Perhydropyrido pyrazines preparation

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). 

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-... 

The 7-(2-oxoethyl) derivative was prepared from 7-formyl-2-(2-pyrimidyl)perhydropyrido[l,2- ]pyrazine by the treatment with MeOCHzP(Ph)3Cl in the presence of Pr 2NH in THF at 0°C, then with BuLi at room temperature < 1999WO99/020622>. Reaction of a 7-mesyloxymethyl group in perhydropyrido[l,2-tf Ipyrazine with NaCN in DMF at 110°C gave a 7-cyanomethyl derivative, which was converted into a 2-oxoethyl group by treatment first with DIBAL-H, then with 2M HC1. The 2-oxoethyl group was reacted with 4-FC6H4MgBr in THF at — 10°C to yield a... 

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>. 

Cyclization of alcohols 334 under Mitsunobu condition was very sluggish, but it happened easily when alcohol was treated with Ph3P, imidazol and I2 to give perhydropyrido[l,2-a]pyrazine-3-carboxylates 335 (08SL702). C3 Epimer of 335 was prepared similarly. 

Hexahydro-l//-pyrido[l,2-a]pyrazin-l-ones were prepared by oxidation of 2-substituted perhydropyrido[l,2-a]pyrazines and perhydro-pyrido[l,2-a]pyrazin-l-one with Hg(OAc)2 in 5% aqueous AcOH (73CPB1248). Oxidation of l,3,4,6,ll,lla-hexahydro-2//-pyrazino[l,2-bjisoquinoline with Hg(OAc)2 in 5% aqueous AcOH gave the 6-oxo derivative [73CPB2039 77IJC(B)70]. l,3,4,6,ll,lla-Hexahydro-2//-... 

Benzylperhydropyrido[l,2-a]pyrazin-6-one was prepared through the cyclization of 287, obtained from 285 via 286 (93JOC690). From the reaction mixture of 2,3-di(2-tetrahydrofuryl)piperazine, treated with HBr gas in AcOH at 90-95°C, then with KOH, l-(2-tetrahydrofuryl)-9-hydroxy-perhydropyrido[l,2-a]pyrazine could be isolated (61BSF2135). Cyclization of 2-(l,2,3,4-tetrahydroxylbutyl)quinoxalines in an acidic media gave 8H-pyrido[l,2-a]quinoxalin-8-ones together with a small amount of their 9-... 

Thionyl chloride has been used to convert the alcohol 56 into the cyclized quaternary salt 57. Reduction of the nitrile 58 with Raney nickel and hydrogen gave the 1-oxo compound 60 (R = H), ° presumably by way of the intermediate 59. This intermediate is also involved in the preparation of compound 60 (R = H) by treatment of the ester 61 with ethyleneimine. The optically active ester 61 has been converted by this route into perhydropyrido[l,2-a]pyrazines of known configuration. When this reaction was repeated with the methyl-substituted piperidine... 

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