反应详情

A sealed tube was charged with a stir bar, 5-amino-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxamide (100 mg, 0.33 mmol), Pd2(dba)3 (30.0 mg, 0.033 mmol), X-PHOS (78 mg, 0.16 mmol), and potassium carbonate (50 mg, 0.36 mmol). The tube was evacuated and backfilled with argon (3×). 2-(6-Bromopyridin-2-yl)-2-morpholin-4-ylethanol (Enantiomer B) (Example 3, Step 1, chiral separation) (94 mg, 0.33 mmol) was placed in a separate vial which was also evacuated and backfilled with argon (3×). Fully degassed tert-amyl alcohol (1.5 mL) was added to the vial containing 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol (Enantiomer B) and the resulting solution was transferred to the sealed tube containing the rest of the reactants. This tube was then sealed and placed in an oil bath at 100° C. and stirred overnight. The reaction was cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification via flash chromatography (silica, 0-15% methanol/ethyl acetate) afforded the title compound as a yellow powder. 1H NMR (500 MHz, d6-DMSO): δ 11.21 (s, 1H), 8.66 (d, 1H), 8.08 (dd, 1H), 7.72 (s, 1H), 7.69 (t, 1H), 7.59 (s, 1H), 7.05 (d, 1H), 6.96 (d, 1H), 6.93 (d, 1H), 4.53 (m, 1H), 3.99 (m, 2H), 3.70 (m, 4H), 3.66 (m, 1H), 3.54 (m, 8H), 2.51 (m, 4H). LRMS (APCI) calc'd for C24H30N7O4S [M+H]+ 512.2, found 512.1. τr=13.5 min using supercritical fluid chromatography supercritical fluid chromatography (CO2, AD-H column (1×25 cm, 5 um), isochratic, 40% Ethanol+0.25% isobutylamine modifier, 10 mL/min, 100 bar, 310 nM)

1. additionA sealed tube was charged with a stir bar
2. customThe tube was evacuated
3. customwas also evacuated
4. additionFully degassed tert-amyl alcohol (1.5 mL) was added to the
5. additionvial containing 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol (Enantiomer B)
6. additioncontaining the rest of the reactants
7. customThis tube was then sealed
8. customplaced in an oil bath at 100° C.
9. additiondiluted with ethyl acetate
10. washwashed with saturated aqueous sodium bicarbonate
11. dry with materialThe organic layer was dried over magnesium sulfate
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure
14. customPurification via flash chromatography (silica, 0-15% methanol/ethyl acetate)