2-AMINO-5-METHOXYPYRIMIDINE

Yellow to Tan Solid

A MW reaction vessel was charged with 2-chloro-5- methoxypyrimidine (0.817 g, 5.65 mmol) and 25percent NHA mixture of 2-chloro-5-methoxypyrimidine (7 g, 48.4 mmol) and ammonium hydroxide (113 mL, 2905 mmol) was heated at 100 °C in a sealed tube for 18 h. The mixture was cooled to rt and was concentrated. The residue was was purified on silica gel using 40-80 percent ethyl acetate in hexanes. The desired fractions were concentrated to give a pale yellow solid (2.75 g, 45 percent). a) 5-Methoxypyrimidin-2-amine (I-22). [0207] Phosphorus pentachloride (8.07 g; 38.78 mmol; 1 eq) was added portion-wise to methoxyacetaldehyde dimethyl acetal (5 mL; 38.78 mmol; 1 eq) kept at 20°C. The reaction mixture was heated at 60°C for 1 hour and 15 minutes, then cooled down to 0°C, before adding anhydrous dimethylformamide (9 mL; 116.3 mmol; 3 eq) dropwise. The reaction mixture was heated at 70°C for 45 minutes, then cooled at 0°C before adding methanol (40 mL) followed by sodium hydroxide (20.1 g; 504 mmol; 13 eq) and guanidine nitrate (9.46 g; 77.56 mmol; 2 eq). The reaction mixture was stirred at 0°C for 15 minutes. The reaction mixture was allowed to reach at room temperature and methanol was evaporated. The resulting solution was heated at 100°C for 1 hour and 30 minutes. Water (200 mL) and ice was added and the aqueous layer was extracted with dichloromethane (3 x 250 mL). The combined organic layers were washed with saturated sodium chloride (150 mL), dried over sodium sulfate, filtered and concentrated to dryness. The title compound 5-methoxypyrimidin-2-amine was obtained in 53 percent yield (2.6 g) as a brown solid. a) 5-Methoxypyrimidin-2-amine (1-22). NaOH, MeOH Phosphorus pentachloride (8.07 g; 38.78 mmol; 1 eq) was added portion-wise to methoxyacetaldehyde dimethyl acetal (5 mL; 38.78 mmol; 1 eq) kept at 20°C. The reaction mixture was heated at 60°C for 1 hour and 15 minutes, then cooled down to 0°C, before adding anhydrous dimethylformamide (9 mL; 116.3 mmol; 3 eq) dropwise. The reaction mixture was heated at 70°C for 45 minutes, then cooled at 0°C before adding methanol (40 mL) followed by sodium hydroxide (20.1 g; 504 mmol; 13 eq) and guanidine nitrate (9.46 g; 77.56 mmol; 2 eq). The reaction mixture was stirred at 0°C for 15 minutes. The reaction mixture was allowed to reach at room temperature and methanol was evaporated. The resulting solution was heated at 100°C for 1 hour and 30 minutes. Water (200 mL) and ice was added and the aqueous layer was extracted with dichloromethane (3 x 250 mL). The combined organic layers were washed with saturated sodium chloride (150 mL), dried over sodium sulfate, filtered and concentrated to dryness. The title compound 5- methoxypyrimidin-2-amine was obtained in 53percent yield (2.6 g) as a brown solid. 1H- NMR (DMSO-dStep 1: Guanidine nitrate (15.0 g, 0.12 mol) and sodium hydroxide (5.25 g, 0.13 mol) were added and the reaction mixture was heated at 60 C. for 3 hours, followed by stirring at room temperature for 3 days. Water was added and the solution was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo yielding the title compound (5.43 g, 43% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3): delta=3.80 (s, 3H), 5.08 (br.s, 2H), 8.04 (s, 2H); HPLC-MS (Method A): m/z=126 (M+H)+; Rt=0.39 min.General procedure: A 0.5 - 2.0 mL microwave vessel was charged with carboxylic acid VII (251 mg, 0.534 mmol) and this was dissolved in NMP (2 mL). HATU (223 mg, 0.587 mmol) andDIPEA (0.102 mL, 0.587 mmol) were then added and the resultant mixture was stirred at room temperature for 30 min. 2-amino-5-trifluoromethylpyridine (130 mg, 0.801 mmol) was then added and the vessel was tightly sealed with a crimp top. The resultant mixture was heated thermally in a heating block to 110 C for 16 h. The mixture was then diluted with EtOAc and washed with successively with sat. NH4Cl (aq) (1X), sat. NaHCO3 (aq) (1X), H2O (1X) and brine (1X). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was then purified by FCC (12 g SiO2, gradient elution with 0-5% MeOH/DCM). The semi-pure material obtained was then further purified by FCC (12 g SiO2, gradient elution with 0-100% EtOAc/hexanes) and then purified further by FCC (12 g SiO2, gradient elution with 0-5% MeOH/EtOAc) to provide 170 mg (52%) of 11d.General procedure: A 0.5 - 2.0 mL microwave vessel was charged with carboxylic acid VII (251 mg, 0.534 mmol) and this was dissolved in NMP (2 mL). HATU (223 mg, 0.587 mmol) andDIPEA (0.102 mL, 0.587 mmol) were then added and the resultant mixture was stirred at room temperature for 30 min. 2-amino-5-trifluoromethylpyridine (130 mg, 0.801 mmol) was then added and the vessel was tightly sealed with a crimp top. The resultant mixture was heated thermally in a heating block to 110 C for 16 h. The mixture was then diluted with EtOAc and washed with successively with sat. NH4Cl (aq) (1X), sat. NaHCO3 (aq) (1X), H2O (1X) and brine (1X). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was then purified by FCC (12 g SiO2, gradient elution with 0-5% MeOH/DCM). The semi-pure material obtained was then further purified by FCC (12 g SiO2, gradient elution with 0-100% EtOAc/hexanes) and then purified further by FCC (12 g SiO2, gradient elution with 0-5% MeOH/EtOAc) to provide 170 mg (52%) of 11d.To a mixture of carboxylic acid (0.10 g, 0.23 mmol) and powdered 4 A molecular sieves (40 mg) in NMP (1 mL) in an oven dried, 0.5-2 mL capacity microwave vial, were added HATU (0.11 g, 0.28 mmol) and DIEA (0.048 mL, 0.28 mmol). The mixture was stirred under N2 atmosphere for 15 min.2-Amino-5- methoxypyrimidine (0.14 g, 1.2 mmol) was added. The vial was tightly capped, and the mixture was heated in a microwave reactor at 120C for 1 h intervals until LCMS analysis of the reaction mixture indicated complete reaction. The mixture was diluted with EtOAc (30 mL), and washed successively with sat. NH4Cl (aq) (1X10 mL), sat. NaHCO3 (aq) (1X10 mL), and brine (1X10 mL). The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by FCC (12 g SiO2, gradient elution with 0-5% MeOH/DCM) followed by further purification by reverse-phase semi- preparative scale HPLC to give21 mgs (17% yield) of Example 5a.1H NMR (400 MHz, CDCl3, ~1.6:1 mixture of 7-membered ring conformers observed): dppm 8.84-6.73 (m, 15H, partially obscured by solvent peak), 5.15-4.38 (m, 3H), 3.91 (s, 3H), 3.61-2.78 (m, 2H);LCMS (Method A) tR= 0.85 min, m/z 543.5/545.5 (M+H)+. Following the method described above for Example5a and substituting the corresponding carboxylic acid-based precursors and reagents, the following Examples were prepared as indicated in Table 9.

Molecular Weight:125.13
XLogP3:-0.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:125.058911855
Monoisotopic Mass:125.058911855
Topological Polar Surface Area:61
Heavy Atom Count:9
Complexity:80.3
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes