1,2-Dimethoxyethane → HCID 118045663, compound

Participants

Reaction Conditions

Reaction Steps

To a microwave reactor was charged with 3-(6-amino-5-bromopyridin-3-yl)tetrahydrothiophene 1,1-dioxide (50 mg, 0.172 mmol), 4-(benzylcarbamoyl)-3-fluorophenylboronic acid (94 mg, 0.343 mmol), 2 M aqueous Na2CO3 (0.34 mL) and PdCl2(dppf)-DCM adduct (14 mg) and DME (3 mL) were charged in a microwave vial and the mixture was purged with Argon, sealed and heated at 105° C. for 20 min. The DME layer of the reaction mixture was collected, concentrated under reduced pressure and the residue was redissolved in EtOAc (5 mL). The EtOAc solution was stripped with 1N HCl (4×1 mL) and the aqueous layers were combined, scrubbed with EtOAc (2×1 mL), then concentrated under reduced pressure and the residue was partitioned between EtOAc/sat. Na2CO3 (5 mL/1 mL), and the EtOAc extract was washed with sat. Na2CO3 (2×1 mL), brine (1 mL), dried (Na2SO4), concentrated and the residue was redissolved in acetonitrile/water (6 mL/6 mL), frozen and lyophilized yielding racemic 4-(2-amino-5-(1,1-dioxidotetrahydrothiophen-3-yl)pyridin-3-yl)-N-benzyl-2-fluorobenzamidein as light yellow powder. LCMS (m/z): 440.2 (MH+), 0.60 min; 1H NMR (CD3OD) δ ppm 7.97 (d, J=2.0 Hz, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.50 (d, J=2.3 Hz, 1H), 7.31-7.44 (m, 6H), 7.22-7.30 (m, 1H), 4.61 (s, 2H), 3.55-3.70 (m, 1H), 3.47 (dd, J=13.3, 7.0 Hz, 1H), 3.33-3.39 (m, 1H), 3.08-3.25 (m, 2H), 2.53 (ddd, J=13.1, 7.4, 5.7 Hz, 1H), 2.18-2.40 (m, 1H). The racemic product was further resolved by chiral SFC (ChiralPak 5mic OJ column, 4.6×100 (mm), 5 mL/min, MeOH+0.1% DEA=50%) to afford (S)-4-(2-amino-5-(1,1-dioxidotetrahydrothiophen-3-yl)pyridin-3-yl)-N-benzyl-2-fluorobenzamide (Rt=1.7 min) and (R)-4-(2-amino-5-(1,1-dioxidotetrahydrothiophen-3-yl)pyridin-3-yl)-N-benzyl-2-fluorobenzamide (Rt=2.22 min). The absolute stereochemistry was arbitrarily assigned.

Provenance & Evidence