Perhydropyrido pyrazine-3,4-dione

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). 

Reduction of a 7-(2-oxoethyl) derivative with NaBH4 in EtOH at room temperature gave 7-(2-hydroxyethyl)-2-(2-pyrimidinyl)perhydropyrido[l, 2-u]pyrazine (99MIP6). Reduction of 7-formyl-8-[(4-cyanophenyl)methoxy]-1,3,4,6,11,1 lu-hexahydro-2//-pyrazino[l,2-A]isoquinoline-l,4-dione with NaBH4 yielded a 7-hydroxymethyl derivative (98MIP7). 

Treatment of the appropriate pipecolic amide 396 with NEta afforded optically active or racemic perhydropyrido[l,2-a]pyrazine-l,4-dione (397) (97USP5703072). (9a5)-Perhydropyrido[l,2-a]pyrazin-3-one (400) was obtained by cyclization of piperidine 398, and the catalytic hydrogenation of quaternary salt 399 over Pd/C (99H(51)2065). 

Substituted perhydropyrido[l,2-a]pyrazine-l,4-diones were obtained when methyl A-[2-(benzyloxycarbonylamino)acetyl]-4-substituted pipecoli-nates were hydrogenated over 10% Pd/C catalyst in MeOH, and then the methanolic solutions were refluxed (00JAP(K)00/86659). 

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). 

Cyclocondensation of 2-aminomethylpiperidine 422 and dimethyl oxalate yielded perhydropyrido[l,2-n]pyrazine-3,4-dione 423 (00T1005). 

Amino-2-methoxyphenyl)perhydropyrido[l,2-tf]pyrazine was prepared from a 2-(5-nitro-2-methoxyphenyl)-3-one derivative by catalytic hydrogenation over Pd/C catalyst, followed by the reduction of the 3-oxo group by treatment with BH3-THF complex <1999WO99/042465>. A nitro group was reduced to an amino group in 2-[4-(3-nitrophenyl)piperazin-l-yl]butyl]perhydropyrido[l,2-tf]pyrazine-l,4-dione <2001JME186>, in 8-hydroxy-... 

Cyclocondensation of 2-aminomethylpiperidine 395 and (C02Me)2 yielded perhydropyrido[l,2-tf]pyrazine-3,4-dione 396 (Equation 73) <2000T1005>. Reaction of a 2-(tosylamino)methylpyridine with (CH2Br)2 afforded a... 

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). 

Oxo groups of perhydropyrido[l,2-a]pyrazine-l,4-dione were reduced to methylene groups with LAH (08WOP2008/101247). Oxo groups of perhydropyrido [1,2-fl] pyrazine-1,4-diones and 2-acylperhydropyrido... 

The Mitsunobu reaction of perhydropyrido[l,2-a]pyrazine-l,4-dione 230 at ambient temperature gave dehydrated product 231 in 15% yield. When the reaction was carried out with excess PBu3 and diethyl azodicar-boxylate at 40 °C the incipient 231 spontaneously underwent enolization and tautomerization, [4+2] aza-Diels-Alder reaction to provide a 2.4 1 mixture of diastereomers 232 and 233 (07T6124). No reaction occurred when isolated 231 was treated under similar conditions. 

Cyclization of pipecolic acid amide 267 on the action of HATU and Hiining s base afforded a 1 1 diastereomeric mixture of perhydropyrido [l,2-a]pyrazine-l,4-dione 268 (06JOC8934). 

Heating pipecolic acids 315 in refluxing AC2O in the presence of catalytic amount of NaOAc for 1 h afforded perhydropyrido[l,2-fl]pyrazine-1,3-diones 316 (05MOL1119). The treatment of piperidine 317 with morpholine in THF at ambient temperature for 2 h afforded diketopiperazine 230 as an inseparable mixture of diastereomers (07T6124). 

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