Perhydropyrido pyrazine-4-ones

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). 

Hydroxy group of rru -7,9u-H-7-(prepared from 7-formyl-2-(2-pyrimidyl)perhydropyrido[l,2-u]pyrazine by the treatment with MeOCH2P(Ph)3Cl in the presence of -Pr2NH in THF at 0°C, than with BuLi at room temperature (99MIP6). 

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). 

Cyclization of (25)-2-(rerc-butoxycarbonylaminomethyl)-l-(2-chloro-acetyl)piperidine on the action of NaH in THF gave (9aS)-2-(rerc-butoxycarbonyl)perhydropyrido[l,2-a]pyrazin-4-one (99H(51)2065). 3-Benzyl-2,3,4,4 ,5,6-hexahydro-l//-pyrazino[l,2-a]quinolin-l-ones 413... 

Methoxy-5-nitrophenyl)perhydropyrido[ 1,2-a]pyrazin-3-one was obtained by cyclization of l-(ethoxycarbonylmethyl)-2-[A-(2-methoxy-5-nitrophenyl)aminomethyl]piperidine on the action of NaH in boiling dioxane (99MIP10). 

Dichlorophenyl)-2-[2-(perhydropyrido[l,2-u]pyrazin-2-yl)benzyli-dene]thiomorpholin-3-one was claimed as a psychotherapeutic agent (98MIP6). Inhibitory concentration and proportion of high and low affinity... 

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-... 

Perhydropyrido[l,2- ]pyrazin-l-one was prepared in the reaction of methyl pipecolinate and ethylene imine in boiling EtOH <19951JSP5461047>. Cyclocondensation of ethyl 2-amino-2-(2-pyridyl)acetate with DMAD, followed by treatment of reaction mixture with NaOMe, gave the 2-(l-methoxycarbonyl)-4-oxo-47/-pyrido[l,2- ]pyrazin-3-yl)acetate <1996JHC639>. 

On the basis of CoMFA and CoMSIA analysis, three conformation-ally restricted selective D3 ligands were successfully constructed and synthesized. One of them is rfs-7H,9flH-7- 2-(2-benzo[fc]thienyl)carbo-nylamino]ethyl -2-(2,3-dichlorophenyl)perhydropyrido[l,2-fl]pyrazine (06BMC5898). 

The treatment of 4-arylperhydropyrido[2,l-c][l,4]oxazin-6-ones (07USA2007/Oil7839, 08WOP2008/013213) and 6-oxo-4-(3,4,5-trifluoro-phenyl)perhydropyrido[l,2-a]pyrazine-2-carboxylate (07USA2007/ 0117839) with Me3SiI and A NdV N -tetramethylethylenediamine in CH2CI2 in a N2 atmosphere at 0 °C followed by the addition of I2 and stirring at 0 °C for another 30 min yielded 7-iodo derivatives. 

Reactions of perhydropyrido[l,2-flJpyrazine with aldehydes in the presence of NaB(OAc)3H and NaBH3CN in AcOH (05USA2005/ 0282811) and in acidified EtOH (07USA2007/0117839) afforded 2-substi-tuted derivatives. 2-(l-Diphenylmethylazetidin-3-yl) derivative was obtained in the reaction of perhydropyrido[l,2-a]pyrazine and diphenyl-methyl-3-azetidin-3-one in the presence of (polystyrylmethyl) trimethy-lammonium cyanoborohydride in MeOH containing 10% AcOH at 120 °C for 5 min under microwave irradiation (06WOP2006/137791). 

Perhydropyrido[l,2-fl]pyrazin-l-one N-oxide 167 was formed from 1-hydroxypipecolic acid amide 261 by reverse Cope elimination by heating in CHCI3. Similar reaction of 1-hydroxypipecolinate 262 resulted an 1 5 30 equilibrium mixture of 262, 263, and 264 (07TL1683). 

Optically active pipecolic acids were synthesized via perhydropyrido[l,2-fl]pyrazin-l-ones to control their stereochemistry (05TA3858, 07LOC4, 07TA1585, 08JOC6877). 

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