|
【结 构 式】 
|
【分子编号】33355 【品名】7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one 【CA登记号】2886-65-9 |
【 分 子 式 】C15H10ClFN2O 【 分 子 量 】288.7083832 【元素组成】C 62.4% H 3.49% Cl 12.28% F 6.58% N 9.7% O 5.54% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (I) with methylamine by means of TiCl4 in refluxing benzene gives 7-chloro-5-(2-fluorophenyl)-2-methylamino-3H-1,4-benzodiazepine (II), which by reaction with NaNO2 in acetic acid is converted into its N-nitroso derivative (III). The treatment of (III) with nitromethane and potassium tert-butoxide in DMF affords 7-chloro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine (IV), which is reduced with H2 over Raney-Ni in THF affording the 2-aminomethyl derivative (V).The acetylation of (V) with acetic anhydride in CH2Cl2 gives the acetamide (VI), which is cyclized with polyphosphoric acid at 150 C yielding 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (VII). The deshydrogenation of (VII) with MnO2 in refluxing toluene affords 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (VIII), which is finally treated with maleic acid (A) in hot ethanol.
| 【1】 Fryer, R.I.; Walser, A.; Benzo or heterocyclic fused imidazodiazepines and pharmaceutical compositions containing them. BE 0833248; DE 2540522; FR 2303016; GB 1527131; JP 51125099 . |
| 【2】 Dhaon, M.K. (Abbott Laboratories Inc.); Process for the preparation of midazolam. WO 0170744 . |
| 【3】 Thorpe, P.; Castaner, J.; Midazolam Maleate. Drugs Fut 1978, 3, 11, 822. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 |
| (I) | 33355 | 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one | 2886-65-9 | C15H10ClFN2O | 详情 | 详情 |
| (II) | 33558 | N-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-yl]-N-methylamine; 7-chloro-5-(2-fluorophenyl)-N-methyl-3H-1,4-benzodiazepin-2-amine | C16H13ClFN3 | 详情 | 详情 | |
| (III) | 33559 | N-[7-Chloro-5-(2-fluorophenyl)-3H-1,3-benzodiazepin-2-yl]-N-methyl-N-nitrosoamine | C16H12ClFN4O | 详情 | 详情 | |
| (IV) | 33560 | 7-chloro-5-(2-fluorophenyl)-2-[(Z)-nitromethylidene]-1,3-dihydro-2H-1,4-benzodiazepine | C16H11ClFN3O2 | 详情 | 详情 | |
| (V) | 33561 | [7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]methanamine; [7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]methylamine | C16H15ClFN3 | 详情 | 详情 | |
| (VI) | 33562 | N-[[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]methyl]acetamide | C18H17ClFN3O | 详情 | 详情 | |
| (VII) | 33563 | 8-chloro-6-(2-fluorophenyl)-1-methyl-3a,4-dihydro-3H-imidazo[1,5-a][1,4]benzodiazepine | C18H15ClFN3 | 详情 | 详情 | |
| (VIII) | 33564 | 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine | 59467-70-8 | C18H13ClFN3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (I) with methylamine by means of TiCl4 in refluxing benzene gives 7-chloro-5-(2-fluorophenyl)-2-(methylamino)-3H-1,4-benzodiazepine (II), which is treated with NaNO2 and HOAc to yield the nitroso derivative (III). The condensation of (III) with dimethyl malonate (IV) by means of potassium tert-butoxide in DMF affords 2-[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-ylidene]malonic acid dimethyl ester (V), which is monodecarboxylated with KOH in refluxing methanol, providing the corresponding acetate (VI). The reaction of (VI) with NaNO2 and HOAc gives the hydroxyimino derivative (VII), which is reduced with H2 over RaNi in hot methanol to provide the expected amino derivative (VIII). The cyclization of (VIII) with triethyl orthoacetate (IX) and HCl in refluxing ethanol affords 8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid methyl ester (X), which is hydrolyzed with KOH in refluxing methanol/water to provide the corresponding free acid (XI). Finally, this compound is decarboxylated by heating in refluxing ethyleneglycol to give the target compound along with some 6H-isomer that is separated by chromatography. Alternatively, the decarboxylation of (XI) can also be performed in mineral oil at 230 C to obtain a better yield of the target compound.
| 【1】 Bhatia, A.V.; Dhaon, M.K.; Davis, D.A.; Esser, G.L. (Abbott Laboratories Inc.); Process for the preparation of midazolam. WO 0102402 . |
| 【2】 Walser, A.; Fryer, R.I. (F. Hoffmann-La Roche AG); Process for the preparation of diazepine derivs.. DE 2609486; GB 1549836 . |
| 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) | 33355 | 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one | 2886-65-9 | C15H10ClFN2O | 详情 | 详情 |
| (II) | 33558 | N-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-yl]-N-methylamine; 7-chloro-5-(2-fluorophenyl)-N-methyl-3H-1,4-benzodiazepin-2-amine | C16H13ClFN3 | 详情 | 详情 | |
| (III) | 33559 | N-[7-Chloro-5-(2-fluorophenyl)-3H-1,3-benzodiazepin-2-yl]-N-methyl-N-nitrosoamine | C16H12ClFN4O | 详情 | 详情 | |
| (IV) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (V) | 44390 | dimethyl 2-[7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylidene]malonate | C20H16ClFN2O4 | 详情 | 详情 | |
| (VI) | 44391 | methyl 2-[7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylidene]acetate | C18H14ClFN2O2 | 详情 | 详情 | |
| (VII) | 44392 | methyl 2-[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]-2-(hydroxyimino)acetate | C18H15ClFN3O3 | 详情 | 详情 | |
| (VIII) | 44393 | methyl 2-amino-2-[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]acetate | C18H17ClFN3O2 | 详情 | 详情 | |
| (IX) | 12940 | 1,1-Diethoxyethyl ethyl ether; 1,1,1-Triethoxyethane; Triethyl orthoacetate | 78-39-7 | C8H18O3 | 详情 | 详情 |
| (X) | 44394 | methyl 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate | C20H15ClFN3O2 | 详情 | 详情 | |
| (XI) | 44395 | 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid | C19H13ClFN3O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXI)The dehydration of the amide (XVIII) with refluxing POCl3 gives the corresponding nitrile (XIX), which by reduction with LiAlH4 in ether is converted into the 2-aminomethyl derivative (XX). The treatment of (XX) with CrO3 in acetic acid yields 5-(2-fluorophenyl)-7chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXI) (1,10), which is finally N-alkylated with cyclopropylmethy bromide (A) by means of phenyllithium in THF.
| 【1】 Yamamoto, H.; et al.; ZA 6806061 . |
| 【2】 Okamoto, T.; et al.; Process for producing 1-substituted benzodiazepine derivatives. DE 2151540; FR 2110017; GB 1338106; NL 7114202; US 3832344 . |
| 【3】 Yamamoto, H.; et al. (Sumitomo Chemical Co., Ltd.); Process for producing benzodiazepine derivatives. US 3632574 . |
| 【4】 Blancafort, P.; Serradell, M.N.; Castaner, J.; KB-509. Drugs Fut 1979, 4, 10, 720. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 22277 | Cyclopropyl bromide; 1-(Bromomethyl)cyclopropane | 7051-34-5 | C4H7Br | 详情 | 详情 |
| (XVIII) | 33352 | 5-chloro-3-(2-fluorophenyl)-1H-indole-2-carboxamide | C15H10ClFN2O | 详情 | 详情 | |
| (XIX) | 33353 | 5-chloro-3-(2-fluorophenyl)-1H-indole-2-carbonitrile | C15H8ClFN2 | 详情 | 详情 | |
| (XX) | 33354 | [5-chloro-3-(2-fluorophenyl)-1H-indol-2-yl]methanamine; [5-chloro-3-(2-fluorophenyl)-1H-indol-2-yl]methylamine | C15H12ClFN2 | 详情 | 详情 | |
| (XXI) | 33355 | 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one | 2886-65-9 | C15H10ClFN2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)By reaction of 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (I) with ethylene oxide (II) by means of AlCl3 in benzene
| 【1】 Derieg, M.E.; et al. (Hoffmann-La Roche, Inc.); DE 1952486 . |
| 【2】 Castaner, J.; Blancafort, P.; Flutazolam. Drugs Fut 1977, 2, 12, 803. |