9-Methyl-3- -4//-pyrido

Pyrido[4,3-rf]pyrimidin-4(3/7)-oiie (138) was prepared from either ethyl 4-aminonicotinate or from 4-aminomcotinamide by fusion with formamide. A parallel to the pyrido[3,2-d]pyrimidines (cf. Section II,B, la) was demonstrated in the conversion of 2-methyl-pyrido[4,3-d][l,3]oxa7in-4-ones (139, Ri = Me) into the corresponding pyrido[4,3-d]pyrimidin-4(377)-ones (142) on treatment with a number of amines.There were certain limitations to the method in this series, however, and the intermediate diamides (140) were more conveniently prepared from the appropriate 4-amidonicotinate (141) and. .Ri... 

Huisgen et al.165 prepared the methyl pyrido[l,2-u]pyrimidine-2-carboxylate (100) from tetrazolo[5,l-u]pyridine and dimethyl maleate or fumarate at 160 C. The reaction presumably proceeds via the intermediates (97-99). Compound 100 was also obtained from 2-aminopyridine and dimethyl acetylenedicarboxylate. 

Neurotropic and antistress properties of 2,4-di methyl pyrido[l, 2-a]pyr-imidinium perchlorate were compared with those of piracetam (95MI7). 4H-Py r i d o [ 1,2 - a ] py r i ni i d i n -4 - o n e binds selectively to rat A3 receptors with a AT, value of 48 /aM. No affinities were observed to rat A i and A2 receptors (96MI17). 4-Oxo-4//-pyrido[l,2-u]pyrimidine-3-carboxylic acid and -3-carbonitrile did not exhibit significant antibacterial activities (97MI6). 

A mixture of 3-(2-hydroxyethyl)-2-methyl-pyrido[2,l-b]pyrimidin-4-one, of acetic acid and of a hydrobromic acid solution 67% in acetic acid was stirred and heated to reflux. Stirring was continued overnight at reflux temperature. The reaction mixture was evaporated and the solid residue was triturated in 2-propanone. The product was filtered off and dried, yielding 3-(2-bromoethyl)-2-methyl-pyrido[l,2-a]pyrimidin-4-one monohydrobromide. 

A mixture of 3-(2-bromoethyl)-2-methyl-pyrido[l,2-a]pyrimidin-4-one monohydrobromide, 3-furan-2-yl-methyl-(3H-imidazo[4,5-b]pyridine-2yl)-4-piperidinyl)-amine dihydrobromide, of sodium carbonate and of N,N-dimethylformamide was stirred and heated overnight at about 70°C. The reaction mixture was poured onto water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (94 6 by volume), saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 3-(2-(4-((3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)-l-piperidinyl)ethyl)-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one melting point 202°C. 

Entsprechend werden auch die 2-Methyl- I und II an der Methyl-Gruppe lithiiert (1 Aquivalent Lithiuxn-diisopropylamid) bzw. die 2-(2-Furyl)-Verbindung III in der 5 -Position. 

Acetylpyridine-3-carbaldehyde, obtained by homologation of the 2-formyl group in pyridine-2,3-dicarbaldehyde with diazomethane, condenses with hydrazine to give 8-methyl-pyrido[2,3-r(]pyridazine (18) in 66% yield.3,60... 

Amino-l-(ethoxyearbonyl)-2-phenyl-7-[(phenylhydrazono)(cyano)methyl pyrido 3,4-[Pg.59]

A combined silylation-animation procedure340 affords a 74% yield of 6-(hydroxymethyl)-pyrido[2,3-flT)pyrimidine-2,4-diamine (14) in one synthetic step directly from 6-(acetoxy-methyl)pyrido[2,3-<7]pyrimidine-2,4(l//,3//)-dione (13).314... 

Pyndo[2,3-()]pyrazines with a partially hydrogenated pyridine moiety have also been aromatized. 7,8-Dihydro-7-methylpyrido 2,3-6]pyrazin-6(5//)-one (7) oxidized by selenium dioxide in acetic acid affords 7-methyl pyrido[2,3-A]pyrazin-6(5//)-one (8),63 and 5,6-dihydro-5-methylpyrido-[2,3-6]pyrazine (9) is oxidized by air to give 5-methylpyrido[2,3-6]pyrazin-6(5//)-one (10).14... 

In an unusual reaction, 2-acetamido-3-cyanopyridine, when refluxed with hydroxylamine in toluene for 1 hr, gave a low yield of 4-amino-2-methyl-pyrido[2,3-d ]pyrimidine 3-oxide.13 5... 

Gangjee, A., Adair, O. and Queener, S. E. 1999. Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase inhibitors and antitumor agents Synthesis and biological activities of 2,4-diamino-5-methyl-6-[(monosubstitutedanilino)methyl] pyrido[2,3-[Pg.248]

There seems to have been no systematic study of tautomerism in the pyridopyridazines, but isolated observations in the pyrido[3,4-d]pyridazinedione (75BSF702, 69CPB2266) and pyrido[2,3-d]pyridazinedione (74JHC351) series have involved methylation studies. The pyrido[2,3-d]pyridazine-5,8-diones are believed to be enolized at the 8-position, from metal complexation results (67MI21500). 

The other main source of various pyridopyridazines from pyridines are the [4 + 2] cycloaddition reactions, already mentioned (Section 2.15.8.3), between vinylpyridines and azodicarboxylic esters (79T2027, 79KGS639) or triazolidinediones e.g. 78KGS651). 2-Vinyl-pyridines gave reduced pyrido[3,2-c]pyridazines (370), 4-vinylpyridines gave [3,4-c] analogues, whilst 2-methyl-5-vinylpyridine furnishes a mixture of the [2,3-c] and [4,3-c] compounds. Yields are low, however, and these remain curiosities for practical synthetic purposes. 

Both 2- and 3-methyl groups in pyrido[2,3-Z ]pyrazines are acylated by ethyl oxalate (71TH21500). They give (preferentially 3-) styryl derivatives with aromatic aldehydes and oximes with pentyl nitrite. 

Pyrido[2,1 -bjbenzothiazolium, 4-ethoxy-5a,6,7,8,9,9a-hexahydro-1 -methyl-9-oxo-X-ray, 6, 670 (72ACS3131)... 

Naphtho[2,1 -/]pyrido[2,1 -h][ 1,3]thiazepinium perchlorate, 7-methyl-ring contraction, 2, 558 Naphthopyrylium salts synthesis, 3, 870, 873... 

H,4H-Oxazolo[5,4,3-y]pyrido[3,2-g]quinolin-4-one, 8-hydroxymethyl-6-methyl — see Nybomyein 5H-Oxazolo[2,3-[Pg.731]

H-Pyrido[2,l-i]purine-9-carboxylic acid, 7-oxo-methyl ester, 5, 566 Pyrido[2,3-6]pyrazine, amino-nucleophilic attack, 3, 253 Pyrido[2,3-h]pyrazine, 6-chloro-reactions... 

Pyrido[3,4-b]pyrazine, 2-hydroxy-IR spectra, 3, 249 Pyrido[3,4-b]pyrazine, 3-hydroxy-IR spectra, 3, 249 structure, 3, 254 Pyrido[3,4-6]pyrazine, methyl-... 

Pyrido[2,3-c]pyridazine, N-amino-synthesis, 3, 243-244 Pyrido[2,3-c]pyridazine, 7-methyl- H NMR, 3, 234... 

Pyridopyridazines, hydroxyalkyl-nucleophilic attack, 3, 241 Pyridopyridazines, methyl-electrophilic reactions, 3, 240 Pyrido[2,3-6]pyridazines nucleophilic substitution, 3, 253-254 Pyrido[2,3-c]pyridazines, 3, 232-233 benzo fused, 3, 233 N-oxide... 

Pyrido[2,3-(i]pyrimidine, /3-ketoalkyl-deacylation, 3, 212 Pyrido[2,3-(i]pyrimidine, methyl-deuterium exchange, 3, 212 Pyrido[2,3-(i]pyrimidine, 2-methyl-acylation, 3, 210... 

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