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【结 构 式】 
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【药物名称】IT-657 【化学名称】1-(2-Amino-4-fluorophenyl)-4-[(6bR,10aS)-1,2,6b,7,8,9,10,10a-octahydropyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzoxazin-8-yl]butan-1-one 【CA登记号】313543-30-5 【 分 子 式 】C23H26FN3O2 【 分 子 量 】395.48097 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS, 5-HT2A Antagonists, Dopamine D2 Antagonists |
合成路线1
Nitrosation of dihydrobenzoxazine (I) with NaNO2 and HOAc, followed by LiAlH4 reduction of the resulting N-nitroso derivative (II), furnished hydrazine (III). Subsequent Fischer indole cyclization of hydrazine (III) with piperidone hydrate (IV) under acidic conditions afforded the tetracyclic system (V). The pyrrole ring double bond of (V) was then reduced employing NaBH3CN and CF3COOH to provide the racemic cis-tetracycle (VI). Resolution of (VI) was carried out by preparative chiral HPLC of the corresponding N-Boc derivative. The desired N-Boc enantiomer (VII) was then deprotected by acidic treatment to give the chiral secondary amine (VIII). This was finally alkylated with 2'-amino-4-chloro-4'-fluorobutyrophenone (IX) to yield the title compound.
| 【1】 Boyle, K.E.; Robichaud, A.J.; Lee, T.; et al.; Novel, highly potent and selective serotonin 5-HT2A/dopamine D2 receptor antagonists as potential antipsychotics. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 98. |
| 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) | 48152 | 3,4-dihydro-2H-1,4-benzoxazine | C8H9NO | 详情 | 详情 | |
| (II) | 48153 | 4-nitroso-3,4-dihydro-2H-1,4-benzoxazine | C8H8N2O2 | 详情 | 详情 | |
| (III) | 48154 | 2,3-dihydro-4H-1,4-benzoxazin-4-amine; 2,3-dihydro-4H-1,4-benzoxazin-4-ylamine | C8H10N2O | 详情 | 详情 | |
| (IV) | 18178 | 4,4-piperidinediol | 73390-11-1 | C5H11NO2 | 详情 | 详情 |
| (V) | 48155 | 1,2,7,8,9,10-hexahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole | C13H14N2O | 详情 | 详情 | |
| (VI) | 48156 | 1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole | C13H16N2O | 详情 | 详情 | |
| (VII) | 48157 | tert-butyl (6bR,10aS)-1,2,6b,9,10,10a-hexahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate | C18H24N2O3 | 详情 | 详情 | |
| (VIII) | 48158 | (6bR,10aS)-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole | C13H16N2O | 详情 | 详情 | |
| (IX) | 48151 | 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone | C10H11ClFNO | 详情 | 详情 |