Chemoselective displacement of methylsulfinyl group with amines to provide 2-alkylamino-4,6-disubstituted pyrimidine-5-carboxylic acid

Article abstract of DOI:10.3987/COM-09-11715

An efficient and rapid method for introducing various kinds of alkylamines at C2 of methyl 6-(benzylamino)-4-chloro-2-(methylsulfinyl)pyrimidine-5-carboxylate using the chemoselective displacement of the methylsulfinyl group (SOMe) against a chlorine atom

Full text of DOI:10.3987/COM-09-11715

HETEROCYCLES, Vol. 78, No. 9, 2009
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HETEROCYCLES, Vol. 78, No. 9, 2009, pp. 2263 - 2275. © The Japan Institute of Heterocyclic Chemistry
Received, 25th March, 2009, Accepted, 1st May, 2009, Published online, 1st May, 2009.
DOI: 10.3987/COM-09-11715
CHEMOSELECTIVE DISPLACEMENT OF METHYLSULFINYL
GROUP WITH AMINES TO PROVIDE 2-ALKYLAMINO-4,6-
DISUBSTITUTED PYRIMIDINE-5-CARBOXYLIC ACID
Shigeki Seto* and Yasushi Kohno
Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1, Nogi,
Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan
E-mail: shigeki.seto@mb.kyorin-pharm.co.jp
Abstract – An efficient and rapid method for introducing various kinds of
alkylamines
at
C2
of
methyl
6-(benzylamino)-4-chloro-2-(methylsulfinyl)pyrimidine-5-carboxylate using the
chemoselective displacement of the methylsulfinyl group (SOMe) against a
chlorine atom with amines was investigated. Further transformation led to the
synthesis of 2-alkylamino-4,6-disubstituted pyrimidine-5-carboxylic acids that
are of biological interest.
INTRODUCTION
Polyfunctionalized pyrimidines are attractive core structures in many biologically active compounds such
as phosphodiesterase V inhibitors, protein tyrosine kinase inhibitors, and protein kinase C inhibitors.1 In
our ongoing drug research program to synthesize a novel peroxysome proliferator-activated receptor 
(PPAR)
agonist,
we
are
focusing
our
attention
on
2-alkylamino-4,6-disubstituted pyrimidine-5-carboxylic acid (1).2 In order to explore the structural
activity relationships of this scaffold, we introduced a variety of substituents at C4 and C6 using a
nine-step procedure starting from pyrrolidine, which can be the substituent at C2.3 However, this
synthetic method is not efficient for introducing various kinds of substituted amino groups at C2 instead
of using the pyrrolidino group. As such we planned a retrosynthetic analysis of the target compound (1)
as shown in Scheme 1. The target compound 1 could be derived from 2, which was constructed by
chemoselective displacement of the methylsulfonyl (SO2Me) or methylsulfinyl group (SOMe) at C2 of 3
with amines in a competitive environment with the chlorine atom at C4. Although such nucleophilic
amination of pyrimidines bearing SO2Me or SOMe has been demonstrated,4,5 the broad scope and

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HETEROCYCLES, Vol. 78, No. 9, 2009
synthetic utility of this method has not been explored. Intermediate 3 could be prepared from
4,6-dichloro-2-(methylthio) pyrimidine-5-carboxylic acid (4)6 in a three-step procedure. Herein, we wish
to report the synthesis of 2-alkylamino-4,6-disubstituted pyrimidine-5-carboxylic acid (1) using
chemoselective displacement of the SOMe in 3 with various kinds of amine nucleophiles as a key
reaction step.
Ph
S
Cl
Cl
4
Cl
4
CO2H
CO2R
CO2R
CO2H
Cl
N
N
N
N
Ra
Ra
Me
Me
6
2
N
Rb
2
N
NH
Ph
N
Rb
2
N
NH
Ph
S
N
NH
Ph
S
N
(O)n
1
2
3
4
Scheme 1. Retrosynthetic analysis of target compound (1).
RESULTS AND DISCUSSION
The intermediate 911 was obtained by the following method as shown in Scheme 2. Esterification of 4
7
with methyl iodide in the presence of K2CO3 or with tert-butylacetoacetate using cH2SO4 afforded
methyl ester 5 or tert-butyl ester 6 in good yield (99%, 82%, respectively). Treatment of 5 or 6 with
benzylamine resulted in the displacement of the chlorine atom at C4 with a benzylamino group. Oxidation
of 7 or 8 with mCPBA (2.2 eq of mCPBA was used for the preparation of 9 and 10, 1.1 eq of mCPBA was
used for the preparation of 11) yielded the corresponding SO2Me compounds (9 and 10) and SOMe
compound (11).
Cl
N
Cl
N
Cl
N
CO2R1
Cl
CO2R1
CO2R1
N
N
N
c
d
Me
b
Me
Me
S
S
NH
Ph
S
NH
Ph
(O)n
4: R1 = H
5: R1 = Me
6: R1 = t-Bu
7: R1 = Me
8: R1 = t-Bu
9: n = 2, R1 = Me
10: n = 2, R1 = t-Bu
11: n = 1, R1 = Me
a
Scheme 2. Reagent and conditions: (a) MeI, K2CO3, DMF, rt, 2 h, 99%; (b) t-butyl acetoacetate, c-
H2SO4, rt, 24 h, 82%; (c) benzylamine, Et3N, THF, 0 oC, 1 h, 95% (for 7), 99% (for 8); (d) mCPBA (2.2
eq for 9 and 10; 1.1 eq for 11), THF, 0 oC, 5 h, 90% (for 9), 85% (for 10), 82% (for 11).
In order to investigate a suitable pyrimidine substrate for the chemoselective displacement reaction at C2,
we demonstrated the reaction with pyrrolidine or dibutylamine as an amine nucleophile in the presence of

HETEROCYCLES, Vol. 78, No. 9, 2009
2265
triethylamine in toluene (Table 1). The displacement of SOMe in 9 with pyrrolidine afforded a
2-pyrrolidino derivative 12a (59%) and a 4-pyrrolidino derivative 14a (17%) (entry 1); however, when
dibutylamine was used, this reaction provided only a modest yield of 2-butylamino derivative 12b (23%)
compared to 4-butylamino derivative 14b (52%) (entry 2). Based on these results, we assumed that a
steric effect is important for selectivity between C2 and C4. Therefore, sterically hindered tert-butyl ester
was introduced at C5, with the aim of interrupting a C4 attack with an amine nucleophile instead of C2
(entry 3 and 4). But no significant steric effect was observed (31:69, C2:C4 for Me (entry2); 14:86 C2:C4
for tert-Bu (entry 4)). By contrast, there was a dramatic improvement in the ratio when SOMe compound
11 was used as a substrate (96:4 and 89:11; C2:C4 for entry 5 and 6, respectively) instead of SO2Me
compound 9 (78:22 and 31:69; C2:C4 for entry 1 and 2, respectively). This improvement effect of SOMe
for the ratio is consistent with the reported results.5
Table 1. Amination at C2 position with pyrrolidine or dibutylamine
Cl
Cl
R2
4
4
4
CO2R1
CO2R1
CO2R1
N
R2H
N
N
+
Me
Me
2
2
2
S
N
NH
Ph
R2
N
NH
Ph
S
N
NH
Ph
toluene, Et3N
0 oC, 5 h
(O)n
(O)n
9: n = 2, R1 = Me
10: n = 2, R1 = t-Bu
11: n = 1, R1 = Me
12a: R1 = Me, R2 = pyrrolidino
12b: R1 = Me, R2 = dibutylamino
13a: R1 = t-Bu, R2 = pyrrolidino
14a: n = 2, R1 = Me, R2 = pyrrolidino
14b: n = 2, R1 = Me, R2 = dibutylamino
15a: n = 2, R1 = t-Bu, R2 = pyrrolidino
15b: n = 2, R1 = t-Bu, R2 = dibutylamino
16a: n = 1, R1 = Me, R2 = pyrrolidino
16b: n = 1, R1 = Me, R2 = dibutylamino
13b: R1 = t-Bu, R2 = dibutylamino
Ratioa of
C2:C4
C2 displacemetnt
C4 displacemetnt
product
R1
R2H
n
2
Entry
1
Substrate
9
product
12a (59%)
14a (17%)
Me
78 : 22
HN
HN(CH2CH2CH2Me)2
HN
12b (23%)
13a (68%)
14b (52%)
15a (19%)
2
3
9
2
2
Me
tBu
31 : 69
78 : 22
10
HN(CH2CH2CH2Me)2
HN
13b (13%)
12a (76%)
12b (70%)
15b (81%)
16a (3%)
16b (9%)
4
5
6
10
11
11
2
1
1
tBu
Me
Me
14 : 86
96 : 4
HN(CH2CH2CH2Me)2
89 : 11
a Ratio are based on isolated yield.
To explore a more optimal condition for this reaction, the solvent effect was examined as shown in Table

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HETEROCYCLES, Vol. 78, No. 9, 2009
2. Using toluene as a solvent, the reaction gave good selectivity for C2 versus C4 (89:11, C2:C4, entry 1).
However, when DMF was used as a solvent, the reaction provided only a modest level of selectivity
(50:50, C2:C4, entry 3). These results indicate that a less polar solvent can be effective for the
chemoselective displacement of SOMe with amine nucleophiles.
Table 2. Solvent effect
Cl
Cl
N
4
CO2Me
CO2Me
CO2Me
HN(CH2CH2CH2Me)2
N
N
N
+
Me
Me
2
solvent, Et3N
0 oC, 5 h
S
N
NH
Ph
N
N
NH
Ph
S
N
NH
Ph
O
O
11
12b
16b
Ratioa
Entry
12b
16b
Solvent
1
2
3
toluene
EtOH
DMF
70%
49%
40%
9%
89 : 11
58:42
50:50
35%
40%
a Ratio are based on isolated yield.
With the optimal reaction condition achieved for the chemoselective displacement reaction of SOMe at
C2, we proceeded to study the generality and efficacy of this method using methyl
6-(benzylamino)-4-chloro-2-(methylsulfinyl)pyrimidine-5-carboxylate (11) and a variety of amine
nucleophiles (Table 3). As shown in entries 19, the reaction with the alkylamines afforded a series of
2-alkylamino pyrimidine-5-carboxylate derivatives in a good yield (70–92%) and with good C2
selectivity versus C4. Interestingly, a 2-anilino derivative was the sole product of this reaction when
aniline was used as an amine nucleophile (entry 10), although the reason is unclear.

HETEROCYCLES, Vol. 78, No. 9, 2009
2267
Table 3. Amination of methyl 4-chloro-2-(methylsulfinyl)pyrimidine-5-carboxylate (11)
Cl
Cl
R2
4
CO2Me
CO2Me
CO2Me
R2H
N
N
N
+
O
O
R2
N
NH
Ph
S
N
NH
Ph
2
S
N
NH
Ph
toluene, Et3N
0 oC, 5 h
Me
Me
11
12a - j
16a - j
C2 displacemetnt
product
C4 displacemetnt
product
Ratioa
R2
Entry
1
2
12a (76)
12c (92)
16a (3)
16c (5)
96 : 4
95 : 5
N
N
O
3
4
5
12d (92)
12e (79)
12f (75)
16d (3)
16e (5)
16f (8)
97 : 3
94 : 6
90 : 10
N
MeN
N
N
6
12b (70)
16b (9)
89 : 11
N
16g (-)b
16h (7)
N
H
7
8
12g (70)
12h (75)
100 : 0
94 : 6
N
H
N
H
9
12i (75)
12j (-)b
16i (4)
95 : 5
H
N
10
16j (84)
0 : 100
a Ratio are based on isolated yield.
b Compound was not detected by TLC.
Finally, treatment of chloride 12a with benzyl mercaptan in the presence of triethylamine, and subsequent
hydrolysis of ester 17 with potassium hydroxide afforded target compound 18 in good yield.
Ph
Ph
Cl
S
S
PhCH2SH
KOH
CO2Me
CO2Me
CO2H
N
N
N
THF, Et3N,
rt, 2 h
THF-MeOH,
reflux, 4 h
N
N
NH
Ph
N
N
NH
Ph
N
N
NH
Ph
(96%)
(76%)
12a
17
18
Scheme 3. Synthesis of new PPAR agonist

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HETEROCYCLES, Vol. 78, No. 9, 2009
In summary, we investigated an efficient method for introducing various kinds of amine nucleophiles at
C2 of methyl 6-(benzylamino)-4-chloro-2-(methylsulfinyl)pyrimidine-5-carboxylate using
a
chemoselective displacement of SOMe with amines. This methodology is suitable for construction of a
small library of 2-alkylamino-4,6-disubstituted pyrimidine-5-carboxylic acid derivatives that are of
biological interest. The biological activity of these compounds will be reported in due course.
EXPERIMENTAL
General.
Melting points were determined with a Yamato MP-500 melting point apparatus and are uncorrected.
1H-NMR spectra were measured in CDCl3 or DMSO-d6 with TMS and the solvent peak as internal
standards, on a JEOL ECA-400 (400 MHz) spectrometer. Mass spectra (MS) were obtained on a Hitachi
M-2000 mass spectrometer. Column chromatography was carried out on Merck silica gel 60. Analytical
thin-layer chromatography (TLC) was performed on Merck precoated silica gel 60F254 plates, and the
compounds were visualized by UV illumination (254 nm) or by heating after spraying with
phosphomolybdic acid in ethanol. The data for elemental analysis are within ±0.4% of theoretical values
and were determined by a Yanaco CHN corder MT-5.
Methyl
4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylate
(5).
To
a
solution
of
4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid (16.7 g, 69.9 mmol) in DMF (150 mL) was
o
added potassium carbonate (11.6 g, 83.9 mmol) and iodomethane (5.50 mL, 88.3 mmol) at 0 C. The
mixture was stirred at the same temperature for 0.5 h, and then rt for 2 h. The resulting mixture was
diluted with AcOEt, and then washed with water and brine. The organic layer was dried over anhydrous
Na2SO4, filtered, then concentrated in vacuo. Flash chromatography (hexane:AcOEt = 10:1) of the
residue gave 5 as a solid (17.6 g, 99%). Mp 48–49 oC. 1H-NMR (400 MHz, CDCl3)  2.59 (3H, s), 3.98
(3H, s). IR (neat) max 1742, 1546, 1479, 1355, 1294, 1219 1065 cm1. HRMS (EI) calcd for
C7H6Cl2N2O2S (M+) 251.9527, found 251.9538. Anal. Calcd for C7H6Cl2N2O2S: C, 33.22; H, 2.39; N,
11.07. Found: C, 32.97; H, 2.18; N, 11.05.
tert-Butyl
4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylate
(6).
To
a
mixture
of
4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid (2.39 g, 10.0 mmol) tert-butyl acetoacetate (10.3
g, 65.1 mmol) and concentrated H2SO4 (50 L, 0.938 mmol) was stirred at room temperature for 24 h.
The resulting mixture was diluted with ethyl acetate, then washed with water and saturated aqueous
sodium hydrogen carbonate. The organic layer was dried over anhydrous Na2SO4, filtered, then
concentrated in vacuo. Flash chromatography (hexane:AcOEt = 10:1) of the residue gave 6 as a solid
o
1
(2.41 g, 82%). Mp 91–93 C. H-NMR (400 MHz, CDCl3)  1.61 (9H, s), 2.58 (3H, s). IR (neat) max

HETEROCYCLES, Vol. 78, No. 9, 2009
2269
1729, 1556, 1483, 1358, 1238, 1151, 1073 cm−1. HRMS (EI) calcd for C10H12Cl2N2O2S (M+) 293.9997,
found 293.9970. Anal. Calcd for C10H12Cl2N2O2S: C, 40.69; H, 4.10; N, 9.49. Found: C, 40.15; H, 3.90;
N, 9.23.
Methyl 6-(benzylamino)-4-chloro-2-(methylthio)pyrimidine-5-carboxylate (7). To a solution of
methyl 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylate (5) (900 mg, 3.56 mmol) in THF (10 mL)
o
was added triethylamine (0.60 mL, 4.30 mmol) and benzylamine (381 mg, 3.56 mmol) at 0 C. The
mixture was stirred at same temperature for 1 h. The resulting mixture was diluted with AcOEt, then
washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, then
concentrated in vacuo. Flash chromatography (hexane:AcOEt = 5:1) of the residue gave 7 as a solid (1.10
g, 95%). Mp 94–97 oC. 1H-NMR (400 MHz, CDCl3) δ 2.47 (3H, s), 3.89 (3H, s), 4.74 (2H, d, J = 6.1 Hz),
7.22–7.38 (5H, m), 8.70–8.78 (1H, br). IR (neat) νmax 3320, 1670, 1571, 1542, 1385, 1313, 1195, 1060,
cm−1. HRMS (EI) calcd for C14H14ClN3O2S (M+) 323.0495, found 323.0500. Anal. Calcd for
C14H14ClN3O2S: C, 51.93; H, 4.36; N, 12.98. Found: C, 51.94; H, 4.26; N, 12.98.
tert-Butyl 6-(benzylamino)-4-chloro-2-(methylthio)pyrimidine-5-carboxylate (8). To a solution of
tert-butyl 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylate (6) (2.30 g, 7.79 mmol) in THF (20 mL)
o
was added triethylamine (1.30 mL, 9.33 mmol) and benzylamine (877 mg, 8.18 mmol) at 0 C. The
mixture was stirred at same temperature for 1 h. The resulting mixture was diluted with AcOEt, then
washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, then
concentrated in vacuo. Flash chromatography (hexane:AcOEt = 5:1) of the residue gave 8 as a solid (2.84
g, 99%). Mp 93–96 oC. 1H-NMR (400 MHz, CDCl3) δ 1.57 (9H, s), 2.45 (3H, s), 4.73 (2H, d, J = 6.1 Hz),
7.25–7.37 (5H, m), 8.61 (1H, t, J = 6.1 Hz). IR (neat) νmax 3302, 1671, 1567, 1545, 1384, 1322, 1204,
1148 cm−1. HRMS (ESI+) calcd for C17H21ClN3O2S (M+H+) 366.10430, found 366.10498. Anal. Calcd
for C17H20ClN3O2S: C, 55.81; H, 5.51; N, 11.48. Found: C, 55.44; H, 5.45; N, 11.27.
Methyl 6-(benzylamino)-4-chloro-2-(methylsulfonyl)pyrimidine-5-carboxylate (9) To a solution of
methyl 4-chloro-6-(benzylamino)-2-(methylthio)pyrimidine-5-carboxylate (7) (4.17 g, 12.9 mmol) in
THF (120 mL) was added mCPBA (5.00 g, 29.0 mmol) portionwise under ice cooling. The mixture was
o
stirred for 5 h at 0 C. The resulting mixture was diluted with AcOEt, then washed with saturated
aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous Na2SO4, filtered, and
then concentrated in vacuo. Flash chromatography (hexane:AcOEt = 2:1) of the residue gave 9 as a
colorless solid (4.12 g, 90%). Mp 137–139 oC. 1H-NMR (400 MHz, CDCl3) δ 3.23 (3H, s), 3.96 (3H, s),
4.77 (2H, d, J = 5.5 Hz), 7.25–7.40 (5H, m), 8.72–8.81 (1H, br). IR (neat) νmax 3374, 1716, 1639, 1600,
1453, 1312, 1222, 1159, 1120, 1044 cm−1. HRMS (EI) calcd for C14H14ClN3O4S (M+) 355.0394, found
355.0352. Anal. Calcd for C14H14ClN3O4S: C, 47.26; H, 3.97; N, 11.81. Found: C, 47.15; H, 3.81; N,

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HETEROCYCLES, Vol. 78, No. 9, 2009
11.82.
tert-Butyl 6-(benzylamino)-4-chloro-2-(methylsulfonyl)pyrimidine-5-carboxylate (10) To a solution
of tert-butyl 4-chloro-6-(benzylamino)-2-(methylthio)pyrimidine-5-carboxylate (8) (1.28 g, 3.50 mmol)
in CH2Cl2 (8 mL) was added mCPBA (1.51 g, 8.75 mmol) portionwise under ice cooling. The mixture
o
was stirred for 5 h at 0 C. The resulting mixture was diluted with AcOEt, and then washed with
saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous Na2SO4,
filtered, and then concentrated in vacuo. Flash chromatography (hexane:AcOEt = 2:1) of the residue gave
o
1
10 as a colorless solid (1.19 g, 85%). Mp 116–119 C. H-NMR (400 MHz, CDCl3) δ 1.59 (9H, s), 3.21
(3H, s), 4.76 (2H, d, J = 5.5 Hz), 7.27–7.40 (5H, m), 8.60–8.68 (1H, br). IR (neat) νmax 3323, 1683, 1574,
1536, 1509, 1319, 1270, 1184, 1156, 1137, 1096, 1061 cm−1. HRMS (ESI+) calcd for C17H21ClN3O4S
(M+H+) 398.09413, found 398.09078. Anal. Calcd for C17H20ClN3O4S: C, 51.32; H, 5.07; N, 10.56.
Found: C, 51.14; H, 4.97; N, 10.29.
Methyl 6-(benzylamino)-4-chloro-2-(methylsulfinyl)pyrimidine-5-carboxylate (11) To a solution of
methyl 4-chloro-6-(benzylamino)-2-(methylthio)pyrimidine-5-carboxylate (7) (480 mg, 1.48 mmol) in
CH2Cl2 (3 mL) was added mCPBA (289 mg, 1.67 mmol) portionwise under ice cooling. The mixture was
o
stirred at 0 C for 5 h. The resulting mixture was diluted with AcOEt, and then washed with saturated
aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous Na2SO4, filtered, and
then concentrated in vacuo. Flash chromatography (hexane:AcOEt = 2:1) of the residue gave 11 as a
colorless solid (411 mg, 82%). Mp 98–100 oC. 1H-NMR (400 MHz, CDCl3) δ 2.87 (3H, s), 3.45 (3H, s),
4.73–4.85 (2H, m), 7.27–7.39 (5H, m), 8.72–8.80 (1H, br). IR (neat) νmax 3007, 1721, 1643, 1571, 1542,
1437, 1385, 1314, 1225, 1181, 1119, 1059 cm−1. HRMS (ESI+) calcd for C14H15ClN3O3S (M+H+)
340.05226, found 340.05320. Anal. Calcd for C14H14ClN3O3S: C, 49.49; H, 4.15; N, 12.37. Found: C,
49.67; H, 4.12; N, 12.08.
General procedure for displacement reaction with amine nucleophile
To a solution of methyl 4-chloro-6-(benzylamino)-2-(methylsulfinyl)pyrimidine-5-carboxylate (11)
(0.100 mmol) in toluene (0.5 mL) were added a mixture of triethylamine (20 µL) and amine (0.101
o
mmol) in toluene (0.5 mL) portionwise under ice cooling. The mixture was stirred at 0 C for 5 h. The
resulting mixture was diluted with AcOEt, and then washed with water and brine. The organic layer was
dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo. Flash chromatography
(hexane:AcOEt = 5:1–1:2) of the residue gave C2 displacement compounds 12a–i and (or) C4
displacement compounds 16a–f, h–j.
Methyl 6-(benzylamino)-4-chloro-2-pyrrolidinopyrimidine-5-carboxylate (12a)

HETEROCYCLES, Vol. 78, No. 9, 2009
2271
o
1
Colorless solid; Mp 110–111 C. H-NMR (400 MHz, CDCl3) δ 1.89–1.96 (4H, m), 3.51 (2H, t, J = 6.7
Hz), 3.60 (2H, t, J = 6.7 Hz), 3.83 (3H, s), 4.67 (2H, d, J = 5.5 Hz), 7.22–7.35 (5H, m), 8.77 (1H, t, J =
5.5 Hz). IR (neat) νmax 3321, 1665, 1563, 1539, 1435, 1381, 1321, 1279, 1194, 1142, 1064 cm−1. HRMS
(EI) calcd for C17H19ClN4O2 (M+) 346.1197, found 346.1167. Anal. Calcd for C17H19ClN4O2: C, 58.87; H,
5.52; N, 16.15. Found: C, 58.87; H, 5.49; N, 16.04.
Methyl 6-(benzylamino)-2-(dibutylamino)-4-chloropyrimidine-5-carboxylate (12b)
Colorless solid; Mp 47–49 oC. 1H-NMR (400 MHz, CDCl3) δ 0.84 (3H, t, J = 7.3 Hz), 0.93 (3H, t, J = 7.3
Hz), 1.16–1.37 (4H, m), 1.42–1.60 (4H, m), 3.43 (2H, t, J = 7.9 Hz), 3.54 (2H, t, J = 7.9 Hz), 3.83 (3H, s),
4.65 (2H, d, J = 5.5 Hz), 7.21–7.35 (5H, m), 8.73 (1H, t, J = 5.5 Hz). IR (neat) νmax 3320, 1654, 1563,
1531, 1436, 1418, 1372, 1312, 1260, 1227, 1198, 1123, 1058 cm−1. HRMS (EI) calcd for C21H29ClN4O2
(M+) 404.1979, found 404.1955. Anal. Calcd for C21H29ClN4O2: C, 62.29; H, 7.22; N, 13.84. Found: C,
62.21; H, 7.26; N, 13.69.
Methyl 6-(benzylamino)-4-chloro-2-morpholinopyrimidine-5-carboxylate (12c)
o
1
Colorless solid; Mp 105–107 C. H-NMR (400 MHz, CDCl3) δ 3.65–3.72 (4H, m), 3.75–3.83 (4H, br),
3.84 (3H, s), 4.64 (2H, d, J = 5.5 Hz), 7.23–7.35 (5H, m), 8.75–8.85 (1H, br). IR (neat) νmax 3321, 1663,
1559, 1532, 1474, 1435, 1353, 1316, 1228, 1195, 1110 cm−1. HRMS (EI) calcd for C17H19ClN4O3 (M+)
362.1146, found 362.1132. Anal. Calcd for C17H19ClN4O3: C, 56.28; H, 5.28; N, 15.44. Found: C, 56.43;
H, 5.23; N, 15.14.
Methyl 6-(benzylamino)-4-chloro-2-piperidinopyrimidine-5-carboxylate (12d)
o
1
Colorless solid; Mp 92–93 C. H-NMR (400 MHz, CDCl3) δ 1.47–1.68 (6H, m), 3.70–3.82 (4H, m),
3.03 (3H, s), 4.64 (2H, d, J = 5.5 Hz), 7.22–7.35 (5H, m), 8.72–8.80 (1H, br). IR (neat) νmax 3314, 1661,
1560, 1526, 1473, 1418, 1365, 1313, 1236, 1215, 1193, 1131 cm−1. HRMS (EI) calcd for C18H21ClN4O2
(M+) 360.1353, found 360.1377. Anal. Calcd for C18H21ClN4O2: C, 59.91; H, 5.87; N, 15.53. Found: C,
60.07; H, 5.86; N, 15.15.
Methyl 6-(benzylamino)-4-chloro-2-(4-methylpiperazinyl)pyrimidine-5-carboxylate (12e)
Colorless solid; Mp 86–88 oC. 1H-NMR (400 MHz, CDCl3) δ 2.31 (3H, s), 2.35–2.44 (4H, br), 3.75–3.90
(4H, br), 3.84 (3H, s), 4.65 (2H, d, J = 5.5 Hz), 7.22–7.35 (5H, m), 8.74–8.82 (1H, br). IR (neat) νmax
3315, 1672, 1564, 1531, 1436, 1363, 1303, 1238, 1217 cm−1. HRMS (EI) calcd for C18H22ClN5O2 (M+)
375.1462, found 375.1467. Anal. Calcd for C18H22ClN5O2: C, 57.52; H, 5.90; N, 18.63. Found: C, 57.54;
H, 5.85; N, 18.54.
Methyl 6-(benzylamino)-2-(N-butyl-N-methylamino)4-chloro-pyrimidine-5-carboxylate (12f)
o
1
Colorless solid; Mp 51–54 C. H-NMR (400 MHz, CDCl3) δ 0.82–0.98 (3H, m), 1.15–1.35 (2H, m),
1.40–1.63 (2H, m), 3.06 and 3.13 (3H, each s), 3.45–3.65 (2H, m), 3.84 (3H, s), 4.62–4.70 (2H, m),

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HETEROCYCLES, Vol. 78, No. 9, 2009
7.21–7.35 (5H, m), 8.75 (1H, t, J = 5.5 Hz). IR (neat) νmax 3326, 1665, 1571, 1533, 1432, 1404, 1306,
1211, 1123 cm−1. HRMS (EI) calcd for C18H23ClN4O2 (M+) 362.1510, found 362.1532. Anal. Calcd for
C18H23ClN4O2: C, 59.58; H, 6.39; N, 15.44. Found: C, 59.85; H, 6.45; N, 15.43.
Methyl 6-(benzylamino)-2-(butylamino)-4-chloropyrimidine-5-carboxylate (12g)
o
1
Colorless solid; Mp 109–110 C. H-NMR (400 MHz, CDCl3) δ 0.85–0.98 (3H, m), 1.25–1.60 (4H, m),
3.30–3.47 (2H, m), 3.84 (3H, s), 4.59–4.73 (2H, m), 5.05–5.27 (1H, m), 7.21–7.37 (5H, m), 8.59–8.95
(1H, m). IR (neat) νmax 3330, 3267, 1660, 1598, 1547, 1434, 1353, 1312, 1256, 1152 cm−1. HRMS (ESI+)
for C17H22ClN4O2 (M+H+): calcd, 349.14313; found, 349.14052. Anal. Calcd for C17H21ClN4O2: C,
58.53; H, 6.07; N, 16.06. Found: C, 58.50; H, 6.00; N, 15.96.
Methyl 6-(benzylamino)-4-chloro-2-(cyclopropylamino)pyrimidine-5-carboxylate (12h)
o
1
Colorless solid; Mp 119–121 C. H-NMR (400 MHz, CDCl3) δ 0.45–0.57 (2H, m), 0.68–0.84 (2H, m),
2.68–2.85 (1H, br), 3.84 (3H, s), 4.60–4.80 (2H, m), 5.27–5.42 (1H, br), 7.21–7.40 (5H, m), 8.80–8.98
(1H, br). IR (neat) νmax 3260, 1660, 1563, 1523, 1438, 1348, 1254, 1139 cm−1. HRMS (EI) calcd for
C16H17ClN4O2 (M+) 332.1040, found 332.1048. Anal. Calcd for C16H17ClN4O2: C, 57.75; H, 5.15; N,
16.84. Found: C, 57.91; H, 5.10; N, 16.71.
Methyl 2,6-bis(benzylamino)-4-chloropyrimidine-5-carboxylate (12i)
o
1
Colorless solid; Mp 142–145 C. H-NMR (400 MHz, CDCl3) δ 3.84 (3H, s), 4.57 (2H, d, J = 5.5 Hz),
4.64 (2H, d, J = 5.5 Hz), 5.31–5.72 (1H, br), 7.17–7.40 (10H, m), 8.60–8.97 (1H, br). IR (neat) νmax 3277,
1663, 1594, 1570, 1543, 1316, 1263, 1228, 1143 cm−1. HRMS (EI) calcd for C20H19ClN4O2 (M+)
382.1197, found 382.1188. Anal. Calcd for C20H19ClN4O2: C, 62.74; H, 5.00; N, 14.63. Found: C, 62.87;
H, 5.02; N, 14.60.
Methyl 6-(benzylamino)-2-(methylsulfinyl)-4-pyrrolidinopyrimidine-5-carboxylate (16a)
1
Colorless oil; H-NMR (400 MHz, CDCl3) δ 1.85–1.95 (4H, m), 2.80 (3H, s), 3.35–3.65 (4H, br), 3.85
(3H, s), 4.66–4.78 (2H, m), 7.22–7.35 (5H, m), 8.11–8.18 (1H, br). IR (neat) νmax 3347, 1670, 1572, 1505,
1455, 1337, 1218, 1073 cm−1. HRMS (ESI+) for C18H23N4O3S (M+H+): calcd, 375.14909; found,
375.14841.
Methyl 6-(benzylamino)-4-(dibutylamino)-2-(methylsulfinyl)pyrimidine-5-carboxylate (16b)
Colorless oil; 1H-NMR (400 MHz, CDCl3) δ 0.90 (6H, t, J = 7.3 Hz), 1.22–1.33 (4H, m), 1.52–1.63 (4H,
m), 2.80 (3H, s), 3.44 (4H, t, J = 7.3 Hz), 3.80 (3H, s), 4.66–4.78 (2H, m), 7.23–7.35 (5H, m), 8.22 (1H, t,
J = 5.5 Hz). IR (neat) νmax 3346, 1671, 1571, 1507, 1433, 1348, 1214, 1119, 1076 cm−1. HRMS (ESI+)
calcd for C22H33N4O3S (M+H+) 433.22734, found 433.22416.
Methyl 6-(benzylamino)-2-(methylsulfinyl)-4-morpholinopyrimidine-5-carboxylate (16c)
1
Colorless oil; H-NMR (400 MHz, CDCl3) δ 2.80 (3H, s), 3.60–3.66 (4H, m), 3.72 (4H, t, J = 4.9 Hz),

HETEROCYCLES, Vol. 78, No. 9, 2009
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3.84 (3H, s), 4.65–4.77 (2H, m), 7.22–7.36 (5H, m), 8.35–8.42 (1H, br). IR (neat) νmax 3342, 1669, 1574,
1506, 1451, 1433, 1267, 1228, 1113, 1076 cm−1. HRMS (ESI+) for C18H23N4O4S (M+H+): calcd,
391.14400; found, 391.14469.
Methyl 6-(benzylamino)-2-(methylsulfinyl)-4-piperidinopyrimidine-5-carboxylate (16d)
1
Colorless oil; H-NMR (400 MHz, CDCl3) δ 1.23–1.37 (2H, m), 1.52–1.72 (4H, m), 2.80 (3H, s),
3.48–3.60 (4H, m), 3.82 (3H, s), 4.66–4.77 (2H, m), 7.21–7.35 (5H, m), 8.34 (1H, t, J = 5.5 Hz). IR (neat)
νmax 3341, 1669, 1573, 1506, 1442, 1377, 1346, 1244, 1202, 1076 cm−1. HRMS (ESI+) for C19H25N4O3S
(M+H+): calcd, 389.16474; found, 389.16516.
Methyl 6-(benzylamino)-4-(4-methylpiperazinyl)-2-(methylsulfinyl)pyrimidine-5-carboxylate (16e)
1
Colorless oil; H-NMR (400 MHz, CDCl3) δ 2.32 (3H, s), 2.44 (4H, t, J = 4.9 Hz), 2.80 (3H, s),
3.58–3.70 (4H, m), 3.83 (3H, s), 4.65–4.78 (2H, m), 7.20–7.38 (5H, m), 8.36 (1H, t, J = 5.5 Hz). IR (neat)
νmax 3336, 1659, 1571, 1509 1433, 1347, 1225, 1134, 1059 cm−1. HRMS (ESI+) for C19H26N5O3S
(M+H+): calcd, 404.17563; found, 404.17486.
Methyl
(16f)
6-(benzylamino)-4-(N-butyl-N-methylamino)-2-(methylsulfinyl)pyrimidine-5-carboxylate
Colorless oil; 1H-NMR (400 MHz, CDCl3) δ 0.94 (3H, t, J = 7.3 Hz), 1.24–1.40 (2H, m), 1.57–1.66 (2H,
m), 2.80 (3H, s), 2.93 (3H, s), 3.57–3.73 (2H, m), 3.11 (3H, s), 4.67–4.86 (2H, m), 7.22–7.36 (5H, m),
8.24 (1H, t, J = 5.5 Hz). IR (neat) νmax 3346, 1670, 1571, 1507, 1411, 1349, 1203, 1116, 1071 cm−1.
HRMS (ESI+) for C19H27N4O3S (M+H+): calcd, 391.18039; found, 391.18119.
Methyl 6-(benzylamino)-4-(cyclopropylamino)-2-(methylsulfinyl)pyrimidine-5-carboxylate (16h)
1
Colorless oil; H-NMR (400 MHz, CDCl3) δ 0.50–0.60 (2H, m), 0.80–0.90 (2H, m), 2.85 (3H, s),
3.05–3.13 (1H, m), 3.87 (3H, s), 4.73–4.86 (2H, m), 7.22–7.40 (5H, m), 8.17–8.27 (1H, br), 8.40–8.52
(1H, br). IR (neat) νmax 3382, 3288, 1665, 1576, 1520, 1454, 1359, 1247, 1210, 1068 cm−1. HRMS (ESI+)
for C17H21N4O3S (M+H+): calcd, 361.13344; found, 361.13280.
Methyl 4,6-bis(benzylamino)-2-(methylsulfinyl)pyrimidine-5-carboxylate (16i)
1
Colorless oil; H-NMR (400 MHz, CDCl3) δ 2.75 (3H, s), 3.87 (3H, s), 4.73–4.86 (2H, m), 7.25–7.38
(10H, m), 8.52–8.60 (2H, br). IR (neat) νmax 3345, 1664, 1575, 1522, 1453, 1410, 1361, 1246, 1217 cm−1.
HRMS (ESI+) for C21H23N4O3S (M+H+): calcd, 411.14909; found, 411.14959.
Methyl 4-anilino-6-(benzylamino)-2-(methylsulfinyl)pyrimidine-5-carboxylate (16j)
Colorless solid; 1H-NMR (400 MHz, CDCl3) δ 2.82 (3H, s), 3.97 (3H, s), 4.78–4.90 (2H, m), 7.13 (1H, t,
J = 7.3 Hz), 7.25–7.40 (7H, m), 7.64 (2H, d, J = 7.3 Hz), 8.40–8.50 (1H, br), 10.40–10.48 (1H, br). IR
(neat) νmax 3342, 1676, 1605, 1573, 1500, 1449, 1408, 1365, 1261, 1201, 1072 cm−1. HRMS (ESI+) for
C20H21N4O3S (M+H+): calcd, 397.13344; found, 397.13327.

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General procedure for the preparation of carboxylic acids 18
Step 1: To a solution of chloride 12a (0.191 mmol) in THF (0.5 mL) were added triethylamine (50 µL,
0.359 mmol) and phenylmethanethiol (28.5 mg, 0.229 mmol) at 0 oC, and the mixture was stirred at rt for
1 h. The reaction mixture was diluted with AcOEt, then washed with water and brine, and dried over
Na2SO4, filtered, then concentrated in vacuo. Flash chromatography (hexane:AcOEt = 5:1) of the residue
gave 17.
Step 2: To a solution of ester 17 (0.140 mmol) in THF-MeOH (1 mL; 1:1 v/v) was added 3mol/L KOH
(0.5 mL) at rt and the mixture was refluxed for 4 h. The resulting mixture was cooled to rt, then added
water and 2N HCl (1 mL). The precipitate was formed and collected by filtration, and dried in vacuo to
give 18.
4-(Benzylamino)-6-(benzylthio)-2-pyrrolidinopyrimidine-5-carboxylic acid (18)
o
1
Colorless solid; Mp 164–166 C. H-NMR (400 MHz, DMSO-d6) δ 1.80–1.95 (4H, m), 3.37–3.48 (2H,
m), 3.48–3.62 (2H, m), 4.27 (2H, s), 4.63 (2H, d, J = 5.5 Hz), 7.17–7.40 (10H, m), 8.85–9.05 (1H, br),
12.70–13.20 (1H, br). IR (neat) νmax 3351, 1623, 1561, 1526, 1423, 1336, 1304, 1284, 1191 cm−1. HRMS
(FAB+) calcd for C23H25N4O2S (M++1) 421.1698, found 421.1694. Anal. Calcd for C23H24N4O2S 0.2H2O:
C, 65.13; H, 5.70; N, 13.21. Found: C, 64.84; H, 5.65; N, 12.95.
ACKNOWLEDGEMENTS
The authors thank Dr. Shiro Terashima, presently at the Sagami Chemical Research Center, for many
valuable suggestions.
REFERENCES AND NOTES
1. (a) K. Yamada, K. Matsuki, K. Omori, and K. Kikkawa, WO 20010315. (b) A. Hirabayashi, H.
Shinohara, H. Kobayashi, Y. Terao, K. Miyazawa, and K. Misawa, JP 20030204. (c) T. Suzuki, K.
Onoda, T. Murakami, K. Negoro, K. Yahiro, T. Maruyama, A. Shimaya, and M. Ohta, WO
20000609.
2. S. Seto, K. Okada, S. Isogai, and M. Suzuki, WO 2006043515.
3. Our previous synthesis of 4,6-disubstituted-2-pyrrolidinopyrimidine-5-carboxylic acid is shown
below.
Ph
Cl
1) PhCH2SH, K2CO3
(74%)
1) 10% HCl-MeOH
2) NH2CN
S
CO2Me
Cl
CO2H
N
NH
N
3) CH2(CO2Et)2,t-BuOK
4) POCl3
5) LDA, CO2
6) MeI, K2CO3
2) PhCH2NH2, K2CO3
(76%)
N
N
N
N
NH
Ph
(10%)
(81%)
(96%)
3) KOH
I
II
(96%)
III

HETEROCYCLES, Vol. 78, No. 9, 2009
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