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【结 构 式】 
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【分子编号】63466 【品名】2-propenyl 6-(1-hydroxyethyl)-3-({5-[2-(5-isothiazolyl)ethenyl]-1-[(2-propenyloxy)carbonyl]-3-pyrrolidinyl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate 【CA登记号】 |
【 分 子 式 】C26H31N3O6S2 【 分 子 量 】545.68076 【元素组成】C 57.23% H 5.73% N 7.7% O 17.59% S 11.75% |
合成路线1
该中间体在本合成路线中的序号：(XLV)3) The cyclization of benzoquinone (XXXVII) with 3-amino-4-methoxycrotonic acid methyl ester (XXXVIII) gives 5-hydroxy-2-(methoxymethyl)-1H-indole-3-carboxylic acid methyl ester (XXXIX), which is methylated to 5-methoxy-2-(methoxymethyl)-1-methylindole-3-carboxylic acid methyl ester (XL). The oxidation of (XL) with DDQ yields the corresponding aldehyde (XLI), which is submitted to a Horner-Emmonds condensation with 2-(dimethoxyphosphoryl)acetic acid ethyl ester (XLII) in a basic medium to afford the corresponding acrylic ester (XLIII). The nitration of (XLIII) gives 3-[5-methoxy-3-(methoxycarbonyl)-1-methyl-4-nitroindol-2-yl]acrylic acid ethyl ester (XLIV), the monoethyl ester analogue of compound (XVIII).The reduction of (XLIV) with Sn and 3N HCl in ethanol/water yields the corresponding 4-amino derivative (XLV), which is oxidized with Fremy's salt (nitrodisulfonic acid potassium salt) to afford 3-[5-methoxy-3-(methoxycarbonyl)-1-methyl-4,7-dioxo-4,7-dihydro-1H-indo l -2-yl]acrylic acid ethyl ester (XLVI). The reduction of (XLVI) with Na2S2O4 in CHCl3/ethanol/water gives the corresponding hydroquinone (XLVII), which is first reduced with DIBAL (diisobutylaluminum hydride) in toluene/dichloromethane and then oxidized again with FeCl3 to afford 3-(hydroxymethyl)-2-(3-hydroxy-1-propenyl)-5-methoxy-1-methyl-4,7-dihydro-1H-indole-4,7-dione (XXII). Finally, this compound is treated with aziridine (XXIII) in hot methanol.
| 【1】 Bailey, S.M.; Lohmeyer, M.; Dimbleby, R.; Castaner, J.; EO9. Drugs Fut 1996, 21, 2, 143. |
| 【2】 Kinugawa, M.; Arai, H.; Nishikawa, H.; Masuda, Y.; Ogasa, T.; Tomioka, S.; Kasai, M.; Synthetic studies of the indoloquinone antitumor agent EO9. 13th Int Symp Med Chem (Sept 19-23, Paris) 1994, Abst P250. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXII) | 12618 | 3-(Hydroxymethyl)-2-[(E)-3-hydroxy-1-propenyl]-5-methoxy-1-methyl-1H-indole-4,7-dione | C14H15NO5 | 详情 | 详情 | |
| (XXIII) | 10151 | Ethyleneimine; Aziridine; Azirane | 151-56-4 | C2H5N | 详情 | 详情 |
| (XXXVII) | 12633 | Quinone; Benzo-1,4-quinone; 2,5-Cyclohexadiene-1,4-dione | 106-51-4 | C6H4O2 | 详情 | 详情 |
| (XXXVIII) | 12634 | methyl (E)-3-amino-4-methoxy-2-butenoate | C6H11NO3 | 详情 | 详情 | |
| (XXXIX) | 12635 | methyl 5-hydroxy-2-(methoxymethyl)-1H-indole-3-carboxylate | C12H13NO4 | 详情 | 详情 | |
| (XL) | 12636 | methyl 5-methoxy-2-(methoxymethyl)-1-methyl-1H-indole-3-carboxylate | C14H17NO4 | 详情 | 详情 | |
| (XLI) | 12637 | methyl 2-formyl-5-methoxy-1-methyl-1H-indole-3-carboxylate | C13H13NO4 | 详情 | 详情 | |
| (XLII) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (XLIII) | 12639 | methyl 2-[(E)-3-ethoxy-3-oxo-1-propenyl]-5-methoxy-1-methyl-1H-indole-3-carboxylate | C17H19NO5 | 详情 | 详情 | |
| (XLIV) | 12640 | methyl 2-[(E)-3-ethoxy-3-oxo-1-propenyl]-5-methoxy-1-methyl-4-nitro-1H-indole-3-carboxylate | C17H18N2O7 | 详情 | 详情 | |
| (XLV) | 63466 | 2-propenyl 6-(1-hydroxyethyl)-3-({5-[2-(5-isothiazolyl)ethenyl]-1-[(2-propenyloxy)carbonyl]-3-pyrrolidinyl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C26H31N3O6S2 | 详情 | 详情 | |
| (XLVI) | 63467 | methyl 2-[(E)-3-ethoxy-3-oxo-1-propenyl]-5-methoxy-1-methyl-4,7-dioxo-4,7-dihydro-1H-indole-3-carboxylate | C17H17NO7 | 详情 | 详情 | |
| (XLVII) | 63468 | methyl 2-[(E)-3-ethoxy-3-oxo-1-propenyl]-4,7-dihydroxy-5-methoxy-1-methyl-1H-indole-3-carboxylate | C17H19NO7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)Propargyl alcohol (I) is oxidized with CrO3 under reduced pressure to give propynal (II), which is treated with sodium thiosulfate to afford the aldehyde dithionite (III). Subsequent cyclization of (III) in liquid ammonia gives rise to isothiazole (IV). The lithiated derivative of (IV) is formylated by means of DMF to provide aldehyde (V), which is further reduced to alcohol (VI) employing NaBH4 in THF (1). Bromination of alcohol (VI) in the presence of CBr4/PPh3 leads to 5-bromomethylisothiazole (VII). This is then converted into the phosphonium salt (VIII) upon treatment with triphenylphosphine in refluxing acetonitrile. Wittig condensation of (VIII) with the formyl pyrrolidine (IX) produces the ethenylpyrrolidine derivative (X). The mesylate group of (X) is displaced with potassium thioacetate to produce thioester (XI), which is subsequently hydrolyzed to thiol (XII) with methanolic NaOH. Condensation of thiol (XII) with the enol phosphate (XIII) in the presence of diisopropylethylamine affords the protected carbapenem derivative (XIV). This is finally deprotected with Bu3SnH and palladium catalyst to furnish the title compound (1,2)
| 【1】 Kang, Y.-K.; Lee, K.-S.; Yoo, K.-H.; Shin, K.-J.; Kim, D.-C.; Lee, C.-S.; Kong, J.Y.; Kim, D.J.; Synthesis and biological evaluation of novel 1beta-methylcarbapenems with isothiazoloethenyl side chains. Bioorg Med Chem Lett 2003, 13, 3, 463. |
| 【2】 Kim, D.J.; Yoo, K.H.; Kang, Y.K.; Park, S.W.; Shin, K.J.; Seo, K.J. (Korea Institute of Science and Technology); Novel 1beta-methylcarbapenem derivs. and process for preparation thereof. WO 0202561 . |
| 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) | 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 |
| (II) | 23544 | propiolaldehyde | C3H2O | 详情 | 详情 | |
| (III) | 63457 | sodium 1-{[oxido(dioxo)-lambda~6~-sulfanyl]sulfanyl}-3-oxo-1-propene | C3H3NaO4S2 | 详情 | 详情 | |
| (IV) | 63458 | isothiazole | C3H3NS | 详情 | 详情 | |
| (V) | 63459 | 5-isothiazolecarbaldehyde | C4H3NOS | 详情 | 详情 | |
| (VI) | 63460 | 5-isothiazolylmethanol | C4H5NOS | 详情 | 详情 | |
| (VII) | 63461 | 5-(bromomethyl)isothiazole | C4H4BrNS | 详情 | 详情 | |
| (VIII) | 63462 | (5-isothiazolylmethyl)(triphenyl)phosphonium bromide | C22H19BrNPS | 详情 | 详情 | |
| (IX) | 49446 | allyl (2S,4R)-2-formyl-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C10H15NO6S | 详情 | 详情 | |
| (X) | 63463 | 2-propenyl 2-[2-(5-isothiazolyl)ethenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C14H18N2O5S2 | 详情 | 详情 | |
| (XI) | 63464 | 2-propenyl 4-(acetylsulfanyl)-2-[2-(5-isothiazolyl)ethenyl]-1-pyrrolidinecarboxylate | C15H18N2O3S2 | 详情 | 详情 | |
| (XII) | 63465 | 2-propenyl 2-[2-(5-isothiazolyl)ethenyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C13H16N2O2S2 | 详情 | 详情 | |
| (XIII) | 32617 | allyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C25H26NO8P | 详情 | 详情 | |
| (XIV) | 63466 | 2-propenyl 6-(1-hydroxyethyl)-3-({5-[2-(5-isothiazolyl)ethenyl]-1-[(2-propenyloxy)carbonyl]-3-pyrrolidinyl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C26H31N3O6S2 | 详情 | 详情 |