2-Methyl-5-pyrimidinamine

(1 S, 2R)-2-(4-(diisobutylamino)-3-(3-(2-methylpyrimidin-5-yl)ureido)phenyl)cyclopropanecarboxylic acid 77A. 2-methylpyrimidine-5-amineA solution of 4, 6-dichloro-2-methylpyrimidin-5-amine (2 g, 11.23 mmol) in ethylether (93 ml) was treated with sodium hydroxide (7.37 g, 184 mmol) in water (22.05 ml)and 10percent palladium on carbon (0.161 g, 1.5 17 mmol). The mixture was shaken at rt on aParr shaker under 50 psi of H2 gas for 22 h. The reaction was filtered through Celite andthe filter cake was washed with DCM. The solvent from the filtrate was evaporated togive a yellow residue. The suspension was re-dissolved in DCM and water. The aqueous layer was neutralized to approximately pH 6 with 4N HC1, then extracted with DCM (3X). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to afford a yellow residue. The aqueous phase still contained product, so thewater was evaporated to give a yellow solid. The solid was taken up in MeOH and DCM and filtered to remove all salts. The filtrate was evaporated to give a yellow residue. A total of two crops were obtained - one from the extraction and one from the aqueous layer. Each crop was purified by flash chromatography and combined to give 77A (off- white solid, 0.968 g, 8.87 mmol, 79 percent yield). ‘H NMR (400MHz, CHLOROFORM-d) ö8.14 (s, 2H), 3.60 (br. s., 2H), 2.61 (s, 3H).2-Methylpyrimidin-5-amine (0.023 g, 0.215 mmol) and pyridine (0.083 mL, 1.032 mmol) were dissolved in DCM (2 mL) To this solution was added Intermediate I-139A(0.035 g, 0.108 mmol) as a solution in DCM (1 mL). The reaction mixture was allowed to stir for lh. The reaction mixture was concentrated under reduced pressure to yield Intermediate 1-139 (0.038 g, 0.096 mmol, 89%). LC-MS: method H, RT = 1.04 mm, MS (ESI) m/z: 398.0 (M+H).2-Methylpyrimidin-5-amine (0.023 g, 0.206 mmol) and pyridine (0.083 mL, 1.032 mmol) were dissolved in DCM (2 mL) To this solution was added Intermediate I-135A15 (0.035 g, 0.103 mmol) as a solution in DCM(1 mL). The reaction mixture was allowed to stir for lh. The reaction mixture was concentrated under reduced pressure to yield Intermediate 1-135 (0.040 g, 0.097 mmol, 94%). LC-MS: method H, RT = 1.09 mm, MS (ESI) m/z: 412.0 (M+H)tTo a solution of Intermediate 1-132 (17 mg, 0.037 mmol) in DCM (1 mL) and THF (0.5 mL) was added 2-Methylpyrimidin-5-amine (13.73 mg, 0.126 mmol) and pyridine (0.068 mL, 0.839 mmol) were dissolved in DCM (3 mL). Intermediate 813C (40 mg, 0.084 mmol) was added as a solution in DCM (1 mL). The reaction mixture was allowed to stir for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by ISCO using a 12 g column with a 0-100% EtOAc in hexanes gradient to yield Example 813 (0.0203 g, 0.035 mmol, 41.8 %yield) as a yellow solid. 'HNMR(400IVIHz, CDC13)8.74 (br. s., 2H), 8.55 (t, J=2.3 Hz, 1H), 8.50 (d, J=2.6 Hz, 1H), 8.01 (s, 1H), 7.98 (d, J=0.9 Hz, 1H), 7.74 (s, 1H), 6.55 (br. s., 1H), 5.75 (dd, J=6.5, 3.4 Hz, 1H), 5.39 (dd, J=6.5, 3.4 Hz, 1H), 4.57 (d, J=7.0 Hz, 3H), 2.64 (s, 3H), 1.52 (d, J=1.5 Hz, 3H), 1.50 (s, 3H), 1.48 (d, J=1 .5 Hz, 3H). LC-MS. method H, RT = 1.27 mm, MS (ESI) m/z: 550.1(M+H). Analytical HPLC Method B: 95% purity.To a solution of Intermediate I-72B (170 mg, 0.332 mmol) in THF (6.5 mL) was added a 15% phosgene solution in toluene (2354 p1, 3.34 mmol). The resulting slurrywas allowed to stir at room temperature for 16 h before being concentrated down to the crude chloroformate intermediate. This crude residue was retaken in THF (6.5 mL) and To a mixture of crude Intermediate 520B (12 mg, 0.022 mmol) and DIPEA (0.057 mL, 0.329 mmol) in THF (1 mL) was added 15% phosgene in toluene (0.108 mL, 0.154 mmol) at room temperature. The solution immediately became smoky and deposited white salts. After 10 mi Intermediate I-72A (300 mg, 0.937 mmol) was dissolved in THF (18.7 mL). Phosgene solution (15% in toluene, 7.14 mL, 9.37 mmol) was then added. After stirring overnight, the reaction mixture was concentrated in vacuo and stored on HIVAC for 3 hours. The reaction mixture was dissolved in THF (18.7 mL). 2-Methylpyrimidin-5-amine (123 mg, 1.12 mmol) and pyridine (758 tL, 9.37 mmol)were added. After 1 hour, the reaction mixture was concentrated in vacuo and purified bycolumn chromatography (ISCO, 24 g silica gel column, 19 minute gradient from 0 to100% EtOAc in hexanes) to give Intermediate 1-13 0 (327 mg, 0.796 mmol, 85%) as awhite solid: 'H NMR (400MHz, CDC13) 8.72 (br. s., 2H), 7.66 (d, J=11.0 Hz, 1H), 7.36(d, J7.7 Hz, 1H), 6.55 (br. s., 1H), 5.14 (dd, J6.5, 3.0 Hz, 1H), 4.60-4.49 (m, 1H), 2.71(s, 3H), 1.44 (d, J=6.6 Hz, 3H), 1.40 (d, J=6.4 Hz, 3H); LC-MS: Method H, RT = 0.95mm, MS (ESI) m/z: 411.0 (M+H).

Molecular Weight:109.13
XLogP3:-0.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:109.063997236
Monoisotopic Mass:109.063997236
Topological Polar Surface Area:51.8
Heavy Atom Count:8
Complexity:66.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes