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【结 构 式】 
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【药物名称】Flumazepil, Flumazenil, RO-151788, Romazicon, Mazicon, Anexate 【化学名称】Ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate 【CA登记号】78755-81-4 【 分 子 式 】C15H14FN3O3 【 分 子 量 】303.29553 |
【开发单位】Roche (Originator), Yamanouchi (Licensee) 【药理作用】Antagonists to Benzodiazepines, Specific Antidotes, TREATMENT OF POISONING, DRUG ABUSE & DEPENDENCY, GABA(A) BZ Site Receptor Antagonists |
合成路线1
The oxidation of 2-nitro-5-fluorotoluene (I) with KMnO4 in water gives 2-nitro-5-fluorobenzoic acid (II), which by reduction with H2 over Pd/C in methanol - aqueous HCl yields 2-amino-5-fluorobenzoic acid (III). The reaction of (III) with phosgene in THF aqueous HCl affords 5-fluoroisatoic acid anhydride (IV), which by cyclization with N-methylglycine (V) in OMS at 100 C affords 7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzodiazepin-2,5(1H)-dione (VI). Finally, this compound is cyclized again with ethyl isocyanacetate (VII) by means of potassium tert-butylate and diethyl chlorophosphate in DMF.
| 【1】 Haefely, W.; Hunkeler, W.; Kyburz, E.; Mohler, H.; Pieri, L.; Polc, P.; Gerecke, M. (F. Hoffmann-La Roche AG); Imidazodiazepine derivatives. EP 0027214; GB 2060632; JP 1156968; US 4316839; US 4346033 . |
| 【2】 Blancafort, P.; Castaner, J.; Hillier, K.; Serradell, M.N.; RO-15-1788. Drugs Fut 1982, 7, 6, 402. |
| 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) | 20612 | 4-Fluoro-2-methyl-1-nitrobenzene; 2-Nitro-5-fluorotoluene | 446-33-3 | C7H6FNO2 | 详情 | 详情 |
| (II) | 31962 | 2-Nitro-5-fluorobenzoic acid; 5-Fluoro-2-nitrobenzoic acid | 320-98-9 | C7H4FNO4 | 详情 | 详情 |
| (III) | 31963 | 2-Amino-5-fluorobenzoic acid | 446-08-2 | C7H6FNO2 | 详情 | 详情 |
| (IV) | 31964 | 6-Fluoro-2H-3,1-benzoxazine-2,4(1H)-dione; 5-Fluoroisatoic acid anhydride | C8H4FNO3 | 详情 | 详情 | |
| (V) | 10429 | N-Methylglycine; Sarcosine; 2-(Methylamino)acetic acid | 107-97-1 | C3H7NO2 | 详情 | 详情 |
| (VI) | 31965 | 7-Fluoro-4-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione; 7-Fluoro-4-methyl-3,4-dihydro-2H-1,4-benzodiazepin-2,5(1H)-dione | C10H9FN2O2 | 详情 | 详情 | |
| (VII) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
合成路线2
The cyclization of anhydride (IV) with N-(2,4-dimethoxybenzyl)glycine (VIII) as before gives 7-fluoro-4-(2,4dimethoxybenzyl)-3,4-dihydro-2H-1,4-benzodiazepin-2,5(1H)-dione (IX), which by a new cyclization with (VII) as before is converted into ethyl-8-fluoro-5-(2,4dimethoxybenzyl)-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (X). The deprotection of (X) with trifluoroacetic acid yields ethyl-8-fluoro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (XI), which is finally methylated with methyl iodide and NaH in DMF.
| 【1】 Haefely, W.; Hunkeler, W.; Kyburz, E.; Mohler, H.; Pieri, L.; Polc, P.; Gerecke, M. (F. Hoffmann-La Roche AG); Imidazodiazepine derivatives. EP 0027214; GB 2060632; JP 1156968; US 4316839; US 4346033 . |
| 【2】 Blancafort, P.; Castaner, J.; Hillier, K.; Serradell, M.N.; RO-15-1788. Drugs Fut 1982, 7, 6, 402. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 31964 | 6-Fluoro-2H-3,1-benzoxazine-2,4(1H)-dione; 5-Fluoroisatoic acid anhydride | C8H4FNO3 | 详情 | 详情 | |
| (VII) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (VIII) | 31966 | N-(2,4-dimethoxybenzyl)glycine; 2-[(2,4-Dimethoxybenzyl)amino]acetic acid | C11H15NO4 | 详情 | 详情 | |
| (IX) | 31967 | 4-(2,4-dimethoxybenzyl)-7-fluoro-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione | C18H17FN2O4 | 详情 | 详情 | |
| (X) | 31968 | Ethyl 5-(2,4-dimethoxybenzyl)-8-fluoro-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate; Ethyl-8-fluoro-5-(2,4dimethoxybenzyl)-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate | C23H22FN3O5 | 详情 | 详情 | |
| (XI) | 31969 | ethyl 8-fluoro-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate | C14H12FN3O3 | 详情 | 详情 |
合成路线3
The reaction of 7-fluoro-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,5-dione (I) with POCl3 and N,N-dimethyl-p-toluidine in hot toluene gives 2-chloro-7-fluoro-4-methyl-4,5-dihydro-3H-1,4-benzodiazepin-5 one (II), which is condensed with N-(dimethylaminomethylene)glycine ethyl ester (III) (obtained by condensation of glycine ethyl ester (IV) with dimethylformamide (V) and TEA in dichloromethane) to yield a mixture of intermediates (VI) and (VII). Finally, these compounds are cyclized in refluxing AcOH to provide the target flumazenil.
| 【1】 Rogers-Evans, M.; Spurr, P.; Hennig, M.; The isolation and use of a benzodiazepine iminochloride for the efficient construction of flumazenil. Tetrahedron Lett 2003, 44, 11, 2425. |
| 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) | 31965 | 7-Fluoro-4-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione; 7-Fluoro-4-methyl-3,4-dihydro-2H-1,4-benzodiazepin-2,5(1H)-dione | C10H9FN2O2 | 详情 | 详情 | |
| (II) | 64506 | 2-chloro-7-fluoro-4-methyl-3,4-dihydro-5H-1,4-benzodiazepin-5-one | C10H8ClFN2O | 详情 | 详情 | |
| (III) | 64507 | ethyl 2-{[(E)-(dimethylamino)methylidene]amino}acetate | C7H14N2O2 | 详情 | 详情 | |
| (IV) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (V) | 33491 | Dimethylformamide | 68-12-2 | C3H7NO | 详情 | 详情 |
| (VI) | 64508 | ethyl 2-{[(E)-(dimethylamino)methylidene]amino}-2-(7-fluoro-4-methyl-5-oxo-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-ylidene)acetate | C17H21FN4O3 | 详情 | 详情 | |
| (VII) | 64509 | ethyl 2-{[(E)-(dimethylamino)methylidene]amino}-2-(7-fluoro-4-methyl-5-oxo-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-ylidene)acetate | C17H21FN4O3 | 详情 | 详情 |