2.3- Dihydro-l,4-benzoxazine

Synthetically, 2,3-dihydro-l,4-benzoxazine-6,7-diones (391) can be prepared from 2,5-bisanilino-3-acetyl- (or methoxycarbonyl)-l,4-benzoquinones and substituted 2-hydroxyethylamines (73T2881). 2-Amino-3-aziridino-1,4-naphthoquinone, when heated in aqueous sodium hydroxide, is claimed to give 392 (69FES732), and the benzo analog was prepared from 2,3-dichloro-... 

The reagent ratio 1 2 leads to a disubstituted product, which reacts with aminoethanol in an alkaline solvent to give 5,8-bis(vinylthio)-6,7-difluoro-2,3-dihydro-l,4-benzoxazine 164 along with other products (92ZOR1463) (Scheme 154). The formation of compound 165 is possibly explained by a Smiles type rearrangement. 

An on-line chromatography/atmospheric pressure chemical ionization tandem mass spectrometry (LC-APCI/MS/MS) methods was developed for rapid screen of pharmacokinetics of different drugs, including 5 (98RCM1216). The electron impact mass spectrum of 5 and ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7Ff-pyrido[l,2,3- fe]-l,4-benzoxazine-6-carboxylate was reported (97MI28). Electron impact/Fourier transform... 

Reaction of 2,3-dihydro-3-hydroxy-3-methyl- 240 (R = Me), or a mixture of 2,3-dihydro-3-hydroxy-3-aryl-57/-pyrido[l,2,3-dfe]-l,4-benzoxazin-5-ones 240 (R = Ar) and (8-aroylmethoxy)quinolin-2(l//)-ones 241 (R = Ar) with ethyl 2-(bromomethyl)acrylate in the presence of activated Zn and hydroquinone gave 8-[(2,3,4,5-tetrahydro-4-methylidene-5-oxo-2-furanyl)-methoxy]quinolin-2(l//)-ones (242) (97HCA1161). 6,7-Dihydro derivatives of 240 reacted similarly (00HCA349). 

Catalytic hydrogenation of 9-(3-hydroxy-l-propynyl)-A-(4-chloroben-zyl)-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- 7e]-l,4-benzoxazine-6-carboxamide over 5%) Pd/C in a 1 1 mixture of THE and MeOH afforded a mixture of... 

Reaction of 9,10-difluoro-3-methyl-2,3-dihydro-7-oxo-7//-pyrido[l,2,3- /e]-l,4-benzoxazine-6-carboxylic acid (252 X = F, R = H, R = Me) with 8 M aquous solution of KOH under reflux for 6 h, and in the presence of an alcohol or phenol afforded 10-hydroxy, 10-alkoxy and 10-aryloxy derivatives, respectively (96JAP(K)96/291144, 99MI5). 

The respective amide was prepared from 7-substituted 5-oxo-2,3-dihydro-5//-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylic acids via acid chlorides with different benzylamines (00M1P3). 6-Carboxamides were N-benzylated, and a side-chain phenolic hydroxy group was O-alkylated. 7-Aryl-5-oxo-2,3-dihydro-5//-pyrido[l, 2,3-r/e]-1,4-benzoxazine-6-carboxylic acid was obtained from the ethyl ester by alkalic hydrolysis. 

Methoxy derivative was obtained from 2-(4,5-dihydro-l//-imidazol-2-yl)-7-hydroxy-8-methyl-2,3-dihydro-5//-pyrido[l,2,3- /e]-l,4-benzoxazin-5-one with methyl tosylate in DMF in the presence of K2CO3 at 50 °C for 1 h (99EUP894796). 

The decarboxylated 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-l-piperazinyl)-7-pyrido[l,2,3- /e]-l,4-benzoxazine-7-one was isolated from 5 injection (96MI16), and from boiling HCl solution of 5 (97MI18) and... 

Oxo-2,3,6,7-tetrahydro-5//-pyrido[l,2,3- /e]-l,4-benzoxazine-2-carbox-ylates (291, X = H2) were obtained by hydrogenation of 4-substituted 3, 4-dihydro-2//-1,4-benzoxazine-2-carboxylates (290, X = H2) over 10% Pd/C catalyst, then by the treatment of free acids with (CF3C0)20 (99EUP894796). 5,7-Dioxo-2,3,6,7-tetrahydro derivatives 291 (X = 0) were prepared similarly from 290 (X = O). The products 291 (X = O) exist in 7-hydroxy-5-oxo-2,3-dihydro-5// tautomeric form. 

R = H, R =Br, R" =Et) was prepared by cyclization of aroylacetate 314 (R = H, R =Br, r2 = H, X = F) (OOMIPIO). 9,10-Difluoro-3(5)-methyl-7-oxo-7//-pyrido[l,2,3- /e]-l,4-benzoxazine-6-carboxylic acid and its racemic form were prepared in the reaction of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-2-ethoxymethyleneacetate and (R)- or (i ,5)-2-aminopropanol and subsequent hydrolysis of the ring closed tricyclic esters (98MI45). Cyclization of ethyl 2-(2,3-difluoro-5-iodobenzoyl)-2-[A-(2-hydroxyethyl)aminomethylene]acetate 315 in the presence of K2CO3 in DMF at 95 °C for 3.5 h yielded 9-iodo-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- /e]-l,4-benzoxazine-6-carboxylate (01MIP2). 

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