Formaldehyde → HCID 10286083, compound

To a 1.0 L jacketed reactor equipped with an overhead stirrer, thermocouple, condenser, addition funnel and positive nitrogen pressure was charged acetylbenzodiazepine (40.0 g, 210 mmol, 1.0 eq.), paraformaldehyde prills (6.30 g, 210 mmol, 1.0 eq.), acetonitrile (480 ml) and cyclopentene (86.0 g, 1.26 mol, 6.0 eq.). To the reaction suspension at 12° C. was added boron trifluoride etherate (80.5 g, 567 mmol, 2.7 eq.) in 20 minutes. The reaction mixture was heated. The reaction was monitored by HPLC. After the completion of the reaction, aqueous sodium hydroxide solution (50.0 g NaOH in 250 ml of water) was added. The resulting mixture was filtered, the top organic layer was washed with brine (50.0 ml). The organic layer was concentrated to 133 ml. Water (160 ml) was added to the hot concentrated mixture. The reaction mixture was cooled to ambient temperature and filtered. The cake was washed with a mixture of water and acetonitrile (5:1, 60 ml, 2 times). The wet product (82.0 g) was dried in a vacuum oven for 20 h at 45° C. to afford compound C (52.8 g, yield 93%) as an off-white solid. HPLC (area %): 94.5% C, 3.15% dimeric impurity compound methylene bis[(±)-4,5,6,7,9,9a,10,11,12,12a-decahydrocydopenta[c][1,4]diazepino[6,7,1-ij]quinoline] 1H NMR (300 MHz, DMSO-d6): δ=7.17-6.94 (m, 2H), 6.85-6.73 (m, 1H), 4.81 (d, j=13.7 Hz, 0.4H), 4.56 (d, j=15.3 Hz, 0.6H), 4.35 (d, j=15.3 Hz, 0.6H), 4.16 (m, 0.6H), 3.98 (d, j=13.7 Hz, 0.4H), 3.73 (m, 0.4H), 3.49 (m, 0.4H), 3.30-2.81 (m, 4.6H), 2.63 (m, 1H), 2.21 (m, 2H), 1.98 (m, 4H), 1.57 (m, 2H), 1.27 (m, 2H) ppm. (two conformers at 25° C.) dimeric impurity compound methylene bis[(±)-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c][1,4]diazepino[6,7,1-ij]quinoline]: δ=7.08-6.77 (m, 4H), 4.95 (m, 0.6H), 4.39 (m, 4H), 4.05 (m, 0.4H), 3.29-267 (m, 3H), 2.33-1.93 (m, 15H), 1.76-1.20 (m, 6H) ppm. LC/MS: (552 m/z)

1. customequipped with an overhead stirrer
2. additionthermocouple, condenser, addition funnel
3. temperatureThe reaction mixture was heated
4. additionwas added
5. filtrationThe resulting mixture was filtered
6. washthe top organic layer was washed with brine (50.0 ml)
7. concentrationThe organic layer was concentrated to 133 ml
8. additionWater (160 ml) was added to the hot concentrated mixture
9. filtrationfiltered
10. washThe cake was washed with a mixture of water and acetonitrile (5:1, 60 ml, 2 times)
11. dry with materialThe wet product (82.0 g) was dried in a vacuum oven for 20 h at 45° C.

ORD record

ord-5a20285c89a14c2881d2ae8a47da94c9

Source dataset

uspto-grants-2010_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07781427B2