Synthesis of some new propanol derivatives analogous to fluconazole

Article abstract of DOI:10.1080/10426500490485066

A series of 2-(2,4-difluorophenyl)-1-(1H-1,2,4 triazol-1-yl-methyl)-3- (substituted heterocycl)-propan-2-ol, which are analogous to fluconazole, were synthesized via the reaction of 2-(2,4-difluorophenyl)-2-[1-(1,2,4- triazolmethide)]oxiran with various heterocyclic systems.

Full text of DOI:10.1080/10426500490485066

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Phosphorus, Sulfur, and Silicon
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SYNTHESIS OF SOME NEW
PROPANOL DERIVATIVES
ANALOGOUS TO FLUCONAZOLE
a
a
Majid M. Heravi & Radineh Motamedi
a
Department of Chemistry, School of Sciences,
Azzahra University, Vanak , Tehran, Iran
b
Darou Pakhsh Pharma. Chem. Co. (D. P. P. C.) ,
Tehran, Iran
Published online: 16 Aug 2010.
To cite this article: Majid M. Heravi & Radineh Motamedi (2004) SYNTHESIS OF
SOME NEW PROPANOL DERIVATIVES ANALOGOUS TO FLUCONAZOLE, Phosphorus,
Sulfur, and Silicon and the Related Elements, 179:11, 2329-2334, DOI:
10.1080/10426500490485066
To link to this article: http://dx.doi.org/10.1080/10426500490485066
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Phosphorus, Sulfur, and Silicon, 179:2329–2334, 2004
Copyright ꢀC Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490485066
SYNTHESIS OF SOME NEW PROPANOL
DERIVATIVES ANALOGOUS TO FLUCONAZOLE
Majid M. Heravia,b and Radineh Motamedia
Department of Chemistry, School of Sciences, Azzahra
a
University, Vanak, Tehran, Iran; and Darou Pakhsh Pharma.
b
Chem. Co. (D. P. P. C.), Tehran, Iran
(
Received March 16, 2004; accepted May 4, 2004)
A series of 2-(2,4-difluorophenyl)-1-(1H-1,2,4 triazol-1-yl-methyl)-3-
substituted heterocycl)-propan-2-ol, which are analogous to flucona-
zole, were synthesized via the reaction of 2-(2,4-difluorophenyl)-2-[1-
1,2,4-triazolmethide)]oxiran with various heterocyclic systems.
(
(
Keywords: Fluconazole; propanol; triazine; triazole
Fluconazole, α(2,4-difluorophenyl)-α-(1H-1,2,4 triazol-1-yl-methyl)-
H-1,2,4 triazol-1-ethanol 4 is a potent inhibitor of the cytochrome
1
P450 (CYP)-mediated metabolism of the antiepileptic agent phenytion,
1
a well-known human and animal tetragon. Fluconazole was intro-
duced in 1990 as one of the most effective water-soluble oral antifungal
2
,3
agent.
In continuation of our interest in the synthesis of heterocycles4
containing sulphur and nitrogen, in this communication we wish to
report the synthesis of some new propanol derivatives analogous to
fluconazole.
Due to its biological importance, several routes have been developed
5
for the synthesis of fluconazole 4. The applicable method at the indus-
trial level involves a one-pot, three-component reaction of 2,4 difluoro-
2
-(1H-1,2,4 triazole-1-yl)acetophenone 1, triazole 2 and trimethylsul-
6
foxonium iodide 3 (Scheme 1).
In order to synthesize compounds analogous to fluconazole, we
applied a similar strategy using other heterocyclic containing thio
and amino groups such as 3-thio-1,2,4 triazoles, 2-thiopyrimidines, 3-
thio-1,2,4 triazines and 3-amino-1,2,4 triazines. These attempts were
unsuccessful. In 1992 Yajing et al.7 reported the reaction of cyclic
Address correspondence to Majid M. Heravi, Department of Chemistry, School of
Sciences, Azzahra University, Vanak, Tehran, Iran. E-mail: mmh1331@yahoo.com
2
329

2
330
M. M. Heravi and R. Motamedi
SCHEME 1
amines with1 in a two-step reaction via the oxirane intermediate 5
7
(
Scheme 2).
SCHEME 2
We applied this two-step strategy and found that the ring opening of
the intermediate epoxide gives bis unsymmetrical heterocyclic deriva-
tives of propanol (Scheme 3). As expected, the intermediate epoxide 5
opens regioselectively to give only one alcohol. It is also notable that
in the presence of an amino group aminoalkylation (formulas 8 and
9) occurred, and in the presence of a thio group thioalkylation (formu-
las 11–13) occurred predominantly over ring nitrogen alkylation with
epoxide 5. It is also worthwhile to mention that in the presence of an
amino group and a thio group on the heterocyclic system s-alkylation
occurs predominantly (Scheme 3, formula 10).
EXPERIMENTAL
Melting points were determined on an electrothermal IA-9100 digital
melting point apparatus and are uncorrected. IR spectra were recorded
1
with a Nicolet Magna spectrometer 750-1992-1997. H NMR Spectra
were recorded on a Brucker spectrometer at 500 MHz using tetra-
methylsilane (TMS) as internal standard. Mass spectra were obtained
on a GC-Mass HP, GC 689 network GC system, mass 5973 at 70 ev. Thin
layer chromatography (TLC) was developed on Merck silica gel-coated

Fluconazole
2331
SCHEME 3

2
332
M. M. Heravi and R. Motamedi
polyester plates containing a 254 mm fluorescent indicator. Triazoles,
pyrimidines, and 1,2,4 triazoles were prepared according to literature.
1
-[2-(2,4 Diflurophenyl)-2,3-epoxypropyl]-1H-1,2,4
triazole Methansulphonate (5)
2,4 difluoro-2-(1H-1,2,4 triazol-1-yl)acetophenone hydrochloride (59.6
g, 0.23 mol), trimethylsulfoxonium iodide (50.6 g, 0.23 mol), and cetrim-
ide (2.1 g) were stirred in a mixture of toluene (370 ml) and 20% w/w
◦
aqueous sodium hydroxide at 60 C for 3 h. The toluene layer was sepa-
rated and concentrated to 110 ml, then ethyl acetate was added (150 ml).
To this mixture a solution of methansulphonic acid (16.6 g, 0.172 mol)
in ethyl acetate (20 ml) was added. More ethyl acetate (100 ml) was
◦
added, and the mixture was stirred at 0 C for 1 h. Filtration of the
mixture gave the title compound (43 g, 56%). The crude product was
◦
dissolved in hot petroleum ether (60–80 C, 140 ml), and charcoal (2 g)
was added. The mixture was filtered, the filtrate was concentrated to
◦
1
00 ml, and then the mixture was stirred at 0 C for 1 h. Filtration of this
◦
1
mixture gave the title compound (7.8 g, 39%), m.p. 128–129 C. H NMR-
δ (d4-MeOH): 2.7 (s, 3H), 2.9 (d, J = 4.57 Hz, 1H), 3.1 (d, J = 4.57 Hz,
1
H), 4.7 (d, J = 14.83 Hz, 1H), 5.1 (d, J = 14.83 Hz, 1H), 6.93 (m, 1H),
1
−
7.0 (m, 1H), 7.3 (m, 1H), 8.7 (s, 1H), 9.8 (s, 1H). IR(KBr): 3120 cm (CH
aromatic), Anal.% Calc. for C12H13F2N3O4S: C, 43.2; H, 3.9; N, 12.6.
Found: C, 42.83; H, 3.92; N, 12.96.
Synthesis of Triazolylpropanol Derivatives 6–13
The appropriate heterocyclic compound (0.001 mol) was dissolved in
NaOMe/MeOH(Na, 0.15 g, 0.002 mol in MeOH 20 ml). The epoxide 5
(
0.3 g, 0.001 mol) was added, the mixture was refluxed for 6–12 h (the
progress of reaction was controlled by TLC analysis). After completion
of the reaction, the solvent was evaporated off under reduced pressure.
To the crude, water was added and extracted with CHCl3 (50 ml). The
organic layer was separated, dried over anhydrous Na2SO4, filtered,
and evaporated under reduced pressure. The crude was subjected to
column chromatography using CHCl3:MeOH (1:60–1: 20) as the eluent
to afford the pure product.
Selected Data for 6
◦
1
Yield: 78%, m.p. 165 C. H NMR-δ (d6-DMSO): 2.03 (s, 3H), 2.5 (d,
J = 12 Hz, 1H), 2.7 (d, J = 12 Hz, 1H), 4.71 (d, J = 14.1 Hz, 1H), 4.78 (d,
J = 14.1 Hz, 1H), 5.6 (s, 1H), 6.2 (s, 1H), 6.8 (m, 1H), 6.9 (m, 1H), 7.4 (m,
−
1
1H), 7.78 (s, 1H), 8.3 (s, 1H), 10.2 (br s,1H). IR(KBr): 3436.70 cm (OH),

Fluconazole
2333
+
Ms, m/z, 379(M ), 239 (14%), 224 (100%), 173 (70%), 155 (28%), 141
39%), 83 (66%).
(
Selected Data for 7
◦
1
Yield: 72%, m.p. 140–142 C. H NMR-δ(d3-MeOD): 2.03 (s, 3H), 2.5
s, 3H), 3.9 (d, J = 13.5 Hz, 1H), 4.0 (d, J = 13.5 Hz, 1H), 4.7 (d, J =
(
1
4.4 Hz, 1H), 4.8 (d, J = 14.4 Hz, 1H), 5.9 (s, 1H), 6.81–6.91 (m, 2H),
1
−
7.0 (s, 1H), 7.4 (m, 1H), 8.3 (s, 1H), 8.5 (s, 1H). IR (KBr): 3480 cm
+
(
OH), Ms, m/z, 393 (M ), 281 (21%), 238 (27%), 224 (100%), 169 (16%),
155 (28%), 82 (8.2%), 63(16%).
Selected Data for 8
◦
1
Yield: 68%, m.p. 181–183 C. H NMR-(d6−DMSO): 2.2 (s,3H), 3.4–
.6 (m, 2H), 4.5 (br s, 1H), 4.6 (d, J = 14.2 Hz, 1H), 4.7 (d, J = 14.2 Hz,
H), 6.8 (s, 1H), 6.9 (m, 1H), 7.1 (m, 1H), 7.3 (m, 1H), 7.7 (s, 1H), 8.3
3
1
−1
+
(
s, 1H), 11.5 (br s,1H). IR(KBr): 3450.22 cm (OH), Ms, m/z: 363 (M ),
2
1
98 (%6.4), 282 (18%), 238 (%19%), 224 (100%), 173 (72%), 127 (73%),
25 (27%), 68 (20%).
Selected Data for 9
◦
1
Yield: 70%, m.p. 173–175 C. H NMR-(d6−DMSO): 3.48–3.54 (m, 2H),
.39 (d, J = 14.4 Hz, 1H), 4.43 (d, J = 14.4 Hz, 1H), 4.8 (br s, 1H), 6.7
4
(
(
3
s, 1H), 6.8 (s, 1H), 6.9 (m, 1H), 7.1 (m, 1H), 7.3 (m, 1H), 7.7 (s, 1H), 8.3
−1
+
s, 1H), 12.0 (br s, 1H). IR(KBr): 3541.38 cm (OH), Ms, m/z: 349 (M ),
32 (9.3%), 267 (30%), 238 (22%), 224 (100%), 125 (32%), 111 (15%), 82
40%).
(
Selected Data for 10
◦
1
Yield: 66%, m.p. 155 C. H NMR-(d6−DMSO): 2.2 (s, 3H), 2.8 (d, J =
2.8 Hz, 1H), 2.9 (d, J = 12.8 Hz, 1H) , 4.6 (d, J = 14.1 Hz, 1H), 4.7 (d,
1
J = 14.1 Hz, 1H), 5.8 (br s, 1H), 6.4 (s, 2H), 7.0 (m, 1H), 7.2 (m, 1H), 7.4
−
1
(
3
1
m, 1H), 7.7 (s, 1H), 8.3 (s, 1H). IR(KBr): 3550.84 cm (OH), Ms, m/z:
95(M ), 327 (27.6%), 282 (23%), 238 (39.5%), 224 (100%), 171 (71%),
57 (26%), 127 (17%), 82 (8%).
+
Selected Data for 11
◦
1
Yield: 64%, m.p. 179 C. H NMR-δ(d3-MeOD): 2.0 (s, 3H), 2.6 (d,
J = 11.5 Hz, 1H), 2.7 (d, J = 11.5 Hz, 1H), 4.6 (d, J = 14.2 Hz, 1H), 4.7
(
d, J = 14.2 Hz, 1H), 5.9 (s, 1H), 6.8 (m, 1H), 6.9 (m, 1H), 7.8 (m, 1H),
1
−
8
.2 (s, 1H), 8.5 (s, 1H), 11.0 (br s, 1H). IR (KBr): 3467.76 cm (OH),
Ms, m/z: 381 (M + 1), 312 (12%), 238 (38%), 224 (100%), 155 (11%), 142
78%), 86 (39%), 68 (15%), 42 (38%).
(

2
334
M. M. Heravi and R. Motamedi
Selected Data for 12
◦
1
Yield: 58%, m.p. 128 C. H NMR-δ(d3-MeOD): 2.1 (s, 3H), 2.5 (d,
J = 12 Hz, 1H), 2.6 (d, J = 12 Hz, 1H), 4.6 (d, J = 14 Hz, 1H), 4.7 (d,
J = 14 Hz , 1H), 5.9 (s, 1H), 6.82–6.89 (m, 2H),7.5 (m, 1H), 7.7 (s, 1H), 8.3
−1
+
(
s, 1H), 8.6 (br s, 1H). IR(KBr): 3400.12 cm (OH). Ms, m/z: 352 (M ),
282 (34%), 270 (60%), 238 (29%), 224 (100%), 128 (21%), 125 (34%), 113
(
22%), 82 (48%), 42 (38%).
Selected Data for 13
◦
1
Yield: 56%, m.p. 149 C. H NMR-δ(d3-MeOD) : 2.6 (d, J = 12.3 Hz,
H), 2.7 (d, J = 12.3 Hz, 1H), 4.6 (d, J = 14.2 Hz, 1H), 4.7 (d, J = 14.2
1
Hz, 1H), 6.1 (s, 1H), 6.82–6.89 (m, 2H), 7.4–7.5 (m, 4H), 7.7 (s, 1H)
7
3
2
.8–7.83 (m, 2H), 8.31 (s, 1H), 8.42 (s, 1H), 8.9 (br s, 1H). IR (KBr):
325.36 cm (OH), Ms, m/z: 414 (M ), 396 (9.4%), 345 (40%), 238 (29%),
24 (100%), 190 (24%), 176 (39%), 82 (57%).
−1
+
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