Regioselective synthesis of substituted isoxazolo[5,4-d]pyrimidines

Article abstract of DOI:10.1016/j.mencom.2008.05.011

A convenient regioselective synthesis of new N- and O-substituted isoxazolo[5,4-d]pyrimidine derivatives is described.

Full text of DOI:10.1016/j.mencom.2008.05.011

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 144–146
Regioselective synthesis of substituted
isoxazolo[5,4-d]pyrimidines
Sergey B. Alyabiev,* Dmitri V. Kravchenko and Alexandre V. Ivachtchenko
Department of Organic Chemistry, Chemical Diversity Research Institute, 114401 Khimki, Moscow Region,
Russian Federation. Fax: +7 495 626 9780; e-mail: alyabjev@iihr.ru
DOI: 10.1016/j.mencom.2008.05.011
A convenient regioselective synthesis of new N- and O-substituted isoxazolo[5,4-d]pyrimidine derivatives is described.
Pyrimidine and fused heterocyclic pyrimidine derivatives have
a broad spectrum of biological activity.1–12 Isoxazolo[5,4-d]-
pyrimidines and their bioisosteric analogues are promising
antiviral, antitumor and antimicrobial agents.13 Isoxazolo[5,4-d]-
pyrimidin-4-one derivatives were found to exhibit activity against
human type V phosphodiesterase PDE V with IC50 = 100 nM.14
Isoxazolo[4,5-d]pyrimidines were described as pesticides15,16 and
CRF antagonists.17 Thus, isoxazolo[5,4-d]pyrimidine derivatives
represent an important class of compounds with promising
chemical and biological potentials.
Although the syntheses of these compounds are well known,18,19
the regioselective alkylation of isoxazolo[5,4-d]pyrimidines is not
well described. Only few synthetic approaches were developed
to prepare 5N-substituted isoxazolo[5,4-d]pyrimidines.20,21 For
example, the cyclization of N,3-substituted 5-aminoisoxazole-
4-carboxamides with (diethoxymethoxy)ethane in the presence
of acetic anhydride led to 5N-substituted isoxazolo[5,4-d]-
pyrimidines.21
In contrast to the results described by Adhikari et al.,23 we
found that the reaction of isoxazolo[5,4-d]pyrimidines 3a–k
with α-chloroester 4a or 4b in the presence of K2CO3 directly
led to corresponding N-alkylated products 5a–j (Scheme 2).‡
The reaction smoothly proceeded in DMF at 70 °C to give the
desired products in 76–98% yields. Previously,23 it was postulated
that an O-alkylated product was formed using isoxazolo[5,4-d]-
pyrimidine 3e and ester 4b as initial reactants under similar
reaction conditions. However, it seems unlikely that the regio-
selective outcome of this reaction was interpreted correctly.
Isoxazolo[5,4-d]pyrimidines 3a,b,e,f were converted into
corresponding 4-chloroisoxazolo[5,4-d]pyrimidines 6a,b,e,f
by treatment with phosphorus oxychloride in N,N-dimethyl-
N-phenylamine (yield 85–96%) (Scheme 3).§
†
Melting points were measured with a Buchi B-520 apparatus and were
not corrected. The NMR spectra were recorded on a Bruker AMX-400
or Varian spectrometer in [2H6]DMSO using TMS as an internal standard.
Commercial reagents (Acros Organics, Aldrich and ChemDiv) were used
without purification.
Here, we report the synthesis of new 5N-substituted isoxazolo-
[5,4-d]pirimidines and 4O-substituted isoxazolo[5,4-d]pirimidines.
General procedure for the preparation of 3,6-disubstituted isoxazolo-
[5,4-d]pyrimidin-4(5H)-ones 3a–k. 5-Aminoisoxazole-4-carboxamide
1a–h (0.2 mol) was suspended in ester 2a,b (1.6 mol); then acetic anhydride
(260 ml) was added to the solution. The reaction mixture was stirred at
120 °C for 3–5 h, and ethyl acetate was evaporated. The reaction was
followed by TLC (5% MeOH in CH2Cl2). On completion, the reaction
mixture was cooled to room temperature, the formed precipitate was
filtered off, washed with methanol and dried in air to yield corresponding
isoxazolo[5,4-d]pyrimidin-4(5H)-ones (yields 63–95%). Compounds 3a–k
were used at the next step without further purification.
3-Ethylisoxazolo[5,4-d]pyrimidin-4(5H)-one 3b: yield 66%, mp 183–
184 °C. 1H NMR (DMSO + CCl4, 400 MHz) d: 1.2 (t, 3H, Me, J 7.5 Hz),
2.8 (q, 2H, CH2, J 7.5 Hz), 8.3 (s, 1H, 6-H), 13.1 (br. s, 1H, NH). Found
(%): C, 51.06; H, 4.65; N, 25.12. Calc. for C7H7N3O2 (%): C, 50.91;
H, 4.27; N, 25.44.
First, we synthesised 3,6-disubstituted isoxazolo[5,4-d]pyrimidin-
4(5H)-ones 3a–k using a modified approach proposed by Taylor
et al.15 (Scheme 1).†
Initial 3-substituted 5-aminoisoxazole-4-carboxamides 1a–h,
obtained by a well-known synthetic method,22 were easily
converted into corresponding isoxazolo[5,4-d]pyrimidin-4(5H)-
ones 3a–k by reaction with esters 2a,b. The cyclization
proceeded smoothly in acetic anhydride at 120 °C to give the
desired products in 61–95% yields.
R1C(OEt)3
O
R
R
CONH2
NH2
2a,b
NH
R1
N
Ac2O
(63–95%)
N
3-Phenylisoxazolo[5,4-d]pyrimidin-4(5H)-one 3e: yield 78%, mp 278–
O
O
1
N
280 °C. H NMR (DMSO + CCl4, 400 MHz) d: 7.5–7.6 (m, 3H, HAr),
8.25 (d, 1H, HAr, J 7.2 Hz), 8.3 (d, 1H, HAr, J 7.2 Hz), 8.45 (s, 1H, 6-H),
13.2 (br. s, 1H, NH). Found (%): C, 62.03; H, 3.11; N, 19.92. Calc. for
C11H7N3O2 (%): C, 61.97; H, 3.31; N, 19.71.
6-Methyl-3-phenylisoxazolo[5,4-d]pyrimidin-4(5H)-one 3f: yield 80%;
mp 310–312 °C. 1H NMR (DMSO + CCl4, 400 MHz) d: 2.11 (s, 3H, Me),
7.44–7.49 (m, 3H, HAr), 8.15–8.19 (m, 2H, HAr), 13.09 (br. s, 1H, NH).
Found (%): C, 63.47; H, 4.03; N, 18.55. Calc. for C12H9N3O2 (%): C,
63.43; H, 3.99; N, 18.49.
3-(4-Methylphenyl)isoxazolo[5,4-d]pyrimidin-4(5H)-one 3h: 83%;
mp 245–247 °C. 1H NMR (DMSO + CCl4, 400 MHz) d: 2.21 (s, 3H,
ArMe), 7.3 (d, 2H, HAr, J 8.1 Hz), 8.15 (d, 2H, HAr, J 8.1 Hz), 8.41 (s,
1H, 6-H), 12.93 (br. s, 1H, NH). Found (%): C, 63.12; H, 3.90; N, 18.12.
Calc. for C12H9N3O2 (%): C, 63.43; H, 3.99; N, 18.49.
1a–h
3a–k
1a R = Me
1b R = Et
1c R = Ph
1d R = 4-FC6H4
1e R = 4-MeC6H4
1f R = 4-MeOC6H4
1g R = 3-FC6H4
1h R = 3-ClC6H4
3a R = Me, R1 = H
3b R = Et, R1 = H
3c R = R1 = Me
3d R = Et, R1 = Me
3e R = Ph, R1 = H
3f R = Ph, R1 = Me
3g R = 4-FC6H4, R1 = H
3h R = 4-MeC6H4, R1 = H
3i R = 4-MeOC6H4, R1 = H
3j R = 3-FC6H4, R1 = H
3k R = 2-FC6H4, R1 = H
2a R1 = H
2b R1 = Me
For characteristics of compounds 3a,c,d,g,i–k see Online Supplementary
Materials.
Scheme 1
– 144 –
© 2008 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2008, 18, 144–146
graphic study (Figure 1).†† Based on these results, we accurately
indicate the stereochemical outcome of this reaction. The stereo-
selective alkylation of isoxazolo[5,4-d]pyrimidine 3e by ethyl
O
N
OR2
O
N
O
R
R
ClCH2CO2R2
4a,b
NH
R1
§
N
N
General procedure for preparation of 4-chloroisoxazolo[5,4-d]pyri-
K2CO3, DMF or acetone
(69–96%)
N
R1
O
O
midines 6a,b,e,f. Phosphorus oxychloride (1 mol) and dimethylaniline
(0.2 mol) were added to a solution of isoxazolo[5,4-d]pyrimidin-4(5H)-
one 3a,b,e,f (0.2 mol) in dry toluene. The resulting suspension was
stirred at reflux for 3–4 h. The reaction was followed by TLC (5% MeOH
in CH2Cl2). The solution was cooled to room temperature, poured onto
crushed ice and neutralised with an aqueous solution of NaOH (10%).
The organic layer was separated; the aqueous layer was extracted with
benzene (3×200 ml). Combined extracts were washed with HCl (6%),
water, NaHCO3 and water again. The extracts were purified by flash
chromatography on a silica gel/aluminium oxide column (eluent, benzene).
The solvent was evaporated in vacuo and the resulting residue was poured
into cold hexane. The formed precipitate was filtered off, washed with
hexane and dried in vacuo over P2O5. Chlorides 6a,b,e,f were obtained
in 85–96% yield.
3a–k
5a–j
4a R2 = Me
4b R2 = Et
5a R = R2 = Me, R1 = H
5b R = Me, R1 = H, R2 = Et
5c R = R1 = R2 = Me
5d R = Ph, R1 = H, R2 = Me
5e R = Ph, R1 = H, R2 = Et
5f R = 4-MeC6H4, R1 = H, R2 = Me
5g R = 4-MeC6H4, R1 = H, R2 = Et
5h R = 4-MeOC6H4, R1 = H, R2 = Me
5i R = 2-FC6H4, R1 = H, R2 = Me
5j R = 2-FC6H4, R1 = H, R2 = Et
Scheme 2
4-Chloro-3-methylisoxazolo[5,4-d]pyrimidine 6a: yield 92%, mp 67–
68 °C. 1H NMR (DMSO + CCl4, 400 MHz) d: 2.71 (s, 3H, Me), 9.01 (s,
1H, 6-H). Found (%): C, 42.61; H, 2.35; Cl, 20.93; N, 24.82. Calc. for
C6H4ClN3O (%): C, 42.50; H, 2.38; Cl, 20.91; N, 24.78.
4-Chloro-3-phenylisoxazolo[5,4-d]pyrimidine 6e: yield 96%, mp 100–
102 °C. 1H NMR (DMSO + CCl4, 400 MHz) d: 7.59–7.67 (m, 3H, HAr),
7.80–7.86 (m, 2H, HAr), 9.10 (s, 1H, 6-H). Found (%): C, 57.11; H, 2.67;
Cl, 15.41; N, 18.22. Calc. for C11H6ClN3O (%): C, 57.04; H, 2.61; Cl,
15.31; N, 18.14.
The reactions of equimolar amounts of 4-chloroisoxazolo[5,4-d]-
pyrimidines 6a,b,e,f and ethyl hydroxyacetate in the presence
of K2CO3 (1.1 equiv.) afforded ethyl [(isoxazolo[5,4-d]pyrimidin-
4-yl)oxy]acetates 7a,b,d–f (Scheme 3).¶ The reaction proceeded
in DMF at 80 °C to give pure products, which were precipitated
from the reaction mixture in good yields (62–68%).
The structures of compounds 5e and 7d were assigned using
NMR spectroscopy and firmly established by an X-ray crystallo-
4-Chloro-6-methyl-3-phenylisoxazolo[5,4-d]pyrimidine 6f: yield 94%,
mp 112–114 °C. 1H NMR (DMSO + CCl4, 400 MHz) d: 2.80 (s, 3H,
Me), 7.56–7.66 (m, 3H, HAr), 7.77–7.82 (m, 2H, HAr). Found (%): C,
58.73; H, 3.33; Cl, 14.45; N, 17.08. Calc. for C12H8ClN3O (%): C, 58.67;
H, 3.28; Cl, 14.43; N, 17.10.
‡
General procedure for the preparation of (4-oxoisoxazolo[5,4-d]-
pyrimidin-5(4H)-yl)acetates 5a–j. α-Chloroester 4a,b (0.12 mol) and
anhydrous K2CO3 (0.13 mol) were added to a solution of isoxazolo[5,4-d]-
pyrimidin-4(5H)-one 3a,c,e,h,i,k in dry DMF (125 ml). The reaction
mixture was stirred at 70 °C for 3–4 h. The reaction was followed by
TLC (5% MeOH in CH2Cl2). The solution was cooled to room tempera-
ture and then poured into cold water (500 ml). The precipitate was
filtered off and washed with water and hexane. The desired esters 5a–j
were obtained in good yields (76–98%).
Ethyl (3-methyl-4-oxoisoxazolo[5,4-d]pyrimidin-5(4H)-yl)acetate 5b:
yield 83%, mp 143–145 °C. 1H NMR (DMSO + CCl4, 400 MHz) d: 1.27
(t, 3H, Me, J 7.0 Hz), 2.52 (s, 3H, Me), 4.26 (q, 2H, OCH2, J 7.0 Hz),
4.79 (s, 2H, NCH2), 8.58 (s, 1H, 6-H). Found (%): C, 50.69; H, 4.61;
N, 17.68. Calc. for C10H11N3O4 (%): C, 50.63; H, 4.67; N, 17.71.
Methyl (3,6-dimethyl-4-oxoisoxazolo[5,4-d]pyrimidin-5(4H)-yl)acetate
5c: yield 76%, mp 50–52 °C. 1H NMR (DMSO + CCl4, 400 MHz) d:
2.44 (s, 3H, Me), 2.54 (s, 3H, Me), 3.76 (s, 3H, OMe), 4.60 (s, 2H,
NCH2). Found (%): C, 50.67; H, 4.71; N, 17.75. Calc. for C10H11N3O4
(%): C, 50.63; H, 4.67; N, 17.71.
Methyl (4-oxo-3-phenylisoxazolo[5,4-d]pyrimidin-5(4H)-yl)acetate 5d:
yield 90%, mp 144–145 °C. 1H NMR (DMSO + CCl4, 400 MHz) d: 3.83
(s, 3H, OMe), 4.79 (s, 2H, NCH2), 7.65–7.69 (m, 3H, ArH), 8.12–8.16
(m, 2H, ArH), 8.68 (s, 1H, 6-H). 13C NMR (DMSO + CCl4, 400 MHz) d:
47.37 (NCH2), 53.15 (OMe), 100.51 (C-3a), 126.97(CAr-4), 128.67
(CAr-3,5), 128.79 (CAr-2,6), 131.03 (CAr-1), 152.41 (C-3), 156.51 (C-4),
159.95 (C-6), 167.06 (COOMe), 175.43 (C-7a). Found (%): C, 58.99;
H, 3.82; N, 14.68. Calc. for C14H11N3O4 (%): C, 58.95; H, 3.89; N, 14.73.
Ethyl (4-oxo-3-phenylisoxazolo[5,4-d]pyrimidin-5(4H)-yl)acetate 5e:
yield 77%, mp 159–161 °C. 1H NMR (DMSO + CCl4, 400 MHz) d: 1.25
(t, 3H, Me, J 7.0 Hz), 4.18 (q, 2H, OCH2, J 7.0 Hz), 4.87 (s, 2H, NCH2),
7.45–7.49 (m, 3H, HAr), 8.20–8.25 (m, 2H, HAr), 8.69 (s, 1H, 6-H).
13C NMR (DMSO + CCl4, 400 MHz) d: 12.44 (Me), 45.82 (NCH2), 60.03
(OCH2), 98.10 (C-3a), 125.47 (CAr-4), 126.97 (CAr-3,5), 127.11 (CAr-2,6),
129.29 (CAr-1), 152.99 (C-3), 154.81 (C-4), 157.77 (C-6), 165.59 (COOEt),
173.90 (C-7a). Found (%): C, 60.24; H, 4.32; N, 13.98. Calc. for
C15H13N3O4 (%): C, 60.20; H, 4.38; N, 14.04.
¶
General procedure for the preparation of (isoxazolo[5,4-d]-pyri-
midin-4-yl)oxyacetates 7a,b,d,e,f. Ethyl hydroxyacetate (0.11 mol) and
anhydrous K2CO3 (0.11 mol) were added to a solution of chloride
6a,b,e,f (0.1 mol) in dry DMF (115 ml). The reaction mixture was
stirred at 80 °C for 4–5 h, then cooled to rt and poured into cold water.
The precipitate was filtered off, washed with hexane and recrystallised
from ethanol or acetonitrile to give desired esters 7a,b,d,e,f in moderate
yields (62–68%).
Methyl [(3-methyl-4,5-dihydroisoxazolo[5,4-d]pyrimidin-4-yl)oxy]-
1
acetate 7a: mp 96–98 °C. H NMR (DMSO + CCl4, 400 MHz) d: 2.64
(s, 3H, Me), 3.74 (s, 3H, OMe), 5.21 (s, 2H, OCH2), 8.70 (s, 1H, 6-H).
Found (%): C, 48.04; H, 4.88; N, 18.69. Calc. for C9H11N3O4 (%): C,
48.00; H, 4.92; N, 18.66.
Methyl [(3-ethyl-4,5-dihydroisoxazolo[5,4-d]pyrimidin-4-yl)oxy]acetate
7b: mp 150–153 °C. 1H NMR (DMSO + CCl4, 400 MHz) d: 1.36 (t, 3H,
Me, J 7.4 Hz), 2.99 (q, 2H, CH2, J 7.4 Hz), 3.72 (s, 3H, OMe), 5.28 (s,
2H, OCH2), 8.79 (s, H, 6-H). Found (%): C, 50.68; H, 4.75; N, 18.82.
Calc. for C10H11N3O4 (%): C, 50.63; H, 4.67; N, 17.71.
Methyl [(3-phenyl-4,5-dihydroisoxazolo[5,4-d]pyrimidin-4-yl)oxy]acetate
7d: mp 122–123 °C. 1H NMR (DMSO + CCl4, 400 MHz) d: 3.73 (s, 3H,
OMe), 5.29 (s, 2H, OCH2), 7.62 (m, 3H, HAr), 8.09 (m, 2H, HAr), 8.87
(s, 1H, 6-H). 13C NMR (DMSO + CCl4, 400 MHz) d: 52.34 (OMe),
64.17 (OCH2), 104.19 (C-3a), 129.54 (CAr-4), 131.45 (CAr-2,6), 134.01
(CAr-3,5), 143.41 (CAr-1), 156.51(CAr-6), 162.28 (C-3), 166.23 (C-7a),
168.08 (C-4), 168.43 (COOMe). Found (%): C, 58.57; H, 4.51; N, 14.66.
Calc. for C14H13N3O4 (%): C, 58.53; H, 4.56; N, 14.63.
Ethyl [(3-phenyl-4,5-dihydroisoxazolo[5,4-d]pyrimidin-4-yl)oxy]acetate
1
7e: mp 96–98 °C. H NMR (DMSO + CCl4, 400 MHz) d: 1.22 (t, 3H,
Me, J 7.1 Hz), 4.19 (q, 2H, OCH2, J 7.1 Hz), 5.27 (s, 2H, OCH2),
7.59–7.63 (m, 3H, Ar), 8.07–8.11 (m, 2H, Ar), 8.88 (s, 1H, 6-H).
13C NMR (DMSO + CCl4, 400 MHz) d: 13.84 (Me), 61.05 (OCH2),
64.43 (OCH2), 105.51 (C-3a), 130.17 (CAr-4), 131.92 (CAr-2,6), 134.99
(CAr-3,5), 143.19 (CAr-1), 157.38 (C-6), 162.18 (C-3), 166.13 (C-7a),
167.98 (C-4), 168.88 (COOEt). Found (%): C, 59.83; H, 4.97; N, 14.01.
Calc. for C15H15N3O4 (%): C, 59.79; H, 5.02; N, 13.95.
Methyl [(6-methyl-3-phenyl-4,5-dihydroisoxazolo[5,4-d]pyrimidin-4-yl)-
oxy]acetate 7f: mp 131–133 °C. 1H NMR (DMSO + CCl4, 400 MHz) d:
2.65 (s, 3H, Me), 3.73 (s, 3H, OMe), 5.25 (s, 2H, OCH2), 7.61 (m, 3H, -
Methyl [3-(4-methylphenyl)-4-oxoisoxazolo[5,4-d]pyrimidin-5(4H)-yl]-
acetate 5f: yield 94%, mp 190–192 °C. 1H NMR (DMSO + CCl4, 400 MHz)
d: 2.39 (s, 3H, Me), 3.72 (s, 3H, OMe), 4.90 (s, 2H, NCH2), 7.37 (d,
2H, HAr, J 8.0 Hz), 8.13 (d, 2H, HAr, J 8.0 Hz), 8.78 (s, 1H, 6-H).
Found (%): C, 60.16; H, 4.31; N, 14.11. Calc. for C15H13N3O4 (%):
C, 60.20; H, 4.38; N, 14.04.
For characteristics of compounds 5a,g,h,j see Online Supplementary
Materials.
H
Ar), 8.09 (m, 2H, HAr). Found (%): C, 59.83; H, 4.98; N, 13.99. Calc.
for C15H15N3O4 (%): C, 59.79; H, 5.02; N, 13.95.
– 145 –

Mendeleev Commun., 2008, 18, 144–146
Table 1 1H NMR spectral data for compounds 5e and 7e.
O
Cl
R
R
Compound 5e
Compound 7e (lit.13
)
Compound 7e
POCl3
NH
R1
N
N
N
PhNMe2, toluene
(85–96%)
8.69 (s, 1H, HAr
)
8.35 (s, 1H, 6-H)
8.88 (s, 1H, 6-H)
R1
O
O
N
N
8.20–8.25 (m, 2H, HAr
7.45–7.49 (m, 3H, HAr
4.87 (s, 2H, NCH2)
4.20 (q, 2H, COOCH2) 4.00 (q, 2H, COOCH2) 4.19 (q, 2H, COOCH2)
1.25 (t, 3H, Me) 1.20 (t, 3H, Me) 1.22 (t, 3H, Me)
)
)
8.07–8.11 (m, 2H, HAr
7.59–7.63 (m, 3H, HAr
5.27 (s, 2H, OCH2)
)
)
7.0–7.3 (m, 5H, HAr
)
3a,b,e,f
6a,b,e,f
4.65 (s, 2H, NCH2)
CH2CO2R2
O
R
7a R = R2 = Me, R1 = H
7b R = Et, R1 = H, R2 = Me
7d R = Ph, R1 = H, R2 = Me
7e R = Ph, R1 = H, R2 = Et
7f R = Ph, R1 = R2 = Me
HOCH2CO2R2
(62–68%)
N
field region (d 8.22 ppm) as against to compound 7d. These
experimental data are consistent with the role of carbonyl oxygen
in a similar molecular environment.24 Based on these arguments,
we can confidently assert that the reaction of isoxazolo[5,4-d]-
pyrimidines 3a–k with α-chloroesters 4a and 4b directly leads
to corresponding N-alkylated products.
N
O
N
R1
7a,b,d–f
Scheme 3
chloroacetate 4b led to corresponding N-substituted isoxazolo-
[5,4-d]pyrimidine 5e as distinct from O-alkylated product.
The structures of compounds synthesised in this work were
determined using elemental analysis and H NMR spectroscopy.
In particular, the H NMR spectra of 5e and 7e were clean and
Online Supplementary Materials
Supplementary data associated with this article can be found
in the electronic version at doi:10.1016/j.mencom.2008.05.011.
1
1
showed characteristic signals from five protons of a phenyl ring
and corresponding substituents at the oxygen and nitrogen
atoms, respectively. These results were compared to the data
obtained by Adhikari (Table 1). As shown in Table 1, the
1H NMR spectra of compound 5e contain the characteristic signals
of five aromatic protons, which can be seen as multipletes in the
ranges d 7.45–7.49 and 8.20–8.25 ppm. On the contrary, in
the 1H NMR spectra of compound 7e suggested by Adhikari23, the
same signals are compactly grouped in the range d 7.0–7.3 ppm.
It is even more important that the chemical shifts of two aliphatic
protons of methylene group of the compound 5e (a singlet at
d 4.87 ppm) obtained in this work and the one postulated by
Adhikari were not significantly different from each other. In
contrast, the 1H NMR spectra of compound 7e, which was
unambiguously established as ethyl [(3-phenylisoxazolo[5,4-d]-
pyrimidin-4-yl)oxy]acetate by X-ray crystallography, contain
two aliphatic protons of the methylene group, which can be
seen as a singlet at d 5.27 ppm. This effect is strongly correlated
with the influence of the oxygen atom of OCH2 (the signal was
shifted downfield by 0.4 ppm). Moreover, the signal of two
phenyl o-protons of compound 5e can also be seen in the lower
References
1
P. Pecorari, M. Rinaldi, L. Costantino, A. Provvisionato, C. Cermelli
and M. Portolani, Farmaco, 1991, 46, 899.
2
3
M. S. Al-Thebeiti, Boll. Chim. Farm., 2001, 140, 221.
B. Tozkoparan, M. Ertan, P. Kelicen and R. Demirdamar, Farmaco,
1999, 54, 588.
4
5
M. S. A. El-Gaby, S. G. Abdel-Hamide, M. M. Ghorab and S. M. El-Sayed,
Acta Pharm., 1999, 49, 149.
C. G. Dave, D. R. Shah, G. K. Shah, P. S. Pandya, K. C. Dave and
V. J. Patel, Indian J. Pharm. Sci., 1986, 48, 75.
6
7
K. Stulik and V. Pacakova, J. Chromatogr., 1983, 1, 77.
P. Zimmermann, J. Senn-Bilfinger, B. Kohl, G. Hanauer, S. Postius,
W. Opferkuch and G. Grundler, WO Patent 9828299, 1998 (Chem.
Abstr., 1998, 129, 109095t).
8
9
M. Bos, T. Godel, C. Riemer and A. Sleight, EP Patent 815861, 1998
(Chem. Abstr., 1998, 128, 145382x).
C. G. Dave, P. R. Shah, V. B. Desai and S. Srinivasan, Indian J. Pharm.
Sci., 1982, 44, 83.
10 D. Bozsing, G. Kovanyi Lax, E. Berenyi Poldermann, K. Magyar,
S. Tuboly and A. Mandi, DE Patent 3743935, 1988 (Chem. Abstr.,
1989, 110, 75547g).
11 S. Shigeta, S. Mori, F. Watanabe, K. Takahashi, T. Nagata, N. Koike,
T. Wakayama and M. Sane-yoshi, Antiviral Chem. Chemother., 2002,
13, 67.
12 A. E. Rashad and M. A. Ali, Nucleotides, 2006, 25, 17.
13 V. A. Adhikari and V. V. Badiger, Arch. Pharm. (Weinheim Ger.), 1987,
320, 1124.
14 B. Dumaitre and N. Dodic, J. Med. Chem., 1996, 39, 1635.
15 E. C. Taylor and E. E. Garcia, J. Org. Chem., 1964, 29, 2116.
16 G. D. Snowling, J. M. Cox, R. A. Burrell and M. C. Shephard, US Patent
4189483, 1980.
(b)
(a)
C(9)
O(3)
C(8)
C(8)
O(3)
O(4)
C(7)
C(6)
O(4)
C(11)
C(12)
C(13)
C(7)
C(6)
N(1)
O(2)
C(1)
C(12)
C(13)
C(10)
O(2)
C(11)
C(10)
C(5)
C(14)
C(5)
C(9)
C(3)
C(4)
C(2)
N(3)
C(4)
17 W. E. Frietze, P. A. Kennett Square, US Patent 6589958, 2002 (Chem.
Abstr., 2003, 132, 180596z).
18 A. Miyashita, K. Fujimoto, T. Okada and T. Higashino, Heterocycles,
C(14)
C(15)
C(2)
N(2)
C(3)
O(1)
N(1)
O(1)
N(3)
C(1)
N(2)
1996, 42, 691.
19 A. Miyashita, I. Nagasaki, A. Kawano, Y. Suzuki, K. Iwamoto and
T. Higashino, Heterocycles, 1997, 45, 745.
Figure 1 Crystal structure of compounds (a) 5e and (b) 7d.
20 Z. Machon and S. Ryng, Acta Poloniae Pharmaceutica, 1984, 41, 37.
21 K. Tanaka and E. B. Pedersen, Acta Chem. Scand., 1986, 40, 760.
22 V. A. Adhikari and V. V. Badiger, Indian J. Chem., Sect. B, 1991, 30, 946.
23 V. A. Adhikari and V. V. Badiger, Indian J. Chem., Sect. B, 1988, 27, 542.
24 R. K. Harris, Nuclear Magnetic Resonance Spectroscopy, Pitman, London,
1983, p. 180.
†† X-ray diffraction data.
For 5e: at 120(2) K crystals of C15H13N3O4 (M = 299.28) are monoclinic,
space group P21/n, a = 14.602(6), b = 4.9659(19) and c = 19.499(8) Å,
b = 106.299(10)°, V = 1357.0(9) Å3, Z = 4; m = 0.109 mm–1; number of
independent reflections, 2618 [Rint = 0.0866]. Final R indices [I > 2s(I)]
R1 = 0.0523, wR2 = 0.1011; R indices (all data) R1 = 0.1452, wR2 = 0.1279.
For 7d: at 100(2) K crystals of C14H11N3O4 (M = 285.26) are ortho-
rhombic, space group Pbca, a = 17.298(6), b = 7.271(3) and c = 20.007(9) Å,
V = 2516.3(17) Å3, Z = 8, m = 0.113 mm–1; number of independent reflec-
tions, 2709 [Rint = 0.0863]. Final R indices [I > 2s(I)] R1 = 0.0631,
wR2 = 0.0919; R indices (all data) R1 = 0.1743, wR2 = 0.1211.
CCDC 686673 and 686674 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2008.
Received: 6th November 2007; Com. 07/3038
– 146 –