Vol. 28, No. 6 (2016)
Design and Synthesis of Novel Dasatinib Analogues 1277
6
4.2, 43.73-43.8, 43.0, 41.0 25.5, 20.5 18.2; Mass: 516.4; IR
2-[[6-[4-[(2S)-2-amino-4-methyl-pentanoyl]-1-
piperazin]-2-methyl-4-pyrimidin]amino]-N-(2-chloro-6-
methylphenyl)-5-thiazolecarboxamide [2(c)]: The obtained
crude compound was purified from column chromatography
-
1
(
KBr, νmax, cm ): 3405.2, 3255.9, 3063.4, 2979.2, 2923.1,
1
632.5, 1577.6, 771.9.
N-(2-Chloro-6-methylphenyl)-2-[[2-methyl-6-[4-[3-
(
trifluoromethylsulfonyl)benzo yl]-1-piperazinyl]-4-
by elution of 5 % methanol in chloroform, m.p.: 160.4 °C;
1
pyrimidinyl]amino]-5- thiazolecarboxamide [2(h)]: m.p.:
1
δ 2.24 (s, 3H), 2.42 (s, 3H), 3.43-3.74 (t, 8H), 6.075 (s, 1H),
7
7
9
1
1
1
HPLC: 99.3 %; H NMR (DMSO-d
6
): δ 0.878-0.91 (d, 6H, J
1
95 °C (MeOH cryst.); HPLC: 97.2 %; H NMR (DMSO-d
6
):
= 6.4 Hz), 1.23-1.290 (m, 3H), 1.75-1.82 (m, 1H), 2.243 (s,
3H), 2.430 (s, 3H), 3.49-3.69 (m, 8H) 6.068 (s, 1H), 7.14-7.3
(m, 2H J = 6.4 Hz), 7.39-7.41 (d, 1H, J = 7.6), 8.22 (s, 1H),
.23-7.2 (q, 2H, J = 7.6 Hz), 7.39-7.41 (d, 1H, J = 6.8 Hz),
13
.94-7.98 (t, 1H), 8.11-8.136 (d, 1H7.6 Hz), 8.20-8.26 (q, 3H),
9.9 (s, 1H), 11.5 (s, 1H); C NMR (DMSO-d ): δ 173.9, 165.1,
6
13
.891 (s, 1H) 11.54 (s, NH); C NMR (DMSO-d
6
): δ 166.4,
162.2-162.5, 159.8, 156.9, 140.7, 138.7, 133.4, 132.4, 128.9,
128.1, 126.9, 125.7, 82.7, 54.4, 44.1, 43.7 43.2, 40.8, 38.3,
65.2, 162.4, 162.2, 159.9, 156.9, 140.8, 138.8, 138.1, 136.0,
33.4, 132.4, 1316, 131.2-131.6, 129.9, 129.0, 128.1, 126.9,
25.7, 120.9, 117.7, 82.9, 46.3, 43.3, 42.8, 41.4, 25.5, 18.2;
-1
25.5, 23.118.2, 16.0, 1 1.4; Mass: 557.38; IR (KBr, νmax, cm ):
3383.53, 3252.17, 2954.94, 2926.14, 2867.48, 1614.54,
1577.76, 771.15.
-1
Mass; 680.27; IR (KBr, νmax, cm ): 3404.72, 3190.92, 2922.51,
1
665.02 1618.07, 1578.07, 766.78.
2-[[6-[4-[(2S,3S)-2-amino-3-methyl-pentanoyl]-1-
piperazinyl]-methyl4pyrimidinyl]amino]-N-(2-chloro-6-
methylphenyl)-5-thiazolecarboxamide [2(d)]: The obtained
crude compound was purified from column chromatography
N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(4,4-difluo-
rocyclohexanecarbonyl)-1-piperazinyl]-2-methyl-4-
pyrimidinyl]amino]-5-thiazolecarboxamide [2(f)]:
Recrystallization from methanol. m.p.: 277.1 °C; HPLC:
by elution of 5 % MeOH in CHCl
3
m.p.: 160.4 °C; HPLC:
1
1
9
1
7.97.6 %; H NMR (DMSO-d
.93 (m, 3H), 2.04-2.06 (t, 2H J = 6.8 Hz), 2.240 (s, 3H) 2.42
6
): δ 1.57-1.63 (q, 2H), 1.75-
99.3 %; H NMR (DMSO-d
6
): δ 0.828-0.866 (q, 6H), 1.016-
1.090 (m, 1H), 1.44-1.53 (m, 2H), 2.24 (s, 3H), 2.42 (s, 3H),
(
s, 3H), 2.80-2.85 (m, 1H), 3.55-3.64 (t, 8H), 6.074 (s, 1H),
.23-7.25 (d, 1H, J = 7.6 Hz), 7.27-7.3 (t, 1H J = 7.2 Hz),
3.47-3.48 (d, 2H, J = 6 Hz), 3.62-3.64 (m, 8H, J = 6.8 Hz),
7
8
d
1
8
1
2
6.2 (s, 1H), 7.23-7.3 (m, 2H, J = 6.4 Hz), 7.39-7.41 (d, 1H, J
13
13
.22 (s, 1H), 9.89 (s, 1H) 11.46 (s, NH); C NMR (DMSO-
): δ 172.5, 165.2, 162.23-162.55, 159.9, 156.9, 140.8, 138.8,
= 7.6), 9.89 (s, 1H); C NMR (DMSO-d
6
): δ 173.9, 165.1,
6
162.2-162.5, 159.8, 156.9, 140.7, 138.7, 133.4, 132.4, 128.9,
128.1, 126.9, 125.7, 82.7, 54.4, 44.1, 43.7 43.2, 40.8, 38.3,
33.5, 132.4, 129.0, 128.1, 126.9 125.74-126.10, 123.7, 121.3,
2.8, 43.8-44.12, 43.1, 40.6, 36.4, 32.00-32.4, 25.4-25.5,
-1
25.5, 23.118.2, 16.0, 11.4: Mass: 557.38; IR (KBr, νmax, cm ):
3387.65, 3252.43, 2962.19, 2927.72, 2874.12, 1613.58,
1577.93, 773.19.
-1
8.26; Mass: 590.42; IR (KBr, νmax, cm ): 3415.12, 3215.13,
940.57, 1665.02 1620.54, 1578.41, 773.58.
N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(3-iodo-4-
methyl-benzoyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]-
2-[[6-[4-[(2S)-2-amino-3-phenylpropanoyl]-1-piperazin-
yl]-2-methyl-4-pyrimidinyl]amino]-N-(2-chloro-6-methyl-
phenyl)-5-thiazolecarboxamide [2(e)]: The obtained crude
compound was purified from column chromatography by
amino]-5-thiazolecarboxamide [2(g)]: Recrystallization from
1
methanol. m.p.: 275.6 °C; HPLC: 97.2 %; H NMR (DMSO-
d
1
8
d
1
1
6
): δ 2.24 (s, 3H), 2.41 (s, 6H), 3.57-3.6 (t, 8H), 6.070 (s,
H), 7.26-7.28 (d, 2H, J = 8.4 Hz), 7.40 (s, 3H), 7.87 (s, 1H),
elution of 5 % methanol in chloroform. m.p.: 156 °C; HPLC:
1
99.3 %; H NMR (DMSO-d
6
): δ 2.23 (s, 3H), 2.41 (s, 3H),
13
.22 (s, 1H), 9.894 (s, 1H), 11.53 (s, NH); C NMR (DMSO-
): δ 167.4, 165.2, 162.5, 162.2, 159.9, 156.9, 142.5, 140.8,
2.65 (q, 1H), 2.77 (q, 1H), 3.04 (brs, 1H), 3.48-3.55 (m, 6H),
3.93 (t, 1H), 6.0 (s, 1H), 7.18-7.40 (m, 8H), 8.22 (s, 1H), 9.8
6
13
38.7, 137.0, 135.0, 133.5, 132.4, 129.6, 128.9, 128.1, 126.9,
25.7, 101.0, 82.8, 46.4, 43.3, 27.4, 25.5 18.2; Mass: 688.42;
(s, 1H); C NMR (DMSO-d ): δ 173.2, 165.1, 162.4, 162.0,
6
159.8, 156.9, 140.7, 138.7, 138.3, 133.4, 132.4, 129.4, 128.9,
128.0, 126.9, 126.1, 125.7, 82.6, 51.6, 43.9, 43.2, 43.0, 42.1,
-1
IR (KBr, νmax, cm ): 3412.03, 3245.36, 2973.01, 2920.82,
-1
1
662.04, 1610.39, 1572.88, 774.4.
40.7, 25.5, 18.2; Mass: 591.3; IR (KBr, νmax, cm ): 3374.4,
3249.7, 3061.1, 2922.5, 1617.9, 1577.6, 1536.8, 1503.8, 770.7
2-[[6-[4-[(2S)-2-Aminopropanoyl]-1-piperazinyl]-2-
methyl-4-pyrimidinyl]amino]-N-(2-chloro-6-methyl-
phenyl)-5-thiazolecarboxamide [2(i)]: The obtained crude
compound was purified from column chromatography by
General procedure for the synthesis of dasatinib analo-
gues 2(c), 2(d), 2(e), 2(i), 2(j) and 2(k): A mixture of compound
N-(2-chloro-6-methylphenyl)-2-{[6-(-1-piperazinyl)-2-methyl-
4
-pyrimidin]amino}-5-thiazole-5-carboxamide (6) (5.1 mol
equivalent), the corresponding fmoc protected amino acid (1:1
mol equivalents), DCC (1:1 mol equivalents) and oxyma (1:1
mol equivalents) were charged into 4-necked round bottomed
flask along with tetrahydrofuran. The slurry was slowly heated
at 63-65 °C for 4-5 h. Then cooled slowly to room temperature.
The reaction mixture was quenched into demineralized water.
The obtained solid was collected by vacuum filtration, washed
with demineralized water. Suck dried thoroughly to afford crude
product. The product obtained was dissolved in 20 % piperidine
solution and stirred at ambiant temperature for 1-2 h. The
compound was extracted into methylenedichloride solvent. The
solid was collected by concentration of the organic layer.
1
elution of 5 % methanol in chloroform; HPLC: 98.7 %; H
NMR (DMSO-d
3.51-3.63 (m, 8H), 3.83 (q, 1H), 6.0 (s, 1H), 7.23 (m, 2H),
7.39 (d, 1H), 8.23 (s, 1H), 9.9 (s, 1H); C NMR (DMSO-d ):
6
): δ 1.12 (d, 3H), 2.24 (s, 3H), 2.43 (s, 3H),
13
6
δ 173.5, 165.1, 162.2-162.4, 159.8, 156.9, 140.8, 138.7, 138.3,
133.4, 132.4, 128.9, 128.1, 126.9, 125.7, 82.7, 79.14, 45.9,
43.12-43.8, 40.9, 25.5, 20.8 18.2; Mass: 515; IR (KBr, νmax
,
-1
cm ): 3405.0, 2921.7, 1611.9, 1577.9, 1539.0, 1500.3, 775.3.
N-(2-Chloro-6-methyl phenyl)-2-[[2-methyl-6-[4-[(2S)-
pyrrolidine-2-carbonyl]-1-piperazin-yl]-4-pyrimidinyl]-
amino]-5-thiazolecarboxamide [2(j)]: The obtained crude