopropyl]-4-pentyn-2-ol | C18H30O2Si | 详情 | 详情 | |
| (IX) | 27123 | 4'-(Tert-butyldimethylsilyloxy)-5'-hydroxy-5',7'-dimethyl-2',4',5',6'-tetrahydro-1'H-spiro[cyclopropane-1,6'-inden]-2'-one | C19H30O3Si | 详情 | 详情 | |
| (X) | 27124 | 7'-(Tert-butyldimethylsilyloxy)-2',4',6'-trimethyl-6',7'-dihydro-5'H-spiro[cyclopropane-1,5'-inden]-6'-ol | C20H32O2Si | 详情 | 详情 | |
| (XI) | 27125 | 2',4',6'-Trimethyl-6',7'-dihydro-5'H-spiro[cyclopropane-1,5'-indene]-6',7'-diol | C14H18O2 | 详情 | 详情 | |
| (XII) | 27126 | 6'-Hydroxy-2',4',6'-trimethyl-6',7'-dihydro-5'H-spiro[cyclopropane-1,5'-inden]-7'-one | C14H16O2 | 详情 | 详情 |
合成路线3
(R)-Compound.- The treatment of illudin S (XIII) with sulfuric acid gives the tricyclic ketone (XII) as a single (R)-enantiomer (R)-(XII), which is hydroxymethylated with formaldehyde and sulfuric acid as before to provide the (R)-enantiomer of the target compound.
| 【1】 Brummond, K.M.; Lu, J.; A short synthesis of the potent antitumor agent (±)-hydroxymethylacylfulvene using allenic pauson-khand type cycloaddition. J Am Chem Soc 1999, 121, 21, 5087. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (R)-(XII) | 26689 | 6(R)-6-Hydroxy-2,4,6-trimethyl-6,7-dihydro-5H-spiro[indene-5,1'-cyclopropan]-7-one; 6(R)-6-Hydroxy-2,4,6-trimethyl-6,7-dihydro-5H-spiro[indene-5,1'-cyclopropan]-7-one | C14H16O2 | 详情 | 详情 | |
| (XIII) | 27127 | (1'R,2'S,5'R)-1',5'-Dihydroxy-2'-(hydroxymethyl)-2',5',7'-trimethyl-2',4',5',6'-tetrahydro-1'H-spiro[cyclopropane-1,6'-inden]-4'-one | C15H20O4 | 详情 | 详情 |
合成路线4
The chiral 6(R) isomer of 213351 has been obtained as follows: The condensation of 1,1-diacetylcyclopropane monoethylene ketal (I) with acetylenic phosphonate (II) by means of NaHMDS in THF gives the silylated pentenyne (III), which is treated with TsOH in acetone/water yielding the acetylcyclopropane (IV). The Sharpless asymetric dihydroxylation of the double bond of (IV) by means of chiral auxiliary (DHQD)2PYR, K2OsO2(OH)4, K3Fe(CN)6 and K2CO3 in tert-butanol/water affords the chiral diol (V), which is monosilylated with TBDMS-OTf providing the silyl ether (VI). The condensation of (VI) with ethynylmagnesium bromide (VII) and CeCl3 gives the diacetylenic diol (VIII), which is regioselectively acetylated with Ac2O, TEA and DMAP yielding the monoacetate (IX). The treatment of the propargylic acetate (IX) with [(PPh3)CuH]6 in methanol affords the allene (X), which is regioselectively desilylated at the terminal acetylenic group furnishing the cyclization precursor (XI). The Mo(CO)6 promoted cyclization of (XI) in refluxing toluene/DMSO gives the chiral tricyclic ketone (XII). The methylation of (XII) with MeLi yields the monosilylated diol (XIII), which is desilylated with TBAF to the chiral diol (XIV). The oxidation of (XIV) with Dess Martin periodinane (DMP) affords the chiral hydroyketone (XV), which is finally hydroxymethylated with formaldehyde and H2SO4 to furnish the target compound.
| 【1】 Brummond, K.M.; et al.; A rapid synthesis of hydroxymethylacylfulvene (HMAF) using the allenic Pauson - Khand reaction. A synthetic approach to either enantiomer of this illudane structure. J Am Chem Soc 2000, 122, 20, 4915. |
| 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) | 36876 | 1-[1-(2-methyl-1,3-dioxolan-2-yl)cyclopropyl]-1-ethanone | C9H14O3 | 详情 | 详情 | |
| (II) | 36877 | diethyl 3-(trimethylsilyl)-2-propynylphosphonate | C10H21O3PSi | 详情 | 详情 | |
| (III) | 36878 | trimethyl[(Z)-4-[1-(2-methyl-1,3-dioxolan-2-yl)cyclopropyl]-3-penten-1-ynyl]silane | C15H24O2Si | 详情 | 详情 | |
| (IV) | 36879 | 1-[1-[(Z)-1-methyl-4-(trimethylsilyl)-1-buten-3-ynyl]cyclopropyl]-1-ethanone | C13H20OSi | 详情 | 详情 | |
| (V) | 36880 | 1-[1-[(1R,2R)-1,2-dihydroxy-1-methyl-4-(trimethylsilyl)-3-butynyl]cyclopropyl]-1-ethanone | C13H22O3Si | 详情 | 详情 | |
| (VI) | 36881 | 1-[1-[(1R,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-1-methyl-4-(trimethylsilyl)-3-butynyl]cyclopropyl]-1-ethanone | C19H36O3Si2 | 详情 | 详情 | |
| (VII) | 17778 | ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium | 4301-14-8 | C2HBrMg | 详情 | 详情 |
| (VIII) | 36882 | (2R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[1-(1-hydroxy-1-methyl-2-propynyl)cyclopropyl]-5-(trimethylsilyl)-4-pentyn-2-ol | C21H38O3Si2 | 详情 | 详情 | |
| (IX) | 36883 | 1-[1-[(1R,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-1-methyl-4-(trimethylsilyl)-3-butynyl]cyclopropyl]-1-methyl-2-propynyl acetate | C23H40O4Si2 | 详情 | 详情 | |
| (X) | 36884 | (2R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[1-(1-methyl-1,2-propadienyl)cyclopropyl]-5-(trimethylsilyl)-4-pentyn-2-ol | C21H38O2Si2 | 详情 | 详情 | |
| (XI) | 36888 | (2R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[1-(1-methyl-1,2-propadienyl)cyclopropyl]-4-pentyn-2-ol | C18H30O2Si | 详情 | 详情 | |
| (XII) | 36885 | C19H30O3Si | 详情 | 详情 | ||
| (XIII) | 36886 | C20H32O2Si | 详情 | 详情 | ||
| (XIV) | 36887 | C14H18O2 | 详情 | 详情 | ||
| (XV) | 26689 | 6(R)-6-Hydroxy-2,4,6-trimethyl-6,7-dihydro-5H-spiro[indene-5,1'-cyclopropan]-7-one; 6(R)-6-Hydroxy-2,4,6-trimethyl-6,7-dihydro-5H-spiro[indene-5,1'-cyclopropan]-7-one | C14H16O2 | 详情 | 详情 |