Ethyl 1,4-benzothiazine-6-carboxylate

Ethyl (3S)-8-amino-3-methyl-10-(2,6-dimethyl-4-pyridyl)-7-oxo-2,3-dihy-dro-7//-pyrido[l,2,3- f< ]-l,4-benzothiazine-6-carboxylate was obtained by the reduction of the respective 8-nitro derivative (OOMIPIO). 

Oxidation of 7-hydroxy- and 7-aryl-5-oxo-2,3-dihydro-5//-pyrido[l,2,3- f< ]-l,4-benzothiazine-6-carboxylates and 6-carboxamides with 3-chloroper-oxybenzoic acid in CH2CI2 yielded sulfoxides and sulfones, depending on the molar ratio of the substrate and oxidizing agent (00MIP7). A sulfoxide was prepared by the oxidation of ethyl (3S)-3-methyl-10-(2,6-dimethyl-4-pyridyl)-7-oxo-2,3-dihydro-7//-pyrido[l,2,3-<7c]-l,4-benzothiazine-6-carbox-ylate (OOMIPIO). 

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). 

Cyclocondensation of 3,4-dihydro-2//-l,4-benzothiazines and diethyl ethoxymethylenemalonate in PPA at 120-160°C yielded ethyl 7-oxo-2,3-dihydro-7//-pyrido[l,2,3- fc]benzothiazine-6-carboxylates (97MI3,... 

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

Reaction of ethyl 9,10-difluoro-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de]-l,4-benzothiazine-6-carboxylate with 1-methylpiperazine in the presence of K2C03 in DMF at 80 °C for 4.5 h gave 10-(4-methylpiperazino)-5-car-boxylate in 88% yield (08MI93). Acidic hydrolysis of this ester in aqueous AcOH containing HC1 at 90 °C for 3 h afforded rufloxacimHCl in 91% yield. 

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-... 

Dihydro-7-oxo-7//-pyrido[l,2,3-de]-l,4-benzothiazine-6-carboxylates (271) were obtained by the cyclization of a mixture of the E- and Z-iso-mers of acrylates 270 on the action of NaH in THF at 0°C (89GEP3913245 91SC2301 93EUP522277). Cyclization of aryl aminomethylenemalonates 272 in PPE at 130-145°C and on the action of Ph3P and ethyl azodicar-boxylate in THF at -20°C gave 7-oxo-2,3-dihydro-7//-pyrido[l,2,3-de]-l,4-benzothiazoles 273 (87USP4636506). 

The preparation of two of the three possible isomeric thieno-1,2-thiazin-4-ones (Schemes 5 and 6)128 involved reactions reported12 for the corresponding benzothiazines (see Scheme 1 ). Thus, methyl 3-chlorosul-fonylthiophene-2-carboxylate (152) with sarcosine ethyl ester gave thiophene sulfonamide (153) which, with methanolic sodium methoxide, yielded 3-methoxycarbonyl-4-hydroxy-2-methyl-2H-thieno[2,3-c]-l,2-thiazine 1,1-dioxide (154). Heating 154 with 2-aminothiazole gave 155, a thieno-1,2-thiazine analog of sudoxicam (20) (Scheme 5). 

Rasmussen8132 obtained tricyclic, 1,2-benzothiazines (181) from ethyl 4-hydroxy-2//-l,2-benzothiazine-3-carboxylate 1,1-dioxide (180) and a,a>-dihalides (e.g., 1, 3-dibromopropane) (Eq. 38). 

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