3- -2-hydroxy-477-pyrido

Known examples are the partial Hofmann degradation of pyridine-2,3-dicarbox-amides,134 the Lossen degradation of pyridine-2,3-bis(hydroxamic) acid,135 this giving both possible products, i.e. 3-hydroxypyrido[2,3-(/]pyrimidine-2,4(l//,3//)-dione and 3-hydroxy-pyrido[3,2-d]pyrimidine-2,4(l//,3//)-dione as a 5 1 mixture, and the conversion of a primary carboxamide function into an intermediate isocyanate in the 2-position by oxidation with lead(IV) acetate.136... 

Ultraviolet spectral and pKa data have been used to show that the cation and the neutral species of 2- and 3- hydroxy pyrido[2,3-fejpyrazine undergo covalent hydration in the pyrazine ring in aqueous solution. Although extensive, the hydration is less than that found for pyrido[3,4- ]pyrazines. Covalent hydration of the parent heterocycle, or other hydroxy derivatives, could not be demonstrated by this technique. However PMR studies" have shown that in aqueous solution the cation of pyrido[2,3-6]pyrazine contains 10% of the dihydrated species 2. 

The UV spectra of pyrido[2,3-d]pyridazine-l,4-diones have been recorded (68MI21501), whilst several of the latter were also used in chemiluminescence studies. Quinolinic and cinchomeronic hydrazides showed no chemiluminescence (60NKK173, 37JPR(148)135), but it was observed in the 8-hydroxy derivative (305) (72YZ703). 

Protonation of pyrido[2,3-f ]pyrazine occurs normally without covalent hydration, although the 2-hydroxy derivative did show such behaviour (63JCS5737). The pyrido[3,4-f)]pyrazine parent base does show the phenomenon, although the exact structure of the covalent hydrate seemed to be in doubt between protonated (392) and (397). The issue was resolved in favour of the former by NMR (79JHC301, 75AG356). The 3-hydroxy derivative also shows hydration effects, as does the 7-amino cation (63JCS5166). 

Nitro groups have been reduced to amino groups, whilst amino groups in the 3- and 6-positions of pyrido[2,3-f ]pyrazines and in the 5-position of the [3,4-f ] isomers have been hydrolyzed to the corresponding hydroxy derivatives with alkali. Protected amino groups have been liberated by hydrolysis or reduction in deazapteridine syntheses. 

E rido[2,3-b]pyrazine, 2,3-dihydroxy-chlorination, 3, 251 Pyrido[2,3-b]pyrazine, 6-hydroxy-formation, 3, 251... 

Pyrido[2,3-6]pyrazine, 8-hydroxy-tautomerism, 3, 250 Pyrido[2,3-h]pyrazine, methyl-acylation, 3, 253 Pyrido[2,3-6]pyrazine, 2-oxo-oxidation, 3, 250-251... 

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-... 

Theoretical calculations (B3LYP/6-31G ) were reported for geometries (bond lengths and bond angles) and chemical shifts of 3-methyl- and 3-phenyl-4-hydroxy-2-oxo-2/7-pyrido[2,l-f>][l, 3]oxazinium inner salts (00JCS(P2)2096). 

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). 

Treatment of alkyl 9-benzyloxycarbonyl-3-methyl-6-oxo-2/7,6//-pyr-ido[2,l-f ][l,3]thiazine-4-carboxylates with BBr3 in CH2CI2 at -70 °C for 0.5-1 h and at room temperature for 3h yielded 9-carboxyl derivatives. The decarboxylation of these acids was unsuccessful. Hydrolysis of diethyl cA-3,4-H-3,4-dihydro-3-methyl-6-oxo-2//,6//-pyrido[2,l-f ][l,3]thiazine-4,9-dicarboxylate in aqueous EtOH with KOH at room temperature for 3 days yielded 4-ethoxycarbonyl-3,4-dihydro-3-methyl-6-oxo-2//,6//-pyrido-[2,l-f ] [1,3]thiazine-9-carboxylic acid (00JCS(P1)4373). Alkyl 9-hydroxy-methyl-3-methyl-6-oxo-3,4-dihydro-2//,6//-pyrido[2,l-f ][l,3]thiazine-4-car-boxylates were O-acylated with AC2O and (PhC0)20 in pyridine at room temperature for 12-48h. 

Stability constants of metal complexes of 9-hydroxy-4//-pyrido[l,2-n]pyrimidin-4-one [Ni(II), Co(II), Zn(II), and Cd(II)] were determined by potentiometric and polarographic investigations (93JCC283). The distribution coefficient of risperidone (11) in H20- -octanol at pH 7.4 (log D — 2.04) was determined by an RP-HPLC method (01JMC2490). 

Diorganotin(IV) complexes with 4//-pyrido[l,2-n]pyrimidin-4-ones 109 (96MI4), complexes of 2-methyl- and 2-methyl-8-nitro-9-hydroxy-4//-pyrido[l,2-n]pyrimidin-4-ones with Ag(I), Cu(II), Ni(II), Co(II), and Mn(II) ions (00MI23), 2,4-dimethyl-9-hydroxypyrido[l, 2-n]pyrimidinium perchlorate and its complexes with prasedynium, neodymium, samarium and europium (00MI24) were characterized by UV spectroscopy. 

IR spectra in conjunction with theoretical calculations (B3LYP/6-31G ) indicate that the n /2ydro-(2-hydroxy-4-oxo-4//-pyrido[l, 2-n]pyrimidinium)-hydroxide form exists in solution and in the crystal, but the 2-hydroxy-4//-pyrido[l,2-n]pyrimidin-4-one tautomer dominates in the gas phase (00JCS(P2)2096). 

The solid state structures of anhydro-(3-methy - and 3-phenyl-2-hydroxy-4-oxo-47/-pyrido[l,2-n]pyridinium)hydroxides, 2-methoxy-3-methyl-47/-and 2-(2-pyridylamino)-47/-pyrido[l, 2-n]pyrimidin-4-ones were established by X-ray diffraction analysis. The amide type N(5)-C(4)-0 bonds are unusually long (144-149 pm) showing no sign of an amide type conjugation. 

The relative stereostructure of 9-acetyl-7-hydroxy-l,2-dimethyl-7-meth-oxycarbonyl-4-phenyl-6-oxo-l, 4,7,8-tetrahydro-6/7-pyrido[l, 2-u]pyri-midine-3-carboxylate 122 was justified by an X-ray diffraction analysis (97JOC3109). The stereochemistry and solid state structure of racemic trans-6,9-//-l, 6-dimethyl-9 z-ethoxy-9-hydroxy-4-oxo-l,6,7,8,9,9 z-hexahydro-4//-pyrido[l,2- z]pyrimidine-3-carboxylate (123), adopting a cw-fused conformation, were determined by X-ray investigations (97H(45)2175). 

Chlorination of 2-hydroxy-4//-pyrido[l,2-n]pyrimidin-4-one with NCS in a mixture of AcOH and TFA at room temperature for 72 h yielded a 3-chloro-2-hydroxy derivative (95JMC4687). Bromination of 2-chloro-4//-pyrido[l, 2-n]pyrimidone with Br2 in a mixture of CH2CI2 and pyridine at room temperature for 15 min gave a 3-bromo derivative (00BMC751). 

Reaction of 2-amino-4/f-pyrido[l,2-n]pyrimidin-4-ones 143 with HNMei -HCl and paraformaldehyde in Dowtherm A afforded a mixture of 3-(A,A-dimethylamino)methyl derivatives 144 and bis-compounds 145 (93FES1225). Mannich reaction of 9-hydroxy-2-methyl-4//-pyri-dor],2-nlpyrimidin-4-one (146) yielded 8-aminomethyl derivatives 147 (94KFZ(10)23). 

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). 

Arylsulfenyl derivatives 151 were obtained from mesoionic 150 with diaryl disulfides in the presence of K2CO3 when air was bubbled through the reaction mixture (99M1147). u / yJro-(2-Hydroxy-4-oxo-4/7-pyrido[l,2-u]pyrimidinium)hydroxide (R = H) afforded 3-dialkylaminothiocarbo-nylthio derivatives 152 in the reaction of tetraalkylthiuram disulfides under similar conditions. 

Methoxy-4//-pyrido[],2-n]pyrimidin-4-one was prepared from 2-chloro-4//-pyrido[],2-n]pyrimidin-4-one with NaOMe in MeOH for 16h, and from n /iyJro-(2-hydroxy-4-oxo-4//-pyrido[l, 2-n]pyridinium)hydroxide with Me2S04 in the presence of NaOMe in MeOH for 3h at room temperature in 93% and 41% yields, respectively (99JCS(P2)1087). 2-(2-Hydroxyethoxy)-4//-pyrido[],2-n]pyrimidin-4-one was prepared from the 2-chloro derivative with HOCH2CH2OH in the presence of K2CO3 at 160 °C for 1 h (00BMC751). 

Piperazinomethyl)-9-hydroxy-4//-pyrido[l,2-u]pyrimidin-4-one was obtained by hydrolysis of the 2-(4-formylpiperazino)methyl derivative in boiling 10% HCl. The hydrolysis of the 2-(4-ethoxycarbonylpiperazino) derivative in NaOH solution was unsuccessful (95EJM27). 

The hydroxy group of ethyl 9-hydroxy-4-oxo-4//-pyrido[l,2-u]pyrimi-dine-3-carboxylate was O-alkylated with 2-chloromethyl-4-isopropyl-l,... 

Reaction of 2-hydroxy-4//-pyrido[l,2-u]pyrimidin-4-ones 168 and 2-chloromethylsaccharins 169 in the presence of a base gave 2-<9-alkylated products 170 (94EUP626378, 95JMC4687, 95USP5378720). From the reaction mixture of 3-chloro derivative 168 (R = H, R = Cl) and... 

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). 

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