4-Amino-6-chloro-5-fluoropyrimidine

A mixture of 4, 6-dichloro-5-fluoro-pyrimidine (1.67 g, 10.0 mmol), butanol (6 mL) and 28percent ammonium hydroxide (12 mL) in a sealed tube was heated at 90 °C for 2 hours. The precipitated white crystals were collected by filtration to give the desired compound (1.31 g, 89percent yield). LCMS (ESI) m/z: 147.9 [M+HTo a stirred solution of 20.2 (120 mg, 0.000722 mol) in n-butanol (0.5 mL) was added NHCompound 5-fluoropyrimidin-4-amine 45b (30.0 mg, 0.2 mmol), 6-Methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-5-amine (32.0 mg, 0.1 mmol)And N, N-dimethylacetamide(2 mL) was mixed, and tris(bisbenzylideneacetone)bispalladium (9.0 mg, 0.01 mmol) was added under argon atmosphere.4, 5-bisdiphenylphosphino-9, 9-dimethylxanthene (12.0 mg, 0.02 mmol)And cesium carbonate (98.0 mg, 0.3 mmol), Argon gas was protected from microwaves at 125 C for 1 hour.After cooling to room temperature, it was extracted with dichloromethane (20 mL×3) and the organic layer was washed with brine. Use organic phase withoutDrying with sodium sulfate, filtering and removing the desiccant, the residue was purified by liquid chromatography (water (0.2% formic acid), 10% to 50% acetonitrile, 15 min).The desired product 1-((2-(trimethylsilyl)ethoxy)methyl)-5-((6-amino-5-fluoropyrimidin-4-yl)amino)-6-methoxy indazole 45c (6.0 mg, 0.015 mmol, white solid), yield: 15%.To a solution of trans-3 -((3 -chloro-S-(trifluoromethyl)phenyl)amino) -2-oxo- [1, 3 ?-bipiperidine] -4?-carboxamide 13 (42 mg, 0.10 mmol, 1.0 equiv) in 1-butanol (2 mL), 6-chloro-S-fluoropyrimidin-4-amine (18 mg, 0.12 mmol, 1.2 equiv) was added DIPEA (26 mg, 0.20 mmol, 2.0 equiv). The reaction solution was stirred at 120 C for 16 h. The mixture was diluted with EtOAc (20 mL), washed with H20 (10 mL) and brine (10 mL), dried (Na2504), filtered, and concentrated in vacuo. The crude was by purified by pre-HPLC (MeOHIH2O with 0.05% TFA as mobile phase) to give the compound (trans)- 1 ?-(6-amino-S -fluoropyrimidin-4-yl)-3 -((3 -chloro-S - (trifluoromethyl)phenyl)amino)-2-oxo-[ 1, 3 ?-bipiperidine] -4?-carboxamide 14 (44 mg, yield:83%) as a yellow solid. ESI-MS (M+H) : 530.0. HPLC: (214 nm: 100%, 254 nm: 100%). 'H NMR (400 MHz, CD3OD) 5: 7.97 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.76 (s, 1H), 4.58-4.52 (m, 2H), 4.09-4.03 (m, 1H), 3.52-3.35 (m, 3H), 3.29-3.27 (m, 4H), 3.12-3.05 (m, 1H), 2.24-2.17 (m, 1H), 2.02-1.91 (m, 3H), 1.80-1.63 (m, 2H).To a solution of (3S', 4S)-3-((naphthalen-2-ylmethylene)amino)piperidin-4-ol (522 g, 1.8 mol, 1.0 equiv) in n-BuOH (10 L) was added DIPEA (580 g, 4.5 mol, 2.5 equiv), 6-chloro-5- fluoro-pyrimidin-4-ylamine (265 g, 1.8 mol, 1.0 equiv) and the mixture was heated to 1 10 C for 72 h. The solution was cooled to room temperature and quenched with 3 N HCl to adjust pH to ~2-3, the aqueous layer was separated, washed with DCM (1 L) and treated with 4 L of acidic exchanged resin (Type 732) overnight. The resin collected by filtration and eluted with 3 N NH3 MeOH solution (15 L). The eluent was concentrated to about 500 mL to give a slurry mixture. The solids were collected by filtration and washed with water, dried at 50 C in vacuo to afford 304 g of compound 17 (75% yield) as light brown solid.To a solution of 6-chloro-5-fluoro-pyrimidin-4-ylamine 14 (59.2 g, 0.40 mol) in 1-propanol (400 mL) was added (3R, 3'S, 4'S)-3-((3-chloro-5-(trifluoromethyl)phenyl)amino)-4'- hydroxy-[1, 3'-bipiperidin]-2-one hydrochloride (200 g, 0.47 mol), NaHCO3 (67.4 g, 0.8 mol) in 3-5 portions followed by addition of DIEA (60.5 g, 84 mL, 0.47 mol). The suspension was heated at 100 C for 36 h and diluted by the addition of H2O (400 mL) and stirred at 70-85 C for 5 min to dissolve the solid. The mixture was allowed to form two layers, the bottom aqueous layer was removed. The organic phase was diluted with propanol (300 mL) and heated the mixture to 70-75 C followed by addition of H2O (300 mL) dropwise over 25-30 min keeping internal temperature 70-75 C. The mixture was cooled to 49 C and seeds of compound I were added when the internal temperature reached 51 to 49 C and stirred at 42-49 C for 1.5 h, when a good seeds bed formed. To the mixture was added H2O (810 mL) over 60-80 min maintaining internal temperature 46-49 C. The mixture was then cooled 0 C in 1.5 h, filtered and the filter cake was washed with H2O (300 mL), dried in vacuo overnight and further dried in vacuum oven at 40 C/15 mbar for 2 h to afford compound I as a crystal solid form 1 (160.2 g, 79.3% yield). 1H NMR (CDCl3, 500 MHz, ) delta 7.92 (s, 1H), 6.91 (s, 1H), 6.73 (d, J = 1.8 Hz, 1H), 6.71 (t, J = 2.0 Hz, 1H), 5.27 (d, J = 4.2 Hz, 1H), 4.87 (s, 2H), 4.43 - 4.37 (m, 2H), 4.14 - 4.00 (m, 2H), 3.92 (ddd, J =11.4, 5.8, 3.8 Hz, 1H), 3.51 (dt, J = 11.6, 6.0 Hz, 1H), 3.40 (dt, J = 12.9, 6.6 Hz, 1H), 3.10 (dd, J = 12.8, 10.7 Hz, 1H), 2.92 (td, J = 13.3, 2.5 Hz, 1H), 2.45 (dq, J = 11.7, 5.7 Hz, 1H), 2.17 - 2.09 (m, 1H), 2.08 - 1.94 (m, 2H), 1.71 -1.55 (m, 2H).13C NMR (CDCl3, 126 MHz) delta 171.4, 152.5 (d, JC-F = 11 -8 Hz), 151.9 (d, JC-F = 10.0 Hz), 149.4, 148.5, 135.5, 132.7 (q, JC-F = 33.2 Hz), 132.5 (d, JC-F = 248.7 Hz), 123.5 (q, JC-F = 247.6 Hz), 115.6, 114.1 (d, J = 4.1 Hz), 108.2, 69.0, 59.6, 53.6, 46.4, 45.2, 43.5, 34.3, 26.3, 20.6.19F NMR (CDCl3, 376 MHz) delta - 63.2 (s, 3F), - 164.2 (s, 1F).To a solution of (3S, 4S)-3-aminopiperidin-4-ol 6 (9.4 g, 81.0 mmol, 1.0 equiv) in n-BuOH (100 ml) was added 6-chloro-5-fluoro-pyrimidin-4-ylamine (11.3 g, 76.9 mmol, 0.95 equiv) and the mixture was heated to 120 C overnight. The solid crystallized upon cooling to 20 C. After stirred for 2 h, the mixture was filtered and the solids were washed with MTBE (100 ml), dry under vacuum at 50 C (-0.08 Mpa) for -4-5 hours to afford 17 as a gray solid (17 g, 79.8%). 1H NMR (DMSO-d6, 400 MHz) delta: 1.40-1.45 (m, 1H), 1.93 (m, 1H), 2.60-2.69 (m, 2H), 2.90 (t, J = 12.0 Hz, 1H), 3.41-3.47 (m, 1H), 3.93-4.01 (m, 2H), 7.59 (s, 1H). MS: 227; MS Found: 228 ([M+1]+

Molecular Weight:147.54
XLogP3:0.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Exact Mass:146.9999530
Monoisotopic Mass:146.9999530
Topological Polar Surface Area:51.8
Heavy Atom Count:9
Complexity:102
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes