Hydrochloric Acid → Ether hydrochloride

Temperature

60 °C

To a solution of 1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-2-one (160 mg; 0.66 mmol) in methanol (5 mL) was added ammonium acetate (5.2 g; 100 equivalent) and NaCNBH3 (415 mg; 6.6 mmol; 10 eq). The mixture was heated to 60° C. and stirred for 3 hours. The reaction mixture was cooled to 10° C., and acidified with 1 N HCl (5 mL) taking care that the flask was vented into a bleach solution due to HCN evolution. The reaction mixture was concentrated at 30° C., and the resulting aqueous layer was diluted with H2O (10 mL). The aqueous layer was then extracted with ethyl acetate (15 mL) to remove nonpolar impurities. The aqueous layer was then adjusted to pH 9 with 1N NaOH, and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to an oily residue. The oil was then dissolved in diethyl ether (5 mL), and the HCl salt was formed by slowly adding HCl/diethyl ether solution (0.5 mL). The slurry was stirred for 30 minutes before filtration. The solids were rinsed with diethyl ether (5 mL) and the compound was quickly transferred to a vacuum dessicator and dried under vacuum for 12 hours to give a white solid (111 mg; 61%). 1H NMR (400 MHz, Methanol-d4) δ ppm 0.68-0.76 (m, 1 H) 1.04-1.11 (m, 1 H) 1.14-1.22 (m, 1 H) 1.25-1.32 (m, 1 H) 1.37-1.51 (m, 1 H) 1.58-1.67 (m, 1 H) 1.78-1.98 (m, 4H) 2.04-2.13 (m, 1H) 2.20-2.33 (m, 3H) 3.97-4.03 (m, 1H) 4.08-4.19 (m, 1H) 7.30-7.42 (m, 1 H) 7.46-7.54 (m, 2 H).

1. temperatureThe reaction mixture was cooled to 10° C.
2. concentrationThe reaction mixture was concentrated at 30° C.
3. additionthe resulting aqueous layer was diluted with H2O (10 mL)
4. extractionThe aqueous layer was then extracted with ethyl acetate (15 mL)
5. customto remove nonpolar impurities
6. extractionthe aqueous layer was extracted with ethyl acetate (2×20 mL)
7. dry with materialThe combined organic layers were dried over MgSO4
8. filtrationfiltered
9. concentrationconcentrated to an oily residue
10. dissolutionThe oil was then dissolved in diethyl ether (5 mL)

ORD record

ord-098c69c2b3ce48c48de7b3e1ba0eaea9

Source dataset

uspto-grants-2012_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08138377B2