Synthesis of 3-hydroxypyrid-2-ones from furfural for treatment against iron overload and iron deficiency

Article abstract of DOI:10.1016/j.ejmech.2007.11.013

Derivatives of 3-hydroxypyrid-2-ones, which posses very high affinity for iron and have anomalous applications in iron overload and iron deficiency, were prepared from furfural in simple reaction conditions.

Full text of DOI:10.1016/j.ejmech.2007.11.013

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 1978e1982
http://www.elsevier.com/locate/ejmech
Short communication
Synthesis of 3-hydroxypyrid-2-ones from furfural for treatment
against iron overload and iron deficiency
Bhupesh S. Samant
Chemical Engineering Division, Institute of Chemical Technology, University of Mumbai, Matunga, Mumbai 400019, India
Received 13 April 2007; received in revised form 4 September 2007; accepted 19 November 2007
Available online 28 November 2007
Abstract
Derivatives of 3-hydroxypyrid-2-ones, which posses very high affinity for iron and have anomalous applications in iron overload and iron
deficiency, were prepared from furfural in simple reaction conditions.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: 3-Hydroxypyrid-2-ones; Iron overload; Iron deficiency; Furfural
1. Introduction
or siderophores, namely hydroxamates [5], ethylenediamine
tetra-acetic acid (EDTA) analogues [6] and catechols [7].
The hydroxamates generally suffer from the same defects as
desferrioxamine, being expensive and acid labile [8], whilst
the other two classes are ineffective at removing iron from
intracellular sites. Moreover, some catechol derivatives are re-
tained by the liver and spleen and EDTA analogues possess
a high affinity for calcium and so are also likely to have as-
sociated toxicity problems. Hence, convenient iron chelating
agents which are easy to synthesize, stable at wide range of
pH, nontoxic and selective for iron are always appealing.
The purpose of this letter is to describe a useful one-pot
preparation of 3-hydroxypyrid-2-ones, which are extensively
used in the treatment against iron overload and iron defi-
ciency. 3-Hydroxypyrid-2-ones possess a high affinity for
iron(III). In addition to the use described hereinbefore for
the treatment of general iron overload, 3-hydroxypyridones
are also of interest for use in certain pathological conditions
where there may be an excess of iron deposited at certain sites
even though the patient does not exhibit a general iron over-
load, this being the case, for example, in certain arthritic
and cancerous conditions [9]. Thus, a mixture of an iron
complex of a 3-hydroxypyridone together with one of the
3-hydroxypyridones in metal-free form will have the effects
of remedying the overall anaemia through the action of the
iron complex whilst the metal-free compound will act to
Iron overload is the most undesirable since, following sat-
uration of the ferritin and transferrin in the body, deposition
of iron can occur and many tissues can be adversely affected,
particular toxic effects being degenerative changes in the myo-
cardium, liver and endocrine organs [1]. Certain pathological
conditions such as thalassaemia, sickle cell anaemia, idio-
pathic haemochromatosis and aplastic anaemia are treated
by regular blood transfusions [2]. It is commonly found that
such transfusions lead to a widespread iron overload, which
can also arise through increased iron absorption by the body
under certain other circumstances. Such iron overload is
most often treated by the use of desferrioxamine [3]. However,
this compound is an expensive natural product obtained from
the culture of Streptomyces [4] and, as it is susceptible to acid
hydrolysis, it cannot be administered orally to the patient and
has to be given by a parenteral route. Since relatively large
amounts of desferrioxamine may be required daily over an ex-
tended period, these disadvantages are particularly relevant
and an extensive amount of research has been directed towards
the development of alternative drugs. However, work has been
concentrated on three major classes of iron chelating agents
E-mail address: ssb1@udct.org
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.11.013

B.S. Samant / European Journal of Medicinal Chemistry 43 (2008) 1978e1982
1979
remove iron from pathological to physiological sites [10]. On
the other hand, 3-hydroxypyrid-2-ones were used in pharma-
ceutical compositions for the treatment of iron deficiency
anaemia. An adequate supply of iron to the body is an essen-
tial requirement for tissue growth in both humans and animals.
Although there is normally an ample amount of iron in the
diet [11], the level of absorption of iron from food is generally
low so that the supply of iron to the body can easily become
critical under a variety of conditions. Iron deficiency anaemia
is commonly encountered in pregnancy [12] and may also
present a problem in the newly born [13], particularly in
certain animal species such as the pig [14] and horse [15].
Moreover, in certain pathological conditions there is a maldis-
tribution of body iron leading to a state of chronic anaemia.
This is seen in chronic diseases [16] such as rheumatoid
arthritis, certain haemolytic diseases and cancer.
chromatography. The formation of products was confirmed
by IR and NMR studies.
Scheme 2 describes the mechanism of formation of N-alkyl
carbamoyl alkyl amines by Ritter reaction. These N-alkyl
carbamoyl alkyl amines were used as reactant in Scheme 1
to form different derivatives of 3-hydroxypyrid-2-ones. Condi-
tions for Ritter reaction are very simple and yield is very high
[21]. In this process, mixture of alcohol and methyl cyanide
was mixed with acetic acid and cooled to 273 K. Sulfuric
acid was added dropwise, keeping temperature below 283 K.
The reaction mixture was allowed to reach room temperature,
stirred for 5 h and poured in ice water. Precipitate was filtered
and retentate was washed with sodium bicarbonate solution. It
was found that the rate of conversion of the nitriles to the cor-
responding amides was highly dependent on the concentration
of sulfuric acid and the amount of water present in reaction
mixture. Conversion increased with increasing concentration
of sulfuric acid and decreased with increasing water content
in the reaction mixture. Table 1 provides % yields of N-alkyl
carbamoyl alkyl amines. It was observed that % yield of
N-alkyl carbamoyl alkyl amines increased with the increasing
alkyl chain length. This is because the increasing alkyl chain
length shows more electron-donating ability, which in turn
increases the rate of reaction.
2. Results and discussion
Though 3-hydroxypyrid-2-ones are very useful in treatment
against iron overload and iron deficiency, the synthesis routes
[10,17e19] for these compounds are not studied so exten-
sively. These synthesis methods which are described in litera-
ture for synthesis of derivatives of 3-hydroxypyrid-2-ones
suffer from issues such as non-availability of starting mate-
rials, tedious product isolation and competing side reactions.
Due to this, the use of 3-hydroxypyrid-2-ones in treatment
against iron overload and iron deficiency is limited. In this let-
ter I am describing a synthesis method with mechanism for
different derivatives of 3-hydroxypyrid-2-ones from furfural.
Furfural is very easily available; economically and ecologi-
cally viable raw material. 3-Hydroxypyrid-2-ones were pre-
pared by oxidation of furfural with sodium hypochloride in
aqueous medium followed by treatment with different amines
(Scheme 1). Mechanism involved in this process is similar to
Chichibabin pyridine synthesis [20]. Sodium hypochloride as
oxidizing agent opens the ring of furfural to give intermediate
(OCHCH:CHeCOCHO) by addition of one oxygen. This
intermediate can be stored at 268 K temperature. Dropwise ad-
dition of different amines to this intermediate solution gave
temperature rise in the range of 273e288 K. The temperature
of the reacting mixture was restricted below 290 K to prevent
the formation of sticky polymer-like substance. The control on
pH range was essential in this process. The pH of the interme-
diate solution became 8 after the addition of amines. The
solution was maintained at the prevailing pH by addition of
40% sodium hydroxide solution. This mixture was then heated
to 348 K for 20 min to get different 3-hydroxypyrid-2-ones. In
the mechanism, one hydrogen atom which came from amine
was removed as a water molecule in the subsequent step.
The formation of six-membered aromatic ring takes place
due to the shifting of lone pair of electrons from nitrogen to
aldehyde. Thus, five-membered ring structure of furfural was
converted into six-membered ring structure of 3-hydroxy-
pyrid-2-ones. Product was extracted by diethyl ether and sub-
jected to rotary evaporation to yield 3-hydroxypyrid-2-ones in
crystalline form. The reaction progress was analyzed by gas
3. Conclusion
3-Hydroxypyrid-2-ones, which are very important chemi-
cal compounds in medicinal science, can be prepared from
furfural as starting material. The high availability of starting
compound (i.e., furfural), satisfactory yields of 3-hydroxy-
pyrid-2-ones derivatives and the easy reaction conditions are
salutary features of this synthesis method.
4. Experimental
4.1. General
The reactions were monitored by GC (Chemito 8610)
with flame ionization detector (FID). A 4 m long and
0.37 ꢀ 10ꢁ2 m internal diameter S.S. column packed with
10% SE-30 on chromosorb WHP was employed for the anal-
ysis. Nitrogen at the flow rate of 0.5 ꢀ 10ꢁ7 m3 secꢁ1 was
used as carrier gas. Injector and detector (FID) temperatures
were maintained at 573 K. The oven temperature program
was as follows: starting at 423 K hold for 5 min rise of temper-
ature 276 K minꢁ1 up to 553 K and hold for 5 min. Samples
(1 ml) were injected in split-less mode. Melting points are un-
corrected. The products were purified by flash chromatography
on Merck silica gel 60 (230400 mesh ASTM). Products were
1
confirmed using H NMR spectra (Varian Gemini 300 MHz)
instrument. IR spectra in Nujol mulls were recorded on a Per-
kin Elmer Spectrum BX FTIR spectrometer. UV spectra were
detrmined by using Chemito 2100 UV spectrophotometer.
Mass spectra of compound 2 was obtained by using Agilent
5975C gas chromatography/mass spectrophotometer.

1980
B.S. Samant / European Journal of Medicinal Chemistry 43 (2008) 1978e1982
H
H
O
C
C
C
NaOCl
RNH2
CHO
C
C
H
H
O
O
O
H
C
H
H
O
O
C
C
C
OH
C
H
C
C
C
H
H
H
H
C
C
O
N
R
OH
O
N
R
O
NHR
1. R = H
2. R = COCH3
3. R = CH2 COOH
4. R = OCH2 COCH3
5. R = OCH2 CH2 COCH3
6. R = CH2 CONHCH3
7. R = CH2 CH2 CONHCH3
8. R = CH2 CH2 CH2 CONHCH3
9. R = CH2 CH2 CH2 CH2 CONHCH3
10. R = CH2 CH(CH3 )−CONHCH3
Scheme 1. Mechanism of preparation of 3-hydroxypyrid-2-ones from furfural.
4.2. Procedure to prepare intermediate
(OCHCH:CHeCOCHO)
this mixture was 8 and held at this pH by addition of 40% so-
dium hydroxide solution for 40 min. This mixture was then
heated to 348 K for 20 min to give 1 as product. Product
was extracted by diethyl ether in 400, 200, 200 ml fractions
and isolated by flash column chromatography in 30% isolated
yield.
Emulsion of 96.1 g of furfural in 700 ml water was formed.
Then dropwise addition of 74 g of sodium hypochloride was
performed at 273 K in 30 min to give intermediate solution.
4.2.1. 3-Hydroxypyrid-2-one (1)
4.2.2. 1-Acetyl-3-hydroxypyrid-2-one (2)
Intermediate solution was treated with 20 g of liqueur
ammonia. Addition of liqueur ammonia was done dropwise,
it gives rise in temperature from 273 to 288 K. The pH of
Intermediate solution was treated with NH2COCH3. Drop-
wise addition of 60 g NH2COCH3 gave rise in temperature
from 273 to 290 K. The pH of this mixture was above 8.
N
C CH3
X
X
OH2
X
X
OH
H3O
H2O
OH2
C
OH2
CH3
N
C
CH3
X
N
C
X
CH3
N
H
O
C
O
H
X
X
X
N
CH3
NH
C
CH3
NH2 CH2
NH2 CH2 CH2
NH2 CH2 CH2 , NH2 CH3 CH
,
3
NH2 CH2 CH2
,
,
2
Scheme 2. Mechanism of formation of N-alkyl carbamoyl alkyl amines.

B.S. Samant / European Journal of Medicinal Chemistry 43 (2008) 1978e1982
1981
Table 1
% yields of N-alkyl carbamoyl alkyl amines
for 20 min to give 5 as product. Product was extracted by
diethyl ether and subjected to rotary evaporation at 323 K to
yield yellow solid. Recrystallisation of this solid from water
yields 51 g of 1-ethoxycarbonylmethyl-3-hydroxypyrid-2-one
(5) as white crystals, m.p. 414e424 K. UV (EtOH): 313 nm
(pyridone ring). IR (KBr) nmax cmꢁ1 (Nujol): 3270 (OeH),
1720 (C]O at 2nd position in pyridone ring), 1645 (C]O
Entry
X
% Yield of XNHCOCH3
1
2
3
4
5
NH2CH2e
25
35
32
33
30
NH2CH2CH2e
NH2(CH2)2CH2e
NH2(CH2)3CH2e
NH2(CH3)CHe
1
from side chain). H NMR (DMSO-d6) (d): 7.05 (s, 1H, e
OH), 5.95e6.60 (m, 3H, aromatic), 4.55 (t, 2H, eOCH2),
2.00 (t, 2H, eCH2CO), 1.95 (s, 3H, eCOCH3).
This mixture was then heated to 348 K for 20 min to give 2 as
product. Product was extracted by diethyl ether and subjected
to rotary evaporation at 323 K to yield 1-acetyl-3-hydroxy-
pyrid-2-one as white crystals (42.8 g), m.p. 413e414 K. UV
(EtOH): 313 nm (pyridone ring). IR (KBr) nmax cmꢁ1 (Nujol):
3120 (eOH), 1715 (C]O from aromatic ring), 1686 (C]O
4.2.6. 3-Hydroxy-1-(N-methylcarbamoylmethyl)pyrid-
2-one (6)
Intermediate solution was treated with NHCH2CONHCH3.
Dropwise addition of 88 g NHCH2CONHCH3 gave rise in
temperature from 273 to 285 K. The pH of this mixture was
above 8. This mixture was then heated to 348 K for 20 min
to give 6 as product. Product was extracted by diethyl ether
and subjected to rotary evaporation at 323 K to yield yellow
solid. This solid is recrystallised from ethanol to give 50 g
of 3-hydroxy-(N-methylcarbamoylmethyl)-pyrid-2-one (6),
m.p. 477e479 K. UV (EtOH): 310 nm (pyridone ring). IR
(KBr) nmax cmꢁ1 (Nujol): 3275 (OeH), 2950 (NeH), 1685
(C]O at 2nd position in pyridone ring), 1645 (C]O from
CONH), 1585 (amide), 1560 (substituted pyridone). 1H
NMR (DMSO-d6) (d): 8.60 (s, 1H, eOH), 7.95 (s, 1H, e
NH), 6.55e6.95 (m, 3H, aromatic), 3.35 (s, 2H, eNCH2CO),
2.80 (s, 3H, eCONHCH3).
1
from side chain). H NMR (DMSO-d6) (d): 7.20 (s, 1H, e
OH), 6.10e6.50 (m, 4H, aromatic), 2.20 (s, 3H, eCOCH3).
ꢂ
Mass spectra (Mþ ) at m/z 585, 472 (M, side chain), 399 (M,
C9H4N3S), 384 (M, C9H5N4S).
4.2.3. 1-Carboxymethyl-3-hydroxypyrid-2-one (3)
Intermediate solution was treated with NH2CH2COOH.
Dropwise addition of 75 g NH2CH2CO gave rise in tempera-
ture from 273 to 288 K. The pH of this mixture was above
8. This mixture was then heated to 348 K for 20 min to give
3 as product. Product was extracted by diethyl ether and sub-
jected to rotary evaporation at 323 K to yield yellow solid.
This solid is recrystallised from water to yield white crystals
(49 g), m.p. 476e478 K. UV (EtOH): 309 nm (pyridone
ring). IR (KBr) nmax cmꢁ1 (Nujol): 3240 (eOH), 1695
(C]O from COOH), 1640 (C]O at 2nd position in pyridone
4.2.7. 1-(N-Ethylcarbamoylmethyl)-3-hydroxypyrid-
2-one (7)
Intermediate solution was treated with NH2CH2CH2CON
HCH3. Dropwise addition of 102 g NH2CH2CH2CONHCH3
gave rise in temperature from 273 to 285 K. The pH of this
mixture was above 8. This mixture was then heated to 348 K
for 20 min to give 7 as product. Product was extracted by
diethyl ether and subjected to rotary evaporation at 323 K to
yield yellow solid. This solid is recrystallised from ethanol
to give 49 g of 1-(N-ethylcarbamoylmethyl)-3-hydroxypyrid-
2-one (7), m.p. 487e489 K. UV (EtOH): 307 nm (pyridone
ring). IR (KBr) nmax cmꢁ1 (Nujol): 3400 (OeH), 3260 (Ne
H), 1675 (C]O at 2nd position in pyridone ring), 1645
(C]O from CONH), 1580 (amide), 1555 (substituted pyri-
1
ring), 1540 (substituted pyridone). H NMR (DMSO-d6) (d):
10.20 (s, 1H, eCOOH), 7.00 (s, 1H, eOH), 5.95e6.60 (m,
3H, aromatic), 3.35 (s, 2H, eCH2COe).
4.2.4. 3-Hydroxy-1-methoxycarbonylmethylpyrid-2-one (4)
Intermediate solution was treated with NH2OCH2COCH3.
Dropwise addition of 90 g NH2OCH2COCH3 gave rise in
temperature from 273 to 288 K. The pH of this mixture was
above 8. This mixture was then heated to 348 K for 20 min
to give 4 as product. Product was extracted by diethyl ether
and subjected to rotary evaporation at 323 K to yield yellow
solid. This solid is recrystallised from water to give 51 g of
3-hydroxy-1-methoxycarbonylmethylpyrid-2-one (4), m.p.
414e416 K. UV (EtOH): 316 nm (pyridone ring). IR (KBr)
nmax cmꢁ1 (Nujol): 3220 (OeH), 1730 (C]O at 2nd position
in pyridone ring), 1700 (OeCH2), 1645 (C]O from side
chain), 1560 (substituted pyridone). 1H NMR (DMSO-d6)
(d): 9.20 (s, 1H, eOH), 6.05e7.10 (m, 3H, aromatic), 4.65
(s, 2H, eOCH2CO), 1.55 (s, 3H, eCOCH3).
1
done). H NMR (DMSO-d6) (d): 8.20 (s, 1H, eOH), 7.05 (s,
1H, NH), 6.05e6.70 (m, 3H, aromatic), 3.10 (t, 2H, e
NCH2), 2.5 (s, 3H, eCONHCH3), 1.80 (t, 2H, eCH2CO).
4.2.8. 3-Hydroxy-1-(N-propylcarbamoylmethyl)-
pyrid-2-one (8)
To prepare, intermediate solution was treated with NH2
CH2CH2CH2CONHCH3. Dropwise addition of 116 g NH2CH2
CH2CH2CONHCH3 gave rise in temperature from 273 to
285 K. The pH of this mixture was above 8. This mixture
was then heated to 348 K for 20 min to give 8 as product.
Product was extracted by diethyl ether and subjected to rotary
evaporation at 323 K to yield yellow solid. This solid is re-
crystallised from ethanol to give 48 g of 3-hydroxy-1-(N-
4.2.5. 1-Ethoxycarbonylmethyl-3-hydroxypyrid-2-one (5)
Intermediate solution was treated with NH2OCH2CH2
COCH3. Dropwise addition of 105 g NH2OCH2CH2COCH3
gave rise in temperature from 273 to 288 K. The pH of this
mixture was above 8. This mixture was then heated to 348 K

1982
B.S. Samant / European Journal of Medicinal Chemistry 43 (2008) 1978e1982
propylcarbamoylmethyl)-pyrid-2-one (8), m.p. 477e478 K.
UV (EtOH): 315 nm (pyridone ring). IR (KBr) nmax cmꢁ1 (Nu-
jol): 3200 (OeH), 3050 (NeH), 1695 (C]O at 2nd position
in pyridone ring), 1640 (C]O from CONH), 1580 (amide),
4.3. General procedure for preparation of N-alkyl
carbamoyl alkyl amines
Mixture of alcohol (5 mmol) and methyl cyanide (10 mmol)
was mixed with acetic acid (0.8 ml) and cooled to 273 K. Sul-
furic acid (0.80 ml, 15 mmol) was added dropwise keeping
temperature below 283 K. The reaction mixture was allowed
to reach room temperature, stirred for 5 h and poured in ice
water. Precipitate was filtered and retentate was washed with
sodium bicarbonate solution to give N-alkyl carbamoyl alkyl
amines as a product.
1
1560 (substituted pyridone). H NMR (DMSO-d6) (d): 8.95
(s, 1H, eOH), 8.10 (s, 1H, eNH), 6.70e7.05 (m, 3H, aro-
matic), 3.85 (t, 2H, eCH2), 3.00 (s, 3H, eCONHCH3), 1.95
(t, 2H, eCH2CO), 0.85 (q, 2H, eCH2).
4.2.9. 1-(N-Butylcarbamoylmethyl)-3-hydroxypyrid-
2-one (9)
Intermediate solution was treated with NH2CH2CH2CH2
CH2CONHCH3. Dropwise addition of 130 g NH2CH2CH2
CH2CH2CONHCH3 gave rise in temperature from 273 to
285 K. The pH of this mixture was above 8. This mixture
was then heated to 348 K for 20 min to give 9 as product. Prod-
uct was extracted by diethyl ether and subjected to rotary evap-
oration at 323 K to yield yellow solid. This solid is
recrystallised from ethanol to give 45 g of 1-(N-butylcarba-
moylmethyl)-3-hydroxypyrid-2-one (9) as colourless needles,
m.p. 472e473 K. UV (EtOH): 309 nm (pyridone ring). IR
(KBr) nmax cmꢁ1 (Nujol): 3270 (OeH), 3100 (NeH), 1680
(C]O at 2nd position in pyridone ring), 1650 (C]O from
CONH), 1595 (amide), 1565 (substituted pyridone). 1H
NMR (DMSO-d6) (d): 8.86 (s, 1H, eOH), 8.00 (s, 1H, e
NH), 6.63e6.96 (m, 3H, aromatic), 2.95 (t, 2H, eNCH2),
2.20 (s, 3H, CONHCH3), 1.95 (m, 2H, eCH2CO), 1.30 (q,
2H, eCH2), 0.95 (m, 2H, eCH2).
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4.2.10. 3-Hydroxy-1-[N-(20-methylethyl)carbamoylmethyl]-
pyrid-2-one (10)
Intermediate solution was treated with NH2CH2CH(CH3)
CONHCH3. Dropwise addition of 116 g NH2CH2CH(CH3)
CONHCH3 gave rise in temperature from 273 to 285 K. The
pH of this mixture was above 8. This mixture was then heated
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511e514 K. UV (EtOH): 318 nm (pyridone ring). IR (KBr)
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position in pyridone ring), 1645 (C]O from CONH), 1595
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(amide), 1570 (substituted pyridone). H NMR (DMSO-d6)
(d): 8.85 (s, 1H, eOH), 7.96 (s, 1H, eNH), 5.95e6.98 (m,
3H, aromatic), 3.50 (d, 2H, eCH2), 2.95 (s, 3H, CONHe
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