Journal of Medicinal Chemistry
Article
at 50 °C for 30 min. The dark-orange solution was cooled to room
temperature, and either BOC or CBZ protected guanidine (1.3 equiv)
and DIEA (3 equiv) were added. The resulting mixture was stirred
overnight, after which time the solvent was removed in vacuo. The
mixture was partitioned between water and ethyl acetate, and the
phases were separated. The organic phase was washed twice with
water, once with brine, dried over Na2SO4, and filtered, and the
solvent was removed in vacuo. The crude material was purified via
silica gel chromatography using the indicated eluent.
1H-Pyrrole-2-carboxylic Acid [1-(4-(N-Carbobenzyloxy)-guanidi-
nocarbonyl-2-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-amide (13a).
Synthesized according to the Mukuyama coupling general procedure
using 12a (50.0 mg, 0.136 mmol). The crude material was purified via
silica gel chromatography using a gradient elution of 0−80% ethyl
acetate/hexanes to afford the desired product (46.2 mg, 63%) as a
glassy solid. 1H NMR (DMSO-d6): δ 11.5 (s, 1H), 8.37 (s, 1H), 8.12−
8.06 (m, 2H), 7.42−7.35 (m, 5H), 7.02 (d, 1H, J = 8.9 Hz), 6.88−6.86
(m, 1H), 6.85−6.81 (m, 1H), 6.08 (app dd, J = 2.4 Hz, 5.9 Hz, 1H),
5.19 (s, 1H), 4.50 (app quintet, J = 6.0 Hz, 1H), 3.74−3.70 (m, 1H),
3.59−3.50 (m, 1H), 3.44−3.40 (m, 1H), 2.25−2.17 (m, 1H), 2.09−
2.03 (m, 1H). MS (ES+): calcd for C26H24F3N6O4 + H+ 543.52, found
543.47.
1H), 6.84 (s, 1H), 6.77 (s, 1H), 6.07 (d, J = 3.5 Hz, 1H), 3.17 (d, J =
4.9 Hz, 1H), 3.11−3.09 (m, 1H), 2.80−2.72 (m, 1H), 2.69−2.57 (m,
1H), 1.92−1.89 (m, 1H), 1.84−1.81 (m, 1H), 1.69−1.66 (m, 1H),
1.54−1.51 (m, 1H). MS (ES+): calcd for C18H18F3N3O3 + H+ 382.36,
found 382.31
1H-Pyrrole-2-carboxylic Acid [1-(4-Guanidinocarbonyl-2-trifluor-
omethyl-phenyl)-piperidin-3-yl]-amide (6). The required protected
acyl guanidine intermediate 13b was synthesized according to the
Mukuyama coupling general procedure using 12b (100 mg, 0.262
mmol) and was used without purification in the next step. The residue
was dissolved in 1,4-dioxane (2.0 mL), and 4 M HCl in 1,4-dioxane
(1.5 mL) was added. The reaction was stirred for 60 h, at which time
the solvent was removed in vacuo. The residue was purified by
preparative HPLC eluting 0−75% acetonitrile/water with 0.1%
trifluoroacetic acid to obtain the desired product as the trifluoroacetic
acid salt (44 mg, 40% over two steps). 1H NMR (DMSO-d6): δ 11.44
(s, 1H), 11.38 (s, 1H), 8.18 (s, 1H), 8.13 (dd, J = 2.2 Hz, 8.6 Hz, 1H),
7.77 (d, J = 7.8 Hz, 9.0 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H,), 6.85 (s,
1H), 6.78 (s, 1H), 6.08 (s, 1H), 4.04−4.02 (m, 1H), 3.34 (d, J = 8.6
Hz, 1H,), 3.19 (app d, J = 12.0 Hz, 1H,), 2.83 (t, J = 9.3 Hz, 1H,), 2.73
(t, J = 10.4 Hz, 1H,), 1.94−1.83 (m, 2H), 1.72−1.51 (m, 2H). MS (ES
+): calcd for C19H21F3N6O2 + H+ 423.41, found 423.44.
General Procedure for the Removal of the CBZ Protecting Group.
To a solution of CBZ-guanidine compound (1 equiv) in ethanol under
an argon atmosphere was added 20 wt % Pd(OH)2 on carbon (3 mol
%) or 10 wt % Pd on carbon (10 mol %), and the mixture was stirred
under a hydrogen atmosphere for 3−16 h. The mixture was filtered
through Celite, and the solvent was removed in vacuo. The resulting
residues were purified by the methods indicated for the specific
compounds.
4-{4-[(1H-Pyrrole-2-carbonyl)-amino]-piperidin-1-yl}-3-trifluoro-
methyl-benzoic Acid (12c). Following the procedure for the first two
steps of the synthesis of 11a using as the starting material piperidin-4-
yl-carbamic acid tert-butyl ester (Astatech, 9c, 0.43 g, 2.25 mmol) and
8 (0.50 g, 2.25 mmol) afforded crude 10c as a yellow solid. HCl gas
was bubbled through a solution of crude 10c in methanol (25 mL) at 0
°C for 5 min. The reaction mixture was then stirred overnight at room
temperature. The solvent was removed in vacuo, and the residue was
washed with diethyl ether (100 mL) to afford the title compound as a
1H-Pyrrole-2-carboxylic Acid [1-(4-Guanidinocarbonyl-2-trifluor-
omethyl-phenyl)-pyrrolidin-3-yl]-amide (5). The CBZ protecting
group of 13a was removed according to the general procedure using
Pd(OH)2 on carbon in ethanol (4.0 mL) for 4 h. The crude residue
was dissolved in minimal 10% methanol/CH2Cl2 and precipitated
using ether. The resulting precipitate was collected by filtration and
triturated with ether to give the desired product as a white solid (10.5
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yellow solid (0.30 g, 44% over two steps). H NMR (DMSO): δ 8.24
(partially obscured br s, 2H), 8.20−8.11 (m, 2H), 7.57 (d, J = 8.40 Hz,
1H), 3.87 (s, 3H), 3.25−3.12 (m, 3H), 2.92−2.80 (m, 2H), 2.09−1.99
(m, 2H), 1.80- 1.60 (m, 2H). MS (EI): calcd for C14H17F3N2O2 + H+
303.30, found 303.10.
Following the procedure for the third step of the synthesis of 11a
using as starting material the product of the previous step (1.00 g, 2.95
mmol) afforded crude 11c as a white solid. Crude 11c (1.00 g, 2.52
mmol) was subjected to the same procedure as for 12a to afford the
1
mg, 28%). H NMR (DMSO-d6): δ 11.41 (s, 1H), 11.36 (s, 1H),
8.47−8.22 (br m, 4H), 8.18 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 6.5 Hz,
1H), 8.05−8.00 (m, 1H), 6.81−6.77 (m, 1H), 6.77−6.71 (m, 1H),
6.04−5.98 (m, 1H), 4.52−4.40 (m, 1H), 3.76−3.66 (m, 1H), 3.64−
3.47 (m, 2H), 3.45−3.37 (m, 1H), 2.27−2.10 (m, 1H), 2.10−1.96 (m,
1H). MS (ES+): calcd for C18H19F3N6O2 + H+ 409.39, found 409.40.
4-{3-[(1H-Pyrrole-2-carbonyl)-amino]-piperidin-3-yl}-3-trifluoro-
methyl-benzoic Acid Methyl Ester (11b). Following the procedure for
the first two steps of the synthesis of compound 11a using as the
starting material 8 (7 g, 31.5 mmol) and tert-butyl piperidin-3-yl-
carbamate (9b) (Oakwood, 6.31 g, 31.5 mmol) afforded the desired
product as a white solid (4.00 g, 41% over two steps) 1H NMR
(DMSO-d6): δ 8.21 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 7.99 (br s, 2H),
7.60 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.24 (m, 1H), 3.02 (d, J = 11.8
Hz, 1H), 2.81−2.79 (m, 2H), 2.03 (m, 1H), 1.86−1.83 (m, 1H),
1.64−1.61 (m, 1H), 1.48 (m, 1H). MS (ES+): calcd for C14H17F3N2O2
+ H+ 303.30, found 303.26.
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title compound as an off-white solid (0.75 g, 67% over two steps). H
NMR (DMSO): δ 13.19 (broad, 1H), 11.39 (s, 1H), 8.15 (partially
obscured d, J = 8.0 Hz, 1H), 8.14 (s, 1H), 7.90−7.82 (m, 1H), 7.58 (d,
J = 8.4 Hz, 1H), 6.83 (s, 2H), 6.07 (s, 1H), 3.95 (br s, 1H), 3.22−3.12
(m, 2H), 3.10−2.85 (m, 2H), 1.95−1.82 (m, 2H), 1.80−1.60 (m, 2H).
MS (EI): calcd for C18H18F3N3O3 + H+ 382.34, found 382.1.
1H-Pyrrole-2-carboxylic Acid [1-(4-Guanidinocarbonyl-2-trifluor-
omethyl-phenyl)-piperidin-4-yl]-amide (7). Following the procedure
for 13a using as the starting material 12c (23.0 mg, 0.06 mmol)
afforded crude 13c as a white solid. This crude material (0.02 g, 0.32
mmol) was treated as in the procedure for 6 to the title compound as a
1
white solid (10.0 mg, 47% over two steps). H NMR (400 MHz,
DMSO): δ 11.72−11.41 (m, 2H), 8.75−8.32 (m, 4H), 8.25 (d, J = 8.4
Hz, 1 H), 8.20 (s, 1H) 7.68- 758 (d, J = 8.92 Hz, 1H), 6.90 (s, 1H),
5.62−5.40 (m, 1H), 4.15−3.90 (m, 1H), 3.85−3.60 (m, 2H), 3.60−
3.18 (obscured by water peak, m, 1H), 2.45−2/07 (m, 2H). MS (EI):
calcd for C18H18F3N5O3 + H+ 410.37, found 410.36.
4-Bromo-3-trifluoromethyl-benzoic Acid Methyl Ester (15). To a
solution of 4-bromo-3-trifluoromethyl-benzoic acid (3B Scientific, 115
g, 428 mmol) in methanol (400 mL) was added concentrated sulfuric
acid (2 mL). The mixture was sealed and heated at 80 °C overnight.
The mixture was cooled to room temperature, and the solvent was
removed in vacuo. The residue was treated with water, and the
resulting solid was collected by filtration to afford the desired product
as a colorless solid (121 g, 98%). 1H NMR (CDCl3): δ 8.21 (d, J = 2.0
Hz, 1H), 7.90 (dd, J = 2.0 Hz, 8.1 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H),
3.82 (s, 3H). MS (EI): calcd for C9H6BrF3O2 + H+ 282.95, 284.95,
found 283.00 and 285.00.
Using the product of the previous step as starting material (1 g, 2.95
mmol) and employing the procedure for 11a step 3 afforded the
desired product as a white solid contaminated with 9 wt %
tetramethylurea (TMU) (0.9 g, 71% yield accounting for presence
of TMU). 1H NMR (CDCl3): δ 9.27 (s, 1H), 8.35 (d, J = 1.8 Hz, 1H),
8.21 (dd, J = 1.6 Hz, 8.2 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 6.92 (d, J =
1.1 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.63 (s, 1H), 6.27 (dd, J = 2.5
Hz, 6.2 Hz, 1H), 3.94 (s, 3H), 3.21−3.18 (m, 1H), 3.14 (d, J = 10.7
Hz, 1H), 3.03−3.00 (m, 1H), 2.76−2.73 (m, 1H), 2.04−1.97 (m, 2H),
1.69−1.64 (m, 2H). MS (ES+): calcd for C19H20F3N3O3+ H+ 396.38,
found 382.26 (pdt − Me + H+).
4-{3-[(1H-Pyrrole-2-carbonyl)-amino]-piperidin-3-yl}-3-trifluoro-
methyl-benzoic Acid (12b). Following the procedure for 12a using as
the starting material 11b (0.90 g, 2.12 mmol) afforded the desired
1
product as a white solid (0.75 g, 87%). H NMR (DMSO-d6): δ 11.4
4-(4-Methoxycarbonyl-2-trifluoromethyl-phenyl)-3,6-dihydro-
2H-pyridine-1-carboxylic Acid tert-Butyl Ester (17). To a solution of
(s, 1H), 8.13 (m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 9.0 Hz,
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dx.doi.org/10.1021/jm300601d | J. Med. Chem. 2012, 55, 7114−7140