F. Ahmadi et al.
Bioorganic Chemistry 110 (2021) 104779
H), 7.82 (t, J = 5 Hz, 1H, Ar-H), 7.70 (d, J = 4.6 Hz, 1H, Ar-H), 7.30 (s,
132.4, 130.3, 128.7, 126.8, 125.8, 117.7, 115. 1, 106.0, 101.7, 43.4,
1
H, NH), 4.97 (bs, 2H, NH
2
), 2.88(s, 2H, CH
2
), 1.99 (dd, J = 31.8, 19.6
38 4 3
43.2, 43.1, 39.6, 36.7, 36.5, 28.8, 28.7. Anal Calcd for: C35H N O (562
1
3
Hz, 4H, 2 × CH
DMSO‑d ) δ 170.1, 151.1, 142.1, 138.7, 137.9, 134.1, 127.3, 123.1,
23.0, 101.5, 47.2, 26.1, 24.8, 22.9. Anal. Calcd for: C16
282.35): %C, 68.06; %H, 6.43; %N, 19.84. Found: %C, 68.28; %H, 6.56;
N, 20.07.
2
), 2.1–1.63 (m, 6H, 3 × CH
2
). C NMR (126 MHz,
0.71): %C, 74.71; %H, 6.81; %N, 9.96. Found: %C, 74.91; %H, 6.91; %N,
10.09.
6
1
18 4
H N O
(
5.3.2.7. Ethyl 2-(4-((3r,5r,7r)-adamantan-1-yl)-3-hydroxy phenoxy) ac-
etate (21). A suspension of 4-(1-adamantyl) resorcinol (1.0 g, 4.38,
mmol), anhydrous potassium carbonate (1.81 g, 13.14 mmol), and ethyl
%
◦
5
.3.2.4. 2-(4-((3r, 5r, 7r)-adamantan-1-yl phenoxy)-N-(5-(piperidine-1-
chloro acetate (0.64 g, 5.25 mmol) in DMF (10 mL) was stirred at 80 C
carbonyl)-1, 4-dihydroindeno [1, 2-c] pyrazol-3-yl) acetamide (14). A
overnight. The reaction mixture was diluted with CH
tially washed with aqueous sodium bicarbonate, brine, and water, and
dried over anhydrous Na SO . The solvent was filtered and evaporated
2 2
Cl and sequen-
mixture of (4-adamantan-1-yl-phenoxy) acetic acid (1.0 g, 3.49 mmol),
3
-amino-1, 4-dihydroindeno [1, 2-c] pyrazol-5-yl) (piperidine-1-yl)
methadone (0.92 g, 3.86 mmol), and HBTU (1.12 g, 2.96 mmol) in DMF
10 mL) was added to DIPEA (0.52 mL, 2.96 m mol). The reaction
2
4
under reduced pressure to give the desired compound as a yellow solid
(0.94 g, yield 94%), and recrystallization was done by chloroform. mp:
(
◦
ꢀ 1
mixture was stirred at room temperature for 12 h, and then partitioned
between EtOAc and brine. The organic layer was separated, dried over
87–89 C. IR (KBr): v (cm ) 3451, 2902, 1742, 1604, 1427, 1179, 1013,
1
836. H NMR (300 MHz, CDCl
J = 9.1 Hz, 1H, Ar-H), 6.32(s, 1H, Ar-H), 5.04 (s, 1H, OH), 4.59 (s, 2H,
CH ), 2.09 (d, J = 8.7 Hz, 9H,
), 4.30 (q, J = 4.5 Hz, 2H, OCH
).
(330.42): %C, 72.70; %H, 7.93. Found: %C,
3
): δ 7.14 (d, J = 9.1 Hz, 1H, Ar-H), 6.41(d,
2 4
anhydrous Na SO , filtered, and concentrated under a vacuum. The
resulting residue was purified by silica gel column chromatography (n-
Hexane: EtOAc = 7:3) until obtaining the target as a brown solid (0.71 g,
2
2
adamantyl-H), 1.78 (bs, 6H, adamantyl-H), 1.33 (t, J = 4.5 Hz, 3H, CH
3
◦
yield 71%).The product recrystallization by methanol. m. p:105–107 C.
Anal. Calcd for: C20
72.83; %H, 8.07.
26 4
H O
ꢀ 1
1
IR (KBr): v (cm ) 3228, 2908, 1693, 1629, 1508, 1215, 1180, 835. H
NMR (500 MHz, DMSO‑d
Ar-H), 7.25 (d, J = 8.8 Hz, 2H, Ar-H), 7.23 (t, J = 2.3 Hz, 1H, Ar-H), 6.91
d, J = 2.6 Hz, 1H, Ar-H), 6.90 (s, 1H, NH), 6.80 (d, J = 8.8 Hz, 2H, Ar-
H), 4.50 (s, 2H, CH ), 2.90 (s, 2H, CH
), 2.74–2.76 (m, 2H), 2.04 (bs,
H), 1.84 (bs, 10H), 1.72 (bs, 7H). 13C NMR (126 MHz, DMSO‑d
) δ
6
): δ 7.97 (s, 1H, NH), 7.27 (d, J = 2.6 Hz, 1H,
5.3.2.8. 2-(4-((3r, 5r, 7r)-adamantan-1-yl)-3-hydroxy phen oxy) –N-(5-
(piperidine-1-carbonyl)-1, 4-dihydroindeno [1, 2-c] pyrazol-3-yl) acet-
amide (22). A suspension of (4-adamantan-1-yl phenoxyhydroxy) acetic
acid ethyl ester (1.0 g, 3.03 mmol), (3-amino-1,4-dihhyroindeno [1, 2-c]
pyrazol-5-yl) (piperidin-1-yl methanone) (0.92 g, 3.86 mmol), and 1, 4-
diazabicyclo [2.2.2] octane (1.0 g, 8.91 mmol) was refluxed in ethanol
for 12 h. Then, the organic layer was separated, dried over anhydrous
Na SO , filtered, and concentrated under a vacuum until obtaining the
(
2
2
6
1
1
3
1
6
71.1, 167.3, 162.7, 156.2, 156.0, 144.2, 143.7, 134.7, 129.0, 126.0,
25.9, 124.9, 115.1, 114.7, 114.5, 114.3, 65.4, 55.3, 43.2, 43.1, 38.7,
38 4 3
6.9, 35.6, 28.8, 20.9. Anal. Calcd for C34H N O (550. 70): %C, 74.
6%; H, 6.96; %N, 10.17. Found: %C, 74.34; % H, 7.04; %N, 10.4.
2
4
target product as a brown solid (0.77 g, yield 77%), which was recrys-
◦
ꢀ 1
5
.3.2.5. (E)-3-(4-adamantan-1-yl-phenoxy)-acrylic acid ethyl ester
tallized by chloroform. mp: 104–106 C. IR (KBr): v (cm ) 3219, 2986,
1
(
16). 4-(adamantan-1-yl)-phenol (0.5 g, 2.19 mmol) and ethyl propio-
6
1606, 1483,1394, 1150, 843. H NMR (500 MHz, DMSO‑d ): δ 7.95 (s,
late (0.368 g, 0. 37 mL, 4.38 mmol) were dissolved in 25 mL of toluene.
1H, NH), 7.18 (t, J = 8.2 Hz, 1H, Ar-H), 7.04 (d, J = 1.4 Hz, 1H, Ar-H),
6.93 (d, J = 6.2 Hz, 1H, Ar-H), 6.80 (d, J = 8.5 Hz, 1H, Ar-H), 6.52 (d, J
= 1.4 Hz, 1H, Ar-H), 6.48 (s, 1H, Ar-H), 6.29 (s, 1H, NH), 6.25 (s, 1H,
◦
3
Then, Ph P (0.575 g, 2.19 mmol) was added and refluxed at 115 C for
1
4 h. The reaction solution was extracted with ethyl acetate and brine.
The organic layer was dried and concentrated over anhydrous Na SO
2
4
.
OH), 4.72 (s, 2H, CH
2
), 2.89 (s, 2H, CH
2
), 2.03(bs, 12H), 1.72–1.68 (m,
1
3
The residue was purified by silica gel column chromatography (n-Hex-
ane: EtOAc = 47:35) to give the compound as a white solid (0.455 g,
7H), 1.59–1.57 (m, 6H). C NMR (126 MHz, DMSO‑d
6
) δ 169.1, 167.8,
159.2, 158.1, 157.2, 156.3, 132.2, 130.4, 129.9, 127.0, 126.8, 107.8,
105.9, 104.1, 101.9, 65.2, 61.0, 46.7, 45.7, 40.6, 37.2, 36.3, 30.5, 28.9.
◦
1
ꢀ 1
yield 91%). m. p: 65–67 C. IR (KBr): v (cm ) 3407, 2908, 2847, 1711,
1
645, 1226, 1169, 839. H NMR (CDCl
Hz, 1H, O-CH), 7.37 (d, J = 8.2 Hz, 2H, Ar-H), 7.02 (d, J = 8.2 Hz, 2H,
Ar-H), 5.53 (d, J = 12.2 Hz, 1H, CH), 4.20 (q, J = 7.2 Hz, 2H, OCH ),
.10 (bs, 3H, adamantyl-H), 1.89 (bs, 6H, adamantyl-H), 1.77 (bs, 6H,
adamantyl-H), 1.29 (t, J = 7.2 Hz, 3H, CH ).
3
, 300 MHz): δ 7.81 (d, J = 12.2
38 4 4
Anal Calcd for C34H N O (566.70): %C, 72.06; %H 7, 6.76; %N 9.89.
Found: %C, 68.28; %H, 6.9; %N, 10.11.
2
2
5.3.2.9. 5-(1-adamantyl)-2-furoic acid (25). A mixture of 2-furoic acid
3
(1.12 g, 10 mmol) in methylene chloride (10 mL) and aluminum chlo-
◦
ride (2.66 g, 20 mmol) was stirred at a temperature below 10 C under
5
.3.2.6. (E)-3-(4-((3r,
5r,
7r)-adamantan-1-yl)
phenoxy)-N-(5-
an argon atmosphere.1-Adamantyl bromide (2.14 g, 10 mmol) in
methylene chloride (10 mL) was added over 1 h. The mixture was
allowed to warm to room temperature and to stand at this temperature.
The mixture was attentively poured onto ice-water and the organic
materials were extracted with ethyl acetate. Then, saturated aqueous
potassium sodium tartrate was added until vanishing the white precip-
(
piperidine-1-carbonyl)-1, 4-dihydroindeno [1, 2-c] pyrazol-3-yl) acryl-
amide (18). A mixture of (E)-3-(4-((3r,5r,7r)-adamantan-1-yl) phenoxy)
acrylic acid (0.3 g, 1.0 mmol), (3-amino-1,4-dihydroindeno[1,2-c]
pyrazol-5-yl) (piperidin-1-yl) methanone (0.28 g, 1.17 mmol), and
HBTU (0.336 g, 0.89 mmol) in DMF (10 mL) was added to DIPEA (0.22
◦
mL, 1.26 mmol). The reaction mixture was stirred at 65 C for 16 h and
2 4
itate. The organic layer was washed with brine and dried with Na SO .
then partitioned between EtOAc and brine. The organic layer was
Methylene chloride was evaporated under reduced pressure and
recrystallization gave the desired product, i.e. a white solid (0.97 g, yield
2 4
separated, dried over anhydrous Na SO , filtered, and concentrated
◦
ꢀ 1
under a vacuum. The resulting residue was purified by silica gel column
chromatography (n-Hexane: EtOAc = 2:8) to give the compound as a
yellow solid (0.20 g, yield 67%).The resulting product was recrystallized
87%). m.p: 224 –226 C. IR (KBr): v (cm ) 3429, 2924, 1707, 1409,
1
1183, 1018, 767. H NMR (300 MHz, DMSO‑d ): δ 9.2 (bs, 1H, OH), 7.25
6
(d, J = 3.2 Hz, 1H), 6.12 (d, J = 3.2 Hz, 1H), 2.10 (bs, 3H, adamantyl-H),
◦
ꢀ 1
by methanol. mp: 107–110 C. IR (KBr): v (cm ) 3436, 3242, 2907,
1.89 (bs, 6H, adamantyl-H), 1.77 (bs, 6H, adamantyl-H).
1
1
1
7
649, 1512, 1236, 832. H NMR (500 MHz, DMSO‑d
6
): δ 7.75 (d, J =
2.1 Hz, 1H, OCH), 7.58 (bs, 1H, NH), 7.49–7.31 (m, 3H, Ar-H),
.39–7.12 (m, 4H, Ar-H, NH), 6.70 (d, J = 8.2 Hz, 1H, Ar-H), 5.47 (d,
5.3.2.10. 5-((3r, 5r, 7r)-adamantan-1-yl)-N-(5-piperidine-1-carbonyl)-1,
4-dihydroindeno [1, 2-c] pyrazol-3-yl) furan-2-carboxamide (26). A
mixture of 5-(1-adamantyl)-2-furoic acid (1.0 g, 4.06 mmol), (3-amino-
1, 4-dihydroindeno [1, 2-c] pyrazol-5-yl) (piperidin-1-yl) methanone
(0.93 g, 3.90 mmol), and HBTU (1.04 g, 2.74 mmol) in DMF (10 mL) was
J = 12.1 Hz, 1H, CH), 2.70 (s, 2H, CH
2
), 2.04 (d, J = 13.2 Hz, 6H), 1.85
1
3
(
d, J = 2.8 Hz, 6H), 1.80 (d, J = 2.8 Hz, 4H), 1.72 (bs, 9H). C NMR
126 MHz, DMSO‑d ) δ 166.2, 158.7, 155.4, 153.7, 147.8, 141.7, 135.6,
(
6
1
1