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【结 构 式】 
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【药物名称】 【化学名称】(4S,7S,12bR)-7(S)-[2(R)-Benzyl-3-(N-hydroxyformamido)propionamido]-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a]benzazepine-4-carboxylic acid 【CA登记号】 【 分 子 式 】C26H29N3O6 【 分 子 量 】479.53753 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors, Neprilysin Inhibitors |
合成路线1
The condensation of N-phthaloyl-L-phenylalanine (I) with 2(S)-amino-6-hydroxyhexanoic acid methyl ester (II) by means of HOBT and EDAC in DMF/dichloromethane gives the dipeptide (III), which is oxidized at the terminal OH with (COCl)2 in dichloromethane yielding the aldehyde (IV). The cyclization of (IV) with TFA in dichloromethane affords the tetrahydropyridine (V), which is cyclized again by means of trifluoromethanesulfonic acid in dichloromethane to provide the tricyclic carboxylic acid (VI). The esterification of (VI) with PhCH2Br and Cs2CO3 in DMF gives the benzyl ester (VII), which is treated with hydrazine to eliminate the phthalimido group and yielding intermediate (VIII). The reaction of the free amino group of (VIII) with 2(R)-benzyl-3-(benzyloxyamino)propionic acid (IX) by means of HOBT and EDAC in dichloromethane affords the amide (X), which is formylated with formic acid and acetic anhydride to provide the formamide (XI). Finally, this compound is debenzylated with H2 over Pd/C in methanol to furnish 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 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (I) | 37293 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropionic acid | 5123-55-7 | C17H13NO4 | 详情 | 详情 |
| (II) | 22488 | methyl (2S)-2-amino-6-hydroxyhexanoate | C7H15NO3 | 详情 | 详情 | |
| (III) | 37294 | methyl (2S)-2-[[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]amino]-6-hydroxyhexanoate | C24H26N2O6 | 详情 | 详情 | |
| (IV) | 37295 | methyl (2S)-2-[[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]amino]-6-oxohexanoate | C24H24N2O6 | 详情 | 详情 | |
| (V) | 37296 | methyl (2S)-1-[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylate | C24H22N2O5 | 详情 | 详情 | |
| (VI) | 37297 | (4S,7S)-7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxo-2,3,4,6,7,8-hexahydropyrido[2,1-a][2]benzazepine-4-carboxylic acid | C23H18N2O5 | 详情 | 详情 | |
| (VII) | 37298 | benzyl (4S,7S)-7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxo-2,3,4,6,7,8-hexahydropyrido[2,1-a][2]benzazepine-4-carboxylate | C30H24N2O5 | 详情 | 详情 | |
| (VIII) | 37299 | benzyl (4S,7S)-7-amino-6-oxo-2,3,4,6,7,8-hexahydropyrido[2,1-a][2]benzazepine-4-carboxylate | C22H22N2O3 | 详情 | 详情 | |
| (IX) | 37283 | (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid | C17H19NO3 | 详情 | 详情 | |
| (X) | 37300 | benzyl (4S,7S)-7-([(2R)-2-benzyl-3-[(benzyloxy)amino]propanoyl]amino)-6-oxo-2,3,4,6,7,8-hexahydropyrido[2,1-a][2]benzazepine-4-carboxylate | C39H39N3O5 | 详情 | 详情 | |
| (XI) | 37301 | benzyl (4S,7S)-7-([(2R)-2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-6-oxo-2,3,4,6,7,8-hexahydropyrido[2,1-a][2]benzazepine-4-carboxylate | C40H39N3O6 | 详情 | 详情 |
合成路线2
The intermediate 2(R)-benzyl-3-(benzyloxyamino)propionic acid (IX) has been obtained as follows: The reaction of benzylmalonic acid (XII) with aqueous formaldehyde and dimethylamine gives 2-benzyl-2-propenoic acid (XIII), which is condensed with O-benzylhydroxylamine (XIV) in refluxing ethanol yielding racemic 2-benzyl-3-(benzyloxyamino)propionic acid (XV). Finally, this compound is submitted to optical resolution with (1R,2S)(-)-ephedrine in acetonitrile to afford the chiral target 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 |
|---|---|---|---|---|---|---|
| (IX) | 37283 | (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid | C17H19NO3 | 详情 | 详情 | |
| (XII) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XIII) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XIV) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XV) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |