1.5- Naphthyridine-3-carboxylates 4-chloro

Treatment of ethyl 4-chloro-7-diethylamino-6-nitro-l,8-naphthyridine 3-carboxylate (104) with the amines RH [R = N(CH2)s NH(CH2)N(C2Hs)2] gives the corresponding 4-amino derivatives [105, R = N(CH2)s, 74% and 105, R = NH(CH2)N(C2Hs)2, 50%]. With diethylamine the 7-chloro-6-nitro derivative of nalidixic acid (i.e., 106) yields the 7-diethylamino compound 107 (62%) (79YZ155). 

The synthesis of the corresponding naphthyridone scaffold was carried out according to the methods reported by Chu et al. [12] and Sanchez et al. [13]. Namely, the hydrolysis of ethyl 2,6-dichloro-5-fluoronicotinate (3) [14] followed by reaction with thionyl chloride results in the formation of 2,6-dichloro-5-fluoronicotinyl chloride (4). Treatment of this compound with monoethyl malonate in THF under n-butyllithium followed by acidification and decarboxylation gives rise to ethyl 2,6-dichloro-5-fluoronicotinylacetate (5). Reaction of compound 5 with ethyl orthoformate in acetic acid followed by cyclopropylamine results in the formation of 3-cyclopropylamino-2-(2,6-dichloro-5-fluoronicotinyl)acrylate (6), the cyclization reaction of which under NaH/THF gives rise to the required ethyl l-cyclopropyl-6-fluoro-7-chloro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate (7), as shown in Scheme 3. 

The final coupling reaction of l-cyclopropyl-6-fluoro-7-chloro-l,4-dihy-dro-4-oxo-l,8-naphthyridine-3-carboxylic acid (7a) and 4-( er -butoxycarbo-nylaminomethyl)pyrrolidin-3-one-0-methyloxime (15a) proceeds according to the methods described by Sanchez et al. [13], Domogala et al. [16], and Kimura et al. [17], followed by acid hydrolysis to afford gemifloxacin, 7 - (4 - (aminomethyl) - 3 - (methoxyimino)pyrrolidin -1 - yl) -1 - cyclopropyl - 6 -fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid and other corresponding derivatives, according to Scheme 5. 

Earlier, it was stated that the cyclization of A-(2-chloro-4-pyridyl) aminomethylenemalonate (902, R = Cl) in diphenyl ether at 250-255°C for 6 min gave 7-chloro-l,6-naphthyridine-3-carboxylate (903, R = Cl) (74GEP2362553), but it was later demonstrated that a roughly 3 1 mixture of isomeric 7- and 5-chloro-1,6-naphthyridine-3-carboxy lates (903 and 904, R = Cl) was formed in 57% yield (82CPB2399). 

Ethyl-7-chloro-l-(2,4-difluorophenyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid... 

The slurry was filtered, and the compound was isolated as a white solid (75.5% yield based on (la,5a,6a)-3-N-benzyl-6-nitro-2,4-dioxo-3-azabicyclo[3.1.0]hexane 96.6% based on ethyl 7-chloro-l-(2,4-difluorophenyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid). The ethyl (la,5a,6a)-7-(6-benzylidenylamino-3-azabicyclo[3.1.0]hex-3yl)-l-(2,4-difluorophenyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate was recrystallized from acetonitrile, melting point 148°-155°C decomp. 

Ethyl 4-oxo-1,4-dihydro-l,5-naphthyridine-3-carboxylate (13, R = H) gave ethyl 4-chloro-l,5-naphthyridine-3-carboxylate (14, R = H) (POCl3 for details, see original) 433 ethyl 6-p-chlorophenoxy-4-oxo-l,4-dihydro-1, 5-naphthyridine-3-carboxylate (13, R = OC,H Cl-p) gave ethyl 4-chloro-6-... 

Ethyl 7-chloro-1 -ethyl-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (45) gave 1 -ethyl-7-methoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (46) (KOH, MeOH, dibenzo-l,8-crown-6 MeCNJ, reflux, 7h 67% it would seem that the crown ether was required to assist alcoholysis of the unactivated chloro substituent note incidental saponification of the ester group).1398... 

Ethyl 4-chloro-6-p-fluorophenoxy-l,5-naphthyridine-3-carboxylate (77) gave ethyl 1 -p-fluorophenoxy-1,4-dihydro-1,5-naphthyridine-3-carboxylate (78) (substrate, Pd/C, Et3N, dioxane, H2, 20°C 51%).967... 

Ethyl 7-chloro-1 -cyclopropyl-8-fluoro-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carboxylate (1, R = Et) gave 7-chloro-l-cyclopropyl-8-fluoro-4-oxo-l,4-dihydro-l,6-naphthyridine-3-carboxylic acid (1, R = H) (HC1, H20, EtOH, reflux, 9h 81%) 1175 analogs likewise.648... 

Dichloro-3-[2-ethoxycarbonyl-3-(thiazol-2-ylamino)acryloyl]-5-fluoropyri-dine (13) gave ethyl 7-chloro-6-fluoro-4-oxo-l-(thiazol-2-yl)-l,4-dihydro-l,8-naphthyridine-3-carboxylate (14) (Bu OK/dioxane 63%).143... 

Dichloro-3-ethoxycarbonylacetyl-5-fluoropyridine (52) with triethyl orthoformate and subsequently cyclopropylamine gave 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-l,8-naphthyridine-3-carboxylic acid (53) ( 60% note hydrolysis of the ester group).487... 

Methyl- gave 2,7-dimethyl-l,8-naphthyridine (MeLi, Et20, —50°C 84%).473 Ethyl 7-chloro-1 -cyclopropyl-6-fluoro-4-oxo-1,2,3,4-tetrahydro- 1,8-naphthyri-dine-3-carboxylate (23, R = H) gave its 5-methyl derivative (23, R = Me) (BuTi then Mel 86%).1158... 

Ethyl 7-chloro-l-(2-hydroxyethyl)- (15, R=OH) gave ethyl 2-chloro-l-(2-chloroethyl)-4-oxo-l,4-dihydro-l,8-naphthyridine-3-carboxylate (15, R = Cl) (SOCl2, CHC13, reflux 70%) 1049 the analogous product, ethyl 7-chloro methyl-1 -ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (16) was made somewhat similarly (SOCl2, ZnCl2, CHC13 25°C 83%).1248... 

Ethyl 6-amino-l-ethyl- (17, R = Et, X = NH2) gave ethyl 6-chloro-l-ethyl-7-methyl-4-oxo-l,4-dihydro-l,8-naphthyridine-3-carboxylate (17, R = Et, X = C1) (HN02, 0°C CuCl, 65°C 64%) 387 an analogous substrate,(17, R = H, X = NH2), likewise gave l-ethyl-6-fluoro-7-methyl-4-oxo-l,4-dihy-dro-l,8-naphthyridine-3-carboxylic acid (17, R = H, X = F) (NaNQ2, HBF4,... 

Chloro- (32, R = C1) gave 7-(/V-methylhydrazino)-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3-carboxylic acid (32, R = NMeNH2) (H2NNHMe/EtOH, reflux 83%).1129... 

Chloro-1 -ethyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (11, R = H) gave its ethyl ester (11, R = Et) (ClCC Et, Et3N, CHCI3 then EtOH 96%) 418 an analogous esterification used oxalyl chloride in the first stage. 

Ethyl 6-amino-7-chloro-1 -ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (21, Q = C1, R = Et) gave 6-amino-1 -ethyl-iV-methyl-7-methylamino-4-oxo-1,4-dihydro-l,8-naphthyridine-3-carboxamide (21, Q = R = NHMe) (MeNH2/ EtOH, 60°C 95% note the additional aminolysis of the chloro substituent).1029... 

Ethyl 7-chloro-6-cyano-l-ethyl- (36, R = CN) gave ethyl 7-chloro-l-ethyl-6-formyl-4-oxo-l,4-dihydro-l,8-naphthyridine-3-carboxylate (36, R = CHO) (HC1 gas, SnCl2, Et20 substrate in, 20°C, 48 h 25%).1211... 

Ethyl 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-5-trimethylsilyl- (41, R=SiMe3) gave ethyl 7-chloro-1 -cyclopropyl-6-fluoro-5-formyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (41, R=CHO) (POCl3, Me2NCHO, o-C 12C6H4, 90°C 24%).1172... 

Unsubstituted 2,7-naphthyridine (50) is probably best made by oxidation of 2,7-naphthyridine-4-carbaldehyde to 2,7-naphthyridine-4-carboxylic acid (49) (KMn04, AcMe, 20°C 88%) and subsequent thermal decarboxylation (Cu powder, gentle heat 78%) 630 earlier syntheses involved direct hydrogenolysis of 1,3,6,8-tetrachloro-2,7 naphthyridine (51 R = Cl) (Pd/C, H2, MeOH, AcOK 71 %)1374 cf 22 or indirect dechlorination of l-chloro-2,7-haphthyridine (51, R = H) by hydrazi-nolysis and subsequent oxidation (ILNNIL-ILO, EtOH, 100°C then CuS04, fUO 76% overall) 1279 also homologs.188... 

Chloro-7-methyl-4-oxo-1,4-dihydro-1,5-naphthyridine-2-carboxylic acid... 

Ethyl 2-chloro-1,5-naphthyridine-3-carboxylate Ethyl 4-chloro-1,5-naphthyridin-3-carboxylate Ethyl 6-chloro-4-oxo-1,4-dihydro-1, 5-naphthyridine-3-carboxylate Ethyl 7-chloro-4-oxo- 1,4-dihydro-1, 5-naphthyridine-3-carboxylate Ethyl l,5-dimethyl-4,8-dioxo-l,4,5,... 

Ethyl 7-chloro-l-cyclopropyl-8-methyl- 4-oxo-l,4-dihydro-l,6-naphthyridine-3-carboxylate 200-202, NMR 648... 

Ethyl 7-acetamido-2-chloro-l, 8-naphthyridine-3-carboxylate Ethyl 4-acetamido-1 -ethyl-2-oxo-1,... 

Ethyl 7-amino-6-chloro-1 -ethyl-4-oxo-1, 4-dihydro-1,8-naphthyridine-3-carboxylate 206-208 364... 

Ethyl 7-chloro-6-cyano- l-ethyl-4-oxo-1,4-dihydro-1, 8-naphthyridine-3-carboxylate 243 or 252-256, IR 387, 1211... 

Ethyl 7-chloro-l-cyclopropyl-5-ethyl-6-fluoro-4-oxo-1,4-dihydro-l,8-naphthyridine-3-carboxylate 158, NMR 452... 

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