New method for preparation of (2-aminopyridin-4-yl)methanol

Abstract

SHORT COMMUNICATIONSImidazo[1,2-a]pyridine is one of the widely used pharmacophores. Published data contain numerous compounds with imidazo[1,2-а]pyridine fragment possessing different types of bioactivity [1]. The basic and the most investigated method of constructing the bicyclic imidazo[1,2-a]pyridine structure consists in the application of substituted 2-aminopyridines. Various methods of production of one of popular 2-aminopyridines, (2-aminopyridin-4-yl)methanol 1, are described in [2][3][4][5]. However the basic drawback of the known methods is their multistage character and low efficiency. Unlike the methods applied previously, implying the preliminary acylation of 2-amino-4-methylpyridine 2, we developed a method of direct oxidizing the methyl group in compound 1 without preliminary protection of amino group obtaining in one stage 2-aminoisonicotine acid 3, the precursor of alcohol 1. The use of elemental sulfur as an oxidizer [6] made it possible to realize a one-pot synthesis of the methyl ester of 2-aminoisonicotine acid 4, suitable for reduction into the target compound 1 with lithium aluminum hydride (Scheme 1).Overall yield of two stages is more than 49% that more than twice exceeds the yield of the best of described methods [2].Methyl 2-aminoisonicotinate (4). A mixture of 108 g of 2-amino-4-methylpyridine, 110 g of sulfur, and 300 g of DMF was heated at 140-160°С during 20 h, then kept at 10 mmHg. To the residue 250 mL of 30% NaOH was added and the mixture was boiled while stirring for 50 h.

Solubility Measurement and Modeling of Methyl 2-Aminopyridine-4-carboxylate in Four Binary Blends and Eight Monosolvents from 278.15 to 323.15 K

“…The test curves of DSC are illustrated in Figure , from which the following information can be obtained: melting point ( T m ) is 418.15 K (uncertainty 0.5 K) and enthalpy of fusion (Δ fus H ) is 25.57 kJ·mol –1 (uncertainty 0.5 kJ·mol –1 ). Besides, some previous publications have reported the melting point of methyl 2-aminopyridine-4-carboxylate. – The T m of methyl 2-aminopyridine-4-carboxylate obtained in this work was similar to the values of 422.65–424.15, 421.15–423.15, 419.65–420.65, and 419.15 K in references. However, there are no data related to the fusion enthalpy of methyl 2-aminopyridine-4-carboxylate in the database, so the data measured this time cannot be compared with the literature value.…”

“…Besides, some previous publications have reported the melting point of methyl 2-aminopyridine-4carboxylate. 25−28 The T m of methyl 2-aminopyridine-4carboxylate obtained in this work was similar to the values of 422.65−424.15, 25 421.15−423.15, 26 419.65−420.65, 27 and 419.15 K 28 in references. However, there are no data related to the fusion enthalpy of methyl 2-aminopyridine-4-carboxylate in the database, so the data measured this time cannot be compared with the literature value.…”

“…Methyl 2-aminopyridine-4-carboxylate (yield 51–89%) is prepared by 2-amino-4-methylpyridine. – However, there are few literature studies about the description of the purification of methyl 2-aminopyridine-4-carboxylate. – So, this work has made the following contributions: (1) the solubility of methyl 2-aminopyridine-4-carboxylate in four mixed systems and eight monosolvents was determined by the isothermal saturation method, (2) the solubility data was calculated by different models, and (3) the thermal characterization [differential scanning calorimetry (DSC)] of methyl 2-aminopyridine-4-carboxylate was made, which provided the basic data for the purification of methyl 2-aminopyridine-4-carboxylate. – …”