4-(4-Bromopyridin-2-yl)morpholine synthesis

Yield: 90%

Reaction Conditions:

with caesium carbonate in N,N-dimethyl-d₆-formamide at 20 - 100; for 12 h;Sealed tube;Solvent;Reagent/catalyst;Temperature;

Steps:

7.1; 24.4 Step 4. 4 -(4 -bromopyridin -2 -yl jmorpholine
4-Bromo-2-fluoropyridine (1.0 g, 5.68 mmol) was dissolved in 5 mL DMF and morpholine (0.60 mL, 6.82 mmol) and Cs₂C0₃ (3.70 g, 11.36 mmol) were added at room temperature. The mixture was stirred in a sealed vial at 100 °C overnight. The mixture was portioned between H₂0 and EtOAc. The phases were separated, the aqueous layer was extracted with EtOAc (2x) and the combined organic layers washed with brine (lx), dried over anhydrous Na₂S0₄ and evaporated to dryness. The crude material was purified via column chromatography on a 50 g silica gel column using as eluent a gradient of EtOAc in cyclohexane from 0 to 50%. The desired fractions were collected together to afford the title compound (1.24 g, 5.10 mmol, 90% yield) as a white solid. NMR (400 MHz, DMSO-d₆) d 8.01 (d, J=5.3 Hz, 1H), 7.06 (d, J=l .3 Hz, 1H), 6.88 (dd, J=l .5, 5.3 Hz, 1H), 3.73 - 3.62 (m, 4H), 3.54 - 3.42 (m, 4H). MS-ESI (m/z) calcd for C₉Hi₂BrN₂0 [M+H]+: 243.01. Found 243.09/245.10.

References:

E-SCAPE BIO, INC.;GAROFALO, Albert W.;ANDREOTTI, Daniele;BERNARDI, Silvia;SERRA, Elena;MIGLIORE, Marco;SABBATINI, Fabio Maria;BEATO, Claudia;VINCETTI, Paolo;BUDASSI, Federica WO2019/222173, 2019, A1 Location in patent:Page/Page column 62-63; 85-87