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【结 构 式】 
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【分子编号】18014 【品名】tert-butyl 4-[2-[2-([[(2S)-2-[[(2-bromo-4-methylphenyl)sulfonyl]amino]-3-(tert-butoxy)-3-oxopropyl]amino]carbonyl)-4-oxo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl]ethyl]-1-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C34H49BrN6O8S 【 分 子 量 】781.7687 【元素组成】C 52.24% H 6.32% Br 10.22% N 10.75% O 16.37% S 4.1% |
合成路线1
该中间体在本合成路线中的序号：(VIII)Treatment of amino acid (I) with isobutylene (II) and H2SO4 in dioxane afforded tert-butyl ester (III), which was coupled with carboxylic acid (IV) in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 1-hydroxybenzotriazole (HOBT) to give (V). Removal of the benzyloxycarbonyl protecting group by hydrogenolysis provided amine (VI) which, on reaction with 2-bromotoluenesulfonyl chloride (VII) and pyridine in refluxing ethyl acetate was converted into sulfonamide (VIII). Deprotection of both tert-butyl groups was effected by treatment with trifluoroacetic acid in dichloromethane, to give (IX) as the trifluoroacetate salt. Tritium labeled compound was then obtained by reductive debromination with tritium gas, using Pearlman's catalyst in the presence of triethylamine.
| 【1】 Thorell, J.O.; et al.; Synthesis of a C-11-labelled nitrated 1,4-dihydroquinoxaline-2,3-dione, the NMDA glycine receptor antagonist ACEA 1021 (Licostinel). J Label Compd Radiopharm 1998, 41, 4, 345-353. |
| 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) | 18008 | (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid | 35761-26-3 | C11H14N2O4 | 详情 | 详情 |
| (II) | 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 |
| (III) | 18009 | tert-butyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate | C15H22N2O4 | 详情 | 详情 | |
| (IV) | 18010 | 5-[2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl]-4-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid | C20H30N4O5 | 详情 | 详情 | |
| (V) | 18011 | tert-butyl 4-[2-[2-([[(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(tert-butoxy)-3-oxopropyl]amino]carbonyl)-4-oxo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl]ethyl]-1-piperidinecarboxylate | C35H50N6O8 | 详情 | 详情 | |
| (VI) | 18012 | tert-butyl 4-[2-[2-([[(2S)-2-amino-3-(tert-butoxy)-3-oxopropyl]amino]carbonyl)-4-oxo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl]ethyl]-1-piperidinecarboxylate | C27H44N6O6 | 详情 | 详情 | |
| (VII) | 18013 | 2-bromo-4-methylbenzenesulfonyl chloride | C7H6BrClO2S | 详情 | 详情 | |
| (VIII) | 18014 | tert-butyl 4-[2-[2-([[(2S)-2-[[(2-bromo-4-methylphenyl)sulfonyl]amino]-3-(tert-butoxy)-3-oxopropyl]amino]carbonyl)-4-oxo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl]ethyl]-1-piperidinecarboxylate | C34H49BrN6O8S | 详情 | 详情 | |
| (IX) | 18015 | (2S)-2-[[(2-bromo-4-methylphenyl)sulfonyl]amino]-3-[([4-oxo-5-[2-(4-piperidinyl)ethyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl]carbonyl)amino]propionic acid | C25H33BrN6O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The indole intermediate (V) has been obtained as follows: The reaction of 4-fluoro-2-nitrotoluene (I) with dimethylformamide dimethylacetal afforded enamine (II). Reductive cyclization of (II) by hydrogenation over Pd/C produced 6-fluoroindole (III). Subsequent condensation of indole (III) with piperidone monohydrate (IV) in the presence of KOH furnished the intermediate indolyl tetrahydropyridine (V).
| 【1】 Fairhurst, J. (Eli Lilly and Company); Substd. 4-(6-fluoro-(1H)-indol-3-yl)-1,2,3,6-tetrahydropyridine for the treatment of CNS-disorders. EP 0854146; WO 9831686 . |
| 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) | 48011 | 4-fluoro-1-methyl-2-nitrobenzene | 446-10-6 | C7H6FNO2 | 详情 | 详情 |
| (II) | 48012 | N-[(E)-2-(4-fluoro-2-nitrophenyl)ethenyl]-N,N-dimethylamine; (E)-2-(4-fluoro-2-nitrophenyl)-N,N-dimethyl-1-ethenamine | C10H11FN2O2 | 详情 | 详情 | |
| (III) | 48013 | 6-Fluoroindole; 6-Fluoro-1H-indole | 399-51-9 | C8H6FN | 详情 | 详情 |
| (IV) | 18178 | 4,4-piperidinediol | 73390-11-1 | C5H11NO2 | 详情 | 详情 |
| (V) | 18014 | tert-butyl 4-[2-[2-([[(2S)-2-[[(2-bromo-4-methylphenyl)sulfonyl]amino]-3-(tert-butoxy)-3-oxopropyl]amino]carbonyl)-4-oxo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl]ethyl]-1-piperidinecarboxylate | C34H49BrN6O8S | 详情 | 详情 |