4-Pyrimidinamine, 2-chloro-N-methyl- (9CI)

2-Chloro-N-methylpyrimidin-4-amine (18)[00413] To a solution of 2, 4-dichloropyrimidine (5.0 g, 33.79 mmol) in anhydrous THF (50 mL) was slowly added 2.0 M methylamine solution in THF (42.2 mL, 84.48 mmol) at -40 °C. The reaction mixture was stirred at 0 °C for 4 h and partitioned between CHCl2, 4-Dichloropyrimidine (104, 500 mg, 3.30 mmol) was dissolved in methanol (5 mL) having 2.0 M monomethylamine dissolved therein, stirred at room temperature for 3 hours. Then, the methanol solvent was removed under reduced pressure and water was added to the reaction mixture. Organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-chloro-4-(N-monomethylamino)pyrimidine (106b, 128 mg, 27percent) as a yellow solid.Into a 50-mL round-bottom flask, was placed 2, 4-dichloropyrimidine (1.1 g, 7.38 mmol, 1.00 equiv.), methanamine hydrochloride (498 mg, 7.38 mmol, 1.00 equiv.), potassium carbonate (3.07 g, 22.21 mmol, 3.00 equiv.), N, N-dimethylformamide (10 mL). The resulting solution was stirred for 18 h at 20 °C. The resulting solution was diluted with 60 mL of H2O. The resulting solution was extracted with 3x80 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x100 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/2). This resulted in 0.67 g (63percent) of 2-chloro-N- methylpyrimidin-4-amine as a white solid.General procedure: To a 250mL round bottom flask equipped with a stir bar was added 9.0g 5-fiuoro- 2, 4-dichloro- pyriniidine, 40mL methanol and 15mL of 8M methylamine in ethanol. The reaction heated up (mild exo-therm) and was allowed to stir at room temperature for -30 minutes. A check by TLC (1 :1 EtOAc: heptane) and LCMS showed complete reaction. The reaction was concentrated down to give 9.77g crude material which was purified on a silica column running a gradient of 1% to 10% MeOH in DCM over 35 minutes to give 6.77 g pure 2-chloro-5-fiuoro-N-methylpyrimidin-4- amine.The same method was used to make the compounds shown in Table 1 below, using the appropriate commercially available substituted 2, 4-dichloro- pyrimidines and amines.Into a 50-mL round-bottom flask, was placed 4-methoxy-3-[lH-pyrrolo[3, 2-c]pyridin-6- yl]aniline ( 180 mg, 0.75 mmol, 1.00 equiv), Into a 100-mL round-bottom flask, was placed Into a 50-mL round-bottom flask, was placed 2-chloro-N-methylpyrimidin-4- amine (400 mg, 2.79 mmol, 1 equiv), trifluoroacetic acid (1109 mg, 9.81 mmol, 4.00 equiv), IPA (10 mL), tert-butyl 4-amino-4-methy Ipiperi dine- 1-carboxy late (573 mg, 2.67 mmol, 1.10 equiv). The resulting solution was stirred for 16 h at 90 C in an oil bath. The crude product was purified by Prep-HPLC C NH4HCO3. This resulted in 34 mg (6%) of N4-methyl-N2-(4- methylpiperidin-4-yl)pyrimidine-2, 4-diamine as a white semisolid.Into a 50-mL round-bottom flask, was placed 2-chloro-N-methylpyrimidin-4- amine (200 mg, 1.39 mmol, 1 equiv), tert-butyl 3-amino-3-methylpiperidine-l -carboxylate (357 mg, 1.67 mmol, 1.20 equiv), trifluoroacetic acid (791 mg, 7.00 mmol, 5.02 equiv), IPA (4 mL). The resulting solution was stirred for 16 h at 90 C in an oil bath. The crude product was purified by Prep-HPLC C NH4HCO3. This resulted in 52.4 mg (17%) N4-methyl-N2-(3- methylpiperidin-3-yl)pyrimidine-2, 4-diamine as a light yellow solid.Into a 50-mL round-bottom flask, was placed 2-chloro-N-methylpyrimidin-4- amine (150 mg, 1.04 mmol, 1 equiv), butan-1 -amine (80 mg, 1.09 mmol, 1.05 equiv), trifluoroacetic acid (380 mg, 3.36 mmol, 3.00 equiv), IPA (5 mL). The resulting solution was stirred for 16 h at 90 C in an oil bath. The crude product was purified by Prep-HPLC C NH4HCO3. This resulted in 35.1 mg (19%) of N2-butyl-N4-methylpyrimidine-2, 4-diamine as white oil. Analytical Data: LC-MS: (ES, m/z): RT = 1.15 min, LCMS 07: m/z = 181.1 [M+l]. 1H NMR (300 MHz, Methanol-d4) delta 7.61 (d, J = 6.0 Hz, 1H), 5.77 (d, J= 6.0 Hz, 1H), 3.34 (t, J= 4.5 Hz, 1H), 3.32 (t, J = 1.5 Hz, 1H), 2.87 (s, 3H), 1.63 - 1.53 (m, 2H), 1.48 - 1.36 (m, 2H), 0.98 (t, J= 7.2 Hz, 3H).Into a 50-mL round-bottom flask, was placed 2-chloro-N-methylpyrimidin-4- amine (150 mg, 1.04 mmol, 1 equiv), trifluoroacetic acid (480 mg, 4.25 mmol, 4.00 equiv), IPA (5 mL), tert-butyl 4-aminopiperi dine- 1-carboxy late (250 mg, 1.25 mmol, 1.19 equiv). The resulting solution was stirred for 16 h at 90 C in an oil bath. The crude product was purified by Prep-HPLC C NH4HC03. This resulted in 42.2 mg (19%) of N4-methyl-N2- (piperidin-4-yl)pyrimidine-2, 4-diamine as light yellow oil.

Molecular Weight:143.57
XLogP3:1.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:143.0250249
Monoisotopic Mass:143.0250249
Topological Polar Surface Area:37.8
Heavy Atom Count:9
Complexity:88.3
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes