Journal of Medicinal Chemistry
Article
1H), 2.40 (s, 3H), 2.24 (s, 6H), 1.54 (br s, 2H), 1.49 (s, 9H). LC−MS
(ESI) m/z 521 (M + H)+.
(92 mg, 25%) using general procedure A, substituting 2,2-dimethyl-1-
(pyrrolidin-3-yl)propan-1-one (10) for pyrrolidine 4i used in general
1
(R)-2-(3-Aminopyrrolidin-1-yl)-N-(4-((4-((5-methyl-1H-pyra-
zol-3-yl)amino)pyrrolo[2,1-f ][1,2,4]triazin-2-yl)thio)phenyl)-
acetamide Dihydrochloride (6). (R)-tert-Butyl (1-(2-((4-((4-((5-
methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f ][1,2,4]triazin-2-yl)thio)-
phenyl)amino)-2-oxoethyl)pyrrolidin-3-yl)carbamate (prepared using
general procedure A from compound 2 and (R)-tert-butyl pyrrolidin-3-
ylcarbamate, 80 mg, 0.14 mmol) was stirred in EtOAc (1.0 mL) at
room temperature, and 4 N HCl in 1,4-dioxane (1.0 mL) was added.
The resulting mixture was stirred at room temperature for 8 h. Diethyl
ether (10 mL) was then added to the mixture, and the precipitate was
collected via filtration, washed with diethyl ether, and dried in a
vacuum oven to give (R)-2-(3-aminopyrrolidin-1-yl)-N-(4-((4-((5-
methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f ][1,2,4]triazin-2-yl)thio)-
phenyl)acetamide dihydrochloride (6) as a white solid (55 mg, 72%).
1H NMR (300 MHz, DMSO-d6) δ 11.20 (br s, 1H), 10.79−11.05 (m,
1H), 10.70 (br s, 1H), 8.67−8.86 (m, 2H), 8.60 (br s, 1H), 7.77 (d, J =
8.3 Hz, 2H), 7.65 (br s, 1H), 7.61 (d, J = 7.3 Hz, 2H), 7.23 (br s, 1H),
6.60 (d, J = 2.3 Hz, 1H), 5.69 (br s, 1H), 4.47 (d, J = 16.4 Hz, 2H),
3.82−4.23 (m, 2H), 3.50−3.81 (m, 2H), 3.38 (d, J = 6.2 Hz, 1H), 2.28
(br s, 1H), 2.08 (br s, 3H). LC−MS (ESI) m/z 462 (M − H)−.
(R)-N-(1-(2-((4-((4-((5-Methyl-1H-pyrazol-3-yl)amino)pyrrolo-
[2,1-f ][1,2,4]triazin-2-yl)thio)phenyl)amino)-2-oxoethyl)-
pyrrolidin-3-yl)isobutyramide (7a). General Procedure B. To a
suspension of compound 6 (92 mg, 0.17 mmol) in anhydrous THF (2
mL) at 0 °C was added dropwise Et3N (95 μL, 0.68 mmol), followed
by a solution of isobutyryl chloride (21 μL, 0.20 mmol) in THF. The
reaction mixture was then stirred at room temperature for 2 h. The
resulting mixture was quenched with water and extracted by EtOAc
(15 mL). The organic layer was separated, dried, and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography, eluting with DCM in MeOH (20:1 to 10:1, v:v) to
give (R)-N-(1-(2-((4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo-
[2,1-f ][1,2,4]triazin-2-yl)thio)phenyl)amino)-2-oxoethyl)pyrrolidin-3-
yl)isobutyramide (7a) (35 mg, 30% yield). 1H NMR (400 MHz,
DMSO-d6) δ 12.13 (s, 1H), 10.82 (s, 1H), 10.64 (d, J = 1.2 Hz, 1H),
10.35 (t, J = 1.6 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.71 (d, J = 8.4 Hz,
2H), 7.63 (d, J = 8.4 Hz, 2H), 7.57 (s, 1H), 7.21 (q, J = 1.2 Hz, 1H),
6.58 (d, J = 2.8 Hz, 1H), 5.68 (s, 1H), 4.31 (d, J = 2.0 Hz, 2H), 3.30−
3.94 (overlapping with solvent, m, 2H), 2.38 (m, 1H), 2.05 (s, 3H),
1.88−1.94 (m, 1H), 1.01 (d, J = 6.8 Hz, 6H). LC−MS (ESI) m/z 534
(M + H)+.
procedure A. H NMR (300 MHz, DMSO-d6) δ 12.08 (br s, 1H),
10.63 (s, 1H), 10.08 (br s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.52−7.64
(m, 3H), 7.22 (br s, 1H), 6.58 (br s, 1H), 5.63 (s, 1H), 3.56−3.75 (m,
1H), 3.34−3.43 (m, 1H), 3.18−3.30 (m, 1H), 2.91 (t, J = 8.6 Hz, 1H),
2.77−2.87 (m, 1H), 2.58−2.67 (m, 1H), 2.56 (br s, 1H), 2.02 (s, 3H),
1.90−2.01 (m, 1H), 1.67−1.86 (m, 1H), 1.10 (s, 9H). LC−MS (ESI)
m/z 533 (M + H)+.
(R)-tert-Butyl 3-(tert-Butylthio)pyrrolidine-1-carboxylate
(14). Step 1. To a stirred solution of (S)-tert-butyl 3-hydroxypyrro-
lidine-1-carboxylate (0.90 g, 4.8 mmol) in THF (5 mL) at 0 °C was
added Et3N (1.39 mL, 10.0 mmol), followed by dropwise addition of
methanesulfonyl chloride (0.68 g, 5.8 mmol). The resulting mixture
was then stirred at room temperature for 8 h before it was partitioned
between EtOAc (50 mL) and water (25 mL). The organic layer was
washed with brine (25 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure to give (S)-tert-butyl 3-
((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (1.07 g, 81%). LC−
MS (ESI) m/z 266 (M + H)+.
Step 2. To a suspension of NaH (60%, 211 mg, 5.27 mmol) in DMF
(3 mL) was added dropwise 2-methylpropane-2-thiol (237 mg, 2.64
mmol) at 0 °C. The reaction mixture was allowed to warm to room
temperature and stirred for 20 min. The resulting mixture was added
to a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesul-
fonate (350 mg, 1.32 mmol) in DMF (2 mL) at 0 °C. The reaction
mixture was stirred at room temperature for 8 h and then quenched
with 10% aqueous citric acid solution. The reaction mixture was
concentrated under reduced pressure and the residue was purified by
flash column chromatography, eluting with 5% EtOAc in petroleum
ether to afford (R)-tert-butyl 3-(tert-butylthio)pyrrolidine-1-carbox-
ylate (14) (300 mg, 88% yield). LC−MS m/z 260 (M + H)+.
(R)-3-(tert-Butylsulfinyl)pyrrolidine Hydrochloride (16). Step
1. To a solution of 14 (400 mg, 1.54 mmol) in DCM (5 mL) at −20
°C was added portionwise 70% 3-chloroperbenzoic acid (417 mg, 1.69
mmol). The reaction mixture was stirred at −30 °C for 20 min, then
quenched with aqueous Na2SO3 (5 mL). The resulting mixture was
partitioned between DCM (25 mL) and 10% NaOH (10 mL). The
organic layer was washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography, eluting with 10% EtOAc in dichloro-
methane to give (R)-tert-butyl 3-(tert-butylsulfinyl)pyrrolidine-1-
carboxylate (220 mg, 52% yield). LC−MS m/z 276 (M + H)+.
Step 2. To a solution of (R)-tert-butyl 3-(tert-butylsulfinyl)-
pyrrolidine-1-carboxylate (275 mg, 1.00 mmol) in MeOH (2 mL)
was added dropwise 4.5 N HCl in EtOAc at 0 °C. The mixture was
allowed to warm to room temperature and was stirred for 1 h. The
organic solvents were removed under reduced pressure and the residue
was dried to afford (R)-3-(tert-butylsulfinyl)pyrrolidine hydrochloride
(16) (190 mg, 90% yield). LC−MS m/z 176 (M + H)+. The crude
product was used directly in the next step without further purification.
2-((R)-3-(tert-Butylsulfinyl)pyrrolidin-1-yl)-N-(4-((4-((5-meth-
yl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f ][1,2,4]triazin-2-yl)thio)-
phenyl)acetamide (7f). Compound 7f was prepared as an off-white
solid (22 mg, 21% yield) using general procedure A, substituting (R)-
3-(tert-butylsulfinyl)pyrrolidine hydrochloride (16) for pyrrolidine 4i
used in general procedure A. 1H NMR (400 MHz, DMSO-d6) δ 12.08
(s, 1H), 10.63 (s, 1H), 10.09 (s, 1H), 7.85 (dd, J = 8.0 Hz, 2H), 7.78
(m, 3H), 7.22 (s, 1H), 6.57 (s, 1H), 5.62 (s, 1H), 4.03(d, J = 7.2 Hz,
1H), 3.47 (s, 2H), 3.17−2.64 (m, 4H), 2.32−1.92 (m, 5H), 1.14 (s,
9H). LC−MS m/z 553 (M + H)+.
(1-(1-Benzylpyrrolidin-3-yl)-2,2-dimethylpropan-1-one (9).
To a stirred solution of ethyl 1-benzylpyrrolidine-3-carboxylate (400
mg, 1.71 mmol) in THF (5 mL) at −78 °C was added tert-
butyllithium in THF (1.7 M, 1.0 mL, 1.7 mmol) dropwise. The
resulting mixture was left at −78 °C for 30 min before it was allowed
to warm to room temperature. After another 90 min, the reaction
mixture was quenched with saturated aqueous NH4Cl (15 mL) and
extracted with EtOAc (50 mL). The organic layer was washed with
brine (15 mL), dried over Na2SO4, and evaporated under reduced
pressure. The residue was purified by silica gel column chromatog-
raphy, eluting with 30−60% EtOAc in hexanes to give (1-(1-
benzylpyrrolidin-3-yl)-2,2-dimethylpropan-1-one (9) as a colorless
oil (200 mg, 48% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.32 (d, J
= 4.0 Hz, 5H), 3.64 (s, 2H), 3.49−3.61 (m, 1H), 2.80−3.02 (m, 2H),
2.29−2.55 (m, 2H), 1.96−2.12 (m, 1H), 1.79−1.95 (m, 1H), 1.12 (s,
9H). LC−MS (ESI) m/z 246 (M + H)+.
2,2-Dimethyl-1-(pyrrolidin-3-yl)propan-1-one (10). General
Procedure C. Compound 9 (210 mg, 0.86 mmol) was dissolved in 1
mL of MeOH. Then 10% Pd/C (35 mg) was added under argon
atmosphere. The mixture was stirred under a hydrogen atmosphere at
60 °C for 2 h. The reaction mixture was then filtered through a Celite
plug and the filtrate was evaporated under reduced pressure to give
2,2-dimethyl-1-(pyrrolidin-3-yl)propan-1-one (10) as a colorless oil
(120 mg, 90% yield). LC−MS (ESI) m/z 156 (M + H)+.
(R)-tert-Butyl 3-(3,3-Difluoropyrrolidine-1-carbonyl)-
pyrrolidine-1-carboxylate (19c). To a stirred solution of (R)-1-
(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (3.8 g, 17.7 mmol)
in DMF (20 mL) were added 3,3-difluoropyrrolidine hydrochloride
(2.8 g, 19.5 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-
tetramethyluronium hexafluorophosphate (8.1 g, 21.3 mmol) sequen-
tially. Triethylamine (7.6 mL, 53.1 mmol) was then slowly added to
the reaction mixture. The resulting mixture was then stirred at room
temperature overnight. The reaction mixture was quenched with water
N-(4-((4-((5-Methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f ]-
[1,2,4]triazin-2-yl)thio)phenyl)-2-(3-pivaloylpyrrolidin-1-yl)-
acetamide (7c). Compound 7c was prepared as an off-white solid
3257
dx.doi.org/10.1021/jm201702g | J. Med. Chem. 2012, 55, 3250−3260