2-Pyrimidinamine, 5-fluoro- (9CI)

Pre Step A Part 1: A 500-mL round-bottom flask was charged with dichloromethane (100 ml)and chlorosulfonyl isocyanate (1.82 ml, 21.0 mmol). The reaction mixture was cooled to 0 C in an ice-water bath before 2-bromoethanol (1.49 mL, 21.0 mmol) was added dropwise via syringe over 5 min. After 1 h, EXAMPLE 304 Synthesis of (f?)-3-chloro-/V-(5-fluoropyrimidin-2-yl)-4-((1 -(1 -phenylethyl)piperidin-4- yl)oxy)benzenesulfonamide Step 1. Preparation of A/-(2, 4-dimethoxybenzyl)-Step A: Following the procedure in Example 36, Part 3, 3-(2-bromoacetyl)-7-fluoro-2H-chromen-2-one (1.32 g, 4.1 mmol) and To a solution of 5-Fluoropyrimidin-2-amine (0.060 g, 0.533 mmol) was dissolved in dimethyl sulfoxide (1.025 ml), and (P)-perfluorophenyl 1-(3', 4'-difluoro-3-methoxy-[1, 1'-biphenyl]-4-yl)-2-oxo-1, 2-dihydroquinoline-6-sulfonate (0.250 g, 0.410 mmol) in tetrahydrofuran (3.08 ml) was added as a solution. The resulting reaction was cooled to 0 C. and LHMDS, 1.0M in THF (0.943 ml, 0.943 mmol) was added drop wise. After 10 minutes, the reaction mixture was diluted with EtOAc and 1N HCl (aq). The layers were separated, and the aqueous was washed (*1) with EtOAc. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was loaded onto a 2-g SCX-2 column, eluting with the methanol wash to yield impure material. The crude material was further purified by reverse-phase preparative HPLC (XBridge Prep C18 column, 10 micron OBD, 19*100 mm) 0.1% TFA in CH3CN/H2O, gradient 25% to 95% over 12 min to provide (P)-1-(3', 4'-difluoro-3-methoxy-[1, 1'-biphenyl]-4-yl)-N-(5-fluoropyrimidin-2-yl)-2-oxo-1, 2-dihydroquinoline-6-sulfonamide as a light-yellow solid. To quantify the ae %, a small sample of product (in DMSO) was heated to 100 C. overnight; method developed on racemate-Whelk-O (S, S) 40% methanol. Sample contains 7.6% minor atropisomer (ee '85%). m/z (ESI) 539.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) delta ppm 3.77 (s, 3 H) 6.77 (d, J=9.02 Hz, 1 H) 6.80 (d, J=9.64 Hz, 1 H) 7.39 (d, J=8.09 Hz, 1 H) 7.45-7.49 (m, 1 H) 7.55-7.62 (m, 2 H) 7.68-7.73 (m, 1 H) 7.94-8.01 (m, 2 H) 8.25 (d, J=9.43 Hz, 1 H) 8.47 (d, J=2.18 Hz, 1 H) 8.62 (d, J=0.73 Hz, 2 H) 11.96 (s, 1 H)

Molecular Weight:113.09
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Exact Mass:113.03892530
Monoisotopic Mass:113.03892530
Topological Polar Surface Area:51.8
Heavy Atom Count:8
Complexity:69.7
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes