|
【结 构 式】 
|
【药物名称】LB-50053 【化学名称】2-[4-[3-(4-Fluorophenyl)pyrrolidin-1-yl]butyl]-1H-benzisothiazol-3(2H)-one 1,1-dioxide 【CA登记号】231622-39-2 【 分 子 式 】C21H23FN2O3S 【 分 子 量 】402.49146 |
【开发单位】LG Chem (Originator) 【药理作用】Antidepressants, Anxiolytics, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT1A Receptor Agonists |
合成路线1
The sulfonylation of 1-benzylpyrrolidin-3-ol by means of mesyl or tosyl chlorides gives the corresponding sulfonates (II) or (III), which are condensed with the bis(4-fluorophenyl)cuprate lithium (IV) yielding 1-benzyl-3-(4-fluorophenyl) pyrrolidine (V). The debenzylation of (V) with ammonium formate over Pd/C in methanol affords 3-(4-fluorophenyl)pyrrolidine (VI), which is finally condensed with 2-(4-bromobutyl)-1,2-benzoisothiazol-3-one S,S-dioxide (VII) by means of triethylamine in acetonitrile.
| 【1】 Lee, C.-H.; Ahn, K.H.; Lee, S.J.; Park, T.K.; Hong, C.Y.; N-Substituted-3-arylpyrrolidines: Potent and selective ligands at serotonin 1A receptor. Bioorg Med Chem Lett 1999, 9, 10, 1379. |
| 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) | 22746 | 1-benzyl-3-pyrrolidinol | C11H15NO | 详情 | 详情 | |
| (II) | 30988 | 1-benzyl-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]pyrrolidine | C14H21NOS | 详情 | 详情 | |
| (III) | 30989 | 1-benzyl-3-pyrrolidinyl 4-methylbenzenesulfonate | C18H21NO3S | 详情 | 详情 | |
| (V) | 30992 | 1-benzyl-3-(4-fluorophenyl)pyrrolidine | C17H18FN | 详情 | 详情 | |
| (VI) | 30993 | 3-(4-fluorophenyl)pyrrolidine | C10H12FN | 详情 | 详情 | |
| (VII) | 17043 | 2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C11H12BrNO3S | 详情 | 详情 |
合成路线2
Treatment of 1-benzyl-3-hydroxypyrrolidine (I) with methanesulfonyl chloride in the presence of DMAP and Et3N affords mesylate (II). Subsequent displacement of the mesylate group of (II) with the diarylcuprate reagent generated from 4-fluorophenyllithium (III) and cuprous bromide gives the 3-aryl pyrrolidine (IV). The N-benzyl group of (IV) is then removed by transfer hydrogenolysis with ammonium formate and Pd/C, yielding the secondary amine (V). This is finally alkylated with 2-(4-bromobutyl)-3-oxo-1,2-benzisothiazole 1,1-dioxide (VI) in the presence of Et3N in refluxing acetonitrile.
| 【1】 Lee, C.-H.; Ahn, K.H.; Lee, S.J.; Park, T.K.; Hong, C.Y.; N-Substituted-3-arylpyrrolidines: Potent and selective ligands at serotonin 1A receptor. Bioorg Med Chem Lett 1999, 9, 10, 1379. |
| 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) | 22746 | 1-benzyl-3-pyrrolidinol | C11H15NO | 详情 | 详情 | |
| (II) | 62833 | 1-benzyl-3-pyrrolidinyl methanesulfonate | C12H17NO3S | 详情 | 详情 | |
| (III) | 62834 | (4-fluorophenyl)lithium | C6H4FLi | 详情 | 详情 | |
| (IV) | 30992 | 1-benzyl-3-(4-fluorophenyl)pyrrolidine | C17H18FN | 详情 | 详情 | |
| (V) | 30993 | 3-(4-fluorophenyl)pyrrolidine | C10H12FN | 详情 | 详情 | |
| (VI) | 17043 | 2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C11H12BrNO3S | 详情 | 详情 |