Hydrochloric Acid → 7-Bromo-3-methyl-5-pyridin-2-yl-1,3-dihydro-benzo[e][1,4]diazepin-2-one

To a stirred solution of ester 124 (16 g, 35.69 mmol) in CHCl3 (300 mL) at rt, hydrogen chloride gas was added in slowly. After 20 min, the addition was stopped and the solution was allowed to stir overnight at rt. The reaction mixture was washed with a saturated solution of sodium bicarbonate (2×50 mL) and water (2×50 mL). The organic layer was concentrated under reduced pressure. The residual oil was dissolved in methanol-water (3:1, 300 mL) and the pH was adjusted to 8.5 by the addition of aq sodium hydroxide (1 N). The reaction mixture was stirred for 10 h at rt. The solution was concentrated under reduced pressure and water (80 mL) was added. The solution was extracted with CH2Cl2 (3×70 mL) and concentrated under reduced pressure. The crude solid 125 was purified by recrystallization from methanol/water to provide pure 125 (9.42 g, 80%). mp 227-229° C.; IR (KBr, cm−1) 2928, 1684, 1611, 1476; 1H NMR (CDCl3) δ 9.47 (bs, 1H), 8.62 (d, J=4.7 Hz, 1H), 8.0 (d, J=7.90 Hz, 1H), 7.81 (td, J=7.7, 1.6 Hz, 1H), 7.56 (dd, J=8.6, 2.2 Hz 1H), 7.50 (dd, J=2.1 Hz, 1H), 7.36 (dd, J=7.4 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 3.85 (q, J=6.5 Hz, 1H), 1.76 (d, J=6.5 Hz, 3H); MS (EI) m/e (relative intensity) 330 (M+, 50), 329 (50), 314 (52), 288 (100), 250 (30), 208 (32), 179(50), 88(72); [α]26D=403.2 (c 0.50, EtOAc).

1. additionthe addition
2. washThe reaction mixture was washed with a saturated solution of sodium bicarbonate (2×50 mL) and water (2×50 mL)
3. concentrationThe organic layer was concentrated under reduced pressure
4. dissolutionThe residual oil was dissolved in methanol-water (3:1, 300 mL)
5. additionthe pH was adjusted to 8.5 by the addition of aq sodium hydroxide (1 N)
6. stirringThe reaction mixture was stirred for 10 h at rt
7. concentrationThe solution was concentrated under reduced pressure and water (80 mL)
8. additionwas added
9. extractionThe solution was extracted with CH2Cl2 (3×70 mL)
10. concentrationconcentrated under reduced pressure
11. customThe crude solid 125 was purified by recrystallization from methanol/water

ORD record

ord-badae198b8a44baa8e6ee71ffdbce4ae

Source dataset

uspto-grants-2009_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07618958B2