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【结 构 式】 
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【分子编号】28418 【品名】(2R)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid 【CA登记号】 |
【 分 子 式 】C10H19NO3Si 【 分 子 量 】229.3513 【元素组成】C 52.37% H 8.35% N 6.11% O 20.93% Si 12.25% |
合成路线1
该中间体在本合成路线中的序号：(I)Silylated 4-oxoazetidine-2-carboxylic acid (I) was converted to the mixed anhydride with isobutyl chloroformate, and then reduced to alcohol (II) with NaBH4. Subsequent Mitsunobu coupling of (II) with mercaptotetrazole (III) provided thioether (IV). Desilylation of (IV) was then achieved by treatment with CsF in MeOH to give (V). Reaction of 4-(trifluoromethyl)benzyl chloride (VI) with methylamine afforded secondary amine (VII). This was reacted with phosgene and diisopropyl ethylamine to produce the carbamoyl chloride (VIII). Finally, condensation of this chloride with azetidinone (V) in the presence of lithium bis(trimethylsilyl)amide furnished the target urea.
| 【1】 Yoakim, C.; Ogilvie, W.W.; Cameron, D.R.; Chabot, C.; Grand-Maitre, C.; Guse, I.; Hache, B.; Kawai, S.; Naud, J.; O'Meara, J.A.; Plante, R.; Deziel, R.; Potent beta-lactam inhibitors of human cytomegalovirus protease. Antivir Chem Chemother 1998, 9, 5, 379. |
| 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) | 28418 | (2R)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid | C10H19NO3Si | 详情 | 详情 | |
| (II) | 28419 | (4R)-1-[tert-butyl(dimethyl)silyl]-4-(hydroxymethyl)-2-azetidinone | C10H21NO2Si | 详情 | 详情 | |
| (III) | 28420 | 5-Mercapto-1-methyl-1H-tetrazole; 1-Methyl-1H-1,2,3,4-tetraazol-5-ylhydrosulfide | 13183-79-4 | C2H4N4S | 详情 | 详情 |
| (IV) | 28421 | (4R)-1-[tert-butyl(dimethyl)silyl]-4-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-2-azetidinone | C12H23N5OSSi | 详情 | 详情 | |
| (V) | 28422 | (4R)-4-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-2-azetidinone | C6H9N5OS | 详情 | 详情 | |
| (VI) | 28423 | 1-(chloromethyl)-4-(trifluoromethyl)benzene | 939-99-1 | C8H6ClF3 | 详情 | 详情 |
| (VII) | 28424 | N-methyl-N-[4-(trifluoromethyl)benzyl]amine | C9H10F3N | 详情 | 详情 | |
| (VIII) | 28425 | 1-[[(chlorocarbonyl)(methyl)amino]methyl]-4-(trifluoromethyl)benzene | C10H9ClF3NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Silylated 4-oxoazetidine-2-carboxylic acid (I) was converted to the mixed anhydride with isobutyl chloroformate, and then reduced to alcohol (II) with NaBH4. Subsequent Mitsunobu coupling of (II) with mercaptotetrazole (III) provided thioether (IV). Desilylation of (IV) was then achieved by treatment with CsF in MeOH to give (V). Reaction of 4-nitrobenzyl chloride (VI) with methylamine afforded secondary amine (VII). This was reacted with phosgene and diisopropyl ethylamine to produce the carbamoyl chloride (VIII). Finally, condensation of this chloride with azetidinone (V) in the presence of lithium bis(trimethylsilyl)amide furnished the target urea.
| 【1】 Yoakim, C.; Ogilvie, W.W.; Cameron, D.R.; Chabot, C.; Grand-Maitre, C.; Guse, I.; Hache, B.; Kawai, S.; Naud, J.; O'Meara, J.A.; Plante, R.; Deziel, R.; Potent beta-lactam inhibitors of human cytomegalovirus protease. Antivir Chem Chemother 1998, 9, 5, 379. |
| 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) | 28418 | (2R)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid | C10H19NO3Si | 详情 | 详情 | |
| (II) | 28419 | (4R)-1-[tert-butyl(dimethyl)silyl]-4-(hydroxymethyl)-2-azetidinone | C10H21NO2Si | 详情 | 详情 | |
| (III) | 28420 | 5-Mercapto-1-methyl-1H-tetrazole; 1-Methyl-1H-1,2,3,4-tetraazol-5-ylhydrosulfide | 13183-79-4 | C2H4N4S | 详情 | 详情 |
| (IV) | 28421 | (4R)-1-[tert-butyl(dimethyl)silyl]-4-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-2-azetidinone | C12H23N5OSSi | 详情 | 详情 | |
| (V) | 28422 | (4R)-4-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-2-azetidinone | C6H9N5OS | 详情 | 详情 | |
| (VI) | 22580 | 1-(chloromethyl)-4-nitrobenzene | 100-14-1 | C7H6ClNO2 | 详情 | 详情 |
| (VII) | 28426 | N-methyl(4-nitrophenyl)methanamine | C8H10N2O2 | 详情 | 详情 | |
| (VIII) | 28427 | 1-[[(chlorocarbonyl)(methyl)amino]methyl]-4-nitrobenzene | C9H9ClN2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Alkylation of the dianion of azetidinonecarboxylic acid (I) with 2-ethoxybenzyl bromide (II) in cold THF affords (III). Oxidative cleavage of the carboxyl group of (III) using lead tetraacetate and HOAc provides the acetate ester (IV), which is desilylated to (V) with tetrabutylammonium fluoride in THF. Azetidinone (V) is coupled with benzhydryl 4-hydroxybenzoate (VI) to yield ether (VII). Curtius rearrangement of carboxylic acid (VIII) provides isocyanate (IX). Coupling between isocyanate (IX) and azetidine (VII) gives rise to urea (X). The benzhydryl ester group of (X) is finally cleaved by treatment with trifluoroacetic acid in the presence of anisole.
| 【1】 Nakajima, M.; Kii, M.; Uenaka, M. (Shionogi & Co. Ltd.); Monocyclic beta-lactam cpds. and chymase inhibitors containing the same. EP 1099690; WO 0005204 . |
| 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) | 28418 | (2R)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid | C10H19NO3Si | 详情 | 详情 | |
| (II) | 56414 | 2-(bromomethyl)phenyl ethyl ether; 1-(bromomethyl)-2-ethoxybenzene | C9H11BrO | 详情 | 详情 | |
| (III) | 56415 | (2R,3S)-1-[tert-butyl(dimethyl)silyl]-3-(2-ethoxybenzyl)-4-oxo-2-azetidinecarboxylic acid | C19H29NO4Si | 详情 | 详情 | |
| (IV) | 56416 | (2S,3S)-1-[tert-butyl(dimethyl)silyl]-3-(2-ethoxybenzyl)-4-oxoazetidinyl acetate | C20H31NO4Si | 详情 | 详情 | |
| (V) | 56417 | (2S,3S)-3-(2-ethoxybenzyl)-4-oxoazetidinyl acetate | C14H17NO4 | 详情 | 详情 | |
| (VI) | 56418 | benzhydryl 4-hydroxybenzoate | C20H16O3 | 详情 | 详情 | |
| (VII) | 56419 | benzhydryl 4-{[(2S,3S)-3-(2-ethoxybenzyl)-4-oxoazetidinyl]oxy}benzoate | C32H29NO5 | 详情 | 详情 | |
| (VIII) | 43492 | 2-chloro-4-fluorobenzonitrile | 60702-69-4 | C7H3ClFN | 详情 | 详情 |
| (IX) | 56420 | 1-[isocyanato(4-methylphenyl)methyl]-4-methylbenzene; bis(4-methylphenyl)methyl isocyanate | C16H15NO | 详情 | 详情 | |
| (X) | 56421 | benzhydryl 4-{[(2S,3S)-1-({[bis(4-methylphenyl)methyl]amino}carbonyl)-3-(2-ethoxybenzyl)-4-oxoazetidinyl]oxy}benzoate | C48H44N2O6 | 详情 | 详情 |