7-Oxo-2,3-dihydro-7H-pyrido

In terms of structural classes, Mitscher described seven cores that fall under the quinolonefamily, as shown below in Figure 4.1 (Mitscher, 2005). Of these cores, three templates have produced the most commercially successful drugs. They include the 4-0X0-1,4-dihydroquinolone (5), 7-oxo-2,3-dihydro-7H-pyrido-[l,2,3-d,e]-l,4-benzo-xazine (6), and the 4-oxo-l,4-dUiydro-[l,8]-naphthyridine cores (7). 

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). 

Reduction of 8-nitro-9,10-difluoro-7-oxo-2,3-dihydro-7H-pyrido[l,2, 3-cfe][l,4]benzoxazine-6-carboxamides with Na2S204 in aqueous MeOH under reflux for 5 h gave 8-amino derivatives in 51-74% yields (09WOP2009/035634). 8-Amino derivative was obtained from (S)-8-nitro-9-fluoro-10-(l-aminocyclopropyl)-7-oxo-2,3-dihydro-7/T-pyrido[l,2,3-de][l,4]benzoxazine-6-carboxylic acid by catalytic hydrogenation over Pd/C catalyst in AcOH (06MIP1). 

A C=C double bond present in a side chain in position 9 on 7-oxo-2, 3-dihydro-7H-pyrido[l,2,3-de][l,4]oxazine-6-carboxylic acid skeleton was catalytically reduced by H2 over 10% Pd/C catalyst (07WOP2007/054296). 

Difluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4] oxazine-6-carboxylate was obtained from 3(S)-CH2SMe and -CH2SCH2Ph derivatives by reductive cleavage with Raney Ni in EtOH at 30 °C (04MIP2). 

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,... 

Reaction of 7-oxo-2,3-dihydro-7H-pyrido[l, 2,3-de] [1,4]benzoxazine-6-carboxylic acid 210 (07WOP2007/090579) and its (S) enantiomer (07WOP2007/141900, 09JAP(K)2009/198177, 09USA2009/0029980,... 

Carboxamides were prepared when suspensions of 8-nitro-9,10-difluoro-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-cfe][l,4]benzoxazine-6-car-boxylic acids were heated in boiling SOCl2 for 2-3 h until clear solutions... 

For double cyclization of enamine 500 in DMSO in the presence of K2C03 at 70 °C for 4 h, at 120 °C for 2 h yielded 7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]benzoxazine-6-carboxylate374in75% yield (05MIP2). When enamine 500 was treated with crushed pellets of KOH under icecooling for 1.5 h, 10% aqueous KOH was added and the reaction mixture was heated at 85 °C for another 2 h the appropriate 9,10-difluoro-3,3-dimethyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]benzoxazine-6-car-boxylic acid was obtained in 83% yield (09WOP2009/035634). 7-Oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]benzoxazine-6-carboxylate 502 (R = Et, R1 = H, R2 = F, R3 = Me) and its racemic form was obtained similarly from... 

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