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【结 构 式】 
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【分子编号】22512 【品名】(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoic acid 【CA登记号】 |
【 分 子 式 】C14H15NO5 【 分 子 量 】277.27684 【元素组成】C 60.64% H 5.45% N 5.05% O 28.85% |
合成路线1
该中间体在本合成路线中的序号：(XXVI)3) The condensation of 2(S)-phthalimido-4-(triphenylmethoxy)butyric acid (XVII) with 2(S)-amino-6,6-dimethoxyhexanoic acid methyl ester (XVIII) by means of BOP in methylene chloride gives the corresponding amide (XIX), which is treated with p-toluenesulfonic acid in methanol to eliminate the trityl group, yielding (XX) with a free hydroxy group. The reaction of (XX) with thioacetic acid by means of triphenylphosphine/diisopropyl azidodicarboxylate in THF affords the thioacetate (XXI), which is cyclized with sodium methoxide in methanol as before, giving the protected pyridothiazepinone (XXII). Finally, this compound is deprotected with hydrazine in methanol to afford the previously reported intermediate (VI). 4) The intermediates 2(S)-phthalimido-4-(triphenylmethoxy)butyric acid (XVII) and 2(S)-amino-6,6-dimethoxyhexanoic acid methyl ester (XVIII) have been obtained as follows: 4a) The condensation of L-homoserine (XXIII) with phthalimide-N-carboxylic acid ethyl ester (XXIV) by means of Na2CO3 in water gives 4-hydroxy-2(S)-phthalimidobutyric acid (XXV), which is then treated with trityl chloride and triethylamine in chloroform to yield intermediate (XVII). 4b) The condensation of 6-hydroxy-L-norleucine (XVI) with phthalimide (XXIV) as before gives 6-hydroxy-2(S)-phthalimidohexanoic acid (XXVI), which is esterified with methyl iodide/Cs2CO3 in DMF to yield the methyl ester (XXVII). The oxidation of (XXVII) with oxalyl chloride in dichloromethane affords aldehyde (XXVIII), which is treated with trimethyl orthoformate/p-toluenesulfonic acid to give the dimethylketal (XXIX). Finally, this compound is deprotected with hydrazine in methanol, yielding intermediate (XVIII).
| 【1】 Graul, A.; Castañer, J.; Leeson, P.; Omapatrilat. Drugs Fut 1999, 24, 3, 269. |
| 【2】 Robl, J.A.; Kronenthal, D.R.; Goderey, J.D. Jr. (Bristol-Myers Squibb Co.); Bicyclic carboxylic acids and their derivs. as NEP and ACE inhibitors. EP 0629627; JP 1995048259; US 5508272 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 22492 | methyl (4S,7S,10aS)-4-amino-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate | C11H18N2O3S | 详情 | 详情 | |
| (XVI) | 22502 | (2S)-2-amino-6-hydroxyhexanoic acid | 6033-32-5 | C6H13NO3 | 详情 | 详情 |
| (XVII) | 22503 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-(trityloxy)butyric acid | C31H25NO5 | 详情 | 详情 | |
| (XVIII) | 22504 | methyl (2S)-2-amino-6,6-dimethoxyhexanoate | C9H19NO4 | 详情 | 详情 | |
| (XIX) | 22505 | methyl (2S)-2-[[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-(trityloxy)butanoyl]amino]-6,6-dimethoxyhexanoate | C40H42N2O8 | 详情 | 详情 | |
| (XX) | 22506 | methyl (2S)-2-[[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-hydroxybutanoyl]amino]-6,6-dimethoxyhexanoate | C21H28N2O8 | 详情 | 详情 | |
| (XXI) | 22507 | methyl (2S)-2-[[(2S)-4-(acetylsulfanyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butanoyl]amino]-6,6-dimethoxyhexanoate | C23H30N2O8S | 详情 | 详情 | |
| (XXII) | 22508 | methyl (4S,7S,10aS)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate | C19H20N2O5S | 详情 | 详情 | |
| (XXIII) | 22509 | (2S)-2-amino-4-hydroxybutyric acid | 672-15-1 | C4H9NO3 | 详情 | 详情 |
| (XXIV) | 10283 | ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide | 22509-74-6 | C11H9NO4 | 详情 | 详情 |
| (XXV) | 22511 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-hydroxybutyric acid | C12H11NO5 | 详情 | 详情 | |
| (XXVI) | 22512 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoic acid | C14H15NO5 | 详情 | 详情 | |
| (XXVII) | 22513 | methyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoate | C15H17NO5 | 详情 | 详情 | |
| (XXVIII) | 22514 | methyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxohexanoate | C15H15NO5 | 详情 | 详情 | |
| (XXIX) | 22515 | methyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6,6-dimethoxyhexanoate | C17H21NO6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)(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3
该中间体在本合成路线中的序号：(III)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 |