HIV Nonnucleoside ReVerse Transcriptase Inhibitor
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 2 735
1H), 7.38-7.42 (m, 2H), 7.28 (d, J ) 8.2 Hz, 2H), 7.16 (d, J )
8.2 Hz, 2H), 6.09 (br s, 1H), 3.71-3.65 (m, 2H), 2.90 (t, J ) 6.8
Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.6, 138.5, 135.6,
133.4, 132.6, 131.2, 129.9, 129.7, 127.9, 42.2, 36.2 ppm.
8.06 (d, J ) 5.6 Hz, 1H), 7.72-7.52 (m, 3H), 7.50-7.40 (m, 3H),
7.26 (br s, 2H), 7.17 (d, J ) 5.6 Hz, 1H), 4.89 (s, 2H), 2.23 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ 185.0, 166.7, 166.6, 162.5
(JCF ) 13, 248 Hz), 160.1, 142.5, 139.1 (JCF ) 12 Hz), 136.3,
132.0, 131.8, 128.4, 124.5, 124.4, 120.0, 119.0, 112.5 (JCF ) 27
Hz), 107.8 (JCF ) 26 Hz), 18.3, 14.4 ppm; MS (ES+) m/z 467 (M
+ H), 489 (M + Na); Anal. (C20H16N2O5F2S2) C, H, N.
N-[3-(1H-Imidazol-1-yl)propyl]-3-methyl-4-nitroaniline (26a):
A mixture of 5-fluoro-2-nitrotoluene (0.24 mL, 2.0 mmol), 1-(3-
aminopropyl)-imidazole (0.41 mL, 3.4 mmol), and sodium bicar-
bonate (0.302 g, 3.6 mmol) in pyridine (5 mL) and water (0.5 mL)
was heated to reflux for 3 h. The reaction mixture was then
partitioned between water (50 mL) and EtOAc (50 mL). The organic
layer was concentrated to give a yellow solid, which was purified
by crystallization from EtOAc/hexanes to give 26a (0.255 g,
49%): 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J ) 9.2 Hz, 1H),
7.60 (s, 1H), 7.16 (s, 1H), 7.08 (t, J ) 5.5 Hz, 1H), 6.87 (s, 1H),
6.47 (dd, J ) 2.4, 9.2 Hz, 1H), 6.40 (d, J ) 2.4 Hz, 1H), 4.04-
3.98 (m, 2H), 3.06-3.01 (m, 2H), 2.47 (s, 3H), 1.98-1.91 (m,
2H) ppm; 13C NMR (100 MHz, CDCl3) δ 153.9, 138.0, 136.9,
129.2, 128.7, 120.0, 114.1, 110.3, 44.2, 30.5, 22.9 ppm.
7-Chloro-1-phenyl-3,4-dihydroisoquinoline (16): Solution of
15 (1.18 g, 4.5 mmol) in p-xylene (25 mL) warmed to reflux to
remove water and then removed from heat. POCl3 (10 g) and P2O5
(5 g) were added, and the mixture was heated at reflux for 6 h.
The xylene was decanted, and the solid residue was dissolved in
water. The aqueous layer was extracted with three portions of ether.
The combined organic layers were then concentrated in vacuo. Silica
gel chromatography (elution with 20-33% EtOAc/hexanes) gave
1
16 (0.5 g, 54%): MS (AP+) m/z 242 (M + H); H NMR (300
MHz, CDCl3) δ 7.60-7.57 (m, 2H), 7.48-7.43 (m, 3H), 7.37 (dd,
J ) 2.1, 8.0 Hz, 1H), 7.26-7.21 (m, 2H), 3.88-3.83 (m, 2H),
2.80-2.75 (m, 2H) ppm.
N-[2-(2-Benzoyl-4-chlorophenyl)ethyl]benzamide (17): A mix-
ture of 16 (0.1 g, 0.41 mmol), benzoyl chloride (0.2 mL, 1.7 mmol),
and triethylamine (0.1 mL, 0.72 mmol) in toluene (1 mL) and a
few drops of water was stirred at room temperature for 2 h. The
reaction mixture was washed with brine, dried over MgSO4, filtered,
and concentrated in vacuo. Silica gel chromatography (elution with
20-50% EtOAc/hexanes) gave 17 (0.053 g, 35%): 1H NMR (300
MHz, CDCl3) δ 7.95-7.92 (m, 2H), 7.86-7.69 (m, 4H), 7.57 (d,
J ) 2.1 Hz, 1H), 7.50 (d, J ) 8.2 Hz, 1H), 7.32-7.29 (m, 5H),
4.22-4.17 (m, 2H), 3.24-3.19 (m, 2H) ppm; 13C NMR (100 MHz,
CDCl3) δ 195.8, 165.6, 137.8, 135.5, 132.4, 132.2, 130.4, 129.9,
129.3, 129.2, 128.7, 126.8, 126.7, 126.5, 125.1, 40.1, 29.3 ppm;
Anal. (C22H18NO2Cl + 0.2 equiv H2O) C, H, N.
N-[4-(Aminosulfonyl)-2-methylphenyl]-2-bromoacetamide
(21b): A solution of 4-amino-3-methylbenzenesulfonamide (20b)7
(5.0 g, 26.85 mmol) and pyridine (2.4 mL, 29.53 mmol) in CHCl3
(150 mL) was cooled to 0 °C in an ice bath. Bromoacetyl bromide
(2.6 mL, 29.53 mmol) was added dropwise over 20 min, and the
resulting mixture was allowed to warm to room temperature
overnight. The reaction mixture was then poured into water (150
mL) and extracted with two 100-mL portions of CH2Cl2. The
aqueous layer was then filtered to give crude product as a beige
solid. The crude material was suspended in 1 N HCl and then
filtered and washed with CH2Cl2, MeOH, and hexane to give 21b
(5.705 g, 69%): 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H),
7.66-7.56 (m, 3H), 7.23 (br s, 2H), 4.09 (s, 2H), 2.24 (s, 3H) ppm;
13C NMR (100 MHz, DMSO-d6) δ 166.0, 141.2. 139.4, 132.3,
128.4, 124.9, 124.4, 30.5, 18.4 ppm; Anal. (C9H11N2O3BrS) C, H,
N.
N4-[3-(1H-Imidazol-1-yl)propyl]-2-methyl-1,4-benzenedi-
amine (27a): A mixture of 26a (0.233 g, 0.90 mmol) and 10%
Pd/C in MeOH (20 mL) was stirred at room temperature under 52
psi of hydrogen gas for 1 h. The reaction mixture was filtered
through Celite and concentrated in vacuo to give 27a (0.166,
80%): 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.07 (s, 1H),
6.92 (s, 1H), 6.58 (d, J ) 8.2 Hz, 1H), 6.40 (d, J ) 2.6 Hz, 1H),
6.36 (dd, J ) 2.6, 8.2 Hz, 1H), 4.08 (t, J ) 6.9 Hz, 2H), 3.49-
3.48 (m, 1H), 3.26 (br s, 2 H), 3.08-3.05 (m, 2H), 2.13 (s, 3H),
2.08-2.02 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 140.9,
137.2, 136.6, 129.7, 124.3, 118.9, 116.6, 116.4, 112.3, 445, 41.9,
31.1, 17.7 ppm.
N-(3-Methyl-4-nitrophenyl)acrylamide (29): A mixture of
3-methyl-4-nitroaniline (28) (1.052 g, 6.91 mmol) and triethylamine
(1.16 mL, 8.29 mmol) in CH2Cl2 (20 mL) was cooled to 0 °C and
acryloyl chloride (0.62 mL, 7.61 mmol) was added dropwise over
5 min. The resulting mixture was stirred 1.5 h at 0 °C and then
diluted with CH2Cl2 (35 mL), washed with brine, dried over MgSO4,
filtered, and concentrated in vacuo to give 29 (1.941 g), which was
used without further purification: MS (ES-) m/z 205.3 (M - H);
1H NMR (400 MHz, CDCl3) δ 8.52 (br s, 1H), 8.01 (d, J ) 9.0
Hz, 1H), 7.75 (d, J ) 2.3 Hz, 1H), 7.65 (dd, J ) 2.3, 9.0 Hz, 1H),
6.49-6.40 (m, 2H), 5.78 (dd, J ) 3.4, 8.1 Hz, 1H), 2.60 (s, 3H)
ppm.
N-(3-Methyl-4-nitrophenyl)-3-(4-morpholinyl)propanamide
(30): A mixture of 29 (6.91 mmol) and morpholine (0.63 mL, 7.26
mmol) in EtOH (25 mL) was warmed to reflux for 2.3 h. The
reaction mixture was then concentrated in vacuo, suspended in
EtOAc, and filtered. The filtrate was concentrated in vacuo,
dissolved in EtOAc, and allowed to crystallize. The crystalline
impurity was removed by filtration, and the filtrate was concentrated
in vacuo to give 30 (1.767 g, 87%): 1H NMR (400 Mz, CDCl3) δ
11.24 (br s, 1H), 8.03 (d, J ) 8.9 Hz, 1H), 7.54 (d, J ) 2.3 Hz,
1H), 7.43 (dd, J ) 2.3, 8.9 Hz, 1H), 3.84-3.82 (m, 4H), 2.76-
2.73 (m, 2H), 2.64 (br s, 4H), 2.62 (s, 3H), 2.58-2.55 (m, 2H)
ppm.
N-(4-Amino-3-methylphenyl)-3-(4-morpholinyl)propana-
mide (31): A mixture of 30 (0.202 g, 0.69 mmol) and 10% Pd/C
(0.018 g) in MeOH (10 mL) was stirred at room temperature under
53 psi of hydrogen gas for 2.17 h. The reaction mixture was then
filtered through Celite and concentrated in vacuo to give 31 (0.192
g, quant.): 1H NMR (400 MHz, CDCl3) δ 10.44 (br s, 1H), 7.38
(d, J ) 2.5 Hz, 1H), 7.27 (dd, J ) 2.5, 8.3 Hz, 1H), 6.76 (d, J )
8.3 Hz, 1H), 3.97-3.92 (m, 4H), 2.91-2.83 (m, 2H), 2.77-2.72
(m, 4H), 2.66-2.62 (m, 2H), 2.25 (s, 3H) ppm.
(3,5-Difluorophenyl)(3-hydroxy-2-thienyl)methanone (23b): A
mixture of 3-methoxythiophene (22) (1.14 g, 10 mmol), AlCl3 (2.70
g, 20.2 mmol), and 3,5-difluorobenzoyl chloride (1.18 mL, 10
mmol) in CH2Cl2 (50 mL) was heated to reflux for 20 h and then
stirred an additional 27 h at room temperature. The reaction mixture
was then poured over ice and stirred for 40 min, and the aqueous
layer was separated and extracted with CH2Cl2 (20 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo to give a dark brown solid (1.214 g).
Purification by flash chromatography using 2% EtOAc/hexanes
gave 23b (0.518 g, 22%) as a yellow solid: 1H NMR (400 MHz,
CDCl3) δ 12.04 (s, 1H), 7.57 (d, J ) 5.5 Hz, 1H), 7.43 (dd, J )
2.1, 7.3 Hz, 2H), 7.02-6.97 (m, 1H), 6.84 (d, J ) 5.5 Hz, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 188.2, 169.7, 163.1 (JCF
)
12.2, 252 Hz), 141.2, 135.9, 120.2, 111.9, 111.6 (JCF ) 7.6, 19.1
Hz), 107.9 (JCF ) 25.2 Hz) ppm.
N-[4-(Aminosulfonyl)-2-methylphenyl]-2-{[2-(3,5-difluoroben-
zoyl)-3-thienyl]oxy}acetamide (24c): A mixture of 23b (0.192 g,
0.80 mmol), 21b (0.252 g, 0.82 mmol), and K2CO3 (0.498 g, 3.6
mmol) in acetone (10 mL) was warmed to reflux for 6 h. The
reaction mixture was then poured into water (30 mL) and extracted
with two 30-mL portions of EtOAc. The combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo to give
0.272 g of crude material. Purification by flash chromatography
using 35-50% EtOAc/hexanes as eluant gave 24c as a yellow solid
3-(3-Methyl-4-nitrophenoxy)propylamine (33): 3-Methyl-4-
nitrophenol (32) (5.0 g, 33 mmol), 3-bromopropyl phthalimide (8.8
g, 33 mmol), and Cs2CO3 (16.1 g, 5.0 mmol) in DMF (60 mL)
were heated to 55 °C for 2 h and then cooled to room temperature.
The mixture was poured into a mixture of Et2O and water, and the
1
(0.103 g, 28%): H NMR (400 MHz, CDCl3) δ 9.47 (br s, 1H),