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

Full text of DOI:10.1134/S1070428015050280

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 5, pp. 744–745. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © А.О. Lifshits, P.N. Ostapchuk, V.K. Brel, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 5, pp. 759–760.
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New Method for Preparation of (2-Aminopyridin-4-yl)methanol
А. О. Lifshitsa, P. N. Ostapchukb, and V. K. Brelb,c
a Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia
b Nesmeyanov Institure of Organoelemental Compounds, Russian Academy of Sciences,
ul. Vavilova 28, GSP-1, Moscow, V-334, 119991 Russia
e-mail: v_brel@mail.ru
c Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow oblast, Russia
Received February 3, 2015
DOI: 10.1134/S1070428015050280
Imidazo[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 [2–5]. 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. The solution was filtered while
hot and after cooling 20% HCl was added to pH 6. The
precipitate was filtered off and dried at 120°С. To the
obtained 2-aminoisonicotine acid was added while
stirring 1 L of methanol, then at cooling 119 g of
Scheme 1.
S
N(CH3)2
CH3
COOH
1. NaOH
2. HCl
S, DMF
N
NH2
N
NH2
N
NH2
2
3
OH
COOCH3
,
1. SOCl2 MeOH
2. K2CO3
LiAlH4
N
NH2
N
NH2
4
1
744

NEW METHOD FOR PREPARATION OF (2-AMINOPYRIDIN-4-YL)METHANOL
745
SOCl2. The reaction mixture was boiled for 10 h,
methanol was distilled off in a vacuum, and 300 mL of
40% K2CO3 was added to the residue. The separated
precipitate of methyl 2-aminoisonicotinate was crystal-
lized from the mixture THF–methyl tert-butyl ether.
1H and 13С NMR spectra were registered on a
spectrometer Bruker AV-400 (400.13 and 100.61 МHz
respectively).
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Yield 103 g (68%), mp 146.5–147.5°С. H NMR spec-
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aluminum hydride was dissolved in 800 mL of
anhydrous THF. A solution of 103 g of methyl ether of
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