Reaction of diethyl 5-hydrazino-2-(4-methylphenyl)-1,3-oxazol-4- ylphosphonate with acyl isothiocyanates

Article abstract of DOI:10.1134/S1070363212110060

The reactions of diethyl 5-hydrazino-2-(4-methylphenyl)-1,3-oxazol-4- ylphosphonate with acetyl, benzoyl, and ethoxycarbonyl isothiocyanates result in the previously unknown (1,3,4-thiadiazol-2-yl)-substituted aminomethylphosphonic acids.

Full text of DOI:10.1134/S1070363212110060

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 11, pp. 1781–1786. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © K.M. Kondratyuk, E.I. Lukashuk, A.V. Golovchenko, V.S. Brovarets, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82,
No. 11, pp. 1789–1795.
Reaction of Diethyl 5-Hydrazino-2-(4-methylphenyl)-1,3-oxazol-
4-ylphosphonate with Acyl Isothiocyanates
K. M. Kondratyuk, E. I. Lukashuk, A. V. Golovchenko, and V. S. Brovarets
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02660 Ukraine
e-mail: brovarets@bpci.kiev.ua
Received September 26, 2011
Abstract—The reactions of diethyl 5-hydrazino-2-(4-methylphenyl)-1,3-oxazol-4-ylphosphonate with acetyl,
benzoyl, and ethoxycarbonyl isothiocyanates result in the previously unknown (1,3,4-thiadiazol-2-yl)-
substituted aminomethylphosphonic acids.
DOI: 10.1134/S1070363212110060
The 2-amino-5-aminomethyl-1,3,4-thiadiazole deri-
vatives obtained from the corresponding 1,4-di-
substituted thiosemicarbazides (XNHNHCSNHY)
exhibit anticonvulsant [1, 2], antimicrobial [3], anti-
neurodegenerative [4], anti-inflammatory [5, 6],
antiviral [7, 8] activity and are also the selective Kv1.5
receptor blockers [9] and the CCR1 receptor
antagonists [10]. The biological activity of the
compounds is known to depend significantly on the
nature of substituents in the molecule. Therefore, the
development of the synthesis methods for new
compounds containing diverse functional groups is of
considerable interest for the biological testing and
obtaining the promising drugs. The glycine derivatives
containing 5-amino-1,3,4-thiadiazol-2-yl substituents
[11–13] were well studied, but the corresponding
carboxylic acids I were not obtained individually
because of their decarboxylation. However, α-amino-
phosphonic acids as the α-amino acids analogs are of
particular interest because they differ by the chemical
behavior from their counterparts. They also have a
certain biological activity [14–18].
methylphosphonic acids II. As a model compound the
easily accessible diethyl 5-hydrazino-2-(4-methyl-
phenyl)-1,3-oxazol-4-yl-phosphonate III was chosen
(Schemes 1, 2) obtained by a method [19] modified by
us, starting from 4-methylbenzamide and chloral, in an
overall yield of 55%.
The reaction of compound III with acetyl iso-
thiocyanate in diethyl ether gives a mixture of two
substances: thiosemicarbazide IVa, an adduct of acetyl
isothiocyanate to the hydrazo group, and the acetyl
derivative A resulting from the substitution of the
isothiocyanate group with the hydrazine moiety
(Scheme 1). This is confirmed by the GC–MS studies
that indicate the presence of two m/z values of the
protonated cation-radicals [M + 1]+·: 427 (IVa) and
368 (A). The composition of the mixture depends
strongly on the reaction temperature. At –15°С the
adduct IVa is produced in an yield of 15% and at 20°C,
in 65% yield. The formation of a mixture of
1
compounds IVa and A was confirmed also by the Н
and 31Р NMR spectral data.
In contrast, the reaction of hydrazine III with
benzoyl or ethoxycarbonyl isothiocyanate in diethyl
ether at 20°C results in the 1,4-disubstituted
thiosemicarbazides IVb or IVc in yields of 89–90%
(Scheme 2).
N N
N N
RHN
RHN
NHR1
NHR1
S
S
P(O)(OH)2
II
CO2H
I
1
In the H NMR spectra of thiosemicarbazides IVb
This work continues the study of the phos-
phorylated derivatives of 1,3,4-thiadiazoles [12, 13] in
order to synthesize new substituted (1,3,4-thiadiazole)-
and IVc there is no broadened two-protons signal at δ
4.01 ppm corresponding to the primary amino group of
the starting hydrazinooxazole. It clearly points to the
1781

1782
KONDRATYUK et al.
Scheme 1.
P(O)(OEt)2
N
Me
N
+
+
NH
NH2
4-MeC6H4
O
S
O
N
III
P(O)(OEt)2
H
P(O)(OEt)2
H
H
N
N
N
N
Me
Me
N
N
H
4-MeC6H4
4-MeC6H4
O
O
S
O
O
H
IVa
A
reaction with the isothiocyanates. The broad one-
proton signal of the NHNHCS fragment of compounds
IVb and IVc is shifted downfield. Also two broad one-
proton signals of NHCSNH moiety appear in the weak
field. The IR spectra of compounds IVb and IVc
contain strong absorption bands at ν 1173 and 1197 cm–1
belonging to the multiple C=S bond. The GC–MS
spectra contain the peaks with m/z values cor-
responding to the protonated cation-radical [M + 1]+· of
the adducts formed.
which are insoluble in water, hexane, and readily
soluble in diethyl ether. They are readily soluble also
in all other organic solvents and in water in the
presence of bases. Compounds IVа–IVc are stable in
air only in the crystalline state at 20–25°C and in
solution or in suspension in the presence of bases
(triethylamine, sodium bicarbonate) under the air-free
conditions. However, even at 20–25°C in a solution
and in a suspension in diethyl ether in the absence of a
base they transform gradually into the new phos-
phorus-containing functional derivatives of 2-amino-
1,3,4-thiadiazole Va–Vc. This can be due to the
instability of the 1,3-oxazole ring in an acidic
Compounds IVb and IVc were isolated in the
analytically pure form. They are white, stable crystals,
Scheme 2.
P(O)(OEt)2
N
RC(O)NCS, MeCN,
20oC, 5 min,
NH
4-MeC6H4
O
RC(O)NCS, Et2O,
20oC, 5 min
80oC, 2 h
NH2
III
P(O)(OEt)2
H
H
N
H
N
O
P(O)(OEt)2
N
MeCN, 80oC, 2 h
S
R
N
R
N
H
4-MeC6H4
4-MeC6H4
N
H
O
S
O
N N
Va_Vc
O
IVa_IVc
H
N
O
P(O)(OH)2
MeCOOH, 100oC,
6 h
HBr/MeCOOH,
25oC, 6 h
S
R
4-MeC6H4
N
H
N N
VIa_VIc
O
R = Me (a), Ph (b), OEt (c).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 11 2012

REACTION OF DIETHYL 5-HYDRAZINO-2-(4-METHYLPHENYL)-1,3-OXAZOL-...
1783
Table 1. Yields, melting points, and elemental analysis data of the obtained compounds
Found, %
P
Calculated, %
P
Comp.
no.
Yield, %
mp, °С а
Formula
N
S
N
S
–
93
64 b
119–120
–
12.85
–
9.40
–
–
C14H20N3O4P
C17H23N4O5PS
C22H25N4O5PS
C18H25N4O6PS
C17H23N4O5PS
C22H25N4O5PS
C18H25N4O6PS
C13H15N4O5PS
C18H17N4O5PS
C14H17N4O6PS
12.92
13.14
11.47
12.27
13.14
11.47
12.27
15.13
12.96
13.99
9.52
III
–
7.26
7.52
6.56
7.03
7.52
6.56
7.03
8.66
7.42
8.01
IVа
IVb
IVc
Vа
90
129–130
124–125
183–184
199–200
174–175
234–235
>250 decomp.
>210 decomp.
11.36
12.03
12.98
11.35
12.11
14.99
12.88
13.90
6.17
6.70
7.19
6.19
6.68
8.25
7.01
7.67
6.66
7.17
7.62
6.63
7.16
8.75
7.51
8.12
6.34
89
6.79
99 c, d
99 d
99 d
92 d
99 d
99 d
7.26
6.34
Vb
6.79
Vc
8.36
VIа
VIb
VIc
7.16
7.74
a
b
After washing with water (III, VIа–VIc), diethyl ether (IVb, IVc), and acetonitrile (Vа–Vc). Content in a mixture in the isolated
crystalline product according to the GC–MS data. c With respect to IVа content in the mixture. d Yield by the а method.
environment created by the acidic proton in the
thiosemicarbazide molecule [11–13]. The complete
conversion IVа–IVc → Va–Vc can be performed by
boiling the reaction mixture in acetonitrile for 2 h. The
spectral data indicate the occurrence of the
recyclization and not only the opening of the 1,3-
oxazole ring without the formation of the 1,3,4-
obtained by the different methods were the same
(Tables 1, 2).
Taking into account the polyfunctionality of the
obtained compounds IV and V, we studied their
behavior in the presence of the acids. The reaction of
the thiadiazole derivatives Va–Vc with the saturated
solution of hydrogen bromide in glacial acetic acid at
20°C for 6 h leads to the regioselective hydrolysis to
form the previously unknown phosphonic acids VIa–
VIc. When compounds Va–Vc were boiled for 1 min
in a mixture of glacial acetic acid and concentrated
hydrochloric acid (10:1), the acids VIa–VIc also form,
but in lower yields. Compounds VIb and VIc were
also obtained by the heating thiosemicarbazides IVb
and IVc for 6 h in glacial acetic acid. In addition,
compound VIb was obtained by keeping the solution
of thiosemicarbazide IVb in concentrated sulfuric acid
for 6 h at 20°C. The transformation IV → VI includes
not only the oxazole ring recyclization, but also the
diethoxyphosphoryl group hydrolysis.
31
thiadiazole ring. Thus, the signals of the P nuclei in
the spectra of Va–Vc are shifted from δP 10.6 ppm to
1
17.0–17.6 ppm. In the H NMR spectra there are the
characteristic signals of CHP group at δ 6.14–6.22
ppm as a doublet of doublets. The IR spectra contain
no absorption bands of the multiple C=S bond, as well
as the bands at ν 1583–1619 cm–1 belonging to the
oxazole ring [20]. The GC–MS spectra of compounds
IVа–IVc and Va–Vc contain the same m/z value, but
different Rf values.
The presence of compound A in the mixture did not
affect the quantitative recyclization of thiosemi-
carbazide IVa. In this case, the acetyl derivative Va
was isolated in an analytically pure form due to the
significant difference in the solubility.
We attempted to carry out the one-pot synthesis of
thiadiazoles Va–Vc starting from hydrazinooxazole III
and the corresponding acyl isothiocyanates without
isolating the intermediate thiosemicarbazides IVа–
IVc. The reactants were mixed in acetonitrile at 20°C,
kept at this temperature for 5 min, and then the
reaction mixture was boiled for 2 h. The melting points
and spectral characteristics of compounds Va–Vc
The structure of the phosphonic acids VIa–VIc was
1
proved by the spectral data. Thus, in the H NMR
spectra the signals of two ethoxyphosphoryl groups are
absent. The GC–MS spectra contain peaks with m/z
values corresponding to the cation-radical [M + 1]+· of
the corresponding protonated acids. The 31P NMR
spectra contain signals at 12.7–12.8 ppm.
Thus, we studied the reaction of diethyl 5-
hydrazino-2-(4-methylphenyl)-1,3-oxazol-4-ylphos-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 11 2012

1784
KONDRATYUK et al.
Table 2. Spectra data of the obtained compounds а
m/z,
[M + 1]+·
(Rf)
Comp. IR spectrum (KBr),
δН, ppm
δС, ppm
δР, ppm
no.
ν, cm–1
3
3344 (N–H), 1667, 1.33 t (6H, 2CH3CH2O, JНH 7.0 Hz), 2.36 s 14.6 (ОСН2СН3), 19.8 (СН3),
12.4
326
III
1
1600 (oxaz.), 1218 (3H, CH3), 4.01 br.s (2Н, NH2), 4.05–4.19 m 61.1 (OCH2CH3), 98 d (CP, JCP
(Р=О), 1026 (Р– (4Н, 2CH3CH2O), 7.06 br.s (1Н, NH), 7.20 and 254.0 Hz), 123.2 124.8, 128.4
ОС), 968 (РО–СС) 7.82 two d (4Н, С6Н4, 3JНН 8.0 Hz)
139.2, 153.1 (oxaz. ОСN), 163.8
(oxaz. ОССР)
IVаb
–
–
–
10.6
10.6
427 (0.54)
489 (0.64)
3
3245 (N–H), 1675 1.37 t (6Н, 2CH3CH2O, JНH 7.0 Hz), 2.38 s 14.6 (ОСН2СН3), 19.9 (CH3),
(C=O), 1612, 1583 (3H, CH3), 4.13–4.30 m (4Н, 2CH3· CH2O), 6 1 . 5 ( O C H 2 C H 3 ) , 6 2 . 0
IVb
3
1
(oxaz.), 1215 (Р=О), 7.22 d (2Н, С6Н4, JНH 7.8 Hz), 7.55 t (2Н, (OCH2CH3), 103.0 d (CP, JCP
3
3
1173 (С=S), 1025 С6Н5, JНH 7.6 Hz), 7.67 t (1Н, С6Н5, JНH 7.6 249.0 Hz), 122.9, 125.2, 126.8,
3
(Р–ОС), 973 (РО– Hz), 7.84 d (2Н, С6Н4, JНH 7.8 Hz), 7.91 d 128.3, 130.3, 133.0, 139.7, 154.7
3
СС)
(2Н, С6Н5, JНH 7.6 Hz), 8.57 br.s (1Н, NH), (oxaz. ОСN), 159.8, (oxaz.
9.22 br.s (1Н, NH), 12.21 br.s (1Н, NH)
ОССР), 165.8 (C=O), 180.3 (C=S)
3262 (N–H), 1712 1.33–1.39 m (9Н, 3CH3CH2O), 2.38 s (3H, 1 2 . 5 ( О С Н 2 С Н 3 ) , 1 4 . 6
(C=O), 1619 (oxaz.), CH3), 4.13–4.34 m (6Н, 3CH3CH2O), 7.22 d (ОСН2СН3), 19.9 (CH3), 61.5
1231 (Р=О), 1197 (2Н, С6Н4, 3JНH 7.8 Hz), 7.83 d (2Н, С6Н4, 3JНH (OCH2CH3), 62.0 (OCH2CH3),
10.6
457 (0.60)
IVc
1
(С=S) 1045 (Р–ОС), 7.8 Hz), 8.34 br.s (1Н, NH), 8.39 br.s (1Н, 101.0 d (CP, JCP 250.0 Hz),
967 (РО–СС)
NH), 11.20 br.s (1Н, NH)
122.9, 125.2, 128.4, 139.7, 151.6,
154.6 (oxaz. ОСN), 160.2 (oxaz.
ОССР), 179.9 (C=S)
3255 (N–H), 1704 1.15–1.24 m (6Н, 2CH3CH2O), 2.18 s (3H, 15.0 (ОСН2СН3), 19.9 (СН3),
17.0
17.9
427 (0.44)
489 (0.54)
Va
Vb
1
(C=O),
1640 CH3), 2.36 s (3H, CH3), 4.00–4.19 m (4Н, 21.3 (СН3), 46.0 d (CP, JCP
3 2
(C=O), 1237 (Р=О), 2CH3CH2O), 6.17 d.d (1Н, СНР, JНH 9.0, JНР 159.0 Hz), 62.2 (OCH2CH3),
3
1018 (Р–ОС), 975 21.0 Hz), 7.30 and 7.85 two d (4Н, С6Н4, JНН 127.4, 128.3, 130.0, 141.5, 158.5,
(РО–СС)
8.0 Hz), 12.56 br.s (1Н, NHСН)
159.7, 166.1, 168.5
3
3226 (N–H), 1671c 1.22 t (6Н, 2CH3CH2O, JНH 6.6 Hz), 2.36 s 15.0 (ОСН2СН3), 19.9 (СН3),
1
(2C=O),
(Р=О),
( Р – ОС) ,
(РО–СС)
1236 (3H, CH3), 4.12 m (4Н, 2CH3CH2O), 6.22 d.d 46.0 d (CP, JCP 159.0 Hz), 62.3
3
2
10 28 (1Н, СНР, JНH 9.0, JНР 21.7 Hz), 7.30 d (2Н, (OCH2CH3), 127.4, 127.9, 128.2,
9 8 2 С6Н4, 3JНH 7.8 Hz), 7.56 t (2Н, С6Н5, 3JНH 7.6 Hz), 128.4, 130.0, 131.0, 132.6, 141.5,
3
7.66 t (1Н, С6Н5, JНH 7.6 Hz), 7.86 d (2Н, 159.0, 160.6, 165.0, 166.2
С6Н4, 3JНH 7.8 Hz), 8.12 d (2Н, С6Н5, 3JНH 7.6 Hz),
9.56 d (1Н, NHСН, 3JНH 9 Hz), 13.09 br.s (1Н, NH)
3
3239 (N–H), 1726 1.20 t (6H, 2CH3CH2O, JНH 7.0 Hz), 1.25 t 1 3 . 1 ( О С Н 2 С Н 3 ) , 1 5 . 1
(C=O), 1665 (C=O), (3H, CH3CH2O), 2.36 s (3H, CH3), 4.10 m (4Н, (ОСН2СН3), 19.9 (СН3), 46.0 d
17.0
457 (0.51)
Vc
1
1239 (Р=О), 1053 2CH3CH2O), 4.23 к (2Н, CH3CH2O), 6.14 d.d (CHP, JCP 160.0 Hz), 61.4
3
2
(Р–ОС), 981 (РО– (1Н, СНР, JНH 9.0, JНР 22.0 Hz), 7.29 and (OCH2CH3), 62.2 (OCH2CH3),
СС)
7.83 two d (4Н, С6Н4, 3JНН 8.0 Hz), 9.48 d (1Н, 127.4, 128.3, 129.9, 141.5, 153.6,
NHСН, 3JНH 9.0 Hz), 12.19 br.s (1Н, NH)
158.5, 162.0, 166.1
3500–2500 (N–H, 2.17 s (3Н, CH3), 2.35 s (3H, CH3), 5.88 d.d 19.9 (СН3), 21.2 (СН3), 47.6 d
12.8
12.8
371
433
VIа
3
2
O–Ha s ),
1697 (1Н, СНР, JНH 8.8, JНР 21.0 Hz), 7.28 d (2Н, (CP, 1JCP 150.0 Hz), 127.3, 128.3,
(C=O), 1646 (C=O), С6Н4, 3JНН 7.6 Hz), 7.83 d (2Н, С6Н4, 3JНН 7.6 Hz), 130.3, 141.3, 159.2, 160.2, 165.9,
3
1208 (Р=О)
8.89 d (1Н, NHСН, JНH 8.8 Hz), 12.47 br.s 168.4
(1Н, NH)d
3
1
3500–2500 (N–H, 2.36 s (3H, CH3), 5.94 d.d (1Н, СНР, JНH 9.0, 19.9 (СН3), 47.7 d (CHP, JCP
VIb
3
O–Has),
(2C=O),
(Р=О)
1680c 2JНР 21.0 Hz), 7.29 d (2Н, С6Н4, JНН 7.8 Hz), 150.0 Hz), 127.9, 128.2, 130.4,
3
1275 7.56 t (2Н, С6Н5, JНН 7.6 Hz), 7.66 t (1Н, 131.1, 132.5, 141.2, 160.3, 160.8,
3
3
С6Н5, JНН 7.6 Hz), 7.85 d (2Н, С6Н4, JНН 7.8 165.0, 166.0
Hz), 8.11 d (2Н, С6Н5, 3JНН 7.6 Hz), 8.94 d (1Н,
NHСН, 3JНH 9 Hz)d,e
3
3500–2500 (N–H, 1.25 t (3H, CH3CH2O, JНH 7.0 Hz), 2.36 s 13.1 (ОСН2СН3), 19.9 (СН3),
12.7
401
VIc
1
O–Ha s ),
1728 (3H, CH3), 4.21 к (2Н, CH3CH2O), 5.85 d.d 47.7 d (CHP, JCP 150.0 Hz), 61.3
(C=O), 1651 (C=O), (1Н, СНР 3JНH 9.0, 2JНР 21.0 Hz), 7.28 and 7.83 (OCH2CH3), 127.3, 128.3, 130.3,
3
1242 (Р=О)
two d (4Н, С6Н4, JНН 8.0 Hz), 8.90 d (1Н, 141.2, 153.6, 160.3, 161.6, 165.9
NHСН, 3JНH 9.0 Hz)d
a
CDCl3 (III, IVа–IVc), DMSO-d6 (Vа–Vc, VIа–VIc). b The signals were extracted from the spectra of a mixture. c Shoulder. d The signal
of ОН was not detected. e The signal of NН was not detected.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 11 2012

REACTION OF DIETHYL 5-HYDRAZINO-2-(4-METHYLPHENYL)-1,3-OXAZOL-...
1785
phonate III with acetyl, benzoyl and ethoxycarbonyl
isothiocyanates. It was found that the qualitative and
quantitative composition of the products was affected
by the nature of acyl isothiocyanate and the solvent as
well as the temperature and the reaction time. The
conditions of the stability of thiosemicarbazides IV
were studied. Also we examined the acid-catalyzed
regioselective hydrolysis of diethoxyphosphoryl group
of the thiadiazole derivatives V, which results in the
new aminomethylphosphonic acids VI. The convenient
preparative methods for the synthesis of the above
compounds were developed. The possibility of the
different approaches to their preparation was shown.
for further transformations without the additional
purification.
Diethyl 5-[1-(4-acyl)thiosemicarbazido]-2-(4-
methylphenyl)-1,3-oxazol-4-ylphosphonates (IVа–
IVc). To a suspension of 2 g (6.15 mmol) of hyd-
razinooxazole III in 50 ml of diethyl ether at 20°C was
added in one portion 6.77 mmol of the appropriate acyl
isothiocyanate. The reaction mixture was stirred for
5 min. The resulting precipitate was filtered off,
washed on a filter with diethyl ether (2 × 10 ml) and
dried in air. Compound IVa cannot be isolated in an
analytically pure form. It contains 35% of diethyl 5-(2-
acetylhydrazino)-2-(4-methylphenyl)-1,3-oxazol-4-yl-
phosphonate A, which, however, does not prevent its
further use.
EXPERIMENTAL
The IR spectra were recorded on a Vertex 70
spectrometer from KBr pellets. The NMR spectra were
obtained on a Bruker Avance DRX-500 instrument [1H
(500 MHz), 31P (202 MHz), and 13C (125 MHz)] using
DMSO-d6 or CDCl3 as the solvents relative to internal
TMS or external 85% phosphoric acid. The melting
points were determined on a Fisher Johns instrument.
The GC–MS spectra were recorded on an Agilent 1100
Series high-performance liquid chromatograph
equipped with a diode array with an Agilent LC\MSD
SL mass selective detector with the quick changeover
ionization positive/negative mode. The GC–MS
(APCI) parameters are as follows: Zorbax SB-C18
column (1.8 mm, 4.6 × 15 mm, PN 821975-932);
acetonitrile–water (95:5) + 0.1% of trifluoroacetic acid
(solvent A), 0.1% aqueous trifluoroacetic acid (solvent
B); the eluent flow is 3 ml min–1; the injection volume
is 1 μm; the UV detectors are for 215, 254, 285 nm;
the scanning range is m/z 80–1000 . The reaction
progress was monitored by the TLC.
Diethyl
(5-acylamino-1,3,4-thiadiazol-2-yl)[(4-
methylbenzoyl)amino]methylphosphonates (Va–Vc).
a. A solution of 3 mmol of the appropriate thio-
semicarbazide IVa–IVc in 10 ml of acetonitrile was
refluxed for 2 h. Then the reaction mixture was cooled
to room temperature. The resulting precipitate was
filtered off, washed with a small amount of aceto-
nitrile. After drying, the analytically pure products
were obtained.
b. To a solution of 2 g (6.15 mmol) of hyd-
razinooxazole III in 20 ml of acetonitrile at 20°C was
added in one portion 6.77 mmol of the appropriate acyl
isothiocyanate. The reaction mixture was stirred for
5 min at 20°C, then boiled for 2 h and cooled to room
temperature. Then the precipitate was filtered off and
recrystallized from acetonitrile. The yields of the
obtained compounds are 64 (Va), 93 (Vb), and 88%
(Vb).
The IR, NMR, and GC–MS spectra of compounds
Va–Vc obtained by two methods are identical. The
mixed samples showed no melting point depression.
Diethyl 5-hydrazino-2-(4-methylphenyl)-1,3-oxa-
zol-4-ylphosphonate (III). To 25 ml (500 mmol) of
hydrazine hydrate was slowly added a solution of 20 g
(49.7 mmol) of diethyl 1-(4-methylphenyl-
carbonylamino)-2,2,2-trichloroethenylphosphonate [20]
in 100 ml of dioxane in an argon atmosphere with
vigorous stirring and cooling with ice water to 10°C.
The reaction mixture was stirred at 20–25°C for 1 h
and allowed to stand for 12 h. The solvent was
evaporated to dryness under reduced pressure at a
temperature not exceeding 50°C. The residue was
triturated with 200 ml of water. The crystalline
precipitate was filtered off, washed on a filter with
water until neutral reaction of the washings and dried
in air. The product, white crystalline powder, was used
(5-Acylamino-1,3,4-thiadiazol-2-yl)-[(4-methyl-
benzoyl)amino]methylphosphonic acids (VIa–VIc).
a. To 3 mmol of the appropriate thiadiazole Va–Vc at
20–25°C was added 10 ml of glacial acetic acid
saturated with the hydrogen bromide. The resulting
mixture was maintained at 20–25°C for 6 h and then
evaporated to dryness under the reduced pressure at
35°C. The residue was triturated in a minimal amount
of water, filtered off, and dried to give the analytically
pure products.
b. To a solution of 3 mmol of the corresponding
thiadiazole Va–Vc in 10 ml of glacial acetic acid was
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1786
KONDRATYUK et al.
7. Akhtar, T., Hameed, S., Al-Masoudi, N.A., and
Khan, K.M., Heteroatom Chem., 2007, vol. 18, no. 3,
p. 316.
8. Abdel-Aal, M.T., El-Sayed, W.A., Aleem, A.H.A., and
Ashry, E.S.H.E., Pharmazie, 2003, vol. 58, no. 11,
p. 788.
9. Lloyd, J., Finlay, H.J., Vacarro, W., Hyunh, T., Kover, A.,
Bhandaru, R., Yan, L., Atwal, K., Conder, M.L.,
Jenkins-West, T., Shi, H., Huang, C., Li, D., Sun, H.,
and Levesque, P., Bioorg. Med. Chem. Lett., 2010,
vol. 20, no. 4, p. 1436.
10. Cook, B.N., Disalvo, D., Fandrick, D.R., Harcken, C.,
Kuzmich, D., Lee, T.W., Liu, P., Lord, J., Mao, C., Neu, J.,
Raudenbush, B.C., Razavi, H., Reeves, J.T., Song, J.J.,
Swinamer, A.D., and Tan, Z., USA Patent 93724, 2010.
11. Shablykin, O.V., Golovchenko, A.V., Brovarets, V.S.,
and Drach, B.S., Zh. Obshch. Khim., 2007, vol. 77,
no. 5, p. 837.
added 1 ml of the concentrated hydrochloric acid. The
mixture was stirred for 1 min at 100°C and then
evaporated to dryness under the reduced pressure. The
residue was triturated with a minimal amount of water,
filtered off, washed on a filter with water and
crystallized. The yields of the obtained compounds are
64 (VIa, crystallized from water), 93 (VIb, from
MeCOOH), and 88% (VIc, from water).
c. A solution of 3 mmol of the appropriate
thiosemicarbazide IVb or IVc in 10 ml of glacial
acetic acid was kept at 100°C for 6 h. Then the
reaction mixture was evaporated under the reduced
pressure to dryness. The residue was triturated with a
minimal amount of water, filtered off, and recrys-
tallized. The yields of the obtained compounds are 92
(VIb, from MeCOOH) and 82% (VIc, from water).
12. Golovchenko, A.V., Pilyo, S.G., Brovarets, V.S.,
Chernega, A.N., and Drach, B.S., Synthesis, 2003,
no. 18, p. 2851.
13. Golovchenko, A.V., Pilyo, S.G., Brovarets, V.S., and
Drach, B.S., Zh. Obshch. Khim., 2003, vol. 73, no. 11,
p. 1933.
14. Aminophosphonic and Aminophosphinic Acids,
Kukhar, V.P. and Hudson, H.R., Eds., Chichester:
Wiley & Sons, 2000.
15. Sienczyk, M., Winiarski, L., Kasperkiewicz, P., Psurski, M.,
Oleksyszyn, J., and Wietrzyk, J., Bioorg. Med. Chem.
Lett., 2011, vol. 21, no. 5, p. 1310.
d. A solution of 1 mmol of thiosemicarbazide IVb
in 5 ml of the concentrated sulfuric acid was heated at
20°C for 6 h. Then the mixture was poured into 20 g of
the crushed ice. The precipitate was filtered off,
washed on a filter with water until the neutral reaction.
After drying, the analytically pure product was
obtained in 92% yield. The IR, NMR, and GC–MS
spectra of compounds VIa–VIc obtained by four
methods were identical.
REFERENCES
16. Balakrishna, A., Narayana Reddy, M.V., Rao, P.V.,
Kumar, M.A., Kumar, B.S., Reddy, C.S., and Nayak, S.K.,
Eur. J. Med. Chem., 2011, vol. 46, no. 5, p. 1798.
17. Dake, S.A., Raut, D.S., Kharat, K.R., Mhaske, R.S.,
Deshmukh, S.U., and Pawar, R.P., Bioorg. Med. Chem.
Lett., 2011, vol. 21, no. 8, p. 2527.
18. Wu, L., Song, B., Bhadury, P.S., Yang, S., Hu, D., and
Jin, L., J. Het. Chem., 2011, vol. 48, no. 2, p. 389.
19. Golovchenko, A.V., Solomyannyi, R.N., and Bro-
varets, V.S., Zh. Obshch. Khim., 2010, vol. 80, no. 4,
p. 563.
1. Srivastava, A.V.K. and Kumar, A., Eur. J. Med. Chem.,
2002, vol. 37, no. 11, p. 873.
2. Srivastava, A.V.K. and Kumar, A., Bioorg. Med. Chem.,
2004, vol. 12, no. 5, p. 1257.
3. Pintilie, O., Profire, L., Sunel, V., Popa, M., and Pui, A.,
Molecules, 2007, vol. 12, no. 1, p. 103.
4. USA Patent 43372, 2005.
5. Sharma, S., Srivastava, V.K., and Kumar, A., Eur. J.
Med. Chem., 2002, vol. 37, no. 8, p. 689.
6. Sharma, S., Srivastava, V.K., and Kumar, A.,
20. Drach, B.S., Sviridov, E.P., and Shaturskii, Ya.P., Zh.
Obshch. Khim., 1974, vol. 44, no. 8, p. 1712.
Arzneimittel Forsch., 2003, vol. 53, no. 1, p. 44.
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