Pyrido pyrazine-2,3 -diones

Structure of 4//-pyrido[l,2-a]pyrazines 348-350 was confirmed by X-ray investigations (99JPR332). The stereostructure of 1,3,4,6,1 l,lla-hexahydro-2/f-pyrazino[l,2-A]isoquinoline-l,4-dione 351 was determined by X-ray investigation (01TL543). 

Racemic or optically active perhydropyrido[l,2-a]pyrazines were obtained by reduction of 9a5-perhydropyrido[l,2-u]pyrazin-4-one with LAH in Et20 at room temperature (99H(51)2065) and by reduction of perhydropyr-ido[l,2-u]pyrazine-l,4-diones with LAH in boiling THF (97USP5703072, 00JAP(K)00/86659). Treatment of (9uS)-2-(fcrf-butoxycarbonyl)perhydro-pyrido[l,2-u]pyrazin-4-one with LAH in Lt20 afforded (9uS)-2-fcrf-butox-ycarbonyl-l,6,7,8,9,9a-hexahydro-2//-pyrido[l,2-a]pyrazine (99H(51)2065). 

Perhydropyrido[l, 2-a]pyrazine-1,6-diones and 6a,7,8,9-tetrahydro-5//-pyrido[l,2-a]quinoxaline-6,10-diones were formed when their precursors bond to a resin were cleaved by an acid (01MIP4). 

Structures of 3-[(4-methylphenyl)amino]-47/-pyrido[l,2-tf]pyrazine-4-thione, iV-tosyl-3-[(4-methylphenyl)a-mino]-4//-pyrido[l,2-tf]pyrazine 4-imine, and 246 were confirmed by X-ray investigations <1999JPR332>. The stereostructures of (4A,llaA)-lla-ethoxycarbonylT,3,4,6,lla-hexahydro-l,3,4,6,ll,lla-hexahydro-4-methox-ycarbonyl-l-oxo-[l,4]oxazino[4,3-A isoquinoline <1995ZK787>, 2//-pyrazino[l,2- ]isoquinolinc-l,4-dione 247 <2001TL543>, 4-benzyl-2-methyl-1,3,4,6,7,11 b-hcxahydro-2//-pyrazino[2,l -zz] isoqu incline-3,6-dione... 

Selective reduction of the 7-oxo group in pyrido[23-synthetic approach to 5,10-dideazatetrahydrofolic acid <00H(53)1207>. Cycloaddition of pyrimido[4,5-c][l,2,5]oxadiazine 96 with 2,3-dihydrofuran affords a new synthesis of dimethyllumazine derivative 97 which undergoes a ring-opening reaction to give pyrazine derivative 98 <00JHC419>. 

Derivatives of pyrido[2,3-f>]pyrazine were prepared from pyridyl-substituted AAs. Reductive cyclization afforded 115 (79CZ387), whereas cyclization with potassium carbonate gave the dione 116 (87TL6363). 

Poly(pyrido[3,4- ]pyrazine vinylene) 693 has been synthesized via condensation of 3,4-diamino-2,5-dibtomopyridine 691 with l,2-bis[3-(2 -ethylhexyloxy)phenyl]-ethane-l,2-dione 692 followed by coupling with l,2-bis(tri- -butyl-stannyl)ethylene in DMF at 110°C in the presence of tetrakis(triphenylphosphine)palladium. The vinylene polymer 693 showed improved stability toward photooxidation compared with similar polymers with purely aliphatic side chains and also had smaller band gaps (Equation 58) <2002SM(131)53>. 

Hydrogenation of 9-benzyloxy-3,4-dihydro-l /T,8/T-pyrido[l, 2-aJpyr-azine-l,8-diones over Pd/C catalyst (10%) in MeOH gave 9-hydroxy derivatives (06WOP2006/066414). Transfer hydrogenation of 2-(4-nitrophenyl)perhydropyrido[l,2-fl]pyrazine over Pd/C catalyst with H2NNH2 H20 in EtOH yielded the respective 2-(4-aminophenyl) derivative (06JMC6351). 

Fluorination of 9-benzyloxy-2-(4-fluorobenzyl)-6-methoxy-3,4-dihy-dro-lH,8H-pyrido[l,2-a]pyrazine-l,8-dione with Selectfluor in the presence of Ce2C03 in MeCN at ambient temperature for 6 h provided 7-fluoro derivative. Reaction of 6-bromo-3,4-dihydro-lH,8H-pyrido[1,2-a]pyra-zine-l,8-diones with phenol cyclohexyl-, and cyclopropylmethanols in the presence of Ce2C03 in DMF in a sealed tube at 25-60 °C for 12-24 h afforded 6-phenoxy, 6-cyclohexyl-, and 6-cyclopropylmethoxy derivatives, respectively (06WOP2006/066414). 

The treatment of cis-7H,9H-frans-8H,9H-7,8,9-tri(pivaloyloxy)perhy-dropyrido[2,l-c][l,4]thiazine with NaOMe in MeOH at room temperature for 8 h gave 7,8,9-trihydroxy derivative (06EUP1657244). Heating 9-methoxy-2-(4-fluorophenyl)-3,4-dihydro-lH,8H-pyrido[l,2-fl]pyrazine-1,8-diones in the HBr-AcOH solution (38%) at 100 °C overnight afforded 9-hydroxy derivatives (06WOP2006/066414). 

Heating l,4-dihydropyridine-2-carboxamide 271 in dioxane containing 2 N HC1 solution at 70 °C for 0.5 h gave 4-hydroxy-l,2,3,4-tetrahydro-8H-pyrido[l,2-fl]pyrazine-l,8-dione 272 (06WOP2006/088173, 07WOP2007/ 049675). 

The treatment of l-propargyl-6-oxo-l,6-dihydropyridine-2-carboxa-mide 320 with Me3OBF4 gave a mixture of tetracyclic 321 and 1H,6H-pyrido[1,2-a]pyrazine-1,6-dione 322 in low yields (070L2003). 

The treatment of 4-acetylpiperazinone 323 with LiHMDS, followed by addition of (C02Et)2 gave three condensation products 324-326. Upon addition of excess LiHMDS 8,9-dihydroxy-3,4-dihydro-lH,6H-pyrido [l,2-fl]pyrazine-l,6-dione 327 was obtained in low yield (07BML5595). The major isomer 324 could be izomerized into 325 on the action of TFA in aqueous MeCN, which readily cyclized to pyrido[l, 2-aJpyrazine-l, 6-dione 327. 14C-labeled 327 was also prepared using 14C-labeled diethyl oxalate. 

Reaction of l-(2-oxoethyl)-4-oxo-l,4-dihydropyridine-2-carboxylate 418 and 2-methoxyethylamine in the presence of AcOH at 140 °C for 0.5 h under microwave irradiation provided l,2-dihydro-8H-pyrido[l,2-a pyrazine-1,8-dione 419 (06WOP2006/088173, 07WOP2007/049675). 

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