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【结 构 式】

【分子编号】29265

【品名】1-[(8R)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-7-yl]-1-ethanone

【CA登记号】

【 分 子 式 】C19H17N3O5

【 分 子 量 】367.3612

【元素组成】C 62.12% H 4.66% N 11.44% O 21.78%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XI)

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

该中间体在本合成路线中的序号:(IV)

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
Extended Information