Ofloxacin → Ethyl 9,10-difluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate

HRID 1603317

Reaktionsgleichung

Reaktionsgleichung von HRID 1603317
CC1N2C3C(C(C(C(O)=O)=C2)=O)=CC(F)=C(N2CCN(C)CC2)C=3OC1.FC1C(F)=C(F)C=CC=1[N+]([O-])=O.OC1C(F)=C(F)C=CC=1[N+]([O-])=O.[OH-].[K+].[CH2:53]([O:57][C:58]1[C:63]([F:64])=[C:62]([F:65])[CH:61]=[CH:60][C:59]=1[N+:66]([O-])=O)[C:54]([CH3:56])=O.FC1C=CC2NC(C)COC=2C=1F.[CH2:82]=[C:83]([C:104]([O-])=[O:105])[C:84]([O:86][CH:87]1[CH:92](C)NC2C(CC)=C(CC)C(F)=C(F)C=2O1)=[O:85]>CS(C)=O>[F:65][C:62]1[C:63]([F:64])=[C:58]2[O:57][CH2:53][CH:54]([CH3:56])[N:66]3[CH:82]=[C:83]([C:84]([O:86][CH2:87][CH3:92])=[O:85])[C:104](=[O:105])[C:60]([CH:61]=1)=[C:59]23

Komponenten

9

Edukt 7

HCID 4583Ofloxacin2×HCID 14797Potassium HydroxideHCID 698711,2,3-Trifluoro-4-nitrobenzeneHCID 12682411-(2,3-Difluoro-6-nitrophenoxy)propan-2-oneHCID 27337452,3-Difluoro-6-nitrophenol2×HCID 102197187,8-Difluoro-2,3-dihydro-3-methyl-4H-(1,4)benzoxazine2×HCID 131720077diethyl-(7,8-difluoro-2,3-dihydro-3-methyl 4H 1,4 benzoxazinyl) methylenemalonate

Produkt 1

HCID 3751628Ethyl 9,10-difluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 679Dimethyl SulfoxideLösungsmittel

Versuchsvorschrift

Hayakawa's method of preparation of Ofloxacin is described in EP 0047005A1 and starts with 2,3,4-trifluoronitrobenzene which is converted to the 2-hydroxy-3,4-difluoronitrobenzene in dimethylsulfoxide in the presence of potassium hydroxide. The yield for this reaction is only 29%. The low yield of this step limits the overall yield of Hayaklawa's process. Other patents cite the use of this material in their routes to Ofloxacin; e.g. U.S. Pat. No. 5,136,059 and EP 0333815 A2. The 2-hydroxy-3,4 difluoronitrobenzene is converted to 2-acetonyloxy-3,4-difluoronitro-benzene which is reductively ring closed to give an isomeric mixture of 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-berizoxazine (Formula 1). This material is converted to diethyl-(7,8-difluoro-2,3-dihydro-3-methyl 4H 1,4 benzoxazinyl) methylenemalonate by reaction with diethylethoxymethylenamalonate. Cyclization of this malonate ester in ethylpolyphosphate gives (+,-)-ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de] [1,4]benzoxazine-6-carboxylate. This benzoxazine carboxylate ester is then hydrolyzed to the corresponding acid. The acid is reacted with N-methylpiperazine in dimethylsulfoxide to form Ofloxacin, 9-fluoro-10-(4-methyl-1-piperazinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de] [1,4]benzoxazine-6-carboxylic acid. The reaction sequence is shown below: ##STR1##

Aufarbeitung

  1. customThe yield for this reaction
  2. customclosed
  3. customto give

Quellen und Nachweise

ORD-Eintrag
ord-df609811ac684c0cb1dda96a560bed73
Quelldatensatz
uspto-grants-1999_11
Patentnummer
US05986140

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