|
【结 构 式】 
|
【药物名称】Homoharringtonine, CGX-635, NSC-141633, HHT, ZJ-C, Myelostat, Ceflatonin 【化学名称】2(R)-(Methoxycarbonylmethyl)-2,6-dihydroxy-5-methylheptanoic cephalotaxine ester 【CA登记号】26833-87-4 【 分 子 式 】C29H39NO9 【 分 子 量 】545.63548 |
【开发单位】Chinese Academy of Medical Sciences (Originator), OncoPharm (Originator), ChemGenex Therapeutics (Not Determined), M.D. Anderson Cancer Center (Codevelopment) 【药理作用】Leukemia Therapy, Lymphoma Therapy, Myeloid Leukemia Therapy, Oncolytic Drugs, Alkaloids, Angiogenesis Inhibitors, Apoptosis Inducers |
合成路线1
The intermediate (racemic)-2-(methoxycarbonylmethyl)-6,6-dimethyltetrahydropyran-2-carboxylic acid (VIII) has been obtained by several related methods: 1. The Grignard condensation of 4-methyl-3-pentenyl bromide (I) with diethyl oxalate (II) in HF gives the 2-oxoheptenoate (III), which is condensed with methyl acetate (IV) by means of LiHMDS in THF to yield 3-(ethoxycarbonyl)-3-hydroxy-7-methyl-6-octenoic acid methyl ester (V). The cyclization of (V) by means of Ts-OH in hot toluene or by means of hot aqueous formic acid affords 2-(methoxycarbonylmethyl)-6,6-dimethyltetrahydropyran-2-carboxylic acid ethyl ester (VI), which is hydrolyzed with KOH in boiling water to provide the corresponding dicarboxylic acid (VII). Finally, this compound is regioselectively monoesterified by means of BF3/MeOH in methanol to furnish the intermediate (racemic)-2-(methoxycarbonylmethyl)-6,6-dimethyltetrahydropyran-2-carboxylic acid (VIII). 2. The reaction of 3-(ethoxycarbonyl)-3-hydroxy-7-methyl-6-octenoic acid methyl ester (V) with HCl in hot methanol gives 3-(ethoxycarbonyl)-3,7-dihydroxy-7-methyloctanoic acid methyl ester (IX), which is then cyclized by means of ZnCl2 in hot dichloroethane to yield the previously described intermediate (VIII). 3. The hydrolysis of 3-(ethoxycarbonyl)-3-hydroxy-7-methyl-6-octenoic acid methyl ester (V) with KOH in refluxing methanol/water gives the corresponding diacid (X), which is regioselectively monoesterified by means of BF3/MeOH in methanol to yield 3-carboxy-3-hydroxy-7-methyl-6-octenoic acid methyl ester (XI). Finally, this compound is cyclized by means of Ts-OH in hot toluene to afford the previously described carboxylic intermediate (VIII). The racemic acid (VIII) is submitted to optical resolution by esterification with quinine (XII) by means of 2,4,6-trichlorobenzoyl chloride and TEA or DCC to give a diastereomeric mixture of esters (XIII) that is separated by preparative HPLC to obtain the desired diastereomer (XIV). The hydrolysis of (XIV) with KOH in refluxing ethanol/water gives the corresponding chiral dicarboxylic acid (XV), which is regioselectively monoesterified with BF3/MeOH in methanol to yield the chiral (R)-2-(methoxycarbonylmethyl)-6,6-dimethyltetrahydropyran-2-carboxylic acid (XVI). The esterification of (XVI) with cephalotaxine (XVII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in toluene affords the corresponding ester (XVIII), which is treated with HBr in dichloromethane/HOAc, providing the bromoester (XIX). Finally, this compound is treated with NaHCO3, CaCO3 or BaCO3 in acetone/water to give the target hydroxyester.
| 【1】 Robin, J.-P.; et al.; The first semi-synthesis of enantiopure homoharringtonine via anhydrohomoharringtonine from a preformed chiral acyl moiety. Tetrahedron Lett 1999, 40, 2931. |
| 【2】 Robin, J.; Robin, J.-P.; Cavoleau, S.; Chauviat, L.; Charbonnel, S.; Dhal, R.; Dujardin, G.; Fournier, F.; Gilet, C.; Girodier, L.; Mevelec, L.; Poutot, S.; Rouaud, S. (OncoPharm Corp.); Novel cephalotaxane derivs. and process for their preparation. EP 1064285; FR 2776292; WO 9948894 . |
| 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) | 31462 | 5-bromo-2-methyl-2-pentene | C6H11Br | 详情 | 详情 | |
| (II) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (III) | 52779 | ethyl 3,6-dimethyl-2-oxo-5-heptenoate | C11H18O3 | 详情 | 详情 | |
| (IV) | 44566 | methyl acetate | 79-20-9 | C3H6O2 | 详情 | 详情 |
| (V) | 52780 | 1-ethyl 4-methyl 2-hydroxy-2-(4-methyl-3-pentenyl)succinate | C13H22O5 | 详情 | 详情 | |
| (VI) | 52781 | ethyl 2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylate | C13H22O5 | 详情 | 详情 | |
| (VII) | 52782 | 2-(carboxymethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylic acid | C10H16O5 | 详情 | 详情 | |
| (VIII) | 52783 | 2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylic acid | C11H18O5 | 详情 | 详情 | |
| (IX) | 52784 | 1-ethyl 4-methyl 2-hydroxy-2-(4-hydroxy-4-methylpentyl)succinate | C13H24O6 | 详情 | 详情 | |
| (X) | 52785 | 2-hydroxy-2-(4-methyl-3-pentenyl)succinic acid | C10H16O5 | 详情 | 详情 | |
| (XI) | 52786 | 2-hydroxy-2-(2-methoxy-2-oxoethyl)-6-methyl-5-heptenoic acid | C11H18O5 | 详情 | 详情 | |
| (XII) | 52787 | (R)-(6-methoxy-4-quinolinyl)[(2S,4S,5R)-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl]methanol | C20H24N2O2 | 详情 | 详情 | |
| (XIII) | 52788 | (R)-(6-methoxy-4-quinolinyl)[(2S,4S,5R)-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl]methyl 2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylate | C31H40N2O6 | 详情 | 详情 | |
| (XIV) | 52789 | (R)-(6-methoxy-4-quinolinyl)[(2S,4S,5R)-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl]methyl (2R)-2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylate | C31H40N2O6 | 详情 | 详情 | |
| (XV) | 52790 | (2R)-2-(carboxymethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylic acid | C10H16O5 | 详情 | 详情 | |
| (XVI) | 52791 | (2R)-2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylic acid | C11H18O5 | 详情 | 详情 | |
| (XVII) | 52792 | (1S,3aR,14bS)-2-methoxy-1,5,6,8,9,14b-hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzazepin-1-ol | C18H21NO4 | 详情 | 详情 | |
| (XVIII) | 52793 | (1S,3aR,14bS)-2-methoxy-1,5,6,8,9,14b-hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzazepin-1-yl (2R)-2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylate | C29H37NO8 | 详情 | 详情 | |
| (XIX) | 52794 | 1-[(1S,3aR,14bS)-2-methoxy-1,5,6,8,9,14b-hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzazepin-1-yl] 4-methyl (2R)-2-(4-bromo-4-methylpentyl)-2-hydroxybutanedioate | C29H38BrNO8 | 详情 | 详情 |
合成路线2
The oxidation of 2-methyl-1-cyclopentene-1-carbaldehyde (I) with O3 and Ag2O gives 2,6-dioxoheptanoic acid (II), which is esterified with cephalotaxine (III) by means of (COCl)2, yielding the ester (IV). Reformatsky reaction of (IV) with methyl bromoacetate (V) and Zn affords the adduct (VI), which is treated with an excess of methylmagnesium iodide to provide the target homoharringtonine (as a single diastereomer), along with some starting cephalotaxine that is separated by chromatography.
| 【1】 Hiranuma, S.; Hudlicky, T.; Synthesis of homoharringtonine and its derivative by partial esterification of cephalotaxine. Tetrahedron Lett 1982, 23, 34, 3431. |
| 【2】 Hiranuma, S.; et al.; Studies in Cephalotaxus alkaloids. Stereospecific total synthesis of homoharringtonine. J Org Chem 1983, 48, 26, 5321. |
| 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) | 52795 | 2-methyl-1-cyclopentene-1-carbaldehyde | C7H10O | 详情 | 详情 | |
| (II) | 52796 | 2,6-dioxoheptanoic acid | C7H10O4 | 详情 | 详情 | |
| (III) | 52797 | (3aS,14bS)-2-ethyl-1,5,6,8,9,14b-hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzazepin-1-ol | C19H23NO3 | 详情 | 详情 | |
| (IV) | 52798 | (3aR,14bS)-2-methoxy-1,5,6,8,9,14b-hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzazepin-1-yl 2,6-dioxoheptanoate | C25H29NO7 | 详情 | 详情 | |
| (V) | 12309 | methyl 2-bromoacetate; methyl bromoacetate | 96-32-2 | C3H5BrO2 | 详情 | 详情 |
| (VI) | 52799 | 1-[(1S,3aR,14bS)-2-methoxy-1,5,6,8,9,14b-hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzazepin-1-yl] 4-methyl 2-hydroxy-2-(4-oxopentyl)succinate | C28H35NO9 | 详情 | 详情 |