InhA from Mycobacterium tuberculosis
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 21 6321
Synthesis of 1-(9H-Fluoren-9-yl)piperazine (Compound 35).36
9-Chlorofluorene (359 mg, 1.8 mmol) and piperazine (464 g, 3.6
mmol) were mixed and refluxed in 2-butanone (25 mL) for 16 h.
The mixture was cooled and 20 mL of ether was added. After
filtration, the ether layer was evaporated in vacuo. The residue was
dissolved in ether, washed with water (15 mL × 3), and then
extracted with a 2 N solution of methanesulfonic acid in water (10
mL × 3). This extract was basified with concentrated ammonium
hydroxide and extracted with ether. After the extract was dried (Na2-
SO4) and evaporated in vacuo, 297 mg (67%) of the desired product
was obtained: LC-MS ([M + H]+) calcd for [C17H18N2H]+ 251.2,
found 251.2; 1H NMR (400 MHz CD3OD) δ 7.65 (dd, 4H), 7.30-
7.36 (m, 2H), 7.22-7.28 (m, 2H), 4.77 (s, 1H), 2.78-2.84 (m,
4H), and 2.56-2.61 (m, 4H).
1H NMR (400 MHz CD3OD) δ 7.36-7.46 (m, 4H), 7.22-7.29
(m, 2H), 7.13-7.19 (m, 1H), 6.95-7.02 (m, 2H), 4.29 (s, 1H),
3.76-3.86 (m, 1H), 3.50-3.62 (m, 6H), 3.28-3.32 (m, 1H), 2.54-
2.64 (m, 2H), 2.30-2.42 (m, 4H), 1.60-1.84 (m, 5H), and 1.08-
1.52 (m, 5H); HPLC2, 14.35 min, purity >95%; HPLC4, 14.11
min, purity >96%.
1-Cyclohexyl-N-(9H-fluoren-1-yl)-5-oxopyrrolidine-3-carbox-
amide (Compound p31): yield 60%; LC-MS ([M + H]+) calcd
1
for [C24H26N2O2H]+ 375.21, found 375.21; H NMR (400 MHz
CD3OD) δ 7.76-8.04 (d, 1H), 7.64-7.70 (d, 1H), 7.50-7.57 (d,
1H), 7.44-7.50 (d, 1H), 7.25-7.42 (m, 3H), 3.80-3.92 (s, 2H, m,
1H), 3.64-3.8 (m, 2H), 3.42-3.52 (m, 1H), 2.70-2.78 (m, 2H),
1.60-1.88 (m, 5H), and 1.00-1.58(m, 5H); HPLC2, 11.29 min,
purity >97%; HPLC4, 10.35 min, purity >97%.
General Procedure for Synthesis of the Amide, As Exempli-
fied by the Synthesis of Compound p21. 1-Cyclohexyl-N-(3-
benzylphenyl)-5-oxopyrrolidine-3-carboxamide (Compound p21).
To a solution of amine (18.4 mg, 0.1 mmol) and acid (23 mg, 0.11
mmol) in 3 mL of dry DMF were added HBTU (50 mg, 0.13 mmol)
and DIEA (50 µL, 0.3 mmol) at 23 °C. The reaction mixture was
stirred for 5 h and was then quenched by the addition of brine and
extracted three times with EtOAc. The organic layers were
combined and washed sequentially with 1 N HCl, saturated aqueous
NaHCO3, and brine before being dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified by preparative TLC
with CH2Cl2/MeOH (40:1 v/v) to give the product (32.2 mg) in
85% yield: LC-MS ([M + H]+) calcd for [C24H28N2O2H]+ 377.22,
1-Cyclohexyl-N-(9-ethyl-9H-carbazol-3-yl)-5-oxopyrrolidine-
3-carboxamide (Compound p33): yield 80%; LC-MS ([M +
1
H]+) calcd for [C25H29N3O2H]+ 404.23, found 404.23; H NMR
(400 MHz CD3OD) δ 8.28-8.32 (d, 1H), 7.96-8.00 (m, 1H),
7.46-7.50 (dd, 1H), 7.34-7.50 (m, 3H), 7.08-7.16 (m, 1H), 4.27-
4.36 (q, 2H), 3.74-3.86 (m, 1H), 3.54-3.66 (m, 1H), 3.24-3.36
(m, 1H), 2.60-2.72 (m, 2H), 1.56-1.80 (m, 5H), and 1.00-1.44
(m, 5H); HPLC2, 12.49 min, purity >97%; HPLC4, 13.00 min,
purity >96%.
4-(1-(Bis(4-fluorophenyl)methyl)piperazine-4-carbonyl)-1-cy-
clohexylpyrrolidin-2-one (Compound p36): yield 77.5%; LC-
MS ([M + H]+) calcd for [C28H33F2N3O2H]+ 482.25, found 482.25;
1H NMR (400 MHz CD3OD) δ 7.40-7.50 (dd, 4H), 6.92-7.06
(dd, 4H), 4.33 (s, 1H), 3.76-3.88 (m, 1H), 3.50-3.65 (m, 6H),
3.28-3.36 (m, 1H), 2.52-2.66 (m, 2H), 2.29-2.44 (m, 4H), 1.60-
1.84 (m, 5H), and 1.08-1.52 (m, 5H); HPLC2, 15.82 min, purity
>99%; HPLC4, 13.45 min, purity >95%.
1-Cyclohexyl-4-(1-(phenyl(4-chlorophenyl)methyl)piperazine-
4-carbonyl)pyrrolidin-2-one (Compound p37): yield 54%; LC-
MS ([M + H]+) calcd for [C25H29N3O2H]+ 480.23, found 480.23;
1H NMR (400 MHz CDCl3) δ 7.33-7.39 (m, 4H), 7.19-7.32 (m,
5H), 4.22 (s, 1H), 3.88-3.98 (m, 1H), 3.64-3.76 (m, 1H), 3.52-
3.64 (m, 1H), 3.44-3.50 (m, 4H), 3.24-3.34 (m, 1H), 2.52-2.70
(m, 2H), 2.30-2.44 (m, 4H),1.62-1.82 (m, 5H), and 1.04-1.44
(m, 5H); HPLC2, 13.67 min, purity >96%; HPLC5, 15.12 min,
purity >96%.
1
found 377.22; H NMR (400 MHz CDCl3) δ 8.47 (s, 1H), 7.36-
7.42 (m, 2H), 7.10-7.28 (m, 5H), 6.88-6.96 (m, 1H), 3.82-3.96
(m, 1H, s, 2H), 3.59-3.64 (m, 1H), 3.44-3.52 (m, 1H), 3.08-
3.20 (m, 1H), 2.68-2.78 (m, 1H), 2.52-2.64 (m, 1H), 1.58-1.82
(m, 5H), and 1.00-1.40 (m, 5H); HPLC1, 12.88 min, purity >97%;
HPLC4, 10.55 min, purity >97%. Compounds p9, p20, p24, p27,
p28, p31, p33, p36, p37, p50, p56, and p62-p68 were prepared
following the same protocol.
N-(3-(Benzyloxy)phenyl)-1-cyclohexyl-5-oxopyrrolidine-3-car-
boxamide (Compound p9): yield 61.3%; LC-MS ([M + H]+)
1
calcd for [C24H28N2O3H]+ 393.21, found 393.21; H NMR (400
MHz CD3OD) δ 7.724-7.46 (m, 6H), 7.16-7.23 (m, 1H), 7.06-
7.12 (m, 1H), 6.72-6.78 (m, 1H), 5.05 (s, 2H), 3.81-3.86 (m,
1H), 3.61-3.72 (m, 1H), 3.56-3.64 (m, 1H), 3.24-3.36 (m, 1H),
2.62-2.74 (m, 2H), 1.60-1.88 (m, 5H), and 1.00-1.58 (m, 5H);
HPLC1, 9.52 min, purity >95%; HPLC4, 12.48 min, purity >97%.
N-((Anthracen-9-yl)methyl)-1-cyclohexyl-N-methyl-5-oxopy-
rrolidine-3-carboxamide (Compound p20): yield 77.6%; LC-
MS ([M + H]+) calcd for [C27H30N2O2H]+ 415.23, found 415.23;
1H NMR (400 MHz CD3OD) δ 8.5 (s, 1H), 8.28-8.32 (d, 2H),
8.00-8.08 (d, 2H), 7.44-7.56(m, 4H), 5.60-5.74 (q, 2H), 3.82-
3.92 (m, 1H), 3.56-3.66 (m, 2H), 3.26-3.32 (m, 1H), 2.58-2.76
(m, 2H, s, 3H), 1.60-1.88 (m, 5H), and 1.00-1.58 (m, 5H);
HPLC3, 10.79 min, purity >99%; HPLC4, 10.79 min, purity >95%.
1-Cyclohexyl-N-(3-phenylphenyl)-5-oxopyrrolidine-3-carbox-
amide (Compound p24): yield 59.2%; LC-MS ([M + H]+) calcd
N-(3-Bromo-4-methylphenyl)-1-cyclohexyl-5-oxopyrrolidine-
3-carboxamide (Compound p50): yield 99%; LC-MS ([M +
1
H]+) calcd for [C19H26N2O2H]+ 315.20, found 315.20; H NMR
(400 MHz CD3OD) δ 7.16-7.20 (s, 2H), 6.72-6.76 (s, 1H), 3.80-
3.90 (m, 1H), 3.56-3.70 (m, 2H), 3.25-3.35 (m, 1H), 2.64-2.69
(m, 2H), 2.26 (s, 6H), 1.60-1.86 (m, 5H), and 1.00-1.56 (m, 5H);
HPLC1, 8.25 min, purity >97%; HPLC4, 13.04 min, purity >97%.
1-Cyclohexyl-N-(3-isopropoxyphenyl)-5-oxopyrrolidine-3-car-
boxamide (Compound p56): yield 69.7%; LC-MS ([M + H]+)
1
calcd for [C25H29N3O2H]+ 345.21, found 345.21; H NMR (400
MHz CDCl3) δ 8.05 (s, 1H), 7.29-7.35 (m, 1H), 7.15-7.22 (m,
1H), 6.95-7.00 (m, 1H), 6.63-6.68 (m, 1H), 4.50-4.58 (m, 1H),
3.88-3.99 (m, 1H), 3.65-3.72 (m, 1H), 3.52-3.60 (m, 1H), 3.15-
3.28 (m, 1H), 2.76-2.84 (m, 1H), 2.62-2.71 (m, 1H), 1.62-1.82
(m, 5H), and 1.04-1.44 (m, 5H); HPLC1, 14.75 min, purity >95%;
HPLC4, 13.24 min, purity >98%.
1-(Bicyclo[2.2.1]heptan-2-yl)-5-oxo-N-(3-phenylphenyl)pyrro-
lidine-3-carboxamide (Compound p62): yield 35%; LC-MS ([M
+ H]+) calcd for [C24H26N2O2H]+ 375.201, found 375.20; 1H NMR
(400 MHz CDCl3) δ 8.18-8.28 (m, 1H), 7.81 (s, 1H), 7.22-7.62
(m, 8H), 3.98-4.12 (m, 1H), 3.56-3.84 (m, 2H), 3.12-3.32 (m,
1H), 2.62-2.88 (m, 1H, s, 3H), 1.40-1.82 (m, 5H), and 1.00-
1.40 (m, 5H); HPLC3, 5.87 min, purity >99%; HPLC4, 10.63 min,
purity >97%.
1
for [C23H26N2O2H]+ 363.21, found 363.21; H NMR (400 MHz
CDCl3) δ 7.78-7.88 (m, 2H), 7.56-7.60 (m, 2H), 7.48-7.54 (m,
1H), 7.32-7.46 (m, 4H), 3.90-4.02 (m, 1H), 3.69-3.78 (m, 1H),
3.54-3.63 (m, 1H), 3.16-3.28 (m, 1H), 2.80-2.888 (m, 1H),
2.67-2.77 (m, 1H), 1.62-1.86 (m, 5H), and 1.04-1.45 (m, 5H);
HPLC3, 10.40 min, purity >98%; HPLC4, 9.19 min, purity >99%.
1-Cyclohexyl-4-(1-(phenyl(p-tolyl)methyl)piperazine-4-carbo-
nyl)pyrrolidin-2-one (Compound p27): yield 76.9%; LC-MS ([M
+ H]+) calcd for [C29H37N3O2H]+ 460.29, found 460.29; 1H NMR
(400 MHz CD3OD) δ 7.40-7.45 (m, 2H), 7.24-7.32 (m, 4H),
7.12-7.20 (m, 1H), 7.06-7.12 (m, 2H), 4.22 (s, 1H), 3.76-3.86
(m, 1H), 3.48-3.62 (m, 6H), 3.28-3.36 (m, 1H), 2.52-2.62 (m,
2H), 2.28-2.42 (m, 4H), 2.26 (s, 3H), 1.76-1.84 (m, 5H), and
1.08-1.52 (m, 5H); HPLC2, 11.79 min, purity >95%; HPLC4,
10.32 min, purity >98%.
N-((Anthracen-9-yl)methyl)-1-(bicyclo[2.2.1]heptan-2-yl)-N-
methyl-5-oxop yrrolidine-3-carboxamide (Compound p63): yield
95%; LC-MS ([M + H]+) calcd for [C28H30N2O2H]+ 427.23, found
1
1-Cyclohexyl-4-(1-((4-fluorophenyl)(phenyl)methyl)piperazine-
4-carbonyl)pyrrolidin-2-one (Compound p28): yield 69.5%; LC-
MS ([M + H]+) calcd for [C28H34FN3O2H]+ 464.26, found 464.26;
427.23; H NMR (400 MHz CDCl3) δ 8.48 (s, 1H), 8.18-8.28
(m, 2H), 8.02-8.08 (m, 2H), 7.44-7.60 (m, 4H), 5.64-5.72 (m,
2H), 4.04-4.16 (m, 1H), 3.82-3.94 (m, 1H), 3.32-3.56 (m, 2H),