9-Hydroxy-2-methyl-4/7-pyrido chloride

Methyl- and 3-phenyl-4-hydroxy-2-oxo-2//-pyrido[2,1 -Z)]oxazinium inner salts were prepared in the reaction of 2-pyridone and 2-substituted malonyl chloride, prepared in situ from 2-substituted malonic acid with PCI5 in CH2CI2 (00JCS(P2)2096). 

Vilsmeier-Haack formylation of 2-(4-methyl-l-piperazinyl)-4//-pyrido-[l,2-n]pyrimidin-4-one with a mixture of POCI3 and DMF at 95°C gave a 3-formyl derivative (93FES1225) while ethyl 4-oxo-6,7,8, 9-tetrahydro-4//-pyrido[l,2-n]pyrimidine-2-acetate at 50 °C yielded a 9-dimethylaminomethylene-3-formyl derivative (01MI4). 3-Formyl-2-hydroxy-8-[2-(4-isopropyl-l,3-thiazol-2-yl)-l-ethenyl]-4//-pyrido[l,2-n]pyri-midin-4-one was obtained from the 3-unsubstituted derivative with oxalyl chloride-DMF reagent in CH2CI2 at room temperature for 3h (OlMIPl). 

The side chain hydroxy group of 3-(2-hydroxyethyl)-2-methyl-9-methoxy-4//-pyrido[l,2-u]pyrimidin-4-one, and that of its 6,7,8,9-tetrahydro derivative was acylated with MeS02Cl in the presence of NEts in CH2CI2 at room temperature (95MIP4, 96MIP2). The hydroxy group of 2-[4-(4-hydro-xybenzoyl)benzyloxy]-3-methyl-4//-pyrido[l, 2-u]-pyrimidin-4-one, its 6-methyl derivative and 2-[4-(4-hydroxybenzoyl)benzylthio]-3-methyl-4//-pyrido[l, 2-u]pyrimidin-4-one was alkylated with 4-(2-chloroethyl)morpholine hydrochloride and 4-picolyl chloride hydrochloride (96EUP733633). 

Acylation of mesoionic pyrido[l,2-u]pyrimidin-4-ones 150 with aroyl chlorides in the presence of NEts yielded 2-aroyloxy-4//-pyrido[l,2-u]pyrimidin-4-ones 178 (96JHC663). None of the esters 178 could be rearranged to the 2-hydroxy-3-aroyl derivatives 179. The hydroxy group of 9-hydroxy-2-methyl-3- 2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl] ethyl -6,7,8,9-tetrahydro-4//-pyrido[l, 2-u]pyrimidin-4-one was acylated with hexadecanoic acid in CH2CI2 in the presence of dicyclohexylcarbodi-imide and 4-pyrrolidinopyridine at room temperature for 3 days in 80% yield (97MIP7). 

Hydroxy-3,4-dihydro-2H-pyrido[2,l-b][l,3]thiazin-5-ium chloride was formed when 2-hydroxy-3-(2-pyridylthio)propyl chloride was stirred in methylene chloride overnight (92JOC6335). When the reaction was carried out in methanolic sodium methylate, 3-(2-oxo-l,2-dihydro-l-pyridyl) thietane was obtained in 58% yield. 

In a phosphoryl chloride-polyphosphoric acid mixture the pyrido[l,2-a]-pyrimidines (78) were formed in high yield, as well as a small amount of the pyridylpyrrole derivatives (83) that were obtained from the pyridylpyrro-linones (79) through hydroxy to chloro exchange under the conditions of the ring closure. From the 6-methyl-substituted succinates (77 R = 6-Me) the pyrido[l,2- ]pyrimidines (78) and the pyridylpyrroles (83) were obtained in approximately equal amounts, in a good overall yield.132134... 

Aminopyridine and its 3-hydroxy and 6-methyl derivatives were reacted with ethyl 2-chloro- and 2-phenoxyacetoacetates by heating in a mixture of phosphoryl chloride-polyphosphoric acid to give the appropriate 3-substituted 2-methyl-4//-pyrido[l,2-a]pyrimidin-4-ones (83H1083). 

The quaternary salt 366 was not obtained from 9-hydroxyl-2-methyl-4 -pyrido[ 1,2-a]pyrimidin-4-one 365 and benzyl chloride by heating in nitromethane (92KGS1660). The hydroxy group of 9-hydroxylpyridopy-rimidin-4-one 365 was alkylated with methyl iodide in dimethyl sulfoxide at 40°C for 30 hours to give 9-methoxy derivative 367 in 9% yield. 

Hydroxy-2-methyl-4.//-pyrido[l,2-a]pyrimidin-4-ones510 (R1 = Hor CN R2 = H, Me) reacted with dimethylthiocarbamoyl chloride in acetone to afford 9-dimethylthiocarbamoyloxy derivatives 511 (R1 = H, CN R2 = H, Me) (Scheme 30) (87EUP218423 89EUP329126). When compounds 511 were heated in Dowtherm A, the 9-dimethylthiocarbamoyloxy group rearranged to give 9-(dimethylcarbamoylthio)-2-methyl-4//-pyrido[l,2-a]pyrimidin-4-ones 512 in excellent yield. The treatment of pyridopyrimidin-4-one 512 (R1 = H, R2 = Me) with sodium hydride... 

The equilibrium mixtures of 3-hydroxy-3-methyl-3,4-dihydro-lH-pyrido [2,l-c][l,4]oxazinium chloride 159a, its 4,4-dideutero derivatives 161a (06PJC1039) and those of 3-hydroxy-3-phenyl-3,4-dihydro-lH-pyrido [2,l-c][l,4]oxazinium bromide 159b and 161b (06JST36) with their ring-opened forms 160 and 162 were characterized by FTIR, 1H, 13C, and 15N NMR spectra in DMSO and D20. 

The nitrogen atom necessary for ring closure to give the pyrido[3,2-c/]pyrimidine system may be introduced by heating methyl 3-acetamidopyridine-2-carboxylate with an arylamine in a free flame for a short time or refluxing the reaction partners in a benzene/phosphoryl chloride mixture.37 The reaction of the pyridine-2-carboxylate with hydroxylamine in methanol/water requires two days at room temperature and affords 3-hydroxy-2-methylpyrido[3,2-t/]-pyrimidin-4(3//>one (11).35... 

---