3- Ethyl-2-methyl-477-pyrido

When 6-aminopyridine-3-carboxamide was reacted with ethyl 2-ethyl-acetoacetate in a mixture of phosphoryl chloride-polyphosphoric acid, 7-cyano-3-ethyl-2-methyl-4//-pyrido[l,2-a]pyrimidin-4-one 94 was obtained... 

Ethyl-2-methyl-4//-pyrido[l,2-a]pyrimidin-4-thione was obtained in... 

Pyrido[4,3-rf]pyrimidin-4(3/7)-oiie (138) was prepared from either ethyl 4-aminonicotinate or from 4-aminomcotinamide by fusion with formamide. A parallel to the pyrido[3,2-d]pyrimidines (cf. Section II,B, la) was demonstrated in the conversion of 2-methyl-pyrido[4,3-d][l,3]oxa7in-4-ones (139, Ri = Me) into the corresponding pyrido[4,3-d]pyrimidin-4(377)-ones (142) on treatment with a number of amines.There were certain limitations to the method in this series, however, and the intermediate diamides (140) were more conveniently prepared from the appropriate 4-amidonicotinate (141) and. .Ri... 

Alkylcathin-5,6-diones are fairly resistant to acidic hydrolysis, but are easily hydrolyzed under basic conditions. For example 3-ethyl derivative 202 gave green-colored l-methyl-2-ethyl-2//-pyrido-[3,4]indole 203 (Scheme 49) (85TL385). 

A mixture of 3-(2-bromoethyl)-2-methyl-pyrido[l,2-a]pyrimidin-4-one monohydrobromide, 3-furan-2-yl-methyl-(3H-imidazo[4,5-b]pyridine-2yl)-4-piperidinyl)-amine dihydrobromide, of sodium carbonate and of N,N-dimethylformamide was stirred and heated overnight at about 70°C. The reaction mixture was poured onto water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (94 6 by volume), saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 3-(2-(4-((3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)-l-piperidinyl)ethyl)-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one melting point 202°C. 

During a presentation at the 1975 TCRC and in a 1977 publication on their study of the water-soluble portion of CSC, Schumacher et al. (3553) reported the identifications of l-methyl-9//-pyrido[3,4-f ]indole (harman), 5//,10//-dipyrrolo[l,2-a T,2 -r(]pyrazine-5,10-dione (pyrocoll), octa-hydro-5//,10//-dipyrrolo[l,2-a T,2 -r(]pyrazine-5,10-dione (octahydropyrocoll), and 2-ethyl-9//-pyrido[2,3-fc]indole. 

Both 2- and 3-methyl groups in pyrido[2,3-Z ]pyrazines are acylated by ethyl oxalate (71TH21500). They give (preferentially 3-) styryl derivatives with aromatic aldehydes and oximes with pentyl nitrite. 

Only one cyclic hydroxamic acid which contains the pyrido[2,3-d]-pyrimidine ring system has been reported.This is 2-methyl-3-hydroxypyrido[2,3-d]pyrimidin-4(3i/)-one (21) which was prepared by the action of acetic anhydride on 2-aminonieotinhydroxamic acid (20) or from ethyl 2-aeetamidonicotinate (22) and hydroxylamine. In view of the known antibacterial activity of certain cyclic hydroxamic acids further work on these compounds would be of interest. 

The yellow colored, sparcely soluble 5-ethyl-2-methyl-l l/f-pyrido[3,4-u] carbazolium 347 isolated from Aspidosperma gilbertii exists as a hydroxide after filtration of the corresponding iodide over basic aluminum oxide. A short synthesis was described (80CB3245). The Pyrido[3,4-a]carbazole ring system is present in the alkaloid AG-1, whereas Cryptolepine (348) possesses the indolo[3,2-b]quinoline moiety (65MI1). 

Ethyl 9-ethoxycarbonyl- and 9-hydroxymethyl-3-methyl-6-oxo-2/f,6//-pyrido[2,l-Z>][l,3]thiazine-4-carboxylates were isomerized into 4H,6H-pyrido[2,l-b][l,3]thiazine-4-carboxylates by treatment with KOH overnight at room temperature and by treatment with NaOEt at 0 °C for 1 h and room temperature for 3h in EtOH, respectively. In another experiment, when the 9-hydroxymethyl derivative was treated with NaOEt in EtOH at — 10°C for 3h, a 2.5 1 mixture of ethyl 3,4-cw-H-9-ethoxymethyl-3-methyl-6-oxo-3,4-dihydro-2//,6//-pyrido[2,l-Z)][l,3]thiazine-4-carboxylate and the aforementioned 4//,6//-isomer were obtained (00JCS(P1)4373). 

An algorithm for an assesment of chromatographic peak purity was proposed. In this study ethyl 8-methyl-4-oxo-4/7-pyrido[l, 2-u]pyrimidine-3-carboxylate was also used (97MI13). Ethyl 7-methyl-4-oxo-4//-pyrido[l,2-u]pyrimidine-3-carboxylate, among other compounds, was applied to show practical mathematical tools for the creation of several figures of merit of nth order instrumentation, namely selectivity, net analyte signal and sensitivity (96ANC1572). 

Polymorphic forms of I and II of 3- 2-[4-(6-fluorobenzo[r/ isoxazol-3-yl)-3,6-dihydro-2//-pyridin-l-yl]ethyl -2-methyl-6,7,8,9-tetrahydro-4//-pyrido [1,2-n]pyrimidin-4-one was characterized by IR spectroscopy (99MIP1). 

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). 

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). 

Treatment of 9-(ethoxymethoxy)-3- 2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-1,2,5,6-tetrahydro-1 -pyridyl] and -1 -piperidyl]ethyl -2-methyl-4/f-pyrido-[1,2-rz]pyrimidin-4-ones with cone. HCl afforded 9-hydroxy derivatives (95MIP4, OOMIPIO). 

The A-substituted derivatives of 4-oxo-4//-pyrido[l,2-n]pyrimidine-3-carboxamides and -3-acetamides and l,6-dimethyl-4-oxo-1,6,7,8-tetrahy-dro-4//-pyrido[l,2-n]pyrimidine-3-carboxamide were prepared by treatment of the appropriate 3-carboxylic acids and acetic acid, first with an alkyl chloroformate in the presence ofNEt3 in CHCI3 below — 10°C, then with an amine (98ACH515). A-Phenethyl and A-[2-(3,4-dimethoxyphenyl)ethyl] derivatives of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetamide were obtained in the reaction of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-n]pyrimidine-3-acetic acid and phenethylamines in boiling xylene under a H2O separator. Hydrazides of 4-oxo-4//- and 4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic acid were prepared from the appropriate ester with H2NNH2 H2O in EtOH. Heating 4-oxo-4//- and 6-methyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic hydrazides in EtOH in the presence of excess Raney Ni afforded fhe appropriafe 4-oxo-6,7,8,9-fefrahydro-4//-pyrido[l,2-n]pyrimidine-3-acefa-mide. In the case of the 4-oxo-4// derivative, in addition to N-N bond... 

Heating diethyl (2-pyridylamino)methylenemalonates 304 (R = COOEt, = Me, OH) in AcOH afforded 4-oxo-4//-pyrido[l, 2-n]pyrimidine-3-carboxylates 305 (R = Me, OH) (96JHC1041). Flash vacuum thermolysis of 2-substituted 3-(2-pyridylamino)acrylates 304 (R = CN, COOEt, R = H) through a packed silica tube (530 °C, 0.01 mmHg) gave 3-substituted 4//-pyrido[l,2-n]pyrimidm-4-ones 306 (R = CN, COOEt) (94AJC1263). Ethyl 7-methyl-4-oxo-l, 4-dihydro-1,8-naphthyridine-3-carboxylate (79%) was... 

Cyclization of ethyl A -(2-pyridyl)-2-methyl)- and A -(5-ehloro-2-pyridyl)-malonamates in a mixture of POCI3 and PPA at 130°C gave 2-ehloro-3-methyl- and 2,7-diehloro-4/7-pyrido[l,2-n]pyrimidin-4-ones in 26 and 61% yields, respeetively (00BMC751). 

Hydroxy-2-methyl-4//-pyrido[l,2-n]pyrimidin-4-one was prepared in the reaction of 2-amino-3-benzyloxypyridine and ethyl acetoacetate at 60 °C, then at 100 °C for 3 h in 22% yield (96MIP1). Reaction of 2-amino-3-hydroxypyridine and ethyl 2-methylacetoacetate in a 1 2 mixture of... 

PPA and AcOH at 100°C for 4 h gave 9-hydroxy-2,3-dimethyl-4/f-pyrido-[1,2-n]pyrimidin-4-one in 24% yield (96EUP733633). Reaetion of 2-aminopyridine and ethyl 2-aeetoxyaeetoaeetate in boiling EtOH gave 2-methyl-3-hydroxy-4//-pyrido[l,2-n]pyrimidin-4-one in 47% yield (94KFZ(10)23). 

Methyl-4//-pyrido[l,2-n]pyrimidin-4-ones were also prepared in the reaetion of 2-aminopyridines and ethyl 3-methoxy-2-butenoate in PPA at 80-85 °C for 3h (93MI2). 

Reaction of 2-aminopyridine with ethyl 2-cyano-3-ethoxy-3-methyl-, -3-ethyl-, -3-phenylacrylates and ethyl 2-ethoxycarbonyl-3-ethoxy-3-methyl-, -3-phenylacrylates in boiling xylene yielded 2-substituted 4/f-pyrido[l,2-u]pyrimidine-3-carbonitriles and -3-carboxylates (99MI7). Similar reactions of 2-aminopyridine with 2-cyano-3-ethoxyacrylonitrile and its 3-methyl, 3-ethyl, -3-phenyl derivatives in boiling MeCN afforded 4-imino-4//-pyrido[l,2-u]-pyrimidine-3-carbonitrile and its 2-substituted derivatives. 

Cyclocondensation of 2-aminopyridine and its 3-, 4-, and 5-methyl derivatives with ethyl 2-(bismethylthiomethylene)cyanoacetate in boiling BuOH for 5 h afforded 2-methylthio-4-oxo-4//-pyrido[l,2-u]pyrimidine-3-carbonitriles in 55-87% yields (96FES781). 

The structures of 5-ethyl-1 ]-methyl-9-oxo-5,l l-dihydro-9/7-pyrido[2,1-6]-quinazohne-8-carboxylic acid (00K669), the chromophore 4 of isopyoverdin siderophores (01T1019), and that of 5,5n,6,7,8,9-hexahydro-l l//-pyrido [2,]-6]quinazoline (99SL1383) were justified by X-ray analysis. 

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