|
【结 构 式】 
|
【药物名称】Midazolam maleate, Ro-21-3981/003(HCl), Ro-21-3981/001, Versed, Hypnovel, Dormicum 【化学名称】8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine maleate 【CA登记号】59467-94-6, 59467-70-8 (free base), 59467-96-8 (HCl) 【 分 子 式 】C22H17ClFN3O4 【 分 子 量 】441.84989 |
【开发单位】Roche (Originator), Yamanouchi (Not Determined) 【药理作用】PSYCHOPHARMACOLOGIC DRUGS, Sedative/Hypnotics, Sleep Disorders, Treatment of, Benzodiazepines, GABA(A) BZ Site Receptor Agonists |
合成路线1
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
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 |