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【结 构 式】 
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【药物名称】Apafant, DE-081, WEB-2086 【化学名称】3-[4-(2-Chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]propionic acid morpholide 【CA登记号】105219-56-5 【 分 子 式 】C22H22ClN5O2S 【 分 子 量 】455.96994 |
【开发单位】Boehringer Ingelheim (Originator), Santen (Licensee) 【药理作用】Antiallergic Ophthalmic Agents, Ocular Antiinflammatory and Antiinfective Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Platelet-Activating Factor (PAF) Antagonists |
合成路线1
Starting from 4-dicarbethoxybutan-1-one (I) and o-chlorocyanoacetophenone (II), in the presence of sufur the aminobenzoylthiophene (III) was obtained. Saponification, decarboxylation and esterification yielded the mono ester (IV), which was acetylated to (V). Amination and ring closure gave the corresponding diazepinone (VII). Sulfuration of (VII), treatment with hydrazine and then with orthoacetate yielded the triazolo compound (X). Saponification of (X) and amidation with morpholine in the presence of carbodiimidazole gave WEB 2086.
| 【1】 Weber, K.-H.; Bechtel, W.D.; Brotizolam radioimmunoassay: Development, evaluati. J Pharm Sci 1985, 74, 1265. |
| 【2】 Weber, K.-H.; Walther, G.; Harreus, A.; Casals Stenzel, J.; Muacevic, G.; Tröger, W. (Boehringer Ingelheim GmbH); Thieno-triazolo-1,4-diazepino-2-carboxamides, proc. AU 8652728; DE 3502392; EP 0194416; ES 8802426; ES 8802523; JP 1986176591; JP 1990191281; US 4968794; US 5082839; US 5155103 . |
| 【3】 Weber, K.H.; WEB 2086. Drugs Fut 1988, 13, 3, 242. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 | |
| (I) | 12923 | 3-(2-Chlorophenyl)-3-oxopropanenitrile | 40018-25-5 | C9H6ClNO | 详情 | 详情 |
| (II) | 22030 | diethyl 2-(3-oxopropyl)malonate | C10H16O5 | 详情 | 详情 | |
| (III) | 22032 | diethyl 2-[[5-amino-4-(2-chlorobenzoyl)-2-thienyl]methyl]malonate | C19H20ClNO5S | 详情 | 详情 | |
| (IV) | 22033 | methyl 3-[5-amino-4-(2-chlorobenzoyl)-2-thienyl]propanoate | C15H14ClNO3S | 详情 | 详情 | |
| (V) | 22034 | methyl 3-[5-[(2-bromoacetyl)amino]-4-(2-chlorobenzoyl)-2-thienyl]propanoate | C17H15BrClNO4S | 详情 | 详情 | |
| (VI) | 22035 | methyl 3-[5-[(2-aminoacetyl)amino]-4-(2-chlorobenzoyl)-2-thienyl]propanoate | C17H17ClN2O4S | 详情 | 详情 | |
| (VII) | 22036 | methyl 3-[5-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepin-7-yl]propanoate | C17H15ClN2O3S | 详情 | 详情 | |
| (VIII) | 22037 | methyl 3-[5-(2-chlorophenyl)-2-thioxo-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepin-7-yl]propanoate | C17H15ClN2O2S2 | 详情 | 详情 | |
| (IX) | 22038 | methyl 3-[5-(2-chlorophenyl)-2-[(Z)hydrazono]-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-7-yl]propanoate | C17H17ClN4O2S | 详情 | 详情 | |
| (X) | 22039 | methyl 3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]propanoate | C19H17ClN4O2S | 详情 | 详情 | |
| (XI) | 22040 | 3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]propionic acid | C18H15ClN4O2S | 详情 | 详情 |