HETEROCYCLES

Paper | Regular issue | Vol. 78, No. 9, 2009, pp. 2263-2275
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 Laboratoires, Kyorin Pharmaceutical Co., Ltd., 2399-1 Nogi, Nogi-mcahi, Shimotsuga-gun, Tochigi, 329-0114, Japan

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 γ (PPARγ) 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 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.

RESULTS AND DISCUSSION
The intermediate 9−11 was obtained by the following method as shown in Scheme 2. Esterification of 4 with methyl iodide in the presence of K2CO3 or with tert-butylacetoacetate using cH2SO47 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).

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 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

To explore a more optimal condition for this reaction, the solvent effect was examined as shown in Table 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.

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.

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.

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 added potassium carbonate (11.6 g, 83.9 mmol) and iodomethane (5.50 mL, 88.3 mmol) at 0 oC. 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) δ 2.59 (3H, s), 3.98 (3H, s). IR (neat) νmax 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 μL, 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 (2.41 g, 82%). Mp 91–93 oC. 1H-NMR (400 MHz, CDCl3) δ 1.61 (9H, s), 2.58 (3H, s). IR (neat) νmax 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) was added triethylamine (0.60 mL, 4.30 mmol) and benzylamine (381 mg, 3.56 mmol) at 0 oC. 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) was added triethylamine (1.30 mL, 9.33 mmol) and benzylamine (877 mg, 8.18 mmol) at 0 oC. 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 stirred for 5 h at 0 oC. 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, 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 was stirred for 5 h at 0 oC. 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 10 as a colorless solid (1.19 g, 85%). Mp 116–119 oC. 1H-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 stirred at 0 oC 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 mmol) in toluene (0.5 mL) portionwise under ice cooling. The mixture was stirred at 0 oC 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)
Colorless solid; Mp 110–111 oC. 1H-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)
Colorless solid; Mp 105–107 oC. 1H-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)
Colorless solid; Mp 92–93 oC. 1H-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)
Colorless solid; Mp 51–54 oC. 1H-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), 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)
Colorless solid; Mp 109–110 oC. 1H-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)
Colorless solid; Mp 119–121 oC. 1H-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)
Colorless solid; Mp 142–145 oC. 1H-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)
Colorless oil; 1H-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)
Colorless oil; 1H-NMR (400 MHz, CDCl3) δ 2.80 (3H, s), 3.60–3.66 (4H, m), 3.72 (4H, t, J = 4.9 Hz), 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)
Colorless oil; 1H-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)
Colorless oil; 1H-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 6-(benzylamino)-4-(N-butyl-N-methylamino)-2-(methylsulfinyl)pyrimidine-5-carboxylate (16f)
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)
Colorless oil; 1H-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)
Colorless oil; 1H-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.
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)
Colorless solid; Mp 164–166 oC. 1H-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

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