Pyrimidines 1.4- dihydropyrido

Dihydropyrido[2,3- /]pyrimidines have also been prepared from 3-acylaminomethyl-2-aminopyridines (53JA656). 

A major type of reaction in this class is the cyclization of 4-amino- or 4-halo-pyrimidines carrying 5-cyanoethyl or 5-ethoxycarbonylethyl groups, which cyclize to 7-amino or 7-oxo derivatives of 5,6-dihydropyrido[2,3- f]pyrimidine, e.g. (131)->(63). The intermediates may sometimes be prepared by reaction of 4(6)-aminopyrimidines with acrylonitrile, or even via a pyrimidine ring synthesis from an amidine and a cyanoacetic ester or malononitrile derivative, e.g. (132) -> (133) (7lJOC2 85, 72BCJ1127). 

Good yields of pyrido[2,3-d]pyrimidiries (37) were also oblaiiied by the action of formamide on o-amino nitriles (36). Reduction of 2-amino-4,6-dimethylnicotinitrilc yields the 3-aminomcthyl compound (38). Acylation to the 3-aoylaminomethyl derivative (39), followed by cyolization, by means of heat or phosphoryl chloride, yielded the dihydropyrido[2,3-d]pyrimidines (40). ... 

Oxidations of pyridopyrimidines are rare, but the covalent hydrates of the parent compounds undergo oxidation with hydrogen peroxide to yield the corresponding pyridopyrimidin-4(3 T)-ones. Dehydrogenation of dihydropyrido[2,3-(i]pyrimidines by means of palladized charcoal, rhodium on alumina, or 2,3-diehloro-5,6-dicyano-p-benzo-quinone (DDQ) to yield the aromatic derivatives have been reported. Thus, 7-amino-5,6-dihydro-1,3-diethylpyrido[2,3-d]-pyri-midine-2,4(lif,3f/)-dione (177) is aromatized (178) when treated with palladized charcoal in refluxing toluene for 24 hours. 

Early reports of analgesic and antiarthritic activity in octahydropjTido[4,3-d]pyrimidines do not appear to have been substantiated, but a number of recent patents refer to the antipyretic, diuretic, bacteriostatic, sedative, and coronary-dilating activities of a series of 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines. Pharmacological properties claimed for, 5,6-dihydropyrido[2,3-[Pg.198]

It was elaimed that eyelization of ethyl 2-ehloro-5-eyelopropyl-6- [(A-(4,5-dimethoxy-2-nitrophenyl)methoxy)earbonyl]-A-(2-fluoro-3-hydroxy-l-oxo-2-propen-l-yl)amino nieotinate (321) in boiling aqueous dioxane in the presenee of K2CO3 overnight yielded l- [(4,5-dimethoxy-2-nitrophe-nyl)methoxy]earbonyl -9-eyelopropyl-3-fluoro-2-oxo-2,6-dihydropyrido[l, 2-n]pyrimidine-7-earboxylate (160) (95MIP1, 96MIP4, 96USP5580872). 

The starting material may be produced by reacting 6-amino-2-methylthiopyrimidine with ethoxymethylene malonic acid diethyl ester. The intermediate thus produced is converted by boiling in diphenyl ether to 6-ethoxycarbonyl-2-methylthio-5-oxo-5,B-dihydropyrido-[2,3-d]pyrimidine. That is hydrolyzed by sodium hydroxide to cleave the ethoxy group and then ethylated with diethyl sulfate to give the starting material. 

N- and O-Substituted terpenyl pyrimidines <05EJM552> as well as dihydropyrido[2,3-rf]-pyrimidines <05BMC6678> were prepared as antileishmanial agents. 5-Alkynyl- and 6-alkyl-furo[2,3-rf]pyrimidine acyclic nucleosides <05BMC1239>, acyclic furo- and... 

Within an SAR study of p38 MAP kinase inhibitors, a series of 3,4-dihydropyrimido[4,5-ri pyrimidin-2-ones and 3,4-dihydropyrido[4,3-rijpyrimidin-2-ones were prepared <06BMCL4400>. 

The reaction of l-amino-5-benzyl-5,8-dihydropyrido[4,3-i/]pyrimidin-8-one and EMME in boiling DMF for 4 hr gave N-(pyridopyrimidin-l-yl)aminomethylenemalonate (85) in 48% yield (84KGS532). 

Methyl 5-(3-fluorophenyl)-7-methyl-l,2,3,4,5,8-hexahydropyrido[2,3-tetrahydro derivative 137 by the action of sodium nitrite in acetic acid <1994T8085>. Oxidation of 2,7-disubstituted-5-trifluoromethyl-l,2-dihydropyrido[2,3-r/]pyrimidin (3//)-ones using active Mn02 in CH2CI2 gave the corresponding pyridopyrimidin-4(3//)-ones 138 <1995IJB587>. 

The tetrahydropyridopyrimidine 394 was obtained via condensation of 5-acetyl-4-arylamino-6-methyl-2-styrylpyr-imidine with benzaldehyde <1997PJC1232>. The 5,8-dihydropyrido[2,3 Pyrimidine derivatives 395 could be obtained from condensing 5-acetyW-amino-2,6-disubstituted pyrimidines with ethyl oxalate in the presence of alkoxide by-products of Friedlander self-condensation of 395 were also obtained <2002RCB1875>. 

Microwave irradiation, for 15-20 min under solvent-free conditions, promoted the regiospecific three-component one-step cyclocondensation of benzoylacetonitrile, an aromatic aldehyde, and aminopyrimidinones 460 to give 6-cyano-5,8-dihydropyrido[2,3-, pyrimidin-4(3/7)-ones 461 rather than the isomers 462. The formation of 461 proceeds via a Michael-type addition of C-5 in aminopyrimidine 460 to the activated double bond of the arylidene-benzoylacetonitrile intermediate followed by cyclization with the removal of a water molecule. Compounds 461 were also prepared conventionally by refluxing the reactants in absolute ethanol for 40 8 h <2001TL5625>. 

Reaction of 6-amino-l,3-dimethyluracil with the Mannich base 524 under nitrogen in boiling H2O gave 5,6-dihydropyrido[2,3- pyrimidine-(17/,37/)-2,4-diones 531 rather than their oxidized analogues 530. The latter could be obtained by boiling the reactants in AcOH (Scheme 22) <2004T11511>. 

Kappe et al. reported the microwave-assisted synthesis of pyrido[2,3-ri ]pyrimidines via a one-pot three component cyclocondensation of a,(3-unsaturated esters, amidines and malonitrile (or ethyl cyanoacetate) (Scheme 3.45)71. Quiroga et al. reported a similar three component cyclocondensation to synthesise regiospecif-ically 5,8-dihydropyrido[2,3-ri ]pyrimidines under solvent-free conditions, starting from a combination of aminopyrimidin-4-ones, benzoylacetonitrile and benzaldehyde (Scheme 3.45)72. 

Quiroga and co-workers55 have described a facile three-component microwave assisted, one-pot synthesis of 5-aryl-6-cyano-7-phenyl-5,8-dihydropyrido[2,3-d]pyrimidin-4 (3/f)-ones suitable also in a combinatorial set-up, Scheme 5.36. Equimolar quantities of the starting compounds were placed in open vessels and irradiated in a domestic microwave oven for 15-20 min at 600 W. When irradiation was complete, the resulting solid was treated with ethanol and filtered to give the products in 70-75% yield. Under reflux in ethanol, a much longer reaction time (40-48 h) was required to provide the product in very modest yields (21-25%). 

When the substrates were irradiated for just 8-12 min, the reaction in all cases resulted in the formation of stable, hydrated intermediates, Fig. 5.3, which were isolated and characterised. If the intermediate was continuously irradiated (an additional 6-10 min) further, dehydration occuredyielding5-aryl-6-cyano-7-phenyl-5,8-dihydropyrido [2,3-d ] pyrimidin-4(3//)-one as the principal product. 

Figure5.3 5-Aryl-6-cyano-7-phenyl-5,8-dihydropyrido [2,3-d] pyrimidin-4 (3H)-ones.

Quiroga, J., Cisneros, C., Insuassty, B., Abonia, R., Nogueras, M. and Sanchez, A., A regiospecific three-component one-step cyclocondensation to 6-cyano-5,8-dihydropyrido[2,3-d]pyrimidin-4(3ff)-ones using microwaves under solvent-free conditions,Tetrahedron Lett., 2001, 42, 5625-5627. 

Ethyl 6-methyl-9-hydrazono-4-ozo-6,7,8,9-tetrahydro-4//-pyrido[l,2-a]-pyrimidines was condensed with benzaldehyde to yield a mixture of tetra-hydro and dihydropyrido[l,2-a]pyrimidines (254 and 255) and was acylated with benzoyl chloride.307... 

Hydroxy-2-oxo-3,4-dihydropyrido[l,2-a]pyrimidine was O-acetylated with acetic anhydride and dehydrated to 2-oxo-2//-pyrido[l,2-u]pyrimidine (18) with phosphorus pentoxide.200... 

Bromination of the 7-bromo- and 7-chloro-2-oxo-3,4-dihydropyrido-[l,2-a]-pyrimidines and the 7-chloro-4-oxo-2,3-dihydropyrido[l,2-a]-pyrimidines with bromine was unsuccessful, yielding only the hydrobromide salts of the starting materials.205... 

Keywords 5-amino pyrimidin-4(3//)-one, cyanomethyl phenyl ketone, benzalde-hyde, microwave irradiation, dihydropyrido[2,3-r/]pyrimidin-4(3/7)-one... 

Dioxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-a]pyrimidines 35 exhibit an oxo-enol tautomerism, which was studied by UV, IR, and NMR methods (85JHC1253). In the solid phase enol tautomers are present, while in a polar solvent an electron withdrawing substituent at position 3 shifts the equilibrium toward the enol form. The analogous 9-amino derivatives exist exclusively as 9-amino-6,7-dihydropyrido[l,2-a]pyrimidin-4-ones. 

Dihydro-2//-pyrido[l,2-a]pyrimidin-2-one 675, a neutral hydrogen chloride acceptor, has been shown to give better yields in regio- and stereospecific thio- and selenolactonizations of hept-4-ynoic and hex-4-ynoic acids 683 with benzenesulfenyl and benzeneselenenyl chlorides than triethylamine [86JCS(P1)1999]. In the case of dihydropyrido[l,2-a] pyrimidinone 675, noncyclized products 685 and 686 were formed only in trace amounts. 

The reaction of 4-(2-hydroxyphenyl)-but-3-en-2-one 21 with l,3-dimethyl-6-aminouracil 305 in trifluoroacetic acid proceeds with the intramolecular addition of the hydroxyl group to the ethylene bond of dihydropyrido[2,3-J pyrimidines and yielded the appropriate tricyclic compounds 308 [230] (Scheme 3.84). 

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