Toluene → 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride

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Reaction Steps

To a −78° C. solution of 1.85 M phosgene in toluene (15.8 mL, 29.3 mmol) and DCM (32 mL) was added 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (4.00 g, 14.6 mmol), prepared as described in Example 1d, in one portion with stirring, followed immediately by the rapid addition of DIEA (2.66 mL, 16.1 mmol) along the walls of the flask over ˜5 sec. The flask was sealed and stirred at −78° C. for another 5 min before placing the flask in an ice bath with stirring at 0° C. for 30 min. The opaque easily stirred slurry was then poured into a mixture of DCM (70 mL), 0.5 M trisodium citrate (60 mL), and ice (60 mL), and partitioned. The aqueous layer was extracted with DCM (1×50 mL) and the organic layers combined, dried (Na2SO4), and concentrated under reduced pressure to give the crude title compound as an orange solid. Purification by flash chromatography (7:1→4:1 DCM/acetone) afforded the title compound as a beige solid (2.50 g, 51%). 1H-NMR (300 MHz, CDCl3) 9.07 (s, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 4.58-4.47 (m, 2H), 4.072 (s, 3H), 4.068 (s, 3H), 3.65 (tt, J=10.9 Hz, 4.0 Hz, 1H), 3.46-3.33 (m, 1H), 3.28-3.14 (m, 1H), 2.30-2.06 (m, 2H), 2.06-1.95 (m, 2H). LC/MS (ESI): calcd mass 335.1, found 336.1 (MH)+.

Provenance & Evidence