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【结 构 式】

【药物名称】Dantrolene sodium, F-440, Dantrium

【化学名称】1-[5-(4-Nitrophenyl)furfurylideneamino]hydantoin sodium salt

【CA登记号】14663-23-1, 7261-97-4 (free acid)

【 分 子 式 】C14H9N4NaO5

【 分 子 量 】336.24143

【开发单位】Procter & Gamble (Originator)

【药理作用】Antispastic Drugs and Drugs for Muscle Spasms, Muscle Spasms, Drugs for, NEUROLOGIC DRUGS, Smooth Muscle Relaxants

合成路线1

Diazotization of 4-nitroaniline (I), followed by copper-catalyzed coupling of the resultant diazonium salt (II) with 2-furaldehyde (III) leads to 5-(p-nitrophenyl)-2-furancarboxaldehyde (IV) (1). Cyclization of semicarbazideacetic acid (V) by heating in aqueous sulfuric acid leads to 1-aminohydantoin (VI) (2). This is then condensed with aldehyde (IV) to furnish the furfurylidene aminohydantoin (VII) (1, 2). Treatment of (VII) with sodium methoxide gives rise to the corresponding sodium salt (1).

1 Frimm, R.; Kovac, S.; Giller, S.A.; Furan derivatives. XXIII. Synthesis and absorption spectra of 5-(nitrophenyl)-2-furaldehyde derivatives. Chem Zvesti 1969, 23, 11-12, 916.
2 Snyder, H.R. Jr.; Davis, C.S.; Bickerton, R.K.; Halliday, R.P.; 1-[(5-Arylfurfurylidene)amino]hydantoins. A new class of muscle relaxants. J Med Chem 1967, 10, 5, 807.
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) 15547 4-nitrophenylamine; p-Nitroaniline; 4-nitroaniline 100-01-6 C6H6N2O2 详情 详情
(II) 61431 4-nitrobenzenediazonium C6H4N3O2 详情 详情
(III) 63582 2-furaldehyde C5H4O2 详情 详情
(IV) 63583 5-(4-nitrophenyl)-2-furaldehyde C11H7NO4 详情 详情
(V) 63584 2-[1-(aminocarbonyl)hydrazino]acetic acid C3H7N3O3 详情 详情
(VI) 63585 1-amino-2,4-imidazolidinedione C3H5N3O2 详情 详情
(VII) 63586 1-({(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}amino)-2,4-imidazolidinedione C14H10N4O5 详情 详情

合成路线2

In an alternative method, condensation of semicarbazide hydrochloride (I) with cyclohexanone (II) yields the semicarbazone (III). Subsequent reaction of (III) with ethyl chloroacetate (IV) in the presence of NaOMe gives rise to the cyclohexylidene aminohydantoin (V). Treatment of (V) with 5-(p-nitrophenyl)furfural (VI) under acidic conditions affords the furfurylidene aminohydantoin (VII). This is finally converted into the corresponding sodium salt employing methanolic NaOMe (3).

1 Martin-Escudero Perez, U.; Izquierdo Sanjose, M.; Process for obtaining 1-[(5-(p-nitrophenyl)furfuryliden)amino]hydantoin and its sodium salt. ES 458000 .
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) 23944 1-Hydrazinecarboxamide 563-41-7 CH5N3O 详情 详情
(II) 11059 Cyclohexanone 108-94-1 C6H10O 详情 详情
(III) 63587 2-cyclohexylidene-1-hydrazinecarboxamide C7H13N3O 详情 详情
(IV) 16601 ethyl chloroacetate; ethyl 2-chloroacetate 105-39-5 C4H7ClO2 详情 详情
(V) 63588 1-(cyclohexylideneamino)-2,4-imidazolidinedione C9H13N3O2 详情 详情
(VI) 63583 5-(4-nitrophenyl)-2-furaldehyde C11H7NO4 详情 详情
(VII) 63586 1-({(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}amino)-2,4-imidazolidinedione C14H10N4O5 详情 详情

合成路线3

The title compound has also been obtained by solid phase synthesis. Bromoacetic acid (I) is coupled to hydroxymethyl polystyrene resin by means of DIC/DMAP to produce the bromoacetyl resin (II). Bromide displacement with tert-butyl carbazate (III) leads to the N-Boc hydrazino ester (IV), which is further deprotected to (V) employing trifluoroacetic acid. The hydrazinoacetic acid-bound resin (V) is then condensed with 5-(p-nitrophenyl)furfural (VI) to furnish hydrazone (VII). Acylation of resin (VII) with p-nitrophenyl chloroformate (VIII) produces the p-nitrophenyl carbamate (IX), which upon treatment with ammonia gives rise to the semicarbazone (X). Finally, concomitant intramolecular ring closure and resin cleavage of (X) produces the target aminohydantoin derivative (XI) (4, 5).

1 Wilson, L.J.; Li, M.; Portlock, D.E.; Solid phase synthesis of 1-aminohydantoin libraries. Tetrahedron Lett 1998, 39, 29, 5135.
2 Portlock, D.E.; Li, M.; Wilson, L.J. (The Procter & Gamble Co.); Solid phase synthesis of 1-aminohydantoins. WO 9942450 .
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) 23660 2-Bromoacetic acid 79-08-3 C2H3BrO2 详情 详情
(II) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(III) 12091 1-Methylhydrazine; Monomethyl hydrazine 60-34-4 CH6N2 详情 详情
(IV) 63589 2-[2-(tert-butoxycarbonyl)hydrazino]acetic acid C7H14N2O4 详情 详情
(V) 63590 2-hydrazinoacetic acid C2H6N2O2 详情 详情
(VI) 63583 5-(4-nitrophenyl)-2-furaldehyde C11H7NO4 详情 详情
(VII) 63591 2-(2-{(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}hydrazino)acetic acid C13H11N3O5 详情 详情
(VIII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(IX) 63592 2-(1-[(4-nitrophenoxy)carbonyl]-2-{(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}hydrazino)acetic acid C20H14N4O9 详情 详情
(X) 63593 2-(1-(aminocarbonyl)-2-{(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}hydrazino)acetic acid C14H12N4O6 详情 详情
(XI) 63586 1-({(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}amino)-2,4-imidazolidinedione C14H10N4O5 详情 详情
Extended Information