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Name Dantrolene sodium;F-440;Dantrium
Chemical Name 1-[5-(4-Nitrophenyl)furfurylideneamino]hydantoin sodium salt
CAS 14663-23-1
Related CAS 7261-97-4 (free acid)
Formula C14H9N4NaO5
Structure
Formula Weight 336.24143
Stage 上市-1971
Company Procter & Gamble (Originator)
Activity/Mechanism Antispastic Drugs and Drugs for Muscle Spasms, Muscle Spasms, Drugs for, NEUROLOGIC DRUGS, Smooth Muscle Relaxants
Syn. Route 3
Route 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).
List of intermediates No.
tert-butyl (3r,5r)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1h-pyrrol-1-yl]-3,5-dihydroxyheptanoate (i)
Reference 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.
Reference 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.

Route 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).
List of intermediates No.
(2r,3s)-1,1,1-trifluoro-4-methyl-3-nitro-2-pentanol (ii)
3,4-dimethoxy-9-phenanthrenamine (iv)
ethyl (e)-3-(2-furyl)-2-propenoate (i)
Reference 1:
    martin-escudero perez, u.; izquierdo sanjose, m.; process for obtaining 1-[(5-(p-nitrophenyl)furfuryliden)amino]hydantoin and its sodium salt. es 458000 .

Route 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).
List of intermediates No.
(7s,9s)-9-acetyl-9-amino-6,7,11-trihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione (iii)
methyl 4-[(2r,3as,8bs)-2-(acetoxy)-1-formyl-2,3,3a,8b-tetrahydro-1h-cyclopenta[b][1]benzofuran-5-yl]butanoate (ii)
2-(4-methoxyphenyl)-2-propanol (viii)
(4ar,4bs,6as,7s,9as,9bs,11ar)-n,n-diethyl-4a,6a-dimethyl-2-oxohexadecahydro-1h-indeno[5,4-f]quinoline-7-carboxamide (i)
Reference 1:
    wilson, l.j.; li, m.; portlock, d.e.; solid phase synthesis of 1-aminohydantoin libraries. tetrahedron lett 1998, 39, 29, 5135.
Reference 2:
    portlock, d.e.; li, m.; wilson, l.j. (the procter & gamble co.); solid phase synthesis of 1-aminohydantoins. wo 9942450 .

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名丹曲林钠;英文名Dantrolene sodium;F-440;Dantrium;CAS[14663-23-1]

 
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