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【结 构 式】

【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%
与该中间体有关的原料药合成路线共 2 条
合成路线1合成路线2

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.

参考文献 中间体
合成目标
【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).

参考文献 中间体
合成目标
【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
Extended Information