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【结 构 式】 
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【药物名称】Olanzapine, LY-170053, Zyprexa Zydis, Zyprexa Velotab, Midax, Olansek, Zyprexa, Lanzac 【化学名称】2-Methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine 【CA登记号】132539-06-1 【 分 子 式 】C17H20N4S 【 分 子 量 】312.43975 |
【开发单位】Lilly (Originator), Gador (Licensee) 【药理作用】Alzheimer's Dementia, Treatment of , Antipsychotic Drugs, Bipolar Disorder, Treatment of, Cognition Disorders, Treatment of, Mood Disorders, Treatment of, NEUROLOGIC DRUGS, PSYCHOPHARMACOLOGIC DRUGS, 5-HT2A Antagonists, Dopamine D2 Antagonists |
合成路线1
The condensation of o-chloronitrobenzene (I) with 2-amino-5-methylthiophene-3-carbonitrile (II) by means of lithium hydroxide in DMSO gives 2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile (III). The reductive cyclization of (III) using stannous chloride in aqueous ethanolic hydrochloric acid gives the primary amidine hydrochloride (IV), which is condensed with N-methylpiperazine (V) in a mixture of 4:1 toluene:DMSO.
| 【1】 Larsen, S.D.; Stephenson, G.A.; Bunnell, C.A.; Reutzel, S.M.; Nichols, J.R. (Eli Lilly and Company); Intermediates and process for preparing olanzapine. US 6020487 . |
| 【2】 Moore, N.A.; Hotten, T.M.; Tupper, D.E.; Olanzapine. Drugs Fut 1994, 19, 2, 114. |
| 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) | 15248 | 1-chloro-2-nitrobenzene | 88-73-3 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 15249 | 5-Amino-4-cyano-2-methylthiophene; 2-amino-5-methyl-3-thiophenecarbonitrile | 138564-58-6 | C6H6N2S | 详情 | 详情 |
| (III) | 15250 | 5-methyl-2-(2-nitroanilino)-3-thiophenecarbonitrile | C12H9N3O2S | 详情 | 详情 | |
| (IV) | 15251 | 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-ylamine hydrochloride; 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-amine hydrochloride; 4-Amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride | 138564-60-0 | C12H12ClN3S | 详情 | 详情 |
| (V) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线2
The synthesis of some metabolites of olanzapine have been described: 1) Synthesis of 4'-N-desmethyl olanzapine: The condensation of 2-fluoronitrobenzene (I) with 5-methylthiophene-2-amine (II) by means of LiOH in DMSO gives the expected secondary amine (III), which is cyclized by means of SnCl2 in ethanol yielding 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine-4-amine (IV). Finally, this compound is condensed with piperazine (V) in toluene/DMSO affording the metabolite 2-methyl-4-(1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.
| 【1】 Calligaro, D.O.; Moore, N.A.; Tupper, D.E.; Fairhurst, J.; Hotten, T.M.; The synthesis and biological activity of some known and putative metabolites of the atypical antipsychotic agent olanzapine (LY170053). Bioorg Med Chem Lett 1997, 7, 1, 25. |
| 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) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 15249 | 5-Amino-4-cyano-2-methylthiophene; 2-amino-5-methyl-3-thiophenecarbonitrile | 138564-58-6 | C6H6N2S | 详情 | 详情 |
| (III) | 15250 | 5-methyl-2-(2-nitroanilino)-3-thiophenecarbonitrile | C12H9N3O2S | 详情 | 详情 | |
| (IV) | 15255 | 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-ylamine; 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-amine | C12H11N3S | 详情 | 详情 | |
| (V) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
合成路线3
2) Synthesis of olanzapine 4'-N-oxide: The condensation of 2-fluoronitrobenzene (I) with 5-methylthiophene-2-amine (II) by means of LiOH in DMSO gives the expected secondary amine (III), which is cyclized by means of SnCl2 in ethanol yielding 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine-4-amine (IV). The condensation of (IV) with N-methylpiperazine (V) in toluene/DMSO affords 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepin e (olanzapine) (VI), which is finally oxidized with m-chloroperbenzoic acid (m-CPBA) in dichloromethane to give the metabolite 2-methyl-4-(4-methyl-4-oxidopiperazinyl-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine.
| 【1】 Calligaro, D.O.; Moore, N.A.; Tupper, D.E.; Fairhurst, J.; Hotten, T.M.; The synthesis and biological activity of some known and putative metabolites of the atypical antipsychotic agent olanzapine (LY170053). Bioorg Med Chem Lett 1997, 7, 1, 25. |
| 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) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 15249 | 5-Amino-4-cyano-2-methylthiophene; 2-amino-5-methyl-3-thiophenecarbonitrile | 138564-58-6 | C6H6N2S | 详情 | 详情 |
| (III) | 15250 | 5-methyl-2-(2-nitroanilino)-3-thiophenecarbonitrile | C12H9N3O2S | 详情 | 详情 | |
| (IV) | 15255 | 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-ylamine; 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-amine | C12H11N3S | 详情 | 详情 | |
| (V) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (VI) | 15262 | 2-methyl-4-(4-methylpiperazino)-10H-thieno[2,3-b][1,5]benzodiazepine | C17H20N4S | 详情 | 详情 |
合成路线4
3) Synthesis of 2-hydroxymethyl olanzapine: The condensation of 2-fluoronitrobenzene (I) with thiophene-2-amine (II) by means of LiOH in DMSO gives the expected secondary amine (III), which is formylated with DMF by means of POCl3 yielding the aldehyde (IV). The reducticyclization of (IV) with SnCl2 in ethanol affords 4-amino-10H-thieno[2,3-b][1,5]benzodiazepine-2-carbaldehyde (V), which is reduced with NaBH4 in ethanol to the corresponding hydroxymethyl derivative (VI). Finally, this compound is condensed with N-methylpiperazine (VII) in toluene/DMSO to give the metabolite 2-(hydroxymethyl)-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benz odiazepine.
| 【1】 Calligaro, D.O.; Moore, N.A.; Tupper, D.E.; Fairhurst, J.; Hotten, T.M.; The synthesis and biological activity of some known and putative metabolites of the atypical antipsychotic agent olanzapine (LY170053). Bioorg Med Chem Lett 1997, 7, 1, 25. |
| 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) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 15263 | 2-amino-3-thiophenecarbonitrile | 4651-82-5 | C5H4N2S | 详情 | 详情 |
| (III) | 15264 | 2-(2-nitroanilino)-3-thiophenecarbonitrile | C11H7N3O2S | 详情 | 详情 | |
| (IV) | 15265 | 5-formyl-2-(2-nitroanilino)-3-thiophenecarbonitrile | C12H7N3O3S | 详情 | 详情 | |
| (V) | 15266 | 4-amino-10H-thieno[2,3-b][1,5]benzodiazepine-2-carbaldehyde | C12H9N3OS | 详情 | 详情 | |
| (VI) | 15267 | (4-amino-10H-thieno[2,3-b][1,5]benzodiazepin-2-yl)methanol | C12H11N3OS | 详情 | 详情 | |
| (VII) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |