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【结 构 式】 
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【药物名称】MHP-34a 【化学名称】4-[(1S,6R,9S,12R)-12-Methoxy-10,11,13-trioxatricyclo[7.2.2.0(1,6)]tridec-9-yl]benzoic acid 【CA登记号】300656-01-3 【 分 子 式 】C18H22O6 【 分 子 量 】334.37244 |
【开发单位】Johns Hopkins University (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Antimalarials, Treatment of Protozoal Diseases |
合成路线1
The reaction of cyclohexanone (I) with acrylonitrile (II) by means of pyrrolidine gives 3-(2-oxocyclohexyl)propionitrile (III), which is condensed with methoxymethyltriphenylphosphonium chloride (IV) in THF to yield the methoxymethylene derivative (V). The condensation of propionitrile (V) with 4-bromostyrene (VI) by means of n-BuLi ethyl ether affords the styryl ketone (VII), which is cyclized by means of triphenyl phosphite and O3 (or air, methylene blue and light) to provide trioxane (VIII) as a diastereomeric mixture that is separated by column chromatography. Finally, the vinyl group of the desired diastereomer (VIII) is oxidized with KMnO4 in acetone to afford the target compound.
| 【1】 Parker, M.H.; Krasavin, M.; Posner, G.H.; Paik, I.-H.; Jeon, H.B.; Shapiro, T.A.; Antimalarial simplified 3-aryltrioxanes: Synthesis and preclinical efficacy/toxicity testing in rodents. J Med Chem 2001, 44, 19, 3054. |
| 【2】 Posner, G.H.; Shapiro, T.A.; Parker, M.H.; Krasavin, M. (Johns Hopkins University); Water-soluble trioxanes as potent and safe antimalarial agents. US 6136847; WO 0059501 . |
| 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) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (II) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (III) | 49235 | 2-(beta-Cyanoethyl)cyclohexanone | C9H13NO | 详情 | 详情 | |
| (IV) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (V) | 49236 | 3-[2-[(Z)-methoxymethylidene]cyclohexyl]propanenitrile | C11H17NO | 详情 | 详情 | |
| (VI) | 49237 | 4-Bromostyrene; p-Bromostyrene | 2039-82-9 | C8H7Br | 详情 | 详情 |
| (VII) | 49238 | 3-[2-[(Z)-methoxymethylidene]cyclohexyl]-1-(4-vinylphenyl)-1-propanone | C19H24O2 | 详情 | 详情 | |
| (VIII) | 49239 | (1S,6R,9S,12R)-12-methoxy-6-methyl-9-(4-vinylphenyl)-10,11,13-trioxatricyclo[7.2.2.0(1,6)]tridecane; methyl (1S,6R,9S,12R)-6-methyl-9-(4-vinylphenyl)-10,11,13-trioxatricyclo[7.2.2.0(1,6)]tridec-12-yl ether | C20H26O4 | 详情 | 详情 |
合成路线2
The cyclization of 3-[2-(methoxymethylene)cyclohexyl]-1-[4-(tert-butyldimethylsilyloxymethyl)phenyl]-1-propanone (I) by means of triphenyl phosphite and O3 gives the silylated trioxane (II), which is deprotected by means of TBAF to yield the hydroxymethyl derivative (III). Finally, this compound is oxidized with KMnO4 to afford the target compound.
| 【1】 Posner, G.H.; Shapiro, T.A.; Parker, M.H.; Krasavin, M. (Johns Hopkins University); Water-soluble trioxanes as potent and safe antimalarial agents. US 6136847; WO 0059501 . |
| 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) | 49240 | 1-[4-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl]-3-[2-[(Z)-methoxymethylidene]cyclohexyl]-1-propanone | C24H38O3Si | 详情 | 详情 | |
| (II) | 49241 | tert-butyl([4-[(1S,6R,12R)-12-methoxy-6-methyl-10,11,13-trioxatricyclo[7.2.2.0(1,6)]tridec-9-yl]benzyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl 4-[(1S,6R,12R)-12-methoxy-6-methyl-10,11,13-trioxatricyclo[7.2.2.0(1,6)]tridec-9-yl]benzyl ether | C25H40O5Si | 详情 | 详情 | |
| (III) | 49242 | [4-[(1S,6R,12R)-12-methoxy-6-methyl-10,11,13-trioxatricyclo[7.2.2.0(1,6)]tridec-9-yl]phenyl]methanol | C19H26O5 | 详情 | 详情 |