【结 构 式】 |
【药物名称】Talampanel, IDR-53773, GYKI-53773, LY-300164, Kinampa, Ampanel 【化学名称】7-Acetyl-5-(4-aminophenyl)-8(R)-methyl-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine 【CA登记号】161832-65-1 【 分 子 式 】C19H19N3O3 【 分 子 量 】337.38158 |
【开发单位】Institute for Drug Research (Originator), Ivax (Originator) 【药理作用】Antiepileptic Drugs, Antispastic Drugs and Drugs for Muscle Spasms, Brain Cancer Therapy, Cerebrovascular Diseases, Treatment of, Extrapyramidal Disorders, Treatment of, Ischemic Stroke, Treatment of, NEUROLOGIC DRUGS, Oncolytic Drugs, Stroke, Treatment of, Tardive Dyskinesia, Treatment of, AMPA Antagonists |
合成路线1
The reaction of 5-bromo-1,3-benzodioxole (I) with (S)-(-)-propylene oxide (II) by means of sec-butyllithium in THF gives the (S)-isopropanol derivative (IV) (also obtained by stereoselective reduction of 1-(1,3-benzodioxol-5-yl)-2-propanone (III) with Z. rouxii ATCC 14462 in a phosphate buffer). The cyclization of (IV) with 4-nitrobenzaldehyde (V) by means of HCl in hot toluene yields the benzopyran (VI), which is oxidized with air in aqueous NaOH affording the carbinol (VII). The reaction of (VII) with acetohydrazide (VIII) and HCl in refluxing ethanol gives the acetyl hydrazone (IX), which is mesylated at the secondary OH group with methanesulfonyl chloride and TEA in dichloromethane yielding the mesylate (X). The cyclization of (X) by means of NaOH in methanol provides the nitro benzodiazepine (XI), which is finally reduced with potassium formate and Pd/C in ethanol/water.
【1】 Andrasi, F.; Talampanel. Drugs Fut 2001, 26, 8, 754. |
【2】 Anderson, B.A.; et al.; Application of a practical biocatalytic reduction to an enantioselective synthesis of the 5H-2, 3-benzodiazepine LY300164. J Am Chem Soc 1995, 117, 49, 12358. |
【3】 Andrasi, F.; Berzsenyi, P.; Botka, P.; Farkas, S.; Goldschmidt, K.; Hamori, T.; Korosi, J.; Moravcsik, I.; Tarnawa, I. (Gyogyszerkutato Intezet Kft.); N-Acyl-2,3-benzodiazepine derivs., pharmaceutical compsns. containing them and process for preparing same. EP 0492485; JP 1993070463; US 5519019; US 5521174; US 5536832; US 5604223; US 5639751 . |
【4】 Varie, D.L.; Hansen, M.M.; Anderson, B.; Vicenzi, J.T.; Zmijewski, M.J. (Eli Lilly and Company); Stereoselective process for producing dihydro-2,3-benzodiazepine derivs.. EP 0699677; US 5665878 . |
【5】 Zmijewski, M.J. Jr.; Varie, D.L.; Hansen, M.M.; Vicenzi, J.T.; Anderson, B.A. (Eli Lilly and Company); Physical form of dihidro-2,3-benzodiazepine deriv.. EP 0699676 . |
【6】 Hansen, M.M.; Vicenzi, J.T.; Groleau, E.G.; Varie, D.L.; Zmijewski, M.J.; Anderson, B.A. (Eli Lilly and Company); Crystalline form of dihydro-2,3-benzodiazepine deriv.. EP 0699678 . |
【7】 Anderson, B.A.; Varie, D.L.; Vicenzi, J.T.; Zmijewski, M.J.; Hansen, M.M. (Eli Lilly and Company); Stereoselective process for producing dihydro-2,3-benzodiazepine derivs.. US 5919954 . |
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) | 10124 | 5-Bromo-1,3-benzodioxole; 4-Bromo-1,2-(methylenedioxy)benzene | 2635-13-4 | C7H5BrO2 | 详情 | 详情 |
(II) | 29268 | (2S)-2-methyloxirane | 16088-62-3 | C3H6O | 详情 | 详情 |
(III) | 28466 | 1-(1,3-benzodioxol-5-yl)acetone | 4676-39-5 | C10H10O3 | 详情 | 详情 |
(IV) | 29259 | (2S)-1-(1,3-benzodioxol-5-yl)-2-propanol | C10H12O3 | 详情 | 详情 | |
(V) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
(VI) | 29260 | (7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromene | C17H15NO5 | 详情 | 详情 | |
(VII) | 29261 | (7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-ol | C17H15NO6 | 详情 | 详情 | |
(VIII) | 29262 | acetohydrazide | 1068-57-1 | C2H6N2O | 详情 | 详情 |
(IX) | 29263 | N'-[(E)-[6-[(2S)-2-hydroxypropyl]-1,3-benzodioxol-5-yl](4-nitrophenyl)methylidene]acetohydrazide | C19H19N3O6 | 详情 | 详情 | |
(X) | 29264 | N'-[(E)-[6-((2S)-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]propyl)-1,3-benzodioxol-5-yl](4-nitrophenyl)methylidene]acetohydrazide | C22H25N3O6S | 详情 | 详情 | |
(XI) | 29265 | 1-[(8R)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-7-yl]-1-ethanone | C19H17N3O5 | 详情 | 详情 |
合成路线2
The regioselective reduction of 8-methyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (I) with borane-THF complex catalyzed by (R)-2-amino-3-methyl-1,1-diphenyl-1-butanol (II) in dichloromethane gives the 8(R)-methyl derivative (III), which is acetylated with acetic anhydride yielding the 7-acetyl-8(R)-methyl derivative (IV). Finally, the nitro group of (IV) is reduced with hydrazine and Ni-Raney in methanol.
【1】 Ling, I.; et al.; Asymmetric reduction of a carbon-nitrogen double bond: Enantioselective synthesis of 4,5-dihydro-3H-2,3-benzodiazepines. J Chem Soc - Perkins Trans I 1995, 11, 1423. |
【2】 Ling, I.; Hamori, T.; Botka, P.; Solyom, S.; Simay, A.; Moravcsik, I. (Gyogyszerkutato Intezet Kft.); Optically active 1-(4-nitrophenyl)-4-methyl-7, 8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine and process for preparing same. WO 9501357 . |
【3】 Andrasi, F.; Berzsenyi, P.; Botka, P.; Farkas, S.; Goldschmidt, K.; Hamori, T.; Korosi, J.; Moravcsik, I.; Tarnawa, I. (Gyogyszerkutato Intezet Kft.); N-Acyl-2,3-benzodiazepine derivs., pharmaceutical compsns. containing them and process for preparing same. EP 0492485; JP 1993070463; US 5519019; US 5521174; US 5536832; US 5604223; US 5639751 . |
【4】 Berzsenyi, P.; Goldschmidt, K.; Moravcsik, I.; Kórösi, J.; Andrási, F.; Farkas, S.; Hámori, T.; Tarnawa, I.; Botka, P. (Gyogyszerkutato Intezet Kft.); N-Acyl-2,3-benzodiazepine derivs., pharmaceutical compsns. containing them and process for preparing same. US 5459137 . |
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) | 29266 | 8-methyl-5-(4-nitrophenyl)-9H-[1,3]dioxolo[4,5-h][2,3]benzodiazepine | C17H13N3O4 | 详情 | 详情 | |
(II) | 10103 | (2R)-2-Amino-3-methyl-1,1-diphenyl-1-butanol | 56755-20-5 (hydrochloride) | C17H21NO | 详情 | 详情 |
(III) | 29267 | (8R)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepine | C17H15N3O4 | 详情 | 详情 | |
(IV) | 29265 | 1-[(8R)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-7-yl]-1-ethanone | C19H17N3O5 | 详情 | 详情 |