1
8
Journal of Chemical Research 43(1-2)
1
point meter and were uncorrected. Nuclear magnetic reso- 72.5%); m.p. 48.5–50.1°C. H NMR (300MHz, CDCl ) δ
3
1
3
nance (NMR) spectra were recorded on a Bruker Avance 8.54 (s, 1H), 2.55 (s, 3H). C NMR (75MHz, CDCl ) δ
3
+
DPX-300MHz/500MHz instrument in CDCl with tetra- 172.1, 159.5, 114.1, 14.7. HRMS ([M+H] ): m/z calcd for
3
methylsilane (TMS) as an internal reference and the chemi- C H BrClN S: 240.9025; found: 240.90203.
5
4
2
cal shifts (δ) were reported in parts per million (ppm).
High-resolution mass spectra (HRMS) were obtained from
Agilent 1100 LC/MS Spectrometry Services.
5
-Bromo-N-cyclopentyl-2-(methylthio)
pyrimidin-4-amine (17)
To a solution of 4-chloro-5-bromo-2-(methylthio)pyrimidine
2
-Methylthio-4-ketopyrimidine (14)
(16, 11.02g, 46.0mmol) in dioxane (40mL), DIPEA
(8.15mL, 46.0mmol) and cyclopentylamine (5.44mL,
To a solution of thiouracil (13, 10g, 78.1mmol), tetrabutyl-
ammonium bromide (12.59g, 39.1mmol), and K CO
55.2mmol) were added into the solution. After completion of
2
3
the addition, the reaction mixture was stirred at 100°C for 4h.
After quenching with water, the solution was extracted with
(16.2g, 117mmol) in dimethylformamide (DMF), dimethyl
carbonate (30mL) was slowly added dropwise when the
temperature was raised to 120°C. After addition, the mixture
was stirred at 120°C for 6h. After filtering K CO , water was
added to the filtrate which was then extracted with ethyl ace-
tate. The organic phases were combined, dried over Na SO ,
and concentrated in vacuo. The residue was purified by pass-
ing the organic extract through a silica gel column using
dichloromethane (DCM)/MeOH (75:1) to give the product
ethyl acetate and saturated NaHCO solution three times. The
3
combined organic phases were dried over MgSO , filtered,
4
2
3
and concentrated in vacuo. The residue was purified by pass-
ing the organic extract through a silica gel column using PE/
EA (15:1) to give product 17 as a yellow oil (11.99g, 90.4%).
2
4
1
H NMR (300MHz, CDCl ) δ 8.03 (s, 1H), 5.24 (s, 1H), 4.38
3
(dd, J=13.6, 6.8Hz, 1H), 2.48 (s, 3H), 2.09 (td, J=11.7,
6
2
5
.0Hz, 2H), 1.77–1.62 (m, 4H), 1.49 (dt, J=12.3, 6.2Hz,
1
4 as a white solid (10.27g, 92.6%); m.p. 204.4–205.3°C.
13
H); C NMR (75MHz, CDCl ) δ 170.3, 157.1, 154.8, 99.8,
1
3
H NMR (300MHz, CDCl ) δ 7.88 (d, J=6.5Hz, 1H), 6.23
(
3
+
2.9, 23.8, 14.4; HRMS ([M+Na] ): m/z calcd for
13
d, J=6.6Hz, 1H), 2.58 (s, 3H); C NMR (75MHz, CDCl )
3
+
C H BrN SNa : 311.9969; found: 311.99651.
+
10 14
3
δ 164.7, 162.8, 155.0, 111.1, 13.4; HRMS ([M+H] ): m/z
calcd for C H N OS: 143.0279; found: 143.02739.
5
6
2
8
-Cyclopentyl-5-methyl-2-(methylthio)
pyrido[2,3-d]pyrimidin-7(8H)-one (11)
4
-Chloro-2-(methylthio)pyrimidine (15)
To a solution of 5-bromo-N-cyclopentyl-2-(methylthio)pyrimi-
din-4-amine (17, 11.99g, 41.6mmol) and crotonic acid (5.37g,
To a solution of 2-methylthio-4-ketopyrimidine (14,
0.27g, 70.4mmol) in DCM (20mL) and DMF (10mL)
1
6
2.4mmol) in DMF (100mL), DIPEA(29.46mL, 166.4mmol)
was added. Then palladium dibenzylcarbonitrile (478mg,
.2mmol) and tri-o-tolylphosphorus (886mg, 3.0mmol) were
mixed solution, thionyl chloride (3.05mL, 42.2mmol)
solution was slowly added dropwise while heating. After
addition, the reaction mixture was stirred at 40°C for 3h.
After quenching with saturated NaHCO , the solution was
adjusted to a neutral pH and the solution was extracted
three times with DCM. The organic phases were washed
with saturated NaHCO solution and saturated NaCl solu-
tion and dried over anhydrous Na SO . After filtering to
remove the anhydrous Na SO , the solution was distilled at
1
added under a nitrogen atmosphere. After completion of the
addition, the reaction mixture was stirred at 130°C for 24h
under nitrogen protection. After 24h, acetic anhydride (15mL)
was added and the solution was stirred at 70°C for 4h. Then the
mixture was cooled, diluted with methyl tert-butyl ether
(MTBE; 100mL) and then extracted with NH Cl, NaHCO ,
3
3
2
4
4
3
2
4
and water. The organic phases were combined, dried over
4
0°C to remove solvents under atmospheric pressure to
MgSO , filtered, and concentrated in vacuo. The residue was
4
1
give product 15 as a yellow oil (10.19g, 87.6%). H NMR
purified by passing the organic extract through a silica gel col-
(
300MHz, CDCl ) δ 8.38 (d, J=5.2Hz, 1H), 6.99 (d,
3
umn using PE/EA (15:1) to give product 11 as a gray solid
1
3
J=5.2Hz, 1H), 2.53 (s, 3H); C NMR (75MHz, CDCl ) δ
1
calcd for C H ClN S: 160.9940; found: 160.99335.
1
3
(4.06g, 76.3%); m.p. 201.2–202.4°C. H NMR (300MHz,
+
74.0, 161.0, 158.0, 116.4, 14.3; HRMS ([M+H] ): m/z
CDCl ) δ 8.68 (s, 1H), 6.41 (s, 1H), 5.97–5.82 (m, 1H), 2.61 (s,
3
5
5
2
3H), 2.36 (d, J=20.9Hz, 5H), 2.06 (s, 2H), 1.87 (s, 2H), 1.69
1
3
(
1
(
d, J=10.3Hz, 3H); C NMR (75MHz, CDCl ) δ 163.0,
3
54.1, 144.0, 122.0, 111.0, 53.8, 28.4, 25.8, 17.2, 14.5.; HRMS
[M+Na] ): m/z calcd for (C H N OSNa ): 298.0990;
4
-Chloro-5-bromo-2-(methylthio)pyrimidine (16)
+
+
14
17
3
To a solution of 4-chloro-2-(methylthio)-pyrimidine (15, found: 298.09853.
0.19g, 63.4mmol) in MeOH (28mL) and MeCN (20mL)
mixed solution, NBS (13.55g, 76.1mmol) was added
2×3.76g). After the additions, the reaction mixture was
1
6
-Bromo-8-cyclopentyl-5-methyl-2-
methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)
1)
(
(
stirred at room temperature. After quenching with saturated
Na SO solution, the solution was extracted with DCM and
(
2
3
saturated NaHCO solution three times. The combined To a solution of 8-cyclopentyl-5-methyl-2-(methylthio)
3
organic phases were dried over MgSO , filtered, and con- pyrido[2,3-d]pyrimidin-7(8H)-one (11, 4.06g, 14.7mmol)
4
centrated in vacuo. The residue was purified by passing the in MeCN (30mL), acetic acid (84µL, 1.47mmol), H O
2
organic extract through a silica gel column using PE/EA (265µL,14.7mmol), and NBS (7.87g, 44.2mmol) were
(
25:1) to give the product 16 as a white solid (11.02g, added. After completion of the addition, the reaction