Pyrido pyrimidinones

Electrophilic substitution at ring nitrogen atoms has been limited to protonation and iV-alkylation of the anion derived from a pyrido-pyrimidinone.i - Thus, the sodium salt of pyrido-[2,3-d]pyrimidine-2,4-(l//,3ir)-dione and dimethylsulfate yield the 1,3-dimethy] derivative (176). 

Similar intermediates including o-ethoxycarbonyl-, o-cyano- and o-dimethyl-aminomethylene-piperidones or their imines have been used to give partially reduced analogues, e.g. (244), in the [2,3-. 

GEP2808070>. The reversed 5-chloro-4-acid chlorides give the corresponding pyrido[3,2-d]pyrimidinones. 

It was assumed that pyridine derivative 181 yielded pyrido[l,2-c]pyrimidine betaine 182 under catalytic hydrogenation conditions over (5,S)-Et-DuPHoS-Ph catalyst (99TL1211). 6,7-Dehydro derivative 184 of trequinsin (3) was obtained from pyrimidinone 183 by heating in an 1 1 mixture of MeOH and cone. HCl under reflux (97IJC(B)349). 

Treatment of l,3,4,6,7,llb-hexahydro[l,3]oxazino[3,4- ]quinazolin-l-one with LAH in boiling THF gave 2-(2-hydroxyethyl)-l-methylquinoline <2003T6785>. Pyrimidinone 107 was obtained from trequinsin 106 on the action of NaH, followed by the treatment with Mel (Equation 17) <1997IJB349>. The reaction of7-(benzotriazol-l-yl)-6,7-dihydro-l//,3/7,5//-pyrido[3,2,l-zy][3,l ]bcnzoxazine with PhMgBr led to ring-opened l-benzyl-4-(benzotriazol-l-yl)-8-hydroxymethyl-l, 2,3,4-tetrahydroquinoline < 1995JOC3993>. 

The pyrido[2,3- pyrimidinones 380 and 381 were thermally obtained from boiling the ethyl acrylate derivatives 378 and 379, respectively, with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and EtNHPd in THF (Scheme 13) <2001W02001055148, 2004USP2004009993>. The acrylates were obtained from reaction of the corresponding pyrimidine-5-carbaldehyde with (carbethoxymethylene)triphenylphosphorane. On the other hand, acrylate 382 was converted into 383 via aza-Wittig cyclization (Equation 32) <1997LA1619>. 

The pyrido[2,3-, pyrimidines 560 and 562 were prepared as analogues of the multitargeted antifolate (MTA) by the reaction of /3-keto ester 558 with either 2,4-diamino-6(l//)pyrimidinone 490 or 2,4,6-triaminopyrimidine 466, followed by saponification of the resulted glutamate products 559 and 561, respectively (Scheme 25) <1997H(45)2229>. 

Oxidation of the 2-substituted 4-oxo-4//-pyrido[l,2-a]pyrimidines and their hydroiodide salts with potassium permanganate yielded 6-substituted 4(3//)pyrimidinones.2"34... 

Investigations of the chiroptical properties of 9-halogen derivatives of 6-methyltetrahydro-4//-pyrido[ 1,2-a]pyrimidin-4-ones 28 (X and X1 = Cl, Br) established that the sign of the most characteristic CD bands is determined by the axial halogen atom in position 9 to the inherently achiral pyrimidinone chromophore (87JHC393). 

Protonation of 9-formyltetrahydropyrido[l,2-a]pyrimidinones takes place at the formyl oxygen, and the protonated enol-imine tautomers on the N(l) atom became the predominant tautomer forms [86JCS)P2)1911]. Similar phenomena were observed for the 9-formyltetrahydro-2// pyrido[l,2-a]pyrimidin-2-ones and their homologs [85JCS)P2)1873 88MI7]. 

Scheme 4. X-Ray structure determination of some pyrido[ l, 2-a]pyrimidinones...

Bis(2,4,6-trichlorophenyl) malonate reacted smoothly with 2-[(cyclo-hexylmethyl)amino]pyridine at 160-175°C under nitrogen to yield pyr-ido[l, 2- ]pyrimidinone 112 (81JMC1284). Reaction of an equimolar mixture of bis(2,4,6-trichlorophenyl) 2-substituted malonates and 2-(phen-ylamino)-, 2-(3-pyridylamino)-, and 2-(3-trifluorophenyl)amino]pyridines at 160-180°C gave cardiotonic mesoionic pyrido[l,2-a]pyrimidinones 113 (91AP863). Mesoionic tetrahydropyridopyrimidinones 114 were obtained in the reaction of 2-(phenylamino)-3,4,5,6-tetrahydropyridine and bis(2,4,6-trichlorophenyl) 2-substituted malonates (85CB4567 86CC687). 

This reaction was extended to prepare 7-nitro- and 9-nitro derivatives of pyrido[l,2-a]pyrimidinone 119 (R = N02, R1 = H R = H, R1 = N02) when the appropriate starting material 118 was heated in boiling dichloro-methane in the presence of triethylamine or when it was stirred in aqueous sodium hydroxide at 20°C (92AJC1825) or treated with sodium azide in aqueous tetrahydrofuran (92AJC2037). Semiempirical molecular orbital calculations (AMI) indicated that the 2-hydroxy-4-oxo tautomeric forms 119 are more stable than the alternative 4-hydroxy-2-oxo tautomeric forms. 

Heating acetylenic pyrimidinones 214 in refluxing naphthalene for 1-2 hours gave 6-methylene-6,7,8,9-tetrahydro-4/f-pyrido[l, 2-u]pyrimidin-4-ones 215 and tricyclic intermediates 216 (83JHC1407). The latter 216 decomposed under the reaction conditions to give cyclopentano(b)pyridine 217 and cycIopentano(6)pyridinones 218 by elimination of HN=C=0 and acetonitrile, respectively. 

The reaction of Dewar pyrimidinone 220 with water in 1 9 mixture of water and acetone at 20°C for 1 hour afforded 4//-pyrido[ 1,2-a]pyrimidin-4-one 108 and enamine 107 in 34% and 64% yields, respectively [89JCS(P1)1231]. Enamine 107 was formed by the cleavage of bond a of 4-hydroxyazetidin-2-one 221, and ring closure of enamine 107 by elimination of water gave 4//-pyrido[l, 2-a]pyrimidin-4-one 108 (Scheme 15). When the solvent polarity was increased, the cleavage of bond b of 4-hydroxyazetidin-2-one 221 also occurred. The reaction in aqueous acetoni-trile-d3 at 35°C for 37 hours gave 4//-pyrido[ 1,2-a]pyrimidin-4-one 109 and lactam 222 in 85% and 10% yields, respectively. The reaction of Dewar... 

Reduction of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l, 2-a]pyrimidin-4-one 353 with sodium borohydride in water at 0°C yielded perhydropyrido-pyrimidinone 354 (82JOC4780). 

Ethyl-l, 2,6-trimethyl-4-oxo-4//-pyrido[l,2-a]pyrimidinium iodide 348 was obtained from pyrido[l,2-a]pyrimidinone 347 with methyl iodide in acetone in a sealed tube at 150°C for 24 hours (81USP4291036). 

The cyano group of 3-cyano-, 3-cyanomethyl-, and 3-(cu-cyanoalkyl)-4//-pyrido[ 1,2-a]pyrimidinones 439 was converted to a 5-tetrazolyl group by treatment with sodium azide in boiling tetrahydrofuran for 2-23 hours in the presence of aluminum chloride or in dimethylformamide at 100-110°C for 8 hours in the presence of ammonium chloride to yield 5-tetrazolyl derivatives 440 [87EUP217673 88JAP(K)88/246375]. 3-(l H-... 

The reaction of 3-aminopyridopyrimidin-4-one 330 with acetone in boiling dichloromethane in the presence of a catalytic amount of acetic acid for 5 hours followed by 24-hour stirring at room temperature or with 37% aqueous formalin in boiling ethanol for 2 hours afforded tricyclic oxazolo[5,4-c/]pyrido[l,2-a]pyrimidinones 462 [91IJC(B)839]. 

When Dewar pyrimidinone 644 (R = /Bu) was left to stand in acetonitrile containing hydrogen sulfide at 0°C for 15-19 hours, hexahydro-4//-pyrido[2,l-fe][l,3]thiazin-4-one 223 and tetrahydro-4f/-pyrido[ 1,2-a] pyrimidin-4-one 643 (R = /Bu) were obtained in 52% and 32% yields, respectively [89JCS(P1)1231]. When pyrido[2,l-/ ][l,3]thiazine 223 was set aside for 64 hours at 35°C in CDC13, pyrido[ 1,2-a]pyrimidin-4-one 643 (R = /Bu) was obtained in 95% yield. The hydrated enamine 107 in methanol at 16-23°C reverted to the bicyclic pyrido[ 1,2-a]pyrimidin-4-one 643 (R = /Bu) after 2 days in almost quantitative yield [85JOC166, 85TL3247 89JCS(P1)1231]. 

Dewar pyrimidinone 657 was obtained in 92% yield when a solution of pyrido[l, 2-a]pyrimidin-4-one 114 (R = Ph) in acetonitrile was irradiated with a medium-pressure mercury lamp at 20°C (86CC687). 

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