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【结 构 式】 
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【药物名称】 【化学名称】2-[3(S)-[2(R)-Benzyl-3-(N-hydroxyformamido)propionamido]-7,7-dimethyl-2-oxoperhydroazepin-1-yl]acetic acid 【CA登记号】 【 分 子 式 】C21H29N3O6 【 分 子 量 】419.48178 |
【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 reaction of (S)-2-amino-6-hydroxyhexanoic acid (I) with N-(ethoxycarbonyl)phthalimide (II) by means of Na2CO3 in water gives 6-hydroxy-2(S)-(phthalimido)hexanoic acid (III), which is esterified with benzyl bromide and Cs2CO3 in DMF yielding the benzyl ester (IV). The oxidation of the terminal OH group of (IV) with (COCl)2 in dichloromethane affords the aldehyde (V), which is methylated with AlMe3 in dichloromethane giving 6-hydroxy-2(S)-(phthalimido)heptanoic acid (VI). The oxidation of (VI) with oxalyl chloride as before yields the ketone (VII), which is methylated with TiCl4 and methylmagnesium chloride to provide the carbinol (VIII). The reaction of (VIII) with trimethylsilyl azide in dichloromethane gives the azido derivative (IX), which is cyclized by reduction with H2 over Pd/C in DMF yielding the perhydroazepinone (X). Elimination of phthalimido protecting group of (X) with hydrazine in methanol/dichloromethane affords 3(S)-amino-7,7-dimethylperhydroazepin-2-one (XI), which is protected with trityl chloride and TEA in dichloromethane to give the tritylamino compound (XII). The condensation of (XII) with ethyl 2-bromoacetate (XIII) by means of LHMDS, followed by deprotection with TFA affords the adduct (XIV) with a free amino group, which is acylated with 2(R)-benzyl-3-(benzyloxyamino)propionic acid (XV) by means of HOBT and EDAD in dichloromethane providing the amide (XVI). The formylation of (XVI) with formic acid and acetic anhydride gives the formamide (XVII), which is deprotected with H2 over Pd/C in ethanol yielding intermediate (XVIII). Finally, this compound is 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 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (I) | 22502 | (2S)-2-amino-6-hydroxyhexanoic acid | 6033-32-5 | C6H13NO3 | 详情 | 详情 |
| (II) | 10283 | ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide | 22509-74-6 | C11H9NO4 | 详情 | 详情 |
| (III) | 22512 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoic acid | C14H15NO5 | 详情 | 详情 | |
| (IV) | 26841 | benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoate | C21H21NO5 | 详情 | 详情 | |
| (V) | 26842 | benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxohexanoate | C21H19NO5 | 详情 | 详情 | |
| (VI) | 26843 | benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyheptanoate | C22H23NO5 | 详情 | 详情 | |
| (VII) | 26844 | benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxoheptanoate | C22H21NO5 | 详情 | 详情 | |
| (VIII) | 26845 | benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxy-6-methylheptanoate | C23H25NO5 | 详情 | 详情 | |
| (IX) | 26846 | benzyl (2S)-6-azido-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-methylheptanoate | C23H24N4O4 | 详情 | 详情 | |
| (X) | 26847 | 2-[(3S)-7,7-dimethyl-2-oxoazepanyl]-1H-isoindole-1,3(2H)-dione | C16H18N2O3 | 详情 | 详情 | |
| (XI) | 26848 | (3S)-3-amino-7,7-dimethyl-2-azepanone | C8H16N2O | 详情 | 详情 | |
| (XII) | 37281 | (3S)-7,7-dimethyl-3-(tritylamino)-2-azepanone | C27H30N2O | 详情 | 详情 | |
| (XIII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (XIV) | 37282 | ethyl 2-[(6S)-6-amino-2,2-dimethyl-7-oxoazepanyl]acetate | C12H22N2O3 | 详情 | 详情 | |
| (XV) | 37283 | (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid | C17H19NO3 | 详情 | 详情 | |
| (XVI) | 37284 | ethyl 2-[(6S)-6-([(2R)-2-benzyl-3-[(benzyloxy)amino]propanoyl]amino)-2,2-dimethyl-7-oxoazepanyl]acetate | C29H39N3O5 | 详情 | 详情 | |
| (XVII) | 37285 | ethyl 2-[(6S)-6-([(2R)-2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-2,2-dimethyl-7-oxoazepanyl]acetate | C30H39N3O6 | 详情 | 详情 | |
| (XVIII) | 37286 | ethyl 2-[(6S)-6-([(2R)-2-benzyl-3-[formyl(hydroxy)amino]propanoyl]amino)-2,2-dimethyl-7-oxoazepanyl]acetate | C23H33N3O6 | 详情 | 详情 |
合成路线2
The intermediate 2(R)-benzyl-3-(benzyloxyamino)propionic acid (XV) has been obtained as follows: The reaction of benzylmalonic acid (XIX) with aqueous formaldehyde and dimethylamine gives 2-benzyl-2-propenoic acid (XX), which is condensed with O-benzylhydroxylamine (XXI) in refluxing ethanol yielding racemic 2-benzyl-3-(benzyloxyamino)propionic acid (XXII). Finally, this compound is submitted to optical resolution with (1R,2S)(-)-ephedrine in acetonitrile to afford the chiral target intermediate (XV).
| 【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 |
|---|---|---|---|---|---|---|
| (XV) | 37283 | (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid | C17H19NO3 | 详情 | 详情 | |
| (XIX) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XX) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XXI) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XXII) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |