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【结 构 式】 
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【药物名称】 【化学名称】3-[5-[3-[N-(1H-Imidazol-2-yl)carbamoyl]propyl]-4,5-dihydroisoxazo-3-carboxamido]-2(S)-(2,4,6-trimethylphenylsulfonamido)propionic acid 【CA登记号】185562-53-2 【 分 子 式 】C23H30N6O7S 【 分 子 量 】534.59555 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Restenosis Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Integrin alphavbeta3 (Vitronectin) Antagonists |
合成路线1
Cycloaddition of 5-hexen-1-ol (I) with (II) in presence of NaHCO3 yields isoxazoline (III). Alternatively (III) can be obtained by treatment of (I) with diethyl nitromalonate (A) in mesitylene. Isoxazoline (III) is then oxidized by means of Jones reagent to provide acid (IV) which is coupled in presence of BOP with the imidazole derivative (V) and hydrolyzed with LiOH affording derivative (VI). Acid (VI) is coupled with derivative (IX) (obtained by reaction of diaminopropionate (VII) with (VIII) in presence of DIEA) by means of BOP, and finally hydrolyzed to afford the desired product.
| 【1】 Withyak, J.; Pitts, W.J.; Smallheer, J.M.; et al.; Isoxazolines as potent antagonists of the integrin alphavbeta3. J Med Chem 2000, 43, 1, 27. |
| 【2】 Voss, M.E.; Jadhav, P.K.; Smallheer, J.M.; Batt, D.G.; Pitts, W.J.; Wityak, J. (DuPont Pharmaceuticals Co.); Isoxazoline and isoxazole derivs. as integrin receptor antagonists. EP 0828737; JP 1999506436; US 5710159; WO 9637492 . |
| 【3】 Jadhav, P.; Repta, A.J.; Pitts, W.J.; Hussain, M.A.; Batt, D.G. (DuPont Pharmaceuticals Co.); Heterocyclic integrin inhibitor prodrugs. WO 9843962 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 41159 | diethyl 2-nitromalonate | C7H11NO6 | 详情 | 详情 | |
| (I) | 41152 | 5-hexen-1-ol | 821-41-0 | C6H12O | 详情 | 详情 |
| (II) | 30424 | 2-ethoxy-N-hydroxy-2-oxoethanimidoyl chloride | 14337-43-0 | C4H6ClNO3 | 详情 | 详情 |
| (III) | 41153 | ethyl 5-(4-hydroxybutyl)-4,5-dihydro-3-isoxazolecarboxylate | C10H17NO4 | 详情 | 详情 | |
| (IV) | 41154 | 4-[3-(ethoxycarbonyl)-4,5-dihydro-5-isoxazolyl]butyric acid | C10H15NO5 | 详情 | 详情 | |
| (V) | 41155 | 1H-imidazol-2-ylamine; 1H-imidazol-2-amine; 2-Aminoimidazole | 7720-39-0 | C3H5N3 | 详情 | 详情 |
| (VI) | 41156 | 5-[4-(1H-imidazol-2-ylamino)-4-oxobutyl]-4,5-dihydro-3-isoxazolecarboxylic acid | C11H14N4O4 | 详情 | 详情 | |
| (VII) | 41157 | tert-butyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C12H24N2O4 | 详情 | 详情 | |
| (VIII) | 41158 | 2,4,6-trimethylbenzenesulfonyl chloride | 773-64-8 | C9H11ClO2S | 详情 | 详情 |
| (IX) | 36588 | tert-butyl (2S)-3-amino-2-[(mesitylsulfonyl)amino]propanoate | C16H26N2O4S | 详情 | 详情 |