Novel synthetic approach to 2-(1′-hydroxyalkyl)- and 2-amido-3-hydroxypyridin-4-ones

Article abstract of DOI:10.1016/S0040-4020(01)00222-8

Novel methods for the synthesis of high pFe³⁺ iron chelators, 2-(1′-hydroxyalkyl)- and 2-amido-3-hydroxypyridin-4-ones, have been developed. The products are obtained, via N-oxide intermediates, from either maltol or ethyl maltol.

Full text of DOI:10.1016/S0040-4020(01)00222-8

TETRAHEDRON
Pergamon
Tetrahedron 57 -2001) 3479±3486
Novel synthetic approach to 2-ꢀ10-hydroxyalkyl)- and
2-amido-3-hydroxypyridin-4-ones
Sirivipa Piyamongkol, Zu D. Liu and Robert C. Hiderp
Department of Pharmacy, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NN, UK
Received 8 December 2000;revised 29 January 2001;accepted 15 February 2001
AbstractÐNovel methods for the synthesis of high pFe31 iron chelators, 2--10-hydroxyalkyl)- and 2-amido-3-hydroxypyridin-4-ones, have
been developed. The products are obtained, via N-oxide intermediates, from either maltol or ethyl maltol. q 2001 Elsevier Science Ltd. All
rights reserved.
1. Introduction
lowers the overall stability constant -log b3) as well as the
af®nity of the ligand for protons, these changes result in an
increase in the binding of iron-III) over the pH range 5±8, as
re¯ected in the increase of the pFe31 value. A selection of
these `second generation' 3-hydroxypyridin-4-ones are
under consideration for pre-clinical development and for
this reason we are investigating synthetic methodology
relating to these and related compounds. In the present
paper we report a more convenient and economical method
for the synthesis of 2--10-hydroxyalkyl)- and 2-amido-3-
hydroxypyridin-4-ones.
The 3-hydroxypyridin-4-ones form one of the main candi-
date groups for the development of orally active iron
chelators,1 in fact the 1,2-dimethyl derivative 1 -deferi-
prone) is already available for clinical use -marketed by
Apotex Inc., Toronto, Canada as Ferriproxe).2 Attempts
have been made to improve the ef®cacy of these bidentate
ligands3,4 and recently we have established that the intro-
duction of either a 10-hydroxyalkyl group or an amido group
at the 2-position of 3-hydroxypyridin-4-ones leads to a
considerable enhancement of the iron-III) chelating ability
monitored by the pFe31 value.4±6 The pFe31 value, de®ned
as the negative logarithm of the concentration of the free
iron-III) in solution, is a more suitable comparator than the
stability constant since it takes into account the effect of
ligand basicity, denticity, degree of protonation and differ-
ences in metal±ligand stoichiometries.2 Chelators with high
pFe31 values are predicted, not only to be able to scavenge
iron more ef®ciently at low ligand concentrations, but also
to dissociate less readily and therefore form lower amounts
of partially co-ordinated complexes. Such iron complexes
render the iron-III) cation surface accessible to oxygen and
hydrogen peroxide and thereby susceptible to the possible
generation of hydroxyl radicals.1 With 3-hydroxypyridin-4-
ones the increase of the pFe31 value results from the lower-
ing of pKa values corresponding to both the 3- and 4-pyri-
dinone oxygens. These differences are associated with the
enhanced stability of the ionised species. Such stability may
result from a combination of intramolecular hydrogen bond-
ing between the 2--10-hydroxyalkyl) group -or 2-amido
group) -2,3) and the adjacent 3-hydroxyl moiety, together
with a powerful inductive effect.5,6 Although such an effect
2. Chemistry and discussion
Pyromeconic acid 4 and allomaltol 5, the starting materials
used in the existing methods -Scheme 1), are not com-
mercially available and require multi-step syntheses.4±6 In
contrast, the method reported herein uses maltol 6a and
ethyl maltol 6b as starting materials which are readily avail-
able.7 The unsubstituted 2-position of both 4 and 5 can be
functionalised by classical aldol condensation.5 This
furnishes the 2--10-hydroxyalkyl)-3-hydroxypyridin-4-ones
and with further derivatisation the 2-amido-3-hydroxy-
pyridin-4-ones -Scheme 1). In contrast, the 2-positions of
Keywords: iron chelators;3-hydroxypyridin-4-one;pyridine
N-oxide;
pFe31 value.
Corresponding author. Tel.: 144-20-7848-4882;fax: 144-20-7848-
4800;e-mail: robert.hider@kcl.ac.uk
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020-01)00222-8

3480
S. Piyamongkol et al. / Tetrahedron 57 ,2001) 3479±3486
Scheme 1. Multi-step syntheses of 2--10-hydroxyalkyl)- and 2-amido-3-hydroxypyridin-4-ones.3±5
6a and 6b both possess an alkyl group substituent which is
not easy to selectively functionalise.
4-oxygen or the 1-nitrogen, producing alkoxypyridines or
N-alkylpyridones in proportions depending on the reaction
conditions.9 However, when the pyridin-4-one oxygen is
protected as for instance as a O-trimethylsilyl ether, alkyl-
ation can occur selectively at the ring nitrogen.10 This
example prompted us to undertake a similar reaction with
compounds 7a and 7b. When both the pyridone oxygens are
protected, the ring nitrogens become electron rich. Silyl
ethers were found to be inappropriate for use as protecting
groups in multi-step syntheses as they are easily cleaved
The novel synthetic route to 2--10-hydroxyalkyl)-3-
hydroxypyridin-4-ones described in this paper -Scheme 2)
starts with the protection of the 3-hydroxyl moieties of 6a
and 6b, followed by conversion to pyridones 7a and 7b
which are generally more resistant to extremes of pH.8 At
this stage some dif®culties were encountered as the
NH-containing pyridones can be alkylated on either the
Scheme 2. Reagents and conditions for novel 2--10-hydroxyalkyl)-3-hydroxypyridin-4-ones synthesis: -a) BnBr, NaOH, MeOH or EtOH, re¯ux, 80±81%;
-b) NH3, EtOH, re¯ux or rt, 71±75%;-c) TPP, DEAD, BnOH, THF, re¯ux, 72±79%;-d) MCPBA, CH 2Cl2, rt, 72±77%;-e) -CH 3CO)2O, re¯ux;-f) 2N NaOH,
re¯ux, 81% -two steps) for 10a and 56% -two steps) for 10b;-g) H 2, Pd/C, MeOH or EtOH, rt then conc HCl, 93±94%;-h) CH 3I, rt, 74±82%;-i) 6N HCl,
re¯ux, 83%;-j) 1 M BBr in CH2Cl2, rt, 86%.
3

S. Piyamongkol et al. / Tetrahedron 57 ,2001) 3479±3486
3481
Scheme 3. Reagents and conditions for novel 2-amido-3-hydroxypyridin-4-ones synthesis: -a) DMSO, Py-SO3, TEA, CHCl3, rt, 62%;-b) NaClO 2, H2NSO3H,
acetone:H2O -1:1), rt, 77%;-c) DCCI, DMAP, 2-mercaptothiazoline, CH 2Cl2, rt;-d) primary amines, rt, 44±48% -two steps);-eandg) H 2, Pd/C, MeOH or
EtOH, rt, 87±91%;-f) PyBOP, TEA, PhNH 2, CH2Cl2, rt, 44%.
under basic conditions. For this reason benzyl ethers were
adopted, their preparation being achieved via the Mitsunobu
reaction11 where only the phenol tautomers of the
N-unsubstituted pyridones 7a and 7b reacted with benzyl
alcohol and gave selectively the corresponding O-benzyl-
ated products 8a and 8b. The dibenzyl protected compounds
were subjected to oxidation with m-chloroperoxybenzoic
acid -MCPBA) to form the N-oxides 9a and 9b.12
hydroxide gave the corresponding 2--10-hydroxyalkyl)-
pyridines 10a and 10b which when subjected to N-methyl-
ation yielded the quaternary pyridinium salts 12a and 12b.
Cleavage of the protected NH-pyridones was undertaken by
hydrogenolysis in order to prepare the 2--10-hydroxyalkyl)-
3-hydroxypyridin-4-ones 11a and 11b. However, hydro-
genolysis was unsuccessful when performed with the
protected N-alkyl derivatives, as the quaternary pyridinium
salts apparently poison the palladium/carbon catalyst.
Consequently compound 12a was subjected to acidic re¯ux
in order to give 13a. The secondary alcohol function of
12b was found to be susceptible to dehydration under
these conditions. Thus debenzylation catalysed by boron
In order to functionalise the 2-alkyl group, the N-oxide
group was acetylated with acetic anhydride. The resulting
intermediate undergoes an intramolecular rearrangement
leading to the formation of an acetylated alcohol on the
2-alkyl group.13±15 Subsequent saponi®cation with sodium
Table 1. Comparison of physicochemical properties and energy minimised structures between compound 3a and 3b
Structure
Energy minimised conformera
pKa
Af®nity constants for Fe-III)b
pFe31c D7.4d -nˆ5)
log K1 log K2 log K3 log b3
2.77, 8.44 -spectrophotometric) 13.41
2.75, 8.47 -potentiometric)
11.47
9.43
34.31
21.7
0.04^0.01
2.32, 6.66 -spectrophotometric) 14.50
2.29, 6.68 -potentiometric)
10.49
7.47
32.46
22.8
0.17^0.01
a
Space ®lling model -Hˆwhite;C ˆlight grey;N ˆblack;O ˆdark grey).
b
c
d
The cumulative stability constant -b3) obtained by summation of the three stepwise equilibrium constants -K1, K2 and K3).
]
pFe31ˆ2log [Fe31] when [ligand]totalˆ1025 M. and [Fe31
ˆ1026 M. at pH 7.45.
total
D7.4ˆdistribution coef®cient -n-octanol/ water) at pH 7.4.

3482
S. Piyamongkol et al. / Tetrahedron 57 ,2001) 3479±3486
tribromide in dichloromethane16 was established as the
method of choice for compound 12b.
graphy was performed on silica gel 220±440 mesh
-Fluka).
The synthetic pathway for the 2-amido-3-hydroxypyridin-4-
ones is summarised in Scheme 3. Direct conversion of the
primary alcohol of 10a to a carboxylic acid was initially
attempted using Jones reagent, however, extensive decom-
position occurred, resulting in poor yields. Thus the inter-
mediate aldehyde was isolated before further oxidation to
the carboxylic acid 14 was attempted. Activation of 14 was
achieved prior to reaction with various aliphatic primary
amines using previously established conditions.6 This
method was found to be less ef®cient with aromatic amines.
For such reactions an alternative method was introduced
3.1.1. 2-Methyl-3-benzyloxypyran-4ꢀ1H)-one. To a solu-
tion of maltol -6a) -100 g, 0.794 mol) in methanol -100 mL)
was added sodium hydroxide -34.9 g, 0.873 mol, 1.1 equiv.)
in water -80 mL). The reaction mixture was heated to re¯ux
before benzyl bromide -104 mL, 0.873 mol, 1.1 equiv.) was
slowly introduced into the ¯ask and the mixture was left to
re¯ux overnight. After the solvent was removed, the residue
was taken into water -200 mL) and dichloromethane
-400 mL). The aqueous fraction was discarded and the
organic fraction washed with sodium hydroxide -5%,
3£200 mL) followed by water -2£200 mL). The combined
fractions were dried over anhydrous sodium sulfate, ®ltered,
and evaporated under reduced pressure. Recrystallisation
from diethyl ether afforded off-white crystals -136.3 g,
80%): mp 54±568C -Lit. 17 value 53±558C); dH -60 MHz,
CDCl3) 2.07 -3H, s, Me), 5.04 -2H, s, CH2Ph), 6.19 -1H, d,
Jˆ6.0 Hz, 5-H), 7.22 -5H, s, CH2Ph), 7.45 -1H, d,
Jˆ6.0 Hz, 6-H).
using
benzotriazolyloxy-tris-pyrrolidino)-phosphonium
hexa¯uorophosphate -PyBOPw) as a coupling reagent
-Scheme 3).
In contrast to the 2--10-hydroxyalkyl)-pyridines, N-alkyl-
ation of the 2-amidopyridines could not be achieved due
to a strong inductive effect of the 2-amido substituent.
However, studies have demonstrated that when there is no
N-alkyl substitution in the ring -compound 3b), the pKa
values are signi®cantly lower than that of the N-methyl
analogue 3a -Table 1). This difference is due to two main
factors, ®rstly the positive inductive effect of the alkyl group
and secondly the existence of coplanar intramolecular
hydrogen bonding between the amide NH and the 3-hydroxyl
group of compound 3b. The intramolecular hydrogen bond-
ing in compound 3a is not so well favoured as appreciable
steric repulsion exists between the 1-methyl group and the
amide oxygen atom. The smaller bulk of the 1-hydrogen in
compound 3b permits the alternative orientation of the
amide function, such that coplanar intramolecular hydrogen
bonding is possible -Table 1). The enhanced hydrophobicity
of compound 3b -Table 1) con®rms the existence of ef®cient
intramolecular hydrogen bonding which reduces the ability
of the compound to interact with water. Because of the
enhanced af®nity for iron-III) of the NH-containing pyridi-
nones no further attempts were made to achieve N-alkyl-
ation of these derivatives.
3.1.2. 2-Ethyl-3-benzyloxypyran-4ꢀ1H)-one. The same
procedure as described for 2-methyl-3-benzyloxypyran-
4-1H)-one was used with ethyl maltol -6b) -200 g,
1.43 mol) in ethanol -150 mL). Recrystallisation from
chloroform/petroleum spirit afforded light yellow crystals
-265.0 g, 81%): mp 34±358C -Lit. 17 value 33±348C); dH
-60 MHz, CDCl3) 0.94 -3H, t, Jˆ7.8 Hz, CH2Me), 2.43 -2H,
q, Jˆ7.8 Hz, CH2Me), 5.03 -2H, s, CH2Ph), 6.18 -1H, d,
Jˆ6.0 Hz, 5-H), 7.20 -5H, s, CH2Ph), 7.46 -1H, d,
Jˆ6.0 Hz, 6-H).
3.1.3. 2-Methyl-3-benzyloxypyridin-4ꢀ1H)-one ꢀ7a). To a
solution of 2-methyl-3-benzyloxypyran-4-1H)-one -26.5 g,
0.123 mol) in ethanol -50 mL) was added ammonia solution
-100 mL) and re¯uxed overnight. The solvent was removed
under reduced pressure, then taken into water -200 mL) and
adjusted to pH 1 with concentrated hydrochloric acid. The
aqueous mixture was washed with ethyl acetate -3£150 mL)
and the pH was adjusted to pH 10 with sodium hydroxide
-2 M.). The aqueous phase was extracted with chloroform
-3£200 mL), dried over anhydrous sodium sulfate, ®ltered,
and evaporated under reduced pressure. Recrystallisation
from methanol/diethyl ether gave brown cubic crystals
-19.9 g, 75%): mp 162±1648C -Lit. 18 value 162±1638C);
dH -60 MHz, CDCl3) 2.14 -3H, s, Me), 4.92 -2H, s, CH2Ph),
6.25 -1H, d, Jˆ6.0 Hz, 5-H), 7.18 -5H, s, CH2Ph), 6.8±7.5
-1H, buried d, 6-H).
3. Experimental
3.1. General chemistry procedure
Melting points were determined using an Electrothermal IA
9100 Digital Melting Point Apparatus and are uncorrected.
IR spectra were performed on a Perkin-Elmer 1605 FTIR
Spectrophotometer and 1H NMR spectra were recorded on a
Perkin±Elmer -60 MHz) or Bruker -400 MHz) spectro-
meters. Chemical shifts -d) are reported in ppm down®eld
from the internal standard tetramethylsilane -TMS). Mass
spectra -FAB) analyses were carried out by Mass Spectro-
metry Facility, Department of Pharmaceutical and Bio-
logical Chemistry, The School of Pharmacy, 29/39
Brunswick Square, London WC1N 1AX. The samples
were dissolved in either 3-nitrobenzylalcohol or a mixture
of thioglycerol, glycerol and tri¯uoroacetic acid matrix.
Elemental analyses were performed by Microanalytical
Laboratories, Department of Chemistry, The University of
Manchester, Manchester M13 9PL. Column chromato-
3.1.4. 2-Ethyl-3-benzyloxypyridin-4ꢀ1H)-one ꢀ7b). To a
solution of 2-ethyl-3-benzyloxypyran-4-1H)-one -55 g,
0.239 mol) in ethanol -100 mL) was added ammonia
solution -200 mL) and left to stir at room temperature
for 7 days. The product was ®ltered and washed with
diethyl ether. The ®ltrate was evaporated under reduced
pressure then crystallised from methanol/diethyl ether to
yield off-white needle crystals -39.0 g, 71%): mp
179±1818C -Lit. 17 value 168±1698C); dH -60 MHz,
CDCl3) 1.14 -3H, t, Jˆ7.8 Hz, CH2Me), 2.63 -2H, q,
Jˆ7.8 Hz, CH2Me), 5.08 -2H, s, CH2Ph), 6.30 -1H, d,
Jˆ7.0 Hz, 5-H), 7.25 -5H, s, CH2Ph), 7.38 -1H, d,
Jˆ7.0 Hz, 6-H).

S. Piyamongkol et al. / Tetrahedron 57 ,2001) 3479±3486
3483
3.1.5. 2-Methyl-3,4-dibenzyloxypyridine ꢀ8a). Triphenyl
phosphine -TPP) -29.3 g, 111.6 mmol, 1.2 equiv.) was
slowly added to a solution of 2-methyl-3-benzyloxypyri-
din-4-1H)-one ꢀ7a) -20 g, 93 mmol) in dry tetrahydrofuran
-150 mL) which was cooled to 208C. Benzyl alcohol
-10.6 mL, 102.3 mmol, 1.1 equiv.) was later introduced
dropwise followed by diethylazodicarboxylate -DEAD)
-17.6 mL, 111.6 mmol, 1.2 equiv.) in the same manner.
After re¯uxing the reaction mixture overnight, the solvent
was removed under reduced pressure and the residue was
extracted with water -200 mL). The mixture was adjusted to
pH 1 with concentrated hydrochloric acid before washing
with diethyl ether -4£200 mL). The pH of the aqueous frac-
tion was increased to 8 with sodium hydroxide -2 M.),
followed by extraction with ethyl acetate -4£200 mL).
The combined organic fractions were dried over anhydrous
sodium sulfate, ®ltered, and concentrated under reduced
pressure to give a white solid -22.4 g, 79%). Recrystallisa-
tion from chloroform/petroleum spirit gave white crystals:
mp 85±878C; nmax -KBr) 3264 -ring C±H), 1589, 1498,
1485 and 1449 -ring CvC), 1218 and 1066 -C±O±C)
cm21; dH -400 MHz, CDCl3) 2.43 -3H, s, Me), 5.00 -2H,
s, 3-OCH2Ph), 5.16 -2H, s, 4-OCH2Ph), 6.78 -1H, d,
Jˆ5.6 Hz, 5-H), 7.31±7.44 -10H, m, 3-OCH2Ph and
4-OCH2Ph), 8.12 -1H, d, Jˆ5.6 Hz, 6-H); m/z -FAB) 306
[-M1H)1];HRMS -FAB): [-M 1H)1], found 306.1504.
C20H20O2N requires 306.1494.
[-M1H)1];HRMS -FAB): [-M 1H)1], found 322.1442.
C20H20O3N requires 322.1443.
3.1.8. 2-Ethyl-3,4-dibenzyloxypyridine N-oxide ꢀ9b).
2-Ethyl-3,4-dibenzyloxypyridine ꢀ8b) -11.3 g, 35.5 mmol)
was treated as 9a and produced a white ¯uffy powder
-8.5 g, 72%): mp 97±998C; nmax -KBr) 3250 -ring C±H),
3040 and 2991 -aliphatic C±H), 1616 and 1531 -ring CvC),
1253 and 1067 -C±O±C) cm21; dH -60 MHz, CDCl3) 1.20
-3H, t, Jˆ7.2 Hz, CH2Me), 2.96 -2H, q, Jˆ7.2 Hz, CH2Me),
5.02 -2H, s, 3-OCH2Ph), 5.11 -2H, s, 4-OCH2Ph), 6.67 -1H,
d, Jˆ7.2 Hz, 5-H), 7.30 -5H, s, 3-OCH2Ph), 7.37 -5H, s,
4-OCH2Ph), 7.96 -1H, d, Jˆ7.2 Hz, 6-H); m/z -FAB) 336
[-M1H)1];HRMS -FAB): [-M 1H)1], found 336.1604.
C21H22O3N requires 336.1600.
3.1.9. 2-Acetoxymethyl-3,4-dibenzyloxypyridine. Acetic
anhydride -100 mL) was added into a ¯ask which contain
2-methyl-3,4-dibenzyloxypyridine N-oxide -9a) -5.1 g,
17.8 mmol) and the reaction mixture was heated to 1308C
for 1 h. The solvent was removed under reduced pressure
and the residue dissolved in water -200 mL). The pH of the
solution was adjusted to 8 with sodium hydroxide -2 M.)
and was then extracted with dichloromethane -3£200 mL).
The organic fractions were dried over anhydrous sodium
sulfate, ®ltered, and concentrated in vacuo to yield brown
oil. Treatment with decolourising charcoal yielded yellow
oil: dH -60 MHz, CDCl3) 1.93 -3H, s, OCOMe), 4.92 -2H, s,
3-OCH2Ph), 4.95 -2H, s, 4-OCH2Ph), 5.05 -2H, s,
CH2OCOMe), 6.65 -1H, d, Jˆ6.0 Hz, 5-H), 7.14 -5H, s,
3-OCH2Ph), 7.20 -5H, s, 4-OCH2Ph), 8.02 -1H, d,
Jˆ6.0 Hz, 6-H).
3.1.10. 2-ꢀ10-Acetoxyethyl)-3,4-dibenzyloxypyridine. The
same procedure as described for 2-acetoxymethyl-3,4-
dibenzyloxypyridine was used with 2-ethyl-3,4-dibenzyl-
oxypyridine N-oxide -9b) to yield brown oil: nmax -Neat)
3031 -ring C±H), 1732 -ester CvO), 1581 -ring CvC),
1245 and 1027 -C±O±C) cm21; dH -60 MHz, CDCl3) 1.20
-3H, d, Jˆ6.6 Hz, CHMe), 1.65 -3H, s, OCOMe), 4.60 -2H,
s, 3-OCH2Ph), 4.75 -2H, s, 4-OCH2Ph), 5.98 -1H, q,
Jˆ6.6 Hz, CHMe), 6.33 -1H, d, Jˆ6.0 Hz, 5-H), 6.92
-10H, s, 3-OCH2Ph and 4-OCH2Ph), 7.80 -1H, d,
Jˆ6.0 Hz, 6-H).
3.1.6. 2-Ethyl-3,4-dibenzyloxypyridine ꢀ8b). The same
procedure as described for 8a was used with 2-ethyl-3-
benzyloxypyridin-4-1H)-one -7b) -20.3 g, 88.8 mmol).
After recrystallisation from chloroform/petroleum spirit,
off-white crystals were obtained -20.5 g, 72%): mp 154±
1568C; nmax -KBr) 3347 -ring C±H), 1498, 1488, 1465
and 1447 1449 -ring CvC), 1253 and 1096 -C±O±C)
cm21; dH -60 MHz, CDCl3) 1.14 -3H, t, Jˆ7.8 Hz,
CH2Me), 2.72 -2H, q, Jˆ7.8 Hz, CH2Me), 4.85 -2H, s,
3-OCH2Ph), 4.94 -2H, s, 4-OCH2Ph), 6.55 -1H, d,
Jˆ6.0 Hz, 5-H), 7.20 -10H, s, 3-OCH2Ph and 4-OCH2Ph),
8.00 -1H, d, Jˆ6.0 Hz, 6-H); m/z -FAB) 320 [-M1H)1];
HRMS -FAB): [-M1H)1], found 320.1639. C21H22O2N
requires 320.1651.
3.1.7. 2-Methyl-3,4-dibenzyloxypyridine N-oxide ꢀ9a). A
solution of m-chloroperoxybenzoic acid -MCPBA) -24 g,
80.9 mmol, 1.1 equiv.) in dichloromethane -100 mL) was
prepared and cooled to 08C. A solution of 2-methyl-3,4-
dibenzyloxypyridine -8a) -22.4 g, 73.5 mmol) in dichloro-
methane -100 mL) was added slowly. The reaction mixture
was left to stir at room temperature for 3 h prior to addition
of dichloromethane -200 mL) to increase the volume. The
solution was washed with sodium carbonate -5%,
3£200 mL). The organic phase was dried over anhydrous
sodium sulfate, ®ltered, and concentrated under reduced
pressure to give yellow oil. Crystallisation in the form of
white ¯uffy powder resulted subsequent to the addition of
diethyl ether -18.1 g, 77%): mp 127±1298C; nmax -KBr)
3245 -ring C±H), 3041 and 2991 -aliphatic C±H), 1533
3.1.11. 2-Hydroxymethyl-3,4-dibenzyloxypyridine ꢀ10a).
To a solution of 2-acetoxymethyl-3,4-dibenzyloxypyridine
-8.3 g, 22.8 mmol) in ethanol -30 mL), sodium hydroxide
-2 M., 50 mL) was added and the reaction mixture re¯uxed
for 2 h. The product was extracted with dichloromethane
-4£200 mL), dried over anhydrous sodium sulfate, ®ltered,
and concentrated under reduced pressure to give an off-
white solid -81% overall yield in two steps). Recrystallisa-
tion from diethyl ether/petroleum spirit gave an off-white
¯uffy powder: mp 83±858C; nmax -KBr) 3165 -br, O±H),
2954 -aliphatic C±H), 1595 -ring CvC), 1301 and 1035
-C±O±C) cm21; dH -60 MHz, CDCl3) 3.69 -1H, s,
CH2OH), 4.61 -2H, s, CH2OH), 5.00 -2H, s, 3-OCH2Ph),
5.14 -2H, s, 4-OCH2Ph), 6.80 -1H, d, Jˆ6.0 Hz, 5-H), 7.28
-5H, s, 3-OCH2Ph), 7.36 -5H, s, 4-OCH2Ph), 8.10 -1H, d,
Jˆ6.0 Hz, 6-H); m/z -FAB) 322 [-M1H)1];HRMS
-FAB): [-M1H)1], found 322.1455. C20H20O3N requires
322.1443.
-ring CvC), 1240 and 1068 -C±O±C) cm21
; dH
-400 MHz, CDCl3) 2.40 -3H, s, Me), 5.00 -2H, s,
3-OCH2Ph), 5.16 -2H, s, 4-OCH2Ph), 6.78 -1H, d,
Jˆ7.3 Hz, 5-H), 7.31±7.45 -10H, m, 3-OCH2Ph and
4-OCH2Ph), 8.12 -1H, d, Jˆ7.3 Hz, 6-H); m/z -FAB) 322

3484
S. Piyamongkol et al. / Tetrahedron 57 ,2001) 3479±3486
3.1.12. 2-ꢀ10-Hydroxyethyl)-3,4-dibenzyloxypyridine ꢀ10b).
The same procedure as reported with 10a was used with
2--10-acetoxyethyl)-3,4-dibenzyloxypyridine. Puri®cation
on a silica gel column -eluant: methanol/chloroform;
10:90 v/v) followed by recrystallisation from chloroform/
petroleum spirit yielded white ¯ake crystals -56% overall
yield in two steps): mp 70±728C; nmax -KBr) 3332 -br,
O±H), 2968 -aliphatic C±H), 1586 -ring CvC), 1297 and
1019 -C±O±C) cm21; dH -60 MHz, CDCl3) 1.38 -3H, d,
Jˆ6.6 Hz, CHMe), 3.80±4.50 -1H, br, CHOH), 4.95 -2H,
s, 3-OCH2Ph), 4.85±5.25 -1H, buried q, CHMe), 5.04 -2H,
s, 4-OCH2Ph), 6.69 -1H, d, Jˆ5.4 Hz, 5-H), 7.21 -5H, s,
3-OCH2Ph), 7.25 -5H, s, 4-OCH2Ph), 8.02 -1H, d,
Jˆ5.4 Hz, 6-H); m/z -FAB) 336 [-M1H)1];HRMS
-FAB): [-M1H)1], found 336.1604. C21H22O3N requires
336.1600.
-2H, s, CH2OH), 7.25 -1H, d, Jˆ6.6 Hz, 5-H), 8.17 -1H, d,
Jˆ6.6 Hz, 6-H), 8.40±9.80 -3H, br, OH); m/z -FAB) 156
[-M2Cl)1];HRMS -FAB): [-M 2Cl)1], found 156.0655.
C7H10O3N requires 156.0661.
3.1.16. 1-Methyl-2-ꢀ10-hydroxyethyl)-3-hydroxypyridin-
4ꢀ1H)-one hydrobromide ꢀ13b). 1-Methyl-2--10-hydroxy-
ethyl)-3,4-dibenzyloxypyridinium iodide -12b) -2.4 g,
5 mmol) was weighed in a 100 mL round bottom ¯ask
which was then sealed and ¯ushed with nitrogen. After
the ¯ask was cooled to 08C, boron tribromide -1 M in
dichloromethane, 4 equiv.) was slowly added and the reac-
tion mixture was allowed to stir at room temperature for 3 h.
The excess boron tribromide was eliminated at the end of
the reaction by the addition of some methanol and left to stir
for another 0.5 h. The mixture was concentrated under
reduced pressure to yield a white solid -1.1 g, 86%). Recrys-
tallisation from methanol/diethyl ether afforded a yellow
powder: mp 141±1438C;[Found: C, 38.62;H, 5.01;N,
3.1.13. 1-Methyl-2-hydroxymethyl-3,4-dibenzyloxypyri-
dinium iodide ꢀ12a). Methyl iodide -20 mL) was added to
2-hydroxymethyl-3,4-dibenzyloxypyridine -10a) -3.1 g,
9.6 mmol) and the reaction mixture was stirred at room
temperature overnight. The product was obtained by ®ltra-
tion of the suspension, washed with diethyl ether, and
isolated as light yellow ¯ake crystals -3.6 g, 82%): mp
127±1298C; nmax -KBr) 3261 -br, O±H), 3055 and 3030
-aliphatic C±H), 1508 -ring CvC), 1258 and 1011
-C±O±C) cm21; dH -60 MHz, DMSO-d6) 3.00±3.50 -1H,
br, CH2OH), 4.18 -3H, s, NMe), 4.68 -2H, s, CH2OH), 4.98
-2H, s, 3-OCH2Ph), 5.45 -2H, s, 4-OCH2Ph), 7.24 -5H, s,
3-OCH2Ph), 7.35 -5H, s, 4-OCH2Ph), 7.76 -1H, d,
Jˆ7.2 Hz, 5-H), 8.70 -1H, d, Jˆ7.2 Hz, 6-H); m/z -FAB)
336 [-M2I)1];HRMS -FAB): [-M 2I)1], found 336.1604.
C21H22O3N requires 336.1600.
5.50;Br, 32.39. C H12BrNO3 requires C, 38.42;H, 4.84;
8
N, 5.60;Br, 31.95%]; nmax -KBr) 3229 -br, O±H, intermo-
lecular hydrogen bonding), 2927 -br, O±H, intramolecular
hydrogen bonding) 1589, 1531, 1501 and 1457 -ring CvC)
cm21; dH -60 MHz, DMSO-d6) 1.45 -3H, d, Jˆ6.6 Hz,
CHMe), 4.16 -3H, s, NMe), 5.48, -1H, q, Jˆ6.6 Hz,
CHMe), 7.10 -1H, d, Jˆ6.6 Hz, 5-H), 8.15 -1H, d,
Jˆ6.6 Hz, 6-H), 8.00±9.80 -3H, br, OH); m/z -FAB) 170
[-M2Br)1].
3.1.17. 2-Formyl-3,4-dibenzyloxypyridine. To a solution
of 2-hydroxymethyl-3,4-dibenzyloxypyridine -10a) -5.7 g,
17.6 mmol) in chloroform -100 mL), was added dimethyl
sulfoxide -DMSO) -27 mL) and triethylamine -TEA)
-14.7 mL, 105.8 mmol, 6 equiv.). The reaction mixture
was then cooled in an ice-bath followed by the slow addition
of sulfur trioxide pyridine complex -14 g, 88.2 mmol,
5 equiv.). The mixture was allowed to thaw at room
temperature and left to stir overnight. Water -2£100 mL)
was used to wash the organic fraction, which was subse-
quently dried over anhydrous sodium sulfate, ®ltered, and
concentrated in vacuo. The dark green residue obtained was
loaded on to a silica gel column -eluant: chloroform:
methanol/ethyl acetate;45:5:50 v/v) to yield an off-white
solid -3.5 g, 62%). Recrystallisation from chloroform/
petroleum spirit yielded off-white ¯uffy crystals: mp 103±
1048C; nmax -KBr) 3065 and 3031 -ring C±H), 2858 -alde-
hyde C±H), 1709 -aldehyde CvO), 1573 -ring CvC), 1251
and 1043 -C±O±C) cm21; dH -60 MHz, CDCl3) 5.12 -4H, s,
3-OCH2Ph and 4-OCH2Ph), 6.95 -1H, d, Jˆ6.0 Hz, 5-H),
7.24 -5H, s, 3-OCH2Ph), 7.34 -5H, s, 4-OCH2Ph), 8.26 -1H,
d, Jˆ6.0 Hz, 6-H), 10.12 -1H, s, CHO); m/z -FAB) 320
[-M1H)1];HRMS -FAB): [-M 1H)1], found 320.1267.
C20H18O3N requires 320.1287.
3.1.14. 1-Methyl-2-ꢀ10-hydroxyethyl)-3,4-dibenzyloxy-
pyridinium iodide ꢀ12b). The same procedure as described
for 12a was used with 2--10-hydroxyethyl)-3,4-dibenzyl-
oxypyridine -10b) -2.5 g, 70.4 mmol). The product was
isolated after ®ltration as yellow ¯ake crystals -2.6 g,
74%): mp 116±1188C; nmax -KBr) 3270 -br, O±H), 3034
-ring C±H), 2983 and 2938 -aliphatic C±H), 1623, 1500 and
1453 -ring CvC), 1253 and 1043 -C±O±C) cm21; dH
-60 MHz, DMSO-d6) 1.30 -3H, d, CHMe), 4.20 -3H, s,
NMe), 4.90 -2H, s, 3-OCH2Ph), 5.40 -2H, s, 4-OCH2Ph),
5.15±5.70 -1H, buried s, CHOH), 5.87 -1H, q, CHMe), 7.11
-5H, s, 3-OCH2Ph), 7.23 -5H, s, 4-OCH2Ph), 7.68 -1H, d,
Jˆ6.6 Hz, 5-H), 8.57 -1H, d, Jˆ6.6 Hz, 6-H); m/z -FAB)
350 [-M2I)1];HRMS -FAB): [-M 2I)1], found 350.1766.
C22H24O3N requires 350.1756.
3.1.15. 1-Methyl-2-hydroxymethyl-3-hydroxypyridin-
4ꢀ1H)-one hydrochloride ꢀ13a). 1-Methyl-2-hydroxy-
methyl-3,4-dibenzyloxypyridinium iodide -12a) -3.2 g,
6.9 mmol) was dissolved in hydrochloric acid -6 M.,
50 mL) and re¯uxed for 6 h. The reaction mixture was
concentrated under reduced pressure to produce a crude
solid -1.1 g. 83%). Methanol was added and evaporated
twice to remove iodine. Recrystallisation from methanol/
acidic diethyl ether -prepared by bubbling hydrogen
chloride gas into diethyl ether) yielded light yellow needle
crystals: mp 157±1598C -Lit. 5 mp 157±1598C);[Found: C,
3.1.18. 2-Carboxy-3,4-dibenzyloxypyridine ꢀ14). 2-Formyl-
3,4-dibenzyloxypyridine -11.6 g, 36.5 mmol) was dissolved
in acetone -100 mL) and water -100 mL). To this solution
was added sulfamic acid -5.0 g, 51.0 mmol, 1.4 equiv.) and
sodium chlorite -80%, 4.5 g, 40.1 mmol, 1.1 equiv.) and
stirred at room temperature for 3 h. in an open ¯ask.
Removal of acetone in vacuo yielded crude product as a
precipitate in the remaining aqueous solution. This
was collected, washed with acetone and dried to yield
43.9;H, 5.4;N, 7.3. C H10ClNO3 requires C, 43.88;H, 5.26;
7
N, 7.31%]; dH -60 MHz, DMSO-d6) 4.06 -3H, s, NMe), 4.64

S. Piyamongkol et al. / Tetrahedron 57 ,2001) 3479±3486
3485
off-white powder -8.2 g, 77%): mp 1208C -dec.); nmax -KBr)
3033 -br, O±H), 1707 -br, acid CvO), 1607 and 1499 -ring
CvC), 1223 and 1026 -C±O±C) cm21; dH -60 MHz,
DMSO-d6) 4.91 -2H, s, 3-OCH2Ph), 5.22 -2H, s,
4-OCH2Ph), 7.16 -5H, s, 3-OCH2Ph), 7.28 -5H, s,
4-OCH2Ph), 6.80±7.60 -1H, buried d, 5-H), 7.60±8.00
-1H, br, COOH), 8.20 -1H, d, Jˆ6.0 Hz, 6-H); m/z -FAB)
336 [-M1H)1];HRMS -FAB): [-M 1H)1], found 336.1232.
C20H18O4N requires 336.1236.
solvent was removed under reduced pressure. The residue
was puri®ed on a silica gel column -eluant: methanol/
chloroform;10:90 v/v) to obtain the product, which was
taken up with ethanol and adjusted to pH 1 with concen-
trated hydrochloric acid. Recrystallisation from methanol/
diethyl ether occurred when the solvent was removed in
vacuo.
3.2.1. 3,4-Dibenzyloxypyridine-2-carboxyamide hydro-
chloride. Ammonia -1 M. in methanol) yielded a pinkish-
white powder after recrystallisation -45% overall yield in
two steps): mp 113±1148C; nmax -KBr) 3463 and 3419
-18amide N±H), 3061 and 3030 -ring C±H), 1687
-amide CvO), 1609, 1524 and 1499 -ring CvC), 1221
and 1046 -C±O±C) cm21; dH -60 MHz, DMSO-d6) 5.00
-2H, s, 3-OCH2Ph), 5.34 -2H, s, 4-OCH2Ph), 7.15 -5H, s,
3-OCH2Ph), 7.28 -5H, s, 4-OCH2Ph), 7.60 -1H, d,
Jˆ6.0 Hz, 5-H), 7.85±8.25 -2H, br, CONH2), 8.35 -1H, d,
Jˆ6.0 Hz, 6-H); m/z -FAB) 335 [-M2Cl)1];HRMS -FAB):
[-M2Cl)1], found 335.1370. C20H19O3N2 requires
335.1396.
3.1.19. N-ꢀ3,4-Dibenzyloxypyridine-2-carbonyl)-1,3-thi-
azolidine-2-thione
ꢀ15).
Dicyclohexylcarbodiimide
-DCCI) -2.9 g, 14.2 mmol, 1.1 equiv.) was added into a
solution of 2-carboxy-3,4-dibenzyloxypyridine -14) -4.3 g,
12.9 mmol) in dichloromethane -100 mL) followed by an
addition of 2-mercaptothiazoline -1.7 g, 14.2 mmol,
1.1 equiv.) and a catalytic amount of dimethylaminopyri-
dine -DMAP) -50 mg). The reaction mixture was stirred
overnight at room temperature then placed in an ice bath
for 1 h. The white precipitate of dicyclohexylurea -DCU)
was ®ltered, discarded and the ®ltrate volume was increased
to 200 mL with dichloromethane. The organic layer was
washed with sodium hydroxide -0.1 M., 3£150 mL), water
-150 mL), dried over anhydrous sodium sulfate, ®ltered, and
concentrated in vacuo to yield a bright yellow oil.
3.2.2. 3,4-Dibenzyloxypyridine-2-carboxy-ꢀN-methyl)-
amide hydrochloride. Methylamine -1 M in tetrahydro-
furan) yielded a pinkish-white ¯uffy powder after recrystal-
lisation -48% overall yield in two steps): mp 164±1668C;
nmax -KBr) 3436 -amide N±H), 3031 -ring C±H), 1683
-amide CvO), 1571 -ring CvC), 1263 and 1026 -C±O±
C) cm21; dH -60 MHz, DMSO-d6) 2.83 -3H, d, Jˆ5.4 Hz,
CONHMe), 5.20 -2H, s, 3-OCH2Ph), 5.47 -2H, s,
4-OCH2Ph), 7.23 -5H, s, 3-OCH2Ph), 7.38 -5H, s,
4-OCH2Ph), 7.75 -1H, d, Jˆ6.6 Hz, 5-H), 8.44 -1H, d,
Jˆ6.6 Hz, 6-H), 9.10 -1H, q, Jˆ5.4 Hz, CONHMe); m/z
-FAB) 349 [-M2Cl)1];HRMS -FAB): [-M 2Cl)1], found
349.1559. C21H21O3N2 requires 349.1552.
3.1.20. 3,4-Dibenzyloxypyridine-2-carboxy-ꢀN-phenyl)-
amide hydrochloride. To a solution of 2-carboxy-3,4-
dibenzyloxypyridine -14) -3 g, 9 mmol) in dichloromethane
-100 mL), benzotriazolyloxy-tris-pyrrolidino)-phosphonium
hexa¯uorophosphate
-PyBOPw)
-5.2 g,
10 mmol,
1.1 equiv.) was added, followed by the addition of triethyl-
amine -2.5 mL, 17.9 mmol, 2 equiv.) and phenylamine
-0.8 mL, 9 mmol, 1 equiv.), respectively. The reaction
mixture was left to stir at room temperature overnight before
it was washed with citric acid -5%, 100 mL), sodium bi-
carbonate -5%, 100 mL) and ®nally water -100 mL). The
organic layer was then dried over anhydrous sodium sulfate,
®ltered, and concentrated under reduced pressure. Further
puri®cation on a silica gel column -eluant: methanol/chloro-
form;10:90 v/v) furnished a white solid, which was taken
into ethanol, adjusted to pH 1 with concentrated hydro-
chloric acid. The solvent was removed again in vacuo to
give a white solid. Recrystallisation from chloroform/
petroleum spirit afforded a white ¯uffy powder -1.5 g,
44%): mp 2208C -dec.); nmax -KBr) 3015 -br, amide
N±H), 1647 -amide CvO), 1599, 1541, 1497 and 1446
3.2.3. 3,4-Dibenzyloxypyridine-2-carboxy-ꢀN-hydroxy-
ethyl)-amide hydrochloride. Neat ethanolamine yielded a
white ¯uffy powder after recrystallisation -44% overall
yield in two steps): mp 127±1298C; nmax -KBr) 3354
-amide N±H), 3281 -O±H intermolecular hydrogen
bonding), 3065 -ring C±H), 1668 -amide CvO), 1603,
1547 and 1514 -ring CvC), 1217 and 1071 -C±O±C)
cm21
; dH -60 MHz, DMSO-d6) 3.00±3.60 -4H, m,
CONHCH2CH2OH), 4.97 -2H, s, 3-OCH2Ph), 5.32 -2H, s,
4-OCH2Ph), 6.50±7.00 -1H, br, CH2CH2OH), 7.14 -5H, s,
3-OCH2Ph), 7.28 -5H, s, 4-OCH2Ph), 7.56 -1H, d,
Jˆ6.0 Hz, 5-H), 8.35 -1H, d, Jˆ6.0 Hz, 6-H), 8.48±8.90
-1H, br, CONH); m/z -FAB) 379 [-M2Cl)1];HRMS
-FAB): [-M2Cl)1], found 379.1660. C22H23O4N2 requires
379.1658.
-ring CvC), 1244 and 1018 -C±O±C) cm21
; dH
-60 MHz, DMSO-d6) 5.01 -2H, s, 3-OCH2Ph), 5.33 -2H, s,
4-OCH2Ph), 6.70±7.70 -17H, m, 3-OCH2Ph and 4-OCH2Ph
and CONHPh and 5-H and 6-H), 8.20±8.55 -1H, br,
CONHPh); m/z -FAB) 411 [-M2Cl)1];HRMS -FAB):
[-M2Cl)1], found 411.1690. C26H23O3N2 requires
411.1709.
3.3. General procedure for the preparation of 2-ꢀ10-
hydroxyalkyl) and 2-amido derivatives of 3-hydroxy-
pyridin-4-ones
3.2. General procedure for the preparation of 2-amido
derivatives of 3,4-dibenzyloxypyridines
2-Amido or 2--10-hydroxyalkyl) derivatives of 3,4-
dibenzyloxypyridines in either methanol or ethanol were
subjected to hydrogenolysis in the presence of 5% Pd/C
-10% w/w of the compound) as a catalyst for 3 h. The cata-
lysts were removed by ®ltration and the ®ltrates acidi®ed to
pH 1 with concentrated hydrochloric acid. After the removal
A solution of primary amine -2 equiv.) in either methanol or
tetrahydrofuran or neat was added into a ¯ask containing
N--3,4-dibenzyloxypyridine-2-carbonyl)-1,3-thiazolidine-
2-thione -15) -as crude 1 equiv.). The reaction mixture was
allowed to stir overnight at room temperature before the

3486
S. Piyamongkol et al. / Tetrahedron 57 ,2001) 3479±3486
of solvents in vacuo, the residues were crystallised from
methanol/ diethyl ether.
amide hydrochloride ꢀ16d). 90% as off-white crystals,
mp 2808C -dec.);[Found: C, 54.2;H, 4.3;N, 10.6.
C12H11ClN2O3 requires C, 54.13;H, 4.17;N, 10.53%];
nmax -KBr) 3325 -O±H), 3119 -br, amide N±H), 1669
3.3.1.
2-Hydroxymethyl-3-hydroxypyridin-4ꢀ1H)-one
-amide CvO), 1598, 1560 and 1503 -ring CvC) cm21
;
hydrochloride ꢀ11a). 93% as a white powder, mp 1708C
-dec.);[Found: C, 40.9;H, 4.7;N, 7.9. C 6H8ClNO3 requires
C, 40.67;H, 4.55;N, 7.91%]; nmax -KBr) 3356 -br, O±H,
intermolecular hydrogen bonding), 3090 -br, O±H, intra-
molecular hydrogen bonding), 2952 -ring C±H), 1562 and
1500 -ring CvC) cm21; dH -60 MHz, DMSO-d6) 4.53 -2H,
s, CH2OH), 4.70±6.10 -3H, br, OH), 7.24 -1H, d, Jˆ6.6 Hz,
5-H), 7.93 -1H, d, Jˆ6.6 Hz, 6-H); m/z -FAB) 142
[-M2Cl)1].
dH -400 MHz, DMSO-d6) 5.80±6.70 -2H, br, OH), 7.16±
7.74 -6H, m, CONHPh and 5-H), 8.03 -1H, d, Jˆ6.2 Hz,
6-H), 11.37 -1H, s, CONHPh); m/z -FAB) 231 [-M2Cl)1];
HRMS -FAB): [-M2Cl)1], found 231.0764. C12H11O3N2
requires 231.0770.
Acknowledgements
3.3.2. 2-ꢀ10-Hydroxyethyl)-3-hydroxypyridin-4ꢀ1H)-one
hydrochloride ꢀ11b). 94% as white needle crystals, mp
1908C -dec.);[Found: C, 43.9;H, 5.4;N, 7.2.
C7H10ClNO3 requires C, 43.88;H, 5.26;N, 7.31%]; nmax
-KBr) 3356 -O±H, intermolecular hydrogen bonding),
3080 -br, O±H, intramolecular hydrogen bonding), 2959
-ring C±H), 1565 and 1500 -ring CvC) cm21; dH
-60 MHz, DMSO-d6) 1.35 -3H, d, Jˆ6.6 Hz, CHMe), 5.07
-1H, q, Jˆ6.6 Hz, CHMe), 7.27 -1H, d, Jˆ6.6 Hz, 5-H),
7.90 -1H, d, Jˆ6.6 Hz, 6-H), 8.00±10.10 -3H, br, OH);
m/z -FAB) 156 [-M2Cl)1].
The authors would like to thank Apotex Research Canada
and Biomed EC grant BMH4-CT97-2149 for supporting
this research project. S. Piyamongkol would like to thank
The Royal Thai Government and The Faculty of Pharmacy,
Chiang Mai University, Chiang Mai, Thailand for a
studentship.
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3.3.3. 3-Hydroxypyridin-4ꢀ1H)-one-2-carboxyamide hydro-
chloride ꢀ16a). 91% as off-white crystals, mp 2408C -dec.);
[Found: C, 34.5;H, 4.2;N, 13.2. C H7ClN2O3.H2O requires
6
2. Hider, R. C.;Liu, Z. D.;Piyamongkol, S. Tran. Sci. 2000, 23,
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C, 34.62;H, 4.33;N, 13.46%]; nmax -KBr) 3406 and 3310
-18amide N±H), 2920 -br, O±H), 1679 -amide CvO), 1587,
1543, 1507 and 1436 -ring CvC) cm21; dH -400 MHz,
DMSO-d6) 7.50 -1H, d, Jˆ6.3 Hz, 5-H), 8.13 -1H, d,
Jˆ6.3 Hz, 6-H), 8.27 -2H, s, OH), 8.61 -2H, s, CONH2);
m/z -FAB) 155 [-M2Cl)1];HRMS -FAB): [-M 2Cl)1],
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3.3.4. 3-Hydroxypyridin-4ꢀ1H)-one-2-carboxy-ꢀN-methyl)-
amide hydrochloride ꢀ16b). 88% as white powder, mp
2368C -dec.);[Found: C, 40.9;H, 4.6;N, 13.5.
C7H9ClN2O3 requires C, 41.09;H, 4.43;N, 13.69%]; nmax
-KBr) 3074 -br, amide N±H), 2908 -br, O±H), 1655 -amide
CvO), 1581, 1538 and 1501 -ring CvC) cm21; dH
-400 MHz, DMSO-d6) 2.92 -3H, d, Jˆ4.7 Hz, CONHMe),
5.60±6.30 -2H, br, OH), 7.49 -1H, d, Jˆ6.3 Hz, 5-H), 8.11
-1H, d, Jˆ6.3 Hz, 6-H), 8.82 -1H, q, Jˆ4.7 Hz, CONHMe);
m/z -FAB) 169 [-M2Cl)1].
8. Katritzky, A. R. In Handbook of Heterocyclic Chemistry,
Pergamon: Oxford, 1986;pp 173.
9. Hopkins, G. C.;Jonak, J. P.;Minnemeyer, H. J.;Tieckelmann,
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10. Guerry, P.;Neier, R. Synthesis 1984, 485±488.
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Synthesis, 3rd ed., Blackie: Oxford, 1994;pp 77.
13. Bullitt, O. H.;Maynard, J. T. J. Am. Chem. Soc. 1954, 76,
1370±1371.
3.3.5. 3-Hydroxypyridin-4ꢀ1H)-one-2-carboxy-ꢀN-hydroxy-
ethyl)-amide hydrochloride ꢀ16c). 87% as off-white
powder, mp 201±2038C;[Found: C, 41.1;H, 4.5;N, 11.9.
C8H11ClN2O4 requires C, 40.95;H, 4.73;N, 11.94%]; nmax
-KBr) 3425 -amide N±H), 3109 -br, O±H), 1671
14. Bodalski, R.;Katritzky, A. R. J. Chem. Soc., B 1968, 831±
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4917±4922.
-amide CvO), 1595, 1544 and 1498 -ring CvC) cm21
;
16. Aytemir, M. D.;Uzbay, T.;Erol, D. D. Arzneim.-Forsch./
Drug Res. 1999, 49 -I), 250±254.
dH -400 MHz, DMSO-d6) 3.45±3.50 -2H, m,
CONHCH2CH2OH), 3.56±3.59 -2H, m, CONHCH2CH2OH),
7.49 -1H, d, Jˆ6.3 Hz, 5-H), 8.12 -1H, d, Jˆ6.3 Hz, 6-H),
8.89 -1H, t, Jˆ5.5 Hz, CONHCH2CH2OH)), 9.10±10.40
-3H, br, OH); m/z -FAB) 199 [-M2Cl)1].
17. Dobbin, P. S.;Hider, R. C.;Hall, A. D.;Taylor, P. D.;
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3.3.6. 3-Hydroxypyridin-4ꢀ1H)-one-2-carboxy-ꢀN-phenyl)-