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药物详细合成路线

Name Danofloxacin mesylate;CP-76136-27;Advocin
Chemical Name 1-Cyclopropyl-6-fluoro-7-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid monomethanesulfonate
CAS 119478-55-6
Related CAS 112398-08-0 (free base)
Formula C20H24FN3O6S
Structure
Formula Weight 453.49318
Stage II 期临床
Company Pfizer (Originator)
Activity/Mechanism Antibacterial Drugs, ANTIINFECTIVE THERAPY, Quinolones
Syn. Route 1
Route 1
danofloxacin (xi) is synthesized by the addition of (1s,4s)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (vii) and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (x), and further converted to its monomethanesulfonate salt as outlined in scheme 17912701a:the diazabicycloalkane sidechain (vii) is prepared in one of two ways, both routes starting with trans-4-hydroxy-l-proline (i). in the first sequence, the amino acid (i) is selectively monotosylated on nitrogen by stirring an aqueous solution of (i) in the presence of p-toluenesulfonyl chloride (tscl) with sodium carbonate as base. the monotosylate (ii) is then reduced to the diol (iii) with diborane generated in situ. the diol (iii) is next converted to either the tritosylate (iv) selectively or to a mixture of (iv) and the monochloride (v) by treatment with excess tscl in pyridine at either 0 c or room temperature, respectively. either pure (iv) or a mixture of (iv) and (v) can be cyclized equally well to the bicyclic intermediate (vi) by treatment with methylamine in a sealed container. finally, (vi) can be deprotected to give the desired (1s,4s)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (vii) in excellent overall yield by treatment with 30% anhydrous hydrogen bromide in acetic acid.by an alternative route, (i) is esterified under fischer conditions and treated with excess p-toluenesulfonyl chloride in the presence of pyridine and triethylamine. the resulting ester (viii) is then treated with methylamine to obtain the amide (ix), which is reductively cyclized with lithium aluminum hydride to the bicyclic intermediate (vi). finally, (vi) is deprotected as described above to give (vii). the reaction of (1s,4s)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (vii) with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (x) to give danofloxacin free base (xi) is effected by the action of 1,8-diazabicyclo[5.4.0]undec-7-ene (dbu) in pyridine. conversion of (xi) to danofloxacin mesylate using one equivalent of methanesulfonic acid in ethanol completes the synthesis.
List of intermediates No.
2-[5-(bis(benzoyloxy)[bis[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1h-indol-5-yl]]-lambda(5)-bismuthanyl)-1h-indol-1-yl]ethyl tert-butyl(dimethyl)silyl ether (i)
3-amino-2-thiophenecarboxamide (ii)
pentanoic anhydride (iii)
2-butylthieno[3,2-d]pyrimidin-4(3h)-one (iv)
2-butyl-4-chlorothieno[3,2-d]pyrimidine (v)
3-amino-2-thiophenecarboxylic acid methyl ester; methyl 3-amino-2-thiophenecarboxylate (vi)
3-amino-2-thiophenecarboxylic acid (vii)
4-(2,4-dichlorophenyl)-3-methyl-1h-pyrazol-5-amine (viii)
3-(2,4-dichlorophenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7(4h)-one (ix)
7-chloro-3-(2,4-dichlorophenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine (x)
benzyl (2s)-2-amino-5-methylhexanoate (xi)
Reference 1:
    fox, d.e.; braish, t.f.; synthesis of (s,s)- and (r,r)-2-alkyl-2,5-diazabicyclo[2.2.1]heptanes. j org chem 1990, 55, 1684-7.
Reference 2:
    braish, t.f.; fox, d.e. (pfizer inc.); process for optically active 2-alkyl-2,5-diazabicyclo(2.2.1)heptanes. us 5013839 .
Reference 3:
    mcguirk, p.r.; jefson, m.r.; mann, d.d.; et al.; synthesis and structure-activity relationships of 7-diazabicycloalkylquinolones, including danofloxacin, a new quinolone antibacterial agent for veterinary medicine. j med chem 1992, 35, 4, 611.
Reference 4:
    jefson, m.r.; shryock, t.r.; schaaf, t.k.; mcguirk, p.r.; the synthesis and antibacterial activity of danofloxacin (cp-76,136): a new quinolone for veterinary medicine. 29th intersci conf antimicrob agents chemother (sept 17-20, houston) 1989, abst 1187.
Reference 5:
    mcguirk, p.r.; jefson, m.r.; danofloxacin mesylate. drugs fut 1992, 17, 2, 93.

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甲磺酸达氟沙星;英文名Danofloxacin mesylate;CP-76136-27;Advocin;CAS[119478-55-6]

 
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