Journal of Medicinal Chemistry
Drug Annotation
and then diispropylethyamine (3.81 mL, 22.28 mmol) was added in
∼0.5 mL portions every 5−10 min over a total of 1 h. The reaction
mixture was added to water and extracted with EtOAc, and the organic
phase was washed with 1 M HCl, 2 M NaOH, water, and brine and
dried (MgSO4). Evaporation and flash chromatography (0−30%
EtOAc-isohexanes gradient elution) afforded an oil, which was taken
into hot DCM and isohexane was added until the solution became
turbid. On cooling, filtration afforded (S)-3-amino-N-(3,3,3-trifluoro-
2-hydroxy-2-methylpropyl)-5,6-bis(trifluoromethyl)picolinamide 29
as awhite solid (1.67 g, 75%). LRMS C12H10F9N3O2 requires M+
399.06, found [MH]+ 400.1. Elemental analysis requires C, 36.10%; H,
2.52%; N, 10.53% found C, 36.20 0.02%; H, 2.49 0.06%; N, 10.56
0.05%. 1H NMR (DMSO-d6) 1.25 (3H s), 3.49 (1H dd J = 14.0, 5.6),
3.67 (1H dd J = 13.8 7.3), 6.33 (1H s), 7.79 (1H s), 7.80 (2H br s), 8.31
(1H t J = 6.4). 13C NMR (DMSO-d6) 18.95 (q), 42.21 (t), 72.14 (s JF =
27), 129.87 (s JF = 272), 121.97 (s JF = 272), 124.28 (d JF = 6), 26.19 (s
JF = 36), 126.32 (s JF = 287), 126.34 (s JF = 34), 127.85 (s), 147.78 (s),
165.22 (s). 19F NMR (DMSO-d6) −59.81(q J = 11), −61.92 (q J = 11),
80.49 (s).
found [MH]+ 361.2. 1H NMR (DMSO-d6) 1.27 (3H s), 2.82 (3H d J =
4.5), 3.45 (1H dd J = 13.8, 5.6), 3.64 (1H dd J = 13.8, 7.3), 5.90 (1H q J
= 4.6), 6.22 (2H br s), 6.32 (1H s), 7.48 (1H s), 8.50 (1H t J = 6.4) and
(ent-2)-3-amino-6-(methylamino)-N-(3,3,3-trifluoro-2-hydroxy-2-
methylpropyl)-5-(trifluoromethyl)picolinamide 30b as a colorless oil
(24 mg, 34%), retention time 4.01 min. LRMS C12H14F6N4O2 requires
M+ 360.1, found [MH]+ 361.2. 1H NMR (DMSO-d6) 1.27 (3H s), 2.82
(3H d J = 4.5), 3.45 (1H dd J = 13.8, 5.6), 3.64 (1H dd J = 13.8, 7.3),
5.90 (1H q J = 4.6), 6.22 (2H br s), 6.32 (1H s), 7.48 (1H s), 8.50 (1H t
J = 6.4).
(ent-1)-3-Amino-6-(dimethylamino)-N-(3,3,3-trifluoro-2-hy-
droxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide (31a)
and (ent-2)-3-Amino-6-(dimethylamino)-N-(3,3,3-trifluoro-2-
hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide
(31b). Dimethylamine (0.209 mL, 1.652 mmol) was added to solution
of 6-bromo-3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethyl)-
picolinic acid 48 (0.300 g, 0.826 mmol), and the reaction was stirred
at RT for 72 h and then partitioned between 0.5 M HCl and EtOAc.
The organic phase was washed with brine, dried (MgSO4) and
evaporated to afford crude 3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(dime-
thylamino)-5-(trifluoromethyl)picolinic acid as an orange oil (0.151 g,
56%) LRMS C15H16F3N3O2 requires M+ 327.12, found [MH]+ 328.2.
HATU (0.193 g, 0.507 mmol) was added to a solution of 3-(2,5-
dimethyl-1H-pyrrol-1-yl)-6-(dimethylamino)-5-(trifluoromethyl)-
picolinic acid (0.151 g, 0.461 mmol) and ( )-3-amino-1,1,1-trifluoro-
2-methylpropan-2-ol hydrochloride 41 (73 mg, 0.507 mmol) in NMP
(1 mL) followed by triethylamine (0.129 mL, 0.923 mmol). The
reaction was stirred at RT for 16 h and then partitioned between EtOAc
and 1 M NaOH. The organic phase was washed with brine, dried
(MgSO4) and evaporated to afford crude 3-(2,5-dimethyl-1H-pyrrol-1-
yl)-6-(dimethylamino)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-
5-(trifluoromethyl)picolinamide as an orange oil (0.165 g, 78%) LRMS
C19H22F6N4O2 requires M+ 452.16, found [MH]+ 453.3.
(ent-1)-3-Amino-6-(methylamino)-N-(3,3,3-trifluoro-2-hy-
droxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide (30a)
and (ent-2)-3-Amino-6-(methylamino)-N-(3,3,3-trifluoro-2-hy-
droxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide (30b).
Two molar aq NaOH (2.52 mL, 5.04 mmol) was added to a solution of
methyl 6-bromo-3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethyl)-
picolinate 43 (1.9 g, 1.504 mmol) in THF (10 mL). The reaction was
stirred at RT for 1 h, then poured into water, adjusted to pH4 with 1 M
HCl and extracted twice with EtOAc. The combined organic phases
were washed with brine, dried (MgSO4), and evaporated to afford crude
6-bromo-3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethyl)picolinic
acid 48 as an orange solid (1.78 g, 97%). LRMS C13H10BrF3N2O2
1
requires M+ 361.99, found [MH]+ 363.1. H NMR (DMSO-d6) 1.92
(6H s), 5.74 (2H s), 8.14 (1H s), 14.3 (1H br s).
Methylamine (2 M THF, 0.826 mL, 1.652 mmol) was added to a
solution of 6-bromo-3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-
(trifluoromethyl)picolinic acid 48 (0.300 g, 0.826 mmol) in THF (1
mL). The reaction was stirred at RT for 10 days, then partitioned
between 0.5 M HCl and EtOAc. The organic phase was washed with
brine, dried (MgSO4), and evaporated to afford crude 3-(2,5-dimethyl-
1H-pyrrol-1-yl)-6-(methylamino)-5-(trifluoromethyl)picolinic acid as
a red oil (0.240 g, 92%). LRMS C14H14F3N3O2 requires M+ 313.10,
found [MH]+ 314.2. 1H NMR (DMSO-d6) 1.89 (6H s), 2.92 (3H d J =
4.3), 5.72 (2H s), 7.03 (1H q J = 4.2), 7.72 (1H s), 13.3 (1H br s).
HATU (0.320 g, 0.843 mmol) was added to a solution of 3-(2,5-
dimethyl-1H-pyrrol-1-yl)-6-(methylamino)-5-(trifluoromethyl)-
picolinic acid (0.240 g, 0.766 mmol) and ( )-3-amino-1,1,1-trifluoro-
2-methylpropan-2-ol hydrochloride 41 (0.121 g, 0.843 mmol) in NMP
(1 mL) followed by triethylamine (0.214 mL, 1.532 mmol). The
reaction was stirred at RT for 16 h then partitioned between EtOAc and
1 M NaOH. The organic phase was washed with brine, dried (MgSO4)
and evaporated to afford crude 3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-
(methylamino)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-
(trifluoromethyl)picolinamide (0.174 g, 52%). LCMS C18H20F6N4O2
requires M+ 438.15, found [MH]+ 439.3.
Hydroxylamine hydrochloride (0.269 g, 3.88 mmol) was added to a
solution of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(methylamino)-N-
(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-
picolinamide (0.170 g, 0.388 mmol) in EtOH (5 mL) and water (3
mL), followed by triethylamine (0.108 mL, 0.776 mmol). The mixture
was heated at reflux for 10 h and stood at RT for 16 h. The reaction was
partitioned between 1 M HCl/EtOAc and the organic phase was
washed with brine, dried (MgSO4), and evaporated. Flash chromatog-
raphy (0−60% EtOAc-isohexanes gradient elution) afforded ( )-3-
amino-6-(methylamino)-N-(3,3,3-trifluoro-2-hydroxy-2-methylprop-
yl)-5-(trifluoromethyl)picolinamide which was separated by prepara-
tive chiral SFC (Chiralpak OJ-H column, eluting with 10%−50%
[MeOH + 0.1% diethylamine]-CO2 gradient to afford (ent-1)-3-amino-
6-(methylamino)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-
(trifluoromethyl)picolinamide 30a as a colorless oil (25 mg, 36%),
retention time 3.22 min. LRMS C12H14F6N4O2 requires M+ 360.1,
Hydroxylamine hydrochloride (0.253 g, 3.65 mmol) was added to a
solution of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(dimethylamino)-N-
(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-
picolinamide (0.165 g, 0.365 mmol) in EtOH (10 mL) and water (5
mL), followed by triethylamine (0.102 mL, 0.729 mmol). The mixture
was heated at reflux for 6 h. The reaction was partitioned between 1 M
HCl/EtOAc, and the organic phase was washed with brine, dried
(MgSO4), and evaporated. Flash chromatography (0−60% EtOAc-
isohexane gradient elution afforded 3-amino-6-(dimethylamino)-N-
(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-
picolinamide, which was separated by preparative chiral SFC (Chiralcel
OD-H column; 12% [2-propanol +0.1% DEA]/88% CO2 elution) to
afford (ent-1)-3-amino-6-(dimethylamino)-N-(3,3,3-trifluoro-2-hy-
droxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide 31a as a col-
orless glassy solid (25 mg, 36%), retention time 4.09 min. LRMS
1
C13H16F6N4O2 requires M+ 374.12, found [MH]+ 375.3. H NMR
(DMSO-d6) 1.26 (3H s), 2.67 (6H s), 3.48 (1H dd J = 13.8, 5.6), 3.64
(1H dd J = 13.8, 7.2), 6.32 (1H s), 6.79 (2H br s), 7.60 (1H s), 8.31 (1H
t J = 6.4) and (ent-2)-3-amino-6-(dimethylamino)-N-(3,3,3-trifluoro-2-
hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide 31b as a
colorless glassy solid (25 mg, 36%), retention time 4.74 min. LRMS
1
C13H16F6N4O2 requires M+ 374.12, found [MH]+ 375.3. H NMR
(DMSO-d6) 1.26 (3H s), 2.67 (6H s), 3.48 (1H dd J = 13.8, 5.6), 3.64
(1H dd J = 13.8, 7.2), 6.32 (1H s), 6.79 (2H br s), 7.60 (1H s), 8.31 (1H
t J = 6.4).
(S)-3-Amino-6-ethoxy-N-(3,3,3-trifluoro-2-hydroxy-2-meth-
ylpropyl)-5-(trifluoromethyl)picolinamide (32). Two molar
NaOH (135 mL, 270 mmol) was added to a solution of methyl 6-
bromo-3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethyl)picolinate
43 (34 g, 90 mmol) in MeOH (460 mL), and the reaction was heated at
90 °C for 3 h. The solvent was evaporated, and the residue was adjusted
to pH 1 with 2 M HCl and extracted twice with EtOAc. The combined
organic phases were washed with brine, dried (MgSO4), and evaporated
to afford 3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methoxy-5-
(trifluoromethyl)picolinic acid 49 as a reddish-brown solid (28.2 g,
100%). LRMS C14H13F3N2O3 requires M+ 314.09, found [MH]+ 315.2.
7256
J. Med. Chem. 2021, 64, 7241−7260