Inhibitors of HIV-1 Reverse Transcriptase
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 5933
overlapping with DMSO), 1.40 (m, 2H, CH2), 0.86 (t, 3H, CH3).
MS (ES+): m/z 284.0 (M + 1).
(m, 8H, CH2), 1.60 (m, 2H, CH2), 1.25 (d, 3H, CH3), 0.73 (t,
3H, CH3). MS (ES+): m/z 320.0 (M + 1).
6-Bromo-4-(cyclopentyloxy)-3-propyl-2(1H)-quinoli-
none (1o). The title compound was prepared from 4j using
the method employed in the synthesis of 1y. A 7% yield of 1o
4-Hydroxy-6-methyl-3-propyl-2(1H)-quinolinone (4n).
The title compound was prepared from 2g and 3a by the
method outlined for the synthesis of 4a in 75% yield. 1H NMR
(Me2SO-d6) δ 11.3 (bs, 1H, OH), 9.8 (bs, 1H, NH), 7.62 (s, 1H,
ArH), 7.21 (d, 1H, ArH), 7.09 (d, 1H, ArH), 2.5 (m, overlapping
with DMSO), 2.31 (s, 3H, CH3), 1.40 (m, 2H, CH2), 0.86 (t, 3H,
CH3). MS (ES+): m/z 218.0 (M + 1).
4-Cyclopentyloxy-6-methyl-3-propyl-2(1H)-quinoli-
none (1u). The title compound was prepared from 4n using
the method employed for the synthesis of 1y except the
reaction was heated for 2 h and a second portion of NaH (0.025
g, 0.50 eq) was added. The reaction was heated overnight. NaH
(0.025 g, 0.50 equiv) was added again and heating at 60 °C
was continued another 4 h. Purification was accomplished by
chromatography on silica gel eluted with CHCl3/MeOH (98:2,
v/v) resulting in 1u (2% yield). 1H NMR (Me2SO-d6) δ 11.5 (bs,
1H, NH), 7.41 (s, 1H, ArH), 7.24 (d, 1H, ArH), 7.15 (d, 1H,
ArH), 4.70 (m, 1H, OCH), 2.5 (m, overlapping with DMSO),
2.32 (s, 3H, CH3), 1.9-1.2 (m, 12H, CH2s), 0.88 (t, 3H, CH3).
MS (ES+): m/z 286.0 (M + 1).
4-Hydroxy-6-methoxy-3-propyl-2(1H)-quinolinone (4o).
The title compound was prepared from 2h and 3a by the
method outlined for the synthesis of 4a in 72% yield. 1H NMR
(Me2SO-d6) δ 11.2 (bs, 1H, OH), 9.9 (bs, 1H, NH), 7.38(s, 1H,
ArH), 7.19 (d, 1H, ArH), 7.1 (d, 1H, ArH), 3,80 (s, 3H, OCH3),
2.5 (m, overlapping with DMSO), 1.40 (m, 2H, CH2), 0.92 (t,
3H, CH3). MS (ES+): m/z 234.0 (M + 1).
4-Cyclopentyloxy-6-methoxy-3-propyl-2(1H)-quinoli-
none (1v). The title compound was prepared from 4o using
the method employed for the synthesis of 1y except the
reaction was heated in a 100 °C oil bath for 24 h. A 16% yield
of 1v was obtained. 1H NMR (Me2SO-d6) δ 11.5 (bs, 1H, NH),
7.20 (s, 1H, ArH), 7.10 (d, 1H, ArH), 7.06 (d, 1H, ArH), 4.70
(m, 1H, OCH), 3.75 (s, 3H, OCH3), 2.5 (m, overlapping with
DMSO), 1.80 (m, 6H, CH2s), 1.60 (m, 2H, CH2s), 1.50 (m, 2H,
CH2), 0.88 (t, 3H, CH3). MS (ES+): m/z 302.0 (M + 1).). Anal.
(C18H23NO3) C, H, N.
4-Hydroxy-3-propyl-6-trifluoromethoxy-2(1H)-quino-
linone (4p). The title compound was prepared from 2i and
3a by the method outlined for the synthesis of 4a in 40% yield.
1H NMR (Me2SO-d6) δ 11.5 (bs, 1H, OH), 10.3 (bs, 1H, NH),
7.8 (s, 1H, ArH), 7.5 (d, 1H, ArH), 7.3 (d, 1H, ArH), 2.5 (m,
overlapping with DMSO), 1.40 (m, 2H, CH2), 0.92 (t, 3H, CH3).
MS (ES+): m/z 288.0 (M + 1).
4-(Cyclopentyloxy)-3-propyl-6-trifluoromethoxy-2(1H)-
quinolinone (1w). The title compound was prepared from 4p
using the method employed in the synthesis of 1y. 1w was
obtained in 9% yield. 1H NMR (Me2SO-d6) δ 11.8 (bs, 1H, NH),
7.50 (s, 1H, ArH), 7.46 (d, 1H, ArH), 7.34 (d, 1H, ArH), 4.68
(m, 1H, OCH), 2.5 (m, overlapping with DMSO), 1.80 (m, 6H,
CH2s), 1.60 (m, 2H, CH2s), 1.50 (m, 2H, CH2), 0.88 (t, 3H, CH3).
MS (ES+): m/z 356.0 (M + 1). Anal. (C18H20F3NO3‚0.05CHCl3)
C, H, N, F.
4-Hydroxy-2-oxo-3-propyl-1,2-dihydro-6-quinolinecar-
bonitrile (4q). The title compound was prepared from 2j and
3a by the method outlined for the synthesis of 4a in 77% yield.
1H NMR (Me2SO-d6) δ 11.7 (bs, 1H, OH), 10.5 (bs, 1H, NH),
8.23 (s, 1H, ArH), 7.77 (d, 1H, ArH), 7.33 (d, 1H, ArH), 2.5
(m, overlapping with DMSO), 1.4 (m, 2H, CH2), 0.87 (t, 3H,
CH3). MS (ES+): m/z 229.0 (M + 1).
1
was obtained. H NMR (Me2SO-d6) δ 11.8 (bs, 1H, NH), 7.70
(s, 1H, ArH), 7.60 (d, 1H, ArH), 7.21 (d, 1H, ArH), 4.69 (m,
1H, OCH), 2.5 (m, overlapping with DMSO), 1.80 (m, 6H,
alkyls), 1.60 (m, 2H, CH2), 1.50 (m, 2H, CH2), 0.88 (t, 3H, CH3).
MS (ES+): m/z 352.0 (M + 1). Anal. (C17H20BrNO2‚0.25C6H14)
C, H, N.
4-Cyclopentyloxy-6-fluoro-3-propyl-2(1H)-quinoli-
none (1p). The title compound was prepared from 4d and
cyclopentyl bromide by the method used in the synthesis of
1y except the oil bath temperature was 50 °C. A 22% yield of
1p was obtained. 1H NMR (Me2SO-d6) δ 11.7 (bs, 1H, NH),
7.32 (m, 3H, ArH), 4.70 (m, 1H, OCH), 2.5 (m, overlapping
with DMSO), 1.80 (m, 6H, alkyls), 1.60 (m, 2H, CH2s), 1.50
(m, 2H, CH2), 0.88 (t, 3H, CH3). MS (ES+): m/z 290.0 (M +
1).
6-Chloro-4-(cyclopentyloxy)-3-propyl-2(1H)-quinoli-
none (1q). Starting from 4a and using the procedure described
for the synthesis of 1y, compound 1q (20% yield) was obtained
after chromatography on silica gel (4 by 7 cm column) eluted
with hexane/EtOAc (2:1, v/v). 1H NMR (Me2SO-d6) δ 11.8 (bs,
1H, NH), 7.56 (s, 1H, ArH), 7.49 (d, 1H, ArH), 7.28 (d, 1H,
ArH), 4.70 (m, 1H, OCH), 2.5 (m, overlapping with DMSO),
1.80 (m, 6H, alkyls), 1.60 (m, 2H, CH2s), 1.50 (m, 2H, CH2),
0.88 (t, 3H, CH3). MS (ES+): m/z 306.0 (M + 1). Anal. (C17H20-
ClNO2) C, H, N, Cl.
6-Chloro-3-ethyl-4-hydroxyl-2(1H)-quinolinone (4k). The
title compound was prepared from 2a and 3c by the method
1
outlined for the synthesis of 4a in 69% yield. H NMR (Me2-
SO-d6) δ 11.4 (bs, 1H, OH), 10.2 (bs, 1H, NH), 7.82 (s, 1H,
ArH), 7.44 (d, 1H, ArH), 7.21 (d, 1H, ArH), 2.5 (m, overlapping
with DMSO), 0.97 (t, 3H, CH3). MS (ES+): m/z 224.0 (M +
1).
6-Chloro-4-(cyclopentyloxy)-3-ethyl-2(1H)-quinoli-
none (1r). The title compound was prepared from 4k and
cyclopentyl bromide using the method employed for the
synthesis of 1y. A 12% yield of 1r was obtained. 1H NMR (Me2-
SO-d6) δ 11.8 (bs, 1H, NH), 7.62 (s, 1H, ArH), 7.5 (d, 1H, ArH),
7.33 (d, 1H, ArH), 4.8 (m, 1H, OCH), 2.5 (m, overlapping with
DMSO), 1.9 (m, 6H, alkyls), 1.60 (m, 2H, CH2s), 1.12 (t, 3H,
CH3). MS (ES+): m/z 292.0 (M + 1).
6-Chloro-4-hydroxyl-3-isobutyl-2(1H)-quinolinone (4l).
The title compound was prepared from 2a and 3e by the
method outlined for the synthesis of 4a except the reaction
was run for 72 h. A 51% yield of 4l was obtained. 1H NMR
(Me2SO-d6) δ 11.4 (bs, 1H, OH), 10.1 (bs, 1H, NH), 7.83 (s,
1H, ArH), 7.44 (d, 1H, ArH), 7.22 (d, 1H, ArH), 2.5 (m,
overlapping with DMSO), 1.86 (m, 1H, CH), 0.82 (m, 6H, CH3).
MS (ES+): m/z 252.0 (M + H).
6-Chloro-4-(cyclopentyloxy)-3-isobutyl-2(1H)-quinoli-
none (1s). The title compound was prepared from 4l using
the method employed for the synthesis of 1y. A 13% yield of
1
1s was obtained. H NMR (CDCl3) δ 10.4 (bs, 1H, NH), 7.70
(s, 1H, ArH), 7.35 (d, 1H, ArH), 7.15 (d, 1H, ArH), 4.73 (m,
1H, OCH), 2.60 (d, 2H, CH2), 2.08-1.54 (m, 9H, alkyls), 0.90
(t, 6H, CH3). MS (ES+): m/z 320.0 (M + 1). Anal. (C18H22-
ClNO2‚0.05CHCl3) C, H, N.
3-(sec-Butyl)-6-chloro-4-hydroxyl-2(1H)-quinolinone
(4m). The title compound was prepared from 2a and 3f by
4-Cyclopentyloxy-2-oxo-3-propyl-1,2-dihydro-6-quino-
linecarbonitrile (1x). The title compound was prepared from
4q using the method employed in the synthesis of 1y. A 15%
1
the method outlined for the synthesis of 4a in 35% yield. H
NMR (Me2SO-d6) δ 11.3 (bs, 1H, OH), 10.0 (bs, 1H, NH), 7.87
(s, 1H, ArH), 7.44 (d, 1H, ArH), 7.22 (d, 1H, ArH), 3.12 (m,
1H, CH), 1.87 (m, 1H, CH), 1.6 (m, 1H, CH), 1.2 (d, 3H, CH3),
0.7 (m, 3H, CH3). MS (ES+): m/z 252.0 (M + H).
1
yield of 1x was obtained. H NMR (Me2SO-d6) δ 12.0 (bs,1H,
NH), 8.00 (s, 1H, ArH), 7.82 (d, 1H, ArH), 7.37 (d, 1H, ArH),
4.74 (m, 1H, OCH), 2.5 (m, overlapping with DMSO), 1.80 (m,
6H, CH2s), 1.60 (m, 2H, CH2s), 1.50 (m, 2H, CH2), 0.88 (t, 3H,
CH3). MS (APCH-): m/z 295.0 (M-1). Anal. (C18H20N2O2) C,
H, N.
3-(sec-Butyl)-6-chloro-4-(cyclopentyloxy)-2(1H)-quino-
linone (1t). The title compound was prepared from 4m and
cyclopentyl bromide using the method employed for the
synthesis of 1y. A 2% yield of 1t was obtained. 1H NMR (Me2-
SO-d6) δ 11.6 (bs, 1H, NH), 7.56 (s, 1H, ArH), 7.49 (d, 1H, ArH),
7.28 (d, 1H, ArH), 4.60 (m, 1H, OCH), 3.0 (m, 1H, CH), 1.80
6-Chloro-4-(cyclohexyloxy)-3-isopropyl-2(1H)-quinoli-
none (1z). The title compound was prepared from 4f by the
method outlined for the synthesis of 1y. 1H NMR (Me2SO-d6)