Improvement of the synthesis of 6-bromo-5-methylimidazo[4,5-b]pyridine, a stabilizer for color photography

Article abstract of DOI:10.1007/s11167-005-0392-y

Procedures were suggested for preparing 6-bromo-5-methylimidazo[4,5-b] pyridine, a stabilizer for TsMF-2 color photographic moment, a component of developing pastes of the photographic kit.

Full text of DOI:10.1007/s11167-005-0392-y

Russian Journal of Applied Chemistry, Vol. 78, No. 5, 2005, pp. 787 790. Translated from Zhurnal Prikladnoi Khimii, Vol. 78, No. 5,
005, pp. 802 806.
Original Russian Text Copyright
2
2005 by Yutilov, Svertilova, Minkina, Kirillova, Smolyar.
ORGANIC SYNTHESIS
AND INDUSTRIAL ORGANIC CHEMISTRY
Improvement of the Synthesis
of 6-Bromo-5-methylimidazo[4,5-b]pyridine,
a Stabilizer for Color Photography
Yu. M. Yutilov, I. A. Svertilova, L. V. Minkina, K. M. Kirillova, and N. N. Smolyar
Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of Ukraine,
Donetsk, Ukraine
Received October 14, 2004; in final form, February 2005
Abstract Procedures were suggested for preparing 6-bromo-5-methylimidazo[4,5-b]pyridine, a stabilizer for
TsMF-2 color photographic moment, a component of developing pastes of the photographic kit.
Imidazo[4,5-b]pyridine derivatives exhibit unique
antifogging properties among color photographic ma-
terials [1 8]. A particular mention should be made of
amount or small excess of bromine in aqueous solu-
tion at 20 70 C results in low yields of the reaction
product. Bromination of II in glacial acetic acid at
room temperature gives the product in almost quanti-
tative yield. To bind HBr that is released in the reac-
tion and may prevent the bromination of II, an equiv-
alent amount of sodium acetate was added to the reac-
tion mixture. The melting point of the resulting bro-
mopyridine III, 73 74 C, somewhat differs from the
value reported in the literature (70 71 C [1]).
6-bromo-5-methylimidazo[4,5-b]pyridine I, which is
simultaneously a stabilizer of a photographic layer and
a component of developing pastes of the Polaroid
color photographic kit; it provides high quality of a
photographic image.
Data on the synthesis of I are available from two
patent [1, 2]. The suggested four-step procedure in-
volves bromination of 2-amino-6-methylpyridine II,
nitration of the resulting 2-amino-5-bromo-6-methyl-
pyridine III, reduction of 2-amino-3-nitro-6-methyl-
pyridine IV to diamine V, and its subsequent cycliza-
tion into I. According to [1, 9], bromo derivative III
is prepared by bromination of II with bromine in 20%
sulfuric acid. An experimental check of the procedures
from [1, 9] shows that the yield of III after purifica-
tion is as low as 50 55%. It is known that amino and
hydroxy derivatives of nitrogen heterocycles are
smoothly halogenated in aqueous solutions or in
glacial acetic acid [10, 11]:
A GLC analysis of this product revealed the pres-
ence of two impurities (10 wt %) along with the main
substance III. The first impurity was unchanged sub-
strate II, and the second, 2-amino-3,5-dibromo-6-
methylpyridine VI, identified by comparison with an
authentic smaple specially prepared by bromination
of II under the conditions described in [9]. When the
bromination of II was performed at 10 15 C, the
content of unchanged II decreased to a minimum, but
the content of dibromo derivative VI remained virtual-
ly the same, 7 8 wt %. By-product VI could be elimi-
nated neither by decreasing the amount of bromine
taken for the reaction, nor by repeated recrystallization
of bromination product III from various organic sol-
vents. We found that the concentration of VI in the
reaction product depends on the rate of adding bro-
mine: The lower the bromine concentration in the
reaction mixture, the lower the probability of dehydro-
bromination. However, we failed to ensure formation
of III as the only product. To separate VI, we took
advantage of the fact that monobromo derivative III
forms with acetic acid a salt readily soluble in water
Br
Br
NO2
Br
HNO
3
2
N
NH2
Me N NH2
Me
N
IV
Me
NH2
II
III
[H],
Raney Ni
H
N
Br
Me
Br
NH2
HCO H
2
N
N
N
M
e
NH2
I
V
(30 g in 100 g of water at 23 C), whereas 3,5-dibromo
Attempted bromination of II with an equivalent
derivative VI does not form such a salt and is virtual-
1
070-4272/05/7805-0787 2005 Pleiades Publishing, Inc.

788
YUTILOV et al.
ly insoluble in water. After the bromination comple-
tion, the acetic acid was distilled off almost to dry-
ness, and water was added to the residue. By-product
VI remained in the insoluble residue, and it was fil-
tered off. By alkalization of the filtrate, we isolated
virtually pure III, without impurity of VI.
obtain pure nitro compound IV after the transforma-
tion of X in concentrated sulfuric acid, the acid solu-
tion after the nitration was neutralized with sodium
acetate. After adding a half of the amount of sodium
acetate required for complete neutralization of the
reaction mixture, a bright yellow precipirtate of IV
containing no by-products is formed. Neutralization of
the filtrate after the isolation of IV to pH 6 7 allows
isolation of the precipitate of dibromo derivative VI.
If salt X taken for the nitration is free of amine VI,
almost quantitative yield of IV can be attained, and its
purity considerably increases. After recrystallization of
IV from DMF, its melting point increases by 2 3 C
The nitration of amine III under the conditions de-
scribed in [1, 2] often yielded, instead of the expected
nitro compound IV, a black precipitate from which we
failed to isolate the desired product by recrystalliza-
tion from solvents in the presence of activated carbon
or alumina, or by reprecipitation with alkalis from
weakly acidic solutions. In nitration of 2-amino-5-
bromopyridine VII under the same conditions, a sig-
nificant amount of 3-nitro-5-bromo-2-pyridone VIII
is formed along with the desired 3-nitro derivative of
VII [13].
(mp 213 C).
When in nitration of III HNO is replaced by a less
3
aggressive and more convenient in handling agent,
e.g., KNO in concentrated H SO , the reaction at
3
2
4
0
4
10 C yields no nitro compound IV, and heating to
0 50 C causes formation of pyridone IX. The nitra-
Nitration of III under the similar conditions is also
accompanied by deamination. From dark tarry prod-
ucts, we isolated a compound identified as 3-nitro-5-
bromo-6-methyl-2-pyridone IX.
tion of III in glacial acetic acid also gives negative
results.
According to [1, 2], nitro compound IV is reduced
to diamine V with hydrogen in the presence of Raney
nickel. Despite a fairly high yield of V, 70%, this
procedure is not quite feasible for industrial applica-
tion, because the catalyst is pyrophoric and hydrogen
is dangerously explosive. In the reduction of IV with
To avoid formation of IX in nitration of III, we
changed the order of mixing the reactants. Fuming
nitric acid was added to a solution of III in sulfuric
acid not at 55 60 but at 0 5 C, after which the
temperature was gradually raised to 55 60 C. By
so doing, we considerably reduced the yield of tars.
However, after recrystallization of the products from
methyl ethyl ketone, we detected IX in an amount
comparable with that of the target product. By-product
IX is insoluble in methyl ethyl ketone, alcohol, water,
and the majority of aprotic solvents. At decreased
nitration temperatures, the amount of IX decreased
considerably (to 5 10 wt % relative to IV).
SnCl in concentrated HCl according to [12], the yield
2
of V does not exceed 60%, and diamine V is contam-
inated with by-products and requires additional purifi-
cation. Taking into account the fact that structurally
related 2-amino-3-nitro-5-chloro(bromo)-6-methylpy-
ridine is smoothly reduced with sodium sulfide in
aqueous solution [10], we examined the applicability
of this procedure to the reduction of IV at 60 100 C.
At 60 C, no reduction occurs, and at 100 C the reac-
tion is accompanied by extensive tarring. At 75 80 C,
the yield of V does not exceed 40%. Experiments on
reduction of IV with iron in aqueous solution contain-
ing a small amount of HCl showed that, when iron
dust is added in small portions to a solution of IV at
We examined the influence exerted by the condi-
tions of nitration of III on the composition of the
reaction products. It is advisable to perform nitration
at 0 5 C in concentrated sulfuric acid with 60 63%
nitric acid. In isolation of the desired nitro compound
IV, to avoid formation of tarry impurities, the mixture
should be neutralized to pH 2 3 with sodium acetate;
in this case, the yield of IV is 80 85%. However,
even with all these conditions observed, a certain
amount of tar is formed; it decreases the melting point
of IV by 10 20 C. Even a slight excess of nitric acid
in nitration of amine III causes strong darkening of
IV. For accurate dosage of nitric acid in nitration, we
used instead of amine IV its nitrate X and added this
salt with vigorous stirring at 15 C to concentrated
sulfuric acid. Salt X is readily formed by mixing a
melt of III with 60 63% nitric acid in water. Salt X
can be obtained from crude III without its drying. To
80 90 C, the reduction occurred readily without self-
heating and could be controlled. The yield of V
reached 80% and did not decrease when the reaction
time and amount of iron were decreased by half.
The most efficient is the reduction of IV with
hydrazine hydrate. Refluxing of IV with a 15-fold
excess of hydrazine hydrate for 5 6 h results in the
formation of V in 68 70% yield. When the process is
performed in a solvent, the consumption of hydrazine
hydrate can be decreased by a factor of more than 3.
1-Butanol appeared to be the best solvent for this
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IMPROVEMENT OF THE SYNTHESIS OF 6-BROMO-5-METHYLIMIDAZO[4,5-b]PYRIDINE
789
purpose, because of high solubility of IV and V in it
and sufficiently high boiling point providing the re-
NaOH to pH 8, and the colorless precipitate of bromo
derivative III was filtered off. The product was
quired reaction temperature. However, the reaction in washed with 5 ml of water, recrystallized from 20%
-butanol requires longer time. To accelerate the re- acetic acid, and dried. Yield 25 g (90%), mp 80
1
duction, we tested the following metals as catalysts:
Raney nickel, iron of various brands, powdered alu-
minum, and zinc dust. The best results were obtained
with zinc dust.
82 C. According to [21], mp 71 72 C.
2
-Amino-5-bromo-6-methylpyridinium nitrate
X. To 16 ml of water heated to 80 85 C we added
with stirring 7.6 g of molten 2-aminopyridine III.
By varying the amounts of hydrazine hydrate, To the resulting emulsion, we added over a period of
1
-butanol, and zinc dust, and also the temperature,
5 10 min 3.4 ml of 60% HNO . In so doing, base III
3
we obtained highly pure diamine V in 87 90% yield.
dissolved, and nitrate X started to precipitate on cool-
ing the reaction mixture to 60 55 C. After cooling to
When optimizing the synthesis of I, we started
from the procedure [1, 12] involving heating of di-
amine V in 98 100% formic acid. Our experiments
showed that the yield of I did not change at the con-
sumption of formic acid decreased by a factor of 3
and the reaction time, by a factor of 2. The by-product
was the N-formyl derivative of V. It seemed appropri-
ate to use as a cyclizing agent pentyl formate sug-
gested previously for the synthesis of a series of imid-
azo[4,5-b]- and -[4,5-c]pyridine derivatives [14]. This
agent has significant advantages over formic acid:
it is less toxic and does not cause scalds and damage
mucous membranes of lungs and eyes. Furthermore,
the consumption of pentyl formate for preparation of
1
9
0 15 C, the precipitate was filtered off. Yield of X
.7 g (95.5%), mp 170 172 C.
Found, %: C 28.59, H 3.16, N 16.61.
C H BrN HNO3.
6
7
2
Calculated, %: C 28.82, H 3.22, N 16.80.
2-Amino-3-nitro-5-bromo-6-methylpyridine IV.
Nitrate X (21 g) was added in small portions to 45 ml
of concentrated sulfuric acid cooled to 10 15 C. The
mixture was stirred for 1 h and poured onto 160 g of
ice, and 110 g of sodium acetate (CH COONa 3H O)
3
2
was added. The light yellow precipitate was filtered
off, washed with 10 ml of water and 5 ml of acetone,
and dried; 19.5 g ( 100%) of nitro compound IV was
obtained, mp 211 213 C (from DMF); according to
1
kg of I is 5 l, whereas the required amount of formic
acid is two times greater. The yield of I in refluxing
of V in pentyl formate is 90 91%.
[12], mp 210 213 C.
2,3-Diamino-5-bromo-6-methylpyridine V. (a) To
EXPERIMENTAL
a mixture of 24 ml of 2-propanol, 6 ml of water, 5.6 g
of aminonitropyridine IV, and 0.8 ml of concentrated
HCl, we added with stirring at 70 75 C 5.6 g of iron
carbonyl in portions over a period of 2 h, so that the
mixture mildly boiled. Then the mixture was refluxed
for 2 h and filtered while hot. The black precipitate on
the filter was washed with hot 2-propanol, and the
wash solution was combined with the filtrate. The
resulting solution was alkalized with 25% aqueous
ammonia to pH 8 and refluxed for 0.5 h. The precipi-
tated iron oxides were filtered off, and 2-propanol and
then water were distilled off in a water-jet-pump vacu-
um to 1/4 of the initial volume. The residue was
cooled to 15 20 C, and the precipitate of diamine V
was filtered off. Yield 4.04 g (80%), mp 135 137 C
The purity of volatile products was checked in an
LKhM-72 analytical chromatograph (2000 4-mm
column, stationary phase 15% Apiezon on Chromaton
N-AW-DMC, carrier gas He, column temperature
2
20 C). Nonvolatile compounds were analyzed by
TLC on Silufol UV-254 plates (eluent ethanol).
2-Amino-5-bromo-6-methylpyridine III. Amine
II (16.1 g) and anhydrous sodium acetate (12.3 g)
were dissolved in 126 ml of glacial acetic acid with
stirring at 20 22 C. Then the mixture was cooled to
1
0 15 C, and a solution of 7.7 ml of bromine in
21 ml of glacial acetic acid was added dropwise at this
temperature. After adding the whole amount of bro-
mine, the mixture was stirred at 15 C for 1 h. The
solvent was distilled off almost to dryness ( 150 ml),
and the residue was filtered off, washed with 10 ml
of glacial acetic acid, and mixed at 20 25 C with
(
from H O). According to [12], mp 136 137 C.
2
(b) To a mixture of 5.8 g of IV, 50 ml of 1-butan-
ol, and 7 ml of hydrazine hydrate, we added with stir-
ring at 100 C 1.0 g of zinc dust in portions over a
period of 2 h. The mixture was refluxed for 3 4 h
until the gas evolution ceased. Then the mixture was
cooled to 60 70 C and filtered. The gray precipitate
100 ml of water. The insoluble residue ot VI was
filtered off, washed with 5 ml of water, and dried in
air. Yield of by-product VI 2.1 g, mp 142 143 C [5].
The aqueous filtrate was alkalized with 6 ml of 30%
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790
YUTILOV et al.
on the filter was washed with 20 ml of hot 1-butanol,
and the wash solution was combined with the filtrate.
Then 55 60 ml of 1-butanol was distilled off in a
water-jet-pump vacuum. The residue was cooled to
( 90.5% yield), an antifogging compound for color
photographic materials.
ACKNOWLEDGMENTS
1
5 20 C, and the precipitate of V was filtered off.
The authors are grateful to L.I. Shcherbina for the
assistance in the manuscript preparation.
Yield 4.55 g (90%), mp 135 137 C (H O).
2
6
-Bromo-5-methylimidazo[4,5-b]pyridine I.
A mixture of 5 g of V and 7 ml of pentyl formate was
heated at 170 175 C for 2 h until 0.4 0.5 ml of
water was released and then at 170 180 C for 2 h
more. Pentyl formate and 1-pentanol were distilled off
in a water-jet-pump vacuum (40 50 C, 25 30 mm
Hg) to dryness, and the residue was crystallized from
ethyl acetate or water 2-propanol (5 : 1). Yield 4.75 g
REFERENCES
1
2
3
4
5
. US Patent 3473924.
. US Patent 3629272.
. US Patent 3687660.
. French Patent 2134750.
. Australian Patent 461229.
(90.5%), mp 206 207 C. According to [12], mp 204
2
05 C.
6. US Patent 4071366.
7
8
9
. US Patent 4102685.
. US Patent 4134768.
. Adams, R. and Schrecker, A.W., J. Am. Chem. Soc.,
CONCLUSION
1
949, vol. 71, no. 4, pp. 1186 1195.
Procedures were suggested for preparing 2-amino-
-bromo-6-methylpyridine by bromination of 2-ami-
5
10. Israel, M. and Day, A.R., J. Org. Chem., 1959, vol. 24,
no. 10, pp. 1455 1460.
11. Weygand Hilgetag, Organisch-chemische Experimen-
tierkunst, Leipzig: Johann Ambrosius Barth, 1964,
no-6-methylpyridine in glacial acetic acid in the pres-
ence of anhydrous sodium acetate in 90% yield, nitra-
tion of the resulting compound in the form of nitrate
in concentrated sulfuric acid at 10 15 C ( 100%
yield), reduction of the product in an acidified alcohol
with iron carbonyl ( 80% yield) or with hydrazine
hydrate and zinc ( 87 90% yield), and cyclization of
3
rd ed.
12. Graboues, H. and Day, A.R., J. Am. Chem. Soc., 1957,
vol. 79, no. 24, pp. 6421 6426.
13. Abramovich, A.B., Pyridine and Its Derivatives, New
York, 1974, vol. 14, part 3.
2
,3-diamino-6-methylpyridine in refluxing pentyl
formate to 6-bromo-5-methylimidazo[4,5-b]pyridine
14. USSR Inventor’s Certificate no. 717055.
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 78 No. 5 2005