Month 2017
New and Practical Synthesis of Momelotinib
were filtered off, and the filtrate was treated with 20% NaOH
aqueous solution below 40°C to pH ~ 12. The resulting solid
was collected by suction filtration, washed with cooled H2O
(100 mL × 3), dried at 40°C for 4 h to afford 12 (85.9 g, 78%)
as a light brown solid; mp 280.5°C (dec.). 1H NMR (DMSO-
d6, δ): 2.98 (m, 4H), 3.72 (m, 4H), 4.99 (brs, 4H), 6.67 (d,
J = 6.8 Hz, 1H), 6.80 (d, J = 6.8 Hz, 1H). ESI-MS (m/z)
221.2 (M + H)+, 442.2 (2M + H)+.
0.8 mL/min; temperature, 30°C; injection load, 2 μL;
solvent, methanol; concentration, 0.1 mg/mL; run time,
25 min; mobile phase, methanol/water = 90/10; tR,
2.490 min; and purity, 97.2%.
Momelotinib (1). A mixture of compound 10 (75.3 g,
0.20 mol), DMF (800 mL), and TEA (69.5 mL,
0.50 mol) was stirred at room temperature. Then,
glycinonitrile hydrochloride (23.1 g, 0.25 mol), HOBt
(40.5 g, 0.30 mol), and EDC.HCl (57.5 g, 0.30 mol) was
added. The suspension was stirred at room temperature
for 10 h. The reaction mixture was poured into H2O
(3 L) and stirred for another 1 h. The resulting solid was
filtered, washed with water (100 mL × 2), and dried at
50°C for 4 h to give the crude product 1, which was
stirred and heated with 1:2 (v/v) EtOH/EtOAc (220 mL)
at reflux for 1 h then cooled to room temperature
overnight; the resulting solid was filtered off and washed
with 1:2 (v/v) EtOH/EtOAc (80 mL × 2) and dried at
50°C for 3 h to afford 1 (72.0 g, 87%) as an off-white
Methyl 4-(3-(dimethylamino)acryloyl)benzoate (14). To
a stirred suspension of methyl 4-acetylbenzoate 13
(89.0 g, 0.50 mol) in toluene (800 mL) was added DMF–
DMA (119.0 g, 1.0 mol). The mixture was stirred and
heated to reflux for 6 h, and then cooled to room
temperature [10]. The resulting solid was collected by
suction filtration, washed with toluene (100 mL × 2), and
dried at 50°C for 4 h to give 14 (95.6 g, 82%) as a light
1
yellow solid; mp 184.9°C (dec.). H NMR (CDCl3, δ):
2.97 (s, 3H), 3.19 (s, 3H), 3.95 (s, 3H), 5.72 (d,
J = 12.4 Hz, 1H), 7.93 (d, J = 12.4 Hz, 1H), 7.94 (d,
J = 8.4 Hz, 2H), 8.08 (d, J = 8.4 Hz, 2H). ESI-MS (m/z)
234.2 (M + H)+, 467.3 (2M + H)+, 489.2 (2M + Na)+.
1
solid; mp 240.5°C (dec.). H NMR (DMSO-d6, δ): 3.06
(m, 4H), 3.75 (m, 4H), 4.36 (d, J = 5.6 Hz, 2H), 6.94 (d,
J = 10.4 Hz, 2H), 7.40 (d, J = 5.2 Hz, 1H), 7.68 (d,
J = 10.4 Hz, 2H), 8.03 (d, J = 9.2 Hz, 2H), 8.27 (d,
J = 9.2 Hz, 2H), 8.54 (d, J = 5.2 Hz, 1H), 9.34 (t,
J = 5.6 Hz, 1H), 9.51 (s, 1H). 13C NMR (100 MHz,
DMSO-d6): δ 28.2, 49.8, 66.7, 108.5, 116.1, 117.9,
120.9, 127.4, 128.4, 133.3, 135.0, 140.5, 146.8, 159.7,
160.9, 162.9, 166.7. ESI-MS (m/z) 415.2 (M + H)+.
HPLC conditions are as follows: column, Acclaim C18
(150 mm × 2.1 mm × 5 μm); detection, 220 nm; flow
rate, 0.8 mL/min; temperature, 30°C; injection load,
1 μL; solvent, methanol; concentration, 0.2 mg/mL; run
time, 15 min; mobile phase, methanol/water = 90/10; tR,
3.527 min; and purity: 99.1%.
Methyl
4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)
benzoate (15). A suspension of compound 12 (66.1 g,
0.30 mol) and compound 14 (70.0 g, 0.30 mol) was
stirred in acetonitrile (1 L) and heated to reflux for 10 h.
The reaction mixture was cooled to room temperature;
the resulting solid was collected by suction filtration,
washed with 50% CH3CN/H2O (300 mL × 2), and dried
at 50°C for 4 h to give product 15 (94.8 g, 81%) as an
1
off-white solid; mp 215.5°C (dec.). H NMR (DMSO-d6,
δ): 3.06 (m, 4H), 3.75 (m, 4H), 3.90 (s, 3H), 6.94 (d,
J = 9.2 Hz, 2H), 7.40 (d, J = 5.6 Hz, 1H), 7.67 (d,
J = 9.2 Hz, 2H), 8.12 (d, J = 8.4 Hz, 2H), 8.28 (d,
J = 8.4 Hz, 2H), 8.55 (d, J = 5.6 Hz, 1H), 9.51 (s, 1H).
ESI-MS (m/z) 391.2 (M + H)+.
4-(2-((4-Morpholinophenyl)amino)pyrimidin-4-yl)benzoic
Acknowledgment. This work was supported by the
Undergraduate Innovative Training Project of Shanghai (No.
cs1504001, cs1604004).
acid (10). A solution of NaOH (12.1 g, 0.30 mol) and H2O
(200 mL) was added to the suspension of methanol (800 mL)
and compound 15 (85.9 g, 0.22 mol). The reaction mixture
was stirred and heated to reflux for 2 h to give a light
yellow clear solution. Around 500-mL methanol was
recovered from the solution under reduced pressure. And
concentrated HCl (~26.0 mL) was then added to the
mixture slowly with vigorous agitation below 40°C until
the solution pH ~ 4. The resulting solid was filtered,
washed with water (20 mL × 2), and dried at 50°C for 4 h
to give product 10 (79.5 g, 96%) as a light brown solid;
mp > 300°C (dec.). 1H NMR (DMSO-d6, δ): 3.06 (m, 4H),
3.75 (m, 4H), 6.94 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 4.4 Hz,
1H), 7.67 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 4.4 Hz, 2H),
8.20 (d, J = 4.4 Hz, 2H), 8.52 (d, J = 4.4 Hz, 1H), 9.47 (s,
1H). ESI-MS (m/z) 377.2 (M + H)+. HPLC conditions are
as follows: column, Agilent Eclipse XDB-C18
(250 mm × 4.6 mm × 5 μm); detection, 220 nm; flow rate,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet