JOURNAL OF CHEMICAL RESEARCH 2016 513
(
4
4) and cyanamide. The other starting material, methyl
-acetylbenzoate (8), was converted into intermediate 9 in the
2 h. After cooling to room temperature, the organic solvent was removed
under reduced pressure and the residue was acidified with hydrochloric
acid (1 M) to pH 3. The solid was filtered, off, washed with water and
dried under reduced pressure to afford compound 6: Yield 3.2 g (85%)
presence of N,N-dimethylformamide dimethylacetal (DMF-DMA)
under reflux. With these two fragments in hand, the cyclisation
reaction proceeded smoothly under alkaline conditions to afford
the 2-aminopyrimidine derivative, which was directly hydrolysed
to compound 6 without further purification. Finally, momelotinib
was successfully formed by the amidation reaction. The overall
yield of momelotinib was 66% based on methyl 4-acetylbenzoate.
In summary, we have developed a novel and efficient approach
for the synthesis of momelotinib. This improved synthetic route
employed 4-morpholinoaniline (4) and methyl 4-acetylbenzoate
(
1
over two steps); m.p. > 250 °C; IR: 2951, 1716, 1686, 1590, 1514 1450,
–1
424, 1118 cm . Anal. calcd for C H N O : C, 67.01; H, 5.36; N, 14.88;
21 20 4 3
+
found: C, 67.25; H, 5.19; N, 15.06%. ESI-MS: 377.2 [M + H] , 375.1 [M
–
-
1
H] ; H NMR (300 MHz, DMSO-d ): δ 9.45 (s, 1H), 8.53 (d, J = 5.1 Hz,
6
1H), 8.23 (d, J = 8.1 Hz, 2H), 8.09 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.7 Hz,
2
H), 7.37 (d, J = 5.1 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 3.74–3.76 (m, 4H),
13
3.04–3.07 (m, 4H); C NMR (75 MHz, DMSO-d ): δ 162.6, 160.3, 159.2,
6
146.2, 140.4, 132.8, 129.6, 128.1, 126.8, 120.3, 115.6, 107.6, 66.1, 49.2 (one
peak was not located, presumably due to fortuitous overlap).
(8) as the starting materials to afford momelotinib by a nucleophilic
substitution reaction, cyclisation, hydrolysis and an amidation
reaction. The overall yield of this procedure was as high as 66%
based on methyl 4-acetylbenzoate. Moreover, this procedure has
simple operating requirements, is without noble metal catalyst and
the new stages are suitable for industrial production.
Synthesis of N-(cyanomethyl)-4-{2-[(4-morpholinophenyl)amino]
pyrimidin-4-yl}benzamide (momelotinib)
Et N (4.1 mL, 30 mmol) was added to a mixture of compound
3
6 (1.88 g, 5.0 mmol) in DMF (20 mL). Then aminoacetonitrile
hydrochloride (0.93 g, 10 mmol) was added followed by
N-hydroxybenzotriazole (HOBt, 0.81 g, 6.0 mmol) and 1-ethyl-3-
Experimental
(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 1.1 g,
All the reagents were obtained from commercial sources and used without
further purification. Melting points were determined on a RY-1 hot stage
microscope and are uncorrected. H NMR and C NMR spectra were
recorded on a Bruker Avance DPX-300 MHz instrument in DMSO-d6.
Chemical shifts (δ) are given in parts per million (ppm) relative to TMS
as an internal standard. Mass spectra (MS) were obtained on an Agilent
6.0 mmol). The mixture was stirred overnight at room temperature.
After removing the solvents under reduced pressure, the residue was
dissolved in CH Cl (100 mL) and washed with NaHCO3 aqueous
1
13
2
2
solution. The organic phase was dried over anhydrous Na SO and the
2
4
solvent was removed under reduced pressure. The residue was purified
by column chromatography on 200–300 mesh silica with EtOAc to afford
1
4
1100 LC/MS spectrometer. IR spectra were obtained on a PerkinElmer
momelotinib as: Yellow solid; yield 1.86 g (90%); m.p. 232–234 °C (lit.
–1
1600 series FTIR spectrometer. Elemental analyses were performed using
238–243 °C); IR: 3365, 3282, 1660, 1596, 1576, 1512, 1456, 1232 cm .
Anal. calcd for C H N O : C, 66.65; H, 5.35; N, 20.28; found: C, 66.78;
an Arial Font Vario EL analyser. All reactions were monitored by TLC on
silica gel GF-254 glass plates.
23
22
6
2
+
+
H, 5.49; N, 20.39%. ESI-MS: 415.1 [M + H] , 437.1 [M + Na] , 413.2 [M
H] ; H NMR (300 MHz, DMSO-d ): δ 9.47 (s, 1H), 9.32 (t, J = 5.4 Hz,
–
1
–
6
Synthesis of 1-(4-morpholinophenyl)guanidine (7)
1H), 8.54 (d, J = 5.1 Hz, 1H), 8.27 (d, J = 8.1 Hz, 2H), 8.03 (d, J = 8.1 Hz,
Concentrated hydrochloric acid (4 mL) was added to a solution of
2
H), 7.67 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 5.1 Hz, 1H), 6.94 (d, J = 8.7 Hz,
H), 4.35 (d, J = 5.1 Hz, 2H), 3.74–3.77 (m, 4H), 3.04–3.07 (m, 4H);
4
-morpholinoaniline (1.78 g, 10 mmol) in EtOH (10 mL) at 0 °C. Then
2
cyanamide (2 mL of 50% solution in water, 25.7 mmol) was added and the
mixture was heated to reflux for 10 h. After cooling to room temperature,
the solvent was removed under reduced pressure. Then saturated sodium
carbonate aqueous solution (10 mL) was added to the residue. The
solid was filtered off, washed with acetone and dried under reduced
1
3
C NMR (75 MHz, DMSO-d ): δ 166.1, 162.4, 160.3, 159.2, 146.2, 139.9,
6
134.5, 132.8, 127.8, 126.9, 120.3, 117.5, 115.6, 107.6, 66.1, 49.2, 27.7.
The authors thank the NSFC (No. 81501529) and the Fundamental
Research Funds for the Central Universities (2015PY001) for
financial support.
1
6
pressure to afford compound 7 as: Off white solid; yield 2.3 g (82%);
–1
m.p. 224–226 °C; IR: 3084, 1693, 1631, 1518, 1450, 1406, 1267 cm .
Anal. calcd for C H N O: C, 59.98; H, 7.32; N, 25.44; found: C, 59.87;
11
16
4
Published online: 22 July 2016
+
– 1
H, 7.49; N, 25.59%. ESI-MS: 221.2 [M + H] , 219.1 [M – H] ; H NMR
300 MHz, DMSO-d ): δ 7.16 (brs, 2H), 6.86–6.89 (m, 4H), 6.59 (brs, 1H),
.25 (brs, 1H), 3.71–3.74 (m, 4H), 3.02–3.05 (m, 4H); C NMR (75 MHz,
(
4
6
13
DMSO-d ): δ 160.0, 154.9, 147.7, 124.7, 116.1, 66.1, 48.9.
References
6
1
2
3
4
5
6
7
8
K. Shuai and B. Liu, Nat. Rev. Immunol., 2003, 3, 900.
C. Schindler, D.E. Levy and T. Decker, J. Biol. Chem., 2007, 282, 20059.
W.J. Leonard and J.J. O’Shea, Annu. Rev. Immunol., 1998, 16, 293.
D.S. Aaronson and C.M. Horvath, Science, 2002, 296, 1653.
A. Tefferi, Blood, 2012, 119, 2721.
A. Tefferi and A. Pardanani, Blood Rev., 2011, 25, 229.
R.P. Hasserjian, Curr. Canc. Ther. Rev., 2012, 8, 14.
R.A. Mesa, U. Yasothan and P. Kirkpatrick, Nat. Rev. Drug Discov., 2012,
Synthesis of methyl (E)-4-[3-(dimethylamino)acryloyl]benzoate (9)
A mixture of methyl 4-acetylbenzoate (2.5 g, 14 mmol) and DMF-DMA
(10 mL) was heated at 85 °C for 20 h. After cooling to room temperature,
the resulting solid was collected by filtration and washed with diethyl ether
to give methyl (E)-4-[3-(dimethylamino)acryloyl]benzoate as: Yellow
17
solid; yield 2.8 g (86%); m.p. 169–171 °C (lit. 177 °C); IR: 1717, 1635,
–
1
1
6
[
578, 1538, 1279 cm . Anal. calcd for C H NO : C, 66.94; H, 6.48; N,
13 15 3
11, 103.
+
.00; found: C, 66.82; H, 6.37; N, 5.87%. ESI-MS: 234.1 [M + H] , 256.1
M + Na] ; H NMR (300 MHz, DMSO-d ): δ 7.98–8.01 (m, 4H), 7.76 (d,
J = 12.0 Hz, 1H), 5.84 (d, J = 12.0 Hz, 1H), 3.88 (s, 3H), 3.17 (s, 3H), 2.94
s, 3H); C NMR (75 MHz, DMSO-d ): δ 184.6, 165.8, 154.7, 144.2, 131.1,
28.9, 127.3, 91.0, 52.2, 44.5, 37.2.
9
C.J. Menet, L. Rompaey and R. Geney, Prog. Med. Chem., 2013, 52, 153.
+
1
6
10 P. Wang, J. Cai, J.Q. Chen and M. Ji, Eur. J. Med. Chem., 2015, 93, 1.
P. Wang, M. Ji and F. Sha, J. Chem. Res., 2014, 38, 622.
1
1
13
(
1
12 J.O. Mascarenhas, N.C.P. Cross and R.A. Mesa, Blood Rev., 2014, 28, 189.
13 A. Rosenthal and R.A. Mesa, Expert. Opin. Pharmacother., 2014, 15, 1265.
14
6
C.J. Burns, A.C. Donohue, J.T. Feutrill, T.L.T. Ngygen, A.F. Wilks and J.
Zeng, 2008, WO2008109943.
Synthesis of 4-{2-[(4-morpholinophenyl)amino]pyrimidin-4-yl}benzoic
acid (6)
15 C.J. Burns, A. Spencer and K.A. Monaghan, 2012, WO2012149602.
16
S.D. Wang, C.A. Midgley, F. Scaerou, J.B. Grabarek, G. Griffiths, W.
Jackson, G. Kontopidis, S.J. McClue, C. McInnes, C. Meades, M. Mezna,
A. Plater, I. Stuart, M.P. Thomas, G. Wood, R.G. Clarke, D.G. Blake, D.I.
Zheleva, D.P. Lane, R.C. Jackson, D.M. Glover and P.M. Fischer, J. Med.
Chem., 2010, 53, 4367.
Compound 7 (2.4 g, 11 mmol) and compound 9 (2.3 g, 10 mmol) were
added to n-butyl alcohol (70 mL). Then NaOH (0.8 g, 20 mmol) was
added to the mixture which was heated to reflux for 24 h. The solid was
filtered off and used for the next step without purification. The filtered
solid was dissolved in acetone (40 mL) and then treated with LiOH
17 S.-I. Murahashi, Y. Mitsue and T. Tsumiyama, Bull. Chem. Soc. Jpn., 1987,
60, 3285.
(
0.5 g, 20.8 mmol) in H O (10 mL). The mixture was heated at reflux for
2