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【结 构 式】 
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【药物名称】 【化学名称】4-(2,4,4-Trimethyl-1,4-dihydro-2H-3,1-benzoxazin-6-yl)thiophene-2-carbonitrile 【CA登记号】304857-74-7 【 分 子 式 】C16H16N2OS 【 分 子 量 】284.38272 |
【开发单位】Wyeth Pharmaceuticals (Originator) 【药理作用】Contraceptives, Disorders of Sexual Function and Reproduction, Treatment of, ENDOCRINE DRUGS, Female Contraceptives, Gynecological Disorders, Treatment of , Hormone Replacement Therapy, Nonsteroidal Contraceptives, Progesterone Receptor Agonists |
合成路线1
Addition of methylmagnesium bromide to methyl 2-amino-5-bromobenzoate (I) provides the tertiary alcohol (II). Subsequent ring closure of the amino carbinol (II) with acetaldehyde leads to the benzoxazine (III). Treatment of the bromobenzoxazine (III) with bis(pinacolato)diboron (IV) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride furnishes the aryl borate (V). This is finally subjected to Suzuki coupling with 5-bromo-2-thiophenecarbonitrile (VI) to produce the title benzoxazinyl thiophene derivative.
| 【1】 Zhang, P.; et al.; Potent nonsteroidal progesterone receptor agonists: Synthesis and SAR study of 6-aryl benzoxazines. Bioorg Med Chem Lett 2002, 12, 5, 787. |
| 【2】 Jones, T.K.; Zhi, L.; Tegley, C.M.; Fensome, A.; Zhang, P.; Terefenko, E.A.; Marschke, K.B. (Ligand Pharmaceuticals, Inc.; Wyeth); Quinazolinone and benzoxazine derivs. as progesterone receptor modulators. EP 1175404; WO 0066560 . |
| 【3】 Jones, T.K.; Zhi, L.; Tegley, C.M.; Marschke, K.B.; Grubb, G.S. (Ligand Pharmaceuticals, Inc.; Wyeth); Contraceptive compsns. containing quinazolinone and benzoxazine derivs.. WO 0066164; WO 0066165 . |
| 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) | 58335 | methyl 2-amino-5-bromobenzoate | C8H8BrNO2 | 详情 | 详情 | |
| (II) | 58336 | 2-(2-amino-5-bromophenyl)-2-propanol | C9H12BrNO | 详情 | 详情 | |
| (III) | 58337 | 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine | C11H14BrNO | 详情 | 详情 | |
| (IV) | 53342 | 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane; Bis(pinacolato)diboron; Diboron pinacol ester | 73183-34-3 | C12H24B2O4 | 详情 | 详情 |
| (V) | 58338 | 2,4,4-trimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-3,1-benzoxazine | C17H26BNO3 | 详情 | 详情 | |
| (VI) | 58339 | 4-bromo-2-thiophenecarbonitrile | C5H2BrNS | 详情 | 详情 |