Synthesis of 2-amino-5-hydroxypyridine via demethoxylation

Article abstract of DOI:10.14233/ajchem.2016.19692

A convenient and efficient four-step synthesis of 2-amino-5-hydroxypyridine can be achieved by protective reaction of 2-amino-5-bromopyridine in the presence of 2,5-hexanedione to yield 5-bromo-2-(2,5-dimethyl-1H-pyrrol-1yl)pyridine, methoxylation with sodium methylate to give 5-methoxy-2-(2,5-dimethyl-1H-pyrrol-1yl)pyridine, deprotective reaction with hydroxylamine hydrochloride to produce 2-amino-5-methoxypyridine and demethylation with 95 % H₂SO₄ to afford the title compound in an overall yield of 45 %.

Full text of DOI:10.14233/ajchem.2016.19692

Asian Journal of Chemistry; Vol. 28, No. 6 (2016), 1403-1404
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2016.19692
NOTE
Synthesis of 2-Amino-5-hydroxypyridine via Demethoxylation
*
J. CHENG and C. LIU
Department of Chemical Engineering, Changzhou Institute of Engineering Technology, Changzhou 213164, P.R. China
Corresponding author: Tel: +86 18118028001; E-mail: 4405313@qq.com
Received: 16 October 2015; Accepted: 28 January 2016;
*
Published online: 29 February 2016;
AJC-17819
A convenient and efficient four-step synthesis of 2-amino-5-hydroxypyridine can be achieved by protective reaction of 2-amino-5-
bromopyridine in the presence of 2,5-hexanedione to yield 5-bromo-2-(2,5-dimethyl-1H-pyrrol-1yl)pyridine, methoxylation with sodium
methylate to give 5-methoxy-2-(2,5-dimethyl-1H-pyrrol-1yl)pyridine, deprotective reaction with hydroxylamine hydrochloride to produce
2
-amino-5-methoxypyridine and demethylation with 95 % H
2
SO to afford the title compound in an overall yield of 45 %.
4
Keywords: Methoxylation, Demethylation, 2-Amino-5-methoxypyridine, 2-Amino-5-hydroxypyridine.
2
-Amino-5-hydroxypyridine (6) is widely used in biological
not be detected by TLC. After cooling to room temperature,
the reaction mixture was washed with a saturated aqueous
and pharmaceutical fields [1-5]. It is a key intermediate in the
preparation of HIV inhibiting 9-hydroxy-6-(4-nitrophenyl)-
pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one [5].
Several syntheses of 2-amino-5-hydroxypyridine (6) have
already been reported [5-8]. Most methods used 48 % HBr
5,6].Also the start material 2-amino-5-iodopyridine is expensive
5,9].A low-cost and clean demethylation technique is desirable.
We report a convenient and efficient synthesis of 2-amino-5-
hydroxypyridine (6) utilizing a low-cost and environmentally
friendly reagent, 2-amino-5-bromo-pyridine (2) as start material
NaHCO
with MgSO
3
solution, water and brine. The organic phase was dried
and concentrated in vacuum. The resulting orange
4
liquid was dried under high vacuum and cooled to orange solid
3 (2.28 g, yield = 91.2 %), m.p. 67.6-68.9 °C (lit. [9] 69 °C);
1
[
[
H NMR (400 Hz, CDCl
3
), δ (ppm): 2.130 (s, 6H, 2*CH ),
3
5.905 (s, 2H, CH), 7.115-7.132 (d, 1H, pyr-H), 7.922-7.944
(dd, 1H, pyr-H), 8.651-8.656 (d, 1H, pyr-H); C NMR (100
MHz, CDCl
13
3
), δ (ppm): 13.19, 107.40, 118.91, 123.01, 128.59,
140.51, 150.41, 150.70.
and 95 % H
2
SO
4
for the demethylation.
5-Methoxy-2-(2,5-dimethyl-1H-pyrrol-1yl)pyridine
(4): Sodium methoxide (40 mmol, 2.16 g) was dissolved in
dry methanol (20 mL). DMF (20 mL), CuI (0.15 equiv., 2.5
mmol, 0.5 g) and 3 (8 mmol, 2.0 g) were added. The reaction
mixture was heated to 80 °C for 3 h. After the mixture had
been allowed to cool to room temperature, isopropylether and
Reagents and solvents were obtained from commercial
suppliers and were used without further purification.All melting
points were determined on a XT34 binocular microscope (Beijing
Tech Instrument Co., China) and were not corrected. NMR
1
spectra were obtained on a Mercuryplus 400 spectrometer ( H
13
NMR at 400 Hz, C NMR at 100 Hz) in CDCl
with tetramethylsilane as an internal standard; chemical shifts
δ) were reported in parts per million relative to tetramethylsilane.
Chemical shifts were reported in ppm relative to the solvent
resonance as the internal standard (CDCl , δ= 7.26 ppm).Analy-
3
or DMSO-d
6
an aqueous NH Cl solution (5 %) were added, the mixture
4
was stirred overnight. The solids were filtered off over Celite
and the filtrate was extracted several times with dichloromethane.
The combined organic phases were washed with a 10 % aqueous
(
3
NH
4
OH solution, dried with MgSO and concentrated in vacuo.
4
tical TLC and column chromatography were performed on silica
gel GF254 and silica gel H60, respectively.
After drying in high vacuo, pure 4 (1.54 g, yield = 95.2 %)
1
was obtained, m.p. 74.5-75.2 °C (lit. [10] 75 °C); H NMR
5
-Bromo-2-(2,5-dimethyl-1H-pyrrol-1yl)pyridine (3):
-Amino-5-bromopyridine (2) (10 mmol, 1.73 g), 2,5-hexane-
dione (12 mmol, 1.13 g) and p-toluene sulfonic acid (3 mmol,
.52 g) was dissolved in toluene (30 mL) and heated to reflux
in a Dean-Stark apparatus for 8-10 h until compound 2 can
(400 Hz, CDCl
OCH ), 5.873 (s, 2H, CH), 7.146-7.163 (d, 1H, pyr-H), 7.312-
7.336 (dd, 1H, pyr-H), 8.267-8.274 (d, 1H, pyr-H). C NMR
(100 MHz, CDCl ), δ (ppm): 12.99, 55.89, 106.31, 122.36,
128.70, 136.23, 145.01, 149.36, 154.74.
3
), δ (ppm): 2.081 (s, 6H, 2*CH
3
), 3.918 (s,
2
3
13
0
3

1
404 Cheng et al.
Asian J. Chem.
N
NH2
N
NH2
N
N
N
NH
2
N
N
c
d
b
a
O
(51.8%)
(
95.2%)
(100%)
(91.2%)
O
HO
Br
Br
5
6
3
4
2
3 2 2 4
Scheme-I: Reagents: a: 1,4-hexanedione, p-TsOH; b: CH ONa, CuI; c: NH OHHCl; d: 95 % H SO
2
-Amino-5-methoxy pyridine (5): A mixture of 4 (7
environmentally friendly reagent (95 % H
2
SO ) and the metho-
4
mmol, 1.41 g), hydroxylamine hydrochloride (45.5 mmol, 1.89
g), triethylamine (14 mmol, 1.41 g), ethanol (20 mL) and water
xylation from a low-cost reagent (2-amino-5-bromo-pyridine
2) were conducted.
(
10 mL) was refluxed for 20 h. The solution was cooled and
Hydrobromic acid (48 %) is a fuming reagent, easily
quenched with 2 M HCl, washed with isopropyl ether and the
pH was adjusted to 9-10 with 6 M NaOH. The resulting mixture
was extracted several times with diethyl ether. The combined
decomposed by oxygen in the air to Br
mentally friendly. Whenever possible, the clean reagents
should be used. 95 % H SO is a non-volatile and stable agent.
Accordingly, 95 % H SO was selected as a demethylating
agent, which was found to be a cleaner agent and can raise the
yield of 2-amino-5-hydroxy pyridine (6) to 51.8 %.
Previously used as start material for the synthesis of
5-methoxy-2-(2,5-dimethyl-1H-pyrrol-1yl)pyridine (4) is
2-amino-5-iodopyridine [10], which is expensive. It was found
that using 2-amino-5-bromo pyridine (2) as starting material
can also produce 5-methoxy-2-(2,5-dimethyl-1H-pyrrol-1yl)-
pyridine (4) in good yield.
2
, which is not environ-
2
4
organic phases were dried with MgSO
removed in vacuo. The oily residue was purified by column
chromatography on silica gel (gradient elution: CH Cl
CH COOC = 1:3→ pure ethyl acetate) to give dark brown
liquid 5 (0.87 g, yield = 100 %). H NMR (400 Hz, CDCl
4
and the solvent was
2
4
2
2
/
3
2
H
5
1
3
), δ
), 6.493-6.462
dd, 1H, pyr-H), 7.070-7.110 (dd, 1H, pyr-H), 7.766-7.775
(
(
(
ppm): 3.772 (s, 3H, OCH
3
), 4.213 (br, 2H, NH
2
13
d, 1H, pyr-H). C NMR (100 MHz, CDCl
09.49, 125.73, 133.11, 148.60, 153.09.
-Amino-5-hydroxy pyridine (6): 95 % H
3
), δ (ppm): 56.28,
1
2
2
SO (10 mL)
4
Conclusion
was stirred at 80 °C, compound 5 (5 mmol, 0.62 g) was added
dropwise to the stirred solution keeping the temperature at
This synthetic route to 2-amino-5-hydroxypyridine (6) is
an environmentally friendly and economical process, which
is suitable for scaling up for use in the industrial production.
8
9
0-85 °C. After the addition, stirring was continued at 90-
3 °C for about 24 h until 5 can not be detected by TLC. The
reaction mixture was poured into crash ice (100 g) and the
solution was adjusted to pH 7-8 by gradual addition of Na CO
The resulting mixture was extracted several times with diethyl
ACKNOWLEDGEMENTS
2
3
.
This project is supported by the fund of Brand-Discipline
construction of Jiangsu.
ether (Scheme-I). The combined organic phases were dried
with anhydrous Na
The residue was purified by column chromatography on silica
gel (gradient elution: CH OH/CH Cl = 1:9) to give taupe solid
(0.29 g, yield = 51.8 %). H NMR (400 Hz, DMSO-d ), δ
ppm): 5.200 (br, 2H, NH ), 6.327-6.350 (t, 1H, pyr-H), 6.893-
.923 (dd, 1H, pyr-H), 7.497-7.506 (dd, 1H, pyr-H), 8.636 (s,
2
SO
4
and the solvent was removed in vacuo.
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