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【结 构 式】 
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【药物名称】KC-12615 【化学名称】2-[3(S)-[1-[2(R)-Carboxy-4-phenylbutyl]cyclopentan-1-ylcarboxamido]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid 【CA登记号】182821-29-0, 204781-69-1 (diNa salt), 182561-00-8 (racemate), 204781-61-3 (stereoisomer), 182560-86-7 (undefined stereoch.) 【 分 子 式 】C29H34N2O6 【 分 子 量 】506.60413 |
【开发单位】Solvay (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Diuretics, Heart Failure Therapy, Hypertension, Treatment of, RENAL-UROLOGIC DRUGS, Endothelin-Converting Enzyme Inhibitors, Neprilysin Inhibitors |
合成路线1
1) The acylation of the chiral amine (I) with the chiral cyclopentanecarboxylic aid (II) by means of N-methylmorphline (NMM), hydroxybenzotriazole (HOBT) and N-(dimethylaminopropyl)-N'-ethylcarbodiimide (EDT) in dichloromethane gives the amide (III), which is then treated with trifluoroacetic acid to elimnate the tert-butyl ester groups.
| 【1】 Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 . |
| 【2】 Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 . |
| 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) | 20717 | tert-butyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C16H22N2O3 | 详情 | 详情 | |
| (II) | 20737 | 1-[(2R)-2-(tert-butoxycarbonyl)-4-phenylbutyl]cyclopentanecarboxylic acid | C21H30O4 | 详情 | 详情 | |
| (III) | 20738 | tert-butyl (2R)-2-([1-[([(3S)-1-[2-(tert-butoxy)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino)carbonyl]cyclopentyl]methyl)-4-phenylbutanoate | C37H50N2O6 | 详情 | 详情 |
合成路线2
2) The chiral intermediates the amine (I) and the acid (II) have been obtained as follows: 2a) The bromination of 1-tetralone (IV) with Br2 in methanol gives the 2-bromotetralone (V), which is treated with hydroxylamine yielding the corresponding oximae (VI). The isomerization of (V) with polyphosphoric acid (PPA) at 80 C affords the benzazepinone (VII), which is treated with potassium phthalimide (VIII) in DMF to give the corresponding phthalimido derivative (IX). The reaction of (IX) with tert-butyl bromoacetate (X) by means of potassium tert-butoxide in DMF yields the benzazepinoacetic ester (XI), which is treated with hot ethanolamine to eliminate the phthalimido group yielding racemic (I). Finally, this racemate is submitted to optical resolution with L-(+)-tartaric acid to afford the chiral (S)-intermediate (I).
| 【1】 Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 . |
| 【2】 Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(I) | 20728 | tert-butyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C16H22N2O3 | 详情 | 详情 | |
| (I) | 20717 | tert-butyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C16H22N2O3 | 详情 | 详情 | |
| (IV) | 20720 | 3,4-dihydro-1(2H)-naphthalenone | 529-34-0 | C10H10O | 详情 | 详情 |
| (V) | 20721 | 2-bromo-3,4-dihydro-1(2H)-naphthalenone | C10H9BrO | 详情 | 详情 | |
| (VI) | 20722 | 2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime | C10H10BrNO | 详情 | 详情 | |
| (VII) | 20723 | 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10BrNO | 详情 | 详情 | |
| (VIII) | 10926 | (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium | C8H4KNO2 | 详情 | 详情 | |
| (IX) | 20725 | 2-(2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-1H-isoindole-1,3(2H)-dione | C18H14N2O3 | 详情 | 详情 | |
| (X) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (XI) | 20727 | tert-butyl 2-[3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C25H26N2O5 | 详情 | 详情 |
合成路线3
2b) The alkylation of 2-(dimethoxyphosphoryl)acetic acid tert-butyl ester (XII) with 2-phenylethyl bromide (XIII) by means of potassium tert-butoxide in DMF gives 2-(dimethoxyphosphoryl)-4-phenylbutyric acid tert-butyl ester (XIV), which is allowed to react with formaldehyde/potasium tert-butoxide in THF to afford the tert-butyl acrylate (XV). The condensation of (XV) with cyclopentanecarboxylic acid (XVI) by means of butyllithium/diisopropylamine in THF affords racemic (II), which is finally submitted to optical resolution with L-(-)-alpha-methylbenzylamine to afford the chiral (R)-intermediate (II).
| 【1】 Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 . |
| 【2】 Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(II) | 20753 | 1-[2-(tert-butoxycarbonyl)-4-phenylbutyl]cyclopentanecarboxylic acid | C21H30O4 | 详情 | 详情 | |
| (XII) | 20748 | tert-butyl 2-(dimethoxyphosphoryl)acetate | C8H17O5P | 详情 | 详情 | |
| (XIII) | 20730 | 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide | 103-63-9 | C8H9Br | 详情 | 详情 |
| (XIV) | 20750 | tert-butyl 2-(dimethoxyphosphoryl)-4-phenylbutanoate | C16H25O5P | 详情 | 详情 | |
| (XV) | 20751 | tert-butyl 2-phenethylacrylate | C15H20O2 | 详情 | 详情 | |
| (XVI) | 20734 | cyclopentanecarboxylic acid | 3400-45-1 | C6H10O2 | 详情 | 详情 |