Sep-Oct 2005
Synthesis of 2-Cyanoacrylates Containing Pyridinyl Moiety
1213
5
c has more potent antitumor activity than 5a, 5b and 5d,
(E)-Ethyl 3-(2-chloro-4-methylpyridin-3-yl-amino)-2-cyano-3-
methylthioacrylate (3).
which shows that the nature of R group affects antitumor
activity to some extent. For example, when R is benzyl,
compound 5c has relatively higher activity to PC3 and
A431 cells than its less active analogues 5a and 5b, in
which the R groups were n-Pr- and n-Bu-, respectively.
To an oven-dried three-necked 50 mL round-bottom flask was
added ethyl 2-cyano-3,3-dimethylthioacrylate (1) (2.17 g, 0.01
mol), 3-amino-2-chloro-4-methylpyridine (2) (1.43 g, 0.01 mol),
6
0% sodium hydride (0.80 g, 0.02 mol), DMF (3 mL) and toluene
(3 mL). The resulting mixture was placed in the ultrasonic clean-
Conclusion.
ing bath at 40-45 °C for 1 h. The reaction progress was monitored
by TLC. The mixture was poured into ice water (100 mL) and
separated. The aqueous phase was acidified with 10% HCl to pH
In summary, we described a practical and efficient pro-
cedure for the preparation of ethyl 2-cyano-3-(2-chloro-4-
methylpyridin-3-ylamino)-3-methylthioacrylate through
the two-component reaction of ethyl 2-cyano-3,3-
dimethylthioacrylate and 2-amino-3-chloro-4-methylpyri-
dine using NaH as the base under ultrasonic irradiation
with DMF-toluene as co-solvent for 1 h at 40-45 °C. The
reactions were, in general, fast, and efficient. Followed by
amination with aliphatic amines, the target compounds
were obtained in moderate yields.
6
-7, and filtered. The residue was dried and recrystallized from
anhydrous ethanol to give a white solid, yield 73.5%, m.p. 113-
14 °C; IR: 3284.7, 2200.8, 1637.5, 1620.2, 1608.6, 1585.4,
1531.4, 1458.1, 1446.6, 1431.1, 1386.8, 1369.4, 1298.0, 1269.1,
1
-1 1
1120.6, 1109.0, 1085.9, 779.2 cm ; H NMR (400MHz, CDCl3):
δ 11.17(s, 1H, NH), 7.22-8.26(m, 2H, Py-H), 4.31(q, 2H, CH ),
2
J=7.9Hz); EIMS: m/z 311(M , 12.2).
Anal. Calcd. for C H ClN O S (311): C, 50.08; H, 4.53; N,
2
.55(s, 3H, SCH ), 2.34(s, 3H, Py-CH ), 1.38(t, 3H, CH -C,
3 3 3
+
1
3
14
3 2
1
3.48. Found: C, 50.00; H, 4.49; N, 13.48.
In the MTT bioassay, these new compounds have moder-
ate antitumor activities to PC3 and A431 cells. For example,
the inhibitive activity of compound 5c to PC3 and A431
cells at 10µM were 80.1% and 87.5%, respectively.
General Procedure for the Preparation of Products 5a-5d.
A solution of ethyl 3-(2-chloro-4-methylpyridin-3-ylamino)-2-
cyano-3-methyl- thioacrylate (3) (0.75 mmol) in EtOH (20 mL)
was stirred, followed by the addition of amine (4) (0.82 mmol).
The mixture was refluxed at 78-80 °C for 4 h. The solvent was
then removed under reduced pressure. The crude solid was puri-
fied by column chromatography on a silica gel (eluent: ethyl
acetate /petroleum ether, 2/8 by v/v) to give the title compounds.
EXPERIMENTAL
The reagents and solvents were all analytical grade or chemi-
cally pure and were obtained from Shanghai Reagent Company.
All solvents were dried, deoxygenated and redistilled before use.
All melting points of the products were determined on a XT-4
binocular microscope (Beijing Tech Instrument Co., China) and
are not corrected. The infrared spectra were recorded on a Bruker
(Z)-Ethyl 3-(2-Chloro-4-methylpyridin-3-ylamino)-3-propy-
lamino-2-cyanoacrylate (5a).
This compound was obtained as white crystal; yield 54.7%;
m.p. 143-145°C. IR: 2196.9, 1666.5, 1600.2, 1595.1, 1448.5,
1
VECTOR22 spectrometer in KBr pellets. H NMR (solvent
-1 1
1
327.0, 1284.5, 1255.6, 1166.9, 1114.8, 1097.5, 1066.6cm ; H
1
3
CDCl ) and C NMR spectra (solvent CDCl ) were performed
3
3
NMR (400MHz, CDCl ): δ10.78(s, 1H, NH-Py), 9.37(s, 1H, NH-
3
on a Varian-Inova 400 MHz spectrometer at room temperature
using TMS as internal standard. D O exchange was applied to
C), 7.17-8.23(m, 2H, Py-H), 4.21(q, 4H, NCH +OCH ), 2.66 (d,
2
2
2
3H, OCH , J=8.1Hz), 2.34 (s, 3H, Py-CH ), 1.31~1.68(m, 5H,
2
3
confirm the assignment of the signals of NH protons. The mass
spectra were taken on an HP5988A spectrometer. Elemental
analysis was performed by an Elementar Vario-III CHN analyzer.
Sonication was performed on a Shanghai Branson-CQX ultra-
sonic cleaner (with frequencies of 25 KHz and a nominal power
of 500 W). Analytical TLC was conducted on GF254 plastic
sheets at room temperature.
13
CH +CH ); 0.88 (d, 3H, CH , J=8.0Hz). C NMR (CDCl3):
3
2
3
1
70.63, 163.24, 148.36, 147.62, 125.11, 60.19, 18.39, 14.44;
+
EIMS: m/z 325(M , 14.8).
Anal. Calcd. for C H ClN O (323): C, 55.81; H, 5.93; N,
1
5
19
4 2
1
7.36. Found: C, 55.81; H, 5.89; N, 17.36.
(
Z)-Ethyl 3-Butylamino-3-(2-chloro-4-methylpyridin-3-
ylamino)-2-cyanoacrylate (5b).
Ethyl 2-cyano-3,3-dimethylthioacrylate (1)
This compound was obtained as white crystal; yield 74.5%;
m.p. 143-145 °C; IR: 2208.4, 1653.0, 1543.0, 1396.4, 1377.1,
This compound was obtained as a white solid (36.7 g), yield
5
6.2%; m.p. 53.5-54.5°C (lit.ref. [12-13], m.p. 53-54°C).
1
8
8
311.5, 1269.1, 1232.5, 1211.3, 1172.7, 1124.5, 1024.2,
-
1 1
81.4cm ; H NMR (400MHz, CDCl ): δ 10.76(s, 1H, NH-Py),
3
3
-Amino-2-chloro-4-methylpyridine (2).
.35(s, 1H, NH-C), 7.28-8.22(m, 2H, Py-H), 4.20(q, 4H, -
A solution of 15% sodium hydroxide (530.0 g, 2.0 mol) was
OCH +NCH ), 2.72(d, 5H, CH +SCH , J=8.2Hz), 2.35(s, 3H,
2 2 2 3
cooled to 0-5 °C. Bromine (80.0 g, 0.5 mol) was added dropwise
with the temperature maintained at 0-5°C. To the resulting pale
yellow solution was added 2-chloro-4-methylpyridine-3-carbox-
amide (85.0 g, 0.5 mol) in 2 h at 0-5 °C. The ice bath was then
removed and the reaction mixture warmed to 65-70 °C for 2 h
and maintained at 75 °C for an additional 2 h. The mixture was
cooled and the crystalline product collected by filtration. The
solid was dried and recrystallized from n-hexane affording white
solid, yield 92.1%, m.p. 68-69 °C (lit. ref. [14], m.p. 62-64 °C).
Py-CH ), 0.8~1.81(m, 5H, CH -CH ); 13C NMR (CDCl ):
3 2 3 3
125.07, 60.12, 18.37, 14.41, 13.36; EIMS: m/z 339(M+, 17.1).
Anal. Calcd. for C H ClN O (337): C, 57.06; H, 6.28; N,
1
6
21
4 2
16.63. Found: C, 57.06; H, 6.24; N, 16.64.
(
Z)-Ethyl 3-Benzylamino-3-(2-chloro-4-methylpyridin-3-yl-
amino)-2-cyanoacrylate (5c).
This compound was obtained as a white solid; yield 55.7%;
m.p. 140-142 °C; IR: 3197.9, 3107.3, 3030.1, 2985.8, 2191.1,