【结 构 式】 |
【分子编号】30511 【品名】1,3,4,5-tetrahydro-2H-1-benzazepin-2-one 【CA登记号】 |
【 分 子 式 】C10H11NO 【 分 子 量 】161.20348 【元素组成】C 74.51% H 6.88% N 8.69% O 9.92% |
合成路线1
该中间体在本合成路线中的序号:(I)The reaction of 2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (I) with PCl5 in hot xylene gives 3,3-dichloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (II), which is treated with sodium acetate and reduced with H2 over Pd/C in acetic acid yielding 3-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (III). The reaction of (III) with sodium azide in DMSO affords 3-azido-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (IV), which is condensed with benzyl bromoacetate (V) by means of NaH in DMF giving 3-azido-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VI). The treatment of (VI) with Raney-Ni in ethanol-water yields 3-amino-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol affording 3-amino-1-(carboxymethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VIII). Finally, this compound is condensed with ethyl 3-benzylpyruvate (IX) by means of sodium cyanoborohydride in methanol acetic acid.
【1】 Watthey, J.W.H. (Novartis AG); Benzazepin-2-ones, process for their preparation, pharmaceutical preparations containing these compounds and the compounds for therapeutical use. EP 0072352; GB 2103614; JP 8338260 . |
【2】 Castaner, J.; Serradell, M.N.; CGS-14824 A. Drugs Fut 1984, 9, 5, 317. |
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) | 30511 | 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H11NO | 详情 | 详情 | |
(II) | 30512 | 3,3-dichloro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H9Cl2NO | 详情 | 详情 | |
(III) | 30513 | 3-chloro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10ClNO | 详情 | 详情 | |
(IV) | 20891 | 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10N4O | 详情 | 详情 | |
(V) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
(VI) | 30514 | benzyl 2-(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C19H18N4O3 | 详情 | 详情 | |
(VII) | 30515 | benzyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C19H20N2O3 | 详情 | 详情 | |
(VIII) | 30516 | 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetic acid | C12H14N2O3 | 详情 | 详情 | |
(IX) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(IV)Sodium azide (I) is treated with sulfuric acid to give hydrazoic acid (II), which is condensed with 1-tetralone (III) in hot aqueous sulfuric acid yielding 2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (IV). The bromination of (IV) with Br2 in chloroform affords the 3-bromo derivative (V), which is treated with sodium azide in DMSO to give the corresponding azido derivative (VI). The condensation of (VI) with ethyl 2-bromoacetate (VII) by means of KOH and tetrabutylammonium bromide in THF yields the adduct (VIII). The azido group of (VIII) is reduced with H2 over Pd/C in ethanol the amine (IX) as a racemic mixture, which is submitted to optical resolution with L-tartaric acid affording the desired (S)-enantiomer (X). The condensation of intermediate (X) with 2(R)-benzyl-3-benzyloxyamino)propionic acid (XI) by means of HOBT and EDAC in dichloromethane provides the amide (XII), which is formylated with formic acid and acetic anhydride yielding the formamide (XIII). The debenzylation of (XIII) with H2 over Pd/C in methanol affords the intermediate (XIV), which is finally hydrolyzed with NaOH in methanol.
【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 |
---|---|---|---|---|---|---|
(II) | 37288 | 1H-triazirine | HN3 | 详情 | 详情 | |
(III) | 20720 | 3,4-dihydro-1(2H)-naphthalenone | 529-34-0 | C10H10O | 详情 | 详情 |
(IV) | 30511 | 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H11NO | 详情 | 详情 | |
(V) | 20723 | 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10BrNO | 详情 | 详情 | |
(VI) | 20891 | 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10N4O | 详情 | 详情 | |
(VII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
(VIII) | 20893 | ethyl 2-(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C14H16N4O3 | 详情 | 详情 | |
(IX) | 37292 | ethyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C14H18N2O3 | 详情 | 详情 | |
(X) | 20894 | ethyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | 109010-60-8 | C14H18N2O3 | 详情 | 详情 |
(XI) | 37283 | (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid | C17H19NO3 | 详情 | 详情 | |
(XII) | 37289 | ethyl 2-[(3S)-3-([(2R)-2-benzyl-3-[(benzyloxy)amino]propanoyl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C31H35N3O5 | 详情 | 详情 | |
(XIII) | 37290 | ethyl 2-[(3S)-3-([(2R)-2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C32H35N3O6 | 详情 | 详情 | |
(XIV) | 37291 | ethyl 2-[(3S)-3-([(2R)-2-benzyl-3-[formyl(hydroxy)amino]propanoyl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C25H29N3O6 | 详情 | 详情 |