Bromine → 3-Bromo-6-methoxypyridin-2-amine

Participants

Reaction Steps

In accordance with scheme 1, the compound of formula V (6-amino-5-bromo-pyridin-2-ol) may be prepared as described in Kelly, T. R.; Jagoe, C. T.; Gu, Z. Tetrahedron Letters 1991, 32, 4263-4266) as follows: To a solution of 6-amino-pyridin-2-ol in acetic acid at room temperature is added bromine and stirred for 15 min. The mixture is diluted with water and the precipitate is filtered off. The filtrate is extracted and the combined organic layers are dried and evaporated to dryness. Then a suspension of 6-amino-5-bromo-pyridin-2-ol is treated with KOH pellets and dimethylsulfate. The mixture is stirred for 4 h at room temperature and evaporated to dryness. The residue is purified and 3-bromo-6-methoxy-pyridin-2-yl-amine (IV) is obtained. Furthermore, a mixture of 3-bromo-6-methoxy-pyridin-2-yl-amine, phenylboronic acid (wherein the phenyl ring may be substituted by R1), Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium II) dichloromethane adduct in dioxane is heated to 110° C. for 2 h. The mixture is concentrated, diluted Na2CO3 aq. is added and extracted. The combined organic phases are dried and evaporated. The residue is purified to yield the corresponding compound of formula II, for example 6-methoxy-3-phenyl-pyridin-2-yl-amine. A mixture 6-methoxy-3-phenyl-pyridin-2-yl-amine (II) and ethoxycarbonyl isothiocyanate is stirred at room temperature for 2 h and afterwards evaporated to dryness. The obtained compound of formula III is then treated with a mixture of hydroxylamine hydrochloride and N-ethyldiisopropylamine (DIPEA). The mixture is heated to 80° C. for 16 h, evaporate to dryness, taken up in water and extracted with diethyl ether. The combined organic phases are dried and evaporated to yield, for example, 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine (Ia). A mixture of 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine and a compound of formula R2Cl, for example 3-fluorophenyl carboxylic acid chloride, and NEt3 in dioxane is heated to 90° C. for 16 h. The mixture is purified to give a compound of formula I, for example 3-fluoro-N-(5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-benzamide.

Provenance & Evidence