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【结 构 式】 
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【分子编号】26847 【品名】2-[(3S)-7,7-dimethyl-2-oxoazepanyl]-1H-isoindole-1,3(2H)-dione 【CA登记号】 |
【 分 子 式 】C16H18N2O3 【 分 子 量 】286.3306 【元素组成】C 67.12% H 6.34% N 9.78% O 16.76% |
合成路线1
该中间体在本合成路线中的序号：(VIII)(S)-6-Hydroxy-2-phthalimidohexanoic acid (I) was converted to benzyl ester (II) by treatment with benzyl bromide and Cs2CO3. Subsequent Swern oxidation of the alcohol function of (II) followed by reaction of the resulting aldehyde (III) with Me3Al afforded secondary alcohol (IV). A new Swern oxidation of (IV) provided ketone (V). Introduction of a further methyl group to give the tertiary alcohol (VI) was achieved by means of methyltitanium trichloride, generated in situ from MeLi and TiCl4. Azide (VII) was then obtained by treatment of (VI) with Me3SiN3 and BF3-Et2O. Palladium-catalyzed hydrogenation effected both reduction of the azide to amine and hydrogenolysis of the benzyl ester. Then, EDC-mediated cyclization of the intermediate amino acid gave azepinone (VIII).
| 【1】 Robl, J.A.; Sulsky, R.; Sieber-McMaster, E.; Ryono DE; Cimarusti MP; Simpkins LM; Karanewsky, D.S.; Chao, S.; Asaad, M.M.; Seymour, A.A.; Fox, M.E.; Smith, P.L.; Trippodo, N.C.; Vasopeptidase inhibitors: Incorporation of geminal and spirocyclic substituted azepinones in mercaptoacyl dipeptides. J Med Chem 1999, 42, 2, 305. |
| 【2】 Karanewsky, D.S.; Barrish, J.C.; Petrillo, E.W. Jr.; Robl, J.A.; Ryono, D.E. (Bristol-Myers Squibb Co.); Dual action inhibitors. EP 0599444; US 5552397 . |
| 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) | 22512 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoic acid | C14H15NO5 | 详情 | 详情 | |
| (II) | 26841 | benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoate | C21H21NO5 | 详情 | 详情 | |
| (III) | 26842 | benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxohexanoate | C21H19NO5 | 详情 | 详情 | |
| (IV) | 26843 | benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyheptanoate | C22H23NO5 | 详情 | 详情 | |
| (V) | 26844 | benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxoheptanoate | C22H21NO5 | 详情 | 详情 | |
| (VI) | 26845 | benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxy-6-methylheptanoate | C23H25NO5 | 详情 | 详情 | |
| (VII) | 26846 | benzyl (2S)-6-azido-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-methylheptanoate | C23H24N4O4 | 详情 | 详情 | |
| (VIII) | 26847 | 2-[(3S)-7,7-dimethyl-2-oxoazepanyl]-1H-isoindole-1,3(2H)-dione | C16H18N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Removal of phthaloyl protecting group of (VIII) provided amine (IX), which was protected as the tert-butyl carbamate (X) with Boc2O. Alkylation at the lactam nitrogen atom of (X) was then achieved employing LiN(SiMe3)2 and ethyl bromoacetate to afford (XI), which was deprotected under acidic conditions to furnish amine (XII). Alternatively, amine (IX) could be protected using a N-trityl group. Coupling of amine (XII) with 2-(acetylthio)benzenepropanoic acid (XIII) using either BOP or EDC as the condensing reagents produced amide (XIV). Finally, both ethyl ester and acetyl thioester of (XIV) were hydrolyzed with NaOH to yield the title compound.
| 【1】 Robl, J.A.; Sulsky, R.; Sieber-McMaster, E.; Ryono DE; Cimarusti MP; Simpkins LM; Karanewsky, D.S.; Chao, S.; Asaad, M.M.; Seymour, A.A.; Fox, M.E.; Smith, P.L.; Trippodo, N.C.; Vasopeptidase inhibitors: Incorporation of geminal and spirocyclic substituted azepinones in mercaptoacyl dipeptides. J Med Chem 1999, 42, 2, 305. |
| 【2】 Karanewsky, D.S.; Barrish, J.C.; Petrillo, E.W. Jr.; Robl, J.A.; Ryono, D.E. (Bristol-Myers Squibb Co.); Dual action inhibitors. EP 0599444; US 5552397 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 26847 | 2-[(3S)-7,7-dimethyl-2-oxoazepanyl]-1H-isoindole-1,3(2H)-dione | C16H18N2O3 | 详情 | 详情 | |
| (IX) | 26848 | (3S)-3-amino-7,7-dimethyl-2-azepanone | C8H16N2O | 详情 | 详情 | |
| (X) | 26849 | tert-butyl (3S)-7,7-dimethyl-2-oxoazepanylcarbamate | C13H24N2O3 | 详情 | 详情 | |
| (XI) | 26850 | methyl 2-[(6S)-6-[(tert-butoxycarbonyl)amino]-2,2-dimethyl-7-oxoazepanyl]acetate | C16H28N2O5 | 详情 | 详情 | |
| (XII) | 26851 | methyl 2-[(6S)-6-amino-2,2-dimethyl-7-oxoazepanyl]acetate | C11H20N2O3 | 详情 | 详情 | |
| (XIII) | 22493 | (2S)-2-(acetylsulfanyl)-3-phenylpropionic acid | C11H12O3S | 详情 | 详情 | |
| (XIV) | 26852 | methyl 2-((6S)-6-[[(2S)-2-(acetylsulfanyl)-3-phenylpropanoyl]amino]-2,2-dimethyl-7-oxoazepanyl)acetate | C22H30N2O5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)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 |