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【结 构 式】 
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【分子编号】20722 【品名】2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime 【CA登记号】 |
【 分 子 式 】C10H10BrNO 【 分 子 量 】240.09954 【元素组成】C 50.03% H 4.2% Br 33.28% N 5.83% O 6.66% |
合成路线1
该中间体在本合成路线中的序号：(VI)A new synthesis of CGS-14824A is given: The reaction of 3-bromo-1-phenylpropane (I) with KCN gives 4-phenylbutyronitrile (II), which is hydrolyzed to the corresponding butyric acid (III). The cyclization of (III) with polyphosphoric acid affords 1-tetralone (IV), which is brominated to 2-bromo-1-tetralone (V) and treated with hydroxylamine to give the oxime (VI). The Beckman rearrangement of (VI) yields 3-bromo-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is treated with sodium azide to afford the azide derivative (VIII). The N-alkylation of (VIII) with ethyl bromoacetate (IX) by means of KOH and tetrabutylammonium bromide in THF gives the N-alkylated azide (X), which is reduced by catalytic hydrogenation to the corresponding amine (XI). The hydrolysis of the ester group of (XI) with NaOH yields the free acetic acid derivative (XII), which is finally reductocondensed with ethyl 2-oxo-4-phenylbutyrate (XIII) by means of sodium cyanoborohydride.
| 【1】 Chaudhuri, N.K.; Patera, R.; Markus, B.; Sung, M.-S.; Synthesis of 14C-labeled 3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid hydrochloride ([14C]CGS 14824A). J Label Compd Radiopharm 1987, 24, 10, 1177-84. |
| 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) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (II) | 20885 | 4-phenylbutanenitrile | 2046-18-6 | C10H11N | 详情 | 详情 |
| (III) | 20886 | Benzenebutyric acid; 4-Phenylbutyric acid | 1821-12-1 | C10H12O2 | 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) | 20891 | 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10N4O | 详情 | 详情 | |
| (IX) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (X) | 20893 | ethyl 2-(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C14H16N4O3 | 详情 | 详情 | |
| (XI) | 20894 | ethyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | 109010-60-8 | C14H18N2O3 | 详情 | 详情 |
| (XII) | 20895 | 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid | C12H14N2O3 | 详情 | 详情 | |
| (XIII) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)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
该中间体在本合成路线中的序号：(VI)2a) The chiral intermediate amine (I) has been obtained as follows: 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】 Sorbera, L.A.; Leeson, P.A.; Castañer, J.; SLV-306. Drugs Fut 2002, 27, 1, 27. |
| 【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 . |
| 【3】 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 |