9-Fluoro-10- oxazine-6-carboxylic acid

Perhydro derivatives of pyrido[l,2-6][l,2]oxazines are frequently applied in the total synthesis of various alkaloids to control the stereochemistry, and 4-(substituted amino)-5-fluoro-7-oxo derivatives of 3,7-dihydro-2//-pyrido[3,2,l-f7][2,l]benzoxazine- and l,2,3,7-tetrahydropyrido[3,2,l-//]cin-noline-8-carboxylic acids are considered as a subfamily of the third generation of antibacterial quinolones. 

The fluoro substituents proved to induce changes in the reactivities of the methyl- (X = H) and trifluoromethyl-substituted (X = F) pyrido[3, 2 4,5]furo[3,2- [l,3]oxazin-4(47r)-ones 105 with nucleophiles. When methyl-substituted compounds 105 (X = H) were reacted with piperidine in toluene, Wacetylamino carboxamides 106 were formed by nucleophilic attack at the carbonyl group of the l,3-oxazin-4-one ring (Scheme 16). However, the similar reactions of the trifluoromethyl-substituted analogs 105 (X = F) resulted in formation of amidino carboxylic acids 107 by attack at electron-poor position 2 <1995JFC(74)1>. 

Reaction of diacetatoboron chelate 198 with cyclic amines (09USA2009/0156577), 2-aminomethylaziridine (06CCL1431), followed by hydrolysis provided 10-substituted 3(S)-methyl-9-fluoro-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]oxazine-6-carboxylic acids. 

Reaction of 9-fluoro-7-oxo-2,3-dihydro7H-pyrido[l,2,3-de][l,4]oxa-zine-6-carboxylate and ferf-butyl (2-mercaptoethyl)carbamate in DMSO at 100 °C for 5 h gave 9-[2-(ferc-butoxycarbonylamino)ethylthio] derivative (06WOP2006/050943). The iodo atom of 9-iodo-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]oxazine-6-carboxylic acids was coupled with 4 -0-(2-allyloxyethyl)azithromicin in MeCONMe2 in the presence of Bu3N and fra s-di-g-acetato-bis[2-(di-o-tolylphosphino)benzyl]dipalladium(II) and di(ferf-butyl)-4-methylphenol at 110-115 °C for 15-17 h to give a mixture of 9-(3-substituted prop-1- and -2-enyl) derivatives (07WOP2007/ 054296). 10-methoxy and 10-cyano-3-hydroxymethyl-2,3-dihydro-5H-pyr-ido[l,2,3-de][l,4]benzoxazin-5-ones were obtained from 10-bromo derivative by reaction with NaOMe in the presence of Cu(I)I at 140 °C in DMF,... 

Optically active pipecolic acid and its derivatives can be prepared via 4-phenylpyrido[2,l-c][l,4]oxazin-l-one derivatives. Representatives of the third generation of quinoline-3-carboxylic acid antibacterial agents ofloxacin (19), its levorotatory enantiomer, levofloxacin (20), and rufloxacin (21) have gained wide acceptance for the treatment of bacterial infections of the respiratory and urinary tracts, skin, and soft tissues, as well as sexually transmitted diseases, and pazufloxacin (22) is under development. Other 10-aryl-9-fluoro-7-oxo-2,3-dihydro-7//-pyrido[l,2,3-de]-l,4-benzox-azine-6-carboxylic acids and 7//-pyrido[l,2,3-de]-l,4-benzothiazine-6-carboxylic acids exhibit mammalian topoisomerase II inhibitory activity. 

Oxidation of 3-hydroxymethyl-2,3-dihydro-5H-pyrido[l,2,3-cfe][1,4] benzoxazin-5-ones with o-iodoxybenzoic acid in DMSO and with Dess-Martin periodinate in CH2CI2 afforded 3-formyl derivatives (08WOP2008/ 120003). Dehydrogenation of ethyl 10-[2-(ferf-butoxycarbonyl)-l,2,3,4,6,8a-hexahydropyrrolo[l,2-a]pyrazin-7-yl]-9-fluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]oxazine-6-carboxylates in the presence of Pd/C with air in MeOH afforded 10-[2-(ferf-butoxycarbonyl)-l, 2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-7-yl] derivatives, which then were deprotected (09BML4933). 

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