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【结 构 式】 
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【药物名称】L-738167 【化学名称】2(S)-(4-Methylphenylsulfonamido)-3-[4-oxo-5-[2-(piperidin-4-yl)ethyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-ylcarboxamido]propionic acid 【CA登记号】163212-43-9 【 分 子 式 】C25H34N6O6S 【 分 子 量 】546.65033 |
【开发单位】Merck & Co. (Originator) 【药理作用】Antiplatelet Therapy, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Integrin alphaIIbbeta3 (Fibrinogen gpIIb/IIIa) Antagonists |
合成路线1
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 |