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【结 构 式】 
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【药物名称】 【化学名称】N-[3-Chloro-4-(2,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepin-6-ylcarbonylphenyl)biphenyl-2-carboxamide 【CA登记号】 【 分 子 式 】C29H21ClN4O2S 【 分 子 量 】525.03332 |
【开发单位】Wyeth Pharmaceuticals (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, Renal Failure, Agents for, RENAL-UROLOGIC DRUGS, Treatment of Renal Diseases, Vasopressin V2 Antagonists |
合成路线1
Tetrahydrobenzothiophene-4-one (I) was treated with hydroxylamine to afford oxime (IIa-b) as a mixture of syn and anti isomers, which were condensed with tosyl chloride yielding the oxime O-tosylate (IIIa-b). Beckmann rearrangement of (IIIa-b) in the presence of KOAc gave rise to lactam (IV), and subsequent reduction with borane provided thienoazepine (V). Condensation of (V) with 2-chloro-4-nitrobenzoyl chloride (VI) gave amide (VII). A 7-oxo group was introduced by oxidation of (VII) with KMnO4 in acetone-water. The resulting ketone (VIII) was treated with Bredereck’s reagent to afford the dimethylaminomethylene ketone (IX). Cyclization of (IX) with hydrazine produced the tricyclic compound (X). The nitro group of (X) was then reduced to amine (XI) using stannous chloride. Coupling of (XI) with 2-biphenylcarbonyl chloride (XII) furnished the diacylated derivative (XIII). Finally, selective monodeacylation of(XIII) with NaOH yielded the title compound.
| 【1】 Mazandarani, H.; Coupet, J.; Dusza, J.P:; Chan, P.S.; Ru, X.; Delos Santos, E.G.; Albright, J.D.; The synthesis and vasopressin (AVP) antagonist activity of a novel series of N-aroyl-2,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepines. Bioorg Med Chem Lett 2000, 10, 8, 695. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIa) | 41567 | (Z)-6,7-dihydro-1-benzothiophen-4(5H)-one oxime | C8H9NOS | 详情 | 详情 | |
| (IIb) | 41568 | (E)-6,7-dihydro-1-benzothiophen-4(5H)-one oxime | C8H9NOS | 详情 | 详情 | |
| (IIIa) | 41569 | (Z)-4-([[(4-methylphenyl)sulfonyl]oxy]imino)-6,7-dihydro-1-benzothiophene | C15H15NO3S2 | 详情 | 详情 | |
| (IIIb) | 41570 | (E)-4-([[(4-methylphenyl)sulfonyl]oxy]imino)-4,5,6,7-tetrahydro-1-benzothiophene | C15H15NO3S2 | 详情 | 详情 | |
| (I) | 11045 | 6,7-Dihydro-1-benzothiophen-4(5H)-one; 4-Keto-4,5,6,7-tetrahydrothianaphthene; Tetrahydrobenzo(b)thiophene-4-one | 13414-95-4 | C8H8OS | 详情 | 详情 |
| (IV) | 41571 | 4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one | C8H9NOS | 详情 | 详情 | |
| (V) | 41572 | 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine | 180340-57-2 | C8H11NS | 详情 | 详情 |
| (VI) | 26674 | 2-chloro-4-nitrobenzoyl chloride | 7073-36-1 | C7H3Cl2NO3 | 详情 | 详情 |
| (VII) | 41573 | (2-chloro-4-nitrophenyl)(5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-4-yl)methanone | C15H13ClN2O3S | 详情 | 详情 | |
| (VIII) | 41574 | 4-(2-chloro-4-nitrobenzoyl)-4,5,6,7-tetrahydro-8H-thieno[3,2-b]azepin-8-one | C15H11ClN2O4S | 详情 | 详情 | |
| (IX) | 41575 | 4-(2-chloro-4-nitrobenzoyl)-7-[(E)-(dimethylamino)methylidene]-4,5,6,7-tetrahydro-8H-thieno[3,2-b]azepin-8-one | C18H16ClN3O4S | 详情 | 详情 | |
| (X) | 41576 | (2-chloro-4-nitrophenyl)[4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-yl]methanone | C16H11ClN4O3S | 详情 | 详情 | |
| (XI) | 41577 | (4-amino-2-chlorophenyl)[4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-yl]methanone | C16H13ClN4OS | 详情 | 详情 | |
| (XII) | 18506 | [1,1'-biphenyl]-2-carbonyl chloride | C13H9ClO | 详情 | 详情 | |
| (XIII) | 41578 | N-(4-[[2-([1,1'-biphenyl]-2-ylcarbonyl)-4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-yl]carbonyl]-3-chlorophenyl)[1,1'-biphenyl]-2-carboxamide | C42H29ClN4O3S | 详情 | 详情 |