Pyrazino pyrimidines

In addition to the pyrazino[2,3-d]pyrimidin-7-yl C-nucleoside 609 and its homo analog 614, which were obtained by the reaction of 5,6-diamino-l,3-dimethyluracil with the 6-hydroxy-6-/8-D-ribofuranosyl-2/7-pyran-3(6//)-one derivative 606 (Section XI,B Scheme 162), the pyrrolo-pyrazino-pyrimidine C-nucleoside 680 was produced in 30% yield according to the mechanism outlined in Scheme 175 (89JOC3927). 

Most syntheses of this type have followed the classical Gould-Jacobs pattern (Section 2.15.5.4.2) in which 2-aminopyrazines bearing a 6-substituent give esters of 8-oxopyrido[2,3-f ]pyrazine-7-carboxylic acids (424) via the usual intermediate ethoxy-methylenemalonate adducts. In some cases the isomeric pyrazino[l,2-a]pyrimidines are formed in addition (e.g. 74CPB1864). 

Examination of the pyrazino[2,3-rf]pyrimidine structure of pteridines reveals two principal pathways for the synthesis of this ring system, namely fusion of a pyrazine ring to a pyrimidine derivative, and annelation of a pyrimidine ring to a suitably substituted pyrazine derivative (equation 76). Since pyrimidines are more easily accessible the former pathway is of major importance. Less important methods include degradations of more complex substances and ring transformations of structurally related bicyclic nitrogen heterocycles. 

Pyrazino[2,3-d]pyridazin-8-one, 5-chloro-synthesis, 3, 347 Pyrazino[l, 2-a]pyrimidine reactions, 3, 350 structure, 3, 339-340 synthesis, 3, 256, 365 Pyrazino[ 1,2-a]pyrimidine, 2-hydroxy-alkylation, 3, 351... 

Pyrazino[2,3-d]pyrimidine — see Pteridines 4//-Pyrazino[l,2-a]pyrimidin-4-one, 3-ethoxycarbonyl-synthesis, 3, 366... 

Pyrazino[l, 2-c]pyrimidin-6-one, 7-ethyl-2-methyl-1,2,3,6,7,8,9a-octahydro-spectra, 3, 340... 

The synthesis of pyrido[2,3-d]pyrimidines has attracted considerable interest in heterocyclic chemistry. This ring system constitutes a deaza-analogue of the pyrazino[2,3-d]pyrimidine heterocychc core of fohc acid, analogues which can exhibit a wide range of biological properties as folate antagonists. Thus, the synthesis of this motif by MCR imder microwave-assisted conditions has the potential to rapidly introduce diversity into a biologically relevant scaffold. 

Partial saturation of the pyridazino ring of 3-acylamino-4//-pyrimido[l,2-A pyridazin-4-ones and the pyrazino ring of 3-acylamino-4//-pyrazino[l,2-tf]pyrimidin-4-ones in EtOH/AcOH system using Pd/C catalyst, resulted in the respective 6,7,8,9-tetrahydro derivatives in good yields <2000JHC783>. 

Unsaturated pyrazino[l,2-tf]pyrimidines were synthesized by formation of two bonds from [3+3] atom fragments. The 3-carbethoxy- and 3-acylamino-pyrazino[l,2-tf]pyrimidin-4-ones 81 and 87 were prepared from the 2-aminopyrazines 78 and 84 as depicted in Schemes 9 and 10, respectively. The mesoionic 95 was prepared as shown in Equation (8). 

The 2-aminopyrazine 123 with the stable (neopentylimino)propanedienone 125 furnished the 2-(neopentyl)-amino-y//-pyrazino[l,2-tf]pyrimidin 4-one 126 (Equation 14) <2002JOC2619>. 

The saturated pyrazino[l,2- ]pyrimidin-9-one 129 was obtained by a tandem cyclization from the ct-keto carboxylic acid 128 and /V-(2-aminocthyl)-l,3-propancdiaminc (Equation 15) <1997ACS742>. 

The syntheses of l,4-dihydro-2/7-pyrazino[2,l-7]quinazoline-3,6-diones can be divided into three groups, depending on how the pyrimidine and the pyrazine rings are constructed. 

Partly saturated pyrazino[l,2-r-]pyrimidines were prepared by formation of the pyrazine ring. 2-Substituted-8-hydroxy-3,4-dihydro-177,277-pyrazino[l,2-r-]pyrimidin-l-ones were prepared by a [6+0] synthesis involving cyclization of 6-hydroxy-pyrimidine-4-(fV-hydroxyethyl)carboxamides <2005W02005/087766>. The 2/7-pyra-zino[l,2-c]pyrimidine-3-carboxamide 164 (Y = NH) was formed from [5+1] atom fragments via the uracil derivative 163 (Y = NH) and DMF-dimethyl acetal. Compounds 163 were prepared from 6-chloromethyluracil and glycine methyl ester 162 (Y = NH) (Scheme 20) <2004W02004/014354>. 

Pyrazino[l,2-z]pyrimidine-6,8-dionc was prepared from [3+3] atom fragments by reacting 6-hydroxypyrimidine-4-carboxylic acid with 2-aminoacetaldehyde dimethyl acetal <2005W02005/016927>. 

Ar-(4-ChIorobenzyI)-7-substituted-4-oxo-4//-pyrazino[l,2-tf]pyrimidine-3-carboxarnidcs have been claimed as compounds to treat atherosclerosis and restenosis <2004W02004/019933> and as antiviral agents, particularly against herpes viruses <2002W02002/004444>. The mesoionic pyrazino[l,2-tf]pyrimidine 95 exhibited platelet aggregation inhibitory activity <2000BMC1917>. 

Arylmethyl-9-hydroxypyrazino[l,2-f]pyrimidine-l,8-dione derivatives have been claimed as anti-HIV agents <2005W02005/016927, 2005W02005/087766> 6,8-dioxo-pyrazino[l,2-f]pyrimidine-3-carboxamides 164 (Y = NH) <2004W02004/014354> and their saturated analogues <2004USP2004/034009> have been claimed as matrix metalloproteinase MMP-13 enzyme inhibitors, useful in the treatment of rheumatoid arthritis. 

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