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【结 构 式】 
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【分子编号】32616 【品名】allyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate 【CA登记号】 |
【 分 子 式 】C13H17NO5 【 分 子 量 】267.28172 【元素组成】C 58.42% H 6.41% N 5.24% O 29.93% |
合成路线1
该中间体在本合成路线中的序号：(XIV)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 |
合成路线2
该中间体在本合成路线中的序号：(II)MK-0826 can be synthesized as follows: The cyclization of 2-diazo-4-[3-(1-hydroxyethyl)-4-oxoazetidin-2-yl]-3-oxopentanoic acid allyl ester (I) by means of rhodium octanoate gives the 2-oxocarbapenam derivative (II), which by reaction with chlorophosphoric acid diphenyl ester (III) and DIEA in acetonitrile yields the enol phosphate (IV). Condensation of (IV) with the sulfanylpyrrolidine (V) by means of DIEA in acetonitrile affords the corresponding addition compound MK-0826 diallyl ester (VI), which is finally deprotected by means of Meldrum's acid and Pd(PPh3)4 in DMF/THF and converted to the sodium salt.
| 【1】 Betts, M.J.; Davies, G.M.; Swain, M.L. (AstraZeneca plc); Carbapenems containing a carboxy substd. phenyl group, processes for their preparation, intermediates and use as antibiotics. EP 0579826; JP 1994506704; US 5478820; US 5652233; US 5856321; WO 9315078 . |
| 【2】 Leeson, P.A.; Rabasseda, X.; Castañer, J.; Sorbera, L.A.; MK-0826. Drugs Fut 2000, 25, 8, 795. |
| 【3】 Houghton, P.; Williams, J.M.; Skerlj, R.; Brands, K.M.J. (Merck & Co., Inc.); Process for synthesizing carbapenem antibiotics. WO 9945010 . |
| 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) | 39645 | allyl (4R)-2-diazo-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate | C13H17N3O5 | 详情 | 详情 | |
| (II) | 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 | |
| (III) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (IV) | 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 | |
| (V) | 39646 | allyl (2S,4S)-2-([3-[(allyloxy)carbonyl]anilino]carbonyl)-4-sulfanyl-1-pyrrolidinecarboxylate | C19H22N2O5S | 详情 | 详情 | |
| (VI) | 39647 | allyl (4R,5S,6S)-3-[[(3S,5S)-1-[(allyloxy)carbonyl]-5-([3-[(allyloxy)carbonyl]anilino]carbonyl)pyrrolidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C32H37N3O9S | 详情 | 详情 |