Pyrido-1 ,2 :4,5-tetrazole

Reaction of 4-imino-4/f-pyrido[l, 2-n]pyrimidine-3-carbonitriles 124 with NaN3 in the presence of NH4CI gave 3-(2-pyridylamino)-2-(I//-tetrazol-5-yl)acrylonitriles 125 (93MIP3). 

The 3-formyl group of 8-substituted 3-formyl-2-hydroxy-4//-pyrido[l,2-n]pyrimidin-4-one was reacted with (cyanomethyl)- and (terr-butoxycarbo-nylmethylene)triphenylphosphorane in THF, and with 5-aminotetrazole in boiling MeOH for 9h to yield ( )-3-propenenitrile, terr-butyl ( )-3-propenoate and 3-[(2//-tetrazol-5-yl)imino]methyl derivatives, respectively (OlMIPl). 

Reaction of 8-substituted 3-[2-(4-methoxybenzyl)-2//-tetrazol-5-yl]-4//-pyrido[l,2-u]pyrimidin-4-ones with CF3COOH for 2 days at room temperature gave 3-(2//-tetrazol-5-yl) derivatives (OlMIPl). The cyano group of a 3-(8-substituted 2-hydroxy-4-oxo-4//-pyrido[l,2-u]pyrimidin-3-yl)-2-propenenitrile was converted into a 5-tetrazolyl group by treatment with NaN3 in the presence of AICI3 in DMF at 100 °C for 2 days. 

Hydrazono-4-oxo-4ff-pyrido[l,2-u]pyrimidines were transformed by sodium nitrite in hydrochloric acid at 0-5 C to the corresponding 2-azido compound (102).166-287 2-Azido-4-oxo-4//-pyrido[l,2-azide-tetrazole tautomerism.290... 

When heated with bases, the 2-azidopyrido[l,2- ]pyrimidine (102) yields pyridyltetrazoles (269 R = CONR R2). This reaction is initiated by nucleophilic addition of the base to the carbonyl group it is followed by ring opening between the C-4 and N-5 atoms and formation of the tetrazole ring involving the azido group and the N-l atom of the starting pyrido-pyrimidine.166 291... 

When the base was diethylamine, the pyrido[l,2-a]pyrimidine (221 R = R1, R2 = H) was formed with the tetrazole (269 R = CONEt2). The ring transformation also took place as a result of photocatalysis.291 When the azido compound (102) was heated in ethanolic hydrogen chloride for 1.5h, the tetrazolylacetic acid (269 R = COOH) and its ethyl ester were obtained, while on prolonged treatment the methyl derivative (269 R = H) was the product.11 6... 

The cyclization of the 3-(phenylthiomethyl)derivative of 160 (R = 3-CH2SPh) was carried out by heating in polyphosphoric acid at 110°C for 1 hour to afford 3-(tetrazol-5-yl)-4//-pyrido[l,2-a]pyrimidin-4-one 159 (R = 9-CH2SPh) in 8% yield (89EUP329126). 

Tetrazolyl)-4//-pyrido[l,2-u]pyrimidin-4-one 159 (R = H) was prepared in 65% yield in a one-pot reaction when 2-aminopyridine, ethyl 1H-tetrazol-5-ylacetate, triethyl orthoformate, and aluminum chloride were heated in 1,1,2,2-tetrachloroethane under nitrogen at 120°C for 3 days (84USP4474953). 

Later, it was also claimed that 3-(tetrazolyl)-4//-pyrido[ 1,2-u]pyrimidin-4-ones 159 were obtained in an one-step procedure by heating the appropriate 2-aminopyridine, ethyl (l//-tetrazol-5-yl)acetate, and triethyl orthoformate in dimethylformamide at 90°C for 1 hour, or in boiling tetra-hydrofuran for 6 hours followed by treatment with 1N potassium hydroxide at 50°C for 1 hour, or with anhydrous aluminum chloride under reflux for 6 hours (91EUP462834). 9-Methyl-3-( 1 //-tetrazolyl)-4//-pyrido[ 1,2-a]-pyrimidin-4-one 159 (R = 9-Me) could be prepared when 2-amino-3-meth-ylpyridine hydrochloride and sodium azide were suspended and stirred in dimethylformamide for 1 hour at room temperature, followed by the addition of ethyl ethoxymethylenecyanoacetate, ethoxymethylenemalo-nonitrile, ethyl cyanoacetate and triethyl orthoformate, or malononitrile and triethyl orthoformate and stirring at 90°C for 6-12 hours. Then the reaction mixture was treated with 1 N potassium hydroxide at 50°C for 1 hour, phosphoryl chloride at 90°C for 5 hours, or with concentrated hydrochloric acid at 110°C for 4 hours to give 26-62% yields. 

When 4-imino-9-methyl-4//-pyrido[l, 2-a]pyrimidine-3-nitrile reacted with sodium azide in a solvent at 60-70°C for 3-6 hours, ring-opened 3 - [(3 - methyl-2- py ridy l)amino]-2- (1 -H- tetrazol-5- yl)-2- propenenitrile was obtained, but the bicyclic 4-imino-9-methyl-3-(l//-tetrazol-5-yl)-4//-pyrido[l,2-a]pyrimidine could be isolated when the reaction was carried out in acetic acid at 115°C (90EUP385634). The latter product was also obtained from the ring-opened product by heating in IN hydrochloric acid at 100°C for 1 hour, or in IN potassium hydroxide at 100°C for 3.5 hours. Reaction in acetic acid was also extended to 9-phenoxymethyl, 9-(4-acetyl-... 

Unsubstituted tetrazolyl derivative 458 was also prepared according to the following procedure (91MIP2). A solution of 5-phenyl-2-trityltetrazole in tetrahydrofuran was first treated with 1.7 M ferf-butyllithium in pentane at -25°C, in two parts. After about 30 minutes, an organolithium salt precipitated. Then a 1 M ethereal solution of zinc chloride was added to the mixture, which was then warmed to room temperature. Bis(triphenyl-phosphine)palladium(Il) chloride and 4//-pyrido[l,2-a]pyrimidin-4-one 457 were added to the reaction mixture, and after boiling for 4 hours, the 2-trityl derivative of 458 was obtained in 56% yield. Finally, detritylation with a mixture of methanol and concentrated hydrochloric acid yielded tetrazole derivative 458. 

Reaction of 4-imino-4//-pyrido[l, 2-a]pyrimidine-3-carbonitriles 168 and sodium azide in the presence of ammonium chloride in dimethylformamide at 80-100°C for 1-3 hours gave 3-(2-pyridylamino)-2-(l//-tetrazol-5-yl)acrylonitriles 700 (93MIP6). 3-(2-Pyridylamino)-2-(l//-tetrazol-5-yl)acrylonitriles 700 were cyclized to 3-(l//-tetrazol-4//-pyrido[l,2-a] pyrimidin-4-ones 701 by heating in concentrated hydrochloric acid under reflux for 1 hour or by heating in polyphosphoric acid at 130-140°C for 2-4 hours (93MIP7). 

Pemirolast. 9-Methyl-3-(l/7-tetrazole-5-yl)-477-pyrido[l,2- ]pirimidin-4-one 600, antiallergic. 

Chemical Name 4FI-Pyrido(l,2-a)pyrimidin-4-one-9-methyl-3-(lFI-tetrazol-5-yl), potassium salt... 

Aluminum chloride (3.51 g, 0.0263 mole) was added to cold (-30°C) tetrahydrofuran (180 ml). Sodium azide (5.12 g, 0.0788 mole) was added and the mixture heated under reflux for 30 min. The mixture was cooled to 5°C. Ethyl 2-cyano-3-(3-methyl-2-pyridylamino)acrylate (5.0 g, 0.0216 mole) was added and the mixture heated under reflux for 18 h. The tetrahydrofuran was removed under reduced pressure. The residue was treated with ice water (100 ml) and acidified to pH 3 with 6 N hydrochloric acid. The mixture was filtered and the collected solid recrystallized from N,N-dimethylformamide to give the 9-methyl-3-(lH-tetrazol-5-yl)-4H-pyrido[l,2-a]pyrimidin-4-one (2.5 g,... 

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