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【结 构 式】

【分子编号】31965

【品名】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

【CA登记号】

【 分 子 式 】C10H9FN2O2

【 分 子 量 】208.1921432

【元素组成】C 57.69% H 4.36% F 9.13% N 13.46% O 15.37%

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:(VI)

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

该中间体在本合成路线中的序号:(I)

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
Extended Information