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【结 构 式】 
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【药物名称】FR-20950 【化学名称】(1R,5S,6S)-6-[1(R)-Hydroxyethyl]-1-methyl-2-[2(R)-[2-(3-methyl-3H-imidazol-1-iumyl)ethyl]pyrrolidin-4(S)-ylsulfanyl]-1-carbapen-2-em-3-carboxylic acid chloride 【CA登记号】156443-34-4 【 分 子 式 】C20H29ClN4O4S 【 分 子 量 】456.99553 |
【开发单位】Fujisawa (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Carbapenems |
合成路线1
Swern oxidation of protected (hydroxymethyl)pyrrolidine (I), followed by Wittig condensation of the resulting aldehyde (II) with methylene triphenylphosphorane provided vinylpyrrolidine (III). Hydroboration of (III) with 9-borabicyclo[3.3.1]nonane and subsequent oxidative treatment with sodium perborate gave alcohol (IV). Interconversion of the N-benzyl protecting group for an allyloxycarbonyl group was achieved by catalytic hydrogenation and then treatment of the deprotected amine (V) with allyloxycarbonyl chloride (VI). Alcohol (VII) was activated as the corresponding mesylate (VIII), which was condensed with imidazole (IX) in the presence of t-BuOK to afford the N-alkylated imidazole (X). Acid deprotection of the silyl ether of (X) yielded the corresponding secondary alcohol, which was further converted to mesylate (XI). Subsequent displacement in (XI) by potassium thioacetate furnished the thioacetate ester (XII).
| 【1】 Barrett, D.; Azami, H.; Matsuda, K.; et al.; Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems. Part III: Novel 2-alkyl substituents containing cationic heteroaromatics linked via a C-N bond. Bioorg Med Chem 1999, 7, 8, 1665. |
| 【2】 Murata, M.; Tsutsumi, H.; Matsuda, K.; Hattori, K.; Nakajima, T. (Fujisawa Pharmaceutical Co., Ltd.); Substd. 3-pyrrolidinylthio-carbapenems as antimicrobial agents. EP 0636133; JP 1995505650; WO 9321186 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12893 | Ethanethioic S-acid | C2H4OS | 详情 | 详情 | ||
| 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 | |
| (I) | 32605 | ((2S,4S)-1-benzyl-4-[[tert-butyl(dimethyl)silyl]oxy]pyrrolidinyl)methanol | C18H31NO2Si | 详情 | 详情 | |
| (II) | 32606 | (2S,4S)-1-benzyl-4-[[tert-butyl(dimethyl)silyl]oxy]-2-pyrrolidinecarbaldehyde | C18H29NO2Si | 详情 | 详情 | |
| (III) | 32607 | (2S,4S)-1-benzyl-4-[[tert-butyl(dimethyl)silyl]oxy]-2-vinylpyrrolidine; (3S,5S)-1-benzyl-5-vinylpyrrolidinyl tert-butyl(dimethyl)silyl ether | C19H31NOSi | 详情 | 详情 | |
| (IV) | 32608 | 2-((2R,4S)-1-benzyl-4-[[tert-butyl(dimethyl)silyl]oxy]pyrrolidinyl)-1-ethanol | C19H33NO2Si | 详情 | 详情 | |
| (V) | 32609 | 2-((2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]pyrrolidinyl)-1-ethanol | C12H27NO2Si | 详情 | 详情 | |
| (VII) | 32610 | allyl (2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate | C16H31NO4Si | 详情 | 详情 | |
| (VIII) | 32611 | allyl (2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-[(methylsulfonyl)oxy]ethyl]-1-pyrrolidinecarboxylate | C17H33NO6SSi | 详情 | 详情 | |
| (IX) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
| (X) | 32612 | allyl (2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-(1H-imidazol-1-yl)ethyl]-1-pyrrolidinecarboxylate | C19H33N3O3Si | 详情 | 详情 | |
| (XI) | 32613 | allyl (2R,4S)-2-[2-(1H-imidazol-1-yl)ethyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C14H21N3O5S | 详情 | 详情 | |
| (XII) | 31614 | (3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoic acid | C21H36ClNO5 | 详情 | 详情 |
合成路线2
Cyclization of diazo azetidinone (XIII) by means rhodium(II) octanoate dimer produced the azabicyclo ketone (XIV), which was converted to the phosphorylated carbapenem (XV) employing diphenylphosphorochloridate. Hydrolysis of the thioacetate ester (XII) with NaOMe gave the intermediate thiol (XVI), which was condensed with phosphate (XV) to yield the (pyrrolidinylthio)carbapenem (XVII). Quaternization of the imidazole nucleus of (XVII) with methyl iodide afforded imidazolium salt (XVIII). Then, both allyl ester and allyloxycarbonyl groups of (XVIII) were deprotected using tributyltin hydride and a palladium catalyst. Finally, the iodide salt was exchanged for the corresponding chloride employing an ion exchange resin.
| 【1】 Barrett, D.; Azami, H.; Matsuda, K.; et al.; Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems. Part III: Novel 2-alkyl substituents containing cationic heteroaromatics linked via a C-N bond. Bioorg Med Chem 1999, 7, 8, 1665. |
| 【2】 Murata, M.; Tsutsumi, H.; Matsuda, K.; Hattori, K.; Nakajima, T. (Fujisawa Pharmaceutical Co., Ltd.); Substd. 3-pyrrolidinylthio-carbapenems as antimicrobial agents. EP 0636133; JP 1995505650; WO 9321186 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 32614 | allyl (2R,4S)-4-(acetylsulfanyl)-2-[2-(1H-imidazol-1-yl)ethyl]-1-pyrrolidinecarboxylate | C15H21N3O3S | 详情 | 详情 | |
| (XIII) | 32615 | (4R)-1-(allyloxy)-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-1,3-dioxo-2-pentanediazonium | C13H18N3O5 | 详情 | 详情 | |
| (XIV) | 32616 | allyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C13H17NO5 | 详情 | 详情 | |
| (XV) | 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 | |
| (XVI) | 32618 | allyl (2R,4S)-2-[2-(1H-imidazol-1-yl)ethyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C13H19N3O2S | 详情 | 详情 | |
| (XVII) | 32619 | allyl (4R,5S,6S)-3-([(3S,5R)-1-[(allyloxy)carbonyl]-5-[2-(1H-imidazol-1-yl)ethyl]pyrrolidinyl]sulfanyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C26H34N4O6S | 详情 | 详情 | |
| (XVIII) | 32620 | 3-[2-[(2R,4S)-1-[(allyloxy)carbonyl]-4-([(4R,5S,6S)-2-[(allyloxy)carbonyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]sulfanyl)pyrrolidinyl]ethyl]-1-methyl-1H-imidazol-3-ium iodide | C27H37IN4O6S | 详情 | 详情 |