7-Substituted pyrido pyrimidines

Triazanaphthalene (449) is the most unstable of the pyrido-pyrimidines to ring-degradation at pH 2 or pH 7.7 The 4-oxo derivative was converted into the 4-thioxo compound via nucleophilic displacement of the acyloxy intermediate formed with phosphorus pentasulfide. The 4-carboxymethylthio-pyridopyrimidine underwent some substitution by hydroxide ion but primarily gave the ring-opening reaction, which is facilitated by resonance activation of the 2-position by the 6-aza moiety. 

Classical methodology was used to prepare the dibenz[b,f]azepine derivative 21 (R = substituted pyrido[2,3-d]pyrimidine) utilising amide ion formation from dibenz[b,f]azepine itself with sodium hydride and then iV-alkylation with 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine. The bulky bis-fused azepine moiety was required to introduce steric bulk in the system and to study the effect of this on inhibition of the enzyme dihydrofolate reductase <00JHC921>. 

Catalytic hydrogenation of the pyridine ring of 4-hydroxy-2-pyrrolidinopyrido[2,3- pyrimidine in the presence of H2/Pt02 in HCl gave 71. 2-(Pivaloylamino)-6-substituted pyrido[2,3-,7 pyrimidin-4(3//)-one gave the 5,6,7,8-tetra-hydro derivative 72 via similar catalytic reduction conditions in the presence of trifluoroacetic acid (TFA) at 800 psi hydrogen pressure for 40 h <1996WO9603406>. 

Cyclocondensation of ethyl 2-aminonicotinate in presence of HC(OEt)3 and various primary amines gave 22 3-substituted pyrido[2,3-,7]pyrimidin-4(377)-ones 371 <1995PHA719>. Fourteen 3,5,7-triarylpyrido[2,3-r7]pyrimi-dine-2,4(l/7,37/)-diones 372 have been prepared from the reaction of either 2-amino-3-cyano-4,6-diarylpyridines or the 3-carboxamido products of alcoholic KOH hydrolysis, with aryl isocyanates better yields were obtained from the amides <1995IJB740>. 4-Aminopyrido[2,3- pyrimidin-5(8//)-one 158 was synthesized by treatment of 2-amino-3-cyano-4-methoxypyridine with trimethylsilyl iodide to give the corresponding pyridin-4(177)-one, which was refluxed with formamidine acetate in ethoxyethanol to effect the cyclization <2000JME3704>. 

An improved synthesis of substituted pyrido[2,3-, pyrimidine-2,4-diamines 477-482 can be carried out by cycloaddition of 2,4,6-triaminopyrimidine 466 with the 1,3-biselectrophiles 467-471 via intermediates 472-476 (Scheme 19) <1994AP221>. 

The second method using the pyrimidine nucleus for preparing 6-substituted pyrido[3,4- pyrimidines 621 and... 

From 2-amino-6-methylpyridine and monosubstituted malonates Buu Hoi and Declerq100 obtained 3-substituted 1,8-naphthyridines of type 66, and from 2-aminopyridine they obtained 3-substituted pyrido[l,2- ]pyrimidines of type 63 (R = H). 

A comparison of the behavior of the R = H, 5-Me-, and 6-Me-substituted succinates (77) in the competitive cyclization reactions (Table I) revealed that in ethanolic sodium ethoxide at 25°C the 6-methyl group fully inhibited the ring closure onto the ring nitrogen. It also revealed that in phosphoryl chloride-polyphosphoric acid at 120 C the formation of 4-oxo-4//-pyrido-[1,2-a]pyrimidine (78 R = 6-Me) was only hindered, whereas at 250 C under the conditions of thermal ring closure, only a slight, if any, steric hindrance occurred. This suggests that the formation of the 6-substituted pyrido[l,2-a]-... 

On heating above 150°C, 4-halo-2-substituted valeronitriles and 1,3-diaminopropane yielded the 9-substituted pyrido[l,2-a]pyrimidines... 

Allen prepared several 2-(rn-dialkylaminoalkoxy)-4-oxo-4/f-pyrido[l, 2-a]-pyrimidines by reacting the 3-substituted derivatives of 63 (R = H) with dialkylaminoalkyl halides.104 3-Substituted pyrido[l,2- ]pyrimidines (63 R = H) have also been treated with methyl iodide98 and methyl sulfate,278 but the structures of the products have not been elucidated. 

Tsuge and Noguchi469 prepared the 3-benzamido-4-oxo-4//-pyrido-[l,2-a]pyrimidine and its methyl substituted derivatives from 2-amino-pyridines and 2-phenyl-4-ethoxymethylene-5-oxazolone in boiling ethanol, without the isolation of the condensation products of type 94. The pyrido-pyrimidine was formed from 2-amino-6-methylpyridine, but in a longer reaction period and in low percentage yield. Condensation product 94 was cyclized in ethanol or polyphosphoric acid or acetic acid. 3-Benzamido-2-methyl-4-oxo-4A/-pyrido[l,2- ]pyrimidine was synthetized from 2-amino-pyridine and the appropriate oxazolone derivative. 

The reaction of 9-mercapto-4-oxo-4//-pyrido[l,2-a]pyrimidine-3-carboxylates 513 (R1 = COOEt) and nitrile oxides in methylene chloride in the presence of trimethylamine at -20°C, then at ambient temperature for 24 hours, afforded 9-substituted pyrido[l,2-a]pyrimidine-3-carboxylates 521 (89EUP329126). 

In a series of 2,7-diphenyl 5-substituted pyrido[4,3-d]pyrimidines (155, R = OH, OEt, Cl, SH, NHNH2) the molecular ions and peaks for the expected phenyl degradation at 65, 63, 52, 51, 50, and 39 were all generally strong. Here again peaks were visible for m/2e ions and for M-l and PhCN ions. The variations in the group R affected the breakdown pattern, but ions for m/e = 282 (156) and m/e= 152 (157) were common. 

The reaction of ethyl 2-(acylamino)nicotinates with hydrochlorides of primary amines, phosphorus pentoxide and N,, V-di methy 1 cyc 1 ohexy 1 amine has been used to synthesize several substituted pyrido[2,3-c/]pyrimidin-4(3/7)-ones 24.36... 

Alkyl-substituted pyrido[2,3-c/]pyrimidin-4(3f/)-ones 40 result from cyclizations of 2-aminonicotinamides with acid chlorides.38,61... 

Starting from 2-chloronicotinonitrile, N1 -substituted pyrido[2,3-t/]pyrimidine-2,4(177,3//)-diones can be synthesized without isolation of the intermediates. The 2-amino group is introduced by the SN reaction of the chlorine substituent with an amine, followed by acid-catalyzed hydrolysis of the nitrile group and final cyclization with urea."... 

In a palladium-mediated oxidative coupling reaction, alkenes such as methyl acrylate, acrylonitrile, or styrenes cyclize with 6- [(diinethylainino)methylene]amino -l,3-dimethyluracil to give the corresponding 6-substituted pyrido[2,3-[Pg.128]

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