Journal of Medicinal Chemistry
Article
reaction mixture was allowed to cool to room temperature and then
diluted with ethyl acetate (160 mL) and a mixture of saturated
aqueous sodium hydrogen carbonate (80 mL) and water (80 mL).
The phases were separated, and the aqueous layer was extracted with
ethyl acetate (2 × 100 mL). The combined organic extracts were
washed with brine, dried (Na SO ), and concentrated. The crude
to afford crude (R)-5-methyl-4-nitro-1-(tetrahydrofuran-3-yl)-1H-
pyrazole (83). This material was dissolved in EtOH (300 mL) and
MeOH (300 mL) (gentle heating with heat gun was used to get
everything into solution) and stirred with activated charcoal (5 g) for
1 h. The suspension was filtered and concentrated under reduced
pressure to afford (R)-5-methyl-4-nitro-1-(tetrahydrofuran-3-yl)-1H-
2
4
product was purified by silica gel column chromatography, eluting
with 60% ethyl acetate in petroleum ether, to afford 2.2 g (54%) of
pyrazole (83) (56.3 g, 83% yield) of sufficient purity for the
1
subsequent step. H NMR (500 MHz, CDCl ) δ: 8.11 (s, 1H), 4.94−
3
(
R)-4-amino-2-chloro-7-methyl-6-(2-methylpyrrolidin-1-yl)-7H-
4.85 (m, 1H), 4.23−4.11 (m, 2H), 4.05 (dd, J = 9.5, 4.4 Hz, 1H), 4.00
(dd, J = 14.6, 7.3 Hz, 1H), 2.70 (s, 3H), 2.47−2.38 (m, 2H). m/z =
198.0 [M + H] .
1
pyrrolo[2,3-d]pyrimidine-5-carbonitrile (78). H NMR (CDCl , 300
3
+
MHz) δ: 5.45 (br, 2H), 4.36−4.30 (m, 1H), 3.90−3.80 (m, 1H), 3.60
(
1
s, 3H), 3.39−3.08 (m, 1H), 2.31−2.24 (m, 1H), 2.08−1.94 (m, 2H),
Step 10. (R)-5-Methyl-4-nitro-1-(tetrahydrofuran-3-yl)-1H-pyra-
zole (83) (20 g, 101 mmol) was dissolved in ethanol (500 mL)
and added to a Parr-flask containing Pd−C (2.70 g, 2.54 mmol, 10%).
.72−1.58 (m, 1H), 1.26−1.24 (d, J = 6.0 Hz, 3H).
Step 7. (S)-Tetrahydrofuran-3-ol (79) (35 g, 397 mmol) and
trimethylamine hydrochloride (3.80 g, 39.7 mmol) were dissolved in
acetonitrile (397 mL). Triethylamine (83.0 mL, 596 mmol) was
added, and the solution was cooled to 0 °C using an ice/water bath.
The suspension was placed in a Parr-shaker [p(H ) = 1.5 bar]. The
2
reaction was shaken overnight at room temperature, leading to the full
consumption of the H . LC−MS at this point showed ∼5−10%
2
4-Methylbenzene-1-sulfonyl chloride (83 g, 437 mmol) was added
starting material left. The reaction was placed in the Parr-Shaker
portion wise (keeping the internal temperature below 10−12 °C),
resulting in the reaction mixture turning red-orange and the formation
of a white precipitate. The cooling bath was allowed to expire upon
overnight stirring (∼16 h). TLC analysis at this point showed almost
full conversion of the starting material. The reaction was diluted with
EtOAc (500 mL) and quenched with water (500 mL). The phases
were separated, and the aqueous layer was extracted with EtOAc (2 ×
[p(H ) = 1.5 bar] and reacted for another 2 h at room temperature,
2
upon which LC−MS showed full conversion into the product. The
reaction was filtered through a glass-filter paper and concentrated
under reduced pressure to afford (R)-5-methyl-1-(tetrahydrofuran-3-
yl)-1H-pyrazol-4-amine (84) (16.6 g, 98% yield) of sufficient purity
1
for the subsequent step. H NMR (600 MHz, CDCl ) δ: 7.19 (s, 1H),
3
4.80−4.73 (m, 1H), 4.15 (dd, J = 15.6, 7.7 Hz, 1H), 4.08 (dd, J = 9.1,
7.0 Hz, 1H), 4.01−3.93 (m, 2H), 2.67 (br s, 2H), 2.46−2.39 (m, 1H),
2.36−2.29 (m, 1H), 2.19 (s, 3H).
4
00 mL). The combined organics were washed with brine (250 mL),
dried over MgSO , filtered, and concentrated under reduced pressure
4
to afford (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (80)
Step 11. (R)-4-Amino-2-chloro-7-methyl-6-(2-methylpyrrolidin-1-
yl)-7H-pyrrolo[2,3-d]pyrimi-dine-5-carbonitrile (78) (250 mg, 0.86
mmol) and (R)-5-methyl-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-
amine (84) (216 mg, 1.29 mmol) were placed in a reaction flask.
p-Toluenesulfonic acid monohydrate (409 mg, 2.15 mmol) was
added, followed by N-methyl-2-pyrrolidone (3.4 mL). The resulting
suspension was heated to 140 °C for approximately 14 h. The
reaction mixture was then allowed to cool to room temperature and
1
(
91.5 g, 95% yield) of sufficient purity for the subsequent step. H
NMR (600 MHz, CDCl ) δ: 7.82−7.77 (m, 2H), 7.38−7.34 (m, 2H),
3
5
3
.13−5.10 (m, 1H), 3.89 (dt, J = 8.5, 7.1 Hz, 1H), 3.87−3.79 (m,
H), 2.46 (s, 2H), 2.13−2.06 (m, 2H).
Step 8. Two reactions were run in parallel under identical
conditions: (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (80)
45.8g, 189 mmol) was dissolved in DMF (275 mL). Potassium
(
carbonate (39 g, 283 mmol) was added followed by 4-nitro-1H-
pyrazole (81) (22.4 g, 198.5 mmol). The resulting suspension was
heated to 75 °C and stirred overnight. The two reactions were cooled
to room temperature and concentrated down to approximately half
the initial volume under reduced pressure. The two reaction mixtures
were combined diluted with water (500 mL) and EtOAc (500 mL).
The phases were separated, and the aqueous layer was washed with
EtOAc (2 × 300 mL). The combined organics were washed with 1 M
quenched with saturated aqueous NaHCO (25 mL) and EtOAc (25
mL). The phases were separated, and the aqueous layer was extracted
3
with EtOAc (2 × 15 mL). The combined organics were washed with
brine (4 × 10 mL), dried over MgSO , filtered, and concentrated
4
under reduced pressure. The crude material was purified using an Isco
Combiflash system (24 g SiO , gradient elution; heptane/EtOAc/
2
TEA = 95:0:5 → 0:95:5) to afford 4-amino-7-methyl-2-({5-methyl-1-
[(3R)-oxolan-3-yl]-1H-pyrazol-4-yl}amino)-6-[(2R)-2-methylpyrroli-
din-1-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (44) (165 mg,
46% yield). [α] + 29 (c 0.13, MeOH). t = 0.89 min (Method A).
NaOH (250 mL), brine (3 × 250 mL), dried over MgSO , filtered,
4
and concentrated under reduced pressure to afford (R)-4-nitro-1-
D
R
+
+
(
tetrahydrofuran-3-yl)-1H-pyrazole (82) (62.8 g, 91% yield of
HRMS (ESI ) calcd for [C H N O + H] : 422.2411; found,
422.2414. H NMR (DMSO-d , 400 MHz) δ: 7.95 (s, 1H, 4-NH),
21 27 9
1
1
sufficient purity for the subsequent step. H NMR (600 MHz,
6
CDCl ) δ: 8.24 (s, 1H), 8.09 (s, 1H), 5.01 (ddt, J = 8.3, 5.6, 2.8 Hz,
7.69 (s, 1H, 3-H), 5.95 (s, 2H), 4.99−4.91 (m, 1H, 1-CH), 4.19−4.09
(m, 1H), 4.06−3.94 (m, 2H), 3.88−3.70 (m, 3H), 3.43 (s, 3H),
3.29−3.21 (m, 1H), 2.32−2.25 (m, 2H), 2.25−2.16 (m, 1H), 2.20 (s,
3H, 5-Me), 2.03−1.79 (m, 2H), 1.63−1.50 (m, 1H), 1.14 (d, J = 6.0
Hz, 3H). In an NOED spectroscopic experiment, irradiation of the
signal at δ 7.95 (pyrazole 4-NH) enhanced the signal at δ 7.69
(pyrazole 3-H) and δ 2.20 (pyrazole 5-Me), irradiation of the signal at
δ 7.69 (pyrazole 3-H) enhanced the signal at δ 7.95 (pyrazole 4-NH),
and irradiation of the signal at δ 2.20 (pyrazole 5-Me) enhanced the
signal at δ 7.95 (pyrazole 4-NH) and δ 4.99−4.91 (pyrazole 1-CH).
3
1
8
1
H), 4.18−4.11 (m, 2H), 4.04 (dd, J = 10.2, 5.7 Hz, 1H), 3.96 (dt, J =
.8, 5.5 Hz, 1H), 2.59−2.49 (m, 1H), 2.37−2.30 (m, 1H). m/z =
+
84.0 [M + H] . SFC (Method B): t = 1.64 min, ee 98.5%.
R
Step 9. Trimethylsulfoxonium iodide (136 g, 618 mmol) was
placed in a three-neck round bottom flask fitted with a thermometer
and an additional funnel. DMSO (anhydrous) (344 mL) was added,
resulting in a suspension. Potassium tert-butoxide (69.3 g, 618 mmol)
was added to the mixture, and the resulting suspension was stirred at
room temperature for 1 h, during which time the reaction almost
became a clear, colorless solution. (R)-4-Nitro-1-(tetrahydrofuran-3-
yl)-1H-pyrazole (82) (62.84 g, 343 mmol) was dissolved in DMSO
1
3
C NMR (DMSO-d , 100 MHz) 158.0, 155.8, 151.2, 149.2, 133.9,
6
1
2
29.7, 121.2, 118.9, 93.4, 72.1, 67.8, 66.2, 57.6, 56.2, 52.6, 34.1, 32.4,
9.7, 24.7, 20.0, 9.4. SFC (Method C): tR = 2.065 min, de 99%
(59 mL) and added to the reaction in a dropwise manner using an
additional funnel (added over ∼2 h 30 min). During the addition, the
internal temperature was kept below 33−35 °C by occasional cooling
with a water/ice bath. The reaction was stirred overnight at room
temperature (approximately 16 h), at which point LC−MS showed
almost complete conversion into the desired product. The reaction
mixture was quenched with aq. HCl (1 M, 400 mL) and diluted with
EtOAc (700 mL). The phases were separated, and the aqueous layer
was extracted with EtOAc (2 × 300 mL). The combined organics
were washed with 5% aq. Na S O (500 mL), brine (3 × 400 mL),
(
determined by comparison with analytical SFC of a 1:1 mixture of 44
and 45 prepared in an analogous manner starting from racemic 79).
The SFC retention time of 44 prepared using the non-stereoselective
route matched the SFC retention time of 44 prepared using the
stereoselective route.
Stereoselective Synthesis of 4-Amino-7-methyl-2-({5-methyl-1-
[(3S)-oxolan-3-yl]-1H-pyrazol-4-yl}amino)-6-[(2R)-2-methylpyrroli-
din-1-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (45). The ster-
eoselective preparation of (45) was conducted in a manner similar to
2
2
3
dried over MgSO4, filtered, and concentrated under reduced pressure
(44), starting from (R)-tetrahydrofuran-3-ol (85): [α] +11 (c 0.12,
D
1
0329
J. Med. Chem. 2021, 64, 10312−10332