Methyl 6-amino-5-nitropyridine-3-carboxylate → Methyl 5,6-diaminopyridine-3-carboxylate

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Reaction Steps

In accordance with scheme 1, the compound of formula V (6-hydroxy-5-nitro-nicotinic acid) is obtained as follows: To a solution of a compound of formula IV (6-hydroxy-nicotinic acid) in concentrated sulfuric acid is added a mixture of concentrated sulfuric acid and concentrated nitric acid below 20° C. and stirred for 1 h at room temperature and afterwards the solution is heated to 80° C. for 4 h. The mixture is then poured onto ice and the precipitate is collected and dried. The obtained compound of formula V is then mixed with POCl3 and heated to 130° C. for 5 h and afterwards the excess POCl3 is distilled under reduced pressure. The residue is cooled to 0° C. and 150 ml methanol were slowly added. The mixture is stirred for 2 h at 0° C. After addition of a 25% NH3 aq. solution the mixture is stirred for 4 h at room temperature. The precipitate is filtered, washed once with diethyl ether and dried under vacuum to yield 6-amino-5-nitro-nicotinic acid methyl ester (VI). A suspension of 6-amino-5-nitro-nicotinic acid methyl ester in methanol and Pd/C (10%) cat is then added and hydrogenated at room temperature during 14 h. The catalyst is filtered off and the solution is concentrated to yield 5,6-diamino-nicotinic acid methyl ester (VII). A mixture of (VII) in dioxane is treated with O-mesitylenesulfonylhydroxylamine (prepared from ethyl-o-mesitylenesulfonylacetohydroxamate and HClO4) for 1 h at room temperature. To thiophene-2-carboxaldehyde or another aldehyde of formula R2CHO, wherein R2 is an aryl or heteroaryl as described in the specification, molecular sieves 4 Å is added and heated to 100° C. for 4 h before addition of KOH in methanol. The mixture is heated to 70° C. for 2 h and stirred at room temperature for 14 h. The volatiles are removed under reduced pressure and the residue is purified by flash column chromatography to yield 8-amino-2-(aryl or heteroaryl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester (II). To obtain a compound of formula 1 (8-amino-2-(aryl or heteroaryl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-piperidin-1-yl-methanone a solution of an amine of formula III (HNR′R″) in dioxane is treated with trimethylaluminum in toluene and stirred for 1 h at room temperature. 8-Amino-2-(aryl or heteroaryl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester (II) in 1 ml dioxane is added and the mixture is heated to 90° C. for 72 h. HCl aq. is added and the volatiles are removed. The residue is taken up in 1 formic acid and methanol and purified by reversed phase preparative HPLC eluting with a gradient of acetonitrile and water.

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