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【结 构 式】 
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【分子编号】37276 【品名】2-benzyl-N-(benzyloxy)-N-formyl-beta-alanine 【CA登记号】 |
【 分 子 式 】C18H19NO4 【 分 子 量 】313.3532 【元素组成】C 68.99% H 6.11% N 4.47% O 20.42% |
合成路线1
该中间体在本合成路线中的序号：(IX)The reaction of N-Boc-L-serine (I) with 2-fluoronitrobenzene (II) by means of NaH in DMF gives N-Boc-O-(2-nitrophenyl)-L-serine (III), which is reduced with H2 over Pd/C in methanol yielding the 2-aminophenyl derivative (IV). The cyclization of (IV) by means of EDAC in DMF affords the benzoxazepinone (V), which is condensed with benzyl 2-bromoacetate (VI) by means of LHMDS in THF providing the benzoxazepinone acetic ester (VII). The deprotection of the carbamate group of (VII) with HCl in dioxane affords (VIII) with a free amino group that is condensed with 2-benzyl-3-[N-(benzyloxy)-N-formylamino]propionic acid (IX) by means of EDAC in dichloromethane giving the corresponding amide (X). The deprotection of the benzyl groups of (X) with H2 over Pd/C in methanol yields the expected mixture of diastereomers that is resolved by preparative HPLC to afford the target compound.
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 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) | 20126 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid | C8H15NO5 | 详情 | 详情 | |
| (II) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (III) | 37271 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-nitrophenoxy)propionic acid | C14H18N2O7 | 详情 | 详情 | |
| (IV) | 37272 | (2S)-3-(2-aminophenoxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C14H20N2O5 | 详情 | 详情 | |
| (V) | 37273 | tert-butyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-ylcarbamate | C14H18N2O4 | 详情 | 详情 | |
| (VI) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (VII) | 37274 | benzyl 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C23H26N2O6 | 详情 | 详情 | |
| (VIII) | 37275 | benzyl 2-[(3S)-3-amino-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C18H18N2O4 | 详情 | 详情 | |
| (IX) | 37276 | 2-benzyl-N-(benzyloxy)-N-formyl-beta-alanine | C18H19NO4 | 详情 | 详情 | |
| (X) | 37278 | benzyl 2-[(3S)-3-([2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C36H35N3O7 | 详情 | 详情 | |
| (XI) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XII) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XIII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XIV) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The reaction of N-Boc-L-serine (I) with 2-fluoronitrobenzene (II) by means of NaH in DMF gives N-Boc-O-(2-nitrophenyl)-L-serine (III), which is reduced with H2 over Pd/C in methanol yielding the 2-aminophenyl derivative (IV). The cyclization of (IV) by means of EDAC in DMF affords the benzoxazepinone (V), which is condensed with benzyl 2-bromoacetate (VI) by means of LHMDS in THF providing the benzoxazepinone acetic ester (VII). The deprotection of the carbamate group of (VII) with HCl in dioxane affords (VIII) with a free amino group that is condensed with 2-benzyl-3-[N-(benzyloxy)-N-formylamino]propionic acid (IX) by means of EDAC in dichloromethane giving the corresponding amide (X). The deprotection of the benzyl groups of (X) with H2 over Pd/C in methanol yields the expected mixture of diastereomers that is resolved by preparative HPLC to afford the target compound. The intermediate 2-benzyl-3-[N-(benzyloxy)-N-formylamino]propionic acid (IX) has been obtained as follows: The reaction of benzylmalonic acid (XI) with aqueous formaldehyde and dimethylamine gives 2-benzyl-2-propenoic acid (XII), which is condensed with O-benzylhydroxylamine (XIII) in refluxing ethanol yielding 2-benzyl-3-(benzyloxyamino)propionic acid (XIV). Finally, this compound is N-formylated with formic acid/acetic anhydride to afford the desired intermediate (IX).
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 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) | 20126 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid | C8H15NO5 | 详情 | 详情 | |
| (II) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (III) | 37271 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-nitrophenoxy)propionic acid | C14H18N2O7 | 详情 | 详情 | |
| (IV) | 37272 | (2S)-3-(2-aminophenoxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C14H20N2O5 | 详情 | 详情 | |
| (V) | 37273 | tert-butyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-ylcarbamate | C14H18N2O4 | 详情 | 详情 | |
| (VI) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (VII) | 37274 | benzyl 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C23H26N2O6 | 详情 | 详情 | |
| (VIII) | 37275 | benzyl 2-[(3S)-3-amino-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C18H18N2O4 | 详情 | 详情 | |
| (IX) | 37276 | 2-benzyl-N-(benzyloxy)-N-formyl-beta-alanine | C18H19NO4 | 详情 | 详情 | |
| (X) | 37278 | benzyl 2-[(3S)-3-([2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C36H35N3O7 | 详情 | 详情 | |
| (XI) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XII) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XIII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XIV) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |