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【结 构 式】 
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【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 |