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【结 构 式】 
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【分子编号】28466 【品名】1-(1,3-benzodioxol-5-yl)acetone 【CA登记号】4676-39-5 |
【 分 子 式 】C10H10O3 【 分 子 量 】178.1876 【元素组成】C 67.41% H 5.66% O 26.94% |
合成路线1
该中间体在本合成路线中的序号：(III)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：(I)Intermediate amine (X) was prepared as follows: Alkylation of 3,4-(methylenedioxy)phenylacetone (I) with iodoacetaldehyde diethyl acetal (II) provided racemic ketone (III), which was diastereoselectively reduced to alcohol (IV) with L-Selectride. Resolution was effected by esterification with (R)-alpha-methoxyphenylacetic acid, followed by chromatographic separation of the diastereoisomeric esters. The required isomer (V) was hydrolyzed under alkaline conditions and the resulting alcohol was converted to mesylate (VI) by treatment with methanesulfonyl chloride and Et3N. Displacement of the mesylate group of (VI) with NaN3 with inversion of the configuration yielded azide (VII), which was reduced to amine (VIII) using PPh3. Then, reductive condensation of (VIII) with 2-naphthalenecarboxaldehyde in the presence of NaBH4 afforded the secondary amine (X).
| 【1】 Aoyama, T.; et al.; A new class of highly potent farnesyl diphosphate-competitive inhibitors of farnesyltransferase. J Med Chem 1998, 41, 2, 143. |
| 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) | 28466 | 1-(1,3-benzodioxol-5-yl)acetone | 4676-39-5 | C10H10O3 | 详情 | 详情 |
| (II) | 28467 | 1,1-diethoxy-2-iodoethane | C6H13IO2 | 详情 | 详情 | |
| (III) | 28468 | 3-(1,3-benzodioxol-5-yl)-5,5-diethoxy-2-pentanone | C16H22O5 | 详情 | 详情 | |
| (IV) | 28469 | (2S,3R)-3-(1,3-benzodioxol-5-yl)-5,5-diethoxy-2-pentanol | C16H24O5 | 详情 | 详情 | |
| (V) | 28470 | (1S,2R)-2-(1,3-benzodioxol-5-yl)-4,4-diethoxy-1-methylbutyl (2R)-2-methoxy-2-phenylethanoate | C25H32O7 | 详情 | 详情 | |
| (VI) | 28471 | (1S,2R)-2-(1,3-benzodioxol-5-yl)-4,4-diethoxy-1-methylbutyl methanesulfonate | C17H26O7S | 详情 | 详情 | |
| (VII) | 28472 | 5-[(1R)-1-[(1R)-1-azidoethyl]-3,3-diethoxypropyl]-1,3-benzodioxole | C16H23N3O4 | 详情 | 详情 | |
| (VIII) | 28473 | (1R,2R)-2-(1,3-benzodioxol-5-yl)-4,4-diethoxy-1-methylbutylamine | C16H25NO4 | 详情 | 详情 | |
| (IX) | 28474 | 2-Naphthaldehyde | 66-99-9 | C11H8O | 详情 | 详情 |
| (X) | 28475 | (2R,3R)-3-(1,3-benzodioxol-5-yl)-5,5-diethoxy-N-(2-naphthylmethyl)-2-pentanamine | C27H33NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The chiral intermediate (S)-alpha-methyl-1,3-benzodioxole-5-ethanol (IV) was prepared by microbiological reduction of 3,4-methylenedioxyphenyl acetone (I) or, alternatively, by lithiation of 4-bromo-1,2-(methylenedioxy)benzene (II) with sec-butyllithium, followed by addition to (S)-propylene oxide (III). Hydrochloric acid-promoted condensation of (IV) with p-nitrobenzaldehyde (V) in hot toluene gave rise to the dioxolobenzopyran system (VIa-b), which was hydroxylated to (VIIa-b) by air oxidation under alkaline conditions. Hydrazone (IXa-b) was obtained as a mixture of E,Z isomers upon treatment of (VIIa-b) with 2-hydrazinopyridine (VIII) in refluxing EtOH. After mesylation of the alcohol group of (IXa-b) with methanesulfonyl chloride and triethylamine, the resulting mesylate (Xa-b) was cyclized to the dioxolo benzodiazepine (XI) using lithium tert-butoxide in THF. The nitro group of (XI) was finally reduced to the target aniline by transfer hydrogenation with potassium formate in the presence of Pd/C.
| 【1】 Anderson, B.A.; Harkness, A.R.; Hansen, M.V.; Harn, N.K.; Lodge, D.; Leander, J.D.; Synthesis and anticonvulsant activity of 3-aryl-5H-2,3-benzodiazepine AMPA antagonists. Bioorg Med Chem Lett 1999, 9, 14, 1953. |
| 【2】 Anderson, B.A.; Hansen, M.M.; Vicenzi, J.T.; Varie, D.L.; Zmijewski, M.J. Jr.; Harkness, A.R. (Eli Lilly and Company); Physical form of dihydro-2,3-benzodiazepine deriv.. EP 0699676; JP 1996081468; JP 1996081469; JP 1996092255; JP 1998505066; US 5795886 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 34410 | (5R,7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromene | C17H15NO5 | 详情 | 详情 | |
| (VIb) | 34411 | (5S,7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromene | C17H15NO5 | 详情 | 详情 | |
| (VIIa) | 34412 | (5R,7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-ol | C17H15NO6 | 详情 | 详情 | |
| (VIIb) | 34413 | (5S,7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-ol | C17H15NO6 | 详情 | 详情 | |
| (IXa) | 34415 | [6-[(2S)-2-hydroxypropyl]-1,3-benzodioxol-5-yl](4-nitrophenyl)methanone N-(2-pyridinyl)hydrazone | C22H20N4O5 | 详情 | 详情 | |
| (IXb) | 34416 | [6-[(2S)-2-hydroxypropyl]-1,3-benzodioxol-5-yl](4-nitrophenyl)methanone N-phenylhydrazone | C23H21N3O5 | 详情 | 详情 | |
| (Xa) | 34417 | (1S)-1-methyl-2-(6-[(4-nitrophenyl)[(E)-2-(2-pyridinyl)hydrazono]methyl]-1,3-benzodioxol-5-yl)ethyl methanesulfonate | C23H22N4O7S | 详情 | 详情 | |
| (Xb) | 34418 | (1S)-1-methyl-2-(6-[(4-nitrophenyl)[(Z)-2-phenylhydrazono]methyl]-1,3-benzodioxol-5-yl)ethyl methanesulfonate | C24H23N3O7S | 详情 | 详情 | |
| (I) | 28466 | 1-(1,3-benzodioxol-5-yl)acetone | 4676-39-5 | C10H10O3 | 详情 | 详情 |
| (II) | 10124 | 5-Bromo-1,3-benzodioxole; 4-Bromo-1,2-(methylenedioxy)benzene | 2635-13-4 | C7H5BrO2 | 详情 | 详情 |
| (III) | 29268 | (2S)-2-methyloxirane | 16088-62-3 | C3H6O | 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 |
| (VIII) | 34414 | 2-hydrazinopyridine | C5H7N3 | 详情 | 详情 | |
| (XI) | 34419 | (8R)-8-methyl-5-(4-nitrophenyl)-7-(2-pyridinyl)-8,9-dihydro-7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepine | C22H18N4O4 | 详情 | 详情 |