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【结 构 式】 
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【分子编号】23834 【品名】allyl (4S,5R,6S)-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-3-(hydroxymethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate 【CA登记号】 |
【 分 子 式 】C18H23NO7 【 分 子 量 】365.38316 【元素组成】C 59.17% H 6.34% N 3.83% O 30.65% |
合成路线1
该中间体在本合成路线中的序号：(XXX)Reaction of the acetoxy azetidinone (XIX) with methyl 2-(bromomethyl)butenoate (XX) in the presence of Zn produced adduct (XXI). Reduction of the ester group of (XXI) with DIBAL-H, followed by protection of the resulting allyl alcohol with trityl chloride gave (XXII). Further ozonolysis of (XXII) generated ketone (XXIII). Condensation of (XXIII) with allyl glyoxylate (XXIV) gave hemiaminal (XXV). After treatment of (XXV) with SOCl2, reaction with triphenylphosphine produced phosphorane (XXVI). Acid deprotection of the trityl and silyl groups of (XXVI), followed by acetylation with AcCl gave acetate ester (XXVII). The secondary hydroxyl group of (XXVII) was then protected with allyl chloroformate to afford carbonate (XXVIII). Then, deprotection of the acetate ester of (XXVIII) with methanolic NaOMe gave hydroxy ketone (XXIX). Finally, cyclization between keto and phosphorane groups of (XXIX) in boiling toluene furnished the carbapenem compound (XXX).
| 【1】 Dininno, F.P.; Dykstra, K.D.; Wildonger, K.J.; Blizzard, T.A.; Wilkening, R.R.; Hammond, M.L.; Ratcliffe, R.W.; Cama, L.D.; Synthesis and in vitro evaluation of 1beta-methyl-2-(sulfonamido) methyl-carbapenems: Discovery of a novel PBP2a-binding, anti-MRSA 1,8-naphthosultamyl pharmacophore. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-33. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (XX) | 30136 | methyl (Z)-2-(bromomethyl)-2-butenoate | C6H9BrO2 | 详情 | 详情 | |
| (XXI) | 30164 | methyl 2-[(1S)-1-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]ethyl]acrylate | C17H31NO4Si | 详情 | 详情 | |
| (XXII) | 30137 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S)-1-methyl-2-[(trityloxy)methyl]-2-propenyl]-2-azetidinone | C35H45NO3Si | 详情 | 详情 | |
| (XXIII) | 30138 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-1-methyl-2-oxo-3-(trityloxy)propyl]-2-azetidinone | C34H43NO4Si | 详情 | 详情 | |
| (XXIV) | 30139 | allyl 2-oxoacetate | C5H6O3 | 详情 | 详情 | |
| (XXV) | 30140 | allyl 2-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(1R)-1-methyl-2-oxo-3-(trityloxy)propyl]-4-oxoazetidinyl]-2-hydroxyacetate | C39H49NO7Si | 详情 | 详情 | |
| (XXVI) | 30141 | allyl 2-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(1R)-1-methyl-2-oxo-3-(trityloxy)propyl]-4-oxoazetidinyl]-2-(triphenylphosphoranylidene)acetate | C57H62NO6PSi | 详情 | 详情 | |
| (XXVII) | 30142 | allyl 2-[(2R,3S)-2-[(1R)-3-(acetoxy)-1-methyl-2-oxopropyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-2-(triphenylphosphoranylidene)acetate | C34H36NO7P | 详情 | 详情 | |
| (XXVIII) | 30143 | allyl 2-[(2R,3S)-2-[(1R)-3-(acetoxy)-1-methyl-2-oxopropyl]-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-4-oxoazetidinyl]-2-(triphenylphosphoranylidene)acetate | C38H40NO9P | 详情 | 详情 | |
| (XXIX) | 30144 | allyl 2-[(2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-2-[(1R)-3-hydroxy-1-methyl-2-oxopropyl]-4-oxoazetidinyl]-2-(triphenylphosphoranylidene)acetate | C36H38NO8P | 详情 | 详情 | |
| (XXX) | 23834 | allyl (4S,5R,6S)-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-3-(hydroxymethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C18H23NO7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXX)Mitsunobu coupling of hydroxymethyl carbapenem (XXX) with protected sultam (VIIIa) produced adduct (XLIII), which was desilylated with trifluoromethanesulfonic acid to give alcohol (XLIV). Conversion of (XLIV) to the corresponding triflate, followed by condensation with 1-carbamoylmethyl-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate (XLV) furnished bisam-monium salt (XLVI). Finally, cleavage of the allyl groups of (XLVI) in the presence of Pd catalyst yielded the title compound.
| 【1】 Morgan, J.D.; Wilkenning, R.R.; Santorelli, G.M.; Parker, D.L. Jr.; Hammond, M.L.; Wildonger, K.J.; Ratcliffe, R.W.; Blizzard, T.A.; Waddell, S.T.; Synthesis and properties of 2-(naphthosultamyl)met. Bioorg Med Chem Lett 1999, 9, 5, 679. |
| 【2】 Wilkening, R.R.; Ratcliffe, R.W.; Blizzard, T.A. (Merck & Co., Inc.); Carbapenem antibacterial cpds., compsns. containing such cpds. and methods of treatment. EP 0906313; JP 1999508279; US 5756725; WO 9740048 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIa) | 23835 | 6-[3-(trimethylsilyl)propyl]-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione; 6-[2-[(trimethylsilyl)oxy]ethyl]-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione | C15H19NO3SSi | 详情 | 详情 | |
| (XXX) | 23834 | allyl (4S,5R,6S)-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-3-(hydroxymethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C18H23NO7 | 详情 | 详情 | |
| (XLIII) | 30155 | allyl (4S,5R,6S)-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-3-[[1,1-dioxo-6-[3-(trimethylsilyl)propyl]-2H-naphtho[1,8-cd]isothiazol-2(1H)-yl]methyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C34H42N2O8SSi | 详情 | 详情 | |
| (XLIV) | 23837 | allyl (4S,5R,6S)-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-3-[[6-(2-hydroxyethyl)-1,1-dioxo-2H-naphtho[1,8-cd]isothiazol-2(1H)-yl]methyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C30H32N2O9S | 详情 | 详情 | |
| (XLV) | 30156 | 1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate | C9H16F3N3O4S | 详情 | 详情 | |
| (XLVI) | 30157 | 1-[2-(2-[[(4S,5R,6S)-2-[(allyloxy)carbonyl]-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]methyl]-1,1-dioxo-1,2-dihydro-2H-naphtho[1,8-cd]isothiazol-6-yl)ethyl]-4-(2-amino-2-oxoethyl)-1,4-diazonia | C40H47F6N5O15S3 | 详情 | 详情 |