1.4- Benzothiazine-3-carboxylic acid

Reaction of 9,10-difluoro-7-oxo-2,3-dihydro-7//-pyrido[l, 2,3- e]-1,4-ben-zothiazine-6-carboxylic acid and its ethyl ester with B(OH)3 in AC2O in the presence of ZnCl2 afforded 6-[(diacetoxyboryl)oxycarbonyl] derivative 323 (R = OAc)], which was reacted with primary and cyclic amines to give 10-amino-9-fluoro-7-carboxylic acid derivatives 324 (97MI41, 98MI30). 6-[(Difluoroboryl)oxycarbonyl derivative 323 (R = F) was obtained from ethyl 9,10-difluoro-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- fe]-l,4-benzothiazine-6-carboxylate with BF3-THF complex. Reaction of 323 (R = F) and 1-methylpiperazine in DMF at 50-60 °C and subsequent acidic hydrolysis afforded 7 (97MI1). 

Hydrolysis of ethyl 9-fluoro-10-(4-methylpiperazino)-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- fe]-l,4-benzothiazine-6-carboxylate in a boiling mixture of AcOH and 35% HCl afforded 7 HCl (97USP5703233). That of (3S)-3-methyl-10-(2,6-dimethyl-4-pyridyl)-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- e]-l,4-benzothiazine-6-carboxylate gave the 6-carboxylic acid (OOMIPIO). 7-Oxo-2,3-dihydro-7//-pyrido[l,2,3- fe]-l,4-benzothiazine-6-carboxylic acid was obtained from its ethyl ester by alkalic hydrolysis in 20% yield (99AP19). 

CN 10//-pyrido[3,2-fc][l,4]benzothiazine-10-carboxylic acid 2-[2-(l-piperidinyl)ethoxy]ethyl ester... 

Hydroxy-2-methyl-1,1dioxo-1,2-dihydro-U6-benzo[e][1,2]thiazine-3-carboxylic acid isoxazo-3-ylamide, 4-hydroxy-2-methyl-/V-(5-methyl-3-isoxa-zolyl)-2H-1,2-benzothiazine-3-carboxamide 1,1 dioxide, Ci4H13N305S, Mr 335.34, mp 265-271 °C (decomp.) sodium salt,... 

Hydroxy-2-methyl-1,1-dioxo-1,2-di-hydro-1A.6-benzo[e][1,2] thia-zine-3-carboxylic acid pyri-din-2-ylamide, 4-hydroxy-2-methyl-/V-2-pyridinyl-2H-1,2-benzothiazine-3-carboxam-ide-1,1-dioxide, C15H13N304S, Mr 331.35, mp 198-200 °C. 

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. 

Ethyl, methyl 10-oxo-6,10-dihydropyrido[2,l-c][l,4]benzothiazine-7,8-dicarboxylate was hydrolyzed by heating with 0.5 N NaOH in ethanol at 60°C to give the corresponding 7,8-dicarboxylic acid, which was decarbox-ylated by heating in Dowtherm A at 230°C to yield 10-oxo-6,10-dihy-dropyrido[2,l-c][l,4]benzothiazine-8-carboxylic acid (86USP4576942). Treatment of diethyl 10-oxo-6,10-dihydropyrido[2,l-c][l,4]benzothiazine-... 

Ty initiates melanin synthesis by the hydroxylation of L-tyrosine to 3,4-dihydroxyphenylalanine (Dopa) and the oxidation of dopa to dopaquinone. In the presence of L-cysteine, dopaquinone rapidly combines with the thiol group to form cysteinyldopas, which undergo nonen-zymatic conversion and polymerization to pheomelanin via benzothiazine intermediates. In the absence of thiol groups, dopaquinone very rapidly undergoes conversion to dopachrome, which is transformed to 5,6-dihydroxyindole-2-carboxylic acid (DHICA) by dopachrome tautomerase. Alternatively, dopachrome is converted nonenzymatically to 5,6-dihydroxyindole (DHI). Oxidation of DHICA and DHI to the corresponding quinones and subsequent polymerization leads to eumelanins. It is still questionable if Ty is involved in this step. 

The earliest report of a l,2-benzothiazin-4-one is that of von Braun.1 Cyclodehydration of carboxylic acid 5 produced, according to elemental analysis, a material assigned the structure of a l,2-benzothiazine-3,4-dione (6) (Eq. 1). Since no additional proof for the structure of 6 was provided,1 the isomeric benzisothiazole dicarboxylic acid (7) cannot be excluded. 

Specific conditions73 hydrolyze the methyl ester 28 to the crystalline 4-hydroxy-2-methyl-2//- l,2-benzothiazine-3-carboxylic acid 1,1-dioxide (115), converted by standard methods to anti-inflammatory amides.73... 

Dihydro-1,4-benzothiazines are generally more reactive, and direct N-alkylation has been reported, but this reaction is not always straightforward.21 Funke et al. could not alkylate 2-phenyldihydro-l,4-benzothiazine with co-chloramines, even under forcing conditions.90 However, later work showed that this reaction was possible in toluene solution,37 and other workers have also reported direct alkylations.143 The l,4-benzothiazin-3-ones are, however, more easily alkylated, and reduction of the N-alkyl derivatives of these compounds, usually with lithium aluminum hydride, affords the corresponding N-alkyldihydro-1,4-benzothiazines.52,56 70 90,154 These products can also be prepared in one step from the corresponding 1,4-benzothiazines, e.g., Ill - 112, presumably via intermediate dihydro-1,4-benzothiazines, by sodium borohydride in the presence of a carboxylic acid. Boron derivatives, such as Na[(RCOO)3BH] and Na[(RCOO)4B] are suggested as the species responsible for N—C bond formation.155... 

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